Effects of sub-chronic nitrate exposure on the thyroidal function in humans.

No experimental data exist on the thyroid toxicity of nitrate among humans. We aimed to show that no significant antithyroid effect could be observed after exposure to a three times the acceptable daily intake of nitrate in humans. In a randomized controlled non-inferiority trial, 10 volunteers received 15 mg/kg sodium nitrate during 28 days whereas 10 control participants received distilled water. We performed 5- and 24-h measurements of thyroidal (131)I uptake (RAIU) before and at the end of the exposure period. Thyroid hormone plasma concentrations of T3, rT3, T4, TSH were also measured prior to and after exposure. Differences in RAIU between the intervention and the control groups at 4 weeks were 3.4% (95% confidence interval -0.5 to 7.3, and 4.8% (95% confidence interval -1.4 to 11.0, respectively, for the 5- and 24-h RAIU measurement. Plasma concentrations of thyroid hormones stayed normal. In conclusion, no significant effects on thyroidal (131)I uptake and thyroid hormones plasma concentrations were observed after sub-chronic exposition to 15 mg/kg sodium nitrate among humans.

Allele loss on chromosome 1p36 in epithelial ovarian cancers.

OBJECTIVES: Prior studies have shown that allelic loss on chromosome 1p36 occurs frequently in ovarian as well as several other types of cancer. This suggests that inactivation of gene(s) in this region may play a role in the pathogenesis of these cancers. The aim of this study was to further delineate the region of loss on chromosome 1p36 in ovarian cancers and to identify associated patient or tumor characteristics. METHODS: Paired normal/cancer DNA samples from 75 ovarian cancers (21 early stage I/II and 54 advanced stage III/IV) were analyzed using microsatellite markers. RESULTS: Forty-nine of 75 (65%) ovarian cancers had loss of at least one marker. The marker demonstrating the most frequent loss was D1S1597, which was lost in 29/57 (51%) informative cases. Allele loss on 1p36 was significantly more common in poorly differentiated ovarian cancers (73%) relative to well or moderately differentiated cases (48%) (P = 0.03). Evidence was obtained for two common regions of deletion: one flanked by D1S1646/D1S244 and another more proximally by D1S244/D1S228. CONCLUSION: These findings further delineate regions on chromosome 1p36 proposed to contain tumor suppressor gene(s) that may play a role in the development and/or progression of epithelial ovarian carcinoma. Allele loss on 1p36 is associated with poor histologic grade.

Effect of patient position on clinical evaluation of pelvic organ prolapse.

OBJECTIVE: To compare the severity of pelvic organ prolapse between examinations performed in dorsal lithotomy position and examinations performed upright in a birthing chair using the Pelvic Organ Prolapse Quantification System (POPQ). METHODS: One hundred eighty-nine consecutive women were evaluated between April 1997 and September 1998. All women were examined in the dorsal lithotomy position and in a birthing chair at a 45 degrees angle. Degree of pelvic organ prolapse was assessed using the POPQ. RESULTS: When examined upright, 133 patients (70%) had the same stage of prolapse, whereas 49 (26%) had a higher stage and seven (4%) had a lower stage. Of patients who were stage 0 or I when examined in lithotomy position, 23 (36%) were stage II or greater when examined upright. Similarly, of patients who were stage II in lithotomy, 17 (23%) were stage III or higher when examined upright. There was a statistically significant increase in the degree of prolapse at all the POPQ measurements (P <.05 for each point), except for measurement of total vaginal length. Forty-eight percent of patients had at least one measurement increase by 2 cm or more when examined upright. Logistic regression identified no patient characteristics that were independently associated with a significant increase in stage or POPQ values with change in examination position. CONCLUSION: The degree of pelvic organ prolapse assessed with the patient in the lithotomy position correlates well with assessment performed upright; however, overall there is a higher degree of prolapse with upright examination.

High frequency of hypermethylation at the 14-3-3 sigma locus leads to gene silencing in breast cancer.

Expression of 14-3-3 final sigma (final sigma) is induced in response to DNA damage, and causes cells to arrest in G(2). By SAGE (serial analysis of gene expression) analysis, we identified final sigma as a gene whose expression is 7-fold lower in breast carcinoma cells than in normal breast epithelium. We verified this finding by Northern blot analysis. Remarkably, final sigma mRNA was undetectable in 45 of 48 primary breast carcinomas. Genetic alterations at final sigma such as loss of heterozygosity were rare (1/20 informative cases), and no mutations were detected (0/34). On the other hand, hypermethylation of CpG islands in the final sigma gene was detected in 91% (75/82) of breast tumors and was associated with lack of gene expression. Hypermethylation of final sigma is functionally important, because treatment of final sigma-non-expressing breast cancer cell lines with the drug 5-aza-2'-deoxycytidine resulted in demethylation of the gene and synthesis of final sigma mRNA. Breast cancer cells lacking final sigma expression showed increased number of chromosomal breaks and gaps when exposed to gamma-irradiation. Therefore, it is possible that loss of final sigma expression contributes to malignant transformation by impairing the G(2) cell cycle checkpoint function, thus allowing an accumulation of genetic defects. Hypermethylation and loss of final sigma expression are the most consistent molecular alterations in breast cancer identified so far.

