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An individual's nutritional status has a powerful effect on sexual maturation. Puberty onset is delayed in response to chronic energy insufficiency and is advanced under energy abundance. The consequences of altered pubertal timing for human health are profound. Late puberty increases the chances of cardiometabolic, musculoskeletal and neurocognitive disorders, whereas early puberty is associated with increased risks of adult obesity, type 2 diabetes mellitus, cardiovascular diseases and various cancers, such as breast, endometrial and prostate cancer. Kennedy and Mitra's trailblazing studies, published in 1963 and using experimental models, were the first to demonstrate that nutrition is a key factor in puberty onset. Building on this work, the field has advanced substantially in the past decade, which is largely due to the impressive development of molecular tools for experimentation and population genetics. In this Review, we discuss the latest advances in basic and translational sciences underlying the nutritional and metabolic control of pubertal development, with a focus on perspectives and future directions. Key papers on the role of nutrition and metabolic cues in puberty timing were published in 1963, and there have been many advances in this field in the subsequent 60 years. This Review discusses the latest advances in basic and translational sciences underlying the nutritional and metabolic control of pubertal development. Key points: In 1963, Kennedy and Mitra published a seminal study in rats demonstrating that body weight is a major determinant of pubertal timing. An increasing incidence of earlier ages at puberty has been documented; early pubertal timing favours the occurrence of type 2 diabetes mellitus, cardiovascular diseases and certain cancers in adulthood. Macronutrients and hormones that modulate growth and/or signal adipose tissue mass serve as metabolic cues conveying the nutritional status and stored energy available for sexual maturation, differentiation and growth. The effect of metabolic cues on puberty is mediated by neural targets upstream of GnRH neurons; considerable progress in defining the neuronal circuitry and glial components has been achieved. A number of molecular pathways and epigenetic mechanisms have been identified as primary components in the modulation of pubertal timing by hormones and nutritional cues. [ABSTRACT FROM AUTHOR]

Reproductive function is critical for species survival; however, it is energetically costly and physically demanding. Reproductive suppression is therefore a physiologically appropriate adaptation to certain ecological, environmental, and/or temporal conditions. This 'allostatic' suppression of fertility enables individuals to accommodate unfavorable reproductive circumstances and safeguard survival. The mechanisms underpinning this reproductive suppression are complex, yet culminate with the reduced secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which in turn suppresses gonadotropin release from the pituitary, thereby impairing gonadal function. The focus of this review will be on the role of RFamide-related peptide (RFRP) neurons in different examples of allostatic reproductive suppression. RFRP neurons release the RFRP-3 peptide, which negatively regulates GnRH neurons and thus appears to act as a 'brake' on the neuroendocrine reproductive axis. In a multitude of predictable (e.g., pre-puberty, reproductive senescence, and seasonal or lactational reproductive quiescence) and unpredictable (e.g., metabolic, immune and/or psychosocial stress) situations in which GnRH secretion is suppressed, the RFRP neurons have been suggested to act as modulators. This review examines evidence for and against these roles. [ABSTRACT FROM AUTHOR]

The article presents the results of the survey of the law of professional responsibility in Indiana from August 2021 to September 2022. Also cited are the per curiam rulings by the state's Supreme Court imposing sanctions for lawyer misconduct, the need for civility in both trials and disciplinary proceedings, and the application of the Rules of Professional Conduct to common ethical dilemmas.

In Fall 2020, all universities in Alberta went with remote delivery of classes due to COVID-19 restrictions. This provided not only teaching challenges, but also opportunities. Professors at three Canadian universities teaching similar undergraduate courses in international political economy decided to use the challenges/opportunities of COVID-19 restrictions to experiment with a World Trade Organization (WTO) simulation across three campuses through remote delivery. Simulations are frequently used for teaching in political science, but what was unusual was doing it through remote delivery. This paper assesses the effectiveness of the experiment. It traces the origins/evolution of the idea, learning objectives for the students, preparation by the professors to design the WTO simulation, and the experience of the actual simulation. It also addresses the challenges (technological, timing, assignments, grading, student anxiety, etc.). In addition, it identifies the steps that were taken to reduce and mitigate the challenges. It also acknowledges the mistakes that were made by the professors in designing and implementing the assignment. These observations and reflections are informed by the materials that the professors prepared, their thoughts on the experience, and the feedback from participating students (through official student evaluations as well as a special survey instrument). It provides lessons for future online simulations. [ABSTRACT FROM AUTHOR]

Orthopedic sports surgery of the knee and shoulder is generally considered to be safe and effective. Vascular complications can occur during or after arthroscopy of either joint. A thorough understanding of anatomy, particularly when placing portals in non-routine locations, is extremely important. Prompt recognition of any vascular complication is of significant importance. This review will discuss the potential vascular complications for both knee and shoulder sports surgery, review the relevant anatomy, and discuss the treatment and expected outcome of each. [ABSTRACT FROM AUTHOR]

Being truthful with patients is a critical foundation of the doctorpatient relationship and is fundamental to development of trust. A professional commitment to truth telling may sometimes contradict other principles of bioethics, which may challenge decision-making for the doctor and/or the treatment team. Practitioners may fail to address all ethical or legal aspects of a case and therefore make inappropriate decisions. [ABSTRACT FROM AUTHOR]

Asthma and chronic obstructive pulmonary disease (COPD) are amongst the most common chronic diseases worldwide, and are largely preventable by improving the quality of the air we breathe. The most commonly deployed treatment, the metered dose inhaler (MDI), uses hydrofluorocarbon propellants, which are powerful greenhouse gases that contribute disproportionately to the climate crisis. Alternative treatment strategies are required if we are to avoid contributing to the worst effects of climate change. These strategies include promoting non-pharmacological therapies like smoking cessation and pulmonary rehabilitation; empowering patients to gain better disease control through written management plans and encouraging preventer, rather than reliever therapies. Pharmacological strategies include: improving inhaler technique and spacer use; minimising propellant release by using smaller volume MDIs and simpler dosing regimes; dose counters to prevent waste; switching to low global warming potential inhalers; and inhaler recycling. There are also opportunities to improve disease control alongside reduced greenhouse gas emissions, including better matching of patients' devices to inhaler technique rather than defaulting to MDIs, stopping unnecessary inhaled steroids in COPD and maintenance and reliever therapy in asthma. New, lower global warming potential propellants are on the horizon, and their introduction could offer a golden opportunity to enhance MDIs usability and sustainability by making them refillable, integrating whistles to optimise inhalation technique, adding integrated caps, optimising materials for recycling and adding dose counters to all MDIs. [ABSTRACT FROM AUTHOR]

Donald Trump's tenure as President of the United States has been among the most disruptive in American history. In many areas, President Trump has upended convention, undermined norms, and cast aspersions on a host of institutions. Trump's imposition of punitive tariffs on steel and aluminum, along with the threat to withdraw from the NAFTA have been significant threats to the Canadian economy. The President's instincts on trade may be one of the few constants in a worldview on foreign policy that has otherwise lacked consistency. This article argues that Trump's actions on trade have other precedents in American history, many of which have similarly embroiled Canada. [ABSTRACT FROM AUTHOR]

A professional commitment to patient confidentiality may sometimes contradict other principles of bioethics. Decisionmaking for doctors and their team can be challenging amidst such conflicting principles, and despite the practitioner's best intentions, withholding information can result in potential consequences such as harm to others. [ABSTRACT FROM AUTHOR]

Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in women. Approximately half of the diagnosed individuals also experience the metabolic syndrome. Central and peripheral resistance to the hormones insulin and leptin have been reported to contribute to both metabolic and reproductive dysregulation. In PCOS and preclinical PCOS animal models, circulating insulin and leptin levels are often increased in parallel with the development of hormone resistance; however, it remains uncertain whether these changes contribute to the PCOS state. In this study, we tested whether central actions of protein tyrosine phosphatase 1B (PTP1B) and suppressor of cytokine signaling 3 (SOCS3), negative regulators of insulin and leptin signaling pathways, respectively, play a role in the development of PCOS-like phenotype. A peripubertal dihydrotestosterone (DHT) excess PCOS-like mouse model was used, which exhibits both metabolic and reproductive dysfunction. Mice with knockout of the genes encoding PTP1B and SOCS3 from forebrain neurons were generated, and metabolic and reproductive functions were compared between knockout and control groups. DHT treatment induced mild insulin resistance but not leptin resistance, so the role of SOCS3 could not be tested. As expected, DHT excess abolished estrous cycles and corpora lutea presence and caused increased visceral adiposity and fasting glucose levels. Knockout mice did not show any rescue of reproductive dysfunction but did have reduced adiposity compared to the control DHT mice. These data suggest that negative regulation of central insulin signaling by PTP1B is not responsible for peripubertal DHT excess-induced reproductive impairments but may mediate its increased adiposity effects. [ABSTRACT FROM AUTHOR]

Reproductive function in mammals is energetically costly and therefore tightly regulated by nutritional status. To enable this integration of metabolic and reproductive function, information regarding peripheral nutritional status must be relayed centrally to the gonadotropin-releasing hormone (GNRH) neurons that drive reproductive function. The metabolically relevant hormones leptin, insulin and ghrelin have been identified as key mediators of this 'metabolic control of fertility'. However, the neural circuitry through which they act to exert their control over GNRH drive remains incompletely understood. With the advent of Cre-LoxP technology, it has become possible to perform targeted gene-deletion and gene-rescue experiments and thus test the functional requirement and sufficiency, respectively, of discrete hormone-neuron signaling pathways in the metabolic control of reproductive function. This review discusses the findings from these investigations, and attempts to put them in context with what is known from clinical situations and wild-type animal models. What emerges from this discussion is clear evidence that the integration of nutritional signals on reproduction is complex and highly redundant, and therefore, surprisingly difficult to perturb. Consequently, the deletion of individual hormone-neuron signaling pathways often fails to cause reproductive phenotypes, despite strong evidence that the targeted pathway plays a role under normal physiological conditions. Although transgenic studies rarely reveal a critical role for discrete signaling pathways, they nevertheless prove to be a good strategy for identifying whether a targeted pathway is absolutely required, critically involved, sufficient or dispensable in the metabolic control of fertility. [ABSTRACT FROM AUTHOR]

Introduction: Conditionally immortalised human neural progenitor cells (hNPCs) represent a robust source of native neural cells to investigate physiological mechanisms in both health and disease. However, in order to recognise the utility of such cells, it is critical to determine whether they retain characteristics of their tissue of origin and generate appropriate neural cell types upon differentiation. To this end, we have characterised the conditionally immortalised, cortically-derived, human NPC line, CTX0E16, investigating the molecular and cellular phenotype of differentiated neurons to determine whether they possess characteristics of cortical glutamatergic neurons. Methods: Differentiated CTX0E16 cells were characterised by assessing expression of several neural fates markers, and examination of developing neuronal morphology. Expression of neurotransmitter receptors, signalling proteins and related proteins were assessed by q- and RT-PCR and complemented by Ca2+ imaging, electrophysiology and assessment of ERK signalling in response to neurotransmitter ligand application. Finally, differentiated neurons were assessed for their ability to form putative synapses and to respond to activity-dependent stimulation. Results: Differentiation of CTX0E16 hNPCs predominately resulted in the generation of neurons expressing markers of cortical and glutamatergic (excitatory) fate, and with a typical polarized neuronal morphology. Gene expression analysis confirmed an upregulation in the expression of cortical, glutamatergic and signalling proteins following differentiation. CTX0E16 neurons demonstrated Ca2+ and ERK1/2 responses following exogenous neurotransmitter application, and after 6 weeks displayed spontaneous Ca2+ transients and electrophysiological properties consistent with that of immature neurons. Differentiated CTX0E16 neurons also expressed a range of pre- and post-synaptic proteins that co-localized along distal dendrites, and moreover, displayed structural plasticity in response to modulation of neuronal activity. Conclusions: Taken together, these findings demonstrate that the CTX0E16 hNPC line is a robust source of cortical neurons, which display functional properties consistent with a glutamatergic phenotype. Thus CTX0E16 neurons can be used to study cortical cell function, and furthermore, as these neurons express a range of disease-associated genes, they represent an ideal platform with which to investigate neurodevelopmental mechanisms in native human cells in health and disease. [ABSTRACT FROM AUTHOR]

Our main result is a local limit law tor the empirical spectral distribution of the anticommutator of independent Wigner matrices, modeled on the local semicircle law. Our approach is to adapt some techniques from recent papers of Erdös-Yau-Yin. We also use an algebraic description of the law of the anlicommutator of free semicircular variables due to Nica-Speicher, the lineatization trick due to Haagerup-Schultz-Thorbjørnsen in a self-adjointness-preserving variant and the Schwinger-Dyson equation. A by-product ot our work is a relatively simple deterministic version of the local semicircle law. [ABSTRACT FROM AUTHOR]

