The Influence of Pericardial Fat on Left Ventricular Diastolic Function.

BACKGROUND: Heart failure is a major cause of morbidity and mortality worldwide; left ventricular diastolic dysfunction plays a leading role in this clinical context. Diastolic dysfunction may be predisposed by increased abdominal fat and, consequently, increased pericardial and epicardial adiposity. This study aimed to determine whether pericardial fat (PF) and epicardial fat (EF) are associated with left ventricular diastolic function. METHODS: A total of 82 patients had their abdominal circumference measured and underwent transthoracic echocardiography to measure the thickness of PF and EF and assess the left ventricular diastolic function. Two groups were created based on mean pericardial fat (PF) thickness (4.644 mm) and were related to abdominal circumference and echocardiographic parameters. RESULTS: Subjects in the PF High group showed a significant decrease in septal e' (p < 0.0001), lateral e' (p < 0.0001), and E/A ratio (p = 0.003), as well as a significant increase in E/e' ratio (p < 0.0001), E wave deceleration time (p = 0.013), left atrial volume (p < 0.0001), the left ventricle mass (p = 0.003), tricuspid regurgitant jet velocity (p < 0.0001), and the left ventricle diameter (p = 0.014) compared to the PF Low group. Correlations were found between pericardial fat and nine echocardiographic parameters in the study, while epicardial fat (EP) only correlated with eight. CONCLUSIONS: Measurement of abdominal circumference, PF, and EF is an early indicator of diastolic changes with transthoracic echocardiography being the gold standard exam.

Insights Into Pediatric Asthma: A Population Study From Alto Minho Health Center.

Background Asthma represents one of the most common diseases in childhood, with a prevalence ranging between 9% and 13% in Portugal. Therefore, it holds significant importance in pediatric health. While existing studies have shed light on asthma in the Portuguese population, they have predominantly concentrated on urban centers, with the population of Alto Minho remaining underrepresented in the literature. This study aims to understand the main factors of exposure, exacerbation, and the most prevalent allergens in a pediatric sample from the Alto Minho Local Health Unit, Portugal. Methodology A retrospective cohort study was conducted among 239 pediatric asthma patients aged between five and 18 years at the Alto Minho Health Center. Data on demographics, clinical information, family history, environmental exposures, exacerbating factors, and prick test results were analyzed. Results Of the 239 patients, 64.44% were male and 35.56% were female. The majority of the sample exhibited a normal body mass index (82.17%) and a family history of atopy (66.67%). Noteworthy patterns emerged in comorbidities, notably an increased association with allergic rhinitis, the most frequent concomitant atopic pathology (79.50%), followed by atopic dermatitis (27.61%) and food allergy (10.88%). Sensitization to dust mites, particularly Dermatophagoides pteronyssinus, was widespread among the participants. Environmental exposures were marked by significant factors such as proximity to plants and trees, soft toys, and living in rural areas. Exacerbating factors included common triggers such as exercise, seasonal variations, and even laughter. Statistically significant associations were found between atopic comorbidities, exacerbation factors, exposure factors, and prick test results. Conclusions Our findings align with global trends, emphasizing the prevalence of atopic pathologies in pediatric asthma. Sensitization patterns and environmental exposures are indicative of regional influences. Study limitations include sample size and data standardization issues. Despite these limitations, the study significantly contributes to understanding pediatric asthma in Alto Minho, offering valuable insights for prompt diagnosis and targeted treatments.

Internações por condições sensíveis à atenção primária à saúde: associação com a cobertura da atenção primária, 2015 ­ 2021 / Hospitalization for sensitive conditions in primary care: association with primary health care support, 2015-2021 / Hospitalizaciones por afecciones sensibles a la atención primaria: asociación con la cobertura de atención primaria, 2015 ­ 2021

