Association among Terminally Differentiated T Cells, Frailty, and Dependency in a Group of Cuban Centenarians.

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

Aging and chronic inflammation: highlights from a multidisciplinary workshop.

Aging is a gradual, continuous series of natural changes in biological, physiological, immunological, environmental, psychological, behavioral, and social processes. Aging entails changes in the immune system characterized by a decrease in thymic output of naïve lymphocytes, an accumulated chronic antigenic stress notably caused by chronic infections such as cytomegalovirus (CMV), and immune cell senescence with acquisition of an inflammatory senescence-associated secretory phenotype (SASP). For this reason, and due to the SASP originating from other tissues, aging is commonly accompanied by low-grade chronic inflammation, termed "inflammaging". After decades of accumulating evidence regarding age-related processes and chronic inflammation, the domain now appears mature enough to allow an integrative reinterpretation of old data. Here, we provide an overview of the topics discussed in a recent workshop "Aging and Chronic Inflammation" to which many of the major players in the field contributed. We highlight advances in systematic measurement and interpretation of biological markers of aging, as well as their implications for human health and longevity and the interventions that can be envisaged to maintain or improve immune function in older people.

Immunosenescence and inflammatory markers in Cuban centenarians: implications for survival.

Centenarians are the best example of successful aging in humans. This work aimed to understand if immune status is associated with survival in Cuban centenarians. In a previous study, our group enrolled 43 centenarians and evaluated their immune status and functional capacity. 41 out of 43 recruited centenarians received follow-up phone calls, during a period of 2 years. Absolute CD4 + T cell count was higher among survivors, while the frequency of CD8 + CCR7-CD45RA + , CD8 + CD45RA + CD28-, and CD4 + CD28- T cells was higher among non-survivors. We also found that higher frequencies of terminally differentiated T cells were related to a higher risk of death, while centenarians with higher frequencies of T cells were more likely to survive. Surprisingly, neither serum inflammatory markers nor frailty/dependency was associated with survival. Our preliminary study suggests that immuno-senescence markers, but not inflammaging or functional capacity, are associated with survival beyond 100 years in a small group of Cuban centenarians.

Chemotherapy-induced differential cell cycle arrest in B-cell lymphomas affects their sensitivity to Wee1 inhibition.

Chemotherapeutic agents, e.g., cytarabine and doxorubicin, cause DNA damage. However, it remains unknown whether such agents differentially regulate cell cycle arrest in distinct types of B-cell lymphomas, and whether this phenotype can be exploited for developing new therapies. We treated various types of B cells, including primary and B lymphoma cells, with cytarabine or doxorubicin, and determined DNA damage responses, cell cycle regulation and sensitivity to a Wee1 inhibitor. We found that cyclin A2/B1 upregulation appears to be an intrinsic programmed response to DNA damage; however, different types of B cells arrest in distinct phases of the cell cycle. The Wee1 inhibitor significantly enhanced the apoptosis of G2 phase-arrested B-cell lymphomas by inducing premature entry into mitosis and mitotic catastrophe, whereas it did not affect G1/S-phase-arrested lymphomas. Cytarabine-induced G1-arrest can be converted to G2-arrest by doxorubicin treatment in certain B-cell lymphomas, which correlates with newly acquired sensitivity to the Wee1 inhibitor. Consequently, the Wee1 inhibitor together with cytarabine or doxorubicin inhibited tumor growth in vitro and in vivo more effectively, providing a potential new therapy for treating B-cell lymphomas. We propose that the differential cell cycle arrest can be exploited to enhance the chemosensitivity of B-cell lymphomas.

[Paniculitis as manifestation of prolonged febrile syndrome: Case report]. / Paniculitis como manifestación de síndrome febril prolongado en pediatría: Caso clínico.

Fever of unknown origin (FUO) is defined as fever over 7 to 10 days without a diagnosis despite a complete initial study. The most frequent causes are infections, autoimmune and tumors. Even though most cases are self-limited there is a minority that has an underlying etiology with an ominous forecast, encouraging a systematized study. OBJECTIVE: To report a rare case of a boy who presented fever of unknown origin associated to panniculitis and was diagnosed of subcutaneous panniculitis-like-T cell lymphoma and to emphasis the importance of a sequential study of FUO, in order to reach a diagnosis in patients who need a timely intervention. CLINICAL CASE: A ten year old boy, previously healthy, presented subcutaneous nodular lesions of 2 month of evolution, located in abdominal region and extremities, given few symptoms, associated with prolonged fever. He was hospitalized for proper study, in first instance infectious and immune causes were discarded and through lesions biopsy the diagnose of subcutaneous panniculitis-like-T cell lymphoma was reached. CONCLUSION: When FUO is diagnosed, most prevalent causes must be discarded. Then, differential diagnosis, such as immune and neoplasic etiologies, have to be considered. If FUO is associated to elemental nodular lesions, biopsy must be indicated early, in order to find potential malignant cases, avoiding therapeutic delay.

CXCL14 suppresses human papillomavirus-associated head and neck cancer through antigen-specific CD8+ T-cell responses by upregulating MHC-I expression.

Evasion of the host immune responses is critical for both persistent human papillomavirus (HPV) infection and associated cancer progression. We have previously shown that expression of the homeostatic chemokine CXCL14 is significantly downregulated by the HPV oncoprotein E7 during cancer progression. Restoration of CXCL14 expression in HPV-positive head and neck cancer (HNC) cells dramatically suppresses tumor growth and increases survival through an immune-dependent mechanism in mice. Although CXCL14 recruits natural killer (NK) and T cells to the tumor microenvironment, the mechanism by which CXCL14 mediates tumor suppression through NK and/or T cells remained undefined. Here we report that CD8+ T cells are required for CXCL14-mediated tumor suppression. Using a CD8+ T-cell receptor transgenic model, we show that the CXCL14-mediated antitumor CD8+ T-cell responses require antigen specificity. Interestingly, CXCL14 expression restores major histocompatibility complex class I (MHC-I) expression on HPV-positive HNC cells downregulated by HPV, and knockdown of MHC-I expression in HNC cells results in loss of tumor suppression even with CXCL14 expression. These results suggest that CXCL14 enacts antitumor immunity through restoration of MHC-I expression on tumor cells and promoting antigen-specific CD8+ T-cell responses to suppress HPV-positive HNC.

The Elevated Rate of Cesarean Section and Its Contribution to Non-Communicable Chronic Diseases in Latin America: The Growing Involvement of the Microbiota.

The current recommendation of the World Health Organization (WHO) regarding cesarean section (C-section) is that this clinical practice should be carried out only under specific conditions, when the health or life of the mother/newborn dyad is threatened, and that its use should not exceed 10-15% of the total deliveries. However, over the last few decades, the frequency of C-section delivery in medium- and high-income countries has rapidly increased worldwide. This review describes the evolution of this procedure in Latin American countries, showing that today more than half of newborns in the region are delivered by C-section. Given that C-section delivery is more expensive than vaginal delivery, its use has increased more rapidly in the private than the public sector; nevertheless, the prevalence of C-section deliveries in the public sector is higher than the WHO's recommendations and continues to increase, representing a growing challenge for Latin America. Although the medium- and long-term consequences of C-section delivery, as opposed to vaginal delivery, on the infant health are unclear, epidemiological studies suggest that it is associated with higher risk of developing asthma, food allergy, type 1 diabetes, and obesity during infancy. These findings are important, as the incidence of these diseases in the Latin American pediatric population is also increasing, particularly obesity. Although the link between these diseases and delivery mode remains controversial, recent studies indicate that the establishment of the gut microbiota is delayed in infants born by C-section during the postnatal period, i.e., during a critical developmental window for the maturation of the newborn's immune system. This delay may favor the subsequent development of inflammatory and metabolic disorders during infancy. Accordingly, from a public health perspective, it is important to slow down and eventually reverse the pattern of increased C-section use in the affected populations.

Obesidad infantil y asma bronquial / Child Obesity and bronchial asthma

Obesity and bronchial asthma have suffered a sustained increase in its prevalence worldwide. The relationship between both entities has been widely studied especially in the adult population. Obesity has been shown to be a risk factor for new bronchial asthma diagnoses and vice versa; and that both alter the evolution of the other. The relationship between them is based on systemic inflammatory factors and cardiometabolic factors rather than the fat load. In this review we will focus on the pathophysiology of metabolic and immunological alterations that link both diseases.

Obesidad y asma bronquial han sufrido un aumento sostenido de su prevalencia a nivel mundial. La relación entre ambas entidades ha sido ampliamente estudiada especialmente en población adulta. Se ha demostrado que obesidad es un factor de riesgo de nuevos diagnósticos de asma bronquial y viceversa; y que ambas alteran la evolución de la otra. La relación entre ellas se sustenta en factores inflamatorios sistémicos y factores cardiometabólicos más que en la carga adiposa. En esta revisión nos centraremos en la fisiopatología de las alteraciones metabólicas e inmunológicas que ligan ambas enfermedades.

