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)     

Preliminary evaluation of vitiligo using in vivo reflectance confocal microscopy

BACKGROUND: Vitiligo is the most common pigmentary disorder with a global incidence from 0.1% to 2% in different geographical areas. Histopathology and histochemistry have shown the reduction of melanocytes in achromic patches, but microscopic changes of lesional and non-lesional skin are still not completely understood. Reflectance confocal microscopy (RCM), based on the different light reflectance index of cutaneous structures, allowed in vivo, en face microscopic evaluation of superficial skin layers with a resolution similar to skin histology. AIM: The purpose of this study was to evaluate RCM features of lesional and non-lesional skin of vitiligo patients. Moreover, re-pigmented areas were taken into consideration in order to evaluate melanocyte response to ultraviolet B (UVB) radiation. SUBJECTS AND METHODS: Sixteen patients of different phototypes affected by active non-segmental vitiligo and 10 controls were enrolled in the study. In vivo skin imaging was done using a commercially available RCM (Lucid, Vivascope 1500. Re-pigmented areas from 6 to 16 patients (after UVB narrow-band therapy) were also examined. RESULTS: Vitiligo lesions showed the disappearance of the bright rings normally seen at the dermo-epidermal junction. Moreover, non-lesional skin of vitiligo patients showed unexpected changes as the presence of half-rings or scalloped border-like features of the bright papillary rings. In re-pigmented areas after UVB narrow band therapy, the presence of activated, dendritic melanocytes was seen. CONCLUSIONS: Considering our results, and following further studies, RCM clinical applications could be used in the therapeutic monitoring and evaluation of the evolution of vitiligo.     

Identification of a Klebsiella pneumoniae strain associated with nosocomial urinary tract infection.

To differentiate between relapse of infection and reinfection of the urinary tract due to Klebsiella pneumoniae, 33 K. pneumoniae isolates collected from 20 patients with spinal cord injury (SCI) over 2 years were typed by genomic fingerprinting by repetitive-element PCR. Clinical isolates obtained from the same patients with recurrent episodes of urinary tract infection (UTI) revealed identical genomic fingerprints indicating relapse of UTI due to K. pneumoniae, despite appropriate antibiotic therapy. Seventeen isolates obtained from 8 of the 20 SCI patients shared a common genotype, termed RD6. Among non-SCI patients residing in other nursing units, the RD6 genotype was found in 5 of 10 patients with K. pneumoniae UTI but in only 1 of 20 patients with K. pneumoniae infection that did not involve the urinary tract, suggesting a strong association of this genotype with UTI. All RD6 isolates exhibited strong adherence (> or =50 adherent bacteria per cell) to HEp-2 cells, whereas other K. pneumoniae isolates generally did not adhere to or adhered very weakly to HEp-2 cells (< or =5 adherent bacteria per cell). Adherence was inhibited either by 4% D-mannose or by anti-type 1 fimbrial rabbit serum. These results suggest that the capacity of K. pneumoniae RD6 isolates to cause UTI may be mediated by its striking adherence to mammalian cells.     

Ultrastructural alterations in caudate nucleus in aged cats

These studies provide information on the changes in the ultrastructure in the caudate nucleus of aged cats. The major findings was that there was a decrease in the density of synapses in caudate neuropil. This decrease occurred in animals after 3 years of age and remained relatively constant in older animals. In conjunction with this change a population of unusually long synapses also occurred. These larger synaptic appositions were associated with enlarged spine heads. The caudate also showed a number of qualitative ultrastructural alterations. Many neurons contained accumulations of lipofuscin or lipopigment granules in aged animals. These inclusions occurred in both soma and dendrites of neurons and all types of glial cells. A unique configuration of collapsed agranular cisterns also was observed in aged animals. The present results indicate that decreases in synaptic density may by one morphological event underlying functional alterations observed in caudate neurons in aged cats.     

Does changing from mercury to electronic blood pressure measurement influence recorded blood pressure? An observational study.

Mercury sphygmomanometers have been commonly used in primary care to measure blood pressure but are associated with bias. Electronic blood pressure machines are being introduced in many practices and have anecdotally been associated with higher recorded blood pressure. This study examined recorded blood pressure in four practices before and after electronic blood pressure machine introduction. No consistent change in mean blood pressure was apparent following their introduction, but there was a large and significant fall in terminal digit preference suggesting improved precision of recording.