Prenatal hypoxia alters the early ontogeny of dopamine neurons.

Dopaminergic (DA) dysfunction is a significant feature in the pathophysiology of schizophrenia. Established developmental risk factors for schizophrenia such as maternal immune activation (MIA) or developmental vitamin D (DVD) deficiency, when modelled in animals, reveal the differentiation of early DA neurons in foetal brains is delayed suggesting this may be a convergent aetiological pathway. Here we have assessed the effects of prenatal hypoxia, another well-known developmental risk factor for schizophrenia, on developing DA systems. Pregnant mice were exposed to a hypoxic environment of 10% oxygen for 48 h from embryonic day 10 (E10) to E12. Embryonic brains were collected and the positioning of mesencephalic cells, expression of DA specification and maturation factors were examined along with the expression of factors that may govern the migration of these neurons. We show that prenatal hypoxia results in a decrease in dopaminergic progenitors retards early DA neuron lateral migration and reduces expression of the receptors known to govern this process. A second time-point, postnatal day 10 (P10) was also examined in order to assess whether prenatal hypoxia alters early presynaptic architecture in the developing striatum. We show reduced expression of tyrosine hydroxylase (TH) in the postnatal striatum along with increases in the density of high-probability DA release sites within TH varicosities. These findings add to the emerging literature showing that multiple epidemiologically validated environmental risk factors for schizophrenia may induce early alterations to develop DA systems. This may represent a possible convergent mechanism in the onset of presynaptic DA dysfunction in patients.

Developmental Vitamin D Deficiency in Pregnant Rats Does Not Induce Preeclampsia.

Preeclampsia is a pregnancy disorder characterized by hypertension. Epidemiological studies have associated preeclampsia with an increased risk of neurodevelopmental disorders in offspring, such as autism and schizophrenia. Preeclampsia has also been linked with maternal vitamin D deficiency, another candidate risk factor also associated with autism. Our laboratory has established a gestational vitamin-D-deficient rat model that shows consistent and robust behavioural phenotypes associated with autism- and schizophrenia-related animal models. Therefore, we explored here whether this model also produces preeclampsia as a possible mediator of behavioural phenotypes in offspring. We showed that gestational vitamin D deficiency was not associated with maternal blood pressure or proteinuria during late gestation. Maternal and placental angiogenic and vasculogenic factors were also not affected by a vitamin-D-deficient diet. We further showed that exposure to low vitamin D levels did not expose the placenta to oxidative stress. Overall, gestational vitamin D deficiency in our rat model was not associated with preeclampsia-related features, suggesting that well-described behavioural phenotypes in offspring born to vitamin-D-deficient rat dams are unlikely to be mediated via a preeclampsia-related mechanism.

Elp2 mutations perturb the epitranscriptome and lead to a complex neurodevelopmental phenotype.

Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders and are characterized by substantial impairment in intellectual and adaptive functioning, with their genetic and molecular basis remaining largely unknown. Here, we identify biallelic variants in the gene encoding one of the Elongator complex subunits, ELP2, in patients with ID and ASD. Modelling the variants in mice recapitulates the patient features, with brain imaging and tractography analysis revealing microcephaly, loss of white matter tract integrity and an aberrant functional connectome. We show that the Elp2 mutations negatively impact the activity of the complex and its function in translation via tRNA modification. Further, we elucidate that the mutations perturb protein homeostasis leading to impaired neurogenesis, myelin loss and neurodegeneration. Collectively, our data demonstrate an unexpected role for tRNA modification in the pathogenesis of monogenic ID and ASD and define Elp2 as a key regulator of brain development.

Developmental vitamin D deficiency increases foetal exposure to testosterone.

