Induction of CIITA by IFN-γ in macrophages involves STAT1 activation by JAK and JNK.

The induction of major histocompatibility complex (MHC) class II proteins by interferon gamma (IFN-γ) in macrophages play an important role during immune responses. Here we explore the signaling pathways involved in the induction by IFN-γ of the MHC II transactivator (CIIta) required for MHC II transcriptional activation. Cyclophilin A (CypA) is required for IFN-γ-dependent induction of MHC II in macrophages, but not when it is mediated by GM-CSF. The effect of CypA appears to be specific because it does not affect the expression of other molecules or genes triggered by IFN-γ, such as FcγR, NOS2, Lmp2, and Tap1. We found that CypA inhibition blocked the IFN-γ-induced expression of CIIta at the transcriptional level in two phases. In an early phase, during the first 2 h of IFN-γ treatment, STAT1 is phosphorylated at Tyrosine 701 and Serine 727, residues required for the induction of the transcription factor IRF1. In a later phase, STAT1 phosphorylation and JNK activation are required to trigger CIIta expression. CypA is needed for STAT1 phosphorylation in this last phase and to bind the CIIta promoter. Our findings demonstrate that STAT1 is required in a two-step induction of CIIta, once again highlighting the significance of cross talk between signaling pathways in macrophages.

Mitofusin 2 in Macrophages Links Mitochondrial ROS Production, Cytokine Release, Phagocytosis, Autophagy, and Bactericidal Activity.

Mitofusin 2 (Mfn2) plays a major role in mitochondrial fusion and in the maintenance of mitochondria-endoplasmic reticulum contact sites. Given that macrophages play a major role in inflammation, we studied the contribution of Mfn2 to the activity of these cells. Pro-inflammatory stimuli such as lipopolysaccharide (LPS) induced Mfn2 expression. The use of the Mfn2 and Mfn1 myeloid-conditional knockout (KO) mouse models reveals that Mfn2 but not Mfn1 is required for the adaptation of mitochondrial respiration to stress conditions and for the production of reactive oxygen species (ROS) upon pro-inflammatory activation. Mfn2 deficiency specifically impairs the production of pro-inflammatory cytokines and nitric oxide. In addition, the lack of Mfn2 but not Mfn1 is associated with dysfunctional autophagy, apoptosis, phagocytosis, and antigen processing. Mfn2floxed;CreLysM mice fail to be protected from Listeria, Mycobacterium tuberculosis, or LPS endotoxemia. These results reveal an unexpected contribution of Mfn2 to ROS production and inflammation in macrophages.

Seudohipoparatiroidismo 1b / Pseudohypoparathyroidism 1b

RESUMEN El seudohipoparatiroidismo 1b se caracteriza por resistencia aislada a la parathormona, en ausencia de las manifestaciones típicas de la osteodisfrofia hereditaria de Albright; debido a alteraciones epigenéticas del locus GNAS. Puede presentarse de forma esporádica, o heredado de manera autosómico dominante por vía materna. Se presenta paciente masculino de 31 años, con antecedentes de tumores óseos y calcificaciones cerebrales diagnosticados a los 14 años; que se consulta por presentar mareo intenso, rigidez del cuello y la boca, dificultad para hablar y tragar, desorientación y trastornos de percepción; con fenotipo y somatometría normales, y signos de tetania latente (Chvostek y Trouseau positivos). Los estudios realizados mostraron: hipocalcemia, hiperfosfatemia, aumento de niveles de parathormona y múltiples calcificaciones en cerebro y cerebelo. Con tales hallazgos se emite el diagnóstico de seudohipoparatiroidismo 1b, el cual se confirma mediante pruebas moleculares con alteración en el patrón de metilación en el locus GNAS. No presentó alteraciones en el estudio de secuenciación de los 13 exones codificantes del GNAS. Se concluyó como un caso esporádico ante la ausencia de historia familiar de hipocalcemia, combinado con amplia pérdida de metilación del gen GNAS y la no evidencia de deleciones. Se presenta el primer reporte de esta enfermedad en Cuba con estudio molecular(AU)

