Cutting edge: mast cells critically augment myeloid-derived suppressor cell activity.

Myeloid-derived suppressor cells (MDSCs) are primarily recognized for their immunosuppressive properties in malignant disease. However, their interaction with other innate immune cells and their regulation of immune responses, such as in parasitic infection, necessitate further characterization. We used our previously published mouse model of MDSC accumulation to examine the immunoregulatory role of MDSCs in B16 melanoma metastasis and Nippostrongylus brasiliensis infection. In this study, we demonstrate that the activity of MDSCs is dependent on the immune stimuli and subset induced. Monocytic MDSCs predictably suppressed antitumor immune responses but granulocytic MDSCs surprisingly enhanced the clearance of N. brasiliensis infection. Intriguingly, both results were dependent on MDSC interaction with mast cells (MCs), as demonstrated by adoptive-transfer studies in MC-deficient (Kit(Wsh)(/)(Wsh)) mice. These findings were further supported by ex vivo cocultures of MCs and MDSCs, indicating a synergistic increase in cytokine production. Thus, MCs can enhance both immunosuppressive and immunosupportive functions of MDSCs.

IL-4 and TGF-beta 1 counterbalance one another while regulating mast cell homeostasis.

Mast cell responses can be altered by cytokines, including those secreted by Th2 and regulatory T cells (Treg). Given the important role of mast cells in Th2-mediated inflammation and recent demonstrations of Treg-mast cell interactions, we examined the ability of IL-4 and TGF-beta1 to regulate mast cell homeostasis. Using in vitro and in vivo studies of mouse and human mast cells, we demonstrate that IL-4 suppresses TGF-beta1 receptor expression and signaling, and vice versa. In vitro studies demonstrated that IL-4 and TGF-beta1 had balancing effects on mast cell survival, migration, and FcepsilonRI expression, with each cytokine cancelling the effects of the other. However, in vivo analysis of peritoneal inflammation during Nippostrongylus brasiliensis infection in mice revealed a dominant suppressive function for TGF-beta1. These data support the existence of a cytokine network involving the Th2 cytokine IL-4 and the Treg cytokine TGF-beta1 that can regulate mast cell homeostasis. Dysregulation of this balance may impact allergic disease and be amenable to targeted therapy.

GM-CSF is one of the main breast tumor-derived soluble factors involved in the differentiation of CD11b-Gr1- bone marrow progenitor cells into myeloid-derived suppressor cells.

Recent reports have shown the involvement of tumor burden as well as GM-CSF in supporting myeloid-derived suppressor cells (MDSC). However, it is not known what progenitor cells may differentiate into MDSC in the presence of GM-CSF, and whether FVBN202 transgenic mouse model of spontaneous breast carcinoma may exhibit distinct subset distribution of CD11b+Gr1+ cells. In addition, it is not known why CD11b+Gr1+ cells derived from tumor-free and tumor-bearing animals exhibit different functions. In this study, we determined that GM-CSF was one of the tumor-derived soluble factors that induced differentiation of CD11b-Gr1- progenitor cells from within monocytic/granulocytic bone marrow cells into CD11b+Gr1+ cells. We also showed that CD11b+Gr1+ cells in FVBN202 mice consisted of CD11b+Ly6G-Ly6C+ suppressive and CD11b+Ly6G+Ly6C+ non-suppressive subsets. Previously reported variations between tumor-free and tumor-bearing animals in the function of their CD11b+Gr1+ cells were found to be due to the variations in the proportion of these two subsets. Therefore, increasing ratios of CD11b+Gr1+ cells derived from tumor-free animals revealed their suppressive activity on T cells, in vitro. Importantly, GM-CSF supported the generation of CD11b+Ly6G-Ly6C+ suppressor subsets that inhibited proliferation as well as anti-tumor function of neu-specific T cells. These findings suggest revisiting the use of GM-CSF for the expansion of dendritic cells, ex vivo, for cell-based immunotherapy or as an adjuvant for vaccines for patients with cancer in whom MDSC play a major role in the suppression of anti-tumor immune responses.

Adoptive transfer of HER2/neu-specific T cells expanded with alternating gamma chain cytokines mediate tumor regression when combined with the depletion of myeloid-derived suppressor cells.

