Somatic multicomorbidity and disability in patients with psychiatric disorders in comparison to the general population: a quasi-epidemiological investigation in 54,826 subjects from 40 countries (COMET-G study).

BACKGROUND: The prevalence of medical illnesses is high among patients with psychiatric disorders. The current study aimed to investigate multi-comorbidity in patients with psychiatric disorders in comparison to the general population. Secondary aims were to investigate factors associated with metabolic syndrome and treatment appropriateness of mental disorders. METHODS: The sample included 54,826 subjects (64.73% females; 34.15% males; 1.11% nonbinary gender) from 40 countries (COMET-G study). The analysis was based on the registration of previous history that could serve as a fair approximation for the lifetime prevalence of various medical conditions. RESULTS: About 24.5% reported a history of somatic and 26.14% of mental disorders. Mental disorders were by far the most prevalent group of medical conditions. Comorbidity of any somatic with any mental disorder was reported by 8.21%. One-third to almost two-thirds of somatic patients were also suffering from a mental disorder depending on the severity and multicomorbidity. Bipolar and psychotic patients and to a lesser extent depressives, manifested an earlier (15-20 years) manifestation of somatic multicomorbidity, severe disability, and probably earlier death. The overwhelming majority of patients with mental disorders were not receiving treatment or were being treated in a way that was not recommended. Antipsychotics and antidepressants were not related to the development of metabolic syndrome. CONCLUSIONS: The finding that one-third to almost two-thirds of somatic patients also suffered from a mental disorder strongly suggests that psychiatry is the field with the most trans-specialty and interdisciplinary value and application points to the importance of teaching psychiatry and mental health in medical schools and also to the need for more technocratically oriented training of psychiatric residents.

Update on the use and management of lithium in neuropsychiatry / Actualización en el uso y el manejo del litio en neuropsiquiatría.

Lithium is an alkaline metal, used for more than 60 years in psychiatry, and currently considered the gold standard in the treatment of bipolar disorder (BD). According to recent evidence, this active ingredient is useful for the treatment of a wide spectrum of clinical varieties of affective disorders. In addition, it is estimated that lithium reduces the risk of suicide and suicidal behavior in people with mood disorders. On the other hand, some novel studies have shown that the cation has a potential efficacy for the treatment of other neuropsychiatric processes, such as the likelihood of reducing the risk of dementia and slowing down the development of neurodegenerative diseases. Despite the enormous evidence in favor of the use of lithium, it is known that, in Argentina, medications containing it are prescribed less than expected. In view of all this, the Asociación Argentina de Psiquiatría Biológica (Argentine Association of Biological Psychiatry) (AAPB or AABP) convened a group of experts to review the available scientific literature and prepare an updated document on the management and use of lithium in neuropsychiatry. In addition to the use of the ion in daily clinical practice, the scope of this review includes other contents that have been considered of interest for the psychiatrist, such as certain pharmacological and pharmacogenetic aspects, possible clinical predictors of response to treatment with lithium, management of ion during perinatal period, management of lithium in child and adolescent population, management of adverse effects linked to cation and interactions with drugs and other substances.

El litio es un metal alcalino, usado hace más de 60 años en psiquiatría, y actualmente es considerado el estándar de oro en el tratamiento del trastorno bipolar (TB). De acuerdo con la evidencia reciente, este principio activo es útil para el tratamiento de un amplio espectro de variedades clínicas de los trastornos afectivos. Además, se estima que desde hace tiempo el litio reduce el riesgo de suicidio y de comportamiento suicida en personas con trastornos del estado de ánimo. Por otro lado, algunos estudios novedosos han demostrado que el catión posee una potencial eficacia para el tratamiento de otros procesos neuropsiquiátricos, tales como la probabilidad de disminuir el riesgo de demencia y la de ralentizar el desarrollo de enfermedades neurodegenerativas. A pesar de la enorme evidencia a favor de la utilización del litio, se sabe que, en la Argentina, las especialidades medicinales que lo contienen se prescriben menos de lo esperado. En virtud de todo lo mencionado, la Asociación Argentina de Psiquiatría Biológica (AAPB) convocó a un grupo de expertos para revisar la literatura científica disponible y elaborar un documento actualizado sobre el manejo y el uso del litio en neuropsiquiatría. Además de la utilización del ion en la práctica clínica diaria, el alcance de esta revisión incluye otros contenidos que se han considerado de interés para el médico psiquiatra, tales como ciertos aspectos farmacológicos y farmacogenéticos, posibles predictores clínicos de la respuesta al tratamiento con litio, el manejo del ion durante el período perinatal, el manejo de litio en la población infantojuvenil, el manejo de los efectos adversos vinculados con el catión y las interacciones con medicamentos y otras sustancias.

