YAP localization mediates mechanical adaptation of human cancer cells during extravasation in vivo.

Biophysical profiling of primary tumors has revealed that individual tumor cells fall along a highly heterogeneous continuum of mechanical phenotypes. One idea is that a subset of tumor cells is "softer" to facilitate detachment and escape from the primary site, a step required to initiate metastasis. However, it has also been postulated that cells must be able to deform and generate sufficient force to exit into distant sites. Here, we aimed to dissect the mechanical changes that occur during extravasation and organ colonization. Using multiplexed methods of intravital microscopy and optical tweezer based active microrheology, we obtained longitudinal images and mechanical profiles of cells during organ colonization in vivo. We determined that cells were softer, more liquid like upon exit of the vasculature but stiffened and became more solid like once in the new organ microenvironment. We also determined that a YAP mediated mechanogenotype influenced the global dissemination in our in vivo and in vitro models and that reducing mechanical heterogeneity could reduce extravasation. Moreover, our high throughput analysis of mechanical phenotypes of patient samples revealed that this mechanics was in part regulated by the external hydrodynamic forces that the cancer cells experienced within capillary mimetics. Our findings indicate that disseminated cancer cells can keep mutating with a continuum landscape of mechano-phenotypes, governed by the YAP-mediated mechanosensing of hydrodynamic flow.

Organ specific microenvironmental MR1 expression in cutaneous melanoma.

The microenvironment is an important regulator of intertumoral trafficking and activity of immune cells. Understanding how the immune system can be tailored to maintain anti-tumor killing responses in metastatic disease remains an important goal. Thus, immune mediated eradication of metastasis requires the consideration of organ specific microenvironmental cues. Using a xenograft model of melanoma metastasis in adult zebrafish, we perturbed the dynamic balance between the infiltrating immune cells in the metastatic setting using a suite of different transgenic zebrafish. We employed intravital imaging coupled with metabolism imaging (FLIM) to visualize and map the organ specific metabolism with near simultaneity in multiple metastatic lesions. Of all the MHC complexes examined for brain and skeletal metastases, we determined that there is an organ specific expression of mhc1uba (human ortholog, MR1) for both the melanoma cells and the resident and infiltrating immune cells. Specifically, immune clusters did not express mhc1uba in brain metastatic lesions in immune competent fish. Finally, the differential immune response drove organ specific metabolism where tumor glycolysis was increased in brain metastases compared to skeletal and parental lines as measured using fluorescence lifetime imaging microscopy (FLIM). As MR1 belongs to the MHC class I molecules and is a target of immunotherapeutic drugs, we believe that our data presents an opportunity to understand the relationship between organ specific tumor metabolism and drug efficacy in the metastatic setting.

Disseminated Mucocutaneous Histoplasmosis Diagnosed in the United Kingdom, Presumably as a Result of Recrudescence Decades After Primary Infection Following Immunosuppressive Treatment of Its Mimic, Sarcoidosis: A Multidisciplinary Cautionary Tale.

ABSTRACT: Histoplasmosis is a dimorphic fungal infection, which is rare outside endemic pockets in North, Central, and South America, Asia, and Africa. Herein, we describe a woman in her 80s living in the Scottish Borders region of the United Kingdom with a recent diagnosis of granulomatous rosacea, who on receiving escalating immunosuppression for suspected sarcoidosis, and long-standing rheumatoid arthritis developed a striking eruption involving her eyelids along with painful ulceration of the oral and nasal mucosa. Histopathologic examination of the skin and mucosal lesions demonstrated granulomatous inflammation with numerous yeast forms of fungal organisms with morphological characteristics of Histoplasma species. This was confirmed to be H. capsulatum on fungal culture and direct panfungal polymerase chain reaction assay. Although the patient had not left the United Kingdom for more than 20 years, she gave a travel history involving multiple trips to countries where histoplasmosis is known to occur, before that. This case exemplifies the challenges involved in making a diagnosis of histoplasmosis in nonendemic regions for both clinicians and pathologists alike. In this particular patient, the diagnostic difficulties were compounded by the clinicopathological overlap with other cutaneous and systemic granulomatous disorders like granulomatous rosacea and suspected sarcoidosis and also the exceptionally long latency period between the purported historical primary infection and recent recrudescence. We highlight this unusual case to increase an awareness of histoplasmosis, which is very rare in nonendemic regions like the United Kingdom and involves cases acquired during residence in or travel to endemic areas, to ensure its prompt recognition and treatment.

Más allá de los límites de la disciplina con niños prematuros: una reflexión holística / Beyond the Limits of Discipline with Premature Children: A Holistic Reflection / Além dos limites da disciplina com bebés prematuros: uma reflexão holística

Introducción. En este artículo se presenta una reflexión sobre la necesidad de tener una visión holística en la problemática de la prematurez, para que los equipos del área de salud puedan tener una comprensión de la multiplicidad de factores presentes en el parto prematuro, y sus consecuencias para el menor, la madre, los familiares y el personal de salud involucrado. Tema de reflexión. El tema se sustenta en dos investigaciones realizadas con las madres, los padres y los niños beneficiarios del Programa Madre Canguro en un hospital del Estado, en dos momentos, 2012 y 2014, con algunos de los autores del presente artículo. Conclusiones. Además de la revisión de la literatura científica relacionada con el tema y la problemática, se concluye que, bajo una mirada holística, se comprende de manera integral la problemática y se propicia una mejor comunicación con los padres; con el equipo de la atención en salud, se logra un manejo transdisciplinario, superando los objetos de estudios aislados. Se da así un abordaje integrador y significativo en la cotidianidad de cada actor, desde la piel, con el Programa Madre Canguro, hasta la racionalidad de la ciencia.

