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.

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.

Cross education is modulated by set configuration in knee extension exercise.

OBJECTIVES: The main aim of this study was to determine the effects of set configuration during five weeks of unilateral knee extension resistance training on untrained knee extensors performance. METHODS: Thirty-five subjects were randomly assigned to traditional training (TTG; n=14), rest-redistribution (RRG; n=10) and control group (CON; n=11). TTG and RRG groups trained the dominant knee extensors twice a week with the 10-repetition maximum (RM) load. TTG performed four sets of eight repetitions with three min-rest between sets and RRG 32 repetitions with 17.4 seconds of rest between each one. Before and after interventions, anthropometry, muscle thickness (MT), pennation angle (PA), 1RM, number of repetitions with 10RM pretest load (N10RM), maximum propulsive power (MPP) and maximum voluntary isometric contraction (MVIC) were measured. RESULTS: 1RM of the untrained leg increased only in the TTG group (p<0.001, 10.3% compared with Pre-test). 1RM, MPP and N10RM increased in the trained leg in both TTG (p<0.001) and RRG (p<0.001). No changes occurred in MT or PA. CONCLUSIONS: These results suggest that, when it is not possible to perform bilateral exercises (e.g., leg injury), traditional set configurations should be recommended to improve maximal voluntary force in the untrained leg.

Set Configuration in Strength Training Programs Modulates the Cross Education Phenomenon.

ABSTRACT: Fariñas, J, Mayo, X, Giraldez-García, MA, Carballeira, E, Fernandez-Del-Olmo, M, Rial-Vazquez, J, Kingsley, JD, and Iglesias-Soler, E. Set configuration in strength training programs modulates the cross education phenomenon. J Strength Cond Res 35(9): 2414-2420, 2021-This study aimed to compare the strength gains in the nontrained arm after 2 independent unilateral training programs differing in the set configuration. Thirty-five subjects were randomly assigned to 3 groups: traditional training (TT; n = 12), cluster training (CT; n = 11), or control (CON; n = 12). The experimental groups performed a 5-week training program of a unilateral biceps curl exercise with the dominant limb using the 10 repetition maximum (10RM) load. Traditional training performed 5 sets of 6 repetitions and 135 seconds of rest between sets. Cluster training completed 30 repetitions with 18.5 seconds of rest between each repetition. Anthropometry (ANT), muscle thickness (MT), 1RM, the number of repetitions with 10RM (n10RM), and isometric maximal voluntary contraction (MVC) were measured before and after the intervention. Regarding the nontrained arm, TT improved 1RM (7.3%, p < 0.001). No changes were observed in CT. Regarding the trained arm, TT improved 1RM (9.1%, p < 0.001), n10RM (p = 0.005), and MVC (p = 0.011), whereas CT only showed a trend for improvement of 1RM (3.4%, p = 0.052). These results suggest that when total volume and repetition-to-rest ratio are equated, a more fatiguing set configuration causes a higher effect on the non-trained limb.

Vulnerability of corneal endothelial cells to mechanical trauma from indentation forces assessed using contact mechanics and fluorescence microscopy.

Corneal endothelial cell (CEC) loss occurs from tissue manipulation during anterior segment surgery and corneal transplantation as well as from contact with synthetic materials like intraocular lenses and tube shunts. While several studies have quantified CEC loss for specific surgical steps, the vulnerability of CECs to isolated, controllable and measurable mechanical forces has not been assessed previously. The purpose of this study was to develop an experimental testing platform where the susceptibility of CECs to controlled mechanical trauma could be measured. The corneal endothelial surfaces of freshly dissected porcine corneas were subjected to a range of indentation forces via a spherical stainless steel bead. A cell viability assay in combination with high-resolution fluorescence microscopy was used to visualize and quantify injured/dead CEC densities before and after mechanical loading. In specimens subjected to an indentation force of 9 mN, the mean ±â€¯SD peak contact pressure P0 was 18.64 ±â€¯3.59 kPa (139.81 ±â€¯26.93 mmHg) in the center of indentation and decreased radially outward. Injured/dead CEC densities were significantly greater (p ≤ 0.001) after mechanical indentation of 9 mN (167 ±â€¯97 cells/mm2) compared to before indentation (39 ±â€¯52 cells/mm2) and compared to the sham group (34 ±â€¯31 cells/mm2). In specimens subjected to "contact only" - defined as an applied indentation force of 0.65 mN - the peak contact pressure P0 was 7.31 ±â€¯1.5 kPa (54.83 ±â€¯11.25 mmHg). In regions where the contact pressures was below 78% of P0 (<5.7 kPa or 42.75 mmHg), injured/dead CEC densities were within the range of CEC loss observed in the sham group, suggesting negligible cell death. These findings indicate that CECs are highly susceptible to mechanical trauma via indentation, supporting the established "no-touch" policy for ophthalmological procedures. While CECs can potentially remain viable below contact pressures of 5.7 kPa (42.75 mmHg), this low threshold suggests that prevention of indentation-associated CEC loss may be challenging.

