Biomedical subjects
Publications and source records attributed to P B Campbell.
A case of catheter-related septicemia, due to Coryneform CDC group A-5, in an 11 yr old boy with acute myelomonocytic leukemia is discussed. The child failed to respond to initial antibiotic therapy, even following the addition of vancomycin. Laboratory studies later showed the organism to be vancomycin resistant but cefotaxime susceptible.
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The leukotactic responsiveness of human peripheral blood monocytes is regulated by the cell-directed inhibitor of monocyte leukotaxis, CDI-MLx. The actions of CDI-MLx on normal monocytes in vitro were abrogated by co-incubation with inhibitors of cyclooxygenase and thromboxane synthetase with indomethacin and dazmegrel (UK-38,485) being most active. The actions of CDI-MLx were mimicked by the thromboxane A2 analogue, U-46619, and by 12-HHT with half-maximal inhibition observed at 10(-10) M; PGE2 was 1000-fold less active. SQ 29,548, a thromboxane A2 receptor antagonist, blocked the effects of CDI-MLx, U-46619, and 12-HHT. Production of PGE2 and thromboxane B2 by purified monocytes was stimulated by CDI-MLx and this effect was also blocked by indomethacin, dazmegrel, and dazoxiben. These data suggest a major regulatory role for thromboxane synthetase products in human monocyte leukotaxis.
Pernasal aspirate (PNA) was obtained from 543 children during a 6-month period when whooping cough was prevalent. Three tests for diagnosing pertussis were performed on the PNA: (a) examination of direct smears by immunofluorescence (IF) for Bordetella pertussis; (b) culture; and (c) estimation of B. pertussis-specific immunoglobulin-A antibody (P-IgA) by an enzyme-linked immunosorbent assay (ELISA). On clinical review, 395 children were assessed to have had pertussis (P children) and 148 children not to have had pertussis (non-P children). The non-P children comprised 66 admitted to hospital for acute respiratory infections and 82 outpatients suspected of having pertussis. Analysis of the results of the tests on the PNAs of the non-P children helped to assess the P-IgA test. The analysis showed that artificial immunisation against pertussis did not affect the antibody results, but that non-specific positive results occur requiring the labelling of many P-IgA results as "doubtful". Among the 395 P children, 36% yielded positive cultures and more than half of these also had positive IF tests. The ELISA for P-IgA was positive in 24% of all the P children, equivalent to nearly 40% of the culture-negative P children. For the 148 non-P children, IF and culture-negative by definition, the P-IgA test was positive in 9%. The antibody test result was doubtful in 28% of the P children and in 40% of the non-P children. Estimation of P-IgA antibodies in PNA is a useful and economic complement to culture and IF in the diagnosis of pertussis.(ABSTRACT TRUNCATED AT 250 WORDS)
Because the accumulation and activation of mononuclear phagocytes are critical to the host response to intracellular microbial pathogens, we evaluated mechanisms of peripheral monocyte leucotactic regulation in leprosy. Plasma from 53 of 67 patients was found to inhibit the locomotion of normal human monocytes. Neither the prevalence nor the magnitude of plasma leucotactic inhibitory activity correlated with disease histology or duration, type or duration of chemotherapy, or history of erythema nodosum leprosum. Plasma leucotactic inhibitory activity resided principally in a non-immunoglobulin, cell-directed inhibitor of 230,000 daltons molecular weight. Fractionation of plasma from patients with lepromatous leprosy revealed an additional, immunoglobulin-containing inhibitor of approximately 400,000 daltons weight, possibly an IgG-IgA immune complex. Production of leucotactic inhibitors by unstimulated and concanavalin A-stimulated peripheral mononuclear cells was normal; however, cutaneous explants from these patients spontaneously produced the 230,000 dalton leucotactic inhibitor in vitro. The ability of the lesions of leprosy to impede monocyte traffic may be an important pathogenetic mechanism.
The leukotactic responsiveness of human peripheral blood monocytes is regulated by the cell-directed inhibitor of monocyte leukotaxis, CDI-MLx. Normal peripheral blood mononuclear cells elaborated CDI-MLx in vitro in response to soluble and cell-associated antigens; concanavalin A and pokeweed mitogen induced production of the inhibitor while phytohemagglutinin and staphylococcal protein A were without effect. By erythrocyte rosetting and immunoadherence, the CDI-producing cell had the phenotype, E-rosette+, OKMI+, and Leu 7+, and thus appeared related to natural killer cells. PBMC and plasma CDI-MLx had similar molecular weights (230,000) and showed similar heterogeneity on chromatofocusing with peaks of activity at pH 5.8 and 5.25. CDI-MLx was immunologically distinct from immunoglobulins, did not inactivate preformed leukotaxins, and was distinct from other lymphokines known to modulate monocyte locomotion.
Sarcoidosis is an immunopathogenic disorder of uncertain cause. Because the regulation of monocyte mobilization and function may be critical to granuloma formation in this disease, we evaluated production of the cell-directed inhibitor of monocyte leukotaxis (CDI-MLx) by peripheral blood and bronchoalveolar lavage mononuclear cells from these patients. Cells obtained from either source during clinically active disease spontaneously produced this leukotactic regulator in vitro in amounts comparable to those achieved with maximal mitogenic stimulation of normal cells. Plasma leukotactic inhibitory activity and spontaneous inhibitor production were significantly associated. Plasma inhibitory activity and CDI-MLx production were normal in patients whose disease was inactive. Spontaneous production continued for at least 7 days in vitro and could not be attributed to alterations in the absolute numbers of specific mononuclear cell populations. Partitioning of peripheral blood mononuclear cells by a combination of E-rosetting and immunoadherence techniques indicated, however, that CDI-MLx was produced by a subpopulation of natural killer-like cells that formed E-rosettes and bore the OKMI and Leu 7 membrane antigens.
To assess the ability of the sarcoidal granuloma to modify peripheral mononuclear cell function, we assayed the culture supernatants of cutaneous granulomata for modulators of monocyte locomotion. The supernatants of granulomata from each of 11 patients contained a cell-directed inhibitor of monocyte leukotaxis. No inhibitory activity was detected in the supernatants of histologically normal skin biopsies. The inhibitor acted only on monocytes, possessed a molecular weight of 230,000 daltons, and was clearly distinct from migration inhibition factor (MIF), leukotactic lymphokines, and immunoglobulins. A physicochemically and functionally indistinguishable inhibitor was present in patient plasma. Production of the inhibitor by the granuloma required active protein synthesis. Culture supernatants also contained MIF and a leukotaxin inactivator. These observations indicate the potential of the sarcoidal granuloma to exert local and, perhaps, systemic regulation of inflammatory processes.
This study determined the incidence of retinopathy of prematurity (ROP) in 2,958 admissions to the Newborn Intensive Care Unit of the James Whitcomb Riley Hospital for Children, Indianapolis, between January 1976 and December 1979. Among 2,484 survivors, acute ROP developed in 72 (2.9%); 60 (83%) of these newborns had birth weights of less than 1,500 g. The incidence of acute ROP among survivors with birth weights of less than 1,000 g (28%) was approximately three times that of the survivors with birth weights between 1,001 and 1,500 g (10.1%). The overall incidence of blindness was 4.5% of surviving infants less than 1,000 g and 1.2% of those surviving with birth weights of 1,000 to 1,500 g. Evidence of the strong influence of immaturity and low birth weight on the risk of development of ROP is reaffirmed. Increasing survival of the most susceptible infants may be the factor contributing most to the overall incidence of ROP.
