Inborn errors of immunity: A field without frontiers.

The study of primary immunodeficiencies or inborn errors of immunity continues to drive our knowledge of the function of the human immune system. From the outset, the study of inborn errors has focused on unraveling genetic etiologies and molecular mechanisms. Aided by the continuous growth in genetic diagnostics, the field has moved from the study of an infection dominated phenotype to embrace and unravel diverse manifestations of autoinflammation, autoimmunity, malignancy, and severe allergy in all medical disciplines. It has now moved from the study of ultrarare presentations to producing meaningful impact in conditions as diverse as inflammatory bowel disease, neurological conditions, and hematology. Beyond offering immunogenetic diagnosis, the study of underlying inborn errors of immunity in these conditions points to targeted treatment which can be lifesaving.

Safety, Tolerability, Bioavailability, and Biological Activity of Inhaled Interferon-α2b in Healthy Adults: The IN2COVID Phase I Randomized Trial.

BACKGROUND AND OBJECTIVES: Interferons have been identified as a potential treatment alternative for coronavirus disease 2019. This study assessed the safety, tolerability, bioavailability, and biological activity of inhaled interferon-α2b (IFN)-α2b in healthy adults. METHODS: A double-blind, randomized, phase I clinical trial was conducted with two cohorts of healthy subjects aged 18-50 years. The first cohort received 2.5 MIU of inhaled IFN-α2b twice daily for 10 days (n = 6) or placebo (n = 3); the second cohort received 5.0 MIU of inhaled IFN-α2b in a similar scheme (n = 6) or placebo (n = 3). The first two doses were administered in an emergency department, then participants completed their treatment at home. Safety was measured through vital signs, new symptoms, and laboratory tests. Tolerability was measured as participants' treatment acceptability. Bioavailability and biological activity were measured from serum IFNα concentrations and real-time quantitative polymerase chain reaction of interferon-induced genes in blood before and after treatments. RESULTS: Exposure to inhaled IFN-α2b at 2.5-MIU or 5-MIU doses did not produce statistically significant changes in participant vital signs, or elicit new symptoms, and standard hematological and biochemical blood measurements were comparable to those recorded in individuals who received placebo. A total of 58 adverse events were observed. All were mild or moderate and did not require medical care. All participants reported very high tolerability towards a twice-daily nebulized treatment for 10 days (98.0, 97.0, and 97.0 in the placebo, 2.5-MIU, and 5-MIU groups, respectively, on a 0- to 100-mm visual analog scale). A dose-dependent mild increase in serum IFN-α concentrations and an increase in serum RNA expression of IFN-induced genes were observed 11 days after treatment (p < 0.05 for all between-group comparisons). CONCLUSIONS: Inhaled IFN-α2b was preliminarily safe and well tolerated, and induced systemic biological activity in healthy subjects. CLINICAL TRIAL REGISTRATION: The trial was registered in ClinicalTrials.gov (NCT04988217), 3 August, 2021.

Deep immune profiling uncovers novel associations with clinical phenotypes of Multisystem Inflammatory Syndrome in Children (MIS-C).

Multisystem Inflammatory Syndrome in Children (MIS-C) is a systemic inflammatory condition that follows SARS-CoV2 infection or exposure in children. Clinical presentations are highly variable and include fever, gastrointestinal (GI) disease, shock, and Kawasaki Disease-like illness (MIS-C/KD). Compared to patients with acute COVID, patients with MIS-C have a distinct immune signature and expansion of TRVB11 expressing T cells. However, the relationship between immunological and clinical phenotypes of MIS-C is unknown. Here, we measured serum biomarkers, TCR repertoire, and SARS-CoV2-specific T cell responses in a cohort of 76 MIS-C patients. Serum biomarkers associated with macrophage and Th1 activation were elevated in patients with shock, consistent with previous reports. Significantly increased SARS-CoV-2-induced IFN-γ, IL-2, and TNF-α production were seen in CD4 + T cells from patients with neurologic involvement and respiratory failure. Diarrhea was associated with a significant reduction in shock-associated serum biomarkers, suggesting a protective effect. TRVB11 usage was highly associated with MIS-C/KD and coronary aneurysms, suggesting a potential biomarker for these manifestations in MIS-C patients. By identifying novel immunologic associations with the different clinical phenotypes of MIS-C, this study provides insights into the clinical heterogeneity of MIS-C. These unique immunophenotypic associations could provide biomarkers to identify patients at risk for severe complications of MIS-C, including shock and MIS-C/KD.

