On the mechanism underlying the action of D-600 on slow inward current and tension in mammalian myocardium

D-600 the methoxy derivative of verapamil, is said to affect the force of cardiac contraction and the slow inward current (LSi) specifically by reducing the membrane conductance for Ca2+ (gsi). However, it is apparent that many effects of D-600 cannot be adequately explained solely by an effect on gsi. We studied the effects of D-600 on membrane current and tension of cat papillary muscle, using a conventional single sucrose gap voltage clamp technique. The results indicate that D-600 not only reduces the maximal Ca conductance but also, depending on concentration and duration of exposure, alters both the kinetics of the Ca-carrying system and the amplitude of the steady state outward current. No changes in the steady state activation and inactivation variables or in the rate of Isi inactivation were found. However, a substantial increase in the time to peak Lsi, as much as 7 times normal, was observed after exposure to D-600 (0.5 X 10(-6) to 2.0 X 10(-6) M) for at least 20 minutes. Because approximately only 75% of the reduction in Lsi induced by D-600 could be attributed to change in the maximum value of gsi (gsi), we conclude that the change in time to peak and about 25% of the reduction in Isi must be due to a change in the activation kinetics of the Ca-carrying system, Calculations suggest that the time to 70% activation of gsi can be prolonged to as much as 10 times normal by prolonged exposure to negatively inotropic concentrations of D-600.     

Differences in tissue fatty acids and cholesterol of swine from different genetic backgrounds

A review of 1,000 consecutive coronary angiograms, most of them performed for evaluation of angina pectoris, yielded 9 examples of congenital anomalies of the coronary arteries. In 2 cases the angina may have been due to malposition of the left coronary artery or one of its branches. There were 2 cases of aberrant origin of the circumflex artery from the right coronary artery, 2 cases of aberrant left anterior descending artery, 3 cases in which all three major coronary branches arose from the right aortic sinus, and 2 cases of coronary artery fistulas. Malposition of the coronary artery should be considered as a possible cause of angina.     

Cost-benefit analysis of walking to prevent coronary heart disease

OBJECTIVE: To quantify the cost-benefit relationship of walking to prevent coronary heart disease. DESIGN: Cost-benefit analysis. PARTICIPANTS: Hypothetical cohorts of sedentary men and women aged 35 to 74 years. MAIN OUTCOME MEASURES: Decision-analysis simulation was used to evaluate the cost-benefit relationship of walking, varying level of benefit from exercise, frequency of exercise to achieve benefit, participation rates, and costs of exercise and injury. RESULTS: At a relative risk of 1.9 for heart disease associated with sedentary behavior, $5.6 billion would be saved annually if 10% of adults began a regular walking program. A $4.3 billion savings is predicted if the entire sedentary population began walking regularly and the cost of the time an individual spends exercising is accounted for in those who dislike exercising. According to our baseline assumptions, walking is economically beneficial for men aged 35 to 64 years and for women aged 55 to 64 years. The threshold of relative risk at which economic benefit is found for walking in this population overall is estimated at 1.7, and under a volunteer model, most adults would benefit even at a relative risk of 1.15. CONCLUSIONS: There are significant sex and age differences in the economic benefits of walking to prevent heart disease. The value assigned to the time an individual spends exercising has a significant impact on the results. Overall, a substantial savings is predicted from encouraging sedentary individuals to participate in a regular walking program.     

Ultrastructural changes in the mycelia of Actinomyces hygroscopicus var. var. enhygrus--a proteolytic enzyme producer--during submerged fermentation

Ultrastructural changes were found to occur in the mycelium of Actinomyces hygroscopicus, strain 33x, which produced an exocellular proteolytic enzyme during submerged fermentation, in both laboratory and semiindustrial conditions (in 100-1 fermenters). In the course of the enzyme accumulation, numerous vacuoles appeared in the hyphae, some hyphae became wider, and the cell walls were more loose. The greatest structural changes were found in the intracytoplasmic membrane systems. The ultrastructural changes of the mycelium are not presumably connected with the accumulation of the enzyme, but are the result of the differentiation of cellular structures during aging of the cells and their transition to the stage of autolysis.     