Bcl10 is not a target for frequent mutation in human carcinomas.

The recently described Bcl10 gene has been suggested to be a major target gene for inactivation in a variety of human cancers. In order to further evaluate the role of this gene in human adult malignancies, we have analysed a series of carcinomas for mutations in the Bcl10 gene. We have screened a panel of 174 carcinoma samples in total, comprised of 47 breast, 36 epithelial ovarian, 36 endometrial, 12 cervical, 23 colorectal and 20 head/neck carcinomas, all unselected for grade or stage. This panel reflects, in part, tumours reported to have involvement of the 1p22 region of chromosome 1, the region harbouring the Bcl10 gene. No deleterious mutations were detected in any of the samples analysed, strongly suggesting that Bcl10 is not a common target for inactivation in adult malignancies and that BCL10 is not the gene targeted for frequent inactivation at 1p22.

Palatability affects satiation but not satiety.

The present study was designed to investigate the effect of the pleasantness of a food on satiation (meal termination) and satiety. It was also studied whether or not the subsequent availability of other attractive foods affected the effect of palatability on intake. In a within-subjects repeated-measures design, 35 (26 female and 9 male) young healthy nonrestrained subjects consumed at lunchtime a preload consisting of tomato soup, and a buffet/test meal consisting of many attractive food items. Three factors were manipulated. The palatability of the preload was manipulated by varying the citric acid concentration of the soup at three levels: 0 (pleasant), 7.5 (less pleasant), and 15 (unpleasant) g citric acid/kg soup. Intake of the soup was either ad lib (for investigation of satiation), or standardized (350 g for women, and 500 g for men; for investigation of satiety). The third factor was the availability of other foods, manipulated by the amount of time between start of preload and start of the test meal (intermeal interval = IMI), which was set at two levels: 15 and 90 min. Subjects rated hunger and satiety feelings, before the preload, and in between preload and test meal. The results showed that the ad lib intakes of the less pleasant and unpleasant soups were about 65 and 40% of the intake of the pleasant soup. Subjects ingested about 20% more soup when the subjects had to wait for the test meal about 90 min, compared to the 15 min IMI condition. The availability of other foods had no effect on the effect of pleasantness on ad lib intake. There was also no effect of the pleasantness on subsequent satiety: hunger ratings and test meal intake were similar after the three standardized soups. One conclusion is that pleasantness of foods has an effect on satiation but not on subsequent satiety. A second conclusion is that people eat more of a food when they know that they have no access to other foods for a particular amount of time.

Mutations in DNA mismatch repair genes are not responsible for microsatellite instability in most sporadic endometrial carcinomas.

Endometrial carcinoma is the second most common tumor type in women with hereditary nonpolyposis colorectal carcinoma. Microsatellite instability (MI) has been observed in the inherited (hereditary nonpolyposis colorectal carcinoma-associated) form of endometrial carcinoma as well as in approximately 20% of presumably sporadic cases. Recent studies suggest that MI in many cell lines or xenografts derived from sporadic colorectal carcinomas is not attributable to mutations in four known human DNA mismatch repair (MMR) genes (hMSH2, hMLH1, hPMS1, and hPMS2). Mutational analyses of these four MMR genes in endometrial carcinomas have not been previously reported. We analyzed nine sporadic MI-positive primary endometrial carcinomas for mutations in the above four MMR genes. Mutations were detected in two tumors (in hMSH2), and both of the mutations were acquired somatically. Immunohistochemical staining revealed a lack of expression of hMSH2 protein in the two tumors containing hMSH2 mutations. Our data suggest that mutations in these four known DNA MMR genes are not responsible for MI in the majority of sporadic endometrial carcinomas displaying this phenotype.

Uncoupler-inhibitor titrations of ATP-driven reverse electron transfer in isolated rat-liver mitochondria.

Uncoupler-inhibitor titrations of ATP-driven reverse electron transfer across the first site of the respiratory chain were performed in isolated rat-liver mitochondria, and the experimental results were compared with the predictions of a simple delocalized chemiosmotic mechanism. The rates of ATP hydrolysis (Jp) and reverse electron transfer (-J0) were measured at different uncoupler (S-13) concentrations, either in the absence or in the presence of rotenone. When the rates -J0 and Jp measured at different uncoupler concentrations were expressed as percentages of the activity at zero uncoupler concentration, it was found that the efficiency of S-13 to uncouple the reverse electron transfer and to stimulate ATP hydrolysis was not significantly changed upon partial inhibition with rotenone. These results are in contrast with data from a study of uncoupler-inhibitor titrations in submitochondrial particles published previously, in which a higher effectiveness of several uncouplers to inhibit ATP-driven reverse electron transfer was observed in the presence of rotenone.