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Purpose: The primary objective of this systematic review was to determine if frenotomy for ankyloglossia improves breastfeeding or speech outcomes in infants and children ages birth to 12.Method: L...

Objective To investigate the association of maternal body mass index (BMI) and recurrent pregnancy loss (RPL). Design Systematic review and meta-analysis. Setting Not applicable. Patient(s) A total of 3,833 women with RPL and 4,083 women as controls. Intervention(s) Studies were identified through a search of PubMed, Embase, Scopus, and Cochrane. Main Outcome Measure(s) The primary outcome of interest was RPL using the mean differences in maternal BMI as the predictor variable. The results of the meta-analysis were reported as the mean difference with a 95% confidence interval. Result(s) In total, 892 studies were reviewed. Pooled data from 25 studies suggested that the maternal BMI of women with a history of recurrent pregnancy loss was significantly higher than the BMI of controls, mean difference 0.7 kg/m2 [95% confidence interval 0.2–1.3]. Conclusion(s) These findings supported an association between maternal BMI and RPL. Large prospective studies are needed to evaluate the influence of maternal BMI on pregnancy outcomes in women with RPL.

The Emergency Department Return Visit Quality Program was launched in Ontario, Canada, to promote a culture of quality. It mandates the province's largest-volume emergency departments (EDs) to audit charts of patients who had a return visit leading to hospital admission, including some of their 72-hour all-cause return visits with admission and all of their 7-day ones with sentinel diagnoses (ie, acute myocardial infarction, subarachnoid hemorrhage, and pediatric sepsis), and submit their findings to a governmental agency. This provides an opportunity to identify possible adverse events and quality issues, which hospitals can then address through quality improvement initiatives. A group of emergency physicians with quality improvement expertise analyzed the submitted audits and accompanying narrative templates, using a general inductive approach to develop a novel classification of recurrent quality themes. Since the Return Visit Quality Program launched in 2016, 125,698 return visits with admission have been identified, representing 0.93% of the 86 participating EDs' 13,559,664 visits. Overall, participating hospitals have conducted 12,852 detailed chart audits, uncovering 3,010 (23.4%) adverse events/quality issues and undertaking hundreds of quality improvement provincewide projects as a result. The inductive analysis revealed 11 recurrent themes, classified into 3 groupings: patient characteristics (ie, patient risk profile and elder care), ED team actions or processes (ie, physician cognitive lapses, documentation, handover/communication between providers, radiology, vital signs, and high-risk medications or medication interactions), and health care system issues (ie, discharge planning/community follow-up, left against medical advice/left without being seen, and imaging/testing availability). The Return Visit Quality Program is the largest mandatory audit program for EDs and provides a novel approach to identify local adverse events/quality issues to target for improved patient safety and quality of care. It provides a blueprint for health system leaders to enable clinicians to develop an approach to organizational quality, as well as for teams to construct an audit system that yields defined issues amenable to improvement.

A substantial amount of evidence suggests that androgen signaling through classical androgen receptors is critical for both normal and pathologic ovarian physiology. Specifically, we and others have shown that, in mouse granulosa cells, androgen actions through both extranuclear and nuclear androgen receptor signaling are critical for normal follicle development and ovulation. Here, we show that androgens through the PI3K/Akt pathway rapidly (within minutes) phosphorylate and inhibit activity of the Polycomb group protein enhancer of zeste homolog 2 (Ezh2). Over the course of 24 to 48 hours, androgens then induce expression of the microRNA miR-101, which targets Ezh2 messenger RNA (mRNA), leading to a nearly complete loss of Ezh2 protein expression. This long-term androgen-induced loss of Ezh2 actions ultimately results in sustained reduction of the H3K27me3-repressive mark in the promoter region of the Runt-related transcription factor-1 (Runx1) gene, a luteinizing hormone (LH)–induced transcription factor essential for ovulation, leading to increased Runx1 mRNA expression. Accordingly, blocking androgen-induced inhibition of Ezh2 in vivo adversely affects LH-induced Runx1 mRNA expression and subsequent ovulation. Importantly, although estrogen treatment of granulosa cells similarly causes rapid activation of the PI3K/Akt pathway and short-term phosphorylation of Ezh2, it does not induce miR-101 expression and thereby does not reduce overall Ezh2 expression, demonstrating the androgen specificity of long-term Ezh2 suppression. Thus, this study provides insight regarding how androgen-induced extranuclear kinase signaling and intranuclear transcription through Ezh2 modifications may influence the expression pattern of genes, ultimately affecting various downstream physiological processes.

