Role of the cardiologist in peripheral vascular disease.
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Cardiology↗
Biomedical subjects
B H Gray
Publications and source records attributed to B H Gray.
Deep venous thrombosis and pulmonary embolism. The importance of heightened awareness.
Left untreated, deep venous thrombosis and pulmonary embolism have a high rate of mortality and long-term morbidity. Physicians therefore must maintain a high index of suspicion for these conditions. Accurate diagnosis is facilitated by knowing the most common sites of thrombus formation, the likelihood of propagation, which patients are at greatest risk, signs and symptoms, and which tests to order. Prompt administration of anticoagulants and, in some cases, thrombolytic agents can minimize the consequences of these diseases. Interruption of the inferior vena cava, thrombectomy, and thromboembolectomy are other treatment options.
Heparin↗
The legislative battle over health services research.
Budget reconciliation legislation in 1989 created the new Agency for Health Care Policy and Research (AHCPR), which folded in the National Center for Health Services Research and Health Care Technology Assessment, among the law's other provisions. The creation of the new agency represented a shift in priorities toward outcomes and effectiveness research in medical practice and made explicit the federal government's role in developing practice guidelines. The new agency was born in the midst of an extraordinary bipartisan budget negotiation process in late 1989; its becoming linked to the contentious issue of physician payment reform nearly killed the new agency before it appeared. The narrative of political wrangling that resulted in the creation of AHCPR spans Capitol Hill, the White House, the agencies of the Department of Health and Human Services, and renowed health services researchers on either coast and in Washington, D.C.
Health Policy↗
Nonsurgical restoration of pulsatile arterial flow.
Percutaneous transluminal angioplasty is an established method of revascularization in a variety of arterial stenotic conditions. When applied to specific morphologic and clinical indications, it can be very effective. It appears to be the procedure of choice for focal stenotic lesions of the iliac and femoropopliteal system. Its role in infrapopliteal atherosclerotic disease is less certain, but more optimistic, with recent reports. New methods for preventing restenosis and abrupt closure are currently being developed, and they appear to be promising as adjunctive therapy with mechanical catheter-directed intervention. The future of these adjunctive agents will likely improve the outcome and reduce the immediate failure rates of angioplasty. Other modalities, including thermal laser angioplasty and atherectomy, also appear to have a promising future. These methods, coupled with better endoluminal guidance, such as ultrasound, will help guide the interventional procedure more precisely and hopefully broaden the application and improve the outcome.
Angiography↗
World blindness and the medical profession: conflicting medical cultures and the ethical dilemmas of helping.
This is an account of a thwarted humanitarian effort and the strategic and ethical issues that is raised. Between 14 and 17 million people in the world are blind with cataract, a condition readily corrected by surgery. In 1989 a proposal was developed to attack this problem by supplying volunteer ophthalmologists to the world's leading private voluntary organizations that carry out programs in less developed countries. The proposal was rejected. This article describes the proposal and the issues on which it foundered: cost effectiveness, appropriate technology, changing ideologies of assistance, and conflict between the cultures of medicine and public health. The account illustrates the far-flung consequences of technological change in medicine, as well as the practical and ethical questions facing organizations that carry out overseas assistance programs.
Altruism↗
Characterization of proteinase-3 (PR-3), a neutrophil serine proteinase. Structural and functional properties.
Proteinase 3 (PR-3) is a human polymorphonuclear leukocyte (PMNL) serine proteinase that degrades elastin in vitro and causes emphysema when administered by tracheal insufflation to hamsters (Kao, R. C., Wehner, N. G., Skubitz, K. M., Gray, B. H., and Hoidal, J. R. (1988) J. Clin. Invest. 82, 1963-1973). We have determined the primary structure of several PR-3 peptides and have analyzed catalytic properties of the enzyme. The enzyme has considerable amino acid sequence homology with two other well characterized PMNL neutral serine proteinases, elastase and cathepsin G. Furthermore, the NH2-terminal amino acid sequence of PR-3 is identical to that of the target antigen of the anti-neutrophil cytoplasmic autoantibodies associated with Wegener's granulomatosis. PR-3 degrades a variety of matrix proteins including fibronectin, laminin, vitronectin, and collagen type IV. It shows no or minimal activity against interstitial collagens types I and III, respectively. The analysis of peptides generated by PR-3 digestion of insulin chains and the activity profile against a panel of chromogenic synthetic peptide substrates show that PR-3 prefers small aliphatic amino acids (alanine, serine, and valine) at the P1 site. The elastase-like specificity of PR-3 is consistent with its striking sequence homology to elastase at substrate binding sites. PR-3 is inhibited by alpha 1-proteinase inhibitor (ka = 8.1 x 10(6) M-1 S-1; delay time = 25 ms) and alpha 2-macroglobulin (ka = 1.1 x 10(7) M-1 S-1; delay time = 114 ms) but not by alpha 1-anti-chymotrypsin. In contrast to elastase and cathepsin G, PR-3 is not inhibited by secretory leukoprotease inhibitor and is weakly inhibited by eglin c. Thus, PR-3 is distinct from the other PMNL proteinases.