Introduction. This article presents a reflection on the need for a holistic view of the problem of premature births, so that healthcare teams can understand the multiplicity of factors present in premature births, and its consequences for the minor, the mother, the family members, and the healthcare staff involved. Topic of reflection. The topic is based on two investigations carried out with mothers, fathers, and children's beneficiaries of the Mother Kangaroo Program in a State hospital, at two moments, 2012 and 2014, with some of the authors of this article. Conclusions. In addition to the review of the scientific literature related to the topic and the problem, it is concluded that, under a holistic view, the problem is understood in a comprehensive way and better communication with the parents is encouraged. With the healthcare team, cross-disciplinary handling is achieved, overcoming the objects of isolated studies. As such, there is an integrative and significant approach in the daily life of each actor, from the skin, with the Mother Kangaroo Program, to the rationality of science.

Introdução. Este artigo apresenta uma reflexão sobre a necessidade de se ter uma visão holística da problemática da prematuridade, para que as equipes da área da saúde possam ter uma compreensão da multiplicidade de fatores presentes no parto prematuro, e suas consequências para a criança, a mãe, os familiares e o pessoal de saúde envolvido. Tópico de reflexão. O tema é baseado em duas pesquisas realizadas com mães, pais e filhos beneficiários do Programa Mãe Canguru em um hospital estadual, em dois momentos, 2012 e 2014, com alguns dos autores deste artigo. Conclusões. Além da revisão da literatura científica relacionada ao tópico e ao problema, conclui-se que, sob uma visão holística, o problema é plenamente compreendido e incentiva-se uma melhor comunicação com os pais; com a equipe de saúde, consegue-se uma gestão transdisciplinar, superando os objetos de estudos isolados. Isto proporciona uma abordagem integradora e significativa no cotidiano de cada ator, desde a pele, com o Programa Mãe Canguru, até a racionalidade da ciência.

A conserved role for the ALS-linked splicing factor SFPQ in repression of pathogenic cryptic last exons.

The RNA-binding protein SFPQ plays an important role in neuronal development and has been associated with several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease. Here, we report that loss of sfpq leads to premature termination of multiple transcripts due to widespread activation of previously unannotated cryptic last exons (CLEs). These SFPQ-inhibited CLEs appear preferentially in long introns of genes with neuronal functions and can dampen gene expression outputs and/or give rise to short peptides interfering with the normal gene functions. We show that one such peptide encoded by the CLE-containing epha4b mRNA isoform is responsible for neurodevelopmental defects in the sfpq mutant. The uncovered CLE-repressive activity of SFPQ is conserved in mouse and human, and SFPQ-inhibited CLEs are found expressed across ALS iPSC-derived neurons. These results greatly expand our understanding of SFPQ function and uncover a gene regulation mechanism with wide relevance to human neuropathologies.

Rasch analysis of the WHOQOL-BREF in older adults from Bucaramanga and Manizales / Análisis rasch del whoqol-bref en adultos mayores de bücaramanga y manizales

Resumen El objetivo de este estudio es valuar las evidencias de validez de una aproximación unidimensional al WHOQOL-BREF en adultos mayores. Se aplicó el instrumento a una muestra probabilística de 510 adultos mayores de Bucaramanga y Manizales adscritos a centros día o centros vida. Se realizaron análisis Rasch de ajuste de categorías de respuesta, ajuste de los ítems y de las personas, funcionamiento diferencial de los ítems, unidimensionalidad y confiabilidad. Fue necesario colapsar las categorías de respuesta de cinco a cuatro opciones. Todos los ítems se ajustaron de forma adecuada al modelo de Rasch, al igual que una alta proporción de adultos mayores. Se identificó funcionamiento diferencial tipo C en cinco ítems, aunque se pudo establecer que este tiene un bajo impacto en la medida. La consistencia interna fue de 0,92, y la confiabilidad de los ítems de 0,98. Se presenta el mapa de Wright. A partir del WHOQOL-BREF se puede obtener una medida unidimensional a nivel de intervalo de calidad de vida en adultos mayores.

Abstract This research aimed to evaluate the validity evidences of a unidimensional approach to WHOQOL-BEF in older adults. The instrument was applied to a probabilistic sample of 510 older adults from Bucaramanga and Manizales beneficiaries of day care institutions. Rasch analyses of category function, item and person fit, differential item functioning, unidimensionality and reliability analyses were performed. The category structure had to be collapsed from five to four choices. All items and a high proportion of older adults showed adequate adjustment to the Rasch model. Differential item functioning was identified in five items, although their impact on overall measure was low. Internal consistency was 0.92 and item reliability 0.98. Wright's map is presented. A unidimensional, interval-scale measure of quality of life can be obtained from the WHOQOL-BREF for older adults.

The factor Xa inhibitor rivaroxaban reduces cardiac dysfunction in a mouse model of myocardial infarction.

INTRODUCTION: Rivaroxaban selectively inhibits factor Xa (FXa), which plays a central role in blood coagulation. In addition, FXa activates protease-activated receptor-2 (PAR-2). We have shown that PAR-2-/- mice exhibit less cardiac dysfunction after cardiac injury. MATERIAL AND METHODS: Wild-type (WT) and PAR-2-/- mice were subjected to left anterior descending artery (LAD) ligation to induce cardiac injury and heart failure. Mice received either placebo or rivaroxaban chow either starting at the time of surgery or 3 days after surgery and continued up to 28 days. Cardiac function was measured by echocardiography pre-surgery and 3, 7 and 28 days after LAD ligation. We also measured anticoagulation, intravascular thrombi, infarct size, cardiac hypertrophy and inflammation at various times. RESULTS: Rivaroxaban increased the prothrombin time and inhibited the formation of intravascular thrombi in mice subjected to LAD ligation. WT mice receiving rivaroxaban immediately after surgery had similar infarct sizes at day 1 as controls but exhibited significantly less impairment of cardiac function at day 3 and beyond compared to the placebo group. Rivaroxaban also inhibited the expansion of the infarct at day 28. Rivaroxaban did not significantly affect the expression of inflammatory mediators or a neutrophil marker at day 2 after LAD ligation. Delaying the start of rivaroxaban administration until 3 days after surgery failed to preserve cardiac function. In addition, rivaroxaban did not reduce cardiac dysfunction in PAR-2-/- mice. CONCLUSIONS: Early administration of rivaroxaban preserves cardiac function in mice after LAD ligation.

Características de la personalidad de los padres o cuidadores de los menores que asisten a controles de salud en entidades de salud públicas y privadas (2013-2015) / Personality traits of parents or caregivers of children attending health check-ups at public and private healthcare entities (2013-2015) / Características da personalidade dos pais ou cuidadores acompanhantes de menores nas consultas periódicas em instituições de saúde públicas e privadas (2013-2015)

Introducción. El estudio de la personalidad resulta complejo por una multiplicidad de factores (biológicos, psicológicos, sociales, culturares, entre otros). Los rasgos indican personalidad funcional (saludable) o disfuncional (patológica). Los estudios de personalidad más destacados se enfocan en trastornos o alteraciones de la personalidad. En el 2017, la Organización Mundial de la Salud (OMS) reportó una mayor prevalencia del trastorno afectivo bipolar (60 millones de pacientes), la esquizofrenia y otras psicosis (21 millones de pacientes), y la demencia (47,5 millones de pacientes). Sin embargo, son escasos los estudios de salud mental en personas con personalidad funcional, como lo plantea esta investigación. La OMS afirma que la salud mental es más que la ausencia de trastornos mentales y es parte integral de la salud, pues no hay salud sin salud mental. El objetivo es describir los rasgos de personalidad de los padres que asisten con sus hijos a controles de salud en entidades de salud públicas y privadas (2013-2015). Metodología. Estudio descriptivo de corte transversal que evalúa 14 variables de personalidad; muestra por conveniencia: 145 padres que asisten a los controles de salud con sus hijos de hospitales locales, públicos de Girón y Bucaramanga y la empresa privada de carácter social, "El Comité de Rehabilitación" (Medellín). Se recolectó información con el cuestionario sociodemográfico y el Test CUIDA (Cuestionario para la Evaluación de Adoptantes, Cuidadores, Tutores y Mediadores). Resultados. El 93.1 % de los padres o cuidadores son mujeres y el 6.9 %, hombres; el 84.8 % está entre los 30 y 59 años de edad; sus estratos socioeconómicos son 1, 2 y 3; el 50 % son madres cabeza de hogar. Los padres o cuidadores con personalidad funcional, presentaron debilidades en los puntajes de las pruebas, pues manifestaron dependencia emocional, baja autoestima, poca tolerancia a la frustración, poca flexibilidad, dificultad para establecer vínculos afectivos y baja capacidad de resolución de duelo, entre otros. Pocos padres tuvieron puntajes altos en los factores que benefician el cuidado de sus hijos; entre el 0 % y el 22.9 %. Conclusiones. En la muestra, compuesta en su mayoría por madres cabeza de hogar, pocas lograron puntajes altos en las pruebas; aquellos que se esperaban en personas con personalidad funcional. Por el contrario, predominaron los puntajes bajos, que poco favorecen el cuidado de la salud de los hijos. Las características de personalidad funcionales o no, son transmitidas en el proceso de crianza maternal más que paternal. [Díaz-Gordon P, Ortega-Ortíz ME, Díaz-Cadavid D, Naranjo-García AS. Características de la personalidad de los padres o cuidadores de los menores que asisten a controles de salud en entidades de salud públicas y privadas (2013-2015). MedUNAB. 2018;21(2):12-28. doi:10.29375/01237047.2424].