Epidemiología de las intoxicaciones accidentales en el servicio de pediatría del Hospital Dr. Gustavo Fricke / Epidemiology of accidental poisonings in the Dr. Gustavo Fricke Hospital pediatric unit

Introducción: Las intoxicaciones son una causa frecuente de consulta al servicio de urgencia, particularmente en niños. La incidencia y características de éstas varían de acuerdo al país y a la edad del paciente. Objetivos: Describir el perfil epidemiológico de los pacientes con el diagnóstico de intoxicación hospitalizados en un servicio de pediatría. Diseño: Estudio descriptivo retrospectivo. Materiales y métodos: Se revisó los registros anuales de ingresos y egresos del servicio de pediatría desde abril del 2012 a diciembre del 2015 y se incluyó a aquellos pacientes con diagnóstico de intoxicación hasta los 10 años de edad. Se realizó análisis descriptivo según características generales de los pacientes, tipo de tóxico y aparición de complicaciones, entre otras variables. Resultados: Fueron analizados 60 casos. De éstos, un 61,67% correspondió a pacientes de sexo femenino y la mayoría fueron preescolares (53,33%). El lugar de ocurrencia fue el hogar en un 93,33% y el tipo de tóxico más frecuentemente involucrado fueron los medicamentos (70%), seguidos por los productos de uso doméstico (16,67%) y los pesticidas (6,67%). Discusión y conclusiones: Los resultados obtenidos son similares a los reportados en la literatura nacional e internacional en cuanto a frecuencia por edad y tipo de tóxico. En la mayoría de los casos el evento de intoxicación ocurrió en el hogar e involucró a medicamentos, lo que sugiere que el manejo de esta problemática de salud debe ser enfocado a la prevención y a la educación acerca del tema tanto a padres como a cuidadores

Introduction: Poisonings are a frequent cause of emergency department visits, particularly in children. The incidence and characteristics of these vary with the country and the patient´s age. Objectives: To describe the epidemiological profile of patients presenting with poisoning who were hospitalized in the pediatric unit. Design: Descriptive and retrospective study. Materials and methods: The annual records of all patients hospitalized in the pediatric unit between 2012 and 2015 were revised. The study included patients up to 10 years of age with a diagnosis of poisoning. Descriptive analysis was performed listing the patient's general characteristics, toxin type, and the occurrence of complications among other variables. Results: 60 cases were analyzed. Of these, 61.67% were female and most were pre-school children (53.33%). 93.33% of poisonings occurred in the home and the most frequently involved toxin types were medications (70%), followed by household products (16.67%) and pesticides (6.67%). Discussion and conclusions: The results are similar in frequency by age and toxin types to those reported in the national and international literature. In most cases the intoxication happened at home and involved medications, suggesting that the management of this health issue should be focused on prevention and education to both parents and caregivers.

Paniculitis como manifestación de síndrome febril prolongado en pediatría: Caso clínico / Paniculitis as manifestation of prolonged febrile syndrome: Case report

El síndrome febril prolongado (SFP) se define en pediatría como la presencia de un episodio febril de al menos 7-10 días de evolución sin diagnóstico etiológico pese a un estudio inicial completo. La etiología más frecuente es la infecciosa, seguida por causas inmunoreumatológicas y neoplásicas. En la mayoría de los casos la evolución suele ser benigna y autolimitada, sin embargo una minoría presenta una causa subyacente con pronóstico sombrío, determinando necesidad de un estudio sistematizado. Objetivo: Presentar caso clínico de un escolar con SFP asociado a paniculitis y enfatizar importancia de estudio secuencial de SFP para pesquisar pacientes que requieren intervención oportuna. Caso clínico: Escolar de sexo masculino, 10 años de edad, previamente sano, quien consultó por cuadro de 2 meses de evolución, caracterizado por aparición de lesiones nodulares en abdomen y extremidades, poco sintomáticas, asociado a fiebre prolongada. Se hospitalizó para estudio, descartando causa infecciosa y reumatológica. Se confirmó diagnóstico de linfoma paniculítico de células T mediante biopsia y análisis histológico e inmunohistoquímico de las lesiones. Conclusiones: Al diagnosticar SFP se debe descartar causas más prevalentes (infecciosa) y luego plantear como diagnóstico diferencial etiología reumatológica y neoplásica. Si SFP se asocia a lesiones elementales nodulares, plantear precozmente la biopsia de modo de pesquisar potencial causa maligna y evitar retraso terapéutico.

Fever of unknown origin (FUO) is defined as fever over 7 to 10 days without a diagnosis despite a complete initial study. The most frequent causes are infections, autoimmune and tumors. Even though most cases are self-limited there is a minority that has an underlying etiology with an ominous forecast, encouraging a systematized study. Objective: To report a rare case of a boy who presented fever of unknown origin associated to panniculitis and was diagnosed of subcutaneous panniculitis-like-T cell lymphoma and to emphasis the importance of a sequential study of FUO, in order to reach a diagnosis in patients who need a timely intervention. Clinical case: A ten year old boy, previously healthy, presented subcutaneous nodular lesions of 2 month of evolution, located in abdominal region and extremities, given few symptoms, associated with prolonged fever. He was hospitalized for proper study, in first instance infectious and immune causes were discarded and through lesions biopsy the diagnose of subcutaneous panniculitis-like-T cell lymphoma was reached. Conclusion: When FUO is diagnosed, most prevalent causes must be discarded. Then, differential diagnosis, such as immune and neoplasic etiologies, have to be considered. If FUO is associated to elemental nodular lesions, biopsy must be indicated early, in order to find potential malignant cases, avoiding therapeutic delay.