Ambulance notes of a Bellevue Hospital intern: May 1938.

In 1938, as a New York University/Bellevue Hospital intern, I recorded notes on the 384 cases I saw during my 1-month ambulance duty. Although I intended to use them to follow up the clinical course of patients I admitted to Bellevue, the long hours and pressure of work made this ambitious goal unachievable. Sixty years later, after retirement from academic medicine and medical practice at New York University School of Medicine, I found the long-lost notes among my papers. They are of historic interest since they provide insight into aspects of primary and emergency medicine of the era when the therapeutic efficacy of the sulfanilamide class of agents was under investigation, a unique view of the life of an intern just before interns were replaced on ambulances by technicians, and a glimpse of the surprising character of several neighborhoods of pre-World War II Manhattan. The notes also provide the basis for a current analysis of case incidence and treatment by disease category. A description of the confluence of social, economic, and political forces that led to the establishment of the Bellevue Hospital Ambulance Service, the first such urban service in the world, is included.

Elastase and neutral, metal-dependent enzyme activity of human leukocyte lysosomal granules.

A neutral protease has been identified in polymorphonuclear leukocyte lysosomal granules that, with elastase, degrades casein and is inhibited by alpha1-antitrypsin. In the present studies, protease inhibitors were used to delineate the elastase and neutral protease activities against casein, because these polymorphonuclear leukeocyte lysosomal enzyme activities may have a role in lung tissue damage in alpha1-antitrypsin deficiency. The highly specific, irreversible elastase inhibitor, N-acetyl-L-analyl-L-alanyl-L-alanine chloromethyl ketone (Ac-Ala-Ala-AlaCH2Cl) inhibited approximately 40 to 50 per cent of the caseinolytic activity of polymorphonuclear leukocyte lysosomal granule preparations. The chelating agent, sodium diethylene diamine tetraacetate (EDTA), which does not inhibit elastase in the concentration used, was almost as effective as Ac-Ala-Ala-AlaCh2cl. Preincubation of polymorphonuclear leukocyte granule extract with Ac-Ala-Ala-AlaCh2cl, followed by the addition of EDTA, resulted in nearly complete inhibition of caseinolysis. These studies have characterized polymorphonuclear leukocyte lysosomal neutral protease as belonging to the class of metal-dependent proteases. Its role in the degradation of tissue remains to be determined.

Human granulocyte lysosomal elastase activity using t-butyloxycarbonyl-L-alanine p-nitrophenyl ester and elastin-rhodamine as substrates.

Polymorphonuclear leukocyte lysosomal esterolytic activity on the synthetic substrate, t-butyloxycarbonyl-L-alanine p-nitrophenyl ester was observed to correlate well with polymorphonuclear leukocyte granule elastase activity measured on the natural substrate, elastin, bound to rhodamine. In addition, the effect of highly specific, irreversible chloromethyl ketone elastase inhibitors on leukocyte lysosomal elastase activity was similar, using t-butyloxycarbonyl-L-alanine p-nitrophenyl ester or elastin-rhodamine as substrate. Whether polymorphonuclear leukocyte lysosomal granules contain two different enzymes, a true elastase with esterase activity and a similar esterase without elastase activity, as found in the human pancreas, is, as yet, unknown. Both enzyme activities have been identified in isoenzymes of purified human polymorphonuclear leukocyte lysosomal elastase. The correlations observed between the two enzymes, if present in polymorphonuclear leukocytes, are sufficiently strong to use the esterase assay for clinical purposes.

Alpha 1-antitrypsin deficiency genes: contributory defect in a subset of psoriatics?

Since proteolytic processes are prominent in psoriasis, sera of forty-five psoriatics were examined for alpha 1-antitrypsin (alpha 1-AT) phenotype and eighteen sera, for alpha 1-AT content and function. Five sera (11.1%) had heterozygous phenotypes (2 MZ and 3 MS), a prevalence of Z and S variants similar to that reported in nonpsoriatic populations. Two of three variants examined for content and function exhibited marked reductions. Since MZ heterozygotes are almost always, and MS phenotypes sometimes, associated with decreased serum alpha 1-AT levels, and since Z and MZ phenotypes are associated with increased hepatic fibrosis or cirrhosis, these variants may be relevant to problems of spontaneous fibrosis or methotrexate-induced hepatotoxicity in psoriasis. alpha 1-AT deficiency may also contribute to guttate flares with infection and to increased O-2 . production by psoriatic sera-stimulated polymorphonuclear leukocytes (PMNs). Although no evidence exists that psoriasis is more prevalent among persons with hypomorphic alpha 1-AT phenotypes, such defects may contribute to severity of inflammation and hyperplasia.

Antioxidant activity of serum ceruloplasmin and transferrin available iron-binding capacity in smokers and nonsmokers.

