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Biomedical subjects

A B Cohen

Publications and source records attributed to A B Cohen.

At least 73 records · Page 4Linked to original sources
PubMed1985

Evaluation readiness: improved evaluation planning using a data inventory framework.

Factors intrinsic to many programs, such as ambiguously stated objectives, inadequately defined performance measures, and incomplete or unreliable databases, often conspire to limit the evaluability of these programs. Current evaluation planning approaches are somewhat constrained in their ability to overcome these obstacles and to achieve full preparedness for evaluation. In this paper, the concept of evaluation readiness is introduced as a complement to other evaluation planning approaches, most notably that of evaluability assessment. The basic products of evaluation readiness--the formal program definition and the data inventory framework--are described, along with a guide for assuring more timely and appropriate evaluation response capability to support the decision making needs of program managers. The utility of evaluation readiness for program planning, as well as for effective management, is also discussed.

Evaluation Studies as Topic↗
PubMed1985

Neutrophil elastase-releasing factors in bronchoalveolar lavage from patients with adult respiratory distress syndrome.

Bronchoalveolar lavage fluid (BAL) was obtained from patients with adult respiratory distress syndrome (ARDS). Controls included BAL from normal subjects and from patients with sarcoidosis or pulmonary fibrosis. Neutrophil elastase measured immunologically was found in all BAL samples, but it was strikingly greater in BAL from patients with ARDS than in the BAL from normal subjects or patients with sarcoidosis. There was no significant difference in the neutrophil elastase antigen concentrations in BAL samples from patients with ARDS and those with pulmonary fibrosis. No elastolytic activity was found in either group. The alpha-1-antitrypsin and the bronchial mucus inhibitor were greater in BAL from patients with ARDS. There was a highly significant correlation between the alveolar-arterial oxygen tension difference and the neutrophil elastase concentration in BAL from the patients with ARDS. Kallikrein, prekallikrein, factor XIa-like activity, and high molecular weight kininogen antigen were found in BAL of patients with ARDS, suggesting that the kallikrein-kinin cascade may be activated in the lungs of patients with ARDS. Kallikrein-like activity in the BAL from the patients with ARDS was significantly correlated with the number of neutrophils in the BAL, the neutrophil elastase concentration, and the ability of the BAL to release elastase from cytochalasin-B-treated neutrophils. There was no correlation between these variables and C5a concentration. These studies demonstrated an association between BAL neutrophil elastase and the clinical state of patients with ARDS.

Adult↗
PubMed1985

A unique elastase in human blood platelets.

Previous investigations suggested that elastolytic activity found in platelets could be due to contamination by neutrophil elastase. In the present study, the lysate of blood platelets free of detectable neutrophils was examined for elastase-like activity using tertiary-butyloxycarbonyl (tBOC)-ala-ala-pro-ala-aminomethyl coumarin (I), tBOC-ala-ala-pro-val-aminomethyl coumarin (II), and succinyl-tri-ala-rho-nitroanilide (SAPNA), and for elastolytic activity using 3H-labeled dog and human lung elastins. The platelet lysate degraded I at a higher rate than II, while the reverse was true of neutrophil elastase. The rate of degradation of I, II, and SAPNA by the lysate increased with reaction time up to 20 min. The rate of I, II, and SAPNA degradation by the lysate was decreased by the presence of 0.5 M NaCl, whereas NaCl greatly potentiated their degradation by neutrophil elastase. Plasma alpha 2-macroglobulin inhibited elastolysis by the platelet lysate, whereas plasma alpha 1-antitrypsin did not. The lysate activity was inhibited by diisopropyl fluorophosphate, phenylmethylsulfonyl fluoride, elastatinal, Trasylol, and furoyl-saccharin. The optimum pH for platelet lysate activity was 8.5-9.0, as in other studies using elastin as substrate. The pH 4.5 eluate obtained after incubation of the lysate with dog lung elastin at neutral pH exhibited the same catalytic properties as the activity in the lysate. The different substrate and inhibitor specificities and the failure of IgG specific for neutrophil elastase to remove elastase-like and elastolytic activities from the lysate indicate that a unique elastase occurs in platelets.

Animals↗
PubMed1985

Changing health policies and clinical laboratory services.

