La presencia de receptores Fc de IgG activadores en macrófagos agrava el desarrollo de aneurisma aórtico abdominal experimental / The presence of activating IgG Fc receptors in macrophages aggravates the development of experimental abdominal aortic aneurysm

Introducción: El aneurisma aórtico abdominal (AAA) es una afección degenerativa y multifactorial caracterizada por una dilatación progresiva de la aorta y activación crónica de inflamación, actividad proteolítica y estrés oxidativo en la pared vascular. La respuesta inmune dependiente de anticuerpos IgG frente a antígenos expuestos en el vaso dañado está implicada en la formación y progresión del AAA, aunque los mecanismos no son del todo conocidos. En este trabajo analizamos la funcionalidad de los receptores Fc de IgG (FcγR), en particular los expresados por el monocito/macrófago, en el desarrollo del AAA experimental. Métodos: En el modelo de AAA inducido por perfusión aórtica de elastasa se examinaron, mediante histología y PCR cuantitativa, las aortas abdominales de ratones de fenotipo salvaje y de ratones deficientes en FcγR, sin y con transferencia adoptiva de macrófagos. In vitro, macrófagos murinos se transfectaron con ARN de interferencia de FcγRIV/CD16.2 o se trataron con un inhibidor de la cinasa Syk antes de la estimulación con inmunocomplejos de IgG. Resultados: La transferencia adoptiva de macrófagos a ratones deficientes en FcγR incrementó su susceptibilidad al desarrollo de AAA. En los ratones que recibieron macrófagos con FcγR funcionales se observó un mayor incremento del diámetro aórtico y del contenido de macrófagos y linfocitos B, así como un aumento en la expresión de la quimiocina CCL2, las citocinas TNF-α e IL-17, la metaloproteinasa MMP2, la enzima prooxidante NADPH oxidasa-2 y las isoformas FcγRIII/CD16 y FcγRIV/CD16.2. In vitro, tanto el silenciamiento génico de FcγRIV/CD16.2 como la inhibición de Syk en macrófagos redujeron la producción de citocinas y anión superóxido inducida por inmunocomplejos...(AU)

Introduction: Abdominal aortic aneurysm (AAA) is a multifactorial, degenerative disease characterized by progressive aortic dilation and chronic activation of inflammation, proteolytic activity, and oxidative stress in the aortic wall. The immune response triggered by antibodies against antigens present in the vascular wall participates in the formation and progression of AAA through mechanisms not completely understood. This work analyses the function of specific IgG receptors (FcγR), especially those expressed by monocytes/macrophages, in the development of experimental AAA. Methods: In the elastase-induced AAA model, the abdominal aortas from wildtype and FcγR deficient mice with/without macrophage adoptive transfer were analysed by histology and quantitative PCR. In vitro, mouse macrophages were transfected with RNA interference of FcγRIV/CD16.2 or treated with Syk kinase inhibitor before stimulation with IgG immune complexes. Results: Macrophage adoptive transfer in FcγR deficient mice increased the susceptibility to AAA development. Mice receiving macrophages with functional FcγR exhibited higher aortic diameter increase, higher content of macrophages and B lymphocytes, and upregulated expression of chemokine CCL2, cytokines (TNF-α and IL-17), metalloproteinase MMP2, prooxidant enzyme NADPH oxidase-2, and the isoforms FcγRIII/CD16 and FcγRIV/CD16.2. In vitro, both FcγRIV/CD16.2 gene silencing and Syk inhibition reduced cytokines and reactive oxygen species production induced by immune complexes in macrophages. Conclusions: Activation of macrophage FcγR contributes to AAA development by inducing mediators of inflammation, proteolysis, and oxidative stress. Modulation of FcγR or effector molecules may represent a potential target for AAA treatment.

The presence of activating IgG Fc receptors in macrophages aggravates the development of experimental abdominal aortic aneurysm. / La presencia de receptores Fc de IgG activadores en macrófagos agrava el desarrollo de aneurisma aórtico abdominal experimental.

