Comprehensive evaluation of ESR2 variation and ovarian cancer risk.

Studies indicate that estrogen receptor beta, encoded by the ESR2 gene on chromosome 14q, may play a role in ovarian carcinogenesis. Using the genetic structure data generated by the Breast and Prostate Cohort Consortium (BPC3), we have comprehensively characterized the role of haplotype diversity in ESR2 and risk of ovarian cancer. Five haplotypes with a frequency of > or =5% were observed in White subjects and five haplotype tagging SNPs (htSNP) were selected to capture the locus diversity with a minimum R(h)(2) of 0.81. The htSNPs were genotyped in 574 White controls, 417 White invasive ovarian cancer cases, and 123 White borderline ovarian cancer cases from case-control studies carried out in Los Angeles County from 1994 through 2004. No statistically significant association was observed between the five htSNPs and related haplotypes and risk of ovarian cancer overall. Haplotype D was associated with a nonstatistically significant increased risk of invasive ovarian cancer overall (odds ratio, 1.38; 95% confidence interval, 0.93-2.02; P = 0.11) relative to the most common haplotype and a statistically significant increased risk of invasive clear cell ovarian cancer (odds ratio, 3.88; 95% confidence interval, 1.28-11.73; P = 0.016). Haplotype D was also reported by the BPC3 to be associated with increased risk of breast cancer. This haplotype warrants further investigation to rule out any effect with invasive ovarian cancer risk.     

Subthreshold binge eating disorder

OBJECTIVE: To examine the clinical features of subthreshold binge eating disorder (BED). METHOD: Participants were recruited directly from the community as part of an ongoing study of risk factors for BED. Forty-four women with subthreshold BED were compared with 44 women with BED and 44 healthy controls on demographic characteristics, body mass index (BMI), eating disorder symptomatology, and psychiatric distress. Diagnoses were established using the Eating Disorder Examination (EDE). Participants completed the EDE-Questionnaire, the Brief Symptom Inventory, and were measured and weighed. RESULTS: Adjusting for significant group differences in BMI, the two eating disorder groups did not differ significantly on measures of weight and shape concern, restraint, psychiatric distress, and history of seeking treatment for an eating or weight problem. DISCUSSION: Given the importance of diagnostic status for access to treatment, further evaluation of the severity criterion specified for BED is needed.     

A reevaluation of estrogen status in postmenopausal women who smoke.

Hypoestrogenism in postmenopausal smokers has been suggested as the mechanism for the observed decreased risk of endometrial cancer and increased risk of osteoporosis. We have prospectively studied a well-matched group of smokers and nonsmokers and have evaluated their estrogen levels and compared them with existing data from the literature. We conclude that increased adrenal activity resulting in increased androgens, mainly androstenedione, is seen in postmenopausal smokers but that estrogen levels are not decreased. We hypothesize that in nonusers, unlike in users of estrogen, smoking is not associated with changes in estrogen levels and that other mechanisms must be responsible for the epidemiologic observations seen.     

Electrophysiologic studies, computed tomography, and neurologic outcome in acute bacterial meningitis

To determine the value of computed tomography and electrophysiologic studies in predicting neurologic outcome, we prospectively studied 41 children with acute bacterial meningitis, using clinical examination, computed tomography of the head, electroencephalography, brain-stem auditory evoked response, and visual evoked potential mapping during the acute illness. Two children died; 32 of the remaining 39 children were reviewed clinically, electrophysiologically, and with computed tomography between 5 and 38 months after the illness. The electrophysiologic data obtained during the illness were not found to alter the acute-stage management. Focal or generalized suppression, demonstrated on the electroencephalogram, was associated with a poor outcome. Cerebral infarction and edema, demonstrated by computed tomography of the head, were predictive of a poor outcome, but enlarged ventricular and subarachnoid spaces and increased subdural effusions were of no predictive value. Neither computed tomographic scans nor electrophysiologic data were better indicators of neurologic prognosis than the clinical examination.     

Congenital rubella syndrome associated with calcific epiphyseal stippling and peroxisomal dysfunction

An infant girl had the clinical and immunologic findings of congenital rubella syndrome but also had arthrogryposis multiplex and calcific epiphyseal stippling. Spastic quadriparesis developed, and both physical and behavioral development were slow. Increased spasticity of the legs at 5 1/2 years was related not to progressive rubella encephalomyelopathy but to spinal cord compression by abnormal cartilaginous tissue. The presence of a peroxisomal disorder was demonstrated by a greatly increased level of phytanic acid and slightly increased levels of hexacosanoate in serum and by reduced activity of peroxisomal dihydroxyacetone phosphate acyltransferase and a slightly increased ratio of cytosolic to peroxisomal catalase activity in cultured fibroblasts. A reduction in the number and size of peroxisomes was demonstrated in cultured fibroblasts, and a needle biopsy specimen of the liver also showed the peroxisomes to have a smaller diameter than usual. We recommend that any child with epiphyseal stippling be assessed for peroxisomal disease and that the potential for spinal cord compression by dysplastic bone or cartilage be recognized. The association of peroxisomal dysfunction with congenital rubella has not been described previously. The interaction between rubella virus infection and peroxisomal function may need further investigation.     