Introduction: Conditionally immortalised human neural progenitor cells (hNPCs) represent a robust source of native neural cells to investigate physiological mechanisms in both health and disease. However, in order to recognise the utility of such cells, it is critical to determine whether they retain characteristics of their tissue of origin and generate appropriate neural cell types upon differentiation. To this end, we have characterised the conditionally immortalised, cortically-derived, human NPC line, CTX0E16, investigating the molecular and cellular phenotype of differentiated neurons to determine whether they possess characteristics of cortical glutamatergic neurons. Methods: Differentiated CTX0E16 cells were characterised by assessing expression of several neural fates markers, and examination of developing neuronal morphology. Expression of neurotransmitter receptors, signalling proteins and related proteins were assessed by q- and RT-PCR and complemented by Ca2+ imaging, electrophysiology and assessment of ERK signalling in response to neurotransmitter ligand application. Finally, differentiated neurons were assessed for their ability to form putative synapses and to respond to activity-dependent stimulation. Results: Differentiation of CTX0E16 hNPCs predominately resulted in the generation of neurons expressing markers of cortical and glutamatergic (excitatory) fate, and with a typical polarized neuronal morphology. Gene expression analysis confirmed an upregulation in the expression of cortical, glutamatergic and signalling proteins following differentiation. CTX0E16 neurons demonstrated Ca2+ and ERK1/2 responses following exogenous neurotransmitter application, and after 6 weeks displayed spontaneous Ca2+ transients and electrophysiological properties consistent with that of immature neurons. Differentiated CTX0E16 neurons also expressed a range of pre- and post-synaptic proteins that co-localized along distal dendrites, and moreover, displayed structural plasticity in response to modulation of neuronal activity. Conclusions: Taken together, these findings demonstrate that the CTX0E16 hNPC line is a robust source of cortical neurons, which display functional properties consistent with a glutamatergic phenotype. Thus CTX0E16 neurons can be used to study cortical cell function, and furthermore, as these neurons express a range of disease-associated genes, they represent an ideal platform with which to investigate neurodevelopmental mechanisms in native human cells in health and disease. [ABSTRACT FROM AUTHOR]

The article discusses problems with using European or Western notions of culture and civilization when they are applied to the historical actions and histories of non-Western or premodern groups of people. Topics include criticisms of historicism and postcolonialism, the ontology used in the field of history, and anthropocentrism.

Excess levels of circulating androgens during prenatal or peripubertal development are an important cause of polycystic ovary syndrome (PCOS), with the brain being a key target. Approximately half of the women diagnosed with PCOS also experience metabolic syndrome; common features including obesity, insulin resistance and hyperinsulinemia. Although a large amount of clinical and preclinical evidence has confirmed this relationship between androgens and the reproductive and metabolic features of PCOS, the mechanisms by which androgens cause this dysregulation are unknown. Neuron‐specific androgen receptor knockout alleviates some PCOS‐like features in a peripubertal dihydrotestosterone (DHT) mouse model, but the specific neuronal populations mediating these effects are undefined. A candidate population is the agouti‐related peptide (AgRP)‐expressing neurons, which are important for both reproductive and metabolic function. We used a well‐characterised peripubertal androgenized mouse model and Cre‐loxP transgenics to investigate whether deleting androgen receptors specifically from AgRP neurons can alleviate the induced reproductive and metabolic dysregulation. Androgen receptors were co‐expressed in 66% of AgRP neurons in control mice, but only in <2% of AgRP neurons in knockout mice. The number of AgRP neurons was not altered by the treatments. Only 20% of androgen receptor knockout mice showed rescue of DHT‐induced androgen‐induced anovulation and acyclicity. Furthermore, androgen receptor knockout did not rescue metabolic dysfunction (body weight, adiposity or glucose and insulin tolerance). While we cannot rule out developmental compensation in our model, these results suggest peripubertal androgen excess does not markedly influence Agrp expression and does not dysregulate reproductive and metabolic function through direct actions of androgens onto AgRP neurons. [ABSTRACT FROM AUTHOR]

Infertility associated with insulin resistance is characterised by abnormal hormone secretion by the hypothalamus, pituitary gland and gonads. These endocrine tissues can maintain insulin sensitivity even when tissues such as the muscle and liver become insulin‐resistant, resulting in excessive insulin stimulation as hyperinsulinaemia develops. Experiments conducted to determine the role of neuronal insulin signalling in fertility were unable to recapitulate early findings of hypogonadotrophic hypogonadism in mice lacking insulin receptors throughout the brain. Rather, it was eventually shown that astrocytes critically mediate the effects of insulin on puberty timing and adult reproductive function. However, specific roles for neurones and gonadotrophs have been revealed under conditions of hyperinsulinaemia and by ablation of insulin and leptin receptors. The collective picture is one of multiple insulin‐responsive inputs to gonadotrophin releasing hormone neurones, with astrocytes being the most important player. [ABSTRACT FROM AUTHOR]

Lawrie and Margaret had five children, and he is survived by Elizabeth - herself a distinguished hepatologist, Mark, Martine and Christa. GLO:EUW/01nov22:jgh16031-gra-0001.jpg PHOTO (COLOR): . gl More than "Mr. Iron", Lawrie Powell was a Foundation Stone of Asia-Pacific Gastroenterology and Liver disease. Remembering Lawrie Powell 1934-2022. [Extracted from the article]

The neuronal ceroid lipofuscinoses (NCLs or Batten disease) are a group of inherited, fatal neurodegenerative disorders of childhood. In these disorders, glial (microglial and astrocyte) activation typically occurs early in disease progression and predicts where neuron loss subsequently occurs. We have found that in themost common juvenile form of NCL (CLN3 disease or JNCL) this glial response is less pronounced in both mouse models and human autopsy material, with the morphological transformation of both astrocytes and microglia severely attenuated or delayed. To investigate their properties, we isolated glia and neurons from Cln3-deficient mice and studied their basic biology in culture. Upon stimulation, both Cln3-deficient astrocytes and microglia also showed an attenuated ability to transform morphologically, and an altered protein secretion profile. These defects were more pronounced in astrocytes, including the reduced secretion of a range of neuroprotective factors, mitogens, chemokines and cytokines, in addition to impaired calcium signalling and glutamate clearance. Cln3-deficient neurons also displayed an abnormal organization of their neurites. Most importantly, using a co-culture system, Cln3-deficient astrocytes and microglia had a negative impact on the survival and morphology of both Cln3-deficient and wildtype neurons, but these effects were largely reversed by growing mutant neurons with healthy glia. These data provide evidence that CLN3 disease astrocytes are functionally compromised. Together with microglia, they may play an active role in neuron loss in this disorder and can be considered as potential targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

The Navy has a need for monitoring conditions and gathering information in marine environments. Sensors can monitor and report environmental parameters and potential activities such as animal movements, ships, or personnel. However, there has to be a means to power these sensors. One promising enabling technology that has been shown to provide long-term power production in underwater environments is the benthic microbial fuel cells (BMFC). BMFCs are devices that generate energy by coupling bioanodes and biocathodes through an external energy harvester. Recent studies have demonstrated success for usage of BMFCs in powering small instruments and other devices on the seafloor over limited periods of time. In this effort, a seven-stranded BMFC linear array of 30 m was designed to power a seafloor magnetometer to detect passing ship movements through Pearl Harbor, Hawaii. The BMFC system was connected to a flyback energy harvesting circuit that charged the battery powering the magnetometer. The deployment was demonstrated the BMFC supplied power to the battery for approximately 38 days. This is the first large-scale demonstration system for usage of the SeptiStrand BMFC technology to power a relevant sensor. [ABSTRACT FROM AUTHOR]

