Effect of Obesity on Surgical Outcomes and Complication Rates in Pediatric Patients: A Comprehensive Systematic Review and Meta-Analysis.

Obesity is one of the primary public health problems faced by children. The increased incidence of obesity in the pediatric population poses significant challenges during and after surgical procedures. This systematic review and meta-analysis aimed to understand to what extent obesity is to surgical complications in pediatric patients. A systematic database search of PubMed, Web of Science, Scopus, and Science Direct was performed in June 2023. According to the inclusion and exclusion criteria, two evaluators independently conducted literature screening, data extraction, and quality evaluation of the retrieved literature. The Newcastle-Ottawa Scale score was used for quality evaluation, and a meta-analysis was performed using Review Manager software 5.4.1. A total of 1,170 relevant articles were initially identified, and 20 articles were finally included for data extraction and meta-analysis. The results of the meta-analysis showed that compared with normal-weight individuals, obese pediatric patients had a higher risk of developing surgical site infection (SSI) (relative risk (RR) = 1.63; 95% confidence interval (CI) = 1.33-2.00), wound dehiscence (RR = 2.01; 95% CI = 1.24-3.23), and underwent procedures that were 11.32 minutes longer (95% CI = 5.36-17.29). There were no differences in bleeding requiring transfusion, deep venous thromboembolism, postoperative abscess rate, and length of stay. Obese pediatric patients have a higher risk of SSI and dehiscence, along with a longer operative time. The established risks in obese adults undergoing surgery suggest a similar risk for obese pediatric patients. The findings of this study hold significant implications for clinical practice, suggesting the potential for additional measures to prevent surgical complications in children.

IGF2 prevents dopaminergic neuronal loss and decreases intracellular alpha-synuclein accumulation in Parkinson's disease models.

Parkinson's disease (PD) is the second most common late-onset neurodegenerative disease and the predominant cause of movement problems. PD is characterized by motor control impairment by extensive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). This selective dopaminergic neuronal loss is in part triggered by intracellular protein inclusions called Lewy bodies, which are composed mainly of misfolded alpha-synuclein (α-syn) protein. We previously reported insulin-like growth factor 2 (IGF2) as a key protein downregulated in PD patients. Here we demonstrated that IGF2 treatment or IGF2 overexpression reduced the α-syn aggregates and their toxicity by IGF2 receptor (IGF2R) activation in cellular PD models. Also, we observed IGF2 and its interaction with IGF2R enhance the α-syn secretion. To determine the possible IGF2 neuroprotective effect in vivo we used a gene therapy approach in an idiopathic PD model based on α-syn preformed fibrils intracerebral injection. IGF2 gene therapy revealed a significantly preventing of motor impairment in idiopathic PD model. Moreover, IGF2 expression prevents dopaminergic neuronal loss in the SN together with a decrease in α-syn accumulation (phospho-α-syn levels) in the striatum and SN brain region. Furthermore, the IGF2 neuroprotective effect was associated with the prevention of synaptic spines loss in dopaminergic neurons in vivo. The possible mechanism of IGF2 in cell survival effect could be associated with the decrease of the intracellular accumulation of α-syn and the improvement of dopaminergic synaptic function. Our results identify to IGF2 as a relevant factor for the prevention of α-syn toxicity in both in vitro and preclinical PD models.

Contribution of Autophagy-Lysosomal Pathway in the Exosomal Secretion of Alpha-Synuclein and Its Impact in the Progression of Parkinson's Disease.

Parkinson's disease (PD) is caused by the degeneration of dopaminergic neurons due to an accumulation of intraneuronal abnormal alpha-synuclein (α-syn) protein aggregates. It has been reported that the levels of exosomal α-syn of neuronal origin in plasma correlate significantly with motor dysfunction, highlighting the exosomes containing α-syn as a potential biomarker of PD. In addition, it has been found that the selective autophagy-lysosomal pathway (ALP) contributes to the secretion of misfolded proteins involved in neurodegenerative diseases. In this review, we describe the evidence that supports the relationship between the ALP and α-syn exosomal secretion on the PD progression and its implications in the diagnosis and progression of this pathology.

Insulin-like growth factor 2 and autophagy gene expression alteration arise as potential biomarkers in Parkinson's disease.