Chronic Trypanosoma cruzi infection activates the TWEAK/Fn14 axis in cardiac myocytes and fibroblasts driving structural and functional changes that affect the heart.

Sustained interaction between the cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its functional receptor, fibroblast growth factor-inducible 14 (Fn14), has been linked to cardiovascular disorders. Chagas cardiomyopathy, elicited by Trypanosoma cruzi infection, is associated with chronic inflammation, fibrosis and hypertrophy. This study aimed to explore the involvement of the TWEAK/Fn 14 axis in development of Chagas heart disease. Parasite infection in vitro triggered Fn14 overexpression in atrial HL-1 myocytes and cardiac MCF fibroblasts. Fn14 levels were also increased in heart tissue from C57BL/6 mice at 130 days post-infection, particularly in myocytes and fibroblasts. Concurrently, TWEAK expression in circulating monocytes from this group was higher than that determined in uninfected controls. TWEAK/Fn14 interaction was functional in myocytes and fibroblasts isolated from infected hearts, leading to TNF receptor-associated factor 2 (TRAF2)-mediated activation of nuclear factor kappa B (NFκB) signaling. Ex vivo stimulation of both cell types with recombinant TWEAK for 24 h boosted the NFκB-regulated production of proinflammatory/profibrotic mediators (IL-1ß, IL-6, TNF-α, IL-8, CCL2, CCL5, MMP-2, MMP-9, ICAM-1, E-selectin) involved in chronic T. cruzi cardiomyopathy. We further evaluated the therapeutic potential of the soluble decoy receptor Fn14-Fc to interfere with TWEAK/Fn14-dependent pathogenic activity. Fn14-Fc treatment of chronically infected mice was effective in neutralizing the ligand and reverting electrocardiographic abnormalities, maladaptive inflammation, adverse remodeling and hypertrophy in myocardium. Altogether, these findings suggest that sustained TWEAK/Fn14 induction by persistent T. cruzi infection is implicated in cardiopathogenesis and make TWEAK/Fn14 axis a promising target for the treatment of chronic Chagas heart disease.

Results of the COVID-19 mental health international for the health professionals (COMET-HP) study: depression, suicidal tendencies and conspiracism.

INTRODUCTION: The current study aimed to investigate the rates of anxiety, clinical depression, and suicidality and their changes in health professionals during the COVID-19 outbreak. MATERIALS AND METHODS: The data came from the larger COMET-G study. The study sample includes 12,792 health professionals from 40 countries (62.40% women aged 39.76 ± 11.70; 36.81% men aged 35.91 ± 11.00 and 0.78% non-binary gender aged 35.15 ± 13.03). Distress and clinical depression were identified with the use of a previously developed cut-off and algorithm, respectively. STATISTICAL ANALYSIS: Descriptive statistics were calculated. Chi-square tests, multiple forward stepwise linear regression analyses, and Factorial Analysis of Variance (ANOVA) tested relations among variables. RESULTS: Clinical depression was detected in 13.16% with male doctors and 'non-binary genders' having the lowest rates (7.89 and 5.88% respectively) and 'non-binary gender' nurses and administrative staff had the highest (37.50%); distress was present in 15.19%. A significant percentage reported a deterioration in mental state, family dynamics, and everyday lifestyle. Persons with a history of mental disorders had higher rates of current depression (24.64% vs. 9.62%; p < 0.0001). Suicidal tendencies were at least doubled in terms of RASS scores. Approximately one-third of participants were accepting (at least to a moderate degree) a non-bizarre conspiracy. The highest Relative Risk (RR) to develop clinical depression was associated with a history of Bipolar disorder (RR = 4.23). CONCLUSIONS: The current study reported findings in health care professionals similar in magnitude and quality to those reported earlier in the general population although rates of clinical depression, suicidal tendencies, and adherence to conspiracy theories were much lower. However, the general model of factors interplay seems to be the same and this could be of practical utility since many of these factors are modifiable.

Treatment-Resistant Depression in Argentina: results from a longitudinal analysis of the TRAL Study / Depresión resistente al tratamiento en Argentina: resultados de un análisis longitudinal del estudio TRAL.