Hematologic parameters and biomarkers predictors of severity in Multisystem Inflammatory Syndrome in children associated with SARS-CoV-2. / Parámetros hematológicos y biomarcadores predictores de gravedad en Síndrome Inflamatorio Pediátrico Multisistémico asociado a SARS-CoV-2.

INTRODUCTION: The multisystem inflammatory syndrome in children associated with SARS-CoV-2 (MIS-C) is cha racterized by a hyperinflammatory state resulting from a cytokine storm, evidenced by alterations in laboratory blood testing and acute-phase proteins. OBJECTIVE: to describe the clinical and labora tory characteristics of patients hospitalized due to MIS-C and identify predictive markers of severity. PATIENTS AND METHOD: Retrospective study of 32 patients. The group was divided into critical and non-critical according to clinical presentation and therapy used. Clinical and laboratory aspects were studied, including complete blood count, coagulation tests, and biomarkers. RESULTS: 18/32 were males, with a median age of 6.8 years. The most frequent manifestations were cardiovascular (84.3%), digestive (84%), and mucocutaneous (59%). The group of critical patients included 15 patients, 12 were males with a median age of 8.9 years, and the non-critical group included 17 patients, 6 were males with a median age of 5.4 years. The laboratory parameters at the admission in the global group showed increased C-reactive protein, D-dimer, leukocytes, neutrophils, ferritin, and fibrinogen. In contrast, albumin and blood sodium levels were decreased. At admission, the critical group was cha racterized by presenting thrombocytopenia, hypoalbuminemia, prolonged prothrombin time, and elevated ferritin. At the time of deterioration, there was an intensification of thrombocytopenia, in creased C-reactive protein together with increased neutrophils level. CONCLUSION: The blood count, C-reactive protein, and albuminemia at admission proved to be significantly important in the identi fication of patients at risk of clinical deterioration.

[Recommendations for the suspected diagnosis and management of Multisystemic Inflammatory Syndrome (MIS-C) in the context of a SARS-CoV-2 pandemic. April 2021]. / Recomendaciones para la sospecha diagnóstica y manejo del Síndrome Inflamatorio Multisistémico (SIM-COVID-19) en contexto pandemia SARS-CoV-2. Abril 2021.

Multisystem inflammatory syndrome temporally associated with COVID-19 (MIS-C) is a post-infectious complication described in children and adolescents with previous exposure to SARS-CoV-2. Because of its potential to evolve to severe disease -including cardiovascular impairment and multiple organ failure it requires a prompt diagnosis and appropriate management, including intensive care for most cases. These guidelines compile recent information from scientific literature, from our local clinical experiences during the past pandemic year, and have been discussed by experts. The recommendations provided are meant to help the clinical work of health teams attending the pediatric population.

Recomendaciones para la sospecha diagnóstica y manejo del Síndrome Inflamatorio Multisistémico (SIM-COVID-19) en contexto pandemia SARS-CoV-2. Abril 2021 / Recommendations for the suspected diagnosis and management of Multisystemic Inflammatory Syndrome (MIS-C) in the context of a SARS-CoV-2 pandemic. April 2021

Resumen El síndrome inflamatorio multisistémico asociado a COVID-19 (SIM-COVID-19) es una complicación post-infecciosa descrita en niños y adolescentes con antecedente de exposición a SARS-CoV-2. Su potencial de evolución clínica grave, con compromiso hemodinámico y de falla de múltiples órganos lo convierten en una identidad que requiere de sospecha temprana, rápido diagnóstico y manejo adecuado, incluyendo terapia intensiva en la mayoría de los casos. Las siguientes recomendaciones recopilan información de la literatura científica, de la experiencia nacional en este año de pandemia y han sido consensuadas con expertos. Se presentan como guías de manejo de modo de facilitar el trabajo de equipos de salud a cargo de la atención pediátrica.

