Fertility preservation in childhood cancer: Endocrine activity in prepubertal human testis xenografts exposed to a pubertal hormone environment

Survivors of childhood cancer are at risk for long-term treatment-induced health sequelae, including gonadotoxicity and iatrogenic infertility. At present, for prepubertal boys there are no viable clinical options to preserve future reproductive potential. We investigated the effect of a pubertal induction regimen with gonadotrophins on prepubertal human testis xenograft development. Human testis tissue was obtained from patients with cancer and non-malignant haematological disorders (n = 6; aged 1–14 years) who underwent testis tissue cryopreservation for fertility preservation. Fresh and frozen-thawed testis fragments were transplanted subcutaneously or intratesticularly into immunocompromised mice. Graft-bearing mice received injections of vehicle or exogenous gonadotrophins, human chorionic gonadotrophin (hCG, 20 IU), and follicle-stimulating hormone (FSH, 12.5 IU) three times a week for 12 weeks. The gross morphology of vehicle and gonadotrophin-exposed grafts was similar for both transplantation sites. Exposure of prepubertal human testis tissue xenografts to exogenous gonadotrophins resulted in limited endocrine function of grafts, as demonstrated by the occasional expression of the steroidogenic cholesterol side-chain cleavage enzyme (CYP11A1). Plasma testosterone concentrations (0.13 vs. 0.25 ng/mL; p = 0.594) and seminal vesicle weights (10.02 vs. 13.93 mg; p = 0.431) in gonadotrophin-exposed recipient mice were comparable to vehicle-exposed controls. Regardless of the transplantation site and treatment, initiation and maintenance of androgen receptor (AR) expression were observed in Sertoli cells, indicating commitment towards a more differentiated status. However, neither exogenous gonadotrophins (in castrated host mice) nor endogenous testosterone (in intact host mice) were sufficient to repress the expression of markers associated with immature Sertoli cells, such as anti-Müllerian hormone (AMH) and Ki67, or to induce the redistribution of junctional proteins (connexin 43, CX43; claudin 11, CLDN11) to areas adjacent to the basement membrane. Spermatogonia did not progress developmentally but remained the most advanced germ cell type in testis xenografts. Overall, these findings demonstrate that exogenous gonadotrophins promote partial activation and maturation of the somatic environment in prepubertal testis xenografts. However, alternative hormone regimens or additional factors for pubertal induction are required to complete the functional maturation of the spermatogonial stem cell (SSC) niche

Evidence of Associations Between Feto-Maternal Vitamin D Status, Cord Parathyroid Hormone and Bone-Specific Alkaline Phosphatase, and Newborn Whole Body Bone Mineral Content

In spite of a high prevalence of vitamin D inadequacy in pregnant women and neonates, relationships among vitamin D status (25(OH)D), parathyroid hormone (PTH), bone specific alkaline phosphatase (BALP), and whole body bone mineral content (WBBMC) in the newborn are poorly characterized. The purpose of the present study was to investigate the relationships between maternal and cord 25(OH)D, PTH, BALP, and WBBMC in newborns in a multiethnic population in Oakland, California and to evaluate the predictive value of the biochemical indices as indicators of WBBMC. Maternal and cord blood were collected from 80 mother-infant pairs and infant WBBMC was measured by dual energy X-ray absorptiometry 8–21 days post-birth. Cord PTH and BALP were each inversely correlated with infant WBBMC (r = −0.28, p = 0.01 and r = −0.26, p = 0.02) and with cord 25(OH)D (r = −0.24, p = 0.03 and r = −0.34, p = 0.002), while cord 25(OH)D and unadjusted or weight-adjusted WBBMC were not significantly correlated with one other. In multivariate regression modeling, infant WBBMC was most strongly predicted by infant weight (p < 0.0001), while either PTH or BALP contributed modestly but significantly to the model (p = 0.006 and p = 0.03 respectively). Cord 25(OH)D was not a significant predictor of infant WBBMC. This study provides evidence of associations between feto-maternal 25(OH)D, cord PTH and BALP, and early infant WBBMC, though neither feto-maternal 25(OH)D nor the measured biochemical indices were suitable indicators of WBBMC

