Timing of maternal immune activation and sex influence schizophrenia-relevant cognitive constructs and neuregulin and GABAergic pathways.

Maternal immune activation (MIA) during pregnancy is an established environmental risk factor for schizophrenia. Timing of immune activation exposure as well as sex of the exposed offspring are critical factors in defining the effects of MIA. However, the specificity of MIA on the component structure of schizophrenia, especially cognition, has been difficult to assess due to a lack of translational validity of maze-like testing paradigms. We aimed to assess cognitive domains relevant to schizophrenia using highly translational touchscreen-based tasks in male and female mice exposed to the viral mimetic, poly(I:C) (5 mg/k, i.p.), during early (gestational day (GD) 9-11) and late (GD13-15) gestational time points. Gene expression of schizophrenia candidate pathways were assessed in fetal brain immediately following poly(I:C) exposure and in adulthood to identify its influence on neurodevelopmental processes. Sex and window specific alterations in cognitive performance were found with the early window of MIA exposure causing female-specific disruptions to working memory and reduced perseverative behaviour, while late MIA exposure caused male-specific changes to working memory and deficits in reversal learning. GABAergic specification marker, Nkx2.1 gene expression was reduced in fetal brains and reelin expression was reduced in adult hippocampus of both early and late poly(I:C) exposed mice. Neuregulin and EGF signalling were initially upregulated in the fetal brain, but were reduced in the adult hippocampus, with male mice exposed in the late window showing reduced Nrg3 expression. Serine racemase was reduced in both fetal and adult brain, but again, adult reductions were specific to male mice exposed at the late time point. Overall, we show that cognitive constructs relevant to schizophrenia are altered by in utero exposure to maternal immune activation, but are highly dependent on the timing of infection and the sex of the offspring. Glutamatergic and epidermal growth factor pathways were similarly altered by MIA in a timing and sex dependent manner, while MIA-induced GABAergic deficits were independent of timing or sex.

Effect of adolescent androgen manipulation on psychosis-like behaviour in adulthood in BDNF heterozygous and control mice.

RATIONALE: Males are more prone to psychosis, schizophrenia and substance abuse and addiction in adolescence and early adulthood than females. However, the role of androgens during this developmental period is poorly understood. OBJECTIVES: This study aimed to examine how androgens in adolescence influence psychosis-like behaviour in adulthood and whether brain-derived neurotrophic factor (BDNF) is a mediator of these developmental effects. METHODS: Wild-type and BDNF heterozygous male mice were castrated at pre-pubescence and implanted with testosterone or dihydrotestosterone (DHT). In adulthood, we assessed amphetamine- and MK-801-induced hyperlocomotion as a model of psychosis-like behaviour. Western blot analysis was used to quantify levels of the dopamine transporter (DAT) and N-methyl-d-aspartate (NMDA) receptor subunits. RESULTS: While castration itself had little effect on behaviour, adolescent testosterone, but not DHT, significantly reduced amphetamine-induced hyperlocomotion, whereas both testosterone and DHT reduced the effect of MK-801. These effects were similar in mice of either genotype. In wildtype mice, both testosterone and DHT treatment reduced DAT expression in the medial prefrontal cortex (mPFC) but these effects were absent in BDNF heterozygous mice. There were no effects on NMDA receptor subunit levels. CONCLUSIONS: The differential effect of adolescent testosterone and DHT on amphetamine-induced hyperlocomotion in adulthood suggests involvement of conversion of testosterone to estrogen and subsequent modulation of dopaminergic signalling. In contrast, the similar effect of testosterone and DHT treatment on NMDA receptor-mediated hyperlocomotion indicates it is mediated by androgen receptors. The involvement of BDNF in these hormone effects remains to be elucidated. These results demonstrate that, during adolescence, androgens significantly influence key pathways related to various mental illnesses prevalent in adolescence.

Hypothalamic-pituitary-gonadal axis dysfunction: An innate pathophysiology of schizophrenia?

