Biomedical subjects
Publications and source records attributed to Laszlo T Vaszar.
Hospital ethics committees provide education, assist in policymaking, and deliver consultation services. In this article, we describe the structure, operation, and institutional framework within which an ethics committee fulfills its missions, with emphasis on the consultation process.
A patient with risk factors of systemic lupus erythematosus, corticosteroid use, and malignancy received a diagnosis of concomitant pneumonia and osteomyelitis caused by Legionella longbeachae. In this report, the first description of Legionella osteomyelitis, previous cases of extrapulmonary Legionella infection are detailed.
Pneumonectomized rats injected with the alkaloid toxin, monocrotaline, develop progressive neointimal pulmonary vascular obliteration and pulmonary hypertension resulting in right ventricular failure and death. The antiproliferative immunosuppressant, triptolide, attenuates neointimal formation and pulmonary hypertension in this disease model (Faul JL, Nishimura T, Berry GJ, Benson GV, Pearl RG, and Kao PN. Am J Respir Crit Care Med 162: 2252-2258, 2000). Pneumonectomized rats, injected with monocrotaline on day 7, were killed at days 14, 21, 28, and 35 for measurements of physiology and gene expression patterns. These data were compared with pneumonectomized, monocrotaline-injected animals that received triptolide from day 5 to day 35. The hypothesis was tested that a group of functionally related genes would be significantly coexpressed during the development of disease and downregulated in response to treatment. Transcriptional analysis using total lung RNA was performed on replicate animals for each experimental time point with exploratory data analysis followed by statistical significance analysis. Marked, statistically significant increases in proteases (particularly derived from mast cells) were noted that parallel the development of vascular obliteration and pulmonary hypertension. Mast-cell-derived proteases may play a role in regulating the development of neointimal pulmonary vascular occlusion and pulmonary hypertension in response to injury.
BACKGROUND: Pulmonary vascular injury by toxins can induce neointimal formation, pulmonary arterial hypertension (PAH), right ventricular failure, and death. We showed previously that simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in pneumonectomized rats injected with the alkaloid toxin monocrotaline. The present study was undertaken to investigate the efficacy of simvastatin and its mechanism of reversing established neointimal vascular occlusion and pulmonary hypertension. METHODS AND RESULTS: Pneumonectomized rats injected with monocrotaline at 4 weeks demonstrated severe PAH at 11 weeks (mean pulmonary artery pressure [mPAP]=42 versus 17 mm Hg in normal rats) and death by 15 weeks. When rats with severe PAH received simvastatin (2 mg x kg(-1) x d(-1) by gavage) from week 11, there was 100% survival and reversal of PAH after 2 weeks (mPAP=36 mm Hg) and 6 weeks (mPAP=24 mm Hg) of therapy. Simvastatin treatment reduced right ventricular hypertrophy and reduced proliferation and increased apoptosis of pathological smooth muscle cells in the neointima and medial walls of pulmonary arteries. Longitudinal transcriptional profiling revealed that simvastatin downregulated the inflammatory genes fos, jun, and tumor necrosis factor-alpha and upregulated the cell cycle inhibitor p27Kip1, endothelial nitric oxide synthase, and bone morphogenetic protein receptor type 1a. CONCLUSIONS: Simvastatin reverses pulmonary arterial neointimal formation and PAH after toxic injury.
Pharmacogenomics is the emerging study of why individuals respond differently to drugs. It aims to replace the current 'one size fits all' therapeutic approach with 'personalized medicine' that will use pharmacogenomic tests to predict drug response. In a simple conceptualization, these tests challenge privacy as a result of two factors: how comprehensive is the test and how is the access to samples or digital information controlled. Point-of-care tests are likely to be limited in scope, fit seamlessly into medical records and do not raise qualitatively new ethical and privacy challenges. In order to define practically relevant pharmacogenomic predictive patterns however, large-scale clinical trials and research on human specimens will be required, resulting in large databases of genomic information. The genomic scans' magnitude, stability, implications to kin and ease of dissemination together represent a qualitatively different challenge compared to traditional, self-limited and often temporally transient medical information.
Hypertensive pulmonary vascular disease is characterized by abnormal proliferation of vascular endothelial and smooth muscle cells, leading to occlusion of pulmonary arterioles, pulmonary hypertension, right ventricular failure, and death. Compounds with antiproliferative effects on vascular endothelial and smooth muscle cells, such as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, may prevent the development of experimental hypertensive pulmonary vascular disease. Pneumonectomized rats injected with monocrotaline at 7 days develop severe hypertensive pulmonary vascular disease with neointimal formation. Rats were randomized to receive either vehicle or treatment with the HMG-CoA reductase inhibitor simvastatin (2 mg/kg per day). By Day 35, rats that received vehicle had higher mean pulmonary arterial pressures (53 +/- 2 mm Hg) and right ventricular hypertrophy (right ventricle/[left ventricle plus septum] [RV/LV+S] = 0.78 +/- 0.09) than rats in Group PMS5-35 that received simvastatin from Day 5 to 35 (mean pulmonary arterial pressure = 27 +/- 3 mm Hg, RV/LV+S = 0.34 +/- 0.08; p < or = 0.001). Pulmonary vascular remodeling with neointimal formation consisting of vascular smooth muscle cells was more severe in vehicle-treated rats (vascular occlusion score, 1.98 +/- 0.02) than in Group PMS5-35 (vascular occlusion score, 0.59 +/- 0.46; p < 0.001). In addition, lung endothelial nitric oxide synthase gene expression was decreased in vehicle-treated animals but was restored toward normal levels in simvastatin-treated animals. Simvastatin attenuates monocrotaline-induced pulmonary vascular remodeling with neointimal formation, pulmonary arterial hypertension, and right ventricular hypertrophy in rats.
Degenerative neuromuscular diseases are characterized by a gradual decline of motor function leading to respiratory collapse, while the patients retain consciousness and cognition. The ethical challenges of caring for such patients result from the need to implement various combinations of initiating, withholding, and withdrawing life-sustaining interventions. In caring for this population of patients physicians should adhere to the ethical principles of autonomy, beneficence, nonmaleficence, and justice. A central goal of care is to avoid a decisional impasse by anticipating end-of-life issues in discussion with patients and families. The evolution of these diseases is usually slow enough to allow ample patient education, and thus physicians should foster early and frank discussions and encourage the patient to set up advance directives, designate a durable power of attorney for health care, and plan end-of-life care. Competent patients have the right to accept or refuse life-sustaining therapies, and such requests should be honored. In delivering palliative care, adequate sedation and analgesia must be provided when needed. If a decision to withhold or withdraw life support is made, patient comfort and dignity are the ultimate objectives.
Assisting smokers to achieve tobacco cessation has always been difficult. The development of pharmacological approaches to the attainment of abstinence from tobacco usage has been very helpful, although our understanding of optimal clinical use is still incomplete and imperfect. Bupropion and nicotine therapy (NT) will help reduce the severity of nicotine withdrawal symptoms, whether used separately or in combination. Effectiveness is greater with the combination of drugs than with either drug alone. Nevertheless, the initial 'quit rate' is usually less than 50%, and there is a considerable decrease in the abstinence rate after the course of therapy has been completed. Effectiveness is increased if higher doses of NT are employed, with or without concomitant bupropion. Much remains to be learned about optimal doses, preferred durations of therapy and tapering, prevention and management of relapses, and selection of modes of delivery of NT. The discovery that nicotine dependence has a major genetic component has stimulated much interest and many research studies. The preliminary results are interesting, to say the least.