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Objective: This study tested the hypothesis that a neuroprotective combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) could be safe for acute ischemic stroke patients, admitting up to 30% of serious adverse events (SAE) with proven causality. Methods: A multi-centric, randomized, open-label, controlled, phase I-II clinical trial with parallel groups was conducted (July 2017 to January 2018). Patients aged 18-80 years with a computed tomography-confirmed ischemic stroke and less than 12 h from the onset of symptoms were randomly assigned to the study groups I (75 µg rEGF + 3.5 mg GHRP6 i.v., n=10), II (75 µg rEGF + 5 mg GHRP6 i.v., n=10), or III (standard care control, n=16). Combined therapy was given BID for 7 days. The primary endpoint was safety over 6 months. Secondary endpoints included neurological (NIHSS) and functional [Barthel index and modified Rankin scale (mRS)] outcomes. Results: The study population had a mean age of 66 ± 11 years, with 21 men (58.3%), a baseline median NIHSS score of 9 (95% CI: 8-11), and a mean time to treatment of 7.3 ± 2.8 h. Analyses were conducted on an intention-to-treat basis. SAEs were reported in 9 of 16 (56.2%) patients in the control group, 3 of 10 (30%) patients in Group I (odds ratio (OR): 0.33; 95% CI: 0.06-1.78), and 2 of 10 (20%) patients in Group II (OR: 0.19; 95% CI: 0.03-1.22); only two events in one patient in Group I were attributed to the intervention treatment. Compliance with the study hypothesis was greater than 0.90 in each group. Patients treated with EGF + GHRP6 had a favorable neurological and functional evolution at both 90 and 180 days, as evidenced by the inferential analysis of NIHSS, Barthel, and mRS and by their moderate to strong effect size. At 6 months, proportion analysis evidenced a higher survival rate for patients treated with the combined therapy. Ancillary analysis including merged treated groups and utility-weighted mRS also showed a benefit of this combined therapy. Conclusion: EGF + GHRP6 therapy was safe. The functional benefits of treatment in this study supported a Phase III study. Clinical Trial Registration: RPCEC00000214 of the Cuban Public Registry of Clinical Trials, Unique identifier: IG/CIGB-845I/IC/1601.

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Objective: To determine factors of bad prognosis in patients with Cerebral Infarction, at the Arnaldo Milián Castro Hospital, Villa Clara, in 2019. Methods: Observational, analytical, transversal study, during January-December 2019, at “Arnaldo Milián Castro” Hospital in Villa Clara, Cuba. The universe was made up of all the patients who were admitted with a diagnosis of Cerebral Infarction in the Neurology ward of the Hospital, in 2019. Through simple random sampling, 153 patients were selected. The information was stored and processed in SPSS v.21. Descriptive statistical analysis was performed for each study variable, in a frequency distribution; A bivariate analysis of groups was applied, comparing epidemiological and clinical variables. Finally, as a mortality predictor model in these patients, a Multilayer Perceptron neural network was created. Results: 65.6% of the patients were discharged alive from the Hospital. There was a total of 48 deaths (31.4%); Of these, all had some motor defect at the time of admission, and in most of them there were disorders of language and state of consciousness. These variables were highly significantly associated from the statistical point of view with patient mortality (p=0.000). The mortality predictor model created showed an average accuracy ± standard deviation of 89 ± 6%. Conclusion: Advanced age, motor defect on admission, language disorders, impaired level of consciousness, as well as neurologicaland non-neurological complications, are poor prognostic factors and determine higher mortality in the acute phase of ischemic stroke. (AU)

Objetivo: Determinar factores de mal pronóstico en pacientes con Infarto Cerebral, en el Hospital Arnaldo Milián Castro, Villa Clara, en el año 2019. Métodos: Estudio observacional, analítico, transversal, durante enero-diciembre de 2019, en Hospital “Arnaldo Milián Castro” en Villa Clara, Cuba. El universo lo constituyeron todos los pacientes que ingresaron con diagnóstico de Infarto Cerebral en la sala de Neurología del Hospital, en el año 2019. Mediante un muestreo aleatorio simple se seleccionaron 153 pacientes. La información fue almacenada y procesada en SPSS v.21. Se realizó el análisis estadístico descriptivo para cada variable de estudio, en una distribución de frecuencias; se aplicó un análisis bivariado de grupos, comparando variables epidemiológicas y clínicas. Finalmente, como modelo predictor de mortalidad en estos pacientes, se creó una red neuronal Perceptrón Multicapa. Resultados: El 65,6% de los pacientes egresaron vivos del Hospital. Hubo un total de 48 fallecidos (31,4%); de estos, la totalidad tenían algún defecto motor al momento del ingreso, y en la mayoría existían trastornos del lenguaje y del estado de conciencia. Estas variables se asociaron muy significativamente desde el punto de vista estadístico con la mortalidad de los pacientes (p=0,000). El modelo predictor de mortalidad creado, mostró una precisión promedio ± desviación estándar de 89 ± 6%. Conclusión: La edad avanzada, el defecto motor al ingreso, los trastornos del lenguaje, el deterioro del nivel de conciencia, así como las complicaciones neurológicas y no neurológicas, constituyen factores de mal pronóstico y determinan una mayor mortalidad en la fase aguda del Ictus Isquémico. (AU)

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Fundamento la enfermedad cerebrovascular representa el problema de salud más frecuente relacionado con la atención neurológica, hecho en que estriba la importancia que reviste su estudio en los diferentes contextos y desde diversos enfoques. Objetivo describir el comportamiento de variables epidemiológicas y clínicas en pacientes ingresados por infarto cerebral. Métodos estudio descriptivo y transversal, realizado en el servicio de Neurología del Hospital Arnaldo Milián Castro, de Villa Clara, Cuba, el cual incluyó a todos los pacientes con diagnóstico clínico de infarto cerebral cardioembólico o aterotrombótico, ingresados en sala durante el año 2019. La información se obtuvo de las historias clínicas almacenadas en el Archivo del Hospital; y fue procesada en el paquete estadístico SPSS. v. 21. Se aplicó un análisis estadístico descriptivo, en una distribución de frecuencias. Resultados predominaron los pacientes del sexo femenino (51,6 %). Hubo mayor incidencia en hombres mayores de 79 años (47,7 %), y en mujeres mayores de 70 (86,0 %). En el 67,3 % se demostró la causa cardioembólica. La hipertensión arterial resultó el principal factor de riesgo asociado (83,6 %). El defecto motor se observó como hallazgo clínico más frecuente al ingreso (96,7 %). Se identificaron la transformación hemorrágica del infarto y la bronconeumonía nosocomial como principales complicaciones neurológicas y no neurológicas respectivamente. Prevalecieron los pacientes egresados vivos (68,6 %). Conclusiones los ictus isquémicos son más frecuentes en pacientes de edad avanzada; la identificación temprana y manejo oportuno de la enfermedad instaurada puede prevenir en gran medida la aparición de complicaciones, y consecuentemente la muerte.

Background cerebrovascular disease represents the most common health problem related to neurological care, it is important to study it in different contexts and from different approaches. Objective to describe epidemiological and clinical variables' behavior in patients admitted for stroke. Methods descriptive and cross-sectional study, carried out in Arnaldo Milián Castro Hospital's Neurology service from Villa Clara, Cuba, which included all patients with a clinical diagnosis of cardioembolic or atherothrombotic stroke, admitted to the ward during 2019. The information was obtained from the medical records stored in the Hospital Archive; and it was processed in the statistical package SPSS. v. 21. A descriptive statistical analysis was applied, in a frequency distribution. Results female patients predominated (51.6%). There was a higher incidence in men older than 79 years (47.7%), and in women older than 70 (86.0%). In 67.3% the cardioembolic cause was demonstrated. Arterial hypertension was the main associated risk factor (83.6%). The motor defect was observed as the most frequent clinical finding on admission (96.7%). Hemorrhagic transformation of the infarct and nosocomial bronchopneumonia were identified as the main neurological and non-neurological complications, respectively. Patients discharged alive prevailed (68.6%). Conclusions ischemic strokes are more frequent in elderly patients; early identification and timely management of the established disease can largely prevent the appearance of complications, and consequently death.