BACKGROUND: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders which are more common in males. The 'prenatal sex steroid' hypothesis links excessive sex-steroid exposure during foetal life with the behavioural differences observed in ASD. However, the reason why sex steroid exposure may be excessive remains unclear. Epidemiological studies have identified several environmental risk factors associated with ASD, including developmental vitamin D (DVD) deficiency. We have demonstrated in an animal model that DVD-deficiency is associated with a hyper-inflammatory response in placentas from male but not female foetuses. Vitamin D also regulates the expression of several steroidogenic enzymes in vitro. Therefore using this animal model, we have examined whether DVD-deficiency leads to increased sex-steroid levels in both the maternal and foetal compartments. METHODS: Female rats are fed a vitamin D deficient diet from 6 weeks before mating until tissue collection at embryonic day 18. We examined the levels of testosterone, androstenedione and corticosterone in maternal plasma, foetal brains and amniotic fluid. We further examined gene expressions of steroidogenic enzymes and DNA methylation of aromatase promoters in foetal brains as a potential molecular mechanism regulating testosterone expression. RESULTS: We show that DVD-deficiency increases testosterone levels in maternal blood. We also show elevated levels of testosterone and androstenedione in the amniotic fluid of female but not male DVD-deficient foetuses. Testosterone levels were also elevated in DVD-deficient male brains. Vitamin D, like other steroid-related hormones, regulates gene expression via methylation. Therefore we examined whether the significant elevation in testosterone in male brains was due to such a potential gene-silencing mechanism. We show that the promoter of aromatase was hyper-methylated compared to male controls. LIMITATIONS: A reduction in aromatase, in addition to causing excessive testosterone, could also lead to a reduction in estradiol which was not examined here. CONCLUSIONS: This study is the first to show how an epidemiologically established environmental risk factor for ASD may selectively elevate testosterone in male embryonic brains. These findings provide further mechanistic support for the prenatal sex steroid theory of ASD.

The Community Analytics Academy Pilot: A Community-Academic Partnership for Building Community Health Care Analytic Capacity.

The ability to analyze data to identify best practices is key to improving quality of care for community-based health care organizations (CBOs). Leading commercial statistical software remains too costly for many CBOs operating in underserved communities. The St Louis Integrated Health Network (IHN) collaborates with CBOs to increase access to health care. IHN and a local university developed the Community Analytics Academy (CAA), a training collaborative designed to meet the need for data-informed decision making among CBOs. Establishing analytics training collaboratives for CBOs empowers organizations to respond to the ever-growing amounts of health care data and the need for data-driven decision making.

The evolution of cultural competence theories in American (United States) nursing curricula: An integrative review.

INTRODUCTION: Baccalaureate nursing students develop cultural competence through curricula of theories and frameworks which evolve to reflect new knowledge, but their synthesis and impact upon health quality outcomes is not known. METHODS: A cross-platform literature review was conducted to identify innovation and use of cultural competency theories and frameworks in nursing. Optimal literature included a formal theory, pedagogy, measures, and outcomes, which were then classified and evaluated. Additional perspectives and interventions were reviewed for potential influence on curricula and impact through the lens of integrative review. RESULTS: A shift in theory from essentialism to constructivism has occurred in undergraduate curricula. Challenges to measuring outcomes have been noted. All studies reported positive outcomes but suffer from self-selection, unvalidated instruments, and little to no longitudinal data. CONCLUSIONS: Nursing students are exposed to culturally competent care via several validated and canonical frameworks, but self-efficacy and long-term impact have not been assessed.

The Role of Social Issues on Food Procurement among Corner Store Owners and Shoppers.