Literature concerning patients with Treatment-Resistant Depression (TRD) treatment response and patient report outcomes (PROs) -such as QoL or disability- in Argentina is scarce. In the scope of the Treatment-Resistant Depression in America Latina (TRAL) study which previous results highlighted the burden of TRD compared to non-TRD patients as well as essential epidemiological data in the region, this paper reports on the outcomes of Standard-of-Care (SOC) over a 1-year follow-up of TRD patients in the subsample for Argentina. From a sample of 220 MDD patients identified in 5 sites in Argentina, 72 patients were diagnosed with TRD. Exclusion criteria included patients with psychosis, schizophrenia, bipolar disorder, schizoaffective disorder, dementia, with severe chemical dependence or currently participating in another clinical trial. MADRS, PHQ-9 and PROs (EQ-5D and SDS) were used as outcomes. Patients' mean age was 54.7 years and 70.3% of the patients were female. Around 61% of the patients achieved a response (reduction of MADRS score ≥ 50%), but over 33% did not achieve a remission (MADRS total score ≤12). Almost 67% of the patients still felt anxious/depressed at the end of the study (EQ-5D), while disruption affected patients in diverse areas -71% in work/school, 69.7% in social life/leisure and 66.6% in their family life/personal responsibilities. The burden of TRD is significant in Argentina, and more effort should be put in the implementation of treatment protocols with better outcomes.

La literatura disponible en relación a la respuesta al tratamiento de los pacientes con Depresión Resistente al Tratamiento (TRD) y los resultados del informe del paciente (PRO) -como la calidad de vida o la discapacidad- es escasa en Argentina. A partir de la submuestra de Argentina del estudio de depresión resistente al tratamiento en América Latina (TRAL), cuyos resultados anteriores destacaron la carga de TRD en comparación con los pacientes sin DRT, así como datos epidemiológicos esenciales en la región, este documento informa sobre los resultados del estándar de atención (Standard-of-Care, SOC) durante un seguimiento de 1 año de pacientes con DRT De una muestra de 220 pacientes con TDM de 5 centros de Argentina, 72 pacientes fueron diagnosticados con DRT. El criterio de exclusión excluyó a los pacientes con psicosis, esquizofrenia, trastorno bipolar, trastorno esquizoafectivo, demencia, dependencia química grave o que estaban participando en otro ensayo clínico. La MADRS, el PHQ-9 y los PRO (EQ-5D y SDS) se utilizaron como resultados. La edad media de los pacientes fue de 54,7 años y el 70,3 % de los pacientes eran mujeres. Alrededor del 61 % de los pacientes lograron una respuesta (reducción del ≥50 % en el puntaje total de MADRS), pero más del 33 %  no logró una remisión (puntuación total MADRS ≤12). Casi el 67 % de los pacientes seguían sintiéndose ansiosos/ deprimidos al final del estudio (EQ-5D), mientras que dicho trastorno afectó a los pacientes en diversas áreas: el 71 % en el trabajo/la escuela, el 69,7 % en la vida social/el tiempo libre y el 66,6 % en su vida familiar/las responsabilidades personales. La carga de la DRT es significativa en Argentina, y se debe hacer más esfuerzo en la implementación de protocolos de tratamiento con mejores resultados.

Third Argentine Consensus statement on management Bipolar Disorders. Section 2 B / Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares. Segunda Parte B.

This document constitutes the second section B of the Third Argentine Consensus on the Management of Bipolar Disorders, focused on synthesizing the most updated evidence on therapeutic approaches for adult patients. The scope of this section is to provide therapeutic recommendations for managing bipolar disorders in adults, (i) acute mania (ii) bipolar depression (iii) mixed stated (iv) suicidality and (vi) psychological interventions. In addition, the current manuscript outlines the assessment and management of side effects of pharmacotherapeutic treatments.

Este documento constituye la segunda parte B del Tercer Consenso Argentino sobre el Manejo de los Trastornos Bipolares llevada a cabo por la Asociación Argentina de Psiquiatría Biológica (AAPB). Siguiendo con el direccionamiento iniciado en el parte 2A sobre el tratamiento integral de los trastornos bipolares, esta sección se ha enfocado en sintetizar la evidencia más actualizada sobre abordajes terapéuticos para pacientes adultos. El alcance de esta sección es proporcionar recomendaciones terapéuticas para el manejo de los trastornos bipolares en adultos, (i) manía aguda, (ii) depresión bipolar, (iii) estado mixto, (iv) el suicidio en el trastorno bipolar, (v) intervenciones psicológicas. Además, el presente manuscrito aborda la evaluación y el manejo de los efectos secundarios de los tratamientos farmacoterapéuticos.

Third Argentine Consensus statement on management Bipolar Disorders. Section 2 A: Comprehensive treatment of the bipolar disorders in adults / Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares. Segunda Parte A: Tratamiento integral de los trastornos bipolares en el adulto.