Abstract Multisystem inflammatory syndrome temporally associated with COVID-19 (MIS-C) is a post-infectious complication described in children and adolescents with previous exposure to SARS-CoV-2. Because of its potential to evolve to severe disease -including cardiovascular impairment and multiple organ failure it requires a prompt diagnosis and appropriate management, including intensive care for most cases. These guidelines compile recent information from scientific literature, from our local clinical experiences during the past pandemic year, and have been discussed by experts. The recommendations provided are meant to help the clinical work of health teams attending the pediatric population.

Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency.

Agammaglobulinemia is the most profound primary antibody deficiency that can occur due to an early termination of B-cell development. We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM). Two of them also presented with intermittent or severe chronic neutropenia. We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein. B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model. Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity. The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM. FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM. Our findings elucidate a functional and relevant role of FNIP1 in B-cell development and metabolism and potentially neutrophil activity.

Compromiso cardiovascular en pacientes con síndrome inflamatorio pediátrico multisistémico, asociado a infección por SARS-CoV-2 / Cardiovascular involvement in pediatric patients with SARS-CoV-2 associated to multisystemic inflammatory syndrome

INTRODUCCION: El Síndrome Inflamatorio Pediátrico Multisistémico (PIMS) ha emergido como una nueva enfermedad en niños, secundaria a infección por SARSCoV-2. Se caracteriza por presentar compromiso multiorgánico con parámetros inflamatorios elevados y manifestaciones clínicas graves, siendo el corazón el órgano más severamente comprometido. OBJETIVO: Describir las características clínicas y de laboratorio de 23 pacientes con diagnóstico de PIMS con compromiso cardiovascular hospitalizados en un centro único. MÉTODO: Se efectuó un estudio retrospectivo analizando los hallazgos clínicos y de laboratorio junto a las manifestaciones cardiovasculares que presentaron estos pacientes. RESULTADOS: 23/29 pacientes con PIMS (78%) presentaron manifestaciones digestivas y mucocutáneas. Las manifestaciones cardiovasculares fueron: Síndrome Kawasaki y "Kawasaki like" sin compromiso coronario en 15/23 (65%) y con compromiso coronario en 3 (13%). Shock en 9 pacientes (39%), injuria miocárdica- miocarditis en 8 (35%) y derrame pericárdico en 13 (56%). Trastornos del ritmo cardíaco se observaron en 6 pacientes (26%). La terapia más utilizada fue inmunoglobulina y corticoides. 18 /23 requirieron manejo en unidades de intermedio y/o intensivo. Un 70% de los pacientes se recuperó del compromiso cardiovascular antes del alta. CONCLUSIÓN: El compromiso cardiovascular en PIMS es la complicación más frecuente de esta enfermedad, que se acompaña de manifestaciones inmunológicas y hematológicas graves lo que hace necesario un tratamiento multidisciplinario para un mejor manejo de estos pacientes.

INTRODUCTION: Pediatric Multisystemic Inflammatory Syndrome (PIMS) has emerged as a new disease in children, secondary to SARSCoV-2 infection. It is characterized by multi-organ involvement with elevated inflammatory parameters and severe clinical manifestations, the heart being the organ most severely involved. OBJETIVE: to describe the clinical and laboratory characteristics of 23 patients diagnosed with PIMS with cardiovascular involvement hospitalized in a single center. METHOD: We conducted a retrospective study in which we analyzed the clinical and laboratory findings along with the cardiovascular manifestations presented by these patients. Results: 23/29 patients with PIMS and cardiovascular involvement were selected, 78% had digestive and mucocutaneous manifestations. Cardiovascular manifestations consisted of KawasakiKawasaki like syndrome without coronary involvement in 15/23 (65%) and coronary involvement in 3 (13%). Nine patients developed shock (39%), 8 (35%) myocardial injury in and 13 (56%) pericardial effusion.. Heart rhythm disorders were observed in 6 patients (26%). The main therapy was immunoglobulin and corticosteroids. 18 /23 required management in intermediate and/or intensive care unit. 70% of patients recovered from cardiovascular involvement before discharge. CONCLUSION: Cardiovascular involvement in PIMS is the most frequent complication of this disease, but it is associated with severe immunological and hematological manifestations, which makes necessary a multidisciplinary treatment for a better management

Espectro clínico de la infección en niños por virus SARS-CoV-2 en un centro de referencia pediátrico en plena pandemia. Reporte del Comité Clínico COVID, Hospital de Niños Roberto del Río, Santiago Chile

