Fatty acid desaturation and lipoxygenase pathways support trained immunity.

Infections and vaccines can induce enhanced long-term responses in innate immune cells, establishing an innate immunological memory termed trained immunity. Here, we show that monocytes with a trained immunity phenotype, due to exposure to the Bacillus Calmette-Guérin (BCG) vaccine, are characterized by an increased biosynthesis of different lipid mediators (LM) derived from long-chain polyunsaturated fatty acids (PUFA). Pharmacological and genetic approaches show that long-chain PUFA synthesis and lipoxygenase-derived LM are essential for the BCG-induced trained immunity responses of human monocytes. Furthermore, products of 12-lipoxygenase activity increase in monocytes of healthy individuals after BCG vaccination. Grasping the underscoring lipid metabolic pathways contributes to our understanding of trained immunity and may help to identify therapeutic tools and targets for the modulation of innate immune responses.

Metabolomic and Lipidomic Analysis of the Colorectal Adenocarcinoma Cell Line HT29 in Hypoxia and Reoxygenation.

The poor availability of oxygen and nutrients in malignant tumors drives the activation of various molecular responses and metabolic reprogramming in cancer cells. Hypoxic tumor regions often exhibit resistance to chemotherapy and radiotherapy. One approach to enhance cancer therapy is to indirectly increase tumor oxygen availability through targeted metabolic reprogramming. Thus, understanding the underlying metabolic changes occurring during hypoxia and reoxygenation is crucial for improving therapy efficacy. In this study, we utilized the HT29 colorectal adenocarcinoma cell line as a hypoxia-reoxygenation model to investigate central carbon and lipid metabolism. Through quantitative NMR spectroscopy and flow injection analysis - differential mobility spectroscopy-tandem mass spectrometry (FIA-DMS-MS/MS) analysis, we observed alterations in components of mitochondrial metabolism, redox status, specific lipid classes, and structural characteristics of lipids during hypoxia and up to 24 h of reoxygenation. These findings contribute to our understanding of the metabolic changes occurring during reoxygenation and provide the basis for functional studies aimed at metabolic pathways in cancer cells.

Recent advances in metabolomics analysis for early drug development.

The pharmaceutical industry adapted proteomics and other 'omics technologies for drug research early following their initial introduction. Although metabolomics lacked behind in this development, it has now become an accepted and widely applied approach in early drug development. Over the past few decades, metabolomics has evolved from a pure exploratory tool to a more mature and quantitative biochemical technology. Several metabolomics-based platforms are now applied during the early phases of drug discovery. Metabolomics analysis assists in the definition of the physiological response and target engagement (TE) markers as well as elucidation of the mode of action (MoA) of drug candidates under investigation. In this review, we highlight recent examples and novel developments of metabolomics analyses applied during early drug development.

Glutathione Metabolism Contributes to the Induction of Trained Immunity.

The innate immune system displays heterologous memory characteristics, which are characterized by stronger responses to a secondary challenge. This phenomenon termed trained immunity relies on epigenetic and metabolic rewiring of innate immune cells. As reactive oxygen species (ROS) production has been associated with the trained immunity phenotype, we hypothesized that the increased ROS levels and the main intracellular redox molecule glutathione play a role in the induction of trained immunity. Here we show that pharmacological inhibition of ROS in an in vitro model of trained immunity did not influence cell responsiveness; the modulation of glutathione levels reduced pro-inflammatory cytokine production in human monocytes. Single nucleotide polymorphisms (SNPs) in genes involved in glutathione metabolism were found to be associated with changes in pro-inflammatory cytokine production capacity upon trained immunity. Also, plasma glutathione concentrations were positively associated with ex vivo IL-1ß production, a biomarker of trained immunity, produced by monocytes of BCG-vaccinated individuals. In conclusion, glutathione metabolism is involved in the induction of trained immunity, and future studies are warranted to explore its functional consequences in human diseases.

Sema7A is crucial for resolution of severe inflammation.