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INTRODUCTION: Centenarians are considered a model of successful aging. Cuba exhibits one of the oldest populations in Latin America with more than two thousand centenarians. METHODS: This study aimed to evaluate the immune phenotype of forty-three Cuban centenarians, their clinical characteristics such as comorbidities, frailty, body mass index, and some hemochemical parameters. RESULTS: Centenarians had normal body mass indexes, relatively good health status, and 21.95% of them had no comorbidities; 53.6% were classified as frail, and 7% were classified as robust. In addition, 17% of centenarians were independent, and 41.46% were moderately dependent. The seroprevalence against cytomegalovirus was 100%. Concerning pro-inflammatory markers, the majority of them had very low cytokine levels and serum C-reactive protein around the normal limit. We also found the predominance of memory subsets over naive compartments in CD4+ and CD8+ T cells. Terminally differentiated CD8+CD28- T cells were higher in frail centenarians than in pre-frail, while CD8+CD57+ and CD8+EMRA T cells were higher in moderately and severely dependent individuals than in independent individuals. Severely dependent centenarians had a lower CD4+/CD8+ ratio. CONCLUSION: This study describes for the first time the predominance of memory subsets over naive compartments in CD4+ and CD8+ T cells, as well as its relation to frailty and/or dependency in a group of Cuban centenarians. Further studies are needed to continue understanding the natural biological aging mechanism and the relationship between terminally differentiated lymphocytes and inflammaging in the context of extreme longevity.

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Objetivo: Describir los mecanismos fisiopatológicos en la relación entre la apnea-hipopnea del sueño y el infarto cerebral.Adquisición de la evidencia: Se realizó una búsqueda bibliográfica en la base de datos Medline entre 2014 y 2019, mediante los términos ischemic stroke prognosis o outcome; sleep apnea o sleep disordered breathing o apnea-hipopnea índex, y pathophysiologymechanistic o endothelial dysfunction o inflammation. Fueron encontrados 41 artículos originales, 5 metaanálisis y 4 revisiones sistemáticas.Resultados: Por cada unidad que aumente el índice de apnea-hipopnea, el riesgo de infarto cerebral se incrementa en un 6 Por ciento. Los episodios de apnea agravan la hipoperfusión en elárea cerebral lesionada mediante un mecanismo de robo de flujo sanguíneo. Después de un primer accidente cerebrovascular, por cada una unidad adicional de índice de apneahipopnea, aumenta en un 5 Por ciento el riesgo de mortalidad. La escala NIHSS aumenta en 17,6 Por ciento en el grupo de pacientes apneicos con infarto cerebral en comparación con 12,5 Por ciento enpacientes no apneicos. La apnea del sueño severa se asocia independientemente a puntuaciones en la escala de Ranquin ≥2 a los 6 meses del ictus (OR: 9,7; 95 Por ciento CI: 1,3-73,8; p= 0,03).Conclusiones: Los principales mecanismos fisiopatológicos involucrados en la relación entre la apnea-hipopnea del sueño y el infarto cerebral fueron la hipoxemia e hipercapnia intermitente, la descarga catecolaminérgica, la disfunción autonómica, el estrés oxidativo, la disfunción endotelial y la inflamación sistémica. Por dicha razón, la apnea del sueño favorece el desarrollo de factores de riesgo vascular y predice resultados adversos después de un ictus isquémico en términos de mortalidad, severidad del déficit neurológico, complicaciones y recuperación funcional(AU)

