Capillary refill time response to a fluid challenge or a vasopressor test: an observational, proof-of-concept study.

BACKGROUND: Several studies have validated capillary refill time (CRT) as a marker of tissue hypoperfusion, and recent guidelines recommend CRT monitoring during septic shock resuscitation. Therefore, it is relevant to further explore its kinetics of response to short-term hemodynamic interventions with fluids or vasopressors. A couple of previous studies explored the impact of a fluid bolus on CRT, but little is known about the impact of norepinephrine on CRT when aiming at a higher mean arterial pressure (MAP) target in septic shock. We designed this observational study to further evaluate the effect of a fluid challenge (FC) and a vasopressor test (VPT) on CRT in septic shock patients with abnormal CRT after initial resuscitation. Our purpose was to determine the effects of a FC in fluid-responsive patients, and of a VPT aimed at a higher MAP target in chronically hypertensive fluid-unresponsive patients on the direction and magnitude of CRT response. METHODS: Thirty-four septic shock patients were included. Fluid responsiveness was assessed at baseline, and a FC (500 ml/30 mins) was administered in 9 fluid-responsive patients. A VPT was performed in 25 patients by increasing norepinephrine dose to reach a MAP to 80-85 mmHg for 30 min. Patients shared a multimodal perfusion and hemodynamic monitoring protocol with assessments at at least two time-points (baseline, and at the end of interventions). RESULTS: CRT decreased significantly with both tests (from 5 [3.5-7.6] to 4 [2.4-5.1] sec, p = 0.008 after the FC; and from 4.0 [3.3-5.6] to 3 [2.6 -5] sec, p = 0.03 after the VPT. A CRT-response was observed in 7/9 patients after the FC, and in 14/25 pts after the VPT, but CRT deteriorated in 4 patients on this latter group, all of them receiving a concomitant low-dose vasopressin. CONCLUSIONS: Our findings support that fluid boluses may improve CRT or produce neutral effects in fluid-responsive septic shock patients with persistent hypoperfusion. Conversely, raising NE doses to target a higher MAP in previously hypertensive patients elicits a more heterogeneous response, improving CRT in the majority, but deteriorating skin perfusion in some patients, a fact that deserves further research.

L-PRF Secretome from Both Smokers/Nonsmokers Stimulates Angiogenesis and Osteoblast Differentiation In Vitro.

Leukocyte and Platelet-Rich Fibrin (L-PRF) is part of the second generation of platelet-concentrates. L-PRF derived from nonsmokers has been used in surgical procedures, with its beneficial effects in wound healing being proven to stimulate biological activities such as cell proliferation, angiogenesis, and differentiation. Cigarette smoking exerts detrimental effects on tissue healing and is associated with post-surgical complications; however, evidence about the biological effects of L-PRF derived from smokers is limited. This study evaluated the impact of L-PRF secretome (LPRFS) derived from smokers and nonsmokers on angiogenesis and osteoblast differentiation. LPRFS was obtained by submerging L-PRF membranes derived from smokers or nonsmokers in culture media and was used to treat endothelial cells (HUVEC) or SaOs-2 cells. Angiogenesis was evaluated by tubule formation assay, while osteoblast differentiation was observed by alkaline phosphatase and osterix protein levels, as well as in vitro mineralization. LPRFS treatments increased angiogenesis, alkaline phosphatase, and osterix levels. Treatment with 50% of LPRFS derived from smokers and nonsmokers in the presence of osteogenic factors stimulates in vitro mineralization significantly. Nevertheless, differences between LPRFS derived from smokers and nonsmokers were not found. Both LPRFS stimulated angiogenesis and osteoblast differentiation in vitro; however, clinical studies are required to determine the beneficial effect of LPRFS in smokers.

Vernix caseosa reveals mechanistic clues linking maternal obesity to atopic dermatitis pathogenesis.

BACKGROUND: Maternal overweight and obesity have been associated with an increased risk of atopic dermatitis (AD) in the offspring, but the underlying mechanisms are unclear. Vernix caseosa (VC) is a proteolipid material covering the fetus produced during skin development. However, whether maternal prepregnancy weight excess influences fetal skin development is unknown. Characterizing the VC of newborns from mothers with prepregnancy overweight and obesity might reveal AD-prone alterations during fetal skin development. OBJECTIVE: We sought to explore AD biomarkers and staphylococcal loads in VC from the offspring of mothers who were overweight/obese (O/O) before pregnancy versus in those from offspring of normal weight mothers. METHODS: The VC of newborns of 14 O/O and 12 normal weight mothers were collected immediately after birth. Biomarkers were determined by ELISA and staphylococcal species by quantitative PCR. RESULTS: The VC from the O/O group showed decreased expression of skin barrier proteins (filaggrin and loricrin) and increased levels of proinflammatory biomarkers (IgA, thymic stromal lymphopoietin [TSLP], S100A8, IL-25, and IL-33). No differences in concentrations of antimicrobial peptides and enzymes were detected. The VC from the O/O group had a lower Staphylococcus epidermidis and Staphylococcus hominis commensal bacterial load, whereas Staphylococcus aureus bacterial load was not significantly different between the 2 groups. Maternal body mass index was negatively correlated with VC filaggrin expression and S epidermidis load and was positively associated with TSLP concentration. One-year follow-up established that the offspring of O/O mothers had a higher incidence of AD that was specifically linked with decreased VC filaggrin expression and lower S epidermidis load. CONCLUSIONS: VC from neonates of mothers with prepregnancy overweight and obesity exhibit skin barrier molecular alterations and staphylococcal dysbiosis that suggest early mechanistic clues to this population's increased risk of AD.

