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Background: Cost-effectiveness analyses for the treatment of aneurysmal subarachnoid hemorrhage are necessary to determine health policy, treatment guidelines, and screening protocols for cerebral aneurysms. To perform these modeling studies, detailed cost data are necessary and are currently lacking., Objective: The goal of this study was to determine detailed inpatient cost of aneurysmal subarachnoid hemorrhage., Methods: A retrospective review of our ruptured subarachnoid hemorrhage database was performed to identify consecutive patients between January 2013 and December 2015. Patients were searched by International Classification of Disease 9 diagnosis and procedure codes. Patient demographics and clinical characteristics were acquired. The cost breakdown was compiled into a comprehensive itemized list encompassing all aspects of hospitalization. A mean cost based on resource used per patient was obtained., Results: There were 269 patients treated, 209 were coiled and 60 were clipped. Mean age in the clipping group was 49 years and 55 years in the coil group (P = 0.006). Other patient demographics and clinical characteristics were found to be statistically similar for both groups. Total cost per patient for treatment and hospital stay was $74,192 for clipping and $85,553 for coiling (P = 0.06). Cost amplified with increasing Hunt and Hess grade in both clipping and coiling groups., Conclusions: The detailed cost information reported in this article can be used to help establish appropriate, standardized costs nationally by improving transparency. It can also help provide critical information necessary to develop cost-effective treatment algorithms and screening protocols., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Timings of human activities are marked by circadian clocks which in turn are entrained to different environmental signals. In an urban environment the presence of artificial lighting and various social cues tend to disrupt the natural entrainment with the sunlight. However, it is not completely understood to what extent this is the case. Here we exploit the large-scale data analysis techniques to study the mobile phone calling activity of people in large cities to infer the dynamics of urban daily rhythms. From the calling patterns of about 1,000,000 users spread over different cities but lying inside the same time-zone, we show that the onset and termination of the calling activity synchronizes with the east-west progression of the sun. We also find that the onset and termination of the calling activity of users follows a yearly dynamics, varying across seasons, and that its timings are entrained to solar midnight. Furthermore, we show that the average mid-sleep time of people living in urban areas depends on the age and gender of each cohort as a result of biological and social factors.

The transforming growth factor β (TGF-β) family has a profound impact on the reproductive function of various organisms. In this review, we discuss how highly conserved members of the TGF-β family influence the reproductive function across several species. We briefly discuss how TGF-β-related proteins balance germ-cell proliferation and differentiation as well as dauer entry and exit in Caenorhabditis elegans. In Drosophila melanogaster, TGF-β-related proteins maintain germ stem-cell identity and eggshell patterning. We then provide an in-depth analysis of landmark studies performed using transgenic mouse models and discuss how these data have uncovered basic developmental aspects of male and female reproductive development. In particular, we discuss the roles of the various TGF-β family ligands and receptors in primordial germ-cell development, sexual differentiation, and gonadal cell development. We also discuss how mutant mouse studies showed the contribution of TGF-β family signaling to embryonic and postnatal testis and ovarian development. We conclude the review by describing data obtained from human studies, which highlight the importance of the TGF-β family in normal female reproductive function during pregnancy and in various gynecologic pathologies., (Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved.)

We study the influence of seasonally and geographically related daily dynamics of daylight and ambient temperature on human resting or sleeping patterns using mobile phone data of a large number of individuals. We observe two daily inactivity periods in the people's aggregated mobile phone calling patterns and infer these to represent the resting times of the population. We find that the nocturnal resting period is strongly influenced by the length of daylight, and that its seasonal variation depends on the latitude, such that for people living in two different cities separated by eight latitudinal degrees, the difference in the resting periods of people between the summer and winter in southern cities is almost twice that in the northern cities. We also observe that the duration of the afternoon resting period is influenced by the temperature, and that there is a threshold from which this influence sets in. Finally, we observe that the yearly dynamics of the afternoon and nocturnal resting periods appear to be counterbalancing each other. This also lends support to the notion that the total daily resting time of people is more or less conserved across the year.

Embryo implantation remains a significant challenge for assisted reproductive technology, with implantation failure occurring in ∼50% of in vitro fertilization attempts. Understanding the molecular mechanisms underlying uterine receptivity will enable the development of new interventions and biomarkers. TGFβ family signaling in the uterus is critical for establishing and maintaining pregnancy. Follistatin (FST) regulates TGFβ family signaling by selectively binding TGFβ family ligands and sequestering them. In humans, FST is up-regulated in the decidua during early pregnancy, and women with recurrent miscarriage have lower endometrial expression of FST during the luteal phase. Because global knockout of Fst is perinatal lethal in mice, we generated a conditional knockout (cKO) of Fst in the uterus using progesterone receptor-cre to study the roles of uterine Fst during pregnancy. Uterine Fst -cKO mice demonstrate severe fertility defects and deliver only 2% of the number of pups delivered by control females. In Fst -cKO mice, the uterine luminal epithelium does not respond properly to estrogen and progesterone signals and remains unreceptive to embryo attachment by continuing to proliferate and failing to differentiate. The uterine stroma of Fst -cKO mice also responds poorly to artificial decidualization, with lower levels of proliferation and differentiation. In the absence of uterine FST, activin B expression and signaling are up-regulated, and bone morphogenetic protein (BMP) signals are impaired. Our findings support a model in which repression of activin signaling by FST enables uterine receptivity by preserving critical BMP signaling., Competing Interests: The authors declare no conflict of interest.

