Search

Reelin is a large extracellular matrix protein abundantly expressed in the developing neocortex of mammals. During embryonic and early postnatal stages in mice, Reelin is secreted by a transient neuronal population, the Cajal-Retzius neurons (CRs), and is mostly known to insure the inside-out migration of neurons and the formation of cortical layers. During the first 2 postnatal weeks, CRs disappear from the neocortex and a subpopulation of GABAergic neurons takes over the expression of Reelin, albeit in lesser amounts. Although Reelin expression requires a tight regulation in a time- and cell-type specific manner, the mechanisms regulating the expression and secretion of this protein are poorly understood. In this study, we establish a cell-type specific profile of Reelin expression in the marginal zone of mice neocortex during the first 3 postnatal weeks. We then investigate whether electrical activity plays a role in the regulation of Reelin synthesis and/or secretion by cortical neurons during the early postnatal period. We show that increased electrical activity promotes the transcription of reelin via the brain-derived neurotrophic factor/TrkB pathway, but does not affect its translation or secretion. We further demonstrate that silencing the neuronal network promotes the translation of Reelin without affecting the transcription or secretion. We conclude that different patterns of activity control various stages of Reelin synthesis, whereas its secretion seems to be constitutive., (© The Author(s) 2023. Published by Oxford University Press.)

During early brain development, homeostatic removal of cortical neurons is crucial and requires multiple control mechanisms. We investigated in the cerebral cortex of mice whether the BAX/BCL-2 pathway, an important regulator of apoptosis, is part of this machinery and how electrical activity might serve as a set point of regulation. Activity is known to be a pro-survival factor; however, how this effect is translated into enhanced survival chances on a neuronal level is not fully understood. In this study, we show that caspase activity is highest at the neonatal stage, while developmental cell death peaks at the end of the first postnatal week. During the first postnatal week, upregulation of BAX is accompanied by downregulation of BCL-2 protein, resulting in a high BAX/BCL-2 ratio when neuronal death rates are high. In cultured neurons, pharmacological blockade of activity leads to an acute upregulation of Bax, while elevated activity results in a lasting increase of BCL-2 expression. Spontaneously active neurons not only exhibit lower Bax levels than inactive neurons but also show almost exclusively BCL-2 expression. Disinhibition of network activity prevents the death of neurons overexpressing activated CASP3. This neuroprotective effect is not the result of reduced caspase activity but is associated with a downregulation of the BAX/BCL-2 ratio. Notably, increasing neuronal activity has a similar, non-additive effect as the blockade of BAX. Conclusively, high electrical activity modulates BAX/BCL-2 expression and leads to higher tolerance to CASP3 activity, increases survival, and presumably promotes non-apoptotic CASP3 functions in developing neurons., (© 2023. The Author(s).)

Anandamide (AEA) is an endogenous ligand of the cannabinoid CB1 and CB2 receptors, being a component of the endocannabinoid signaling system, which supports the maintenance or regaining of neural homeostasis upon internal and external challenges. AEA is thought to play a protective role against the development of pathological states after prolonged stress exposure, including depression and generalized anxiety disorder. Here, we used the chronic social defeat (CSD) stress as an ethologically valid model of chronic stress in male mice. We characterized a genetically modified mouse line where AEA signaling was reduced by deletion of the gene encoding the AEA synthesizing enzyme N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) specifically in neurons activated at the time of CSD stress. One week after the stress, the phenotype was assessed in behavioral tests and by molecular analyses. We found that NAPE-PLD deficiency in neurons activated during the last three days of CSD stress led to an increased anxiety-like behavior. Investigating the molecular mechanisms underlying this phenotype may suggest three main altered pathways to be affected: (i) desensitization of the negative feedback loop of the hypothalamic-pituitary-adrenal axis, (ii) disinhibition of the amygdala by the prefrontal cortex, and (iii) altered neuroplasticity in the hippocampus and prefrontal cortex., (© 2023. The Author(s).)

