The agonist-antagonist myoneural interface (AMI), a surgical method to reinnervate physiologically-relevant proprioceptive feedback for control of limb prostheses, has demonstrated the ability to provide natural afferent sensations for limb amputees when actuating their prostheses. Following an AMI surgery, one potential challenge is atrophy of the disused muscles, which would weaken the reinnervation efficacy of AMI. It is well known that electrical muscle stimulus (EMS) can reduce the muscle atrophy. In this study, we conducted an animal investigation to explore whether the EMS can significantly improve the electrophysiological performance of AMI. The AMI surgery was performed in 14 rats, in which the distal tendons of bilateral solei donors were connected and positioned on the surface of the left biceps femoris. Subsequently, the left tibial nerve and the common peroneus nerve were sutured onto the ends of the connected donor solei. Two stimulation electrodes were affixed onto the ends of the donor solei for EMS delivery. The AMI rats were randomly divided into two groups. One group regularly received the EMS treatment (designated as EMS_on) for eight weeks and another was no EMS (designated as EMS_off). Two physiological parameters, nerve conduction velocity (NCV) and motor unit number, were derived from the electrically evoked compound action potential (CAP) signals to assess the electrophysiological performance of AMI. Our experimental results demonstrated that the reinnervated muscles of the EMS_on group generated higher CAP signals in comparison to the EMS_off group. Both NCV and motor unit number were significantly elevated in the EMS_on group. Moreover, the EMS_on group displayed statistically higher CAP signals on the indirectly activated proprioceptive afferents than the EMS_off group. These findings may suggested that the EMS treatment would be promise in enhancing the electrophysiological performance and facilitating the reinnervation process of AMI.

Glial cells provide physical and chemical support and protection for neurons. Secreted neurotrophic factors, scaffolds and vesicles regulate in addition to normal homeostasis, repair following neural tissue injury or degeneration. We previously demonstrated that human CNS glia have revascularization capacity by inducing endothelial cell sprouting and microchanneling driven by glial cell secreted components. The clinical potential of using secreted factors and vesicles generated by glial cells in conditioned media was shown by their re-normalization of pathological blood vessels and 3D tissue wound healing and remodeling capacity. To identify secreted components of glial cells and how CNS and PNS glial cells differentially regulate neural tissue homeostasis, disease and injury response, we developed a novel culture method for various types of glial cells that allow for isolating and characterizing secreted glial components, free of animal factors and contaminants normally associated with serum-based culture conditions. Our culture method will enable to identify secreted components using ultrasensitive RNA, glycoconjugate and protein analysis technologies. The characterization of glial secreted factors involved microchanneling may help in development of new clinical therapies for glial and neural cells or axons to migrate and reform connections.

Patients with Peripheral-artery-disease (PAD) are prone to risks of major-adverse-limb-events (MALE), and major-adverse-cardiovascular-events (MACE). CHA2DS2-VASc is a prognostic score for Atrial fibrillation stroke risk, however, no study exists that evaluated its predictability for MALE and MACE in PAD patients. In this study, patients with PAD were stratified into four risk groups based on CHA2DS2-VASc score. Cox-proportional hazards models,10-fold cross-validation and Receiver operating characteristic (ROC) analyses were utilized to evaluate the predictability of CHA2DS2-VASc for predicting MALE, MACE, and MALE+MACE. Kaplan-Meier analysis estimated the survival-probability of risk-groups. CHA2DS2-VASc was found to be a significant predictor of MACE (hazard ratio (95% confidence interval; P) = 3.47 (0.99 - 12.18; 0.052), 4.12 (1.19 - 14.14; 0.024), and 5.06 (1.48 – 17.28; 0.009), for moderate-, high- and very-high-risk groups, respectively, while for MALE and MALE+MACE significance was achieved only for high-risk group. MACE demonstrated AUC > 0.8, good-discrimination (c-index > 0.8) and good-calibration. However, MALE and MALE+MACE models failed to achieve good performances. Based on all findings, CHA2DS2-VASc could potentially serve as a risk stratification score for predicting MACE in patients with PAD but failed to qualify as a good predictor for MALE.