Amino Acid Sequence↗
Proteinase-3 (PR-3): a polymorphonuclear leukocyte serine proteinase.
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Amino Acids↗
Comparison of granule proteins from human polymorphonuclear leukocytes which are bactericidal toward Pseudomonas aeruginosa.
Killing of Pseudomonas aeruginosa by a 55-kDa bactericidal protein (BP 55), a 30-kDa protein (BP 30), cathepsin G, elastase, and proteinase 3 has been compared. P. aeruginosa was resistant to killing by elastase and proteinase 3. BP 55 at a 50% lethal dose (LD50) of 0.23 micrograms of protein per 5 x 10(6) bacteria per ml killed P. aeruginosa and was far more active than BP 30 and cathepsin G. The LD50s of BP 30 and cathepsin G were 16.9 and 28.3 micrograms of protein per 5 x 10(6) bacteria per ml, respectively. Preincubation of BP 55 or BP 30 with lipopolysaccharide (LPS) from P. aeruginosa inhibited bactericidal activity. The N-terminal amino acid sequence of BP 55 and BP 30 revealed no relationship between the two proteins. However, a monoclonal antibody (AHN-15) reacted with both proteins by Western immunoblot. The bactericidal activity of cathepsin G toward P. aeruginosa appeared to be dependent on the availability of the active site of the enzyme; bactericidal activity was inhibited by phenylmethylsulfonyl fluoride (PMSF) and by the specific cathepsin G inhibitor, Z-Gly-Leu-Phe-CH2Cl. The enzyme and bactericidal activities of cathepsin G were also inhibited by LPS from P. aeruginosa. LPS from P. aeruginosa was shown to be a competitive inhibitor of the enzyme activity of cathepsin G. Elastase enzyme activity was also inhibited noncompetitively by LPS, but the enzyme was not bactericidal. We have concluded that all three bactericidal proteins (BP 55, BP 30, and cathepsin G) may bind to the LPS of the outer membrane of P. aeruginosa. It appears that the enzyme active site must be available for cathepsin G to kill P. aeruginosa and that the active site may be involved in the binding of cathepsin G to P. aeruginosa.
Amino Acid Sequence↗
Pseudomonas aeruginosa variants isolated from patients with cystic fibrosis are killed by a bactericidal protein from human polymorphonuclear leukocytes.
The susceptibility of paired mucoid and nonmucoid variants of Pseudomonas aeruginosa isolated from 13 patients with cystic fibrosis (CF) to killing by a 55,000-Da bactericidal protein (BP55) from human polymorphonuclear leukocytes was studied. Mucoid and nonmucoid variants were equally sensitive to killing by BP55 at both pH 5.6 and pH 7.2. Eleven of the isolates were resistant to the bactericidal activity of 10% normal human serum but were as sensitive as the serum-sensitive isolates to BP55. Similarly, the 15 isolates with lipopolysaccharides (LPS) containing O-polysaccharide side chains (smooth LPS) were as sensitive to BP55 as those isolates with rough LPS.P. aeruginosa isolates from patients in poor clinical condition were more likely to have LPS of the smooth type and to be resistant to killing by 10% human serum than the isolates from patients in good clinical condition. We have concluded that the susceptibility of the P. aeruginosa isolates from patients with CF to killing by BP55 does not correlate with mucoid or nonmucoid variations, with the presence or absence of smooth LPS, or with the sensitivity or resistance to killing by normal human serum.
Adolescent↗
Safety and efficacy of thrombolytic therapy for superior vena cava syndrome.
