Use of ketogenic dietary therapy for drug-resistant epilepsy in early infancy.

OBJECTIVE: There is growing evidence that ketogenic dietary therapy (KDT) can be safely and efficiently used in young children, but little evidence exists on its use in newborns. Developmental and epileptic encephalopathies starting in the neonatal period or early infancy usually present a poor prognosis. The aim of this study was to evaluate effectiveness, safety, and survival of infants younger than 3 months of age with drug-resistant epilepsy in whom KDT was used. METHODS: A retrospective study was conducted to evaluate neonates and infants younger than 3 months who started KDT for drug-resistant developmental and epileptic encephalopathies at three referral centers. Data were collected on demographic features, time of epilepsy onset, epilepsy syndrome, seizure type, seizure frequency at diet onset, etiology, details regarding diet initiation, type of ketogenic formula, breastfeeding, route of administration, blood ketones, growth, length of NICU stay, and survival. RESULTS: Nineteen infants younger than 12 weeks of life who received KDT with a minimum follow-up of 1 month were included; 13 had early-infantile developmental and epileptic encephalopathy, four epilepsy of infancy with migrating focal seizures, and two focal epilepsy. A >50% response was observed in 73.7% at 1 month on the diet; 37% achieved a > 75% seizure reduction, and 10.5% became seizure free. At 3 months, a >50% decrease in seizure frequency was observed in 72.2%; 15.8% had a >75% reduction; 21% became seizure free. Overall survival was 76% at 1 year on diet. Incidence of acute and late adverse effects was low and most adverse effects were asymptomatic and manageable. SIGNIFICANCE: Our experience suggests that KDT is safe and effective in newborns and very young infants; however, further studies on the management of the diet in this vulnerable age group are necessary.

Crisis neonatales y evolución a epilepsia en un hospital de tercer nivel / Neonatal seizures and progression to epilepsy in a tertiary hospital

Introducción Las convulsiones neonatales son un reto diagnóstico, dada la inmadurez del recién nacido. La mayoría son secundarias a un evento agudo. Un pequeño porcentaje constituye el inicio de una epilepsia. Objetivos Analizar a los neonatos ingresados en un hospital de tercer nivel con diagnóstico de crisis entre noviembre de 2009 y mayo de 2021, y su evolución posterior a epilepsia. Material y métodos. Se ha realizado un estudio observacional retrospectivo utilizando la base de datos del hospital. Se ha recogido la información de los neonatos con diagnóstico en el alta de ‘convulsiones’ o ‘encefalopatía hipóxico-isquémica moderada o grave’. Se analizaron distintas variables: etiología de las crisis, tipo, persistencia temporal, tratamiento y correlato electroclínico. Resultados De 165 pacientes, 55 presentaron crisis neonatales. En cuanto a la etiología, 43 pacientes (78%) tuvieron crisis secundarias a un evento agudo, de las cuales 19 (34%) fueron encefalopatías hipóxico-isquémicas, y 22 (40%), otras alteraciones agudas. En seis (11%) se encontró alteración genética. Trece pacientes (24%) evolucionaron a una epilepsia posterior, de los cuales siete presentaron una epilepsia sintomática, con un período de latencia tras el evento agudo en dos pacientes. Seis pacientes tuvieron epilepsia neonatal con crisis no provocadas. Veintidós (62%) mostraron correlato electroclínico. El 100% de las crisis confirmadas fueron focales. Todas las crisis se trataron. El fármaco de elección fue el fenobarbital. Conclusiones El diagnóstico de convulsiones neonatales requiere una alta sospecha clínica y una confirmación electroclínica. La mayoría tiene evolución favorable, pero un porcentaje constituye el inicio de una epilepsia, cuya identificación determinará su manejo terapéutico. (AU)

INTRODUCTION Given the immaturity of the newborn, neonatal seizures are a diagnostic challenge. Most of them are secondary to an acute event. A small percentage constitute the onset of epilepsy. AIMS. The aim was to analyse neonates with a diagnosis of seizures admitted to a tertiary hospital between November 2009 and May 2021, and their subsequent progression to epilepsy. Material and methods. A retrospective observational study was carried out using the hospital database. Information was collected on neonates with a discharge diagnosis of ‘seizures’ or ‘moderate or severe hypoxic-ischaemic encephalopathy’. Different variables were analysed: aetiology of the seizures, type, persistence over time, treatment and electroclinical correlates. RESULTS Of 165 patients, 55 presented neonatal seizures. As regards aetiology, 43 patients (78%) had seizures secondary to an acute event, of which 19 (34%) were hypoxic-ischaemic encephalopathies, and 22 (40%) had other acute disorders. Genetic alteration was found in six of them (11%). Thirteen patients (24%) progressed to subsequent epilepsy, of whom seven had symptomatic epilepsy, with a period of latency after the acute event in two patients. Six patients had neonatal epilepsy with unprovoked seizures. Twenty-two (62%) showed electroclinical correlates. All of the confirmed crises (100%) were focal. All the seizures were treated. The drug of choice was phenobarbital. CONCLUSIONS Diagnosis of neonatal seizures requires high clinical suspicion and electroclinical confirmation. Most of them progress favourably, but a percentage constitute the onset of epilepsy, the identification of which will determine their therapeutic management. (AU)

ESTUDIO DEL IMPACTO DE LA DIETA CETOGÉNICA EN LA CALIDAD DE VIDA DE PACIENTES PEDIÁTRICOS CON EPILEPSIA Y SUS FAMILIAS / STUDY OF THE IMPACT OF THE KETOGENIC DIET ON THE QUALITY OF LIFE OF PEDIATRIC PATIENTS WITH EPILEPSY AND THEIR FAMILIES

Introducción: El tratamiento mediante los distintos tipos de dietas cetogénicas ha demostrado en diversos trabajos efectividad en la reducción de las crisis convulsivas, de manera total o parcial. Sin embargo, se reportan tasas de deserción en la realización a largo plazo. Objetivo: Este trabajo tiene como objetivo identificar beneficios y dificultades que perciben las familias de niños en el tratamiento de Epilepsia resistente a fármacos que lleven a cabo la dieta cetogénica y que podrían influir en la adherencia o deserción. Materiales y métodos: Se realizó un estudio descriptivo transversal retrospectivo, en el Servicio de Neurología Infantil del HIBA, sección Dieta Cetogénica. Para el estudio, se realizó una encuesta para recabar características sociodemográficas de la población bajo estudio y también sobre dificultades y beneficios hallados en la terapia cetogénica. Se analizaron frecuencias, medias y chi cuadrado para establecer diferencias significativas con intervalo de confianza de 95%. Resultados: La muestra estuvo compuesta por 51 participantes, de 0 a 18 años. Al indagar sobre si percibían mejoras tras realizar terapia cetogénica, el 81% respondió que sí, el 11% no percibió mejoras y el 8% no sabía. Acerca de la presencia de dificultades para llevar a cabo el tratamiento, el 71% respondió que se encontraba con dificultades, el 23% no registró dificultades y el 6% manifestó que a veces. Al relacionar la presencia de dificultades con el nivel socioeconómico, se observaron diferencias significativas entre los grupos, siendo de mayor incidencia en familias de ingresos más bajos. Respecto de la variable edad, no se encontraron diferencias significativas en relación con las dificultades percibidas. Conclusiones: Es importante continuar trabajando con las familias en las dificultades que presentan para evitar deserción del tratamiento. Asimismo, resulta indispensable destacar el alto porcentaje de mejorías que perciben sus padres para lograr mayor adherencia

Introduction: Treatment using the different types of ketogenic diets has been shown in various studies to be effective in reducing seizures, which can be total or partial. However, dropout rates are reported in the long-term completion of it. Objetive: The objective of this work is to identify the benefits and difficulties perceived by the families of children undergoing treatment for drug-resistant epilepsy who follow the ketogenic diet and that could influence adherence or desertion. Materials and methods: A retrospective cross-sectional descriptive study was carried out at the HIBA Child Neurology Service, Ketogenic Diet section. For the study, a survey was carried out to collect sociodemographic characteristics of the population under study and also about difficulties and benefits found in ketogenic therapy. Frequencies, measures and chi square were analyzed to establish significant differences with a 95% confidence interval. Results: The sample consisted of 51 participants, from 0 to 18 years old. When asked if they perceived improvements after performing ketogenic therapy, 81% answered yes, 11% did not perceive improvements and 8% did not know. About the presence of difficulties to carry out the treatment, 71% answered that they had difficulties, 23% did not have them and 6% sometimes.When relating the presence of difficulties with the socioeconomic level, significant differences were observed between the groups, with a higher incidence in lower-income families. Regarding the age variable, no significant differences were found in relation to the perceived difficulties. Conclusion: It is important to continue working with families on the difficulties they present to avoid dropping out of treatment. Likewise, it is essential to highlight the high percentage of improvements that their parents perceive to achieve greater adherence

An interventional nationwide surveillance program lowers postoperative infection rates in elective colorectal surgery. A cohort study (2008-2019).

BACKGROUND: Colorectal surgery is associated with the highest rate of surgical site infection (SSI). This study analyses the effectiveness of an interventional surveillance program on SSI rates after elective colorectal surgery. MATERIAL AND METHODS: Cohort study showing temporal trends of SSI rates and Standardized Infection Ratio (SIR) in elective colorectal surgery over a 12-year period. Prospectively collected data of a national SSI surveillance program was analysed and the effect of specific interventions was evaluated. Patient and procedure characteristics, as well as SIR and SSI rates were stratified by risk categories and type of SSI analysed using stepwise multivariate logistic regression models. RESULTS: In a cohort of 42,330 operations, overall cumulative SSI incidence was 16.31%, and organ-space SSI (O/S-SSI) was 8.59%. There was a 61.63% relative decrease in SSI rates (rho = -0.95804). The intervention which achieved the greatest SSI reduction was a bundle of 6 measures. SSI in pre-bundle period was 19.73% vs. 11.10% in post-bundle period (OR 1.969; IC 95% 1.860-2.085; p < 0.0001). O/S-SSI were 9.08% vs. 6.06%, respectively (OR 1.547; IC 95% 1.433-1.670; p < 0.0001). Median length of stay was 7 days, with a significant decrease over the studied period (rho = -0.98414). Mortality of the series was 1.08%, ranging from 0.35% to 2.0%, but a highly significant decrease was observed (rho = -0.67133). CONCLUSIONS: Detailed analysis of risk factors and postoperative infection in colorectal surgery allows strategies for reducing SSI incidence to be designed. An interventional surveillance program has been effective in decreasing SIR and SSI rates.

Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites.

Introduction: Alzheimer's disease (AD) is characterized by neurotoxic immuno-inflammation concomitant with cytotoxic oligomerization of amyloid beta (Aß) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. Methods: We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic-molecular mechanisms of cytokine-mediated and Aß-mediated neurotoxicities in AD.  Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small-molecule therapeutics for AD. Results: In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aß is released as an early responder immunopeptide triggering an innate immunity cascade in which Aß exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon "self" neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane-penetrating attack by antimicrobial peptides (AMPs) such as Aß. After this self-attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aß, leading to a chronic self-perpetuating autoimmune cycle.  AD thus emerges as a brain-centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti-AD molecules capable of chemical modification into multi-site therapeutic modulators targeting AD's complex immunopathic-proteopathic pathogenesis. Discussion:  Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug-like analogues of these endogenous regulators represents a novel therapeutic approach for AD.

The persistent breach between evidence and practice in the prevention of surgical site infection. Qualitative study.

BACKGROUND: Despite the dissemination of guidelines for surgical site infection (SSI) prevention, a gap between the theoretical measures and their compliance persists. Accurate estimates of the implementation of preventative measures is crucial before planning dissemination strategies. METHODS: A web-based survey was distributed to members of 11 Associations of operative nurses and surgeons. Questions aimed to determine their awareness of evidence, personal beliefs and actual use of the main preventative measures. RESULTS: Of 1105 responders, 50.5% receive no feed-back of their SSI rate. Responders show a moderate rate of awareness of the recommendations about not removing hair, hair clipping, skin antisepsis with alcoholic solutions, and normothermia. Antibiotic prophylaxis is given for more than 24 h by 18.8% of respondents. Screening for S. aureus is performed by 27.6%. Hair removal by shaving is used by 16.6% of responders. The most common antiseptic solutions are alcoholic chlorhexidine (57.2%) and aqueous povidone (23.3%). 62.8% of surgeons allow the solution to air dry before applying surgical drapes. Adhesive drapes in the surgical field are used routinely in 33.4% of cases. Perioperative normothermia, glucose control and hyperoxia are used in 84.3%, 65.9% and 23.3% of cases. Antimicrobial sutures and negative pressure therapy are used by 20.2% and 43.5% of teams, respectively. Prior to closing the incision, 83.9% replace surgical instruments always or selectively. Wound irrigation before closing is used in 78.1% of cases, mostly with saline. Check-lists, standardized orders, surveillance, feed-back and educational programs were rated most highly by respondents as a means to improve compliance with preventative guidelines, but few of these strategies were in place at their institutions. CONCLUSION: Gaps in the translation of evidence into practice remain in the prevention of SSI among different surgical specialities. Several areas for improvement have been identified, as some core prevention measures are not in common use.

Different alterations of glomerular filtration rate and their association with uric acid in children and adolescents with type 1 diabetes or with overweight/obesity.

BACKGROUND: Hyperfiltration (HF) occurs early in diabetes or obesity (OB)-associated renal disease. Alterations of glomerular filtration rate (GFR) in childhood OB remain unclear. OBJECTIVES: To compare the prevalence of GFR alterations and its association with uric acid in children and adolescents with type 1 diabetes (T1D) vs overweight (OW)/OB. METHODS: Cross-sectional study of 29 youths (aged: 13 ± 2 years) with T1D (disease duration: 7 ± 3 years) and 165 with OW/OB (aged: 11 ± 3 years). Patients with an albumin-creatinine ratio >3.39 mg/mmol were excluded. GFR was estimated with creatinine-cystatin C Zappitelli equation. HF and low GFR were defined by a GFR > 135 and <90 mL/min.1.73 m2 , respectively. RESULTS: HF was higher in children with T1D vs OW/OB (28% vs 10%, P < .005). Children with OW/OB also showed a 10% of low GFR. In patients with T1D, HbA1c (ß = .8, P < .001), and systolic blood pressure (ß = 11.4, P < .005) were independent predictors of GFR (R2 = .65). In OW/OB, HF cases were almost limited to prepubertal children and low GFR to pubertal ones. GFR in OW/OB was associated with age (ß = -2.2, P < .001), male sex (ß = -11.6, P < .001), and uric acid (ß = -.05, P < .001) in adjusted models (R2 = .33). CONCLUSIONS: GFR alterations were different between youths with T1D and with OW/OB. Higher uric acid, older age, and puberty were related to lower GFR values in OW/OB children. Longitudinal studies will determine if low GFR is consequence of a rapid GFR decline in pediatric patients with OW/OB.

Artificial Intelligence for COVID-19 Drug Discovery and Vaccine Development.

SARS-COV-2 has roused the scientific community with a call to action to combat the growing pandemic. At the time of this writing, there are as yet no novel antiviral agents or approved vaccines available for deployment as a frontline defense. Understanding the pathobiology of COVID-19 could aid scientists in their discovery of potent antivirals by elucidating unexplored viral pathways. One method for accomplishing this is the leveraging of computational methods to discover new candidate drugs and vaccines in silico. In the last decade, machine learning-based models, trained on specific biomolecules, have offered inexpensive and rapid implementation methods for the discovery of effective viral therapies. Given a target biomolecule, these models are capable of predicting inhibitor candidates in a structural-based manner. If enough data are presented to a model, it can aid the search for a drug or vaccine candidate by identifying patterns within the data. In this review, we focus on the recent advances of COVID-19 drug and vaccine development using artificial intelligence and the potential of intelligent training for the discovery of COVID-19 therapeutics. To facilitate applications of deep learning for SARS-COV-2, we highlight multiple molecular targets of COVID-19, inhibition of which may increase patient survival. Moreover, we present CoronaDB-AI, a dataset of compounds, peptides, and epitopes discovered either in silico or in vitro that can be potentially used for training models in order to extract COVID-19 treatment. The information and datasets provided in this review can be used to train deep learning-based models and accelerate the discovery of effective viral therapies.

Effects of the Novel IDO Inhibitor DWG-1036 on the Behavior of Male and Female 3xTg-AD Mice.

The kynurenine pathway metabolizes tryptophan into nicotinamide adenine dinucleotide, producing a number of intermediary metabolites, including 3-hydroxy kynurenine and quinolinic acid, which are involved in the neurodegenerative mechanisms that underlie Alzheimer's disease (AD). Indolamine 2,3-dioxygenase (IDO), the first and rate-limiting enzyme of this pathway, is increased in AD, and it has been hypothesized that blocking this enzyme may slow the progression of AD. In this study, we treated male and female 3xTg-AD and wild-type mice with the novel IDO inhibitor DWG-1036 (80 mg/kg) or vehicle (distilled water) from 2 to 6 months of age and then tested them in a battery of behavioral tests that measured spatial learning and memory (Barnes maze), working memory (trace fear conditioning), motor coordination and learning (rotarod), anxiety (elevated plus maze), and depression (tail suspension test). The 3xTg-AD mice treated with DWG-1036 showed better memory in the trace fear conditioning task and significant improvements in learning but poorer spatial memory in the Barnes maze. DWG-1036 treatment also ameliorated the behaviors associated with increased anxiety in the elevated plus maze and depression-like behaviors in the tail suspension test in 3xTg-AD mice. However, the effects of DWG-1036 treatment on the behavioral tasks were variable, and sex differences were apparent. In addition, high doses of DWG-1036 resulted in reduced body weight, particularly in females. Taken together, our results suggest that the kynurenine pathway is a promising target for treating AD, but more work is needed to determine the effective compounds, examine sex differences, and understand the side effects of the compounds.

Nanomolar-Potency 1,2,4-Triazoloquinoxaline Inhibitors of the Kidney Urea Transporter UT-A1.

Urea transporter A (UT-A) isoforms encoded by the Slc14a2 gene are expressed in kidney tubule epithelial cells, where they facilitate urinary concentration. UT-A1 inhibition is predicted to produce a unique salt-sparing diuretic action in edema and hyponatremia. Here we report the discovery of 1,2,4-triazoloquinoxalines and the analysis of 37 synthesized analogues. The most potent compound, 8ay, containing 1,2,4-triazolo[4,3- a]quinoxaline-substituted benzenesulfonamide linked by an aryl ether, rapidly and reversibly inhibited UT-A1 urea transport by a noncompetitive mechanism with IC50 ≈ 150 nM; the IC50 was ∼2 µM for the related urea transporter UT-B encoded by the Slc14a1 gene. Molecular modeling suggested a putative binding site on the UT-A1 cytoplasmic domain. In vitro metabolism showing quinoxaline ring oxidation prompted the synthesis of metabolically stable 7,8-difluoroquinoxaline analogue 8bl, which when administered to rats produced marked diuresis and reduced urinary osmolality. 8bl has substantially improved UT-A1 inhibition potency and metabolic stability compared with prior compounds.

Substituted 2-Acylaminocycloalkylthiophene-3-carboxylic Acid Arylamides as Inhibitors of the Calcium-Activated Chloride Channel Transmembrane Protein 16A (TMEM16A).

Transmembrane protein 16A (TMEM16A), also called anoctamin 1 (ANO1), is a calcium-activated chloride channel expressed widely mammalian cells, including epithelia, vascular smooth muscle tissue, electrically excitable cells, and some tumors. TMEM16A inhibitors have been proposed for treatment of disorders of epithelial fluid and mucus secretion, hypertension, asthma, and possibly cancer. Herein we report, by screening, the discovery of 2-acylaminocycloalkylthiophene-3-carboxylic acid arylamides (AACTs) as inhibitors of TMEM16A and analysis of 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa). Structure-activity studies indicated the importance of benzene substituted as 2- or 4-methyl, or 4-fluoro, and defined the significance of thiophene substituents and size of the cycloalkylthiophene core. The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had IC50 of ∼30 nM, ∼3.6-fold more potent than the most potent previously reported TMEM16A inhibitor 4 (Ani9), and >10-fold improved metabolic stability. Direct and reversible inhibition of TMEM16A by 10bm was demonstrated by patch-clamp analysis. AACTs may be useful as pharmacological tools to study TMEM16A function and as potential drug development candidates.

[National consensus on the modified Atkins diet]. / Consenso nacional de dieta Atkins modificada.

INTRODUCTION: Epilepsy is a chronic disease that affects 0.5-1% of the population. One third of the patients become refractory to antiepileptic drugs. Among the non-pharmacological treatments available, the modified Atkins diet is an effective treatment used since 2003 as another alternative for children and adults with refractory epilepsy. DEVELOPMENT: The Ketogenic Diet National Committee, which depends on the Argentine Society of Pediatric Neurology, elaborated this consensus on the modified Atkins diet, basing itself on a review of the literature and on their clinical experience. This consensus in Spanish explains the different aspects to be taken into account regarding the modified Atkins diet, patient selection, implementation, different controls and adverse effects. Unlike the classic ketogenic diet, the modified Atkins diet is initiated without fasting or hospital stay, nor does it require protein, calorie or fluid restriction, thus improving patient palatability and consequently patient tolerability. CONCLUSIONS: The modified Atkins diet is a useful treatment for patients with intractable epilepsy. The publication of this consensus offers the possibility for new centers to get oriented regarding this diet implementation.

TITLE: Consenso nacional de dieta Atkins modificada.Introduccion. La epilepsia es una enfermedad cronica que afecta al 0,5-1% de la poblacion, y un tercio de los pacientes evoluciona hacia una forma refractaria a los farmacos antiepilepticos. Dentro de los tratamientos no farmacologicos disponibles, la dieta cetogenica Atkins modificada es un tratamiento efectivo utilizado desde 2003 como otra alternativa en niños y adultos con epilepsia refractaria. Desarrollo. El Comite Nacional de Dieta Cetogenica, dependiente de la Sociedad Argentina de Neurologia Infantil, elaboro este consenso sobre dieta Atkins modificada basandose en una revision de la bibliografia y en su experiencia clinica. Este consenso explica los distintos aspectos que hay que tener en cuenta sobre la dieta Atkins modificada, eleccion de pacientes, forma de implementacion, diversos controles y efectos adversos. A diferencia de la dieta cetogenica clasica, se inicia sin ayuno ni hospitalizacion, y no hay restriccion proteica, calorica o hidrica, por lo que mejora la palatabilidad y, consecuentemente, la tolerabilidad. Conclusiones. La dieta Atkins modificada es un tratamiento util para pacientes con epilepsia intratable. La publicacion de este consenso ofrece la posibilidad de orientar a nuevos centros en su implementacion.

Consenso nacional de dieta Atkins modificada / National consensus on the modified Atkins diet

Introducción. La epilepsia es una enfermedad crónica que afecta al 0,5-1% de la población, y un tercio de los pacientes evoluciona hacia una forma refractaria a los fármacos antiepilépticos. Dentro de los tratamientos no farmacológicos disponibles, la dieta cetogénica Atkins modificada es un tratamiento efectivo utilizado desde 2003 como otra alternativa en niños y adultos con epilepsia refractaria. Desarrollo. El Comité Nacional de Dieta Cetogénica, dependiente de la Sociedad Argentina de Neurología Infantil, elaboró este consenso sobre dieta Atkins modificada basándose en una revisión de la bibliografía y en su experiencia clínica. Este consenso explica los distintos aspectos que hay que tener en cuenta sobre la dieta Atkins modificada, elección de pacientes, forma de implementación, diversos controles y efectos adversos. A diferencia de la dieta cetogénica clásica, se inicia sin ayuno ni hospitalización, y no hay restricción proteica, calórica o hídrica, por lo que mejora la palatabilidad y, consecuentemente, la tolerabilidad. Conclusiones. La dieta Atkins modificada es un tratamiento útil para pacientes con epilepsia intratable. La publicación de este consenso ofrece la posibilidad de orientar a nuevos centros en su implementación (AU)

Introduction. Epilepsy is a chronic disease that affects 0.5-1% of the population. One third of the patients become refractory to antiepileptic drugs. Among the non-pharmacological treatments available, the modified Atkins diet is an effective treatment used since 2003 as another alternative for children and adults with refractory epilepsy. Development. The Ketogenic Diet National Committee, which depends on the Argentine Society of Pediatric Neurology, elaborated this consensus on the modified Atkins diet, basing itself on a review of the literature and on their clinical experience. This consensus in Spanish explains the different aspects to be taken into account regarding the modified Atkins diet, patient selection, implementation, different controls and adverse effects. Unlike the classic ketogenic diet, the modified Atkins diet is initiated without fasting or hospital stay, nor does it require protein, calorie or fluid restriction, thus improving patient palatability and consequently patient tolerability. Conclusions. The modified Atkins diet is a useful treatment for patients with intractable epilepsy. The publication of this consensus offers the possibility for new centers to get oriented regarding this diet implementation (AU)

Recommendations for the clinical management of children with refractory epilepsy receiving the ketogenic diet.

The ketogenic diet, a non-drug treatment with proven effectiveness, has been the most commonly used therapy in the past decade for the management of refractory epilepsy in the pediatric population. Compared to adding a new drug to a pre-existing treatment, the ketogenic diet is highly effective and reduces the number of seizures by 50-90% in approximately 45-60% of children after six months of treatment. For this reason, the Argentine Society of Pediatric Neurology established the Ketogenic Diet Working Group. It is integrated by pediatric dietitians, pediatricians, pediatric neurologists and B.S. in Nutrition, who developed recommendations for the optimal management of patients receiving the classical ketogenic diet based on expert consensus and scientific publications in this field.

La dieta cetogénica constituye el tratamiento no farmacológico de eficacia probada más utilizado en la última década para el manejo de la epilepsia refractaria en la población pediátrica. En comparación con el agregado de un nuevo fármaco a un tratamiento preexistente, esta terapia es altamente efectiva, con una reducción de las crisis de entre un 50% y un 90% en aproximadamente 45%-60% de los niños tras 6 meses de tratamiento. Es por ello por lo que la Sociedad Argentina de Neurología Infantil creó el Grupo de Trabajo de Dieta Cetogénica. Este está conformado por médicos nutricionistas infantiles, pediatras, neurólogos infantiles y licenciados en Nutrición, quienes elaboraron estas recomendaciones para un manejo óptimo de los pacientes que reciben la dieta cetogénica clásica, basándose en el consenso de los expertos y la bibliografía publicada en el tema.

Diversification of edaravone via palladium-catalyzed hydrazine cross-coupling: Applications against protein misfolding and oligomerization of beta-amyloid.

N-Aryl derivatives of edaravone were identified as potentially effective small molecule inhibitors of tau and beta-amyloid aggregation in the context of developing disease-modifying therapeutics for Alzheimer's disease (AD). Palladium-catalyzed hydrazine monoarylation protocols were then employed as an expedient means of preparing a focused library of 21 edaravone derivatives featuring varied N-aryl substitution, thereby enabling structure-activity relationship (SAR) studies. On the basis of data obtained from two functional biochemical assays examining the effect of edaravone derivatives on both fibril and oligomer formation, it was determined that derivatives featuring an N-biaryl motif were four-fold more potent than edaravone.

Probing a 3,4'-bis-guanidinium diaryl derivative as an allosteric inhibitor of the Ras pathway.

Mutations in the Ras-pathway occur in 40-45% of colorectal cancer patients and these are refractory to treatment with anti-EGFR-targeted therapies. With this in mind, we have studied novel guanidinium-based compounds with demonstrated ability to inhibit protein kinases. We have performed docking studies with several proteins involved in the Ras-pathway and evaluated 3,4'-bis-guanidinium derivatives as inhibitors of B-Raf. Compound 3, the most potent in this series, demonstrated strong cytotoxicity in (WT)B-Raf colorectal cancer cells and also cells with (V600E)B-Raf mutations. Cell death was induced by apoptosis, detected by cleavage of PARP. Compound 3 also potently inhibited ERK1/2 signalling, inhibited EGFR activation, as well as Src, STAT3 and AKT phosphorylation. Mechanistically, compound 3 did not inhibit ATP binding to B-Raf, but direct assay of B-Raf activity was inhibited in vitro. Summarizing, we have identified a novel B-Raf type-III inhibitor that exhibits potent cellular cytotoxicity.

Consenso nacional sobre dieta cetogénica / National consensus on the ketogenic diet

Introducción. La epilepsia es una enfermedad crónica que afecta al 0,5-1% de la población, mayormente de inicio durante la infancia. Un tercio de los pacientes evoluciona hacia una forma refractaria al tratamiento con fármacos antiepilépticos, lo que plantea al equipo de salud un desafío terapéutico. La dieta cetogénica (DC) es un tratamiento no farmacológico efectivo utilizado como un método alternativo para el tratamiento de la epilepsia refractaria. Objetivos. Es necesario establecer directrices para utilizar la DC adecuadamente y así expandir su conocimiento y utilización en países hispanoparlantes. El Comité Nacional de Dieta Cetogénica, dependiente de la Sociedad Argentina de Neurología Infantil, elaboró este consenso para estandarizar el uso de la DC basándose en la bibliografía publicada y la experiencia clínica. El grupo está formado por neuropediatras, médicos nutricionistas y licenciadas en nutrición de cinco provincias de Argentina pertenecientes a 10 centros que aplican la DC como tratamiento de la epilepsia refractaria. Desarrollo. Se exponen temas tales como la selección del paciente, el asesoramiento a la familia antes del tratamiento, las interacciones de la DC con la medicación anticonvulsionante, los suplementos, el control de efectos adversos y la retirada de dicha dieta. Conclusiones. La DC es un tratamiento útil para los pacientes pediátricos con epilepsia intratable. Es fundamental la educación y colaboración del paciente y la familia. El tratamiento debe llevarlo a cabo un equipo interdisciplinar experimentado, siguiendo un protocolo. La formación de un grupo nacional interdisciplinar, y la publicación de este consenso, ofrece la posibilidad de orientar a nuevos centros en su implantación (AU)

Introduction. Epilepsy is a chronic disease with onset in infancy affecting 0.5-1% of the population. One third of the patients is refractory to antiepileptic drugs and they pose a challenge for the health care team. The ketogenic diet is an effective, non-pharmacological, alternative treatment for the management of refractory epilepsy. Aims. There is a need to establish guidelines for the adequate and increased use of the ketogenic diet in Spanish-speaking countries. The National Committee on the Ketogenic Diet, consisting of paediatric neurologists, clinical nutritionists, and dietitians, of the Argentine Society of Child Neurology has developed this consensus statement to standardize the use of the ketogenic diet based on the literature and clinical experience. Development. Patient selection, pre-treatment family counseling, drug interactions, micronutrient supplementation, adverse effects, and discontinuation of the diet are discussed. Conclusions. The ketogenic diet is an effective treatment for children with refractory epilepsy. Education and collaboration of the patient and their family is essential. The patient should be managed by an experienced multidisciplinary team using a protocol. The formation of a national multidisciplinary team and the publication of this document provide possibilities for new centers to integrate the ketogenic diet into their treatment options (AU)

[National consensus on the ketogenic diet]. / Consenso nacional sobre dieta cetogénica.

INTRODUCTION: Epilepsy is a chronic disease with onset in infancy affecting 0.5-1% of the population. One third of the patients is refractory to antiepileptic drugs and they pose a challenge for the health care team. The ketogenic diet is an effective, non-pharmacological, alternative treatment for the management of refractory epilepsy. AIMS: There is a need to establish guidelines for the adequate and increased use of the ketogenic diet in Spanish-speaking countries. The National Committee on the Ketogenic Diet, consisting of paediatric neurologists, clinical nutritionists, and dietitians, of the Argentine Society of Child Neurology has developed this consensus statement to standardize the use of the ketogenic diet based on the literature and clinical experience. DEVELOPMENT: Patient selection, pre-treatment family counseling, drug interactions, micronutrient supplementation, adverse effects, and discontinuation of the diet are discussed. CONCLUSIONS: The ketogenic diet is an effective treatment for children with refractory epilepsy. Education and collaboration of the patient and their family is essential. The patient should be managed by an experienced multidisciplinary team using a protocol. The formation of a national multidisciplinary team and the publication of this document provide possibilities for new centers to integrate the ketogenic diet into their treatment options.

TITLE: Consenso nacional sobre dieta cetogenica.Introduccion. La epilepsia es una enfermedad cronica que afecta al 0,5-1% de la poblacion, mayormente de inicio durante la infancia. Un tercio de los pacientes evoluciona hacia una forma refractaria al tratamiento con farmacos antiepilepticos, lo que plantea al equipo de salud un desafio terapeutico. La dieta cetogenica (DC) es un tratamiento no farmacologico efectivo utilizado como un metodo alternativo para el tratamiento de la epilepsia refractaria. Objetivos. Es necesario establecer directrices para utilizar la DC adecuadamente y asi expandir su conocimiento y utilizacion en paises hispanoparlantes. El Comite Nacional de Dieta Cetogenica, dependiente de la Sociedad Argentina de Neurologia Infantil, elaboro este consenso para estandarizar el uso de la DC basandose en la bibliografia publicada y la experiencia clinica. El grupo esta formado por neuropediatras, medicos nutricionistas y licenciadas en nutricion de cinco provincias de Argentina pertenecientes a 10 centros que aplican la DC como tratamiento de la epilepsia refractaria. Desarrollo. Se exponen temas tales como la seleccion del paciente, el asesoramiento a la familia antes del tratamiento, las interacciones de la DC con la medicacion anticonvulsionante, los suplementos, el control de efectos adversos y la retirada de dicha dieta. Conclusiones. La DC es un tratamiento util para los pacientes pediatricos con epilepsia intratable. Es fundamental la educacion y colaboracion del paciente y la familia. El tratamiento debe llevarlo a cabo un equipo interdisciplinar experimentado, siguiendo un protocolo. La formacion de un grupo nacional interdisciplinar, y la publicacion de este consenso, ofrece la posibilidad de orientar a nuevos centros en su implantacion.

Tratamiento de la epilepsia refractaria con dieta de Atkins modificada / Treatment of refractory epilepsy with the modified Atkins diet

La dieta de Atkins modificada (DAM) es una alternativa dietaria terapéutica en el tratamiento de la epilepsia fármaco-resistente. Consiste en una dieta con un aporte de 60% de grasas, 30% de proteínas y 10% de carbohidratos. El objetivo es presentar una serie de 9 pacientes con diagnóstico de epilepsia refractaria de diferentes etiologías, que recibieron tratamiento con DAM en nuestro hospital. En nuestro grupo de 9 pacientes, obtuvimos resultados similares a los publicados por otros autores, con buena adherencia, tolerancia y respuesta. Del total de pacientes, dos lograron una reducción en más del 90% del número de crisis; cuatro, del 50-90%; dos, menos del 50% de control; y solo uno no presentó respuesta a la DAM. Ningún paciente presentó aumento del número de crisis, y fue bien tolerada en todos los casos

The modified Atkins diet (MAD) is an alternative therapeutic diet for the treatment of drug-resistant epilepsy. It consists of a diet with 60% energy from fat, 30% from protein, and 10% from carbohydrates. The objective of this article is to present a series of nine patients diagnosed with refractory epilepsy of different etiologies treated with the MAD at our hospital. In our group of nine patients, results obtained were similar to those published by other authors, with adequate adherence, tolerance and response. Of all patients, two achieved a reduction of more than 90% in the number of seizures; four experienced a reduction of 50-90%; two had a reduction of less than 50% in seizure control; and only one patient did not respond to the MAD. No patient had an increase in the number of seizures, and the diet was well-tolerated in all cases.