Objetivo: Avaliar as tendências e associações relacionadas as coberturas e internações por condições sensíveis à atenção primária à saúde no município de Fortaleza/Ceará/Brasil, no período de 2015 a 2021. Métodos: Estudo transversal com dados secundários (Sistema de Informações Hospitalares do Sistema Único de Saúde, E- gestor atenção básica e o Instituto Brasileiro de Geografia e Estatística). Utilizou-se o coeficiente de correlação de Pearson para as associações. Resultados: Foram registrados 176.330 internações por condições sensíveis, totalizando 8 principais, correspondendo a 78.5% do total. Obteve-se correlação inversa significativa entre a cobertura de atenção primária e internações por condições sensíveis: r=-0.86, (IC95%: -0.91/-0.61); p<0.001, bem como uma correlação moderada com cobertura de agente comunitário e internações (r=-0.59 (IC95%: -0.68/-0.54); p<0.001) Conclusão: O aumento das internações por condições sensíveis está diretamente relacionado com a cobertura da atenção primária. Além disso, enfrenta-se uma dupla carga de doenças, coexistindo as doenças infecciosas/parasitárias em concomitância com as crônicas.

Objective: To assess trends and associations related to coverage and hospitalizations for conditions sensitive to primary health care in the city of Fortaleza/Ceará/Brazil, from 2015 to 2021. Methods: Cross-sectional study with secondary data (Hospital Information System of the National Unified Health System, E- manager for primary care and the Brazilian Institute of Geography and Statistics). Pearson's correlation coefficient was used to measure associations. Results: 176,330 hospitalizations for sensitive conditions were recorded, totaling 8 main ones, corresponding to 78.5% of the total. A significant inverse correlation was obtained between primary care coverage and hospitalizations for sensitive conditions: r=-0.86, (95%CI: -0.91/-0.61); p<0.001, as well as a moderate correlation with community agent coverage and hospitalizations (r=-0.59 (95%CI: -0.68/-0.54); p<0.001) Conclusion: The increase in hospitalizations for sensitive conditions is directly associated to the primary care coverage. In addition, there is a double burden of disease, with infectious/parasitic diseases coexisting with chronic ones.

Evaluar las tendencias y asociaciones relacionadas con la cobertura y hospitalizaciones por condiciones sensibles a la atención primaria de salud en la ciudad de Fortaleza/Ceará/Brasil de 2015 a 2021. Métodos: Estudio transversal con datos secundarios (Sistema de Informações Hospitalares do Sistema Único de Saúde, E-gestor atenção básica e Instituto Brasileiro de Geografia e Estatística). Se utilizó el coeficiente de correlación de Pearson para las asociaciones. Resultados: Hubo 176.330 hospitalizaciones por condiciones sensibles, totalizando 8 condiciones principales, correspondiendo a 78,5% del total. Se obtuvo una correlación inversa significativa entre la cobertura de atención primaria y las hospitalizaciones por afecciones sensibles: r=- 0,86, (IC 95%: -0,91/-0,61); p<0,001, así como una correlación moderada con la cobertura de agentes comunitarios y las hospitalizaciones (r=-0,59 (IC 95%: -0,68/-0,54); p<0,001) Conclusión: El aumento de las hospitalizaciones por afecciones sensibles está directamente relacionado con la cobertura de atención primaria. Además, se enfrenta a una doble carga de enfermedad, coexistiendo enfermedades infecciosas/parasitarias en concomitancia con enfermedades crónicas.

Uncovering the Early Events Associated with Oligomeric Aß-Induced Src Activation.

Soluble Aß1-42 oligomers (AßO) are formed in the early stages of Alzheimer's disease (AD) and were previously shown to trigger enhanced Ca2+ levels and mitochondrial dysfunction via the activation of N-methyl-D-aspartate receptors (NMDAR). Src kinase is a ubiquitous redox-sensitive non-receptor tyrosine kinase involved in the regulation of several cellular processes, which was demonstrated to have a reciprocal interaction towards NMDAR activation. However, little is known about the early-stage mechanisms associated with AßO-induced neurodysfunction involving Src. Thus, in this work, we analysed the influence of brief exposure to oligomeric Aß1-42 on Src activation and related mechanisms involving mitochondria and redox changes in mature primary rat hippocampal neurons. Data show that brief exposure to AßO induce H2O2-dependent Src activation involving different cellular events, including NMDAR activation and mediated intracellular Ca2+ rise, enhanced cytosolic and subsequent mitochondrial H2O2 levels, accompanied by mild mitochondrial fragmentation. Interestingly, these effects were prevented by Src inhibition, suggesting a feedforward modulation. The current study supports a relevant role for Src kinase activation in promoting the loss of postsynaptic glutamatergic synapse homeostasis involving cytosolic and mitochondrial ROS generation after brief exposure to AßO. Therefore, restoring Src activity can constitute a protective strategy for mitochondria and related hippocampal glutamatergic synapses.