The experience at the Cleveland Clinic from 1982 to 1990 using thrombolytic therapy for superior vena cava (SVC) syndrome was retrospectively reviewed. Sixteen patients, 11 of whom had indwelling central venous catheters, were treated with either urokinase (n = 11) or streptokinase (n = 5). Either urokinase (4,400 U/kg bolus followed by 4,400 U/kg/h) or streptokinase (250,000 U bolus followed by 100,000 U/h) was used, and venograms were performed before and after. Overall, 56 percent of patients had complete clot lysis and relief of symptoms. Thrombolytic therapy was effective in eight (73 percent) of 11 patients receiving urokinase and one (20 percent) of five patients receiving streptokinase. Of those with a central venous catheter, eight (73 percent) of 11 patients were successfully lysed, whereas only one (20 percent) of five patients was successfully lysed if no catheter was present. If thrombolytic therapy was performed less than or equal to five days of symptom onset, seven (88 percent) of eight patients were successful, if thrombolytic therapy was performed greater than five days after symptom onset, two (25 percent) of eight patients were successful. Symptoms were relieved and the catheter was preserved in patients in whom thrombolytic therapy was effective. Factors predicting success were as follows: (1) the use of urokinase compared with streptokinase; (2) the presence of a central venous catheter; and (3) a duration of symptoms less than or equal to five days.
Catheterization, Central Venous↗
Inhibitors of human leukocyte proteinase-3.
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Animals↗
The neutrophil and chronic allergic inflammation. Immunochemical localization of neutrophil elastase.
To test whether neutrophils infiltrate and degranulate in areas of chronic respiratory allergic inflammation, we developed an indirect immunofluorescence technique to localize neutrophil elastase in formalin-fixed, paraffin-embedded tissues. The affinity-purified antielastase stained only neutrophils on peripheral blood buffy coat smears, and in lung tissue from patients with pneumonia. We examined tissue specimens from four patients with fatal asthma, 10 patients with chronic sinusitis, and 10 patients with nasal polyposis for the presence of elastase, as well as eosinophil granule major basic protein (MBP). Neutrophil infiltration and extracellular elastase deposition in association with damage to respiratory epithelium were generally sparse in most specimens; the exceptions were one patient with asthma, one patient with chronic sinusitis, and two patients with nasal polyposis. In contrast, eosinophil infiltration and extracellular MBP deposition were generally marked in most specimens; the exceptions were one patient with asthma and one patient with nasal polyps where extracellular MBP deposition did not coincide with damage to respiratory epithelium. The results suggest that the neutrophil does not usually infiltrate tissues showing allergic inflammation; however, on occasion, it may participate in these inflammatory reactions.
Adult↗
Extracellular deposition of eosinophil and neutrophil granule proteins in the IgE-mediated cutaneous late phase reaction.
Intradermal injection of allergens in sensitive subjects produces an IgE-dependent prolonged inflammatory reaction, the late phase reaction (LPR). Histologically, eosinophils are present in the LPR but are not as numerous as neutrophils or mononuclear cells. We determined whether extracellular deposition of eosinophil and neutrophil granule proteins occurs in the LPR by immunofluorescent localization of eosinophil granule major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and neutrophil elastase. Before intradermal challenge, eosinophils and neutrophils were present only in blood vessels, and MBP, EDN, and elastase were localized to cells. At 15 minutes, small amounts of MBP, EDN and elastase were found outside of cells in focal areas. By 1 to 3 hours, MBP, EDN and elastase were extensively deposited throughout the dermis in a granular and diffuse manner; these deposits persisted up to 56 hours. Both actively and passively sensitized subjects showed similar MBP and elastase deposition. Skin sites passively sensitized by sera depleted of IgE showed essentially no MBP or elastase deposition. Electron microscopy showed degenerating eosinophils and free eosinophil granules in the dermis. Mast cell numbers diminished during the LPR when extracellular eosinophil and neutrophil granule protein deposition was maximal. These results demonstrate that striking dermal eosinophil and neutrophil granule protein deposits are prominent features of the cutaneous LPR, are IgE-dependent and precede the maximal clinical expression of the LPR. The possible significance of these findings in the pathophysiology of the LPR is discussed.
Administration, Cutaneous↗
Should we regulate 'utilization management?'.
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Government↗
Preparation and characterization of a monoclonal antibody that inhibits human neutrophil elastase activity.
Neutrophil proteases are believed to play a role in the pathogenesis of a variety of human diseases. While many studies of proteases in models of disease have focused on elastase, neutrophils contain several proteases some of which share a high degree of homology. This report describes the production and characterization of an IgG1 murine monoclonal antibody (AHN-10) that reacts with human neutrophil elastase but not with the other major neutrophil neutral proteases: cathepsin G, proteinase 3, collagenase, or the newly purified neutral protease, esterase N. AHN-10 inhibited the elastinolytic activity of purified human neutrophil elastase and could detect elastase in alcohol-fixed cytospin preparations. The epitope recognized by AHN-10 was resistant to treatment with NaIO4, suggesting that the epitope is not a carbohydrate. AHN-10 should be useful for the immunolocalization of neutrophil elastase in tissue specimens and as a stable source of characterized antibody for quantitative identification of neutrophil elastase.
Animals↗
Proteinase 3. A distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters.