Reproductive function is tightly regulated by both environmental and physiological factors. The adipose-derived hormone leptin has been identified as one such critical factor that relays information about peripheral energy availability to the centrally-governed HPG axis to ensure there is sufficient energy availability to support the high energy demands of mammalian reproduction. In the absence of adequate central leptin signaling, reproductive function is suppressed. While leptin levels are predominantly regulated by adiposity, circulating leptin levels are also under the modulatory influence of other factors, such as stress system activation, circadian rhythmicity, and immune activation and the inflammatory response. Furthermore, changes in leptin sensitivity can affect the degree to which leptin exerts its influence on the neuroendocrine reproductive axis. This review will discuss the different mechanisms by which leptin serves to integrate and relay information about metabolic, psychological, environmental and immune conditions to the central neuronal network that governs reproductive function. [ABSTRACT FROM AUTHOR]

Agouti‐related peptide (AgRP) neurons are thought to indirectly regulate the activity of hypothalamic gonadotrophin‐releasing hormone neurons which control fertility. AgRP neurons also drive caloric intake and are modulated by metabolically‐relevant hormones, providing a link to the hypothalamic–pituitary‐gonadal axis. In mice expressing Cre‐dependant designer receptors (DREADDs) in AgRP neurons, we activated or silenced these neurons in vivo using the synthetic ligand clozapine‐N‐oxide (CNO) to observe the effect of AgRP neuron activity on timing of puberty. To validate these animals, we chronically treated both stimulatory (hM3Dq) and inhibitory (hM4Di) DREADD × AgRP‐Cre mice with CNO, observing a pronounced increase and decrease of food intake, respectively, consistent with the known orexigenic effects of these neurons. RNAscope was performed to visually confirm the activation of AgRP neurons. Puberty onset was assessed in males and females. There was no effect on preputial separation in males or vaginal opening and first oestrus in females after CNO treatment from day 26 to 30 to chronically modulate AgRP neurons. Next, to determine whether the delay in puberty onset occurring in response to neonatal underfeeding could be overcome by inhibiting AgRP neuronal activity, mice were raised in large (neonatally underfed) or normal litter sizes. The delay in puberty from underfeeding was completely reversed in CNO‐treated AgRP‐hM4Di male mice. These data highlight the inhibitory role of AgRP neurons to delay puberty onset when undernutrition occurs during the neonatal period, at least in male mice. Trail registration number: JNE‐22‐0081‐OA.R2 [ABSTRACT FROM AUTHOR]

Female anti-Müllerian hormone (AMH) overexpressing (Thy1.2-AMHTg/0) mice experience fetal resorption (miscarriage) by mid-gestation. This study examined whether the ovary, uterine implantation sites and hypothalamus are potential sites of AMH action, as AMH type-2 receptor (AMHR2) expression is reported in each tissue. Pregnancy in Thy1.2-AMHTg/0 mice was compared to wild-type (WT) mice via histological examination of implantation sites, hormone assays, embryo culture and embryo transfer. Uterine AMH and AMHR2 expression was examined by RT-qPCR and immunohistochemistry. The first signs of fetal resorption in the Thy1.2-AMHTg/0 dams occurred at embryonic day 9.5 (E9.5) with 100% of fetuses resorbing by E13.5. Cultured embryos from Thy1.2-AMHTg/0 dams had largely normal developmental rates but a small proportion experienced a minor developmental delay relative to embryos from WT dams. However, embryos transferred from WT donor females always failed to survive to term when transferred into Thy1.2-AMHTg/0 dams. Amh and Amhr2 mRNA was detected in the gravid uterus but at very low levels relative to expression in the ovaries. Progesterone and estradiol levels were not significantly different between WT and Thy1.2-AMHTg/0 dams during pregnancy but luteinizing hormone (LH) levels were significantly elevated in Thy1.2-AMHTg/0 dams at E9.5 and E13.5 relative to WT dams. Collectively, these experiments suggest that AMH overexpression does not cause fetal resorption through an effect on oocytes or preimplantation embryo development. The Thy1.2-AMHTg/0 fetal resorption phenotype is nearly identical to that of transgenic LH overexpression models, suggesting that neuroendocrine mechanisms may be involved in the cause of the miscarriage. [ABSTRACT FROM AUTHOR]

Coupling of haloarenes to arenes has been facilitated by a diverse range of organic additives in the presence of KOtBu or NaOtBu since the first report in 2008. Very recently, we showed that the reactivity of some of these additives (e.g., compounds 6 and 7) could be explained by the formation of organic electron donors in situ, but the role of other additives was not addressed. The simplest of these, alcohols, including 1,2-diols, 1,2-diamines, and amino acids are the most intriguing, and we now report experiments that support their roles as precursors of organic electron donors, underlining the importance of this mode of initiation in these coupling reactions. [ABSTRACT FROM AUTHOR]

Purpose – The purpose of this paper is to report progress concerning the design of a computer-assisted simulation training (CAST) platform for developing decision-making skills in police students. The overarching aim is to outline a theoretical framework for the design of CAST to facilitate police students’ development of search techniques in complex interactions within the built environment, learning to apply and perform the five “quick peek” techniques for information gathering, and subsequent risk evaluation. Design/methodology/approach – The paper draws on Luckin's ecology of resources model of learner context informed with perspectives on reflective thinking from John Dewey and Donald Schön. The paper discusses design issues within the ecology of resources model applied on CAST for complex police situations. Findings – It is suggested that Luckin's framework with its focus on the interaction between different elements and filters in the learner's context together with Schön's perspective on reflection challenge educational designers to look beyond the immediate development of specific tools (such as the CAST in this project) and examine how these tools will be effectively embedded in the overall learning experience. Originality/value – This paper has presented two theoretical perspectives, Luckin's ecology of resources model and Schön's perspective on reflective practice as foundations for the educational design of CAST. Applying Luckin's framework as informed by Schön helps focus attention on issues that are important in the design process in order to facilitate educational transfer. [ABSTRACT FROM AUTHOR]

The adipocyte-derived 'satiety promoting' hormone, leptin, has been identified as a key central regulator of body weight and fertility, such that its absence leads to obesity and infertility. Plasma leptin levels reflect body adiposity, and therefore act as an 'adipostat', whereby low leptin levels reflect a state of low body adiposity (under-nutrition/starvation) and elevated leptin levels reflect a state of high body adiposity (over-nutrition/obesity). While genetic leptin deficiency is rare, obesity-related leptin resistance is becoming increasingly common. In the absence of adequate leptin sensitivity, leptin is unable to exert its 'anti-obesity' effects, thereby exacerbating obesity. Furthermore, extreme leptin resistance and consequent low or absent leptin signalling resembles a state of starvation and can thus lead to infertility. However, leptin resistance occurs on a spectrum, and it is possible to be resistant to leptin's metabolic effects while retaining leptin's permissive effects on fertility. This may be because leptin exerts its modulatory effects on energy homeostasis and reproductive function through discrete intracellular signalling pathways, and these pathways are differentially affected by the molecules that promote leptin resistance. This review discusses the potential mechanisms that enable leptin to exert differential control over metabolic and reproductive function in the contexts of healthy leptin signalling and of diet-induced leptin resistance. [ABSTRACT FROM AUTHOR]