Endogenous mediators regulating acute inflammatory responses in both the induction and resolution phases of inflammatory processes are pivotal in host defense and tissue homeostasis. Recent studies have identified neuronal guidance proteins characterized in axonal development that display immunomodulatory functions. Here, we identify the neuroimmune guidance cue Semaphorin 7A (Sema7A), which appears to link macrophage (MΦ) metabolic remodeling to inflammation resolution. Sema7A orchestrated MΦ chemotaxis and chemokinesis, activated MΦ differentiation and polarization toward the proresolving M2 phenotype, and promoted leukocyte clearance. Peritoneal MΦSema7A-/- displayed metabolic reprogramming, characterized by reductions in fatty acid oxidation and oxidative phosphorylation, increases in glycolysis and the pentose phosphate pathway, and truncation of the tricarboxylic acid cycle, which resulted in increased levels of the intermediates succinate and fumarate. The low accumulation of citrate in MΦSema7A-/- correlated with the decreased synthesis of prostaglandins, leading to a reduced impact on lipid-mediator class switching and the generation of specialized pro resolving lipid mediators. Signaling network analysis indicated that Sema7A induced the metabolic reprogramming of MΦ by activating the mTOR- and AKT2-signaling pathways. Administration of Sema7ASL4cd orchestrated the resolution response to tissue homeostasis by shortening the resolution interval, promoting tissue protection in murine peritonitis, and enhancing survival in polymicrobial sepsis.

Congenital intrahepatic portosystemic venous shunt embolization: A two-case experience.

Congenital intrahepatic portosystemic venous shunts are rare vascular malformations which are incidentally discovered on imaging or once hepatic encephalopathy becomes clinically apparent. Surgical ligation and endovascular embolization are potential treatments.

Lipid metabolism of leukocytes in the unstimulated and activated states.

Lipidomics has emerged as a powerful technique to study cellular lipid metabolism. As the lipidome contains numerous isomeric and isobaric species resulting in a significant overlap between different lipid classes, cutting-edge analytical technology is necessary for a comprehensive analysis of lipid metabolism. Just recently, differential mobility spectrometry (DMS) has evolved as such a technology, helping to overcome several analytical challenges. We here set out to apply DMS and the Lipidyzer™ platform to obtain a comprehensive overview of leukocyte-related lipid metabolism in the resting and activated states. First, we tested the linearity and repeatability of the platform by using HL60 cells. We obtained good linearities for most of the thirteen analyzed lipid classes (correlation coefficient > 0.95), and good repeatability (%CV < 15). By comparing the lipidome of neutrophils (PMNs), monocytes (CD14+), and lymphocytes (CD4+), we shed light on leukocyte-specific lipid patterns as well as lipidomic changes occurring through differential stimulation. For example, at the resting state, PMNs proved to contain higher amounts of triacylglycerides compared to CD4+ and CD14+ cells. On the other hand, CD4+ and CD14+ cells contained higher levels of phospholipids and ceramides. Upon stimulation, diacylglycerides, hexosylceramides, phosphatidylcholines, phosphoethanolamines, and lysophosphoethanolamines were upregulated in CD4+ cells and PMNs, whereas CD14+ cells did not show significant changes. By exploring the fatty acid content of the significantly upregulated lipid classes, we mainly found increased concentrations of very long and polyunsaturated fatty acids. Our results indicate the usefulness of the Lipidyzer™ platform for studying cellular lipid metabolism. Its application allowed us to explore the lipidome of leukocytes. Graphical abstract.

¿Cuál es el nivel de desarrollo esperable para un niño con síndrome de Down en sus primeros años de vida? / What is the Level of Development Expected for a Child with Down syndrome in their First Years of Life?

