Gold Nanorod-Loaded Nano-Contrast Agent with Composite Shell-Core Structure for Ultrasonic/Photothermal Imaging-Guided Therapy in Ischemic Muscle Disorders.

Purpose: This study aims to broaden the application of nano-contrast agents (NCAs) within the realm of the musculoskeletal system. It aims to introduce novel methods, strategies, and insights for the clinical management of ischemic muscle disorders, encompassing diagnosis, monitoring, evaluation, and therapeutic intervention. Methods: We developed a composite encapsulation technique employing O-carboxymethyl chitosan (OCMC) and liposome to encapsulate NCA-containing gold nanorods (GNRs) and perfluoropentane (PFP). This nanoscale contrast agent was thoroughly characterized for its basic physicochemical properties and performance. Its capabilities for in vivo and in vitro ultrasound imaging and photothermal imaging were authenticated, alongside a comprehensive biocompatibility assessment to ascertain its effects on microcirculatory perfusion in skeletal muscle using a murine model of hindlimb ischemia, and its potential to augment blood flow and facilitate recovery. Results: The engineered GNR@OCMC-liposome/PFP nanostructure exhibited an average size of 203.18±1.49 nm, characterized by size uniformity, regular morphology, and a good biocompatibility profile. In vitro assessments revealed NCA's potent photothermal response and its transformation into microbubbles (MBs) under near-infrared (NIR) irradiation, thereby enhancing ultrasonographic visibility. Animal studies demonstrated the nanostructure's efficacy in photothermal imaging at ischemic loci in mouse hindlimbs, where NIR irradiation induced rapid temperature increases and significantly increased blood circulation. Conclusion: The dual-modal ultrasound/photothermal NCA, encapsulating GNR and PFP within a composite shell-core architecture, was synthesized successfully. It demonstrated exceptional stability, biocompatibility, and phase transition efficiency. Importantly, it facilitates the encapsulation of PFP, enabling both enhanced ultrasound imaging and photothermal imaging following NIR light exposure. This advancement provides a critical step towards the integrated diagnosis and treatment of ischemic muscle diseases, signifying a pivotal development in nanomedicine for musculoskeletal therapeutics.

[Sarcoid Peripheral Neuropathy and Myopathy: A Diagnostic and Therapeutic Challenge].

Sarcoidosis is an idiopathic granulomatous multi-organ disease, primarily affecting the respiratory system, eyes, and skin, with less involvement in peripheral neurons and muscles. Sarcoid peripheral neuropathy encompasses cranial and spinal nerve impairment. Muscle involvement is often asymptomatic and revealed through imaging. Symptomatic muscle involvement is categorized into three clinical types: nodular myopathy, acute myopathy, and chronic myopathy. The identification of noncaseating granulomas in peripheral nerves or muscles, coupled with the exclusion of other diseases, is essential for establishing a definitive diagnosis of sarcoid peripheral neuropathy and myopathy. Sarcoid neuropathy and myopathy are typically managed with high-dose corticosteroids, immunosuppressants, or a combination of both. In recent times, the use of TNF-alpha inhibitors has notably increased. However, these conditions often exhibit resistance to treatment and may necessitate prolonged therapeutic interventions. Therefore, comprehensive examinations should be conducted before considering immunotherapy. Due to the rarity of these conditions, research on manifestation-specific treatments is lacking, and standard treatments for sarcoid neuropathy and myopathy have not been established. Additional treatment options for sarcoid neuropathy and myopathy are expected to become available in the future.

[Peripheral Nerve and Muscle Disorders Associated with Sjögren's Syndrome].

Sjögren's syndrome is often accompanied by various neurological complications, among which peripheral neuropathy is the most common. A variety of clinical phenotypes of peripheral neuropathy, including axonal polyneuropathy and sensory ataxic neuropathy are reported in the literature. We present an overview of the pathophysiology and differential diagnosis of each phenotype. Immunotherapy using corticosteroids and high-dose intravenous immunoglobulin therapy tends to elicit varied therapeutic responses depending on the peripheral neuropathy phenotype. We also discuss myositis, a possible complication of Sjögren's syndrome.

Immune-Mediated Necrotizing Myopathies: Current Landscape.