Transcriptional Profiling of Human Endothelial Cells Unveils PIEZO1 and Mechanosensitive Gene Regulation by Prooxidant and Inflammatory Inputs.

PIEZO1 is a mechanosensitive cation channel implicated in shear stress-mediated endothelial-dependent vasorelaxation. Since altered shear stress patterns induce a pro-inflammatory endothelial environment, we analyzed transcriptional profiles of human endothelial cells to determine the effect of altered shear stress patterns and subsequent prooxidant and inflammatory conditions on PIEZO1 and mechanosensitive-related genes (MRG). In silico analyses were validated in vitro by assessing PIEZO1 transcript levels in both the umbilical artery (HUAEC) and vein (HUVEC) endothelium. Transcriptional profiling showed that PIEZO1 and some MRG associated with the inflammatory response were upregulated in response to high (15 dyn/cm2) and extremely high shear stress (30 dyn/cm2) in HUVEC. Changes in PIEZO1 and inflammatory MRG were paralleled by p65 but not KLF or YAP1 transcription factors. Similarly, PIEZO1 transcript levels were upregulated by TNF-alpha (TNF-α) in diverse endothelial cell types, and pre-treatment with agents that prevent p65 translocation to the nucleus abolished PIEZO1 induction. ChIP-seq analysis revealed that p65 bonded to the PIEZO1 promoter region, an effect increased by the stimulation with TNF-α. Altogether this data showed that NF-kappa B activation via p65 signaling regulates PIEZO1 expression, providing a new molecular link for prooxidant and inflammatory responses and mechanosensitive pathways in the endothelium.

Maternal obesity and high leptin levels prime pro-inflammatory pathways in human cord blood leukocytes.

INTRODUCTION: Maternal obesity alters the immune function in the offspring. We hypothesize that maternal obesity and pro-inflammatory pathways induce leptin-related genes in neonatal monocytes, whereby high leptin levels enhance their inflammatory response. METHODS: Transcriptional profiles of cord blood leukocytes (CBL) in basal and pro-inflammatory conditions were studied to determine differentially expressed genes (DEG). The DNA methylation profile of CB monocytes (CBM) of neonates born to control BMI mothers and women with obesity was assayed to identify differentially methylated probes (DMP). CBM-derived macrophages were cultured with or without leptin (10-100 ng/ml) and then stimulated with lipopolysaccharide (LPS, 100 ng/ml) and interferon-gamma (20 ng/ml) to assess the induction of TNF-α and IL-10 transcripts. RESULTS: CBL from pregnancies with obesity (CBL-Ob) showed 12,183 DEG, affecting 49 out of 78 from the leptin pathway. Control CBM exposed to LPS showed 45 leptin-related DEG, an effect prevented by the co-exposure to LPS and IL-10. Conversely, CBM-Ob showed 5279 DMP enriched in insulin- and leptin-related genes, and Lasso regression of leptin-related DMP showed high predictive value for plasma leptin levels (r2 = 0.9897) and maternal BMI categories (AUC = 1). Chronic exposure to leptin increased TNF-α and decreased IL-10 levels in control BMI samples but not in Ob-CBM. Enhanced TNF-α induction after proinflammatory stimulation was observed in leptin-treated control BMI samples. DISCUSSION: Obesity in pregnancy is associated with a distinctive expression and DNA methylation profile of leptin-related genes in cord blood monocytes, meanwhile, leptin enhances the expression of pro-inflammatory cytokines upon stimulation with M1-skewing agents.

Smoking habits do not affect biological responses induced by leucocyte and platelet-rich fibrin in periodontal ligament cells.

BACKGROUND AND OBJECTIVE: Leucocyte- and platelet-rich fibrin has been developed to stimulate wound healing response. However, it is currently unknown whether smoking affects the biological responses elicited by leucocyte- and platelet-rich fibrin on periodontal ligament-derived mesenchymal stromal cells. This study analyzes the kinetics of biomolecule release from leucocyte- and platelet-rich fibrin derived from smokers and nonsmokers and their effect on periodontal ligament cell proliferation and migration as essential biological activities during wound healing. METHODS: Biomolecules present in leucocyte- and platelet-rich fibrin exudates and conditioned media collected from smokers and nonsmokers were analyzed by Luminex arrays. Periodontal ligament-derived mesenchymal stromal cell obtained from one nonsmoker were treated with leucocyte- and platelet-rich fibrin exudates or leucocyte- and platelet-rich fibrin conditioned media derived from both smokers and nonsmokers. The parameters evaluated included cell proliferation, determined by Ki67 immunostaining and migration assessed using transwell assays. Also, cells were treated with nicotine in the presence of fetal bovine serum 10% or leucocyte- and platelet-rich fibrin conditioned media. RESULTS: A similar biomolecular profile was detected in leucocyte- and platelet-rich fibrin exudates and leucocyte- and platelet-rich fibrin conditioned media from smokers and nonsmokers, stimulating (periodontal ligament-derived mesenchymal stromal cell) proliferation, and migration to a comparable degree. Nicotine reduced cell proliferation and migration of periodontal cells; however, this effect was recovered in the presence of leucocyte- and platelet-rich fibrin conditioned media. CONCLUSION: Leucocyte- and platelet-rich fibrin derived from smokers could be an autologous source of biomolecules to stimulate cell biological activities involved in wound healing in smokers who have difficulties in ceasing this habit. Clinical trials are required to evaluate the impact of leucocyte- and platelet-rich fibrin on healing responses in smokers.

Procesamiento sensorial en menores de seis años con trastorno específico del lenguaje

Introducción: El procesamiento sensorial determina e influencia el nivel de desarrollo que presentan los individuos en la infancia y cuando se afecta alguno de los sistemas que lo integran, se alteran dominios del desarrollo que impiden a los niños desenvolverse de manera adecuada en su entorno. Objetivos: Describir y comparar el procesamiento sensorial de los niños con trastorno específico del lenguaje y con desarrollo típico del lenguaje. Métodos: La muestra estuvo conformada por 60 niños con edades de 4 a 5 años de la escuela especial de lenguaje San Clemente, asignados a dos grupos de acuerdo con la presencia o ausencia de trastorno específico del lenguaje. El procesamiento sensorial se evaluó mediante la escala de procesamiento sensorial. Se evaluó el tipo de distribución de las variables de la escala para su posterior análisis. Resultados: Los niños con trastorno específico del lenguaje obtuvieron 275 puntos y se ubicaron por debajo del puntaje de corte, en cambio los menores con desarrollo típico obtuvieron 309 puntos y se situaron por sobre el puntaje de corte. Es decir, los niños con trastorno específico del lenguaje presentaron un procesamiento sensorial más bajo en comparación con los niños que poseen desarrollo típico del lenguaje con diferencias significativas en el sistema auditivo y propioceptivo. Conclusiones: Los niños con trastorno específico del lenguaje exhiben un desempeño más bajo en tareas de procesamiento sensorial, es por ello, que este último debe ser considerado en la evaluación y diagnóstico de niños con este trastorno para generar un abordaje más integral.

Introduction: Sensory processing determines and influences the level of development presented by individuals in childhood and when any of the systems that integrate it are affected. Developmental domains are altered and they prevent children from developing adequately in their environment. Objectives: To describe and compare sensory processing in children with specific language impairment and typical language development. Methods: The sample consisted of 60 children aged 4 to 5 years from the San Clemente Special Language School, whom were assigned to two groups according to the presence or absence of specific language disorder. Sensory processing was assessed using the sensory processing scale. The type of distribution of the scale variables was evaluated for further analysis. Results: Children with specific language disorder obtained 275 points and were below the cut-off score, while children with typical development obtained 309 points and were above the cut-off score. That is, children with specific language disorder have lower sensory processing compared to children with typical language development with significant differences in the auditory and proprioceptive system. Conclusions: Children with specific language disorder show lower performance in sensory processing tasks, which is why the latter should be considered in the evaluation and diagnosis of children with this disorder to generate a more comprehensive approach.

Interacciones sociales, bullying y conducta suicida en niños y adolescentes con trastorno del espectro autista / Social Interactions, Bullying, and Suicidal Behavior in Children and Adolescents with Autism Spectrum Disorder

Introducción: La evidencia plantea que el trastorno del espectro autista puede asociarse con un aumento, en el pensamiento, del deseo de querer morir; ante esta situación se hace necesario investigar los factores de riesgo que afectan a menores con esta condición. Objetivo: Explorar en la literatura de qué forma las interacciones sociales y el bullying son factores de riesgo en la conducta suicida en niños y adolescentes con trastorno del espectro autista. Métodos: Se realizó una búsqueda que incluyó las principales bases de datos y de gestores de la información (PubMed, SciELO, WoS, Google académico, Scopus, Dialnet), entre marzo y agosto de 2021. Se utilizaron términos como suicidal behavior; trastorno del espectro autista; intimidación; nteracción social. Análisis y síntesis de la información: Se entregan argumentos de cómo el bullying representa un factor de riesgo para la conducta suicida, también de cómo los intercambios comunicativos se encuentran afectados en los menores con trastornos del espectro autista y esto puede aumentar el riesgo suicida. Se describe la escasa literatura vinculada a la evaluación de la conducta suicida en los menores con estos trastornos y de la necesidad de continuar investigando en esta temática. Conclusión: Los niños y adolescentes con necesidades educativas especiales, entre los que se encuentran los niños con trastornos del espectro autista, están expuestos a un mayor número de factores de riesgo para la aparición de conducta suicida. Estos elementos deben considerarse a la hora de programar y planificar protocolos de prevención del suicidio en el contexto sanitario y educativo(AU)