Primary congenital hypothyroidism is readily diagnosed based on elevated plasma TSH levels. In contrast, in the rare disorders of thyroid hormone resistance, TSH and often also thyroid hormone levels are within the normal range. Thyroid hormone resistance is caused by defects in hormone metabolism, transport, or receptor activation and has the same severe consequences for childhood development as congenital hypothyroidism. A total of 23,522 data points from a large cohort of children and young adults were used to generate normal values and sex-specific percentiles for the ratio of free T3 to free T4 (fT3/fT4 ratio). The aim was to determine whether cases with genetically confirmed thyroid hormone resistance (MCT8, THRα, and SECSIBP2 defects) had an abnormal fT3/fT4 ratio. Indeed, we were able to demonstrate a clear separation of patient values for the fT3/fT4 ratio from normal and pathological controls (e.g., children with severe cerebral palsy). We therefore recommend the use of the fT3/fT4 ratio as a readily available screening parameter in children with developmental delay for the identification of thyroid hormone resistance syndromes. The fT3/fT4 ratio can be plotted on centile charts using our free online tool at http://www.thyroid-hormone-ratio.org that accepts various SI and non-SI units.

Background: Vascular inflammation plays a crucial role in peripheral arterial disease (PAD), although the role of the mediators involved has not yet been properly defined. The aim of this work is to investigate gene expression and plasma biomarkers in chronic limb-threating ischemia (CLTI). Methods: Using patients from the GHAS trial, both blood and ischemic muscle samples were obtained to analyze plasma markers and mRNA expression, respectively. Statistical analy-sis was performed by using univariate (Spearman, t-Student, X2) and multivariate (multiple lo-gistic regression) tests. Results: 35 patients were available at baseline (29 for mRNA expression). Baseline characteristics (mean): Age:71.4±12.4 (79.4% male); TNF-α:10.7±4.9; hs-CRP:1.6±2.2; Neutrophil-to-lymphocyte ratio (NLR):3.5±2.8. Plasma TNF-α was found elevated (≥8.1) in 68.6% of patients, while high hs-CRP (≥0.5) in 60.5%. Diabetic patients with high level of inflammation showed significantly higher levels of NOX4 expression at baseline (p=0.0346). Plasma TNF-α had a negative correlation with eNOS expression (-0.5, p=0.015) and hs-CRP with VEGF-A (-0.63, p=0.005). The expression of NOX4 was parallel to that of plasma TNF-α (0.305, p=0.037), especial-ly in DM. Cumulative mortality at 12-month was related to NLR ≥3 (p=0.019) and TNF-α ≥8.1 (p=0.048). The best cut-off point for NLR to predict mortality was 3.4. Conclusions: NOX4 and TNF-α are crucial for the development and complications of lower limb ischemia, especially in DM. hs-CRP could have a negative influence on angiogenesis too. NLR and TNF-α represent suita-ble markers of mortality in CLTI. These results are novel because they connect muscle gene expres-sion and plasma information in patients with advanced PAD, deepening the search of new and ac-curate targets for this condition.

Zebrafish have been found to be the premier model organism in biological and biomedical research, specifically offering many advantages in developmental biology and genetics. This unique aquatic species has been found to have the capacity to regenerate their spinal cord after injury. However, the complete molecular and cellular mechanisms behind glial bridge formation in the central and peripheral nervous systems upon glial cell injury remains unclear. This review paper focuses on the molecular mechanisms and cellular processes that underlie spinal cord regeneration in four initial phases: proliferation and initial migration; migration and differentiation; glial bridge formation; and remodeling. We propose that within these four phases the cellular mechanisms that underlie spinal cord regeneration each express a terminating signal that aborts one step of the process and initiates the next. Specifically, future studies would be devoted to investigate transmitting signals in the spinal cord injury micro-environment in hope to contribute to the understanding of underlying cellular mechanisms by connecting each process of spinal cord regeneration in zebrafish.

To date, the patent foramen ovale (PFO) does not get the deserved medical attention. The PFO poses a serious threat to health and even life of mankind. The first respective case report in the medical literature dates back to the 19th century. It led to death. The fact that a PFO is present in roughly 25% of people underscores its overall potential to do harm. Yet at the same time by the sheer number, it discourages the medical community from screening for it and from treating it. About 5% of the population have particularly dangerous forms of PFOs. Such PFOs portray a high enough risk for clinical events, the likes of death, stroke, myocardial infarction, or ocular, visceral, and peripheral embolism, to justify screening for them. Highly significant health incidents being at stake, it appears obvious that PFO closure should be used for primary prevention. This is supported by the fact that closing a PFO is the simplest intervention in cardiology, with presumably the highest clinical yield. Being mainly a preventive measure, PFO closure represents a mechanical vaccination. When closing PFOs for one of the rarer therapeutic indications (migraine, platypnea orthodeoxia, etc.), patients automatically profit from the collateral benefit of getting at the same time mechanically vaccinated for life against paradoxical embolism. Vice versa, closing a PFO for prevention of paradoxical embolism not infrequently betters or cures migraine or exercise dyspnea, thereby improving quality of life as a collateral benefit.