The use of indigenous knowledge in development: problems and challenges

The use of indigenous knowledge has been seen by many as an alternative way of promoting development in poor rural communities in many parts of the world. By reviewing much of the recent work on indigenous knowledge, the paper suggests that a number of problems and tensions has resulted in indigenous knowledge not being as useful as hoped for or supposed. These include problems emanating from a focus on the (arte)factual; binary tensions between western science and indigenous knowledge systems; the problem of differentiation and power relations; the romanticization of indigenous knowledge; and the all too frequent decontextualization of indigenous knowledge

Don't Let Me Be Misunderstood: Comparing Intentions and Perceptions in Online Discussions

Discourse involves two perspectives: a person's intention in making an utterance and others' perception of that utterance. The misalignment between these perspectives can lead to undesirable outcomes, such as misunderstandings, low productivity and even overt strife. In this work, we present a computational framework for exploring and comparing both perspectives in online public discussions. We combine logged data about public comments on Facebook with a survey of over 16,000 people about their intentions in writing these comments or about their perceptions of comments that others had written. Unlike previous studies of online discussions that have largely relied on third-party labels to quantify properties such as sentiment and subjectivity, our approach also directly captures what the speakers actually intended when writing their comments. In particular, our analysis focuses on judgments of whether a comment is stating a fact or an opinion, since these concepts were shown to be often confused. We show that intentions and perceptions diverge in consequential ways. People are more likely to perceive opinions than to intend them, and linguistic cues that signal how an utterance is intended can differ from those that signal how it will be perceived. Further, this misalignment between intentions and perceptions can be linked to the future health of a conversation: when a comment whose author intended to share a fact is misperceived as sharing an opinion, the subsequent conversation is more likely to derail into uncivil behavior than when the comment is perceived as intended. Altogether, these findings may inform the design of discussion platforms that better promote positive interactions.Comment: Proceedings of The Web Conference (WWW) 202

Health care help seeking behaviour among prisoners in Norway

<p>Abstract</p> <p>Background</p> <p>Prisoners are associated with high health care needs compared with the general population. This study aims to investigate prisoners' use of health service.</p> <p>Methods</p> <p>A cross-sectional study of 29 prisons in central and southern parts of Norway. A questionnaire was distributed to 1, 454 prisoners (90% response rate). Multilevel analyses were employed to analyse help seeking behaviour among the prisoners.</p> <p>Results</p> <p>Help seeking was substantially associated with sleep problems and drug problems. There was also a tendency for closed prisons as well as high staffing levels of healthcare professionals to be associated with elevated health care use.</p> <p>Conclusions</p> <p>This study suggests that sleep problems and drug use are most frequently associated with health service use. The differences in health care use between prisons suggest that the implementation of prison health care standards should be addressed.</p

Intermittent energy restriction induces changes in breast gene expression and systemic metabolism

Background: Observational studies suggest weight loss and energy restriction reduce breast cancer risk. Intermittent energy restriction (IER) reduces weight to the same extent as, or more than equivalent continuous energy restriction (CER) but the effects of IER on normal breast tissue and systemic metabolism as indicators of breast cancer risk are unknown. Methods: We assessed the effect of IER (two days of 65 % energy restriction per week) for one menstrual cycle on breast tissue gene expression using Affymetrix GeneChips, adipocyte size by morphometry, and systemic metabolism (insulin resistance, lipids, serum and urine metabolites, lymphocyte gene expression) in 23 overweight premenopausal women at high risk of breast cancer. Unsupervised and supervised analyses of matched pre and post IER biopsies in 20 subjects were performed, whilst liquid and gas chromatography mass spectrometry assessed corresponding changes in serum and urine metabolites in all subjects after the two restricted and five unrestricted days of the IER. Results: Women lost 4.8 % (±2.0 %) of body weight and 8.0 % (±5.0 %) of total body fat. Insulin resistance (homeostatic model assessment (HOMA)) reduced by 29.8 % (±17.8 %) on the restricted days and by 11 % (±34 %) on the unrestricted days of the IER. Five hundred and twenty-seven metabolites significantly increased or decreased during the two restricted days of IER. Ninety-one percent of these returned to baseline after 5 days of normal eating. Eleven subjects (55 %) displayed reductions in energy restriction-associated metabolic gene pathways including lipid synthesis, gluconeogenesis and glycogen synthesis. Some of these women also had increases in genes associated with breast epithelial cell differentiation (secretoglobulins, milk proteins and mucins) and decreased collagen synthesis (TNMD, PCOLCE2, TIMP4). There was no appreciable effect of IER on breast gene expression in the other nine subjects. These groups did not differ in the degree of changes in weight, total body fat, fat cell size or serum or urine metabolomic markers. Corresponding gene changes were not seen in peripheral blood lymphocytes. Conclusion: The transcriptional response to IER is variable in breast tissue, which was not reflected in the systemic response, which occurred in all subjects. The mechanisms of breast responsiveness/non-responsiveness require further investigation. Trial registration:ISRCTN7791648731/07/2012

