Los anticuerpos anti-Ro52/TRIM21 están asociados a circuitos inflamatorios aberrantes en pacientes con enfermedades reumáticas autoinmunes sistémicas / Anti-Ro52/TRIM21 antibodies are associated with aberrant inflammatory circuits in patients with systemic autoimmune rheumatic diseases

Resumen Introducción: Los anticuerpos anti-Ro52/TRIM21 son marcadores de varias enfermedades reumáticas autoinmunes sistémicas (ERAS). Objetivo: Evaluar si los anticuerpos anti-Ro52/TRIM21 están relacionados con anomalías en los circuitos inflamatorios. Métodos: Estudio transversal de pacientes consecutivos y ambulatorios con ERAS. Los anticuerpos anti-Ro52/TRIM21 y la proteína amiloide sérica se midieron mediante ELISA; los paneles para 18 citocinas y nueve quimiocinas se analizaron en una plataforma de lectura Luminex; la proteína C reactiva (hs-CRP) y el complemento se midieron mediante nefelometría. Resultados: Se incluyeron 167 pacientes, 143 con lupus eritematoso sistémico (LES), 16 con síndrome de Sjögren primario y ocho con esclerosis sistémica; 41 fueron positivos para anticuerpos anti-Ro52/TRIM21 (24 %). Los pacientes con anticuerpos anti-Ro52/TRIM21 tuvieron niveles séricos más altos de IL-2, IL-4, IL-6, GM-CSF, IL-21, IL-22, hs-CRP y quimiocinas CCL4, CXCL8, CXCL10 y CXCL12; y más bajos de complemento C4. Los títulos de anticuerpos anti-Ro52/TRIM21 correlacionaron positivamente con IL-2, IL-4, IL-6, IL-10, IL-21, IL-22, CXCL10 y hs-CRP; y negativamente con complemento C3 y C4. Al incluir solo LES, no se identificó asociación entre los anticuerpos anti-Ro52/TRIM21 y la actividad de la enfermedad o la afectación específica de órganos. Conclusiones: Los anticuerpos anti-Ro52/TRIM21 se asocian a circuitos aberrantes de citocinas y niveles elevados de moléculas angiogénicas y quimioatrayentes de neutrófilos y monocitos, lo que sugiere un papel activo de esos anticuerpos en las ERAS.

Abstract Introduction: Anti-Ro52/TRIM21 antibodies are markers for several systemic autoimmune rheumatic diseases (SARD). Objective: To assess whether anti-Ro52/TRIM21 antibodies are related to abnormalities in inflammatory circuits. Methods: Cross-sectional study of consecutive outpatients with SARD. Anti-Ro52/TRIM21 antibodies and serum amyloid A protein were measured by ELISA; panels for 18 cytokines and nine chemokines were analyzed on a Luminex reading platform, while high-sensitivity C-reactive protein (hs-CRP) and complement were measured by nephelometry. Results: Among 167 included patients, 143 had systemic lupus erythematosus (SLE), 16 had primary Sjögren's syndrome and eight had systemic sclerosis; 41 (24%) were positive for anti-Ro52/TRIM21 antibodies. Patients with anti-Ro52/TRIM21 antibodies had higher serum levels of IL-2, IL-4, IL-6, GM-CSF, IL-21, IL-22, hs-CRP and chemokines CCL4, CXCL8, CXCL10 and CXCL12, but lower levels of complement C4. Anti-Ro52/TRIM21 antibody titers were positively correlated with IL-2, IL-4, IL-6, IL-10, IL-21, IL-22, CXCL10, and hs-CRP, and negatively with complement C3 and C4. When only SLE patients were included, no association was identified between anti-Ro52/TRIM21 antibodies and disease activity or organ-specific involvement. Conclusions: Anti-Ro52/TRIM21 antibodies are associated with aberrant cytokine circuits and elevated levels of angiogenic molecules and neutrophil and monocyte chemoattractants, which suggests an active role for these antibodies in SARD.

Relación entre la disbiosis de la microbiota oral y la enfermedad cardiovascular aterosclerótica / Relationship between oral microbiota dysbiosis and the atherosclerotic cardiovascular disease

Resumen Considerando la alta incidencia de las enfermedades cardiovasculares (ECV) en México y el mundo, la presente revisión proporciona un panorama general sobre la relación entre el desarrollo de periodontitis y la patogenia de estas enfermedades, describiendo aspectos sobre la alteración de la microbiota oral y los mecanismos asociados con el establecimiento de la respuesta inmunitaria local y sistémica en los pacientes con ECV. Además, proporciona las bases para considerar el análisis de la microbiota de la cavidad oral como un blanco terapéutico potencialmente útil en la regulación de la respuesta inmunitaria, lo que permitiría conseguir mejores pronósticos en pacientes con ECV.