Resumen Introducción: La infección por virus SARS-CoV-2 responsable de la pandemia actual, es una entidad clínica y fisiopatológica nueva y en desarrollo, cuyo control aún es incierto mientras no contemos con una vacuna efectiva y de distribución universal. Descrita inicialmente como una enfermedad respiratoria mayoritariamente de adultos, los niños también pueden enfermar y se ha visto que en ellos las manifestaciones clínicas de enfermedad suelen diferir a las de los adultos expresándose como cuadros benignos en su mayoría. Si requieren hospitalización o algún tipo de asistencia, el cuadro se resuelve con tratamiento de soporte y sin complicaciones, mayoritariamente. Sin embargo, en el síndrome inflamatorio multisistémico asociado a COVID-19 (SIM-C) es de vital importancia la sospecha precoz y la derivación a un centro de alta complejidad para otorgar el soporte y tratamiento adecuado para lograr una buena y adecuada sobrevida. Objetivo: Describir el espectro clínico de enfermedad por virus SARS-CoV-2 en un centro de referencia pediátrico con la pandemia aún en desarrollo. Método: Se presenta la casuística de 537 pacientes con infección por SARS-CoV-2 atendidos entre marzo 1 y julio 15, 2020, con descripción de aquellos que fueran hospitalizados. Resultados: 127 (23%) de ellos fueron internados y de éstos 69% sintomáticos. Veintiséis pacientes (20%) de los hospitalizados presentaron SIM-C y sólo uno falleció por complicaciones de sus patologías de base.

Abstract Background: SARS-CoV-2 virus infection responsible for de pandemic in course, is a new clinical and physiopathological entity, whose control is still uncertain till we can provide an effective and universal vaccine. In the beginning it was described as a respiratory disease which affects mainly adults, children can have the disease too and in this group the disease can be different than the adult disease. Acute infection in children is mostly mild and when it requires hospital assistance it resolves with support therapy and without complications most of the time. However, in the Pediatric Inflammatory Multisystemic Syndrome is vital the early clinical suspect and refers to a tertiary center to bring support and properly treatment. Aim: To describe the clinical spectrum of SARS-CoV-2 virus disease in a pediatric referral center with the pandemic still in development. Method: A case series of 537 patients with SARS-CoV-2 infection treated between March 1 and July 15, 2020 is presented with a description of those who were hospitalized. Results: 127 (23%) of them were hospitalized and of these 69% were symptomatic. Twenty-six patients (20%) of those hospitalized presented PIMS, only one died for complications of his chronic diseases.

[Clinical manifestations of SARS-CoV-2 infection in children in the middle of pandemic season in a pediatric tertiary center. Report of local COVID Clinical Committee, Hospital de Niños Roberto del Río, Santiago Chile]. / Espectro clínico de la infección en niños por virus SARS-CoV-2 en un centro de referencia pediátrico en plena pandemia. Reporte del Comité Clínico COVID, Hospital de Niños Roberto del Río, Santiago Chile.

BACKGROUND: SARS-CoV-2 virus infection responsible for de pandemic in course, is a new clinical and physiopathological entity, whose control is still uncertain till we can provide an effective and universal vaccine. In the beginning it was described as a respiratory disease which affects mainly adults, children can have the disease too and in this group the disease can be different than the adult disease. Acute infection in children is mostly mild and when it requires hospital assistance it resolves with support therapy and without complications most of the time. However, in the Pediatric Inflammatory Multisystemic Syndrome is vital the early clinical suspect and refers to a tertiary center to bring support and properly treatment. AIM: To describe the clinical spectrum of SARS-CoV-2 virus disease in a pediatric referral center with the pandemic still in development. METHOD: A case series of 537 patients with SARS-CoV-2 infection treated between March 1 and July 15, 2020 is presented with a description of those who were hospitalized. RESULTS: 127 (23%) of them were hospitalized and of these 69% were symptomatic. Twenty-six patients (20%) of those hospitalized presented PIMS, only one died for complications of his chronic diseases.

Repercussions of inborn errors of immunity on growth.

