A prospective study of reproductive factors and risk of epithelial ovarian cancer

BACKGROUND: Parity and long term use of oral contraceptives have been associated consistently with a decreased risk of ovarian cancer. However, previous reports of the relationship of other reproductive factors (time since first use or last use of oral contraceptives, age at menarche or menopause, age at first birth) with ovarian cancer have been inconsistent. METHODS: The authors studied these relationships in the Nurses' Health Study, a prospective cohort study of 121,700 female registered nurses aged 30-55 years in 1976 when the study began. From 1976 to 1988, 260 cases of confirmed epithelial ovarian cancer occurred among 1.2 million person-years of follow-up. RESULTS: A statistically significant inverse association was observed between parity and ovarian cancer risk (relative risk [RR] = 0.84; 95% confidence interval [CI] = 0.77-0.91 per pregnancy); age at first birth was not associated independently with risk. In age-adjusted analyses, a significant inverse association was noted between long term use of oral contraceptives and ovarian cancer, which was no longer significant after controlling for other ovarian cancer risk factors (RR with > or = 5 years' use: 0.65; 95% CI = 0.40-1.05). After control for duration of use, a weak nonsignificant inverse association was observed with time since first oral contraceptive use and no independent effect of time since last use. Neither age at menarche nor age at menopause was associated significantly with ovarian cancer risk. CONCLUSIONS: In this large prospective study, parity was the only reproductive factor that had a substantial independent association with ovarian cancer. Long term oral contraceptive use also appeared to have an inverse relationship with ovarian cancer, although this association was of borderline significance (P = 0.11) after adjustment for other risk factors.     

Diabetic eye disease

Diabetic retinopathy accounts for most visual loss in the United States among working-age individuals. With appropriate detection, evaluation, and treatment, the risk for severe visual loss from this condition is dramatically reduced. This article details the natural history, pathophysiology, complications, grading, evaluation, and treatment for patients with diabetic retinopathy and discusses potential novel treatment modalities currently under investigation.     

A conserved 90 nucleotide element mediates translational repression of nanos RNA

Correct formation of the Drosophila body plan requires restriction of nanos activity to the posterior of the embryo. Spatial regulation of nanos is achieved by a combination of RNA localization and localization-dependent translation such that only posteriorly localized nanos RNA is translated. Cis-acting sequences that mediate both RNA localization and translational regulation lie within the nanos 3' untranslated region. We have identified a discrete translational control element within the nanos 3' untranslated region that acts independently of the localization signal to mediate translational repression of unlocalized nanos RNA. Both the translational regulatory function of the nanos 3'UTR and the sequence of the translational control element are conserved between D. melanogaster and D. virilis. Furthermore, we show that the RNA helicase Vasa, which is required for nanos RNA localization, also plays a critical role in promoting nanos translation. Our results specifically exclude models for translational regulation of nanos that rely on changes in polyadenylation.     

Results of a genome-wide genetic screen for panic disorder

There is some controversy over whether or not a discrete site that integrates vomiting activities in somatic and autonomic nerves is present in the medulla oblongata. On the basis of our previous studies, we hypothesized that the temporal patterns of muscle contractions in vomiting are generated by a central pattern generator in the retrofacial area of the rostral medulla. To investigate this hypothesis further, the effects of electrical and chemical lesions of the medullary area were observed in decerebrate paralyzed dogs. Efferent activities of the phrenic and abdominal muscle nerves were recorded to recognize fictive vomiting. The right half of the medulla oblongata was transversely severed about 3 mm rostral to the obex. Fictive vomiting responses to vagal stimulation still appeared after hemisection in all 11 dogs. In addition, stimulation of the contralateral reticular area dorsomedial to the retrofacial nucleus produced fictive vomiting even after hemisection. An electrical lesion or injection of kainic acid (0.5-1.0 microl) was applied at the point where reticular stimulation induced fictive vomiting. After this destruction, no activities that corresponded to fictive vomiting could be induced by stimulation of vagal afferents or the reticular site. Salivation was decreased by hemisection, and decreased further, but was not completely abolished, with destruction of the reticular area. Kainic acid is known to selectively destroy neural cell bodies. Therefore, we concluded that neuronal somata in the reticular formation dorsomedial to the retrofacial nucleus play an essential role in the central patterning of vomiting activities in peripheral motor nerves.     

Allograft heart valve viability and valve-processing variables

BACKGROUND: The impact of allograft valve viability on valve durability remains controversial. Analyses of our clinical results have demonstrated the superiority of the cryopreserved valve viable at the time of implantation over the 4 degrees C stored valve nonviable at the time of implantation. In this study, we quantitatively assessed the effects on viability of current and past valve-processing protocols at The Prince Charles Hospital. METHODS: The viability of pulmonary valves was quantitatively analyzed by thin-layer autoradiography to assess the effects of donor type, antibiotics, and valve storage. RESULTS: Control valve segments obtained from beating-heart donor valves had a higher initial viability (0.92+/-0.02) than nonbeating-heart donor valves (0.66+/-0.03). Cryopreservation after low-dose antibiotic sterilization significantly reduced viability to 50% to 60% of the control, and in the presence of amphotericin B, viability dropped further to 10% to 36% of the control. After 7 days' storage at 4 degrees C, viability was reduced to 2% of control and to 0% viability after 21 days. CONCLUSIONS: For maximal preimplantation viability, valves should be procured as soon as possible after cessation of heart beat and should be cryopreserved if they are not to be clinically implanted within 1 to 2 days. Amphotericin B should not be used in conjunction with cryopreservation if viability is to be maximized.     

