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The blink reflex (BR) is integrated at the brainstem; however, it is modulated by inputs from various structures such as the striatum, globus pallidus, substantia nigra, and nucleus raphe magnus but also from afferent input from the peripheral nervous system. Therefore, it provides information about the pathophysiology of numerous peripheral and central nervous system disorders. The BR is a valuable tool for studying the integrity of the trigemino-facial system, the relevant brainstem nuclei, and circuits. At the same time, some neurophysiological techniques applying the BR may indicate abnormalities involving structures rostral to the brainstem that modulate or control the BR circuits. This is a state-of-the-art review of the clinical application of BR modulation; physiology is reviewed in part 1. In this review, we aim to present the role of the BR and techniques related to its modulation in understanding pathophysiological mechanisms of motor control and pain disorders, in which these techniques are diagnostically helpful. Furthermore, some BR techniques may have a predictive value or serve as a basis for follow-up evaluation. BR testing may benefit in the diagnosis of hemifacial spasm, dystonia, functional movement disorders, migraine, orofacial pain, and psychiatric disorders. Although the abnormalities in the integrity of the BR pathway itself may provide information about trigeminal or facial nerve disorders, alterations in BR excitability are found in several disease conditions. BR excitability studies are suitable for understanding the common pathophysiological mechanisms behind various clinical entities, elucidating alterations in top-down inhibitory systems, and allowing for follow-up and quantitation of many neurological syndromes., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Migraine presents with high prevalence and similar clinical course with different disorders such as neurological, psychiatric, cardio- and cerebrovascular, gastrointestinal, metabolic-endocrine, and immunological conditions, which can often cooccur themselves. Multifaceted mechanisms subtend these comorbidities with a bidirectional link. First, a shared genetic load can explain the cooccurrence. Second, comorbid pathologies can promote disproportionate energetic needs, thalamocortical network dysexcitability, and systemic transient or persistent proinflammatory state, which may trigger the activation of a broad self-protective network that includes the trigeminovascular system in conjunction with the neuroendocrine hypothalamic system. This response results in maintenance of brain homeostasis by modulating subcortical-cortical excitability, energetic balance, osmoregulation, and emotional response. In this process, the CGRP is released in the trigeminovascular system. However, the calcitonin gene-related peptide (CGRP) plays several actions also outside the brain to maintain the homeostatic needs and is involved in the physiological functions of different systems, whose disorders are associated with migraine. This aspect further increases the complexity of migraine treatment, where standard therapies often have systemic adverse effects. On the other hand, some preventives can improve comorbid conditions. In summary, we propose that migraine management should involve a multidisciplinary approach to identify and mitigate potential risk factors and comorbidity and tailor therapies individually., (Copyright © 2024 Elsevier B.V. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Violet LED has been used for internal bleaching, however its implications on coronary dentin composition are unclear. The present study aims to evaluate the effect of bleaching with violet LED, either associated with 35 % hydrogen peroxide or not, on microhardness, chemical composition, and morphological characteristics of coronal dentin., Methods: Thirty maxillary canines were selected to obtain 30 blocks of coronal dentin, distributed in 3 groups (n = 10): 35 % hydrogen peroxide (HP); violet LED (LED); HP 35 % + LED, (HP+LED). The chemical analysis was performed by FTIR and the morphological evaluation of the dentin structure by confocal laser scanning microscopy before (T0) and after treatment (T1). The microhardness analysis was performed by microdurometer after bleaching. The data were submitted to repeated measures ANOVA test (P> 0.05)., Results: The intensity of the inorganic peaks decreased after bleaching for all groups (P = 0.003). There was an increase in the organic peak intensity after bleaching with HP, a decrease for LED, while HP+LED did not change the intensity (P = 0.044). Moreover, the inorganic/organic ratio decreased for HP (P = 0.022), while for LED and HP+LED there was no significant changes (P>0.05). HP and HP+LED showed lower microhardness values compared to LED (P< 0.05). Regarding morphological changes, an increase in the perimeter of the dentinal tubules was found for all groups, with the smallest increase being observed for LED., Conclusion: HP bleaching decreased the chemical stability and microhardness of the coronal dentin, while the violet LED treatments had no significant impact on dentin stability. In all groups, there was an increase in exposure of the dentinal tubules after bleaching, which was less pronounced with the violet LED bleaching., Competing Interests: Declaration of Competing Interest The authors report no conflict of interest in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In the last decades a significant increase of the migratory phenomenon from South Asian countries to the Western World has occurred for social, economic and geopolitical reasons. The aim of this review is to describe cardiovascular risk factors, pathogenesis and treatments of coronary artery disease in South Asian patients. It is well established that South Asian populations have a higher prevalence of coronary artery disease and premature onset of myocardial infarction episodes than other populations. This higher predisposition might be caused by genetic factors, common in both South Asian patients residing in their birth country and in those residing abroad, but it may also be due to the new spatial environment in which they live. It will be important to examine the leading cardiovascular risk factors determining increasing incidence of coronary artery disease in the South Asian population. These include: insulin resistance, hypertension, dyslipidaemia and abdominal obesity caused by a diet rich in refined carbohydrates and saturated fats. Furthermore, it is important to examine emerging cardiovascular risk factors strictly related to this particular ethnic group. The evidence of higher levels of prothrombotic and proinflammatory factors, for example lipoprotein(a) and proinflammatory adipokines, as well as the influence of air pollution and psychosocial stress, may have consequences on the risk, treatment and outcomes of the coronary artery disease in this population. Migrants from South Asia deserve to be addressed and framed with particular care in terms of cardiovascular risk and especially in the management of acute coronary events., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Over the past two decades, developments in regenerative medicine in gastroenterology have been greatly enhanced by the application of stem cells, which can self-replicate and differentiate into any somatic cell. The discovery of induced pluripotent stem cells has opened remarkable perspectives on tissue regeneration, including their use as a bridge to transplantation or as supportive therapy in patients with organ failure. The improvements in DNA manipulation and gene editing strategies have also allowed to clarify the physiopathology and to correct the phenotype of several monogenic diseases, both in vivo and in vitro. Further progress has been made with the development of three-dimensional cultures, known as organoids, which have demonstrated morphological and functional complexity comparable to that of a miniature organ. Hence, owing to its protean applications and potential benefits, cell and organoid transplantation has become a hot topic for the management of gastrointestinal diseases. In this review, we describe current knowledge on cell therapies in hepatology and pancreatology, providing insight into their future applications in regenerative medicine., (Copyright © 2022. Published by Elsevier Ltd.)

