Corticotropin-releasing hormone and proopiomelanocortin-derived peptides are present in human myometrium

CRH and POMC-derived peptides are produced at a number of intrauterine sites in both the nonpregnant and pregnant states. It is hypothesized that CRH and POMC-derived peptides may be produced locally by the uterus to modulate myometrial contractility. This study has examined the distribution of these peptides in human uterine tissue during the ovulatory cycle and pregnancy. The immunoperoxidase staining method was used to localize CRH and POMC-derived peptides: ACTH, beta-endorphin, and alphaMSH. Immunoreactive (IR-) CRH and IR-POMC-derived peptides, beta-endorphin and alphaMSH, were observed in the myometrial smooth muscle, vascular smooth muscle, endometrial glandular epithelium, and luminal epithelium of the nonpregnant uterus (n = 17). Staining for IR-CRH did not change during the cycle from the proliferative (n = 8) to the secretory phases (n = 9). Conversely, staining for IR-beta-endorphin and IR-alphaMSH was only observed during the secretory phase of the cycle (n = 9). In uterine tissue obtained from pregnant women (n = 20) IR-CRH was present in the myometrial smooth muscle, vascular smooth muscle, decidua, and glandular epithelium. IR-POMC-derived peptides were not detectable at any uterine site during pregnancy (n = 20). IR-CRH was measurable in myometrial extracts collected from pregnant women undergoing cesarean section (20.9+/-3.8 ng/g wet wt; n = 7) and from nonpregnant premenopausal women undergoing hysterectomy (7.7+/-2.1 ng/g wet wt; n = 6). IR-CRH concentrations significantly increased with pregnancy. Levels of messenger ribonucleic acid encoding for CRH were examined in nonpregnant (n = 4) and pregnant (n = 10) myometrial smooth muscle and were also significantly increased with pregnancy. This study has demonstrated that levels of CRH and POMC peptide in human uterine tissue change with pregnancy and that CRH is produced locally by myometrial smooth muscle cells. These studies are consistent with the possibility that the CRH peptide has an autocrine/paracrine activity during pregnancy and labor that may be related to the modulation of myometrial contractility.     

A multifactorial trial design to assess combination therapy in hypertension. Treatment with bisoprolol and hydrochlorothiazide

BACKGROUND: The safety and effectiveness of different dosages and combinations of antihypertensive agents can be efficiently studied using a multifactorial trial design. In consultation with the Cardio-Renal Division of the Food and Drug Administration, we conducted a randomized, double-blind, placebo-controlled, 3 x 4 factorial trial of bisoprolol, a beta 1-selective adrenergic blocking agent, and hydrochlorothiazide. METHODS: A total of 512 patients with mild to moderate essential hypertension were randomized to once-daily treatment with bisoprolol (0, 2.5, 10, or 40 mg), hydrochlorothiazide (0, 6.25, or 25 mg), and all possible combinations. Diastolic and systolic blood pressures were monitored during this 12-week trial. RESULTS: The effects of bisoprolol and hydrochlorothiazide were additive with respect to reductions in diastolic and systolic blood pressures over the dosage ranges studied. The addition of hydrochlorothiazide (or bisoprolol) to therapy with bisoprolol (or hydrochlorothiazide) produced an incremental reduction in blood pressure. Dosages of hydrochlorothiazide as low as 6.25 mg/d contributed a significant antihypertensive effect. A hydrochlorothiazide dosage of 6.25 mg/d produced significantly less hypokalemia and less of an increase in uric acid levels than a dosage of 25 mg/d. The low-dose combination of bisoprolol, 2.5 mg/d, and hydrochlorothiazide, 6.25 mg/d, reduced diastolic blood pressure to lower than 90 mm Hg in 61% of patients and demonstrated a safety profile that compared favorably with that of placebo. CONCLUSIONS: The utility of factorial design trials to characterize dose-response relationships and to test the potential interactions between various antihypertensive agents has been demonstrated. The combination of low dosages of bisoprolol and hydrochlorothiazide may be a rational alternative to conventional stepped-care therapy for the initial treatment of patients with mild to moderate hypertension.     

Tamoxifen increases the proliferation of human endometrial stromal cells in in vitro. A model for evaluation of endometrial hyperplasia

Tamoxifen given for breast cancer therapy, has a complex and an unclear action on the endometrium. A large number of literatures has attributed the proliferous changes in the endometrium caused by tamoxifen (Tam). No report has appeared on the endometrial cellular changes induced by Tam. The present study shows a significant (P < 0.001) increase in the proliferative activity due to Tam in endometrial stromal cells over control and estradiol (E2). This in vitro model is useful for the study of the hyperplasic effect of Tam at the cellular level.     

Receptor subtype and density determine the coupling repertoire of the 5-HT2 receptor subfamily

The 5-Hydroxytryptamine (5-HT)2C receptor (originally known as the 5-HT1C receptor) is a member of the 5-HT2 subfamily of G protein coupled receptors, which is known to couple to phospholipase C. Within the 5-HT2 subfamily, only the 5-HT2C receptor also coupled to inhibition of forskolin-stimulated cAMP production when expressed at high density (12 pmol/mg membrane protein) in stably transformed AV12 cells. The 5-HT2C receptor coupled with high efficacy to both phospholipase C as measured by IP3 (inositol 1,4,5-trisphosphate) production and to inhibition of forskolin-stimulated cAMP production (EC50 = 2.98 nM +/- 0.9 and IC50 = 47.99 nM +/- 10.25 respectively). The 5-HT2A and 5-HT2B receptors, while coupling to phospholipase C with high affinity (EC50s of 19.24 nM +/- 6.44 and 1.24 nM +/- 0.136 respectively), did not decrease adenylyl cyclase activity. The 5-HT2C receptor actions in both systems showed the expected pharmacology for the 5-HT2C receptor, e.g., mesulergine antagonized the effects of 5-HT and spiperone did not. Preincubation of cells with PTX showed that the G protein coupling of the 5-HT2C receptor to phospholipase C is PTX insensitive, while the G protein coupling to inhibition of adenylyl cyclase is PTX sensitive, even to concentrations as low as 20 ng/ml of PTX. PTX pretreatment of the 5-HT2C bearing cells also unmasked a small stimulatory effect on adenylyl cyclase. When expressed at low density the 5-HT2C receptor potentiated forskolin-stimulated cAMP production by 2 fold while still maintaining its ability to enhance PI hydrolysis. A more modest potentiation of cAMP production was noted with low density expression of the 5-HT2B receptor. Thus the ability of the 5-HT2C receptor to interact with several effectors through at least two different G proteins is, in part, receptor subtype specific but also influenced by receptor density.     

Threshold intrauterine perfusion pressures for intraperitoneal spill during hydrotubation and correlation with tubal adhesive disease

OBJECTIVE: To determine the minimum intrauterine perfusion pressure that will produce spill from the fallopian tubes into the peritoneal cavity and to correlate this pressure with the extent of tubal adhesive disease. DESIGN: Hydrotubation was performed at laparoscopy and intrauterine perfusion pressure was measured. The extent of peritubal and fimbrial adhesions was graded at laparoscopy. SETTING: Ambulatory surgery suites. PATIENTS: Ten patients with infertility and/or pelvic pain were enrolled in the study. Data from nine patients were analyzed. INTERVENTIONS: Measurement of intrauterine perfusion pressures. MAIN OUTCOME MEASURES: The minimum pressure that produced spill of dye from each fallopian tube and the correlation between extent of external tubal pathology and this threshold pressure. RESULTS: The median threshold pressure at which dye spilled from at least one fallopian tube was 100 mm Hg, and no spill occurred at pressures < 70 mm Hg. The threshold pressure was correlated negatively with the extent of tubal disease. CONCLUSIONS: Fluid with the same viscosity as hydrotubation dye will not spill into the peritoneal cavity through normal fallopian tubes until the intrauterine perfusion pressure exceeds 70 mm Hg. The threshold pressure is higher when tubal adhesive disease that can be visualized by laparoscopy is present.     

Selective alterations of extracellular brain amino acids in relation to function in experimental portal-systemic encephalopathy: results of an in vivo microdialysis study

Portal-systemic encephalopathy (PSE) is characterized by neuropsychiatric symptoms progressing through stupor and coma. Previous studies in human autopsy tissue and in experimental animal models of PSE suggest that alterations in levels of brain amino acids may play a role in the pathogenesis of PSE. To assess this possibility, levels of amino acids were measured using in vivo cerebral microdialysis in frontal cortex of portacaval-shunted rats administered ammonium acetate (3.85 mmol/kg, i.p.) to precipitate severe PSE. Sham-operated rats served as controls. Portacaval shunting resulted in significant increases of levels of extracellular glutamine (threefold, p < 0.001), alanine (38%, p < 0.01), aspartate (44%, p < 0.05), phenylalanine (170%, p < 0.001), tyrosine (140%, p < 0.001), tryptophan (63%, p < 0.001), leucine (75%, p < 0.001), and serine (60%, p < 0.001). Administration of ammonium acetate to sham-operated animals led to a significant increase in extracellular glutamine and taurine content, but this response was absent in shunted rats. The lack of taurine release into extracellular fluid following ammonium acetate administration in portacaval-shunted rats could relate to the phenomenon of brain edema in these animals. Ammonium acetate administration resulted in significant increases in the extracellular concentrations of phenylalanine and tyrosine in both sham-operated and portacaval-shunted rats. Severe PSE was not accompanied by significant increases in extracellular fluid concentrations of glutamate, aspartate, GABA, tryptophan, leucine, or serine, suggesting that increased spontaneous release of these amino acids in cerebral cortex is not implicated in the pathogenesis of hepatic coma.     

Validity of self-reported rheumatoid arthritis in elderly women

OBJECTIVE: To determine the validity of a self-reported physician diagnosis of rheumatoid arthritis (RA) in elderly women. METHODS: Women with self-reported RA were contacted and permission requested to contact their physician. Physicians were mailed a questionnaire requesting information on the subject's arthritic condition. Hand radiographs obtained at study entry were read for changes of RA. RESULTS: The self-reported diagnosis of RA could be confirmed in 26 (21%) individuals. CONCLUSION: The positive predictive value of self-reported RA was low in this cohort. Caution needs to be exercised in the use and interpretation of self-report data concerning arthritic conditions in epidemiologic studies.     

The regulation of calcium homeostasis in nerve cells

We have reviewed the major cellular elements related to the release and buffering of calcium in neurons. Voltage-operated, chemical-operated calcium channels and mechanisms of stability of intercellular calcium homeostasis (mitochondria, endoplasmic reticulum, calcium binding proteins, calcium exchange and calcium pump) are demonstrated in normal and pathological condition (105 ref.).