Purines and Neuronal Excitability: Links to the Ketogenic Diet [post-print]

ATP and adenosine are purines that play dual roles in cell metabolism and neuronal signaling. Acting at the A(1) receptor (A(1)R) subtype, adenosine acts directly on neurons to inhibit excitability and is a powerful endogenous neuroprotective and anticonvulsant molecule. Previous research showed an increase in ATP and other cell energy parameters when an animal is administered a ketogenic diet, an established metabolic therapy to reduce epileptic seizures, but the relationship among purines, neuronal excitability and the ketogenic diet was unclear. Recent work in vivo and in vitro tested the specific hypothesis that adenosine acting at A(1)Rs is a key mechanism underlying the success of ketogenic diet therapy and yielded direct evidence linking A(1)Rs to the antiepileptic effects of a ketogenic diet. Specifically, an in vitro mimic of a ketogenic diet revealed an A(1)R-dependent metabolic autocrine hyperpolarization of hippocampal neurons. In parallel, applying the ketogenic diet in vivo to transgenic mouse models with spontaneous electrographic seizures revealed that intact A(1)Rs are necessary for the seizure-suppressing effects of the diet. This is the first direct in vivo evidence linking A(1)Rs to the antiepileptic effects of a ketogenic diet. Other predictions of the relationship between purines and the ketogenic diet are discussed. Taken together, recent research on the role of purines may offer new opportunities for metabolic therapy and insight into its underlying mechanisms

Purines and the Anti-Epileptic Actions of Ketogenic Diets

Ketogenic diets are high in fat and low in carbohydrates and represent a well-established and effective treatmentalternative to anti-epileptic drugs. Ketogenic diets are used for the management of a variety of difficult-to-treat or intractableseizure disorders, especially pediatric refractory epilepsy. However, it has been shown that this dietary therapycan reduce seizures in people of all ages, and ketogenic diets are being applied to other prevalent medical conditions suchas diabetes. Although used effectively to treat epilepsy for nearly 90 years, the mechanism(s) by which ketogenic dietswork to reduce seizures remain ill-understood. One mechanism receiving increased attention is based on findings that ketogenicdiets increase the brain energy molecule ATP, and may also increase the levels and actions of the related endogenousinhibitory neuromodulator adenosine. ATP and adenosine have both been identified as important modulators of seizures;seizures increase the actions of these purines, these purines regulate epileptic activity in brain, adenosine receptorantagonists are pro-convulsant, and adenosinergic mechanisms have been implicated previously in the actions of approvedanti-epileptic therapeutics. Here we will review recent literature and describe findings that shed light on mechanistic relationshipsbetween ketogenic diets and the purines ATP and adenosine. These emerging mechanisms hold great promisefor the effective therapeutic management of epileptic seizures and other neurological conditions

The impact of methodology on the reproducibility and rigor of DNA methylation data

Epigenetic modifications are crucial for normal development and implicated in disease pathogenesis. While epigenetics continues to be a burgeoning research area in neuroscience, unaddressed issues related to data reproducibility across laboratories remain. Separating meaningful experimental changes from background variability is a challenge in epigenomic studies. Here we show that seemingly minor experimental variations, even under normal baseline conditions, can have a significant impact on epigenome outcome measures and data interpretation. We examined genome-wide DNA methylation and gene expression profiles of hippocampal tissues from wild-type rats housed in three independent laboratories using nearly identical conditions. Reduced-representation bisulfite sequencing and RNA-seq respectively identified 3852 differentially methylated and 1075 differentially expressed genes between laboratories, even in the absence of experimental intervention. Difficult-to-match factors such as animal vendors and a subset of husbandry and tissue extraction procedures produced quantifiable variations between wild-type animals across the three laboratories. Our study demonstrates that seemingly minor experimental variations, even under normal baseline conditions, can have a significant impact on epigenome outcome measures and data interpretation. This is particularly meaningful for neurological studies in animal models, in which baseline parameters between experimental groups are difficult to control. To enhance scientific rigor, we conclude that strict adherence to protocols is necessary for the execution and interpretation of epigenetic studies and that protocol-sensitive epigenetic changes, amongst naive animals, may confound experimental results

A Ketogenic Diet Suppresses Seizures in Mice through Adenosine A1 Receptors

A ketogenic diet (KD) is a high-fat, low-carbohydrate metabolic regimen; its effectiveness in the treatment of refractory epilepsy suggests that the mechanisms underlying its anticonvulsive effects differ from those targeted by conventional antiepileptic drugs. Recently, KD and analogous metabolic strategies have shown therapeutic promise in other neurologic disorders, such as reducing brain injury, pain, and inflammation. Here, we have shown that KD can reduce seizures in mice by increasing activation of adenosine A1 receptors (A1Rs). When transgenic mice with spontaneous seizures caused by deficiency in adenosine metabolism or signaling were fed KD, seizures were nearly abolished if mice had intact A1Rs, were reduced if mice expressed reduced A1Rs, and were unaltered if mice lacked A1Rs. Seizures were restored by injecting either glucose (metabolic reversal) or an A1R antagonist (pharmacologic reversal). Western blot analysis demonstrated that the KD reduced adenosine kinase, the major adenosine-metabolizing enzyme. Importantly, hippocampal tissue resected from patients with medically intractable epilepsy demonstrated increased adenosine kinase. We therefore conclude that adenosine deficiency may be relevant to human epilepsy and that KD can reduce seizures by increasing A1R-mediated inhibition

Translations: effects of viewpoint, feature, naming and context on identifying repeatedly copied drawings

We explored the tension between bottom – up and top – down contributions to object recognition in a collaboration between a visual artist and a cognitive psychologist. Initial pictorial renderings of objects and animals from various viewpoints were iteratively copied, and a series of drawings that changed from highly concrete images into highly abstract images was produced. In drawing identification in which sets were shown in reverse order, participants were more accurate, more confident, and quicker to correctly identify the evolving image when it was originally displayed from a canonical viewpoint with all salient features present. In drawing identification in which images were shown in random order, more abstract images could be resolved as a result of previously identifying a more concrete iteration of the same drawing. The results raise issues about the influence of viewpoint and feature on the preservation of pictorial images and about the role of labelling in the interpretation of ambiguous stimuli. In addition, the study highlights a procedure in which visual stimuli can degrade without necessitating a substantial loss of complexity

Cross-Platform Microarray Data Normalisation for Regulatory Network Inference

Background Inferring Gene Regulatory Networks (GRNs) from time course microarray data suffers from the dimensionality problem created by the short length of available time series compared to the large number of genes in the network. To overcome this, data integration from diverse sources is mandatory. Microarray data from different sources and platforms are publicly available, but integration is not straightforward, due to platform and experimental differences. Methods We analyse here different normalisation approaches for microarray data integration, in the context of reverse engineering of GRN quantitative models. We introduce two preprocessing approaches based on existing normalisation techniques and provide a comprehensive comparison of normalised datasets. Conclusions Results identify a method based on a combination of Loess normalisation and iterative K-means as best for time series normalisation for this problem

The impact of inpatient suicide on psychiatric nurses and their need for support

<p>Abstract</p> <p>Background</p> <p>The nurses working in psychiatric hospitals and wards are prone to encounter completed suicides. The research was conducted to examine post-suicide stress in nurses and the availability of suicide-related mental health care services and education.</p> <p>Methods</p> <p>Experiences with inpatient suicide were investigated using an anonymous, self-reported questionnaire, which was, along with the Impact of Event Scale-Revised, administered to 531 psychiatric nurses.</p> <p>Results</p> <p>The rate of nurses who had encountered patient suicide was 55.0%. The mean Impact of Event Scale-Revised (IES-R) score was 11.4. The proportion of respondents at a high risk (≥ 25 on the 88-point IES-R score) for post-traumatic stress disorder (PTSD) was 13.7%. However, only 15.8% of respondents indicated that they had access to post-suicide mental health care programmes. The survey also revealed a low rate of nurses who reported attending in-hospital seminars on suicide prevention or mental health care for nurses (26.4% and 12.8%, respectively).</p> <p>Conclusions</p> <p>These results indicated that nurses exposed to inpatient suicide suffer significant mental distress. However, the low availability of systematic post-suicide mental health care programmes for such nurses and the lack of suicide-related education initiatives and mental health care for nurses are problematic. The situation is likely related to the fact that there are no formal systems in place for identifying and evaluating the psychological effects of patient suicide in nurses and to the pressures stemming from the public perception of nurses as suppliers rather than recipients of health care.</p

Accuracy of telepsychiatric assessment of new routine outpatient referrals

<p>Abstract</p> <p>Background</p> <p>Studies on the feasibility of telepsychiatry tend to concentrate only on a subset of clinical parameters. In contrast, this study utilises data from a comprehensive assessment. The main objective of this study is to compare the accuracy of findings from telepsychiatry with those from face to face interviews.</p> <p>Method</p> <p>This is a primary, cross-sectional, single-cluster, balanced crossover, blind study involving new routine psychiatric referrals. Thirty-seven out of forty cases fulfilling the selection criteria went through a complete set of independent face to face and video assessments by the researchers who were blind to each other's findings.</p> <p>Results</p> <p>The accuracy ratio of the pooled results for DSM-IV diagnoses, risk assessment, non-drug and drug interventions were all above 0.76, and the combined overall accuracy ratio was 0.81. There were substantial intermethod agreements for Cohen's kappa on all the major components of evaluation except on the Risk Assessment Scale where there was only weak agreement.</p> <p>Conclusion</p> <p>Telepsychiatric assessment is a dependable method of assessment with a high degree of accuracy and substantial overall intermethod agreement when compared with standard face to face interview for new routine outpatient psychiatric referrals.</p

Identifying Patients at High Risk of a Cardiovascular Event in the Near Future Current Status and Future Directions: Report of a National Heart, Lung, and Blood Institute Working Group

The National Heart, Lung, and Blood Institute convened a working group to provide basic and clinical research recommendations to the National Heart, Lung, and Blood Institute on the development of an integrated approach for identifying those individuals who are at high risk for a cardiovascular event such as acute coronary syndromes (ACS) or sudden cardiac death in the “near term.” The working group members defined near-term as occurring within 1 year of the time of assessment. The participants reviewed current clinical cardiology practices for risk assessment and state-of-the-science techniques in several areas, including biomarkers, proteomics, genetics, psychosocial factors, imaging, coagulation, and vascular and myocardial susceptibility. This report presents highlights of these reviews and a summary of suggested research directions