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Three patients with acute pulmonary histoplasmosis presented with extensive, diffuse bilateral infiltrates on chest roentgenograms. Fungal elements were seen in the bronchial secretions of two patients; Histoplasma capsulatum was grown from the third patient and from soil from the patients' workplace. Two patients were severely hypoxemic and required short courses of amphotericin B therapy; in one of these two, progressive deterioration dictated corticosteroid therapy as well, with a dramatic clinical response. Radiologic resolution of disease occurred more quickly in the treated patients. Initial pulmonary function tests suggested mild restriction in each, with normal test results by the fourth month of follow-up. Our experience suggests that amphotericin B may shorten the course of acute histoplasmosis and that corticosteroid therapy may be efficacious in controlling the symptoms related to hyperresponsiveness in fulminant primary disease.
Because the accumulation of macrophages and their precursors, peripheral blood monocytes, in foci of infection is an important feature of the host reponse to mycobacterial challenge, the leukotactic responsiveness of monocytes from patients with active tuberculosis was evaluated. With a double-filter, in vitro technique, defective leukotaxis was demonstrated in monocytes from 19 of 20 untreated patients, whereas normal leukotactic responses were found in monocytes from 11 of 15 patients with chronic, nontuberculous pulmonary inflammatory diseases. This defect may be related to increased activity of a naturally occurring, heat-stable plasma substance with a molecular mass of approximately 2.3 x 10(5) daltons that inhibited leukotactic responsiveness. Monocyte leukotaxis improved and the leukotactic inhibitory activity of plasma disappeared in most patients while they were on therapy; these phenomena were unrelated to bacteriologic conversion or resolution of symptoms. In vitro studies with isoniazid, ethambutol, and rifampin excluded a direct effect of these drugs or their metabolites on monocytes or on the leukotactic inhibitor in plasma. Thus, defective leukotaxis of monocytes in patients with pulmonary tuberculosis may be an epiphenomenon of the local tissue reaction.
Monocyte leukotactic function was studied in 25 untreated patients with histologically confirmed sarcoidosis. Monocyte leukotactic responses were significantly depressed (P less than 0.001), most strikingly in patients with stage I disease; however, the severity of the leukotactic defect did not correlate with duration, activity, or extrathoracic dissemination of disease. Preincubation of normal monocytes in sarcoid plasma, but not normal plasma, resulted in partial inhibition of leukotactic responsiveness. The leukotactic inhibition was not reversed by washing the cells after preincubation or by subsequent exposure to normal plasma. The inhibitory activity, which was found in all sarcoid plasma samples, was nondialyzable, was heat stable, and could be localized to the 25 to 35 per cent saturated ammonium sulfate fraction of plasma. Lesser amounts of similar inhibitory activity were detected in comparable fractions of normal plasma. A highly significant correlation between monocyte leukotactic responses and plasma leukotactic inhibitory activity was found in patients with sarcoidosis, suggesting an important in vivo modulatory nole for this substance.
An adaptation of the double-filter technique has been developed for the in vitro evaluation of monocyte leukotaxis. The assay, which employs a sandwich of a cell-permeable polycarbonate and a cell-impermeable cellulose nitrate filter membrane, is more reliable, reproducible, and sensitive than previous techniques without sacrificing their rapidity and simplicity. Leukotactic responses were directly proportional to monocyte concentrations varying from 1 X 10(5)/ml to 6 X 10(6)/ml. Kinetic studies indicated that there was a linear increase in leukotactic responses at incubation periods from 60 to 180 min. At incubation periods less than 60 min, leukotactic responses also increased linearly but at an accelerated rate. The leukotactic and chemokinetic effects of a leukoattractant may be discriminated and appear to exert antagonistic effects in this assay system.
Bundle-shaped tubular (BST) inclusions were identified by electron microscopy in 1 to 6 percent of peripheral blood mononuclear cells obtained from 10 to 11 patients with sarcoidosis. The frequency of the inclusions within mononuclear cells did not correlate with the clinical status of the patients. The relationship, if any, of BST inclusions to sarcoidosis and the immunologic defects in sarcoid patients remains to be determined.
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