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Biomedical subjects

M Lesser

Publications and source records attributed to M Lesser.

At least 37 records · Page 2Linked to original sources
PubMed1990

Immunohistochemical localization of endopeptidase 24.15 in rat trachea, lung tissue, and alveolar macrophages.

Endopeptidase 24.15 (EP 24.15; EC 3.4.24.15), a zinc-metalloendopeptidase purified from rat brain and testes and also present in many other tissues, including the lung, degrades substance P, neurotensin, bradykinin, luteinizing hormone-releasing hormone, and some other bioactive peptides. The enzyme, present both as soluble cytoplasmic and membrane-bound forms, also rapidly converts dynorphin, alpha- and beta-neoendorphin, and some other opioid peptides into their respective enkephalins. In this study, a rabbit antibody to EP 24.15 purified from rat testes was used to study distribution of the enzyme in rat trachea, lung tissue, and alveolar macrophages (AMs) by immunohistochemical techniques. We found intense immunoreactivity to EP 24.15 within the cytoplasm of ciliated epithelial cells of tracheobronchial mucosa extending from trachea to terminal bronchioles. In addition, large myelinated paratracheal and peribronchial nerve fibers showed immunoreactivity. Blood vessels and alveolar lining cells were negative. AMs also showed intense diffuse cytoplasmic immunoreactivity. The findings of EP 24.15 immunoreactivity in airway epithelium, AMs, and paratracheal and peribroncheal nerve fibers suggest that the enzyme may modulate the activities of bioactive peptides within the lung.

Amino Acid Sequence↗
PubMed1990

Predictive initial parameters for response of stage D prostate cancer to treatment with the luteinizing hormone-releasing hormone agonist goserelin.

One hundred eighteen patients with stage D (D1 or D2) prostate cancer with a mean age of 69 years were treated with monthly goserelin (Zoladex; ICI 118, 630; ICI Americas Inc, Wilmington, DE, property of Imperial Chemical Industries PLC) injections and the data were analyzed for predictive parameters for best response and time to treatment failure (National Prostatic Cancer Project [NPCP] and Eastern Cooperative Oncology Group [ECOG] criteria). For best response in a univariate analysis, the performance status (PS 0-1 v 2-3) (P = .01), hematocrit (P = .04), and pain (P = .04) were significant. For time to treatment failure by univariate analysis, ECOG performance status (0-1 v 2-3) was most predictive (P less than .0001), followed by pain at entry (P = .0002), initial testosterone (T) level (greater than 250 ng/dL) (P = .0005), age less than 69 years (P = .02), alkaline phosphatase (less than 115 IU/L) (P = .03), hemoglobin (less than 14 g/dL) (P = .03), whereas normal acid phosphatase (less than 3 IU/mL) (P = .29) was not predictive. In multivariate analysis for time to treatment failure, only the ECOG performance status was of significance (P = .01). Estimated median time to treatment failure for PS of 0-1 was 88 weeks and for PS of 2-3 was 31 weeks.

Age Factors↗
PubMed1989

Substrate specificity and inhibitors of a capillary injury-related protease from sheep lung lymph.

A serine protease (Mr 70,000 to 75,000) appearing in sheep lung lymph after capillary damage induced by Escherichia coli endotoxin, oleic acid, or air emboli, was studied for its specificity toward a series of synthetic peptide and thioester substrates containing an Arg residue in the P1 position. High specificity constants (kcat/Km) were generally obtained with substrates having two or more basic amino acid residues, and with those having a Gln residues in the P2 position. Secondary enzyme-substrate interactions at sites more removed from the scissile bond are of importance, since a few peptides with two basic residues were hydrolyzed slowly, and the site of cleavage of natural peptides was influenced by the amino acid sequence beyond the immediate vicinity of the hydrolyzed bond. The properties of the enzyme and its pattern of specificity distinguish it from enzymes of the clotting cascade, from components of the complement system, and from lung and skin tryptase. The enzyme was inactivated by p-amidinophenylmethanesulfonyl fluoride and by a series of mechanism-based isocoumarin derivatives, the most potent inhibitor being 4-chloro-7-guanidino-3-(2-phenylethoxy)isocoumarin. Enzyme solutions inactivated by reaction with isocoumarin inhibitors could be completely reactivated after 30 h by treatment with hydroxylamine at neutral pH. Formation of a stable sheep lymph acyl enzyme--in contrast to thrombin and other trypsin-like enzymes--is not followed by alkylation of an active site nucleophile that leads to irreversible enzyme inactivation. The high activity toward substrates with two basic residues suggests that the enzyme may potentially function in processing of precursors of bioactive peptides.