Spontaneous activity plays a crucial role in brain development by coordinating the integration of immature neurons into emerging cortical networks. High levels and complex patterns of spontaneous activity are generally associated with low rates of apoptosis in the cortex. However, whether spontaneous activity patterns directly encode for survival of individual cortical neurons during development remains an open question. Here, we longitudinally investigated spontaneous activity and apoptosis in developing cortical cultures, combining extracellular electrophysiology with calcium imaging. These experiments demonstrated that the early occurrence of calcium transients was strongly linked to neuronal survival. Silent neurons exhibited a higher probability of cell death, whereas high frequency spiking and burst behavior were almost exclusively detected in surviving neurons. In local neuronal clusters, activity of neighboring neurons exerted a pro-survival effect, whereas on the functional level, networks with a high modular topology were associated with lower cell death rates. Using machine learning algorithms, cell fate of individual neurons was predictable through the integration of spontaneous activity features. Our results indicate that high frequency spiking activity constrains apoptosis in single neurons through sustained calcium rises and thereby consolidates networks in which a high modular topology is reached during early development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Warm, Bassetti, Schroer, Luhmann and Sinning.)

Throughout early phases of brain development, the two main neural signaling mechanisms-excitation and inhibition-are dynamically sculpted in the neocortex to establish primary functions. Despite its relatively late formation and persistent developmental changes, the GABAergic system promotes the ordered shaping of neuronal circuits at the structural and functional levels. Within this frame, interneurons participate first in spontaneous and later in sensory-evoked activity patterns that precede cortical functions of the mature brain. Upon their subcortical generation, interneurons in the embryonic brain must first orderly migrate to and settle in respective target layers before they can actively engage in cortical network activity. During this process, changes at the molecular and synaptic level of interneurons allow not only their coordinated formation but also the pruning of connections as well as excitatory and inhibitory synapses. At the postsynaptic site, the shift of GABAergic signaling from an excitatory towards an inhibitory response is required to enable synchronization within cortical networks. Concomitantly, the progressive specification of different interneuron subtypes endows the neocortex with distinct local cortical circuits and region-specific modulation of neuronal firing. Finally, the apoptotic process further refines neuronal populations by constantly maintaining a controlled ratio of inhibitory and excitatory neurons. Interestingly, many of these fundamental and complex processes are influenced-if not directly controlled-by electrical activity. Interneurons on the subcellular, cellular, and network level are affected by high frequency patterns, such as spindle burst and gamma oscillations in rodents and delta brushes in humans. Conversely, the maturation of interneuron structure and function on each of these scales feeds back and contributes to the generation of cortical activity patterns that are essential for the proper peri- and postnatal development. Overall, a more precise description of the conducting role of interneurons in terms of how they contribute to specific activity patterns-as well as how specific activity patterns impinge on their maturation as orchestra members-will lead to a better understanding of the physiological and pathophysiological development and function of the nervous system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Warm, Schroer and Sinning.)

Synchronization and bursting activity are intrinsic electrophysiological properties of in vivo and in vitro neural networks. During early development, cortical cultures exhibit a wide repertoire of synchronous bursting dynamics whose characterization may help to understand the parameters governing the transition from immature to mature networks. Here we used machine learning techniques to characterize and predict the developing spontaneous activity in mouse cortical neurons on microelectrode arrays (MEAs) during the first three weeks in vitro. Network activity at three stages of early development was defined by 18 electrophysiological features of spikes, bursts, synchrony, and connectivity. The variability of neuronal network activity during early development was investigated by applying k-means and self-organizing map (SOM) clustering analysis to features of bursts and synchrony. These electrophysiological features were predicted at the third week in vitro with high accuracy from those at earlier times using three machine learning models: Multivariate Adaptive Regression Splines, Support Vector Machines, and Random Forest. Our results indicate that initial patterns of electrical activity during the first week in vitro may already predetermine the final development of the neuronal network activity. The methodological approach used here may be applied to explore the biological mechanisms underlying the complex dynamics of spontaneous activity in developing neuronal cultures., (© 2021. The Author(s).)

A substantial proportion of neurons undergoes programmed cell death (apoptosis) during early development. This process is attenuated by increased levels of neuronal activity and enhanced by suppression of activity. To uncover whether the mere level of activity or also the temporal structure of electrical activity affects neuronal death rates, we optogenetically controlled spontaneous activity of synaptically-isolated neurons in developing cortical cultures. Our results demonstrate that action potential firing of primary cortical neurons promotes neuronal survival throughout development. Chronic patterned optogenetic stimulation allowed to effectively modulate the firing pattern of single neurons in the absence of synaptic inputs while maintaining stable overall activity levels. Replacing the burst firing pattern with a non-physiological, single pulse pattern significantly increased cell death rates as compared to physiological burst stimulation. Furthermore, physiological burst stimulation led to an elevated peak in intracellular calcium and an increase in the expression level of classical activity-dependent targets but also decreased Bax/BCL-2 expression ratio and reduced caspase 3/7 activity. In summary, these results demonstrate at the single-cell level that the temporal pattern of action potentials is critical for neuronal survival versus cell death fate during cortical development, besides the pro-survival effect of action potential firing per se.

