Emerging scaffold‑ and cellular‑based strategies for brain tissue regeneration and imaging

Stimulating brain tissue regeneration is a major challenge after central nervous system (CNS) injury, such as those observed from trauma or cerebrovascular accidents. Full regeneration is difficult even when a neurogenesis-associated repair response may occur. Currently, there are no effective treatments to stimulate brain tissue regeneration. However, biomaterial scaffolds are showing promising results, where hydrogels are the materials of choice to develop these supportive scaffolds for cell carriers. Their combination with growth factors, such as brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor (bFGF), or vascular endothelial growth factor (VEGF), together with other cell therapy strategies allows the prevention of further neuronal death and can potentially lead to the direct stimulation of neurogenesis and vascularisation at the injured site. Imaging of the injured site is particularly critical to study the reestablishment of neural cell functionality after brain tissue injury. This review outlines the latest key advances associated with different strategies aiming to promote the neuroregeneration, imaging, and functional recovery of brain tissue.The authors thank the fnancial support from the Portuguese Foundation for Science and Technology for the funds provided under the project NanOptoNerv (ref. PTDC/NAN-MAT/29936/2017) and to INTERREG V A España Portugal (POCTEP) under the project 2IQBIONEURO (ref. 0624_2IQBIONEURO_6_E). The authors would like to thank the funding provided by the Irish Research Council through the IRC Postdoctoral Fellowship (GOIPG/2021/75) for FZ and through the IRC Enterprise Partnership Scheme with Johnson and Johnson (EPSPG/2020/78) for A

Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Publisher Copyright: © 2021 The Authors, some rights reserved.Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-alpha and/or IFN-omega are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-alpha and/or IFN-omega (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-beta. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-alpha and/or IFN-omega are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-beta do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases.Peer reviewe

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

SignificanceThere is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population

Plasma Serotonin is Elevated in Adult Patients with Sudden Sensorineural Hearing Loss

International audienceAbstract Background The roles of thrombophilia and cardiovascular risk factors in sudden sensorineural hearing loss (SSNHL) remain controversial. Cochlear microthrombosis and vasospasm have been hypothesized as possible pathogenic mechanisms of SSNHL. This article investigates the circulating serotonin and homocysteine levels besides thrombophilia screening in patients with idiopathic SSNHL. Methods A total of 133 SSNHL patients and age- and sex-matched controls were investigated (discovery cohort). Measurement included common inherited natural coagulation inhibitors, factor VIII, von Willebrand factor (VWF), antiphospholipid antibodies, homocysteine, and serotonin (whole blood, platelet, and plasma) levels, along with frequent relevant genetic variants. A validation cohort (128 SSNHL patients) was studied for homocysteine and serotonin levels. Results and Conclusion In the discovery cohort, 58.6% of patients exhibited thrombophilia, of which most had a low to moderate titers of antiphospholipid antibodies and high levels of factor VIII/VWF. Twenty-seven patients (20%) had mild-to-moderate hyperhomocysteinemia or were homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T mutation. Regarding serotonin, SSNHL patients had elevated whole blood levels that remained within the normal range and normal platelet content. However, approximately 90% patients of both cohorts had elevated plasma serotonin. Elevated plasma serotoninemia was accompanied by serotonylation of platelet rhoA protein. This study shows that increased plasma serotonin appears as a biomarker of SSNHL (specificity: ∼96%, sensitivity: ∼90%) and could participate in the pathophysiology of SSNHL

Factors Influencing anti-Xa assays: A Multicenter Prospective Study in Critically Ill and Noncritically Ill Patients Receiving Unfractionated Heparin

International audienceBackground: The presence of dextran sulfate (DS) in reagents and the type of blood collection tube (citrate/citrated-theophylline-adenosine-dipyridamole [CTAD]) can lead to discrepancies between unfractionated heparin (UFH) anti-Xa levels.Objectives: To evaluate the extent of the effect (1) of different reagents containing or not containing DS and (2) of the blood collection tubes, on UFH anti-Xa levels, in various clinical situations (NCT04700670).Methods: We prospectively included patients from eight centers: group (G)1, cardiopulmonary bypass (CPB) after heparin neutralization (n = 39); G2, cardiothoracic intensive care unit (ICU) after CPB (n = 35); G3, medical ICU (n = 53); G4, other medical inpatients (n = 38). Blood was collected into citrated and CTAD tubes. Chromogenic anti-Xa assays were centrally performed, using seven reagent/analyzer combinations including two without DS. The association between anti-Xa levels and covariates was tested using a linear mixed-effects model.Results: We analyzed 4,546 anti-Xa values from 165 patients. Median anti-Xa levels were systematically higher with reagents containing DS, whatever the patient group, with the greatest effect observed in G1 (0.32 vs. 0.05 IU/mL). Anti-Xa levels were slightly higher in CTAD than in citrate samples, irrespective of the assay. The model showed: (1) a significant dextran-patient group interaction (p < 0.0001), the effect of DS on anti-Xa levels varying from 30.9% in G4 to 296% in G1, and (2) a significant effect of CTAD, varying between patient groups (p = 0.0302).Conclusion: The variability of anti-Xa levels with a great overestimation of the values, using a reagent containing DS, can lead to different treatment decisions, especially after heparin neutralization by protamine. Clinical consequences of these differences remain to be demonstrated

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-alpha, IFN-omega, and/or IFN-beta are found in similar to 20% of deceased patients across age groups, and in similar to 1% of individuals aged 4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-alpha 2 or IFN-omega, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals = 70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals = 80 y old for autoantibodies neutralizing IFN-alpha 2 or IFN-omega, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-alpha 2 and IFN-omega. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.GR-F

Autoantibodies neutralizing type I IFNs are present in

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/mL, in plasma diluted 1 to 10) of IFN-α and/or -ω are found in about 10% of patients with critical COVID-19 pneumonia, but not in subjects with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or -ω (100 pg/mL, in 1/10 dilutions of plasma) in 13.6% of 3,595 patients with critical COVID-19, including 21% of 374 patients \u3e 80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1,124 deceased patients (aged 20 days-99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected subjects from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or -ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% \u3e80 years. Moreover, the proportion of subjects carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individualsyears, 2.3% between 70 and 80 years, and 6.3% \u3e80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over-80s, and total fatal COVID-19 cases