Adoptive immunotherapy (AIT) using ex vivo-expanded HER-2/neu-specific T cells has shown initial promising results against disseminated tumor cells in the bone marrow. However, it has failed to promote objective responses against primary tumors. We report for the first time that alternating gamma chain cytokines (IL-2, IL-7 and IL-15) ex vivo can expand the neu-specific lymphocytes that can kill breast tumors in vitro. However, the anti-tumor efficacy of these neu-specific T cells was compromised by the increased levels of myeloid-derived suppressor cells (MDSC) during the premalignant stage in FVBN202 transgenic mouse model of breast carcinoma. Combination of AIT with the depletion of MDSC, in vivo, resulted in the regression of neu positive primary tumors. Importantly, neu-specific antibody responses were restored only when AIT was combined with the depletion of MDSC. In vitro studies determined that MDSC caused inhibition of T cell proliferation in a contact-dependent manner. Together, these results suggest that combination of AIT with depletion or inhibition of MDSC could lead to the regression of mammary tumors.

Radiofrequency thermal ablation of breast tumors combined with intralesional administration of IL-7 and IL-15 augments anti-tumor immune responses and inhibits tumor development and metastasis.

Tumor development or recurrence is always a matter of concern following radiofrequency thermal ablation (RFA) of tumors. To determine whether combining RFA with immunologically active cytokines might induce tumor-specific immune responses against mammary carcinoma and inhibit tumor development or metastasis, we evaluated intralesional injection of IL-7 and IL-15 in RFA-treated murine tumors. We used two different breast carcinoma models: neu-overexpressing mouse mammary carcinoma (MMC) in FVBN202 transgenic mouse and 4T1 tumors in Balb/c mouse. MMC tend to relapse even in the presence of neu-specific immune responses, and 4T1 is a weakly immunogenic, aggressive and highly metastatic transplantable tumor. In vivo growth of both of these tumors is also associated with increased numbers of CD11b+Gr1+ myeloid-derived suppressor cells (MDSC). We showed for the first time that unlike RFA alone, RFA combined with the administration of intralesional IL-7 and IL-15 (after RFA), induced immune responses to tumors, inhibited tumor development and lung metastasis, and reduced MDSC.

Manifestaciones cardiovasculares en pacientes con enfermedades reumáticas y COVID-19 / Cardiovascular manifestations in patients with rheumatic diseases and COVID-19

Introducción: La COVID-19 causa una variada gama de manifestaciones clínicas. En pacientes con enfermedades reumáticas destacan, además de las manifestaciones respiratorias, las manifestaciones articulares, dermatológicas, generales y cardiovasculares. Objetivo: Identificar las manifestaciones cardiovasculares que con mayor frecuencia se presentan en pacientes con enfermedades reumáticas afectados por la COVID-19. Métodos: Se realizó una investigación básica, no experimental, con alcance exploratorio, descriptivo y explicativo de un universo constituido por 37 pacientes con diagnóstico previo de enfermedad reumática y diagnóstico confirmado de COVID-19. Se empleó la observación dirigida y la revisión documental como técnicas de investigación para identificar la presencia de manifestaciones cardiovasculares en este tipo de pacientes. Resultados: Predominaron las pacientes femeninas (59,56 por ciento), con diagnóstico de osteoartritis (72,97 por ciento) y artritis reumatoide (72,97 por ciento) y con comorbilidades asociadas (83,78 por ciento). La hipertensión arterial (61,29 por ciento) y el hipotiroidismo (38,71 por ciento) fueron las comorbilidades más frecuentes. El 70,27 por ciento de los pacientes presentaron manifestaciones cardiovasculares: hipertensión arterial (65,38 por ciento), trastornos del ritmo cardiaco (57,69 por ciento) y el síndrome de Raynaud (53,85 por ciento). El 80,0 por ciento de los pacientes masculinos presentaron manifestaciones cardiovasculares, al igual que el 80,64 por ciento de los casos con enfermedad reumática, COVID-19 y comorbilidades asociadas. Conclusiones: Las manifestaciones cardiovasculares se presentaron con elevada frecuencia en los pacientes reumáticos con diagnóstico de COVID-19, sobre todo pacientes masculinos con comorbilidades asociadas. Las manifestaciones cardiovasculares más frecuentes fueron la hipertensión arterial, los trastornos del ritmo y el síndrome de Raynaud(AU)

