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Biomedical subjects

R C Strunk

Publications and source records attributed to R C Strunk.

At least 37 records · Page 2Linked to original sources
PubMed1991

Rehabilitation of a patient with asthma in the outpatient setting.

Although traditional rehabilitation medicine approaches are necessary in patients with the most severe asthma, principles of rehabilitation described in this article are useful for almost all patients. These principles are perhaps most useful early in a patient's course when the setting of appropriate expectations is important in minimizing restrictions from both disease and its treatment. Once a patient has developed restrictions, prompt institution of rehabilitation is essential to prevent significant disability, which can be avoided or even reversed. Once rehabilitation has been instituted, progress with rehabilitation goals should be monitored in visits to the physician so that communication with the appropriate health care professional can be established to readjust therapy. Physician interest in the process of rehabilitation can stimulate motivation of the patient.

Asthma↗
PubMed1991

Synthesis of C1 inhibitor in fibroblasts from patients with type I and type II hereditary angioneurotic edema.

Patients with hereditary angioneurotic edema (HANE) have serum levels of functionally active inhibitor of the first component of complement (C1 INH) between 5 and 30% of normal, instead of the 50% expected from the single normal allele. Increases in rates of catabolism have been documented in patients with HANE and certainly account for some of decrease in C1 INH level. A possible role for a decrease in synthesis of C1 INH in producing serum levels of C1 INH below the expected 50% of normal has not been well studied. We studied the synthesis of C1 INH in skin fibroblast lines, which produce easily detectable amounts of C1 INH. In type I HANE cells, C1 INH synthesis was 19.6 +/- 4.0% (mean +/- SD) of normal, much less than the 50% predicted. In type II HANE cells, the total amount of C1 INH synthesis (functional and dysfunctional) was 98.9 +/- 17% of normal; the functional protein comprised 43% of the total. Thus, type II HANE cells synthesized functional C1 INH at a much greater rate than for the type I cells. In both type I and II HANE cells, amounts of steady-state C1 INH mRNA levels paralleled rates of C1 INH synthesis, indicating that control of C1 INH synthesis occurred at pretranslational levels. Both type I and type II fibroblasts synthesized normal amounts of C1r and C1s. These data suggest that the lower than expected amounts of functionally active C1 INH in type I HANE may be due, in part, to a decrease in rate of synthesis of the protein, and that the expressions of the normal C1 INH allele in HANE is influenced by the type of abnormal allele present.

Adult↗
PubMed1990

Enhanced synthesis of factor B induced by tumor necrosis factor in human skin fibroblasts is decreased by IL-4.

IL-4 is a T cell-derived lymphokine that has multiple biologic functions, affecting B cells, T cells, mast cells, monocytes, macrophages, and hematopoietic progenitor cells. We report that IL-4 also affects human skin fibroblasts. These effects were primarily in modulating the effects of other mediators of inflammation on these cells, with IL-4 producing little or no effects by itself. Synthesis of C proteins in human skin fibroblasts is modulated by TNF and other mediators of inflammation. TNF increased synthesis of factor B by 18.6-fold; IL-4 reduced the TNF effect on factor B synthesis by 83%. This effect started with concentrations of IL-4 as low as 0.1 ng/ml. The effect of IL-4 on the TNF-induced increase in synthesis of factor B occurred after 2 h incubation, the time when the effects of TNF alone were first observed. IL-4 also abrogated the effects of IL-1 and LPS on factor B synthesis, but did not affect the increase in synthesis of factor B induced by IFN-gamma. In contrast to the pattern for effect of IL-4 on factor B synthesis, the TNF-induced rate of synthesis of C3 was augmented by IL-4. The specificity of the IL-4 effect was also apparent when comparing the effect of IL-4 on the TNF-induced synthesis of factor B to the effects on total protein synthesis (increased 1.5-fold) and the TNF-induced increases in synthesis in C1r, C1s, C1 inhibitor, C2, and factor H (no changes). The IL-4-induced decrease in synthesis of factor B was mediated at a pretranslational level and was dependent on synthesis of a new protein. This interaction between IL-4 and mediators of inflammation can potentially modulate the inflammatory response in the setting of activation of Th cells.