PURPOSE OF REVIEW: Immune-mediated necrotizing myopathy (IMNM), characterized by acute or subacute onset, severe weakness, and elevated creatine kinase levels, poses diagnostic and therapeutic challenges. This article provides a succinct overview of IMNM, including clinical features, diagnostic strategies, and treatment approaches. RECENT FINDINGS: Recent insights highlight the different clinical presentations and therapeutic options of IMNM stratified by autoantibody positivity and type. Additionally, recent findings call into question the reported link between statin use and IMNM. This review synthesizes current knowledge on IMNM, emphasizing its distinct clinical features and challenging management. The evolving understanding of IMNM underscores the need for a comprehensive diagnostic approach that utilizes a growing range of modalities. Early and aggressive immunomodulatory therapy remains pivotal. Ongoing research aims to refine diagnostic tools and therapeutic interventions for this challenging muscle disorder, underscoring the importance of advancing our understanding to enhance patient outcomes.

ER stress and ERO1: Potential therapeutic targets for inherited myopathies.

Selenoprotein N-related myopathy (SEPN1-RM) is a genetic disease that causes muscle weakness and respiratory failure. Germani et al.1 demonstrate that diaphragm weakness in SEPN1-RM is prevented by the inhibition of ER stress or ERO1 oxidoreductase regulated by transcription factor CHOP.

Glucocorticoid-Induced Myopathy: Typology, Pathogenesis, Diagnosis, and Treatment.

Glucocorticoid-induced myopathy is a non-inflammatory toxic myopathy typified by proximal muscle weakness, muscle atrophy, fatigue, and easy fatigability. These vague symptoms coupled with underlying disorders may mask the signs of glucocorticoid-induced myopathy, leading to an underestimation of the disease's impact. This review briefly summarizes the classification, pathogenesis, and treatment options for glucocorticoid-induced muscle wasting. Additionally, we discuss current diagnostic measures in clinical research and routine care used for diagnosing and monitoring glucocorticoid-induced myopathy, which includes gait speed tests, muscle strength tests, hematologic tests, bioelectrical impedance analysis (BIA), dual-energy X-ray absorptiometry (DXA), computed tomography (CT), magnetic resonance imaging (MRI), electromyography, quantitative muscle ultrasound, histological examination, and genetic analysis. Continuous monitoring of patients receiving glucocorticoid therapy plays an important role in enabling early detection of glucocorticoid-induced myopathy, allowing physicians to modify treatment plans before significant clinical weakness arises.

Single-cell analysis of refractory anti-SRP necrotizing myopathy treated with anti-BCMA CAR-T cell therapy.

Immune-mediated necrotizing myopathy (IMNM) is an autoimmune disorder associated with the presence of autoantibodies, characterized by severe clinical presentation with rapidly progressive muscular weakness and elevated levels of creatine kinase, while traditional pharmacological approaches possess varying and often limited effects. Considering the pathogenic role of autoantibodies, chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA) have emerged as a promising therapeutic strategy. We reported here a patient with anti-signal recognition particle IMNM refractory to multiple available therapies, who was treated with BCMA-targeting CAR-T cells, exhibited favorable safety profiles, sustained reduction in pathogenic autoantibodies, and persistent clinical improvements over 18 mo. Longitudinal single-cell RNA, B cell receptor, T cell receptor sequencing analysis presented the normalization of immune microenvironment after CAR-T cell infusion, including reconstitution of B cell lineages, replacement of T cell subclusters, and suppression of overactivated immune cells. Analysis on characteristics of CAR-T cells in IMNM demonstrated a more active expansion of CD8+ CAR-T cells, with a dynamic phenotype shifting pattern similar in CD4+ and CD8+ CAR-T cells. A comparison of CD8+ CAR-T cells in patients with IMNM and those with malignancies collected at different timepoints revealed a more NK-like phenotype with enhanced tendency of cell death and neuroinflammation and inhibited proliferating ability of CD8+ CAR-T cells in IMNM while neuroinflammation might be the distinct characteristics. Further studies are warranted to define the molecular features of CAR-T cells in autoimmunity and to seek higher efficiency and longer persistence of CAR-T cells in treating autoimmune disorders.

Hospital admissions from the emergency department of adult patients affected by myopathies.

