Consensus Recommendations Based on Evidence for Abdominal Sepsis in the Pediatric and Adult Population of Colombia / Consenso colombiano de la sepsis abdominal en la poblacion pediatrica y de adultos: Recomendaciones basadas en la evidencia

Abstract Intra-abdominal infections are frequent at all levels of health care, therefore, it is necessary to maintain a high level of clinical suspicion, performing the fastest and most cost-effective measures to confirm the diagnosis and offer a precise and targeted multidisciplinary therapy, this being the only way to have an impact on the morbidity of this infection, reducing mortality and minimizing the complications and costs of health care. Intra-abdominal infections are linked to the appearance and selection of resistant mutants in both bacteria and fungi, becoming currently a major public health problem. Increasing bacterial resistance when associated with a greater possibility of difficulties in antimicrobial treatment increases mortality. This evidence-based consensus brings together the recommendations for the diagnosis and treatment of intra-abdominal infections in the pediatric and adult population. With strict monitoring of bacterial resistance and stimulating the control of the risk factors that have the greatest impact on the appearance of this phenomenon, this consensus is intended to be a practical guide that is easy to implement, and with periodic updates it will favor and facilitate multidisciplinary and the adequacy of the therapeutic management of intra-abdominal infections.

Resumen Las infecciones intrabdominales son frecuentes en todos los niveles de atención en salud, por ende, es necesario mantener un alto nivel de sospecha clínica, realizando las medidas más rápidas y costoefectivas para confirmar el diagnóstico y así ofrecer de una forma precisa y dirigida la terapéutica multidisciplinaria, siendo esta la única manera de tener impacto en la morbilidad de esta infección, disminuyendo la mortalidad y minimizando las complicaciones y los costos de la atención en salud. Las infecciones intrabdominales se encuentran ligadas a la aparición y selección de las mutantes resistentes tanto en las bacterias como en los hongos, convirtiéndose en la actualidad en una gran problemática en la salud pública. La creciente resistencia bacteriana al asociarse a mayor posibilidad de dificultades en el tratamiento antimicrobiano incrementa la mortalidad. Este consenso basado en la evidencia, reúne las recomendaciones en el diagnóstico y en el tratamiento de las infecciones intrabdominales en la población pediátrica y de adultos. Con un estricto seguimiento de la resistencia bacteriana y estimulando el control de los factores de riesgo que tienen mas impacto en la aparición de este fenómeno, este consenso pretende ser una practica guía de fácil implementación, y con periódicas actualizaciones favorecerá y facilitará el manejo multidisciplinario y la adecuación del manejo terapéutico de las infecciones intrabdominales.

Perivascular lymphocytic aggregates in hip prosthesis-associated adverse local tissue reactions demonstrate Th1 and Th2 activity and exhausted CD8+ cell responses.

Hip implants are a successful solution for osteoarthritis; however, some individuals with metal-on-metal (MoM) and metal-on-polyethylene (MoP) prosthetics develop adverse local tissue reactions (ALTRs). While MoM and MoP ALTRs are presumed to be delayed hypersensitivity reactions to corrosion products, MoM- and MoP-associated ALTRs present with different histological characteristics. We compared MoM- and MoP-associated ALTRs histopathology with cobalt and chromium levels in serum and synovial fluid. We analyzed the gene expression levels of leukocyte aggregates and synovial fluid chemokines/cytokines to resolve potential pathophysiologic differences. In addition, we classified ALTRs from 79 patients according to their leukocyte infiltrates as macrophage-dominant, mixed, and lymphocyte-dominant. Immune-related transcript profiles from lymphocyte-dominant MoM- and MoP-associated ALTR patients with perivascular lymphocytic aggregates were similar. Cell signatures indicated predominantly macrophage, Th1 and Th2 lymphocytic infiltrate, with strong exhausted CD8+ signature, and low Th17 and B cell, relative to healthy lymph nodes. Lymphocyte-dominant ALTR-associated synovial fluid contained higher levels of induced protein 10 (IP-10), interleukin-1 receptor antagonist (IL-1RN), IL-8, IL-6, IL-16, macrophage inflammatory protein 1 (MIP-1α), IL-18, MCP-2, and lower cell-attracting chemokine levels, when compared with prosthetic revisions lacking ALTRs. In addition, the higher levels of IP-10, IL-8, IL-6, MIP-1α, and MCP-2 were observed within the synovial fluid of the lymphocyte-dominant ALTRs relative to the macrophage-dominant ALTRs. Not all cytokines/chemokines were detected in the perivascular aggregate transcripts, suggesting the existence of other sources in the affected synovia. Our results support the hypothesis of common hypersensitivity pathogenesis in lymphocyte-dominant MoM and MoP ALTRs. The exhausted lymphocyte signature indicates chronic processes and an impaired immune response, although the cause of the persistent T-cell activation remains unclear. The cytokine/chemokine signature of lymphocyte-dominant-associated ATLRs may be of utility for diagnosing this more aggressive pathogenesis.

