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The binding of SARS-CoV-2 spikes to the cell receptor angiotensin-converting enzyme 2 (ACE2) is a crucial target both in the prevention and in the therapy of COVID-19. We explored the involvement of oxidoreductive mechanisms by investigating the effects of oxidants and antioxidants on virus uptake by ACE2-expressing cells of human origin (ACE2-HEK293). The cell uptake of pseudoviruses carrying the envelope of either Delta or Omicron variants of SARS-CoV-2 was evaluated by means of a cytofluorimetric approach. The thiol N-acetyl-L-cysteine (NAC) inhibited the uptake of both variants in a reproducible and dose-dependent fashion. Ascorbic acid showed modest effects. In contrast, neither hydrogen peroxide (H2O2) nor a system-generating reactive oxygen species (ROS), which play an important role in the intracellular alterations produced by SARS-CoV-2, were able to affect the ability of either Delta or Omicron SARS-CoV-2 pseudoviruses to be internalized into ACE2-expressing cells. In addition, neither H2O2 nor the ROS generating system interfered with the ability of NAC to inhibit that mechanism. Moreover, based on previous studies, a preventive pharmacological approach with NAC would have the advantage of decreasing the risk of developing COVID-19, irrespective of its variants, and at the same time other respiratory viral infections and associated comorbidities.

IntroductionAdipose tissue mesenchymal stem/stromal cells (ASC) can be used as advanced therapy medicinal product in regenerative and cancer medicine. We previously demonstrated Supernatant Rich in Growth Factors (SRGF) can replace fetal bovine serum (FBS) to expand ASC by a clinical grade compliant protocol. The therapeutic potential of ASC is based also on their homing capacity toward inflammatory/cancer sites: oriented cell migration is a fundamental process in this scenario. We investigated the impact of SRGF on ASC migration properties.MethodsThe motility/migration potential of ASC expanded in 5% SRGF was analyzed, in comparison to 10% FBS, by standard wound healing, bidimensional chemotaxis and transwell assays, and by millifluidic transwell tests. Mechanisms involved in the migration process were investigated by transient protein overexpression.ResultsIn comparison to standard 10% FBS, supplementation of the cell culture medium with 5% SRGF, strongly increased migration properties of ASC along the chemotactic gradient and toward cancer cell derived soluble factors, both in static and millifluidic conditions. We showed that, independently from applied migratory stimulus, SRGF expanded ASC were characterized by far lower expression of α-smooth muscle actin (αSMA), a protein involved in the cell migration machinery. Overexpression of αSMA induced a significant and marked decrease in migration capacity of SRGF expanded ASC.DiscussionIn conclusion, 5% SRGF addition in the cell culture medium increases the migration potential of ASC, reasonably through appropriate downregulation of αSMA. Thus, SRGF could potentially improve the therapeutic impact of ASC, both as modulators of the immune microenviroment or as targeted drug delivery vehicles in oncology.

Iron is an essential metal ion implicated in several cellular processes. However, the reactive nature of iron renders this metal ion potentially dangerous for cells, and its levels need to be tightly controlled. Alterations in the intracellular concentration of iron are associated with different neuropathological conditions, including neurodegeneration with brain iron accumulation (NBIA). As the name suggests, NBIA encompasses a class of rare and still poorly investigated neurodegenerative disorders characterized by an abnormal accumulation of iron in the brain. NBIA is mostly a genetic pathology, and to date, 10 genes have been linked to familial forms of NBIA. In the present review, after the description of the principal mechanisms implicated in iron homeostasis, we summarize the research data concerning the pathological mechanisms underlying the genetic forms of NBIA and discuss the potential involvement of iron in such processes. The picture that emerges is that, while iron overload can contribute to the pathogenesis of NBIA, it does not seem to be the causal factor in most forms of the pathology. The onset of these pathologies is rather caused by a combination of processes involving the interplay between lipid metabolism, mitochondrial functions, and autophagic activity, eventually leading to iron dyshomeostasis.

The supraspinatus tendon is one of the most involved tendons in the development of shoulder pain. Extracorporeal shockwave therapy (ESWT) has been recognized as a valid and safe treatment. Sometimes the symptoms cannot be relieved, or a relapse develops, affecting the patient’s quality of life. Therefore, a prediction protocol could be a powerful tool aiding our clinical decisions. An artificial neural network was run, in particular a multilayer perceptron model incorporating input information such as the VAS and Constant–Murley score, administered at T0 and at T1 after six months. It showed a model sensitivity of 80.7%, and the area under the ROC curve was 0.701, which demonstrates good discrimination. The aim of our study was to identify predictive factors for minimal clinically successful therapy (MCST), defined as a reduction of ≥40% in VAS score at T1 following ESWT for chronic non-calcific supraspinatus tendinopathy (SNCCT). From the male gender, we expect greater and more frequent clinical success. The more severe the patient’s initial condition, the greater the possibility that clinical success will decrease. The Constant and Murley score, Roles and Maudsley score, and VAS are not just evaluation tools to verify an improvement; they are also prognostic factors to be taken into consideration in the assessment of achieving clinical success. Due to the lower clinical improvement observed in older patients and those with worse clinical and functional scales, it would be preferable to also provide these patients with the possibility of combined treatments. The ANN predictive model is reasonable and accurate in studying the influence of prognostic factors and achieving clinical success in patients with chronic non-calcific tendinopathy of the supraspinatus treated with ESWT.