Abstract Considering the high incidence of cardiovascular disease (CVD) worldwide, the present review provides a general panorama of the relation between the pathogenesis of these diseases and the development of periodontitis. Specific associations are described between an altered oral microbiota (and associated mechanisms) and the local and systemic immune response in patients with CVD. Additionally, the basis is established for considering an imbalance in the microbiota of the oral cavity as a potentially useful therapeutic target for the regulation of the immune response, which could possibly allow for better therapeutic outcomes in the case of patients with CVD.

Resection of the atrial appendages and its impact in the natriuretic homeostasis: development and validation of an animal model in an academic medical center

ABSTRACT Background: The left atrial appendage (LAAp) resection is an effective treatment approach to reduce the risk of thromboembolism in patients with atrial fibrillation. Objective: To study was to study the impact of removing atrial appendages in the production of natriuretic peptides (NPs) in conditions of volume overload and to develop an experimental model of LAAp resection. Materials and Methods: In a swine model of ischemic heart failure (HF), serum NP levels were measured before (Basal-1A) and after (Basal-1B) a fluid overload. Animals were grouped as follows: (0) preserved appendages, (1) resected LAAp, and (2) both atrial appendages resected. Levels of NP were measured before (2A) and after a fluid overload (2B). Results: Furin levels were higher in Group 0-2A than in Group 2-2A, and a significant increase was found in Group 0-2B compared to Groups 1-2B and 2-2B. Corin levels increased in Basal-1B versus Basal-1A. Atrial NP (ANP) decreased in Basal-1B compared to Basal-1A. After HF induction, ANP increased in Groups 2-2A and 2-2B. Conclusions: Resection of atrial appendages drastically modifies the natriuretic mechanisms of cardiac homeostasis, especially after a fluid overload challenge. Herein, we describe the face and predictive validation of an animal model of atrial appendage resection useful to investigations in translational medicine.

Frequency of depression and anxiety symptoms in mexican patients with rheumatic diseases determined by self-administered questionnaires adapted to the spanish language

Abstract Background The frequency of depression and anxiety symptoms in Spanish-speaking patients suffering from rheumatic conditions is unknown when using self-administered detection tools. Methods A single-center, cross-sectional survey including 413 patients (341 women) with well-defined rheumatic diseases was conducted. The patient health questionnaire-9 (PHQ-9) and generalized anxiety disorder (GAD)-7 questionnaires were used to detect depression and anxiety symptoms, respectively. Results A total of 193 patients (46.7%) reported depression symptoms, and increased PHQ-9 scores were more frequently observed in women than in men (23% vs. 13%; p = 0.038), particularly in association with osteoarthritis, fibromyalgia, Sjögren’s syndrome, and osteoporosis. From 88 patients (21.3%) with PHQ-9 scores ≥ 10 points (moderate-to-severe depression symptoms), 27 (30.6%) were previously diagnosed to have depression and only four were under antidepressant treatment. Anxiety symptoms were observed in 168 patients (40.6%) and classified as moderate-to-severe by elevated GAD-7 scores in 68 subjects (16.4%). Of them, 12 (17.6%) were previously diagnosed with GAD, but only 4 (5.8%) were under therapy. Conclusions An unexpected and unusually high frequency of undiagnosed depression and anxiety symptoms was found in rheumatic patients. Self-administered screening tools adapted to the Spanish language are useful and may help clinicians to suspect these conditions.

Effect of fresh frozen plasma on the in vitro activation of U937 monocytes: a potential role for the age of blood donors and their underlying cytokine profile

BACKGROUND: Fresh frozen plasma (FFP) administration may increase the risk of nosocomial infections in parallel with the development of immune modulation. This could be driven by soluble mediators, possibly influencing the in vitro activation of human U937 monocyte cells, in a manner dependent on the age of the donors. METHODS: FFP donors were stratified into groups of 19-30 years, 31-40 years or 41-50 years, and U937 cells were cultured with FFP (alone or plus lipopolysaccharide-LPS) for 24 h. Both in FFP and supernatants, TNF, IL-1ß, IL-6, and IL-10 levels were measured by ELISA. Additionally, CD11B, TLR2, and CASP3 gene expression were measured by qtPCR in U937 cells. Total phagocytic activity was also assayed. RESULTS: Elevated IL-10, but low TNF and IL-1ß levels were measured in FFP from individuals aged 19-40 years, whereas in individuals aged 41-50 years FFP were characterized by equalized TNF and IL-10 levels. Elevated IL-6 levels were found in all FFP samples, especially in those from the oldest individuals. FFP stimulation was associated with striking modifications in cytokine production in an age-dependent way. Exposure to FFP attenuates the response to LPS. TLR2 and CD11B expression were enhanced regardless of the age of plasma donors, although CASP3 expression was increased only when FFP from individuals aged 19-40 years were tested. Phagocytosis decreased after exposure to FFP regardless of donor age. CONCLUSION: Our results suggest that soluble mediators in FFP may modulate the functioning of monocytes. Interestingly, this effect appears to be partially influenced by the age of donors.