Since the first electroencephalographic recordings obtained by Golla and Winter in 1959, researchers have used a variety of neurophysiological techniques to determine the mechanisms underlying recurrent migraine attacks. Neurophysiological methods have shown that the brain during the interictal phase of an episodic migraine is characterized by a general hyperresponsiveness to sensory stimuli, a malfunction of the monoaminergic brainstem circuits, and by functional alterations of the thalamus and thalamocortical loop. All of these alterations vary plastically during the phases of the migraine cycle and interictally with the days following the attack. Both episodic migraineurs recorded during an attack and chronic migraineurs are characterized by a general increase in the cortical amplitude response to peripheral sensory stimuli; this is an electrophysiological hallmark of a central sensitization process that is further reinforced through medication overuse. Considering the large-scale functional involvement and the main roles played by the brainstem-thalamo-cortical network in selection, elaboration, and learning of relevant sensory information, future research should move from searching for one specific primary site of dysfunction at the macroscopic level, to the chronic, probably genetically determined, molecular dysfunctions at the synaptic level, responsible for short- and long-term learning mechanisms., (Copyright © 2023 Elsevier B.V. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Purpose: To report the efficacy and tolerability of brivaracetam (BRV) in add-on therapy in pediatric patients with severe drug-resistant epilepsy. Prognostic factors of clinical outcome were also analyzed., Methods: This Italian multicenter retrospective observational study was conducted on 45 pediatric patients with severe drug-resistant epilepsy, treated with BRV for at least 1 month and with a follow-up >6 months. Demographic, clinical, and treatment variables were assessed at T0 (baseline, BRV introduction) and T1 (6 months after BRV introduction). The response was defined as ≥50% seizure frequency reduction; responders and non-responders were then compared to assess potential prognostic factors., Results: Forty-five patients (M = 28, mean age 12.4+/-4.4 years) were enrolled (focal epilepsy=14; generalized epilepsy=2; epileptic encephalopathy=29). At T1, 19/45 patients (42.2%) were responders (≥50% seizure frequency reduction), with 4 patients (8.9%) achieving a ≥ 75% seizure reduction and 2 patients (4.4%) becoming seizure free. Epilepsy onset at >12 months of age (p = 0.001), disease duration ≤6 years (p = 0.036), and lower seizure frequency at baseline (p = 0.008) were the prognostic factors significantly associated with a better prognosis. No significant difference emerged for demographics, epilepsy types/etiology, intellectual disability, or therapy variables. At T1, 21 patients (46.6%) discontinued BRV, mainly due to lack of efficacy (13 subjects; 28.9%) and adverse events in 8 patients (17.8%)., Conclusion: Brivaracetam was an effective and tolerated treatment in pediatric patients with severe drug-resistant epilepsy, especially when the seizure onset was at >12 months of age, the epilepsy duration ≤6 years, and the seizure frequency before BRV treatment was low. Further and controlled studies are needed., Competing Interests: Declaration of Competing Interest The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022. Published by Elsevier Ltd.)

Agricultural activity is responsible of considerable negative effects on the environment. In this context, in the last years, organic cultivation is increasing being perceived as more sustainable for the environmental. Nevertheless, this higher sustainability compared to conventional agricultural systems is debated. This applied for crops but also for livestock systems. For some of the main crops (i.e., cereals, soybean) comparative analysis were carried out but for most of the other annual and perennial crops there is a lack of information about the environmental impact related to conventional and organic cultivation In this study, the environmental impact of the conventional and organic farming systems of hazelnuts production in Viterbo province in Italy was evaluated using the Life Cycle Assessment (LCA) approach. Even if originally developed for industrial processes, LCA is more and more applied also to agriculture systems to quantify the environmental impact. Primary data were collected by the main Producer Organization and elaborated considering 1 kg of hazelnuts as functional unit and a from cradle to gate approach considering the 50-years as life cycle duration of the crop. Finally, using the Recipe characterization method, 15 midpoint impact categories were evaluated. The results show how, except than for ecotoxicity related impact categories, organic cultivation practice shows higher impact (from +5% to +285%) respect to the conventional production. For ecotoxicity related impact categories, organic hazelnut production performs better (from -42% to -81%) than the conventional one because no synthetic pesticides are applied. The sensitivity analysis carried shows how yield is the main driver of the environmental results while the uncertainty analysis performed with the Monte Carlo technique shows that the to the selection of the data source, model imprecision and data variability does not significantly affect the environmental results for the evaluated impact categories., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: The aims of this study were to analyse the incidence of visceral malperfusion syndrome (MPS) following Frozen Elephant trunk operations in patients affected by chronic aortic dissection and the associated risk factors., Methods: Between January 2007 and February 2019, 165 patients underwent surgery with FET for chronic aortic dissection. Post-operative computer tomography angiogram parameters (diameters, early post-operative false lumen enhancement and involving of aortic branches by the dissection) were collected