In women, the window of implantation is limited to a brief 2- to 3-day period characterized by optimal levels of circulating ovarian hormones and a receptive endometrium. Although the window of implantation is assumed to occur 8 to 10 days after ovulation in women, molecular markers of endometrial receptivity are necessary to determine optimal timing prior to embryo transfer. Previous studies showed that members of the bone morphogenetic protein (BMP) family are expressed in the uterus necessary for female fertility; however, the role of BMP7 during implantation and in late gestation is not known. To determine the contribution of BMP7 to female fertility, we generated Bmp7flox/flox-Pgr-cre+/- [BMP7 conditional knockout (cKO)] mice. We found that absence of BMP7 in the female reproductive tract resulted in subfertility due to uterine defects. At the time of implantation, BMP7 cKO females displayed a nonreceptive endometrium with elevated estrogen-dependent signaling. These implantation-related defects also affected decidualization and resulted in decreased expression of decidual cell markers such as Wnt4, Cox2, Ereg, and Bmp2. We also observed placental abnormalities in pregnant Bmp7 cKO mice, including excessive parietal trophoblast giant cells and absence of a mature placenta at 10.5 days post coitum. To establish possible redundant roles of BMP5 and BMP7 during pregnancy, we generated double BMP5 knockout/BMP7 cKO [BMP5/7 double knockout (DKO)] mice; however, we found that the combined deletion had no additive disruptive effect on fertility. Our studies indicate that BMP7 is an important factor during the process of implantation that contributes to healthy embryonic development., (Copyright © 2017 Endocrine Society.)

Social networks require active relationship maintenance if they are to be kept at a constant level of emotional closeness. For primates, including humans, failure to interact leads inexorably to a decline in relationship quality, and a consequent loss of the benefits that derive from individual relationships. As a result, many social species compensate for weakened relationships by investing more heavily in them. Here we study how humans behave in similar situations, using data from mobile call detail records from a European country. For the less frequent contacts between pairs of communicating individuals we observe a logarithmic dependence of the duration of the succeeding call on the time gap with the previous call. We find that such behaviour is likely when the individuals in these dyadic pairs have the same gender and are in the same age bracket as well as being geographically distant. Our results indicate that these pairs deliberately invest more time in communication so as to reinforce their social bonding and prevent their relationships decaying when these are threatened by lack of interaction., Electronic Supplementary Material: The online version of this article (doi:10.1140/epjds/s13688-016-0097-x) contains supplementary material., (© The Author(s) 2017.)

Each stage of the human life course is characterised by a distinctive pattern of social relations. We study how the intensity and importance of the closest social contacts vary across the life course, using a large database of mobile communication from a European country. We first determine the most likely social relationship type from these mobile phone records by relating the age and gender of the caller and recipient to the frequency, length, and direction of calls. We then show how communication patterns between parents and children, romantic partner, and friends vary across the six main stages of the adult family life course. Young adulthood is dominated by a gradual shift of call activity from parents to close friends, and then to a romantic partner, culminating in the period of early family formation during which the focus is on the romantic partner. During middle adulthood call patterns suggest a high dependence on the parents of the ego, who, presumably often provide alloparental care, while at this stage female same-gender friendship also peaks. During post-reproductive adulthood, individuals and especially women balance close social contacts among three generations. The age of grandparenthood brings the children entering adulthood and family formation into the focus, and is associated with a realignment of close social contacts especially among women, while the old age is dominated by dependence on their children., Competing Interests: The authors have declared that no competing interests exist.

Objective: To determine the expression and biological roles of serum and glucocorticoid-regulated kinase (SGK1) in tissues and cells from patients with endometriosis and from healthy control subjects., Design: Case-control., Setting: University research setting., Patient(s): Premenopausal women., Intervention(s): Endometriotic tissues were obtained from women with ovarian endometriosis, and normal endometrial tissues were obtained from women undergoing hysterectomy for benign conditions., Main Outcome Measure(s): Expression levels of SGK1, the role of SGK1 in endometriosis pathology, and regulation of SGK1 by estrogen receptor (ER) β., Result(s): Transcript and protein levels of SGK1 were significantly higher in endometriotic tissues and cells compared with normal endometrium. SGK1 mRNA and protein levels were stimulated by E2, by the ERβ-selective agonist diarylpropionitrile, and by prostaglandin E2. SGK1 was transcriptionally regulated by ERβ based on small interfering RNA knockdown and chromatin immunoprecipitation of ERβ followed by quantitative polymerase chain reaction. SGK1 knockdown led to increased cleavage of poly(ADP-ribose) polymerase, and SGK1 activation was correlated with the phosphorylation of FOXO3a, a proapoptotic factor., Conclusion(s): ERβ leads to SGK1 overexpression in endometriosis, which contributes to the survival of endometriotic lesions through inhibition of apoptosis., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Age and gender are two important factors that play crucial roles in the way organisms allocate their social effort. In this study, we analyse a large mobile phone dataset to explore the way life history influences human sociality and the way social networks are structured. Our results indicate that these aspects of human behaviour are strongly related to age and gender such that younger individuals have more contacts and, among them, males more than females. However, the rate of decrease in the number of contacts with age differs between males and females, such that there is a reversal in the number of contacts around the late 30s. We suggest that this pattern can be attributed to the difference in reproductive investments that are made by the two sexes. We analyse the inequality in social investment patterns and suggest that the age- and gender-related differences we find reflect the constraints imposed by reproduction in a context where time (a form of social capital) is limited.

