Toxic cardiomyopathy: the effect of antipsychotic-antidepressant drugs and calcium on myocardial protein degradation and structural integrity

In the nonrecirculating isolated perfused rat heart it has recently been described that basal myocardial protein degradation is suppressed by 30% within 5 min of maximal beta-adrenergic receptor occupancy under 5 X 10(-7) M isoproterenol (Lockwood, 1985, Biochem. J. 231, 299-308). This adrenergic-controlled proteolytic process presumably contributes to the well-known normal coordination of myocardial protein mass with functional demand. It is presently reported that elevated intracellular calcium is among the messengers that somehow suppress protein degradation. Acute elevation of extracellular calcium to a maximal concentration of 9.0 mM mimicked the simultaneous effects of isoproterenol on increasing inotropy and decreasing protein degradation, although this concentration was eventually lethal. Conversely, infusion of trifluoperazine (TFP), a calmodulin-blocking antipsychotic drug, caused stimulation of protein degradation above basal levels within 5 min. The stimulation of degradation by 30-60% was transient at 5 X 10(-7) M and returned to the control level in 5-10 min. However, TFP produced massive irreversible release of amino acid peptides and proteins at 10(-5) M within 30 min, followed by grossly observable cell structural disruption and cell separation. The degradative stimulation caused by TFP was potentiated by lowering the normal 2.5-mM extracellular Ca2+ concentration to 1.25 mM. Trifluoperazine at 10(-5) M caused longitudinal separation of myofibrils by disrupting lateral attachments between adjacent Z lines, leading to a loss of lateral myofibrillar registry followed by myofibrillar degeneration. Spot desmosomes were disrupted, leading to lateral cell separation; however, the fascia adherens region of the intercalated disks remained intact and cells maintained end-to-end attachment. Perfusion under the low extracellular Ca2+ concentration of 0.1 mM for 0.5 hr caused separation of the fascia adherens region and spot desmosomes of the intercalated disks as well as disruption of cytoplasmic myofibrils and other changes. Although the structural disorganization caused by perfusion with low (0.1 mM) Ca2+ were similar to those caused by TFP, cells also lost end to end attachment under low Ca2+. Amitriptyline (10(-5) M), thioridazine (10(-5) M), and calmidazolium (10(-6) M) stimulated protein degradation and caused structural damage. It is speculated that the above Ca2+-related phenomena describe the mechanism of the well-known toxic cardiomyopathy resulting from overdoses of some of the antipsychotic-antidepressant drugs.(ABSTRACT TRUNCATED AT 400 WORDS)     

Activation of cAMP dependent protein kinase during surfactant release from type II pneumocytes

Release of surfactant from pulmonary type II epithelial cells was stimulated by the beta-adrenergic agonist terbutaline and the diterpene forskolin. Cytosolic cyclic adenosine monophosphate (cAMP) concentrations increased significantly following exposure to terbutaline or forskolin and reached maximal levels within 5 min after treatment. Terbutaline and forskolin had a synergistic effect on cytosolic cAMP levels when added simultaneously. cAMP-dependent protein kinase activity was identified in cytosolic preparations of type II pneumocytes by phosphorylation of the peptide substrate Kemptide (Leu-Arg-Arg-Ala-Ser-Leu-Gly) and binding of 3H-cAMP to the regulatory components of cAMP-dependent protein kinase. Type I and type II regulatory subunits of the cANP-dependent kinase were present in approximately equal concentrations in type II cell cytosol. Activation ratio of cAMP-dependent protein kinase in cultured type II cells increased significantly in the presence of terbutaline, forskolin, or terbutaline plus forskolin. Activation ratios increased from 0.45 +/- 0.03 for control cells to 0.96 +/- 0.06 for cells exposed to terbutaline (10 microM) plus forskolin (5 microM) for 20 min. Release of 3H-phosphatidylcholine was also stimulated by terbutaline and forskolin. Effects of terbutaline and forskolin on surfactant release were approximately additive. Our results demonstrated increased cytosolic cAMP levels, increased cAMP-dependent protein kinase activation ratios, and subsequent augmented surfactant release from isolated type II pneumocytes in response to terbutaline and forskolin. These data support a role for activation of cAMP-dependent protein kinase as a mediator of surfactant release and document the utility of forskolin for study of cAMP-mediated effects in isolated type II cells.     