Cells, Cultured↗
PubMed1990

Antiinflammatory effects of polypeptide growth factors. Platelet-derived growth factor, epidermal growth factor, and fibroblast growth factor inhibit the cytokine-induced expression of the alternative complement pathway activator factor B in human fibroblasts.

The synthesis of complement components in human fibroblasts is modulated by mediators of inflammation such as cytokines. In particular, interleukin-1 (IL-1) and tumor necrosis factor (TNF) induce time- and dose-dependent increases in the synthesis of complement proteins factor B (FB), C3, and factor H (FH). Polypeptide growth factors are also soluble mediators released during inflammation and able to modulate many fibroblast functions. We have studied the effects of polypeptide growth factors platelet-derived growth factor (PDGF), epidermal growth factor (EGF), and fibroblast growth factor (FGF) on the synthesis of complement proteins in cultured human fibroblasts. PDGF, EGF, and FGF alone did not affect the level of synthesis of any of the complement proteins analyzed, but simultaneous incubation of PDGF, EGF, or FGF with IL-1 and TNF resulted in a dose-dependent inhibition of the cytokine-enhanced expression of FB. Inhibition of FB synthesis was observed between 4 and 8 h of exposure to PDGF and persisted for 4 h after the removal of the growth factor. Analysis of steady-state levels of specific FB mRNA suggested that PDGF-induced inhibition of FB synthesis is mediated at a pretranslational level and that it requires new protein synthesis. The effect of the growth factors was limited to FB, with marginal or no inhibition on the cytokine-enhanced synthesis of C3 and FH, excluding the possibility that the inhibitory effects of PDGF, EGF, and FGF on FB synthesis were due to a negative modulation of the growth factors on cytokine cell membrane receptors. Specific inhibition of cytokine-induced increases in FB synthesis by the growth factors may represent down regulation of the acute inflammatory process, further permitting progression to processes of tissue repair and remodeling. Study of the interactions between cytokines and growth factors in the regulation of synthesis of complement proteins may also provide a system for investigating mechanisms of signal transduction of both polypeptide growth factors and cytokines.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1990

Dysfunctional C1 inhibitor Ta: deletion of Lys-251 results in acquisition of an N-glycosylation site.

Hereditary angioneurotic edema is inherited as an autosomal dominant disorder and is characterized by potentially life-threatening episodic angioedema. In type II hereditary angioneurotic edema, a dysfunctional C1 inhibitor molecule is present together with low levels of normal C1 inhibitor. About 70% of these dysfunctional proteins result from reactive center (Arg-444) mutations. We describe the deletion of nucleotides encoding Lys-251 (AAG) in C1 inhibitor Ta, the dysfunctional C1 inhibitor from a family with type II hereditary angioneurotic edema. DNA sequence analysis was derived from clones obtained through polymerase chain reaction amplification of blood monocyte C1 inhibitor mRNA. As expected, clones with both normal and abnormal sequence were isolated. The deletion was verified by protein sequence analysis. These data, together with biochemical analysis of the protein and cell-free translation studies, suggest that this deletion, by altering the normal amino acid sequence from Asn-Lys-Ile-Ser to Asn-Ile-Ser, creates a new glycosylation site. The additional carbohydrate accounts for the larger size on SDS/PAGE and very likely interferes with protein function.

Amino Acid Sequence↗
PubMed1989

IL-1 and tumor necrosis factor. Similarities and differences in stimulation of expression of alternative pathway of complement and IFN-beta 2/IL-6 genes in human fibroblasts.

IL-1 and TNF induced concentration-related increases in the synthesis of factor B, C3, and IFN-beta 2/IL-6 in human skin fibroblasts. Effects of both stimuli were apparent with concentrations as low as 0.1 ng/ml and maximal responses were observed between 1 and 10 ng/ml; only for IL-1 induction of IFN-beta 2/IL-6 was there a further increase in response up to 100 ng/ml. For factor B and C3, maximal increases induced by IL-1 and TNF were similar: 119- and 109-fold for factor B and 15-fold and 11-fold for C3, respectively. Although both IL-1 and TNF increase synthesis of factor B and C3 in hepatocytes, the increases observed in fibroblasts were approximately 50- and 8-fold more for factor B and C3, respectively. Neither protein synthesis nor mRNA for IFN-beta 2/IL-6 was present in HepG2 cells either before or after stimulation with IL-1 or TNF. In contrast to the similarities between the effects of IL-1 and TNF on synthesis of factor B, C3, and IFN-beta 2/IL-6, only TNF increased synthesis of factor H. Because TNF induces membrane IL-1 in fibroblasts, it is possible to speculate that the effects of TNF on fibroblasts are due to induction of IL-1. An autocrine action of TNF through IL-1 is possible for TNF-induced synthesis of IFN-beta 2/IL-6, but the effects of TNF on synthesis of factor B, C3, and factor H indicated that TNF has effects on fibroblasts separate from IL-1. The effects of IL-1 and TNF on the synthesis of factor B and C3 in fibroblasts may be a part of an acute phase response occurring at a local level. However, the large responses in synthesis of factor B and C3 to IL-1 and TNF may suggest that factor B and C3 have a role, as yet undescribed, in tissues in addition to the role these proteins are known to play in inflammation.

