To investigate whether clinical and magnetic resonance imaging (MRI) outcomes of patients with multiple sclerosis (MS) who required a reduction of administration frequency of interferon-beta (IFNB) were similar to those of patients who did not.
The objective of this paper is to investigate four-year outcomes of interferon beta (IFNB)-treated patients with multiple sclerosis (MS) according to their clinical or magnetic resonance imaging (MRI) activity status at first year of treatment.
To evaluate whether balance deficit in patients with multiple sclerosis (MS), as assessed with eyes opened (EO) and closed (EC), is associated with damage of different structures of the central nervous system (CNS).
Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system, traditionally considered to be an autoimmune, demyelinating disease. Based on this understanding, initial therapeutic strategies were directed at immune modulation and inflammation control. At present, there are five licensed first-line disease-modifying drugs for MS in Europe, and two second-line treatments. Currently available MS therapies have shown significant efficacy throughout many trials, but they produce different side effects. Despite disease-modifying drugs being well known and safe, they require regular and frequent parenteral administration and are associated with limited long-term treatment adherence. Therefore, the development of new therapeutic strategies is warranted. Several oral compounds are in late stages of development for treating MS. fingolimod is an oral sphingosine-1-phosphate receptor modulator that has demonstrated superior efficacy compared with placebo and interferon ?-1a in phase III studies. It has already been approved in the treatment of MS. This review focuses on advances in current and novel oral treatment approaches in MS. We summarily review the oral compounds in this study, focusing on the recent development, approval, and the clinical experience with fingolimod.
Several purine receptors have been localised on skeletal muscle membranes. Previous data support the hypothesis that extracellular guanosine 5-triphosphate (GTP) is an important regulatory factor in the development and function of muscle tissue. We have previously described specific extracellular binding sites for GTP on the plasma membrane of mouse skeletal muscle (C2C12) cells. Extracellular GTP induces an increase in intracellular Ca(2+) concentrations that results in membrane hyperpolarisation through Ca(2+)-activated K(+) channels, as has been demonstrated by patch-clamp experiments. This GTP-evoked increase in intracellular Ca(2+) is due to release of Ca(2+) from intracellular inositol-1,4,5-trisphosphate-sensitive stores. This enhances the expression of the myosin heavy chain in these C2C12 myoblasts and commits them to fuse into multinucleated myotubes, probably via a phosphoinositide-3-kinase-dependent signal-transduction mechanism. To define the signalling of extracellular GTP as an enhancer or modulator of myogenesis, we investigated whether the gene-expression profile of differentiated C2C12 cells (4 and 24 h in culture) is affected by extracellular GTP. To investigate the nuclear activity and target genes modulated by GTP, transcriptional profile analysis and real-time PCR were used. We demonstrate that in the early stages of differentiation, GTP up-regulates genes involved in different pathways associated with myogenic processes, including cytoskeleton structure, the respiratory chain, myogenesis, chromatin reorganisation, cell adhesion, and the Jak/Stat pathway, and down-regulates the mitogen-activated protein kinase pathway. GTP also increases the expression of three genes involved in myogenesis, Pp3ca, Gsk3b, and Pax7. Our data suggests that in the myogenic C2C12 cell line, extracellular GTP acts as a differentiative factor in the induction and sustaining of myogenesis.
Needle biopsy is widely used to obtain specimens for physiological, anatomical and biochemical studies of skeletal muscle (SM). We optimized a procedure which we termed tiny percutaneous needle biopsy (TPNB), to efficiently gather good numbers of human satellite cells and single dissociated fibers for the functional study of skeletal muscle; these samples permit isolation of high-quality RNA and sufficient amounts of proteins to allow molecular analysis. Moreover, TPNB showed a clear advantage in that the technique was easier than other procedures used on healthy volunteers in human trials. TPNB is a very safe minor surgical procedure. It is less traumatic than needle aspiration biopsy, and significant complications are improbable. TPNB should become established as an important tool in the investigation of SM and may be employed to study various physiological aspects of SM in human subjects. We suggest that TPNB should also be used in the study of muscle diseases and disorders including muscular dystrophy, congenital myopathy, and metabolic defects.