Non-pharmacological treatment-related changes of molecular biomarkers in major depressive disorder: A systematic review and meta-analysis

Background: Major depressive disorder (MDD) is a serious mood disorder and leading cause of disability. Despite treatment advances, approximately 30% of individuals with MDD do not achieve adequate clinical response. Better understanding the biological mechanism(s) underlying clinical response to specific psychopharmacological interventions may help fine tune treatments in order to further modulate their underlying mechanisms of action. However, little is known regarding the effect of non-pharmacological treatments (NPTs) on candidate molecular biomarker levels in MDD. This review aims to identify molecular biomarkers that may elucidate NPT response for MDD. Methods: We performed a systematic review and a multilevel linear mixed-effects meta-analyses, and a meta-regression. Searches were performed in PubMed, Scopus, and PsycINFO in October 2020 and July 2021. Results: From 1387 retrieved articles, 17 and six studies were included in the systematic review and meta-analyses, respectively. Although there was little consensus associating molecular biomarker levels with symptomology and/or treatment response, brain metabolites accessed via molecular biomarker-focused neuroimaging techniques may provide promising information on whether an individual with MDD would respond positively to NPTs. Furthermore, non-invasive brain stimulation interventions significantly increased the expression of neurotrophic factors (NTFs) compared to sham/placebo, regardless of add-on pharmacological treatment. Conclusions: NTFs are candidate biomarkers to fine-tune NIBS for MDD treatment. (AU)

Non-pharmacological treatment-related changes of molecular biomarkers in major depressive disorder: A systematic review and meta-analysis.

Background: Major depressive disorder (MDD) is a serious mood disorder and leading cause of disability. Despite treatment advances, approximately 30% of individuals with MDD do not achieve adequate clinical response. Better understanding the biological mechanism(s) underlying clinical response to specific psychopharmacological interventions may help fine tune treatments in order to further modulate their underlying mechanisms of action. However, little is known regarding the effect of non-pharmacological treatments (NPTs) on candidate molecular biomarker levels in MDD. This review aims to identify molecular biomarkers that may elucidate NPT response for MDD. Methods: We performed a systematic review and a multilevel linear mixed-effects meta-analyses, and a meta-regression. Searches were performed in PubMed, Scopus, and PsycINFO in October 2020 and July 2021. Results: From 1387 retrieved articles, 17 and six studies were included in the systematic review and meta-analyses, respectively. Although there was little consensus associating molecular biomarker levels with symptomology and/or treatment response, brain metabolites accessed via molecular biomarker-focused neuroimaging techniques may provide promising information on whether an individual with MDD would respond positively to NPTs. Furthermore, non-invasive brain stimulation interventions significantly increased the expression of neurotrophic factors (NTFs) compared to sham/placebo, regardless of add-on pharmacological treatment. Conclusions: NTFs are candidate biomarkers to fine-tune NIBS for MDD treatment.

NRF2 Activation Reprograms Defects in Oxidative Metabolism to Restore Macrophage Function in Chronic Obstructive Pulmonary Disease.

Rationale: Chronic obstructive pulmonary disease (COPD) is a disease characterized by persistent airway inflammation and disordered macrophage function. The extent to which alterations in macrophage bioenergetics contribute to impaired antioxidant responses and disease pathogenesis has yet to be fully delineated. Objectives: Through the study of COPD alveolar macrophages (AMs) and peripheral monocyte-derived macrophages (MDMs), we sought to establish if intrinsic defects in core metabolic processes drive macrophage dysfunction and redox imbalance. Methods: AMs and MDMs from donors with COPD and healthy donors underwent functional, metabolic, and transcriptional profiling. Measurements and Main Results: We observed that AMs and MDMs from donors with COPD display a critical depletion in glycolytic- and mitochondrial respiration-derived energy reserves and an overreliance on glycolysis as a source for ATP, resulting in reduced energy status. Defects in oxidative metabolism extend to an impaired redox balance associated with defective expression of the NADPH-generating enzyme, ME1 (malic enzyme 1), a known target of the antioxidant transcription factor NRF2 (nuclear factor erythroid 2-related factor 2). Consequently, selective activation of NRF2 resets the COPD transcriptome, resulting in increased generation of TCA cycle intermediaries, improved energetic status, favorable redox balance, and recovery of macrophage function. Conclusions: In COPD, an inherent loss of metabolic plasticity leads to metabolic exhaustion and reduced redox capacity, which can be rescued by activation of the NRF2 pathway. Targeting these defects, via NRF2 augmentation, may therefore present an attractive therapeutic strategy for the treatment of the aberrant airway inflammation described in COPD.

Restoration of c-Src/Fyn Proteins Rescues Mitochondrial Dysfunction in Huntington's Disease.

Aims: Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder with no effective therapies. Mutant huntingtin protein (mHTT), the main HD proteinaceous hallmark, has been linked to reactive oxygen species (ROS) formation and mitochondrial dysfunction, among other pathological mechanisms. Importantly, Src-related kinases, c-Src and Fyn, are activated by ROS and regulate mitochondrial activity. However, c-Src/Fyn involvement in HD is largely unexplored. Thus, in this study, we aimed at exploring changes in Src/Fyn proteins in HD models and their role in defining altered mitochondrial function and dynamics and redox regulation. Results: We show, for the first time, that c-Src/Fyn phosphorylation/activation and proteins levels are decreased in several human and mouse HD models mainly due to autophagy degradation, concomitantly with mHtt-expressing cells showing enhanced TFEB-mediated autophagy induction and autophagy flux. c-Src/Fyn co-localization with mitochondria is also reduced. Importantly, the expression of constitutive active c-Src/Fyn to restore active Src kinase family (SKF) levels improves mitochondrial morphology and function, namely through improved mitochondrial transmembrane potential, mitochondrial basal respiration, and ATP production, but it did not affect mitophagy. In addition, constitutive active c-Src/Fyn expression diminishes the levels of reactive species in cells expressing mHTT. Innovation: This work supports a relevant role for c-Src/Fyn proteins in controlling mitochondrial function and redox regulation in HD, revealing a potential HD therapeutic target. Conclusion: c-Src/Fyn restoration in HD improves mitochondrial morphology and function, precluding the rise in oxidant species and cell death. Antioxid. Redox Signal. 38, 95-114.

Restored Fyn Levels in Huntington's Disease Contributes to Enhanced Synaptic GluN2B-Composed NMDA Receptors and CREB Activity.

N-methyl-D-aspartate receptors (NMDARs) are important postsynaptic receptors that contribute to normal synaptic function and cell survival; however, when overactivated, as in Huntington's disease (HD), NMDARs cause excitotoxicity. HD-affected striatal neurons show altered NMDAR currents and augmented ratio of surface to internal GluN2B-containing NMDARs, with augmented accumulation at extrasynaptic sites. Fyn protein is a member of the Src kinase family (SKF) with an important role in NMDARs phosphorylation and synaptic localization and function; recently, we demonstrated that Fyn is reduced in several HD models. Thus, in this study, we aimed to explore the impact of HD-mediated altered Fyn levels at post-synaptic density (PSD), and their role in distorted NMDARs function and localization, and intracellular neuroprotective pathways in YAC128 mouse primary striatal neurons. We show that reduced synaptic Fyn levels and activity in HD mouse striatal neurons is related to decreased phosphorylation of synaptic GluN2B-composed NMDARs; this occurs concomitantly with augmented extrasynaptic NMDARs activity and currents and reduced cAMP response element-binding protein (CREB) activation, along with induction of cell death pathways. Importantly, expression of a constitutive active form of SKF reestablishes NMDARs localization, phosphorylation, and function at PSD in YAC128 mouse neurons. Enhanced SKF levels and activity also promotes CREB activation and reduces caspase-3 activation in YAC128 mouse striatal neurons. This work supports, for the first time, a relevant role for Fyn protein in PSD modulation, controlling NMDARs synaptic function in HD, and favoring neuroprotective pathways and cell survival. In this respect, Fyn Tyr kinase constitutes an important potential HD therapeutic target directly acting at PSD.

Mitochondrial function and dynamics in neural stem cells and neurogenesis: Implications for neurodegenerative diseases.

Mitochondria have been largely described as the powerhouse of the cell and recent findings demonstrate that this organelle is fundamental for neurogenesis. The mechanisms underlying neural stem cells (NSCs) maintenance and differentiation are highly regulated by both intrinsic and extrinsic factors. Mitochondrial-mediated switch from glycolysis to oxidative phosphorylation, accompanied by mitochondrial remodeling and dynamics are vital to NSCs fate. Deregulation of mitochondrial proteins, mitochondrial DNA, function, fission/fusion and metabolism underly several neurodegenerative diseases; data show that these impairments are already present in early developmental stages and NSC fate decisions. However, little is known about mitochondrial role in neurogenesis. In this Review, we describe the recent evidence covering mitochondrial role in neurogenesis, its impact in selected neurodegenerative diseases, for which aging is the major risk factor, and the recent advances in stem cell-based therapies that may alleviate neurodegenerative disorders-related neuronal deregulation through improvement of mitochondrial function and dynamics.

Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation.

Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS.

Effect of High Pressure on the Properties of Chocolate Fillings during Long-Term Storage.

The aim of this study was to evaluate the impact of high-pressure processing (HPP) on the long-term storage of chocolate fillings at room temperature, compared with conventional storage at lower temperatures. Dark chocolate fillings were treated at different pressure levels, holding times and stored at 20 °C for 12 months. Unprocessed batches were stored at 4 °C and at -12 °C. Moisture, water activity (aw), pH, colour, G'1Hz and indigenous microflora were measured at 2, 4, 6, 8, 10 and 12 months of storage. Results showed that 600 MPa/20 min processing was the most effective controlling mesophilic group, presenting 3.8 log cfu/g after 12 months of storage, and inactivating moulds and yeasts after HPP treatment. Colour was affected by storage, including a reduction in the L* parameter in all conditions to final values between 37.8 and 39.3, while the a* parameter increased during storage time at -12 °C and 4 °C to final values of around 12, and parameter b* decreased at storage temperature 20 °C to 5.3. Storage time affected the rheological behaviour of HPP-treated samples, increasing G'1Hz from the 2nd to 12th month of storage time to the final values between 1603 kPa and 2139 kPa. Moisture, aw and pH were not affected by HPP treatment nor storage time.

Neutrophil HIF-1α stabilization is augmented by mitochondrial ROS produced via the glycerol 3-phosphate shuttle.

Neutrophils are predominantly glycolytic cells that derive little ATP from oxidative phosphorylation; however, they possess an extensive mitochondrial network and maintain a mitochondrial membrane potential. Although studies have shown neutrophils need their mitochondria to undergo apoptosis and regulate NETosis, the metabolic role of the respiratory chain in these highly glycolytic cells is still unclear. Recent studies have expanded on the role of reactive oxygen species (ROS) released from the mitochondria as intracellular signaling molecules. Our study shows that neutrophils can use their mitochondria to generate ROS and that mitochondrial ROS release is increased in hypoxic conditions. This is needed for the stabilization of a high level of the critical hypoxic response factor and pro-survival protein HIF-1α in hypoxia. Further, we demonstrate that neutrophils use the glycerol 3-phosphate pathway as a way of directly regulating mitochondrial function through glycolysis, specifically to maintain polarized mitochondria and produce ROS. This illustrates an additional pathway by which neutrophils can regulate HIF-1α stability and will therefore be an important consideration when looking for treatments of inflammatory conditions in which HIF-1α activation and neutrophil persistence at the site of inflammation are linked to disease severity.

Pyranoanthocyanins Interfering with the Quorum Sensing of Pseudomonas aeruginosa and Staphylococcus aureus.

Bacterial quorum sensing (QS) is a cell-cell communication system that regulates several bacterial mechanisms, including the production of virulence factors and biofilm formation. Thus, targeting microbial QS is seen as a plausible alternative strategy to antibiotics, with potentiality to combat multidrug-resistant pathogens. Many phytochemicals with QS interference activity are currently being explored. Herein, an extract and a compound of bioinspired origin were tested for their ability to inhibit biofilm formation and interfere with the expression of QS-related genes in Pseudomonas aeruginosa and Staphylococcus aureus. The extract, a carboxypyranoanthocyanins red wine extract (carboxypyrano-ant extract), and the pure compound, carboxypyranocyanidin-3-O-glucoside (carboxypyCy-3-glc), did not cause a visible effect on the biofilm formation of the P. aeruginosa biofilms; however, both significantly affected the formation of biofilms by the S. aureus strains, as attested by the crystal violet assay and fluorescence microscopy. Both the extract and the pure compound significantly interfered with the expression of several QS-related genes in the P. aeruginosa and S. aureus biofilms, as per reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results. Indeed, it was possible to conclude that these molecules interfere with QS at distinct stages and in a strain-specific manner. An extract with anti-QS properties could be advantageous because it is easily obtained and could have broad, antimicrobial therapeutic applications if included in topical formulations.

Anthocyanin-Related Pigments: Natural Allies for Skin Health Maintenance and Protection.

Human skin is commonly described as a particularly dynamic and complex environment, with a physiological balance continuously orchestrated by numerous internal and external factors. Intrinsic aging, exposure to UV radiation and skin pathogens are some of the key players that account for dermatological alterations and ailments. In this regard, this study intended to explore the potential skin-health beneficial properties of a group of molecules belonging to the anthocyanin family: cyanidin- and malvidin-3-O-glucosides and some of their structurally related pigments, resulting in a library of compounds with different structural properties and color hues. The inclusion of both purified compounds and crude extracts provided some insights into their distinctive effects when tested as individual agents or as part of multicomponent mixtures. Overall, most of the compounds were found to reduce biofilm production by S. aureus and P. aeruginosa reference strains, exhibit UV-filter capacity, attenuate the production of reactive oxygen species in human skin keratinocytes and fibroblasts and also showed inhibitory activity of skin-degrading enzymes, in the absence of cytotoxic effects. Carboxypyranocyanidin-3-O-glucoside stood out for its global performance which, combined with its greater structural stability, makes this a particular interesting compound for potential incorporation in topical formulations. Results provide strong evidence of the skin protective effects of these pigments, supporting their further application for cosmeceutical purposes.

Evaluation of Lower Limb Arteriovenous Diameters in Indoor Soccer Athletes: Arterial Doppler Ultrasound Study.

The purpose of this study was to analyze the arterial and venous diameters of lower limbs in indoor soccer athletes and non-athletes using Doppler ultrasound to identify the differences in the variation of arterial and venous diameters between groups. Additionally, we intended to verify the differences of arterial and venous diameters between the skilled member (right member) and the not skilled member in each group. 74 male volunteers, aged between 19 and 30 years old, were divided in a group of athletes (n = 37, 24 ± 2.7 years, soccer players from national championship), and a group of non-athletes (n = 37, 26 ± 2.83 years). Vascular lower limb was assessed using Doppler ultrasound (Philips HD7 echograph with linear transducer 7-12 MHz). The athletes showed higher diameters of right common femoral artery (p = 0.009; moderate), left common femoral artery (p = 0.005; moderate), right deep femoral artery (p = 0.013; moderate), right popliteal artery (p = 0.003; moderate), and left popliteal artery (p = 0.017; small) than non-athletes. Veins' diameters were also higher in athletes, specifically the right deep femoral vein (p ≤ 0.001; large), left deep femoral vein (p ≤ 0.001; large), right popliteal vein (p ≤ 0.001; large), and left popliteal vein (p ≤ 0.001; large). Differences were found between the skilled and non-skilled leg in athletes in the popliteal vein (7.68 ± 1.44 mm vs. 7.22 ± 1.09 mm, respectively, p < 0.003). It seems that futsal athletes have superior mean diameters of lower limbs arteries and veins of the deep venous system to non-athletes. Moreover, the veins presented greater dilation, namely of the leg of the skilled lower limb.

-------A type I IFN, prothrombotic hyperinflammatory neutrophil signature is distinct for COVID-19 ARDS--.

Background: Acute respiratory distress syndrome (ARDS) is a severe critical condition with a high mortality that is currently in focus given that it is associated with mortality caused by coronavirus disease 2019 (COVID-19). Neutrophils play a key role in the lung injury characteristic of non-COVID-19 ARDS and there is also accumulating evidence of neutrophil mediated lung injury in patients who succumb to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: We undertook a functional proteomic and metabolomic survey of circulating neutrophil populations, comparing patients with COVID-19 ARDS and non-COVID-19 ARDS to understand the molecular basis of neutrophil dysregulation. Results: Expansion of the circulating neutrophil compartment and the presence of activated low and normal density mature and immature neutrophil populations occurs in ARDS, irrespective of cause. Release of neutrophil granule proteins, neutrophil activation of the clotting cascade and upregulation of the Mac-1 platelet binding complex with formation of neutrophil platelet aggregates is exaggerated in COVID-19 ARDS. Importantly, activation of components of the neutrophil type I interferon responses is seen in ARDS following infection with SARS-CoV-2, with associated rewiring of neutrophil metabolism, and the upregulation of antigen processing and presentation. Whilst dexamethasone treatment constricts the immature low density neutrophil population, it does not impact upon prothrombotic hyperinflammatory neutrophil signatures. Conclusions: Given the crucial role of neutrophils in ARDS and the evidence of a disordered myeloid response observed in COVID-19 patients, this work maps the molecular basis for neutrophil reprogramming in the distinct clinical entities of COVID-19 and non-COVID-19 ARDS.

The Sigma-1 Receptor Mediates Pridopidine Rescue of Mitochondrial Function in Huntington Disease Models.

Pridopidine is a selective Sigma-1 receptor (S1R) agonist in clinical development for Huntington disease (HD) and amyotrophic lateral sclerosis. S1R is a chaperone protein localized in mitochondria-associated endoplasmic reticulum (ER) membranes, a signaling platform that regulates Ca2+ signaling, reactive oxygen species (ROS) and mitochondrial fission. Here, we investigate the protective effects of pridopidine on various mitochondrial functions in human and mouse HD models. Pridopidine effects on mitochondrial dynamics were assessed in primary neurons from YAC128 HD mice expressing the mutant human HTT gene. We observe that pridopidine prevents the disruption of mitochondria-ER contact sites and improves the co-localization of inositol 1,4,5-trisphosphate receptor (IP3R) and its chaperone S1R with mitochondria in YAC128 neurons, leading to increased mitochondrial activity, elongation, and motility. Increased mitochondrial respiration is also observed in YAC128 neurons and in pridopidine-treated HD human neural stem cells (hNSCs). ROS levels were assessed after oxidative insult or S1R knockdown in pridopidine-treated YAC128 neurons, HD hNSCs, and human HD lymphoblasts. All HD models show increased ROS levels and deficient antioxidant response, which are efficiently rescued with pridopidine. Importantly, pridopidine treatment before H2O2-induced mitochondrial dysfunction and S1R presence are required for HD cytoprotection. YAC128 mice treated at early/pre-symptomatic age with pridopidine show significant improvement in motor coordination, indicating a delay in symptom onset. Additionally, in vivo pridopidine treatment reduces mitochondrial ROS levels by normalizing mitochondrial complex activity. In conclusion, S1R-mediated enhancement of mitochondrial function contributes to the neuroprotective effects of pridopidine, providing insight into its mechanism of action and therapeutic potential.