Subcellular concentrations of estrone, estradiol, androstenedione and 17 beta-hydroxysteroid dehydrogenase (17-beta-OH-SDH) activity in malignant and non-malignant human breast tissues

Total and subcellular (cytosol and nuclear) concentrations of estrone (E1), estradiol (E2), and androstenedione were determined in non-malignant (n = 61) and malignant (n = 65) human breast tissues obtained from post-menopausal women. The 17 beta-hydroxysteroid dehydrogenase (17 beta-OH-SDH) activity was determined in 800g supernatant fraction. Total estrogens, E1 and E2 levels and 17 beta-OH-SDH activity were significantly (p less than 0.005, 0.0005, 0.001, respectively) higher in malignant than in non-malignant breast tissues. We failed to observe significant changes in subcellular steroid concentrations or enzyme activity associated with patients' obesity or tumor estrogen receptor status. When the steroid levels were analyzed in relation to clinical staging of the disease, nuclear contents of estradiol were significantly higher (p less than 0.005) in Stage-IV patients than in those with less advanced disease (Stages I to III). 17 beta-OH-SDH activity was significantly (p less than 0.001) lower in patients with advanced disease than in those with relatively less advanced (Stages I to III) disease and was positively correlated with tissue concentration of androstenedione. Our present data indicate that differential intracellular metabolism of steroid hormones may have some influence on availability of estradiol at nuclear sites. In postmenopausal women, local interconversion of estrogens may provide sufficient estrogenic stimulus to enhance the growth and progression of breast tumors.     

Distal metatarsal osteotomy for hallux valgus in the middle-aged patient

Thirty-eight distal metatarsal osteotomies for hallux valgus in middle-aged patients between the ages of 50 and 67 years were performed over a period of five years. None of the patients could be rated with an excellent result. Good results were noted in only 52.6%. Poor results were attributable to imperfect surgical technique, severity of preoperative deformity, osteoporosis, and preexisting osteoarthritic changes at the first metatarsophalangeal joint.     

Phorbol ester potentiates alpha 1-adrenoceptor-mediated positive inotropic effect in rat papillary muscle

Tumor-promoting phorbol esters may alter alpha 1-adrenoceptor-mediated cardiac response by stimulating protein kinase C activity. We investigated the effect of phorbol-12,13-dibutyrate (PDBu) on the positive inotropic effect (PIE) in rat left ventricular papillary muscle. PDBu (1-100 nM) potentiated the phenylephrine (PE)-induced PIE in a dose- and time-dependent manner. The PIE induced by PE and PDBu was abolished by pretreatment with 3 x 10(-7) M prazosin. PDBu also enhanced PE-induced slow responses 2- to 3-fold. These results suggest that PDBu enhances alpha 1-adrenoceptor-mediated PIE by potentiating slow Ca2+ channels, presumably through the activation of protein kinase C.     

Perinatal lung development following maternal exposure to methylmercuric chloride

Mercury ingested from dietary sources has potent neurotoxic and teratogenic effects. Initial studies have shown that mercury may also affect fetal lung development. Since these pulmonary effects may play a role in subsequent neonatal morbidity and mortality due to compromising of the development of the lung, mercury effects in fetal and neonatal lung were investigated. Methylmercuric chloride (MMC), 1,000 ppm (15 mg/kg of body weight), was administered via an intragastric tube to timed-pregnant Swiss/Webster mice on day 9 of gestation. Lungs from fetuses on gestational day 18 and from neonates on days 1, 5, or 10 after birth were studied. Significant changes in MMC-exposed lungs compared to controls occurred at postnatal day 1. At this time, lung weight per gram body weight increased, phospholipid content per gram of lung or per microgram of DNA decreased, while DNA per gram of lung increased. Methylmercury appears to have delayed lung maturation. Cuboidal epithelial cells in alveolar tubules contained conspicuous glycogen deposits, and differentiation of alveolar type II cells was adversely affected. These results suggest that prenatal exposure to methylmercury may be detrimental to lung development, specifically to the initiation of surfactant synthesis, by delaying the normal pattern of maturation of the alveolar type II cells within the lungs. Pediatr Pulmonol. 1994; 17:11–21 . © 1994 Wiley-Liss. Inc.     

Congenital thrombophilia among patients with venous thromboembolism.

During a 3-year period we studied 393 adult patients (382 of whom were unrelated) with a history of acute venous thromboembolism. A congenital deficiency state known to predispose to thrombosis was found in 27.2%. Of these, most were due to deficiencies of protein C (9.2%), protein S (7.6%), antithrombin III (5%) or to increased plasma PAI-1 concentration (3.1%) which, in the absence of any known factor that predisposes towards thrombosis, results in a diminished fibrinolytic activity. There was a characteristic pattern between the age of onset (mean 34 years) of thrombosis and individual protein deficiency. Thrombosis appeared spontaneously in 73% of cases with recurrence in 80%. In contrast, in the remaining unrelated patients, 138 (35.1%) in whom venous thromboembolism was secondary and occurred at a mean age of 43 years, and in the other 140 (35.6%) who suffered thromboembolism spontaneously at a later age (mean age 55), there was no permanent protein deficiency state or alteration in fibrinolytic activity and thrombosis recurrence was lower (53.6% and 20.7% respectively). Of the 393 patients, deep vein thrombosis was the most common manifestation; however, in congenital thrombophilia, thrombosis of visceral vessels and Raynaud's syndrome (6%) were also detected.     

Pharmacokinetic evaluation of conventional and controlled release dosage form of propranolol

A comparative pharmacokinetic study of a new controlled release multiple unit propranolol formulation and a conventional propranolol tablet was carried out in twelve healthy human volunteers in a randomized balanced crossover design. Under a single dosage regimen, subjects were administered either a single capsule containing controlled release propranolol equivalent to 160 mg of the drug or 80 mg of conventional propranolol tablet, twelve hourly. Peak plasma propranolol concentrations were low which occurred later after controlled release administration than after the administration of the conventional tablet. Analysis of the area under the plasma concentration-time curve (AUC) for the two formulations indicate no significant difference of bioavailability despite a prolonged absorption time and maintenance of effective plasma concentration for the controlled release preparation.