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Background: A higher risk of colorectal cancer (CRC) in patients with diabetes has been well documented. However, little is known regarding diabetes incidence in CRC survivors. This may have substantial impact on CRC survivorship care as well as enhancing the understanding of the interplay between the two diseases. We explored whether the incidence of diabetes was higher among patients with CRC than matched control subjects., Methods: Using population-based data from Ontario, Canada, we generated a dataset comprising 39 707 incident CRC cases and 198 535 age- and sex-matched control subjects (1:5) dating from April 2002 to March 2010. We used cause-specific hazard models to estimate the hazard ratios (HRs) for diabetes overall and in subgroups stratified by receipt of systemic chemotherapy, diagnosis of metastatic disease, and site of cancer., Results: During a mean follow-up of 4.81 years, the association between CRC and diabetes varied: The rate of developing diabetes was 53% higher among CRC patients compared with control subjects in the first year postdiagnosis (HR = 1.53, 95% confidence interval [CI] = 1.42 to 1.64) and remained increased by 19% in the fifth year postdiagnosis (HR = 1.19, 95% CI = 1.05 to 1.35). Findings were similar in subgroups of patients who had colon cancer, received systemic chemotherapy, or had no evidence of metastasis., Conclusion: We found that CRC patients were statistically significantly more likely to develop subsequent diabetes than persons without CRC for up to five years after the diagnosis. Our study suggests that active screening and counseling regarding modifiable risk factors may be warranted in this high-risk group., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: The purpose of this article was to systematically compare the developmental trajectory of neurobehavior over the first postnatal month for infants with prenatal exposure to pharmacologically untreated maternal depression, selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors (collectively: SSRIs), SSRIs with concomitant benzodiazepines (SSRI plus benzodiazepine), and no maternal depression or drug treatment (no exposure)., Method: Women (N=184) were assessed at two prenatal time points to determine psychiatric diagnoses, symptom severity, and prenatal medication usage. Infants were examined with a structured neurobehavioral assessment (Neonatal Intensive Care Unit Network Neurobehavioral Scale) at multiple time points across the first postnatal month. SSRI exposure was confirmed in a subset of participants with plasma SSRI levels. General linear-mixed models were used to examine group differences in neurobehavioral scores over time with adjustment for demographic variables and depression severity., Results: Infants in the SSRI and SSRI plus benzodiazepine groups had lower motor scores and more CNS stress signs across the first postnatal month, as well as lower self-regulation and higher arousal at day 14. Infants in the depression group had low arousal throughout the newborn period. Infants in all three clinical groups had a widening gap in scores from the no-exposure group at day 30 in their response to visual and auditory stimuli while asleep and awake. Infants in the SSRI plus benzodiazepine group had the least favorable scores on the Neonatal Intensive Care Unit Network Neurobehavioral Scale., Conclusions: Neonatal adaptation syndrome was not limited to the first 2 weeks postbirth. The profile of neurobehavioral development was different for SSRI exposure than depression alone. Concomitant benzodiazepine use may exacerbate adverse behavioral effects.

Objectives: To evaluate the effects of postoperative rehabilitation on the outcomes of older adults with dementia who experienced hip fracture., Design: Retrospective cohort study., Setting: Ontario, Canada., Participants: Community-dwelling adults with dementia who underwent hip fracture surgery between 2003 and 2011. Participants were categorized as no rehabilitation, complex continuing care (CCC), home-care based rehabilitation (HCR), and inpatient rehabilitation (IPR)., Measurements: Time to long-term care (LTC) placement, mortality, and risk of repeat hip fracture and falls., Results: Of 11,200 individuals with dementia who experienced a hip fracture during the study period, 4,494 (40.1%) received no rehabilitation, 2,474 (22.1%) were admitted to CCC, 1,157 (10.3%) received HCR, and 3,075 (27.4%) received IPR. HCR and IPR were associated with less risk of LTC admission after discharge from hospital than no rehabilitation. All three forms of rehabilitation were associated with lower risk of mortality than no rehabilitation, with the greatest effect observed with IPR. HCR was associated with a higher risk of falls than no rehabilitation (P=.03); there were no other significant between-group differences in risk of falls or repeat fractures (P>.05)., Conclusion: Postfracture rehabilitation for older adults with dementia is associated with lower risk of LTC placement and mortality. Improving access to rehabilitation services for this vulnerable population may improve postfracture outcomes., (© 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.)

Insulin signalling in the brain plays an important role in the central regulation of energy homeostasis and fertility, such that mice exhibiting widespread deletion of insulin receptors (InsR) throughout the brain and peripheral nervous system display diet sensitive obesity and hypothalamic hypogonadism. However, the specific cell types mediating the central effects of insulin on fertility remain largely unidentified. To date, the targeted deletion of InsR from individual neuronal populations implicated in the metabolic control of fertility has failed to recapitulate the hypogonadic and subfertile phenotype observed in brain-specific InsR knockout mice. Because insulin and leptin share similar roles as centrally-acting metabolic regulators of fertility, we used the Cre-loxP system to generate mice with a selective inactivation of the Insr gene from the same widespread neuronal population previously shown to mediate the central effects of leptin on fertility by crossing Insr-flox mice with calcium/calmodulin-dependent protein kinase type IIα (CamkIIα)-Cre mice. Multiple reproductive and metabolic parameters were then compared between male and female Insr-flox/Cre-positive (CamK-IRKO) and Insr-flox/Cre-negative control mice. Consistent with brain-specific InsR knockout mice, CamK-IRKO mice exhibited a mild but significant obesogenic phenotype. Unexpectedly, CamK-IRKO mice exhibited normal reproductive maturation and function compared to controls. No differences in the age of puberty onset, oestrous cyclicity or fecundity were observed between CamK-IRKO and control mice. We conclude that the central effects of insulin on the neuroendocrine reproductive axis are not critically mediated via the same neuronal populations targeted by leptin., (© 2015 British Society for Neuroendocrinology.)

Background: There is a clinical need for evidence-based psychotherapy response biomarkers in major depressive disorder (MDD). Based on previous studies, we hypothesized that lower 24-h urinary cortisol levels and a history of early life stress/trauma would predict an improved antidepressant response to cognitive-behavioral therapy (CBT)., Methods: 50 currently depressed MDD subjects were enrolled. 24-h urine was collected and measured for cortisol levels by radioimmunoassay (RIA). Subjects were also administered early life stress/trauma measures at baseline: Global Perceived Early-Life Stress (GPELS), The Early Life Trauma Inventory (ELTI) and Klein Loss Scale (KLS). The efficacy of a twelve-week course of once-weekly CBT was evaluated by the primary outcome measure, the 24-item Hamilton Depression Rating Scale (HDRS24), at baseline and every four weeks, and the Beck Depression Inventory at baseline and weekly thereafter. 42 subjects had at least one complete follow-up visit (≥4 weeks of CBT), and 30 subjects completed the full 12-week course., Results: Baseline 24-h urinary cortisol levels did not correlate with CBT's antidepressant response. Higher KLS scores, a measure of early life parental loss or separation, correlated with delta HDRS24 (rs=-0.39, padjusted=0.05). Complementary general linear model analysis revealed enhanced CBT efficacy in patients with a history of early life parental loss or separation [F(1,35)=6.65, p=0.01]., Limitations: Small sample size, Treatment-naïve population., Conclusions: Early life parental separation or loss positively correlated with CBT's antidepressant efficacy in our sample and may warrant further study in larger clinical samples., (Copyright © 2015 Elsevier B.V. All rights reserved.)

RFamide-related peptide-3 (RFRP-3) is a recently discovered neuropeptide that has been proposed to play a role in the stress response. We aimed to elucidate the role of RFRP-3 and its receptor, neuropeptide FF (NPFF1R), in modulation of stress and anxiety responses. To achieve this, we characterized a new NPFF1R antagonist because our results showed that the only commercially available putative antagonist, RF9, is in fact an agonist at both NPFF1R and the kisspeptin receptor (KISS1R). We report here the identification and pharmacological characterization of GJ14, a true NPFFR antagonist. In in vivo tests of hypothalamic-pituitary-adrenal (HPA) axis function, GJ14 completely blocked RFRP-3-induced corticosterone release and neuronal activation in CRH neurons. Furthermore, chronic infusion of GJ14 led to anxiolytic-like behavior, whereas RFRP-3 infusion had anxiogenic effects. Mice receiving chronic RFRP-3 infusion also had higher basal circulating corticosterone levels. These results indicate a stimulatory action of RFRP-3 on the HPA axis, consistent with the dense expression of NPFF1R in the vicinity of CRH neurons. Importantly, coinfusion of RFRP-3 and GJ14 completely reversed the anxiogenic and HPA axis-stimulatory effects of RFRP-3. Here we have established the role of RFRP-3 as a regulator of stress and anxiety. We also show that GJ14 can reverse the effects of RFRP-3 both in vitro and in vivo. Infusion of GJ14 causes anxiolysis, revealing a novel potential target for treating anxiety disorders.

We assessed the effects of pairing a target object with its familiar color on eye movements in visual search, under conditions where the familiar color could or could not be predicted. In Experiment 1 participants searched for a yellow- or purple-colored corn target amongst aubergine distractors, half of which were yellow and half purple. Search was more efficient when the color of the target was familiar and early eye movements more likely to be directed to targets carrying a familiar color than an unfamiliar color. Experiment 2 introduced cues which predicted the target color at 80 % validity. Cue validity did not affect whether early fixations were to the target. Invalid cues, however, disrupted search efficiency for targets in an unfamiliar color whilst there was little cost to search efficiency for targets in their familiar color. These results generalized across items with different colors (Experiment 3). The data are consistent with early processes in selection being automatically modulated in a bottom-up manner to targets in their familiar color, even when expectancies are set for other colors.

A network conceptualization might contribute to understanding the occurrence and interacting nature of behavioral traits in the autism realm. Networks were constructed based on correlations of item scores of the Autism Diagnostic Observation Schedule for Modules 1, 2 and 3 obtained for a group of 477 Dutch individuals with developmental disorders. After combining Modules, networks were obtained and compared for male versus female, high- versus low-functioning, seizure versus non-seizure, autism spectrum disorder versus intellectual disability, and younger versus older subjects. The network visualizations and calculated network parameters provide new perspectives that generate new hypothesis and suggest follow-up studies. The approach should be useful in characterizing individuals and groups, in elucidating mechanisms of trait generation and routes to outcome phenotypes, and in suggesting points of intervention.

Background: To address the challenges of caring for a growing number of older people with a mix of both health problems and functional impairment, programmes in different countries have different approaches to integrating health and social service supports., Objective: The goal of this analysis is to identify important lessons for policy makers and service providers to enable better design, implementation and spread of successful integrated care models., Methods: This paper provides a structured cross-case synthesis of seven integrated care programmes in Australia, Canada, the Netherlands, New Zealand, Sweden, the UK and the USA., Key Findings: All seven programmes involved bottom-up innovation driven by local needs and included: (1) a single point of entry, (2) holistic care assessments, (3) comprehensive care planning, (4) care co-ordination and (5) a well-connected provider network. The process of achieving successful integration involves collaboration and, although the specific types of collaboration varied considerably across the seven case studies, all involved a care coordinator or case manager. Most programmes were not systematically evaluated but the two with formal external evaluations showed benefit and have been expanded., Conclusions: Case managers or care coordinators who support patient-centred collaborative care are key to successful integration in all our cases as are policies that provide funds and support for local initiatives that allow for bottom-up innovation. However, more robust and systematic evaluation of these initiatives is needed to clarify the 'business case' for integrated health and social care and to ensure successful generalization of local successes.

Importance: Antibiotics are frequently and often inappropriately prescribed to patients in nursing homes. These antibiotics pose direct risks to recipients and indirect risks to others residing in the home., Objective: To examine whether living in a nursing home with high antibiotic use is associated with an increased risk of antibiotic-related adverse outcomes for individual residents., Design, Setting, and Participants: In this longitudinal open-cohort study performed from January 1, 2010, through December 31, 2011, we studied 110,656 older adults residing in 607 nursing homes in Ontario, Canada., Exposures: Nursing home-level antibiotic use was defined as use-days per 1000 resident-days, and facilities were classified as high, medium, and low use according to tertile of use. Multivariable logistic regression modeling was performed to assess the effect of nursing home-level antibiotic use on the individual risk of antibiotic-related adverse outcomes., Main Outcomes and Measures: Antibiotic-related harms included Clostridium difficile, diarrhea or gastroenteritis, antibiotic-resistant organisms (which can directly affect recipients and indirectly affect nonrecipients), allergic reactions, and general medication adverse events (which can affect only recipients)., Results: Antibiotics were provided on 2,783,000 of 50,953,000 resident-days in nursing homes (55 antibiotic-days per 1000 resident-days). Antibiotic use was highly variable across homes, ranging from 20.4 to 192.9 antibiotic-days per 1000 resident-days. Antibiotic-related adverse events were more common (13.3%) in residents of high-use homes than among residents of medium-use (12.4%) or low-use homes (11.4%) (P < .001); this trend persisted even among the residents who did not receive antibiotic treatments. The primary analysis indicated that residence in a high-use nursing home was associated with an increased risk of a resident experiencing an antibiotic-related adverse event (adjusted odds ratio, 1.24; 95% CI, 1.07-1.42; P = .003). A sensitivity analysis examining nursing home-level antibiotic use as a continuous variable confirmed an increased risk of resident-level antibiotic-related harms (adjusted odds ratio, 1.004 per additional day of nursing home antibiotic use; 95% CI, 1.001-1.006; P = .01)., Conclusions and Relevance: Antibiotic use is highly variable across nursing homes; residents of high-use homes are exposed to an increased risk of antibiotic-related harms even if they have not directly received these agents. Antibiotic stewardship is needed to improve the safety of all nursing home residents.

Fragile X syndrome (FXS) and autism spectrum disorders (ASD) are characterized by impaired social functioning. We examined the spontaneous discrimination of happy and disgusted facial expressions, from neutral faces, in individuals with FXS (n  =  13, Mage  =  19.70) and ASD (n  =  15, Mage  =  11.00) matched on adaptive behavior and verbal abilities measured by the Vineland Adaptive Behavior Scale. Eye gaze to the eyes and mouth of neutral faces was also measured. Results suggest individuals with FXS and ASD distinguish facial expressions spontaneously in the same way. Individuals with FXS looked significantly less at the eye region of neutral faces than individuals with ASD. These results provide insight into similarities and differences in face processing in two neurodevelopmental disorders noted for their similarities in social behavior.

Network perspectives, in their emphasis on components and their interactions, might afford the best approach to the complexities of the ASD realm. Categorical approaches are unlikely to be fruitful as one should not expect to find a single or even predominant underlying cause of autism behavior across individuals. It is possible that the complex, highly interactive, heterogeneous and individualistic nature of the autism realm is intractable in terms of identifying clinically useful biomarker tests. It is hopeful from an emergenic perspective that small corrective changes in a single component of a deleterious network/configuration might have large beneficial consequences on developmental trajectories and in later treatment. It is suggested that the relationship between ASD and intellectual disability might be fundamentally different in single-gene versus nonsyndromic ASD. It is strongly stated that available biomarker "tests" for autism/ASD will do more harm than good. Finally, the serotonin-melatonin-oxidative stress-placental intersection might be an especially fruitful area of biological investigation.

Background: Breast cancer stage at diagnosis is an important predictor of survival. Our goal was to compare breast cancer stage at diagnosis (by American Joint Committee on Cancer criteria) in Chinese and South Asian women with stage at diagnosis in the remaining general population in Ontario., Methods: We used the Ontario population-based cancer registry to identify all women diagnosed with breast cancer during 2005-2010, and we applied a validated surname algorithm to identify South Asian and Chinese women. We used logistic regression to compare, for Chinese or South Asian women and for the remaining general population, the frequency of diagnoses at stage ii compared with stage i and stages ii-iv compared with stage i., Results: The registry search identified 1304 Chinese women, 705 South Asian women, and 39,287 women in the remaining general population. The Chinese and South Asian populations were younger than the remaining population (mean: 54, 57, and 61 years respectively). Adjusted for age, South Asian women were more often diagnosed with breast cancer at stage ii than at stage i [odds ratio (or): 1.28; 95% confidence interval (ci): 1.08 to 1.51] or at stages ii-iv than at stage i (or: 1.27; 95% ci: 1.08 to 1.48); Chinese women were less likely to be diagnosed at stage ii than at stage i (or: 0.82; 95% ci: 0.72 to 0.92) or at stages ii-iv than at stage i (or: 0.73; 95% ci: 0.65 to 0.82)., Conclusions: Breast cancers were diagnosed at a later stage in South Asian women and at an earlier stage in Chinese women than in the remaining population. A more detailed analysis of ethnocultural factors influencing breast screening uptake, retention, and care-seeking behavior might be needed to help inform and evaluate tailored health promotion activities.

There is a growing interest in the role of biological and behavioral rhythms in typical and atypical development. Recent studies in cognitive and developmental psychology have highlighted the importance of rhythmicity and synchrony of motor, emotional, and interpersonal rhythms in early development of social communication. The synchronization of rhythms allows tuning and adaptation to the external environment. The role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of the circadian clocks network suggests that this hormone might be also involved in the synchrony of motor, emotional, and interpersonal rhythms. Autism provides a challenging model of physiological and behavioral rhythm disturbances and their possible effects on the development of social communication impairments and repetitive behaviors and interests. This article situates autism as a disorder of biological and behavioral rhythms and reviews the recent literature on the role of rhythmicity and synchrony of rhythms in child development. Finally, the hypothesis is developed that an integrated approach focusing on biological, motor, emotional, and interpersonal rhythms may open interesting therapeutic perspectives for children with autism. More specifically, promising avenues are discussed for potential therapeutic benefits in autism spectrum disorder of melatonin combined with developmental behavioral interventions that emphasize synchrony, such as the Early Start Denver Model.

Background: Existing literature suggests differences in face scanning in individuals with different socio-behavioural characteristics. Cornelia de Lange syndrome (CdLS) and Rubinstein-Taybi syndrome (RTS) are two genetically defined neurodevelopmental disorders with unique profiles of social behaviour., Methods: Here, we examine eye gaze to the eye and mouth regions of neutrally expressive faces, as well as the spontaneous visual preference for happy and disgusted facial expressions compared to neutral faces, in individuals with CdLS versus RTS., Results: Results indicate that the amount of time spent looking at the eye and mouth regions of faces was similar in 15 individuals with CdLS and 17 individuals with RTS. Both participant groups also showed a similar pattern of spontaneous visual preference for emotions., Conclusions: These results provide insight into two rare, genetically defined neurodevelopmental disorders that have been reported to exhibit contrasting socio-behavioural characteristics and suggest that differences in social behaviour may not be sufficient to predict attention to the eye region of faces. These results also suggest that differences in the social behaviours of these two groups may be cognitively mediated rather than subcortically mediated.

A major goal of regenerative medicine is to restore the function of damaged or missing organs through the implantation of bioengineered or donor-derived components. It is necessary to understand the signals and cues necessary for implanted structures to innervate the host, as organs devoid of neural connections provide little benefit to the patient. While developmental studies have identified neuronal pathfinding molecules required for proper patterning during embryogenesis, strategies to initiate innervation in structures transplanted at later times or alternate locations remain limited. Recent work has identified membrane resting potential of nerves as a key regulator of growth cone extension or arrest. Here, we identify a novel role of bioelectricity in the generation of axon guidance cues, showing that neurons read the electric topography of surrounding cells, and demonstrate these cues can be leveraged to initiate sensory organ transplant innervation. Grafts of fluorescently labeled embryological eye primordia were used to produce ectopic eyes in Xenopus laevis tadpoles. Depolarization of host tissues through anion channel activation or other means led to a striking hyperinnervation of the body by these ectopic eyes. A screen of possible transduction mechanisms identified serotonergic signaling to be essential for hyperinnervation to occur, and our molecular data suggest a possible model of bioelectrical control of the distribution of neurotransmitters that guides nerve growth. Together, these results identify the molecular components of bioelectrical signaling among cells that regulates axon guidance, and suggest novel biomedical and bioengineering strategies for triggering neuronal outgrowth using ion channel drugs already approved for human use.

Coupling of haloarenes to arenes has been facilitated by a diverse range of organic additives in the presence of KO(t)Bu or NaO(t)Bu 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.

Background: Reports of higher stress responsivity, altered sleep-wake cycle and a melatonin deficit in autism have stimulated interest in the cortisol circadian rhythm in individuals with autism., Methods: The study was conducted on 55 low-functioning children and adolescents with autism (11.3 ± 4.1 years-old) and 32 typically developing controls (11.7 ± 4.9 years-old) matched for age, sex and puberty. Behavioral assessment was performed using the Autism Diagnostic Observation Schedule (ADOS). Salivary samples for measurement of cortisol were collected during a 24-h period (at least 0800 h-Day 1, 1600 h, 0800 h-Day 2 for 46 individuals with autism and 27 controls, and 0800 h-Day 1, 1100 h, 1600 h, 2400 h, 0800 h-Day 2 for 13 individuals with autism and 20 controls). Overnight (2000 h-0800 h) urinary cortisol excretion was also measured., Results: The autism group displayed significantly higher levels of salivary cortisol at all time-points, flatter daytime and nighttime slopes, higher 0800 h cortisol levels on Day 2 compared to Day 1, and greater variances of salivary and urinary cortisol. There was a significant relationship between salivary cortisol levels and impairments in social interaction and verbal language. Overnight urinary cortisol excretion was similar in the autism and control groups., Conclusion: Anticipation of the stressful collection procedure appears to contribute to the higher 0800 h-Day 2 versus 0800 h-Day 1 salivary cortisol levels in autism. This sensitization to stressors might be as, or even more, important clinically than exposure to novelty in autism. The similar group means for overnight urinary cortisol excretion indicate that basal HPA axis functioning is unaltered in low-functioning autism. The elevated salivary cortisol levels observed in autism over the 24-h period in a repeated stressful condition, flattened diurnal cortisol patterns and the apparent effect of anticipation are consistent with prior findings in high trait anxiety., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: To examine the association between anesthetic technique and postoperative complications in older adults with dementia undergoing hip fracture surgery., Design: Population-based, retrospective cohort study., Setting: Ontario, Canada., Participants: All older adults with dementia who underwent surgery for hip fracture repair in Ontario, Canada, between April 1, 2003 and March 31, 2011., Measurements: The baseline characteristics of individuals who received general anesthesia (GA) and regional anesthesia (RA) were compared. Individuals who received GA were matched to similar individuals who received RA using propensity scores to control for confounding, and their outcomes compared, including 30-day mortality, intensive care unit (ICU) admissions, specific postoperative medical complications, and hospital length of stay (LOS)., Results: In the 6,135 matched pairs, there was no statistically significant difference in postoperative 30-day mortality (GA, 11.3%; RA, 10.8%, P = .44). There were no statistically significant differences in the rates of specific postoperative medical complications or LOS in the two anesthetic groups, but GA was associated with higher rates of ICU admissions (6.1% vs 4.2%, P < .001)., Conclusion: For older adults with dementia undergoing hip fracture surgery, GA and RA are associated with similar rates of most perioperative adverse events. Further studies are required to determine the optimal methods of providing anesthesia and perioperative care for older adults with dementia undergoing surgical procedures., (© 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society.)

Background: The earlier onset of puberty seen in young American girls has led researchers to question if a causal relation exists between dietary sources of estrogenic compounds and precocious puberty., Objective: Using the prepubertal gilt (young female pig) as an animal model, our hypothesis is that feeding beef obtained from cattle receiving growth-promoting steroidal implants postweaning does not alter the onset of puberty or the peripubertal body composition of gilts compared with contemporaries fed nonimplanted "natural" beef or a common meat alternative, tofu., Method: The base diet was formulated using canola meal replacing soybean meal to reduce diet estrogenicity. Feed intake was monitored and controlled to ensure similar intake. Gilts were assigned to treatments based on dam and initial body weight (mean: 24.5 ± 3.20 kg) at 61 d of age. The negative control base diet was supplemented with daily feedings of a cooked patty from nonimplanted steers (natural), from steers that had been treated with growth promotants [100 mg trenbolone acetate and 14 mg estradiol (E2) benzoate; implanted], or cooked tofu patty., Results: E2 equivalents (nanogram per kilogram, as fed as analyzed by E-Screen) of the tofu (a soy-based product) supplement were ∼570 times the natural and ∼170 times the implanted supplements. There were no observed differences across treatments in live weight gain (P = 0.90), longissimus muscle area developed at the 10th and 11th rib interface (P = 0.46), and subcutaneous fat deposition (P = 0.41) at the same location over time or in the number of days to reach estrus (P = 0.55)., Conclusions: Consumption of beef from growth implanted or natural steers or tofu at levels similar to those typically consumed by humans did not impact growth or onset of estrus in these prepubertal gilts., (© 2014 American Society for Nutrition.)

Insulin signaling in the brain plays an important role in the central regulation of energy homeostasis and fertility, such that mice exhibiting brain-specific deletion of insulin receptors (InsRs) display a diet-sensitive obesogenic phenotype and hypothalamic hypogonadism. However, the specific neurons mediating insulin's central effects on fertility remain largely unidentified. The neurotransmitters γ-aminobutyric acid (GABA) and glutamate are important modulators of fertility and energy homeostasis and are widely distributed in the hypothalamus. We therefore investigated whether insulin signaling via GABAergic or glutamatergic neurons plays an important role in the metabolic regulation of fertility. We used the Cre-loxP system to generate mice with a selective inactivation of the Insr gene from GABAergic (Vgat(+)) or glutamatergic (Vglut2(+)) cells by crossing Insr-flox mice with Vgat-Cre or Vglut2-Cre mice, respectively. Multiple reproductive and metabolic parameters were then compared between male and female Insr-flox/Vgat-Cre(+) (VgatIRKO), Insr-flox/Vglut2-Cre(+) (VglutIRKO), and Insr-flox/Cre-negative control (CON) mice. Female VgatIRKO mice exhibited a significant increase in adult body weight, abdominal fat mass, and fasting plasma insulin and leptin concentrations, but normal fasting glucose concentration and glucose tolerance compared with CON mice. Surprisingly, VgatIRKO and VglutIRKO mice exhibited normal reproductive maturation and function compared with CONs. No differences in the age of puberty onset, estrous cyclicity, or fertility were observed between VgatIRKO, VglutIRKO, and CON mice. However, male VgatIRKO mice exhibited significantly augmented LH concentration and a trend toward reduced seminal vesicle weight compared with CON mice, which may be indicative of primary hypogonadism. Our results therefore demonstrate that insulin signaling via GABAergic and glutamatergic cells is not required for fertility in mice, but show that GABAergic neurons encompass circuitry through which insulin acts to modulate energy homeostasis.

Objective: To describe and compare onset and intensity of thoracic duct (TD) coloration after injection of methylene blue into the diaphragmatic crus and mesenteric lymph node., Study Design: Experimental study., Animals: Adult dogs (n = 18)., Methods: Methylene blue (≤0.5 mg/kg 1% solution) was injected into the left (n = 9) or right (n = 9) diaphragmatic crus via right 10th intercostal thoracotomy. TD coloration was graded over 10 minutes. A right paracostal laparotomy was then performed in all dogs, and an equal volume of methylene blue injected into a mesenteric lymph node (n = 18). TD color grading was repeated. Statistical analysis was performed on subject weight, volume of contrast agent injected between left and right crus, and number of successful outcomes between diaphragmatic crus injection and mesenteric lymph node injection., Results: TD coloration occurred in 6 dogs with left crus injection and 4 dogs with right crus injection with obvious staining present in 2 and 3 dogs, respectively. Successful outcome was noted in all dogs with mesenteric lymph node injection. The number of successful outcomes was significantly greater after mesenteric lymph node injection compared with diaphragmatic crus injection (P < .001)., Conclusions: Methylene blue injected into the diaphragmatic crura and mesenteric lymph node was successful in coloring the TD; however, mean thoracic duct color grade and number of successful outcomes were significantly higher after mesenteric injection., (© Copyright 2014 by The American College of Veterinary Surgeons.)

Importance: Hospital readmissions are common and costly, and no single intervention or bundle of interventions has reliably reduced readmissions. Virtual wards, which use elements of hospital care in the community, have the potential to reduce readmissions, but have not yet been rigorously evaluated., Objective: To determine whether a virtual ward-a model of care that uses some of the systems of a hospital ward to provide interprofessional care for community-dwelling patients-can reduce the risk of readmission in patients at high risk of readmission or death when being discharged from hospital., Design, Setting, and Patients: High-risk adult hospital discharge patients in Toronto were randomly assigned to either the virtual ward or usual care. A total of 1923 patients were randomized during the course of the study: 960 to the usual care group and 963 to the virtual ward group. The first patient was enrolled on June 29, 2010, and follow-up was completed on June 2, 2014., Interventions: Patients assigned to the virtual ward received care coordination plus direct care provision (via a combination of telephone, home visits, or clinic visits) from an interprofessional team for several weeks after hospital discharge. The interprofessional team met daily at a central site to design and implement individualized management plans. Patients assigned to usual care typically received a typed, structured discharge summary, prescription for new medications if indicated, counseling from the resident physician, arrangements for home care as needed, and recommendations, appointments, or both for follow-up care with physicians as indicated., Main Outcomes and Measures: The primary outcome was a composite of hospital readmission or death within 30 days of discharge. Secondary outcomes included nursing home admission and emergency department visits, each of the components of the primary outcome at 30 days, as well as each of the outcomes (including the composite primary outcome) at 90 days, 6 months, and 1 year., Results: There were no statistically significant between-group differences in the primary or secondary outcomes at 30 or 90 days, 6 months, or 1 year. The primary outcome occurred in 203 of 959 (21.2%) of the virtual ward patients and 235 of 956 (24.6%) of the usual care patients (absolute difference, 3.4%; 95% CI, -0.3% to 7.2%; P = .09). There were no statistically significant interactions to indicate that the virtual ward model of care was more or less effective in any of the prespecified subgroups., Conclusions and Relevance: In a diverse group of high-risk patients being discharged from the hospital, we found no statistically significant effect of a virtual ward model of care on readmissions or death at either 30 days or 90 days, 6 months, or 1 year after hospital discharge., Trial Registration: clinicaltrials.gov Identifier: NCT01108172.

STEP (STriatal-Enriched protein tyrosine Phosphatase) is a neuron-specific phosphatase that regulates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking, as well as ERK1/2, p38, Fyn, and Pyk2 activity. STEP is overactive in several neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease (AD). The increase in STEP activity likely disrupts synaptic function and contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we describe the first large-scale effort to identify and characterize small-molecule STEP inhibitors. We identified the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-amine hydrochloride (known as TC-2153) as an inhibitor of STEP with an IC50 of 24.6 nM. TC-2153 represents a novel class of PTP inhibitors based upon a cyclic polysulfide pharmacophore that forms a reversible covalent bond with the catalytic cysteine in STEP. In cell-based secondary assays, TC-2153 increased tyrosine phosphorylation of STEP substrates ERK1/2, Pyk2, and GluN2B, and exhibited no toxicity in cortical cultures. Validation and specificity experiments performed in wild-type (WT) and STEP knockout (KO) cortical cells and in vivo in WT and STEP KO mice suggest specificity of inhibitors towards STEP compared to highly homologous tyrosine phosphatases. Furthermore, TC-2153 improved cognitive function in several cognitive tasks in 6- and 12-mo-old triple transgenic AD (3xTg-AD) mice, with no change in beta amyloid and phospho-tau levels., Competing Interests: The authors declare that they have no competing interests.

Our purpose was to evaluate the association of new benzodiazepine use relative to non-use with adverse clinical respiratory outcomes among older adults with chronic obstructive pulmonary disease (COPD). This was a retrospective population-based cohort study of Ontario, Canada, residents between 2003 and 2010. A validated algorithm was applied to health administrative data to identify adults aged 66 years and older with COPD. Relative risks (RRs) of several clinically important respiratory outcomes were examined within 30 days of incident benzodiazepine use compared with non-use, applying propensity score matching. New benzodiazepine users were at significantly higher risk for outpatient respiratory exacerbations (RR 1.45, 95% CI 1.36-1.54) and emergency room visits for COPD or pneumonia (RR 1.92, 95% CI 1.69-2.18) compared to non-users. Risk of hospitalisation for COPD or pneumonia was also increased in benzodiazepine users, but was nonsignificant (RR 1.09, 95% CI 1.00-1.20). There were no significant differences in intensive care unit admissions between the two groups and all-cause mortality was slightly lower among new versus non-users. Benzodiazepines were associated with increased risk for several serious adverse respiratory outcomes among older adults with COPD. The findings suggest that decisions to use benzodiazepines in older patients with COPD need to consider potential adverse respiratory outcomes., (©ERS 2014.)

Insulin in the brain plays an important role in regulating reproductive function, as demonstrated via conditional brain-specific insulin receptor (Insr) deletion (knockout). However, the specific neuronal target cells mediating the central effects of insulin on the reproductive axis remain unidentified. We first investigated whether insulin can act via direct effects on gonadotrophin-releasing hormone (GnRH) neurones. After clearly detecting Insr mRNA in an immunopurified GnRH cell fraction, we confirmed the presence of insulin receptor protein (InsR) in approximately 82% of GnRH neurones using dual-label immunohistochemistry. However, we did not observe any insulin-induced phospho-Akt (pAkt) or phospho-extracellular-signal-regulated kinase 1/2 in GnRH neurones, and therefore we investigated whether insulin signals via kisspeptin neurones to modulate GnRH release. Using dual-label immunohistochemistry, InsRs were detected only in approximately 5% of kisspeptin-immunoreactive cells. Insulin-induced pAkt was not observed in any kisspeptin-immunoreactive cells in either the rostral periventricular region of the third ventricle or arcuate nucleus in response to 200 mU of insulin treatment, although a more pharmacological dose (10 U) induced pronounced (> 20%) pAkt-kisspeptin coexpression in both regions. To confirm that insulin signalling via kisspeptin neurones does not critically modulate reproductive function, we generated kisspeptin-specific InsR knockout (KIRKO) mice and assessed multiple reproductive and metabolic parameters. No significant differences in puberty onset, oestrous cyclicity or reproductive competency were observed in the female or male KIRKO mice compared to their control littermates. However, significantly decreased fasting insulin (P < 0.05) and a nonsignificant trend towards reduced body weight were observed in male KIRKO mice. Thus, InsR signalling in kisspeptin cells is not critical for puberty onset or reproductive competency, although it may have a small metabolic effect in males., (© 2014 British Society for Neuroendocrinology.)

Objective: To evaluate the association between dementia and postoperative outcomes of older adults with hip fractures., Design: Population-based, retrospective cohort study., Setting: Province of Ontario, Canada., Participants: All individuals with hip fractures who underwent hip fracture surgery in Ontario, Canada between April 1, 2003 and March 31, 2010 were identified. Physician-diagnosed dementia, prior to hip fracture, was identified using a diagnostic algorithm in the administrative databases., Measurements: The preoperative characteristics of older adults with and without dementia were compared separately for individuals admitted to hospital from community or long-term care (LTC). Multivariable regression was used to compare postoperative health service utilization, time with LTC admission, and mortality for individuals with and without dementia., Results: A total of 45,602 older adults had hip fractures and individuals with dementia accounted for 23.9% and 83.5% of all hip fractures from the community and LTC settings, respectively. Compared with those without dementia, individuals with dementia were less likely to be admitted to rehabilitation facilities. Among community-dwelling older adults, dementia was associated with an increased risk of LTC admission [hazard ratio (HR) = 2.49, 95% confidence interval (CI): 2.38-2.61, P < .0001]. Dementia was also associated with a higher mortality for older adults from community (HR = 1.47, 95% CI: 1.41-1.52, P < .0001) and LTC (HR = 1.10; 95% CI: 1.02-1.18, P = .005) settings., Conclusions: Dementia is common among older adults with hip fractures and associated with poor prognosis following hip fracture surgery. Specialized services targeting the growing number of older adults with dementia may help to prevent hip fractures and optimize postoperative care for this vulnerable population., (Copyright © 2014 American Medical Directors Association, Inc. Published by Elsevier Inc. All rights reserved.)

Researchers have investigated visual search behavior for almost a century. During that time, few studies have examined the cognitive processes involved in hiding items rather than finding them. To investigate this, we developed a paradigm that allowed participants to indicate where they would hide (or find) an item that was to be found (or hidden) by a friend or a foe. We found that (i) for friends more than foes, participants selected the pop-out item in the display, and (ii) when the display was homogeneous, they selected nearby and corner items. These behaviors held for both hiding and finding, although hide and find behaviors were not identical. For pop-out displays, decision times were unusually long when hiding an item from a foe. These data converge on the conclusion that the principles of search and concealment are similar, but not the same. They also suggest that this paradigm will provide researchers a powerful method for investigating theory of mind in adults.

Leptin, a permissive hormonal regulator of fertility, provides information about the body's energy reserves to the hypothalamic gonadotrophin-releasing hormone (GnRH) neuronal system that drives reproduction. Leptin does not directly act on GnRH neurones, and the neuronal pathways that it uses remain unclear. RFamide-related peptide-3 (RFRP-3) neurones project to GnRH neurones and primarily inhibit their activity. We tested whether leptin could act via RFRP-3 neurones to potentially modulate GnRH activity. First, the effects of leptin deficiency or high-fat diet-induced obesity on RFRP-3 cell numbers and gene expression were assessed in male and female mice. There was no significant difference in Rfrp mRNA levels or RFRP-3-immunoreactive cell counts in wild-type versus leptin-deficient ob/ob animals, or in low-fat versus high-fat diet fed wild-type mice. Second, the presence of leptin-induced signalling in RFRP-3 neurones was examined in male and female wild-type mice and rats. Dual label immunohistochemistry revealed leptin-induced phosphorylated signal transducer and activator of transcription-3 in close proximity to RFRP-3 neurones, although there was very little (2-13%) colocalisation and no significant differences between vehicle and leptin-treated animals. Furthermore, we were unable to detect leptin receptor mRNA in a semi-purified RFRP-3 cell preparation. Because GABA neurones form critical leptin-responsive GnRH inputs, we also determined whether RFRP-3 and GABA cells were colocalised. No such colocalisation was detected. These results support the concept that leptin has little or no effects on RFRP-3 neurones, and that these neurones are unlikely to be an important neuronal pathway for the metabolic regulation of fertility by leptin., (© 2014 British Society for Neuroendocrinology.)

Objective: More women with schizophrenia are becoming pregnant, such that contemporary data are needed about maternal and newborn outcomes in this potentially vulnerable group. We aimed to quantify maternal and newborn health outcomes among women with schizophrenia., Design: Retrospective cohort study., Setting: Population based in Ontario, Canada, from 2002 to 2011., Population: Ontario women aged 15-49 years who gave birth to a liveborn or stillborn singleton infant., Methods: Women with schizophrenia (n = 1391) were identified based on either an inpatient diagnosis or two or more outpatient physician service claims for schizophrenia within 5 years prior to conception. The reference group comprised 432 358 women without diagnosed mental illness within the 5 years preceding conception in the index pregnancy., Main Outcome Measures: The primary maternal outcomes were gestational diabetes mellitus, gestational hypertension, pre-eclampsia/eclampsia, and venous thromboembolism. The primary neonatal outcomes were preterm birth, and small and large birthweight for gestational age (SGA and LGA). Secondary outcomes included additional key perinatal health indicators., Results: Schizophrenia was associated with a higher risk of pre-eclampsia (adjusted odds ratio, aOR 1.84; 95% confidence interval, 95% CI 1.28-2.66), venous thromboembolism (aOR 1.72, 95% CI 1.04-2.85), preterm birth (aOR 1.75, 95% CI 1.46-2.08), SGA (aOR 1.49, 95% CI 1.19-1.86), and LGA (aOR 1.53, 95% CI 1.17-1.99). Women with schizophrenia also required more intensive hospital resources, including operative delivery and admission to a maternal intensive care unit, paralleled by higher neonatal morbidity., Conclusions: Women with schizophrenia are at higher risk of multiple adverse pregnancy outcomes, paralleled by higher neonatal morbidity. Attention should focus on interventions to reduce the identified health disparities., (© 2014 Royal College of Obstetricians and Gynaecologists.)

Objectives: We compared seasonal influenza hospital use among older adults in long-term care (LTC) and community settings., Methods: We used provincial administrative data from Ontario to identify all emergency department (ED) visits and hospital admissions for pneumonia and influenza among adults older than 65 years between 2002 and 2008. We used sentinel laboratory reports to define influenza and summer seasons and estimated mean annual event rates and influenza-associated rates., Results: Mean annual pneumonia and influenza ED visit rates were higher in LTC than the community (rate ratio [RR] for influenza season = 3.9; 95% confidence interval [CI] = 3.8, 4.0; for summer = 4.9; 95% CI = 4.8, 5.1) but this was attenuated in influenza-associated rates (RR = 2.4; 95% CI = 2.1, 2.8). The proportion of pneumonia and influenza ED visits attributable to seasonal influenza was 17% (15%-20%) in LTC and 28% (27%-29%) in the community. Results for hospital admissions were comparable., Conclusions: We found high rates of hospital use from LTC but evidence of lower impact of circulating influenza in the community. This differential impact of circulating influenza between the 2 environments may result from different influenza control policies.

Background: Impairment in activities of daily living (ADL) is an important predictor of outcomes although many administrative databases lack information on ADL function. We evaluated the impact of ADL function on predicting postoperative mortality among older adults with hip fractures in Ontario, Canada., Methods: Sociodemographic and medical correlates of ADL impairment were first identified in a population of older adults with hip fractures who had ADL information available prior to hip fracture. A logistic regression model was developed to predict 360-day postoperative mortality and the predictive ability of this model were compared when ADL impairment was included or omitted from the model., Results: The study sample (N = 1,329) had a mean age of 85.2 years, were 72.8% female and the majority resided in long-term care (78.5%). Overall, 36.4% of individuals died within 360 days of surgery. After controlling for age, sex, medical comorbidity and medical conditions correlated with ADL impairment, addition of ADL measures improved the logistic regression model for predicting 360 day mortality (AIC = 1706.9 vs. 1695.0; c -statistic = 0.65 vs 0.67; difference in - 2 log likelihood ratios: χ(2) = 16.9, p = 0.002)., Conclusions: Direct measures of ADL impairment provides additional prognostic information on mortality for older adults with hip fractures even after controlling for medical comorbidity. Observational studies using administrative databases without measures of ADLs may be potentially prone to confounding and bias and case-mix adjustment for hip fracture outcomes should include ADL measures where these are available.

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objectives: To better understand how centenarians use the healthcare system as an important step toward improving their service delivery., Design: Population-based retrospective cohort study using linked health administrative data., Setting: Ontario--Canada's largest province., Participants: All individuals living in Ontario aged 65 and older on April 1 of each year between 1995 and 2010 were identified and divided into three age groups (65-84, 85-99, ≥ 100). A detailed description was obtained on 1,842 centenarians who were alive on April 1, 2010., Measurements: Sociodemographic characteristics and use of health services., Results: The number of centenarians increased from 1,069 in 1995 to 1,842 in 2010 (72.3%); 6.7% were aged 105 and older. Over the same period, the number of individuals aged 85 to 99 grew from 119,955 to 227,703 (89.8%). Women represented 85.3% of all centenarians and 89.4% of those aged 105 and older. Almost half of centenarians lived in the community (20.0% independently, 25.3% with publicly funded home care). Preventive drug therapies (bisphosphonates and statins) were frequently dispensed. In the preceding year, 18.2% were hospitalized and 26.6% were seen in an emergency department. More than 95% saw a primary care provider, and 5.3% saw a geriatrician., Conclusion: The number of centenarians in Ontario increased by more than 70% over the last 15 years, with even greater growth among older people who could soon become centenarians. Almost half of centenarians live in the community, most are women, and almost all receive care from a primary care physician., (© 2013, Copyright the Authors Journal compilation © 2013, The American Geriatrics Society.)

Serotonergic antidepressants (SAds) are associated with bleeding-related adverse events. An increased risk of bleeding with SAds may have important implications in surgical settings. Our study evaluates the risk of red blood cell (RBC) transfusions and postoperative complications associated with SAds among older adults undergoing hip fracture surgery. We conducted a retrospective cohort study of individuals 66 years or older who underwent hip fracture surgery in Ontario, Canada. The risk of RBC transfusion among current users of SAds and nonserotonergic antidepressants (NSAds) was compared with recent former SAd users. Secondary outcomes included measures of postoperative morbidity and mortality. Subgroup analyses were undertaken in groups who were coprescribed other medications known to effect bleeding. Multivariable logistic regression was utilized to determine the odds ratios (ORs) for antidepressants and postoperative outcomes. A total 11,384 individuals were included in the study sample. Current SAd users had an increased risk of RBC transfusion compared with recent former users of SAds (OR, 1.28; 95% confidence interval, 1.14-1.43) as did current NSAd users (OR, 1.17; 95% confidence interval, 1.03-1.33). The risk of RBC transfusion with SAds or NSAds was further increased among individuals receiving antiplatelet agents. However, postoperative morbidity and mortality were not increased among either group of antidepressant users. In conclusion, SAds are associated with an increased risk of RBC transfusions, although this does not appear to result in major postoperative complications. Clinicians should be aware of this increased risk, although routine discontinuation of antidepressants before surgery is likely unwarranted in most cases.

Relationships between parental broader autism phenotype (BAP) scores, gender, selective serotonin reuptake inhibitor (SSRI) treatment, serotonin (5HT) levels, and the child's symptoms were investigated in a family study of autism spectrum disorder (ASD). The Broader Autism Phenotype Questionnaire (BAPQ) was used to measure the BAP of 275 parents. Fathers not taking SSRIs (F-SSRI; n = 115) scored significantly higher on BAP Total and Aloof subscales compared to mothers not receiving treatment (M-SSRI; n = 136.) However, mothers taking SSRIs (M + SSRI; n = 19) scored higher than those not taking medication on BAP Total and Rigid subscales, and they were more likely to be BAPQ Total, Aloof, and Rigid positive. Significant correlations were noted between proband autism symptoms and parental BAPQ scores such that Total, Aloof, and Rigid subscale scores of F-SSRI correlated with proband restricted repetitive behavior (RRB) measures on the ADOS, CRI, and RBS-R. However, only the Aloof subscale score of M + SSRI correlated with proband RRB on the ADOS. The correlation between the BAPQ scores of mothers taking SSRIs and child scores, as well as the increase in BAPQ scores of this group of mothers, requires careful interpretation and further study because correlations would not withstand multiple corrections. As expected by previous research, significant parent-child correlations were observed for 5HT levels. However, 5HT levels were not correlated with behavioral measures. Study results suggest that the expression of the BAP varies not only across parental gender, but also across individuals using psychotropic medication and those who do not., (© 2013 International Society for Autism Research, Wiley Periodicals, Inc.)

The adipocyte-derived hormone leptin acts in the brain to modulate the central driver of fertility: the gonadotropin releasing hormone (GnRH) neuronal system. This effect is indirect, as GnRH neurons do not express leptin receptors (LEPRs). Here we test whether GABAergic or glutamatergic neurons provide the intermediate pathway between the site of leptin action and the GnRH neurons. Leptin receptors were deleted from GABA and glutamate neurons using Cre-Lox transgenics, and the downstream effects on puberty onset and reproduction were examined. Both mouse lines displayed the expected increase in body weight and region-specific loss of leptin signaling in the hypothalamus. The GABA neuron-specific LEPR knock-out females and males showed significantly delayed puberty onset. Adult fertility observations revealed that these knock-out animals have decreased fecundity. In contrast, glutamate neuron-specific LEPR knock-out mice displayed normal fertility. Assessment of the estrogenic hypothalamic-pituitary-gonadal axis regulation in females showed that leptin action on GABA neurons is not necessary for estradiol-mediated suppression of tonic luteinizing hormone secretion (an indirect measure of GnRH neuron activity) but is required for regulation of a full preovulatory-like luteinizing hormone surge. In conclusion, leptin signaling in GABAergic (but not glutamatergic neurons) plays a critical role in the timing of puberty onset and is involved in fertility regulation throughout adulthood in both sexes. These results form an important step in explaining the role of central leptin signaling in the reproductive system. Limiting the leptin-to-GnRH mediators to GABAergic cells will enable future research to focus on a few specific types of neurons.

Abnormalities in melatonin physiology may be involved or closely linked to the pathophysiology and behavioral expression of autistic disorder, given its role in neurodevelopment and reports of sleep-wake rhythm disturbances, decreased nocturnal melatonin production, and beneficial therapeutic effects of melatonin in individuals with autism. In addition, melatonin, as a pineal gland hormone produced from serotonin, is of special interest in autistic disorder given reported alterations in central and peripheral serotonin neurobiology. More specifically, the role of melatonin in the ontogenetic establishment of circadian rhythms and the synchronization of peripheral oscillators opens interesting perspectives to ascertain better the mechanisms underlying the significant relationship found between lower nocturnal melatonin excretion and increased severity of autistic social communication impairments, especially for verbal communication and social imitative play. In this article, first we review the studies on melatonin levels and the treatment studies of melatonin in autistic disorder. Then, we discuss the relationships between melatonin and autistic behavioral impairments with regard to social communication (verbal and non-verbal communication, social interaction), and repetitive behaviors or interests with difficulties adapting to change. In conclusion, we emphasize that randomized clinical trials in autism spectrum disorders are warranted to establish potential therapeutic efficacy of melatonin for social communication impairments and stereotyped behaviors or interests.

Background: Previously, we identified multiple, rare serotonin (5-HT) transporter (SERT) variants in children with autism spectrum disorder (ASD). Although in our study the SERT Ala56 variant was over-transmitted to ASD probands, it was also seen in some unaffected individuals, suggesting that associated ASD risk is influenced by the epistatic effects of other genetic variation. Subsequently, we established that mice expressing the SERT Ala56 variant on a 129S6/S4 genetic background display multiple biochemical, physiological and behavioral changes, including hyperserotonemia, altered 5-HT receptor sensitivity, and altered social, communication, and repetitive behavior. Here we explore the effects of genetic background on SERT Ala56 knock-in phenotypes., Methods: To explore the effects of genetic background, we backcrossed SERT Ala56 mice on the 129 background into a C57BL/6 (B6) background to achieve congenic B6 SERT Ala56 mice, and assessed autism-relevant behavior, including sociability, ultrasonic vocalizations, and repetitive behavior in the home cage, as well as serotonergic phenotypes, including whole blood serotonin levels and serotonin receptor sensitivity., Results: One consistent phenotype between the two strains was performance in the tube test for dominance, where mutant mice displayed a greater tendency to withdraw from a social encounter in a narrow tube as compared to wildtype littermate controls. On the B6 background, mutant pup ultrasonic vocalizations were significantly increased, in contrast to decreased vocalizations seen previously on the 129 background. Several phenotypes seen on the 129 background were reduced or absent when the mutation was placed on the B6 background, including hyperserotonemia, 5-HT receptor hypersensivity, and repetitive behavior., Conclusions: Our findings provide a cogent example of how epistatic interactions can modulate the impact of functional genetic variation and suggest that some aspects of social behavior may be especially sensitive to changes in SERT function. Finally, these results provide a platform for the identification of genes that may modulate the risk of ASD in humans.

RFamide-related peptide-3 (RFRP-3) neurons have been shown to inhibit gonadotropin-releasing hormone (GnRH) neuronal activity and hence reproduction in birds and eutherian mammals. They have also been proposed to have a direct hypophysiotropic effect on pituitary gonadotropin release. We used a new RFRP-3 antibody to characterize the cell body distribution and fiber projections of RFRP-3 neurons in the adult female brushtail possum brain. RFRP-3-immunoreactive cell bodies were found scattered within the dorsomedial hypothalamus and the dorsomedial half of the ventromedial hypothalamus, while GnRH neurons were observed scattered rostrocaudally along the lateral septum, rostral to the medial septum. There was a significant 2-fold increase in the RFRP-3 cell body number during the nonbreeding season (summer) compared to the breeding season (winter). Immunoreactive RFRP-3 fibers were distributed throughout the thalamus, preoptic area, and hypothalamus. Very few fibers were observed in the median eminence, especially in the external zone. Intraperitoneal injection of the retrograde tracer Fluoro-Gold resulted in the labeling of 40% of hypophysiotropic tuberoinfundibular dopaminergic (tyrosine hydroxylase-positive) neurons; however, <10% of zona incerta dopaminergic neurons (which are not hypophysiotropic) or RFRP-3 neurons were labeled with this tracer. These observations suggest that RFRP-3 exhibits a seasonal fluctuation in cell numbers, as seen in sheep and birds, which is consistent with an increased inhibitory tone during the nonbreeding season. The lack of RFRP-3 fibers in the median eminence and of Fluoro-Gold uptake from the periphery imply that the actions of this peptide occur primarily centrally rather than at the anterior pituitary gland., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Deletion of the Williams-Beuren syndrome (WBS) critical region (WBSCR), at 7q11.23, causes a developmental disorder commonly characterized by hypersociability and excessive talkativeness and often considered the opposite behavioral phenotype to autism. Duplication of the WBSCR leads to severe delay in expressive language. Gene-dosage effects on language development at 7q11.23 have been hypothesized., Methods: Molecular characterization of the WBSCR was performed by fluorescence in situ hybridization and high-resolution single-nucleotide polymorphism array in two individuals with severe autism enrolled in a genetic study of autism who showed typical WBS facial dysmorphism on systematic clinical genetic examination. The serotonin transporter promoter polymorphism (5-HTTLPR, locus SLC6A4) was genotyped. Platelet serotonin levels and urinary 6-sulfatoxymelatonin excretion were measured. Behavioral and cognitive phenotypes were examined., Results: The two patients had common WBSCR deletions between proximal and medial low copy repeat clusters, met diagnostic criteria for autism and displayed severe impairment in communication, including a total absence of expressive speech. Both patients carried the 5-HTTLPR ss genotype and exhibited platelet hyperserotonemia and low melatonin production., Conclusions: Our observations indicate that behaviors and neurochemical phenotypes typically associated with autism can occur in patients with common WBSCR deletions. The results raise intriguing questions about phenotypic heterogeneity in WBS and regarding genetic and/or environmental factors interacting with specific genes at 7q11.23 sensitive to dosage alterations that can influence the development of social communication skills. Thus, the influence of WBSCR genes on social communication expression might be dramatically modified by other genes, such as 5-HTTLPR, known to influence the severity of social communication impairments in autism, or by environmental factors, such as hyperserotonemia, given that hyperserotonemia is found in WBS associated with autism but not in WBS without autism. In this regard, WBS provides a potentially fruitful model with which to develop integrated genetic, cognitive, behavioral and neurochemical approaches to study genotype-phenotype correlations, possible gene-environment interactions and genetic background effects. The results underscore the importance of considering careful clinical and molecular genetic examination of individuals diagnosed with autism.

The hormone leptin is critical for the regulation of energy balance and fertility. The long-form leptin receptor (LepR) regulates multiple intracellular signaling cascades, including the classic Janus kinase-signal transducer and activator of transcription (STAT) pathways. Previous studies have shown that deletion of STAT3 or the closely related STAT5 from the brain results in an obese phenotype, but their roles in fertility regulation are not clear. This study tested whether STAT3 and STAT5 pathways of leptin signaling are required for fertility, and whether absence of one pathway might be compensated for by the other in a redundant manner. A Cre-loxP approach was used to generate 3 models of male and female transgenic mice with LepR-specific deletion of STAT3, STAT5, or both STAT3 and STAT5. Body weight, puberty onset, estrous cyclicity, and fertility were measured in all knockout (KO) mice and their control littermates. Knocking out STAT3 or both STAT3 and 5 from LepR expressing cells, but not STAT5 alone, led to significant increase in body weight. All STAT3 and STAT5 single KO mice exhibited normal puberty onset and subsequent fertility compared to their control littermates. Surprisingly, all STAT3 and STAT5 double KO mice also exhibited normal puberty onset, estrous cyclicity, and fertility, although they had severely disrupted body weight regulation. These results suggest that, although STAT3 signaling is crucial for body weight regulation, neither STAT3 nor STAT5 is required for the regulation of fertility by leptin. It remains to be determined what other signaling molecules mediate this effect of leptin, and whether they interact in a redundant manner.

Background: A key priority in developing policies for providing affordable cancer care is measuring the value for money of new therapies using cost-effectiveness analyses (CEAs). For CEA to be useful it should focus on relevant outcomes and include thorough investigation of uncertainty. Randomized controlled trials (RCTs) of five years of aromatase inhibitors (AI) versus five years of tamoxifen in the treatment of post-menopausal women with early stage breast cancer, show benefit of AI in terms of disease free survival (DFS) but not overall survival (OS) and indicate higher risk of fracture with AI. Policy-relevant CEA of AI versus tamoxifen should focus on OS and include analysis of uncertainty over key assumptions., Methods: We conducted a systematic review of published CEAs comparing an AI to tamoxifen. We searched Ovid MEDLINE, EMBASE, PsychINFO, and the Cochrane Database of Systematic Reviews without language restrictions. We selected CEAs with outcomes expressed as cost per life year or cost per quality adjusted life year (QALY). We assessed quality using the Neumann checklist. Using structured forms two abstractors collected descriptive information, sources of data, baseline assumptions on effectiveness and adverse events, and recorded approaches to assessing parameter uncertainty, methodological uncertainty, and structural uncertainty., Results: We identified 1,622 citations and 18 studies met inclusion criteria. All CE estimates assumed a survival benefit for aromatase inhibitors. Twelve studies performed sensitivity analysis on the risk of adverse events and 7 assumed no additional mortality risk with any adverse event. Sub-group analysis was limited; 6 studies examined older women, 2 examined women with low recurrence risk, and 1 examined women with multiple comorbidities., Conclusion: Published CEAs comparing AIs to tamoxifen assumed an OS benefit though none has been shown in RCTs, leading to an overestimate of the cost-effectiveness of AIs. Results of these CEA analyses may be suboptimal for guiding policy.

Importance: Given that most common bacterial infections can be treated with antibiotic courses of 7 or fewer days, reducing standard antibiotic treatment durations may be an avenue to curtailing antibiotic overuse in long-term care., Objectives: To describe the variability in the duration of antibiotic treatment courses in long-term care across resident recipients and prescribing physicians and to determine whether this variability is influenced by prescriber preference., Design and Setting: Province-wide retrospective analysis of residents of Ontario, Canada, long-term care facilities in 2010., Participants: All adults aged 66 years or older who received an incident treatment course with a systemic antibiotic while residing in an Ontario long-term care facility., Main Outcome Measure: Antibiotic treatment duration was examined across residents and prescribing physicians. The proportion of a physician's treatment courses that exceeded 7 days was used to classify short-, average-, and long-duration prescribers., Results: Of 66 901 long-term care residents from 630 long-term care facilities, 50 061 (77.8%) received an incident antibiotic treatment course (with 51 540 antibiotic courses prescribed). The most commonly selected antibiotic treatment course was 7 days (in 21 136 courses [41.0%]), but 23 124 (44.9%) exceeded 7 days. Among the 699 physicians responsible for 20 or more antibiotic treatment courses, the median (interquartile range) proportion of treatment courses beyond 7 days was 43.5% (26.9%-62.9%) (range, 0%-97.1%). Twenty-one percent of prescribers had a higher-than-expected proportion of prescriptions beyond the 7-day threshold. Patient characteristics were similar across short-, average-, and long-duration prescribers. A mixed logistic model confirmed that prescribers were an important determinant of treatment duration (P < .001), with a relative odds of prolonged prescription of 3.84 for 75th vs 25th percentile prescribers., Conclusions and Relevance: Antibiotic treatment courses in long-term care facilities are often prescribed for long durations, and this appears to be influenced by prescriber preference more than patient characteristics. Future trials should evaluate antibiotic stewardship interventions targeting prescriber preferences to systematically shorten average treatment durations to reduce the complications, costs, and resistance associated with antibiotic overuse.

Several markers identify cancer stem cell-like populations, but little is known about the functional roles of stem cell surface receptors in tumor progression. Here, we show that the endothelial protein C receptor (EPCR), a stem cell marker in hematopoietic, neuronal and epithelial cells, is crucial for breast cancer growth in the orthotopic microenvironment of the mammary gland. Mice with a hypomorphic allele of EPCR show reduced tumor growth in the PyMT-model of spontaneous breast cancer development and deletion of EPCR in established PyMT tumor cells significantly attenuates transplanted tumor take and growth. We find expansion of EPCR(+) cancer stem cell-like populations in aggressive, mammary fat pad-enhanced human triple negative breast cancer cells. In this model, EPCR-expressing cells have markedly increased mammosphere- and tumor-cell initiating activity compared to another stable progenitor-like subpopulation present at comparable frequency. We show that receptor blocking antibodies to EPCR specifically attenuate in vivo tumor growth initiated by either EPCR(+) cells or the heterogenous mixture of EPCR(+) and EPCR(-) cells. Furthermore, we have identified tumor associated macrophages as a major source for recognized ligands of EPCR, suggesting a novel mechanism by which cancer stem cell-like populations are regulated by innate immune cells in the tumor microenvironment.

We provide novel evidence for a two-stage model of visual search applied to the selection based on top-down cues to stimulus colour and orientation. The model supposes that visual displays are first parsed into colour based groups, a process that is modulated by the presence of an initial cue to the target's colour. Subsequently search is directed to other featural properties represented within the colour-based groups. Cues to the orientation of the target are only effective at this second stage. The results provide strong evidence that colour and orientation cues operate in different ways to guide search., (Copyright © 2013 Elsevier Ltd. All rights reserved.)