Autoimmunity as a possible predisposing factor for Stenotrophomonas maltophilia endocarditis / Autoinmunidad como posible factor predisponente para endocarditis por Stenotrophomonas maltophilia

Only 40 cases of Stenotrophomonas maltophilia (S. maltophilia) endocarditis have been reported to date, and there is no description in patients with underlying autoimmunity. A 23-year-old woman with systemic lupus erythematosus (SLE) overlapping rheumatoid arthritis (RA) and no risk factors for endocarditis was admitted in our hospital because of community-acquired tricuspid valve endocarditis. During hospitalization, she was complicated with pulmonary thromboembolism and pneumonia. Laboratory showed autoimmune diathesis featured by anti-cyclic citrullinated peptide (anti-CCP), anti-Sm, anti-Ro/SSA, anti-cardiolipin, anti-(β2 glycoprotein 1, and antinuclear antibodies, rheumatoid factor (RF), low complement, lymphopenia and C-reactive protein (CRP) of 425 mg/L. S. maltophilia grew in serial blood culture sets. Empirical broad-spectrum antimicrobials were ineffective until trimethoprim/sulfamethoxazole (TMP/SMX) was added to therapy. One month after admission, the patient underwent successful surgical replacement of the tricuspid valve and the subsequent course was satisfactory, allowing her to be discharged 14 days after. Nowadays, she remains free of complaints and her cardiac, renal and pulmonary functioning is stable. Noteworthy is that all auto-antibodies have been persistently raised over time. Here, we present a compilation of the available information about S. maltophilia endocarditis, and suggest that autoimmunity could be included as a novel predisposing factor for S. maltophilia endocarditis.

Actualmente sólo existen 40 casos descritos de endocarditis por Stenotrophomonas maltophilia (S. maltophilia), ninguno de los cuales tenía una enfermedad autoinmune subyacente. Una mujer de 23 años con imbricación de lupus eritematoso sistémico (LES) y artritis reuma-Artritis reumatoide; toide (AR), ingresó a nuestro Instituto por endocarditis de la válvula tricúspide adquirida en México comunidad. La paciente presentó como complicaciones tromboembolia pulmonar y neumonía, se encontraron anticuerpos contra péptidos cíclicos citrulinados (anti-CCP), antinucleares, anti-Sm, anti-Ro/SSA, anti-cardiolipina y anti-(β2 glucoproteína 1, factor reumatoide (FR), complementopenia, linfopenia y proteína C reactiva (PCR) de 425 mg/L. Se observó crecimiento de S. maltophilia en hemocultivos seriados y el tratamiento antimicrobiano empírico no fue efectivo, sino hasta que se incluyó trimetoprim/sulfametoxazol (TMP/SMX). Después de un mes de hospitalización, la paciente fue sometida a remplazo quirúrgico de la válvula tricúspide y la evolución clínica subsecuente fue satisfactoria, permitiendo su egreso 14 días después. Actualmente, la paciente se encuentra asintomática y su función cardiaca, renal y pulmonar es estable. Llama la atención que todos los autoanticuerpos han permanecido elevados a través del tiempo. Presentamos una recopilación de la información disponible acerca de la endocarditis por S. maltophilia, y proponemos que la autoinmunidad podría ser incluida como un nuevo factor de predisposición para esta entidad.

Proteína C reactiva: aspectos cardiovasculares de una proteína de fase aguda / C-reactive protein: cardiovascular issues of an acute-phase protein

C-reactive protein (CRP) is a nonspecific acute phase protein that has been used as an inflammatory marker for decades. More recently, it has been proposed as a predictor of cardiovascular disease (myocardial infarction, stroke, peripheral artery disease and sudden heart death). Physiologic functions of CRP as an anti-inflammatory scavenger molecule have begun to emerge. CRP binds to damaged lipoproteins and facilitates their removal by phagocytes, partially activating the complement cascade. Increased levels of CRP may result in direct effects on vascular cells, including the induction of cytokines and prothrombotic factors. Although previous studies suggested a potent independent association of CRP levels with cardiac events, the strength of this association has been shown to be weaker than previously reported in a recent large meta-analysis and in prospective studies. Therapy with statins in patients with coronary artery disease has been found to reduce adverse outcomes in association with reductions of CRP levels, independently of their effects on the lipid profile.