Introduction: COVID-19 generates a wide range of clinical manifestations in general. In patients with rheumatic diseases, in addition to respiratory manifestations, joint, dermatological, general and cardiovascular manifestations, among others, stand out. Objective: To identify the cardiovascular manifestations that most frequently occur in patients with rheumatic diseases and COVID-19. Methods: A basic, non-experimental research was carried out, with an exploratory, descriptive and explanatory scope. Universe made up of 37 patients with a previous diagnosis of rheumatic disease and a confirmed diagnosis of COVID-19. Directed observation and documentary review were used as research techniques to identify the presence of cardiovascular manifestations in this type of patient. Results: Predominance of female patients (59.56 percent), diagnosed with osteoarthritis (72.97 percent) and rheumatoid arthritis (72.97 percent) and with associated comorbidities (83.78 percent). Hypertension (61.29 percent) and hypothyroidism (38.71 percent) were the most frequent comorbidities. 70.27 percent of the patients presented cardiovascular manifestations, predominantly arterial hypertension (65.38 percent), rhythm disorders (57.69 percent) and Raynaud´s syndrome (53.85 percent). 80.0 percent of the male patients presented cardiovascular manifestations, as did 80.64 percent of the cases with rheumatic disease, COVID-19 and associated comorbidities. Conclusions: Cardiovascular manifestations occurred with high frequency in rheumatic patients diagnosed with COVID-19; being more frequent in male patients and with associated comorbidities. High blood pressure, rhythm disorders and Raynaud's syndrome were the most frequent(AU)

La gota como factor de riesgo cardiovascular / Gout as a cardiovascular risk factor

Introducción: La gota es una enfermedad inflamatoria crónica que generalmente cursa con hiperuricemia sobre añadida. Objetivo: Identificar la presencia de afectación cardiovascular en pacientes con diagnóstico confirmado de artropatía gotosa. Metodología: Investigación básica, no experimental, descriptiva, retrospectiva y con enfoque mixto. El universo estuvo constituido por 69 pacientes atendidos en unidades del primer nivel de atención de salud de la ciudad de Riobamba durante el periodo comprendido entre enero de 2019 y enero de 2021. La muestra quedó conformada por un total de 60 pacientes. Se realizó revisión de la historia clínica de los pacientes para obtener la información necesaria. Resultado: Promedio de edad de 53,02 años. El 35,00 por ciento de ellos presentó al menos una comorbilidad asociada, y la diabetes mellitus fue la más representada (57,14 por ciento). El 71,67 por ciento de los pacientes tenía valores normales de ácido úrico en sangre en el momento del diagnóstico y el 18,33 por ciento presentaba algún tipo de daño renal. El 36,67 por ciento de los pacientes con gota también padecían afección cardiovascular; la hipertensión arterial (59,09 por ciento) fue la más frecuentemente reportada. Conclusiones: La artropatía gotosa es una enfermedad que genera un elevado porciento de afecciones cardiovasculares dentro de las que destacan la hipertensión arterial y la insuficiencia cardiaca(AU)

Introduction: Gout is a chronic inflammatory disease that generally progresses with added hyperuricemia. Objective: To identify the presence of cardiovascular involvement in patients with a confirmed diagnosis of gouty arthropathy. Methodology: A basic, non-experimental, descriptive, retrospective and mixed-focus research was developed. The universe consisted of 69 patients treated in first-level health care units in the city of Riobamba during the period between January 2019 and January 2021. The sample was made up of a total of 60 patients. A review of the clinical history of the patients was carried out to obtain the necessary information. Result: Average age of 53.02 years. 35.00 percent of them presented at least one associated comorbidity, where diabetes mellitus was the most represented (57.14 percent). with presence of comorbidities. 71.67 percent of the patients had normal blood uric acid values at the time of diagnosis and 18.33 percent had some type of kidney damage. 36.67 percent of the patients with gout also presented cardiovascular disease, where arterial hypertension (59.09 percent) was the most frequently reported. Conclusions: Gouty arthropathy is a disease that theoretically generates a high percentage of cardiovascular diseases within of which arterial hypertension and heart failure stand out(AU)

Evaluación del rendimiento diagnóstico de los criterios predictivos de la sociedad británica para el diagnóstico de coledocolitiasis en una población colombiana / Diagnostic performance of the British Society of Gastroenterology predictive criteria for the diagnosis of choledocholithiasis in a Colombian population