Introduction. The study of personality is complex due to a multiplicity of factors (biological, psychological, social and cultural, among others). Traits indicate a personality that is functional (healthy) or dysfunctional (pathological). The most outstanding personality studies focus on personality disorders or abnormalities. In 2017, the World Health Organization (WHO) reported a higher prevalence of bipolar affective disorder (60 million patients), schizophrenia and other psychoses (21 million patients), and dementia (47.5 million patients). However, there are few studies of mental health in people with a functional personality, as considered in this research. The WHO assets that mental health is more than the absence of mental disorders and it is an integral part of health, since there is no health without mental health. The objective is to describe the personality traits of parents attending health check-ups with their children at public and private healthcare entities (2013-2015). Methodology. Descriptive cross-sectional study that assesses 14 personality variables; convenience sample: 145 parents attending health check-ups with their children at local public hospitals in Girón and Bucaramanga, and private social company "The Rehabilitation Committee" (Medellín). Information was gathered using the sociodemographic questionnaire and the CUIDA Test (Questionnaire for the Assessment of Adoptive Parents, Caregivers, Guardians and Mediators). Results. 93.1% of the parents or caregivers are women and 6.9% are men; 84.8% aged between 30 and 59; their socioeconomic levels are 1, 2 and 3; 50% are single mothers. The parents or caregivers with a functional personality showed weaknesses on test scores, as they showed emotional dependency, low self-esteem, low frustration tolerance, limited flexibility, difficulty in establishing emotional ties and low grief resolution capacity, among others. Few parents had high scores on the factors that benefit the care of their children: between 0% and 22.9%. Conclusions. In the sample, mostly made up of single mothers, few achieved the high-test scores that were expected in people with a functional personality. On the contrary, low scores predominated, which are not very favorable for the care for children's health. Personality traits, whether they are functional or not, are transmitted more in the child rearing process by mothers than by fathers. [Díaz-Gordon P, Ortega-Ortíz ME, Díaz-Cadavid D, Naranjo-García AS. Personality traits of parents or caregivers of children attending health checkups at public and private healthcare entities (2013-2015). MedUNAB.2018;21(2):12-28. doi:10.29375/01237047.2424].

Introdução. O estudo da personalidade é complexo por uma multiplicidade de fatores (biológicos, psicológicos, sociais, culturais, entre outros). Traços indicam personalidade funcional (saudável) ou disfuncional (patológica). Os estudos de personalidade mais destacados focam em transtornos ou alterações da personalidade. Em 2017, a Organização Mundial da Saúde (OMS) relatou uma maior prevalência de transtorno afetivo bipolar (60 milhões de pacientes), esquizofrenia e outras psicoses (21 milhões de pacientes), e demência (47,5 milhões de pacientes). Entretanto, existem poucos estudos de saúde mental em pessoas com personalidade funcional, como sugere esta pesquisa. A OMS afirma que a saúde mental é mais que a ausência de transtornos mentais e é uma parte importante da saúde, já que não há saúde sem saúde mental. O objetivo é descrever os traços de personalidade dos pais que acompanham seus filhos nas consultas periódicas de saúde em instituições de saúde públicas e privadas (2013-2015). Métodos. Estudo descritivo transversal que avalia 14 variáveis de personalidade; amostra por conveniência: 145 pais que acompanham seus filhos nas consultas periódicas ou check-up de saúde em hospitais locais públicos de Girón e Bucaramanga, e na empresa privada de natureza social "El Comité de Rehabilitación" (Medellín). As informações foram coletadas usando um questionário sociodemográfico e o Questionário para Avaliação de Adotantes, Cuidadores, Tutores e Mediadores ou Teste CUIDA (por suas siglas em espanhol). Resultados.93,1% dos pais ou cuidadores são mulheres e 6,9% homens; 84,8% têm entre 30 e 59 anos de idade; suas classes socioeconômicas são 1, 2 e 3; 50% são mães chefes de família. Os pais ou cuidadores com personalidade funcional, mostraram fraquezas nos resultados dos testes, pois manifestaram ter dependência emocional, baixa autoestima, pouca tolerância à frustração, inflexibilidade, dificuldade em estabelecer laços afetivos e pouca capacidade para lidar com o processo de luto, entre outros. Poucos pais tiveram altas pontuações nos fatores que beneficiam o cuidado dos filhos; entre 0% e 22,9%. Conclusões: Na amostra, composta principalmente por mães chefes de família, poucas delas conseguiram altas pontuações nos testes, como esperado em pessoas com personalidade funcional. Pelo contrário, predominaram as pontuações baixas, o que não favorece a atenção à saúde dos filhos. As características da personalidade funcional, ou não, são transmitidas no processo de criação materna mais do que paterna. [Díaz-Gordon P, Ortega-Ortíz ME, Díaz-Cadavid D, Naranjo-García AS. Características da personalidade dos pais ou cuidadores acompanhantes de menores nas consultas periódicas em instituições de saúde públicas e privadas (2013-2015). MedUNAB. 2018;21(2):12-28. doi:10.29375/01237047.2424].

Personality traits of parents or caregivers of children attending health check-ups at public and private healthcare entities (2013-2015) / Características de la personalidad de los padres o cuidadores de los menores que asisten a controles de salud en entidades de salud públicas y privadas (2013-2015) / Características da personalidade dos pais ou cuidadores acompanhantes de menores nas consultas periódicas em instituições de saúde públicas e privadas (2013-2015)