Changes in the Force-Velocity Mechanical Profile After Short Resistance Training Programs Differing in Set Configurations.

The main aim of this study was to analyze the effect of resistance training programs differing in set configuration on mechanical force-velocity profiles. Thirteen participants performed 10 unilateral knee extension training sessions over 5 weeks. Each limb was randomized to one of the following set configurations: traditional (4 sets of 8 repetitions at maximum intended velocity, 10RM load, 3-min pause between sets) or interrepetition rest (32 maximum intended velocity repetitions, 10RM load, 17.4 s of rest between each repetition). Velocity of each repetition was recorded throughout the program. Before and after training, individual linear force velocities were calculated, and the following parameters were obtained: force and velocity axis intercept, slope, and estimated maximum power. Mean velocity was higher throughout the program for interrepetition rest configuration (0.54 ± 0.01 vs. 0.48 ± 0.01 m∙s-1 for interrepetition rest, and traditional configuration respectively; main effect of set configuration: P < .001). There was a significant increase in force and velocity intercepts, but a steeper negative slope after both training protocols (main effect of time: P < .001 for every variable). Differences in resistance training velocity did not affect the adaptations. Our results suggest that, in a short-term program, maximum intended rather than actual velocity is a key factor to modulate strength adaptations.

Diastolic Mitral Regurgitation as a Rare Cause of Acute Respiratory Failure Following Complete Atrioventricular Block.

A 77-year-old male presented to the emergency department with dyspnea. A third-degree atrioventricular block was present in the electrocardiogram and an echocardiography showed a moderate mitral regurgitation with a diastolic functional insufficiency. Hemodynamic variations were assessed in the context of heart rhythm disturbances. (Level of Difficulty: Intermediate.).

Acute psychophysiological responses during exercise while using resistive respiratory devices: A systematic review.

Different studies have observed that respiratory muscle training (RMT) improve the endurance and strength of the respiratory muscles, having a positive impact on performance of endurance sports. Nevertheless, it remains to be clarified how to improve the efficiency of such training. The objective of this systematic review was to evaluate the acute physiological responses produced by training the respiratory muscles during exercise with flow resistive devices because such information may support us improve the efficiency of this type of training. A search in the Medline, Science Direct, Web of Science and Scopus databases was conducted, following the PRISMA guidelines. The methodological quality of the articles was assessed using the PEDro scale. Nineteen studies met the inclusion criteria and a total of 212 subjects were included in the studies. The RMT method used in all studies was flow resistive loading, whereas the constant load exercise was the most common type of exercise among the studies. The results obtained seem to indicate that the use of this type of training during exercise reduces the performance, the lactate (La-) values and the ventilation, whereas the end - tidal partial pressure of carbon dioxide (PCO2) is increased.

Neurocognitive and emotional status after one-year of mindfulness-based intervention in patients with relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is the most common disabling neurological disease among young adults. The diagnosis of this disease usually leads to uncertainty, stress, and anxiety, which in turn can lead to negative outcomes. Consequently, the development of healthy lifestyle strategies can lead to better emotional management of perceived stress. Due to the importance of the patient's emotional response during the development and management of the disease and the repercussions of the cognitive deficits, the objective of this study is to develop a mindfulness-based intervention to provide to patients a tool for stress management. This study offers data on neuropsychological, functional and emotional outcomes in a sample of 30 patients with remitting relapsing form of MS after one year of intervention compared to 30 controls. We tested a model of intervention with a program of Mindfulness-Based Cognitive Therapy, based on an adapted Jon Kabat-Zinn's MBSR program. Results showed cognitive and emotional benefits after one year following this program. Discussion about the opportunities of these types of intervention in neurological diseases is provided in light of results obtained. This study represents pioneering research in MS and psychological treatment of this neurological autoimmune disease and it offers positive results of applying mindfulness-based intervention in this population.

Comparison of Physical Fitness Profiles Obtained before and during COVID-19 Pandemic in Two Independent Large Samples of Children and Adolescents: DAFIS Project.

COVID-19 pandemic restrictions might have negatively affected the health-related physical fitness of children and adolescents. The aim of this study was to contrast the body composition and physical fitness data of two independent samples of children and adolescents obtained from an online database (DAFIS project) before (n = 15,287) and during (n = 2101) the first academic year of the COVID-19 pandemic. The results revealed higher values for the body mass index (p = 0.002), waist circumference (p < 0.001), and waist to hip and waist to height ratios (p < 0.001) during than before the pandemic, particularly in the case of boys. On the other hand, lower muscular fitness was observed for girls during the pandemic. Quantitative and qualitative analysis did not detect relevant changes in cardiorespiratory fitness in children or adolescents (p > 0.05). Our data suggested that pandemic constraints might have affected body composition and muscular fitness of children and adolescents. These results might be of interest for designing specific interventions oriented toward counteracting the negative effects of pandemic restrictions on health-related physical fitness.

Communication Styles and Attention Performance in Primary School Children.

Communication styles are the three communication patterns that result from merging the verbal elements of communication, the non-verbal elements and the paraverbal elements. The objective of this study was to test what effect different communication styles have on attention performance in primary school children. We administered the assertive behavior scale for children (CABS), the symbol digit modalities test (SDMT) and the d2 attention test to a sample of 77 participants of primary school. A statistically significant and proportional correlation was found between the assertive communication style and the total number of correct answers of the SDMT. We also found positive correlations between the assertive communication style and d2 attention test performance. Children with an assertive communication style have better attention performance than children with passive or aggressive communication styles.

Percentiles and Principal Component Analysis of Physical Fitness From a Big Sample of Children and Adolescents Aged 6-18 Years: The DAFIS Project.

Assessing physical fitness has emerged as a proxy of the health status of children and adolescents and therefore as relevant from a public health point of view. DAFIS is a project included in Plan Galicia Saudable (Healthy Galicia Plan) of the regional government of Galicia (Spain). DAFIS consists of an on-line software devoted to record the results of a standard physical fitness protocol carried out as a part of the physical education curriculum. The aims of this study were: to obtain normative values of physical fitness of the Galician school population evaluated in the DAFIS project, and to identify a reduced number of components and tests able to capture a significant amount of the variability in the physical fitness of children and adolescents. From an initial sample of 27784 records, 15287 cases (7543 males, 7744 females) were considered after filtering. Generalized Additive Models for Location, Scale and Shape were used for obtaining percentile curves and tables for each sex. Furthermore, a principal components analysis was performed, selecting the number of components by applying the Kaiser's rule and selecting a subset of variables considering the correlation between each variable and the components. Percentile curves and normative values are reported for each test and sex. Physical fitness was better in boys than in girls throughout age groups, except for flexibility that was consistently higher in girls. Two main components were detected throughout age groups: the first one representing body composition and partially cardiorespiratory fitness and the second one muscular fitness. For boys and girls, waist to height ratio had the highest correlations with the first component in four out of six age groups. The highest correlation with the second component, was most frequently observed for the handgrip test both in boys and girls (four out of six age groups). This study provides evidence about the utility of school community actions like DAFIS aimed to track the health-related fitness of children and adolescents. The results suggest that fat mass distribution (i.e., waist to height ratio and waist circumference) and muscular performance (mainly handgrip) concentrate a high proportion physical fitness variance.

Neutrophils Fuel Effective Immune Responses through Gluconeogenesis and Glycogenesis.

Neutrophils can function and survive in injured and infected tissues, where oxygen and metabolic substrates are limited. Using radioactive flux assays and LC-MS tracing with U-13C glucose, glutamine, and pyruvate, we observe that neutrophils require the generation of intracellular glycogen stores by gluconeogenesis and glycogenesis for effective survival and bacterial killing. These metabolic adaptations are dynamic, with net increases in glycogen stores observed following LPS challenge or altitude-induced hypoxia. Neutrophils from patients with chronic obstructive pulmonary disease have reduced glycogen cycling, resulting in impaired function. Metabolic specialization of neutrophils may therefore underpin disease pathology and allow selective therapeutic targeting.

Hypoxia compromises the mitochondrial metabolism of Alzheimer's disease microglia via HIF1.

Genetic Alzheimer's disease (AD) risk factors associate with reduced defensive amyloid ß plaque-associated microglia (AßAM), but the contribution of modifiable AD risk factors to microglial dysfunction is unknown. In AD mouse models, we observe concomitant activation of the hypoxia-inducible factor 1 (HIF1) pathway and transcription of mitochondrial-related genes in AßAM, and elongation of mitochondria, a cellular response to maintain aerobic respiration under low nutrient and oxygen conditions. Overactivation of HIF1 induces microglial quiescence in cellulo, with lower mitochondrial respiration and proliferation. In vivo, overstabilization of HIF1, either genetically or by exposure to systemic hypoxia, reduces AßAM clustering and proliferation and increases Aß neuropathology. In the human AD hippocampus, upregulation of HIF1α and HIF1 target genes correlates with reduced Aß plaque microglial coverage and an increase of Aß plaque-associated neuropathology. Thus, hypoxia (a modifiable AD risk factor) hijacks microglial mitochondrial metabolism and converges with genetic susceptibility to cause AD microglial dysfunction.

Macrophage miR-210 induction and metabolic reprogramming in response to pathogen interaction boost life-threatening inflammation.

Unbalanced immune responses to pathogens can be life-threatening although the underlying regulatory mechanisms remain unknown. Here, we show a hypoxia-inducible factor 1α-dependent microRNA (miR)-210 up-regulation in monocytes and macrophages upon pathogen interaction. MiR-210 knockout in the hematopoietic lineage or in monocytes/macrophages mitigated the symptoms of endotoxemia, bacteremia, sepsis, and parasitosis, limiting the cytokine storm, organ damage/dysfunction, pathogen spreading, and lethality. Similarly, pharmacologic miR-210 inhibition improved the survival of septic mice. Mechanistically, miR-210 induction in activated macrophages supported a switch toward a proinflammatory state by lessening mitochondria respiration in favor of glycolysis, partly achieved by downmodulating the iron-sulfur cluster assembly enzyme ISCU. In humans, augmented miR-210 levels in circulating monocytes correlated with the incidence of sepsis, while serum levels of monocyte/macrophage-derived miR-210 were associated with sepsis mortality. Together, our data identify miR-210 as a fine-tuning regulator of macrophage metabolism and inflammatory responses, suggesting miR-210-based therapeutic and diagnostic strategies.

Non-productive angiogenesis disassembles Aß plaque-associated blood vessels.

The human Alzheimer's disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD.

Hinged total knee arthroplasty in the presence of ligamentous deficiency.

BACKGROUND: Rotating-hinge total knee prostheses may be used for the treatment of global instability about the knee. The designs of previous generations were associated with suboptimal outcomes. QUESTIONS/PURPOSES: We evaluated the clinical and radiographic outcomes of salvage knee reconstructions using modern-generation, modular, kinematic rotating-hinge total knee prostheses. METHODS: We retrospectively reviewed 26 rotating-hinge arthroplasty devices to examine whether acceptable results were obtainable using a single arthroplasty design. The average age of the patients was 77 years (SD, 9 years); the minimum followup was 24 months (mean, 46 months; range, 24-107 months). The indication was revision surgery in 21 patients and complex primary surgery in five. Patients were evaluated clinically (Knee Society score) and radiographically (positions of components, signs of loosening, bone loss). RESULTS: Knee Society pain scores improved from 40 preoperatively to 77 postoperatively, and function scores improved from 36 to 51. ROM improved from -15 masculine to -10 masculine. None of the patients' knee pain or function worsened. No loosening of implants was observed. Nonprogressive radiolucent lines were identified around the femoral and tibial components in three knees. Three patients required reoperations: one showed a supracondylar periprosthetic fracture treated by open reduction and internal fixation, whereas the other two had periprosthetic infections. CONCLUSIONS: Reconstruction with rotating-hinge total knee prostheses can provide substantial improvement in function and a reduction in pain in extreme circumstances, such as gross instability. We believe this salvage procedure should be reserved for severe ligamentous deficiencies in elderly and sedentary patients or whenever revision surgery techniques fail. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Computer assistance increases precision of component placement in total knee arthroplasty with articular deformity.

BACKGROUND: The accuracy of computer navigation applied to total knee arthroplasty (TKA) in knees with severe deformity has not been studied. QUESTIONS/PURPOSES: The purpose of this study was to compare the radiographic alignment achieved in total knee replacements performed with and without navigation and to search for differences in the final alignment of two groups of patients (with and without previous joint deformities) using the same system of surgical navigation. METHODS: The first series comprised 40 arthroplasties with minimal preoperative deformity. In 20 of them, surgical navigation was used, whereas the other 20 were performed with conventional jig-based technique. We compared the femoral angle, tibial angle, and femorotibial angle (FTA) by performing a post-TKA CT of the entire limb. In the second series, 40 additional TKAs were studied; in this case, however, they presented preoperative deformities greater than 10 masculine in the frontal plane. RESULTS: The positioning of the femoral and tibial component was more accurate in the group treated with surgical navigation and FTA improvement was statistically significant. When comparing the results of both series, FTA precision was always higher when using computer-assisted surgery. As for optimal FTA, data showed the use of surgical navigation improved the results both in the group with preoperative deformity greater than 10 degrees in the frontal plane and in the group with minimal preoperative knee deformity. CONCLUSIONS: Surgical navigation obtains better radiographic results in the positioning of the femoral and tibial components and in the final axis of the limb in arthroplasties performed on both deformed and more normally aligned knees. LEVEL OF EVIDENCE: Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Individualized Characterization of the Distribution of Collagen Fibril Dispersion Using Optical Aberrations of the Cornea for Biomechanical Models.

Purpose: The spatial distribution of collagen fibril dispersion has a significant impact on both corneal biomechanical and optical behaviors. The goal of this study was to demonstrate a novel method to characterize collagen fibril dispersion using intraocular pressure (IOP)-induced changes in corneal optical aberrations for individualized finite-element (FE) modeling. Methods: The method was tested through both numerical simulations and ex vivo experiments. Inflation tests were simulated in FE models with three assumed patterns of collagen fibril dispersion and experimentally on three rhesus monkey corneas. Geometry, matrix stiffness, and the IOP-induced changes in wavefront aberrations were measured, and the collagen fibril dispersion was characterized. An individualized corneal model with customized collagen fibril dispersion was developed, and the estimated optical aberrations were compared with the measured data. Results: For the theoretical investigations, three assumed distributions of fibril dispersion were all successfully characterized. The estimated optical aberrations closely matched the measured data, with average root-mean-square (RMS) differences of 0.29, 0.24, and 0.10 µm for the three patterns, respectively. The overall features of the IOP-induced changes in optical aberrations were estimated for two ex vivo monkey corneas, with average RMS differences of 0.57 and 0.43 µm. Characterization of the fibril dispersion in the third cornea might have been affected by corneal hydration, resulting in an increased RMS difference, 0.8 µm. Conclusions: A more advanced corneal model with individualized distribution of collagen fibril dispersion can be developed and used to improve our ability to understand both biomechanical and optical behaviors of the cornea.