The female hormone 17ß-estradiol is postulated to be protective against schizophrenia onset and severity. Hypoestrogenism is a common phenomenon in women with schizophrenia that has serious effects that adds to the burden of an already very onerous disease. The cause of hypoestrogenism is largely attributed to antipsychotic-induced hyperprolactinemia. Evidence suggest however that a significant portion of female schizophrenia patients develop hypoestrogenism either before antipsychotic treatment or without regard to the level of prolactin, suggesting that for a sizeable segment of female patients, gonadal abnormality may be an innate and early aspect of the disease. This review aims to summarise the available literature that examines gonadal dysfunction in schizophrenia through this prism as well as to outline some recent developments in treatment strategies that may provide feasible ways to successfully tackle hypoestrogenism in schizophrenia.

Prefrontal cortical parvalbumin and somatostatin expression and cell density increase during adolescence and are modified by BDNF and sex.

Brain-derived neurotrophic factor (BDNF) is known to play a critical role early in the development of cortical GABAergic interneurons. Recently our laboratory and others have shown protracted development of specific subpopulations of GABAergic interneurons extending into adolescence. BDNF expression also changes significantly across adolescent development. However the role of BDNF in regulating GABAergic changes across adolescence remains unclear. Here, we performed a week-by-week analysis of the protein expression and cell density of three major GABAergic interneurons, parvalbumin (PV), somatostatin (SST) and calretinin (Cal) in the medial prefrontal cortex from prepubescence (week 3) to adulthood (week 12). In order to assess how BDNF and sex might influence the adolescent trajectory of GABAergic interneurons we compared WT as well as BDNF heterozygous (+/-) male and female mice. In both males and females PV expression increases during adolescent development in the mPFC. Compared to wild-types, PV expression was reduced in male but not female BDNF+/- mice throughout adolescent development. This reduction in protein expression corresponded with reduced cell density, specifically within the infralimbic prefrontal cortex. SST expression increased in early adolescent WT females and this upregulation was delayed in BDNF+/-. SST cell density also increased in early adolescent mPFC of WT female mice, with BDNF+/- again showing a reduced pattern of expression. Cal protein expression was also sex-dependently altered across adolescence with WT males showing a steady decline but that of BDNF+/- remaining unaltered. Reduced cell density in on the other hand was observed particularly in male BDNF+/- mice. In females, Cal protein expression and cell density remained largely stable. Our results show that PV, SST and calretinin interneurons are indeed still developing into early adolescence in the mPFC and that BDNF plays a critical, sex-specific role in mediating expression and cell density.

Change in Nox4 expression is accompanied by changes in myogenic marker expression in differentiating C2C12 myoblasts.

Myoblast differentiation is mediated by a cascade of changes in gene expression including transcription factors such as myogenin. Subsequent to myoblast differentiation, there is an increase in expression of the transmembrane protein NADPH oxidase (Nox). Nox is one of the primary factors for the generation of reactive oxygen species (ROS) in myogenic (C2C12) cells. Recently, ROS have been shown to be important regulators of several intracellular signaling pathways, and the full extent of their regulatory roles is yet to be discovered. In the present study, qRT PCR analysis demonstrated that Nox4 isoform is primarily expressed in differentiating C2C12 cells and contributes to the generation of ROS in C2C12 myoblast during differentiation. Over-expression and silencing of Nox4 expression during myoblast differentiation was accompanied by a reduction in intracellular ROS concentrations and an alteration in the expression patterns of Myf5, Pax7, MyoD1, and myogenin. This modulation was found to be associated with ERK1/2 phosphorylation. In both over-expression and reduced expression of Nox4, we found significant reductions in ERK1/2 phosphorylation. This indicates that cellular differentiation may be affected by Nox4-mediated endogenous ROS generation. These data suggest a new opportunity to study the temporal expression of Nox4 in the generation of ROS accompanying changes in myogenic differentiation.

What is a nurse? Is there an international consensus?