Anti-Müllerian hormone (AMH) is a member of the transforming growth factor-β superfamily and plays a crucial role in testicular and ovarian functions. In clinical practice, AMH is used as a diagnostic and/or prognostic marker in women in association with ovulation induction and in various pathophysiological conditions. Despite widespread clinical use of AMH, our mechanistic understanding of AMH actions in regulating follicular development is limited. Using a mouse model, we in this study report that in vivo AMH treatment while stalls follicular development and inhibits ovulation, also prevents follicular atresia. We further show that these AMH actions are mediated through induction of two miRNAs, miR-181a and miR-181b, which regulate various aspects of FSH signaling and follicular growth, ultimately affecting downstream gene expression and folliculogenesis. We also report that in this mouse model AMH pre-treatment prior to superovulation improves oocyte yield. These studies, therefore, offer new mechanistic insight into AMH actions in folliculogenesis and point toward potential utilization of AMH as a therapeutic agent.

Obesity is considered detrimental to women's reproductive health. Although most of the attention has been focused on the effects of obesity on hypothalamic function, studies suggest a multifactorial impact. In fact, obesity is associated with reduced fecundity even in women with regular cycles, indicating that there may be local ovarian effects modulating fertility. Here we describe a novel mechanism for leptin actions directly in the ovary that may account for some of the negative effects of obesity on ovarian function. We find that normal cycling, obese, hyperleptinemic mice fed with a high-fat diet are subfertile and ovulate fewer oocytes compared with animals fed with a normal diet. Importantly, we show that leptin induces expression of the neuropeptide cocaine- and amphetamine-regulated transcript (CART) in the granulosa cells (GCs) of ovarian follicles both in vitro and in vivo. CART then negatively affects intracellular cAMP levels, MAPK signaling, and aromatase mRNA expression, which leads to lower estradiol synthesis in GCs and altered ovarian folliculogenesis. Finally, in human samples from patients undergoing in vitro fertilization, we show a significant positive correlation between patient body mass index, CART mRNA expression in GCs, and CART peptide levels in follicular fluid. These observations suggest that, under obese conditions, CART acts as a local mediator of leptin in the ovary to cause ovarian dysfunction and reduced fertility.

Glioma stem cells (GSCs), with neural stem cell (NSC) like properties are key factors behind therapeutic resistance in pediatric high-grade gliomas (HGG), the second most formidable childhood cancers. Targeting GSCs is a promising pathway for enhancing therapeutic effect and improving patient outcomes. Histone post-translational modifications (PTMs) regulate gene expression patterns dictate stem cell fate and regulate drug resistance. Tri-methylation on histone 3 lysine 4 (H3K4me3) has been associated with human NSCs and GSCs, with its reduction results in cell differentiation and increases chemotherapeutic efficacy in pediatric HGGs. Human SETD1A facilitates H3K4me3 on active gene promoters. Levels of SETD1A and H3K4me3 are high in NSCs and malignant gliomas, highlighting potentially novel treatment targets. BMP4 increases cell sensitivity to cytotoxic therapies. However, BMP4 effects on H3K4me3 in human NSCs and pediatric HGGs are unknown. In this study, cellular phenotype, levels of H3K4me3 and SETD1A following BMP4 treatment in human NSC and pediatric HGGs are investigated. The results indicate BMP4 promotes differentiation and decreases H3K4me3 and SETD1A levels, as well as H3K4me3 occupancy on stemness and drug resistant genes’ promoters decreased in NSC and pediatric HGGs, respectively. BMP4 also increases chemosensitivity in pediatric HGGs. The results demonstrate that BMP4 differentiates human NSCs and increases chemotherapy sensitivity through regulation of SETD1A by altering H3K4me3 levels at key stemness and drug resistance genes’ promoter. Subsequently, targeting SETD1A concomitantly with conventional chemotherapy may provide novel therapeutic strategies to improve prognosis for children with HGGs.