ABSTRACT Pseudohypoparathyroidism 1b is characterized by isolated resistance to parathormone, in the absence of the typical manifestations of hereditary Albright osteodysphrophy; due to epigenetic alterations of the GNAS locus. It can occur sporadically, or inherited in an autosomal dominant way through the mother. We report the case of a 31-year-old male patient, with history of bone tumors and cerebral calcifications diagnosed at age 14. She came to consultation due to severe dizziness, stiff neck and mouth, difficulty speaking and swallowing, disorientation and perception disorders; he showed normal phenotype and somatometry, and signs of latent tetany (positive Chvostek and Trouseau). Studies have shown hypocalcaemia, hyperphosphatemia, increased levels of parathormone and multiple calcifications in the brain and cerebellum. These findings, pseudohypoparathyroidism 1b is diagnosed confirmed by molecular tests showing alteration in the methylation pattern in the GNAS locus. There were no alterations in the sequencing study of the 13 exons coding for GNAS. It was concluded as a sporadic case in the absence of a family history of hypocalcemia, combined with extensive loss of GNAS gene methylation and no evidence of deletions. This is the first report this disease with molecular study in Cuba(AU)

Mitogen-Activated Protein Kinases and Mitogen Kinase Phosphatase 1: A Critical Interplay in Macrophage Biology.

Macrophages are necessary in multiple processes during the immune response or inflammation. This review emphasizes the critical role of the mitogen-activated protein kinases (MAPKs) and mitogen kinase phosphatase-1 (MKP-1) in the functional activities of macrophages. While the phosphorylation of MAPKs is required for macrophage activation or proliferation, MKP-1 dephosphorylates these kinases, thus playing a balancing role in the control of macrophage behavior. MKP-1 is a nuclear-localized dual-specificity phosphatase whose expression is regulated at multiple levels, including at the transcriptional and post-transcriptional level. The regulatory role of MKP-1 in the interplay between MAPK phosphorylation/dephosphorylation makes this molecule a critical regulator of macrophage biology and inflammation.

NBS1 is required for macrophage homeostasis and functional activity in mice.

Nijmegen breakage syndrome 1 (NBS1) is a component of the MRE11 complex, which is a sensor of DNA double-strand breaks and plays a crucial role in the DNA damage response. Because activated macrophages produce large amounts of reactive oxygen species (ROS) that can cause DNA lesions, we examined the role of NBS1 in macrophage functional activity. Proliferative and proinflammatory (interferon gamma [IFN-γ] and lipopolysaccharide [LPS]) stimuli led to increased NBS1 levels in macrophages. In mice expressing a hypomorphic allele of Nbs1, Nbs1(∆B/∆B), macrophage activation-induced ROS caused increased levels of DNA damage that were associated with defects in proliferation, delayed differentiation, and increased senescence. Furthermore, upon stimulation, Nbs1(∆B/∆B) macrophages exhibited increased expression of proinflammatory cytokines. In the in vivo 2,4-dinitrofluorobenzene model of inflammation, Nbs1(∆B/∆B) animals showed increased weight and ear thickness. By using the sterile inflammation by zymosan injection, we found that macrophage proliferation was drastically decreased in the peritoneal cavity of Nbs1(∆B/∆B) mice. Our findings show that NBS1 is crucial for macrophage function during normal aging. These results have implications for understanding the immune defects observed in patients with NBS and related disorders.

An Intensive Lifestyle Intervention Is an Effective Treatment of Morbid Obesity: The TRAMOMTANA Study-A Two-Year Randomized Controlled Clinical Trial.

Bariatric surgery is currently the most effective therapy to induce weight loss in morbidly obese patients. Objective. This controlled, clinical trial with a two-year intervention was aimed at comparing the efficacy of two nonsurgical approaches versus bariatric surgery, on body weight changes and metabolic parameters in morbidly obese patients. Methods. Patients were randomized to an Intensive Lifestyle Intervention (ILI) (n = 60) or Conventional Obesity Therapy (COT) (n = 46). The ILI group received behavioral therapy and nutritional counseling. The COT group received standard medical treatment. They were compared with a third group, Surgical Obesity Group (SOG) (n = 37). Results. Patients who received ILI had a greater percentage of weight loss than patients receiving COT (-11.3% versus -1.6%; p < 0.0044). Interestingly 31.4% of patients included in the ILI group were no longer morbidly obese after just six months of intervention, increasing to 44.4% after 24 months of intervention. The percentage weight loss in SOG was -29.6% after that same period of time. Conclusions. ILI was associated with significant weight loss when compared to COT, in a group of patients with obesity. An ILI approach could be an alternative therapy to patients with obesity, who are not candidates to undergo bariatric surgery. This trial is registered with EudraCT 2009-013737-24.