OBJECTIVES: This study aimed to review the literature on the repercussions of the different inborn errors of immunity on growth, drawing attention to the diagnosis of this group of diseases in patients with growth disorders, as well as to enable the identification of the different causes of growth disorders in patients with inborn errors of immunity, which can help in their treatment. DATA SOURCES: Non-systematic review of the literature, searching articles since 2000 in PubMed with the terms "growth", "growth disorders", "failure to thrive", or "short stature" AND "immunologic deficiency syndromes", "immune deficiency disease", or "immune deficiency" NOT HIV. The Online Mendelian Inheritance in Man (OMIN) database was searched for immunodeficiencies and short stature or failure to thrive. DATA SUMMARY: Inborn errors of immunity can affect growth in different ways, and some of them can change growth through multiple simultaneous mechanisms: genetic syndromes; disorders of the osteoarticular system; disorders of the endocrine system; reduction in caloric intake; catabolic processes; loss of nutrients; and inflammatory and/or infectious conditions. CONCLUSIONS: The type of inborn errors of immunity allows anticipating what type of growth disorder can be expected. The type of growth disorder can help in the diagnosis of clinical conditions related to inborn errors of immunity. In many inborn errors of immunity, the causes of poor growth are mixed, involving more than one factor. In many cases, impaired growth can be adjusted with proper inborn errors of immunity treatment or proper approach to the mechanism of growth impairment.

Repercussions of inborn errors of immunity on growth / Repercussões dos erros inatos da imunidade sobre o crescimento

Abstract Objectives: This study aimed to review the literature on the repercussions of the different inborn errors of immunity on growth, drawing attention to the diagnosis of this group of diseases in patients with growth disorders, as well as to enable the identification of the different causes of growth disorders in patients with inborn errors of immunity, which can help in their treatment. Data sources: Non-systematic review of the literature, searching articles since 2000 in PubMed with the terms "growth", "growth disorders", "failure to thrive", or "short stature" AND "immunologic deficiency syndromes", "immune deficiency disease", or "immune deficiency" NOT HIV. The Online Mendelian Inheritance in Man (OMIN) database was searched for immunodeficiencies and short stature or failure to thrive. Data summary: Inborn errors of immunity can affect growth in different ways, and some of them can change growth through multiple simultaneous mechanisms: genetic syndromes; disorders of the osteoarticular system; disorders of the endocrine system; reduction in caloric intake; catabolic processes; loss of nutrients; and inflammatory and/or infectious conditions. Conclusions: The type of inborn errors of immunity allows anticipating what type of growth disorder can be expected. The type of growth disorder can help in the diagnosis of clinical conditions related to inborn errors of immunity. In many inborn errors of immunity, the causes of poor growth are mixed, involving more than one factor. In many cases, impaired growth can be adjusted with proper inborn errors of immunity treatment or proper approach to the mechanism of growth impairment.

Resumo Objetivos: Revisão da literatura sobre as repercussões dos diferentes erros inatos da imunidade sobre o crescimento, chamar a atenção para o diagnóstico desse grupo de doenças em pacientes que apresentem desordens do crescimento, assim como permitir que se identifiquem as diferentes causas de alterações do crescimento em pacientes com erros inatos da imunidade, o que pode auxiliar em seu manejo. Fonte dos dados: Revisão não sistemática da literatura, com busca de artigos desde 2000 no Pubmed com os termos "growth" ou "growth disorders" ou "failure to thrive" ou "short stature" AND "immunologic deficiency syndromes" ou "immune deficiency disease" ou "imune deficiency" NOT HIV. E buscas na base OMIN (Online Mendelian Inheritance in Man) por imunodeficiências e baixa estatura ou falha no crescimento ("failure to thrive"). Síntese dos dados: Há diferentes modos pelos quais os erros inatos da imunidade podem afetar o crescimento e alguns deles podem alterar o crescimento por múltiplos mecanismos simultâneos: síndromes genéticas; afecções do aparelho osteoarticular; afecções do sistema endócrino; redução de aporte calórico; processos catabólicos: perda de nutrientes, assim como afecções inflamatórias e/ou infecciosas. Conclusões: O tipo de erros inatos da imunidade permite prever que tipo de alteração no crescimento devemos esperar. O tipo de alteração no crescimento pode auxiliar no diagnóstico de condições clínicas associadas aos erros inatos da imunidade. Em muitos erros inatos da imunidade, as causas do crescimento deficiente são mistas, envolvem mais de um fator. Em muitos casos, o prejuízo do crescimento pode ser corrigido com o adequado tratamento dos erros inatos da imunidade ou adequada abordagem do mecanismo que causa o prejuízo do crescimento.