This document constitutes the second section A of the Third Argentine Consensus on the Management of Bipolar Disorders, focused on synthesizing the most updated evidence on therapeutic approaches for adult patients. The aim of this section (2A) is to provide therapeutic recommendations for managing bipolar disorders in adults. In addition, the scope of this current manuscript outlines recommendations on the use of treatment guidelines, levels of evidence available to support these recommendations, general considerations for the treatment of bipolar disorders, the so-called pseudoresistance and adherence to treatment, general considerations on psychological therapies, as well as long term treatment of bipolar disorders.

Este documento corresponde a la segunda parte del Tercer Consenso Argentino sobre el manejo de los trastornos bipolares, enfocada en sintetizar la evidencia actualizada sobre los abordajes terapéuticos de esta patología en los pacientes adultos. Siguiendo la metodología descripta en la primera parte del Consenso, el panel de expertos realizó una exhaustiva revisión de la bibliografía y, como consecuencia de un posterior debate sobre la información disponible, se generó esta sección A del segundo documento que abarca el tratamiento integral de las personas adultas que padecen este trastorno. Durante la etapa de debate y discusión de estas guías, se decidió incorporar algunos puntos que estimamos serán de gran utilidad para el equipo interdisciplinario encargado del manejo de pacientes con trastornos bipolares.  En tal sentido, en la sección A de la segunda parte de este documento, se podrán encontrar las recomendaciones generales para el uso de las guías de tratamiento, los niveles de evidencia disponibles para sustentar las recomendaciones, las consideraciones generales del tratamiento de los trastornos bipolares, el fenómeno de pseudorresistencia y adherencia al tratamiento, las consideraciones generales sobre el abordaje psicológico, así como el tratamiento a largo plazo de los trastornos bipolares.

Third Argentine Consensus statement on management Bipolar Disorders. Section3: Bipolar Disorder in the context of special situations / Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares. Tercera parte: Manejo de los Trastornos Bipolares en el contexto de situaciones especiales.

This document constitutes the third and last part of the Third Argentine Consensus on the Management of Bipolar Disorders carried out by the Argentine Association of Biological Psychiatry (AAPB). Continuing with the initial objective, this section of the Consensus on the Management of Bipolar Disorders is focused on the management of bipolar disorders in special populations. This section constitutes a comprehensive review and expert consideration of the scientific evidence on: a) the management of bipolar disorders in treatment-resistant patients; b) the management of bipolar disorder in childhood and adolescence; c) the management of bipolar disorders in women during their perinatal period and, d) the management of bipolar disorders in older adults.

Este documento constituye la tercera y última parte del Tercer Consenso Argentino sobre el Manejo de los Trastornos Bipolares llevada a cabo por la Asociación Argentina de Psiquiatría Biológica (AAPB). Siguiendo con el objetivo propuesto por el comité de expertos, en la actual versión del Consenso sobre el manejo de los trastornos bipolares, esta sección está enfocada al abordaje de los Trastornos Bipolares en situaciones especiales. Esto configura una revisión exhaustiva de la evidencia científica  sobre: a) el manejo de los trastornos bipolares en pacientes resistentes al tratamiento, b) el manejo de los trastornos bipolares en la mujer en el período perinatal, c) el manejo del trastorno bipolar en la etapa infantojuvenil y d) el manejo de los trastornos bipolares en los adultos mayores.

The combined action of glycoinositolphospholipid from Trypanosoma cruzi and macrophage migration inhibitory factor increases proinflammatory mediator production by cardiomyocytes and vascular endothelial cells.

Cardiomyopathy is the most serious complication of chronic Chagas disease, caused by infection with the protozoan Trypanosoma cruzi. Exacerbated inflammation of the myocardium constitutes a major pathologic component of the disease. In the myocardial microenvironment, parasite antigens and host inflammatory mediators may aggravate tissue damage. The glycoinositolphospholipid (GIPL) from T. cruzi is an inflammation-eliciting antigen recognized by Toll-like receptor 4 (TLR4), whereas the proinflammatory cytokine macrophage migration inhibitory factor (MIF) promotes progression of chronic Chagas cardiomyopathy. We herein aimed to examine the involvement of GIPL and MIF in molecular mechanisms leading to a pathogenic inflammatory response in HL-1 cardiomyocytes and HMEC microvascular endothelial cells. Immunofluorescence analysis revealed that GIPL enhanced TLR4 expression in both cell types. We found that TLR4/GIPL interaction and MIF activity modulated the arachidonic acid pathway implicated in persistent inflammation. The combination of GIPL at 50 µg/ml and MIF at 50 ng/ml upregulated type 2 cyclooxygenase (COX-2) levels in HL-1 and HMEC cells, in a stronger way than each molecule acting independently. Moreover, increased expression of prostanoid synthases and release of prostaglandin E2 (PGE2) and thromboxane B2 (TxB2) were detected in stimulated cells. Transfection experiments in HL-1 and HMEC cells showed that COX-2 induction was transcriptionally regulated through GIPL-TLR4 engagement and NFκB signaling cascade. (GIPL + MIF)-triggered NFκB activation was markedly attenuated by treatment with 100 µM Fenofibrate, a PPAR-α ligand. Fenofibrate reduced COX-2-dependent generation of bioactive lipids in HL-1 and HMEC cells. In addition, Fenofibrate abolished (GIPL + MIF)-fostered release of NO, IL-1ß, IL-6, TNF-α, and CCL2. The combined actions of GIPL and MIF display potential for amplifying the inflammatory response in myocardium of parasite-infected hosts. Our current findings might help develop more effective measures to ameliorate cardiovascular abnormalities associated with Chagas heart disease.