How can we predict which morbidly obese patients will adhereto weight-loss programs based on life style changes?

Introduction Dropout is a highly prevalent and serious problem in assessing the effectiveness of weight loss studies and a major cause of treatment failure in the management of morbidly obese patients. Objectives To determine which tests used for the psychometric evaluation of morbidly obese patients are more predictive of success/dropout in a weight loss program. Methods Sixty patients aged 18–65 attending the Outpatient Obesity Clinic between 2009 and 2011, were recruited for an intensive life style weight loss program. We compared the results obtained in Hamilton Depression scale, Hamilton Anxiety scale, Golombok Rust Inventory of Sexual Satisfaction, Eating Disorders Inventory-2, SF-36 Health Survey and Plutchik's Impulsivity questionnaire between patients who completed the intervention with those obtained in patients who did not complete it. Results The rate of decline in the patients attending our program was 41.6% in the first year. Our results suggest that the Plutchik Impulsivity questionnaire, could be used as a predictive tool for success/attrition in intensive life style weight loss program. Conclusions Our results suggest that the Plutchik Impulsivity questionnaire, could be used as a predictive tool for success/attrition in intensive life style weight loss program. The screening of patients prior to inclusion in these programs should help to optimize its efficacy and efficiency (AU)

Introducción Los abandonos son un problema muy frecuente y serio cuando se valora la eficacia de los estudios sobre la pérdida de peso y una causa importante de fracaso del tratamiento en los pacientes con obesidad mórbida. Objetivos Determinar qué pruebas empleadas en la evaluación psicométrica de obesos mórbidos predicen mejor el éxito o el abandono de un programa de pérdida de peso. Métodos Se reclutó a 60 pacientes de 18–65 años de edad que acudían a la consulta externa de obesidad entre 2009 y 2011 para un programa intensivo de pérdida de peso basado en el modo de vida. Se compararon los resultados obtenidos en la escala de depresión de Hamilton, la escala de ansiedad de Hamilton, el Golombok Rust Inventory of Sexual Satisfaction, el Eating Disorders Inventory-2, la encuesta de salud SF-36 y el Plutchik's Impulsivity Questionnaire de los pacientes que completaron y no completaron la intervención. Resultados La tasa de descenso en los pacientes que acudían a nuestro programa fue del 41,6% en el primer año. Nuestros resultados sugieren que el Plutchik Impulsivity Questionnaire podría ser una herramienta útil para identificar a los sujetos predispuestos a abandonar el programa. Conclusiones Nuestros resultados indican que el Plutchik Impulsivity Questionnaire puede utilizarse como herramienta pronóstica del éxito o deserción de un programa intensivo de pérdida de peso basado en el modo de vida. La selección de los pacientes antes de su inclusión en estos programas debe ayudar a optimizar su eficacia y eficiencia (AU)

How can we predict which morbidly obese patients will adhere to weight-loss programs based on life style changes?

INTRODUCTION: Dropout is a highly prevalent and serious problem in assessing the effectiveness of weight loss studies and a major cause of treatment failure in the management of morbidly obese patients. OBJECTIVES: To determine which tests used for the psychometric evaluation of morbidly obese patients are more predictive of success/dropout in a weight loss program. METHODS: Sixty patients aged 18-65 attending the Outpatient Obesity Clinic between 2009 and 2011, were recruited for an intensive life style weight loss program. We compared the results obtained in Hamilton Depression scale, Hamilton Anxiety scale, Golombok Rust Inventory of Sexual Satisfaction, Eating Disorders Inventory-2, SF-36 Health Survey and Plutchik's Impulsivity questionnaire between patients who completed the intervention with those obtained in patients who did not complete it. RESULTS: The rate of decline in the patients attending our program was 41.6% in the first year. Our results suggest that the Plutchik Impulsivity questionnaire, could be used as a predictive tool for success/attrition in intensive life style weight loss program. CONCLUSIONS: Our results suggest that the Plutchik Impulsivity questionnaire, could be used as a predictive tool for success/attrition in intensive life style weight loss program. The screening of patients prior to inclusion in these programs should help to optimize its efficacy and efficiency.