Introduction: Evidence suggests that autism spectrum disorder may be associated with an increase, in thinking of the wish to die; given this situation, it is necessary to investigate the risk factors that affect children with this condition. Objective: To explore in the literature how social interactions and bullying are risk factors for suicidal behavior in children and adolescents with autism spectrum disorder. Methods: A search including the main databases and information managers (PubMed, SciELO, WoS, Google Scholar, Scopus, Dialnet) was carried out between March and August 2021. Terms such as suicidal behavior; autism spectrum disorder; bullying; social interaction were used. Analysis and synthesis of information: Arguments are given on how bullying represents a risk factor for suicidal behavior, also on how communicative exchanges are affected in children with autism spectrum disorders and this may increase suicidal risk. It is described the scarce literature related to the evaluation of suicidal behavior in children with these disorders and the need for further research on this topic. Conclusion: Children and adolescents with special educational needs, including children with autism spectrum disorders, are exposed to a greater number of risk factors for the development of suicidal behavior. These elements should be considered when programming and planning suicide prevention protocols in the health and educational context(AU)

Bullying a personas con trastornos de la comunicación integradas en establecimientos escolares: rol de la fonoaudiología y sus implicancias en la salud comunicativa / Bullying of people with communication disorders integrated in schools: role of speech therapy and its implications for communicative health

El bullying es un fenómeno definido como una forma de agresión intencional que incluye actos verbales, físicos o psicológicos que ocurren en una relación con otras personas de manera reiterada, sistemática y sostenida en el tiempo. La mayor parte de los estudios se concentran en el bullying y las consecuencias en población escolar normotípica, sin embargo, existe poca exploración en el bullying que es resultado de un trastorno comunicativo. Es por ello que la labor de los fonoaudiólogos insertos en ámbitos educativos no es clara en explicitar los lineamientos de acciones terapéuticas que favorezcan la prevención de este fenómeno. El propósito de esta investigación es conocer las principales concepciones que los fonoaudiólogos tienen sobre el bullying en personas con trastornos de la comunicación en edad escolar. Con este objetivo, se realizó una investigación con métodos cuantitativos y cualitativos, mediados por encuestas y entrevistas en profundidad respectivamente. Se encontró que más del 65% del bullying entre personas dentro de los establecimientos educacionales se relaciona con niños de entre 9 y 12 años de edad con trastornos de la comunicación. En cuanto a la autopercepción del rol fonoaudiológico en el tema de la prevención e/o intervención en temas de bullying, emergen los conceptos de favorecer los aspectos del lenguaje y/o del habla en los niños que tienen dificultad, la sensibilización de los actores involucrados, el refuerzo del autoestima y el trabajo en equipo interdisciplinario. Finalizando el tratamiento analítico de las entrevistas, se establece que la Fonoaudiología cumpliría un papel fundamental en el abordaje del bullying en poblaciones con trastornos de la comunicación, siendo el profesional que actúa directamente sobre la salud comunicativa.

Bullying is a phenomenon defined as a form of intentional aggression that includes verbal, physical or psychological acts that occur in a relationship with other people in a repeated, systematic and sustained manner over time. Most of the studies focus on bullying and its consequences in the normal school population, however, there is little exploration of bullying that is the result of a communication disorder. This is why the work of speech therapists inserted in educational settings is not clear in explaining the guidelines for therapeutic actions that favor the prevention of this phenomenon. The purpose of this research is to know the main conceptions that speech-language pathologists have about bullying in people with communication disorders at school age. With this objective, an investigation was carried out with quantitative and qualitative methods, mediated by surveys and in-depth interviews, respectively. It was found that more than 65% of bullying between people within educational establishments is related to children between 9 and 12 years of age with communication disorders. Regarding the self-perception of the speech-language pathology role in the issue of prevention and/or intervention in bullying issues, the concepts of favoring aspects of language and/or speech in children who have difficulty emerge, raising awareness of the actors involved, the reinforcement of self-esteem and interdisciplinary teamwork. Completing the analytical treatment of the interviews, it is established that speech therapy would play a fundamental role in addressing bullying in populations with communication disorders, being the professional who acts directly on communicative health.

Investigación en pregrado de las escuelas de Medicina de Chile: percepción sobre facilitadores y limitantes entre los asistentes al III Congreso Chileno de Estudiantes de Medicina (CoCEM) / Involvement of medical students in research. Facilitators and constraints

BACKGROUND: Scientific research is fundamental to the education of medical students. However, their involvement in research is limited. AIM: To describe the perceptions of medical students about facilitators and constraints to perform undergraduate research. MATERIAL AND METOHDS: Medical students attending the Chilean Congress of Medical Students in the Metropolitan Region in 2018, were surveyed. The responses obtained were subjected to a qualitative content analysis and were grouped according to perceptions of facilitators and constraints. RESULTS: The main facilitators reported were linkage with research teachers, personal motivation towards research, and research-oriented curriculum. The main constraints were lack of time for research, lack of access to formal information channels to engage in research, and sub-optimal conditions for research. CONCLUSIONS: The main factor promoting research at the undergraduate level was the link with the teacher, mainly through informal channels. The lack of official information provided through formal instances and lack of time hampers the access to research.

