The accuracy of prehospital triage decisions in English trauma networks - a case-cohort study.

BACKGROUND: Care for injured patients in England is provided by inclusive regional trauma networks. Ambulance services use triage tools to identify patients with major trauma who would benefit from expedited Major Trauma Centre (MTC) care. However, there has been no investigation of triage performance, despite its role in ensuring effective and efficient MTC care. This study aimed to investigate the accuracy of prehospital major trauma triage in representative English trauma networks. METHODS: A diagnostic case-cohort study was performed between November 2019 and February 2020 in 4 English regional trauma networks as part of the Major Trauma Triage Study (MATTS). Consecutive patients with acute injury presenting to participating ambulance services were included, together with all reference standard positive cases, and matched to data from the English national major trauma database. The index test was prehospital provider triage decision making, with a positive result defined as patient transport with a pre-alert call to the MTC. The primary reference standard was a consensus definition of serious injury that would benefit from expedited major trauma centre care. Secondary analyses explored different reference standards and compared theoretical triage tool accuracy to real-life triage decisions. RESULTS: The complete-case case-cohort sample consisted of 2,757 patients, including 959 primary reference standard positive patients. The prevalence of major trauma meeting the primary reference standard definition was 3.1% (n=54/1,722, 95% CI 2.3 - 4.0). Observed prehospital provider triage decisions demonstrated overall sensitivity of 46.7% (n=446/959, 95% CI 43.5-49.9) and specificity of 94.5% (n=1,703/1,798, 95% CI 93.4-95.6) for the primary reference standard. There was a clear trend of decreasing sensitivity and increasing specificity from younger to older age groups. Prehospital provider triage decisions commonly differed from the theoretical triage tool result, with ambulance service clinician judgement resulting in higher specificity. CONCLUSIONS: Prehospital decision making for injured patients in English trauma networks demonstrated high specificity and low sensitivity, consistent with the targets for cost-effective triage defined in previous economic evaluations. Actual triage decisions differed from theoretical triage tool results, with a decreasing sensitivity and increasing specificity from younger to older ages.

Identification of the Neural Correlates Underlying Conflict Resolution Performance Using a Rodent Analogue of the Stroop Tests.

The Stroop test is a widely used neuropsychological test measuring attention and conflict resolution, which shows sensitivity across a range of diseases, including Alzheimer's, Parkinson's and Huntington's diseases. A rodent analogue of the Stroop test, the Response-Conflict task (rRCT), allows for systematic investigation of the neural systems underpinning performance in this test. Little is known about the involvement of the basal ganglia in this neural process. The aim of this study was to use the rRCT to determine whether striatal subregions are recruited during conflict resolution processing. To achieve this, rats were exposed to Congruent or Incongruent stimuli in the rRCT and the expression patterns of the immediate early gene Zif268 were analysed throughout cortical, hippocampal and basal ganglia subregions. The results confirmed the previously reported involvement of prefrontal cortical and hippocampal regions, as well as identifying a specific role for the dysgranular (but not granular) retrosplenial cortex in conflict resolution. Finally, performance accuracy correlated significantly with reduced neural activation in the dorsomedial striatum. Involvement of the basal ganglia in this neural process has not previously been reported. These data demonstrate that the cognitive process of conflict resolution requires not only prefrontal cortical regions, but also recruits the dysgranular retrosplenial cortex and the medial region of the neostriatum. These data have implications for understanding the neuroanatomical changes that underpin impaired Stroop performance in people with neurological disorders.

Multi-disciplinary assessment of the entrustable professional activities of surgery residents.

Purpose: Medicine is practiced in a collaborative and interdisciplinary manner. However, medical training and assessment remain largely isolated in traditional departmental silos. Two Entrustable Professional Activities (EPAs) developed by the American Board of Surgery are multidisciplinary in nature and offer a unique opportunity to study interdisciplinary assessment. Methods: EPA microassessments were collected from Surgery and Emergency Medicine (EM) faculty between July 2018 and May 2020. Differences in feedback provided by faculty were assessed using natural language processing (NLP) techniques, (1) automated algorithms; and (2) topic modeling. Summative content analysis was used to identify themes in text feedback. We developed automated coding algorithms for these themes using regular expressions. Topic modeling was performed using latent Dirichlet allocation. Results: 549 assessments were collected for two EPAs: 198 for GS Consultation and 351 for Trauma. 27 EM and 27 Surgery faculty provided assessments for 71 residents. EM faculty were significantly more likely than Surgery faculty to submit feedback coded as Communication, Demeanor, and Timeliness, (all chi-square test p-values < 0.01). No significant differences were found for Clinical Performance, Skill Level, or Areas for Improvement. Similarly, topic modeling indicated that assessments submitted by EM faculty focused on communication, timeliness, and interpersonal skills, while those submitted by Surgery faculty focused on the residents' abilities to effectively gather information and correctly diagnose the underlying pathology. Conclusions: Feedback from EM and Surgery faculty differed significantly based on NLP analyses. EPA assessments should stem from multiple sources to avoid assessment gaps and represent a more holistic picture of performance.

