Biomedical subjects
Publications and source records attributed to A Borkowski.
A patient with Wegener's granulomatosis is reported. The diagnosis was confirmed by parotid gland biopsy. The patient responded to treatment with cyclophosphamide and prednisone. After many years, urethral stricture and subglottic stenosis developed and responded satisfactorily to surgery.
Certain regions of the human aorta are at greater risk for early and more severe atherosclerotic lesions development than others. Cornhill and coworkers (Cornhill FJ et al.: Arteriosclerosis 5:415, 1985) created maps for the probability of developing atherosclerosis defining the high-probability region (HPR) in the dorsal descending thoracic aorta and the low-probability region (LPR) in the ventral descending thoracic aorta. Our study examines the hypothesis that transforming growth factor beta -1 (TGF-beta 1), a well-known suppressor of growth and function in many human cell lines, is one of the inhibitors of human atherogenesis. The present experiment analyzes the expression of mRNA for TGF-beta 1 in both the HPR and the LPR of aortas from young (age 17 to 25 y) males of black (n = 8) and white (n = 7) race. The level of TGF-beta 1 gene expression was assessed in the aortic intima in both the HPR and the LPR, using National Institutes of Health Image 1.47, an Apple Macintosh application capable of digital image processing, analysis, and morphometric measurement. There was significantly lower (P = 0.002, alpha = 0.05) TGF-beta 1 gene expression in the HPR than in the LPR in the 22- to 25-y age group. There was no significant difference in the 17- to 21-y age group and between the HPR and the LPR in the entire study group.(ABSTRACT TRUNCATED AT 250 WORDS)
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We present a case of a 65 year-old woman with a late vesicovaginal fistula after colporrhaphy. Too late proper diagnosis of that complication caused perivesical tissue inflammation and led to damage to the urinary bladder, occlusion of the urethra as well as created a massive inflammatory tumor in the minor pelvis, which suggested a cancerous process. Bilateral hydronephrosis forced us to make bilateral nephrostomy. After intensive antiinflammatory therapy, anterior exenteration and Bricker's operation were performed with a finally good effect.
The paradigm of pathology research as an endeavor among grant-funded principal investigators resulting in first-author publications is unsupported by quantitative examination of author profiles extracted from the scientific literature. Publications in six pathology journals (Modern Pathology, American Journal of Surgical Pathology, Human Pathology, Acta Cytologica, Archives of Pathology and Laboratory Medicine, and American Journal of Clinical Pathology) and three general science journals (Science, New England Journal of Medicine, and Proceedings of the U.S. National Academy of Sciences) were reviewed. Twenty articles per journal from each of three years (1987, 1989, and 1991) were examined (a total of 520 articles). Of these, 295 articles were first-authored by a member of a department of pathology. Of the 295 articles first-authored by a member of a pathology department, 47 (16%) articles listed competitive grant support. Of the grant-supported articles, 20 articles listed NIH support, but only four had an NIH-supported principle investigator as the first author of the article. Unfunded research represented the vast majority (84%) of work produced by pathologists. A review of the ISI Citation Index showed that those articles written by funded pathologists averaged 8.7 (S.D. 7.8) citations per article, compared to 10.4 (S.D. 12.1) citations per article for unfunded pathologists. Results suggest that unfunded research accounts for the majority of pathology research activity as well as their resulting literature citations.