INTRODUCTION: Abdominal aortic aneurysm (AAA) is a multifactorial, degenerative disease characterized by progressive aortic dilation and chronic activation of inflammation, proteolytic activity, and oxidative stress in the aortic wall. The immune response triggered by antibodies against antigens present in the vascular wall participates in the formation and progression of AAA through mechanisms not completely understood. This work analyses the function of specific IgG receptors (FcγR), especially those expressed by monocytes/macrophages, in the development of experimental AAA. METHODS: In the elastase-induced AAA model, the abdominal aortas from wildtype and FcγR deficient mice with/without macrophage adoptive transfer were analysed by histology and quantitative PCR. In vitro, mouse macrophages were transfected with RNA interference of FcγRIV/CD16.2 or treated with Syk kinase inhibitor before stimulation with IgG immune complexes. RESULTS: Macrophage adoptive transfer in FcγR deficient mice increased the susceptibility to AAA development. Mice receiving macrophages with functional FcγR exhibited higher aortic diameter increase, higher content of macrophages and B lymphocytes, and upregulated expression of chemokine CCL2, cytokines (TNF-α and IL-17), metalloproteinase MMP2, prooxidant enzyme NADPH oxidase-2, and the isoforms FcγRIII/CD16 and FcγRIV/CD16.2. In vitro, both FcγRIV/CD16.2 gene silencing and Syk inhibition reduced cytokines and reactive oxygen species production induced by immune complexes in macrophages. CONCLUSIONS: Activation of macrophage FcγR contributes to AAA development by inducing mediators of inflammation, proteolysis, and oxidative stress. Modulation of FcγR or effector molecules may represent a potential target for AAA treatment.

Persistent decrease in alpha current density in fully remitted subjects with major depressive disorder treated with fluoxetine: A prospective electric tomography study.

Major depressive disorder (MDD) is recurrent, and its pathophysiology is not fully understood. Studies using electric tomography (ET) have identified abnormalities in the current density (CD) of MDD subjects in regions associated with the neurobiology of MDD, such as the anterior cingulate cortex (ACC) and medial orbitofrontal cortex (mOFC). However, little is known regarding the long-term CD changes in MDD subjects who respond to antidepressants. The aim of this study was to compare CD between healthy and MDD subjects who received 1-year open-label treatment with fluoxetine. Thirty-two-channel electroencephalograms (EEGs) were collected from 70 healthy controls and 74 MDD subjects at baseline (pre-treatment), 1 and 2weeks and 1, 2, 6, 9 and 12months. Variable-resolution ET (VARETA) was used to assess the CD between subject groups at each time point. The MDD group exhibited decreased alpha CD (αCD) in the occipital and parietal cortices, ACC, mOFC, thalamus and caudate nucleus at each time point. The αCD abnormalities persisted in the MDD subjects despite their achieving full remission. The low sub-alpha band was different between the healthy and MDD subjects. Differences in the amount of αCD between sexes and treatment outcomes were observed. Lack of a placebo arm and the loss of depressed patients to follow-up were significant limitations. The persistence of the decrease in αCD might suggest that the underlying pathophysiologic mechanisms of MDD are not corrected despite the asymptomatic state of MDD subjects, which could be significant in understanding the highly recurrent nature of MDD.

ADHD prevalence in adult outpatients with nonpsychotic psychiatric illnesses.

OBJECTIVE: The prevalence of ADHD in the general adult population has been estimated to be about 4.4%. However, few studies exist in which the prevalence of ADHD in psychiatric adult outpatient samples has been estimated. These studies suggest that the prevalence is higher than in the general population. The objective of this study is to estimate the prevalence of ADHD in a psychiatric nonpsychotic adult outpatient sample and to compare this data with the prevalence of a group of nonclinical participants. METHOD: The structured clinical interview Mini International Neuropsychiatric Interview (M.I.N.I.-Plus) was applied to 161 consecutive nonpsychotic psychiatric adult outpatients and to 149 healthy participants from the community. In addition, clinical rating scales were applied to measure the severity of general psychopathology such as mania, anxiety, depression, ADHD, and alcohol consumption in both groups. RESULTS: The prevalence of ADHD in psychiatric nonpsychotic adult outpatients was 16.80% and 5.37% in nonclinical participants. In male psychiatric outpatients the prevalence of ADHD was 8.5% and for females was 21.6%. CONCLUSION: This study concludes that a higher prevalence of ADHD exists in psychiatric nonpsychotic adult outpatients compared with nonclinical participants. In the psychiatric adult outpatients, females showed a higher prevalence of ADHD than males. Implications and limitations are discussed.