BACKGROUND AND PURPOSE: Myopathies are associated with classic signs and symptoms, but also with possible life-threatening complications that may require assistance in an emergency setting. This phenomenon is understudied in the literature. We aimed to assess the presentation, management, and outcomes of clinical manifestations potentially related to a muscle disorder requiring referral to the adult emergency department (ED) and hospitalization. METHODS: Anonymized patient data retrieved using the International Classification of Diseases, Ninth Revision codes related to muscle disorders over 4 years were retrospectively analyzed. Medical reports were evaluated to extract demographic and clinical variables, along with outcomes. Two groups were defined based on the presence (known diagnosis [KD] group) or absence (unknown diagnosis [UD] group) of a diagnosed muscle disorder at arrival. RESULTS: A total of 244 patients were included, 51% of whom were affected by a known myopathy, predominantly limb-girdle muscular dystrophies and myotonic dystrophies. The main reasons for ED visits in the KD group were respiratory issues, worsening of muscle weakness, and gastrointestinal problems. Heart complications were less prevalent. In the UD group, 27 patients received a new diagnosis of a specific primary muscle disorder after the ED access, mostly an inflammatory myopathy. Death during hospitalization was recorded in 26 patients, with a higher rate in the KD group and in patients affected by mitochondrial and inflammatory myopathies. Sepsis and dyspnea were associated with increased death risk. CONCLUSIONS: Respiratory complications are the most common reason for myopathic patients accessing the ED, followed by gastrointestinal issues. Infections are severe threats and, once hospitalized, these patients have relatively high mortality.

Myopathies of endocrine origin: A review for physicians.

Myopathies are a common manifestation of endocrine disorders. Endocrine myopathies are often overlooked while considering differential diagnoses in patients with musculoskeletal symptoms. The hindrance to mobility and the musculoskeletal discomfort owing to these myopathies are important causes of disability and depreciated quality of life in these patients. Endocrine myopathies occur due to the effects of endogenous or iatrogenic hormonal imbalance on skeletal muscle protein and glucose metabolism, disrupting the excitation-contraction coupling. Abnormalities of the pituitary, thyroid, parathyroid, adrenal, and gonadal hormones have all been associated with myopathies and musculoskeletal symptoms. Endocrine myopathies can either be the complication of a secondary endocrine disorder or a presenting symptom of a missed underlying disorder. Therefore, an underlying endocrine abnormality must always be excluded in all patients with musculoskeletal symptoms. This review presents a compilation of various endocrine myopathies, their etiopathogenesis, clinical presentation, diagnostic modalities, and treatment protocols.

Femoral nerve palsy as a complication due to COVID-19 coagulopathy and iliopsoas muscle hematoma - case report.

BACKGROUND: COVID-19 (Coronavirus disease 2019) pandemic is the main medical problem around the world from the end of 2019. We found until now many symptoms of this disease, but one of the most problematic was thrombosis. Wide recommendation on COVID-19 treatment was pharmacological thromboprophylaxis. In some papers we found that clinicians face the problem of bleeding in those patients. Is still unknown that coronavirus could led to the coagulopathy. CASE PRESENTATION: We described case report of patient who with COVID-19 disease present femoral nerve palsy caused by the iliopsoas hematoma. There were no deviations in coaguology parameters, patient got standard thromboprophylaxis, besides above probably COVID-19 was risk factor of hematoma formation. Non-operative treatment was applied, thrombophylaxis was discontinued. In the follow up in the radiological exam we saw reduction of the haematoma and patient report decrease of symptoms. CONCLUSIONS: We should assess individually patient with COVID-19 according to thrombosis risk factors. Probably we should be more careful in ordering thrombophylaxis medications in COVID-19 patients.

Pembrolizumab-induced Myopathy with Anti-striated Muscle Antibodies Successfully Treated by Plasma Exchange.

A 70-year-old woman with advanced endometrial cancer developed right ptosis and muscle weakness in the right quadriceps after pembrolizumab administration. Serum creatine kinase (CK) levels were elevated, and anti-striated muscle antibodies were positive. On magnetic resonance imaging, the right vastus lateral muscle showed an abnormal signal. She was diagnosed with pembrolizumab-induced myopathy. We initiated plasma exchange (PE), and the ptosis immediately resolved. We then introduced oral corticosteroids, which improved her muscle weakness. We were able to rapidly diagnose her with ocular symptoms and serum CK level elevation. The early initiation of PE might prevent the exacerbation of pembrolizumab-induced myopathy.