El síndrome de Down es la causa genérica más frecuente de discapacidad vinculada con el desarrollo. La falca de valores normativos para los niños que padecen este trascomo, dificulta una valoración temprana y seguimiento del curso evolutivo. El objetivo del presente artículo es describir el perfil evolutivo de escos niños durante los primeros tres años de vida. Se realizó un estudio de cohorte de cipo prospectivo durante 9 años, en el cual se incluyeron 156 niños menores de 37 meses. Ellos tuvieron 528 evaluaciones con la "Escala Abreviada del Desarrollo" (EAD4), una prueba válida y confiable estandarizada en Colombia para valorar el nivel evolutivo en niños menores de 6 años. Se establecieron los cocientes de desarrollo por trimestres, valores percentil, las variaciones entre las áreas evaluadas, las curvas evolutivas estudiadas en cada área y los períodos más críticos en los diferentes semestres. Estos valores posibilitarán el seguimiento al curso evolutivo de estos niños, la identificación temprana de las áreas de mayor vulnerabilidad y necesidad de intervención, la evaluación del impacto de acciones terapéuticas o programas de estimulación, y la orientación a los padres y agentes sociales y de salud vinculados al desarrollo y la supervivencia del niño y la niña.

Down syndrome is the most frequent genetic cause of disability associated with development. The lack of normative values for these children, hinders an early assessment and monitoring of the clinical course. The objective was to describe the evolutionary profile of these children during the first three years of life. A prospective cohort study was performed, for 9 years, in which 156 children under 37 months were included. They had 528 evaluations by "Abbreviated Scale Development" (EAD -I), a valid and reliable standardized test in Colombia to assess the developmental level in children under 6 years. We obtained quarterly developmental quotients, percentile values, variations between the areas assessed, the evolutionary curve in each area studied and the most critical periods in different semesters. These values will enable monitoring the clinical course of these children, early identificación of areas of greatest vulnerability and need for intervención, assessment of the impact of therapeucic interventions or programs of stimulation and guidance co parents and related health and social agencs to development and survival of che boy and che girl.

Calidad de vida relacionada con la salud en escolares de 10 a 14 años con sobrepeso y obesidad en la ciudad de Medellín, Colombia / Health Related-quality of Life in Schoolchildren with Obesity and Overweight in Medellin, Colombia

El exceso de peso a tempranas edades afecta la salud física y mental de niños y niñas y puede repercutir en su calidad de vida. Objetivo: evaluar la calidad de vida relacionada con salud (CVRS) en escolares con y sin sobrepeso y obesidad de una institución educativa de Medellín (Colombia). Población y Métodos: Se realizó un estudio transversal de tipo descriptivo-comparativo. La muestra fue probabilística con 679 escolares participantes de ambos sexos, con edades entre los 10 y 14 años de edad. El instrumento usado para determinar el estado nutricional fue el ANTHRO-PLUS y para medir CVRS utilizó el KIDSCREEN-27. Resultados: el 24 % de los participantes tenían exceso de peso, 19.9 % de ellos con sobrepeso y el 4.1 % con obesidad. En relación con la CVRS, los escolares con sobrepeso y obesidad se perciben con más problemas de actividad física y salud (AF) y menos aceptación social (AS). Para los hombres, el exceso de peso afecta las posibilidades de realizar la misma actividad física que sus pares, convirtiéndose fácilmente en objeto de burla e intimidación. Para las mujeres, la percepción de su CVRS no varió significativamente tuvieran normo o sobrepeso. Conclusiones: la percepción de CVRS de los escolares no es homogénea, está afectada por la edad, el sexo y los condicionantes culturales alrededor de la construcción de la imagen corporal.

Excess weight affects the physical and mental health of children and can affect their quality of life. Objetive: Evaluate the quality of life related to health (HRQOL) in schoolchildren with and without overweight and obesity of an educational institution of Medellin (Colombia). Methods: A descriptive crosssectional study was conducted comparative type. The sample was probabilistic school with 679 participants of both sexes aged between 10 and 14 years old. The instrument used to determine the nutritional status was ANTHRO-PLUS and measure HRQOL used the KIDSCREEN-27. Results: Participants were overweight 24%; overweight children were 19% and 4% of them were obese. Regarding school HRQOL overweight and obesity are perceived more problems physical activity and health (AF) and less social acceptance (AS). For men being overweight it affects the chances of performing the same physical activity as their peers and becoming easily mocked and intimidation. For women, the perception of HRQOL did not differ significantly had normal or overweight. Conclusions: The perception of HRQOL of school is not homogeneous, is affected by age, sex and cultural conditions around the construction of body image.