Recent changes in Medicare financing policy and in state certificate of need (CON) policies have greatly altered the environment in which hospitals and physicians must operate. These policy changes likely will influence the development, adoption, and use of new technologies, including those employed in clinical laboratories. Some hospitals, particularly large academic health centers, are responding to the new incentives under Medicare prospective payment by (1) implementing integrated case mix and financial information systems, (2) monitoring and evaluating physician practice patterns, (3) improving the quality of analyses underlying their technology acquisition decisions, and (4) striving toward improved relations with medical staff. Clinical laboratories are also responding to these financial pressures through (1) more cautious adoption of new technologies, (2) selective automation of tests that reduce direct costs, (3) more prudent "make-or-buy" decisions regarding test performance sites, and (4) focused effort to improve turnaround times for inpatient testing and reporting.

Certificate of Need↗
PubMed1985

Bronchoalveolar lavage in patients with the adult respiratory distress syndrome.

BAL in patients with ARDS provides material containing the soluble and cellular constituents of the alveolar compartment, and hence is a useful tool for the study of the pathogenesis of ARDS. The technique is imperfect as it is prone to problems of data acquisition and interpretation. However, it is lung-specific and may be used in serial studies of patients over the course of their disease. A large amount of evidence is rapidly being accumulated which documents the presence of effectors of inflammation in the BAL fluids of patients with ARDS. Confirmation of the importance of such mediators, pathways, or cellular constituents of BAL fluid in establishing the pathogenesis of ARDS ultimately depends upon proof of the efficacy of specific clinical interventions which both arrest the activity of the effector and predictably alter the course of the disease.

Capillary Permeability↗
PubMed1983

Human plasma kallikrein releases neutrophil elastase during blood coagulation.

Elastase is released from human neutrophils during the early events of blood coagulation. Human plasma kallikrein has been shown to stimulate neutrophil chemotaxis, aggregation, and oxygen consumption. Therefore, the ability of kallikrein to release neutrophil elastase was investigated. Neutrophils were isolated by dextran sedimentation, and elastase release was measured by both an enzyme-linked immunosorbent assay, and an enzymatic assay using t-butoxy-carbonyl-Ala-Ala-Pro-Val-amino methyl coumarin as the substrate. Kallikrein, 0.1-1.0 U/ml, (0.045-0.45 microM), was incubated with neutrophils that were preincubated with cytochalasin B (5 micrograms/ml). The release of elastase was found to be proportional to the kallikrein concentration. Kallikrein released a maximum of 34% of the total elastase content, as measured by solubilizing the neutrophils in the nonionic detergent Triton X-100. A series of experiments was carried out to determine if kallikrein was a major enzyme involved in neutrophil elastase release during blood coagulation. When 10 million neutrophils were incubated in 1 ml of normal plasma in the presence of 30 mM CaCl2 for 90 min, 2.75 micrograms of elastase was released. In contrast, neutrophils incubated in prekallikrein-deficient or Factor XII-deficient plasma released less than half of the elastase, as compared with normal plasma. The addition of purified prekallikrein to prekallikrein-deficient plasma restored neutrophil elastase release to normal levels. Moreover, release of elastase was enhanced in plasma deficient in C1-inhibitor, the major plasma inhibitor of kallikrein. This release was not dependent upon further steps in the coagulation pathway, or on C5a, since levels of elastase, released in Factor XI- or C5-deficient plasma, were similar to that in normal plasma, and an antibody to C5 failed to inhibit elastase release. These data suggest that kallikrein may be a major enzyme responsible for the release of elastase during blood coagulation.

Blood Coagulation↗
PubMed1982

Reduction of the elastase inhibitory capacity of alpha 1-antitrypsin by peroxides in cigarette smoke: an analysis of brands and filters.