Resumen Introducción: la coledocolitiasis (CLDL) puede ser difícil de diagnosticar. Su importancia radica en sus potenciales complicaciones y en que el tratamiento se realiza mediante colangiopancreatografía retrógrada endoscópica (CPRE), un procedimiento con riesgo de generar complicaciones. Se han propuesto guías para su diagnóstico y la más empleada es la de la ASGE (American Society for Gastrointestinal Endoscopy), cuyo rendimiento no es ideal. Recientemente, se ha publicado la guía británica. Este estudio se realizó para establecer el rendimiento de ambas guías. Materiales y métodos: estudio prospectivo realizado entre agosto 1 de 2017 y julio 31 de 2018. Resultados: se incluyeron 300 pacientes para el análisis. Se realizó una CPRE en 145 pacientes y se confirmó la existencia de CLDL en 124 de ellos (85,5 %). La mediana de aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) fue mayor en los que tuvieron CLDC (207 mg/dL y 290 mg/dl, respectivamente). Entre tanto, la tasa de complicaciones posteriores a la CPRE fue del 5,5 %. El análisis multivariado no encontró una asociación significativa para alguna variable predictora de CLDL. En pacientes con alta probabilidad, las guías británicas tuvieron una sensibilidad del 65 % y una especificidad del 33 %, mientras que las guías ASGE mostraron una sensibilidad del 74 % y una especificidad del 28 %. En probabilidad intermedia fueron menos eficientes. Conclusiones: los criterios de la ASGE y la BSG (British Society of Gastroenterology) no tienen un buen desempeño en la población estudiada, a fin de discriminar la existencia o no de CLDL. La guía de la ASGE mostró un mejor rendimiento en general que las guías británicas.

Abstract Introduction: Choledocholithiasis (CDL) may be difficult to diagnose. The relevance of making a timely diagnosis lies in its potential negative effects and the fact that treatment requires performing endoscopic retrograde cholangiopancreatography (ERCP), which is a procedure with a high risk of complications. Several guidelines have been proposed for its diagnosis, including the ASGE Guidelines, which are the most widely used although they do not have an ideal performance, and the guidelines recently published by the BSG. The objective of this study was to compare the performance of both guidelines. Materials and methods: Prospective study carried out between August 1, 2017, and July 31, 2018. Results: 300 patients were included for analysis. 145 underwent ERCP and choledocholithiasis was confirmed in 124 of them (85.5%). Median AST and ALT levels were higher in patients with choledocholithiasis (207 mg/dL and 290 mg/dL). The rate of post-ERCP complications was 5.5%. Multivariate analysis found no significant association for any predictor of CDL. Regarding the "high probability" score, the BSG guidelines had sensitivity of 65% and specificity of 33%, while the ASGE guidelines had sensitivity of 74% and specificity of 28%. Both guidelines were less efficient for "intermediate probability". Conclusions: The ASGE and BSG criteria do not perform well in the population studied to determine whether they had CDL. The ASGE guidelines had a better overall performance than the BSG guidelines.

Implementation of highly sophisticated flow cytometry assays in multicenter clinical studies: considerations and guidance.

Flow cytometry is increasingly becoming an important technology for biomarkers used in drug discovery and development. Within clinical development flow cytometry is used for the determination of PD biomarkers, disease or efficacy biomarkers or patient stratification biomarkers. Significant differences exist between flow cytometry methodology and other widely used technologies measuring soluble biomarkers including ligand binding and mass spectrometry. These differences include the very heavy reliance on aspects of sample processing techniques as well as sample stabilization to ensure viable samples. These differences also require exploration of new approaches and wider discussion regarding method validation requirements. This paper provides a review of the current challenges, solutions, regulatory environment and recommendations for the application of flow cytometry to measure biomarkers in clinical development.

Factores de riesgo cardiovascular en pacientes con enfermedades reumáticas / Cardiovascular risk factors in patients with rheumatic diseases

Introducción: Las enfermedades reumáticas son un grupo de alrededor de 250 enfermedades que se caracterizan por afectar fundamentalmente el sistema osteomioarticular. En su mayoría se consideran enfermedades sistémicas, ya que pueden afectar cualquier órgano o sistema de órganos del cuerpo humano. Una de las complicaciones más graves es el daño al sistema cardiovascular. Objetivo: Describir el comportamiento de los factores de riesgo de afectación cardiovascular en los pacientes con enfermedades reumáticas. Método: Se realizó un estudio descriptivo, de corte transversal, en 87 pacientes con diagnóstico de distintas enfermedades reumáticas. Para el diagnóstico positivo se tuvieron en cuenta los criterios del American College of Rheumatology. Se aplicó un cuestionario creado específicamente para la investigación; se realizaron exámenes complementarios; se determinaron medidas antropométricas; y se revisaron las historias clínicas para comprobar los factores de riesgo cardiovascular. Se empleó el índice de correlación de Pearson para determinar la correlación entre las variables del estudio. Resultados: El promedio de edad de la muestra de estudio fue de 57,82 años, con predominio de pacientes con artritis reumatoide (63,33 por ciento) y tiempo de evolución entre 1 y 5 años (59,77 por ciento). Solo el 25,29 por ciento presentaba normopeso y el 28,74 por ciento tenía daño cardiovascular. Conclusiones: Las enfermedades reumáticas constituyen por sí solas un factor de riesgo de daño cardiovascular; el tiempo de evolución de la enfermedad y las alteraciones del estado nutricional son los elementos que mayor incidencia tienen en la afectación cardiovascular de estos pacientes.