OBJECTIVE: We assessed corner store shopper and owner perceptions, barriers, and enablers related to food procurement in a sample of neighborhood corner stores where over 50% of families are SNAP eligible. DESIGN: We conducted semi-structured interviews to identify inventory stocking, shopping and marketing approaches, and perspectives on healthy eating. PARTICIPANTS: Five corner store owners and 20 corner store shoppers. RESULTS: Corner store owners: 1) did not feel as though they belonged to the community where their corner store was located; 2) had difficulty in becoming authorized WIC retailers because of the perceived complexity of the process, and 3) stated tobacco products and hot food items are their best-selling items; fruits and vegetables were perceived as unmarketable. Corner store shoppers preferred shopping at local corner stores because: 1) lack of transportation made corner stores easier to access than full-service grocery stores; 2) hot foods are readily available and inexpensive; 3) some home kitchens lacked an oven or stovetop for meal preparation; 4) they need to shop daily for children or other family members. CONCLUSIONS: Social issues such as housing quality, corner store owner sense of community, and acculturation should be addressed when considering food environment in limited resource communities.

Developmental Vitamin D Deficiency Produces Behavioral Phenotypes of Relevance to Autism in an Animal Model.

Emerging evidence suggests that gestational or developmental vitamin D (DVD) deficiency is associated with an increased risk of autism spectrum disorder (ASD). ASD is a neurodevelopmental disorder characterized by impairments in social interaction, lack of verbal and non-verbal communications, stereotyped repetitive behaviors and hyper-activities. There are several other clinical features that are commonly comorbid with ASD, including olfactory impairments, anxiety and delays in motor development. Here we investigate these features in an animal model related to ASD-the DVD-deficient rat. Compared to controls, both DVD-deficient male and female pups show altered ultrasonic vocalizations and stereotyped repetitive behavior. Further, the DVD-deficient animals had delayed motor development and impaired motor control. Adolescent DVD-deficient animals had impaired reciprocal social interaction, while as adults, these animals were hyperactive. The DVD-deficient model is associated with a range of behavioral features of interest to ASD.

The placental immune response is dysregulated developmentally vitamin D deficient rats: Relevance to autism.

Emerging evidence suggests that maternal or developmental vitamin D (DVD) deficiency is a risk factor for Autism Spectrum Disorders. A well-established association has also been found between gestational infection and increased incidence of autism. Placenta mediates the maternal immune response in respect to the foetus. The placenta is also a major source of vitamin D and locally produced vitamin D is an essential regulator of immune function during pregnancy. Here we investigate the effects of DVD-deficiency on baseline placental immune status and in response to the well-known viral and bacterial immune activating agents polyriboinosinic-polyribocytidylic acid (poly(I:C) and lipopolysaccharide (LPS). We show DVD-deficiency does not affect baseline inflammatory cytokines in placenta. However, when challenged with poly(I:C) but not LPS, DVD-deficient placentas from male foetuses had higher production of IL-6 and 1L-1ß compared to control placentas. This suggests the developing DVD-deficient male foetus may be particularly vulnerable to maternal viral exposures. This in turn may have adverse implications for the developing male brain. In conclusion, a dysregulated placental immune response may provide a plausible mechanism for both the epidemiological links between DVD-deficiency and increased male incidence of developmental conditions such as autism.

Developmental Vitamin D (DVD) Deficiency Reduces Nurr1 and TH Expression in Post-mitotic Dopamine Neurons in Rat Mesencephalon.

Developmental vitamin D (DVD) deficiency has been proposed as an important risk factor for schizophrenia. Our previous study using Sprague Dawley rats found that DVD deficiency disrupted the ontogeny of mesencephalic dopamine neurons by decreasing the mRNA level of a crucial differentiation factor of dopamine cells, the nuclear receptor related 1 protein (Nurr1). However, it remains unknown whether this reflects a reduction in dopamine cell number or in Nurr1 expression. It is also unclear if any particular subset of developing dopamine neurons in the mesencephalon is selectively affected. In this study, we employed state-of-the-art spinning disk confocal microscopy optimized for the imaging of tissue sections and 3D segmentation to assess post-mitotic dopamine cells on a single-cell basis in the rat mesencephalon at embryonic day 15. Our results showed that DVD deficiency did not alter the number, morphology, or positioning of post-mitotic dopamine cells. However, the ratio of Nurr1+TH+ cells in the substantia nigra pars compacta (SNc) compared with the ventral tegmental area (VTA) was increased in DVD-deficient embryos. In addition, the expression of Nurr1 in immature dopamine cells and mature dopamine neurons in the VTA was decreased in DVD-deficient group. Tyrosine hydroxylase was selectively reduced in SNc of DVD-deficient mesencephalon. We conclude that DVD deficiency induced early alterations in mesencephalic dopamine development may in part explain the abnormal dopamine-related behaviors found in this model. Our findings may have broader implications for how certain environmental risk factors for schizophrenia may shape the ontogeny of dopaminergic systems and by inference increase the risk of schizophrenia.

Developmental vitamin D deficiency alters multiple neurotransmitter systems in the neonatal rat brain.

BACKGROUND: Epidemiological evidence suggests that developmental vitamin D (DVD) deficiency is a risk factor for neuropsychiatric disorders, such as schizophrenia. DVD deficiency in rats is associated with altered brain structure and adult behaviours indicating alterations in dopamine and glutamate signalling. Developmental alterations in dopamine neurotransmission have also been observed in DVD-deficient rats but a comprehensive assessment of brain neurochemistry has not been undertaken. Thus, the current study determined the regional concentrations of dopamine, noradrenaline, serotonin, glutamine, glutamate and γ-aminobutyric acid (GABA), and associated metabolites, in DVD-deficient neonates. METHODS: Sprague-Dawley rats were fed a vitamin D deficient diet or control diet six weeks prior to mating until birth and housed under UVB-free lighting conditions. Neurotransmitter concentration was assessed by high-performance liquid chromatography on post-mortem neonatal brain tissue. RESULTS: Ubiquitous reductions in the levels of glutamine (12-24%) were observed in DVD-deficient neonates compared with control neonates. Similarly, in multiple brain regions DVD-deficient neonates had increased levels of noradrenaline and serine compared with control neonates. In contrast, increased levels of dopamine and decreased levels of serotonin in DVD-deficient neonates were limited to striatal subregions compared with controls. CONCLUSIONS: Our results confirm that DVD deficiency leads to changes in multiple neurotransmitter systems in the neonate brain. Importantly, this regionally-based assessment in DVD-deficient neonates identified both widespread neurotransmitter changes (glutamine/noradrenaline) and regionally selective neurotransmitter changes (dopamine/serotonin). Thus, vitamin D may have both general and local actions depending on the neurotransmitter system being investigated. Taken together, these data suggest that DVD deficiency alters neurotransmitter systems relevant to schizophrenia in the developing rat brain.

Risperidone induces long-lasting changes in the conditioned avoidance response and accumbal gene expression selectively in animals treated as adolescents.

Adolescence is a period of dynamic remodeling and maturation in the brain. Exposure to psychotropic drugs during adolescence can potentially alter neural maturation in the adolescent brain subsequently altering neural function at maturity. In this regard, antipsychotic drugs (APDs) are important given a notable global increase in prescription of these APDs to adolescents for a variety of behavioural symptoms and conditions over the past twenty years. However, there is a paucity of data on the long-term consequences of APDs on the adolescent brain. In this preclinical study, we have examined whether the adolescent brain is more susceptible than the adult brain to long-term neural changes induced by risperidone, which is the APD most frequently prescribed to adolescents. Rats were chronically treated (21 days) with 1.3 mg/kg/day risperidone or vehicle either as adolescents (postnatal day (PND) 36-56)) or adults (PND80-100). Behaviour was assessed using the well-described suppression of the conditioned avoidance response (CAR) by APDs. We examined CAR after all animals had reached maturity (PND127). We show that mature rats treated with risperidone as adolescents had increased CAR suppression compared to adults when rechallenged with this same drug. In the nucleus accumbens, significant downregulation of serotonergic 5HT2A receptors and catechol-o-methyl transferase mRNA levels was observed only in the adolescent treated animals. Impaired 5HT2A receptor signaling may explain the increased CAR suppression observed in rats treated with risperidone as adolescents. Magnetic resonance imaging (MRI), however, did not detect any risperidone-induced long-term brain structural change at maturity. These findings confirm that APD administration during adolescence may produce long-term behavioural and neurochemical alterations.

Usp9x-deficiency disrupts the morphological development of the postnatal hippocampal dentate gyrus.

Within the adult mammalian brain, neurogenesis persists within two main discrete locations, the subventricular zone lining the lateral ventricles, and the hippocampal dentate gyrus. Neurogenesis within the adult dentate gyrus contributes to learning and memory, and deficiencies in neurogenesis have been linked to cognitive decline. Neural stem cells within the adult dentate gyrus reside within the subgranular zone (SGZ), and proteins intrinsic to stem cells, and factors within the niche microenvironment, are critical determinants for development and maintenance of this structure. Our understanding of the repertoire of these factors, however, remains limited. The deubiquitylating enzyme USP9X has recently emerged as a mediator of neural stem cell identity. Furthermore, mice lacking Usp9x exhibit a striking reduction in the overall size of the adult dentate gyrus. Here we reveal that the development of the postnatal SGZ is abnormal in mice lacking Usp9x. Usp9x conditional knockout mice exhibit a smaller hippocampus and shortened dentate gyrus blades from as early as P7. Moreover, the analysis of cellular populations within the dentate gyrus revealed reduced stem cell, neuroblast and neuronal numbers and abnormal neuroblast morphology. Collectively, these findings highlight the critical role played by USP9X in the normal morphological development of the postnatal dentate gyrus.

Reflection on observation: A qualitative study using practice development methods to explore the experience of being a hand hygiene auditor in Australia.

BACKGROUND: Within the Australian public health care system, an observation model is used to assess hand hygiene practice in health care workers, culminating in a publicly available healthcare service performance indicator. The intent of this study was for the results to inform the development of a strategy to support individual auditors and local sustainability of the hand hygiene auditing program. METHOD: This qualitative study used a values clarification tool to gain an understanding of the experiences of hand hygiene auditors. The methodology involved qualitative interpretation of focus group discussions to identify the enablers and barriers to successful performance of the auditors' role. RESULTS: Twenty-five participants identified congruous themes of the need for peer and managerial support, improved communication and feedback, and consideration for succession planning. There was consistency in the participants' most frequently identified significant barriers in undertaking the role. CONCLUSION: Hand hygiene auditors take pride in their role and work toward the goal of reducing health care-associated infections by having a part to play in improving hand hygiene practices of all staff members. Important themes, barriers, and enablers were identified in this study. This research will be of interest nationally and globally, considering the dearth of published information on the experience of hand hygiene auditors. This study provides evidence of the need to support individual hand hygiene auditors.

Developmentally vitamin D-deficient rats show enhanced prepulse inhibition after acute Δ9-tetrahydrocannabinol.

Developmental vitamin D (DVD) deficiency has been proposed as a risk factor for schizophrenia. DVD-deficient rats show selective cognitive deficits and novelty-induced hyperlocomotion and enhanced locomotor responses from acute treatment with psychomimetic drugs, such as amphetamine and MK-801. Here we aimed to examine the effect of a drug from a different class of psychomimetic/psychoactive compounds, Δ9-tetrahydrocannabinol (THC), on tasks of relevance to the cognitive and positive symptoms of schizophrenia. The aim of this study was to investigate whether DVD deficiency modulates the behavioural effects of THC on tests of delay-dependent memory, sensorimotor gating and locomotion. Adult control and DVD-deficient rats were injected with THC (0, 0.3, 0.6, 1.25, 2.5 mg/kg) 15 min before a delay match to sample (DMTS) task using variable delays (0-24 s). A separate group of rats was injected with either 2.5 mg/kg THC or vehicle before tests of either prepulse inhibition (PPI) of the acoustic startle response or in the open field. Control and DVD-deficient rats showed a similar dose-dependent impairment in performance on the DMTS. The greatest impairment was observed at 2.5 mg/kg for all delays (0-24 s). DVD-deficient rats showed THC-induced enhancement of PPI, which was not observed in control rats. There was no effect of maternal diet on acoustic startle response or locomotor responses in the open field. This study reports the novel findings that DVD-deficient rats were more sensitive to the acute effects of THC on PPI. It appears that prenatal vitamin D deficiency has long-term effects on sensitivity to the behavioural effects of cannabinoids.