Animals↗
PubMed1989

Relation of personality and attentional factors to cognitive deficits in human immunodeficiency virus-infected subjects.

In view of the evidence that patients with human immunodeficiency virus infection experience reactive depression and anxiety, it is important to determine whether these factors might account for some of the cognitive deficiencies observed in this group, as is often the case in psychiatric populations. An extensive battery of cognitive, personality, and attention tests was administered to 26 patients who tested positive for the human immunodeficiency virus. In this group were patients who demonstrated no symptoms, patients who had acquired immunodeficiency syndrome-related complex, and patients who had acquired immunodeficiency syndrome. Pearson Product Moment correlations were computed between scores on the three types of measures. The results of this correlational study suggest that cognitive decline in patients infected with human immunodeficiency virus is independent of mood and attentional changes.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Lipopolysaccharide stimulates alveolar macrophage adherence in vivo and in vitro.

The number of alveolar macrophages (AM) obtained from rats by bronchoalveolar lavage (BAL) decreases significantly within two hours after infusion of E. coli lipopolysaccharide (LPS). To investigate the mechanism of this phenomenon, we evaluated adherence properties of AM obtained from rats 4 hours after intravenous injection of E. coli LPS (3 mg/kg) or normal saline (NS). Significantly fewer AM were present in BAL samples from LPS-treated rats (4.09 x 10(6] compared to NS-treated rats (7.55 x 10(6]. When a 17 mM lidocaine solution (LDC) was used for lavage, the number of AM in BAL samples from LPS-treated rats increased significantly (7.38 x 10(6]. Adherence of AM from LPS-treated rats to rotating plastic tubes was significantly greater than that of AM from NS-treated rats. Incubation of normal AM with LPS (5 or 15 micrograms/ml) in serum-free media increased AM adherence to plastic. LPS-induced adherence was significantly greater at the higher LPS dose. Thus, the decreased number of AM obtained by BAL of LPS-treated rats appears to be due to increased adherence of AM to alveolar structures. This phenomenon may be mediated by direct effects of LPS on AM.

Animals↗
PubMed1989

Cathepsin B and D activity in alveolar macrophages from rats with pulmonary granulomatous inflammation or acute lung injury.

Cathepsin B and D activity was determined using specific synthetic substrates in alveolar macrophages (AMs) obtained from Sprague-Dawley rats with experimentally induced pulmonary granulomatous inflammation. Increased cathepsin B activity was found 4 days after intravenous injection of complete Freund's adjuvant (CFA), but not after injection of live bacillus Calmette-Guérin organisms (BCG), indicating that the enzyme response was unrelated to the subsequent development of granulomatous inflammation. Findings of comparable increases in enzyme activity following injection of mineral oil (MO) indicate that the response to CFA was due to the oil component. Significantly, oleic acid (OA), a natural fatty acid, did not stimulate enzyme activity although the agent, like MO, caused acute lung injury as assessed by 125I albumin uptake. At 7 and 28 days following injection of CFA, cathepsin B levels in AMs were the same as those in animals given normal saline (NS), although bronchoalveolar lavage (BAL) samples still contained increased numbers of AMs, and cells obtained at 28 days phagocytosed more polystyrene microspheres. Cathepsin D activity did not increase 4 days after injection of CFA or BCG + CFA; at 28 days following injection of BCG + CFA activity was significantly decreased as compared to animals given NS. The data reveal a differential response of two lysosomal enzymes during the early phases of granulomatous inflammation.

Albumins↗
PubMed1989

Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome: diagnosis using minilavage samples.

Over a 30-month period, we evaluated 74 patients with acquired immunodeficiency syndrome (AIDS) for suspected opportunistic pulmonary infection. All had abnormal findings on chest roentgenogram. Sixty patients (81%) were found to have Pneumocystis carinii pneumonia (PCP). We assessed the yield of various diagnostic methods, and found that bronchoalveolar lavage samples obtained by the instillation of 20 to 50 ml of normal saline (minilavage) contained detectable organisms in 51 of 53 patients (sensitivity of 96%) when the samples were embedded in plastic, cut in thick sections (1 micron), stained with toluidine blue O, and evaluated by light microscopy. In comparison, the diagnostic yield was 94% for lung biopsy, 85% for touch preparation of lung tissue, 32% for bronchial washing, and 14% for brush biopsy. It is significant that minilavage samples embedded in plastic were positive in all seven patients who did not have transbronchial lung biopsy because they were at high risk for complications. We conclude that the process of embedding minilavage samples in plastic and evaluating thick sections stained with toluidine blue O is a sensitive method of diagnosing PCP in patients with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Lung lymph capillary injury-related protease.

Capillary damage induced in sheep by intravenous infusion of Escherichia coli endotoxin, oleic acid, or air emboli causes the appearance in lung lymph of a serine protease with trypsin-like activity. The time course of the appearance of the enzyme and the extent of its activity increase indicate a close association with capillary injury. The enzyme was isolated from active lymph after a 9,000-fold purification by affinity chromatography on Reactive Blue-agarose, aprotinin-agarose, and p-amino-benzamidine-agarose columns. The protein, molecular mass of 70-75 kDa, is composed of two polypeptide chains of 31 and 43 kDa linked by disulfide bonds. Studies with synthetic peptide and thioester substrates showed preferential cleavage of substrates having two or more basic amino acids and the importance for activity of secondary enzyme-substrate interactions at sites removed from the scissile bond. The specificity of the enzyme and its pattern of sensitivity to inhibition by a series of isocoumarin derivatives distinguish it from enzymes of the clotting and complement systems and also from tissue plasminogen activator and lung and skin tryptase. The origin of the enzyme, its role in capillary damage, and its physiological function remain to be established.

Amino Acid Sequence↗
PubMed1989

Cathepsin D activity is increased in alveolar macrophages and bronchoalveolar lavage fluid of smokers.

Cathepsin D activity was determined in alveolar macrophages (AM) and cell-free bronchoalveolar lavage fluid (BALF) from volunteers who were current cigarette smokers and compared with that found in lifetime nonsmokers. Enzyme activity was determined with a highly sensitive and specific substrate [D-Phe-Ser(0-CH2-C6H5)-Phe-Phe-Ala-Ala-pAB]. Specific activity was more than three times higher in AM from smokers than in cells from nonsmokers (37,880 +/- 2,090 versus 10,300 +/- 1,200; p less than 0.001) and approximately seven times higher in BALF from smokers than from nonsmokers (3,620 +/- 490 versus 515 +/- 165; p less than 0.001). This study demonstrated that cigarette smoke is a potent inducer of cathepsin D activity in AM in vivo. Because cathepsin D is capable of degrading a variety of proteins, the finding of high concentrations of the enzyme in AM and BALF from smokers, along with previous observations of elevated cathepsin B activity, suggests that lysosomal enzymes may cause or contribute to structural lung damage associated with cigarette smoking.

Adult↗
PubMed1989

Cathepsin L activity in alveolar macrophages of rats: response to cigarette smoke.

Cathepsin L activity was quantitated in alveolar macrophages (AMs) and bronchoalveolar lavage (BAL) fluid from Sprague-Dawley rats exposed through the nose only to fresh mainstream smoke from University of Kentucky reference cigarettes (2Rl), and in AMs and BAL fluid of room control (RC) and sham control (SH) animals. Activity was determined with the methylcoumarylamide substrate, benzyloxycarbonyl-Phe-Arg-4-methyl-7-coumarylamide (Z-Phe-Arg-NMec). Total activity of cysteine proteinases in AM homogenates towards Z-Phe-Arg-NMec was measured by determining inhibition with E-64 (0.5 microM), a specific inhibitor of this class of enzymes. The activities of cathepsin B and L towards the substrate were differentiated by use of the diazomethane inhibitor, Z-Phe-Phe-CHN2 (0.01 microM), which selectively inhibits cathepsin L at this concentration. We found that cathepsin L activity was significantly elevated in AMs of animals exposed to 10 puffs of cigarette smoke, twice a day, 7 days/wk for 22 wk (1,620 +/- 870 units/mg protein) as compared with cells from RC (420 +/- 150) and SH (550 +/- 160) animals. Cathepsin B activity was also increased in AMs from animals exposed to cigarette smoke (2,360 +/- 890) as compared to RC (930 +/- 170) and SH (1,020 +/- 70) animals. Cathepsin L and B activity was also present in unconcentrated BAL fluid, but levels did not differ significantly among the three groups. The results demonstrate that AMs contain significant levels of cathepsin L activity as measured with methylcoumarylamide substrates, and that activity increases in cells from rats exposed to cigarette smoke in amounts comparable to those inhaled by a healthy 70-kg human smoker using 20 cigarettes a day.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Cigarette smoke stimulates cathepsin B activity in alveolar macrophages of rats.