Identifying Genes Whose Mutant Transcripts Cause Dominant Disease Traits by Potential Gain-of-Function Alleles.

Premature termination codon (PTC)-bearing transcripts are often degraded by nonsense-mediated decay (NMD) resulting in loss-of-function (LoF) alleles. However, not all PTCs result in LoF mutations, i.e., some such transcripts escape NMD and are translated to truncated peptide products that result in disease due to gain-of-function (GoF) effects. Since the location of the PTC is a major factor determining transcript fate, we hypothesized that depletion of protein-truncating variants (PTVs) within the gene region predicted to escape NMD in control databases could provide a rank for genic susceptibility for disease through GoF versus LoF. We developed an NMD escape intolerance score to rank genes based on the depletion of PTVs that would render them able to escape NMD using the Atherosclerosis Risk in Communities Study (ARIC) and the Exome Aggregation Consortium (ExAC) control databases, which was further used to screen the Baylor-Center for Mendelian Genomics disease database. This analysis revealed 1,996 genes significantly depleted for PTVs that are predicted to escape from NMD, i.e., PTVesc; further studies provided evidence that revealed a subset as candidate genes underlying Mendelian phenotypes. Importantly, these genes have characteristically low pLI scores, which can cause them to be overlooked as candidates for dominant diseases. Collectively, we demonstrate that this NMD escape intolerance score is an effective and efficient tool for gene discovery in Mendelian diseases due to production of truncated or altered proteins. More importantly, we provide a complementary analytical tool to aid identification of genes associated with dominant traits through a mechanism distinct from LoF.

IL-2 in the tumor microenvironment is necessary for Wiskott-Aldrich syndrome protein deficient NK cells to respond to tumors in vivo.

To kill target cells, natural killer (NK) cells organize signaling from activating and inhibitory receptors to form a lytic synapse. Wiskott-Aldrich syndrome (WAS) patients have loss-of-function mutations in the actin regulator WASp and suffer from immunodeficiency with increased risk to develop lymphoreticular malignancies. NK cells from WAS patients fail to form lytic synapses, however, the functional outcome in vivo remains unknown. Here, we show that WASp KO NK cells had decreased capacity to degranulate and produce IFNγ upon NKp46 stimulation and this was associated with reduced capacity to kill MHC class I-deficient hematopoietic grafts. Pre-treatment of WASp KO NK cells with IL-2 ex vivo restored degranulation, IFNγ production, and killing of MHC class I negative hematopoietic grafts. Moreover, WASp KO mice controlled growth of A20 lymphoma cells that naturally produced IL-2. WASp KO NK cells showed increased expression of DNAM-1, LAG-3, and KLRG1, all receptors associated with cellular exhaustion and NK cell memory. NK cells isolated from WAS patient spleen cells showed increased expression of DNAM-1 and had low to negative expression of CD56, a phenotype associated with NK cells exhaustion. Finally, in a cohort of neuroblastoma patients we identified a strong correlation between WASp, IL-2, and patient survival.

Guía clínica GES de artritis idiopática juvenil 2014 / 2014 GES clinical guideline of juvenile idiopathic arthritis

La artritis idiopática juvenil (AIJ) ha sido definida por la Liga Internacional de Asociaciones de Reumatología (ILAR) como artritis de etiología desconocida que se inicia antes de los 16 años y dura por al menos seis semanas, habiendo excluido otras condiciones conocidas. La AIJ es una enfermedad cubierta por el sistema de Garantías Explícitas en Salud (GES) del Ministerio de Salud de Chile desde 2010. La presente guía, desarrollada por el Grupo Pediátrico de la Sociedad Chilena de Reumatología, consiste en una actualización de la Guía Clínica de AIJ 2010, incorporando nuevos protocolos terapéuticos y medicamentos que han demostrado un claro beneficio para niños con AIJ...