We investigated in 39 healthy smokers (20 female, 19 male) and 38 healthy nonsmokers (18 female, 20 male): the impact of smoking and smoking-related factors on the concentration of serum ceruloplasmin, transferrin, transferrin available iron-binding capacity (AIBC), and serum antioxidant activity (AOA); the relative contribution of serum ceruloplasmin and AIBC to serum AOA; the association and possible interactive effects of serum ceruloplasmin, AIBC, and smoking with serum AOA; and the relation of pulmonary function in healthy smokers to serum AOA, ceruloplasmin, and AIBC. We found that: as compared with healthy nonsmokers, healthy smokers had higher serum ceruloplasmin concentration, similar serum transferrin and AIBC concentration, and lower serum AOA; ceruloplasmin, AIBC, and smoking acted additively, accounting for about 60% of the variability of serum AOA; the impact of AIBC on serum AOA was significantly greater than that of ceruloplasmin; and pulmonary function in the smokers was not significantly related to serum AOA, ceruloplasmin, or AIBC. Our findings suggest that: serum AIBC has a greater role in serum AOA than has previously been attributed to it; suppression of the AOA of serum constituent(s) other than those we measured may account for the significantly lower serum AOA in healthy smokers than in healthy nonsmokers; and normal air flow in healthy cigarette smokers is unrelated to serum AOA, ceruloplasmin, or AIBC concentration.

Ceruloplasmin. Increased serum concentration and impaired antioxidant activity in cigarette smokers, and ability to prevent suppression of elastase inhibitory capacity of alpha 1-proteinase inhibitor.

Bronchoalveolar lavage fluid of smokers and nonsmokers contains significant concentrations of ceruloplasmin, the major serum inhibitor of lipid peroxidation, with limited superoxide dismutase activity. This suggested that ceruloplasmin may protect the lower respiratory tract against oxidant(s) in cigarette smoke and air pollutants. We investigated (1) serum ceruloplasmin concentration and antioxidant activity (percentage inhibition of autoxidation of ox-brain homogenate) in healthy male and female smokers and nonsmokers, and (2) the capacity of ceruloplasmin to prevent suppression of the elastase inhibitory capacity of alpha 1-proteinase inhibitor by the oxidant chloramine T and by cigarette smoke solution. Mean ceruloplasmin concentration was 18% higher in 35 female smokers than in 46 male smokers (p less than 0.001), 17% higher in 22 female nonsmokers than in 18 male nonsmokers (p less than 0.005), 15% higher in the female smokers than in the female nonsmokers (0.02 greater than p greater than 0.01), and 14% higher in the male smokers than in the male nonsmokers (p less than 0.001). Serum antioxidant activity showed significant linear correlations with serum ceruloplasmin in smokers and nonsmokers of both sexes; correlation coefficients, all significant, ranged from 0.65 to 0.50. For comparable ceruloplasmin concentrations, serum antioxidant activity was significantly lower in smokers (males: 9%, p less than 0.001; females: 7%, 0.05 greater than p greater than 0.01) than in nonsmokers. There was a linear relationship between ceruloplasmin concentration and its ability to prevent suppression of the elastase inhibitory capacity of alpha 1-proteinase inhibitor by chloramine T and cigarette smoke solution. Our findings indicate: (1) that cigarette smoking can cause partial inactivation of serum antioxidant activity accompanied by insufficient compensatory increase in ceruloplasmin concentration, and (2) that ceruloplasmin may protect the lung against oxidant(s) in cigarette smoke and air pollutants.

Degradation of tropoelastin and elastin substrates by human neutrophil elastase, free and bound to alpha2-macroglobulin in serum of the M and Z (Pi) phenotypes for alpha1-antitrypsin.

Human neutrophil elastase degraded tropoelastin approximately 9 times faster than it did solubilized elastin and approximately 19 times faster than it did lung elastin. When bound to alpha2-M, the enzyme retained approximately 6 per cent of its activity toward tropoelastin and solubilized latter observations suggest that alpha2-M--bound elastase, cleared slowly from lung extracellular tissue space, may participate normally in the turnover of soluble precursor (s) of elastin and may contribute to the development of emphysema in alpha1-antitrypsin deficiency.

Nicotine enhances expression of the neutrophil elastase gene and protein in a human myeloblast/promyelocyte cell line.

The pathogenesis of emphysema is considered to be an imbalance of protease and antiprotease activity in the lower respiratory tract leading to uninhibited degradation of lung interstitium by elastolytic enzymes. An increased amount of the serine protease neutrophil elastase (NE) is though to play a major role in this degradation. Because the expression of NE is limited to neutrophil precursors in the bone marrow, we hypothesized that nicotine, which is readily absorbed from lung and distributed to tissue, including bone marrow, would increase expression of the NE gene and protein. HL-60 cells, a myeloblast/promyelocyte cell line, were cultured in the presence or absence of 0.06 and 0.8 microM nicotine for 5 d. Both concentrations of nicotine caused a 2.4- to 3.3-fold increase, respectively, in NE gene expression over unstimulated cells, and NE protein increased 4.8- to 3.4-fold over unstimulated cells, respectively, similar to our positive control DMSO. Nicotine did not induce upregulation of the NE gene by initiating cell differentiation. Both low and high nicotine concentrations upregulate the NE gene in HL-60 cells leading to increased NE protein concentration per cell suggesting a pathophysiologic mechanism for emphysema.