Adult↗
PubMed1989

Synthesis and regulation of C1 inhibitor in human skin fibroblasts.

Proteins of the C1 complex, C1q, C1r, and C1s, of the classical pathway of complement activation are known to be synthesized in human skin fibroblasts. Using metabolic labeling with [35S]methionine, immunoprecipitation, and SDS-PAGE, we demonstrate that human skin fibroblasts synthesize and secrete C1 inhibitor with an apparent molecular mass of 78 kDa in the cell lysate and 102 kDa in the extracellular medium. This C1 inhibitor had the capacity to bind activated C1s. Fibroblasts synthesized 30- to 50-fold more C1 inhibitor than was synthesized in monocytes. As previously reported, fibroblasts also synthesized C1r and C1s. IFN-gamma, IFN-beta 1, and TNF had significant, but distinct, effects on synthesis of C1 inhibitor, C1r, and C1s. Incubation of the cells with IFN-gamma, 1000 U/ml, for 24 h induced increases in the synthesis of C1 inhibitor, C1r, and C1s by 4.2-, 1.9- and 1.6-fold, respectively. IFN-beta 1 had effects similar to IFN-gamma, although smaller in magnitude. TNF, 12.5 ng/ml, induced increases in the synthesis of C1 inhibitor, C1r, and C1s by 1.5-, 1.4- and 2.6-fold. IL-1, IFN-beta 2 (IL-6), and LPS did not affect synthesis of C1 inhibitor, C1r, or C1s. Fibroblasts are present in large amounts in most tissues. Synthesis of C1 inhibitor, C1r, and C1s by these cells could provide a source of these important proteins in body tissues. In addition, fibroblasts should be a good model for the in vitro study of genetic diseases involving the synthesis of these proteins.

Adult↗
PubMed1989

Determinants of school performance in children with chronic asthma.

We have documented performance on standardized academic achievement tests for reading and mathematics in 99 children with moderately severe to severe chronic asthma. Academic performance and intelligence test scores indicated that, overall, the academic capabilities of the children with asthma were average to above average. A stepwise regression analysis was used to examine relationships between the dependent variables of reading and mathematics and the independent variables of socioeconomic status, school attendance, medical factors relating to asthma, age, and emotional and behavioral problems of the children. Factors that were associated significantly with low performance scores were low socioeconomic status, older age, history of continuous oral steroid use (prednisone or methyl prednisolone taken at least every other day for the year prior to evaluation), and presence of emotional and behavioral problems. School absenteeism, use of medical resources, oral steroid dosage, other medications used to treat asthma, and pulmonary functions were not associated with academic performance. Investigation of poor classroom performance of a child with chronic asthma should include investigation of the roles of socioeconomic status, oral steroid therapy, and emotional and behavioral problems.

Absenteeism↗
PubMed1989

Circumstances surrounding the deaths of children due to asthma. A case-control study.