KLEPTOSE® CRYSMEB is a methylated cyclodextrin derivative displaying less methylated group substitution than randomly methylated cyclodextrin. It has demonstrated an impact on atherosclerosis and neurological diseases. linked in part to cholesterol complexation and immune response, but the impact on inflammatory cascade pathways was not clear. Thus, the impact of KLEPTOSE® CRYSMEB on various pharmacological targets was assessed using human umbilical vein endothelial cells in physiological and inflammatory conditions, followed by screening against twelve human primary cell-based systems designed to model complex human tissue and disease biology of the vasculature, skin, lung, and inflammatory tissues using the BioMAP® Diversity PLUS® Panel. Finally, the anti-inflammatory mechanism was investigated on peripheral blood mononuclear cells to evaluate anti-inflammatory or pro-resolving properties. The results showed that KLEPTOSE® CRYSMEB can modulate the immune system in vitro and potentially manage vascular issues by stimulating the expression of molecules involved in the crosstalk between immune cells and other cell types. It showed anti-inflammatory effects driven by pro-inflammatory cytokine secretion inhibition and could have different impacts on different tissue types. Moreover, this cyclodextrin showed no clear impact on pro-resolving lipid mediators. Finally, it appeared that the mechanism of action of KLEPTOSE® CRYSMEB seems to not be shared by well-known anti-inflammatory molecules.

While Spinal Cord Stimulation (SCS) provides satisfaction to almost 2/3 of Persistent Spinal Pain Syndrome-Type 2 (PSPS-T2) patients implanted for refractory chronic back and/or leg pain when not adequately addressed the back pain component, leaves patients in a therapeutic cul-de-sac. Peripheral Nerve field Stimulation (PNfS) has shown interesting results addressing back pain in the same population. Far from placing these two techniques in opposition, we suggest that these approaches could be combined to better treat PSPS-T2 patients. We designed a RCT (CUMPNS), with a 12-month follow-up, to assess the potential added value of PNfS, as a salvage therapy, in PSPS-T2 patients experiencing a “Failed SCS Syndrome” in the back pain component. Fourteen patients were included in this study and randomized into 2 groups (“SCS + PNfS” group/n=6 vs “SCS only” group/n=8). The primary objective of the study was to compare the percentage of back pain surface decrease after 3 months, using a computerized interface to obtain quantitative pain mappings, combined with multi-dimensional SCS outcomes. Back pain surface decreased significantly greater for the ”SCS+PNfS” group (80.2% ± 21.3%) compared to the “SCS only” group (13.2% ± 94.8%) (p=0.012), highlighting the clinical interest of SCS+PNfS, in cases where SCS fails to address back pain.

Without protective and/or therapeutic agents the SARS-CoV-2 infection known as coronavirus disease 2019 (COVID-19) is quickly spreading worldwide. It has surprising transmissibility potential, since it could infect all ages, gender, and human sectors. It attacks respiratory, gastrointestinal, urinary, hepatic, and endovascular systems and can reach the peripheral nervous system (PNS) and central nervous system (CNS) through known and unknown mechanisms. The reports on the neurological manifestations and complications of the SARS-CoV-2 infection are increasing exponentially. Herein, we enumerate seven candidate routes, which the mature or immature SARS-CoV-2 components could use to reach the CNS and PNS, utilizing the within-body crosstalk between organs. The majority of SARS-CoV-2 infected patients suffer from some neurological manifestations (e.g., confusion, anosmia, and ageusia). It seems that although the mature virus did not reach the CNS or PNS of the majority of patients, its unassembled components and/or the accompanying immune-mediated responses may be responsible for the observed neurological symptoms. The viral particles and/or its components have been specifically documented in endothelial cells of lung, kidney, skin, and CNS. This means that the blood-endothelial-barrier may be considered as the main route for SARS-CoV-2 entry into the nervous system, with the barrier disruption being more logical than barrier permeability, as evidenced by postmortem analyses.