The genetic epidemiology of early-onset epithelial ovarian cancer: a population-based study

We conducted a population-based study to determine the contribution of germline mutations in known candidate genes to ovarian cancer diagnosed at age <30 years. Women with epithelial ovarian cancer were identified through cancer registries. DNA samples were analyzed for mutations in BRCA1, the "ovarian cancer-cluster region" (nucleotides 3139-7069) of BRCA2, and the mismatch-repair genes hMSH2 and hMLH1. Probable germline mutations in hMLH1 were identified in 2 (2%; 95% confidence interval 1%-8%) of 101 women with invasive ovarian cancer diagnosed at age <30 years. No germline mutations were identified in any of the other genes analyzed. There were no striking pedigrees suggestive of families with either breast/ovarian cancer or hereditary nonpolyposis colorectal cancer (HNPCC). There was a significantly increased incidence of all cancers in first-degree relatives of women with invasive disease (relative risk [RR] = 1.6, P=.01) but not in second-degree relatives or in relatives of women with borderline cases. First-degree relatives of women with invasive disease had increased risks of ovarian cancer (RR = 4.8, P=.03), myeloma (RR = 10, P=.01), and non-Hodgkin lymphoma (RR = 7, P=.004). Germline mutations in BRCA1, BRCA2, msh2, and mlh1 contribute to only a minority of cases of early-onset epithelial ovarian cancer. Our data suggest that early-onset ovarian cancer is not associated with a greatly increased risk of cancer in close relatives.     

Observation and characterization of the interaction between a single immunoglobulin binding domain of protein L and two equivalents of human kappa light chains

Detailed stopped-flow studies in combination with site-directed mutagenesis, isothermal titration calorimetry data and x-ray crystallographic knowledge have revealed that the biphasic pre-equilibrium fluorescence changes reported for a single Ig-binding domain of protein L from Peptostreptococcus magnus binding to kappa light chain are due to the binding of the kappa light chain at two separate sites on the protein L molecule. Elimination of binding site 2 through the mutation A66W has allowed the K(d) for kappa light chain binding at site 1 to be measured by stopped-flow fluorescence and isothermal titration calorimetry techniques, giving values of 48.0 +/- 8.0 nM and 37.5 +/- 7.3 nM respectively. Conversely, a double mutation Y53F/L57H eliminates binding at site 1 and has allowed the K(d) for binding at site 2 to be determined. Stopped-flow fluorimetry suggests this to be 3.4 +/- 0.8 microM in good agreement with the value of 4.6 +/- 0.8 microM determined by isothermal titration calorimetry. The mutation Y53F reduces the affinity of site 1 to approximately that of site 2.     

Time course of a repetition effect on saccadic reaction time in non-human primates

Repeated training in a stimulus response task can lead to adaptive changes in the resulting behavior. Using a simple saccade task, we investigated the effect that the location of the target in the preceding trial had on the saccadic reaction time (SRT) of the current trial. To determine the time course of this effect, we varied the intertrial interval (ITI). Finally, we examined the pretarget discharge of single neurons in the intermediate layers of the superior colliculus (SC) during the task. Our data reveal that monkeys have a robust repetition effect in which there was an overall decrease in SRT and increase in SC pretarget activity when the target of the previous saccade was in the same location as that of the current trial. Additionally, we have shown a robust time course of this repetition effect, revealing that it exists for only a limited amount of time.     

Sural Nerve Interposition Grafting during Radical Prostatectomy

In 1997, autologous sural nerve grafting to reconstruct bilaterally resected cavernosal nerves was successfully performed in patients undergoing radical retropubic prostatectomy. After 12 months, one third of these patients had erections sufficient for intercourse. Since that time, patients who have had neurovascular bundle resection and sural nerve grafting have continued to show promising results. For example, within one large cohort of men who had unilateral, nerve-sparing radical prostatectomy, significantly more men who had sural nerve grafting regained potency, and did so in less time, than men who did not have grafting. More importantly, however, with better predictions of the presence of extracapsular disease, nerve-sparing surgery can be performed more selectively, reserving wide resection and sural nerve grafting for patients likely to have extracapsular extension. A multicenter, randomized clinical trial is needed to substantiate the positive outcomes observed with sural nerve grafting.     

Cyclic [beta]-1,6 -1,3 Glucans Are Synthesized by Bradyrhizobium japonicum Bacteroids within Soybean (Glycine max) Root Nodules

We have previously reported that free-living cultures of Bradyrhizobium species produce novel oligosaccharides that are cyclic, contain between 10 and 13 glucose residues, and are linked by [beta]-1,6 and [beta]-1,3 glycosidic bonds (K.J. Miller, R.S. Gore, R. Johnson, A.J. Benesi, V.N. Reinhold [1990] J Bacteriol 172: 136-142). In the present study, we show that these glucans are also synthesized by bacteroids of Bradyrhizobium japonicum USDA 110 within Glycine max root nodules.     

The effects of lipid phase transitions on the interaction of mitochondrial NADH--ubiquinone oxidoreductase with ubiquinol--cytochrome c oxidoreductase.

1. The endogenous phosphatidylcholine and phosphatidylethanolamine of Complexes I and III from bovine heart mitochondria may be completely replaced with 1,2-ditetradecanoyl-sn-glycero-3-phosphocholine with at least partial retention of activity. 2. The lipid-replaced enzymes associate in 1:1 molar ratio to give a Complex I--III unit catalysing NADH-cytochrome c oxidoreductase activity. 3. On increasing the concentration of ubiquinone-10 and the synthetic phospholipid, the lipid-replaced Complexes appear to operate independently of each other as in the natural membrane. Thus the lipid-replaced enzymes associate in exactly the same ways as the enzymes containing natural phospholipids. 4. Arrhenius plots of NADH--cytochrome c oxidoreductase activity reconstituted from lipid-replaced Complexes I and III exhibit changes in slope at 24 degrees C. When the concentrations of phospholipid and ubiquinone-10 are increased, the Arrhenius plots show discontinuities at 24 degrees C as well as changes in slope. 5. The kinetics of cytochrome b reduction by NADH were measured in mixtures containing 2 mol of Complex III/mol of Complex I. When the enzymes contained natural phospholipids. the reduction kinetics were biphasic. When the enzymes had been supplemented with further phospholipid and ubiquinone-10 the kinetics were monophasic. When lipid-replaced enzymes were supplemented with 1,2-ditetradecanoyl-sn-glycero-3-phosphocholine and ubiquinone-10, reduction of cytochrome b was monophasic above the phase-transition temperature of the lipid but biphasic below it. 6. These findings are interpreted in terms of the model for the interaction of Complexes in the natural membrane proposed by Heron, Ragan & Trum-power [(1978) Biochem. J. 174, 791--800].     

2-Imidazolethiones protect ascorbic acid from oxidation induced by copper

The oxidation of ascorbic acid to dehydroascorbic acid was accelerated by metal ions such as copper. This stimulation of ascorbate oxidation was inhibited by the addition of 2-imidazolethiones and other sulfhydryl-containing compounds, but not by 2-imidazolones or phenytoin. Although the 2-imidazolethiones interacted with copper, as shown by a decrease in the ultraviolet absorbance of the compounds, the product formed still protected ascorbate from oxidation. The 2-imidazolethiones are proposed to complex copper through their free -SH groups.