Perceptions of anonymised data use and awareness of the NHS data opt-out amongst patients, carers and healthcare staff.

BACKGROUND: England operates a National Data Opt-Out (NDOO) for the secondary use of confidential health data for research and planning. We hypothesised that public awareness and support for the secondary use of health data and the NDOO would vary by participant demography and healthcare experience. We explored patient/public awareness and perceptions of secondary data use, grouping potential researchers into National Health Service (NHS), academia or commercial. We assessed awareness of the NDOO system amongst patients, carers, healthcare staff and the public. We co-developed recommendations to consider when sharing unconsented health data for research. METHODS: A patient and public engagement program, co-created and including patient and public workshops, questionnaires and discussion groups regarding anonymised health data use. RESULTS: There were 350 participants in total. Central concerns for health data use included unauthorised data re-use, the potential for discrimination and data sharing without patient benefit. 94% of respondents were happy for their data to be used for NHS research, 85% for academic research and 68% by health companies, but less than 50% for non-healthcare companies and opinions varied with demography and participant group. Questionnaires showed that knowledge of the NDOO was low, with 32% of all respondents, 53% of all NHS staff and 29% of all patients aware of the NDOO. Recommendations to guide unconsented secondary health data use included that health data use should benefit patients; data sharing decisions should involve patients/public. That data should remain in close proximity to health services with the principles of data minimisation applied. Further, that there should be transparency in secondary health data use, including publicly available lists of projects, summaries and benefits. Finally, organisations involved in data access decisions should participate in programmes to increase knowledge of the NDOO, to ensure public members were making informed choices about their own data. CONCLUSION: The majority of participants in this study reported that the use of healthcare data for secondary purposes was acceptable when accessed by NHS. Academic and health-focused companies. However, awareness was limited, including of the NDOO. Further development of publicly-agreed recommendations for secondary health data use may improve both awareness and confidence in secondary health data use.

Health data from routine care can be pseudonymised (with a link remaining to the patient but identifying features removed) or anonymised (with identifying features removed and the link to the patient severed) and used for research and health planning; termed "secondary use". The National Health Service (NHS) is a single publicly-funded health service for the United Kingdom (UK). The NHS supports secondary data use with a National Data opt-out system. The potential benefits of data secondary use are clear but concerns have been raised. Although the Data Opt-Out is publicised, it is unclear how much public awareness there is of this scheme. We report a patient and publicly created and delivered series of activities including > 350 people; with young adults, patients, NHS staff and the public; to assess concerns, knowledge and acceptance of data sharing.Perceptions of and support for secondary health data use varied depending on who was asked (by age, gender) and their experience of health services (Staff member, patient, member of the public). Knowledge of schemes to limit secondary data use (such as the UK National Data Op-Out) was low, even among NHS staff. The main concerns of sharing health data included onward data use, the potential for discrimination and exploitation and commercial gain from data use with no benefit to patients. Despite this, most participants agreed with health data sharing with NHS, academic and commercial health-based entities. Agreed, co-created themes to increase the acceptability of health data secondary use included education about 'Opt-out' schemes, health service oversight of data use (as the most trusted partner), public and patient involvement in data sharing decisions and public transparency.

Automated Assessment of Movement Impairment in Huntington's Disease.