[Major depressive disorder and treatment-resistant depression: an epidemiological analysis in Argentina of the Study of Treatment-Resistant Depression in Latin America]. / Trastorno depresivo mayor y depresión resistente al tratamiento: un análisis epidemiológico en Argentina del estudio de Depresión resistente al tratamiento en América Latina.

Treatment-Resistant Depression (TRD) prevalence varies considerable between regions and epidemiology of TRD in Argentina is lacking. Based on the Treatment-Resistant Depression in America Latina (TRAL) study, epidemiology and burden of TRD in MDD patients from Argentina is reported in this paper. A sample of adult MDD patients (n=396) from 5 sites in Argentina, with clinical diagnosis were included. Patients with psychosis, schizophrenia, bipolar disorder, schizoaffective disorder, dementia, with severe chemical dependence or currently participating in another clinical trial were excluded. Patient reported outcomes and clinical assessment scales were used as outcomes. The prevalence of TRD in MDD patients in Argentina is 33.2%, based on TRAL data. Patients in TRD are older compared to those without TRD, and was more evident in married/consensual union MDD patients. Higher suicidality, greater comorbidity based on MINI, and worse scores in MADRS and PHQ-9 were identified in TRD patients. The prevalence identified in TRAL study for Argentina is substantial comparing with other Latin American countries and worldwide prevalence. TRD represents a disproportional burden to society, and efforts should be placed on reducing the burden of MDD and TRD in Argentina by improving early diagnosis, therapeutic management and ensuring that all patients have better access to mental healthcare.

Third Argentine Consensus statement on management Bipolar Disorders. Section1: introduction and general concepts / Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares. Primera Parte: introducción, método de trabajo y generalidades.

The Third Argentine Consensus on the management of bipolar disorders (TB) is an initiative of the Argentine Association of Biological Psychiatry (AAPB). As a reference document, this consensus pursues two main objectives: on the one hand, to summarize and systematize the best available evidence on the comprehensive management of this pathology; on the other, to provide a useful, up-to-date instrument for psychiatrists, multidisciplinary teams dedicated to mental health, and government agencies. During a period of approximately six months of work -that is, from May to October 2022- a committee of experts made up of 18 professionals and representatives of the three most important Psychiatry and Mental Health associations in Argentina (that is, the AAPB, the Argentine Association of Psychiatrists, AAP, and the Association of Argentine Psychiatrists, APSA) have focused on updating the information regarding TB. Finally, this document was prepared as a result of an exhaustive review of the bibliography published to date, which was strategically divided into three parts: the first deals with the generalities of TB; the second deals with the comprehensive treatment of the pathology; finally, the third analyzes TB in the context of special situations.

El Tercer Consenso Argentino sobre el manejo de los Trastornos Bipolares (TB) es una iniciativa de la Asociación Argentina de Psiquiatría Biológica (AAPB). Como documento de referencia, este consenso persigue dos objetivos principales: por un lado, resumir y sistematizar la mejor evidencia disponible sobre el manejo integral de esta patología; por el otro, proporcionar un instrumento útil y actualizado a psiquiatras, a equipos multidisciplinarios abocados a la salud mental y a organismos gubernamentales. Durante un período de aproximadamente seis meses de trabajo -desde mayo a octubre de 2022- un comité de expertos integrado por 18 profesionales y por representantes de las tres asociaciones de Psiquiatría y Salud Mental más importantes de la Argentina: la AAPB, la Asociación Argentina de Psiquiatras, (AAP) y la Asociación de Psiquiatras Argentinos (APSA), se abocaron a actualizar la información respecto de los TB. Finalmente, y como resultado de una exhaustiva revisión de la bibliográfica publicada hasta la actualidad, se confeccionó este documento que fue dividido estratégicamente en tres partes: la primera versa acerca de las generalidades del TB; la segunda aborda el  tratamiento integral de la patología; y, por último, la tercera analiza los TB en el contexto de situaciones especiales.