The window of implantation is defined by the inhibition of uterine epithelial proliferation, structural epithelial cell remodeling, and attenuated estrogen (E2) response. These changes occur via paracrine signaling between the uterine epithelium and stroma. Because implantation defects are a major cause of infertility in women, identifying these signaling pathways will improve infertility interventions. Bone morphogenetic proteins (BMPs) are TGF-β family members that regulate the postimplantation and midgestation stages of pregnancy. In this study, we discovered that signaling via activin-like kinase 3 (ALK3/BMPR1A), a BMP type 1 receptor, is necessary for blastocyst attachment. Conditional knockout (cKO) of ALK3 in the uterus was obtained by producing Alk3(flox) (/flox)-Pgr-cre-positive females. Alk3 cKO mice are sterile and have defects in the luminal uterine epithelium, including increased microvilli density and maintenance of apical cell polarity. Moreover, Alk3 cKO mice exhibit an elevated uterine E2 response and unopposed epithelial cell proliferation during the window of implantation. We determined that dual transcriptional regulation of Kruppel-like factor 15 (Klf15), by both the transforming growth factor β (TGF-β) transcription factor SMAD family member 4 (SMAD4) and progesterone receptor (PR), is necessary to inhibit uterine epithelial cell proliferation, a key step for embryo implantation. Our findings present a convergence of BMP and steroid hormone signaling pathways in the regulation of uterine receptivity.

The placenta is the first organ to develop after fertilization. It forms an interface between the maternal uterus and growing fetus to allow nutrient uptake, waste elimination, and gas exchange for a successful pregnancy in both mice and humans. In the past 2 decades, in vivo and in vitro approaches have been used to show that several members of the TGF-β superfamily regulate embryo implantation and placental development. Nodal, a TGF-β superfamily ligand, is essential for mesendoderm formation and left-right axis patterning during embryogenesis, and Nodal null mutants exhibit abnormal placental organization with expansion of trophoblast giant cells and a decrease of spongiotrophoblast and labyrinth. To better understand the importance of Nodal signaling in the uterus, we established a mouse model to conditionally ablate activin-like kinase 4 (ALK4; the Nodal type 1 receptor) using Cre recombinase driven by the progesterone receptor promoter sequences (Pgr-Cre). Alk4 conditional knockout females are subfertile due to placental abnormalities and fetal loss in pregnancy, with a placental disorganization phenotype similar to what is observed in Nodal null mice. Thus, Nodal likely functions as an indirect regulator of placental development by binding to type 1 and type 2 receptors on maternal decidual cells to stimulate expression of unknown regulators of placental development. Our findings not only describe the generation of a mouse model that enables study of Nodal signaling in placentation but also provides insights into the pathogenesis of pregnancy complications in humans, including spontaneous abortion, preeclampsia, intrauterine growth restriction, and preterm birth.