Chemotherapy is an adjuvant treatment for glioblastomas, however, chemotherapy remains palliative because of the development of multidrug resistance (MDR). Following prolonged chemotherapy, MDR protein 1 (MDR1) and CD133 increase in recurrent glioblastomas. CD133 positive (CD133+) glioma cancer stem-like cells (GCSCs) markedly promote drug resistance and exhibit increased DNA damage repair capability; thus they have a key role in determining tumor chemosensitivity. Although CD133, DNA-dependent protein kinase (DNA-PK), and MDR1 are elevated in CD133+ GCSCs, the relationship among these molecules has not been elucidated. In this study, MDR glioblastoma cell lines were created in response to prolonged doxorubicin chemotherapy. CD133, DNA-PK and MDR1 were markedly elevated in these cells. CD133 and DNA-PK may increase MDR1 via the phosphatidylinositol-3-kinase (PI3K)-Akt signal pathway. PI3K downstream targets Akt and nuclear factor (NF)-κB, which interacts with the MDR1 promoter, were also elevated in these cells. Downregulation of CD133 and DNA-PK by small interfering RNA, or inhibition of PI3K or Akt, decreased Akt, NF-κB and MDR1 expression. The results indicate that CD133 and DNA-PK regulate MDR1 through the PI3K- or Akt-NF-κB signal pathway. Consequently, a novel chemotherapeutic regimen targeting CD133 and DNA-PK in combination with traditional protocols may increase chemotherapeutic efficacy and improve prognosis for individuals who present with glioblastoma.

Environmental endocrine disruptors are implicated as putative contributors to the burgeoning metabolic disease epidemic. Tolylfluanid (TF) is a commonly detected fungicide in Europe, and previous in vitro and ex vivo work has identified it as a potent endocrine disruptor with the capacity to promote adipocyte differentiation and induce adipocytic insulin resistance, effects likely resulting from activation of glucocorticoid receptor signaling. The present study extends these findings to an in vivo mouse model of dietary TF exposure. After 12 weeks of consumption of a normal chow diet supplemented with 100 parts per million TF, mice exhibited increased body weight gain and an increase in total fat mass, with a specific augmentation in visceral adipose depots. This increased adipose accumulation is proposed to occur through a reduction in lipolytic and fatty acid oxidation gene expression. Dietary TF exposure induced glucose intolerance, insulin resistance, and metabolic inflexibility, while also disrupting diurnal rhythms of energy expenditure and food consumption. Adipose tissue endocrine function was also impaired with a reduction in serum adiponectin levels. Moreover, adipocytes from TF-exposed mice exhibited reduced insulin sensitivity, an effect likely mediated through a specific down-regulation of insulin receptor substrate-1 expression, mirroring effects of ex vivo TF exposure. Finally, gene set enrichment analysis revealed an increase in adipose glucocorticoid receptor signaling with TF treatment. Taken together, these findings identify TF as a novel in vivo endocrine disruptor and obesogen in mice, with dietary exposure leading to alterations in energy homeostasis that recapitulate many features of the metabolic syndrome.

Objective: Our aim was to assess the impact of creating a female-only area within a mixed-gender inpatient psychiatry service, on female patient safety and experience of care. Method: The Alfred hospital reconfigured one of its two psychiatry wards to include a female-only area. Documented incidents compromising the safety of women on each ward in the 6 months following the refurbishment were compared. Further, a questionnaire assessing perceived safety and experience of care was administered to female inpatients on both wards, and staff feedback was also obtained. Results: The occurrence of documented incidents compromising females’ safety was found to be significantly lower on the ward containing a female-only area. Women staying on this ward rated their perceived safety and experience of care significantly more positively than women staying where no such gender segregation was available. Further, the female-only area was identified by the majority of surveyed staff to provide a safer environment for female patients. Conclusions: Establishing female-only areas in psychiatry wards is an effective way to improve the safety and experience of care for female patients.

Although androgen excess is considered detrimental to women's health and fertility, global and ovarian granulosa cell-specific androgen-receptor (AR) knockout mouse models have been used to show that androgen actions through ARs are actually necessary for normal ovarian function and female fertility. Here we describe two AR-mediated pathways in granulosa cells that regulate ovarian follicular development and therefore female fertility. First, we show that androgens attenuate follicular atresia through nuclear and extranuclear signaling pathways by enhancing expression of the microRNA (miR) miR-125b, which in turn suppresses proapoptotic protein expression. Second, we demonstrate that, independent of transcription, androgens enhance follicle-stimulating hormone (FSH) receptor expression, which then augments FSH-mediated follicle growth and development. Interestingly, we find that the scaffold molecule paxillin regulates both processes, making it a critical regulator of AR actions in the ovary. Finally, we report that low doses of exogenous androgens enhance gonadotropin-induced ovulation in mice, further demonstrating the critical role that androgens play in follicular development and fertility. These data may explain reported positive effects of androgens on ovulation rates in women with diminished ovarian reserve. Furthermore, this study demonstrates mechanisms that might contribute to the unregulated follicle growth seen in diseases of excess androgens such as polycystic ovary syndrome.