BACKGROUND: Historical experience and health service modernization partly account for the variation seen in definitions of what a 'nurse' is from country to country. It is unclear if international disparities in nursing provision, apparent in health data for developed countries, demonstrate real differences in staffing patterns or simply reflect the wide variations in understanding and use of terms for different categories of nurse. AIM: This paper is an opinion piece of international interest discussing the need for standardization in definitions of different categories of nurse internationally. DISCUSSION: The International Council for Nurses (ICN), the World Health Organization and the Organisation for Economic Cooperation and Development (OECD) all have different ways of defining a nurse. The wide variation in terms is particularly apparent from OECD countries however, where nursing density data present wide disparities, not readily accounted for by gross national product. Skill mix and clinical role developments may account for these better. CONCLUSION: Until proper consensus is reached on what a nurse is and does, any skill mix or clinical role developments will only have limited international relevance, especially in OECD countries. If nursing qualifications are to be valid even across the European Union, then recommended standards such as those of the ICN, must be specified in terms of what different categories of nurses actually can do, and their responsibilities and roles within that scope of practice. Standardization of definitions of categories of nurse internationally should reduce confusion and promote better understanding of patterns of nurse staffing and the effect these may have on patient outcomes.

Bazedoxifene - a promising brain active SERM that crosses the blood brain barrier and enhances spatial memory.

Over 20 years of accumulated evidence has shown that the major female sex hormone 17ß-estradiol can enhance cognitive functioning. However, the utility of estradiol as a therapeutic cognitive enhancer is hindered by its unwanted peripheral effects (carcinogenic). Selective estrogen receptor modulators (SERMs) avoid the unwanted effects of estradiol by acting as estrogen receptor antagonists in some tissues such as breast and uterus, but as agonists in others such as bone, and are currently used for the treatment of osteoporosis. However, understanding of their actions in the brain are limited. The third generation SERM bazedoxifene has recently been FDA approved for clinical use with an improved biosafety profile. However, whether bazedoxifene can enter the brain and enhance cognition is unknown. Using mice, the current study aimed to explore if bazedoxifene can 1) cross the blood-brain barrier, 2) rescue ovariectomy-induced hippocampal-dependent spatial memory deficit, and 3) activate neural estrogen response element (ERE)-dependent gene transcription. Using liquid chromatography-mass spectrometry (LC-MS), we firstly demonstrate that a peripheral injection of bazedoxifene can enter the brain. Secondly, we show that an acute intraperitoneal injection of bazedoxifene can rescue ovariectomy-induced spatial memory deficits. And finally, using the ERE-luciferase reporter mouse, we show in vivo that bazedoxifene can activate the ERE in the brain. The evidence shown here suggest bazedoxifene could be a viable cognitive enhancer with promising clinical applicability.

Antimicrobial activity of Coniothyrium minitans and its macrolide antibiotic macrosphelide A.

AIMS: Assessment of antimicrobial activity of the mycoparasite Coniothyrium minitans and its macrolide antibiotic macrosphelide A. METHODS AND RESULTS: Thirteen isolates of C. minitans were tested for ability to inhibit a number of filamentous fungi, yeasts, oomycetes and bacteria in agar based tests. Activity was found against some ascomycetes, basidiomycetes, oomycetes and Gram-positive bacteria, but not against zygomycetes, yeasts or Gram-negative bacteria tested. Six C. minitans isolates (Conio, Contans, IVT1, CM/AP/3118, B279/1, A1/327/1) were found to produce macrosphelide A in liquid culture and no other antibiotics were detected. On agar, macrosphelide A inhibited growth of some ascomycetes, basidiomycetes, oomycetes and all four Gram-positive bacteria tested, including the medically important Staphylococcus aureus with a minimum inhibitory concentration of < or =500 microg ml(-1). There was no inhibition observed against the yeasts and Gram-negative bacteria when macrosphelide A was tested at 700 microg ml(-1). CONCLUSIONS: The spectrum and level of activity of macrosphelide A produced by C. minitans against micro-organisms are extended markedly compared to previous reports. SIGNIFICANCE AND IMPACT OF THE STUDY: Macrosphelide A was effective against Staph. aureus. Further study on the control of this bacterium is merited in view of the development of antibiotic resistance.

Posteromedial bowing of the tibia: a benign condition or a case for limb reconstruction?

PURPOSE: To review the initial deformity and subsequent remodelling in posteromedial bowing of the tibia and the outcome of limb reconstruction in this condition. PATIENTS AND METHODS: In all, 38 patients with posteromedial bowing of the tibia presenting between 2000 and 2016 were identified. Mean follow-up from presentation was 78 months. A total of 17 patients underwent lengthening and deformity correction surgery, whilst three further patients are awaiting lengthening and deformity correction procedures. RESULTS: The greatest correction of deformity occurred in the first year of life, but after the age of four years, remodelling was limited. The absolute leg-length discrepancy (LLD) increased throughout growth with a mean 14.3% discrepancy in tibial length. In the lengthening group, mean length gained per episode was 45 mm (35 to 60). Mean duration in frame was 192 days, with a mean healing index of 42.4 days/cm. Significantly higher rates of recurrence in LLD were seen in those undergoing lengthening under the age of ten years (p = 0.046). Four contralateral epiphysiodeses were also performed. CONCLUSION: Posteromedial bowing of the tibia improves spontaneously during the first years of life, but in 20/38 (53%) patients, limb reconstruction was indicated for significant residual deformity and/or worsening LLD. For larger discrepancies and persistent deformity, limb reconstruction with a hexapod external fixator should be considered as part of the treatment options. LEVEL OF EVIDENCE: Level IV (Case series).

Nitrogen inputs drive nitrogen concentrations in U.S. streams and rivers during summer low flow conditions.

Ecological and human health impairments related to excess nitrogen (N) in streams and rivers remain widespread in the United States (U.S.) despite recent efforts to reduce N pollution. Many studies have quantified the relationship between N loads to streams in terms of N mass and N inputs to watersheds; however, N concentrations, rather than loads, are more closely related to impacts on human health and aquatic life. Additionally, concentrations, rather than loads, trigger regulatory responses. In this study, we examined how N concentrations are related to N inputs to watersheds (atmospheric deposition, synthetic fertilizer, manure applied to agricultural land, cultivated biological N fixation, and point sources), land cover characteristics, and stream network characteristics, including stream size and the extent of lakes and reservoirs. N concentration data were collected across the conterminous U.S. during the U.S. Environmental Protection Agency's 2008-09 National Rivers and Streams Assessment (n = 1966). Median watershed N inputs were 15.7 kg N ha-1 yr-1. Atmospheric deposition accounted for over half the N inputs in 49% of watersheds, but watersheds with the highest N input rates were dominated by agriculture-related sources. Total N input to watersheds explained 42% and 38% of the variability in total N and dissolved inorganic N concentrations, respectively. Land cover characteristics were also important predictors, with wetland cover muting the effect of agricultural N inputs on N concentrations and riparian disturbance exacerbating it. In contrast, stream variables showed little correlation with N concentrations. This suggests that terrestrial factors that can be managed, such as agricultural N use practices and wetland or riparian areas, control the spatial variability in stream N concentrations across the conterminous U.S.

Drug-eluting stents: a systematic review and economic evaluation.