Objective: To define the expression and function of DNA methyltransferases (DNMTs) in response to decidualizing stimuli in endometriotic cells compared with healthy endometrial stroma., Design: Basic science., Setting: University research center., Patient(s): Premenopausal women with or without endometriosis., Intervention(s): Primary cultures of stromal cells from healthy endometrium (E-IUM) or endometriomas (E-OSIS) were subjected to in vitro decidualization (IVD) using 1 μM medroxyprogesterone acetate, 35 nM 17β-estradiol, and 0.05 mM 8-Br-cAMP., Main Outcome Measure(s): Expression of DNMT1, DNMT3A, and DNMT3B in E-IUM and E-OSIS were assessed by quantitative real-time polymerase chain reaction and immunoblotting. Recruitment of DNMT3B to the promoters of steroidogenic factor 1 (SF-1) and estrogen receptor α (ESR1) was examined by chromatin immunoprecipitation., Result(s): IVD treatment reduced DNMT3B messenger RNA (74%) and protein levels (81%) only in E-IUM; DNMT1 and DNMT3A were unchanged in both cell types. Significantly more DNMT3B bound to the SF-1 promoter in E-IUM compared with E-OSIS, and IVD treatment reduced binding in E-IUM to levels similar to those in E-OSIS. Enrichment of DNMT3B across 3 ESR1 promoters was reduced in E-IUM after IVD, although the more-distal promoter showed increased DNMT3B enrichment in E-OSIS after IVD., Conclusion(s): The inability to downregulate DNMT3B expression in E-OSIS may contribute to an aberrant epigenetic fingerprint that misdirects gene expression in endometriosis and contributes to its altered response to steroid hormones., (Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Members of the transforming growth factor β (TGF-β) superfamily are key regulators in most developmental and physiological processes. However, the in vivo roles of TGF-β signaling in female reproduction remain uncertain. Activin receptor-like kinase 5 (ALK5) is the major type 1 receptor for the TGF-β subfamily. Absence of ALK5 leads to early embryonic lethality because of severe defects in vascular development. In this study, we conditionally ablated uterine ALK5 using progesterone receptor-cre mice to define the physiological roles of ALK5 in female reproduction. Despite normal ovarian functions and artificial decidualization in conditional knockout (cKO) mice, absence of uterine ALK5 resulted in substantially reduced female reproduction due to abnormalities observed at different stages of pregnancy, including implantation defects, disorganization of trophoblast cells, fewer uterine natural killer (uNK) cells, and impairment of spiral artery remodeling. In our microarray analysis, genes encoding proteins involved in cytokine-cytokine receptor interactions and NK cell-mediated cytotoxicity were down-regulated in cKO decidua compared with control decidua. Flow cytometry confirmed a 10-fold decrease in uNK cells in cKO versus control decidua. According to these data, we hypothesize that TGF-β acts on decidual cells via ALK5 to induce expression of other growth factors and cytokines, which are key regulators in luminal epithelium proliferation, trophoblast development, and uNK maturation during pregnancy. Our findings not only generate a mouse model to study TGF-β signaling in female reproduction but also shed light on the pathogenesis of many pregnancy complications in human, such as recurrent spontaneous abortion, preeclampsia, and intrauterine growth restriction.

Endometriosis has been initially described as the presence of ectopic endometrial tissue on pelvic organs or in extrapelvic sites; and this has been used as its key pathologic feature ever since. Endometriosis responds to fluctuations in estrogen and progesterone by growth and inflammation, leading to pain aggravated by menses. It was proposed that pelvic endometriosis primarily originate from retrograde menstruation of a critical number of eutopic endometrial cells with stem characteristics. This postulate is supported by the molecular defects found in ectopic endometriotic tissue. Genome-wide differences in CpG methylation between eutopic endometrial and endometriotic stromal cells are present. Defective CpG methylation affecting several genes that encode key transcription factors such as GATA6, steroidogenic factor-1, and estrogen receptor-β in endometriosis gives rise to overproduction of local estrogen and prostaglandins and suppression of progesterone receptor. Progesterone receptor deficiency leads to progesterone resistance, resulting in decreased retinol uptake and retinoic acid production and altered retinoic acid action. These molecular defects collectively give rise to poor cellular differentiation, enhanced survival, and increased inflammation, which are the biological hallmarks of endometriotic tissue., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Context: Uterine leiomyoma is the most common benign tumor in reproductive-age women. Using a dye-exclusion technique, we previously identified a side population of leiomyoma cells exhibiting stem cell characteristics. However, unless mixed with mature myometrial cells, these leiomyoma side population cells did not survive or grow well in vitro or in vivo., Objective: The objective of this study was to identify cell surface markers to isolate leiomyoma stem/progenitor cells., Design: Real-time PCR screening was used to identify cell surface markers preferentially expressed in leiomyoma side population cells. In vitro colony-formation assay and in vivo tumor-regeneration assay were used to demonstrate functions of leiomyoma stem/progenitor cells., Results: We found significantly elevated CD49b and CD34 gene expression in side population cells compared with main population cells. Leiomyoma cells were sorted into three populations based on the expression of CD34 and CD49b: CD34(+)/CD49b(+), CD34(+)/CD49b(-), and CD34(-)/CD49b(-) cells, with the majority of the side population cells residing in the CD34(+)/CD49b(+) fraction. Of these populations, CD34(+)/CD49b(+) cells expressed the lowest levels of estrogen receptor-α, progesterone receptor, and α-smooth muscle actin, but the highest levels of KLF4, NANOG, SOX2, and OCT4, confirming their more undifferentiated status. The stemness of CD34(+)/CD49b(+) cells was also demonstrated by their strongest in vitro colony-formation capacity and in vivo tumor-regeneration ability., Conclusions: CD34 and CD49b are cell surface markers that can be used to enrich a subpopulation of leiomyoma cells possessing stem/progenitor cell properties; this technique will accelerate efforts to develop new therapies for uterine leiomyoma.