Direct evidence for the deoxyribonuclease activity of the plant ribosome inactivating protein gelonin

Several plant ribotoxins, including gelonin, were reported to have additional weak nuclease activities on supercoiled DNA. The potential contribution of this activity to their cytotoxicity has not been given serious consideration due to concerns about contaminating nucleases in the protein preparations. We now report the degradation of single-stranded DNA by preparations of native plant gelonin and recombinant gelonin produced in E. coli. The DNase activity of both preparations is similarly modulated by zinc. An SDS-PAGE DNase assay identifies gelonin as the polypeptide responsible for deoxyribonuclease activity.     

An animal model of Peyronie's-like condition associated with an increase of transforming growth factor beta mRNA and protein expression

PURPOSE: Transforming growth factor beta (TGF-beta) is involved in numerous vital processes including tissue fibrosis. Our objective was to study the role of TGF-beta in the induction of a Peyronie's-like condition and to produce an animal model for the further study of Peyronie's disease. MATERIALS AND METHODS: Twenty-four adult male Sprague-Dawley rats were divided into two groups. Different concentrations of cytomodulin, a synthetic heptopeptide with TGF-beta-like activity, were injected into the tunica of each rat from the first group (n = 18). Rats in the second group (n = 6) received saline injections as a control. The tunical tissues were taken after 3 days, 2 weeks, and 6 weeks and were examined using Hart and Trichrome stains. In the same tissue samples, TGF-beta mRNA and protein expression were studied. RESULTS: Histological alterations were observed in 15 out of 18 cytomodulin-injected rats, especially in tissue examined after 6 weeks. The most prominent changes were chronic cellular infiltration, focal and diffuse elastosis, thickening, disorganization and clumping of the collagen bundles. Results from immunoblot revealed remarkable TGF-beta1 protein expression in all the cytomodulin-injected rats only after 2 and 6 weeks. No remarkable TGF-beta2 or TGF-beta3 protein expression was observed. TGF-beta1 mRNA expression in the cytomodulin-injected rats was noticed in rats injected with higher concentrations after 3 days, while it was expressed in all rats after 2 weeks. There was no expression in the control group after either 3 days or 2 weeks. CONCLUSIONS: Cytomodulin can induce Peyronie's-like condition in the rat penis, which may explain the role of TGF-beta in the pathogenesis of Peyronie's disease.     

CD19 expression levels regulate B lymphocyte development: human CD19 restores normal function in mice lacking endogenous CD19

Establishing signal transduction thresholds that regulate B lymphocyte responses to foreign Ags and tolerance to self Ags is critical for humoral immune responses. The effects of altered signaling thresholds in B lymphocytes were examined in CD19-deficient mice and transgenic mice that expressed human CD19 at varying densities. Human CD19 restored normal B cell function and development to CD19-deficient mice when expressed at levels comparable to those of circulating human B cells. While CD19 expression levels were found to be developmentally regulated and tightly controlled in normal mice, two- or threefold changes in cell surface CD19 expression in transgenic mice dramatically affected B cell development, mitogen responses, serum Ig levels, humoral immune responses, and germinal center formation. B cells from mice that overexpressed CD19 also had decreased levels of surface IgM and a cell surface phenotype consistent with increased signaling in these cells. These results suggest that CD19 may serve similar functions in humans and mice and that CD19 defines signaling thresholds in vivo for the Ag receptor as well as other cell surface receptors that regulate B lymphocyte selection, activation, and differentiation.     

Incorporating social support into a community-wide smoking-cessation contest

Exposure to foreign particles sometimes causes inflammatory reactions through production of cytokines and chemoattractants by phagocytic cells. In this study, we focused on macrophage migration inhibitory factor (MIF) to evaluate its pathophysiological role in the phagocytic process. Immunohistochemical analysis of human pseudosynovial tissues retrieved at revision of total hip arthroplasty showed that infiltrating mononuclear and multinuclear cells were positively stained by both an anti-CD68 antibody and anti-human MIF antibody. For in vitro study, MIF was released from murine macrophage-like cells (RAW 264.7) in response to phagocytosis of fluorescent-latex beads in a particle dose-dependent manner. Northern blot analysis showed marked elevation of the MIF mRNA level in the phagocytic macrophage-like cells. Moreover, pretreatment of RAW 264.7 cells with rat recombinant MIF increased the extent of phagocytosis by 1.6-fold compared with the control. Taken together, these results suggest that MIF plays an important role by activating macrophages in autocrine and paracrine fashion to phagocytose foreign particles.