Histories of abuse predict stronger within-person covariation of ovarian steroids and mood symptoms in women with menstrually related mood disorder.

OBJECTIVE: Individual differences in sensitivity to cyclical changes in ovarian steroids estradiol (E2) and progesterone (P4) have been implicated in the pathophysiology of menstrually related mood disorder (MRMD). However, no prospective studies have investigated psychosocial risk factors for sensitivity to hormone effects on mood in MRMD. Using a repeated measures approach and multilevel models, we tested the hypothesis that a history of abuse provides a context in which within-person elevations of E2 and P4 prospectively predict daily symptoms. METHOD: 66 women with prospectively-confirmed MRMD recruited for a trial of oral contraceptives provided 1 month of baseline hormone and mood data prior to randomization. Lifetime physical and sexual abuse experiences were assessed. Across one cycle, women completed daily measures of symptoms and provided blood samples on 5 days across the menstrual cycle. Current E2 and P4 were centered within person (CWP) such that higher values represented cyclical elevations in hormones. RESULTS: Rates of physical (27%) and sexual (29%) abuse were high, consistent with previous work documenting a link between trauma and MRMD. In women with a history of physical abuse, cyclical increases in P4 predicted greater mood and interpersonal symptoms on the three days following that sample. In women with a history of sexual abuse, cyclical increases in E2 predicted greater anxiety symptoms on the three days following that sample. CONCLUSIONS: Results inform further inquiry into the role of severe life stressors and stress response systems in MRMD. We discuss areas for future research on the psychosocial and physiological pathways through which abuse may influence the link between hormones and symptoms.

A history of depression in women is associated with an altered GABAergic neuroactive steroid profile.

The 3α,5α- and 3α,5ß-reduced metabolites of progesterone, deoxycorticosterone, and dehydroepiandrosterone (DHEA) have potent effects on neurotransmission mediated by GABA(A) receptors, and dysregulation of these receptors has been implicated in depression. Using gas chromatography-mass spectrometry, we compared neuroactive steroid concentrations in women with a history of depressive disorders, but who were in full remission at the time of testing (n=11) to never depressed women (n=17) both before and after a challenge with oral micronized progesterone (300 mg). Serum concentrations of the following were obtained: four progesterone-derived GABAergic neuroactive steroids, the precursor pregnenolone, androstenedione-derived neuroactive steroids, and the precursor DHEA. As an index of conversion of progesterone to neuroactive steroids, we also examined ratios of neuroactive steroids to progesterone following the oral progesterone challenge. Results indicated that both before and after oral progesterone, women with histories of depression showed lower concentrations of all GABAergic neuroactive steroids than never depressed women. Those with a history of depression also had lower cortisol concentrations. Because serum neuroactive steroids are mainly synthesized in the adrenals, we hypothesize that histories of depression may be associated with persistent adrenal suppression. Following the progesterone challenge, ratios of the progesterone-derived neuroactive steroids to plasma progesterone concentrations were elevated in women with depression histories, suggesting there may be an adaptive shift in the metabolism of progesterone that compensates for lower circulating neuroactive steroid concentrations.

Characterization of human embryonic stem cell lines by the International Stem Cell Initiative.

The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide. Despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers of human embryonic stem cells. They expressed the glycolipid antigens SSEA3 and SSEA4, the keratan sulfate antigens TRA-1-60, TRA-1-81, GCTM2 and GCT343, and the protein antigens CD9, Thy1 (also known as CD90), tissue-nonspecific alkaline phosphatase and class 1 HLA, as well as the strongly developmentally regulated genes NANOG, POU5F1 (formerly known as OCT4), TDGF1, DNMT3B, GABRB3 and GDF3. Nevertheless, the lines were not identical: differences in expression of several lineage markers were evident, and several imprinted genes showed generally similar allele-specific expression patterns, but some gene-dependent variation was observed. Also, some female lines expressed readily detectable levels of XIST whereas others did not. No significant contamination of the lines with mycoplasma, bacteria or cytopathic viruses was detected.

Sampling strategy for prostate tissue microarrays for Ki-67 and androgen receptor biomarkers.

OBJECTIVE: To develop an optimal sampling strategy for tissue microarrays using automated digital analysis for androgen receptor (heterogeneous expression) and the cellular proliferation marker Ki-67 (homogeneous expression and evaluated by others using nonautomated methods). STUDY DESIGN: Tissue microarrays were constructed from 23 radical prostatectomy specimens and immunostained for androgen receptor expression and cellular proliferation. Automated digital image analysis was used, and the minimum number of cores necessary to capture variance change <3% was determined. Androgen receptor immunostaining was described by percent positive nuclei (PPN) and mean optical density (MOD). RESULTS: Androgen receptor PPN variance measurements showed that 5 cores should be obtained when a single block of a radical prostatectomy specimen contained cancer. If all of 15 blocks contained cancer, 2 cores should be obtained from each of 6 blocks. An optimal sampling strategy was developed for androgen receptor PPN, androgen receptor MOD and Ki-67 PPN. CONCLUSION: The selection of the number of cores to sample is a tradeoff between the number of cores available that contain cancer and the amount of work involved in the analysis. Sampling no fewer than 5 but no more than 12 cores per radical prostatectomy specimen can capture tissue heterogeneity.