Illness Weakness, Polyneuropathy and Myopathy: Diagnosis, treatment, and long-term outcomes.

BACKGROUND: Severe weakness associated with critical illness (CIW) is common. This narrative review summarizes the latest scientific insights and proposes a guide for clinicians to optimize the diagnosis and management of the CIW during the various stages of the disease from the ICU to the community stage. MAIN BODY: CIW arises as diffuse, symmetrical weakness after ICU admission, which is an important differentiating factor from other diseases causing non-symmetrical muscle weakness or paralysis. In patients with adequate cognitive function, CIW can be easily diagnosed at the bedside using manual muscle testing, which should be routinely conducted until ICU discharge. In patients with delirium or coma or those with prolonged, severe weakness, specific neurophysiological investigations and, in selected cases, muscle biopsy are recommended. With these exams, CIW can be differentiated into critical illness polyneuropathy or myopathy, which often coexist. On the general ward, CIW is seen in patients with prolonged previous ICU treatment, or in those developing a new sepsis. Respiratory muscle weakness can cause neuromuscular respiratory failure, which needs prompt recognition and rapid treatment to avoid life-threatening situations. Active rehabilitation should be reassessed and tailored to the new patient's condition to reduce the risk of disease progression. CIW is associated with long-term physical, cognitive and mental impairments, which emphasizes the need for a multidisciplinary model of care. Follow-up clinics for patients surviving critical illness may serve this purpose by providing direct clinical support to patients, managing referrals to other specialists and general practitioners, and serving as a platform for research to describe the natural history of post-intensive care syndrome and to identify new therapeutic interventions. This surveillance should include an assessment of the activities of daily living, mood, and functional mobility. Finally, nutritional status should be longitudinally assessed in all ICU survivors and incorporated into a patient-centered nutritional approach guided by a dietician. CONCLUSIONS: Early ICU mobilization combined with the best evidence-based ICU practices can effectively reduce short-term weakness. Multi-professional collaborations are needed to guarantee a multi-dimensional evaluation and unitary community care programs for survivors of critical illnesses.

Mimicking Ding's Roll Method on Notexin-Induced Muscle Injury in Rats.

Ding's roll method is one of the most commonly used manipulations in traditional Chinese massage (Tuina) clinics and one of the most influential contemporary Tuina manipulations in China. It is based on the traditional rolling method commonly used in the one finger Zen genre and named Ding's roll method. Due to its anti-inflammatory and blood circulation-promoting effects, Ding's rolling method has sound therapeutic effects on myopathy. Because of the large area of force applied to human skin, Ding's roll method is challenging to perform on experimental animals with small skin areas, such as rats and rabbits. Additionally, the strength of Tuina applied to the human body differs from that applied to experimental animals, so it may happen that the strength is too high or too low to achieve the therapeutic effect of Tuina during the experiment. This experiment aims to create a simple massager suitable for rats based on Ding's rolling manipulation parameters (strength, frequency, Tuina duration). The device can standardize manipulation in animal experiments and reduce the variation in Tuina force applied to different animals due to subjective factors. A rat model of notexin-induced skeletal muscle injury was established, and plasma injury markers creatine kinase (CK) and fatty acid binding protein 3 (FABP3) were used to assess the therapeutic effect of Tuina on skeletal muscle injury. The results showed that this Tuina massager could reduce the levels of CK and FABP3 expression and slow down the degree of skeletal muscle injury. Therefore, the Tuina massager described here, mimicking Ding's roll method, contributes to standardizing Tuina manipulation in experimental research and is of great help for subsequent research on the molecular mechanism of Tuina for myopathy.

[Application of "eliminating stagnation and bloodletting/fire needling" in treatment of jingjin diseases].

Based on the development of conditions, the etiology and pathogenesis of jingjin (muscle region of meridian) diseases are summarized as 3 stages, i.e. stagnation due to over-exertion at early stage, manifested by tendon-muscle contracture and tenderness; cold condition due to stagnation, interaction of stasis and cold, resulting in clustered nodules at the middle stage; prolonged illness and missed/delayed treatment, leading to tendon-muscle contracture and impairment of joint function at the late stage. It is proposed that the treatment of jingjin diseases should be combined with the characteristic advantages of fire needling and bloodletting technique, on the base of "eliminating stagnation and bloodletting/fire needling". This combined therapy warming yang to resolve stasis and dispels cold to remove nodules, in which, eliminating the stagnation is conductive to the tissue regeneration, and the staging treatment is delivered in terms of the condition development at different phases.

Acellular collagen-glycosaminoglycan matrix promotes functional recovery in a rat model of volumetric muscle loss.

Aim: Volumetric muscle loss (VML) is a composite loss of skeletal muscle, which heals with fibrosis, minimal muscle regeneration, and incomplete functional recovery. This study investigated whether collagen-glycosaminoglycan scaffolds (CGS) improve functional recovery following VML. Methods: 15 Sprague-Dawley rats underwent either sham injury or bilateral tibialis anterior (TA) VML injury, with or without CGS implantation. Results: In rats with VML injuries treated with CGS, the TA exhibited greater in vivo tetanic forces and in situ twitch and tetanic dorsiflexion forces compared with those in the non-CGS group at 4- and 6-weeks following injury, respectively. Histologically, the VML with CGS group demonstrated reduced fibrosis and increased muscle regeneration. Conclusion: Taken together, CGS implantation has potential augment muscle recovery following VML.

Volumetric muscle loss (VML) is a large injury to skeletal muscle. VML heals with scarring, little muscle regeneration, and incomplete strength recovery. The current treatment for VML involves transferring muscle from one part of the body to the injury site. However, this is limited by weakness of the donor site and incomplete recovery of muscle function. Therefore, other treatments have been developed to aid in muscle healing. One such treatment involves using three dimensional templates, known as scaffolds, to aid in muscle regeneration. Our goal is to determine whether a collagen­glycosaminoglycan scaffold (CGS), which is already used for other medical purposes, can improve healing of VML injuries in rats. CGS placement in rat muscle injuries resulted in decreased scarring, increased muscle regeneration, and increased strength recovery compared with the non-CGS group.

Identifying dysregulated immune cell subsets following volumetric muscle loss with pseudo-time trajectories.

Volumetric muscle loss (VML) results in permanent functional deficits and remains a substantial regenerative medicine challenge. A coordinated immune response is crucial for timely myofiber regeneration, however the immune response following VML has yet to be fully characterized. Here, we leveraged dimensionality reduction and pseudo-time analysis techniques to elucidate the cellular players underlying a functional or pathological outcome as a result of subcritical injury or critical VML in the murine quadriceps, respectively. We found that critical VML resulted in a sustained presence of M2-like and CD206hiLy6Chi 'hybrid' macrophages whereas subcritical defects resolved these populations. Notably, the retained M2-like macrophages from critical VML injuries presented with aberrant cytokine production which may contribute to fibrogenesis, as indicated by their co-localization with fibroadipogenic progenitors (FAPs) in areas of collagen deposition within the defect. Furthermore, several T cell subpopulations were significantly elevated in critical VML compared to subcritical injuries. These results demonstrate a dysregulated immune response in critical VML that is unable to fully resolve the chronic inflammatory state and transition to a pro-regenerative microenvironment within the first week after injury. These data provide important insights into potential therapeutic strategies which could reduce the immune cell burden and pro-fibrotic signaling characteristic of VML.

Gut-muscle axis and sepsis-induced myopathy: The potential role of gut microbiota.

Sepsis is described as an immune response disorder of the host to infection in which microorganisms play a non-negligible role. Most survivors of sepsis experience ICU-acquired weakness, also known as septic myopathy, characterized by skeletal muscle atrophy, weakness, and irreparable damage/regenerated or dysfunctional. The mechanism of sepsis-induced myopathy is currently unclear. It has been believed that this state is triggered by circulating pathogens and their related harmful factors, leading to impaired muscle metabolism. Sepsis and its resulting alterations in the intestinal microbiota are associated with sepsis-related organ dysfunction, including skeletal muscle wasting. There are also some studies on interventions targeting the flora, including fecal microbiota transplants, the addition of dietary fiber and probiotics in enteral feeding products, etc., aiming to improve sepsis-related myopathy. In this review, we critically assess the potential mechanisms and therapeutic prospects of intestinal flora in the development of septic myopathy.