Ultrasound-guided perineural hydrodissection (HD) is a novel technique that has been found to be effective in providing mechanical release of perineural adhesions and decompression of the nerve, reducing inflammation and edema and restoring its physiological function. It has a significant impact on chronic neuropathic pain (20 ± 4 weeks with VAS < 5 or VAS diminished by 2 points after the procedure). Carpal tunnel syndrome (CTS) is a common entrapment mononeuropathy, and its distribution is typically innervated by the median nerve. Patients with mild or moderate CTS may benefit from nonsurgical treatments or conservative therapies. This review was conducted following the preferred reporting items for systematic reviews and meta-analysis (PRISMA) statement guidelines. Four investigators assessed each title, abstract, and full-text article for eligibility, with disagreements being resolved by consensus with two experienced investigators. The qualitative assessment of the studies was carried out using the modified Oxford quality scoring system, also known as the modified Jadad score. Furthermore, risk of possible biases was assessed using the Cochrane collaboration tool. The results of this review suggest that US-guided HD is an innovative, effective, well-tolerated, and safe technique (11 out of 923 patients had collateral or side effects after the procedure). However, further studies comparing all drugs and with a larger sample population are required to determine the most effective substance.

BackgroundStroke is a main cause of disability worldwide and its neuro-rehabilitative management is not limited to the acute phase but requires continuity in the rehabilitation approach especially in the chronic phase. The aim of this scoping review was to highlight the different treatment opportunities available in neurorehabilitation, effective for patients with chronic stroke sequelae, not only in terms of maintaining motor function but also improving it.MethodsThe literature search was conducted using the following databases: MEDLINE (PubMed), PEDro, Scopus, Web of Science (WOS), Cochrane from 2012 to February 2023. We selected Randomized Clinical Trials in English dealing with neurorehabilitation strategies in chronic hemiplegic patients after stroke focusing on motor function, muscular strength, gait, postural balance, spasticity, and quality of life.ResultsAccording to the inclusion criteria, 47 articles were selected for our review. All of them were analyzed following the primary outcome and the rehabilitation technique used. Despite the different protocols used within the same technique and despite the chronicity of the disease, all studies report an improvement after the rehabilitation treatment of motor function and quality of life.ConclusionThe literature analyzed invites us to reflect respect to neurorehabilitation approach to the patient with chronic stroke sequelae often considered to have as its objective the maintenance of the present motor function and contain disability: instead, the review reports how, even in chronicity, the patient always reports margins of statistically and clinically significant improvement. The chronic stroke rehabilitation over 6 months has been proved effective in obtaining recovery in different settings.

Background and Objectives: Acute and chronic injuries are frequent in volleyball. Biomechanics of sport-specific tasks can influence the risk of injury, which is also related to specific court positions. We investigated posture at raster-stereography, balance, and dynamic tasks using inertial motion units to find differences between roles, which can be predictive of a higher risk of injury. Materials and Methods: We cross-sectionally evaluated amateur volleyball athletes. Participants were divided into roles as outside hitters, setters, middle blockers, and opposite hitters. We excluded the “libero” position from our analysis. Results: Sixteen players were included in the analysis. A statistically significant difference was found in left lower limb stiffness among the outside hitter and setter groups. Conclusions: Differences in stiffness might be related to the different training and the different abilities among the two groups. Raster-stereography is extending its indications and should be implemented for non-invasive postural analysis. The use of inertial motion units provides objective measurements of variables that could go unrecognized within a clinical evaluation; its use should be considered in injury preventive programs.

Rehabilitation after rotator cuff repair is crucial for functional recovery and for minimizing the risk of retear. There are two rehabilitation protocols (early and traditional) and the debate about which is the best is open. This umbrella review aimed to compare the effect of these rehabilitation protocols in terms of reduction in pain, functional recovery, and retear risk. We selected systematic reviews and meta-analyses published between 2012 and 2022 dealing with the aim. Nineteen systematic reviews were included. No significant differences were found between early and traditional protocols in terms of pain reduction. Early rehabilitation provided better short-term results regarding Range of Motion improvement, but long-term functional outcomes were similar. Retear risk remains a significant concern for the early protocol. We found major differences between the analyzed protocols. This review suggests that both protocols are useful to recover global shoulder function, but the standard protocol has a greater safety profile for larger tears. On the other hand, the early protocol may be preferable for smaller lesions, allowing a faster recovery and having less impact on medical costs. Further research is needed to identify optimal rehabilitation strategies tailored to the individual patient’s needs and characteristics.

