La contribution du récepteur B1 des kinines dans les complications diabétiques chez le rat traité au glucose, un modèle de résistance à l'insuline

Les kinines agissent sur deux types de récepteurs couplés aux protéines G, nommés B1 et B2, lesquels jouent un rôle important dans le contrôle cardiovasculaire, la nociception et l’inflammation. Nous considérons l’hypothèse que le récepteur B1 des kinines est induit et contribue aux complications diabétiques, incluant l’hypertension artérielle, les polyneuropathies sensorielles, l’augmentation du stress oxydatif vasculaire, l’inflammation vasculaire et l’obésité chez le rat traité au D-glucose (10% dans l’eau de boisson) pendant 8 ou 12 semaines. Dans ce modèle de résistance à l’insuline, nous avons évalué les effets d’un traitement pharmacologique d’une semaine avec un antagoniste du récepteur B1 des kinines, le SSR240612 (10 mg/kg/jr). Les résultats montrent que le SSR240612 renverse l’hypertension, l’allodynie tactile et au froid, la production de l’anion superoxyde et la surexpression de plusieurs marqueurs inflammatoires dans l’aorte (iNOS, IL-1β, macrophage (CD68, CD11), ICAM-1, E-selectine, MIF ainsi que le B1R) et dans les adipocytes (iNOS, IL-1β, TNF-α et macrophage CD68). De plus, le SSR240612 corrige la résistance à l’insuline, les anomalies du profil lipidique plasmatique et le gain de poids et de masse adipeuse. Ces données supportent l’implication des kinines dans les complications diabétiques dans un modèle animal de résistance à l’insuline et suggèrent que le récepteur B1 est une cible thérapeutique potentielle dans le diabète et l’obésité.Kinins act on two G-protein-coupled receptors, denoted as B1 and B2, and play an important role in cardiovascular regulation, nociception and inflammation. We have considered the hypothesis that kinin B1 receptor is upregulated and involved in diabetic complications, notably hypertension, pain sensory neuropathy, the oxidative stress in the vasculature, vascular inflammation, insulin resistance and obesity in rats treated for 8 or 12 weeks with D-glucose (10% of glucose in their drinking water). In this model of insulin resistance, we assessed the effects of one-week treatment with SSR240612 (10 mg/kg/day), a selective kinin B1 receptor antagonist. Data show that SSR240612 reverses high blood pressure, tactile and cold allodynia, the production of oxidative stress (superoxyde anion) in the aorta, the overexpression of iNOS, IL-1β, macrophage (CD68, CD11), ICAM-1, E-selectine, MIF and B1R in the aorta and iNOS, IL-1β, TNF-α and macrophage (CD68) in adipocytes. Moreover, SSR240612 reverses insulin resistance, plasma fatty acids composition changes and body and tissue fat gain. These data support a key role for kinins in diabetic complications in a rat model of insulin resistance and suggest that kinin B1 receptor is a promising therapeutic target in diabetes and obesity

Key role for spinal dorsal horn microglial kinin B1 receptor in early diabetic pain neuropathy

<p>Abstract</p> <p>Background</p> <p>The pro-nociceptive kinin B₁receptor (B₁R) is upregulated on sensory C-fibres, astrocytes and microglia in the spinal cord of streptozotocin (STZ)-diabetic rat. This study aims at defining the role of microglial kinin B₁R in diabetic pain neuropathy.</p> <p>Methods</p> <p>Sprague-Dawley rats were made diabetic with STZ (65 mg/kg, i.p.), and 4 days later, two specific inhibitors of microglial cells (fluorocitrate, 1 nmol, i.t.; minocycline, 10 mg/kg, i.p.) were administered to assess the impact on thermal hyperalgesia, allodynia and mRNA expression (qRT-PCR) of B₁R and pro-inflammatory markers. Spinal B₁R binding sites ((¹²⁵I)-HPP-desArg¹⁰-Hoe 140) were also measured by quantitative autoradiography. Inhibition of microglia was confirmed by confocal microscopy with the specific marker Iba-1. Effects of intrathecal and/or systemic administration of B₁R agonist (des-Arg⁹-BK) and antagonists (SSR240612 and R-715) were measured on neuropathic pain manifestations.</p> <p>Results</p> <p>STZ-diabetic rats displayed significant tactile and cold allodynia compared with control rats. Intrathecal or peripheral blockade of B₁R or inhibition of microglia reversed time-dependently tactile and cold allodynia in diabetic rats without affecting basal values in control rats. Microglia inhibition also abolished thermal hyperalgesia and the enhanced allodynia induced by intrathecal des-Arg⁹-BK without affecting hyperglycemia in STZ rats. The enhanced mRNA expression (B₁R, IL-1β, TNF-α, TRPV1) and Iba-1 immunoreactivity in the STZ spinal cord were normalized by fluorocitrate or minocycline, yet B₁R binding sites were reduced by 38%.</p> <p>Conclusion</p> <p>The upregulation of kinin B₁R in spinal dorsal horn microglia by pro-inflammatory cytokines is proposed as a crucial mechanism in early pain neuropathy in STZ-diabetic rats.</p

Propuesta de implementación del programa de salud ocupacional en Acción Contra el Hambre

En los años de 1915 con la Ley de 57 en Colombia se empezó a tener en cuenta el tema de Salud Ocupacional en cuanto a la normatividad de los accidentes y enfermedades laborales, tema que ha venido tomando mayor importancia a través de los años por dos aspectos que refieren a las organizaciones, como es el cumplimiento legal que exige las distintas reglamentaciones que se han creado al respecto, debido a que su incumplimiento pueden poner en riesgo financiero o desestabilizar la permanencia en el tiempo de las mismas. El segundo aspecto hace referencia a una mejor productividad en la organización por medio de acciones que permiten el bienestar de los colaboradores en sus lugares de trabajo. La Propuesta de implementación del Programa de Salud Ocupacional en Acción contra el Hambre en base a las exigencias legales plantea los ejes fundamentales que componen el Programa, el cual busca un beneficio entre el empresario y el colaborador, pues el llevar a cabo una serie de actividades organizadas con el propósito de proveer un ambiente seguro y bienestar físico, social y mental de sus integrantes, son hechos que promueven una mejora en el clima de una organización y mejores resultados en el trabajo que se realiza dentro de ella

La imagen y la narrativa como herramientas para el abordaje psicosocial en escenarios de violencia. Tunja, Villa de Leyva y Zetaquira Boyacá.

La imagen y la narrativa como herramientas para el abordaje psicosocial en escenarios de violencia. Tunja, Villa de Leyva y Zetaquira Boyacá.El siguiente trabajo presenta un análisis de dos casos de violencia social producto del conflicto armado en Colombia, el caso escogido en relatos de vida y el caso de Pandurí, donde los estudiantes analizan los impactos psicosociales que estos temas implican y por medio de un análisis reflexivo se realiza un abordaje desde la psicología y posible intervención psicosocial, a través de preguntas orientadoras, formulación de preguntas de tipo reflexivas, circulares y estratégicas y el estudio de las unidades propuestas, el estudiante podrá aplicar los conocimientos adquiridos y desarrollar habilidades de intervención, manejo de conflictos, identificación de eventos, así como profundizar en el tema de la elaboración de un diagnostico psicosocial enfocado al empoderamiento de la comunidad o personas víctimas de conflicto armado u otro tipo de violencia. También se presenta la actividad número 3 de este Diplomado de la foto voz para complementar los conocimientos y el proceso psicosocial que se puede realizar desde diferentes enfoques y contextos sociales. Por medio de las actividades propuestas se analizan las consecuencias más significativas que han tenido la violencia y el conflicto armado en el entorno familiar, social y comunitario. Los relatos reflejan los impactos psicosociales y desde ahí se inician las propuestas de intervención psicosocial para transformar y reconstruir sucesos de gran impacto social y comunitario que influyeron en el ámbito familiar.The following work presents an analysis of two cases of social violence resulting from the armed conflict in Colombia, the case chosen in life stories and the case of Pandurí, where the students analyze the psychosocial impacts that these themes imply and through a reflexive analysis an approach is made from psychology and possible psychosocial intervention, through guiding questions, the formulation of reflective, circular and strategic questions and the study of the proposed units the student can apply the acquired knowledge and develop intervention skills, management of conflicts, identification of events, as well as to deepen in the topic of the elaboration of a psychosocial diagnosis focused on the empowerment of the community or people victims of armed conflict or other type of violence. The activity number 3 of this Diploma of the photo voice is also presented to complement the knowledge and the psychosocial process that can be done from different approaches and social contexts. Through the proposed activities, the most significant consequences of violence and armed conflict in the family, social and community environment are analyzed. The stories reflect the psychosocial impacts and from there the psychosocial intervention proposals are initiated to transform and reconstruct events of great social and community impact that influenced the family environment

Neurons and Microglia; A Sickly-Sweet Duo in Diabetic Pain Neuropathy

Diabetes is a common condition characterized by persistent hyperglycemia. High blood sugar primarily affects cells that have a limited capacity to regulate their glucose intake. These cells include capillary endothelial cells in the retina, mesangial cells in the renal glomerulus, Schwann cells, and neurons of the peripheral and central nervous systems. As a result, hyperglycemia leads to largely intractable complications such as retinopathy, nephropathy, hypertension, and neuropathy. Diabetic pain neuropathy is a complex and multifactorial disease that has been associated with poor glycemic control, longer diabetes duration, hypertension, advanced age, smoking status, hypoinsulinemia, and dyslipidemia. While many of the driving factors involved in diabetic pain are still being investigated, they can be broadly classified as either neuron -intrinsic or -extrinsic. In neurons, hyperglycemia impairs the polyol pathway, leading to an overproduction of reactive oxygen species and reactive nitrogen species, an enhanced formation of advanced glycation end products, and a disruption in Na+/K+ ATPase pump function. In terms of the extrinsic pathway, hyperglycemia leads to the generation of both overactive microglia and microangiopathy. The former incites a feed-forward inflammatory loop that hypersensitizes nociceptor neurons, as observed at the onset of diabetic pain neuropathy. The latter reduces neurons' access to oxygen, glucose and nutrients, prompting reductions in nociceptor terminal expression and losses in sensation, as observed in the later stages of diabetic pain neuropathy. Overall, microglia can be seen as potent and long-lasting amplifiers of nociceptor neuron activity, and may therefore constitute a potential therapeutic target in the treatment of diabetic pain neuropathy

The harm in conflating aging with accessibility

Including older adults as full stakeholders in digital society. </p

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome

Kinin B1 Receptor Enhances the Oxidative Stress in a Rat Model of Insulin Resistance: Outcome in Hypertension, Allodynia and Metabolic Complications

BACKGROUND: Kinin B(1) receptor (B(1)R) is induced by the oxidative stress in models of diabetes mellitus. This study aims at determining whether B(1)R activation could perpetuate the oxidative stress which leads to diabetic complications. METHODS AND FINDINGS: Young Sprague-Dawley rats were fed with 10% D-Glucose or tap water (controls) for 8-12 weeks. A selective B(1)R antagonist (SSR240612) was administered acutely (3-30 mg/kg) or daily for a period of 7 days (10 mg/kg) and the impact was measured on systolic blood pressure, allodynia, protein and/or mRNA B(1)R expression, aortic superoxide anion (O(2)(*-)) production and expression of superoxide dismutase (MnSOD) and catalase. SSR240612 reduced dose-dependently (3-30 mg/kg) high blood pressure in 12-week glucose-fed rats, but had no effect in controls. Eight-week glucose-fed rats exhibited insulin resistance (HOMA index), hypertension, tactile and cold allodynia and significant increases of plasma levels of glucose and insulin. This was associated with higher aortic levels of O(2)(*-), NADPH oxidase activity, MnSOD and catalase expression. All these abnormalities including B(1)R overexpression (spinal cord, aorta, liver and gastrocnemius muscle) were normalized by the prolonged treatment with SSR240612. The production of O(2)(*-) in the aorta of glucose-fed rats was also measured in the presence and absence of inhibitors (10-100 microM) of NADPH oxidase (apocynin), xanthine oxidase (allopurinol) or nitric oxide synthase (L-NAME) with and without Sar[D-Phe(8)]des-Arg(9)-BK (20 microM; B(1)R agonist). Data show that the greater aortic O(2)(*-) production induced by the B(1)R agonist was blocked only by apocynin. CONCLUSIONS: Activation of kinin B(1)R increased O(2)(*-) through the activation of NADPH oxidase in the vasculature. Prolonged blockade of B(1)R restored cardiovascular, sensory and metabolic abnormalities by reducing oxidative stress and B(1)R gene expression in this model

Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes. An Individual-Participant Data Meta-Analysis

IMPORTANCE: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. OBJECTIVE: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. DESIGN, SETTING, AND PARTICIPANTS: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. EXPOSURES: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). MAIN OUTCOMES AND MEASURES: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. RESULTS: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). CONCLUSIONS AND RELEVANCE: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations