Senolytics: A Novel Strategy for Neuroprotection in ALS?

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system (CNS) cells, leading to excess neuroinflammation and neurodegeneration. Damage to the upper and lower motor neurons results in neural and muscular dysfunction, leading to death most often due to respiratory paralysis. A new therapeutic strategy is targeting glial cells affected by senescence, which contribute to motor neuron degeneration. Whilst this new therapeutic approach holds much promise, it is yet to be trialled in ALS-relevant preclinical models and needs to be designed carefully to ensure selectivity. This review summarizes the pathways involved in ALS-related senescence, as well as known senolytic agents and their mechanisms of action, all of which may inform strategies for ALS-focused drug discovery efforts.

Muscle Physiopathology in Parathyroid Hormone Disorders

Parathyroid hormone disorders are a group of diseases in which secretion of parathormone (PTH) is impaired. The disorders that result are characterized by signs and symptoms associated with the persistent presence of high blood calcium levels (hypercalcemia) related to hyperparathyroidism (PHPT), or reduced blood calcium levels (hypocalcemia) associated with hypoparathyroidism (HypoPT). In addition to the resulting alteration in bone microarchitecture and mass for both pathologies, patients also report problems with skeletal muscle due to a decrease in muscular strength, muscular dysfunction, and myopathies, which can be responsible for an increased risk of instability and fracture. Although the effect of PTH on bone is well established, and numerous studies suggest that PTH has an effect on skeletal muscle, knowledge about cellular e molecular mechanisms of action on skeletal muscle is very limited. Skeletal muscle is a tissue well known for its structural and mechanical actions and is endowed with an extraordinary ability to adapt to physiological changes. Research in skeletal muscle has increased over the last decade, its importance as an endocrine tissue also emerging, becoming itself a target of numerous substances and hormones. Parathyroid hormone disorders represent a starting point to understand whether PTH may have an effect on skeletal muscle. This review analyzes the basic research data reported to date on PTH and skeletal muscle, highlighting the importance of increasing our knowledge in this field of research.

Acupuncture E_cacy Study Using Electromyographic Signals

Acupuncture is a centuries-old therapeutic technique. However, because of the large number of complicating circumstances, it has been difficult to clearly prove the treatment's therapeutic effectiveness.As a result, acupuncture has failed to acquire acceptance in the mainstream clinical sector. An electromyography (EMG) sensor was built and used to test the efficacy of acupuncture in alleviating muscular stiffness in this study. Electrodes, differential and inverting amplifiers, filters, and a full-wave rectifier made up the EMG circuit. The output of the circuit was sent to a microcontroller for analog-to-digital transformation in order to perform data acquisition. Acupuncture was used to treat four participants who had muscular dysfunction in various regions of their bodies in our case study. Before and after the therapy, EMG signals at the damaged regions were recorded. The findings revealed that the therapy had no immediate conceivable impact on the patients, since the levels of muscular contraction before and after the treatment were comparable. When the EMG signals were measured 30 minutes after the therapy, signs of muscular alleviation were found. This shows that acupuncture does supply patients with beneficial medicine, although slowly. The act of placing the highly conducting needles into the acupuncture sites, we believe, is similar to connecting a parallel wire to a circuit, resulting in a short-circuited route at the meridian. It permits the meridian's polarized in- ner energy, or qi, to pass through. The equilibrium in qi regulation can therefore be restored by unclogging the ow of qi.The repair process is relatively slow, and the treatment impact may not be immediately apparent, because the consti- tutive qualities at the acupuncture points where the needles are pricked may not alter quickly.

The Assessment of Muscle Mass and Function in Patients with Long-Standing Rheumatoid Arthritis

Muscular dysfunction in rheumatoid arthritis (RA) can affect the quality of life and comorbidities. We enrolled 320 patients with RA, and evaluated their muscle mass, grip strength, and physical performance. Seven (2.2%) and 21 RA patients (6.6%) had sarcopenia, as defined by the European and Asian Working Group for Sarcopenia (EWGS and AWGS), respectively; 54 patients (16.9%) were determined to have low muscle mass with normal muscle function, as defined by the EWGS; 38 patients (11.9%) reported sarcopenia by SARC-F questionnaire. Male sex (odds ratio (OR) 140.65), low body mass index (BMI) (OR 0.41), and use of tumor necrosis factor (TNF) inhibitors (OR 4.84) were associated with a low muscle mass as defined by the EWGS, while male sex, old age, and low BMI were associated with sarcopenia as defined by the AWGS. Old age (OR 1.11), high BMI (OR 1.13), and a high Disease Activity Score 28 (OR 1.95) were associated with sarcopenia as reported on the SARC-F. Male, low BMI, and use of TNF inhibitors were associated with a low muscle mass, while male sex, old age, and low BMI were associated with sarcopenia in patients with long-standing RA.

Evaluation of clinical practice guidelines (CPG) on the management of female chronic pelvic pain (CPP) using the AGREE II instrument