Introduction. The study of personality is complex due to a multiplicity of factors (biological, psychological, social and cultural, among others). Traits indicate a personality that is functional (healthy) or dysfunctional (pathological). The most outstanding personality studies focus on personality disorders or abnormalities. In 2017, the World Health Organization (WHO) reported a higher prevalence of bipolar affective disorder (60 million patients), schizophrenia and other psychoses (21 million patients), and dementia (47.5 million patients). However, there are few studies of mental health in people with a functional personality, as considered in this research. The WHO assets that mental health is more than the absence of mental disorders and it is an integral part of health, since there is no health without mental health. The objective is to describe the personality traits of parents attending health checkups with their children at public and private healthcare entities (2013-2015). Methodology. Descriptive cross-sectional study that assesses 14 personality variables; convenience sample: 145 parents attending health checkups with their children at local public hospitals in Girón and Bucaramanga, and private social company "The Rehabilitation Committee" (Medellín). Information was gathered using the sociodemographic questionnaire and the CUIDA Test (Questionnaire for the Assessment of Adoptive Parents, Caregivers, Guardians and Mediators). Results. 93.1% of the parents or caregivers are women and 6.9% are men; 84.8% aged between 30 and 59; their socioeconomic levels are 1, 2 and 3; 50% are single mothers. The parents or caregivers with a functional personality showed weaknesses on test scores, as they showed emotional dependency, low self-esteem, low frustration tolerance, limited flexibility, difficulty in establishing emotional ties and low grief resolution capacity, among others. Few parents had high scores on the factors that benefit the care of their children: between 0% and 22.9%. Conclusions. In the sample, mostly made up of single mothers, few achieved the high test scores that were expected in people with a functional personality. On the contrary, low scores predominated, which are not very favorable for the care for children's health. Personality traits, whether they are functional or not, are transmitted more in the child rearing process by mothers than by fathers. [Díaz-Gordon P, Ortega-Ortíz ME, Díaz-Cadavid D, Naranjo-García AS. Personality traits of parents or caregivers of children attending health checkups at public and private healthcare entities (2013-2015). MedUNAB.2018;21(2): 29-44. doi:10.29375/01237047.2424].

Introducción. El estudio de la personalidad resulta complejo por una multiplicidad de factores (biológicos, psicológicos, sociales, culturares, entre otros). Los rasgos indican personalidad funcional (saludable) o disfuncional (patológica). Los estudios de personalidad más destacados se enfocan en trastornos o alteraciones de la personalidad. En el 2017, la Organización Mundial de la Salud (OMS) reportó una mayor prevalencia del trastorno afectivo bipolar (60 millones de pacientes), la esquizofrenia y otras psicosis (21 millones de pacientes), y la demencia (47,5 millones de pacientes). Sin embargo, son escasos los estudios de salud mental en personas con personalidad funcional, como lo plantea esta investigación. La OMS afirma que la salud mental es más que la ausencia de trastornos mentales y es parte integral de la salud, pues no hay salud sin salud mental. El objetivo es describir los rasgos de personalidad de los padres que asisten con sus hijos a controles de salud en entidades de salud públicas y privadas (2013-2015). Metodología. Estudio descriptivo de corte transversal que evalúa 14 variables de personalidad; muestra por conveniencia: 145 padres que asisten a los controles de salud con sus hijos de hospitales locales, públicos de Girón y Bucaramanga, y la empresa privada de carácter social, "El Comité de Rehabilitación" (Medellín). Se recolectó información con el cuestionario sociodemográfico y el Test CUIDA (Cuestionario para la Evaluación de Adoptantes, Cuidadores, Tutores y Mediadores). Resultados. El 93.1% de los padres o cuidadores son mujeres y el 6.9%, hombres; el 84.8% está entre los 30 y 59 años de edad; sus estratos socioeconómicos son 1, 2 y 3; el 50% son madres cabeza de hogar. Los padres o cuidadores con personalidad funcional, presentaron debilidades en los puntajes de las pruebas, pues manifestaron dependencia emocional, baja autoestima, poca tolerancia a la frustración, poca flexibilidad, dificultad para establecer vínculos afectivos y baja capacidad de resolución de duelo, entre otros. Pocos padres tuvieron puntajes altos en los factores que benefician el cuidado de sus hijos; entre el 0% y el 22.9%. Conclusiones. En la muestra, compuesta en su mayoría por madres cabeza de hogar, pocas lograron puntajes altos en las pruebas; aquellos que se esperaban en personas con personalidad funcional. Por el contrario, predominaron los puntajes bajos, que poco favorecen el cuidado de la salud de los hijos. Las características de personalidad funcionales o no, son transmitidas en el proceso de crianza maternal más que paternal. [Díaz-Gordon P, Ortega-Ortíz ME, Díaz-Cadavid D, Naranjo-García AS. Características de la personalidad de los padres o cuidadores de los menores que asisten a controles de salud en entidades de salud públicas y privadas (2013-2015). MedUNAB.2018;21(2):29-44. doi:10.29375/01237047.2424].