Insulin-like growth factor 2 (IGF2) and autophagy-related genes have been proposed as biomolecules of interest related to idiopathic Parkinson's disease (PD). The objective of this study was to determine the IGF2 and IGF1 levels in plasma and peripheral blood mononuclear cells (PBMCs) from patients with moderately advanced PD and explore the potential correlation with autophagy-related genes in the same blood samples. IGF1 and IGF2 levels in patients' plasma were measured by ELISA, and the IGF2 expression levels were determined by real-time PCR and Western blot in PBMCs. The expression of autophagy-related genes was evaluated by real-time PCR. The results show a significant decrease in IGF2 plasma levels in PD patients compared with a healthy control group. We also report a dramatic decrease in IGF2 mRNA and protein levels in PBMCs from PD patients. In addition, we observed a downregulation of key components of the initial stages of the autophagy process. Although IGF2 levels were not directly correlated with disease severity, we found a correlation between its levels and autophagy gene profile expression in a sex-dependent pattern from the same samples. To further explore this correlation, we treated mice macrophages cell culture with α-synuclein and IGF2. While α-synuclein treatment decreased levels Atg5, IGF2 treatment reverted these effects, increasing Atg5 and Beclin1 levels. Our results suggest a relationship between IGF2 levels and the autophagy process in PD and their potential application as multi-biomarkers to determine PD patients' stages of the disease.

Small molecules to perform big roles: The search for Parkinson's and Huntington's disease therapeutics.

Neurological motor disorders (NMDs) such as Parkinson's disease and Huntington's disease are characterized by the accumulation and aggregation of misfolded proteins that trigger cell death of specific neuronal populations in the central nervous system. Differential neuronal loss initiates the impaired motor control and cognitive function in the affected patients. Although major advances have been carried out to understand the molecular basis of these diseases, to date there are no treatments that can prevent, cure, or significantly delay the progression of the disease. In this context, strategies such as gene editing, cellular therapy, among others, have gained attention as they effectively reduce the load of toxic protein aggregates in different models of neurodegeneration. Nevertheless, these strategies are expensive and difficult to deliver into the patients' nervous system. Thus, small molecules and natural products that reduce protein aggregation levels are highly sought after. Numerous drug discovery efforts have analyzed large libraries of synthetic compounds for the treatment of different NMDs, with a few candidates reaching clinical trials. Moreover, the recognition of new druggable targets for NMDs has allowed the discovery of new small molecules that have demonstrated their efficacy in pre-clinical studies. It is also important to recognize the contribution of natural products to the discovery of new candidates that can prevent or cure NMDs. Additionally, the repurposing of drugs for the treatment of NMDs has gained huge attention as they have already been through clinical trials confirming their safety in humans, which can accelerate the development of new treatment. In this review, we will focus on the new advances in the discovery of small molecules for the treatment of Parkinson's and Huntington's disease. We will begin by discussing the available pharmacological treatments to modulate the progression of neurodegeneration and to alleviate the motor symptoms in these diseases. Then, we will analyze those small molecules that have reached or are currently under clinical trials, including natural products and repurposed drugs.

Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration.

Alteration to endoplasmic reticulum (ER) proteostasis is observed in a variety of neurodegenerative diseases associated with abnormal protein aggregation. Activation of the unfolded protein response (UPR) enables an adaptive reaction to recover ER proteostasis and cell function. The UPR is initiated by specialized stress sensors that engage gene expression programs through the concerted action of the transcription factors ATF4, ATF6f, and XBP1s. Although UPR signaling is generally studied as unique linear signaling branches, correlative evidence suggests that ATF6f and XBP1s may physically interact to regulate a subset of UPR target genes. In this study, we designed an ATF6f/XBP1s fusion protein termed UPRplus that behaves as a heterodimer in terms of its selective transcriptional activity. Cell-based studies demonstrated that UPRplus has a stronger effect in reducing the abnormal aggregation of mutant huntingtin and α-synuclein when compared to XBP1s or ATF6 alone. We developed a gene transfer approach to deliver UPRplus into the brain using adeno-associated viruses (AAVs) and demonstrated potent neuroprotection in vivo in preclinical models of Parkinson's disease and Huntington's disease. These results support the concept in which directing UPR-mediated gene expression toward specific adaptive programs may serve as a possible strategy to optimize the beneficial effects of the pathway in different disease conditions.

On the Right Track to Treat Movement Disorders: Promising Therapeutic Approaches for Parkinson's and Huntington's Disease.