Features of the courses in 12 children who died of an acute attack of asthma were compared with those in 12 children of comparable age and sex who had a life-threatening attack of asthma but survived. Information obtained by structured interviews with the families and physicians and from the medical records was used to characterize (1) the patient, family, severity, and treatment of asthma primarily in the 6 months before the attack and (2) medical circumstances and patient characteristics present on the day of and/or during the acute episode. Patients in the study (mean age, 14.1 years) and controls (mean age, 13.8 years) were in early to late adolescence, had similar long-term medication use histories and an overall rating of the severity of asthma. For the analysis of the information concerning the 6 months before the attacks, the study patients had a greater frequency of respiratory failure requiring intubation, a decrease in steroid use in the month before the attack, history of family disturbance, abnormal reaction to separation or loss, and expressed hopelessness and despair. For the period more immediately surrounding the acute attack, study patients more often had attacks starting during sleep, but less frequently experienced vomiting during the course of the attacks. Treatment of the attack by the parents was poor (primarily because of delays) in 7 of the 12 children who died, but was also a factor in 6 of the 12 controls. Our data suggest that certain characteristics of asthmatic children may place them at greater risk for death due to their asthma. In addition, we postulate that there may be inherent differences in the mechanisms of the acute attacks between the children who died and those who survived.

Adolescent↗
PubMed1989

Interleukin 6 stimulates synthesis of complement proteins factor B and C3 in human skin fibroblasts.

Human interleukin (IL) 6 is a multifunctional cytokine which is synthesized by fibroblasts in response to many stimuli, including bacterial lipopolysaccharide (LPS). During acute-phase response, liver cells secrete a specific group of proteins among which components of the complement system and IL 6 appear to be an important mediator of this response. Human skin fibroblasts also synthesize at least seven proteins of the complement system. Each of these seems to be characteristically regulated by soluble mediators of the inflammatory process. Here we report that in fibroblasts, IL 6 induces increases in the rate of synthesis of factor B and C3, activator proteins of the alternative pathway of complement activation. The increases in factor B and C3 were concentration dependent reaching about 40- and 15-fold, respectively. The protein increases were observed within 4 h after IL 6 addition to the cells and were accompanied by increase in factor B and C3 mRNA. The data suggest that the induction of factor B and C3 by LPS may be mediated, at least in part, by IL 6 induced by LPS. This new function of IL 6 could provide a local protection against invading agents through activation of the antibody-independent alternative pathway of complement activation.

Blotting, Northern↗
PubMed1989

Investigation of a cluster of deaths of adolescents from asthma: evidence implicating inadequate treatment and poor patient adherence with medications.

We investigated a cluster of five deaths of adolescents from asthma in St. Louis during a 3-month period in 1987. Although the cluster represented a statistically significant increase in the number of asthma deaths in this age group over that observed in previous years, no common exposure to environmental, infectious, or therapeutic agents could be identified. The patterns of hospital admissions for asthma and emergency room visits at the two pediatric hospitals in the community did not suggest an increase in the frequency or severity of asthma during this time. Despite the lack of evidence for common exposure, the decedents shared many personal and medical characteristics. All decedents were black patients and were of lower socioeconomic status. All were adolescents and were responsible for regulating their own medication schedules. Lack of appreciation of the severity of their asthma by medical personnel and the patients' families was evident. For example, two patients with severe asthma had not been prescribed inhaled corticosteroids. In addition, the four decedents tested had markedly subtherapeutic or zero serum theophylline levels measured at the time of the fatal episode, even though appropriate amounts of theophylline had been prescribed. Their theophylline levels were substantially lower than levels in patients of the same age observed at the emergency room or hospitalized for asthma during the same time period. Continued efforts to educate adolescent patients, their families, and medical care providers about the treatment of asthma are warranted.

Adolescent↗
PubMed1989

Outcome of long-term hospitalization for asthma in children.

Children whose asthma continues to be poorly controlled with outpatient management are often referred to a long-term hospital program for care. Although these programs have been in existence since the 1950s, there has been no systematic study of their effectiveness. The purpose of the present study was to determine outcome in 103 children discharged consecutively after a long-term hospitalization. These children had both severe asthma and significant psychologic problems. Eighty-three of the 103 children had required continuous or frequent intermittent steroids for asthma control. In the year before admission, they had been hospitalized for asthma a mean of 2.6 times for 11.8 days and had had 4.6 visits to emergency rooms and 6.6 visits to physician offices for acute wheezing. Use of medical resources for asthma decreased significantly in the year after long-term hospitalization compared to the year before hospitalization (hospitalization: -34%, p less than 0.0001; hospital days: -39%, p less than 0.0002; emergency room visits: -46%, p less than 0.00001; physician office visits for acute asthma, -42%; p less than 0.00001; and a composite score giving increasing weight to more intensive and costly care: -30%, p less than 0.0001). Long-term hospitalization for children with asthma not responsive to outpatient management is associated with improvement in their use of medical resources.

Adolescent↗
PubMed1989

Cardiovascular fitness in children with asthma correlates with psychologic functioning of the child.

Abnormalities in fitness in asthmatic children are assumed to derive from illness severity. We studied 90 children with moderately severe to severe but stable asthma for (1) fitness levels using bicycle ergometry, (2) measures of asthma severity, (3) clinician's impression of child (Child Global Assessment Scale), and (4) mother's rating of child's behavior (Child Behavior Checklist). Fitness values ranged from 15% to 120% of normal values for age, sex, and body surface area: 48% were abnormal (less than 2 SD below mean) and 5% were borderline (1 to 2 SD below mean). Associations between levels of fitness and medical and psychologic criteria were tested using regression analyses. Of the 11 medical variables used to define the severity of asthma, recent exacerbation of disease, forced expiratory volume in 1 second, and specific airway conductance together accounted for 8.1% of the variability in the workload ratios (ie, R2 = 0.081). The importance of the psychologic factors in determining the variability in the workload ratios was tested after the importance of the medical variables had been considered: Child Global Assessment Scale accounted for a significant amount of variability, improving the R2 to 0.180 (an increase to 0.100, P = .003). These data suggest that, within the spectrum of disease presented by the patients in this study, adjustment to the disease is at least as important as severity of disease in determining fitness.

Adolescent↗
PubMed1988

Synthesis and regulation of complement protein factor H in human skin fibroblasts.

The alternative pathway of C activation is Ag-independent and forms a first line of defense against infection before immune response. The C3 convertase, C3bBb, formed during activation of the alternative pathway is tightly regulated, with destabilization produced by factor H. Using metabolic labeling with [35S]methionine, immunoprecipitation, and SDS-PAGE, we demonstrated that human skin fibroblasts synthesized and secreted factor H protein. Two forms of the protein were identified, the approximately 160-kDa form seen more prominently in serum and a 45-kDa form that has also been identified in serum. The cells contained two forms of factor H mRNA, 4.4 and 1.8 kb. IFN-gamma increased factor H protein synthesis and mRNA content. No effect was observed with LPS. Neither HepG2 cells or human peripheral blood monocytes synthesized factor H protein or contained factor H mRNA.

Cell Line↗
PubMed1988

Differential regulation of gene expression during macrophage activation with a polyribonucleotide. The role of endogenously derived IFN.

The activation of macrophages by exposure to the polyribonucleotide, poly [I:C], is accompanied by a large stimulation of the synthesis of the C components factor B and C3, and a concomitant inhibition of the synthesis of the lysosomal enzyme beta-glucuronidase. Northern blot analysis of poly [A+] RNA extracted from poly [I:C]-stimulated cells revealed that the changes in the synthesis of factor B and C3 were related to changes in the levels of their respective mRNA and hence the expression of these proteins appeared to be regulated at a pre-translational level. The down-regulation of the synthesis of beta-glucuronidase appeared to be regulated at both translational and pre-translational levels. In view of the proposed role of macrophage-derived IFN in the regulation of macrophage activation, we investigated the possible role of IFN-alpha/beta in the regulation of the synthesis of factor B, C3, and beta-glucuronidase. Exposure of macrophages to mouse IFN-alpha and IFN-beta induced limited changes in the synthesis of factor B, C3, and beta-glucuronidase. However, pretreatment of macrophages with only 500 U/ml of IFN-beta primed the cells thereby increasing their sensitivity to poly [I:C]. IFN-alpha was less effective as a priming agent. When macrophages were exposed to poly [I:C] in the presence of an anti-mouse IFN-alpha/beta antiserum, the changes in the synthesis of factor B, C3, and beta-glucuronidase were partially inhibited. Collectively, these data indicate first, that exposure of mouse bone marrow-derived macrophages to poly [I:C] differentially regulates the expression of the products of the genes for factor B, C3, and beta-glucuronidase. Second, IFN-alpha and IFN-beta prime macrophages to increase the sensitivity of macrophages to poly [I:C]. Third, in the absence of exogenous IFN, macrophage-derived IFN appears to participate in priming the cells in an autocrine or paracrine fashion.

Animals↗