Cathepsin B activity was determined in alveolar macrophages and cell-free bronchoalveolar lavage fluid from Sprague-Dawley rats exposed only through the nose to fresh mainstream smoke from University of Kentucky high-tar, high-nicotine reference cigarettes, and in cells and fluid from room control and sham control animals. Increased levels of blood carboxyhemoglobin and pulmonary aryl hydrocarbon hydroxylase activity in smoke-exposed animals indicated effective exposure of animals to cigarette smoke. Cathepsin B activity was quantitated with alpha-N-benzyloxycarbonyl-leucine-leucine-arginine-2-naphthylamide as substrate. Specific activity (nanomoles of substrate cleaved per milligram of protein per hour) in alveolar macrophages was increased by 43% at both 4- and 10-week exposure points in animals exposed twice daily to 10 puffs of cigarette smoke. These data indicate that maximal stimulation of the enzyme occurs within 4 weeks of the initiation of smoke exposure. When the activity was expressed on a per-cell basis, cathepsin B activity was also increased in the smoke-exposed group at both exposure points. Activity in bronchoalveolar lavage fluid of smoke-exposed animals was increased by approximately 50% at 4 and 10 weeks, but the differences were not statistically significant. These findings demonstrate that cigarette smoke is a potent inducer of cathepsin B activity in alveolar macrophages of rats.

Animals↗
PubMed1988

Pharmacologic studies of tardive dyskinesia.

Based on the results of two preliminary studies, we concluded that late-developing persistent drug-induced movement disorders are pharmacologically heterogeneous, and this heterogeneity is seen between individual patients (and groups of patients) as well as within body areas of individual patients; dystonic pathology has a distinct and more consistent response to pharmacologic stimulation than does nondystonic tardive dyskinesia (TD); and, although disturbances in dopamine and acetylcholine appear to be involved in these disorders, they do not in all cases exist in functionally opposite relationships. The observed pharmacologic heterogeneity in TD response reflects the limitations of the dopamine/acetylcholine model of TD, which oversimplifies the neuroanatomy of the basal ganglia and the pathophysiology of TD. The chemical and anatomical complexity of this region suggests that other neurotransmitter systems and neuronal circuits within and extending from the basal ganglia may be disturbed in the pathogenesis of TD.

Adult↗
PubMed1988

Hyperamylasemia in inflammatory bowel disease.

We determined the prevalance and significance of hyperamylasemia in 180 patients with idiopathic inflammatory bowel disease (IBD) (83 with ulcerative colitis, and 97 with Crohn's disease). Serum total amylase and pancreatic and salivary isoamylase activity were measured in all patients. In all patients with hyperamylasemia, we measured isoamylase activity by cellulose acetate electrophoresis and lipase activity, assayed for the presence of macroamylase, and carried out pancreatic ultrasound examination and barium studies of the upper gastrointestinal tract. Eight of 97 patients with Crohn's disease (8%) had hyperamylasemia; 4 of them had an elevated pancreatic isoamylase and 2 a raised lipase activity. All patients with hyperamylasemia had normal ultrasonographic scans of the pancreas and no evidence of duodenal involvement on barium meal. None had macroamylasemia. We found no relationship of hyperamylasemia to disease site, activity, and duration or therapy and no patient developed clinical evidence of pancreatitis. We conclude that a small but important number of patients with Crohn's disease have hyperamylasemia not associated with overt pancreatitis. In the absence of appropriate indications, it requires no investigation.

Amylases↗
PubMed1988

High cathepsin B activity in alveolar macrophages occurs with elastase-induced emphysema but not with bleomycin-induced pulmonary fibrosis in hamsters.

Cathepsin B activity was quantitated in alveolar macrophages obtained from hamsters 10, 21, and 105 days after the intratracheal instillation of porcine pancreatic elastase, bleomycin, or normal saline. Alveolar macrophages lavaged from animals receiving elastase contained significantly higher enzyme levels at 21 and 105 days (16,200 and 17,000 U/mg protein/hr, respectively) as compared with saline-treated animals (12,300 units). In contrast, cells from animals receiving bleomycin showed a decrease in activity at 21 and 105 days (9700 and 9900 units, respectively). At 10 days enzyme levels did not differ significantly. The results suggest that cathepsin B levels in alveolar macrophages reflect differences in lung destruction and connective tissue repair in vivo. In addition, the finding of high cathepsin B activity in animals with emphysema suggests the possibility that cysteine proteases contribute to progressive lung destruction initiated by the intratracheal instillation of elastase.

Animals↗
PubMed1988

Pharmacologic characterization of tardive dyskinesia.

Tardive dyskinesia (TD) occurs in approximately 20% of patients treated chronically with antipsychotic drugs and constitutes a major public health problem. The cause of this disorder remains unknown, and no effective treatment has yet been found. The major etiologic theory (dopamine [DA] supersensitivity hypothesis) suggests that TD is the pharmacologic opposite of Parkinson's disease and implies that all patients with TD should respond uniformly to specific pharmacologic agents. Clinical research, however, has not borne this out. To evaluate pharmacologic response in TD syndromes, 15 patients underwent single dose acute administration of four different drugs: a DA agonist (bromocriptine 5 mg orally), a DA antagonist (haloperidol 5 mg intravenously), a cholinergic agonist (physostigmine 2 mg intravenously) and a cholinergic antagonist (benztropine 4 mg intravenously), individually in separate procedures at weekly intervals for four consecutive weeks in randomized order and under controlled double-blind conditions. Patients were evaluated for their clinical and endocrine responses. Pre- and post-drug administration TD exams were blindly rated. Results were not consistent with the DA supersensitivity theory; instead they demonstrated marked inter- and intrasubject variability in pharmacologic responses. Greatest uniformity in response was found among the tardive dystonic subjects, although this also was not consistent with a DA supersensitivity hypothesis. TD appears to be a pharmacologically heterogeneous condition, which may reflect the neurochemical complexity of the basal ganglia.

Adult↗
PubMed1987

Isolation and properties of a capillary injury-related protease from lung lymph.

Lung microvascular injury induced in sheep by intravenous infusion of Escherichia coli endotoxin, oleic acid, or air emboli caused the appearance in lung lymph of high levels of a protease with trypsin-like activity. The enzyme was isolated as an apparently homogeneous protein from pooled samples of active lung lymph, after an almost 9000-fold purification by affinity chromatography on columns of Reactive Blue 2-agarose, aprotinin-agarose, and p-aminobenzamidine-agarose, and chromatography on a column of Sephadex G-100. A molecular weight of about 70,000 to 75,000 was determined from mobility in polyacrylamide gel electrophoresis in the presence of sodium dodecyl sulfate. The pH optimum was between 7.3 and 7.6. The isolated enzyme was quite labile, rapidly losing activity at both 37 and 25 degrees C. Addition of albumin to enzyme solutions protected against inactivation. Inhibition by diisopropylfluorophosphate and phenylmethanesulfonyl fluoride indicated that the enzyme belongs to the class of serine proteases. The enzyme cleaved peptide bonds on the carboxyl side of arginine residues and showed a relatively high affinity toward peptides containing several basic amino acid residues. Bonds involving the carboxyl group of lysine were cleaved at a much slower rate. The enzyme showed no plasminogen activator activity and its substrate specificity was quite different from that of several proteases of the clotting cascade. Its appearance in lymph was not influenced by lymph clotting and the isolated enzyme was not capable of correcting the clotting defect of plasmas deficient in factors XII, XI, IX, VII, and X.

Animals↗