Differential Effects of Cytokine Versus Hypoxic Preconditioning of Human Mesenchymal Stromal Cells in Pulmonary Sepsis Induced by Antimicrobial-Resistant Klebsiella pneumoniae.

Background: Pulmonary sepsis is a leading cause of hospital mortality, and sepses arising from antimicrobial-resistant (AMR) bacterial strains are particularly difficult to treat. Here we investigated the potential of mesenchymal stromal cells (MSCs) to combat established Klebsiella pneumoniae pneumosepsis and further evaluated MSC preconditioning and pre-activation methods. Methods: The potential for naïve and preconditioned MSCs to enhance wound healing, reduce inflammation, preserve metabolic activity, and enhance bacterial killing was assessed in vitro. Rats were subjected to intratracheal K. pneumoniae followed by the intravenous administration of MSCs. Physiological indices, blood, bronchoalveolar lavage (BAL), and tissues were obtained 72 h later. Results: In vitro assays confirmed that preconditioning enhances MSC function, accelerating pulmonary epithelial wound closure, reducing inflammation, attenuating cell death, and increasing bacterial killing. Cytomix-pre-activated MSCs are superior to naïve and hypoxia-exposed MSCs in attenuating Klebsiella pneumosepsis, improving lung compliance and oxygenation, reducing bacteria, and attenuating histologic injuries in lungs. BAL inflammatory cytokines were reduced, correlating with decreases in polymorphonuclear (PMN) cells. MSCs increased PMN apoptosis and the CD4:CD8 ratio in BAL. Systemically, granulocytes, classical monocytes, and the CD4:CD8 ratio were reduced, and nonclassical monocytes were increased. Conclusions: Preconditioning with cytokines, but not hypoxia, enhances the therapeutic potential of MSCs in clinically relevant models of K. pneumoniae-induced pneumosepsis.

Aerosolized Pulmonary Delivery of mRNA Constructs Attenuates Severity of Escherichia coli Pneumonia in the Rat.

Acute respiratory distress syndrome (ARDS), a rapid onset inflammatory lung disease with no effective specific therapy, typically has pathogenic etiology termed pneumonia. In previous studies nuclear factor-κB (NF-κB) inhibitor α super-repressor (IκBα-SR) and extracellular superoxide dismutase 3 (SOD3) reduced pneumonia severity when prophylactically delivered by viral vector. In this study, mRNA coding for green fluorescent protein, IκBα-SR, or SOD3 was complexed with cationic lipid, passed through a vibrating mesh nebulizer, and delivered to cell culture or directly to rats undergoing Escherichia coli pneumonia. Injury level was then assessed at 48 h. In vitro, expression was observed as early as 4 h in lung epithelial cells. IκBα-SR and wild-type IκBα mRNAs attenuated inflammatory markers, while SOD3 mRNA induced protective and antioxidant effects. In rat E. coli pneumonia, IκBα-SR mRNA reduced arterial carbon dioxide (pCO2) and reduced lung wet/dry ratio. SOD3 mRNA improved static lung compliance and alveolar-arterial oxygen gradient (AaDO2) and decreased bronchoalveolar lavage (BAL) bacteria load. White cell infiltration and inflammatory cytokine concentrations in BAL and serum were reduced by both mRNA treatments compared to scrambled mRNA controls. These findings indicate nebulized mRNA therapeutics are a promising approach to ARDS therapy, with rapid expression of protein and observable amelioration of pneumonia symptoms.

Enhancement strategies for mesenchymal stem cells and related therapies.

Cell therapy, particularly mesenchymal stem/stromal (MSC) therapy, has been investigated for a wide variety of disease indications, particularly those with inflammatory pathologies. However, recently it has become evident that the MSC is far from a panacea. In this review we will look at current and future strategies that might overcome limitations in efficacy. Many of these take their inspiration from stem cell niche and the mechanism of MSC action in response to the injury microenvironment, or from previous gene therapy work which can now benefit from the added longevity and targeting ability of a live cell vector. We will also explore the nascent field of extracellular vesicle therapy and how we are already seeing enhancement protocols for this exciting new drug. These enhanced MSCs will lead the way in more difficult to treat diseases and restore potency where donors or manufacturing practicalities lead to diminished MSC effect.

Hypercapnia in the critically ill: insights from the bench to the bedside.

Carbon dioxide (CO2) has long been considered, at best, a waste by-product of metabolism, and at worst, a toxic molecule with serious health consequences if physiological concentration is dysregulated. However, clinical observations have revealed that 'permissive' hypercapnia, the deliberate allowance of respiratory produced CO2 to remain in the patient, can have anti-inflammatory effects that may be beneficial in certain circumstances. In parallel, studies at the cell level have demonstrated the profound effect of CO2 on multiple diverse signalling pathways, be it the effect from CO2 itself specifically or from the associated acidosis it generates. At the whole organism level, it now appears likely that there are many biological sensing systems designed to respond to CO2 concentration and tailor respiratory and other responses to atmospheric or local levels. Animal models have been widely employed to study the changes in CO2 levels in various disease states and also to what extent permissive or even directly delivered CO2 can affect patient outcome. These findings have been advanced to the bedside at the same time that further clinical observations have been elucidated at the cell and animal level. Here we present a synopsis of the current understanding of how CO2 affects mammalian biological systems, with a particular emphasis on inflammatory pathways and diseases such as lung specific or systemic sepsis. We also explore some future directions and possibilities, such as direct control of blood CO2 levels, that could lead to improved clinical care in the future.

Análisis acústico en el diagnóstico del deterioro cognitivo: revisión sistemática de la literatura, 2008-2020 / Acoustic Analysis in Mild Cognitive Diagnosis: Systematic Review of the Literature in 2008­2020 / Análise acústica no diagnóstico da deterioração cognitiva: revisão sistemática da literatura 2008-2020

Introducción: investigaciones recientes han descrito que en la adultez mayor pueden presentarse cambios en la producción del tono y timbre de la voz. Dichos cambios pueden ser indicadores de alteraciones cog-nitivas tempranas, incluso en estadios preclínicos del deterioro cognitivo. El propósito de este estudio fue identificar en la literatura hallazgos relevantes sobre el análisis acústico en personas mayores con dete-rioro cognitivo. Materiales y métodos: se llevó a cabo un estudio de revisión sistemática de la literatura, en el que se consultaron las siguientes bases de datos: PlosOne, Science Direct, PubMed/pmc y Google Scholar. Se utilizaron metabuscadores como: acoustic analysis, Alzheimer's disease, mild cognitive impairment, prosody, voice analysis y voice production; además, se incluyeron artículos empíricos que describieran un análisis acústico en población adulta mayor con deterioro cognitivo. La evaluación fue realizada de manera independiente por dos evaluadores, quienes determinaron el riesgo de sesgo en la revisión. Se encontraron 59 artículos relacionados con el tema, de los cuales solo 25 cumplieron con los criterios de inclusión. Resultados: los artículos revisados identificaron cambios en la prosodia lingüística y paralingüística, el timbre y la tonalidad de la voz, asociados con el deterioro cognitivo del adulto mayor. Conclusión: los protocolos de estudio en el análisis acústico podrían ser una buena herramienta para el apoyo en el diagnóstico clínico diferencial del deterioro cognitivo en la vejez y una buena oportunidad para la identificación de riesgo en etapas preclínicas de las demencias

Introduction: In recent research, changes in the vocal tone and timbre production that occur in late adulthood have been described. These changes indicate early cognitive disturbances, even in preclini-cal stages of cognitive decline. This study aims to identify relevant findings from the literature regard-ing acoustic analysis in elderly adults with cognitive impairment. Material and methods: A systematic review study was conducted, in which the following databases were consulted: PlosOne, Science Direct, PubMed/pmc, and Google Scholar. Search engines such as acoustic analysis, Alzheimer's disease, mild cognitive impairment, prosody, voice analysis, and voice production were used. Additionally, empirical articles describing the acoustic analysis in elderly adults with cognitive risk are included. The evalua-tion was independently performed by two evaluators, who determined the risk of bias in the review. A total of 59 articles related to the topic were found, of which 25 met the inclusion criteria. Results: The reviewed articles identified changes in linguistic and paralinguistic prosody, timbre, and vocal tonality, which are associated with cognitive decline in the elderly. Conclusion: Study protocols in the acoustic analysis could be a good tool to support the differential clinical diagnosis of cognitive deterioration in late adulthood and a good opportunity to identify the risk in preclinical stages of dementia

Introdução: pesquisas recentes descrevem que mudanças na produção do tom e timbre da voz podem ocorrer na idade adulta avançada; essas mudanças podem ser indicadores de alterações cognitivas pre-coces, inclusive em estágios pré-clínicos de deterioração cognitiva. O objetivo deste estudo foi identifi-car achados relevantes na literatura sobre análise acústica em idosos com déficit cognitivo. Materiais e métodos: foi realizado um estudo de revisão sistemática da literatura, no qual foram consultadas as seguintes bases de dados: PlosOne, Science Direct, PubMed/pmc e Google Scholar; foram utilizados meca-nismos de procura, tais como: acousticanalysis, alzheimer'sdisease, mildcognitiveimpairment, prosody, voiceanalysis e voiceproduction. Foram incluídos artigos empíricos que descrevem a análise acústica na população idosa com déficit cognitivo. A avaliação foi realizada de forma independente por dois avalia-dores, que determinaram o risco de viés na revisão. Foram encontrados 59 artigos relacionados ao tema, dos quais apenas 25 atenderam aos critérios de inclusão. Resultados: os artigos revisados identificaram alterações na prosódia linguística e para-linguística, no timbre e no tom de voz, associadas à deteriora-ção cognitiva em idosos. Conclussão: os protocolos de estudo em análise acústica podem ser uma boa ferramenta para apoiar o diagnóstico clínico diferencial do comprometimento cognitivo na velhice e uma boa oportunidade para identificar o risco em estágios pré-clínicos de demência

GLP-1 receptor agonist ameliorates experimental lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease. This disease is characterized by an excessive accumulation of extracellular matrix deposition that modify normal lung physiology. Up to date, there are not efficient therapeutic tools to fight IPF. Glucagon-like peptide-1 receptor (GLP-1R) activation plays an essential role in lung functions in normal and in pathological conditions. The aim of the present study was to study the possible beneficial effects of the administration of the GLP-1R agonist, liraglutide, in the pathogenesis of the fibrotic process in an animal model of pulmonary fibrosis induced by bleomycin. We observed that liraglutide decreased mRNA expression of collagen, hydroxyproline and key enzymes for the synthesis of collagen. In addition, GLP-1R activation restored the ACE2 mRNA levels modulating the activities of the RAS components, increased the production of surfactant proteins (SFTPa1, SFTPb, SFTPc) and promoted an improvement in pulmonary and cardiac functionality, including a partial restoration of lung alveolar structure. Liraglutide effects are shown at both the pro-inflammatory and fibrosis phases of the experimental disease. For these reasons, GLP-1 might be regarded as a promising drug for treating pulmonary fibrosis.

Sublingual dermoid cyst in an infant: A case report and review of the literature.

Dermoid cysts usually occur later in the second decade of life; we present the approach of an unusual case of an infant who presented a cyst within the oral cavity, which is important because it can be confused with other pathologies.

Perinatal Undernutrition, Metabolic Hormones, and Lung Development.

Maternal and perinatal undernutrition affects the lung development of litters and it may produce long-lasting alterations in respiratory health. This can be demonstrated using animal models and epidemiological studies. During pregnancy, maternal diet controls lung development by direct and indirect mechanisms. For sure, food intake and caloric restriction directly influence the whole body maturation and the lung. In addition, the maternal food intake during pregnancy controls mother, placenta, and fetal endocrine systems that regulate nutrient uptake and distribution to the fetus and pulmonary tissue development. There are several hormones involved in metabolic regulations, which may play an essential role in lung development during pregnancy. This review focuses on the effect of metabolic hormones in lung development and in how undernutrition alters the hormonal environment during pregnancy to disrupt normal lung maturation. We explore the role of GLP-1, ghrelin, and leptin, and also retinoids and cholecalciferol as hormones synthetized from diet precursors. Finally, we also address how metabolic hormones altered during pregnancy may affect lung pathophysiology in the adulthood.

Stressing diabetes? The hidden links between insulinotropic peptides and the HPA axis.

Diabetes mellitus exerts metabolic stress on cells and it provokes a chronic increase in the long-term activity of the hypothalamus-pituitary-adrenocortical (HPA) axis, perhaps thereby contributing to insulin resistance. GLP-1 receptor (GLP-1R) agonists are pleiotropic hormones that not only affect glycaemic and metabolic control, but they also produce many other effects including activation of the HPA axis. In fact, several of the most relevant effects of GLP-1 might involve, at least in part, the modulation of the HPA axis. Thus, the anorectic activity of GLP-1 could be mediated by increasing CRF at the hypothalamic level, while its lipolytic effects could imply a local increase in glucocorticoids and glucocorticoid receptor (GC-R) expression in adipose tissue. Indeed, the potent activation of the HPA axis by GLP-1R agonists occurs within the range of therapeutic doses and with a short latency. Interestingly, the interactions of GLP-1 with the HPA axis may underlie most of the effects of GLP-1 on food intake control, glycaemic metabolism, adipose tissue biology and the responses to stress. Moreover, such activity has been observed in animal models (mice and rats), as well as in normal humans and in type I or type II diabetic patients. Accordingly, better understanding of how GLP-1R agonists modulate the activity of the HPA axis in diabetic subjects, especially obese individuals, will be crucial to design new and more efficient therapies for these patients.

Heridas por mordedura animal en la región maxilofacial: revisión de literatura y presentación de casos / Animal bite wounds in the maxillofacial region: a review of the literature and case reports

Las heridas por mordida en la región maxilofacial son relativamentecomunes y se consideran de tratamiento complejo; son contaminadas con una flora oral bacteriana única y, en ocasiones, tienen resultados estéticos devastadores. Las heridas pueden ser ocasionadas por animales domésticos, salvajes y humanos. El clínico debe tener una comprensión multidisciplinaria del manejo de las mismas, incluyendo el abordaje médico, quirúrgico, viral, bacteriológico y la secuencia propia del tratamiento. Se presenta una revisión de la literatura, así como casos clínicos para el tratamiento integral de este tipo de trauma.

Bite wounds in the maxillofacial region are relatively common and are regarded as diffi cult to treat given the associated contamination with what is a unique polymicrobial inoculum. The aesthetic consequences can occasionally prove devastating. The wounds can be caused by both domestic and wild animals, as well as by humans. Clinicians need to have a multidisciplinary understanding of how to manage such wounds, including surgical, medical, virological, and bacteriological aspects, and the proper sequence of treatment. We present a review of the literature and a number of clinical cases for the comprehensive management of this type of trauma.

Eficacia y seguridad de la aplicación de subgalato y subsalicilato de bismuto como agentes hemostáticos después de la extracción quirúrgica de terceros molares / Efficacy and safety of applying bismuth subgallate and subsalicilate as hemostatic agents after surgical extraction of third molars

El subgalato y subsalicilato de bismuto son sustancias que se han utilizado como agentes hemostáticos en adenoamigdalectomías, activando el factor XII de la coagulación. Pregunta: ¿son eficaces y seguros, después de la extracción de terceros molares? Objetivo: valorar su eficacia y seguridad como agentes hemostáticos. Hipótesis: son agentes eficaces y seguros para detener el sangrado por extracciones de terceros molares. Justificación: no se cuenta con un agentes eficaz, segurofácil de conseguir y económico para ayudar al control de la hemorragia. Tipo de estudio: ensayo clínico controlado aleatorizado placebo controlado. Método: pacientes con indicación de extracción quirúrgica de 4 terceros molares, se aplicó de manera aleatoria subgalato o subsalicilato de bismuto en forma tópica en uno de los alvéolos y colocando una sustancia control en el alvéolo contralateral. Resultados: se obtuvieron por varianza (ANOVA). Se incluyeron en el estudio 71 pacientes. Se realizaron 284 extracciones quirúrgicas. Setenta y uno con cada una de las sustancias, cada una con su control. El grupo manejado con subgalato de bismuto, obtuvo 1.97 min y el control 2 (3.52 min), observando una diferencia estadísticamente significativa (F = 146.62, p<0.05). Conclusión: el subgalato y subsalicilato de bismuto con eficaces y seguros para el control del sangrado, sin encontrar efectos adversos