and analysed to evaluate their impact on the occurrence of visceral malperfusion., Results: Visceral (renal and mesenteric) MPS (with both clinical and radiological signs of MPS) was detected in 10 cases (6.1%). Post-operative visceral malperfusion was strongly related with in hospital mortality. The involvement of the visceral branches in the dissection was not a risk factor for visceral malperfusion occurrence, while a larger post-operative total aortic diameter at level of the coeliac trunk increased the risk of visceral MPS (OR 1.05; CI 1.002-1.102, p-value = 0.04). Furthermore, visceral MPS was associated to a complete thrombosis of the false lumen at level of the distal descending thoracic aorta., Conclusions: The development of post-operative MPS in frozen elephant trunk is strongly related to in-hospital mortality. The involvement of aortic branches by the dissection does not represent a real predictive risk factor for MPS, while early larger aortic diameters and false lumen thrombosis represent independent risk factors for MPS and in-hospital mortality., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aims: In the present study, we aimed to compare the clinical and coronary angiography features between South Asian and Caucasian patients with Acute Coronary Syndrome (ACS). In particular, we focused our analysis on the evaluation of recent cardiovascular risk markers, such as remnant cholesterol, corresponding to all plasma cholesterol minus HDL-C (high-density lipoprotein cholesterol) and LDL-C (low-density lipoprotein cholesterol), and the Monocyte-to-HDL-cholesterol ratio. We also compared values of several lipoprotein ratios and the Platelet-to-lymphocyte ratio, accurate predictors of coronary events and coronary artery disease., Methods and Results: We recruited 40 South Asian and 40 Caucasian patients admitted for ACS. Data were collected by consulting patients' medical records. We used Chi-square test and Student's t-test to analyse qualitative and quantitative variables, respectively. South Asian patients, compared to Caucasians, showed higher mean values of the parameters analysed: remnant cholesterol (32.6 ± 17 vs 26.5 ± 9.6), Monocyte-to-HDL-cholesterol ratio (26.4 ± 48.7 vs 16.5 ± 8.3), Platelet-to-lymphocyte ratio (124.7 ± 130.7 vs 120.5 ± 58.8). Moreover, higher mean values of several lipoprotein ratios were also found in South Asian patients compared to the control group. However, statistical significance was not reached for any of these differences observed., Conclusions: The evaluation of the parameters analysed in this study might provide accurate information regarding the cardio-metabolic risk in South Asian patients. However, further studies with larger samples are needed to obtain more significant results., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Atrial fibrillation (AF) represents the arrhythmia of greatest clinical impact and catheter ablation of AF (CAAF) has become the most effective strategy for rhythm control in selected patients. Therefore, appropriate anticoagulation strategies are of paramount importance for patients undergoing CAAF, especially those at high risk, such those with high CHA2DS2VASc scores. Optimal management of anticoagulation before, during, and after CAAF is crucial. Several studies have evaluated the use of different anticoagulation strategies in the periprocedural period. Randomized controlled trial seem to suggest that in patients undergoing CAAF, uninterrupted (or minimally interrupted) direct oral anticoagulants (DOACs) provides an alternative to continuous vitamin K antagonists strategy, with low thromboembolic and bleeding risk., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Brugada syndrome (BrS) was first described in 1992 as an aberrant pattern of ST segment elevation in right precordial leads with a high incidence of sudden cardiac death (SCD) in patients with structurally normal heart. It represents 4% ∼ 12% of all SCD and 20% of SCD in patients with structurally normal heart. The extremely wide genetic heterogeneity of BrS and other inherited cardiac disorders makes this new area of genetic arrhytmology a fascinating one. This review shows the state of art in diagnosis, management, and treatment of BrS focusing all the aspects regarding genetics and Preimplant Genetic Diagnosis (PGD) of embryos, overlapping syndromes, risk stratification, familial screening, and future perspectives. Moreover the review analyzes key points like electrocardiogram (ECG) criteria, the role of electrophysiological study (the role of ventricular programmed stimulation and the need of universal accepted protocol) and the importance of a correct risk stratification to clarify when implantable cardioverter defibrillator or a close follow-up is needed. In recent years, cardiovascular studies have been focused on personalized risk assessment and to determine the most optimal therapy for an individual. The BrS syndrome has also benefited of these advances although there remain several key points to be elucidated. We will review the present knowledge, progress made, and future research directions on BrS., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To study lateral inhibition and habituation/sensitization in the somatosensory cortex of patients with chronic migraine (CM) and to identify correlations with clinical migraine features., Methods: Sixteen patients with CM without medication overuse, and 17 healthy volunteers (HVs) received somatosensory evoked potentials (SSEPs) elicited by separate electrical stimulation of the right median (M) and ulnar (U) nerves at the wrist and by simultaneous nerve stimulation (MU). We measured the N20-P25 amplitudes and calculated the lateral inhibition (LI) percentage using the formula {100-[MU/(M + U) * 100]}. We also calculated sensitization (SSEP amplitude during block 1) and delayed habituation to M-nerve stimulation., Results: The percentage of LI did not differ between the groups (40.2% in HV, 47.4% in CM, p = 0.276) and was negatively correlated with the monthly headache-day number (r = -0.532, p = 0.034). Patients showed a generalized increase in SSEP amplitudes compared to HVs and habituated normally., Conclusions: We showed a pattern of somatosensory response in CM similar to that observed during attacks of episodic migraine., Significance: In the transition process between episodic migraine and CM, LI attempts to physiologically counteract the mounting increase in attack frequency, but this is insufficient to allow patients to exit the chronic phase., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: 22q11.2 copy number variants are among the most highly penetrant genetic risk variants for developmental neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the specific mechanisms through which they confer risk remain unclear., Methods: Using a functional genomics approach, we integrated transcriptomic data from the developing human brain, genome-wide association findings for SCZ and ASD, protein interaction data, and gene expression signatures from SCZ and ASD postmortem cortex to 1) organize genes into the developmental cellular and molecular systems within which they operate, 2) identify neurodevelopmental processes associated with polygenic risk for SCZ and ASD across the allelic frequency spectrum, and 3) elucidate pathways and individual genes through which 22q11.2 copy number variants may confer risk for each disorder., Results: Polygenic risk for SCZ and ASD converged on partially overlapping neurodevelopmental modules involved in synaptic function and transcriptional regulation, with ASD risk variants additionally enriched for modules involved in neuronal differentiation during fetal development. The 22q11.2 locus formed a large protein network during development that disproportionately affected SCZ-associated and ASD-associated neurodevelopmental modules, including loading highly onto synaptic and gene regulatory pathways. SEPT5, PI4KA, and SNAP29 genes are candidate drivers of 22q11.2 synaptic pathology relevant to SCZ and ASD, and DGCR8 and HIRA are candidate drivers of disease-relevant alterations in gene regulation., Conclusions: This approach offers a powerful framework to identify neurodevelopmental processes affected by diverse risk variants for SCZ and ASD and elucidate mechanisms through which highly penetrant, multigene copy number variants contribute to disease risk., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: Infantile spasms (IS) represent a severe seizure disorder of infancy and early childhood characterized by epileptic spasms along with hypsarrhythmia often accompanied by intellectual disability. According to the current classification and terminology (3) IS can be categorized as known etiology, formerly known as "symptomatic", when an underlying cause has been observed prior to the onset of spasms, or of "unknown cause" with "unfavorable" and "favorable" outcome (previously referred as "cryptogenic" or "idiopathic", respectively). Single reports described children with "unknown cause and favorable outcome" (UC/FO) IS who later developed childhood absence epilepsy (CAE). This study aims to determine the prevalence of CAE following IS., Methods: a multicenter retrospective chart review was performed; children with UC/FO IS who subsequently developed CAE during follow-up were identified. Eight Italian pediatric epilepsy centers participated in this study., Results: seven out of 24 (29 %) children (3 males) showing a favorable outcome (UC/FO) IS received a second diagnosis of CAE during follow-up. Mean age at IS presentation was 5.8 months (SD ± 0.9). All achieved seizure control of IS at a mean age of 8.5 months (SD ± 1.3) (3 monotherapy, 4 polytherapy). CAE was diagnosed at a mean age of 8.0 years (SD ± 3.0). Six children achieved sustained remission of CAE with valproic acid, whereas 1 child required dual therapy by adding ethosuximide., Conclusion: although it is not possible to determine whether the association between UC/FO IS and CAE implies a causality relationship, the later occurrence of CAE in patients with UC/FO IS might support a possible role of thalamo-cortical dysfunction., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To test the hypothesis that a functional polymorphism of the serotonin transporter gene (serotonin-transporter-linked polymorphic region [5-HTTLPR]), which is thought to be associated with differential environmental sensitivity, moderates the association between low levels of empathic accuracy (i.e., ability to recognize emotions in others) in patients with neurodegenerative disease and caregivers' well-being., Methods: Participants were 54 patients with neurodegenerative disease and their caregivers. Patients' empathic accuracy was measured using a dynamic tracking task in which they continuously rated the emotions of a character in a film; accuracy was determined by comparing patient ratings with those made by an expert panel. Caregivers provided a saliva sample for genotyping. Caregivers' well-being was measured as a latent construct indicated by validated measures of depression, anxiety, and negative affect., Results: Lower levels of patients' empathic accuracy were associated with lower levels of caregivers' well-being. Importantly, caregivers' 5-HTTLPR genotype moderated this association such that lower empathic accuracy in patients predicted lower well-being for caregivers with the short/short genotype (standardized β = 0.66), but not for caregivers with the short/long (standardized β = 0.05) or long/long genotypes (standardized β = -0.21)., Conclusion: Consistent with previous findings that the short/short variant of 5-HTTLPR is associated with greater sensitivity to environmental influences, caregivers with the short/short variant manifest lower well-being when caring for a patient with low levels of empathic accuracy than caregivers with the other variants. This finding contributes to the authors' understanding of biological factors associated with individual differences in caregiver vulnerability and resilience., (Copyright © 2019. Published by Elsevier Inc.)

Objective: A novel supervised method that is based on the Multi-Proportion Channel Ensemble Model (MPC-EM) is proposed to obtain more vessel details with reduced computational complexity., Methods: Existing Retinal Vessel Segmentation (RVS) algorithms only work using the single G channel (Green Channel) of fundus images because that channel normally contains the most details with the least noise, while the red and blue channels are usually saturated and noisy. However, we find that the images that are composed of the αG-channel and (1-α) R-channel (Red Channel) with different values of α produce multiple particular global features. This enables the model to detect more local vessel details in fundus images. Therefore, we provide a detailed description and evaluation of the segmentation approach based on the MPC-EM for the RVS. The segmentation approach consists of five identical submodels. Each submodel can capture various vessel details by being trained using different composition images. These probabilistic maps that are produced by five submodels are averaged to achieve the final refined segmentation results., Results: The proposed approach is evaluated using 4 well-established datasets, i.e., DRIVE, STARE, HRF and CHASE&#95;DB1, with accuracies of 95.74%, 96.95%, 96.31%, and 96.54%, respectively. Additionally, quantitative comparisons with other existing methods and cross-training results are included., Conclusion: The segmentation results showed that the proposed algorithm based on the MPC-EM with simple submodels can achieve state-of-the-art accuracy with reduced computational complexity., Significance: Compared with other existing methods that are trained using only the G channel and raw images, the proposed approach based on the MPC-EM, submodels of which are trained using different proportional compositions of R and G channels, obtains better segmentation accuracy and robustness. Additionally, the experimental results show that the R channel of fundus images can also produce performance gains for RVS., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Repetitive convergent inputs to a single post-synaptic neuron can induce long-term potentiation (LTP) or depression (LTD) of synaptic activity in a spike timing-dependent manner., Objective: Here we set a protocol of visual paired associative stimulation (vPAS) of the primary visual cortex (V1) in humans to induce persistent changes in the excitatory properties of V1 with a spike timing rule., Methods: We provided convergent inputs to V1 by coupling transcranial magnetic stimulation (TMS) pulses of the occipital cortex with peripheral visual inputs, at four interstimulus intervals of -50/-25/+25/+50 ms relative to the visual evoked potential (VEP) P1 latency. We analysed VEP amplitude and delayed habituation before and up to 10 min after each vPAS protocol., Results: VEP amplitude was reduced after vPAS+25. Delayed VEP habituation was increased after vPAS-25 while it was reduced after vPAS+25., Conclusions: We provide evidence that associative bidirectional synaptic plasticity is a feature not only of the sensorimotor but also of the human visual system., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative syndromes associated with several causative and susceptibility genes. Herein, we aimed to determine the incidence of the most common causative dementia genes in a cohort of 118 unrelated Greek FTD spectrum patients. We also screened for novel possible disease-associated variants in additional 21 genes associated with FTD or amyotrophic lateral sclerosis. Pathogenic or likely pathogenic variants were identified in 16 cases (13.6%). These included repeat expansions in C9orf72 and loss-of-function GRN variants, and likely pathogenic variants in TARDBP, MAPT, and PSEN1. We also identified 14 variants of unknown significance in other rarer FTD or amyotrophic lateral sclerosis genes that require further segregation and functional analysis. Our genetic screen revealed a high genetic burden in familial Greek FTD cases (30.4%), whereas only two of the sporadic cases (3.5%) carried a likely pathogenic variant. A substantial number of familial cases still remain without an obvious causal variant, suggesting the existence of other FTD genetic causes besides those currently screened in clinical routine., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: We aimed to understand the impact of dopamine receptor D 4 (DRD 4 ) polymorphisms on neurodegeneration in patients with dementia. We hypothesized that DRD 4 dampened-variants with reduced functional potency would be associated with greater atrophy in regions with higher receptor density. Given that DRD 4 is concentrated in anterior regions of the limbic and cortical forebrain we anticipated genotype effects in patients with a more rostral pattern of neurodegeneration., Methods: 337 subjects, including healthy controls, patients with Alzheimer's disease (AD) and frontotemporal dementia (FTD) underwent genotyping, structural MRI, and cognitive/behavioral testing. We conducted whole-brain voxel-based morphometry to examine the relationship between DRD 4 genotypes and brain atrophy patterns within and across groups. General linear modeling was used to evaluate relationships between genotype and cognitive/behavioral measures., Results: DRD 4 dampened-variants predicted gray matter atrophy in disease-specific regions of FTD in anterior cingulate, ventromedial prefrontal, orbitofrontal and insular cortices on the right greater than the left. Genotype predicted greater apathy and repetitive motor disturbance in patients with FTD. These results covaried with frontoinsular cortical atrophy. Peak atrophy patterned along regions of neuroanatomic vulnerability in FTD-spectrum disorders. In AD subjects and controls, genotype did not impact gray matter intensity., Conclusions: We conclude that DRD 4 polymorphisms with reduced functional potency exacerbate neuronal injury in sites of higher receptor density, which intersect with syndrome-specific regions undergoing neurodegeneration in FTD., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Mutations in progranulin (GRN) cause heterogeneous clinical syndromes, including behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), corticobasal syndrome (CBS) and Alzheimer-type dementia (AD-type dementia). Human studies have shown that presymptomatic GRN carriers feature reduced connectivity in the salience network, a system targeted in bvFTD. Mice with homozygous deletion of GRN, in contrast, show thalamo-cortical hypersynchrony due to aberrant pruning of inhibitory synapses onto thalamo-cortical projection neurons. No studies have systematically explored the intrinsic connectivity networks (ICNs) targeted by the four GRN-associated clinical syndromes, or have forged clear links between human and mouse model findings. We compared 17 preclinical GRN carriers (14 "presymptomatic" clinically normal and three "prodromal" with mild cognitive symptoms) to healthy controls to assess for differences in cognitive testing and gray matter volume. Using task-free fMRI, we assessed connectivity in the salience network, a non-fluent variant primary progressive aphasia network (nfvPPA), the perirolandic network (CBS), and the default mode network (AD-type dementia). GRN carriers and controls showed similar performance on cognitive testing. Although carriers showed little evidence of brain atrophy, markedly enhanced connectivity emerged in all four networks, and thalamo-cortical hyperconnectivity stood out as a unifying feature. Voxelwise assessment of whole brain degree centrality, an unbiased graph theoretical connectivity metric, confirmed thalamic hyperconnectivity. These results show that human GRN disease and the prevailing GRN mouse model share a thalamo-cortical network hypersynchrony phenotype. Longitudinal studies will determine whether this network physiology represents a compensatory response as carriers approach symptom onset, or an early and sustained preclinical manifestation of lifelong progranulin haploinsufficiency., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy with a prevalence of 1-2% of all patients with epilepsy. It is characterized by multiple pharmaco-resistant seizure types, including tonic, atypical absences and tonic or atonic drop attacks, and the presence of electroencephalographic abnormalities, such as slow-spike waves and paroxysmal fast rhythms. Intellectual disability, behavioural and psychiatric disorders are common comorbidities; these disturbances have a multi-factorial pathogenesis. The selection of the most appropriate drug must be tailored to each patient and guided by the prevalent seizure type. In this paper available pharmacological options are discussed and for each pharmacological agent, current evidence of efficacy and tolerability is provided. Valproic acid represents one of the first-line options in the treatment of LGS. Anyway, other antiepileptic drugs (AEDs) may be considered and added: lamotrigine, rufinamide, topiramate, clobazam can be efficacious. The use of felbamate must be carefully evaluated because of its adverse events. Perampanel, zonisamide, levetiracetam and fenfluramine have shown to be useful in the treatment of selected patients; nevertheless, the lack of RCTs does not allow to recommend their use in a systematic way. Recently, cannabidiol has provided high evidence of efficacy against LGS seizures; however, these data must be confirmed by long-term extensive studies and by trials comparing different AEDs, one to each other., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Heterozygous point mutations or deletions of the NKX2-1 gene cause benign hereditary chorea (BHC) or a various combinations of primary hypothyroidism, respiratory distress and neurological disorders. Deletions proximal to, but not encompassing, NKX2-1 have been described in few subjects with brain-lung-thyroid syndrome. We report on a three-generation Italian family, with 6 subjects presenting BHC and harboring a genomic deletion adjacent to NKX2-1 and including the gene MBIP, recently proposed to be relevant for the pathogenesis of brain-lung-thyroid syndrome. We observed a clear reduction of NKX2-1 transcript levels in fibroblasts from our patients compared to controls; this finding suggests that MBIP deletion affects NKX2-1 expression, mimicking haploinsufficiency caused by classical NKX2-1 related mutations., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Fast, inexpensive, and noninvasive identification of Alzheimer's disease (AD) before clinical symptoms emerge would augment our ability to intervene early in the disease. Individuals with fully penetrant genetic mutations causing autosomal dominant Alzheimer's disease (ADAD) are essentially certain to develop the disease, providing a unique opportunity to examine biomarkers during the preclinical stage. Using a generalization task that has previously shown to be sensitive to medial temporal lobe pathology, we compared preclinical individuals carrying ADAD mutations to noncarrying kin to determine whether generalization (the ability to transfer previous learning to novel but familiar recombinations) is vulnerable early, before overt cognitive decline. As predicted, results revealed that preclinical ADAD mutation carriers made significantly more errors during generalization than noncarrying kin, despite no differences between groups during learning or retention. This impairment correlated with the left hippocampal volume, particularly in mutation carriers. Such identification of generalization deficits in early ADAD may provide an easily implementable and potentially linguistically and culturally neutral way to identify and track cognition in ADAD., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: "Single Nucleotide Polymorphisms (SNPs)" could be an important explanation of drug resistance in epilepsy. The aim of this study was to investigate if genetic polymorphisms (SNPs) of the SCN1A gene could influence the response to anti - epileptic drugs (AED) and if they could predispose to a drug resistant epilepsy in pediatric patients., Methods: We investigated SNPs in exon and intronic regions of the SCN1A gene in a sample of 120 pediatric patients, in both drug-resistant and drug-responsive patients. Association between polymorphisms and refractory epilepsy were investigated by comparing SNPs in exon and intronic regions between the two groups. The genotypes of each intronic polymorphism in the drug-resistant group was analyzed. Odds ratios and confidence intervals were calculated., Results: None of the SNPs identified in exons of the SCN1A gene were associated with drug-resistance. In the intronic regions, a statistically significant difference was found in the prevalence of three polymorphisms was found between the two patient groups (rs6730344A/C, rs6732655A/T, rs10167228A/T). The analysis of the genotypes of each intronic polymorphism in the drug-resistant group revealed that the AA and AT genotypes for the rs1962842 polymorphism are associated with an increased risk of developing drug resistance compared to TT genotype., Conclusion: The intronic rs6730344, rs6732655 and rs10167228 polymorphisms of the SCN1A gene are a potential risk factors for drug resistance. AA e AT genotype of the rs1962842 intronic polymorphism also emerged as a risk factor in the drug resistant group. Therefore, polymorphisms of the SCN1A gene could play a role in the response to AED in patients with drug-resistant epilepsy, with important implications for clinical practice., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

High-throughput, low-cost sequencing technologies have begun to yield new insights into biology and medicine. New data enable the interrogation of the molecular biology of disease from DNA to RNA to protein, charting the central dogma. This chapter reviews some of the key advances and resources in the application of bioinformatics to understanding, and ultimately diagnosing and treating, diseases of the nervous system. Array genotyping, exome sequencing, and whole-genome sequencing, in both disease and healthy populations, have enabled the interpretation of new genetic data. Profiling of epigenetic markers, such as histone modifications, has added to our understanding of the regulatory machinery of the genome. Downstream, mRNA, and protein expression data from published experiments and high-throughput studies enable complex analyses of gene function across many experimental conditions and tissues. Further delineation of molecular mechanism arises from the concept of genes working together in pathways or networks, reflecting direct protein interactions and regulatory relationships. The rapidly moving field of bioinformatics has made significant contributions to neurology in these early days; continued advances promise to transform medicine from basic science to clinical practice, as more genomics data are generated, combined, and analyzed in the future., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Autosomal dominant Alzheimer's disease (ADAD) is a small subset of Alzheimer's disease that is genetically determined with 100% penetrance. It provides a valuable window into studying the course of pathologic processes that leads to dementia. Arterial spin labeling (ASL) MRI is a potential AD imaging marker that non-invasively measures cerebral perfusion. In this study, we investigated the relationship of cerebral blood flow measured by pseudo-continuous ASL (pCASL) MRI with measures of cerebral metabolism (FDG PET) and amyloid deposition (Pittsburgh Compound B (PiB) PET). Thirty-one participants at risk for ADAD (age 39 ± 13 years, 19 females) were recruited into this study, and 21 of them received both MRI and FDG and PiB PET scans. Considerable variability was observed in regional correlations between ASL-CBF and FDG across subjects. Both regional hypo-perfusion and hypo-metabolism were associated with amyloid deposition. Cross-sectional analyses of each biomarker as a function of the estimated years to expected dementia diagnosis indicated an inverse relationship of both perfusion and glucose metabolism with amyloid deposition during AD development. These findings indicate that neurovascular dysfunction is associated with amyloid pathology, and also indicate that ASL CBF may serve as a sensitive early biomarker for AD. The direct comparison among the three biomarkers provides complementary information for understanding the pathophysiological process of AD.

Background: Cardiac resynchronization therapy (CRT) is a successful strategy for heart failure (HF) patients. The pre-requisite for the response is the evidence of electrical dyssynchrony on the surface electrocardiogram usually as left bundle branch block (LBBB). Non-response to CRT is a significant problem in clinical practice. Patient selection, inadequate delivery and sub-optimal left ventricle lead position may be important causes., Objectives: In an effort to improve CRT response multimodality imaging (especially echocardiography, computed tomography and cardiac magnetic resonance) could play a decisive role and extensive literature has been published on the matter. However, we are so far from routinary use in clinical practice. Electrocardiography (with respect to left ventricle capture and QRS narrowing) may represent a simple and low cost approach for early prediction of potential non-responder, with immediate practical implications., Conclusion: This brief review covers the current recommendations for CRT in HF patients with particular attention to the potential benefits of multimodality imaging and electrocardiography in improving response rate., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Hexanucleotide repeat expansions in C9ORF72 are the most common known genetic cause of familial and sporadic frontotemporal dementia and amyotrophic lateral sclerosis. Previous work has shown that patients with behavioral variant frontotemporal dementia due to C9ORF72 show salience and sensorimotor network disruptions comparable to those seen in sporadic behavioral variant frontotemporal dementia, but it remains unknown how early in the lifespan these and other changes in brain structure and function arise. To gain insights into this question, we compared 15 presymptomatic carriers (age 43.7 ± 10.2 years, nine females) to matched healthy controls. We used voxel-based morphometry to assess gray matter, diffusion tensor imaging to interrogate white matter tracts, and task-free functional MRI to probe the salience, sensorimotor, default mode, and medial pulvinar thalamus-seeded networks. We further used a retrospective chart review to ascertain psychiatric histories in carriers and their non-carrier family members. Carriers showed normal cognition and behavior despite gray matter volume and brain connectivity deficits that were apparent as early as the fourth decade of life. Gray matter volume deficits were topographically similar though less severe than those in patients with behavioral variant frontotemporal dementia due to C9ORF72 , with major foci in cingulate, insula, thalamus, and striatum. Reduced white matter integrity was found in the corpus callosum, cingulum bundles, corticospinal tracts, uncinate fasciculi and inferior longitudinal fasciculi. Intrinsic connectivity deficits were detected in all four networks but most prominent in salience and medial pulvinar thalamus-seeded networks. Carrier and control groups showed comparable relationships between imaging metrics and age, suggesting that deficits emerge during early adulthood. Carriers and non-carrier family members had comparable lifetime histories of psychiatric symptoms. Taken together, the findings suggest that presymptomatic C9ORF72 expansion carriers exhibit functionally compensated brain volume and connectivity deficits that are similar, though less severe, to those reported during the symptomatic phase. The early adulthood emergence of these deficits suggests that they represent aberrant network patterning during development, an early neurodegeneration prodrome, or both.

The mechanisms underlying presenilin 1 (PSEN1) mutation-associated spastic paraparesis (SP) are not clear. We compared diffusion and volumetric magnetic resonance measures between 3 persons with SP associated with the A431E mutation and 7 symptomatic persons with PSEN1 mutations without SP matched for symptom duration. We performed amyloid imaging and central motor and somatosensory conduction studies in 1 subject with SP. We found decreases in fractional anisotropy and increases in mean diffusivity in widespread white-matter areas including the corpus callosum, occipital, parietal, and frontal lobes in PSEN1 mutation carriers with SP. Volumetric measures were not different, and amyloid imaging showed low signal in sensorimotor cortex and other areas in a single subject with SP. Electrophysiological studies demonstrated both slowed motor and sensory conduction in the lower extremities in this same subject. Our results suggest that SP in carriers of the A431E PSEN1 mutation is a manifestation of widespread white-matter abnormalities not confined to the corticospinal tract that is at most indirectly related to the mutation's effect on amyloid precursor protein processing and amyloid deposition., Competing Interests: The authors have no conflict of interest to disclose., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Several studies have investigated the association between native QRS duration (QRSd) or QRS narrowing and response to biventricular pacing. However, their results have been conflicting. The aim of our study was to determine the association between the relative change in QRS narrowing index (QI) and clinical outcome and prognosis in patients who undergo cardiac resynchronization therapy (CRT) implantation., Methods and Results: We included 311 patients in whom a CRT device was implanted in accordance with current guidelines for CRT. On implantation, the native QRS, the QRSd and the QI during CRT were measured. After 6months, 220 (71%) patients showed a 10% reduction in LVESV. The median [25th-75th] QI was 14.3% [7.2-21.4] and was significantly related to reverse remodeling (r=+0.22; 95%CI: 0.11-0.32, p=0.0001). The cut-off value of QI that best predicted LV reverse remodeling after 6months of CRT was 12.5% (sensitivity=63.6%, specificity=57.1%, area under the curve=0.633, p=0.0002). The time to the event death or cardiovascular hospitalization was significantly longer among patients with QI>12.5% (log-rank test, p=0.0155), with a hazard ratio (HR) of 0.3 [95%CI: 0.11-0.78]. In the multivariate regression model adjusted for baseline parameters, a 10% increment in QI (HR=0.61[0.44-0.83], p=0.002) remained significantly associated with CRT response., Conclusions: Patients with a larger decrease in QRSd after CRT initiation showed greater echocardiographic reverse remodeling and better outcome from death or cardiovascular hospitalization. QI is an easy-to-measure variable that could be used to predict CRT response at the time of pacing site selection or pacing configuration programming., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: The aim of this study was to evaluate in patients with cardiac syndrome X (CSX), using validated angiography indices, coronary blood flow and myocardial perfusion of the microcirculation to assess whether there is greater microvascular dysfunction in patients with increase of carotid intima media thickness (C-IMT), compared to those who do not have., Methods: Our study was performed on a population 124 patients with CSX that underwent coronary angiography and carotid ultrasound. We divided the sample into two categories: patients with increase of C-IMT and those without increase. We calculated Gibson and Yusuf indices for each patient based on angiographic images, including TIMI Frame Count (TFC), Myocardial Blush Grade (MBG) and Total Myocardial Blush Score (TMBS)., Results: Our sample compared two groups: patients with increase of C-IMT (n-63) and patients without increase of C-IMT (n-61). We showed that patients with increase C-IMT had a longest TFC of three major coronary arteries (TFC LAD 44.7±12.5; TFC RCA 26.2±6.9; TFC CX 27±5.9), than control group. We found lower MBG on three coronary arteries (MBG LAD 2.5±0.3; MBG RCA 2.3±0.3; MBG CX 2.1±0.32) in patients with increase of C-IMT than control group, with good statistical significance., Conclusion: Analysis of microcirculation trough angiography indexes in patients with CSX with increase of C-IMT and without has led to asses that patients with increase of C-IMT population has a greater involvement of microcirculation than patients without., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Mutations in the granulin (GRN) gene cause frontotemporal dementia (FTD) due to progranulin haploinsufficiency. Compounds that can increase progranulin production and secretion may be considered as potential therapeutic drugs; however, very few of them have been directly tested on human cortical neurons. To this end, we differentiated 9 induced pluripotent stem cell lines derived from a control subject, a sporadic FTD case and an FTD patient with progranulin S116X mutation. Treatment with 1 μM suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, increased the production of progranulin in cortical neurons of all subjects at both the mRNA and protein levels without affecting their viability. Microarray analysis revealed that SAHA treatment not only reversed some gene expression changes caused by progranulin haploinsufficiency but also caused massive alterations in the overall transcriptome. Thus, histone deacetylase inhibitors may be considered as therapeutic drugs for GRN mutation carriers. However, this class of drugs also causes drastic changes in overall gene expression in human cortical neurons and their side effects and potential impacts on other pathways should be carefully evaluated., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The precise physiologic function of many of the recently discovered Alzheimer's disease risk variants remains unknown. The downstream effects of genetic variants remain largely unexplored. We studied the relationship between the top 10 non-APOE genes with cortical and hippocampal atrophy as markers of neurodegeneration using 1.5T magnetic resonance imaging, 1-million single nucleotide polymorphism Illumina Human Omni-Quad array and Illumina Human BeadChip peripheral blood expression array data on 50 cognitively normal and 98 mild cognitive impairment subjects. After explicit matching of cortical and hippocampal morphology, we computed in 3D, the cortical thickness and hippocampal radial distance measures for each participant. Associations between the top 10 non-APOE genome-wide hits and neurodegeneration were explored using linear regression. Map-wise statistical significance was determined with permutations using threshold of p < 0.01. MS4A6A rs610932 and ABCA7 rs3764650 demonstrated significant associations with cortical and hippocampal atrophy. Exploratory MS4A6A and ABCA7 peripheral blood expression analyses revealed a similar pattern of associations with cortical neurodegeneration. To our knowledge, this is the first report of the effect of ABCA7 and MS4A6A on neurodegeneration., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Genome-wide association studies have not revealed any risk-conferring common genetic variants in Tourette syndrome (TS), requiring the adoption of alternative approaches to investigate the pathophysiology of this disorder., Methods: We obtained the basal ganglia transcriptome by RNA sequencing in the caudate and putamen of nine TS and nine matched normal control subjects., Results: We found 309 downregulated and 822 upregulated genes in the caudate and putamen (striatum) of TS individuals. Using data-driven gene network analysis, we identified 17 gene coexpression modules associated with TS. The top-scoring downregulated module in TS was enriched in striatal interneuron transcripts, which was confirmed by decreased numbers of cholinergic and gamma-aminobutyric acidergic interneurons by immunohistochemistry in the same regions. The top-scoring upregulated module was enriched in immune-related genes, consistent with activation of microglia in patients' striatum. Genes implicated by copy number variants in TS were enriched in the interneuron module, as well as in a protocadherin module. Module clustering revealed that the interneuron module was correlated with a neuronal metabolism module., Conclusions: Convergence of differential expression, network analyses, and module clustering, together with copy number variants implicated in TS, strongly implicates disrupted interneuron signaling in the pathophysiology of severe TS and suggests that metabolic alterations may be linked to their death or dysfunction., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: Previous studies showed that a single oral administration of a synthetic ketone ester (1,3-butanediol acetoacetate diester, BD-AcAc2) could elevate blood ketones with promising acute anti-epileptic effects. The aim of the present work was to evaluate the tolerability of a prolonged administration of BD-AcAc2 and the anti-epileptic efficacy of such treatment., Methods: The threshold for seizure induction with progressive intravenous infusion of pentylenetrazole (PTZ) was evaluated in anesthetized Wistar rats after a ten-day oral administration of BD-AcAc2 (gavage). The effects of this treatment were compared to those of: (1) a ten-day water gavage administration, (2) a ten-day ketogenic diet, (3) a standard rodent chow diet., Results: Compared to the standard diet, all other treatments produced a calorie restriction and an elevation of the seizure threshold., Conclusion: These results indicate that supplementation with an oral synthetic ketone can have anti-seizure effects, but the formulation has to be further ameliorated to be more palatable; further studies are also needed to better understand the role played by ketone bodies alone in vivo, without any calorie restriction., (Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)