There are many complex interrelationships between the endocrine system and the nervous system. Important connections between hormones and mental health have been observed. In this chapter, we briefly explore significant historical aspects of psychoneuroendocrinology and then describe the current classification and physiological systems of the key hormones of the hypothalamus, pituitary, and target organs. The hypothalamic-pituitary-gonadal axis is discussed in some detail, with a focus on the role that estrogen plays in neurotransmitter modulation, particularly in schizophrenia. Next, the role of prolactin, which is a potent dopamine antagonist, is reviewed. Many antipsychotic drugs exert their therapeutic actions by causing hyperprolactinemia; however, there are potential clinical adverse effects with prolonged hyperprolactinemia such as osteoporosis. A section on the hypothalamic-pituitary-adrenal (HPA) axis is included since it is closely regulated by central mechanisms involving the limbic system and hypothalamus, and therefore, it has an important role in people with schizophrenia. A key hormone of the HPA axis is cortisol, and hypercortisolemia may precipitate or exacerbate psychotic symptoms. The thyroid hormones have been studied for many decades, but in more recent times, the relationship of hyperthyroidism to the onset of schizophrenia has increased evidence. In this section, we examine the direct impact of the thyroid axis hormones on the key neurotransmitters implicated in the development of psychosis, namely dopamine, serotonin, and glutamate. We conclude that hormones play a huge role in the development, perpetuation, and prognosis of people with schizophrenia.

A 34-year-old female community nurse in her first trimester of pregnancy presented with a 2-week history of a tender, swollen and hyperkeratotic lesion on her chest with no history of trauma. The lesion started as a red ‘spot’, became crusted, pustular and formed an eschar. A generous incisional biopsy was taken. Review the high-quality, interactive digital Aperio slide at http://virtualacp.com/JCPCases/jclinpath-2017-204459 and consider your diagnosis. 1. Anthrax 2. Cowpox 3. Orf 4. Pseudocowpox (Milker’s nodule) 5. Varicella zoster The correct answer is after the discussion. Histopathology shows superficial ulceration, …

Summary Background About 47% of preschool children worldwide are anaemic. Daily oral iron supplementation is a commonly recommended intervention for treatment and prevention of anaemia, but the efficacy and safety of iron supplementation programmes is debated. Thus, we systematically reviewed the evidence for benefit and safety of daily iron supplementation in children aged 4–23 months. Methods We searched Scopus and Medline, from inception to Feb 5, 2013, WHO databases, theses repositories, grey literature, and references. Randomised controlled trials that assigned children 4–23 months of age to daily oral iron supplementation versus control were eligible. We calculated mean difference (MD) or standard MD (SMD) for continuous variables, risk ratios for dichotomous data, and rate ratios for rates. We quantified heterogeneity with the I 2 test and synthesised all data with a random-effects model. This review is registered with the International Prospective Register of Systematic Reviews, number CRD42011001208. Findings Of 9533 citations identified by the search strategy, 49 articles from 35 studies were eligible; these trials included 42 306 children. Only nine studies were judged to be at low risk of bias. In children receiving iron supplements, the risk ratio for anaemia was 0·61 (95% CI 0·50–0·74; 17 studies, n=4825), for iron deficiency was 0·30 (0·15–0·60; nine studies, n=2464), and for iron deficiency anaemia was 0·14 (0·10–0·22; six studies, n=2145). We identified no evidence of difference in mental (MD 1·65, 95% CI −0·63 to 3·94; six studies, n=1093) or psychomotor development (1·05, −1·36 to 3·46; six studies, n=1086). We noted no significant differences in final length or length-for-age, or final weight or weight-for-age. Children randomised to iron had slightly lesser length (SMD −0·83, −1·53 to −0·12; eight studies, n=868) and weight gain (–1·12, −1·19 to −0·33) over the course of the studies. Vomiting (risk ratio 1·38, 95% CI 1·10–1·73) and fever (1·16, 1·02–1·31) were more prevalent in children receiving iron. Interpretation In children aged 4–23 months, daily iron supplementation effectively reduces anaemia. However, the adverse effect profile of iron supplements and effects on development and growth are uncertain. Adequately powered trials are needed to establish the non-haematological benefits and risks from iron supplementation in this group. Funding Victoria Fellowship (Government of Victoria, Australia); CRB Blackburn Scholarship (Royal Australasian College of Physicans); Overseas Research Experience Scholarship, University of Melbourne.