Echocardiometric evaluation of cardiovascular abnormalities in Marfan syndrome / Valoración ecocardiométrica de las anomalías cardiovasculares en el síndrome de marfán

Marfan syndrome is an inherited disorder of connective tissue with manifestations in various organ-systems including cardiovascular system. The aim of this study was to characterize and determine the frequency of cardiovascular alterations by echocardiography in 2 age cohorts of Mexican patients with Marfan syndrome and their comparisons with control groups. Material and methods: Sixty six with Marfan syndrome and 33 control patients were evaluated by echocardiography. Segments of the aorta and pulmonary artery were measured at different levels, cardiac valves were examined for prolapse and the interatrial septum was assessed for septal aneurysm. Numeric values were corrected forthe body surface area and compared with the control group. Results: Mean significant values between group I (children) and Group II (adults) were as follows: aortic annulus 16.62 ± 4.57 mm/m² vs 12.81 ± 1.95 (p< 0.001), aortic root 23.30 ±7.49 mm/m²vs 18.36 ± 2.97 (p < 0.001), sinuses of Valsalva 24.14 ± 7.29 mm/m² vs 19.84 ± 3.59 (p < 0.001), ascending aorta 18.43 ± 5.90 mm/m² vs 17.02 ± 4.79 (p < 0.001), aortic arch 16.12 ± 4.73 mm/m² vs 14.20 ± 2.68 (p < 0.001). Pulmonary valve prolapse was seen in 10/22 (45.5%) vs 7/44 (15.9%), p < 0.03. Interatrial septal aneurysm was found in 3/22 (13.6%) vs 20/44 (45.5%), p < 0.03. There was a significative diference in the presence of atrial septal aneurysm between the adult group and control group (p < 0.001). Conclusions: The incidence of cardiovascular abnormalities in our series is similar to that in the literature with the exception of the very high incidence of pulmonary valve prolapse vs control groups, then it suggests that the clinical manifestations of MFS are strikingly severe in the Mexican population. Also a high incidence of interatrial septal aneurysm (34.9%) in comparison to control groups (18.2%) was found.

El síndrome de Marfán es una enfermedad hereditaria del tejido conectivo con manifestaciones en varios órganos incluyendo el sistema cardiovascular. El objetivo del estudio fue caracterizar y determinar la frecuencia de las alteraciones cardiovasculares mediante ecocardiografía en 2 grupos de pacientes mexicanos con síndrome de Marfán en comparación con los grupos controles. Material y métodos: Se estudiaron mediante ecocardiografía a 66 pacientes con síndrome de Marfán y 33 pacientes del grupo control. Se midieron los segmentos de la aorta y de la arteria pulmonar a diferentes niveles, se valoró prolapso valvular y presencia de aneurisma del septum interatrial. Los valores numéricos fueron corregidos por área de superficie corporal y comparados con el grupo control. Resultados: Los variables con valor significativo entre el grupo I (niños) y el grupo II (adultos) fueron: Anillo aórtico: 16.62 ± 4.57 mm/m² vs 12.81 ± 1.95 (p< 0.001), raíz aórtica 23.30 ±7.49 mm/m²vs 18.36 ± 2.97 (p < 0.001), senos de Valsalva 24.14 ± 7.29 mm/m² vs 19.84 ± 3.59 (p < 0.001), aorta ascendente 18.43 ± 5.90 mm/m² vs 17.02 ± 4.79 (p < 0.001), arco aórtico 16.12 ± 4.73 mm/m² vs 14.20 ± 2.68 (p < 0.001). Se encontró prolapso valvular pulmonar en 10/22 (45.5%) vs 7/44 (15.9%), p < 0.03. Aneurisma del septum interatrial en 3/22 (13.6%) vs 20/44 (45.5%), p < 0.03. Hubo diferencia significativa para la presencia de aneurisma del septum interatrial entre el grupo de adultos y el grupo control (p < 0.001). Conclusiones: La incidencia de anormalidades cardiovasculares en nuestra serie es similar a la reportada en la literatura excepto la alta incidencia de prolapso valvular pulmonar en relación al grupo control, lo que sugiere que las manifestaciones clínicas cardiovasculares del síndrome de Marfán son más severas en la población mexicana. Se encontró también una alta incidencia de aneurisma del septum interatrial (34.9%) en comparación al grupo control (18.2%). (Arch Cardiol Mex 2005; 75: 133-140).