In pulmonary sarcoidosis an activation of alveolar T lymphocytes and alveolar macrophages (AM) has been demonstrated. There is evidence that in contrast to acute disease a heightened T-cell response cannot be observed in the chronic phase of sarcoidosis. The role of AM in the inflammatory process of chronic sarcoidosis is not yet intensively evaluated. To address this question we measured the release of tumor necrosis factor alpha (TNF alpha) and interleukin-1 (IL-1) by AM of 39 patients with chronic sarcoidosis (duration greater than 4 years; 30 active, 9 inactive diseases) without therapy and correlated the monokine release with parameters of T-cell alveolitis and the course of the disease. The T4/T8 ratio was higher in the active than in the inactive group without reaching statistical significance. TNF alpha as well as IL-1 is spontaneously released by AM of the active group 2,099 +/- 518 pg/ml TNF alpha/10(6) cells/24 h and 8/13 (IL-1+/total) respectively. In the inactive group the AM release 375 +/- 246 pg/ml TNF alpha/10(6) cells/24 h which is in the range of the control and 1 out of 5 patients was IL-1-positive. There was no correlation between the monokine release and any parameter of T-cell alveolitis. These data support the hypothesis that the inflammatory process in chronic sarcoidosis is dominated by the activity of AM and that this activity determines the course of the disease.
We recently reported that a subpopulation of immunoglobulin G (IgG) in man interacts with the hormone-binding site of estrogen receptors (ER), competes with [3H]estradiol (E2) uptake, and decreases effective ER concentrations in cell cultures. The present work further characterizes the immunological properties of these antibodies and defines their biological activity. Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting techniques, enriched preparations of the natural anti-ER IgG subpopulation (IgGs) were found to specifically immunoprecipitate ER extracted from MCF-7 mammary carcinoma cells and to compete with [3H]tamoxifen-aziridine for ER binding. During 18-h incubations IgGs decreased [3H]E2 binding capacity of MCF-7 cells in a dose-dependent manner similar to E2. Like E2 but unlike antiestrogens, this biological effect corresponded to down-regulation of the receptor protein and depended on a mechanism specifically inhibited by actinomycin D. Moreover, IgGs antagonized the decrease of [3H]E2 binding capacity produced by the strong antiestrogen methyl-hydroxytamoxifen; this antagonism was additive to that of E2. On the other hand, IgGs like estrogens increased progesterone receptor concentrations and cathepsin D secretion. The biological activity of IgGs was neutralized by anti-IgG antibodies and by ICI 164,384, a "pure" steroid antagonist of E2, confirming that immunoglobulins G were responsible for this activity and acted at the E2-binding site. These observations indicate that some natural antibodies in man can function like potent estrogens on ER and mammary cells.
Circulating human lymphocytes possess specific and functional receptors for calcitriol and PTH. We sought to determine if they also possessed receptors for calcitonin (CT), the third classical calciotropic hormone. We isolated blood mononuclear cells from healthy volunteers to separate monocytes, total lymphocytes, and T-lymphocytes; the purity of the three cell populations was more than 90%, 95%, and 85%, respectively. Salmon CT (sCT) was labeled by the chloramine-T method (SA, 254 muCi/micrograms) without loss of biological activity. We found saturable (16 h at 8 C), specific, high affinity binding sites for [125I]sCT on unstimulated lymphocytes. As for CT receptors on other cells, binding of [125I]sCT was poorly reversible. Binding specificity was demonstrated by the total absence of competing effect of several unrelated hormones; human CT and CT gene-related peptide competed much less efficiently than sCT for the binding sites, whereas PDN-21 had no effect. When plotted according to the method of Scatchard, binding data on the mixed population of T- and B-lymphocytes showed an apparent Kd (mean +/- SD) of 2.9 +/- 1.0 x 10(-10) M (n = 34), with an estimation of 91-8338 (median, 1971) binding sites/cell. The data were repeatedly compatible with an aspect of positive cooperativity between the binding sites, as confirmed by a Hill coefficient greater than 1 (1.18 +/- 0.13). However, this aspect of positive cooperativity in CT binding was not observed on isolated T-lymphocytes (Hill coefficient, 0.96 +/- 0.08; n = 9; P less than 0.001 vs. the mixed population of lymphocytes). CT did not induce a significant increase in cAMP levels, but regulation of receptor concentration was demonstrated by the finding of down-regulation of CT-binding sites after sCT or human CT preincubation. In summary, we have found saturable, specific, high affinity receptors for CT on unstimulated normal human T-lymphocytes, which could, thus, be target sites for CT action on bone metabolism or on the immune system.
Intravenous aminohydroxypropylidene bisphosphonate (APD) normalizes serum calcium in most hypercalcemic cancer patients, however the optimal therapeutic scheme has not been established. We compared in a randomized prospective trial the efficacy and the tolerance of APD given as a 3-day treatment of daily 2-h infusions of 0.5 mg/k.d in 250 ml of saline (group A) with single 24-h infusions of 1.5 mg/kg (group B) or of 0.5 mg/kg in 1 liter of saline (group C). Thirty-three cancer patients remaining hypercalcemic after a 48-h rehydration period were included and monitored daily until normocalcemia or treatment failure was documented. Serum calcium became normal in all but 1 patient (in group C) but remained normal for only 1 or 2 days in 4 other patients (1 in A, 1 in B, 2 in C). The decline in total or ionized serum calcium was slightly less marked in group C than in the two other groups, but the differences were not significant. The fall of fasting urinary calcium excretion was however significantly less rapid in group C (p less than 0.05 from day 1 to day 4). Serum concentrations of iPTH and 1,25-dihydroxyvitamin D [1,25-(OH)2D] increased significantly in the three groups. Serum magnesium concentrations fell slightly from 1.41 +/- 0.05 to 1.28 +/- 0.04 mEq/liter (p less than 0.001) after rehydration but returned to normal after APD administration (day 5, 1.52 +/- 0.04 mEq/liter, p less than 0.001 versus day 0).(ABSTRACT TRUNCATED AT 250 WORDS)
Carbetimer is a new antineoplastic agent whose limiting toxicity consists of dose- and treatment duration-dependent hypercalcemia. We examined the short-term effects of Carbetimer on calcium metabolism on days, 1, 3 and 5 during 11 5-day courses (6.5-8.2 g/m2/day given over daily 2-h infusions, q 3-4 weeks). Blood parameters were measured before and after Carbetimer, whereas urinary parameters were studied in three consecutive 2-h collections before, during and after Carbetimer infusions. Carbetimer effects were similar regardless of the infusion day. We found a consistent decrease of plasma ionized Ca (Ca2+) levels from 4.56 +/- 0.05 mg/dl before infusion to 4.28 +/- 0.06 mg/dl after infusion (P less than 0.001) whereas total serum Ca (corrected for protein levels) did not change. The fall of Ca2+ stimulated parathyroid function, as suggested by the increased plasma PTH levels, the decreased serum phosphorus and TmP/GFR index, or the increased urinary phosphate and cyclic AMP excretion. Carbetimer infusions also induced a marked increase in urinary Ca excretion (expressed as mg Ca/mg creatinine) from 0.093 +/- 0.011 before to 0.359 +/- 0.042 during and 0.177 +/- 0.031 after infusion (P less than 0.011). These changes were best explained by Carbetimer-induced Ca chelation that we confirmed in vitro by incubating Carbetimer at various concentrations in whole blood for 2 h at 37 degrees C, e.g. 2 mg of Carbetimer/ml lowered Ca2+ from 4.82 to 3.20 mg/dl without changing total Ca levels. On the other hand, a direct effect of Carbetimer on bone cannot be excluded since we observed an increase of serum osteocalcin levels from 2.0 +/- 0.3 to 2.5 +/- 0.4 ng/ml after infusion (P less than 0.001). In summary, the short-term effects of Carbetimer on calcium metabolism markedly differ from the long-term effects. They mainly consist of a dose-related calcium chelation leading to a decrease in Ca2+ levels, an increase in urinary Ca excretion and a stimulation of parathyroid function.