OBJECTIVES: To assess the effectiveness and cost-effectiveness of the use of drug-eluting coronary artery stents in percutaneous coronary intervention (PCI) in patients with coronary artery disease. DATA SOURCES: Bibliographic databases, including MEDLINE, EMBASE and the Cochrane Library, were searched from December 2002 to August 2005. Hand-searching was also done. REVIEW METHODS: A systematic literature review of effectiveness was conducted focusing primarily on randomised controlled trials (RCTs). Full economic evaluations that compared two or more options and considered both costs and consequences were eligible for inclusion in the economics review. A critique of manufacturer submissions to the National Institute for Health and Clinical Excellence and an economic evaluation in the form of cost-utility analysis were also carried out. RESULTS: In the 17 RCTs of drug-eluting stents (DES) versus bare metal stents (BMS), no statistically significant differences in mortality or myocardial infarction (MI) were identified up to 3 years. Significant reductions in repeat revascularisations were determined for DES compared with BMS [for example, at 1 year: target lesion revascularisation (TLR) relative risk 0.24; 95% confidence interval (CI) 0.19 to 0.31; and target vessel revascularisation (TVR) relative risk 0.43; 95% CI 0.33 to 0.55]. This estimated benefit appears to be stable from 1 to 3 years. Binary restenosis and late luminal loss also favoured DES. In the eight RCTs of DES versus DES, no statistically significant differences in mortality or MI were detected between DES designs. In meta-analyses of TLR, TVR and composite event rate, marginal improvement in efficacy of Cypher trade mark over Taxus trade mark was observed. These results await confirmation beyond 1 year and differences in study design may have influenced reporting of outcomes. Ten full economic evaluations were included in the review and the balance of evidence indicated that DES are more cost-effective in higher risk patients. The review of submitted models confirmed the view that DES may be cost-effective only under very limited circumstances when realistic assumptions and data values were used. In the cost-utility analysis of DES versus BMS, the use of DES appears to reduce the rate of repeat revascularisations; benefit estimates used in the economic assessment are defined as 'broad' (i.e. cases involving any TLR/TVR irrespective of any other lesions/vessels undergoing revascularisation) and 'narrow' (i.e. cases involving TLR/TVR only). The incremental benefit to the patient is therefore described as the loss of quality-adjusted life-years (QALYs) avoided by not having to undergo a repeat revascularisation. Univariate sensitivity analysis and extreme values analysis indicate that the price premium, numbers of stents used in the index procedure and absolute risk reduction in repeat interventions most significantly influence the cost-effectiveness ratios. Sensitivity analyses also permit a range of values for efficacy and effectiveness to be considered for individual designs of DES. The cost-effectiveness results reveal that, all patients considered together, the calculated cost per QALY ratios are high (183,000-562,000 pounds) and outside the normal range of acceptability. Cost-effectiveness is only achieved for those non-elective patients who have undergone a previous coronary artery bypass graft and have small vessels. 'Real-world' data show that patient numbers in this latter group are very small (one in 3100 of all patients treated with PCI). CONCLUSIONS: The conclusions of the assessment are that the use of DES would be best targeted at the subgroups of patients with the highest risks of requiring reintervention, and could be considered cost-effective in only a small percentage of such patents. This is similar to the conclusion of our previous assessment. Trials of DES compared with new generation BMS and with DES would be useful, as would further evaluation of newer BMS in combination with drug administration.

The BDNF Val66Met polymorphism regulates glucocorticoid-induced corticohippocampal remodeling and behavioral despair.

The BDNF Val66Met polymorphism has been associated with sensitivity to stress and affective disorders. We therefore sought to model the inter-causality of these relationships under controlled laboratory conditions. We subjected humanized BDNF Val66Met (hBDNFVal66Met) transgenic mice to a history of stress, modeled by chronic late-adolescent corticosterone (CORT) exposure, before evaluating affective-related behavior using the forced-swim test (FST) in adulthood. While hBDNFMet/Met mice had a depression-like phenotype in the FST irrespective of CORT, hBDNFVal/Val wildtype mice had a resilient phenotype but developed an equally robust depressive-like phenotype following CORT. A range of stress-sensitive molecules were studied across the corticohippocampal axis, and where genotype differences occurred following CORT they tended to inversely coincide with the behavior of the hBDNFVal/Val group. Notably, tyrosine hydroxylase was markedly down-regulated in the mPFC of hBDNFVal/Val mice as a result of CORT treatment, which mimicked expression levels of hBDNFMet/Met mice and the FST behavior of both groups. The expression of calretinin, PSD-95, and truncated TrkB were also concomitantly reduced in the mPFC of hBDNFVal/Val mice by CORT. This work establishes BDNFVal66Met genotype as a regulator of behavioral despair, and identifies new biological targets of BDNF genetic variation relevant to stress-inducible disorders such as depression.

The Potential of Gonadal Hormone Signalling Pathways as Therapeutics for Dementia.