One year weight loss in the TRAMOMTANA study. A randomized controlled trial.

BACKGROUND: Morbid obesity is a major health problem and bariatric surgery is currently the most effective therapy available to induce weight loss in these patients. This report describes 1-year changes in weight and metabolic parameters, in a trial designed to examine the effects of a nonsurgical approach, Intensive Life style Intervention (ILI) on the therapy of morbid obesity. METHODS: The primary outcome was change in body weight. Patients were randomized to ILI (n = 60) or conventional obesity therapy (COT) (n = 46). The ILI group received behavioural therapy and nutritional/physical activity counselling. The COT group received the standard medical treatment available for these patients. A third group consisted of the patients already included in our bariatric surgery waiting list (n = 37). FINDINGS: We present here 1-year data showing that patients who received ILI with no restrictions in calorie intake had a greater percentage of weight loss than patients receiving COT (-11·58% vs -0·4%; P < 0·001). Importantly, 31·4% of patients included in the ILI group were not morbidly obese after 6 months of intervention. This number increased to 42·8% after 12 months of intervention. INTERPRETATION: ILI was associated with significant weight loss compared with COT in a group of morbidly obese patients. The weight loss effect was already obtained after 6 months of ILI intervention. These results seriously question the efficacy of the COT approach to morbid obesity. Furthermore, they underscore the use of ILI programmes in the hospital setting to effectively treat morbidly obese patients and might help to reduce the number of candidate patients for bariatric surgery.

ACTYBOSS: activity, behavioral therapy in young subjects--after-school intervention pilot project on obesity prevention.

AIMS: To test the feasibility of a school-based intervention, which combines an incentive-driven physical activity program with lifestyle lectures, and its potential beneficial outcome on children's metabolic parameters. METHODS: We conducted a 6-month pilot intervention in two high schools in Mallorca, Spain, consisting of a program which involved free supervised exercise sessions and nutritional lectures, where children received credit points as a reward for the hours spent exercising and attendance to the lectures. The credit-earned points obtained were exchanged for gifts. We developed personalized cards and a web application for the participants to check the gifts they were eligible for (www.actyboss.com). Percentage body fat, percentage of fat-free mass and BMI were measured. Secondary measures included fitness parameters, blood pressure and blood lipids levels. 90 children signed up the consent form and 56 completed the program until the endpoint. RESULTS: We found a beneficial effect on body composition, fitness parameters, and systolic blood pressure in children who participated in ACTYBOSS compared to children who did not start the intervention. CONCLUSIONS: We describe the incentive-driven, after-school intervention pilot program to promote physical activity and a healthy lifestyle. The program had a positive effect on anthropometric measurements. A larger incentive-driven healthy lifestyle program is now ongoing.

Puntos clave en la puesta en marcha y desarrollo de un Ensayo Clínico. De la pregunta a la realidad de un Ensayo Clínico investigador iniciado (I) / Key points in the start and conduct of a clinical trial. From question to reality in an investigator-initiated clinical trial (I)

La práctica clínica basada en la evidencia requiere la integración de la experiencia profesional individual con los mejores datos objetivos para tomar la mejor decisión terapéutica. Los datos científicos de mejor grado de evidencia derivan de ensayos clínicos controlados y aleatorizados e investigaciones de vigilancia farmacológica poscomercialización y metaanálisis. En muchas ocasiones durante nuestras actividades clínicas buscamos sin éxito el ensayo clínico que conteste a nuestras preguntas científicas. Es en estos momentos cuando en ocasiones nos planteamos la puesta en marcha de un ensayo clínico. Si usted como investigador clínico tiene una pregunta científica (relevante), que potencialmente requeriría la realización de un Ensayo Clínico para alcanzar una respuesta y carece del respaldo de una Compañía Farmacéutica para llevarlo a cabo, quizá encuentre de utilidad la lectura de este artículo, en el que intentamos presentar de forma breve y clarificadora la normativa regulatoria para planificar un Ensayo Clínico, con la humilde intención de que se convierta en una herramienta útil para cualquier investigador independiente (AU)