During aging, skeletal muscles show reduced mass and functional capacity largely due to loss of the regenerative ability of satellite cells (SCs), the quiescent stem cells located beneath the basal lamina surrounding each myofiber. While both the external environment and intrinsic properties of SCs appear to contribute to the age-related SC deficiency, the latter ones have been poorly investigated especially in humans. In the present work, we analyzed several parameters of SCs derived from biopsies of vastus lateralis muscle from healthy non-trained young (28.7 ± 5.9 years; n = 10) and aged (77.3 ± 6.4 years; n = 11) people. Compared with young SCs, aged SCs showed impaired differentiation when cultured in differentiation medium, and exhibited the following: (1) reduced proliferation; (2) higher expression levels of S100B, a negative regulator of myoblast differentiation; (3) undetectable levels in growth medium of full-length RAGE (receptor for advanced glycation end products), a multiligand receptor of the immunoglobulin superfamily, the engagement of which enhances myoblast differentiation; and (4) lower expression levels of the transcription factors, MyoD and Pax7. Also, either overexpression of full-length RAGE or knockdown of S100B in aged SCs resulted in enhanced differentiation, while overexpression of either a non-transducing mutant of RAGE (RAGE?cyto) or S100B in young SCs resulted in reduced differentiation compared with controls. Moreover, while aged SCs maintained the ability to respond to mitogenic factors (e.g., bFGF and S100B), they were no longer able to secrete these factors, unlike young SCs. These data support a role for intrinsic factors, besides the extracellular environment in the defective SC function in aged skeletal muscles.
Several studies have examined the effects of vibrations on muscle mass and performance in young healthy people. We studied the effects of vibrations on muscles of elderly male and female volunteers (65-85 years of age) diagnosed with sarcopenia. We applied mechanical vibrations locally (local vibrational training) to the thigh muscles at 300 Hz for a period of 12 weeks, starting with a session of 15 min stimulation once a week and increasing to three sessions of 15 min per week. Treated muscles displayed enhanced maximal isometric strength and increased content of fast MyHC-2X myosin. Single muscle fiber analysis did not show any change in cross-sectional area or in specific tension. Analysis of transcriptional profiles by microarray revealed changes in gene expression after 12 weeks of local vibrational training. In particular, pathways related with energy metabolism, sarcomeric protein balance and oxidative stress response were affected. We conclude that vibration treatment is effective in counteracting the loss of muscular strength associated with sarcopenia and the mode of action of vibration is based on cellular and molecular changes which do not include increase in fiber or muscle size.
Sarcopenia is the age-related loss of muscle mass, strength and function. Human muscle proteins are synthesized at a slower rate in the elderly than in young adults, leading to atrophy and muscle mass loss with a decline in the functional capability. Additionally, aging is accompanied by a decrease in the ability of muscle tissue to regenerate following injury or overuse due to the impairment of intervening satellite cells, in which we previously reported oxidative damage evidences. The aim of the present study was to determine the effects of aging on myoblasts and myotubes obtained from human skeletal muscle, and characterize the transcriptional profile as molecular expression patterns in relation to age-dependent modifications in their regenerative capacity. Our data show that the failure to differentiate does not depend on reduced myogenic cell number, but difficulty to complete the differentiation program. Data reported here suggested the following findings: (i) oxidative damage accumulation in molecular substrates, probably due to impaired antioxidant activity and insufficient repair capability, (ii) limited capability of elderly myoblasts to execute a complete differentiation program; restricted fusion, possibly due to altered cytoskeleton turnover and extracellular matrix degradation and (iii) activation of atrophy mechanism by activation of a specific FOXO-dependent program.
Ageing has been defined as the process of deterioration of many body functions over the lifespan of an individual. In spite of the number of different theories about ageing, there is a general consensus in identifying ageing effects in a reduced capacity to regenerate injured tissues or organs and an increased propensity to infections and cancer. In recent years the stem cell theory of ageing has gained much attention. Adult stem cells residing in mammalian tissues are essential for tissue homeostasis and repair throughout adult life. With advancing age, the highly regulated molecular signalling necessary to ensure proper cellular, tissue, and organ homeostasis loses coordination and leads, as a consequence, to a compromised potential of regeneration and repair of damaged cells and tissues. Although a complete comprehension of the molecular mechanisms involved in stem cell ageing and apoptosis is far to be reached, recent studies are beginning to unravel the processes involved in stem cell ageing, particularly in adult skeletal muscle stem cells, namely satellite cells. Thus, the focus of this review is to analyse the relationship between stem cell ageing and apoptosis with a peculiar attention to human satellite cells as compared to haematopoietic stem cells. Undoubtedly, the knowledge of age-related changes of stem cells will help in understanding the ageing process itself and will provide novel therapeutic challenges for improved tissue regeneration.
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