Background: Knee osteoarthritis (KOA) is one of the most common causes of disability in elderly patients and tends to be a major burden on social and health care spending. Despite its severe socioeconomic impact, KOA remains, to date, an incurable disease. Due to its proper characteristics, KOA represents a favorable disease model for experimenting with senotherapeutics, a group of treatments that counteract the development of age-related disorders and chronic diseases. In recent years, the use of intra-articular hyaluronic acid (IAHA) in the treatment of diseases related to the wear and tear of the articular cartilage has been gaining popularity. Given its ability in joint lubrification, shock absorption, and cell signaling, our aim is to investigate, through the existing scientific literature, its potential role as a senomorphic agent, emphasizing its crucial function in KOA patients. Indeed, senomorphics are a particular group of senotherapeutics capable of modulating the functions and morphology of senescent cells to those of young cells or delaying the progression of young cells to senescent cells in tissues. Methods: A search in the scientific literature (PubMed, Cochrane Library, and Google Scholar) was carried out from 2019 to 2023, thus the last 5 years. Results: One hundred thirty-eight articles were found concerning the role of hyaluronic acid injections in KOA patients. In these studies, its therapeutic efficacy, its anti-inflammatory properties, and its low risk of side effects emerged. Conclusion: IAHA injections are a valuable treatment option for KOA while they can provide pain relief, improve joint function, and slow the progression of joint degeneration. The inhibitory effect of HA on MMP13 and its action as a senomorphic agent suggests that it may have additional benefits beyond its lubricating and shock-absorbing properties. In order to clarify its mechanisms of action and to optimize its clinical use, further studies are definitely needed.

The protein DJ-1 is mutated in rare familial forms of recessive Parkinson's disease and in parkinsonism accompanied by amyotrophic lateral sclerosis symptoms and dementia. DJ-1 is considered a multitasking protein able to confer protection under various conditions of stress. However, the precise cellular function still remains elusive. In the present work, we evaluated fruit flies lacking the expression of the DJ-1 homolog dj-1β as compared to control aged-matched individuals. Behavioral evaluations included lifespan, locomotion in an open field arena, sensitivity to oxidative insults, and resistance to starvation. Molecular analyses were carried out by analyzing the mitochondrial morphology and functionality, and the autophagic response. We demonstrated that dj-1β null mutant flies are hypoactive and display higher sensitivity to oxidative insults and food deprivation. Analysis of mitochondrial homeostasis revealed that loss of dj-1β leads to larger and more circular mitochondria, characterized by impaired complex-I-linked respiration while preserving ATP production capacity. Additionally, dj-1β null mutant flies present an impaired autophagic response, which is suppressed by treatment with the antioxidant molecule N-Acetyl-L-Cysteine. Overall, our data point to a mechanism whereby DJ-1 plays a critical role in the maintenance of energy homeostasis, by sustaining mitochondrial homeostasis and affecting the autophagic flux through the maintenance of the cellular redox state. In light of the involvement of DJ-1 in neurodegenerative diseases and considering that neurons are highly energy-demanding cells, particularly sensitive to redox stress, our study sheds light on a key role of DJ-1 in the maintenance of cellular homeostasis.

The surgical intervention rate and the subsequent rehabilitation plan for anterior cruciate ligament (ACL) injury was crucially affected by the COVID-19 pandemic due to the necessity in the face of the emergency. This review aimed to evaluate potential persistent and residual symptoms after COVID-19 disease, including fatigue and neuromuscular disorders. A scoping review design and methodology were used due to the exploratory nature of the research question, according to literature searches on PubMed/Medline, Scopus, Web of Science (WoS), and Physiotherapy Evidence Database (PEDro) electronic databases using the following keywords: “Anterior Cruciate Ligament”, “ACL”, “SARS-CoV-2”, and “COVID-19”. Undertraining and muscular knee imbalance might cause inefficient movement strategies, lack of knee stability, and increasing load with negative implications in ACL injuries. In the post-surgery period, during COVID-19, telerehabilitation approaches appeared to be successfully applied to maintain strength and range of motion in this condition. However, no definitive data are available regarding the most effective interventions. This scoping review showed the influence of the COVID-19 pandemic and associated restrictions on postoperative and rehabilitative care of ACL injuries.

Multiple myeloma (MM) is an aggressive malignancy that shapes, during its progression, a pro-tumor microenvironment characterized by altered protein secretion and the gene expression of mesenchymal stem cells (MSCs). In turn, MSCs from MM patients can exert an high pro-tumor activity and play a strong immunosuppressive role. Here, we show, for the first time, greater cell mobility paralleled by the activation of FilaminA (FLNA) in MM-derived MSCs, when compared to healthy donor (HD)-derived MSCs. Moreover, we suggest the possible involvement of the IRE1a-FLNA axis in the control of the MSC migration process. In this way, IRE1a can be considered as a good target candidate for MM therapy, considering its pro-survival, pro-osteoclast and chemoresistance role in the MM microenvironment. Our results suggest that IRE1a downregulation could also interfere with the response of MSCs to MM stimuli, possibly preventing cell–cell adhesion-mediated drug resistance. In addition, further investigations harnessing IRE1a-FLNA interaction could improve the homing efficiency of MSC as cell product for advanced therapy applications.