[Extensive cerebral vein thrombosis as first manifestation of Behçet's disease. Report of one case]. / Trombosis de senos venosos encefálicos como posible primera manifestación de enfermedad de Behçet: caso clínico.

Behçet's disease (BD) is a systemic inflammatory vascular disease with several clinical manifestations and geographical differences in disease expression. In Middle Eastern countries it is one of the most common causes of cerebral venous thrombosis. We report a 29-year-old female admitted for acute headache and vomiting. A magnetic resonance image showed a large thrombosis of sagital and transverse sinuses. She developed oral and genital ulcers a week later. Ophthalmologic examination revealed left anterior uveitis and ipsilateral papilledema. Multiple studies ruled out a hypercoagulability syndrome. The patient used oral contraceptives. Anticoagulant therapy was prescribed. A biopsy of a genital ulcer demonstrated diffuse lymphocytic infiltration with vasculitis. After treatment with topical and systemic corticoids, her condition improved. Venous sinus thrombosis followed by oral and genital ulcers is an unusual presentation of Behçet's disease.

Trombosis de senos venosos encefálicos como posible primera manifestación de enfermedad de Behçet: Caso clínico / Extensive cerebral vein thrombosis as first manifestation of Behçet's disease: Report of one case

Behçet’s disease (BD) is a systemic inflammatory vascular disease with several clinical manifestations and geographical differences in disease expression. In Middle Eastern countries it is one of the most common causes of cerebral venous thrombosis. We report a 29-year-old female admitted for acute headache and vomiting. A magnetic resonance image showed a large thrombosis of sagital and transverse sinuses. She developed oral and genital ulcers a week later. Ophthalmologic examination revealed left anterior uveitis and ipsilateral papilledema. Multiple studies ruled out a hypercoagulability syndrome. The patient used oral contraceptives. Anticoagulant therapy was prescribed. A biopsy of a genital ulcer demonstrated diffuse lymphocytic infiltration with vasculitis. After treatment with topical and systemic corticoids, her condition improved. Venous sinus thrombosis followed by oral and genital ulcers is an unusual presentation of Behçet’s disease.

Nuevo algoritmo de tratamiento para una enfermedad frecuente: el neumotórax / New algorithm for pneumothorax treatment

El neumotórax se define como una enfermedad producida por la entrada de aire en el espacio virtual que separa las pleuras visceral y parietal (la cavidad plural); este aire provoca pérdida del contacto entre ellas y un colapso pulmonar, que tendra mayor o menor inmediatez y cuantía en dependencia de la causa, de la presencia o no de adherencias y de la rigidez pulmonar. El neumotórax es una de las enfermedades mas comunes del tórax y la mayor causa de intervención quirúrgica en la región torácica. Teniendo en cuenta estos elementos, el grupo de Cirugía Torácica del Hospital Universitario Comandante Manuel Fajardo creó un algoritmo de trabajo, realizándo un estudio descriptivo, prospectivo, de corte transversal, en 154 pacientes con diagnóstico clínico y radiológico de neumotórax, atendidos entre enero de 1988 y julio de 2003, debido a la necesidad de la creación de este instrumento de trabajo

Nuevo algoritmo de tratamiento para una enfermedad frecuente: el neumotórax / New algorithm for pneumothorax treatment

El neumotórax se define como una enfermedad producida por la entrada de aire en el espacio virtual que separa las pleuras visceral y parietal (la cavidad plural); este aire provoca pérdida del contacto entre ellas y un colapso pulmonar, que tendra mayor o menor inmediatez y cuantía en dependencia de la causa, de la presencia o no de adherencias y de la rigidez pulmonar. El neumotórax es una de las enfermedades mas comunes del tórax y la mayor causa de intervención quirúrgica en la región torácica. Teniendo en cuenta estos elementos, el grupo de Cirugía Torácica del Hospital Universitario Comandante Manuel Fajardo creó un algoritmo de trabajo, realizándo un estudio descriptivo, prospectivo, de corte transversal, en 154 pacientes con diagnóstico clínico y radiológico de neumotórax, atendidos entre enero de 1988 y julio de 2003, debido a la necesidad de la creación de este instrumento de trabajo(AU)