Apoptosis in the failing human heart

BACKGROUND: Loss of myocytes is an important mechanism in the development of cardiac failure of either ischemic or nonischemic origin. However, whether programmed cell death (apoptosis) is implicated in the terminal stages of heart failure is not known. We therefore studied the magnitude of myocyte apoptosis in patients with intractable congestive heart failure. METHODS: Myocardial samples were obtained from the hearts of 36 patients who underwent cardiac transplantation and from the hearts of 3 patients who died soon after myocardial infarction. Samples from 11 normal hearts were used as controls. Apoptosis was evaluated histochemically, biochemically, and by a combination of histochemical analysis and confocal microscopy. The expression of two proto-oncogenes that influence apoptosis, BCL2 and BAX, was also determined. RESULTS: Heart failure was characterized morphologically by a 232-fold increase in myocyte apoptosis and biochemically by DNA laddering (an indicator of apoptosis). The histochemical demonstration of DNA-strand breaks in myocyte nuclei was coupled with the documentation of chromatin condensation and fragmentation by confocal microscopy. All these findings reflect apoptosis of myocytes. The percentage of myocytes labeled with BCL2 (which protects cells against apoptosis) was 1.8 times as high in the hearts of patients with cardiac failure as in the normal hearts, whereas labeling with BAX (which promotes apoptosis) remained constant. The near doubling of the expression of BCL2 in the cardiac tissue of patients with heart failure was confirmed by Western blotting. CONCLUSIONS: Programmed death of myocytes occurs in the decompensated human heart in spite of the enhanced expression of BCL2; this phenomenon may contribute to the progression of cardiac dysfunction.     

Evaluation of the efficacy of sequential intravenous-oral administration of pefloxacin in community-acquired lower respiratory tract infections in patients with underlying conditions

We studied the efficacy of sequential intravenous-oral pefloxacin therapy in community-acquired lower respiratory tract infection in 24 patients with one or more underlying conditions. Twenty-eight patients were enrolled into the study but only 24 patients were evaluated. There were 16 males and 8 females with a mean age of 66.9 +/- 11.2 years (mean +/- SD, range 46 to 87 years). The underlying conditions present were bronchiectasis, chronic obstructive lung disease and diabetes mellitus. Patients who were older than 70 years but without any underlying condition were also enrolled. All received 4 days of intravenous pefloxacin 400 mg twice a day followed by oral pefloxacin 400 mg twice a day for another 10 days. Assessment of success was based on clinical, microbiological and radiological improvement. Pefloxacin produced 79.2% clinical cure rate. Another 8.3% showed improvement. Pefloxacin was well tolerated. There were few adverse effects and none of the patients required a change of antibiotic. Pefloxacin was an effective and well tolerated treatment for respiratory tract infection and had the advantage of broad in-vitro antibacterial activity, twice daily dosing and sequential availability in an intravenous and oral formulation.     

Bacillary angiomatosis and bacillary peliosis in patients infected with human immunodeficiency virus: clinical characteristics in a case-control study

Clinical characteristics associated with bacillary angiomatosis and bacillary peliosis (BAP) in patients with human immunodeficiency virus (HIV) infection were evaluated in a case-control study; 42 case-patients and 84 controls were matched by clinical care institution. Case-patients presented with fever (temperature, > 37.8 degrees C; 93%), a median CD4 lymphocyte count of 21/mm3, cutaneous or subcutaneous vascular lesions (55%), lymphadenopathy (21%), and/or abdominal symptoms (24%). Many case-patients experienced long delays between medical evaluation and diagnosis of BAP (median, 4 weeks; range, 1 day to 24 months). Case-patients were more likely than controls to have fever, lymphadenopathy, hepatomegaly, splenomegaly, a low CD4 lymphocyte count, anemia, or an elevated serum level of alkaline phosphatase (AP) (P < .001). In multivariate analysis, a CD4 lymphocyte count of < 200/mm3 (matched odds ratio [OR], 9.9; P < .09), anemia reflected by a hematocrit value of < 0.36 (OR, 19.7; P < .04), and an elevated AP level of > or = 2.6 mukat/L (OR, 23.9; P < .05) remained associated with disease after therapy with zidovudine was controlled for. BAP should be considered an AIDS-defining opportunistic infection and should be included in the differential diagnosis for febrile, HIV-infected patients with cutaneous or osteolytic lesions, lymphadenopathy, abdominal symptoms, anemia, or an elevated serum level of AP.     

High-dose chemotherapy with carboplatin, etoposide and cyclophosphamide followed by a haematopoietic stem cell rescue in patients with high-risk retinoblastoma: a SFOP and SFGM study

This study investigates the role of high-dose chemotherapy with haematopoietic stem cell rescue as consolidation treatment in high-risk retinoblastoma (extraocular disease at diagnosis or relapse or invasion of cut end of optic nerve). 25 patients received high-dose chemotherapy including carboplatin (250 mg/m2/day from day 1 to day 5 for the 6 first patients and 350 mg/m2/day from day 1 to day 5 for the other patients), etoposide (350 mg/m2/day from day 1 to day 5) and cyclophosphamide (1.6 g/m2/day from day 2 to day 5) (CARBOPEC) followed by autologous haematopoietic stem cell rescue. 19 patients received this drug combination for chemosensitive extraocular relapse. The other 6 patients with histological high-risk factors were given this treatment as consolidation after enucleation and conventional chemotherapy. The three year disease-free survival was 67.1%. In 7 of the 9 relapsing patients, the first site of relapse was the central nervous system. All patients with central nervous system disease died except one. The main toxicity was haematological and digestive (mucositis and diarrhoea). 2 of the 13 evaluable patients had grade III and IV ototoxicity. One patient experienced an acute grade I reversible cardiotoxicity. The CARBOPEC regimen seems to be a promising therapeutic strategy in patients with high-risk retinoblastoma, especially those with bone and/or bone marrow involvement. This treatment did not improve the outcome of patients with central nervous system disease.     

The differential regulation and secretion of proteinases from fetal and neonatal fibroblasts by growth factors

Until recently, research on the pathogenesis of glomerulonephritis has been mainly focused on the characterization of humoral immune responses in the initiation of glomerular injury. However, there is a growing recognition that both cellular and humoral immune responses, in varying proportions, are involved in the pathogenesis of immunologically-mediated glomerulonephritis. T lymphocytes are essential cellular elements of cell-mediated immunity. Both in experimental models of immune-mediated renal disease and in histopathological analyses of human nephropathies, the involvement of T cells has been demonstrated in the immunoregulation of nephritogenic immune responses and in the immune injury in the kidney. T cell activation resulting in either delayed-type hypersensitivity, cytolytic reactions, abnormal expression of major histocompatibility complex (MHC) molecules, or B cell activation can result in glomerulonephritis. These different types of responses are exerted by distinct T cell subsets defined by cell surface markers and cytokine profiles. CD4+ T cells in vivo are functionally heterogeneous with respect to cytokine production and the CD45 isoforms that are found on their surface. Like CD4+ T cells, CD8+ T cells may also be heterogeneous at the level of cytokine production. The roles of CD4+ and CD8+ cells and their cytokine profiles in glomerulonephritis have not been extensively investigated yet, but such studies might improve the understanding of the pathogenesis and possibly lead to new therapeutic approaches of human glomerulonephritis. In this review the role of distinct T lymphocyte subsets in experimental and human glomerulonephritis will be discussed.     

Effects of a quick-release form of bromocriptine (Ergoset) on fasting and postprandial plasma glucose, insulin, lipid, and lipoprotein concentrations in obese nondiabetic hyperinsulinemic women

OBJECTIVE: To assess the effect on various aspects of carbohydrate and lipid metabolism of administering a quick-release formulation of bromocriptine (Ergoset) to obese, nondiabetic, hyperinsulinemic women. RESEARCH DESIGN AND METHODS: Hourly concentrations of prolactin, glucose, insulin, free fatty acid (FFA), and triglyceride were measured for 24 h before and after approximately 8 weeks of treatment with Ergoset. In addition, fasting lipid and lipoprotein concentrations and the steady-state plasma glucose (SSPG) concentration in response to a continuous infusion of somatostatin, insulin, and glucose were determined before and after Ergoset administration. RESULTS: Circulating prolactin concentrations were dramatically decreased (P < 0.001) following treatment, associated with a significant fall (P < 0.05) in 24-h-long plasma glucose, FFA, and triglyceride concentrations. Neither circulating plasma insulin concentrations nor the ability of insulin to mediate glucose disposal changed with treatment. Finally, fasting total cholesterol fell (P < 0.05) and the ratio of total to HDL cholesterol decreased (P = 0.06) in association with Ergoset treatment. CONCLUSIONS: The fact that significant metabolic improvement was seen in the obese nondiabetic hyperinsulinemic women studied suggests that Ergoset could be of therapeutic benefit in clinical conditions of hyperglycemia and/or dyslipidemia.     

Assessment of bog-body tissue preservation by pyrolysis-gas chromatography/mass spectrometry

Flash pyrolysis-gas chromatography/mass spectrometry (py-GC/MS) was used to assess the quality and mechanism of protein preservation in the tissue of Iron Age bog bodies from Lindow, UK, and south-eastern Drenthe, The Netherlands. Abundant pyrolysis products of the fresh skin tissue, including 2,5-diketopiperazines of Pro-Gly, Pro-Ala, Pro-Val, Pro-Pro and Hyp, were readily assigned to specific amino acid or dipeptide moieties. Comparison of the pyrolysates of the bog-body tissues with that of modern samples revealed qualitative similarities suggesting good preservation of the collagen and non-collagenous proteins in the ancient tissues. Examination of the pyrolysates of samples of fresh calf skin, which had been treated with various vegetable tanning agents, clearly revealed markers of non-hydrolysable tannins including 1,2-benzenediol, 1,3-benzenediol and 1,2,3-benzenetriol, although chromatographic quality inevitably diminished with increasing functionalization of the compounds. Such markers were not detected in the pyrolysates of the bog-body tissues. Instead 4-isopropenylphenol, a characteristic pyrolysis product of Sphagnum moss, was detected in both solvent-extracted and base-treated samples of tissue. The presence of 4-isopropenylphenol in the pyrolysates of the bog-body tissues provides evidence that their preservation involves reactions of amino acids with sphagnum acid, and possibly other agents derived from the peat. The study constitutes the first chemical characterization of the pyrolysis products of modern and ancient collagen.