Juvenile idiopathic arthritis (JIA) has been defined by the International League of Associations for Rheumatology as arthritis of unknown etiology that begins before the sixteenth birthday and persists for at least 6 weeks with other known conditions excluded. JIA is a disease that is covered by the Explicit Health Guarantees system of the Chilean Ministry of Health since 2010. The present guideline developed by the Pediatric Group of the Chilean Rheumatology Society is an update of the 2010 JIA Clinical Guideline incorporating new treatment protocols and medications that have demonstrated clear benefits in children with JIA...

Oxygen permeability measurements of contact lenses: a proposal for accuracy improvement.

Contact lens are a widespread medical device. In view of the importance of a proper oxygenation of the cornea, new materials are continuously being tested, with a high permeability to oxygen. Taking into account the limitations of the methods for testing soft contact lenses, as presented in the relevant international standards, this paper focuses on the polarographic method and on the approach of measuring oxygen permeability of stacked contact lenses. The effect of the interspersed saline solution layers on the measurable permeability of the stack is considered, using Fick's law of diffusive flux, and a proposal for accuracy improvement in oxygen permeability measurements is presented.

[Pneumoparotitis or pneumoparotid: a differential diagnosis to consider]. / Neumoparotiditis o neumoparótida en el niño: un diagnóstico diferencial a considerar.

Childhood parotid swelling has a number of differential diagnosis mostly of inflammatory origin. Pneumoparotitis is an uncommon cause of parotid inflammation. It is caused by an excessive increase of intraoral pressure and secondary passage of air into the Stensen or Stenon duct and its glandular branches. Diagnostic clues can usually be obtained by a directed anamnesis. Ultrasonography (US) and computed tomography are essential diagnostic tools for this condition that has a benign course with spontaneous resolution in most cases. We present four cases of pneumoparotitis diagnosed by US in children 5 to 13 years of age. One of the cases occurred after the child chewed gum and made bubbles for a prolonged time-period and the other three after inflating baloons, making bubbles inside a pool and after playing the flute. All cases resolved spontaneously after two days. We suggest to consider pneumoparotitis in the differential diagnosis of parotid swelling in children.

NIR is a novel INHAT repressor that modulates the transcriptional activity of p53.

Most transcriptional repression pathways depend on the targeted deacetylation of histone tails. In this report, we characterize NIR, a novel transcriptional corepressor with inhibitor of histone acetyltransferase (INHAT) activity. NIR (Novel INHAT Repressor) is ubiquitously expressed throughout embryonic development and adulthood. NIR is a potent transcriptional corepressor that is not blocked by histone deacetylase inhibitors and is capable of silencing both basal and activator-driven transcription. NIR directly binds to nucleosomes and core histones and prevents acetylation by histone acetyltransferases, thus acting as a bona fide INHAT. Using a tandem affinity purification approach, we identified the tumor suppressor p53 as a NIR-interacting partner. Association of p53 and NIR was verified in vitro and in vivo. Upon recruitment by p53, NIR represses transcription of both p53-dependent reporters and endogenous target genes. Knock-down of NIR by RNA interference significantly enhances histone acetylation at p53-regulated promoters. Moreover, p53-dependent apoptosis is robustly increased upon depletion of NIR. In summary, our findings describe NIR as a novel INHAT that plays an important role in the control of p53 function.

Fhl2 deficiency results in osteopenia due to decreased activity of osteoblasts.

Osteoporosis is one of the major health problems today, yet little is known about the loss of bone mass caused by reduced activity of the bone-forming osteoblasts. Here we show that mice deficient for the transcriptional cofactor four and a half LIM domains 2 (Fhl2) exhibit a dramatic decrease of bone mass in both genders. Osteopenia is caused by a reduced bone formation rate that is solely due to the diminished activity of Fhl2-deficient osteoblasts, while their number remains unchanged. The number and activity of the bone-resorbing cells, the osteoclasts, is not altered. Enforced expression of Fhl2 in differentiated osteoblasts boosts mineralization in cell culture and, importantly, enhances bone formation in transgenic animals. Fhl2 increases the transcriptional activity of runt-related transcription factor 2 (Runx2), a key regulator of osteoblast function, and both proteins interact in vitro and in vivo. In summary, we present Fhl2-deficient mice as a unique model for osteopenia due to decreased osteoblast activity. Our data offer a novel concept to fight osteoporosis by modulating the anabolic activity of osteoblasts via Fhl2.