Introduction: Rheumatic diseases are a group of around 250 diseases that are characterized by fundamentally affecting the osteomyoarticular system. Most of them are considered as systemic diseases because they can affect any organ or organ system of the human body. Cardiovascular damage is one of the most frequent complications among rheumatic diseases patients. Objective: To describe risk factor's behavior of cardiovascular affectation in patients with rheumatic diseases. Methods: A descriptive, cross-sectional study was carried out in 87 patients diagnosed with different rheumatic diseases. For the positive diagnosis, the criteria of the American College of Rheumatology were taken into account. A questionnaire created specifically for the research was applied, complementary tests were carried out, anthropometric measures were determined and the clinical history was reviewed to determine the cardiovascular risk factors. The Pearson correlation index was used to determine correlation among the study variables. Results: The average age of studied patients was 57.82 years old, with predominance of patients with rheumatoid arthritis (63.22 percent) and time evolution between 1 and 5 years (59.77 percent). Only 25.29 percent had normal weight and 28.74 percent presented cardiovascular damage. Conclusions: Rheumatic diseases are by themselves a risk factor for cardiovascular damage; the time of evolution of the disease and the alterations of the nutritional status are the elements that have the highest incidence on the presence of cardiovascular affectation(AU)

Relación entre el estado nutricional y la actividad clínica en pacientes con artritis reumatoide / Relationship between nutritional status and clinical activity in patients with rheumatoid arthritis

Introducción: La artritis reumatoide es una enfermedad autoinmune, inflamatoria, sistémica y crónica que se caracteriza por la afectación de pequeñas articulaciones y causa distintos grados de discapacidad funcional y disminución de la percepción de la calidad de vida relacionada con la salud. Objetivo: Determinar la relación existente entre el estado nutricional y la actividad clínica en pacientes con diagnóstico de artritis reumatoide. Métodos: Estudio descriptivo y correlacional de 96 pacientes con diagnóstico de artritis reumatoide, según los criterios del American College of Rheumatology, quienes fueron atendidos en el Hospital Andino de Chimborazo. Se determinó el estado nutricional mediante el índice de masa corporal y la actividad clínica mediante el sistema Disease Activity Score-28 (DAS 28). Se utilizó la prueba de correlación de Pearson para hallar la relación existente entre el estado nutricional y la actividad clínica. Resultados: El promedio de edad fue de 64,23 años; predominaron los pacientes de 60 años o más (51,04 por ciento) y del sexo femenino (78,12 por ciento). El 67,71 por ciento de los casos presentaban comorbilidades asociadas, específicamente hipertensión arterial (43,07 por ciento), hipotiroidismo (35,38 por ciento) y fibromialgia (32,31 por ciento). El 37,50 por ciento tenía sobrepeso y el 16,67 por ciento, obesidad; el 46,88 por ciento de los pacientes presentó actividad clínica ligera y el 29,17 por ciento moderada. El 14,58 por ciento se encontraba en remisión. Conclusiones: Existe una relación positiva considerable entre el estado nutricional y la actividad clínica de la artritis reumatoide en la población estudiada, conclusión que se basa en el resultado del coeficiente de correlación de Pearson(AU)

Introduction: rheumatoid arthritis is an autoimmune, inflammatory, systemic and chronic disease that is characterized by the involvement of small joints of the hands and feet generating different degrees of functional disability and decreased perception of health-related quality of life. Objective: to determine the relationship between nutritional status and clinical activity in patients diagnosed with rheumatoid arthritis. Methods: descriptive and correlational study in 96 patients diagnosed with rheumatoid arthritis according to the criteria of the American College of Rheumatology who were treated at the Andean Hospital of Chimborazo. Nutritional status was determined by body mass index and clinical activity by DAS 28. Pearson's correlation test was used to determine the relationship between nutritional status and clinical activity. Results: average age of 64.23 years, patients between 60 years or older (51.04 percent) and female (78.12 percent) predominated. 67.71 percent of the cases presented comorbidities associated with a predominance of arterial hypertension (43.07 percent), hypothyroidism (35.38 percent) and fibromyalgia (32.31 percent). Overweight was present in 37.50 percent and obesity in 16.67 percent of cases; 46.88 percent of the patients presented mild clinical activity and 29.17 percent moderate, 14.58 percent were in remission. Conclusions: the presence of nutritional alterations due to excess (overweight and obesity) positively influence the clinical activity of patients with rheumatoid arthritis, finding a significant positive correlation between them(AU)