Guía de Práctica Clínica para el Diagnóstico y Manejo de las Infecciones de Piel y Tejidos Blandos en Colombia / Clinical Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections in Colombia

Las infecciones de piel y tejidos blandos (IPTB) representan la tercera causa de consulta por enfermedad infecciosas a los servicios médicos, después de las infecciones respiratorias y urinarias. Se presenta una guía de práctica clínica (GPC) con 38 recomendaciones basadas en la evidencia, graduadas bajo el sistema SIGN, para el diagnóstico y tratamiento de pacientes adultos con IPTB en el contexto colombiano, posterior a un proceso de adaptación de GPC publicadas y la búsqueda sistemática y síntesis de literatura para la actualización de la evidencia científica. Además, se realizó un consenso de expertos para la evaluación de las potenciales barreras para la implementación de las recomendaciones y la evaluación del grado de recomendación en el contexto local.

Skin and soft tissue infections (SSTI) represent the third leading cause of infectious disease consultation for medical services after respiratory and urinary tract infections. This document generates a clinical practice guideline with 38 recommendations based on evidence, graduated under the SIGN system for the diagnosis and treatment for SSTI infections in adult patients in Colombia, following a process of adaptation of guidelines published, and the systematic search and synthesis of literature for the updating of scientific evidence. In addition, a consensus of experts was made for the evaluation of the potential barriers for the implementation of the recommendations and the evaluation of the degree of recommendation in the local context.

Leukocyte Overexpression of Intracellular NAMPT Attenuates Atherosclerosis by Regulating PPARγ-Dependent Monocyte Differentiation and Function.

OBJECTIVE: Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) mediates inflammatory and potentially proatherogenic effects, whereas the role of intracellular NAMPT (iNAMPT), the rate limiting enzyme in the salvage pathway of nicotinamide adenine dinucleotide (NAD)+ generation, in atherogenesis is largely unknown. Here we investigated the effects of iNAMPT overexpression in leukocytes on inflammation and atherosclerosis. APPROACH AND RESULTS: Low-density lipoprotein receptor-deficient mice with hematopoietic overexpression of human iNAMPT (iNAMPThi), on a western type diet, showed attenuated plaque burden with features of lesion stabilization. This anti-atherogenic effect was caused by improved resistance of macrophages to apoptosis by attenuated chemokine (C-C motif) receptor 2-dependent monocyte chemotaxis and by skewing macrophage polarization toward an anti-inflammatory M2 phenotype. The iNAMPThi phenotype was almost fully reversed by treatment with the NAMPT inhibitor FK866, indicating that iNAMPT catalytic activity is instrumental in the atheroprotection. Importantly, iNAMPT overexpression did not induce any increase in eNAMPT, and eNAMPT had no effect on chemokine (C-C motif) receptor 2 expression and promoted an inflammatory M1 phenotype in macrophages. The iNAMPT-mediated effects at least partly involved sirtuin 1-dependent molecular crosstalk of NAMPT and peroxisome proliferator-activated receptor γ. Finally, iNAMPT and peroxisome proliferator-activated receptor γ showed a strong correlation in human atherosclerotic, but not healthy arteries, hinting to a relevance of iNAMPT/peroxisome proliferator-activated receptor γ pathway also in human carotid atherosclerosis. CONCLUSIONS: This study highlights the functional dichotomy of intracellular versus extracellular NAMPT, and unveils a critical role for the iNAMPT-peroxisome proliferator-activated receptor γ axis in atherosclerosis.