Dementia is an ever-expanding problem facing an ageing society. Currently, there is a sharp paucity of treatment strategies. It has long been known that sex hormones, namely 17ß-estradiol and testosterone, possess neuroprotective- and cognitive-enhancing qualities. However, certain lacunae in the knowledge underlying their molecular mechanisms have delayed their use as treatment strategies in dementia. With recent advancements in pharmacology and molecular biology, especially in the development of safer selective oestrogen receptor modulators and the recent discovery of the small-molecule brain-derived neurotrophic factor receptor agonist, 7,8-dihydroxyflavone, the exploitation of these signalling pathways for clinical use has become possible. This review aims to adumbrate the evidence and hurdles underscoring the use of sex hormones in the treatment of dementia as well as discussing some direction that is required to advance the translation of evidence into practise.

Transporters as Drug Targets in Neurological Diseases.

Membrane transport proteins have central physiological function in maintaining cerebral homeostasis. These transporters are expressed in almost all cerebral cells in which they regulate the movement of a wide range of solutes, including endogenous substrates, xenobiotic, and therapeutic drugs. Altered activity/expression of central nervous system (CNS) transporters has been implicated in the onset and progression of multiple neurological diseases. Neurological diseases are heterogeneous diseases that involve complex pathological alterations with only a few treatment options; therefore, there is a great need for the development of novel therapeutic treatments. To that end, transporters have emerged recently to be promising therapeutic targets to halt or slow the course of neurological diseases. The objective of this review is to discuss implications of transporters in neurological diseases and summarize available evidence for targeting transporters as decent therapeutic approach in the treatment of neurological diseases.

Discrete hierarchical organization of social group sizes.

The 'social brain hypothesis' for the evolution of large brains in primates has led to evidence for the coevolution of neocortical size and social group sizes, suggesting that there is a cognitive constraint on group size that depends, in some way, on the volume of neural material available for processing and synthesizing information on social relationships. More recently, work on both human and non-human primates has suggested that social groups are often hierarchically structured. We combine data on human grouping patterns in a comprehensive and systematic study. Using fractal analysis, we identify, with high statistical confidence, a discrete hierarchy of group sizes with a preferred scaling ratio close to three: rather than a single or a continuous spectrum of group sizes, humans spontaneously form groups of preferred sizes organized in a geometrical series approximating 3-5, 9-15, 30-45, etc. Such discrete scale invariance could be related to that identified in signatures of herding behaviour in financial markets and might reflect a hierarchical processing of social nearness by human brains.

Percutaneous transluminal coronary angioplasty with stents versus coronary artery bypass grafting for people with stable angina or acute coronary syndromes.

BACKGROUND: Coronary artery bypass graft surgery (CABG) replaces obstructed vessels with ones from other parts of the body. Alternatively, obstructions are remodelled using catheter-based techniques such as percutaneous coronary angioplasty with the use of stents. Though less invasive, stenting techniques are limited by the re-narrowing of treated vessels (restenosis). We examined evidence on cardiac-related outcomes occurring after CABG or stenting, with implications for resource use, resource allocation and informing patient choice. OBJECTIVES: To examine evidence from randomised controlled trials (RCTs) on benefit of stents or CABG in reducing cardiac events in people with stable angina or acute coronary syndrome (ACS). SEARCH STRATEGY: CENTRAL (Issue 2 2004), EMBASE (1990 to 2004), MEDLINE (1990 to 2004) and handsearching to July 2004. SELECTION CRITERIA: Only RCTs comparing stents used with PTCA with CABG were included. Participants were adults with stable angina or ACS and unstable angina and had either single or multiple vessel disease. Published and unpublished sources were considered. DATA COLLECTION AND ANALYSIS: Outcomes included composite event rate (major adverse cardiac event, event free survival), death, acute myocardial infarction (AMI), repeat revascularisation and binary restenosis as well as information on design and baseline characteristics. Quality assessment was completed independently. Meta-analyses are presented as odds ratios, 95% confidence intervals (CI) using a fixed-effect model. Heterogeneity between trials was assessed. MAIN RESULTS: Nine studies (3519 patients) were included. Four RCTs included patients with multiple vessel disease, five focused on single vessel disease. Four studies reported beyond 1 year. No statistical differences were observed between CABG and stenting for meta-analysis of mortality or AMI, but there was heterogeneity. Composite cardiac event and revascularisation rates were lower for CABG than for stents. Odds ratios resulting from meta-analysis of event rate data at 1 year were, odds ratio 0.43 (95% CI 0.35 to 0.54) and at 3 years, odds ratio 0.37 (95% CI 0.29 to 0.48). Odds ratios for revascularisation at 1 year were, odds ratio 0.18 (95% CI 0.13 to 0.25) and at 3 years, odds ratio 0.09 (95% CI 0.02 to 0.34). Binary restenosis at 6 months (single vessel trials) favoured CABG, odds ratio 0.29 (95% CI 0.17 to 0.51). AUTHORS' CONCLUSIONS: CABG is associated with reduced rates of major adverse cardiac events, mostly driven by reduced repeat revascularisation. However, the RCT data are limited by follow-up, unrepresentative samples and rapid development of both surgical techniques and stenting. Research on real-world patient population or patient level data meta-analyses may identify risk factors and groupings who may benefit most from one strategy over the other.