Studies were designed to explore the possibility that human polymorphonuclear leukocyte granule constituents in addition to elastase (HLE) had the potential to cause emphysema. A two-step purification of three serine proteinases was developed. Granule extract proteins were initially separated by dye-ligand affinity chromatography. Fractions eluted were divided into four pools. Hamsters were given a single intratracheal instillation of saline +/- 0.1 mg protein of each pool. While pool 2 contained HLE and cathepsin G, the most dramatic bullous emphysema developed in animals treated with pool 4. The esterase from pool 4, designated proteinase 3 (PR-3) was purified, characterized in vitro, and tested for its ability to cause emphysema. PR-3 is a neutral serine proteinase with isoenzyme forms. Its ability to degrade elastin at pH 6.5 is slightly greater than that of HLE, but it is less active than HLE at pH 7.4 or 8.9. PR-3 has weak activity against azocasein. Its ability to degrade hemoglobin is intermediate to that of HLE and cathepsin G at pH 7.4. PR-3 has no activity against chromogenic substrates specific for HLE or cathepsin G. Its pI is substantially less than HLE or cathepsin G. It is also immunologically distinct from HLE. It induces emphysema in hamsters commensurate with that of HLE. We conclude that PR-3 may be important in the pathogenesis of human emphysema.
Animals↗
tri-n-Butyltin: a membrane toxicant.
Increased use of the biocidal compound tri-n-butyltin (TBT) in antifouling paints has prompted research aimed at determining the mechanism for TBT toxicity. Past investigations indicate that the primary cellular target for TBT is the cell membrane. Erythrocyte suspensions treated with TBT concentrations 2 greater than or equal to 5 microM undergo hemolysis described by a sigmoidal kinetic pattern. Transformation of cell shape from discocyte to echinocyte occurs at TBT concentrations greater than or equal to 0.1 microM, indicating that the compound enters the outer membrane bilayer. TBT at concentrations greater than or equal to 10 microM forms electron-dense aggregates that are intercalated within plasma membranes as viewed in ultrathin sections by transmission electron microscopy. Qualitative X-ray microanalysis of these aggregates confirms the presence of tin. The size of these structures can be modified by either 10 mM cyanide or 2,3-dimercaptopropanol (British Anti-Lewisite, BAL). Adding 10 mM cyanide to hemolytic TBT concentrations resulted in a synergistic stimulation of hemolysis attributable to high cyanide anion concentrations in or near the cell membrane. The elevated cyanide anion levels are thought to contribute to membrane lysis. The lipophilic dimercapto compounds BAL, dithiothreitol, and 2,3-dimercaptosuccinate are effective inhibitors of TBT-induced lysis. Water-soluble 2,3-dimercapto-1-propane sulfonate, a BAL analog, was largely ineffective as an inhibitor. The detailed molecular mechanism for TBT-induced membrane lysis is not yet clear. Cellular ATP depletion could be induced by TBT as well as by delipidation of anionic phospholipids or even formation of tributylstannylperoxy radicals, resulting in lipid peroxidation.
Chemical Phenomena↗
Organotin-induced hemolysis, shape transformation and intramembranous aggregates in human erythrocytes.
Organotin compounds examined in this study exhibited a relative order of potency for induction of in vitro hemolysis in human erythrocytes as follows: tri-n-butyltin greater than tri-n-propyltin greater than tetra-n-butyltin greater than triphenyltin chloride greater than tri-n-ethyltin bromide greater than dibutyltin dichloride greater than stannous chloride greater than tri-n-methyltin chloride = butyltin chloride dihydroxide. All of the organotin compounds induced erythrocyte shape transformation from the normal discocyte to an echinocyte and, in addition, triphenyltin chloride, tetra-n-butyltin and tri-n-ethyltin bromide also elicited stomatocyte formation at higher concentrations. Select organotin compounds also formed tin-containing aggregates within the plasma membrane. The relative order of effectiveness for organotin induction of intramembranous aggregates was tri-n-butyltin greater than tri-n-propyltin greater than tetra-n-butyltin greater than tri-n-ethyltin bromide, which was based upon the lowest concentration at which they were observed. These results support the previously suggested theory that organotins are membrane effectors because of their comparatively high hydrophobic, lipid partitioning properties. The relatively lipophilic compound, triphenyltin chloride, appeared to be anomalous because it did not readily promote hemolysis or induce the formation of intramembranous aggregates in human erythrocytes. A log-linear statistical model demonstrated an association of hemolysis with both tri-n-butyltin aggregate formation and shape transformation. Select organotin compounds should be useful probes in membrane studies because of their numerous effects.
Erythrocyte Aggregation↗