Developmental vitamin D deficiency alters MK-801-induced behaviours in adult offspring.

RATIONALE: Developmental vitamin D (DVD) deficiency is a candidate risk factor for developing schizophrenia in humans. In rodents DVD deficiency induces subtle changes in the way the brain develops. This early developmental insult leads to select behavioural changes in the adult, such as an enhanced response to amphetamine-induced locomotion in female DVD-deficient rats but not in male DVD-deficient rats and an enhanced locomotor response to the N-methyl-D: -aspartate (NMDA) receptor antagonist, MK-801, in male DVD-deficient rats. However, the response to MK-801-induced locomotion in female DVD-deficient rats is unknown. Therefore, the aim of the current study was to further examine this behavioural finding in male and female rats and assess NMDA receptor density. METHODS: DVD-deficient Sprague Dawley rats were assessed for locomotion, ataxia, acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR to multiple doses of MK-801. The NMDA receptor density in relevant brain regions was assessed in a drug-naive cohort. RESULTS: DVD deficiency increased locomotion in response to MK-801 in both sexes. DVD-deficient rats also showed an enhanced ASR compared with control rats, but PPI was normal. Moreover, DVD deficiency decreased NMDA receptor density in the caudate putamen of both sexes. CONCLUSIONS: These results suggest that a transient prenatal vitamin D deficiency has a long-lasting effect on NMDA-mediated signalling in the rodent brain and may be a plausible candidate risk factor for schizophrenia and other neuropsychiatric disorders.

Developmental vitamin D (DVD) deficiency alters pup-retrieval but not isolation-induced pup ultrasonic vocalizations in the rat.

Evidence from animal experiments now demonstrates that prenatal vitamin D levels influence brain development. The aims of this study were to examine isolation-induced pup ultrasonic vocalizations and maternal-infant interactions using a pup-retrieval test in developmental vitamin D (DVD) deficient and control rats. Sprague-Dawley rats were fed a vitamin D deficient diet or control diet six weeks prior to mating until birth and housed under UVB-free lighting conditions. In two separate experiments we recorded ultrasonic vocalizations at 46KHz in isolated pups and we performed a pup-retrieval test on the day of birth. There was no significant effect of maternal diet on the calling rate of isolation-induced ultrasonic vocalizations by pups. We found that DVD-deficient dams retrieved their pups sooner than control dams and engaged in more pup directed activities (sniffing and carrying pups) and had a longer latency for self-grooming and rearing than control dams. We also assessed vitamin D related measures from a terminal blood sample immediately after the pup-retrieval test and found that DVD-deficient dams and pups had significantly lower levels of 25 OH D3, 1,25 (OH)2D3 and phosphate, elevated levels of parathyroid hormone (PTH) but there was no significant effect of maternal diet on calcium levels. We speculate that the altered maternal-pup interactions identified in the DVD model may impact on early periods of brain development and behaviour.

T-cell lymphoma of the tympanic bulla in a feline leukemia virus-negative cat.

This report constitutes the first description of a T-cell lymphoma of the tympanic bulla in a cat. This feline leukemia virus (FeLV)-negative cat originally presented with signs referable to middle ear disease; it deteriorated rapidly after definitive diagnosis. Lymphoma of the middle ear is extremely rare in all species.