[Argentine consensus on the diagnosis and therapeutics of treatment resistant schizophrenia]. / Consenso argentino sobre diagnóstico y tratamiento de la esquizofrenia resistente al tratamiento.

Approximately 30% of people with schizophrenia fail to respond to first-line antipsychotic treatment which impacts the burden of the disease. Treatment-resistant schizophrenia (TRS) denotes patients with failure to respond to at least two adequate trials of different antipsychotics. Clozapine is a unique drug approved for treating treatment-resistant schizophrenia, however 1/3 of patients fail to respond to clozapine. Even though different strategies have been proposed for treating clozapine-resistant schizophrenia, the evidence is very limited, unclear, and of poor quality. A formal literature search was conducted and then, panel members were asked to complete 35 questions addressing different aspects of TRS. A modified Delphi method was used to unify expert opinion and achieve consensus. The expert consensus in diagnostic and treatment of TRS is the result of experts from the main national scientific societies under the organization of the Argentine Association of Biological Psychiatric (AAPB). The consensus statement aims to guide on diagnosis and treatment.

HIF-1α-regulated MIF activation and Nox2-dependent ROS generation promote Leishmania amazonensis killing by macrophages under hypoxia.

Increasing attention is given to the finding that macrophages under hypoxia are capable of controlling infection by the intracellular protozoan parasite Leishmania amazonensis. The hypoxia-inducible factor (HIF)-1α has been shown to play an essential role in this enhanced innate immune response. Our study aimed to explore the HIF-1α-dependent mechanisms leading to reduced survival of the parasites residing in macrophages under low oxygen conditions. Hypoxia triggered (P < 0.01) NADPH oxidase 2 (Nox2) expression and reactive oxygen species (ROS) production in J774 macrophages upon 24-h infection with L. amazonensis. Furthermore, increased (P < 0.01) expression levels of HIF-1α and macrophage migration inhibitory factor (MIF) were detected in the infected cells grown at 3% oxygen tension. We found that either HIF-1α silencing, Nox2 inhibition or MIF antagonism caused a significant (P < 0.05) reversal of the improved leishmanicidal activity displayed by the hypoxic phagocytes. Taken together, our current results suggest that, under conditions of limited availability of oxygen, activation of the HIF-1α/MIF axis via Nox2/ROS induction promotes killing of L. amazonensis amastigotes by macrophages. Such protective mechanism might operate in L. amazonensis-infected tissues where low oxygen levels prevail.

Endogenous osteopontin induces myocardial CCL5 and MMP-2 activation that contributes to inflammation and cardiac remodeling in a mouse model of chronic Chagas heart disease.

Cardiac dysfunction with progressive inflammation and fibrosis is a hallmark of Chagas disease caused by persistent Trypanosoma cruzi infection. Osteopontin (OPN) is a pro-inflammatory cytokine that orchestrates mechanisms controlling cell recruitment and cardiac architecture. Our main goal was to study the role of endogenous OPN as a modulator of myocardial CCL5 chemokine and MMP-2 metalloproteinase, and its pathological impact in a murine model of Chagas heart disease. Wild-type (WT) and OPN-deficient (spp1 -/-) mice were parasite-infected (Brazil strain) for 100days. Both groups developed chronic myocarditis with similar parasite burden and survival rates. However, spp1 -/- infection showed lower heart-to-body ratio (P<0.01) as well as reduced inflammatory pathology (P<0.05), CCL5 expression (P<0.05), myocyte size (P<0.05) and fibrosis (P<0.01) in cardiac tissues. Intense OPN labeling was observed in inflammatory cells recruited to infected heart (P<0.05). Plasma concentration of MMP-2 was higher (P<0.05) in infected WT than in spp1 -/- mice. Coincidently, specific immunostaining revealed increased gelatinase expression (P<0.01) and activity (P<0.05) in the inflamed hearts from T. cruzi WT mice, but not in their spp1 -/- littermates. CCL5 and MMP-2 induction occurred preferentially (P<0.01) in WT heart-invading CD8+ T cells and was mediated via phospho-JNK MAPK signaling. Heart levels of OPN, CCL5 and MMP-2 correlated (P<0.01) with collagen accumulation in the infected WT group only. Endogenous OPN emerges as a key player in the pathogenesis of chronic Chagas heart disease, through the upregulation of myocardial CCL5/MMP-2 expression and activities resulting in pro-inflammatory and pro-hypertrophic events, cardiac remodeling and interstitial fibrosis.