The protective action of estrogens on bone mass may be mediated by an increase in calcitonin (CT) secretion. We reevaluated this hypothesis using a method for measuring CT in extracts of serum that allows sensitive specific measurement of CT monomer. We studied seven healthy postmenopausal women before and on the 7th and 28th days of each of three 4-week treatment periods: estrogen (estradiol valerate; 2 mg/day), calcium supplement (1500 mg/day), and estrogen plus calcium; the three cycles were separated by intervals of 4 weeks. Serum extractable CT (exCT) levels were measured before and after a short calcium stimulation test (2 mg Ca/kg in 5 min) to assess the C-cell secretory response on each day. Estrogen had the expected biological effects, decreasing (P less than 0.05) serum gonadotropin concentrations and fasting or 24-h urinary calcium excretion. The calcium supplement caused a significant increase in 24-h urinary calcium excretion. However, there was no increase in basal or stimulated serum exCT levels during any of the three cycles. On the contrary, basal serum exCT concentrations decreased slightly but significantly during estrogen treatment from 1.9 +/- 0.5 (+/- SE) to 1.5 +/- 0.4 ng/L on day 7 and 1.2 +/- 0.2 ng/L on day 28 (P less than 0.05). This decrease in basal exCT levels did not occur during the combined estrogen and calcium administration period, probably because the slight decrease in serum calcium induced by estrogen did not occur during combined estrogen and calcium administration. In summary, estrogens do not stimulate CT secretion; variations in serum exCT levels appear to be related to the changes in bone metabolism induced by estrogens.
Interstitial lung diseases are characterised by chronic inflammatory processes in the lower respiratory tract, parenchymal cell injury and progressive fibrosis of the alveolar structure. Oxygen radicals are claimed to be a major cause of the tissue damage in the lung. We evaluated the spontaneous and stimulated oxygen radical release of bronchoalveolar lavage (BAL) cells in 35 patients with sarcoidosis and 17 patients with IPF. In comparison with the control in both diseases the spontaneous as well as the stimulated oxygen radical release of the BAL cells is markedly increased. In IPF alveolar macrophages produce the buk part of radicals (84%). Due to their low percentage and in spite of a higher activity on a per cell basis the contribution of neutrophils to the total radical burden is only marginal. In sarcoidosis there is a positive correlation between the oxygen radical release of AM and the CD4/CD8 ratio of BAL lymphocytes. Our results demonstrate that the clinical activity of sarcoidosis and IPF is reflected by the oxygen radical release of BAL cells.
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Bisphosphonates (or diphosphonates) constitute a major advance in the treatment of tumor-associated hypercalcemia and also have the potential to prevent or reverse osteolysis in normocalcemic patients. Available information on adequate therapeutic doses and potential toxicity is, however, very fragmentary. This report describes a phase I study of one of the most promising bisphosphonates currently available, aminohydroxypropylidene bisphosphonate (AHPrBP or APD), in tumor-associated hypercalcemia. Only patients remaining hypercalcemic after 48 hours of rehydration were evaluated, and antineoplastic therapy was delayed at least until a normal serum calcium level was reached. AHPrBP was given as two-hour daily infusions for three days, and three different patients were treated at each of the six following dosage levels: 0.01, 0.05, 0.25, 0.75, 1.5, and 3.0 mg/kg per day. The two lowest dosages levels were insufficient to normalize serum and urinary calcium levels, but the efficacy of the four other dosages was very similar. Plasma immunoreactive parathyroid hormone levels increased as a function of calcium levels, whereas urinary hydroxyproline levels did not prove to be a very useful measure of AHPrBP's effects on bone resorption. The drug was generally very well tolerated: only six patients had transient fever and/or decreases in lymphocyte count that were not clearly related to AHPrBP dosage. The only real problem was observed at the highest dosage of 3.0 mg/kg per day in an obese woman in whom high fever and hypotension developed. Efficacy and tolerance in dehydrated patients were verified by treating seven other patients, not previously rehydrated, at 1.0 mg/kg per day for three days. In summary, the therapeutic range of AHPrBP, given for three days as a two-hour infusion daily, lies between 0.25 and 1.5 mg/kg per day. Fasting urinary calcium levels are probably the most reliable and easily measured parameter to monitor AHPrBP's inhibition of bone resorption in normocalcemic patients.
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