Background: Organizations of all types require the use of teams. Poor team member engagement costs billions of US dollars annually. Objective: This study aimed to explain how team building can be accomplished with team video gaming based on a team cohesion model enhanced by team flow theory. Methods: In this controlled experiment, teams were randomly assigned to a team video gaming treatment or a control treatment. Team productivity was measured during both pretreatment and posttreatment team tasks. After the pretest, teams who were involved in the team video gaming treatment competed against other teams by playing the Halo or Rock Band video game for 45 minutes. After the pretest, teams in the control treatment worked alone for 45 minutes. Then, all teams completed the posttest team activity. This same experimental protocol was conducted on 2 different team tasks. Results: For both tasks, teams in the team video gaming treatment increased their productivity significantly more (F1=8.760, P=.004) on the posttest task than teams in the control treatment. Our flow-based theoretical model explained team performance improvement more than twice as well (R²=40.6%) than prior related research (R²=18.5%). Conclusions: The focused immersion caused by team video gaming increased team performance while the enjoyment component of flow decreased team performance on the posttest. Both flow and team cohesion contributed to team performance, with flow contributing more than cohesion. Team video gaming did not increase team cohesion, so team video gaming effects are independent of cohesion. Team video gaming is a valid practical method for developing and improving newly formed teams. [ABSTRACT FROM AUTHOR]

Chronic stress exerts multiple negative effects on the physiology and health of an individual. In the present study, we examined hypothalamic, pituitary and endocrine responses to 14 days of chronic variable stress (CVS) in male and female C57BL/6J mice. In both sexes, CVS induced a significant decrease in body weight and enhanced the acute corticosterone stress response, which was accompanied by a reduction in thymus weight only in females. However, single‐point blood measurements of basal prolactin, thyroid‐stimulating hormone, luteinising hormone, growth hormone and corticosterone levels taken at the end of the CVS were not different from those of controls. Similarly, pituitary mRNA expression of Fshb, Lhb, Prl and Gh was unchanged by CVS, although Pomc and Tsh were significantly elevated. Within the adrenal medulla, mRNA for Th, Vip and Gal were elevated following CVS. Avp transcript levels within the paraventricular nucleus of the hypothalamus were increased by CVS; however, levels of Gnrh1, Crh, Oxt,Sst, Trh, Ghrh, Th and Kiss1 remained unchanged. Oestrous cycles were lengthened slightly by CVS and ovarian histology revealed a reduction in the number of preovulatory follicles and corpora lutea. Taken together, these observations indicate that 14 days of CVS induces an up‐regulation of the neuroendocrine stress axis and creates a mild disruption of female reproductive function. However, the lack of changes in other neuroendocrine axes controlling anterior and posterior pituitary secretion suggest that most neuroendocrine axes are relatively resilient to CVS. [ABSTRACT FROM AUTHOR]

The human neural progenitor cell line CTX0E16 is a robust source of forebrain-like glutamatergic cortical neurons that display intrinsic functional properties (Anderson et al., 2015, Stem Cell Res). This cell line was obtained from the embryonic cortex of a 12-week gestation XY fetus, and conditionally immortalised by ectopic expression of the c-MycER TAM transgene. This construct allows the stem cells to be maintained in a proliferative state under the presence of hydroxytamoxifen (4-OHT), while removal of 4-OHT and growth factors stimulates progenitor differentiation. The cortex is generally smaller in schizophrenia patients, and understanding the global gene expression changes occurring during cortical development, and its relationship to genetic risk for schizophrenia, might reveal clues as to which genetic mechanisms are responsible for mediating the differences observed in patients. Our hypothesis is that neurodevelopmental diseases such as schizophrenia might share a genetic component with processes driving early cortical maturation, which can be modelled in vitro. The CTX0E16 cell line was provided by ReNeuron and total RNA was extracted from proliferating neural progenitor cells (NPCs, n=3) and from cells that underwent a 28-day differentiation protocol (n=3). RNA samples were then processed on Illumina HT12 v4 chips. Raw fluorescence probe intensity values were extracted using GenomeStudio, and were subsequently background-corrected and log-transformed in R using the lumi package. Differentially expressed probes were determined using t-tests and the false-discovery rate of multiple testing correction was applied (q<0.05). Genes surviving correction were submitted to Gene Ontology (GO) analysis. Gene-set enrichment analysis (MAGMA) was also used to investigate if the list of differentially expressed genes showed positive associative enrichment for genes associated with schizophrenia in genome-wide association studies (GWAS). We expect to identify and annotate sets of genes involved in cortical maturation that are additionally involved in the aetiology of schizophrenia. The discussion will focus on the role of cortical maturation as a process that may be involved in schizophrenia aetiology. [ABSTRACT FROM AUTHOR]

RF-amide related peptide 3 (RFRP-3) is a neuropeptide thought to inhibit central regulation of fertility. We investigated whether alterations in RFRP neuronal activity led to changes in puberty onset, fertility, and stress responses, including stress and glucocorticoid-induced suppression of pulsatile luteinizing hormone secretion. We first validated a novel RFRP-Cre mouse line, which we then used in combination with Cre-dependent neuronal ablation and DREADD technology to selectively ablate, stimulate, and inhibit RFRP neurons to interrogate their physiological roles in the regulation of fertility and stress responses. Chronic RFRP neuronal activation delayed male puberty onset and female reproductive cycle progression, but RFRP-activated and ablated mice exhibited apparently normal fertility. When subjected to either restraint- or glucocorticoid-induced stress paradigms. However, we observed a critical sex-specific role for RFRP neurons in mediating acute and chronic stress-induced reproductive suppression. Female mice exhibiting RFRP neuron ablation or silencing did not exhibit the stress-induced suppression in pulsatile luteinizing hormone secretion observed in control mice. Furthermore, RFRP neuronal activation markedly stimulated glucocorticoid secretion, demonstrating a feedback loop whereby stressful stimuli activate RFRP neurons, which in turn further activate the stress axis. These data provide evidence for a neuronal link between the stress and reproductive axes. [ABSTRACT FROM AUTHOR]

Female reproductive success relies on proper integration of circadian- and ovarian- signals to the hypothalamic-pituitary-gonadal axis in order to synchronize the preovulatory LH surge at the end of the ovarian follicular stage with the onset of the main active period. In this study, we used a combination of neuroanatomical and electrophysiological approaches to assess whether the hypothalamic neurons expressing Arg-Phe amide- related peptide (RFRP-3), a gonadotropin inhibitory peptide, exhibit daily and estrous stage dependent variations in female mice. Furthermore, we investigated whether arginine vasopressin (AVP), a circadian peptide produced by the suprachiamatic nucleus regulates RFRP-3 neurons. The number of c-Fos-positive RFRP-3 immunoreactive neurons is significantly reduced at the day-to-night transition with no difference between diestrus and proestrus. Contrastingly, RFRP neuron firing rate is higher in proestrus as compared to diestrus, independently of the time of the day. AVP immunoreactive fibers contact RFRP neurons with the highest density observed during the late afternoon of diestrus and proestrus. Application of AVP increases RFRP neurons firing in the afternoon (ZT6-10) of diestrus, but not at the same time point of proestrus, indicating that AVP signaling on RFRP neurons may depend on circulating ovarian steroids. Together, these studies show that RFRP neurons integrate both daily and estrogenic signals, which downstream may help to properly time the preovulatory LH surge. [ABSTRACT FROM AUTHOR]

