Replication of Integrative Data Analysis for Adipose Tissue Dysfunction, Low-Grade Inflammation, Postprandial Responses and OMICs Signatures in Symptom-Free Adults.

We previously reported preliminary characterization of adipose tissue (AT) dysfunction through the adiponectin/leptin ratio (ALR) and fasting/postprandial (F/P) gene expression in subcutaneous (SQ) adipose tissue (AT) biopsies obtained from participants in the GEMM study, a precision medicine research project. Here we present integrative data replication of previous findings from an increased number of GEMM symptom-free (SF) adults (N = 124) to improve characterization of early biomarkers for cardiovascular (CV)/immunometabolic risk in SF adults with AT dysfunction. We achieved this goal by taking advantage of the rich set of GEMM F/P 5 h time course data and three tissue samples collected at the same time and frequency on each adult participant (F/P blood, biopsies of SQAT and skeletal muscle (SKM)). We classified them with the presence/absence of AT dysfunction: low (<1) or high (>1) ALR. We also examined the presence of metabolically healthy (MH)/unhealthy (MUH) individuals through low-grade chronic subclinical inflammation (high sensitivity C-reactive protein (hsCRP)), whole body insulin sensitivity (Matsuda Index) and Metabolic Syndrome criteria in people with/without AT dysfunction. Molecular data directly measured from three tissues in a subset of participants allowed fine-scale multi-OMIC profiling of individual postprandial responses (RNA-seq in SKM and SQAT, miRNA from plasma exosomes and shotgun lipidomics in blood). Dynamic postprandial immunometabolic molecular endophenotypes were obtained to move towards a personalized, patient-defined medicine. This study offers an example of integrative translational research, which applies bench-to-bedside research to clinical medicine. Our F/P study design has the potential to characterize CV/immunometabolic early risk detection in support of precision medicine and discovery in SF individuals.

Acute/subacute paracoccidioidomycosis with associated eosinophilia

Paracoccidioidomycosis is an endemic mycosis whose initial diagnosis may be difficult, as it shares the clinical characteristics of granulomatous and neoplastic diseases. Although its chronic form is the most frequent, we present the case of a young patient with an acute/ subacute presentation with lymphadenopathy, peripheral eosinophilia and a false-positive hepatitis C serology. The diagnosis was confirmed by histopathology and tissue culture, and he was treated with amphotericin B due to clinical deterioration secondary to progression of systemic involvement. (Acta Med Colomb 2021; 46. DOI: https://doi.org/10.36104/amc.2021.1921).

La paracoccidiodomicosis es una micosis endémica cuyo diagnóstico inicial puede ser difícil al compartir características clínicas de enfermedades granulomatosas y neoplásicas. Aunque su forma más frecuente es la crónica presentamos el caso de un paciente joven con un cuadro agudo/subagudo con linfadenopatías, eosinofilia periférica y una serología para hepatitis C falsamente positiva. El diagnóstico fue confirmado por histopatología y cultivo de tejidos y se dio manejo con anfotericina B ante el deterioro clínico por progresión del compromiso sistémico.

Interleukin 6 Dependent Synaptic Plasticity in a Social Defeat-Susceptible Prefrontal Cortex Circuit.

The role of the pro-inflammatory cytokine interleukin-6 (IL-6) in the etiology of stress-induced synaptic plasticity is yet unknown. We took advantage of a genetically modified mouse (TG) in which IL-6 trans-signaling via the soluble IL-6 receptor was blocked, to determine the role of IL-6 trans-signaling in the effects of a Social Defeat protocol (SD) on synaptic function of the medial prefrontal cortex (mPFC). Synaptic function in stress-sensitive (S) and stress-resilient (R) animals was studied in a mPFC slice preparation with whole-cell patch-clamp recording. SD altered numerous synaptic properties of the mPFC: R WT (but not TG) displayed a decreased ratio between N methyl-D-aspartate receptor (NMDAR-) dependent and amino propionic acid receptor (AMPAR-) dependent-current (INMDA/IAMPA), while S WT animals (but not TG) showed a reduced ratio between AMPA and γ-amino-butyric acid receptor type A (GABAAR)-dependent currents (IAMPA/IGABA). Also, SD induced an increase in the frequency but a decrease in the amplitude of excitatory action-potential dependent PSCs (sEPSCs), both in an IL-6 dependent manner, as well as a generalized (S/R-independent) decrease in the frequency of action potential independent (miniature) excitatory (IL-6 dependent) as well as inhibitory (IL-6 independent) postsynaptic current frequency. Interestingly, corner preference (measuring the intensity of social defeat) correlated positively with INMDA/IAMPA and eEPSC frequency and negatively with IAMPA/IGABA. Our results suggest that SD induces behaviorally-relevant synaptic rearrangement in mPFC circuits, part of which is IL-6 dependent. In particular, IL-6 is necessary to produce synaptic plasticity leading to stress resilience in some individuals, but to stress sensitivity in others.