Heterogeneity of B cell involvement in acute nonlymphocytic leukemia

In order to study the pattern of B cell involvement in acute nonlymphocytic leukemia (ANLL), multiple B lymphoid cell lines were established by Epstein-Barr virus transformation of peripheral blood mononuclear cells from two patients with the disease who were heterozygous for the X chromosome-linked glucose-6-phosphate dehydrogenase (G6PD). In one patient, the progenitor cells involved by the leukemia exhibited multipotent differentiative expression, whereas in the other patient the cells showed differentiative expression restricted to the granulocytic pathway. In the patient whose abnormal clone showed multipotent expression, the ratio of B-A G6PD in B lymphoid cell lines was skewed in the direction of type B (the enzyme characteristic of the leukemia clone) and significantly different from the 1:1 ratio expected. It is, therefore, likely that the neoplastic event occurred in a stem cell common to the lymphoid series as well as to the myeloid series. In contrast, evidence for B cell involvement was not detected in the patient whose ANLL progenitor cells exhibited restricted differentiative expression. These findings underscore the heterogeneity of ANLL. Clinically and morphologically similar malignancies in these two patients originated in progenitors with different patterns of stem cell differentiative expression. This difference may reflect differences in cause and pathogenesis.     

CGA-7 and HHF, two monoclonal antibodies that recognize muscle actin and react with adherent cells in human long-term bone marrow cultures

The CGA-7, a monoclonal antibody that reacts with smooth muscle cell actin but not with endothelial cell or fibroblast actin, and HHF, a monoclonal antibody that reacts with smooth muscle, skeletal muscle, and cardiac muscle actin, both recognize microfilaments present within adherent cells from actively hematopoietic human long-term marrow cultures. Macrophages, monocytes, and cultured marrow fibroblasts do not react with either antibody. These data suggest that the anti-actin antibodies may serve as useful markers for in vitro microenvironmental cells and lend support to the hypothesis that stromal cells from long- term marrow cultures are different from marrow fibroblasts and may constitute a unique cell lineage.     

Self-reported health of Persian Gulf War veterans: a comparison of help-seeking and randomly ascertained cases

The objective of this study was to compare self-selected Persian Gulf War veterans attending a health assessment program with veterans ascertained in an epidemiological study to determine why Gulf War veterans do, or do not, present for clinical assessment. A postal survey was sent to randomly selected United Kingdom Armed Forces personnel who served in the Persian Gulf conflict. Outcome measures included a symptom checklist, health perception, physical functioning, psychological distress, post-traumatic stress symptoms, and health attributions. A total of 173 survey respondents had also attended the Medical Assessment Program (MAP). MAP attendees were more likely to be female, older, and working part time or not working at all. They had poorer health perception and reported higher levels of illness, and they differed in terms of their health attributions. The belief that one had Gulf War syndrome and attributing health problems to Gulf War service were the most powerful predictors of MAP attendance, even when controlling for the level of physical functioning. The findings suggest that health beliefs rather than symptoms are more important predictors of attendance of an assessment program and that Gulf War veterans who attended the MAP have different characteristics than those who did not. This suggests that MAP patients are unrepresentative of the wider deployment to the Persian Gulf.     

Women in the Persian Gulf: lack of gender differences in long-term health effects of service in United Kingdom Armed Forces in the 1991 Persian Gulf War

A cross-sectional postal survey was conducted to evaluate the health of a random sample of United Kingdom Armed Forces personnel who were deployed to the 1990-1991 Persian Gulf conflict compared with nondeployed controls and controls deployed to Bosnia. The health of service women was examined and compared with that of United Kingdom service men. The main outcome measures were physical symptoms and ailments, functional capacity on the 36-item Short-Form Health Survey, the 12-item General Health Questionnaire, the Centers for Disease Control and Prevention multisymptom criteria for Gulf War illness, and post-traumatic stress reactions. There were 645 (65.3%) valid responses. The women from the Gulf cohort reported each symptom and the majority of health outcomes more frequently than either control group. No gender differences were found for 32 of the 50 symptoms assessed. Of the remaining 18 symptoms, women reported significantly more than men for only 6 of them, and there were no gender differences in 5 of the 6 principal health outcome measures. Women deployed to the Persian Gulf had similar rates of ill health as their male counterparts. Nothing was found to suggest that, other than for gender-specific health effects, any special considerations need to be made on health grounds for service women in any future deployments.     

Extent of tibiofemoral osteoarthritis before knee arthroplasty: multicenter data from the osteoarthritis initiative

Background  

Knee arthroplasty traditionally is recommended for persons with substantial disability and disabling pain attributable to moderate or severe osteoarthritis (OA). Pain and functional status after arthroplasty may be influenced by the extent of knee OA before surgery and recent evidence suggests persons with less severe knee OA before undergoing TKA have greater pain levels and worse function than persons with more severe knee OA.