Vitamin D metabolites in adolescents and young adults with cystic fibrosis: effects of sun and season

To assess mineral metabolism in patients with cystic fibrosis and to study the effects of season and sunlight exposure on generation of vitamin D metabolites, we quantified serum levels of calcidiol and calcitriol, other measures of bone metabolism, and radiographic bone mass in 20 adolescents and young adults with CF and 20 age-matched normal volunteers. Levels of calcidiol were lower in patients with CF than in controls and lower in Massachusetts than in Arizona in both study groups. Controls in Arizona had higher (P less than 0.05) levels of calcitriol than in Massachusetts throughout the year. All control subjects in both states had higher levels of calcitriol than did patients with CF. Patients in Massachusetts had significantly lower levels of calcitriol in winter than in summer. Summer levels of calcitriol in CF were significantly higher in Massachusetts than in Arizona; during winter, lower levels were found in Massachusetts than in Arizona. Mean bone density in patients with CF was 88% and 89% of normal American standards in Massachusetts and Arizona, respectively. These data indicate a seasonal, sunlight-related influence on levels of vitamin D metabolites in patients with CF receiving approximately 1000 IU vitamin D per day. Older patients with CF with progressively diminishing sunlight exposure may be at increased risk for development of osteopenia. The detected radiographic abnormalities of bone mineralization may also be related to malabsorptive deficiencies of calcium and phosphorus.     

Failure of implantation in human in vitro fertilization and embryo transfer patients: the effects of altered progesterone/estrogen ratios in humans and mice

Daily blood samples were taken for progesterone (P) and estradiol (E2) measurements from women who showed a platelet response consistent with the presence of viable embryos after in vitro fertilization and embryo transfer procedures. A comparison of steroid levels between those women who became pregnant and those who did not revealed the following: at and after the time of transfer, women who failed to become pregnant had significantly higher E2 levels and a lower ratio of P/E2 than women who became pregnant. The P/E2 ratio was a better predictor of implantation failure than was the absolute level of either hormone. Experiments were done in mice to test the hypothesis that P could protect implantation of the embryo against the inhibitory effects of high E2. In mice, implantation was inhibited by relatively high levels of E2. This effect was overcome by concomitant administration of P. There was a significant dose-response-related interaction of P with the E2.     

Sexual, reproductive, and other risk factors for adenocarcinoma of the cervix: results from a population-based case-control study (California, United States)

The incidence of adenocarcinoma of the cervix increased steadily in young women in the United States between the early 1970s and the mid-1980s. Despite this increase, little is known about the etiology of this cancer, although a role for risk factors for both squamous cell carcinoma of the cervix and endometrial adenocarcinoma has been suggested. Incident cases of adenocarcinoma of the cervix diagnosed in women born after 1935 (ages 42 to 56 at diagnosis) were identified from the Los Angeles (California) County Cancer Surveillance Program (LACCSP). Data from personal interviews with 195 cases and 386 controls (matched on age, race, and neighborhood) were analyzed. Compared with women in the highest categories of education and income, women in the lowest categories had a 2.5 and 3.1-fold elevated risk of adenocarcinoma of the cervix. Number of sexual partners, especially before age 20, was strongly predictive of risk (odds ratio = 5.6, 95 percent confidence interval = 1.4–22.0 for 10 or more compared with no partners before age 20). Smoking was not associated significantly with risk. Weight gain and long-term use of oral contraceptives increased risk, while long-term diaphragm use was protective. This study suggests that both sexual and hormonal factors are important etiologic factors for adenocarcinoma of the cervix.Drs Ursin, Pike, Preston-Martin, and Peters are with the Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, CA, USA. Dr D'Ablaing, now deceased, was with the Department of Pathology at the University of Southern California School of Medicine. Address correspondence to Dr Ursin, Department of Preventive Medicine, University of Southern California Norris Comprehensive Cancer Center, 1441 Eastlake Ave., MS#44, P.O. Box 33800, Los Angeles, CA 90033-0800, USA. This study was supported by grants P01 CA1754 and CA 44401-05 from the US National Cancer Institute, and by the California Department of Health Services, through the California Public Health Foundation, as part of its statewide cancer reporting program, mandated by Health and Safety Code Sections 210 and 211.3. The ideas and opinions expressed herein are those of the authors, and no endorsement by the State of California Department of Health Services or the California Public Health Foundation is intended or should be inferred.     

Synthesis of (+)- and (-)-cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopropane derivatives as high affinity probes for sigma1 and sigma2 binding sites

Selective ligands for either sigma1 (sigma1) or sigma2 binding sites are potentially useful for gaining a better understanding of the physiological functions of these proteins. Moreover, potent and selective homochiral sigma1 and sigma2 binding site ligands represent leads to potential radioligands for tumour imaging with positron emission tomography (PET). On the basis of their structural similarity to previous leads, new (+)- and (-)-cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopropane derivatives were synthesised and their binding affinities for sigma1 and sigma2 binding sites were determined. Each enantiomer showed high affinity for both sigma1 and sigma2 binding sites, but only (-)-cis-methyl-2-[[1-adamantyl(methyl)amino]methyl]-1-phenylcyclopropane-carboxylate, (-)-4, showed appreciable selectivity for binding to sigma1 versus sigma2 sites. The enantiomers of cis-(2-[[1-adamantyl(methyl)amino]methyl]-1-phenylcyclopropyl)methanol, 6, expressed the highest affinity for sigma1 and sigma2 binding sites. Ligands (-)-4, (+)-6 and (-)-6 might be rapidly labelled in their N-methyl groups by methylation of the N-desmethyl analogues with [11C]iodomethane to provide prospective radioligands for PET. The N-desmethyl analogues, which are also high affinity ligands, were prepared and shown to undergo satisfactory methylation with iodomethane.