Introduction and hypothesis Variations in guidelines may result in differences in treatments and potentially poorer health-related outcomes. We aimed to systematically review and evaluate the quality of national and international guidelines and create an inventory of CPG recommendations on CPP. Methods We searched EMBASE and MEDLINE databases from inception till August 2020 as well as websites of professional organizations and societies. We selected national and international CPGs reporting on the diagnosis and management of female CPP. We included six CPGs. Five researchers independently assessed the quality of included guidelines using the AGREE II tool and extracted recommendations. Results Two hundred thirty-two recommendations were recorded and grouped into six categories: diagnosis, medical treatment, surgical management, behavioural interventions, complementary/alternative therapies and education/research. Thirty-nine (17.11%) recommendations were comparable including: a comprehensive pain history, a multi-disciplinary approach, attributing muscular dysfunction as a cause of CPP and an assessment of quality of life. Two guidelines acknowledged sexual dysfunction associated with CPP and recommended treatment with pelvic floor exercises and behavioural interventions. All guidelines recommended surgical management; however, there was no consensus regarding adhesiolysis, bilateral salpingo-oophorectomy during hysterectomy, neurectomy and laparoscopic uterosacral nerve ablation. Half of recommendations (106, 46.49%) were unreferenced or made in absence of good-quality evidence or supported by expert opinion. Based on the AGREE II assessment, two guidelines were graded as high quality and recommended without modifications (EAU and RCOG). Guidelines performed poorly in the “Applicability”, “Editorial Independence” and “Stakeholder Involvement” domains. Conclusion Majority of guidelines were of moderate quality with significant variation in recommendations and quality of guideline development.

Increased Creatine Kinase May Predict A Worse COVID-19 Outcome

Early reports from Asia suggested that increased serum levels of the muscular enzyme creatine-(phospho)-kinase (CK/CPK) could be associated with a more severe prognosis in COVID-19. The aim of this single-center retrospective cohort study of 331 consecutive COVID-19 patients who were hospitalized during Italy’s “first wave” was to verify this relationship, and to evaluate the role of possible confounding factors (age, body mass index, gender, and comorbidities). We subdivided our cohort in two groups, based on “severe” (n = 99) or “mild” (n = 232) outcomes. “Severe” disease is defined here as death and/or mechanical invasive ventilation, in contrast to “mild” patients, who were discharged alive with no need for invasive ventilation; this latter group could also include those patients who were treated with non-invasive ventilation. The CK levels at admission were higher in those subjects who later experienced more severe outcomes (median, 126; range, 10–1672 U/L, versus median, 82; range, 12–1499 U/L, p = 0.01), and hyperCKemia >200 U/L was associated with a worse prognosis. Regression analysis confirmed that increased CK acted as an independent predictor for a “severe” outcome. HyperCKemia was generally transient, returning to normal during hospitalization in the majority of both “severe” and “mild” patients. Although the direct infection of voluntary muscle is unproven, transient muscular dysfunction is common during the course of COVID-19. The influence of this novel coronavirus on voluntary muscle really needs to be clarified.

Pharmacological activation of SERCA ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscular weakness due to the loss of dystrophin. Extracellular Ca2+ flows into the cytoplasm through membrane tears in dystrophin-deficient myofibers, which leads to muscle contracture and necrosis. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) takes up cytosolic Ca2+ into the sarcoplasmic reticulum (SR), but its activity is decreased in dystrophic muscle. Here, we show that an allosteric SERCA activator, CDN1163, ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice. Administration of CDN1163 prevented exercise-induced muscular damage and restored mitochondrial function. In addition, treatment with CDN1163 for seven weeks enhanced muscular strength and reduced muscular degeneration and fibrosis in mdx mice. Our findings provide preclinical proof-of-concept evidence that pharmacological activation of SERCA could be a promising therapeutic strategy for DMD. Moreover, CDN1163 improved muscular strength surprisingly in wild-type mice, which may pave the new way for the treatment of muscular dysfunction.

Myopenia and Musculoskeletal Aging in Rheumatoid Arthritis

Rheumatoid arthritis (RA), the commonest inflammatory arthritis, is a debilitating disease leading to decreased functional capacity, social disability and reduced quality of life. RA affects multisystems with chronic inflammatory disease characterized by destructive synovitis and muscular dysfunction leading to premature musculoskeletal aging, which has been coined with many terms including myopenia, sarcopenia, cachexia, muscle failure and muscle wasting. Myopenia is described as the presence of clinically relevant muscle wasting due to any illness at any age, associated with impaired muscle function, increased morbidity and mortality. RA myopenia has significantly less muscle mass compared to the general population muscle loss showing preservation or slight increase in fat mass. RA myopenia is unique compared to chronic disease-related myopenia in cancer, chronic heart failure, kidney disease and chronic infection as it is rarely accompanied by a net weight loss. RA myopenia has younger-age onset compared to elderly primary sarcopenia, while higher-grade inflammation has been considered as the pathophysiology of muscle wasting. Research, however, indicates that inflammation itself cannot fully explain the high prevalence of muscle wasting in RA. This chapter aims to review the literature on the casual relationships among RA myopenia, premature musculoskeletal aging and management strategies to delay musculoskeletal aging.

Prevention of scoliotic spinal deformity in children with mild neuro-orthopedic pathology

Objective. To describe in details the prevention of scoliotic spinal deformity in children with mild neuro-orthopedic pathology. Materials and methods. The health status of 125 children aged 3 to 15 years was studied. To investigate in details the neuro-orthopedic pathology and estimate the efficiency of treatment, the method of computed optic topography and electroneuromyography was used. Results. Clinical and functional features in children with mild neuro-orthopedic disorders were characterized by the combination of vegetative, topographic and electromyographic changes. Scoliosis and spinal deformity progressed in children, who were not treated. Computer-topographic method of diagnosis determines the degree of severity of spinal state. Electroneuromyographic study is the method that permits to assess and predict the muscular dysfunction degree. All the children had conservative complex treatment at ambulatory-polyclinic rehabilitation institutions. The total efficiency of treatment was 95 %. Conclusions. 1. Mild neuro-orthopedic pathology is formed and progresses against the background of neuro-muscular and vegetative disorders while a child is growing and developing. 2. Computed optic topography is a reliable early diagnostic and prognostic criterion for estimation of scoliosis in the therapeutic program. 3. Purposeful conservative treatment and follow-up of children and adolescents prevent the progression of neuro-orthopedic pathology.