Movement disorders are neurological conditions in which patients manifest a diverse range of movement impairments. Distinct structures within the basal ganglia of the brain, an area involved in movement regulation, are differentially affected for every disease. Among the most studied movement disorder conditions are Parkinson's (PD) and Huntington's disease (HD), in which the deregulation of the movement circuitry due to the loss of specific neuronal populations in basal ganglia is the underlying cause of motor symptoms. These symptoms are due to the loss principally of dopaminergic neurons of the substantia nigra (SN) par compacta and the GABAergic neurons of the striatum in PD and HD, respectively. Although these diseases were described in the 19th century, no effective treatment can slow down, reverse, or stop disease progression. Available pharmacological therapies have been focused on preventing or alleviating motor symptoms to improve the quality of life of patients, but these drugs are not able to mitigate the progressive neurodegeneration. Currently, considerable therapeutic advances have been achieved seeking a more efficacious and durable therapeutic effect. Here, we will focus on the new advances of several therapeutic approaches for PD and HD, starting with the available pharmacological treatments to alleviate the motor symptoms in both diseases. Then, we describe therapeutic strategies that aim to restore specific neuronal populations or their activity. Among the discussed strategies, the use of Neurotrophic factors (NTFs) and genetic approaches to prevent the neuronal loss in these diseases will be described. We will highlight strategies that have been evaluated in both Parkinson's and Huntington's patients, and also the ones with strong preclinical evidence. These current therapeutic techniques represent the most promising tools for the safe treatment of both diseases, specifically those aimed to avoid neuronal loss during disease progression.

Genotoxic stress triggers the activation of IRE1α-dependent RNA decay to modulate the DNA damage response.

The molecular connections between homeostatic systems that maintain both genome integrity and proteostasis are poorly understood. Here we identify the selective activation of the unfolded protein response transducer IRE1α under genotoxic stress to modulate repair programs and sustain cell survival. DNA damage engages IRE1α signaling in the absence of an endoplasmic reticulum (ER) stress signature, leading to the exclusive activation of regulated IRE1α-dependent decay (RIDD) without activating its canonical output mediated by the transcription factor XBP1. IRE1α endoribonuclease activity controls the stability of mRNAs involved in the DNA damage response, impacting DNA repair, cell cycle arrest and apoptosis. The activation of the c-Abl kinase by DNA damage triggers the oligomerization of IRE1α to catalyze RIDD. The protective role of IRE1α under genotoxic stress is conserved in fly and mouse. Altogether, our results uncover an important intersection between the molecular pathways that sustain genome stability and proteostasis.

Salud intercultural desde la visión de las comunidades mapuche de Canete y Tirúa / Intercultural Health from the Perspective of the Mapuche Communities of Cahete and Tirúa / Saúde intercultural desde a visão das comunidades mapuche de Cahete e Tirúa

Resumen Introducción: a más de dos décadas de la introducción del concepto de salud intercultural en América Latina, su definición no está clara, pues ha adquirido diferentes significados dependiendo de su uso. Existen tensiones entre la tendencia a reducir la salud intercultural a la conciliación entre la biomedicina y la medicina indígena, y una perspectiva crítica que hace visible las inequidades entre ambas. Este estudio tuvo por objetivo comprender el concepto de salud intercultural, desde la visión de dos comunidades mapuche que han implementado programas de salud intercultural y que mantienen acciones de reivindicación de derechos indígenas. Desarrollo: se realizo un estudio cualitativo. Los datos se recogieron mediante entrevistas semiestructuradas a usuarios mapuche, profesionales de salud, facilitadores interculturales e informantes clave de las comunas de Canete y Tirúa. Esta información se analizó mediante un análisis temático. Los hallazgos acerca de la visión de la salud intercultural se agruparon en cuatro temas: atender las necesidades de salud más urgentes de la comunidad; respetar al usuario y su cultura; respetar el sistema de salud indígena; y respetar los derechos colectivos del pueblo mapuche. Conclusiones: la salud intercultural se considera un enfoque que debe asegurar la atención de calidad, la participación de la comunidad y el respeto a la salud tradicional. En esta, los derechos de los pueblos indígenas son la piedra angular. En un contexto marcado por la inequidad y la discriminación hacia los pueblos indígenas, la complementariedad entre sistemas médicos no es un tema prioritario.

Abstract Introduction: More than two decades after the introduction of the concept intercultural health in Latin America, its definition is not clear, as it has acquired different meanings depending on its use. There are tensions between the tendency to reduce intercultural health to the conciliation between biomedicine and indigenous medicine, and a critical perspective that makes visible the inequalities between the two. The aim of this study was to understand the concept of intercultural health from the perspec tive of two Mapuche communities that have implemented intercultural health programs that maintain actions to claim indigenous rights. Content: This is a qualitative study. The data were collected through semi-structured interviews with Mapuche users, health professionals, intercultural facilitators, and key informants in the cities of Canete and Tirúa. This information was analyzed through thematic analysis. The findings on the vision of intercultural health were grouped into four themes: addressing the most urgent health needs of the community, respecting the user and their culture, respecting the indigenous health system, and respecting the collective rights of the Mapuche people. Conclusions: Intercultural health is seen as an approach that must ensure quality care, community participation, and respect for traditional health, in which the rights of indigenous peoples are the cornerstone. In a context marked by inequality and discrimination against indigenous peoples, complementarity between medical systems is not a priority issue.

Resumo Introdução: depois de mais de duas décadas da introdução do conceito de saúde intercultural na América Latina, sua definição não está clara, pois têm adquirido diferentes significados dependendo de seu uso. Existem tensões entre a tendência a reduzir a saúde intercultural à conciliação entre a biomedicina e a medicina indígena, e uma perspectiva crítica que faz visível as inquietudes entre ambas as duas. Este estudo teve por objetivo compreender o conceito de saúde intercultural, desde a visão de duas comunida des mapuche que têm implementado programas de saúde intercultural e que mantém ações de reivindi cação de direitos indígenas. Desenvolvimento: se realizou um estudo qualitativo. Os dados se recolheram através de entrevistas semiestruturadas a usuários mapuche, profissionais de saúde, facilitadores inter-culturais e informantes chave das comunas de Canete e Tirúa. Esta informação foi analisada através de análise temática. Os resultados acerca da visão da saúde intercultural agruparam-se em quatro temas: atender as necessidades de saúde mais urgentes da comunidade, respeitar ao usuário e sua cultura, res peitar o sistema de saúde indígena e respeitar os direitos coletivos do povo mapuche. Conclusões: a saúde intercultural é vista como um enfoque que deve assegurar a atenção de qualidade, a participação da comunidade e o respeito à saúde tradicional, onde os direitos dos povos indígenas são a pedra angular. Em um contexto marado pela inequidade e a discriminação para os povos indígenas, a complementariedade entre sistemas médicos não é um tema prioritário.

Impaired IRE1α/XBP-1 pathway associated to DNA methylation might contribute to salivary gland dysfunction in Sjögren's syndrome patients.

Objectives: Labial salivary glands (LSGs) of SS patients show alterations related to endoplasmic reticulum stress. Glandular dysfunction could be partly the consequence of an altered inositol-requiring enzyme 1α (IRE1α)/X box-binding protein 1 (XBP-1) signalling pathway of the unfolded protein response, which then regulates genes involved in biogenesis of the secretory machinery. This study aimed to determine the expression, promoter methylation and localization of the IRE1α/XBP-1 pathway components in LSGs of SS patients and also their expression induced by IFN-γ in vitro. Methods: IRE1α, XBP-1 and glucose-regulated protein 78 (GRP78) mRNA and protein levels were measured by qPCR and western blot, respectively, in LSGs of SS patients (n = 47) and control subjects (n = 37). Methylation of promoters was evaluated by methylation-sensitive high resolution melting, localization was analysed by immunofluorescence and induction of the IRE1α/XBP-1 pathway components by IFN-γ was evaluated in 3D acini. Results: A significant decrease of IRE1α, XBP-1u, XBP-1s, total XBP-1 and GRP78 mRNAs was observed in LSGs of SS patients, which was correlated with increased methylation levels of their respective promoters, and consistently the protein levels for IRE1α, XBP-1s and GRP78 were observed to decrease. IFN-γ decreased the mRNA and protein levels of XBP-1s, IRE1α and GRP78, and increased methylation of their promoters. Significant correlations were also found between IRE1α/XBP-1 pathway components and clinical parameters. Conclusion: Decreased mRNA levels for IRE1α, XBP-1 and GRP78 can be partially explained by hypermethylation of their promoters and is consistent with chronic endoplasmic reticulum stress, which may explain the glandular dysfunction observed in LSGs of SS patients. Additionally, glandular stress signals, including IFN-γ, could modulate the expression of the IRE1α/XBP-1 pathway components.

Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1α.

Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). IRE1α is a major UPR transducer, determining cell fate under ER stress. We used an interactome screening to unveil several regulators of the UPR, highlighting the ER chaperone Hsp47 as the major hit. Cellular and biochemical analysis indicated that Hsp47 instigates IRE1α signaling through a physical interaction. Hsp47 directly binds to the ER luminal domain of IRE1α with high affinity, displacing the negative regulator BiP from the complex to facilitate IRE1α oligomerization. The regulation of IRE1α signaling by Hsp47 is evolutionarily conserved as validated using fly and mouse models of ER stress. Hsp47 deficiency sensitized cells and animals to experimental ER stress, revealing the significance of Hsp47 to global proteostasis maintenance. We conclude that Hsp47 adjusts IRE1α signaling by fine-tuning the threshold to engage an adaptive UPR.

Taller de salud mental: programa psicoeducativo dirigido a comunidad de adultos jubilados de una institución de gendarmería / Mental health workshop: psychoeducative program to a retired people in a gendarmerie institution

El grupo objetivo al cual está dirigido el presente programa psicoeducativo de salud mental corresponde a una comunidad de adultos mayores jubilados de Gendarmería de Chile. Mediante la generación de un diagnóstico participativo por parte de los integrantes de la comunidad, se constató la necesidad de desarrollar herramientas para la superación de problemas de la vida, lo que se enmarca en la promoción de la resiliencia. La realización del taller de salud mental constó de once sesiones. Primero, se abarcaron los cambios fisiológicos y patológicos del envejecimiento, para luego trabajar en conjunto la resiliencia en la adultez. Al inicio de las sesiones educativas, se aplicó la escala de resiliencia de SV-RES 60 de Saavedra y Villalta (2008), validada en nuestro país, con el fin de conocer los niveles basales de resiliencia. Luego de finalizadas las intervenciones, se realizó una nueva toma, para así poder evaluar el impacto de estas en los participantes. Se constató un aumento del nivel de resiliencia desde un 49.8% a un 75.1%, lo que se traduce en un ascenso desde un nivel promedio a un nivel alto, evidenciando la efectividad de la metodología aplicada.

The target group for this psychoeducative program in mental health is a community of elderly retired Gendarmerie of Chile. Through a participatory diagnosis with the participants, it could be possible to identify necessities about working and creating tools to resolve problems of life, in the framework of the resiliency. This workshop in mental health takes eleven sessions. At the first time, it includes physiological and pathological changes in the aging, and in the second part, the program includes working together in the resiliency. At the beginning of the sessions, it was applicated the Saavedra and Villata's resiliency scale SV-RES 60, which is validated in Chile, with the objective to know the baseline of resiliency of the group. When the workshop was finished, it was taken in a second opportunity the same scale to evaluate the impact of the sessions in the participants. It was verified an increment of the resiliency levels since the first time with a 49,8%, to a 75,1% in the finish, which it could be traduced in a increase to an average level of resiliency to a high level of resiliency, making evident the effectiveness of the methodology.

Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 1. An overview.

Increased demand on the protein folding capacity of the endoplasmic reticulum (ER) engages an adaptive reaction known as the unfolded protein response (UPR). The UPR regulates protein translation and the expression of numerous target genes that contribute to restore ER homeostasis or induce apoptosis of irreversibly damaged cells. UPR signaling is highly regulated and dynamic and integrates information about the type, intensity, and duration of the stress stimuli, thereby determining cell fate. Recent advances highlight novel physiological outcomes of the UPR beyond specialized secretory cells, particularly in innate immunity, metabolism, and cell differentiation. Here we discuss studies on the fine-tuning of the UPR and its physiological role in diverse organs and diseases.

Interplay between the oxidoreductase PDIA6 and microRNA-322 controls the response to disrupted endoplasmic reticulum calcium homeostasis.

The disruption of the energy or nutrient balance triggers endoplasmic reticulum (ER) stress, a process that mobilizes various strategies, collectively called the unfolded protein response (UPR), which reestablish homeostasis of the ER and cell. Activation of the UPR stress sensor IRE1α (inositol-requiring enzyme 1α) stimulates its endoribonuclease activity, leading to the generation of the mRNA encoding the transcription factor XBP1 (X-box binding protein 1), which regulates the transcription of genes encoding factors involved in controlling the quality and folding of proteins. We found that the activity of IRE1α was regulated by the ER oxidoreductase PDIA6 (protein disulfide isomerase A6) and the microRNA miR-322 in response to disruption of ER Ca2+ homeostasis. PDIA6 interacted with IRE1α and enhanced IRE1α activity as monitored by phosphorylation of IRE1α and XBP1 mRNA splicing, but PDIA6 did not substantially affect the activity of other pathways that mediate responses to ER stress. ER Ca2+ depletion and activation of store-operated Ca2+ entry reduced the abundance of the microRNA miR-322, which increased PDIA6 mRNA stability and, consequently, IRE1α activity during the ER stress response. In vivo experiments with mice and worms showed that the induction of ER stress correlated with decreased miR-322 abundance, increased PDIA6 mRNA abundance, or both. Together, these findings demonstrated that ER Ca2+, PDIA6, IRE1α, and miR-322 function in a dynamic feedback loop modulating the UPR under conditions of disrupted ER Ca2+ homeostasis.