Objective: To describe the pathophysiological mechanisms in the relationship between sleep apnea-hypopnea and cerebral infarction.Evidence acquisition: A bibliographic search in Medline database was carried out, using the terms ischemic stroke prognosis or outcome; sleep apnea or sleep disordered breathing or apnea-hypopnea index, and pathophysiology mechanistic or endothelial dysfunction orinflammation. Forty-one original articles, 5 meta-analyzes and 4 systematic reviews, covering the topic from 2014 to 2019, were found.Results: For each unit that increases the apnea-hypopnea index, the risk of cerebral infarction increases by 6 Per cent. Apnea episodes aggravate hypoperfusion in the injured brainarea through a weak blood flow mechanism. After a first stroke, for each additional unit apnea-hypopnea index, the risk of mortality increases by 5 Per Cent. The NIHSS scale increases by 17.6 Per Cent in the group of apneic patients with cerebral infarction compared to 12.5 Per Cent in non-apneic patients. Severe sleep apnea is self-sufficiently associated with Ranquin scale scores ≥2 6 months after stroke (OR: 9.7; 95 Per Cent CI: 1.3-73.8; p = 0.03). Conclusions: The main pathophysiological mechanisms involved in the relationship between sleep apnea-hypopnea and cerebral infarction were intermittent hypoxemia and hypercapnia, catecholaminergic discharge, autonomic dysfunction, oxidative stress, endothelial dysfunction, and systemic inflammation. Therefore, sleep apnea favors thedevelopment of vascular risk factors and predicts adverse outcomes after an ischemic stroke in terms of mortality, severity of the neurological deficit, complications, and functionalrecovery(AU)

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Objetivo: Describir la asociación entre la topografía del infarto cerebral y la aparición de disfunción autonómica cardíaca después de un ictus isquémico.Adquisición de la evidencia: Se realizó una búsqueda bibliográfica en la base de datos Medline entre 2014 y 2018, con los términos en inglés: autonomic heart regulation o autonomic nervous system,ischemic stroke o cerebral infarction, cardiac autonomic dysfunction o heart rate variability o HRV, hypothesis of lateralization, insula, y en español. Se encontraron 48 artículos originales y dosrevisiones sistemáticas. De ellos un estudio sobre las bases neuroanatómicas y fisiológicas del control autonómico cardiovascular, tres sobre evaluación de la variabilidad de la frecuencia cardíaca, y 46 acerca de los efectos del infarto cerebral y su topografía en la función autonómica cardíaca Resultados. La corteza insular se considera un centro de integración autonómica cardiovascular.Valores significativamente más altos de la relación de frecuencia baja/frecuencia alta se han encontradoen pacientes con infarto insular derecho. El papel prominente de la ínsula derecha en el control parasimpático de la función cardíaca explica por qué el infarto cerebral de esta región puede conducir aun desequilibrio autonómico y una regulación positiva de la función simpática.Conclusiones: La topografía del infarto cerebral se asocia con la disfunción autonómica cardíaca luego de un ictus isquémico. El infarto insular es el principal responsable de la mayoría de los disturbios autonómicos cardiovasculares provocados por un ictus isquémico. Los hallazgos sobre la lateralización hemisférica para el control autonómico cardiovascular son contradictorios. No obstante, la mayoría de los estudios coinciden en que las lesiones cerebrales derechas se asocian con un aumento del tono simpático(AU)

Objective: To describe the association between topography of cerebral infarction and the appearance of cardiac autonomic dysfunction after an ischemic stroke.Acquisition of evidence: A bibliographic search was conducted in Medline database from 2014 to 2018, using the English terms autonomic heart regulation or autonomic nervous system, ischemic stroke or cerebral infarction, cardiac autonomic dysfunction or heart rate variability (HRV), hypothesisof lateralization, insula, in English and Spanish. The search resulted in 48 original articles and two systematic reviews: a study on the neuroanatomic and physiological basis of cardiovascular autonomic control, three on the evaluation of heart rate variability. In addition 46 articles on the effects of cerebral infarction and its topography on cardiac autonomic function were found.Results: The insular cortex is considered a center of cardiovascular autonomic integration.Significantly higher values of low frequency / high frequency ratio have been found in patients with right insular infarction. The prominent role of the right insula in the parasympathetic control of cardiac function explains why cerebral infarction in this region can lead to autonomic imbalance and positiveregulation of sympathetic function.Conclusions: The topography of cerebral infarction is associated with cardiac autonomic dysfunction after an ischemic stroke. Insular infarction is primarily responsible for the majority of autonomiccardiovascular disorders caused by an ischemic stroke. The findings on hemispheric lateralization for autonomic cardiovascular control are contradictory. However, most studies agree that right brain injuries are associated with sympathetic tone increase(AU)

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RESUMEN Fundamento: El comportamiento epidemiológico del infarto cerebral conlleva a la necesidad de estudios encaminados a caracterizar el pronóstico de los pacientes, y a establecer factores correlacionados con la evolución, resumidos en modelos que permitan dirigir acciones de tratamiento hacia dichos determinantes. Objetivo: describir los principales factores pronósticos, clínicos y epidemiológicos en pacientes con infarto cerebral total de circulación anterior. Métodos: estudio descriptivo, en pacientes adultos (N=35) con infarto cerebral total de circulación anterior, ingresados en la Unidad de Ictus, del Hospital Arnaldo Milián Castro, desde marzo de 2017 hasta marzo de 2018. Se analizaron variables clínico-demográficas y relacionadas con la lesión isquémica, y se asociaron con el pronóstico global de los pacientes. Se aplicaron el Test de independencia basado en la Distribución Chi-cuadrado y la Prueba t de Student. Resultados: el 81,82 % de los pacientes entre 75 y 85 años evolucionó desfavorablemente, y fue mayor la probabilidad de un peor pronóstico en los pacientes más longevos (X2=10,59; p=0,007). En los que presentaron cifras más elevadas de presión arterial media y mayor tiempo con saturación de oxígeno menor que 90 % durante el sueño, la probabilidad de un pronóstico final desfavorable fue mayor (p=0,000). Ninguno de los factores asociados a la lesión isquémica se relacionó significativamente con el pronóstico (p>0,05). Conclusión: la edad, el promedio de presión arterial media, y el tiempo de saturación de oxígeno menor de 90 % durante el sueño en la fase aguda del ictus, se asocian con mayor probabilidad de presentar un pronóstico global desfavorable.

ABSTRACT Foundation: The epidemiological behavior of cerebral infarction leads to the need for studies aimed at characterizing the prognosis of patients, and establishing factors correlated with evolution, summarized in models that allow directing treatment actions towards these determinants. Objective: to describe the main prognostic, clinical and epidemiological factors in patients with total cerebral infarction of anterior circulation. Methods: descriptive study, in adult patients (N=35) with total cerebral infarction of previous circulation, admitted to the Stroke Unit, of the Arnaldo Milián Castro Hospital, from March 2017 to March 2018. Clinical-demographic variables were analyzed and related to ischemic injury, and were associated with the overall prognosis of patients. The Independence Test based on the Chi-square Distribution and the Student t-test were applied. Results: 81.82 % of patients between 75 and 85 years evolved unfavorably, and the probability of a worse prognosis in older patients was higher (X2 = 10.59; p = 0.007). In those who presented higher levels of mean blood pressure and longer time with oxygen saturation less than 90 % during sleep, the probability of an unfavorable final prognosis was higher (p =0.000). None of the factors associated with ischemic injury was significantly related to the prognosis (p>0.05). Conclusion: age, average mean blood pressure, and oxygen saturation time of less than 90 % during sleep in the acute phase of stroke are associated with a higher probability of presenting an unfavorable overall prognosis.

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Active Cdc42 GTPase, a key regulator of cell polarity, displays oscillatory dynamics that are anticorrelated at the two cell tips in fission yeast. Anticorrelation suggests competition for active Cdc42 or for its effectors. Here we show how 14-3-3 protein Rad24 associates with Cdc42 guanine exchange factor (GEF) Gef1, limiting Gef1 availability to promote Cdc42 activation. Phosphorylation of Gef1 by conserved NDR kinase Orb6 promotes Gef1 binding to Rad24. Loss of Rad24-Gef1 interaction increases Gef1 protein localization and Cdc42 activation at the cell tips and reduces the anticorrelation of active Cdc42 oscillations. Increased Cdc42 activation promotes precocious bipolar growth activation, bypassing the normal requirement for an intact microtubule cytoskeleton and for microtubule-dependent polarity landmark Tea4-PP1. Further, increased Cdc42 activation by Gef1 widens cell diameter and alters tip curvature, countering the effects of Cdc42 GTPase-activating protein Rga4. The respective levels of Gef1 and Rga4 proteins at the membrane define dynamically the growing area at each cell tip. Our findings show how the 14-3-3 protein Rad24 modulates the availability of Cdc42 GEF Gef1, a homologue of mammalian Cdc42 GEF DNMBP/TUBA, to spatially control Cdc42 GTPase activity and promote cell polarization and cell shape emergence.

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Glycogen synthase kinase 3 (GSK3) is one of the few master switch kinases that regulate many aspects of cell functions. Recent studies on cell polarization and migration have shown that GSK3 is also essential for proper regulation of these processes. GSK3 influences cell migration as one of the regulators of the spatiotemporally controlled dynamics of the actin cytoskeleton, microtubules, and cell-to-matrix adhesions. In this mini-review, the effects of GSK3 on these three aspects of cell migration will be discussed.

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DPYK3, a member of the Dictyostelium TKL (tyrosine kinase like) kinase family, was ablated by homologous recombination. dpyk3- cells displayed aberrant pattern formation during development. The prestalk O zone was not properly formed and, instead, the prespore zone was expanded in dpyk3- slugs. During development, the transcription factor STATc (signal transducers and activators of transcription c) was persistently phosphorylated and ecmAO expression level was kept low in dpyk3- cells. Furthermore, in response to differentiation inducing factor-1 (DIF-1) in suspension culture, dpyk3- cells displayed persistent STATc phosphorylation and reintroduction of DPYK3 in dpyk3- cells restored transient STATc phosphorylation similarly to wild type cells. In contrast to the positive STAT regulation by Janus Kinase in metazoans, Dictyostelium DPYK3 negatively regulates STATc during development in response to DIF-1 signaling.

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The novel Dictyostelium phosphatase MPL1 contains six leucine-rich repeats at the amino-terminal end and a phosphatase domain at the carboxyl end. Similarly architectured phosphatases exist among other protozoa, such as Entamoeba histolytica, Leishmania major, and Trypanosoma cruzi. MPL1 was strongly induced after 5 h of development; ablation by homologous recombination led to defective streaming and aggregation during development. In addition, cyclic AMP (cAMP)-pulsed mpl1(-) cells showed reduced random and directional motility. At the molecular level, mpl1(-) cells displayed higher prestimulus and persistent poststimulus ERK2 phosphorylation in response to cAMP stimulation. Consistent with their phenotype of persistent ERK2 phosphorylation, mpl1(-) cells also displayed an aberrant pattern of cAMP production, resembling that of the regA(-) cells. Reintroduction of a full-length MPL1 into mpl1(-) cells restored aggregation, ERK2 regulation, random and directional motility, and cAMP production similar to wild-type cells. We propose that MPL1 is a novel phosphatase essential for proper regulation of ERK2 phosphorylation and optimal motility during development.

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