Oxygen reactive species (ROS) are a group of molecules generated from the incomplete reduction of oxygen. Due to their high reactivity, ROS can interact with and influence the function of multiple targets, which include DNA, lipids, and proteins. Among the proteins affected by ROS, AMP-activated protein kinase (AMPK) is considered a major sensor of the intracellular energetic status and a crucial hub involved in the regulation of key cellular processes, like autophagy and lysosomal function. Thanks to these features, AMPK has been recently demonstrated to be able to perceive signals related to the variation of mitochondrial dynamics and to transduce them to the lysosomes, influencing the autophagic flux. Since ROS production is largely dependent on mitochondrial activity, through the modulation of AMPK these molecules may represent important signaling agents which participate in the crosstalk between mitochondria and lysosomes, allowing the coordination of these organelles’ functions. In this review, we will describe the mechanisms through which ROS activate AMPK and the signaling pathways that allow this protein to affect the autophagic process. The picture that emerges from the literature is that AMPK regulation is highly tissue-specific and that different pools of AMPK can be localized at specific intracellular compartments, thus differentially responding to altered ROS levels. For this reason, future studies will be highly advisable to discriminate the specific contribution of the activation of different AMPK subpopulations to the autophagic pathway.

IntroductionThe aim of this randomized controlled trial was to evaluate the effect of an embodied rehabilitative protocol, in improving interoceptive awareness respect balance and motor performance in patients with mild multiple sclerosis (pwMS).MethodsIn this study patients with relapsing-remitting multiple sclerosis were enrolled. The rehabilitative treatment group (TG) participated in an embodied physiotherapy program consisting of 8 one-hour sessions in groups of 4 patients at a time, 1 per week and 2 one-hour sessions of neuro-cognitive exercise in single session during the rehabilitation program. All pwMS underwent a clinical assessment to measure the interoception sense for the Multidimensional Assessment of Interoceptive Awareness scale, balance for the Tinetti Mobility test and stabilometry, quality of life for the Short Form Health Survey-12 and body image perception for Trunk Appearance Perception Scale and Body Image Scale. All previous scales and tests were performed at baseline (T0), at the end of treatment (T1) and after 2 months of follow up (T2).ResultsSixty patients were enrolled and randomized into two groups: TG (n = 30), aged 43.0 ± 10.2 years, and a control/waiting list (WLG) group (n = 30), aged 40.7 ± 10.4 years. Statistically significant improvements in interoceptive awareness, body image perception, balance and quality of life were reported in TG versus WLG (p < 0.05).DiscussionThis study suggests that enhancing interoceptive awareness could improve postural balance. Future studies with a larger sample of patients will be needed to better quantify the effects of an embodied rehabilitation.

Fibromyalgia (FM) syndrome is characterized by the close correlation of chronic widespread pain and other non-pain related symptoms. Aim of this study was to investigate whether telerehabilitation that provides physical and psychological support services of the mind-body techniques can affect the clinical profile and pain relief of FM patients. The study included twenty-eight female FM patients, mean aged 56.61 ± 8.56 years. All patients underwent a rehabilitation treatment (8 sessions, 1/week, 1 h/each) through Zoom platform, with the following principles of rehabilitation treatment: Anchoring to a positive emotion; listen and perceive your “own” body; conscious breathing; improve interoceptive awareness; relax. All patients then underwent clinical assessment of the physical distress and fear of movement for the Numeric Rating Scale (NRS); the Fatigue Assessment Scale (FAS); the Fear Avoidance Belief Questionnaire (FABQ); with measures of physical and mental disability for the Fibromyalgia Impact Questionnaire (FIQ); the 12-Items Short Form Survey; the Resilience Scale for Adults and the Coping Strategies Questionnaire-Revised. The evaluations were performed at T0 (baseline), T1 (after 8 weeks of treatment), and T2 (after 1 month of follow-up). The main finding was that telerehabilitation reduced physical and mental distress, fear, and disability (p < 0.001). Resilience and coping ability were less affected by the rehabilitative treatment. Our attempt of mind-body technique telerehabilitation has shown good results in the improvement of painful symptoms and quality of life for the FM patients but showed fewer positive impacts for the resilience and coping abilities aspects.

Background: Magnetic Resonance Imaging (MRI) and Ultrasound (US) in combination with clinical data could contribute to the diagnosis, staging and follow-up of Patello-Femoral Syndrome (PFS), which often overlaps with other pathologies of the knee. Purpose of the Study: To evaluate the diagnostic role of MRI and US findings associated with PFS and define the range values of instrumental measurements obtained in pathological cases and healthy controls, the performance of the two methods in comparison, and the correlation with clinical data. Materials and Methods: 100 subjects were examined: 60 patients with a high suspicion of PFS at the clinical evaluation and 40 healthy controls. All measurements obtained by MRI and US examination were correlated with clinical data. A descriptive analysis of all measurements was stratified for pathological cases and healthy controls. A Student’s t-test for continuous variables was used to compare patients to controls and US to MRI. Logistic regression analysis was applied to test the correlation between MRI and US measurements with clinical data. Results: Statistical descriptive analysis determined the MRI and US range values of medial patello-femoral distance and the thickness of retinacles and cartilages in pathological cases and healthy controls. In pathological cases, the retinacle results of both increased; the medial appeared to be slightly more increased than the lateral. Furthermore, in some cases, the thickness of the cartilage decreased in both techniques; the medial cartilage was more thinned than the lateral. According to logistic regression analyses, the best diagnostic parameter was the medial patello-femoral distance due to the overlapping results of the US and MRI. Furthermore, all clinical data obtained by different tests showed a good correlation with patello-femoral distance. In particular, the correlation between medial patello-femoral distance and the VAS score is direct and equal to 97–99%, which is statistically significant (p < 0.001), and the correlation with the KOOS score is inverse and equal to 96–98%, which is statistically significant. Conclusions: MRI and Ultrasound examination in combination with clinical data demonstrated high-value results in the diagnosis of PFS.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by the preferential loss of dopaminergic neurons and by the accumulation of intracellular inclusions mainly composed of α-synuclein (α-Syn). While the etiopathogenesis of the disorder is still elusive, recent experimental evidence supports the involvement of ferroptosis, an iron-dependent cell death pathway, in the pathogenesis of PD. In the present work, using different ferroptosis inducers and inhibitors, we evaluated, in vivo, the involvement of iron in the α-Syn-mediated toxicity. Using a Drosophila melanogaster model of PD based on the selective over-expression of α-Syn within dopaminergic neurons, we demonstrated that the over-expression of α-Syn promotes the accumulation of protein aggregates, which is accompanied by dopaminergic neurodegeneration, locomotor impairment, and lifespan reduction. These pathological phenotypes were further exacerbated by reduced intracellular levels of glutathione or increased concentrations of iron. Coherently, both the use of an iron chelator and the presence of the antioxidant compound N-acetylcysteine exerted protective effects. Overall, our results support the involvement of ferroptosis in the α-Syn-mediated toxicity.

In Chronic Obstructive Pulmonary Disease (COPD), hypoxemia is associated with multiple underlying mechanisms, of which one of the most significant is ventilation-perfusion (V/Q) mismatch, which is correctable with supplemental oxygen (O2) therapy. Hypoxemia that is refractory to very high concentration of inspired O2 can be indicative of cardiac defect with shunt, e.g., a patent foramen ovale (PFO) with right-to-left (R-T-L) shunt. In hypoxemic COPD patients, the diagnosis of a PFO requires a heightened sense of clinical suspicion along with careful assessment of other underlying possibilities. Platypnea-orthodeoxia and a non-response to the hyperoxia test, while not diagnostic, increase suspicion. A correct diagnosis of interatrial bypass needs to be confirmed with transthoracic echocardiogram and contrast transesophageal echocardiography. Presently, no data are available supporting the effectiveness of PFO closure in COPD patients to relieve symptoms and correct hypoxemia.We report a case of hypoxemic COPD with platypnea-orthodeoxia syndrome due to PFO. The decision of its closure with device after echocardiographic evaluation of right ventricular function has completely corrected refractory hypoxemia with improvement of SpO2 and functional capacity. Thus, in selected COPD with refractory hypoxemia, closure of PFO should be considered as novel therapeutic target with improvement of quality of life and less likelihood of hospitalization.

Knee osteoarthritis is one of the leading causes of chronic disability worldwide and is a significant social and economic burden on healthcare systems; hence it has become essential to develop methods to identify patients at risk for developing knee osteoarthritis at an early stage. Standard morphological MRI sequences are focused mostly on alterations seen in advanced stages of osteoarthritis. However, they possess low sensitivity for early, subtle, and potentially reversible changes of the degenerative process. In this review, we have summarized the state of the art with regard to innovative quantitative MRI techniques that exploit objective and quantifiable biomarkers to identify subtle alterations that occur in early stages of osteoarthritis in knee cartilage before any morphological alteration occurs and to capture potential effects on the brain. These novel MRI imaging tools are believed to have great potential for improving the current standard of care, but further research is needed to address limitations before these compositional techniques can be robustly applied in research and clinical settings.

Redox homeostasis is a vital process the maintenance of which is assured by the presence of numerous antioxidant small molecules and enzymes and the alteration of which is involved in many pathologies, including several neurodegenerative disorders. Among the different enzymes involved in the antioxidant response, SOD1 and DJ-1 have both been associated with the pathogenesis of amyotrophic lateral sclerosis and Parkinson’s disease, suggesting a possible interplay in their mechanism of action. Copper deficiency in the SOD1-active site has been proposed as a central determinant in SOD1-related neurodegeneration. SOD1 maturation mainly relies on the presence of the protein copper chaperone for SOD1 (CCS), but a CCS-independent alternative pathway also exists and functions under anaerobic conditions. To explore the possible involvement of DJ-1 in such a pathway in vivo, we exposed Drosophila melanogaster to anoxia and evaluated the effect of DJ-1 on fly survival and SOD1 levels, in the presence or absence of CCS. Loss of DJ-1 negatively affects the fly response to the anoxic treatment, but our data indicate that the protective activity of DJ-1 is independent of SOD1 in Drosophila, indicating that the two proteins may act in different pathways.

The post-COVID-19 syndrome may affect patients after the COVID-19 post-acute phase. In particular, the 69% of patients reported persistent fatigue at the discharge. To date, no clear data are available regarding the most effective rehabilitative approaches for the treatment of this condition. Thus, this systematic review aimed to evaluate the rehabilitation treatment’s efficacy on fatigue in post-COVID-19 patients. We systematically searched PubMed, Scopus, and Web of Science databases to find longitudinal study designs presenting: post-COVID-19 patients as participants; a rehabilitative approach aimed to reduce post-COVID-19 syndrome as intervention; and fatigue intensity assessed through an evaluation tool that quantified the perceived exertion (i.e., fatigue severity scale, FSS; Borg Scale (BS); Borg Category Ratio 10, CR10; Checklist Individual Strength (CIS) fatigue scale; FACIT (Functional Assessment of Chronic Illness Therapy) fatigue scale). The present systematic review protocol was registered on PROSPERO (registration number CRD42021284058). Out of 704 articles, 6 studies were included. Nearly all patients showed COVID-19-related fatigue, and after the rehabilitation treatment, only 17% of subjects reported the persistency of symptoms. The overall effect size reported a −1.40 decrease in Borg Category Ratio 10 with a SE of 0.05 and a 95% CI between −1.50 and −1.30 (p < 0.001). The present systematic review and meta-analysis underlines the rehabilitation role in the fatigue reduction in patients affected by post-COVID-19 syndrome.

Background: Cervical spine manipulations (CSM) have been performed for centuries and are a widely practiced intervention to manage cervical spine musculoskeletal disorders. We aimed to perform an overview of the literature concerning the effects and the adverse events of CSM in the Physical and Rehabilitation Medicine (PRM) field with a forensic medicine perspective. Methods: A search in the scientific literature (PubMed, Google Scholar, PEDro and Cochrane) was carried out from inception until October 2020. Results: Fourteen articles were included in this narrative summary. The possible development of side effects requires a careful mandatory balance of benefits and risks even when there is an indication for this approach. Moreover, a qualified professional is essential to perform CSM–a non-invasive therapeutic procedure that can be potentially harmful. Conclusions: In conclusion, it is essential to perform the diagnosis, to treat, and to manage complications within the PRM field, both for the reduction of malpractice claims and, most importantly, for the safety of the patient.

(1) Background: Plantar fasciitis (PF) is the most common cause of heel pain in adults. Extracorporeal shockwave therapy (ESWT) is a minimally invasive treatments commonly used for treating PF. Our aim is to provide a complete overview of which treatments have been compared to ESWT, with a focus on the modalities that have been used. (2) Methods: A thorough search of the literature was performed on Medline via Pubmed, Cochrane Database of Systematic Reviews (CDSR) of the Cochrane Library and Physiotherapy Evidence Databases (PEDro) up to 18 November 2021. In the study were included only systematic reviews and meta-analysis in English language, published from 2010 to date. (3) Results: A total of 14 systematic reviews and meta-analysis were included in the umbrella review. A total of eight studies compared the efficacy of ESWT treatment with placebo, three studies compared ESWT with another therapy (two studies compared ESWT and corticosteroids, one study ESWT and ultrasound therapy), and three studies had more than one comparison. (4) Conclusions: When compared to placebo, ESWT demonstrated to be effective. More randomized trials with specific comparisons between different types and intensity of SW are needed to obtain more precise information on SW effectiveness.

There is a lack of data on patient and diagnostic factors for prognostication of complete recovery in patients with peripheral facial palsy. Thus, the aim of this study was to evaluate the role of a telerehabilitave enhancement through the description of a case report with the use of short-wave diathermy and neuromuscular electrical stimulation combined to facial proprioceptive neuromuscular facilitation (PNF) rehabilitation in unrecovered facial palsy, in a COVID-19 pandemic scenario describing a paradigmatic telerehabilitation report. A 43-year-old woman underwent a facial rehabilitation plan consisting of a synergistic treatment with facial PNF rehabilitation, short-wave diathermy, and neuromuscular electrical stimulation (12 sessions lasting 45 min, three sessions/week for 4 weeks). Concerning the surface electromyography evaluation of frontal and orbicularis oris muscles, the calculated ratio between amplitude of the palsy side and normal side showed an improvement in terms of movement symmetry. At the end of the outpatient treatment, a daily telerehabilitation protocol with video and teleconsultation was provided, showing a further improvement in the functioning of a woman suffering from unresolved facial paralysis. Therefore, an adequate telerehabilitation follow-up seems to play a fundamental role in the management of patients with facial palsy.

Radiofrequency (RF) is a minimally invasive procedure used to interrupt or alter nociceptive pathways for treating musculoskeletal pain. It seems a useful tool to relieve chronic pain syndromes, even if, to date, solid evidence is still needed about the effectiveness of this therapy. By this systematic review and meta-analysis, we aimed to evaluate the efficacy of RF in treating musculoskeletal pain. PubMed, Medline, Cochrane, and PEDro databases were searched to identify randomized controlled trials (RCTs) presenting the following: patients with chronic musculoskeletal pain as participants; RF as intervention; placebo, anesthetic injection, corticosteroid injection, prolotherapy, conservative treatment, physiotherapy, and transcutaneous electrical nerve stimulation as comparisons; and pain and functioning as outcomes. Continuous random-effect models with standardized mean difference (SMD) were used to compare the clinical outcomes. Overall, 26 RCTs were eligible and included in the systematic review. All of them analyzed the efficacy of RF in four different regions: cervical and lumbar spine, knee, sacroiliac (SI) joint, shoulder. The outcomes measures were pain, disability, and quality of life. A medium and large effect in favor of the RF treatment group (SMD < 0) was found for the shoulder according to the Visual Analogical Scale and for the SI joint according to the Oswestry Disability Index. A small effect in favor of the RF treatment group (SMD > 0) was found for the spine according to the 36-item Short Form Survey. Non-significant SMD was found for the other outcomes. RF represents a promising therapy for the treatment of chronic musculoskeletal pain, especially when other approaches are ineffective or not practicable. Further studies are warranted to better deepen the effectiveness of RF for pain and joint function for each anatomical region of common application.

In this data article, we present a dataset made up of personal, social and clinical records related to patients undergoing a rehabilitation program. Data refers to records registered in the “Acceptance/Discharge Report for the rehabilitation area” (ADR) which implements the Italian law (DGR 731/2005) and refer to hospitalization at the rehabilitation hospital of Rome “San Raffaele” in the years from 2015 to 2018 of patients suffering from orthopedic and neurological pathologies. For each ADR report, the clinical status of the patient at the date of acceptance and discharge is reported using, among other, the Barthel index as a measure of the Activities Daily Living of the patient.These data can be used to understand the influence of many different factors in the rehabilitation progress of clinical patients.

Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow. Despite novel therapies, MM still remains an incurable cancer and new strategies are needed. Increased expression of the transcription factor Sex-determining region Y-related high-mobility-group box transcription factor 4 (SOX4) has been correlated with tumor development and progression through a variety of distinct processes, including inhibition of apoptosis, increased cell invasion and metastasis, and induction and maintenance of cancer-initiating cells. The role of SOX4 in MM is largely unknown. Since SOX4 is a known target of miR-335, we used miR-335 to assess whether SOX4 modulation could promote apoptosis in MM cells. Using an MM cell model we show that miR-335 acts both on SOX4-related genes (AKT, PI3K) and hypoxia-inducible factor 1-alpha (Hif1-α). In addition, we show miR-335-laden extracellular vesicles induced in B cells (iEVs) are also effective in targeting SOX4, causing apoptosis. Collectively, we propose that miR-335-laden iEVs could be developed as a novel form of gene therapy in MM.

Background & aims: Arachidonic (AA) and eicosapentaenoic (EPA) polyunsaturated fatty acids can play respectively a pro- and an anti-inflammatory role. We hypothesized that, at the end of 5-week experimental bed rest, baseline AA/EPA in red blood cells (RBC) membranes, considered the result of dietary fat intake over the previous month, could influence lean body mass wasting in twenty-six healthy volunteers (age: 23.5 ± 0.5 years; body mass index: 22.9 ± 0.5 kg/m2). Methods: We measured AA and EPA content in RBC membranes at baseline ambulatory conditions and at the end of the study protocol, to verify the PUFA concentrations stability. We assessed changes, between beginning and end of bed, in lean body mass (bioimpedance), insulin resistance (homeostasis model assessment), systemic inflammation (C-reactive protein) and oxidative stress (thiobarbituric acid reactive substances). Volunteers were divided in two groups according to the AA/EPA ratio median value (i.e. AA/EPA = 44): High AA/EPA group (60 ± 3; n = 13) and Low AA/EPA group (37 ± 1; n = 13). Results: At baseline, all analyzed anthropometrical and biochemical indices were similar in the two groups. Bed rest induced a major decrease in lean body mass in High AA/EPA group (−5.2 ± 0.5%), when compared to Low AA/EPA group (−3.7 ± 0.5%; p = 0.03; ANOVA). Bed rest mediated-changes of insulin resistance, fat mass, systemic inflammation and oxidative stress, failed to show significant interaction with baseline AA/EPA (ANOVA). In pooled data, baseline AA/EPA ratio and percent lean body mass delta changes showed a significant inverse correlation (n = 26; R = −0.50; p

Abstract Background Standardized animal-free components are required for manufacturing cell-based medicinal products. Human platelet concentrates are sources of growth factors for cell expansion but such products are characterized by undesired variability. Pooling together single-donor products improves consistency, but the minimal pool sample size was never determined. Methods Supernatant rich in growth factors (SRGF) derived from n = 44 single-donor platelet-apheresis was obtained by CaCl2 addition. n = 10 growth factor concentrations were measured. The data matrix was analyzed by a novel statistical algorithm programmed to create 500 groups of random data from single-donor SRGF and to repeat this task increasing group statistical sample size from n = 2 to n = 20. Thereafter, in created groups (n = 9500), the software calculated means for each growth factor and, matching groups with the same sample size, the software retrieved the percent coefficient of variation (CV) between calculated means. A 20% CV was defined as threshold. For validation, we assessed the CV of concentrations measured in n = 10 pools manufactured according to algorithm results. Finally, we compared growth rate and differentiation potential of adipose-derived stromal/stem cells (ASC) expanded by separate SRGF pools. Results Growth factor concentrations in single-donor SRGF were characterized by high variability (mean (pg/ml)–CV); VEGF: 950–81.4; FGF-b: 27–74.6; PDGF-AA: 7883–28.8; PDGF-AB: 107834–32.5; PDGF-BB: 11142–48.4; Endostatin: 305034–16.2; Angiostatin: 197284–32.9; TGF-β1: 68382–53.7; IGF-I: 70876–38.3; EGF: 2411–30.2). In silico performed analysis suggested that pooling n = 16 single-donor SRGF reduced CV below 20%. Concentrations measured in 10 pools of n = 16 single SRGF were not different from mean values measured in single SRGF, but the CV was reduced to or below the threshold. Separate SRGF pools failed to differently affect ASC growth rate (slope pool A = 0.6; R2 = 0.99; slope pool B = 0.7; R2 0.99) or differentiation potential. Discussion Results deriving from our algorithm and from validation utilizing real SRGF pools demonstrated that pooling n = 16 single-donor SRGF products can ameliorate variability of final growth factor concentrations. Different pools of n = 16 single donor SRGF displayed consitent capability to modulate growth and differentiation potential of expanded ASC. Increasing the pool size should not further improve product composition.

Abstract Background The use of fetal bovine serum (FBS) as a media supplement for the ex vivo expansion of bone-marrow derived mesenchymal stromal cells (BM-MSC) has been discouraged by regulatory agencies, due to the risk of transmitting zoonoses and to elicit immune reactions in the host once transplanted. Platelet derivatives are valid FBS substitutes due to their content of growth factors that can be released disrupting the platelets by physical methods or physiological stimuli. We compared platelet derivatives produced by freezing/thawing (platelet lysates, PL) or after CaCl2 activation (platelet releasate surnatant rich in growth factors, PR-SRGF) for their content in growth factors and their ability to support the ex vivo expansion of BM-MSC. Methods The cytokine content in the two platelet derivatives was evaluated. BM-MSC were expanded in complete medium containing 10, 7.5 and 5% PL or PR-SRGF and the cell phenotype, clonogenic capacity, immunomodulation properties and tri-lineage differentiation potential of the expanded cells in both media were investigated. Results The concentration of PDGF-AB, PDGF-AA, PDGF-BB in PR-SRGF resulted to be respectively 5.7×, 1.7× and 2.3× higher compared to PL. PR-SRGF promoted a higher BM-MSC proliferation rate compared to PL not altering BM-MSC phenotype. Colony forming efficiency of BM-MSC expanded in PR-SRGF showed a frequency of colonies significantly higher than cells expanded in PL. BM-MSC expanded in PL or PR-SRGF maintained their immunomodulatory properties against activated lymphocytes even if BM-MSC expanded in FBS performed significantly better. Conclusions The method used to release platelet factors significantly affects the enrichment in growth factors and overall product performance. The standardization of the production process of platelet derivatives and the definition of their release criteria requires further investigation.

Background: Neuropathic pain is an injury or disease of the central and/or peripheral somatosensory nervous system, and it has a significant impact on quality of life, especially since it is often refractory to treatment. Rehabilitative intervention is considered in various guidelines on neuropathic pain treatment, although not in an organic nor detailed way. The aim of this systematic review was to analyze the most indicated therapeutic strategies, providing rehabilitative recommendations in the management of neuropathic pain. Methods: A systematic review was performed according to PRISMA guidelines. The scientific search, carried out until July 2020, considered guidelines in English language of the last thirteen years. Results: Six guidelines were analyzed, from which emerges that a multidisciplinary approach, comprehensive of pharmacologic and nonpharmacologic interventions, should drive neuropathic pain management. A relevant role in non-pharmacological intervention is played by rehabilitation, through an adequate tailored rehabilitation program and physical therapies. Conclusion: This analysis highlights the importance of rehabilitation but also the lack of evidence on various rehabilitative practices. Arises hence the need for further studies in this field to better define a rehabilitative treatment strategy.

INTRODUCTION:Ex vivo cell expansion under Good Manufacturing Practice (GMP) guidelines can be performed using medium additives containing human growth factors from platelets. These products can differently affect proliferation of adipose mesenchymal stromal stem cells (ASC). Qualification of medium additive performance is required for validation under GMP regulations: assessment of growth factor concentrations is not sufficient to predict the biological activity of the product batch. Proton nuclear magnetic resonance spectrometry (1H-NMR) and matrix-assisted laser desorption/ionization time of flight mass spectroscopy (MALDI-TOF MS) provide wide molecular characterization of samples. AIMS:We aimed to assess if 1H-NMR and MALDI-TOF MS techniques can be used as quality control test potentially predicting the impact of a medium additive on cell proliferation. METHODS:We tested the impact on ASC growth rate (cell proliferation assessment and cell morphology analysis) of four medium additives, obtained by different methods from human platelet apheresis product. In order to classify each medium additive, we evaluated growth factor concentrations and spectra obtained by 1H-NMR and by MALDI-TOF MS. RESULTS:Medium additive obtained by CaCl2 activation of platelet rich products induced higher proliferation rate vs additive derived from platelet depleted ones. Additives obtained by freeze-and-thaw methods weakly induced ASC proliferation. As expected, principal component analysis of growth factor concentrations did not unravel specific biochemical features characterizing medium additives in relation with their biological activity. Otherwise, while 1H-NMR showed a partial resolution capacity, analysis of MALDI-TOF MS spectra allowed unambiguous distinction between the medium additives we used to differently stimulate cell growth in vitro. DISCUSSION:MALDI-TOF and, despite limitations, 1H-NMR are promising cost effective and reliable quality controls to classify the potential of a medium additive to promote ASC growth. This can represent, after further investigations and appropriate validation, a significant advantage for GMP compliant manufacturing of advanced cell therapy products.