The authors wish to retract this paper owing to the use of misidentified cell lines in the study. According to the description on the ATCC official website and reanalysis of the STR for cell line authentication, two misidentified glioblastoma cell lines, U251MG and U373MG, were used in this work.

Schizophrenia is a debilitating and pervasive mental illness with devastating effects on psychological, cognitive and social wellbeing, and for which current treatment options are far from ideal. Gender differences and the influence of the female reproductive life cycle on the onset, course and symptoms of schizophrenia and the discovery of estrogen's remarkable psychoprotective properties in animal models led to the proposal of the 'estrogen protection hypothesis' of schizophrenia. This has fueled the recent successful investigation of estradiol as a potential adjuvant therapeutic agent in the management of schizophrenia in women. This review explains the scientific rationale behind the estrogen hypothesis and how it can be clinically utilized to address concerns unique to the care of women with schizophrenia.

Schizophrenia is a debilitating and pervasive mental illness with devastating effects on many aspects of psychological, cognitive and social wellbeing. Epidemiological and life-cycle data point to significant differences in the incidence and course of schizophrenia between men and women, suggesting that estrogen plays a “protective” role . Adjunctive estrogen therapy has been shown to be effective in enhancing the treatment of schizophrenia in women. In men, consideration of estrogen therapy has been impacted by concerns of feminisation, however, clinical trials using estrogen to treat prostate cancer, bone density loss and even aggression in men with dementia or traumatic brain injury, show estrogen to be a safe and effective therapy. Findings do, however, suggest that further exploration of a therapeutic role for adjunctive estradiol treatment in men with schizophrenia is warranted. The development of the new estrogen compounds - Selective Estrogen Receptor Modulators (SERMs) which do not cause feminisation - opens up the possibility of using a different type of estrogen for a longer period of time at higher doses. Estrogen could therefore prove to be an important component in the treatment of psychotic symptoms in men with schizophrenia. This review explains the scientific rationale behind the estrogen hypothesis and how it can be clinically utilised to address concerns unique to the care of men with schizophrenia.

Increasing evidence from epidemiological, preclinical and clinical studies suggests that estrogens may exert psychoprotective effects in schizophrenia. Observations of gender differences in the onset and course of schizophrenia have prompted exploration of the effects of estrogen on the CNS. The aim of this paper is to provide an overview of different applications of adjunctive estrogen as a possible treatment for symptoms of schizophrenia in both men and women. Recent trials have suggested that estrogen augmentation therapy may be able to enhance the management of schizophrenia; however, the clinical application of estrogen as a treatment has been limited by potential side effects, the most worrying being breast and uterine cancer in women, and feminization in men. Selective estrogen receptor modulators (SERMs), however, may offer therapeutic benefits for both men and women with schizophrenia without posing threat to breast and uterine tissue and without feminizing effects. The use of estrogen opens up new possibilities for both men and women in the treatment of severe mental illnesses such as schizophrenia. With further preclinical and clinical research, it is hoped that this promising field of hormone modulation can continue to evolve and eventually be translated into real therapeutic potential.

The theory that many serious mental illnesses, in particular psychoses such as schizophrenia, may have a significant hormonal aetiological component is fast gaining popularity and the support of scientific evidence. Oestrogen in particular has been substantially investigated as a potential mediator of brain function in schizophrenia. Epidemiological and life-cycle data point to significant differences in the incidence and course of schizophrenia between men and women suggests a protective role of oestrogen.In vitroandin vivopreclinical research confirms oestradiol’s interactions with central neurotransmitter systems implicated in the pathogenesis of schizophrenia, while results from randomised controlled trials investigating the antipsychotic potential of oestrogen have been positive. Research into other neuroactive hormones with possible effects on mental state is a rapidly evolving field that may hold new promise. Given that schizophrenia and related psychoses are pervasive and debilitating conditions for which currently available treatments are often only partially effective and entail a high risk of serious side-effects, novel therapeutic strategies are needed. The literature reviewed in this paper suggests that hormones such as oestrogen could be a viable option, and it is hoped that with further research and larger trials, the oestrogen hypothesis can be translated into effective clinical practice.