Differential increase of Col I and Col III leads to an increased Col I/Col III ratio in DCM myocardium. Because Col I provides substantial tensile strength and stiffness, this may contribute to systolic and in particular diastolic dysfunction in DCM.
How cancer cells become resistant to chemotherapy is not completely understood, but it is believed that resistance is usually associated with overexpression of drug resistance genes. Drug resistance mediated by the MDR‐1 gene is the first well characterized form of drug resistance in human cancer. MDR‐1 encodes a phosphoglycoprotein, P‐GP, that serves as an energy‐dependent drug efflux pump, reducing intracellular drug accumulation and thereby cytotoxicity. We have used ribozymes to reverse the multiple drug resistance phenotype. A hammerhead ribozyme recognizing the GUC sequence at position ‐6 to ‐4 close to the translation start site of the 4.5 kb MDR‐1 mRNA was prepared by in vitro transcription (MDR‐1‐RZiv) or chemical synthesis (MDR‐1‐RZs). Both MDR‐1‐RZiv and MDR‐1‐RZs specifically cleaved the MDR‐1 mRNA into two parts of the expected size under physiological conditions in an extracellular system with MDR‐1‐RZiv being more effective. Site‐specific cleavage was dependent on time, temperature and [MgCl2]. To examine the in vivo potential of MDR‐1‐RZ, MDR‐1‐RZiv and MDR‐1‐RZs were transfected into a human pleural mesothelioma cell line and into one adriamycin‐resistant and one vindesine‐resistant subline thereof by liposome‐mediated transfer. Incorporation of ribozymes resulted in significantly reduced expression of the MDR‐1 gene, with MDR‐1‐RZs being more potent than MDR‐1‐RZiv in vitro. MDR‐1‐RZ reduces P‐GP overexpression at the protein level. Liposome‐mediated transfer of MDR‐1‐RZiv or MDR‐1‐RZs reversed the multiple drug resistance phenotype and restored sensitivity towards chemotherapeutic drugs.
The role of enteroviral myocardial infection in the development of dilated cardiomyopathy could only be substantiated after the introduction of molecular biological techniques (polymerase chain reaction, in-situ hybridization) in virological diagnostics of dilated cardiomyopathy. By using histological and especially immunohistological techniques for the detection of myocardial inflammation in patients with the tentative clinical diagnosis of dilated cardiomyopathy, a differentiation between inflammatory cardiomyopathy and idiopathic dilated cardiomyopathy on the basis of the WHO classification 1995 (31) was made. Inflammatory cardiomyopathy is defined by myocarditis in association with cardiac dysfunction and is diagnosed by established histological and especially immunohistological techniques. The combination of histological, immunohistological, and molecularbiological techniques enabled a subgroup analysis of the incidence of enteroviral myocardial RNA in patients with inflammatory cardiomyopathy in comparison to patients with idiopathic dilated cardiomyopathy. The study involved a total of 75 patients with impaired left ventricular function (EF < 50%) and the tentative clinical diagnosis of dilated cardiomyopathy. Right ventricular endomyocardial biopsies were obtained from all patients for further clarification of the cause of left ventricular functional disorder. All biopsies were analyzed for the presence of acute and chronic inflammatory myocardial alterations by histological ("Dallas" criteria) and immunohistological techniques (lymphocytic infiltrates, MHC antigen expression). Furthermore, each biopsy was examined by reverse transcriptase polymerase chain reaction (RT-PCR) in combination with Southern blot hybridization for the presence of enteroviral RNA. Active myocarditis was excluded in all patients by histological examination according to the "Dallas" criteria. Using immunohistological techniques, 26/75 patients (35%) had evidence for chronic inflammatory myocardial alterations in the sense of lymphocytic infiltrates (> or = 2,0 CD3 T-lymphocytes/ visual field at 400 magnification (HPF); > or = 7 CD3 T-lymphocytes/mm2). These patients were diagnosed as having inflammatory cardiomyopathy. To differentiate between patients with and without myocardial inflammation, cases with focal cellular infiltration and an average cell number between 2.5 and 2.0 CD3 T-lymphocytes/HPF and an increased expression of additional immune markers, i.e., MHC antigens, were not addressed in the group of patients with inflammatory cardiomyopathy. This is in contrast to Kühl et al (19). Consequently these patients were classified as patients with idiopathic dilated cardiomyopathy. These criteria of diagnosing myocardial inflammation were based on published results (20, 23, 26, 27, 49) and on our own control group (n = 85) (19) in which mean CD3 T-lymphocyte count/HPF in normal myocardial tissue were 0.7 (range 0.0-1.4). In addition, a subgroup analysis was performed of patients with a CD3 T-lymphocyte count > or = 3 CD3 T-lym...
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