Health-related quality of life in outpatients with schizophrenia: factors that determine changes over time.

PURPOSE: The objective of this study was to analyze the clinical factors associated with changes in HRQoL in outpatients with schizophrenia using both generic and condition-specific HRQoL scales. METHODS: Adult outpatients with schizophrenia at least 18 years of age who did not have an acute psychotic exacerbation in the 3 months prior to baseline were recruited. PANSS dimensions were calculated based on Lindenmayer et al.'s five factors. HRQoL data were assessed by patients using the Schizophrenia Quality of Life Scale (SQLS), the Short Form-36 (SF-36), and the EuroQol-5 Dimension (EQ-5D) questionnaires. RESULTS: Out of the 1345 patients included at baseline, 1196 (89%) were evaluated at 12 months. Regression models showed that the factor most consistently associated with HRQoL at endpoint was change in the PANSS negative symptoms score. A decrease in the PANSS negative symptoms score from baseline to 1 year was associated with a decrease in HRQoL during the same period. There were also significant associations of the change in PANSS excitatory factor with all the HRQoL scales except the SF-36 PCS. Female gender was associated with a decrease in all HRQoL ratings. There was also a relationship between years since onset and HRQoL. The longer the time since illness onset, the larger the decrease in HRQoL. CONCLUSIONS: This study has found that, in outpatients with schizophrenia, changes in negative and excitement symptoms may have a greater an association with HRQoL than changes in positive, cognitive and depressive symptoms.

Curcumin exerts anti-inflammatory and vasoprotective effects through amelioration of NFAT-dependent endothelin-1 production in mice with acute Chagas cardiomyopathy.

BACKGROUND: The anti-inflammatory and cardioprotective properties of curcumin (Cur), a natural polyphenolic flavonoid isolated from the rhizomes of Curcuma longa, are increasingly considered to have beneficial effects on the progression of Chagas heart disease, caused by the protozoan parasite Trypanosoma cruzi. OBJECTIVE: To evaluate the effects of oral therapy with Cur on T. cruzi-mediated cardiovasculopathy in acutely infected mice and analyse the in vitro response of parasite-infected human microvascular endothelial cells treated with this phytochemical. METHODS: Inflammation of heart vessels from Cur-treated and untreated infected mice were analysed by histology, with benznidazole (Bz) as the reference compound. Parasitaemia was monitored by the direct method. Capillary permeability was visualised by Evans-blue assay. Myocardial ET-1, IL-6, and TNF-α mRNA expressions were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Microvascular endothelial HMEC-1 cells were infected in vitro with or without addition of Cur or Bz. Induction of the Ca2+/NFAT pathway was assessed by fluorometry, immunoblotting, and reporter assay. FINDINGS: Oral Cur therapy of recently infected mice reduced inflammatory cell infiltration of myocardial arteries without lowering parasite levels. Compared to that of the phosphate-buffered saline-receiving group, hearts from Cur-treated mice showed significantly decreased vessel inflammation scores (p < 0.001), vascular permeabilities (p < 0.001), and levels of IL-6/TNF-α (p < 0.01) and ET-1 (p < 0.05) mRNA. Moreover, Cur significantly (p < 0.05 for transcript; p < 0.01 for peptide) downregulated ET-1 secretion from infected HMEC-1 cells. Remarkably, Cur addition significantly (p < 0.05 at 27.0 µM) interfered with T. cruzi-dependent activation of the Ca2+/NFATc1 signalling pathway that promotes generation of inflammatory agents in HMEC-1 cells. CONCLUSIONS: Oral treatment with Cur dampens cardiovasculopathy in acute Chagas mice. Cur impairs the Ca2+/NFATc1-regulated release of ET-1 from T. cruzi-infected vascular endothelium. These findings identify new perspectives for exploring the potential of Cur-based interventions to ameliorate Chagas heart disease.

Systematic Identification of Machine-Learning Models Aimed to Classify Critical Residues for Protein Function from Protein Structure.

Protein structure and protein function should be related, yet the nature of this relationship remains unsolved. Mapping the critical residues for protein function with protein structure features represents an opportunity to explore this relationship, yet two important limitations have precluded a proper analysis of the structure-function relationship of proteins: (i) the lack of a formal definition of what critical residues are and (ii) the lack of a systematic evaluation of methods and protein structure features. To address this problem, here we introduce an index to quantify the protein-function criticality of a residue based on experimental data and a strategy aimed to optimize both, descriptors of protein structure (physicochemical and centrality descriptors) and machine learning algorithms, to minimize the error in the classification of critical residues. We observed that both physicochemical and centrality descriptors of residues effectively relate protein structure and protein function, and that physicochemical descriptors better describe critical residues. We also show that critical residues are better classified when residue criticality is considered as a binary attribute (i.e., residues are considered critical or not critical). Using this binary annotation for critical residues 8 models rendered accurate and non-overlapping classification of critical residues, confirming the multi-factorial character of the structure-function relationship of proteins.

