Elucidation of mitochondrial effects by tetrahydroaminoacridine (tacrine) in rat, dog, monkey and human hepatic parenchymal cells

Tetrahydroaminoacridine (tacrine) causes morphological and functional changes in the endoplasmic reticulum, ribosomes, and mitochondria in the liver of humans and animals. In order to investigate species differences as well as to understand the morphological changes, we examined the effects of tacrine on respiration and electron transport in mitochondria isolated from rat, dog, monkey, and human liver. Tacrine produced significantly decreased respiratory control ratios (RCR) in all species at concentrations ranging from 5 to 25 microg/ml. Human mitochondria were more sensitive to tacrine effects with RCR decreased 24% at 5 microg/ml while other species were unaffected at this concentration. The tacrine effects were characterized by increased hepatic mitochondrial State 4 respiration in rats and decreased State 3 respiration in humans. Mitochondria from aged rats were more sensitive to the effects of tacrine than mitochondria from young animals, with significantly decreased RCR at 10 microg/ml in aged rats while mitochondria from young rats were unaffected at this concentration. Concomitant with the respiratory changes, mitochondrial DNA synthesis was impaired. Since tacrine undergoes extensive biotransformation, we also explored the possibility that metabolites could exert detrimental effects. The ranking order of potency for decreasing RCR caused by monohydroxylated metabolites was: tacrine > 4-OH and 7-OH > 2-OH, 1-OH, and velnacrine with the latter group of metabolites having no effect on mitochondrial respiration at concentrations up to 50 microg/ml. In vivo administration of 20 mg/kg tacrine to rats for up to 20 days caused a paradoxical increase in RCR and P/O on Day 1 and decreased RCR on Days 9 and 20, the later findings being consistent with in vitro data. From these data we propose that tacrine does not necessarily have to be metabolized to exert effects on mitochondria at different sites in the electron transport chain that differ among species. These effects are exacerbated in mitochondria from older animals and humans appear to be more sensitive than the laboratory animals studied.     

The effects of phosphorylation of cardiac troponin-I on its interactions with actin and cardiac troponin-C

It is known that the phosphorylation of two serine residues on the NH2-terminal extension specific to cardiac troponin-I (Tn-I) modulates the calcium-dependent activation of the myofilaments. The process by which this occurs remains an unsolved puzzle. We have applied a dissective approach to study the effect of this phosphorylation on the interactions between Tn-I and its partner proteins, actin and troponin-C (Tn-C). Using N-[14C]ethylmaleimide-labelled Tn-I in sedimentation assays with F-actin, we found that the dephosphorylated Tn-I binds to F-actin with pronounced positive cooperativity, both in the absence and the presence of tropomyosin. Phosphorylation of the protein slightly weakens the interaction in the absence of tropomyosin, but the cooperativity remained. In the presence of tropomyosin, phosphorylation of the Tn-I also appeared to slightly weaken the interaction as well but, more significantly, the cooperativity was eliminated. These data can only be explained simply by a cooperative interaction between the monomer units in the actin filament. The interactions between cardiac Tn-I and Tn-C were studied by labelling the Tn-C with the fluorescent probe dansyl aziridine. As expected, the binding of the dephosphorylated Tn-I to Tn-C was strengthened by over 20-fold upon the addition of calcium to the assay. Phosphorylation of the protein, however, had a dramatic effect on the interaction in that it appeared to desensitise the complex to the effect of calcium: the Ka values obtained for both interactions (+/- Ca2+) were almost identical. These results clearly indicate that the phosphorylation of Tn-I in the cardiac system has dramatic effects on the isolated inter-protein interactions. We also discuss the possible significance of such an effect on the interactions of the isolated proteins in their roles within the intact cardiac regulatory complex.     

The effect of LH, FSH and pregnant mares' serum gonadotrophin on ornithine decarboxylase activity in thecal and granulosa tissue during follicular growth and atresia in laying hens (Gallus domesticus)

The effect of ovine LH, porcine FSH and pregnant mares' serum gonadotrophin (PMSG) on the activity of ornithine decarboxylase activity in theca and granulosa tissue during folliculogenesis in laying hens is described. The changes in the activity of ornithine decarboxylase induced by hormonal challenge was used to measure the sensitivity of the tissue to the hormone. Thecal tissue from small (< 6 mm) follicles showed a large increase in the activity of ornithine decarboxylase 3 h after treatment with LH, FSH and PMSG, in vivo, whereas ornithine decarboxylase activity in thecal tissue from large (> 8 mm) preovulatory follicles and atretic follicles did not respond to any of the hormonal treatments. Ornithine decarboxylase activity in granulosa tissue from the largest preovulatory follicle increased significantly 3 h after treatment with LH and PMSG in vivo; no effect was observed with FSH. Granulosa tissue from the third largest and fifth largest preovulatory follicles were refractory to the hormonal treatments. Basal activity of ornithine decarboxylase in granulosa tissue from preovulatory follicles increased as the follicles approached ovulation, whereas the activity in thecal tissue from the same follicles decreased. The difference in sensitivity of thecal tissue from small and large preovulatory follicles towards gonadotrophin treatment in vivo is correlated with the difference in the observed rate of atresia occurring within the two groups of follicles. Atresia is the common fate for small follicles, whereas it is a rare event for large preovulatory follicles under normal physiological conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Merkel cell carcinoma. Comparison of Mohs micrographic surgery and wide excision in eighty-six patients

In patients with cervical instability as the primary injury, either ligamentous or bony, a posterior approach and stabilization is the most likely definitive treatment. The goals should be to obtain and maintain satisfactory alignment, promote fusion, and allow safe and early mobilization. Many techniques that differ in safety, ease of application, cost, biomechanical strength, and postoperative requirements of immobilization are available. This article reviews different methods of posterior surgical interventions in subaxial cervical spine injuries and discusses the advantages and disadvantages of each.     

Paraneoplastic syndromes in patients with ovarian neoplasia

The prevalence of several paraneoplastic syndromes associated with ovarian cancer was determined from a clinicopathological study of 908 patients with primary ovarian malignancy in the North East Thames Region. The diversity and rarity of these manifestations are great and the explanation for them is difficult. Circumstantial evidence suggests that in some cases an autoimmune phenomenon is the most plausible cause.     

Global self-ratings of health and mortality: hazard in the North Carolina Piedmont

We analyzed the first 5 years of surveillance data from the Established Population for the Epidemiologic Studies of the Elderly (EPESE) in the Piedmont of North Carolina (n = 4162) to estimate the effect of a global self-rating of health on survival. Covariates used in Cox proportional hazard models included sociodemographic factors, chronic medical conditions, activities of daily living, use of health services, health risk behaviors, cognitive function, affective mood, and negative life events. Adjusted risk of mortality associated with poor (compared to excellent) self-ratings of health was significantly elevated among urban men only. Confounders of the association between survival and overall health assessment varied widely by subgroup. Pooled estimates from heterogeneous populations may mask significant subgroup differences both in the pattern of variables that mediate crude risk and also in the magnitude of residual risk of global self-ratings of health.