Introdução. O estudo da personalidade é complexo por uma multiplicidade de fatores (biológicos, psicológicos, sociais, culturais, entre outros). Traços indicam personalidade funcional (saudável) ou disfuncional (patológica). Os estudos de personalidade mais destacados focam em transtornos ou alterações da personalidade. Em 2017, a Organização Mundial da Saúde (OMS) relatou uma maior prevalência de transtorno afetivo bipolar (60 milhões de pacientes), esquizofrenia e outras psicoses (21 milhões de pacientes), e demência (47.5 milhões de pacientes). Entretanto, existem poucos estudos de saúde mental em pessoas com personalidade funcional, como sugere esta pesquisa. A OMS afirma que a saúde mental é mais que a ausência de transtornos mentais e é uma parte importante da saúde, já que não há saúde sem saúde mental. O objetivo é descrever os traços de personalidade dos pais que acompanham seus filhos nas consultas periódicas de saúde em instituições de saúde públicas e privadas (2013-2015). Métodos. Estudo descritivo transversal que avalia 14 variáveis de personalidade; amostra por conveniência: 145 pais que acompanham seus filhos nas consultas periódicas ou check-up de saúde em hospitais locais públicos de Girón e Bucaramanga, e na empresa privada de natureza social "El Comité de Rehabilitación" (Medellín). As informações foram coletadas usando um questionário sociodemográfico e o Questionário para Avaliação de Adotantes, Cuidadores, Tutores e Mediadores ou Teste CUIDA (por suas siglas em espanhol). Resultados. 93.1% dos pais ou cuidadores são mulheres e 6.9% homens; 84,8% têm entre 30 e 59 anos de idade; suas classes socioeconômicas são 1, 2 e 3; 50% são mães chefes de família. Os pais ou cuidadores com personalidade funcional, mostraram fraquezas nos resultados dos testes, pois manifestaram ter dependência emocional, baixa autoestima, pouca tolerância à frustração, inflexibilidade, dificuldade em estabelecer laços afetivos e pouca capacidade para lidar com o processo de luto, entre outros. Poucos pais tiveram altas pontuações nos fatores que beneficiam o cuidado dos filhos; entre 0% e 22.9%. Conclusões. Na amostra, composta principalmente por mães chefes de família, poucas delas conseguiram altas pontuações nos testes, como esperado em pessoas com personalidade funcional. Pelo contrário, predominaram as pontuações baixas, o que não favorece a atenção à saúde dos filhos. As características da personalidade funcional, ou não, são transmitidas no processo de criação materna mais do que paterna. [Díaz-Gordon P, Ortega-Ortíz ME, Díaz-Cadavid D, Naranjo-García AS. Características da personalidade dos pais ou cuidadores acompanhantes de menores nas consultas periódicas em instituições de saúde públicas e privadas (2013-2015). MedUNAB.2018;21(2):29-44. doi:10.29375/01237047.2424].

Non-nuclear Pool of Splicing Factor SFPQ Regulates Axonal Transcripts Required for Normal Motor Development.

Recent progress revealed the complexity of RNA processing and its association to human disorders. Here, we unveil a new facet of this complexity. Complete loss of function of the ubiquitous splicing factor SFPQ affects zebrafish motoneuron differentiation cell autonomously. In addition to its nuclear localization, the protein unexpectedly localizes to motor axons. The cytosolic version of SFPQ abolishes motor axonal defects, rescuing key transcripts, and restores motility in the paralyzed sfpq null mutants, indicating a non-nuclear processing role in motor axons. Novel variants affecting the conserved coiled-coil domain, so far exclusively found in fALS exomes, specifically affect the ability of SFPQ to localize in axons. They broadly rescue morphology and motility in the zebrafish mutant, but alter motor axon morphology, demonstrating functional requirement for axonal SFPQ. Altogether, we uncover the axonal function of the splicing factor SFPQ in motor development and highlight the importance of the coiled-coil domain in this process. VIDEO ABSTRACT.

An interstitial deletion within 9p21.3 and extending beyond CDKN2A predisposes to melanoma, neural system tumours and possible haematological malignancies.

Familial atypical multiple mole melanoma syndrome (FAMMM) is characterised by dysplastic naevi, malignant melanoma and pancreatic cancer. Given that large deletions involving CDKN2A (cyclin-dependent kinase inhibitor 2A) account for only 2% of cases, we describe a family that highlights the co-occurrence of both melanoma and neural system tumours to aid clinical recognition and propose a management strategy. A patient with multiple neurofibromas was referred with a provisional diagnosis of neurofibromatosis type 1 (NF1). Prior molecular testing, though, had failed to identify an NF1 mutation by sequencing and multiplex ligation-dependent probe amplification. His family history was significant for multiple in situ/malignant melanomas at young ages and several different cancers reminiscent of an underlying syndrome. A search of the Familial Cancer Database, FaCD Online, highlighted several families with cutaneous melanoma and nervous system tumours who were subsequently identified to have large deletions spanning CDKN2A Although sequencing of CDKN2A and TP53 failed to identify a mutation, a heterozygous CDKN2A deletion was identified by targeted array comparative genomic hybridisation (CGH). Whole-genome oligonucleotide array CGH and SNP analysis identified an interstitial deletion of at least 1.5 Mb within 9p21.3 and spanning approximately 25 genes. Identification of the underlying molecular abnormality permits predictive testing for at-risk relatives. Given the young cancer diagnoses, a surveillance regimen was developed and a clinical team organised for ongoing management so that genetic testing could be offered to both adults and minor children. Surveillance recommendations addressed cancer risks associated with FAMMM, and other cancers exhibited by this family with a large contiguous gene deletion.

Complex Abdominal Wall Reconstruction: A Novel Approach to Postoperative Care Using Physical Medicine and Rehabilitation.

BACKGROUND: Abdominal wall defects remain a significant cause of morbidity and mortality in the United States. Postoperative rehabilitation programs have been used consistently in many surgical subspecialties with exceptional results. Such programs have proven to decrease the total time patients require to resume daily activities. The authors describe a systematic rehabilitation protocol developed with the physical medicine and rehabilitation department that has significantly decreased recurrence rates in patients undergoing complex abdominal wall reconstruction. METHODS: A retrospective analysis was carried out on patients presenting for open repair of an abdominal wall defect performed by a single surgeon. Over a 5-year period, there were 275 consecutive patients divided into two similar groups: one group consisted of 137 patients that received abdominal wall rehabilitation; a second group of 138 patients did not. Patient demographics including body mass index, number of hernia defects, number of previous repairs/abdominal operations, defect size, operative time, blood loss, and postoperative complications including recurrence were collected. RESULTS: Patients enrolled in the abdominal wall rehabilitation program were found to have fewer recurrences at follow-up, with statistical significance compared with those that were not enrolled in the program. CONCLUSIONS: The implementation of the abdominal wall rehabilitation program has resulted in a decrease in recurrence rates following complex abdominal wall hernia repair and reconstruction. This is an innovative system that uses rehabilitation and physical therapy to enhance the psychosocial and occupational status of patients by improving recurrence rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Understanding the implications of the breast cancer pathology report: a case study.