Context: Uterine leiomyoma, or fibroids, represent the most common benign tumors of the female reproductive tract. A newly discovered epigenetic modification, 5-hydroxymethylation (5-hmC), and its regulators, the TET (Ten Eleven Translocation) enzymes, were implicated in the pathology of malignant tumors; however, their roles in benign tumors, including uterine fibroids, remain unknown., Objective: To determine the role of 5-hmC and TET proteins in the pathogenesis of leiomyoma using human uterine leiomyoma and normal matched myometrial tissues and primary cells., Design: 5-hmC levels were determined by ELISA and immunofluorescent staining in matched myometrial and leiomyoma tissues. TET expression was analyzed by quantitative RT-PCR and immunoblotting. TET1 or TET3 were silenced or inhibited by small interfering RNA or 2-hydroxyglutarate to study their effects on 5-hmC content and cell proliferation., Results: We demonstrated significantly higher 5-hmC levels in the genomic DNA of leiomyoma tissue compared to normal myometrial tissue. The increase in 5-hmC levels was associated with the up-regulation of TET1 or TET3 mRNA and protein expression in leiomyoma tissue. TET1 or TET3 knockdown significantly reduced 5-hmC levels in leiomyoma cells and decreased cell proliferation. Treatment with 2-hydroxyglutarate, a competitive TET enzyme inhibitor, significantly decreased both 5-hmC content and cell proliferation of leiomyoma cells., Conclusion: An epigenetic imbalance in the 5-hmC content of leiomyoma tissue, caused by up-regulation of the TET1 and TET3 enzymes, might lead to discovery of new therapeutic targets in leiomyoma.

Purpose: To describe difficulties associated with the business-related aspects of practice in role transition of rural nurse practitioners (NPs), and to give practice implications., Data Sources: This focused ethnographic study derived data from semi-structured interviews. Participants provided information about rural NP practice ownership and barriers. The sample consisted of 24 rural NPs living throughout the United States. The majority were 51-60 years of age (45%) and females (93%) who had been in rural practice for 1 to over 20 years., Conclusions: NP social entrepreneurs experience difficulties related to scope of practice, business skills, and role conflict., Implications for Practice: To decrease barriers for NP clinic ownership and management, NPs need to receive education related to financing a rural practice, legal/regulatory practices, strategic planning, leadership, and clinic management., (©2014 American Association of Nurse Practitioners.)

Neuropathic pain is a chronic condition lacking effective management and responding poorly to standard treatment protocols. Motor cortex stimulation has emerged as a new and promising therapeutic tool with outcomes potentially affected by the specific causes and location. In this study we report a series of eight cases in the neurosurgery practice of one of the authors (R.J.B.), including neuropathic pain syndromes of trigeminal or thalamic origin with or without anesthesia dolorosa. Pain relief was evaluated on the basis of comparison of Visual Analog scores at baseline and at 3 months after surgery. In addition, we assessed differences in pain relief outcomes between cases with trigeminal neuralgia and thalamic stroke, as well as cases with or without anesthesia dolorosa (i.e. pain with numbness of the affected area). Visual Analog Scale scores showed a statistically significant decrease of 4.19 (P=0.002) at 3 months follow-up compared with baseline. Pain relief levels in four of five patients in the subgroup with facial pain were higher than 50%, and none of the patients in the subgroup with thalamic and phantom limb pain showed such a good outcome. Furthermore, we found larger pain relief levels in facial pain conditions with versus without anesthesia dolorosa. These results point to utility of motor cortex stimulation in relieving neuropathic pain, as well as better outcomes for patients with facial pain and anesthesia dolorosa. Future studies should incorporate methods to noninvasively trial those patients who may benefit from surgical implantation to predict the outcomes and maximize their negative predictive value.

Endometriosis is a gynecological disease defined by the extrauterine growth of endometrial-like cells that cause chronic pain and infertility. The disease is limited to primates that exhibit spontaneous decidualization, and diseased cells are characterized by significant defects in the steroid-dependent genetic pathways that typify this process. Altered DNA methylation may underlie these defects, but few regions with differential methylation have been implicated in the disease. We mapped genome-wide differences in DNA methylation between healthy human endometrial and endometriotic stromal cells and correlated this with gene expression using an interaction analysis strategy. We identified 42,248 differentially methylated CpGs in endometriosis compared to healthy cells. These extensive differences were not unidirectional, but were focused intragenically and at sites distal to classic CpG islands where methylation status was typically negatively correlated with gene expression. Significant differences in methylation were mapped to 403 genes, which included a disproportionally large number of transcription factors. Furthermore, many of these genes are implicated in the pathology of endometriosis and decidualization. Our results tremendously improve the scope and resolution of differential methylation affecting the HOX gene clusters, nuclear receptor genes, and intriguingly the GATA family of transcription factors. Functional analysis of the GATA family revealed that GATA2 regulates key genes necessary for the hormone-driven differentiation of healthy stromal cells, but is hypermethylated and repressed in endometriotic cells. GATA6, which is hypomethylated and abundant in endometriotic cells, potently blocked hormone sensitivity, repressed GATA2, and induced markers of endometriosis when expressed in healthy endometrial cells. The unique epigenetic fingerprint in endometriosis suggests DNA methylation is an integral component of the disease, and identifies a novel role for the GATA family as key regulators of uterine physiology-aberrant DNA methylation in endometriotic cells correlates with a shift in GATA isoform expression that facilitates progesterone resistance and disease progression.

Uterine leiomyomas are extremely common estrogen and progesterone-dependent tumors of the myometrium and cause irregular uterine bleeding, severe anemia, and recurrent pregnancy loss in 15-30% of reproductive-age women. Each leiomyoma is thought to arise from a single mutated myometrial smooth muscle stem cell. Leiomyoma side-population (LMSP) cells comprising 1% of all tumor cells and displaying tumor-initiating stem cell characteristics are essential for estrogen- and progesterone-dependent in vivo growth of tumors, although they have remarkably lower estrogen/progesterone receptor levels than mature myometrial or leiomyoma cells. However, how estrogen/progesterone regulates the growth of LMSP cells via mature neighboring cells is unknown. Here, we demonstrate a critical paracrine role of the wingless-type (WNT)/β-catenin pathway in estrogen/progesterone-dependent tumorigenesis, involving LMSP and differentiated myometrial or leiomyoma cells. Estrogen/progesterone treatment of mature myometrial cells induced expression of WNT11 and WNT16, which remained constitutively elevated in leiomyoma tissues. In LMSP cells cocultured with mature myometrial cells, estrogen-progesterone selectively induced nuclear translocation of β-catenin and induced transcriptional activity of its heterodimeric partner T-cell factor and their target gene AXIN2, leading to the proliferation of LMSP cells. This effect could be blocked by a WNT antagonist. Ectopic expression of inhibitor of β-catenin and T-cell factor 4 in LMSP cells, but not in mature leiomyoma cells, blocked the estrogen/progesterone-dependent growth of human tumors in vivo. We uncovered a paracrine role of the WNT/β-catenin pathway that enables mature myometrial or leiomyoma cells to send mitogenic signals to neighboring tissue stem cells in response to estrogen and progesterone, leading to the growth of uterine leiomyomas.

Knowledge surrounding estrogen and estrogen receptor biology continues to evolve, and the diversity of their actions and complexity of their mechanisms are becoming increasingly evident. Estrogen receptor (ER) regulation of reproduction is no exception. Although it is well established that estrogen and ERα play key roles in mediating several reproductive biological processes, such as myometrial and endometrial growth, increasing evidence suggests that ERβ is also an important factor. ERβ is a key mediator in folliculogenesis and may also play a role in stimulating ovulation and regulating aspects of luteinization. ERβ is also expressed in higher quantities than ERα in the human myometrium and cervix during pregnancy, and thus it may play a part in the initiation of labor and parturition. Finally, ERβ is the sole ER expressed within the endothelium of the endometrium and the fetoplacental vasculature, and studies suggest that its role may contribute to angiogenic and vasomotor changes that play a role in both implantation and regulation of fetoplacental blood flow., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Uterine leiomyomas, or fibroids, represent the most common benign tumor of the female reproductive tract. Fibroids become symptomatic in 30% of all women and up to 70% of African American women of reproductive age. Epigenetic dysregulation of individual genes has been demonstrated in leiomyoma cells; however, the in vivo genome-wide distribution of such epigenetic abnormalities remains unknown., Principal Findings: We characterized and compared genome-wide DNA methylation and mRNA expression profiles in uterine leiomyoma and matched adjacent normal myometrial tissues from 18 African American women. We found 55 genes with differential promoter methylation and concominant differences in mRNA expression in uterine leiomyoma versus normal myometrium. Eighty percent of the identified genes showed an inverse relationship between DNA methylation status and mRNA expression in uterine leiomyoma tissues, and the majority of genes (62%) displayed hypermethylation associated with gene silencing. We selected three genes, the known tumor suppressors KLF11, DLEC1, and KRT19 and verified promoter hypermethylation, mRNA repression and protein expression using bisulfite sequencing, real-time PCR and western blot. Incubation of primary leiomyoma smooth muscle cells with a DNA methyltransferase inhibitor restored KLF11, DLEC1 and KRT19 mRNA levels., Conclusions: These results suggest a possible functional role of promoter DNA methylation-mediated gene silencing in the pathogenesis of uterine leiomyoma in African American women.

Background: Uterine leiomyoma is the most common benign tumor in reproductive-age women. Each leiomyoma is thought to be a benign monoclonal tumor arising from a single transformed myometrial smooth muscle cell; however, it is not known what leiomyoma cell type is responsible for tumor growth. Thus, we tested the hypothesis that a distinct stem/reservoir cell-enriched population, designated as the leiomyoma-derived side population (LMSP), is responsible for cell proliferation and tumor growth., Principal Findings: LMSP comprised approximately 1% of all leiomyoma and 2% of all myometrium-derived cells. All LMSP and leiomyoma-derived main population (LMMP) but none of the side or main population cells isolated from adjacent myometrium carried a mediator complex subunit 12 mutation, a genetic marker of neoplastic transformation. Messenger RNA levels for estrogen receptor-α, progesterone receptor and smooth muscle cell markers were barely detectable and significantly lower in the LMSP compared with the LMMP. LMSP alone did not attach or survive in monolayer culture in the presence or absence of estradiol and progestin, whereas LMMP readily grew under these conditions. LMSP did attach and survive when directly mixed with unsorted myometrial cells in monolayer culture. After resorting and reculturing, LMSP gained full potential of proliferation. Intriguingly, xenografts comprised of LMSP and unsorted myometrial smooth muscle cells grew into relatively large tumors (3.67 ± 1.07 mm(3)), whereas xenografts comprised of LMMP and unsorted myometrial smooth muscle cells produced smaller tumors (0.54 ± 0.20 mm(3), p<0.05, n = 10 paired patient samples). LMSP xenografts displayed significantly higher proliferative activity compared with LMMP xenografts (p<0.05)., Conclusions: Our data suggest that LMSP, which have stem/reservoir cell characteristics, are necessary for in vivo growth of leiomyoma xenograft tumors. Lower estrogen and progesterone receptor levels in LMSP suggests an indirect paracrine effect of steroid hormones on stem cells via the mature neighboring cells.

Background: Progesterone, via its nuclear receptor (PR), exerts an overall tumorigenic effect on both uterine fibroid (leiomyoma) and breast cancer tissues, whereas the antiprogestin RU486 inhibits growth of these tissues through an unknown mechanism. Here, we determined the interaction between common or cell-specific genome-wide binding sites of PR and mRNA expression in RU486-treated uterine leiomyoma and breast cancer cells., Principal Findings: ChIP-sequencing revealed 31,457 and 7,034 PR-binding sites in breast cancer and uterine leiomyoma cells, respectively; 1,035 sites overlapped in both cell types. Based on the chromatin-PR interaction in both cell types, we statistically refined the consensus progesterone response element to G•ACA• • •TGT•C. We identified two striking differences between uterine leiomyoma and breast cancer cells. First, the cis-regulatory elements for HSF, TEF-1, and C/EBPα and β were statistically enriched at genomic RU486/PR-targets in uterine leiomyoma, whereas E2F, FOXO1, FOXA1, and FOXF sites were preferentially enriched in breast cancer cells. Second, 51.5% of RU486-regulated genes in breast cancer cells but only 6.6% of RU486-regulated genes in uterine leiomyoma cells contained a PR-binding site within 5 kb from their transcription start sites (TSSs), whereas 75.4% of RU486-regulated genes contained a PR-binding site farther than 50 kb from their TSSs in uterine leiomyoma cells. RU486 regulated only seven mRNAs in both cell types. Among these, adipophilin (PLIN2), a pro-differentiation gene, was induced via RU486 and PR via the same regulatory region in both cell types., Conclusions: Our studies have identified molecular components in a RU486/PR-controlled gene network involved in the regulation of cell growth, cell migration, and extracellular matrix function. Tissue-specific and common patterns of genome-wide PR binding and gene regulation may determine the therapeutic effects of antiprogestins in uterine fibroids and breast cancer.

Context: Fetal growth restriction (FGR) due to placental dysfunction impacts short- and long-term neonatal outcomes. Abnormal umbilical artery Doppler velocimetry indicating elevated fetoplacental vascular resistance has been associated with fetal morbidity and mortality. Estrogen receptors are regulators of vasomotor tone, and fetoplacental endothelium expresses estrogen receptor-β (ESR2) as its sole estrogen receptor., Objective: Our objective was to elucidate the mechanism whereby ESR2 regulates placental villous endothelial cell prostanoid biosynthesis., Design and Participants: We conducted immunohistochemical analysis of human placental specimens and studies of primary fetoplacental endothelial cells isolated from subjects with uncomplicated pregnancies., Main Outcome Measures: We evaluated in vivo levels of ESR2 and cyclooxygenase-2 (PTGS2) in villous endothelial cells from fetuses with or without FGR and/or abnormal umbilical artery Doppler indices and in vitro effects of ESR2 on prostanoid biosynthetic gene expression., Results: ESR2 and PTGS2 expression were significantly higher within subjects with FGR with abnormal umbilical artery Doppler indices in comparison with controls (P < 0.01). ESR2 knockdown led to decreased cyclooxygenase-1 (PTGS1), PTGS2, prostaglandin F synthase (AKR1C3), and increased prostacyclin synthase (PTGIS), with opposing results found after ESR2 overexpression (P < 0.05). ESR2 mediates prostaglandin H2 substrate availability and, in the setting of differential regulation of AKR1C3 and PTGIS, altered the balance between vasodilatory and vasoconstricting prostanoid production., Conclusions: Higher ESR2 expression in the placental vasculature of FGR subjects with abnormal blood flow is associated with an endothelial cell phenotype that preferentially produces vasoconstrictive prostanoids. Endothelial ESR2 appears to be a master regulator of prostanoid biosynthesis and contributes to high-resistance fetoplacental blood flow, thereby increasing morbidity and mortality associated with FGR.

