Motoneuron deafferentation and gliosis occur in association with neuromuscular regressive changes during ageing in mice

Background The cellular mechanisms underlying the age‐associated loss of muscle mass and function (sarcopenia) are poorly understood, hampering the development of effective treatment strategies. Here, we performed a detailed characterization of age‐related pathophysiological changes in the mouse neuromuscular system. Methods Young, adult, middle‐aged, and old (1, 4, 14, and 24-30 months old, respectively) C57BL/6J mice were used. Motor behavioural and electrophysiological tests and histological and immunocytochemical procedures were carried out to simultaneously analyse structural, molecular, and functional age‐related changes in distinct cellular components of the neuromuscular system. Results Ageing was not accompanied by a significant loss of spinal motoneurons (MNs), although a proportion (~15%) of them in old mice exhibited an abnormally dark appearance. Dark MNs were also observed in adult (~9%) and young (~4%) animals, suggesting that during ageing, some MNs undergo early deleterious changes, which may not lead to MN death. Old MNs were depleted of cholinergic and glutamatergic inputs (~40% and ~45%, respectively, P < 0.01), suggestive of age‐associated alterations in MN excitability. Prominent microgliosis and astrogliosis [~93% (P < 0.001) and ~100% (P < 0.0001) increase vs. adults, respectively] were found in old spinal cords, with increased density of pro‐inflammatory M1 microglia and A1 astroglia (25‐fold and 4‐fold increase, respectively, P < 0.0001). Ageing resulted in significant reductions in the nerve conduction velocity and the compound muscle action potential amplitude (~30%, P < 0.05, vs. adults) in old distal plantar muscles. Compared with adult muscles, old muscles exhibited significantly higher numbers of both denervated and polyinnervated neuromuscular junctions, changes in fibre type composition, higher proportion of fibres showing central nuclei and lipofuscin aggregates, depletion of satellite cells, and augmented expression of different molecules related to development, plasticity, and maintenance of neuromuscular junctions, including calcitonin gene‐related peptide, growth associated protein 43, agrin, fibroblast growth factor binding protein 1, and transforming growth factor‐β1. Overall, these alterations occurred at varying degrees in all the muscles analysed, with no correlation between the age‐related changes observed and myofiber type composition or muscle topography. Conclusions Our data provide a global view of age‐associated neuromuscular changes in a mouse model of ageing and help to advance understanding of contributing pathways leading to development of sarcopenia.This work was supported by Abbott and a grant from the Ministerio de Ciencia, Innovación y Universidades cofinancedby Fondo Europeo de Desarrollo Regional (RTI2018-099278-B-I00 to J.C. and J.E.

Impact of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients: A nationwide study in Spain

Objective To assess the effect of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients in Spain. Settings The initial flood of COVID-19 patients overwhelmed an unprepared healthcare system. Different measures were taken to deal with this overburden. The effect of these measures on neurosurgical patients, as well as the effect of COVID-19 itself, has not been thoroughly studied. Participants This was a multicentre, nationwide, observational retrospective study of patients who underwent any neurosurgical operation from March to July 2020. Interventions An exploratory factorial analysis was performed to select the most relevant variables of the sample. Primary and secondary outcome measures Univariate and multivariate analyses were performed to identify independent predictors of mortality and postoperative SARS-CoV-2 infection. Results Sixteen hospitals registered 1677 operated patients. The overall mortality was 6.4%, and 2.9% (44 patients) suffered a perioperative SARS-CoV-2 infection. Of those infections, 24 were diagnosed postoperatively. Age (OR 1.05), perioperative SARS-CoV-2 infection (OR 4.7), community COVID-19 incidence (cases/10 5 people/week) (OR 1.006), postoperative neurological worsening (OR 5.9), postoperative need for airway support (OR 5.38), ASA grade =3 (OR 2.5) and preoperative GCS 3-8 (OR 2.82) were independently associated with mortality. For SARS-CoV-2 postoperative infection, screening swab test <72 hours preoperatively (OR 0.76), community COVID-19 incidence (cases/10 5 people/week) (OR 1.011), preoperative cognitive impairment (OR 2.784), postoperative sepsis (OR 3.807) and an absence of postoperative complications (OR 0.188) were independently associated. Conclusions Perioperative SARS-CoV-2 infection in neurosurgical patients was associated with an increase in mortality by almost fivefold. Community COVID-19 incidence (cases/10 5 people/week) was a statistically independent predictor of mortality. Trial registration number CEIM 20/217

Canvis neuromusculars en l’envelliment: efectes de la suplementació dietètica amb flavonoides del te verd i del cacau sobre la sarcopènia

La pèrdua de la massa i la força musculars (sarcopènia) és un procés característic associat a l'envelliment que té lloc en totes les espècies. En ratolins, s'han observat defectes en les habilitats motores i canvis en els patrons electromiogràfics amb l'edat. Aquestes alteracions es donen en absència d'una mort significativa de motoneurones (MNs). La disfunció de les MNs podria ser la causa per la qual les unions neuromusculars (NMJs), els axons motors i els músculs esquelètics pateixen alteracions estructurals i moleculars durant la senescència. En aquest estudi posem de manifest que el procés d'envelliment comporta la degeneració dels nervis motors i la presència de fenòmens d'sprouting dels terminals nerviosos. Així mateix, les fibres musculars esquelètiques experimenten cicles continus de degeneració-regeneració. Si bé l'envelliment indueix canvis similars en els diferents tipus de músculs examinats, el perfil d'algunes alteracions és molt variable entre ells. Aquesta variabilitat es dona fins i tot entre músculs que tenen una localització propera i amb una composició de fibres d'una tipologia similar, el que suggereix que el grau d'activitat i la funció específica dels músculs, més que no pas la seva topografia i la tipologia de les seves fibres, tenen un gran impacte en els canvis musculars relacionats amb l'edat. Les dietes suplementades amb flavonoides del te verd o del cacau augmenten la taxa de supervivència dels ratolins vells i prevenen alguns dels canvis estructurals regressius que es donen durant la senescència en el múscul esquelètic i l'NMJ. Ambdues dietes frenen el progrés de la senescència dels músculs esquelètics i milloren la seva capacitat regenerativa, reduint els cicles de degeneració-regeneració de les miofibres, mantenint la població de cèl·lules satèl·lit i fent augmentar l'expressió de PGC-1α, un regulador transcripcional de la biogènesi mitocondrial, a més de mantenir la innervació i el grau de maduresa de les NMJs. Les diferències entre els resultats obtinguts amb les dietes suplementades amb l'extracte del te verd o amb cacau sobre les alteracions que s'observen en el múscul amb l'edat indiquen que la combinació de diferents flavonoides podria tenir un major efecte a l'hora de contrarestar els canvis al sistema neuromuscular relacionats amb l'envelliment.La pérdida de la masa y la fuerza musculares (sarcopenia) es un proceso característico asociado al envejecimiento que se da en todas las especies. En ratones, se han observado defectos en las habilidades motoras y cambios en los patrones electromiográficos con la edad. Estos cambios se dan en ausencia de una muerte significativa de motoneuronas (MNs). La disfunción de las MNs podría ser la causa por la cual las uniones neuromusculares (NMJs), los axones motores y los músculos esqueléticos sufren alteraciones estructurales y moleculares durante la senescencia. En este estudio ponemos de manifiesto que el proceso de envejecimiento comporta la degeneración de los nervios motores i la presencia de fenómenos de sprouting de los terminales nerviosos. Asimismo, las fibras musculares esqueléticas experimentan ciclos continuos de degeneración-regeneración. Si bien el envejecimiento induce cambios similares en los distintos tipos de músculos examinados, el perfil de algunas alteraciones es muy variable entre ellos. Esta variabilidad se da incluso entre músculos que tienen una localización cercana y con una composición de fibras de una tipología similar, lo que sugiere que el grado de actividad y la función específica de los músculos, más que su topografía y la tipología de sus fibras, tienen un gran impacto en los cambios musculares relacionados con la edad. Las dietas suplementadas con flavonoides del té verde o del cacao aumentan la tasa de supervivencia de los ratones viejos y previenen algunos de los cambios estructurales regresivos que se dan durante la senescencia en el músculo esquelético y la NMJ. Ambas dietas frenan el progreso de la senescencia de los músculos esqueléticos y mejoran su capacidad regenerativa, reduciendo los ciclos de degeneración-regeneración de las miofibras, manteniendo la población de células satélite y haciendo aumentar la expresión de PGC-1α, un regulador transcripcional de la biogénesis mitocondrial, además de mantener la inervación y el grado de madurez de las NMJs. Las diferencias entre los resultados obtenidos con las dietas suplementadas con el extracto del té verde o con cacao sobre las alteraciones que se observan en el músculo con la edad indican que la combinación de distintos flavonoides podría tener un mayor efecto a la hora de contrarrestar los cambios en el sistema neuromuscular relacionados con el envejecimiento.Loss of muscle mass and strength (sarcopenia) is a characteristic process associated with aging that occurs in all species. In mice, defects in motor skills and changes in electromyographic patterns have been observed with age. These alterations occur in the absence of a significant death of motoneurons (MNs). The dysfunction of MNs could be the reason why neuromuscular junctions (NMJs), motor axons and skeletal muscles suffer structural and molecular alterations during senescence. In this study we highlight that the aging process involves motor nerve degeneration and sprouting phenomena of the nerve terminals. Likewise, skeletal muscle fibers undergo continuous cycles of degeneration-regeneration Although aging induces similar changes in the different types of muscles examined, the profile of some alterations is very variable between them. This variability occurs even between muscles that have a close localization and having similar fibre type composition, which suggests that the degree of activity and the specific function of the muscles, rather than their topography and the typology of their fibres, have a great impact on muscle changes related to age. Diets supplemented with green tea or cocoa flavonoids boost the survival rate of old mice and prevent some of the regressive structural changes that occur during senescence in skeletal muscle and the NMJ. Both diets slow down the progress of skeletal muscle senescence and improve their regenerative capacity, reducing myofibre degeneration-regeneration cycles, maintaining the population of satellite cells and increasing the expression of PGC-1α, a transcriptional regulator of mitochondrial biogenesis, as well as maintaining the innervation and the degree of maturation of the NMJs. The differences between the results obtained with the diets supplemented with green tea extract or with cocoa on the alterations observed in the muscle with age indicate that the combination of different flavonoids could have a greater effect on counteracting the changes in the neuromuscular system related to aging

Comorbidity Patterns in Patients with Atopic Dermatitis Using Network Analysis in the EpiChron Study.

Background: Atopic dermatitis (AD) is associated with different comorbidities. Methods: Retrospective, observational study based on clinical information from the individuals of the EpiChron Cohort Study (Aragon, Spain) with a diagnosis of AD between 1 January 2010 and 31 December 2018. We calculated the tetrachoric correlations of each pair of comorbidities to analyze the weight of the association between them. We used a cut-off point for statistical significance of p-valu

Seroprevalence of SARS-CoV-2 in Patients with Multiple Sclerosis under Disease-Modifying Therapies: A Multi-Centre Study

Background: The EMCOVID project conducted a multi-centre cohort study to investigate the impact of COVID-19 on patients with Multiple Sclerosis (pwMS) receiving disease-modifying therapies (DMTs). The study aimed to evaluate the seroprevalence and persistence of SARS-CoV-2 antibodies in MS patients enrolled in the EMCOVID database. The DMTs were used to manage MS by reducing relapses, lesion accumulation, and disability progression. However, concerns arose regarding the susceptibility of pwMS to COVID-19 due to potential interactions between SARS-CoV-2 and the immune system, as well as the immunomodulatory effects of DMTs. Methods: This prospective observational study utilized data from a Multiple Sclerosis and COVID-19 (EMCOVID-19) study. Demographic characteristics, MS history, laboratory data, SARS-CoV-2 serology, and symptoms of COVID-19 were extracted for pwMS receiving any type of DMT. The relationship between demographics, MS phenotype, DMTs, and COVID-19 was evaluated. The evolution of SARS-CoV-2 antibodies over a 6-month period was also assessed. Results: The study included 709 pwMS, with 376 patients providing samples at the 6-month follow-up visit. The seroprevalence of SARS-CoV-2 antibodies was higher among pwMS than the general population, with Interferon treatment being significantly associated with greater seroprevalence (16.9% vs. 8.4%; p 0.003). However, no other specific DMT showed a significant association with antibody presence. A total of 32 patients (8.5%) tested positive for IgG, IgM, or IgA antibodies against SARS-CoV-2 at baseline, but then tested negative at 6 months. Most of the pwMS in the cohort were asymptomatic for COVID-19 and, even among symptomatic cases, the prognosis was generally favourable. Conclusion: pwMS undergoing DMTs exhibited a higher seroprevalence of COVID-19 than the general population. Interferon treatment was associated with a higher seroprevalence, suggesting a more robust humoral response. This study provides valuable insights into the seroprevalence and persistence of SARS-CoV-2 antibodies in pwMS and contributes to our understanding of the impact of COVID-19 amongst this population

Patients awaiting surgery for neurosurgical diseases during the first wave of the COVID-19 pandemic in Spain: a multicentre cohort study.

The large number of infected patients requiring mechanical ventilation has led to the postponement of scheduled neurosurgical procedures during the first wave of the COVID-19 pandemic. The aims of this study were to investigate the factors that influence the decision to postpone scheduled neurosurgical procedures and to evaluate the effect of the restriction in scheduled surgery adopted to deal with the first outbreak of the COVID-19 pandemic in Spain on the outcome of patients awaiting surgery. This was an observational retrospective study. A tertiary-level multicentre study of neurosurgery activity between 1 March and 30 June 2020. A total of 680 patients awaiting any scheduled neurosurgical procedure were enrolled. 470 patients (69.1%) were awaiting surgery because of spine degenerative disease, 86 patients (12.6%) due to functional disorders, 58 patients (8.5%) due to brain or spine tumours, 25 patients (3.7%) due to cerebrospinal fluid (CSF) disorders and 17 patients (2.5%) due to cerebrovascular disease. The primary outcome was mortality due to any reason and any deterioration of the specific neurosurgical condition. Second, we analysed the rate of confirmed SARS-CoV-2 infection. More than one-quarter of patients experienced clinical or radiological deterioration. The rate of worsening was higher among patients with functional (39.5%) or CSF disorders (40%). Two patients died (0.4%) during the waiting period, both because of a concurrent disease. We performed a multivariate logistic regression analysis to determine independent covariates associated with maintaining the surgical indication. We found that community SARS-CoV-2 incidence (OR=1.011, p Patients awaiting neurosurgery experienced significant collateral damage even when they were considered for scheduled procedures

Switching TNF antagonists in patients with chronic arthritis: An observational study of 488 patients over a four-year period

The objective of this work is to analyze the survival of infliximab, etanercept and adalimumab in patients who have switched among tumor necrosis factor (TNF) antagonists for the treatment of chronic arthritis. BIOBADASER is a national registry of patients with different forms of chronic arthritis who are treated with biologics. Using this registry, we have analyzed patient switching of TNF antagonists. The cumulative discontinuation rate was calculated using the actuarial method. The log-rank test was used to compare survival curves, and Cox regression models were used to assess independent factors associated with discontinuing medication. Between February 2000 and September 2004, 4,706 patients were registered in BIOBADASER, of whom 68% had rheumatoid arthritis, 11% ankylosing spondylitis, 10% psoriatic arthritis, and 11% other forms of chronic arthritis. One- and two-year drug survival rates of the TNF antagonist were 0.83 and 0.75, respectively. There were 488 patients treated with more than one TNF antagonist. In this situation, survival of the second TNF antagonist decreased to 0.68 and 0.60 at 1 and 2 years, respectively. Survival was better in patients replacing the first TNF antagonist because of adverse events (hazard ratio (HR) for discontinuation 0.55 (95% confidence interval (CI), 0.34-0.84)), and worse in patients older than 60 years (HR 1.10 (95% CI 0.97-2.49)) or who were treated with infliximab (HR 3.22 (95% CI 2.13-4.87)). In summary, in patients who require continuous therapy and have failed to respond to a TNF antagonist, replacement with a different TNF antagonist may be of use under certain situations. This issue will deserve continuous reassessment with the arrival of new medications. © 2006 Gomez-Reino and Loreto Carmona; licensee BioMed Central Ltd