Aim: We evaluated the introduction of a predictive risk stratification model (PRISM) into primary care. Contemporaneously National Health Service (NHS) Wales introduced Quality and Outcomes Framework payments to general practices to focus care on those at highest risk of emergency admission to hospital. The aim of this study was to evaluate the costs and effects of introducing PRISM into primary care., Methods: Randomised stepped wedge trial with 32 general practices in one Welsh health board. The intervention comprised: PRISM software; practice-based training; clinical support through two 'general practitioner (GP) champions' and technical support. The primary outcome was emergency hospital admissions., Results: Across 230 099 participants, PRISM implementation increased use of health services: emergency hospital admission rates by 1 % when untransformed (while change in log-transformed rate Δ L =0.011, 95% CI 0.010 to 0.013); emergency department (ED) attendance rates by untransformed 3 % (while Δ L =0.030, 95% CI 0.028 to 0.032); outpatient visit rates by untransformed 5 % (while Δ L =0.055, 95% CI 0.051 to 0.058); the proportion of days with recorded GP activity by untransformed 1 % (while Δ L =0.011, 95% CI 0.007 to 0.014) and time in hospital by untransformed 3 % (while Δ L =0.029, 95% CI 0.026 to 0.031). Thus NHS costs per participant increased by £76 (95% CI £46 to £106)., Conclusions: Introduction of PRISM resulted in a statistically significant increase in emergency hospital admissions and use of other NHS services without evidence of benefits to patients or the NHS., Competing Interests: Competing interests: HS is a member of the National Institute of Health Research (NIHR) Health Technology Assessment(HTA) editorial board and a scientific advisor to the NIHR Health Services and Delivery Research (HS&DR) Programme., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Domoic acid (DOM) is an excitatory amino acid analog of kainic acid (KA) that acts through glutamic acid (GLU) receptors, inducing a fast and potent neurotoxic response. Here, we present evidence for an enhancement of excitotoxicity following exposure of cultured cerebellar granule cells to DOM in the presence of lower than physiological Na+ concentrations. The concentration of DOM that reduced by 50% neuronal survival was approximately 3 µM in Na+-free conditions and 16 µM in presence of a physiological concentration of extracellular Na+. The enhanced neurotoxic effect of DOM was fully prevented by AMPA/KA receptor antagonist, while N-methyl-D-aspartate-receptor-mediated neurotoxicity did not seem to be involved, as the absence of extracellular Na+ failed to potentiate GLU excitotoxicity under the same experimental conditions. Lowering of extracellular Na+ concentration to 60 mM eliminated extracellular recording of spontaneous electrophysiological activity from cultured neurons grown on a multi electrode array and prevented DOM stimulation of the electrical activity. Although changes in the extracellular Na+ concentration did not alter the magnitude of the rapid increase in intracellular Ca2+ levels associated to DOM exposure, they did change significantly the contribution of voltage-sensitive calcium channels (VScaCs) and the recovery time to baseline. The prevention of Ca2+ influx via VSCaCs by nifedipine failed to prevent DOM toxicity at any extracellular Na+ concentration, while the reduction of extracellular Ca2+ concentration ameliorated DOM toxicity only in the absence of extracellular Na+, enhancing it in physiological conditions. Our data suggest a crucial role for extracellular Na+ concentration in determining excitotoxicity by DOM., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: An ageing population increases demand on health and social care. New approaches are needed to shift care from hospital to community and general practice. A predictive risk stratification tool (Prism) has been developed for general practice that estimates risk of an emergency hospital admission in the following year. We present a protocol for the evaluation of Prism., Methods/design: We will undertake a mixed methods progressive cluster-randomised trial. Practices begin as controls, delivering usual care without Prism. Practices will receive Prism and training randomly, and thereafter be able to use Prism with clinical and technical support. We will compare costs, processes of care, satisfaction and patient outcomes at baseline, 6 and 18 months, using routine data and postal questionnaires. We will assess technical performance by comparing predicted against actual emergency admissions. Focus groups and interviews will be undertaken to understand how Prism is perceived and adopted by practitioners and policy makers. We will model data using generalised linear models and survival analysis techniques to determine whether any differences exist between intervention and control groups. We will take account of covariates and explanatory factors. In the economic evaluation we will carry out a cost-effectiveness analysis to examine incremental cost per emergency admission to hospital avoided and will examine costs versus changes in primary and secondary outcomes in a cost-consequence analysis. We will also examine changes in quality of life of patients across the risk spectrum. We will record and transcribe focus groups and interviews and analyse them thematically. We have received full ethical and R and D approvals for the study and Information Governance Review Panel (IGRP) permission for the use of routine data. We will comply with the CONSORT guidelines and will disseminate the findings at national and international conferences and in peer-reviewed journals., Discussion: The proposed study will provide information on costs and effects of Prism; how it is used in practice, barriers and facilitators to its implementation; and its perceived value in supporting the management of patients with and at risk of developing chronic conditions., Trial Registration: Controlled Clinical Trials ISRCTN no. ISRCTN55538212.

Interest in the field of patient safety incident reporting and analysis with respect to Health Information Technology (HIT) has been growing over recent years as the development, implementation and reliance on HIT systems becomes ever more prevalent. One of the rationales for capturing patient safety incidents is to learn from failures in the delivery of care and must form part of a feedback loop which also includes analysis; investigation and monitoring. With the advent of new technologies and organizational programs of delivery the emphasis is increasingly upon analyzing HIT incidents. This thematic review had two objectives, to test the applicability of a framework specifically designed to categorize HIT incidents and to review the Welsh incidents as communicated via the national incident reporting system in order to understand their implications for healthcare. The incidents were those reported as IT/ telecommunications failure/ overload. Incidents were searched for within a national reporting system using a standardized search strategy for incidents occurring between 1(st) January 2009 and 31(st) May 2011. 149 incident reports were identified and classified. The majority (77%) of which were machine related (technical problems) such as access problems; computer system down/too slow; display issues; and software malfunctions. A further 10% (n = 15) of incidents were down to human-computer interaction issues and 13% (n = 19) incidents, mainly telephone related, could not be classified using the framework being tested. On the basis of this review of incidents, it is recommended that the framework be expanded to include hardware malfunctions and the wrong record retrieved/missing data associated with a machine output error (as opposed to human error). In terms of the implications for clinical practice, the incidents reviewed highlighted critical issues including the access problems particularly relating to the use of mobile technologies.

Background: Debates surrounding the use of conventional approaches in public health and the existence of perceived barriers to using the results of economic evaluations have led to questions posed as to how to establish priorities within public health schemes. The aims of this study were therefore to explore the feasibility and validity of economic evaluation techniques in developing priorities within public health programmes and consider the extent to which different presentational approaches are likely to be incorporated into decision-making, from perspectives of relevant stakeholders., Methods: An advisory board, representative of potential users of economic evaluations, was set up to identify preferences for how findings from economic evaluations might be presented to decision makers and to test the impact of different approaches, different outputs and different presentational styles. The board was divided into two groups, each of which was given three hypothetical 'scenarios' to consider. The scenarios comprised descriptions of methods and outputs, with costs, effects, target population and context of intervention constant across all scenarios., Results: The perceived validity of estimates of effectiveness was vitally important, along with sufficient information to gauge whether designs were appropriate and to assess implementation practicalities. Cost-benefit analysis and cost-utility analysis were the preferred approaches despite their complexity, although participants required benchmarks to place net-benefit estimates from cost-benefit analyses into context., Conclusion: Further research is required to substantiate and build on these preliminary findings and collaborations between economists and policy makers are needed to develop clear, rigorous and standard guidance relating to economic evaluation, recognizing the diversity of public health strategies.

Objective: To assess the effect of brief interventions during the "watchful waiting" period for hypertension., Design: Factorial trial., Setting: General practice., Methods: 296 patients with blood pressure > 160/90 mm Hg were randomised to eight groups defined by three factors: an information booklet; low sodium, high potassium salt; prompt sheets for high fruit, vegetable, fibre; and low fat., Main Outcome Measures: Blood pressure (primary outcome); secondary outcomes of diet, weight, and dietary biomarkers (urinary sodium:potassium (Na:K) ratio; carotenoid concentrations)., Results: Blood pressure was not affected by the booklet (mean difference (diastolic blood pressure) at one month 0.2, 95% confidence interval 1.6 to 2.0), salt (0.13; 1.7 to 2.0), or prompts (0.52; 1.3 to 2.4). The salt decreased Na:K ratio (difference 0.32; 0.08 to 0.56, P = 0.01), and the prompts helped control weight (difference 0.39 (0.85 to 0.05) kg at one month, P = 0.085; 1.2 (0.1 to 2.25) kg at six months, P = 0.03). Among those with lower fruit and vegetable consumption (< 300 g per day), prompts increased fruit and vegetable consumption and also carotenoid concentrations (difference 143 (16 to 269) mmol/l, P < 0.03) but did not decrease blood pressure., Conclusion: During watchful waiting, over and above the effect of brief advice and monitoring, an information booklet, lifestyle prompts, and low sodium salt do not reduce blood pressure. Secondary analysis suggests that brief interventions-particularly lifestyle prompts-can make useful changes in diet and help control weight, which previous research indicates are likely to reduce the long term risk of stroke.

The aim of this paper is to highlight the importance of an evidence-based approach to the development, implementation and evaluation of policies aimed at improving nutrition-related health in the population. Public Health Nutrition was established to realise a population-level approach to the prevention of the major nutrition-related health problems world-wide. The scope is broad and integrates activity from local, national, regional and international levels. The aim is to inform and develop coherent and effective policies that address the key rate-limiting steps critical to improving nutrition-related public health. This paper sets out the rationale for an evidence-based approach to Public Health Nutrition developed under the umbrella of the European Network for Public Health Nutrition.

Effective population-based strategies require people trained and competent in the discipline of Public Health Nutrition. Since 1997, a European Master's Programme in Public Health Nutrition has been undergoing planning and implementation, by establishing initial quality assurance systems with the aid of funding from the European Commission (DG SANCO/F3). Partners from 17 European countries have been involved in the process. A European Network of Public Health Nutrition has been developed and accredited by the European Commission.

Diet is important in the aetiology and management of many conditions in primary care. Although valid dietary assessment is required for both clinical work and research, no dietary assessment instruments have been validated among patients seen in primary care. A range of simple self-completion dietary assessment questionnaires and established research instruments were compared with an accepted reference standard, a seven-day weighed record, in 111 subjects assessed in a practice nurse-run treatment room. Simple self-completion tools based on food groups and portion sizes perform as well (likelihood ratios for a positive test = 2 to 3) as much more time-consuming instruments. The error in using such instruments is comparable with the error of the standard itself. There is little justification for using time-consuming dietary assessment questionnaires, since simple tools are accurate enough to be clinically useful--to allow practice nurses to target patients for counselling and waste less time on inappropriate counselling--and also useful for research.

For the majority of European adults, who neither smoke nor drink excessively, the most significant controllable risk factors affecting their long-term health are what they eat, and how physically active they are. Scientists are supposed to clarify to policy makers and health professionals the usefulness of their health messages. However, to be able to do that, a more detailed understanding is needed of the basic mechanisms behind the effects on health of diet and physical activity and, especially, the two in combination. Further, better methods for assessment of nutrition and physical activity in the population have to be developed, and more and better baseline data have to be collected. Increased and more efficient interventions are then needed. People trained and competent in the new discipline of Public Health Nutrition are required. Through the stimulating support that the European Commission, as well as other national and international partners, are presently giving to the development of Public Health Nutrition across Europe, we can hope for an increased mobility, networking and understanding between European nutrition and physical activity professionals. This will most likely result in greater and better policy making, strategy development, implementation and evaluation. We now have a great possibility to develop the integrated field of preventive nutrition and health enhancing physical activity.

Scientists in basic research and epidemiology deliver messages to policy makers. Effective population based strategies then require people trained and competent in the discipline of Public Health Nutrition (PHN). Since 1997, a European Master's Programme in PHN has been undergoing planning and implementation with the aid of funding from the European Commission (DGV). PHN is used as a broad term covering Nutrition and Physical Activity as well as Health Promotion and Disease Prevention. The partners in this project are academic departments from 17 countries. The students will undertake core modules and electives for a year and a half, followed by a research project for six months. In order to set up formalised procedures for the evaluation of the quality assurance of individual modules from across Europe, a quality assurance system has been set up. The academic year 1999-2000 will allow an opportunity for Universities and Institutes to start new modules, to develop other modules, assess the movement of students between modules, tackle funding issues and allow further marketing of the programme. Future activities include strengthening of the European Network for Public Health Nutrition (ENPHN), the establishment of a consortium with universities, the co-ordination of programme activities with other European Master's Programmes in Public Health, and the incorporation of new Member States from Eastern Europe. We can look forward to a new brand of professionals, who are truly European in their training, but who also have an integrated view of nutrition and physical activity, health promotion and disease prevention and who are prepared for policy making, action planning, implementation and evaluation.