Unmethylated CpG motifs in Toxoplasma gondii DNA induce TLR9- and IFN-ß-dependent expression of α-defensin-5 in intestinal epithelial cells.

The gut epithelial barrier is a strategic place to prevent, or at least to limit, parasite dissemination upon oral infection with Toxoplasma gondii. Innate immunity to this pathogen results from delicate interactions involving different components of the infecting agent and the host. We herein aimed to examine the molecular mechanism by which protozoan DNA boosts the production of α-defensin-5 (DEFA-5), the main antimicrobial peptide at the target site of infection. The present study shows that DEFA-5 is rapidly upregulated in intestinal epithelial cells following intracellular Toll-like receptor 9 (TLR9) activation by unmethylated CpG motifs in DNA from T. gondii (CpG-DNA). Concomitantly, CpG-DNA purified from the pathogen markedly increased TLR9 mRNA expression levels in the Caco-2 cell line. We further verified that DEFA-5 production was dependent on interferon-ß released from these cells upon treatment with CpG-DNA prepared from tachyzoites. Our results suggest that, in protozoan DNA-stimulated intestinal epithelial cells, the TLR9/interferon-ß/DEFA-5 pathway may initiate an innate anti-T. gondii response without the need of parasite invasion. These findings highlight the key role of the gut epithelium in Toxoplasma recognition and amplification of local host defence against this microbe, thereby contributing to gain insight into immunoprotective mechanisms and to improve therapeutic strategies.

Effectiveness of agomelatine on anhedonia in depressed patients: an outpatient, open-label, real-world study.

OBJECTIVE: The aim of this real-world study was to evaluate the effect of agomelatine on anhedonia as primary endpoint in outpatients under treatment of major depressive episodes. METHODS: The study was an open-label, multicenter, 8-week phase IV trial. Two hundred fifty-seven (257) patients were recruited, and 143 patients were included in the analysis. Agomelatine was administered orally as a 25-mg tablet. The dose could be increased to 50 mg after 2 weeks of treatment. RESULTS: An improvement in the severity of anhedonia (Snaith-Hamilton Pleasure Scale total score) was observed from 8.5 points at baseline to 4.1 at week 8, statistically significant (p < 0.05) from the first week. Significant decreases in scores on the severity of depression (Quick Inventory of Depressive Symptomatology 16-item Self-Report [QIDS-SR-16]), anxiety (Generalized Anxiety Disorder 7-item scale), and in overall clinical status (CGI) were also found over 8 weeks, independently from the presence of a first or recurrence episode. Response (QIDS-SR-16 score ≥ 50% of baseline) at week 8 was observed in 65.7% of the patients, while 49.6% of the patients achieved remission (QIDS-SR-16 score ≤ 5). CONCLUSION: Agomelatine was shown to be effective on anhedonia, depression, and anxiety in subjects with major depression. The pragmatic design of the study reflects real-world clinical practice providing interesting insights into routine care management.

Trypanosoma cruzi infection induces the expression of CD40 in murine cardiomyocytes favoring CD40 ligation-dependent production of cardiopathogenic IL-6.

The inflammatory response in the myocardium is an important aspect of the pathogenesis of Chagas' heart disease raised by Trypanosoma cruzi. CD40, a transmembrane type I receptor belonging to the tumor necrosis factor receptor (TNFR) family, is expressed in a broad spectrum of cell types and is crucial in several inflammatory and autoimmune diseases. Activation of CD40 through ligation to CD40L (CD154) induces multiple effects, including the secretion of proinflammatory molecules. In the present study, we examined the ability of T. cruzi to trigger the expression of CD40 in cardiac myocytes in vitro and in a murine model of chagasic cardiomyopathy. Our results indicate, for the first time, that T. cruzi is able to induce the expression of CD40 in HL-1 murine cardiomyocytes. Moreover, ligation of CD40 receptor upregulated interleukin-6 (IL-6), associated with inflammation. Furthermore, the induction of this costimulatory molecule was demonstrated in vivo in myocardium of mice infected with T. cruzi. This suggests that CD40-bearing cardiac muscle cells could interact with CD40L-expressing lymphocytes infiltrating the heart, thus contributing to inflammatory injury in chagasic cardiomyopathy.