Reconstituted keratin is a novel bone graft material when prepared as a rigid scaffold. Understanding the immunogenicity of this material is important to determine whether this substance is a viable surgical option. Previous studies have shown no innate immune system activation in response to reconstituted keratin implants. To examine antibody-mediated immune responses to reconstituted keratin implants, bone and blood samples were taken from twelve sheep with surgically created tibial defects containing such implants. RT-PCR was used to detect mRNA of the inflammatory marker SOCS 3 in local bony tissue, and a novel immunohistochemistry assay developed to detect antikeratin antibodies in serum. Two animals were sacrificed per time-point at weeks 1, 2, 4, 6, 8 and 12. Time points for serum analysis included baseline (pre-surgery) and all other time points; mRNA analysis examined samples from all time points. No upregulation in antikeratin antibodies or SOCS 3 mRNA was observed at any time point, indicating that reconstituted keratin implants do not trigger an adaptive immune response in vivo in an ovine model. These findings provide the platform for further development of keratin implants in other mammalian models to define its immunogenic profile and safety. [ABSTRACT FROM AUTHOR]

Objective: There is an increased incidence of some mental health disorders such as post-traumatic stress disorder (PTSD) in some members of the military and in some public safety personnel (PSP) such as firefighters, police officers, paramedics, and dispatchers. Upon retirement from the armed forces, many individuals go on to second careers as PSP. Individuals with prior military experience may be at even greater risk than nonveterans for developing mental health disorders. The present study was designed to examine the relationship between prior military service and symptoms of mental health disorders in PSP.Methods: This is a cross-sectional, observational study. Data for this study were collected from an anonymous, web-based, self-report survey of PSP in Canada. Invitations to participate were sent to PSP via their professional organizations. Indications of mental disorder(s) and symptom severity were assessed using well-validated self-report screening measures.Results: Of the survey respondents who provided this information, 631 (6.8%) had prior armed forces experience; however, not all responses were complete. Ex-military PSP reported significantly more exposure to traumatic events and were approximately 1.5 times more likely to screen positive for indications of PTSD, mood, anxiety, or acute stress disorders and to have contemplated suicide than those without prior armed forces experience.Conclusions: In our study, individuals in PSP with prior service experience in the armed forces were more likely to screen positive for indicators of some mental health disorders. Accordingly, mental health practitioners should inquire about previous service in the armed forces when screening, assessing, and treating PSP. [ABSTRACT FROM AUTHOR]

Migration is an effective behavioral strategy for prolonging access to seasonal resources and may be a resilient strategy for ungulates experiencing changing climatic conditions. In the Greater Yellowstone Ecosystem (GYE), elk are the primary ungulate, with approximately 20,000 individuals migrating to exploit seasonal gradients in forage while also avoiding energetically costly snow conditions. How climate‐induced changes in plant phenology and snow accumulation are influencing elk migration timing is unknown. We present the most complete record of elk migration across the GYE, spanning 9 herds and 414 individuals from 2001 to 2017, to evaluate the drivers of migration timing and test for temporal shifts. The timing of elk departure from winter range involved a trade‐off between current and anticipated forage conditions, while snow melt governed summer range arrival date. Timing of elk departure from summer range and arrival on winter range were both influenced by snow accumulation and exposure to hunting. At the GYE scale, spring and fall migration timing changed through time, most notably with winter range arrival dates becoming almost 50 days later since 2001. Predicted herd‐level changes in migration timing largely agreed with observed GYE‐wide changes—except for predicted winter range arrival dates which did not reflect the magnitude of change detected in the elk telemetry data. Snow melt, snow accumulation, and spring green‐up dates all changed through time, with different herds experiencing different rates and directions of change. We conclude that elk migration is plastic, is a direct response to environmental cues, and that these environmental cues are not changing in a consistent manner across the GYE. The impacts of changing elk migration timing on predator–prey dynamics, carnivore–livestock conflict, disease ecology, and harvest management across the GYE are likely to be significant and complex. [ABSTRACT FROM AUTHOR]

Highlights • Copolymer species act as collagen inter-fibrillary spacers, facilitating diffusion of EGCG. • Functionalized EGCG copolymers protect dentin matrices against degradation. • Proteomic results infer a selective EGCG-non-collagenous proteins binding mechanism. Abstract Objectives We investigated the biostability of dentin organic matrices treated with epigallocatechin gallate (EGCG) in comparison to chlorhexidine (CHX), both extracted from functionalized copolymers. Methods Copolymers were prepared with bis-GMA:TEGDMA and incorporated with 1% of EGCG or CHX (w/w). Blank copolymers were used as control. Copolymer samples were individually stored in 1 mL deionized water to produce copolymer extracts. Dentin matrices were obtained by demineralization of dentin disks in 10% phosphoric acid solution. Matrices were individually treated with 1 mL of the copolymer extracts or distilled water for 48 h. Collected extracts were analyzed by high-performance liquid chromatography (HPLC) for the presence and quantification of EGCG, CHX, and copolymer by-products. Treated dentin matrices were tested for ultimate tensile strength, gravimetric changes, and swelling ratio. The treatment media were tested for total protein concentration, and dentin protease activity through solubilized telopeptide (ICTP- and CTX-ELISA) assays. The treatment media were also submitted to proteomic analysis. Results HPLC identified released unreacted copolymer species and showed higher release of CHX compared to EGCG from respective copolymer extracts. EGCG extract inhibited activity of dentin proteolytic enzymes and promoted collagen biomodification observed by the telopeptide assays and in the changes to dentin matrix properties. The proteomic results showed less collagenous peptide hits in the EGCG extract media compared to CHX, and suggest compound-specific dentin protein binding interactions. Significance This study demonstrates specific antiproteolytic effect and protein interactions of EGCG copolymer extract directly on dentin. This represents an advancement in dental materials which can impact the clinical procedures. [ABSTRACT FROM AUTHOR]

Abstract Leptin and insulin's hunger-suppressing and activity-promoting actions on hypothalamic neurons are well characterized, yet the mechanisms by which they modulate the midbrain dopamine system to influence energy balance remain less clear. A subset of midbrain dopamine neurons express receptors for leptin (Lepr) and insulin (Insr). Leptin-dopamine signaling reduces running reward and homecage activity. However, dopamine-specific deletion of Lepr does not affect body weight or food intake in mice. We hypothesized insulin-dopamine signaling might compensate for disrupted leptin-dopamine signaling. To investigate the degree to which insulin and leptin exert overlapping (i.e. redundant) versus discrete control over dopamine neurons, we generated transgenic male and female mice exhibiting dopamine-specific deletion of either Lepr (Lepr KO), Insr (Insr KO) or both Lepr and Insr (Dbl KO) and assessed their feeding behavior, voluntary activity, and energy expenditure compared to control mice. No differences in body weight, daily food intake, energy expenditure or hyperphagic feeding of palatable chow were observed between Lepr, Insr or Dbl KO mice and control mice. However, consistent with previous findings, Lepr KO (but not Insr or Dbl KO) male mice exhibited significantly increased running wheel activity compared to controls. These data demonstrate that insulin and leptin do not exert redundant control of dopamine neuron-mediated modulation of energy balance. Furthermore, our results indicate neither leptin nor insulin plays a critical role in the modulation of dopamine neurons regarding hedonic feeding behavior or anxiety-related behavior. Highlights • Leptin and insulin do not exert redundant control over dopamine neurons. • Direct leptin-dopamine signaling suppresses voluntary running behavior in mice. • Leptin signaling via dopamine neurons is not required for normal feeding behavior. • Dopamine-specific insulin receptor knockout mice do not exhibit a phenotype. [ABSTRACT FROM AUTHOR]

Study Design: A retrospective review.Objective: The purpose of this study is to determine the differential improvement of the various individual items of the Oswestry Disability Index (ODI) and to determine their relationship to other measures of Health Related Quality of Life (HRQOL).Summary Of Background Data: The ODI is an easily scored, common, 10-item questionnaire about symptoms relevant to lumbar spine pathology. It is not clear if all of the items can be reliably applied to spine surgery. The purpose of this study is to determine the differential improvement of the various individual items of the ODI and to determine their relationship to other measures of HRQOL.Methods: Analysis of a prospective registry of patients treated at an academic medical center was undertaken. At baseline, standardized outcome measures including ODI and SF12 PCS were collected on all patients undergoing elective fusion surgery for degenerative spondylolisthesis. Multiple linear regressions were performed using change in SF12 PCS as the dependent variable and change in ODI components as the independent variables.Results: Baseline and 1-year follow-up data were collected on 196 patients (mean age 60.4 years). There were statistically significant differences in improvement among ODI items. Surprisingly, the most improvement after surgery was noted in the standing, sex life, and social life domains. The least improvement was noted in the personal care, sleeping, and sitting domains. Linear regression for change in ODI components versus change in SF-12 PCS revealed a significant correlation (R = 0.353, P ≤ 0.001). The only retained domains in the final model were change in lifting, standing, and traveling as predictors for ΔPCS.Conclusion: All domains of the ODI do not improve equally after surgery for degenerative spondylolisthesis. Some of the domains that improve most (e.g., sex life) have no discernible relationship to the known pathophysiology of degenerative spondylolisthesis. Based upon these results, we conclude that the item bank and composite scoring of the ODI are inappropriate for evaluating quality of life in studies of surgically treated degenerative spondylolisthesis patients.Level Of Evidence: 3. [ABSTRACT FROM AUTHOR]

Background and Aim Women who are homozygous for the p.C282Y mutation in the HFE gene are at much lower risk of iron overload-related disease than p.C282Y homozygous men, presumably because of the iron-depleting effects of menstruation and pregnancy. We used data from a population cohort study to model the impact of menstruation cessation at menopause on serum ferritin (SF) levels in female p.C282Y homozygotes, with p.C282Y/p.H63D simple or compound heterozygotes and those with neither p.C282Y nor p.H63D mutations ( HFE wild types) as comparison groups. Methods A sample of the Melbourne Collaborative Cohort Study was selected for the 'HealthIron' study ( n = 1438) including all HFE p.C282Y homozygotes plus a random sample stratified by HFE-genotype (p.C282Y and p.H63D). The relationship between the natural logarithm of SF and time since menopause was examined using linear mixed models incorporating spline smoothing. Results For p.C282Y homozygotes, SF increased by a factor of 3.6 (95% CI (1.8, 7.0), P < 0.001) during the first 10 years postmenopause, after which SF continued to increase but at less than half the previous rate. In contrast, SF profiles for other HFE genotype groups increase more gradually and did not show a distinction between premenopausal and postmenopausal SF levels. Only p.C282Y homozygotes had predicted SF exceeding 200 μg/L postmenopause, but the projected SF did not increase the risk of iron overload-related disease. Conclusions These data provide the first documented evidence that physiological blood loss is a major factor in determining the marked gender difference in expression of p.C282Y homozygosity. [ABSTRACT FROM AUTHOR]

The cellular processes that cause high caloric diet (HCD)-induced infertility are poorly understood but may involve upregulation of suppressor of cytokine signaling (SOCS-3) proteins that are associated with hypothalamic leptin resistance. Deletion of SOCS-3 from brain cells is known to protect mice from diet-induced obesity, but the effects on HCD-induced infertility are unknown. We used neuron-specific SOCS3 knock-out mice to elucidate this and the effects on regional hypothalamic leptin resistance. As expected, male and female neuron-specific SOCS3 knock-out mice were protected from HCD-induced obesity. While female wild-type mice became infertile after 4 months of HCD feeding, infertility onset in knock-out females was delayed by 4 weeks. Similarly, knock-out mice had delayed leptin resistance development in the medial preoptic area and anteroventral periventricular nucleus, regions important for generation of the surge of GnRH and LH that induces ovulation. We therefore tested whether the suppressive effects of HCD on the estradiol-induced GnRH/LH surge were overcome by neuron-specific SOCS3 knock-out. Although only 20% of control HCD-mice experienced a preovulatory-like LH surge, LH surges could be induced in almost all neuron-specific SOCS3 knock-out mice on this diet. In contrast to females, HCD-fed male mice did not exhibit any fertility decline compared with low caloric diet-fed males despite their resistance to the satiety effects of leptin. These data show that deletion of SOCS3 delays the onset of leptin resistance and infertility in HCD-fed female mice, but given continued HCD feeding this state does eventually occur, presumably in response to other mechanisms inhibiting leptin signal transduction. [ABSTRACT FROM AUTHOR]

ABSTRACT Fibronectin (FN) is a widely expressed molecule that can participate in development of osteoarthritis (OA) affecting cartilage, meniscus, and synovial membrane (SM). The alternatively spliced isoforms of FN in joint tissues other than cartilage have not been extensively studied previously. The present study compares FN splice variation in patients with varying degrees of osteoarthritic change. Joint tissues were collected from asymptomatic donors and patients undergoing arthroscopic procedures. Total RNA was amplified by PCR using primers flanking alternatively spliced Extra Domain A (EDA), Extra Domain B (EDB) and Variable (V) regions. EDB+, EDB− and EDA− and V+ variants were present in all joint tissues, while the EDA+ variant was rarely detected. Expression levels of EDB+ and EDV+ variants were similar in cartilage, synovium, and meniscal tissues. Synovial expression of V+ FN in arthroscopy patients varied with degree of cartilage degeneration. Two V− isoforms, previously identified in cartilage, were also present in SM and meniscus. Fibronectin splicing in meniscus and SM bears striking resemblance to that of cartilage. Expression levels of synovial V+ FN varied with degree of cartilage degeneration. V+ FN should be investigated as a potential biomarker of disease stage or progression in larger populations. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:556-562, 2015. [ABSTRACT FROM AUTHOR]