Afectación cardiovascular en una paciente con arteritis de Takayasu, a propósito de un caso / Cardiovascular involvement in a patient with Takayasu arteritis, in relation to a case

Introducción: la arteritis de Takayasu es una vasculitis sistémica que provoca alteraciones en distintos sistemas de órganos, las más características y peligrosas ocurren en el sistema cardiovascular. Objetivo: socializar las manifestaciones cardiovasculares que con mayor frecuencia se presentan en el curso de la arteritis de Takayasu. Caso clínico: se presenta el caso de una paciente femenina, de 46 años de edad, con manifestaciones clínicas que permiten llegar al diagnóstico de arteritis de Takayasu; dentro del cuadro clínico se presentan múltiples afectaciones cardiovasculares que ensombrecen el pronóstico de la paciente. Conclusiones: las manifestaciones cardiovasculares en la arteritis de Takayasu no solo forman parte de los criterios diagnósticos y de las manifestaciones clínicas de la enfermedad; sino que también forman parte de las complicaciones de la arteritis y su presencia empeora la evolución clínica de la enfermedad y complica el pronóstico del paciente(AU)

Introduction: Takayasu's arteritis is a systemic vasculitis that causes alterations in different organ systems, the most characteristic and dangerous occur in the cardiovascular system. Objective: to socialize the cardiovascular manifestations that most frequently occur in the course of Takayasu's arteritis. Clinical case: the case of a female patient, 46 years of age, with clinical manifestations that lead to the diagnosis of Takayasu arteritis; Within the clinical picture there are multiple cardiovascular affectations that overshadow the prognosis of the patient. Conclusions: the cardiovascular manifestations in Takayasu's arteritis are not only part of the diagnostic criteria and the clinical manifestations of the disease; they are also part of the complications of arteritis and their presence worsens the clinical evolution of the disease and complicates the patient's prognosis(AU)

Hiperlisinemia Como Hallazgo Sugestivo De Acidemia Propiónica. Reporte De Caso / Hyperlisinemia As A Suggestive Finding Of Propionic Acidemia. Case Report

RESUMEN Introducción: La acidemia propiónica (AP) es una acidemia orgánica (AO) con presentación clínica de inicio neonatal o de forma tardía. Causada por deficiencia de la enzima propionil-CoA carboxilasa que ocasiona acumulación de ácido propiónico y metabolitos relacionados con propionil-CoA en los tejidos. Es característica la hiperglicinemia, pero puede presentarse hiperlisinemia. Este trabajo describe un caso clínico de AP de inicio neonatal con desenlace fatal y alteración llamativa de los aminoácidos. Caso clínico: Recién nacido (RN) femenina ingresa a unidad neonatal al tercer día de vida por hipoactividad, vómito y letargia. Posterior dificultad respiratoria y realiza paros cardiacos, falleciendo antes de establecer un diagnóstico bioquímico. Paraclínicos iniciales evidenciaron acidosis metabólica, leucopenia, hipoglicemia, posteriormente se documenta hiperglicininemia, hipercistinemia y severa hiperlisininemia. La cromatografía de ácidos orgánicos en orina identificó ácido 3-hidroxi-propionico, metilcitrato y propionilglicina entre otros metabolitos tóxicos, confirmando el diagnóstico. Conclusiones: La AP es un error innato del metabolismo autosómico recesivo de baja incidencia. La presencia de acidosis metabólica severa, pancitopenia, hipoglicemia y antecedentes familiares deben alertar sobre este diagnóstico. Adicionalmente, aunque el diagnóstico bioquímico definitivo son los ácidos orgánicos en orina, la presencia de hiperamonemia, hiperglicinemia e hiperlisinemia pueden ser altamente sugestivas de este trastorno.