Effects of the benzodiazepine inverse agonist RO19-4603 alone and in combination with the benzodiazepine receptor antagonists flumazenil, ZK 93426 and CGS 8216, on ethanol intake in alcohol-preferring (P) rats

The present study investigated dose dependence and time course effects of the benzodiazepine (BDZ) partial inverse agonist, RO19-4603 (0.005-0.30 mg/kg) alone, and in combination with the BDZ receptor antagonists flumazenil, ZK 93426, and CGS 8216 (20 mg/kg) in selectively bred alcohol-preferring (P) rats provided a two-bottle choice test between ethanol (EtOH) (10% v/v), and a palatable saccharin (0.0125% g/v) solution. A single dose of RO19-4603 as low as 0.009 mg/kg selectively reduced EtOH drinking during the initial 15 min of a 4 h access to 19-0% of control levels on day 1. The 0.08, 0.15 and 0.30 mg/kg doses of RO19-4603 significantly reduced total EtOH intake in the 4 h access period to 57-45% of controls on day 1. On day 2, no RO19-4603 injections were given; however, six of the seven doses of RO19-4603 (0.009, 0.02, 0.04, 0.08, 0.15, and 0.30 mg/kg) continued to reduce EtOH intake to 42-3% of control levels at the initial 15 min interval, while the 0.005, 0.009, 0.08, and 0.30 mg/kg doses reduced total 4 h EtOH intake to 60-42% of controls. Saccharin intake was either not altered by RO19-4603 or showed increases during the initial 15 min intervals and the total 4 h sessions on days 1 and 2. Food intake was also unaffected by RO19-4603. The CGS 8216, but neither flumazenil nor ZK 93426, reliably reversed the RO19-4603-induced suppression of EtOH intake on days 1 and 2. That certain BDZ inverse agonists can attenuate motivated behavior for EtOH reinforcement over a prolonged time course may provide a possible therapeutic approach to reducing EtOH consumption associated with alcoholism.     

Recombinant bone morphogenetic protein (BMP)-2 regulates costochondral growth plate chondrocytes and induces expression of BMP-2 and BMP-4 in a cell maturation-dependent manner

This study examined the effect of recombinant human bone morphogenetic protein-2 on several parameters of growth, differentiation, and matrix synthesis and on the endogenous production of mRNA of bone morphogenetic proteins 2 and 4 by growth plate chondrocytes in culture. Chondrocytes from resting and growth zones were obtained from rat costochondral cartilage and cultured for 24 or 48 hours in medium containing 0.05-100 ng/ml recombinant human bone morphogenetic protein-2 and 10% fetal bovine serum. Incorporation of [3H]thymidine, cell number, alkaline phosphatase specific activity, incorporation of [3H]proline into collagenase-digestible protein and noncollagenase-digestible protein, and incorporation of [35S]sulfate were assayed as indicators of cell proliferation, differentiation, and extracellular matrix synthesis. mRNA levels for bone morphogenetic proteins 2 and 4 were determined by Northern blot analysis. Recombinant human bone morphogenetic protein-2 increased the incorporation of [3H]thymidine by quiescent resting-zone and growth-zone cells in a similar manner, whereas it had a differential effect on nonquiescent cultures. At 24 and 48 hours, 12.5-100 ng/ml recombinant human bone morphogenetic protein-2 caused a dose-dependent increase in cell number and DNA synthesis in resting-zone chondrocytes. No effect was seen in growth-zone cells. Recombinant human bone morphogenetic protein-2 stimulated alkaline phosphatase specific activity in resting-zone chondrocytes in a bimodal manner, causing significant increases between 0.2 and 0.8 ng/ml and again between 25 and 100 ng/ml. In contrast, alkaline phosphatase specific activity in growth-zone chondrocytes was significantly increased only between 12.5 and 100 ng/ml. Recombinant human bone morphogenetic protein-2 increased the production of both collagenase-digestible protein and noncollagenase-digestible protein by resting-zone and growth-zone cells, but incorporation of [35S]sulfate was unaffected. Administration of recombinant human bone morphogenetic protein-2 also increased incorporation of [3H]uridine in both resting-zone and growth-zone chondrocytes; these cells produced mRNA for bone morphogenetic proteins 2 and 4. Bone morphogenetic protein-2 mRNA levels in both resting-zone and growth-zone chondrocytes increased in the presence of recombinant human bone morphogenetic protein-2; however, bone morphogenetic protein-4 mRNA levels in growth-zone cells decreased under its influence, and those in resting-zone cells were upregulated only with a dose of 10 ng/ml. This indicates that recombinant human bone morphogenetic protein-2 regulates chondrocyte proliferation, differentiation, and matrix production, and the effects are dependent on the stage of cell maturation. Resting-zone chondrocytes were more sensitive, suggesting that they are targeted by bone morphogenetic protein-2 and that this growth factor may have autocrine effects on these cells.