Epithelial proliferation and hormone receptor status in the normal post-menopausal breast and the effects of hormone replacement therapy

The proliferation rate (as assessed by Ki67 expression) and expression of oestrogen-regulated progesterone receptor (PR) was studied in normal post-menopausal breast epithelium. Normal breast epithelium from patients receiving hormone replacement therapy (HRT) at the time of surgery containing either oestrogen alone (E2) or oestrogen and progesterone combined activities (E2 + P) was also studied, as HRT has been linked to an increased breast cancer risk. Samples of breast tissue, containing normal epithelium, from 185 patients undergoing surgery for benign or malignant disease were immunocytochemically stained for PR and Ki67. The percentage of labelled cells was expressed as the labelling index (LI). The median Ki67 LI in normal post-menopausal breast epithelium was 0.19 and median PR LI was 4.75, and both were unaffected by patient age, duration of menopause or if the tissue sample originated from a breast with benign or malignant disease. Proliferation did not alter significantly in patients taking HRT (P = 0.61); however, PR expression was up-regulated in both E2 and E2 + P users (P = 0.01). The dose and duration of HRT had no effect on either parameter. A possible attenuation of sensitivity to oestradiol-induced proliferation but not to PR expression occurs in the post-menopausal breast.     

Clinical improvement after atrioventricular nodal ablation for atrial fibrillation does not correlate with improved ejection fraction

A retrospective review of 15 patients with atrial fibrillation and class III to IV congestive heart failure who underwent atrioventricular nodal ablation demonstrated a marked improvement in their functional abilities. This improvement, however, could not be explained by the improvement in ejection fraction alone.     

Phosphoinositide 3-kinase in rat liver nuclei

Biochemical and immunochemical data from the present investigation reveal the existence of a p85/p110 phosphoinositide 3-kinase (PI 3-kinase) in rat liver nuclei. 32P-Labeling of membrane phosphoinositides by incubating intact nuclei with [gamma-32P]ATP results in the formation of [32P]phosphatidyl-inositol 3,4, 5-trisphosphate [PtdIns(3,4,5)P3], accompanied by small quantities of [32P]phosphatidylinositol 3-phosphate [PtdIns(3)P]. Studies with subnuclear fractions indicate that the PI 3-kinase is not confined to nuclear membranes. The nuclear soluble fraction also contains PI 3-kinase and an array of inositide-metabolizing enzymes, including phospholipase C (PLC), phosphoinositide phosphatase, and diacylglycerol (DAG) kinase. As a result, exposure of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] to the nuclear extract in the presence of [gamma-32P]ATP generates a series of 32P-labeled D-3 phosphoinositides and phosphatidic acid (PA) in an interdependent manner. On the basis of the immunological reactivity and kinetic behavior, the nuclear PI 3-kinase is analogous, if not identical, to PI 3-kinase alpha, and constitutes about 5% of the total PI 3-kinase in the cell. Moreover, we test the premise that nuclear PI 3-kinase may, in part, be regulated through the control of substrate availability by PtdIns(4,5)P2-binding proteins. Effect of CapG, a nuclear actin-regulatory protein, on PI 3-kinase activity is examined in view of its unique Ca2+-dependent PtdIns(4, 5)P2-binding capability. In vitro data show that the CapG-mediated inhibition of nuclear PI 3-kinase is prompted by PKC phosphorylation of CapG and elevated [Ca2+]. This CapG-dependent regulation provides a plausible link between nuclear PLC and PI 3-kinase pathways for cross-communications. Taken together, these findings provide definite data concerning the presence of an autonomous PI 3-kinase cycle in rat liver nuclei. The nuclear location of PI 3-kinase may lead to a better understanding regarding its functional role in transducing signals from the plasma membrane to the nucleus in response to diverse physiological stimuli.     

Activation of alpha 1-adrenoceptors to lower cerebrocortical neuropeptide Y (NPY)-like immunoreactivity in rats receiving pargyline treatment

To determine if inhibition of a Ca(2+)-dependent slow afterhyperpolarization (AHPslow) contributes to prostaglandin E2 (PGE2)-induced sensitization of DRG neurons, we have used patch-clamp electrophysiological techniques on cultured dorsal root ganglion (DRG) neurons from the adult rat. In support of a role for AHPslow in sensitization of DRG neurons, we demonstrate that: (1) AHPslow expression is restricted to a subpopulation of putative nociceptors; (2) burst duration is controlled by AHPslow in these neurons; and (3) in some neurons, PGE2 decreases AHPslow and produces a concomitant increase in the number of action potentials generated in response to depolarizing current injection. However, our results also demonstrate that AHPslow modulation is not sufficient to explain PGE2-induced sensitization in the majority of DRG neurons because: (1) the size of the population of DRG neurons expressing AHPslow is less than half the size of the population of DRG neurons sensitized by PGE2; (2) PGE2 produces a decrease in action potential threshold as well as an increase in the number of action potentials in response to current injection, while inhibition of AHPslow has little effect on threshold; and (3) the sensitizing effects of PGE2 are dissociated from its effects on AHPslow in more than half of neurons tested. We conclude that PGE2-induced sensitization must involve the modulation of ionic currents in addition to that underlying AHPslow.     

Synthesis of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2, 3-benzodiazepin-4-ones as novel and potent noncompetitive AMPA receptor antagonists

A group of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2, 3-benzodiazepin-4-ones was synthesized and assayed for antagonism of rat brain alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors expressed in Xenopus oocytes. The benzodiazepinones inhibited AMPA-activated membrane current responses in a manner consistent with noncompetitive, allosteric inhibition of the receptor-channel complex. The most potent compound in the series was 1-(4-aminophenyl)-7,8-(methylenedioxy)-3,5-dihydro-4H-2, 3-benzodiazepin-4-one (6), which had an IC50 of 2.7 microM. For comparison, the reference compound GYKI 52466 (2) had an IC50 of 6.9 microM. Compound 6 also had potent anticonvulsant activity in a mouse maximum electroshock-induced seizure (MES) assay: the ED50 was 2.8 mg/kg iv, whereas the ED50 for GYKI 52466 was 4.6 mg/kg iv. In contrast to a previous report, the 7,8-dimethoxy analogue of 6 was a low-potency AMPA antagonist (IC50 >100 microM) and weak anticonvulsant (ED50 >10 mg/kg iv). The benzodiazepinones described herein are potent noncompetitive AMPA receptor antagonists that could have therapeutic potential as anticonvulsants and neuroprotectants.     

Effects of low-dose morphine on gastric emptying in healthy volunteers

BACKGROUND: Type 2 diabetes mellitus is a major and increasing cause of morbidity and early mortality among the Aboriginal population of northern Australia. Due to differing social, dietary and probably metabolic factors, management needs differ from the mainstream Australian diabetic population. OBJECTIVE: This paper concentrates on the options for oral therapy in the control of glycaemia, taking into account various current guidelines and recent trials of oral antihyperglycaemic therapy, and the specific metabolic and clinical associations with type 2 diabetes mellitus in this population. DISCUSSION: In the abscence of specific contraindications, and in variance with some present guidelines, the evidence suggests that initial therapy with metformin rather than the sulphonylureas is likely to provide greater clinical benefit, and have a greater margin of safety.     

Factors involved in Schistosoma mansoni infection in rural areas of northeast Brazil

Two contiguous villages in Tracunhaém county (State of Pernambuco), endemic for schistosomiasis, were studied: Itapinassu (138 inhabitants) and S?o Joaquim (91 inhabitants). Agriculture predominates in the former region while ceramics is the main activity in the latter. Although no statistical difference was found regarding prevalence, severe infection (> 400 epg) predominated in Itapinassu, probably related to the kind of occupation. No association was found between parasite burden and severity of disease, in spite of the high infection rates for Schistosoma mansoni in both communities (approx. 60%). Typical epidemiological features of schistosomiasis such as age-related prevalences and intensities of infection (high in children, low in adults) were also mutual characteristics. Nutritional status determined through anthropometric evaluation was carried out by measuring specific anthropometric indicators. A deficit of energy intake, as well as vitamin A and riboflavin deficiencies were detected. The prevalence of moderate or severe undernutrition in patients under 18 years old was 21.9% in Itapinassu and 24.1% in S?o Joaquim. In this group an association was found between prevalence of schistosomiasis and chronic undernutrition. Similarly, for patients over 18 year old the prevalence of undernutrition was higher than 20%. However, in this case no association between nutritional status and either prevalence of schistosomiasis or parasite burden could be detected. The two communities had not been treated for eight years.