ABSTRACT Introduction: Propionic acidemia (AP) is an organic acidemia (AO) with clinical presentation of neonatal onset or late. Caused by deficiency of the enzyme propionil-CoA carboxilasa that causes accumulation of propionic acid and metabolites related to propionyl-CoA in tissues. Hyperglycinemia is characteristic, but hyperlysinemia may occur. This work describes a clinical case of AP of neonatal onset with fatal outcome and striking alteration of amino acids. Clinical case: Female newborn (RN) admitted in the neonatal unit on the third day of life due to hypoactivity, vomiting and lethargy. Subsequent respiratory distress and cardiac arrest occurred, dying before a biochemical diagnosis was established. Initial paraclinics evidenced metabolic acidosis, leukopenia, hypoglycemia, later documented hyperglycinemia, hypercystinemia and severe hyperlysinemia. The organic acid chromatography in urine identified 3-hydroxy-propionic acid, methyl citrate and propionylglycine among other toxic metabolites, confirming the diagnosis. Conclusions: AP is an inborn error of autosomal recessive metabolism of low incidence. The presence of severe metabolic acidosis, pancytopenia, hypoglycemia and family history should alert about this diagnosis. Additionally, although the definitive biochemical diagnosis is organic acids in urine, the presence of hyperammonemia, hyperglycinemia and hyperlysinemia can be highly suggestive of this disorder.

Myeloid-derived suppressor cells enhance IgE-mediated mast cell responses.

Mast cells and MDSCs are increased by parasitic infection and tumor growth. We previously demonstrated that enhanced MDSC development in ADAM10 transgenic mice yielded resistance to Nb infection and that coculturing MDSCs and mast cells enhanced cytokine production. In the current work, we show that MDSC-mast cell coculture selectively enhances IgE-mediated cytokine secretion among mast cells, without increasing MDSC cytokine production. This effect was independent of cell contact and elicited by Ly6C(+) and Ly6C/G+ MDSC subsets. These interactions were functionally important. MDSC depletion with the FDA-approved drug gemcitabine exacerbated Nb or Trichinella spiralis infection and reduced mast cell-dependent AHR and lung inflammation. Adoptive transfer of MDSC worsened AHR in WT but not mast cell-deficient Wsh/Wsh mice. These data support the hypothesis that MDSCs enhance mast cell inflammatory responses and demonstrate that this interaction can be altered by an existing chemotherapeutic.

Biogenic volatile organic compounds from the urban forest of the Metropolitan Region, Chile.

Tropospheric ozone is a secondary pollutant whose primary sources are volatile organic compounds and nitrogen oxides. The national standard is exceeded on a third of summer days in some areas of the Chilean Metropolitan Region (MR). This study reports normalized springtime experimental emissions factors (EF) for biogenic volatile organic compounds from tree species corresponding to approximately 31% of urban trees in the MR. A Photochemical Ozone Creation Index (POCI) was calculated using Photochemical Ozone Creation Potential of quantified terpenes. Ten species, natives and exotics, were analysed using static enclosure technique. Terpene quantification was performed using GC-FID, thermal desorption, cryogenic concentration and automatic injection. Observed EF and POCI values for terpenes from exotic species were 78 times greater than native values; within the same family, exotic EF and POCI values were 28 and 26 times greater than natives. These results support reforestation with native species for improved urban pollution management.

Pancreatitis aguda en el Hospital Provincial General Docente de Riobamba / Acute pancreatitis in the Hospital Provincial General Docente de Riobamba

La pancreatitis con sus variantes aguda y crónica es una enfermedad grave, cuya frecuencia ha ido incrementando al rededor del mundo, con las respectivas consecuencias sobre la calidad de vida del paciente, así como sobre su situación socioeconómica. La pancreatitis aguda (PA), constituye el problema sanitario más frecuente a nivel del sistema de salud y de hospitalización a nivel mundial. El objetivo del presente estudio fue determinar la incidencia y prevalencia de PA en el Hospital Provincial General Docente (HPGD) de Riobamba durante el período comprendido entre 2014­2017. Por este motivo se llevó a cabo un estudio retrospectivo observacional de corte transversal, con los siguientes criterios de inclusión: mujeres o hombres de todas las edades, diagnóstico de PA, encontrarse en hospitalización de cirugía y/o medicina interna y cumplir los criterios de PA. Se excluyeron los pacientes que no cumplieron los criterios de diagnóstico de PA y ambulatorios. Nuestros hallazgos demuestran que esta patología afecta con frecuencia las mujeres en relación con los hombres.

Pancreatitis and its variants acute and chronic is a serious disease, whose frequency has been increasing worldwide.It has a huge impact over the quality of life of patients, as well as their socio­economical status. Acute pancreatitis (AP) is the most frequent health problem in the health and hospitalization systen around the world. The objective of the present study was to determinate the incidence and prevalence of AP in the Hospital Provincial General Docente (HPGD)de Riobamba during the period between 2014­2017. In this way we performed an observational, retrospective, cross­sectional study, taking into account the following incluion criteria: women or men of all ages, with a diagnosis of AP, hospitalized in the service of surgery or internal medicine that meet the criteria of AP. Patients that did not meet the criteria of AP or attended outpatient services were excluded of the study. Our findings suggest that this pathology affects more often to women than to men.