[Involvement of medical students in research. Facilitators and constraints]. / Investigación en pregrado de las escuelas de Medicina de Chile: percepción sobre facilitadores y limitantes entre los asistentes al III Congreso Chileno de Estudiantes de Medicina (CoCEM).

BACKGROUND: Scientific research is fundamental to the education of medical students. However, their involvement in research is limited. AIM: To describe the perceptions of medical students about facilitators and constraints to perform undergraduate research. MATERIAL AND METHODS: Medical students attending the Chilean Congress of Medical Students in the Metropolitan Region in 2018, were surveyed. The responses obtained were subjected to a qualitative content analysis and were grouped according to perceptions of facilitators and constraints. RESULTS: The main facilitators reported were linkage with research teachers, personal motivation towards research, and research-oriented curriculum. The main constraints were lack of time for research, lack of access to formal information channels to engage in research, and sub-optimal conditions for research. CONCLUSIONS: The main factor promoting research at the undergraduate level was the link with the teacher, mainly through informal channels. The lack of official information provided through formal instances and lack of time hampers the access to research.

Regional Brain Perfusion Is Associated with Endothelial Dysfunction Markers in Major Depressive Disorder.

BACKGROUND: Major depressive disorder (MDD) is an important independent risk factor for cardiovascular disease. Cumulative data suggest that depressive patients exhibit derangement in regional cerebral blood flow (rCBF), although underlying mechanisms remain mostly unknown. Endothelial dysfunction (ED), defined as different forms of abnormal endothelial activity, plays a key role in the pathogenesis of vascular disease. ED is associated with several clinical conditions characterized by high cardiovascular risk. Diverse ED markers have been found in mood disorders. PURPOSE: To evaluate the association between rCBF and peripheral ED markers in MDD patients, at baseline and after selective serotonin receptor inhibitors (SSRIs) therapy. PATIENTS AND METHODS: Twenty-seven untreated unipolar MDD patients in their first episode were evaluated with the Hamilton Depression Rating Scale (HAM-D) and brain perfusion SPECT at baseline and after 2 months of SSRIs. Statistical Parametric Mapping (SPM) was employed to evaluate rCBF; circulating endothelial cells (CECs), plasma soluble intercellular adhesion molecule (sICAM), and high-sensitivity C-reactive protein (hsCRP) were used as independent covariates. RESULTS: Baseline CECs and sICAM were increased in MDD patients compared with matching controls (p = 0.0001) and hsCRP (p = 0.03). HAM-D scores (21 items) and CECs diminished after SSRI therapy in MDD patients (p < 0.0001). There was a significant rCBF decrease, mainly in deep central structures. HAM-D change was associated with rCBF decrease at the left amygdala, right striatum levels, and Brodmann area 25. CEC change was associated with rCBF at deep brain level and sICAM with large rCBF areas at the left caudate and tectum; hsCRP was associated, to a lesser extent, with the left dorsal striatum and mesencephalic tectum. CONCLUSION: ED markers in patients with MDD are associated with significant changes in rCBF which are features of depression. These findings suggest that systemic damage/activation of the endothelium may contribute to the abnormal rCBF observed in MDD patients.

La valoración de la percepción de padres/cuidadores sobre manual de estimulación del movimiento y lenguaje: Para niños con trastorno específico del lenguaje entre 3 a 4 años / The assesment of the perception of parents caregives on the manual of movement and languaje stimulación: For children with specific language disorder between 3 and 4 years of age

El lenguaje es una función cognitiva, esta es muy importante ya que nos permite compartir y organizar nuestra vida cotidiana; al mismo tiempo es un pilar fundamental de las relaciones humanas. Sin embargo, no todos los menores desarrollan el lenguaje de manera adecuada. En Chile es posible observar una alta prevalencia del Trastorno Específico del Lenguaje (TEL), siendo necesaria la creación de Manuales para la estimulación de los niños en el hogar, donde Padres/Cuidadores actúan como agentes principales en esta tarea, complementando lo entregado en los establecimientos a los cuales asisten estos menores. El objetivo del presente estudio fue valorar la percepción de padres/ cuidadores sobre el Manual de Estimulación del Movimiento y Lenguaje, para niños con Trastorno específico del Lenguaje (TEL) entre 3 a 4 años de edad. El estudio fue abordado bajo un alcance descriptivo, donde participaron 109 padres. Dentro de los resultados fue posible observar que más del 50% de ellos consideró que el contenido, la forma de presentación y los ejercicios eran adecuados seleccionando la opción muy de acuerdo. De lo anterior, es posible concluir que la percepción que presentan los padres/cuidadores sobre el Manual de Estimulación del Movimiento y Lenguaje, es favorable para su difusión. Esto representa una oportunidad de utilizar este manual como una herramienta de entrenamiento para cuidadores de niños con diagnóstico de trastornos específicos del lenguaje y posteriormente evaluar la efectividad del mismo en el progreso de los menores.

Language is a cognitive function, which is important because it allows us to share and organize our daily lives; at the same time it is a fundamental pillar of human relationships. However, not all children develop language adequately. In Chile it is possible to observe a high prevalence of specific language disorder, being necessary the creation of manuals for the stimulation of children at home, where parents/caregivers act as main agents in this task, complementing what is delivered in the establishments attended by these minors. The objective of this study is to assess the perception of parents/caregivers about the Movement and Language Stimulation Manual for children with Specific Language Disorder (SLD) between 3 and 4 years of age. The study was approached under a descriptive scope, where 109 parents participated. Within the results, it was possible to observe that more than 50% of them considered that the content, the form of presentation and the exercises were adequate, selecting the option with strong agreement. From the above, it is possible to conclude that the perception presented by parents/caregivers about the Movement and Language Stimulation Manual is favorable for its dissemination. This represents an opportunity to use this manual as a training tool for caregivers of children diagnosed with specific language disorders and subsequently evaluate the effectiveness of the program in the children's progress.

Investigación en pregrado de las escuelas de medicina de Chile: Motivación y participación de estudiantes de medicina asistentes al Congreso Chileno de Estudiantes de Medicina (COCEM)

Background: The participation of medical students in research generates professional, scientific, and personal benefits for the student. Aim: To evaluate the interest and opportunities for medical students in Chile to participate in scientific research and their perceptions about factors influencing research. Material and Methods: All students attending the 2018 Chilean Congress for Medical Students were invited to answer a 44 questions survey about interest and opportunities to participate in research. Results: The survey was answered by 489 of the 538 students attending the congress. Eighty five percent referred interest in conducting scientific research, but only 47% had the opportunity to actively participate in a research project. The main research area providing opportunities was epidemiology and the main form to access a research project was through direct contact with a medical professor or researcher. Seventy seven percent of respondents had courses of scientific investigation in their medical curriculum and 92% had a scientific society for medical students in their university. Conclusions: Respondents showed a great deal of interest in participating in scientific research. However, there is a gap between this interest and the available opportunities. Medical professors should promote and facilitate the participation of their students in research.

Older adults with frailty syndrome present an altered platelet function and an increased level of circulating oxidative stress and mitochondrial dysfunction biomarker GDF-15.

INTRODUCTION: The elderly population is increasing worldwide and in Chile, it is expected to grow rapidly. The World Health Organization (WHO) ICOPE guideline (Integrated Care for Older People) emphasizes the importance of frailty diagnosis to prevent dependence. Frailty in older adults is considered an indicator of vulnerability and poor health outcomes, of multifactorial etiology. Our objective was to investigate the association of activation of coagulation and increased risk of thrombosis with frailty in people older than 64 years. A prevalent-case control study was designed with 28 frail older and 27 robust older adults (non-frail, control group) older than 64 years. Frailty was defined by Fried's Phenotype, Platelet aggregation and activation plasma levels of Thromboxane B2 (TXB2), 8-isoprostane and Growth Differentiation Factor-15 (GDF-15) were determined. RESULTS: Compared to healthy controls, frail older adults, had a) higher percentage of platelet aggregation induction with ADP 4 µM (82.85% (3.35) and 73.41% (3.26), p-value = 0.024) and subaggregant dose of ADP (30.83% (7.47) and 13.25% (3.21), p-value = 0.002); b) higher platelet activation: P-selectin exposure (18.23% (4.41) and 6.96% (1.08), p-value = 0.011), and activated GPIIß-IIIα (21.51% (3.41) and 8.26% (1.18), p-value = 0.001), at the baseline level and against a subaggregant dose ADP: P-selectin exposure (46.93% (5.95) and 13.41% (3.35), p-value = 0.002) and activated GPIIß-IIIα (43.29% (6.04) and 26.71% (4.92), p-value = 0.024); c) higher plasma levels of TXB2 (201.8 ng/mL (59.53-236.3) and 45.77 ng/mL (25.14-98.26), p-value<0.0001), d) elevated plasma levels of 8-isoprostane (70.94 pg/mL, IQ: 65.89-99,96 and 56.24 pg/mL, IQ: 42.18-74.81, p-value = 0.001), and e) higher plasma GDF-15 levels (2,379 pg/mL, IQ: 1,845-4,121and 1367 pg/mL, IQ: 1190-1747, p-value = 0.0001). DISCUSSION: Older adults with frailty syndrome have an upregulated platelet activity that may contribute to an increased risk of thrombosis and aspirin resistance. The elevated oxidative stress and increases of GDF-15 levels might be related to altered platelet responsiveness in frail patients. CONCLUSION: The determination of biomarkers of platelet dysfunction, oxidative stress and cell senescence/mitochondrial dysfunction may contribute to frailty diagnosis, and approaches aimed at regulating platelet function in frail older adults could contribute to its prevention and treatment.

[Participation of Chilean undergraduate medical students in scientific research]. / Investigación en pregrado de las escuelas de medicina de Chile: Motivación y participación de estudiantes de medicina asistentes al Congreso Chileno de Estudiantes de Medicina (COCEM).

BACKGROUND: The participation of medical students in research generates professional, scientific, and personal benefits for the student. AIM: To evaluate the interest and opportunities for medical students in Chile to participate in scientific research and their perceptions about factors influencing research. MATERIAL AND METHODS: All students attending the 2018 Chilean Congress for Medical Students were invited to answer a 44 questions survey about interest and opportunities to participate in research. RESULTS: The survey was answered by 489 of the 538 students attending the congress. Eighty five percent referred interest in conducting scientific research, but only 47% had the opportunity to actively participate in a research project. The main research area providing opportunities was epidemiology and the main form to access a research project was through direct contact with a medical professor or researcher. Seventy seven percent of respondents had courses of scientific investigation in their medical curriculum and 92% had a scientific society for medical students in their university. CONCLUSIONS: Respondents showed a great deal of interest in participating in scientific research. However, there is a gap between this interest and the available opportunities. Medical professors should promote and facilitate the participation of their students in research.

Coagulation Factor Xa Promotes Solid Tumor Growth, Experimental Metastasis and Endothelial Cell Activation.

Hypercoagulable state is linked to cancer progression; however, the precise role of the coagulation cascade is poorly described. Herein, we examined the contribution of a hypercoagulative state through the administration of intravenous Coagulation Factor Xa (FXa), on the growth of solid human tumors and the experimental metastasis of the B16F10 melanoma in mouse models. FXa increased solid tumor volume and lung, liver, kidney and lymph node metastasis of tail-vein injected B16F10 cells. Concentrating on the metastasis model, upon coadministration of the anticoagulant Dalteparin, lung metastasis was significantly reduced, and no metastasis was observed in other organs. FXa did not directly alter proliferation, migration or invasion of cancer cells in vitro. Alternatively, FXa upon endothelial cells promoted cytoskeleton contraction, disrupted membrane VE-Cadherin pattern, heightened endothelial-hyperpermeability, increased inflammatory adhesion molecules and enhanced B16F10 adhesion under flow conditions. Microarray analysis of endothelial cells treated with FXa demonstrated elevated expression of inflammatory transcripts. Accordingly, FXa treatment increased immune cell infiltration in mouse lungs, an effect reduced by dalteparin. Taken together, our results suggest that FXa increases B16F10 metastasis via endothelial cell activation and enhanced cancer cell-endothelium adhesion advocating that the coagulation system is not merely a bystander in the process of cancer metastasis.

Efecto de la terapia de resincronización ventricular en los parámetros de disfunción endotelial y función sistólica izquierda en pacientes con insuficiencia cardíaca crónica y bloqueo completo de rama izquierda / Endothelial dysfunction, left ventricular function, and chronic heart failure with complete left bundle branch block: effect of resynchronization therapy

Resumen: Introducción: La insuficiencia cardíaca crónica (ICC) es una condición compleja asociada a inflamación sistémica y a disfunción endotelial (DE) cuya patogénesis no es bien comprendida. Objetivo: Evaluar una posible relación entre marcadores de DE periférica con la respuesta a terapia de resincronización ventricular (TRV). Método: 20 pacientes con ICC, QRS ≥120ms y fracción de eyección ventricular izquierda (FEVI) ≤35% se estudiaron pre y 6 meses post-TRV con: Minnesota Living with Heart Failure Questionnaire (MLHFQ); test de marcha (TM-6min); Ecocardiografía-2D y SPECT de perfusión gatillado en reposo; proteína C-reactiva ultra sensible (us-PCR); péptido natriurético cerebral (pro-BNP); células endoteliales circulantes (CEC); moléculas de adhesión soluble vascular (sVCAM) e intercelular (sICAM); interleukina-6 (IL-6) y Factor von Willebrand (FvW). Se clasificaron como respondedores o no a TRV según criterios preestablecidos. Resultados: Promedios basales: pro-BNP 5.290pg/ml; us-PCR 1,7ug/mL; MLHFQ 72; TM-6min 391 metros. Las CEC y sICAM estaban sobre límites normales. Post-TRV, el 50% fue respondedor: 11/20 mejoraron ≥1 clase NYHA y ≥10% del TM-6min; ML-HFQ disminuyó (p<0.0001); FEVI mejoró (p=0.003); volumen final sistólico disminuyó (p=0.008) y también pro-BNP (p=0.03). En los respondedores, las CEC disminuyeron, persistiendo elevadas, sobre lo normal. Existieron correlaciones entre cambios de pro-BNP con TM-6min y entre us-PCR con MLHFQ y FvW (p≤0.004 en todas). Conclusiones: En ICC existe evidencia de significativa DE, expresada por sICAM y CEC, biomarcador periférico sensible. Estas disminuyeron 6 meses post-TRV, persistiendo sobre el límite normal. Otros parámetros funcionales e inflamatorios se correlacionaron en el grupo total, sin diferencias entre grupos respondedores y no respondedores.

Abstract: Introduction: Chronic heart failure (CHF) is a complex condition associated with systemic inflammation and endothelial dysfunction (ED) whose pathogenesis is not well understood. Objective: to evaluate a possible relationship between peripheral ED markers and response to cardiac resynchronization therapy (CRT). Method: 20 patients with CHF, QRS ≥120ms and left ventricular ejection fraction (LVEF) ≤35% were studied before and 6 months post-CRT. Minnesota Living with Heart Failure Questionnaire (MLHFQ); walking test (6min-WT); 2D-echocardiography and gated perfusion SPECT at rest; ultra-sensitive C-reactive protein (us-CRP); brain natriuretic peptide (pro-BNP); circulating endothelial cells (CEC); vascular soluble adhesion (sVCAM) and intercellular adhesion molecules (sICAM); interleukin-6 (IL-6) and von Willebrand Factor (vWF) were measured in all subjects. They were classified as responders or not to CRT, according to pre-established criteria. Results: Basal means: pro-BNP 5,290 pg / ml; us-CRP 1.7 ug/mL; MLHFQ 72; 6min-WT 391 meters. The CEC and IL-6 were above normal limits. Post-CRT, 50% were responders: 11/20 improved ≥1 NYHA class and ≥10% increase in 6min-WT; MLHFQ decreased (p <0.0001); LVEF improved (p = 0.003); final systolic volume decreased (p = 0.008) and also pro-BNP (p= 0.03). In responders CEC decreased, persisting over normal limits. There were correlations between changes of pro-BNP with TM-6min and between us-PCR with MLHFQ and vWF (p≤0.004 in all). Conclusions: In CHF there is evidence of significant ED, expressed by sICAM and CEC, a sensitive peripheral biomarker that decreased 6 months post-CRT although persisting above normal limits. Other functional and inflammatory parameters were correlated in the total group, without differences between responders and non-responders.

Human platelet interaction with E. coli O111 promotes tissue-factor-dependent procoagulant activity, involving Toll like receptor 4.

Platelets have a major role in clotting activation and contribute to the innate immune response during systemic infections. Human platelets contain tissue factor (TF) and express functional Toll-like receptor 4 (TLR4). However, the role of TLR4 in triggering the procoagulant properties of platelets, upon challenge with bacteria, is yet unknown. Our hypothesis is that E. coli O111-TLR4 interaction activates platelets and elicits their procoagulant activity. We demonstrated that the strain, but not ultrapure LPS, increased surface P-selectin expression, platelet dependent TF procoagulant activity (TF-PCA) and prompted a faster thrombin generation (TG). Blockade of TLR4 resulted in decreased platelet activation, TF-PCA and TG, revealing the participation of this immune receptor on the procoagulant response of platelets. Our results provide a novel mechanism by which individuals with bacterial infections would have an increased incidence of blood clots. Furthermore, the identification of platelet TF and TLR4 as regulators of the effect of E. coli O111 might represent a novel therapeutic target to reduce the devastating consequences of the hemostatic disorder during sepsis.

Inhibition of angiogenesis by platelets in systemic sclerosis patients.

INTRODUCTION: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by microvascular damage, inflammation, and fibrosis. It has become increasingly evident that platelets, beyond regulating hemostasis, are important in inflammation and innate immunity. Platelets may be an important source of proinflammatory and profibrotic cytokines in the vascular microenvironment. In this study, we sought to assess the contribution of platelet-derived factors in patients with SSc to the angiogenesis of human dermal microvascular endothelial cells (DMVECs) in a tubule formation assay and to characterize the secretion of profibrotic and proinflammatory cytokines in these platelets. METHODS: We analyzed platelets obtained from 30 patients with SSc and 12 healthy control subjects. Angiogenesis was evaluated in vitro with a DMVEC tubule formation assay on Matrigel and platelet-derived angiogenic factors such as vascular endothelial growth factor (VEGF), 165b isoform (VEGF165b), and cytokine secretion was evaluated. Platelet serotonin content was also determined. RESULTS: When DMVECs were incubated with SSc platelet releasates, tubule formation was significantly inhibited (p < 0.01, t test), and higher expression of endothelin-1 in these cells was observed compared with control subjects (p < 0.05, Mann-Whitney U test). In SSc platelet releasates, VEGF165b was significantly higher (p < 0.05, t test), and the VEGF165b/VEGF ratio was increased compared with that of control subjects. Higher secretion of transforming growth factor ß (p < 0.01, t test) and CD40L (p < 0.01, t test) was observed compared with control subjects. Also, intraplatelet serotonin levels were lower in platelets obtained from patients with diffuse SSc compared with patients with limited SSc and control subjects (p < 0.05, t test). CONCLUSIONS: Our findings suggest that antiangiogenic factors such as VEGF165b, together with proinflammatory and profibrotic factors secreted by platelets, can contribute to the progression of peripheral microvascular damage, defective vascular repair, and fibrosis in patients with SSc.