Evidence-based clinical practice requires integration of individual professional experience with the best objective data to make the best therapeutic decision. The best degree of scientific evidence derives from controlled, randomized clinical trials and post-marketing drug surveillance studies and meta-analyses. During our clinical activities, we often search unsuccessfully for a clinical trial which answers our scientific questions. It is at those times that we may sometimes consider the conduct of a clinical trial. If you, as a clinical investigator, have a (relevant) scientific question that could potentially require the conduct of a clinical trial to achieve a response and have no support from a pharmaceutical company to perform it, you may find it useful to read this article, in which an attempt has been made to briefly and clearly explain the applicable regulations for planning a clinical trial. Our humble intention is that this publication becomes a useful tool for any independent researche (AU)

TRAMOMTANA (Tratamiento Multidisciplinar de la Obesidad Mórbida: Medicamentos, Terapia de comportamiento, Apoyo Nutricional y Actividad física). De la pregunta a la realidad de un ensayo clínico investigador iniciado (II) / TRAMOMTANA (Multidisciplinary treatment of morbid obesity: Medication, behavioral therapy, nutritional support, and physical activity). From question to reality in an investigator-initiated clinical trial (II)

Comunicamos la puesta en marcha de un programa intensivo y multidisciplinar de pérdida de peso en pacientes con obesidad mórbida (OM). Este ensayo clínico se basa en la educación para la salud, el apoyo en el proceso de cambio, los medicamentos y las sesiones de terapia de grupo. Nuestra intención es demostrar que los resultados obtenidos con este programa de pérdida de peso a 2 años son, cuando menos, comparables a los resultados que se obtienen con la cirugía bariátrica en estos pacientes con OM. Es nuestra intención igualmente (..) (AU)

Implementation of an intensive, multidisciplinary weight loss program in patients with morbid obesity is reported. This program is based on behavioral changes, lifestyle intervention, medication, and group therapy sessions. Our objective is to show that the results achieved with this two-year weight loss program will be at least similar to those achieved with bariatric surgery in patients with morbid obesity. We also intend to show that this multidisciplinary treatment induces an improvement in the comorbidity rate associated to smaller costs for our national health system (AU)

[TRAMOMTANA (Multidisciplinary treatment of morbid obesity: medication, behavioral therapy, nutritional support, and physical activity). From question to reality in an investigator-initiated clinical trial (II)]. / TRAMOMTANA (Tratamiento Multidisciplinar de la Obesidad Mórbida: Medicamentos, Terapia de comportamiento, Apoyo Nutricional y Actividad física). De la pregunta a la realidad de un ensayo clínico investigador iniciado (II).

Implementation of an intensive, multidisciplinary weight loss program in patients with morbid obesity is reported. This program is based on behavioral changes, lifestyle intervention, medication, and group therapy sessions. Our objective is to show that the results achieved with this two-year weight loss program will be at least similar to those achieved with bariatric surgery in patients with morbid obesity. We also intend to show that this multidisciplinary treatment induces an improvement in the comorbidity rate associated to smaller costs for our national health system.

[Key points in the start and conduct of a clinical trial. From question to reality in an investigator-initiated clinical trial (I)]. / Puntos clave en la puesta en marcha y desarrollo de un Ensayo Clínico. De la pregunta a la realidad de un Ensayo Clínico investigador iniciado (I).

Evidence-based clinical practice requires integration of individual professional experience with the best objective data to make the best therapeutic decision. The best degree of scientific evidence derives from controlled, randomized clinical trials and post-marketing drug surveillance studies and meta-analyses. During our clinical activities, we often search unsuccessfully for a clinical trial which answers our scientific questions. It is at those times that we may sometimes consider the conduct of a clinical trial. If you, as a clinical investigator, have a (relevant) scientific question that could potentially require the conduct of a clinical trial to achieve a response and have no support from a pharmaceutical company to perform it, you may find it useful to read this article, in which an attempt has been made to briefly and clearly explain the applicable regulations for planning a clinical trial. Our humble intention is that this publication becomes a useful tool for any independent researcher.

Salidas terapéuticas: espacio lúdico para la integración / Therapeutic outings: a playing space for integration

Las actividades de ocio y tiempo libre deben ser una parte importante de cualquier programa integral de rehabilitación en personas con enfermedad mental grave (AU)

A Program for preparation for leisure time it seems to us a esencial element of a Rehabilitation Unit for patients with an important mental illness (AU)