The Fyn-STAT5 Pathway: A New Frontier in IgE- and IgG-Mediated Mast Cell Signaling.

Mast cells are central players in immune surveillance and activation, positioned at the host-environment interface. Understanding the signaling events controlling mast cell function, especially those that maintain host homeostasis, is an important and still less understood area of mast cell-mediated disease. With respect to allergic disease, it is well established that IgE and its high affinity receptor FcεRI are major mediators of mast cell activation. However, IgG-mediated signals can also modulate mast cell activities. Signals elicited by IgG binding to its cognate receptors (FcγR) are the basis for autoimmune disorders such as lupus and rheumatoid arthritis. Using knowledge of IgE-mediated mast cell signaling, recent work has begun to illuminate potential overlap between FcεRI and FcγR signal transduction. Herein we review the importance of Src family kinases in FcεRI and FcγR signaling, the role of the transcription factor STAT5, and impingement of the regulatory cytokines IL-4, IL-10, and TGFß1 upon this network.

Essential roles of sphingosine-1-phosphate receptor 2 in human mast cell activation, anaphylaxis, and pulmonary edema.

Systemic exacerbation of allergic responses, in which mast cells play a critical role, results in life-threatening anaphylactic shock. Sphingosine-1-phosphate (S1P), a ligand for a family of G protein-coupled receptors, is a new addition to the repertoire of bioactive lipids secreted by activated mast cells. Yet little is known of its role in human mast cell functions and in anaphylaxis. We show that S1P(2) receptors play a critical role in regulating human mast cell functions, including degranulation and cytokine and chemokine release. Immunoglobulin E-triggered anaphylactic responses, including elevation of circulating histamine and associated pulmonary edema in mice, were significantly attenuated by the S1P(2) antagonist JTE-013 and in S1P(2)-deficient mice, in contrast to anaphylaxis induced by administration of histamine or platelet-activating factor. Hence, S1P and S1P(2) on mast cells are determinants of systemic anaphylaxis and associated pulmonary edema and might be beneficial targets for anaphylaxis attenuation and prophylaxis.

Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice.

Myeloid derived suppressor cells (MDSCs) accumulate in 4T1 mammary carcinoma bearing mice and present a barrier to the success of adoptive immunotherapy (AIT) by suppressing T cell immunity. In this study, we investigated the inhibition of MDSCs by gemcitabine (GEM), a chemotherapy agent that may have favorable immunologic effects. BALB/c mice were inoculated with 4T1 mammary carcinoma cells and treated with GEM either once a week starting 5 days after tumor inoculation (EARLY GEM) or as a single dose at days 20-25 (LATE GEM). Splenic mononuclear cells were isolated, activated in vitro, expanded, and stimulated with tumor antigen. T cells were then used for AIT to treat tumor-bearing mice. EARLY GEM treatment of 4T1 tumor-bearing mice significantly inhibited tumor growth, reduced splenomegaly, and significantly decreased MDSC proportion in the spleen. Support for a direct effect was demonstrated through suppression of MDSCs in spleens, bone marrow, and blood harvested 24 and 48 h after LATE GEM treatment, despite no significant decrease in tumor burden. Interestingly, treatment of tumor-bearing mice with GEM augmented in vitro expansion of splenic T cells and boosted IFN-gamma secretion in response to stimulation by tumor antigen. However, despite GEM-mediated inhibition of MDSC suppression, splenic T cells from mice with advanced tumors were ineffective in vivo against established tumors. This study provides support for direct inhibition of MDSCs and direct reduction of tumor burden by GEM in 4T1 tumor-bearing mice. GEM treatment of mice with advanced tumors improves T cell function and growth in vitro.

Mast cell regulation of the immune response.

Mast cells are well known as principle effector cells of type I hypersensitivity responses. Beyond this role in allergic disease, these cells are now appreciated as playing an important role in many inflammatory conditions. This review summarizes the support for mast cell involvement in resisting bacterial infection, exacerbating autoimmunity and atherosclerosis, and promoting cancer progression. A commonality in these conditions is the ability of mast cells to elicit migration of many cell types, often through the production of inflammatory cytokines such as tumor necrosis factor. However, recent data also demonstrates that mast cells can suppress the immune response through interleukin-10 production. The data encourage those working in this field to expand their view of how mast cells contribute to immune homeostasis.