Quantitative assessment of movement impairment in Huntington's disease (HD) is essential to monitoring of disease progression. This paper aimed to develop and validate a novel low cost, objective automated system for the evaluation of upper limb movement impairment in HD in order to eliminate the inconsistency of the assessor and offer a more sensitive, continuous assessment scale. Patients with genetically confirmed HD and healthy controls were recruited to this observational study. Demographic data, including age (years), gender, and unified HD rating scale total motor score (UHDRS-TMS), were recorded. For the purposes of this paper, a modified upper limb motor impairment score (mULMS) was generated from the UHDRS-TMS. All participants completed a brief, standardized clinical assessment of upper limb dexterity while wearing a tri-axial accelerometer on each wrist and on the sternum. The captured acceleration data were used to develop an automatic classification system for discriminating between healthy and HD participants and to automatically generate a continuous movement impairment score (MIS) that reflected the degree of the movement impairment. Data from 48 healthy and 44 HD participants was used to validate the developed system, which achieved 98.78% accuracy in discriminating between healthy and HD participants. The Pearson correlation coefficient between the automatic MIS and the clinician rated mULMS was 0.77 with a p-value < 0.01. The approach presented in this paper demonstrates the possibility of an automated objective, consistent, and sensitive assessment of the HD movement impairment.

Alterations in the metabolic and cardiorespiratory response to exercise in Huntington's Disease.

BACKGROUND: Limited data suggests that an altered metabolic and cardiorespiratory exercise response may affect exercise performance in individuals with Huntington's disease (HD). There is no clear exploration of the response in individuals at different stages of the disease or in relation to genetic markers. This study aimed to examine the exercise response and recovery of HD participants, and the relationship to genetic and clinical markers. METHOD: HD gene-positive participants (n = 31; 9 pre-manifest; 22 manifest HD) and a healthy control group (n = 29) performed an incremental exercise test until exhaustion. Performance, cardiorespiratory, metabolic and perceptual responses to exercise were determined from a maximal cycle ergometer test throughout the exercise test and during a recovery period. RESULTS: During sub-maximal exercise, metabolic (lactate levels, oxygen uptake) and cardiorespiratory markers (heart rate) were elevated in HD participants compared to controls. Lactate elevation was specific to pre-manifest HD participants. Work capacity was reduced in both pre-manifest and manifest HD participants with tests terminated with no difference in metabolic, perceptual or cardiorespiratory markers. Submaximal oxygen uptake was correlated with motor score, whilst peak measures were unrelated to genetic or clinical markers. Heart rate recovery was attenuated in pre-manifest and manifest HD participants. CONCLUSIONS: Our findings confirm metabolic and cardiorespiratory deficits reduce exercise performance and affect recovery from an early stage in HD, with submaximal deficits related to phenotypic expression. Exercise capacity appears to be limited by an altered movement economy, thus clinicians should consider an altered exercise response and recovery may affect prescription in HD.

Recurrent tuberculosis in the pre-elimination era.

Recurrent tuberculosis (TB), defined as TB that recurs after a patient has been considered cured, constitutes a challenge to TB control. In low TB burden countries, the underlying causes and consequences of recurrent TB are poorly understood. We conducted a literature review to summarise the evidence of recurrent TB in low-burden settings and to address current gaps in knowledge. We included peer-reviewed publications on studies conducted in countries with an estimated TB incidence of <100 cases per 100 000 population. The Newcastle-Ottawa scale was used to assess study quality. The review yielded 44 manuscripts, 39 of which were reports of observational studies and 5 of clinical trials. The median percentage of TB patients experiencing an episode of recurrent TB after treatment completion was 3.4% (interquartile range [IQR] 1.6-6.0, range 0.4-16.7) in studies with a median follow-up of 7.8 years (IQR 5-12, range 2-33). The median percentage of recurrences attributable to endogenous reactivation (rather than exogenous reinfection) was 81% (IQR 73.1-85.5, range 49-100). Commonly identified risk factors for recurrence in low-burden settings included infection by the human immunodeficiency virus, low socio-economic status, foreign birth and infection with drug-resistant TB. Current understanding of recurrence in low-burden settings is limited, in part due to substantial methodological differences between studies. Further research is required to delineate the mechanisms of TB recurrence, its health and clinical impact, as well as the implications for TB elimination efforts in low-burden countries.

Clinical characterization of dystonia in adult patients with Huntington's disease.