A procedure for measuring the oxidant content of aqueous condensates of tobacco cigarette smoke is described. The procedure was used in conjunction with analysis of the ability of the smoke solutions to inactivate the elastase inhibitory capacity (EIC) of alpha 1-antitrypsin. The ability of the smoke of a brand to inactivate alpha 1-antitrypsin correlates well with the known tar and nicotine and with the amount of oxidants as measured using o-dianisidine. Filters were found to remove about 73% of the oxidants from smoke. Smoke from a commercial nontobacco cigarette was also found to contain a significant amount of oxidants and to also destroy alpha 1-antitrypsin. Catalase and superoxide dismutase reduce the effect of solutions containing smoke on the EIC of alpha 1-antitrypsin, suggesting that peroxides and superoxide anions in smoke contribute to the oxidant capacity of the smoke. The extent of apparent oxidation by a given quantity of smoke condensate increases for as long as an hour from the time the condensate is collected. The addition of hydrogen peroxide to the smoke solution increases both its oxidant content and its ability to inactivate alpha 1-antitrypsin. These data suggest that occurrence of hydrogen peroxide caused by secretion from macrophages found in the small airways of smokers may contribute to a locally damaging environment for alpha 1-antitrypsin in the presence of cigarette smoke that could promote the development of centrilobular emphysema.

Catalase↗
PubMed1982

The release of elastase, myeloperoxidase, and lysozyme from human alveolar macrophages.

Human alveolar macrophages from lungs of cigarette smokers were retrieved by lavage of surgical specimens. The macrophage secretions were harvested after 18 h of incubation. The medium contained at least 2 acid-stable factors that could release enzymes from cytochalasin-B-treated human neutrophils. Our study focused on the largest of these factors, which had an apparent mass ratio of 5,400 by gel filtration chromatography in 10% acetic acid. The high molecular weight (HMW) factor was partially degraded by trypsin. Chymotrypsin completely destroyed the factor, but human neutrophil elastase did not affect it. The factor is partially extractable into chloroform indicating that it is very hydrophobic and may contain a lipid. High concentrations of the HMW factor inhibited the release of lysozyme and myeloperoxidase. Because elastases can cause emphysema when introduced into alveoli of animals, the most important observation may be that the HMW factor was able to release elastase from human neutrophils attached to Millipore membranes in the absence of cytochalasin B. The enzyme-releasing factors may be identical to neutrophil chemotactic factors recently described by others. The contribution of the released elastase to the protease load in the lung may be augmented by the simultaneous release from neutrophils of myeloperoxidase, which can inactivate alpha 1-antitrypsin. This interaction between alveolar macrophages and neutrophils may have importance in the pathogenesis of emphysema.

Chemotaxis, Leukocyte↗
PubMed1982

Studies on the pathogenesis of the adult respiratory distress syndrome.

Bronchoalveolar lavage (BAL) fluid was obtained from 24 sequentially studied patients with adult respiratory distress syndrome (ARDS) for assessment of potential activating and mediating factors. Proteolytic activity of the fluids was observed by measuring cleavage of radiolabeled proteins of the contact (Hageman factor) and complement systems. Proteolytic activity was observed in 17 of 24 (71%) patients with ARDS, and BAL fluid of the 7 ARDS patients without demonstrable, active, enzyme exhibited inhibitory activity for the proteolytic activity. The enzymes cleaved Hageman factor, prekallikrein, plasminogen, high molecular weight kininogen, C4, C3, C5, and Factor B of the complement system. Cleavage of the contact system proteins producted fragments similar or identical in size to the fragments observed during activation of these molecules, although continued incubation invariably reduced the protein to small peptide fragments. None of 7 normal individuals, and 29 of 99 patients (29%) with other forms of pulmonary disease contained measurable enzymes. The proteolytic activity in BAL fluid of ARDS patients was blocked by diisopropylphosphofluoridate (0.1 mM), Trasylol, soybean trypsin inhibitor, and normal plasma, or plasma deficient in inhibition of the first component of complement. Alpha(1)-proteinase inhibitor (alpha1-PI)-deficient plasma failed to inhibit the proteolytic activity and addition of alpha1-PI to the deficient plasma reconstituted the inhibition. MUCH OF THE PROTEOLYTIC ACTIVITY OF THE BAL FLUID FROM ARDS PATIENTS WAS IDENTIFIED AS NEUTROPHIL ELASTASE: the fluids cleaved elastin and synthetic peptide substrate of neutrophil elastase, neutrophil elastase antigen was present in the BAL fluids as determined immunologically using antineutrophil elastase, alpha1-PI was the major inhibitor in plasma, and the enzyme was inhibited by diisopropylphosphofluoridate but not chelation. In addition, purified neutrophil elastase produced cleavage fragments of proteins of the contact system similar to those of the BAL fluids. In each of the seven BAL fluids of ARDS patients that did not reveal active elastase, alpha1-PI was present in active form (as determined by (125)I-trypsin binding). In 9 of the 17 patients with active elastase in the BAL fluid, alpha1-PI antigen was present in the fluid, but was inactive (no binding of (125)I-trypsin). Immunoelectrophoretic analysis of elastase and alpha1-PI throughout proteins in these BAL fluids revealed the presence of both elastase and alpha1-PI that migrated with the same R(f), suggesting the presence of an enzyme-inhibitor complex. Free, inactive alpha1-PI was also observed in these fluids. The data reveal that in BAL fluids from all 24 patients with ARDS, leukocytic elastase and/or alpha1-PI exist. A complex of elastase and alpha1-PI was observed in BAL fluids, and in some cases where active enzyme and alpha1-PI coexisted, free, but inactive alpha1-PI was present.

Adult↗
PubMed1982

Neutrophil turnover in normal rabbit lungs.

Neutrophil turnover was studied in the blood and alveoli of normal rabbits. Blood neutrophil turnover was examined by two different methods. In the first method, donor rabbit neutrophils were labeled in vivo by injecting tritium-labeled thymidine intravenously. After 72 h recipient rabbits received blood from the donors. The decline of the specific radioactivity of blood neutrophils was used to determine that their half-life was 4.03 h. In the second method, rabbit peritoneal exudative neutrophils were elicited with oyster glycogen. These cells were labeled with 111Indium oxine and infused into the blood of recipient animals. By their decline in specific radioactivity, the half-life of the blood neutrophil was 4.08 h. These half-lives are not significantly different. Lung lavage was performed on the animals that received the 111Indium-labeled neutrophils and the turnover time of the lung neutrophil was found to be 2.63 h. The turnover of the alveolar neutrophil pool accounted for only 0.19% of the total turnover of the blood neutrophils. Therefore, the lung appears to contribute only minimally to the total capacity of the body to dispose of neutrophils.

Animals↗
PubMed1982

Inactivation of factor XIa by plasma protease inhibitors: predominant role of alpha 1-protease inhibitor and protective effect of high molecular weight kininogen.

Factor XIa is a plasma protease that, by activating Factor IX, plays an important role in the early phase of the intrinsic pathway of blood coagulation. Four plasma protease inhibitors, alpha(1)-protease inhibitor, antithrombin III, C1-inhibitor, and alpha(2)-plasmin inhibitor, have been reported to inactivate human Factor XIa, but their quantitative contribution to the inactivation of Factor XIa in plasma has not been fully assessed. Using purified systems, we observed that the second-order rate constants for the reaction of Factor XIa with alpha(1)-protease inhibitor, antithrombin III, and CI-inhibitor were 4.08, 10, and 14.6 M(-1) min(-1) x 10(3), respectively. The pseudo-first-order rate constants, at plasma concentration of the inhibitors, were 1.86 x 10(-1), 4.68 x 10(-2), and 2.4 x 10(-2) min(-1), respectively. These kinetic data predict that alpha(1)-protease inhibitor should account for 68%, antithrombin III for 16%, and C1-inhibitor and the equipotent alpha(2)-plasmin inhibitor each for 8% of the total inhibitory activity of plasma against Factor XIa. The rate of inactivation of Factor XIa in various plasma samples specifically deficient in inhibitors was consistent with these predictions. Factor XI, the zymogen form of Factor XIa, circulates in plasma associated with the contact system cofactor, high molecular weight kininogen (HMW kininogen). Kinetic analysis indicated the existence of a reversible bimolecular Factor XIa-HMW kininogen complex with a dissociation constant (K(d)) = 0.17 muM. The light chain derived from HMW kininogen decreased the inactivation rate of Factor XIa by C1-inhibitor with a K(d) of 0.08 muM for a complex of Factor XIa and the light chain derived from HMW kininogen. The protective effect of HMW kininogen was confirmed by the finding that the inactivation rate of Factor XIa in kininogen-deficient plasma was increased over normal plasma. The present study confirms that alpha(1)-protease inhibitor is the major inhibitor of Factor XIa in plasma, and that the formation of a reversible complex between Factor XIa and HMW kininogen decreases the rate of inactivation of the enzyme by its inhibitors.

Antithrombin III↗