Case Study A.K. is a 50-year-old Caucasian female who was recently diagnosed with breast cancer and is presenting for an opinion regarding adjuvant therapy following a right segmental mastectomy and sentinel lymph node biopsy. The advanced practitioner (AP) in the outpatient oncology treatment center will be expected to participate in the discussion regarding the patient's care plan. In her review of the final pathology, the AP notes that the breast tumor is infiltrating ductal carcinoma, the most common type of invasive breast cancer. It starts in the cells that line the milk ducts in the breast, grows outside the ducts, and often spreads to the lymph nodes. Infiltrating ductal carcinoma represents 65% to 85% of all breast cancer cases (College of American Pathologists, 2011). The breast tumor measures 1.2 × 0.9 × 1.0 cm(3) (T1), is estrogen receptor positive with an H score of 280, is progesterone receptor negative with an H score of 0, and is HER2 equivocal 2+ by immunohistochemistry with a fluorescence in situ hybridization ratio of 1.9 with a copy number of 5. The Ki-67 proliferation rate is 60%, and the nuclear grade is 2/3, with a Nottingham score of 5/9. The surgical margins from the segmental mastectomy are clear by 0.4 mm. There is lymphovascular invasion present. Of two sentinel lymph nodes, none is positive (N0). There has been no workup for metastatic disease. Additionally, the AP notes that the patient is premenopausal and that A.K.'s family history is positive for a maternal aunt diagnosed with a stage I breast cancer at age 75. What is the recommended plan of care for A.K.?

Transplanted bone marrow mononuclear cells and MSCs impart clinical benefit to children with osteogenesis imperfecta through different mechanisms.

Transplantation of whole bone marrow (BMT) as well as ex vivo-expanded mesenchymal stromal cells (MSCs) leads to striking clinical benefits in children with osteogenesis imperfecta (OI); however, the underlying mechanism of these cell therapies has not been elucidated. Here, we show that non-(plastic)-adherent bone marrow cells (NABMCs) are more potent osteoprogenitors than MSCs in mice. Translating these findings to the clinic, a T cell-depleted marrow mononuclear cell boost (> 99.99% NABMC) given to children with OI who had previously undergone BMT resulted in marked growth acceleration in a subset of patients, unambiguously indicating the therapeutic potential of bone marrow cells for these patients. Then, in a murine model of OI, we demonstrated that as the donor NABMCs differentiate to osteoblasts, they contribute normal collagen to the bone matrix. In contrast, MSCs do not substantially engraft in bone, but secrete a soluble mediator that indirectly stimulates growth, data which provide the underlying mechanism of our prior clinical trial of MSC therapy for children with OI. Collectively, our data indicate that both NABMCs and MSCs constitute effective cell therapy for OI, but exert their clinical impact by different, complementary mechanisms. The study is registered at www.clinicaltrials.gov as NCT00187018.

A multidisciplinary clinic for individualizing management of patients at increased risk for breast and gynecologic cancer.

Increasing awareness of the hereditary component of breast and ovarian cancer has driven interest in creating clinics for the patient population at high risk for these cancers. Identifying adequate space and appropriate staff, coordinating multiple providers' schedules, establishing referral criteria, and addressing billing and reimbursement concerns are just some of the issues that are involved in the creation of a multidisciplinary high risk breast and ovarian cancer program. We provide an overview of the clinic structure at the Magee-Womens Hospital High Risk Breast and Ovarian Cancer Program (HRBOCP), which was created in 2002 due to recognition of a need for a more coordinated model of providing care for women at increased risk for breast and ovarian cancer. The goals of the HRBOCP are to evaluate women at high risk for breast and ovarian cancer and to organize their clinical care in a multidisciplinary setting staffed by experts in the field; to provide updates on new data regarding screening recommendations, prevention options, and risk factors pertinent to an individual's cancer risk; to provide ongoing support to patients and to coordinate family communication when appropriate; and to facilitate enrollment in appropriate research studies and registries.

Correlation of Global MicroRNA Expression With Basal Cell Carcinoma Subtype.

Basal cell carcinomas (BCCs) are the most common cancers in the United States. The histologic appearance distinguishes several subtypes, each of which can have a different biologic behavior. In this study, global miRNA expression was quantified by high-throughput sequencing in nodular BCCs, a subtype that is slow growing, and infiltrative BCCs, aggressive tumors that extend through the dermis and invade structures such as cutaneous nerves. Principal components analysis correctly classified seven of eight infiltrative tumors on the basis of miRNA expression. The remaining tumor, on pathology review, contained a mixture of nodular and infiltrative elements. Nodular tumors did not cluster tightly, likely reflecting broader histopathologic diversity in this class, but trended toward forming a group separate from infiltrative BCCs. Quantitative polymerase chain reaction assays were developed for six of the miRNAs that showed significant differences between the BCC subtypes, and five of these six were validated in a replication set of four infiltrative and three nodular tumors. The expression level of miR-183, a miRNA that inhibits invasion and metastasis in several types of malignancies, was consistently lower in infiltrative than nodular tumors and could be one element underlying the difference in invasiveness. These results represent the first miRNA profiling study in BCCs and demonstrate that miRNA gene expression may be involved in tumor pathogenesis and particularly in determining the aggressiveness of these malignancies.