7,8-Dihydroxyflavone as a pro-neurotrophic treatment for neurodevelopmental disorders.

Neurodevelopmental disorders are a group of conditions that arises from impairments of the central nervous system during its development. The causes of the various disorders are heterogeneous and the symptoms likewise are multifarious. Most of these disorders currently have very little available treatment that is effective in combating the plethora of serious symptoms. Brain-derived neurotrophic factor (BDNF) is a fundamental neurotrophin with vital functions during brain development. Pre-clinical studies have shown that increasing BDNF signalling may be a potent way to prevent, arrest or even reverse abnormal neurodevelopmental events arising from a variety of genetic or environmental causes. However, many difficulties make BDNF problematic to administer in an efficient manner. The recent discovery of a small BDNF-mimetic, the naturally occurring flavonoid 7,8-dihydroxyflavone (7,8-DHF), may provide an avenue to allow efficient and safe activation of the BDNF pathway in tackling the symptoms of neurodevelopmental disorders. Here, evidence will be provided to support the potential of 7,8-DHF as a novel treatment for several neurodevelopmental disorders where the BDNF signalling pathway is implicated in the pathophysiology and where benefits are therefore most likely to be derived from its implementation.

Brain-derived neurotrophic factor heterozygous mutant rats show selective cognitive changes and vulnerability to chronic corticosterone treatment.

Brain-derived neurotrophic factor (BDNF) is a widely expressed neurotrophin involved in neurodevelopment, neuroprotection and synaptic plasticity. It is also implicated in a range of psychiatric disorders such as schizophrenia, depression and post-traumatic stress disorder. Stress during adolescence/young adulthood can have long-term psychiatric and cognitive consequences, however it is unknown how altered BDNF signaling is involved in such effects. Here we investigated whether a congenital deficit in BDNF availability in rats increases vulnerability to the long-term effects of the stress hormone, corticosterone (CORT). Compared to wildtype (WT) littermates, BDNF heterozygous (HET) rats showed higher body weights and minor developmental changes, such as reduced relative brain and pituitary weight. These animals furthermore showed deficits in short-term spatial memory in the Y-maze and in prepulse inhibition and startle, but not in object-recognition memory. CORT treatment induced impairments in novel-object recognition memory in both genotypes but disrupted fear conditioning extinction learning in BDNF HET rats only. These results show selective behavioral changes in BDNF HET rats, at baseline or after chronic CORT treatment and add to our understanding of the role of BDNF and its interaction with stress. Importantly, this study demonstrates the utility of the BDNF HET rat in investigations into the pathophysiology of various psychiatric disorders.

Evaluation of the effect of alternative measurements of body weight gain and dry matter intake for the calculation of residual feed intake in growing purebred Charolais and Red Angus cattle.

