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Spinal cord injury (SCI) results in severe atrophy of skeletal muscle in paralyzed regions, and a decrease in the force generated by muscle per unit of cross-sectional area. Oxidation of skeletal muscle ryanodine 1 receptors (RyR1) reduces contractile force as a result of reduced binding of calstabin 1 to RyR1. One cause of RyR1 oxidation is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4). We have previously shown that, in rats, RyR1 was oxidized and bound less to calstabin 1 at 56 days after SCI by spinal cord transection. Here, we used a conditional knockout (KO) mouse model of Nox4 in skeletal muscle to investigate the role of Nox4 in reduced muscle specific force after SCI. Peak twitch force of extensor digitorum longus muscles in control mice after SCI was reduced by 42% compared with sham-operated controls, but was increased by ?43% in SCI Nox4 conditional KO mice compared with SCI controls, although it remained less than that for sham-operated controls. Unlike what was previously observed in rats after SCI, the expression of Nox4 was not increased in gastrocnemius muscle, and binding of calstabin 1 to RyR1 was not reduced in this muscle. The results suggest that Nox4 is directly involved in reduction in muscle twitch force after SCI, although further studies are needed to understand the mechanistic basis for this linkage.

Here, we investigated the mechanisms by which aging-related reductions of the levels of Numb in skeletal muscle fibers contribute to loss of muscle strength and power, two critical features of sarcopenia. Numb is an adaptor protein best known for its critical roles in development, including asymmetric cell division, cell-type specification, and termination of intracellular signaling. Numb expression is reduced in old humans and mice. We previously showed that, in mouse skeletal muscle fibers, Numb is localized to sarcomeres where it is concentrated near triads; conditional inactivation of Numb and a closely related protein Numb-like (Numbl) in mouse myofibers caused weakness, disorganization of sarcomeres, and smaller mitochondria with impaired function. Here, we found that a single knockout of Numb in myofibers causes reduction in tetanic force comparable to a double Numb, Numbl knockout. We found by proteomics analysis of protein complexes isolated from C2C12 myotubes by immunoprecipitation using antibodies against Numb that Septin 7 is a potential Numb-binding partner. Septin 7 is a member of the family of GTP-binding proteins that organize into filaments, sheets, and rings, and is considered part of the cytoskeleton. Immunofluorescence evaluation revealed a partial overlap of staining for Numb and Septin 7 in myofibers. Conditional, inducible knockouts of Numb led to disorganization of Septin 7 staining in myofibers. These findings indicate that Septin 7 is a Numb-binding partner and suggest that interactions between Numb and Septin 7 are critical for structural organization of the sarcomere and muscle contractile function.

Abstract In the course of military operations in modern war theaters, blast exposures are associated with the development of a variety of mental health disorders associated with a post-traumatic stress disorder-related features, including anxiety, impulsivity, insomnia, suicidality, depression, and cognitive decline. Several lines of evidence indicate that acute and chronic cerebral vascular alterations are involved in the development of these blast-induced neuropsychiatric changes. In the present study, we investigated late occurring neuropathological events associated with cerebrovascular alterations in a rat model of repetitive low-level blast-exposures (3 × 74.5 kPa). The observed events included hippocampal hypoperfusion associated with late-onset inflammation, vascular extracellular matrix degeneration, synaptic structural changes and neuronal loss. We also demonstrate that arteriovenous malformations in exposed animals are a direct consequence of blast-induced tissue tears. Overall, our results further identify the cerebral vasculature as a main target for blast-induced damage and support the urgent need to develop early therapeutic approaches for the prevention of blast-induced late-onset neurovascular degenerative processes.

Many military veterans who experienced blast-related traumatic brain injuries (TBIs) in the conflicts in Iraq and Afghanistan suffer from chronic cognitive and mental health problems, including post-traumatic stress disorder (PTSD). Male rats subjected to repetitive low-level blast exposure develop chronic cognitive and PTSD-related traits that develop in a delayed manner. Ketamine has received attention as a treatment for refractory depression and PTSD. (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a ketamine metabolite that exerts rapid antidepressant actions. (2R,6R)-HNK has become of clinical interest because of its favorable side-effect profile, low abuse potential, and oral route of administration. We treated three cohorts of blast-exposed rats with (2R,6R)-HNK, beginning 7?11 months after blast exposure, a time when the behavioral phenotype is established. Each cohort consisted of groups (n?=?10?13/group) as follows: 1) Sham-exposed treated with saline, 2) blast-exposed treated with saline, and 3) blast-exposed treated with a single dose of 20?mg/kg of (2R,6R)-HNK. (2R,6R)-HNK rescued blast-induced deficits in novel object recognition (NOR) and anxiety-related features in the elevated zero maze (EZM) in all three cohorts. Exaggerated acoustic startle was reversed in cohort 1, but not in cohort 3. (2R,6R)-HNK effects were still present in the EZM 12 days after administration in cohort 1 and 27 days after administration in NOR testing of cohorts 2 and 3. (2R,6R)-HNK may be beneficial for the neurobehavioral syndromes that follow blast exposure in military veterans. Additional studies will be needed to determine whether higher doses or more extended treatment regimens may be more effective.

ABSTRACT Introduction: Due to Brazilian population aging, prevalence of aortic stenosis, and limited number of scores in literature, it is essential to develop risk scores adapted to our reality and created in the specific context of this disease. Methods: This is an observational historical cohort study with analysis of 802 aortic stenosis patients who underwent valve replacement at Hospital São Lucas, Pontifícia Universidade Católica do Rio Grande do Sul, from 1996 to 2018. With the aid of logistic regression, a weighted risk score was constructed based on the magnitude of the coeficients β of the logistic equation. Two performance statistics were obtained: area under the receiver operating characteristic curve and the chi-square (χ2) of Hosmer-Lemeshow goodness-of-fit with Pearson’s correlation coeficient between the observed events and predicted as a model calibration estimate. Results: The risk predictors that composed the score were valve replacement surgery combined with coronary artery bypass grafting, prior renal failure, New York Heart Association class III/IV heart failure, age > 70 years, and ejection fraction < 50%. The receiver operating characteristic curve area was 0.77 (95% confidence interval: 0.72-0.82); regarding the model calibration estimated between observed/predicted mortality, Hosmer-Lemeshow test χ2 = 3,70 (P=0.594) and Pearson’s coeficient r = 0.98 (P

Blast-induced neurotrauma has received much attention over the past decade. Vascular injury occurs early following blast exposure. Indeed, in animal models that approximate human mild traumatic brain injury or subclinical blast exposure, vascular pathology can occur in the presence of a normal neuropil, suggesting that the vasculature is particularly vulnerable. Brain endothelial cells and their supporting glial and neuronal elements constitute a neurovascular unit (NVU). Blast injury disrupts gliovascular and neurovascular connections in addition to damaging endothelial cells, basal laminae, smooth muscle cells, and pericytes as well as causing extracellular matrix reorganization. Perivascular pathology becomes associated with phospho-tau accumulation and chronic perivascular inflammation. Disruption of the NVU should impact activity-dependent regulation of cerebral blood flow, blood–brain barrier permeability, and glymphatic flow. Here, we review work in an animal model of low-level blast injury that we have been studying for over a decade. We review work supporting the NVU as a locus of low-level blast injury. We integrate our findings with those from other laboratories studying similar models that collectively suggest that damage to astrocytes and other perivascular cells as well as chronic immune activation play a role in the persistent neurobehavioral changes that follow blast injury.

Abstract Background Septic shock is a severe form of sepsis marked by hypotension with an ominous outcome despite the introduction of modern intensive care. The aim of the present study is to obtain a panel with biomarkers, echocardiographic and vascular parameters to better risk stratify patients and identify those at higher risk of ominous outcome. Methods Between May 2013 and April 2016, 35 consecutive patients admitted at the Intensive Care Unit (ICU) of ASST Great Metropolitan Hospital Niguarda with the diagnosis of severe sepsis or septic shock were enrolled. All patients underwent rest echocardiography and several circulating biomarkers of myocardial damage or oxidative stress. Results The multivariate Cox’s proportional hazard model showed that the only independent prognostic predictor for 30-day mortality was the angiopoietin-2, (HR 1.017, 95% CI 1.000–1.034; P = 0.049). An angiopoietin-2 concentrations ≥ of 33,418 pg/mL was identified as the optimal threshold for the discrimination between survivors and non survivors at the time of admission in ICU, with a sensitivity of 80% and a specificity of 68%. Conclusions Septic shock has a poor in-hospital outcome even when the best of care is implemented. Among the biochemical parameters angiopoietin was able to identify patients at risk of death. The lowest the value at admission, the highest the risk of in-hospital death. No echocardiographic nor vascular parameter was able to predict outcome in this setting.

Abstract Background The role of Numb, a protein that is important for cell fate and development and that, in human muscle, is expressed at reduced levels with advanced age, was investigated; adult mice skeletal muscle and its localization and function within myofibres were determined. Methods Numb expression was evaluated by western blot. Numb localization was determined by confocal microscopy. The effects of conditional knock out (cKO) of Numb and the closely related gene Numb‐like in skeletal muscle fibres were evaluated by in situ physiology, transmission and focused ion beam scanning electron microscopy, three‐dimensional reconstruction of mitochondria, lipidomics, and bulk RNA sequencing. Additional studies using primary mouse myotubes investigated the effects of Numb knockdown on cell fusion, mitochondrial function, and calcium transients. Results Numb protein expression was reduced by ~70% (P

This study examines the role of community-based mutual support networks in shaping caring cities. Taking four neighborhoods in Madrid as a case study, we investigate the dynamics, organization, and impact of these networks in addressing vulnerabilities and fostering resilience within the city. In Madrid, community support networks, herein also referred to as “care networks,” emerged as key actors in mitigating the impact of the COVID-19 crisis on vulnerable populations. We document how they establish relations with the existing social services to show that public-common partnerships may be a way to tackle future crises. Politicizing care at the level of the commons helps ensure better attention is paid to vulnerability, understood as both a human condition and a political issue that must be addressed collectively. Their repertory of action, part of a micro-local geopolitics of care which ought to be care-fully described, contributes to the development of a theory of urban care in the commons. [ABSTRACT FROM AUTHOR]

Many military veterans who experienced blast-related traumatic brain injuries (TBIs) in the conflicts in Iraq and Afghanistan suffer from chronic cognitive and mental health problems, including post-traumatic stress disorder (PTSD). Transcranial laser therapy (TLT) uses low-power lasers emitting light in the far- to near-infrared ranges. Beneficial effects of TLT have been reported in neurological and mental-health?related disorders in humans and animal models, including TBI. Rats exposed to repetitive low-level blast develop chronic cognitive and PTSD-related behavioral traits. We tested whether TLT treatment could reverse these traits. Rats received a 74.5-kPa blast or sham exposures delivered one per day for 3 consecutive days. Beginning at 34 weeks after blast exposure, the following groups of rats were treated with active or sham TLT: 1) Sham-exposed rats (n?=?12) were treated with sham TLT; 2) blast-exposed rats (n?=?13) were treated with sham TLT; and 3) blast-exposed rats (n?=?14) were treated with active TLT. Rats received 5?min of TLT five times per week for 6 weeks (wavelength, 808?nm; power of irradiance, 240?mW). At the end of treatment, rats were tested in tasks found previously to be most informative (novel object recognition, novel object localization, contextual/cued fear conditioning, elevated zero maze, and light/dark emergence). TLT did not improve blast-related effects in any of these tests, and blast-exposed rats were worse after TLT in some anxiety-related measures. Based on these findings, TLT does not appear to be a promising treatment for the chronic cognitive and mental health problems that follow blast injury.

Abstract Cerebral vascular injury as a consequence of blast-induced traumatic brain injury is primarily the result of blast wave-induced mechanical disruptions within the neurovascular unit. In rodent models of blast-induced traumatic brain injury, chronic vascular degenerative processes are associated with the development of an age-dependent post-traumatic stress disorder-like phenotype. To investigate the evolution of blast-induced chronic vascular degenerative changes, Long-Evans rats were blast-exposed (3 × 74.5 kPa) and their brains analyzed at different times post-exposure by X-ray microcomputed tomography, immunohistochemistry and electron microscopy. On microcomputed tomography scans, regional cerebral vascular attenuation or occlusion was observed as early as 48 h post-blast, and cerebral vascular disorganization was visible at 6 weeks and more accentuated at 13 months post-blast. Progression of the late-onset pathology was characterized by detachment of the endothelial and smooth muscle cellular elements from the neuropil due to degeneration and loss of arteriolar perivascular astrocytes. Development of this pathology was associated with vascular remodeling and neuroinflammation as increased levels of matrix metalloproteinases (MMP-2 and MMP-9), collagen type IV loss, and microglial activation were observed in the affected vasculature. Blast-induced chronic alterations within the neurovascular unit should affect cerebral blood circulation, glymphatic flow and intramural periarterial drainage, all of which may contribute to development of the blast-induced behavioral phenotype. Our results also identify astrocytic degeneration as a potential target for the development of therapies to treat blast-induced brain injury.

This research had the general objective of: analyzing the relationships between the BNCC and the training of teachers in continuing education in the Northwest region of the state of Rio Grande do Sul (RS). It was characterized by the qualitative approach, with the research typology in the presuppositions of action-research. As data collection instruments, a questionnaire was used, with 9 open questions. Through Discursive Textual Analysis (DTA) it was possible to identify a total of 40 Meaning Units (US) in two metatexts: - Technical Rationality (27 US); - Practical Rationality (13 US). From the analysis of the US and the theoretical basis, it was possible to evidence in the training of Mathematics teachers the preponderance of technical rationality, compared to practical rationality. Furthermore, through the analyses, we found the prescriptiveness from the understanding of most teachers about teacher training and the BNCC, thus reinforcing the perspective of a technical rationality based on the BNCC.

Summary: Background: Previous Randomised controlled trials (RCT) evaluating chloroquine and hydroxychloroquine in non-hospitalised COVID-19 patients have found no significant difference in hospitalisation rates. However, low statistical power precluded definitive answers. Methods: We conducted a multicenter, double-blind, RCT in 56 Brazilian sites. Adults with suspected or confirmed COVID-19 presenting with mild or moderate symptoms with ≤ 07 days prior to enrollment and at least one risk factor for clinical deterioration were randomised (1:1) to receive hydroxychloroquine 400 mg twice a day (BID) in the first day, 400 mg once daily (OD) thereafter for a total of seven days, or matching placebo. The primary outcome was hospitalisation due to COVID-19 at 30 days, which was assessed by an adjudication committee masked to treatment allocation and following the intention-to-treat (ITT) principle. An additional analysis was performed only in participants with SARS-CoV-2 infection confirmed by molecular or serology testing (modified ITT [mITT] analysis). This trial was registered at ClinicalTrials.gov, NCT04466540. Findings: From May 12, 2020 to July 07, 2021, 1372 patients were randomly allocated to hydroxychloroquine or placebo. There was no significant difference in the risk of hospitalisation between hydroxychloroquine and placebo groups (44/689 [6·4%] and 57/683 [8·3%], RR 0·77 [95% CI 0·52–1·12], respectively, p=0·16), and similar results were found in the mITT analysis with 43/478 [9·0%] and 55/471 [11·7%] events, RR 0·77 [95% CI 0·53–1·12)], respectively, p=0·17. To further complement our data, we conducted a meta-analysis which suggested no significant benefit of hydroxychloroquine in reducing hospitalisation among patients with positive testing (69/1222 [5·6%], and 88/1186 [7·4%]; RR 0·77 [95% CI 0·57–1·04]). Interpretation: In outpatients with mild or moderate forms of COVID-19, the use of hydroxychloroquine did not reduce the risk of hospitalisation compared to the placebo control. Our findings do not support the routine use of hydroxychloroquine for treatment of COVID-19 in the outpatient setting. Funding: COALITION COVID-19 Brazil and EMS.

Abstract Military veterans who experience blast-related traumatic brain injuries often suffer from chronic cognitive and neurobehavioral syndromes. Reports of abnormal tau processing following blast injury have raised concerns that some cases may have a neurodegenerative basis. Rats exposed to repetitive low-level blast exhibit chronic neurobehavioral traits and accumulate tau phosphorylated at threonine 181 (Thr181). Using data previously reported in separate studies we tested the hypothesis that region-specific patterns of Thr181 phosphorylation correlate with behavioral measures also previously determined and reported in the same animals. Elevated p-tau Thr181 in anterior neocortical regions and right hippocampus correlated with anxiety as well as fear learning and novel object localization. There were no correlations with levels in amygdala or posterior neocortical regions. Particularly striking were asymmetrical effects on the right and left hippocampus. No systematic variation in head orientation toward the blast wave seems to explain the laterality. Levels did not correlate with behavioral measures of hyperarousal. Results were specific to Thr181 in that no correlations were observed for three other phospho-acceptor sites (threonine 231, serine 396, and serine 404). No consistent correlations were linked with total tau. These correlations are significant in suggesting that p-tau accumulation in anterior neocortical regions and the hippocampus may lead to disinhibited amygdala function without p-tau elevation in the amygdala itself. They also suggest an association linking blast injury with tauopathy, which has implications for understanding the relationship of chronic blast-related neurobehavioral syndromes in humans to neurodegenerative diseases.

Here, we investigated the mechanisms by which aging-related reductions of the levels of Numb in skeletal muscle fibers contribute to loss of muscle strength and power, two critical features of sarcopenia. Numb is an adaptor protein best known for its critical roles in development, including asymmetric cell division, cell-type specification, and termination of intracellular signaling. Numb expression is reduced in old humans and mice. We previously showed that, in mouse skeletal muscle fibers, Numb is localized to sarcomeres where it is concentrated near triads; conditional inactivation of Numb and a closely related protein Numb-like (Numbl) in mouse myofibers caused weakness, disorganization of sarcomeres, and smaller mitochondria with impaired function. Here, we found that a single knockout of Numb in myofibers causes reduction in tetanic force comparable to a double Numb, Numbl knockout. We found by proteomics analysis of protein complexes isolated from C2C12 myotubes by immunoprecipitation using antibodies against Numb that Septin 7 is a potential Numb-binding partner. Septin 7 is a member of the family of GTP-binding proteins that organize into filaments, sheets, and rings, and is considered part of the cytoskeleton. Immunofluorescence evaluation revealed a partial overlap of staining for Numb and Septin 7 in myofibers. Conditional, inducible knockouts of Numb led to disorganization of Septin 7 staining in myofibers. These findings indicate that Septin 7 is a Numb-binding partner and suggest that interactions between Numb and Septin 7 are critical for structural organization of the sarcomere and muscle contractile function. [ABSTRACT FROM AUTHOR]

Abstract Background Jehovah’s Witnesses represent a tremendous clinical challenge when indicated to liver transplantation because they refuse blood transfusion on religious grounds and the procedure is historically associated with potential massive peri-operative blood loss. We herein describe a peri-operative management pathway with strategies toward a transfusion-free environment with the aim not only of offering liver transplant to selected Jehovah’s Witnesses patients but also, ultimately, of translating this practice to all general surgical procedures. Methods This is a retrospective review of prospective medical records of JW patients who underwent LT at our Institution. The peri-operative multimodal strategy to liver transplantation in Jehovah’s Witnesses includes a pre-operative red cell mass optimization package and the intra-operative use of normovolemic haemodilution, veno-venous bypass and low central venous pressure. Results In a 9-year period, 13 Jehovah’s Witness patients received liver transplantation at our centre representing the largest liver transplant program from deceased donors in Jehovah’s Witnesses patients reported so far. No patient received blood bank products but 3 had fibrinogen concentrate and one tranexamic acid to correct ongoing hyper-fibrinolysis. There were 4 cases of acute kidney injury (one required extracorporeal renal replacement treatment) and one patient needed vasoactive medications to support blood pressure for the first 2 postoperative days. Two patients underwent re-laparotomy. Finally, of the 13 recipients, 12 were alive at the 1 year follow-up interview and 1 died due to septic complications. Conclusions Our experience confirms that liver transplantation in selected Jehovah’s Witnesses patients can be feasible and safe provided that it is carried out at a very experienced centre and according to a multidisciplinary approach.

The importance of assessing neurochemical processes in the cetacean brain as a tool for monitoring their cognitive health and to indirectly model human neurodegenerative conditions is increasingly evident, although available data are largely semiquantitative. High-resolution MRI for post-mortem brains and stereology allow for quantitative assessments of the cetacean brain. In this study, we scanned two brains of bottlenose dolphins in a 7-Tesla (7T) MR scanner and assessed the connectivity of the inferior colliculi and ventral cochlear nuclei using diffusion tensor imaging (DTI). Serial thick sections were investigated stereologically in one of the dolphins to generate rigorous quantitative estimates of identifiable cell types according to their morphology and expression of molecular markers, yielding reliable cell counts with most coefficients of error