Hard exercise, affect lability, and personality among individuals with bulimia nervosa

The current study explores the personality traits of compulsivity (e.g., sense of orderliness and duty to perform tasks completely) and restricted expression (e.g., emotion expression difficulties) as potential moderators of the relation between affect lability and frequency of hard exercise episodes in a sample of individuals with bulimic pathology. Participants were 204 adult females recruited in five Midwestern cities who met criteria for threshold or subthreshold bulimia nervosa (BN). Compulsivity was found to significantly moderate the relation between affect lability and number of hard exercise episodes over the past 28 days, such that among those with high compulsivity, level of affect lability was associated with the number of hard exercise episodes; whereas, among those with low compulsivity, affect lability was not associated with the number of hard exercise episodes. The same pattern of findings emerged for restricted expression; however, this finding approached, but did not reach statistical significance. As such, it appears that affect lability is differentially related to hard exercise among individuals with BN depending upon the level of compulsivity and, to a more limited extent, restricted expression. These results suggest that, for individuals with BN with either compulsivity or restricted expression, focusing treatment on increasing flexibility and/or verbal expression of emotions may help them in the context of intense, fluctuating affect

The InterLACE study: design, data harmonization and characteristics across 20 studies on women's health

The International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE) project is a global research collaboration that aims to advance understanding of women's reproductive health in relation to chronic disease risk by pooling individual participant data from several cohort and cross-sectional studies. The aim of this paper is to describe the characteristics of contributing studies and to present the distribution of demographic and reproductive factors and chronic disease outcomes in InterLACE

Tolerability of breast ductal lavage in women from families at high genetic risk of breast cancer

<p>Abstract</p> <p>Background</p> <p>Ductal lavage (DL) has been proposed as a minimally-invasive, well-tolerated tool for obtaining breast epithelial cells for cytological evaluation of breast cancer risk. We report DL tolerability in <it>BRCA1/2 </it>mutation-positive and -negative women from an IRB-approved research study.</p> <p>Methods</p> <p>165 <it>BRCA1/2 </it>mutation-positive, 26 mutation-negative and 3 mutation unknown women underwent mammography, breast MRI and DL. Psychological well-being and perceptions of pain were obtained before and after DL, and compared with pain experienced during other screening procedures.</p> <p>Results</p> <p>The average <b><it>anticipated </it></b>and <b><it>experienced </it></b>discomfort rating for DL, 47 and 48 (0–100), were significantly higher (<it>p </it>< 0.01) than the <b><it>anticipated </it></b>and <b><it>experienced </it></b>discomfort of mammogram (38 and 34), MRI (36 and 25) or nipple aspiration (42 and 27). Women with greater pre-existing emotional distress experienced more DL-related discomfort than they anticipated. Women reporting DL-related pain as worse than expected were nearly three times more likely to refuse subsequent DL than those reporting it as the same or better than expected. Twenty-five percent of participants refused repeat DL at first annual follow-up.</p> <p>Conclusion</p> <p>DL was anticipated to be and experienced as <b>more </b>uncomfortable than other procedures used in breast cancer screening. Higher underlying psychological distress was associated with decreased DL tolerability.</p