Biocompatible and biodegradable ε-poly- l-lysine (EPL)/poly (ε-caprolactone) (PCL) copolymer was designed and synthesized. The amphiphilic EPL-PCL copolymer could easily self-assembled into monodispersed nanoparticles (NPs), which showed a broad-spectrum antibacterial activity against Escherichia coli, Staphylococcus aureus and Bacillus subtilis. Interestingly, the antibacterial efficacy of the novel NPs is more potent than the cationic peptide EPL. To explore the underlying mechanism of the biodegradable cationic NPs, various possible antibacterial pathways have been validated. The NPs have been found that they can disrupt bacterial walls/membranes and induce the increasing in reactive oxygen species and alkaline phosphatase levels. More importantly, the self-assembled NPs induced the changes in bacterial osmotic pressure, resulting in cell invagination to form holes and cause the leakage of cytoplasm. Taken together, our results suggest that the EPL-PCL NPs can be further developed to be a promising antimicrobial agent to treat infectious diseases as surfactants and emulsifiers to enhance drug encapsulation efficiency and antimicrobial activity. [ABSTRACT FROM AUTHOR]

Background Incidental durotomies occur in up to 17% of spinal operations. Controversy exists regarding the short- and long-term consequences of durotomies. Purpose The primary aim of this study was to assess the effect of incidental durotomies on the immediate postoperative complications and patient-reported outcome measures. Study design Prospective study. Patient sample A total of 1,741 patients undergoing index lumbar spine fusion were selected from a multi-institutional prospective data registry. Outcome measures Patient-reported outcome measures used in this study included back pain (BP-Visual Analog Scale), leg pain (LP-Visual Analog Scale), and Oswestry Disability Index. Methods A total of 1,741 patients were selected from a multi-institutional prospective data registry, who underwent primary lumbar fusion for low back pain and/or radiculopathy between January 2003 and December 2010. We collected and analyzed data on patient demographics, postoperative complications, back pain, leg pain, and functional disability over 2 years, with risk-adjusted propensity score modeling. Results Incidental durotomies occurred in 70 patients (4%). Compared with the control group (n=1,671), there was no significant difference in postoperative infection (p=.32), need for reoperation (p=.85), or symptomatic neurologic damage (p=.66). At 1- and 2-year follow-up, there was no difference in patient-reported outcomes of back pain (BP-Visual Analog Scale), leg pain (LP-Visual Analog Scale), or functional disability (Oswestry Disability Index) (p>.3), with results remaining consistent in the propensity-matched cohort analysis (p>.4). Conclusion Within the context of an on-going debate on the consequences of incidental durotomy, we found no difference in neurologic symptoms, infection, reoperation, back pain, leg pain, or functional disability over a 2-year follow-up period. [ABSTRACT FROM AUTHOR]

The ferritin core is composed of fine nanoparticulate Fe3+ oxohydroxide, and we have developed a synthetic mimetic, nanoparticulate Fe3+ poly-oxohydroxide (nanoFe3+). The aim of this study was to determine how dietary iron derived in this fashion is absorbed in the duodenum. Following a 4 wk run-in on an Fe-deficient diet, mice with intestinal-specific disruption of the Fpn-1 gene (Fpn-KO), or littermate wild-type (WT) controls, were supplemented with Fe2+ sulfate (FeSO4), nanoFe3+, or no added Fe for a further 4 wk. A control group was Fe sufficient throughout. Direct intestinal absorption of nanoFe3+ was investigated using isolated duodenal loops. Our data show that FeSO4 and nanoFe3+ are equally bioavailable in WT mice, and at wk 8 the mean ± SEM hemoglobin increase was 18 ± 7 g/L in the FeSO4 group and 30 ± 5 g/L in the nanoFe3+ group. Oral iron failed to be utilized by Fpn-KO mice and was retained in enterocytes, irrespective of the iron source. In summary, although nanoFe3+ is taken up directly by the duodenum its homeostasis is under the normal regulatory control of dietary iron absorption, namely via ferroportin-dependent efflux from enterocytes, and thus offers potential as a novel oral iron supplement. [ABSTRACT FROM AUTHOR]

Systemic iron overload is multifactorial in patients suffering from myelodysplastic syndrome (MDS). Disease-immanent ineffective erythropoiesis together with chronic red blood cell transfusion represent the main underlying reasons. However, like the genetic heterogeneity of MDS, iron homeostasis is also diverse in different MDS subtypes and can no longer be generalized. While a certain amount of iron and reactive oxygen species (ROS) are indispensable for proper hematological output, both are harmful if present in excess. Consequently, iron overload has been increasingly recognized as an important player in MDS, which is worth paying attention to. This review focuses on iron- and ROS-mediated effects in the bone marrow niche, their implications for hematopoiesis and their yet unclear involvement in clonal evolution. Moreover, we provide recent insights into hepcidin regulation in MDS and its interaction between erythropoiesis and inflammation. Based on Tet methylcytosine dioxygenase 2 (TET2), representing one of the most frequently mutated genes in MDS, leading to disturbances in both iron homeostasis and hematopoiesis, we highlight that different genetic alteration may have different implications and that a comprehensive workup is needed for a complete understanding and development of future therapies. [ABSTRACT FROM AUTHOR]

HFE-related hereditary hemochromatosis (HH) is characterized by marked phenotypic heterogeneity. Homozygosity for p.C282Y is a low penetrance genotype suggesting that the HFE-HH is a multifactorial disease resulting from a complex interaction involving a major gene defect, genetic background and environmental factors. We performed a targeted NGS-based gene panel to identify new candidate modifiers by using an extreme phenotype sampling study based on serum ferritin and iron removed/age ratio. We found an increased prevalence of the HIF1A p.Phe582Ser and p.Ala588Thr variants in patients with a severe iron and clinical phenotype. Accordingly, Huh-7 cells transfected with both variants showed significantly lower HAMP promoter activity by luciferase assay. The qRT-PCR assays showed a downregulation of hepcidin and an upregulation of the HIF1A target genes (VEGF, HMOX, FUR, TMPRSS6) in cells transfected with the HIF1A-P582S vector. We identified mutations in other genes (e.g., Serpina1) that might have some relevance in single cases in aggravating or mitigating disease manifestation. In conclusion, the present study identified HIF1A as a possible modifier of the HFE-HH phenotype cooperating with the genetic defect in downregulating hepcidin synthesis. In addition, this study highlights that an NGS-based approach could broaden our knowledge and help in characterizing the genetic complexity of HFE-HH patients with a severe phenotype expression. [ABSTRACT FROM AUTHOR]