A new theory of depression based on the serotonin/kynurenine relationship and the hypothalamicpituitary- adrenal axis

The serotonergic and immunological hypothesis of depression proposes that certain types of excessive stress distort the relationship between the activities of the innate immune and central nervous systems, so that the stress caused by an infection, or excessive psychological stress, activate toll-like receptors such as the TLR-4, the transcription factor NF-kB, the inflammasome NLRP3, as well as the secretion of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and other factors of the innate immune response, causing first, the general symptoms of the disease which appear with any infection, but also those characteristic of depressive illness such as dysphoria and anhedonia. The evidence indicates that, if the stimulus persists or recurs within 24 hours, the indole-2, 3-dioxygenase enzyme (IDO) of the kynurenine metabolic pathway, which increases the synthesis of quinolinic acid, is activated with an associated reduction of serotonin synthesis. Quinolinic acid activates NMDA receptors in the central nervous system and stimulates the secretion of interleukins IL-6 and 1L-1ß, among others, promoting hyper-activity of the HPA axis and reinforcing a bias of the tryptophan metabolism to produce quinolinic acid, and interleukins by the innate immune system, further reducing the synthesis of serotonin and consolidating the depressive process. We discuss the evidence showing that this process can be initiated by either interleukin stimulated by an infection or some vaccines or excessive psychological stress that activates the HPA axis together with said innate immune response, causing a process of aseptic inflammation in the central nervous system.

Nueva teoría sobre la depresión: un equilibrio del ánimo entre el sistema nervioso y el inmunológico, con regulación de la serotonina-quinurenina y el eje hipotálamo-hipófiso-suprarrenal / A new theory of depression based on the serotonin/kynurenine relationship and the hypothalamic-pituitary-adrenal axis

La hipótesis sobre las causas de la depresión basada en la acción de la serotonina y del sistema inmunológico, propone que ciertos tipos de estrés distorsionan la relación entre la actividad del sistema inmunitario innato y la del sistema nervioso central. El estrés causado por una infección o el estrés psicológico excesivo activan receptores de tipo toll, como el TLR-4, el factor de transcripción NF-kB, el inflamasoma NLRP3, así como la secreción de interleucina 1 beta (IL-1ß) e interleucina 6 (IL-6); esto causa, en primer lugar, los síntomas generales de enfermedad que aparecen con cualquier infección, pero también los síntomas característicos de la depresión como disforia y anhedonia. Las evidencias indican que, si el estímulo persiste o se repite en las siguientes 24 horas, se activa la enzima indolamina 2,3-dioxigenasa (IDO) de la vía metabólica de la quinurenina, lo cual incrementa la síntesis del ácido quinolínico y reduce la síntesis de serotonina. El ácido quinolínico activa los receptores de N-metil-D-aspartato (NMDA) en el sistema nervioso central y estimula la secreción de, entre otras, las interleucinas IL-6 e 1L-1ß, las cuales promueven la hiperactividad del eje hipotálamohipófiso-suprarrenal y refuerzan la desviación del metabolismo del triptófano hacia la producción de ácido quinolínico, así como de las interleucinas de la inmunidad innata, con lo cual se reduce más la síntesis de serotonina y se consolida el proceso depresivo. Este proceso puede ser iniciado por las interleucinas estimuladas por una infección, así como por algunas vacunas o por un estrés psicológico excesivo que active el eje hipotálamo-hipófiso-suprarrenal simultáneamente con la respuesta inmunológica innata, con lo que se provocaría un proceso de inflamación estéril en el sistema nervioso central.

The serotonergic and immunological hypothesis of depression proposes that certain types of excessive stress distort the relationship between the activities of the innate immune and central nervous systems, so that the stress caused by an infection, or excessive psychological stress, activate toll-like receptors such as the TLR-4, the transcription factor NF-kB, the inflammasome NLRP3, as well as the secretion of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6) and other factors of the innate immune response, causing first, the general symptoms of the disease which appear with any infection, but also those characteristic of depressive illness such as dysphoria and anhedonia. The evidence indicates that, if the stimulus persists or recurs within 24 hours, the indole-2, 3-dioxygenase enzyme (IDO) of the kynurenine metabolic pathway, which increases the synthesis of quinolinic acid, is activated with an associated reduction of serotonin synthesis. Quinolinic acid activates NMDA receptors in the central nervous system and stimulates the secretion of interleukins IL-6 and 1L-1ß, among others, promoting hyper-activity of the HPA axis and reinforcing a bias of the tryptophan metabolism to produce quinolinic acid, and interleukins by the innate immune system, further reducing the synthesis of serotonin and consolidating the depressive process. We discuss the evidence showing that this process can be initiated by either interleukin stimulated by an infection or some vaccines or excessive psychological stress that activates the HPA axis together with said innate immune response, causing a process of aseptic inflammation in the central nervous system.

[Not Available]. / Nutritional assessment of hospitalized patients in Latin America: association with prognostic variables. The ENHOLA study.

BACKGROUND AND AIM: The prevalence of hospital malnutrition (HM) is variable, explained by the variability of patients, the nutritional evaluation method used among others. The aim is to determine the frequency of malnutrition in hospitals in Latin America, and estimate its association with mortality and length of hospital stay. METHODS: This is an analytical, observational cohort study that included 7,973 patients of both genders, 18 and older, who provided their consent. The survey was administered during the first three days of admission. The nutritional status was estimated using Subjective Global Assessment (SGA) and the Nutrition Risk Screening (NRS), body mass index (BMI), percentage of change of weight (PCW) and co-morbidities. Serum albumin was obtained from the clinical chart. Length of stay (LOS) and the survival status at discharge (dead or alive) were also recorded. RESULTS: By SGA: 10.9% had severe malnutrition and 34% moderate malnutrition. By NRS: 36.9% had nutritional risk. Univariate analysis showed that NRS score and serum albumin were prognostic factors for mortality: NRS 3-4 (OR: 2.3, 95% CI: 1.9-2.8), NRS 5-7 (OR: 5.8, 95% CI: 4.9-6.9), serum albumin < 2.5 g/dl, (OR: 2.9, 95% CI: 2.2-3.8). These results were consistent and similar to a multivariate analysis. Both NRS and serum albumin were also independently and clinically associated to LOS. CONCLUSIONS: The prevalence of hospital malnutrition in Latin America is high. Our results show that screening with NRS and serum albumin can identify hospital malnutrition as well as providing clinically relevant prognostic value.

Curso clínico de pacientes de trasplante autógeno de médula ósea portadores del virus linfotrópico humano / Clinical evolution of carriers of human T-lymphotropic virus 1 after autologous hematopoietic stem cell transplantation

La infección por virus linfotrópico humano 1 es frecuente en la costa pacífica colombiana y se ha relacionado con leucemia/linfoma de células T del adulto y mielopatía en una proporción baja de los seropositivos. En pacientes con trasplante de órganos sólidos pareciera que estas patologías se desarrollan más rápidamente que en los otros escenarios pero se desconoce el curso de la infección por virus linfotrópico humano 1 en trasplante de médula ósea por lo cual describimos 3 casos de pacientes seropositivos y linfoma que fueron llevados a trasplante autógeno. Uno de ellos tuvo recaída de su patología hematológica y falleció a consecuencia de la misma, otra paciente presentó un cuadro compatible con mielopatía asociada al virus linfotrópico humano 1 y la última, una enfermedad injerto contra hospedero. En las personas seropositivas y que necesitan un trasplante de células hematopoyéticas se requiere una búsqueda activa de este virus para hacer seguimientos y evaluar su impacto real en los desenlaces y saber si el curso de la infección podría cambiar con el régimen condicionante del trasplante.

Human T-lymphotropic virus 1 infection is common in Colombia´s Pacific coast and has been linked to adult T-cell leukemia/lymphoma and human T-lymphotropic virus 1-associated myelopathy in a low percentage of cases. In patients with solid organ transplantation, these diseases occur more quickly than in other scenarios but in bone marrow transplantation the true impact is unknown. We describe 3 seropositive patients with lymphoma who underwent autologous stem cell transplantation; in one case there was relapse of the hematologic malignancy and death occurred as a result. Another patient had symptoms compatible with human T-lymphotropic virus 1-associated myelopathy and the last patient had a graft vs. host disease. In seropositive people who need hematopoietic cell transplantation, an active search for this virus is required to be able to follow and assess the virus´s impact on outcomes, as well as to assess whether the evolution could change according to the transplant conditioning regimen.

Delta opioids reduce the neurotransmitter release probability by enhancing transient (KV4) K+-currents in corticostriatal synapses as evaluated by the paired pulse protocol.

Field recordings were used to determine the influence of delta-opioid receptor activation on corticostriatal synaptic transmission. Application of the selective delta-opioid receptor agonist, [Tyr-D-Pen-Gly-Phe-D-Pen]-enkephalin (DPDPE, 1 microM), decreased the amplitude of the field-excitatory synaptic potential and at the same time increased the paired pulse ratio (PPR) suggesting a presynaptic site of action. This response reversed rapidly when DPDPE was washed and blocked by 1 nM of the selective delta-receptor antagonist naltrindole. Neither omega-conotoxin GVIA (1 microM) nor omega-agatoxin TK (400 nM), blockers of N- and P/Q-type Ca2+-channels, respectively, nor TEA (1 mM), blocker of some classes of K+-channels, occluded the effects of DPDPE. Instead, 1 mM 4-AP or 400 microM Ba2+ occluded completely the effects of DPDPE. Therefore, the results suggest that the modulation by delta opioids at corticostriatal terminals is mediated by transient (KV4) K+-conductances.