Hck/Fgr Kinase Deficiency Reduces Plaque Growth and Stability by Blunting Monocyte Recruitment and Intraplaque Motility.

BACKGROUND: Leukocyte migration is critical for the infiltration of monocytes and accumulation of monocyte-derived macrophages in inflammation. Considering that Hck and Fgr are instrumental in this process, their impact on atherosclerosis and on lesion inflammation and stability was evaluated. METHODS AND RESULTS: Hematopoietic Hck/Fgr-deficient, LDLr(-/-) chimeras, obtained by bone marrow transplantation, had smaller but, paradoxically, less stable lesions with reduced macrophage content, overt cap thinning, and necrotic core expansion as the most prominent features. Despite a Ly6C(high)-skewed proinflammatory monocyte phenotype, Hck/Fgr deficiency led to disrupted adhesion of myeloid cells to and transmigration across endothelial monolayers in vitro and atherosclerotic plaques in vivo, as assessed by intravital microscopy, flow cytometry, and histological examination of atherosclerotic arteries. Moreover, Hck/Fgr-deficient macrophages showed blunted podosome formation and mesenchymal migration capacity. In consequence, transmigrated double-knockout macrophages were seen to accumulate in the fibrous cap, potentially promoting its focal erosion, as observed for double-knockout chimeras. CONCLUSIONS: The hematopoietic deficiency of Hck and Fgr led to attenuated atherosclerotic plaque formation by abrogating endothelial adhesion and transmigration; paradoxically, it also promoted plaque instability by causing monocyte subset imbalance and subendothelial accumulation, raising a note of caution regarding src kinase-targeted intervention in plaque inflammation.

HIV-1 Nef triggers macrophage fusion in a p61Hck- and protease-dependent manner.

Macrophages are a major target of HIV-1 infection. HIV-1-infected macrophages form multinucleated giant cells (MGCs) using poorly elucidated mechanisms. In this study, we show that MGC formation was reduced when human macrophages were infected with nef-deleted HIV-1. Moreover, expression of Nef, an HIV-1 protein required in several aspects of AIDS, was sufficient to trigger the formation of MGCs in RAW264.7 macrophages. Among Nef molecular determinants, myristoylation was dispensable, whereas the polyproline motif was instrumental for this phenomenon. Nef has been shown to activate hematopoietic cell kinase (Hck), a Src tyrosine kinase specifically expressed in phagocytes, through a well-described polyproline-SH3 interaction. Knockdown approaches showed that Hck is involved in Nef-induced MGC formation. Hck is expressed as two isoforms located in distinct subcellular compartments. Although both isoforms were activated by Nef, only p61Hck mediated the effect of Nef on macrophage fusion. This process was abolished in the presence of a p61Hck kinase-dead mutant or when p61Hck was redirected from the lysosome membrane to the cytosol. Finally, lysosomal proteins including vacuolar adenosine triphosphatase and proteases participated in Nef-induced giant macrophage formation. We conclude that Nef participates in HIV-1-induced MGC formation via a p61Hck- and lysosomal enzyme-dependent pathway. This work identifies for the first time actors of HIV-1-induced macrophage fusion, leading to the formation of MGCs commonly found in several organs of AIDS patients.