Introduction: Sonic hedgehog (SHH) is an essential regulator of smooth muscle apoptosis in the penis that has significant clinical potential as a therapy to suppress post-prostatectomy apoptosis, an underlying cause of erectile dysfunction (ED). Thus an understanding of how SHH signaling is regulated in the adult penis is essential to move the field of ED research forward and to develop new treatment strategies. We propose that hedgehog-interacting protein (HIP), which has been shown to bind SHH protein and to play a role in SHH regulation during embryogenesis of other organs, is a critical regulator of SHH signaling, penile morphology, and apoptosis induction., Aims: We have examined HIP signaling in the penis and cavernous nerve (CN) during postnatal differentiation of the penis, in CN-injured, and a diabetic model of ED., Methods: HIP localization/abundance and RNA abundance were examined by immunohistochemical (IHC) analysis and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in Sprague-Dawley rats between the ages of 7 and 92 days old, in CN-injured Sprague-Dawley rats and in BioBreeding/Worcester diabetic rats. HIP signaling was perturbed in the pelvic ganglia and in the penis and TUNEL assay was performed in the penis. CN tie, lidocaine, and anti-kinesin experiments were performed to examine HIP signaling in the CN and penis., Results: In this study we are the first to demonstrate that HIP undergoes anterograde transport to the penis via the CN, that HIP perturbation in the pelvic ganglia or the penis induces apoptosis, and that HIP plays a role in maintaining CN integrity, penile morphology, and SHH abundance., Conclusions: These studies are significant because they show HIP involvement in cross-talk (signaling) between the pelvic ganglia and penis, which is integral for maintenance of penile morphology and they suggest a mechanism of how nerves may regulate target organ morphology and function.

The objective was to develop an integrated review of quantitative and qualitative research regarding the influence of patients' beliefs and attitudes toward pain medication prescribed for the treatment of nonmalignant chronic pain on use of the pain medication. Studies involving patients at least 18 years old with nonmalignant chronic pain were included. Studies of patients with acquired immune deficiency syndrome, cancer, and acute pain were excluded. Medline, CINAHL, PsychInfo, and Cochrane databases from 1985 to 2005 were searched. Reference lists were screened for relevant articles. Abstracts were screened for compliance with the study criteria, and the articles were obtained for those that met criteria. By using a systematic process, each article was subjected to repeated review and data abstracted to the collection sheets. Evidence tables were created to assist with data review. High levels of concern positively correlate with nonadherence, preconceived ideas about when the drug should start working can cause the patient to discontinue it before it begins to work, and patients may perceive that if medication is taken on a regular basis to control pain it may not be effective in the future if the pain increases. Research also showed that if patients perceived the benefits of taking the pain medication to be high, they were willing to risk the side effects.

The Hispanic Health Disparities Research Center, a collaborative venture between the University of Texas at El Paso and the University of Texas at Houston Health Sciences Center, supports the research capabilities of junior faculty through a variety of programs. Novice researchers often need practical help in conducting literature reviews, extracting data, evaluating the evidence, and formulating a research question of significant importance to be funded yet narrow enough to fit within the scope of the proposal. The authors discuss a successful proposal development program that includes mentoring by more senior faculty and structured sessions with a medical writer and editor.

The purpose of this article is to examine the concept of self-organization in chronic pain using Rodgers' (2000) evolutionary approach. This article describes the antecedents, attributes, and consequences of self-organization in chronic pain. Self-organization in chronic pain may be achieved through the attributes of being believed, accessing credible resources, and taking action and responsibility. Self-organization occurs when the patient with pain develops a transformed identity, new insights, and is an active, in-control participant in care. Chronic pain is a common and costly problem, and recognition of the key attributes of self-organization in this condition is an important step in promoting positive health outcomes. Rehabilitation nurses play a key role in providing credible resources and working with the patient to take action and responsibility.

Nurses should be involved in all aspects of patient education, including the development of print and web resources, but most nurses have not been educated in how to develop these resources. This article discusses the rationale for nurse involvement, describes guidelines for evaluating existing material for credibility and readability, and provides recommendations for rewriting material at an easier-to-read level.

Assessment and psychological concerns in caring for the child and parents contemplating pediatric microsurgery to repair hand defects are issues nurses will face. Assessing the patient's perception of self, assessing the perception of expected postoperative results, and assessing the parents' adjustment to the disability will be discussed in this article.

This study evaluates the course of carpal tunnel syndrome in a group of manual laborers who declined surgery for personal or social reasons. Thirty-five patients and 67 extremities with carpal tunnel syndrome were evaluated in a group of manual laborers. The carpal tunnel syndrome was classified as mild, moderate, or severe on the basis of initial evaluation data. Sensory batteries, motor and sensory conduction velocities, and electrical studies were performed on a scheduled basis. Follow-up ranged between 14 and 58 months, with an average of 34.3 months. Three patients became worse and one improved during the study period. All others remained unchanged. Six patients returned to work, but only three returned to their original jobs. Although carpal tunnel syndrome does not appear to be a progressive condition once the triggering cause is removed, nonsurgical treatment does not seem to be the treatment of choice for patients who must continue in a manual labor position.

1. Cumulative trauma disorders comprise more than half of all occupational injuries reported in the U.S. 2. Lack of clear definition about cumulative trauma disorders causes confusion for clients in the workers' compensation system. 3. A teaching poster about cumulative trauma disorders was developed (describing prevention, acute care, and rehabilitation) to assist clients in understanding this disorder. Emphasis was placed on clients' choice in decision making about treatment. 4. Evaluation was carried out using a survey questionnaire. The majority of clients thought the poster was "helpful" or "very helpful." Actual behavioral change was most noticeable in the categories of "took steps to reduce risk factors" and "asked more questions about care."