BACKGROUND AND PURPOSE: Huntington's disease (HD) is an autosomal dominant, neurodegenerative movement disorder, typically characterized by chorea. Dystonia is also recognized as part of the HD motor phenotype, although little work detailing its prevalence, distribution, severity and impact on functional capacity has been published to date. METHODS: Patients (>18 years of age) were recruited from the Cardiff (UK) HD clinic, each undergoing a standardized videotaped clinical examination and series of functional assessment questionnaires (Unified Huntington's Disease Rating Scale, Burke-Fahn-Marsden Dystonia Rating Scale and modified version of the Toronto Western Spasmodic Torticollis Rating Scale). The presence and severity of dystonia were scored by four independent neurologists using the Burke-Fahn-Marsden Dystonia Rating Scale and Unified Huntington's Disease Rating Scale. Statistical analysis included Fisher's exact test, Wilcoxon test, anova and calculation of correlation coefficients where appropriate. RESULTS: Forty-eight patients [91% (48/53)] demonstrated evidence of dystonia, with the highest prevalence in the left upper limb (n = 44, 83%), right upper limb most severely affected and eyes least affected. Statistically significant positive correlations (P < 0.05) were observed between dystonia severity and increasing HD disease stage and motor disease duration. Deterioration in functional capacity also correlated with increasing dystonia severity. No significant relationship was observed with age at motor symptom onset or CAG repeat length. CONCLUSIONS: We report a high prevalence of dystonia in adult patients with HD, with worsening dystonia severity with increasing HD disease stage and motor disease duration. The recognition and management of dystonic symptoms in routine clinical practice will aid overall symptomatic treatment and functional improvement.

The societal cost of Huntington's disease: are we underestimating the burden?

BACKGROUND AND PURPOSE: Approximately 9000 people in the UK are affected by Huntington's disease (HD). People with HD require ongoing health and social care support. There is a knowledge gap about costs of health and social care use associated with HD in the UK. This paper estimates the economic cost in the UK. METHODS: Data on UK patients for the year 2013 were extracted from the European Huntington's Disease Network REGISTRY study, a full clinical dataset, including the full medical history and medication history for patients with HD. National unit costs for the price year 2013 were applied to health and social care services. RESULTS: Data were available for 131 people. The mean annual cost per person with HD was £21 605. The largest proportion of this cost (65%) was due to informal care (£14 085). CONCLUSIONS: Informal care was the largest driver of costs across all stages of HD; thus there is a need to also consider the needs of carers when planning services for people with HD.

FoxP1 marks medium spiny neurons from precursors to maturity and is required for their differentiation.

Identifying the steps involved in striatal development is important both for understanding the striatum in health and disease, and for generating protocols to differentiate striatal neurons for regenerative medicine. The most prominent neuronal subtype in the adult striatum is the medium spiny projection neuron (MSN), which constitutes more than 85% of all striatal neurons and classically expresses DARPP-32. Through a microarray study of genes expressed in the whole ganglionic eminence (WGE: the developing striatum) in the mouse, we identified the gene encoding the transcription factor Forkhead box protein P1 (FoxP1) as the most highly up-regulated gene, thus providing unbiased evidence for the association of FoxP1 with MSN development. We also describe the expression of FoxP1 in the human fetal brain over equivalent gestational stages. FoxP1 expression persisted through into adulthood in the mouse brain, where it co-localised with all striatal DARPP-32 positive projection neurons and a small population of DARPP-32 negative cells. There was no co-localisation of FoxP1 with any interneuron markers. FoxP1 was detectable in primary fetal striatal cells following dissection, culture, and transplantation into the adult lesioned striatum, demonstrating its utility as an MSN marker for transplantation studies. Furthermore, DARPP-32 expression was absent from FoxP1 knock-out mouse WGE differentiated in vitro, suggesting that FoxP1 is important for the development of DARPP-32-positive MSNs. In summary, we show that FoxP1 labels MSN precursors prior to the expression of DARPP-32 during normal development, and in addition suggest that FoxP1 labels a sub-population of MSNs that are not co-labelled by DARPP-32. We demonstrate the utility of FoxP1 to label MSNs in vitro and following neural transplantation, and show that FoxP1 is required for DARPP-32 positive MSN differentiation in vitro.

Prevalence and predictors of hospital prealerting in acute stroke: a mixed methods study.

BACKGROUND: Thrombolysis can significantly reduce the burden of stroke but the time window for safe and effective treatment is short. In patients travelling to hospital via ambulance, the sending of a 'prealert' message can significantly improve the timeliness of treatment. OBJECTIVE: Examine the prevalence of hospital prealerting, the extent to which prealert protocols are followed and what factors influence emergency medical services (EMS) staff's decision to send a prealert. METHODS: Cohort study of patients admitted to two acute stroke units in West Midlands (UK) hospitals using linked data from hospital and EMS records. A logistic regression model examined the association between prealert eligibility and whether a prealert message was sent. In semistructured interviews, EMS staff were asked about their experiences of patients with suspected stroke. RESULTS: Of the 539 patients eligible for this study, 271 (51%) were recruited. Of these, only 79 (29%) were eligible for prealerting according to criteria set out in local protocols but 143 (53%) were prealerted. Increasing number of Face, Arm, Speech Test symptoms (1 symptom, OR 6.14, 95% CI 2.06 to 18.30, p=0.001; 2 symptoms, OR 31.36, 95% CI 9.91 to 99.24, p<0.001; 3 symptoms, OR 75.84, 95% CI 24.68 to 233.03, p<0.001) and EMS contact within 5 h of symptom onset (OR 2.99, 95% CI 1.37 to 6.50 p=0.006) were key predictors of prealerting but eligibility for prealert as a whole was not (OR 1.92, 95% CI 0.85 to 4.34 p=0.12). In qualitative interviews, EMS staff displayed varying understanding of prealert protocols and described frustration when their interpretation of the prealert criteria was not shared by ED staff. CONCLUSIONS: Up to half of the patients presenting with suspected stroke in this study were prealerted by EMS staff, regardless of eligibility, resulting in disagreements with ED staff during handover. Aligning the expectations of EMS and ED staff, perhaps through simplified prealert protocols, could be considered to facilitate more appropriate use of hospital prealerting in acute stroke.

Amelioration of non-motor dysfunctions after transplantation of human dopamine neurons in a model of Parkinson's disease.

BACKGROUND: Patients suffering from Parkinson's disease (PD) display cognitive and neuropsychiatric dysfunctions, especially with disease progression. Although these impairments have been reported to impact more heavily upon a patient's quality of life than any motor dysfunctions, there are currently no interventions capable of adequately targeting these non-motor deficits. OBJECTIVES: Utilizing a rodent model of PD, we investigated whether cell replacement therapy, using intrastriatal transplants of human-derived ventral mesencephalic (hVM) grafts, could alleviate cognitive and neuropsychiatric, as well as motor, dysfunctions. METHODS: Rats with unilateral 6-hydroxydopamine lesions to the medial forebrain bundle were tested on a complex operant task that dissociates motivational, visuospatial and motor impairments sensitive to the loss of dopamine. A subset of lesioned rats received intrastriatal hVM grafts of ~9 weeks gestation. Post-graft, rats underwent repeated drug-induced rotation tests and were tested on two versions of the complex operant task, before post-mortem analysis of the hVM tissue grafts. RESULTS: Post-graft behavioural testing revealed that hVM grafts improved non-motor aspects of task performance, specifically visuospatial function and motivational processing, as well as alleviating motor dysfunctions. CONCLUSIONS: We report the first evidence of human VM cell grafts alleviating both non-motor and motor dysfunctions in an animal model of PD. This intervention, therefore, is the first to improve cognitive and neuropsychiatric symptoms long-term in a model of PD.

Isothermal Recombinase Polymerase amplification (RPA) of Schistosoma haematobium DNA and oligochromatographic lateral flow detection.

BACKGROUND: Accurate diagnosis of urogenital schistosomiasis is vital for surveillance/control programs. Amplification of schistosome DNA in urine by PCR is sensitive and specific but requires infrastructure, financial resources and skilled personnel, often not available in endemic areas. Recombinase Polymerase Amplification (RPA) is an isothermal DNA amplification/detection technology that is simple, rapid, portable and needs few resources. FINDINGS: Here a Schistosoma haematobium RPA assay was developed and adapted so that DNA amplicons could be detected using oligochromatographic Lateral Flow (LF) strips. The assay successfully amplified S. haematobium DNA at 30-45 °C in 10 mins and was sensitive to a lower limit of 100 fg of DNA. The assay was also successful with the addition of crude urine, up to 5% of the total reaction volume. Cross amplification occurred with other schistosome species but not with other common urine microorganisms. CONCLUSION: The LF-RPA assay developed here can amplify and detect low levels of S. haematobium DNA. Reactions are rapid, require low temperatures and positive reactions are interpreted using lateral flow strips, reducing the need for infrastructure and resources. This together with an ability to withstand inhibitors within urine makes RPA a promising technology for further development as a molecular diagnostic tool for urogenital schistosomiasis.

Exercise testing and training in people with Huntington's disease.

OBJECTIVE: To explore exercise response in people with Huntington's disease (HD). DESIGN: Experimental observational study with a randomly allocated subgroup before/after interventional study. SETTING: Community. SUBJECTS: People with HD (n=30) and a healthy comparator group (n=20). Thirteen people from the HD group were randomly allocated to an exercise training program. MAIN MEASURES: Heart rate (HR) and perceived exertion on the Borg-CR10 scale (RPE) during a submaximal cycle ergometer exercise test (three minute unloaded and nine minute 65%-75%HRmaximum phase). Expired air and lactate measures were available for 8 people with HD during the exercise. INTERVENTION: A 12 week gym and home walking exercise programme (n=13). RESULTS: People with HD achieved a lower work rate at nine minutes (82±42(0-195) v 107±35(50 -185) Watts (p<0.05)), but higher RPE at both three (3±2(0-7) v 1±1(0-4)) and nine minutes (7±3(1-10) v 5± 2(2-9)) both p<0.01, compared to the healthy group and did not achieve a steady state HR during unloaded cycling. People with HD also demonstrated higher than expected lactate at three 2.5±2.5(1.1-8)mmo.L-1 and nine 3.8±1.9(1.2-6.6)mmo.L-1 minutes and respiratory exchange ratio at three 0.78±0.03 (0.74-0.81) and nine minutes 0.94±0.11(0.81-1.15). After exercise training there were no changes observed in HR or RPE responses during the exercise test. CONCLUSIONS: There was a large variability in the observed metabolic and physiological responses to exercise in people with HD. The observed exercise responses suggest that altered exercise prescription parameters may be required for people with HD and that exercise response and factors' affecting this requires further investigation.

Hypercalcaemia mimicking Huntington's disease: lessons learned from delayed diagnosis.

Diagnosis can prove challenging when a patient with a chronic neurological disease presents with acute deterioration. This is especially true in Huntington's disease, where cognitive impairment is prominent. We present a case of hypercalcaemia causing an acute deterioration in physical and cognitive function in a patient with Huntington's disease. Similarity in clinical phenotype between hypercalcaemia and Huntington's disease, as well as failure to appreciate the acute nature of the deterioration resulted in diagnostic delay and prolonged admission. With treatment, the patient improved dramatically. The case highlights key learning points regarding assessment of patients with chronic neurological disease.

Expression of glutamatergic genes in healthy humans across 16 brain regions; altered expression in the hippocampus after chronic exposure to alcohol or cocaine.

We analyzed global patterns of expression in genes related to glutamatergic neurotransmission (glutamatergic genes) in healthy human adult brain before determining the effects of chronic alcohol and cocaine exposure on gene expression in the hippocampus. RNA-Seq data from 'BrainSpan' was obtained across 16 brain regions from nine control adults. We also generated RNA-Seq data from postmortem hippocampus from eight alcoholics, eight cocaine addicts and eight controls. Expression analyses were undertaken of 28 genes encoding glutamate ionotropic (AMPA, kainate, NMDA) and metabotropic receptor subunits, together with glutamate transporters. The expression of each gene was fairly consistent across the brain with the exception of the cerebellum, the thalamic mediodorsal nucleus and the striatum. GRIN1, encoding the essential NMDA subunit, had the highest expression across all brain regions. Six factors accounted for 84% of the variance in global gene expression. GRIN2B (encoding GluN2B), was up-regulated in both alcoholics and cocaine addicts (FDR corrected P = 0.008). Alcoholics showed up-regulation of three genes relative to controls and cocaine addicts: GRIA4 (encoding GluA4), GRIK3 (GluR7) and GRM4 (mGluR4). Expression of both GRM3 (mGluR3) and GRIN2D (GluN2D) was up-regulated in alcoholics and down-regulated in cocaine addicts relative to controls. Glutamatergic genes are moderately to highly expressed throughout the brain. Six factors explain nearly all the variance in global gene expression. At least in the hippocampus, chronic alcohol use largely up-regulates glutamatergic genes. The NMDA GluN2B receptor subunit might be implicated in a common pathway to addiction, possibly in conjunction with the GABAB1 receptor subunit.

Cross-regulation of Connexin43 and ß-catenin influences differentiation of human neural progenitor cells.

Connexin43 (Cx43) is the most widely and abundantly expressed gap junction (GJ) protein and it is strongly associated with the regulation of cell cycle progression. Emerging roles for Cx43 in cell adhesion and migration during neural differentiation have also been recently recognized, and this has emphasized the involvement of Cx43 in different physiological process beyond its role as a GJ protein. In this study, we explore the function of Cx43 in the differentiation of human neural progenitor cells (hNPCs) using viral vectors that mediate the overexpression or knockdown of the protein. Results showed that in the absence of this protein fetal cortex-derived hNPCs differentiated toward a neuronal phenotype at expenses of a glial phenotype. Furthermore, the silencing of Cx43 did not affect hNPC proliferation rate or numbers of apoptotic cells. The increase in the number of neurons was not recapitulated when GJ intercellular communications were pharmacologically blocked, and this suggested that Cx43 was influencing hNPCs differentiation with a GJ-independent effect. In addition, Cx43 knockdown significantly increased ß-catenin signaling, which has been shown to regulate the transcription of pro-neuronal genes during embryonic neural development. Our results add further support to the hypothesis that Cx43 protein itself regulates key signaling pathways during development and neurogenesis beyond its role as GJ protein.

The lateral neostriatum is necessary for compensatory ingestive behaviour after intravascular dehydration in female rats.

Aberrant striatal function results in an array of physiological symptoms, including impaired consummatory and regulatory behaviours, which can lead to weight loss and dehydration. It was hypothesised, therefore, that cell loss in the neostriatum may contribute to altered fluid intake by regulating physiological signals related to dehydration status. To test this theory, rats with lesions of the lateral neostriatum and sham controls underwent a series of physiological challenges, including the experimental induction of intracellular and intravascular dehydration. No baseline differences in prandial or non-prandial drinking were observed, nor were differences in locomotor activity evident between groups. Furthermore, intracellular dehydration increased water intake in lesion rats in a manner comparable to sham rats. Interestingly, a specific impairment was evident in lesion rats after subcutaneous injection of poly-ethylene glycol was used to induce intravascular dehydration, such that lesion rats failed to adapt their water intake to this physiological change. The results suggest that the striatal lesions resulted in regulatory dysfunction by impairing motivational control over compensatory ingestive behaviour after intravascular hydration, while the physiological signals related to dehydration remain intact. Loss of these cells in neurodegenerative disorders, such Huntington's disease, may contribute to regulatory changes evident in the course of the disease.

Use of dietary supplementation with ß-guanidinopropionic acid to alter the muscle phosphagen system, postmortem metabolism, and pork quality.

Rate and extent of postmortem metabolism control pork quality development. Our objective was to evaluate the role of the phosphagen system (phosphocreatine, PCr; and creatine, Cr) on metabolism and pork quality. Muscle PCr and Cr were manipulated by feeding pigs the creatine analogue, ß-guanidinopropionic acid (ß-GPA). In experiment 1, pigs received standard (control) diet or ß-GPA supplemented (2%) diet (1 wk or 2 wk). Supplementation with ß-GPA (2 wk) decreased total Cr (PCr+Cr; P=0.02) and improved pork color (decreased reflectance, P=0.003); however, ß-GPA supplementation reduced growth performance (P=0.007). To separate effects of phosphagen system and growth, a second experiment was conducted with control, pair-fed, and 2 wk ß-GPA (1%) supplementation; pigs were also offered a control or ß-GPA supplemented flavored beverage. Neither treatment influenced pork quality. Immediately postmortem, ATP/ADP was higher in control compared to pair-fed (P<0.05); subsequently, ATP/ADP was similar among all groups. Loss of the phosphagen system may lead to adaptive changes that promote conservation of cellular ATP.

Molecular regulation of striatal development: a review.

The central nervous system is composed of the brain and the spinal cord. The brain is a complex organ that processes and coordinates activities of the body in bilaterian, higher-order animals. The development of the brain mirrors its complex function as it requires intricate genetic signalling at specific times, and deviations from this can lead to brain malformations such as anencephaly. Research into how the CNS is specified and patterned has been studied extensively in chick, fish, frog, and mice, but findings from the latter will be emphasised here as higher-order mammals show most similarity to the human brain. Specifically, we will focus on the embryonic development of an important forebrain structure, the striatum (also known as the dorsal striatum or neostriatum). Over the past decade, research on striatal development in mice has led to an influx of new information about the genes involved, but the precise orchestration between the genes, signalling molecules, and transcription factors remains unanswered. We aim to summarise what is known to date about the tightly controlled network of interacting genes that control striatal development. This paper will discuss early telencephalon patterning and dorsal ventral patterning with specific reference to the genes involved in striatal development.