Association of 1,25-dihydroxyvitamin D levels with physical performance and thigh muscle cross-sectional area in chronic kidney disease stage 3 and 4.

BACKGROUND: Declines in 1,25-dihydroxyvitamin D (1,25(OH)2D) levels and physical functioning follow the course of chronic kidney disease (CKD). Although the molecular actions of vitamin D in skeletal muscle are well known, and muscle weakness and atrophy are observed in vitamin D-deficient states, there is little information regarding vitamin D and muscle function and size in CKD. OBJECTIVE: To examine associations of vitamin D with physical performance (PF) and muscle size. DESIGN: Cross-sectional. SETTING: CKD clinic. SUBJECTS: Twenty-six patients (61 ± 13 years, 92% men) with CKD stage 3 or 4. MAIN OUTCOME MEASURES: Gait speed, 6-minute walk, sit-to-stand time, 1-legged balance, and thigh muscle cross-sectional area (MCSA), measured by magnetic resonance imaging (MRI). RESULTS: Overall, 73% were 25-hydroxyvitamin D (25(OH)D) deficient (n = 10) or insufficient (n = 9) (Kidney Disease Outcomes Quality Initiative guidelines). 25(OH)D level was associated with normal gait speed only (r = 0.41, P = .04). Normal and fast gait speed, the distance walked in 6 minutes, and sit-to-stand time were best explained by 1,25(OH)2D and body mass index (P < .05 for all) and 1-legged stand by 1,25(OH)2D (r = 0.40, P < .05) only. There were no associations of age, estimated glomerular filtration rate (eGFR), intact parathyroid hormone (iPTH), or albumin with any PF measures. MCSA was associated with eGFR (r = 0.54, P < .01) only. Variance in MCSA was best explained by a model containing 1,25(OH)2D, plasma Ca²âº, and daily physical activity (by accelerometry) (P < .05 for all). Once these variables were in the model, there was no contribution of eGFR. CONCLUSION: These results suggest that 1,25(OH)2D is a determinant of PF and muscle size in patients with stage 3 and 4 CKD.

Serine protease inhibition reduces post-ischemic granulocyte recruitment in mouse intestine.

Proteases and proteinase-activated receptor (PAR) activation are involved in several intestinal inflammatory conditions. We hypothesized that serine proteases and PAR activation could also modulate the intestinal injury induced by ischemia-reperfusion (I-R). C57Bl/6 mice were subjected to 90 minutes of intestinal ischemia followed or not by reperfusion. Sham-operated animals served as controls. After ischemia, plasma and tissue serine protease activity levels were increased compared to the activity measured in plasma and tissues from sham-operated mice. This increase was maintained or further enhanced after 2 and 5 hours of reperfusion, respectively. Trypsin (25 kDa) was detected in tissues both after ischemia and 2 hours of reperfusion. Treatment with FUT-175 (10 mg/kg), a potent serine protease inhibitor, increased survival after I-R, inhibited tissue protease activity, and significantly decreased intestinal myeloperoxidase (MPO) activity and chemokine and adhesion molecule expression. We investigated whether serine proteases modulate granulocyte recruitment by a PAR-dependent mechanism. MPO levels and adhesion molecule expression were significantly reduced in I-R groups pre-treated with the PAR(1) antagonist SCH-79797 (5 mg/kg) and in Par(2)(-/-)mice, compared, respectively, to vehicle-treated group and wild-type littermates. Thus, increased proteolytic activity and PAR activation play a pathogenic role in intestinal I-R injury. Inhibition of PAR-activating serine proteases could be beneficial to reduce post-ischemic intestinal inflammation.

Host phenotype characteristics and MC1R in relation to early-onset basal cell carcinoma.

Basal cell carcinoma (BCC) incidence is increasing, particularly among adults under the age of 40 years. Pigment-related characteristics are associated with BCC in older populations, but epidemiologic studies among younger individuals and analyses of phenotype-genotype interactions are limited. We examined self-reported phenotypes and melanocortin 1 receptor gene (MC1R) variants in relation to early-onset BCC. BCC cases (n=377) and controls with benign skin conditions (n=390) under the age of 40 years were identified through Yale's Dermatopathology database. Factors most strongly associated with early-onset BCC were skin reaction to first summer sun for 1 hour (severe sunburn vs. tan odds ratio (OR)=12.27, 95% confidence interval (CI)=4.08-36.94) and skin color (very fair vs. olive OR=11.06, 95% CI=5.90-20.74). Individuals with two or more MC1R non-synonymous variants were 3.59 times (95% CI=2.37-5.43) more likely to have BCC than those without non-synonymous variants. All host characteristics and MC1R were more strongly associated with multiple BCC case status (37% of cases) than a single BCC case status. MC1R, number of moles, skin reaction to first summer sun for 1 hour, and hair and skin color were independently associated with BCC. BCC risk conferred by MC1R tended to be stronger among those with darker pigment phenotypes, traditionally considered to be at low risk of skin cancer.

Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma.

Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or NOTCH2 mutations in ~75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression. NOTCH aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key functional domains that abrogate signaling in cell-based assays. Oncogenic gain-of-function mutations in NOTCH1 commonly occur in human T-cell lymphoblastic leukemia/lymphoma and B-cell chronic lymphocytic leukemia. The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies.