Regulation of elastase-catalyzed hydrolysis of insoluble elastin by synthetic and naturally occurring hydrophobic ligands.
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Biomedical subjects
Publications and source records attributed to W Lewis.
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The antidiuretic effect of two chemically related drugs, clofibrate and halofenate, was tested in a patient with pitressin-sensitive diabetes insipidus. The conventional daily dosage of 2 g clofibrate failed to control the symptoms of this patient; in order to obtain an adequate response the dosage had to be increased to 4 g daily.Halofenate at a dosage of 2 g daily, an amount equivalent in hypolipidemic activity to 4 g per day of clofibrate, significantly reduced water intake and output, while urinary osmolarity was markedly increased.It is concluded that (1) the antidiuretic effect of clofibrate may be dose-related, and that (2) halofenate also possesses some antidiuretic activity.
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This report addresses issues of pathogenesis, pathophysiology, and epidemiology of an increasingly prevalent cardiomyopathy in acquired immunodeficiency syndrome (AIDS). As patient survival increases with more effective antiretroviral therapy, cardiomyopathy in AIDS will become more apparent. The interactions of cellular and organism factors in AIDS and their relationships to the development of cardiomyopathy are reviewed herein. Amongst the factors addressed in this review are: (1) comorbid conditions found with AIDS, (2) the role of inflammatory heart disease and cytokines in the development of AIDS cardiomyopathy, (3) the pathogenetic role of vascular cells and myocardial cells in the development of cardiomyopathy, (4) the role of myocardial retroviral infection in AIDS, and (5) the impact of toxicity from antiretroviral therapy on the development of cardiomyopathy. Because it is possible that more than 1 of these factors is present in a given patient inflicted with AIDS, a multifactorial pathogenesis in AIDS cardiomyopathy must be considered.
The clinical course of a patient is described who experienced respiratory insufficiency as the primary manifestation of immunoblastic lymphadenopathy. Respiratory symptoms preceded the enlargement of lymph nodes, improved spontaneously at first and then after steroid therapy. Subsequently these symptoms reappeared concurrent with lymph node enlargement. Hypergammaglobulinemia was noted with marked elevation of polyclonal immunoglobulin M.
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Adult rats underwent surgical placement of heterotopic cardiac isografts. From 14 to 60 days postoperatively, native heart and transplanted heart protein synthesis was determined. Right ventricle and left ventricle free walls from native and transplanted hearts were dissected, minced into cubes, and incubated in medium containing sulfur-35 methionine. Tissue was harvested, washed, and homogenized in buffer and fractionated centrifugally. Specific radioactivity of polypeptides from transplant isograft right and left ventricle fractions were 6.36 +/- 5.1 and 4.93 +/- 3.6 (mean +/- SD, x 10(-6) cpm/mg protein), respectively. In contrast, native isograft right and left ventricle specific radioactivity was 1.71 +/- 1.49 and 1.07 +/- 0.88 (mean +/- SD, x 10(-6) cpm/mg protein), respectively. Autoradiograms of two-dimensional electrophoretograms revealed increased radiodensity of resolved polypeptides from transplanted and native hearts, which comigrated with nonsarcomeric (beta, gamma) actins. Skeletin and tubulin were prominent on one-and two-dimensional autoradiograms from 14 to 60 days. Radiolabeling of alpha actin polypeptide maximized at 14 days and was found to decrease at 30 and 60 days in comparison with nonsarcomeric actin isoforms. Correlative myocardial microscopic sections showed no fiber hypertrophy, but fiber atrophy was found. Results suggest a relative increase in polypeptide synthesis in the heterotopic transplanted heart samples.
Ischemic necrosis is implicated as a major cause of dehiscence and stenosis of the airway anastomosis in double and single lung transplants. A new surgical technique to maintain systemic arterial blood flow to the transplanted airways by preserving the donor tracheobronchial arterial circulation was investigated. In a primate model, the tracheobronchial arterial circulation to the transplanted airways was maintained by inclusion of an aortic segment with its bronchial arteries and tracheal collaterals in continuity with the lung bloc. The aortic segment, from just proximal to the left subclavian artery to the level of the pulmonary hilum, was vascularized by anastomosis of the subclavian artery to the recipient left subclavian artery or ascending aorta. Double lung transplantation was performed in three baboons; two survived 48 hours, and one was killed at 30 days. One baboon with a left single lung transplant was killed at 30 days, and one baboon with a right single lung transplant survived 22 days. Angiograms obtained 14 days after transplantation showed patent subclavian anastomoses and aortic segments. Postmortem examination revealed patent subclavian anastomoses without thrombi in the aortic segments. There was no airway necrosis, dehiscence, or stenosis. Tracheal and bronchial anastomoses of surviving animals were healed. Histologic examination revealed typical respiratory tissues without ischemia or necrosis. Radiographic examination of aortic segments injected with lead oxide showed patent bronchial arteries extending along the donor trachea and bronchi and to the anastomotic sites. These experimental studies demonstrate that this technique maintains the donor tracheobronchial arterial circulation and may improve tracheal and bronchial anastomotic healing.
HHT was performed between minimally genetic mismatched inbred strains of rats. There was no evidence of rejection and immunosuppressive therapy was not instituted. Immunohistochemical analysis using peroxidase conjugated monoclonal anti-rat ASMA of cardiac arterioles in which AGAS developed revealed a decreased peroxidase signal. The data suggest that modulation of actin expression in subintimal cells of cardiac arterioles may play a critical role in the pathologic development of AGAS.
Mild acute rejection progresses to moderate rejection in approximately one third of the cases. Standard rejection therapy would then be instituted with the attendant risk of infection and other side effects. We randomized 40 episodes of mild acute rejection (20 episodes in each group) to receive no additional therapy or to have the oral cyclosporine dose increased for 7 to 10 days with repeat endomyocardial biopsy performed. In the group with no additional therapy 30% progressed to moderate rejection, whereas in the group with increased doses of oral cyclosporine, 10% progressed to moderate rejection (p = 0.10). As the purpose of our study was to assess the efficacy of increased cyclosporine levels for preventing progression from mild to moderate rejection, the treated group was redefined according to whether the cyclosporine level increased by greater than or equal to 50% during the study. In this treated group average cyclosporine levels increased from 169 +/- 78 to 413 +/- 267 ng/ml. Progression to moderate rejection occurred in one of 21 cases (5%) compared with seven of 19 cases (37%) in the group without an increase in cyclosporine level (p less than 0.05). The transient increase in cyclosporine levels was well tolerated. This study demonstrates that the use of high dose oral cyclosporine to treat mild acute rejection is well tolerated and may reduce progression to moderate rejection when a significant increase in cyclosporine level is achieved.
Sequential postoperative samples of 43 human right ventricular endomyocardial biopsies from four heart transplant patients were evaluated histopathologically to assess microscopic parameters of rejection. Selected pieces of these myocardial biopsies were weighed and homogenized in low ionic strength buffer containing Triton X-100 to extract and to quantitate cardiac actin. Aliquots of the soluble fractions were subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Residual pellets were solubilized and also underwent SDS-PAGE. Electrophoretograms were analyzed densitometrically. Actin from biopsies from transplanted human hearts accounted for approximately 40% of Triton X-100 soluble polypeptides. Actin and myosin heavy chain content in the pellet fractions was unchanged as a function of allograft duration. A polypeptide band resolved between 14,000 and 21,000 daltons in the Triton-soluble fraction of four fresh samples correlated with histopathologic changes of moderate acute allograft rejection. A similar band was noted in 11 frozen endomyocardial biopsy specimens without changes of acute rejection. Small actin differences may be found in the transplanted heart, but they do not correlate with rejection. The presence on SDS-PAGE of the polypeptide band found between 14,000 and 21,000 daltons may correlate with proteolysis of cytoplasmic proteins either from rejection or possibly from autolysis after freezing.