The objective of this study was to determine the effects of alternative-measurements of body weight and DMI used to evaluate residual feed intake (RFI). Weaning weight (WW), ADG, and DMI were recorded on 970 growing purebred Charolais bulls (n = 519) and heifers (n = 451) and 153 Red Angus growing steers (n = 69) and heifers (n = 84) using a GrowSafe (GrowSafe, Airdrie, Alberta, Canada) system. Averages of individual DMI were calculated in 10-d increments and compared to the overall DMI to identify the magnitude of the errors associated with measuring DMI. These incremental measurements were also used in calculation of RFI, computed from the linear regression of DMI on ADG and midtest body weight0.75 (MMWT). RFI_Regress was calculated using ADG_Regress (ADG calculated as the response of BW gain and DOF) and MMWT_PWG (metabolic midweight calculated throughout the postweaning gain test), considered the control in Red Angus. A similar calculation served as control for Charolais; RFI was calculated using 2-d consecutive start and finish weights (RFI_Calc). The RFI weaning weight (RFI_WW) was calculated using ADG_WW (ADG from weaning till the final out weight of the postweaning gain test) and MMWT_WW, calculated similarly. Overall average estimated DMI was highly correlated to the measurements derived over shorter periods, with 10 d being the least correlated and 60 d being the most correlated. The ADG_Calc (calculated using 2-d consecutive start and finish weight/DOF) and ADG_WW were highly correlated in Charolais. The ADG_Regress and ADG_Calc were highly correlated, and ADG_Regress and ADG_WW were moderately correlated in Red Angus. The control measures of RFI were highly correlated with the RFI_WW in Charolais and Red Angus. The outcomes of including abbreviated period DMI in the model with the weaning weight gain measurements showed that the model using 10 d of intake (RFI WW_10) was the least correlated with the control measures. The model with 60 d of intake had the largest correlation with the control measures. The fewest measured intake days coupled with the weaning weight values providing acceptable predictive value was RFI_WW_40, being highly correlated with the control measures. As established in the literature, at least 70 d is required to accurately measure ADG. However, we conclude that a shorter period, possibly as few as 40 d is needed to accurately estimate DMI for a reliable calculation of RFI.

Analyzing the influence of BDNF heterozygosity on spatial memory response to 17ß-estradiol.

The recent use of estrogen-based therapies as adjunctive treatments for the cognitive impairments of schizophrenia has produced promising results; however the mechanism behind estrogen-based cognitive enhancement is relatively unknown. Brain-derived neurotrophic factor (BDNF) regulates learning and memory and its expression is highly responsive to estradiol. We recently found that estradiol modulates the expression of hippocampal parvalbumin-positive GABAergic interneurons, known to regulate neuronal synchrony and cognitive function. What is unknown is whether disruptions to the aforementioned estradiol-parvalbumin pathway alter learning and memory, and whether BDNF may mediate these events. Wild-type (WT) and BDNF heterozygous (+/-) mice were ovariectomized (OVX) at 5 weeks of age and simultaneously received empty, estradiol- or progesterone-filled implants for 7 weeks. At young adulthood, mice were tested for spatial and recognition memory in the Y-maze and novel-object recognition test, respectively. Hippocampal protein expression of BDNF and GABAergic interneuron markers, including parvalbumin, were assessed. WT OVX mice show impaired performance on Y-maze and novel-object recognition test. Estradiol replacement in OVX mice prevented the Y-maze impairment, a Behavioral abnormality of dorsal hippocampal origin. BDNF and parvalbumin protein expression in the dorsal hippocampus and parvalbumin-positive cell number in the dorsal CA1 were significantly reduced by OVX in WT mice, while E2 replacement prevented these deficits. In contrast, BDNF(+/-) mice showed either no response or an opposite response to hormone manipulation in both behavioral and molecular indices. Our data suggest that BDNF status is an important biomarker for predicting responsiveness to estrogenic compounds which have emerged as promising adjunctive therapeutics for schizophrenia patients.