miR-486 is an epigenetic modulator of Duchenne muscular dystrophy pathologies

Duchenne muscular dystrophy (DMD) is an X-linked progressive muscle disorder resulting in muscle weakness and cardiomyopathy. MicroRNAs have been shown to play essential roles in muscle development, metabolism, and disease pathologies. We demonstrated that miR-486 expression is reduced in DMD muscles and its expression levels correlate with dystrophic disease severity. MicroRNA-486 knockout mice developed disrupted myofiber architecture, decreased myofiber size, decreased locomotor activity, increased cardiac fibrosis, and metabolic defects that were exacerbated on the dystrophic mdx5cv background. We integrated RNA-sequencing and chimeric eCLIP-sequencing data to identify direct in vivo targets of miR-486 and associated dysregulated gene signatures in skeletal muscle. In comparison to our DMD mouse muscle transcriptomes, we identified several of these miR-486 muscle targets including known modulators of dystrophinopathy disease symptoms. Together, our studies identify miR-486 as a driver of muscle remodeling in DMD, a useful biomarker for dystrophic disease progression, and highlight chimeric eCLIP-sequencing as a useful tool to identify direct in vivo microRNA target transcripts.

Selective ablation of Nfix in Macrophages preserves Muscular Dystrophy by inhibiting FAPs-dependent fibrosis

Muscular dystrophies are genetic diseases characterized by chronic inflammation and fibrosis. Macrophages are immune cells that sustain muscle regeneration upon acute injury but seem deleterious in the context of chronic muscle injury such as muscular dystrophies. Here we observed that the number of macrophages expressing the transcription factor Nfix increases in two distinct murine models of muscular dystrophies. Plus, we showed that the deletion of Nfix in macrophages in dystrophic mice delays fibrosis establishment and muscle wasting until 6 months of life. Indeed, macrophages lacking Nfix express more TNFα and less TGFβ1 thus promoting apoptosis of fibro-adipogenic progenitors. Moreover, pharmacological treatment of dystrophic mice with ROCK inhibitor accelerates fibrosis through the increase of Nfix expression by macrophages. Thus, we identify Nfix as a macrophage profibrotic actor in muscular dystrophies, whose inhibition could be a therapeutic way to rescue the dystrophic disease.

The essence of physical therapy of children 7-10 years with chronic gastritis in the hospital period: problems and prospects

The article substantiates the essence of physical therapy of children 7-10 years old with chronic gastritis in the hospital period: problems and prospects. Chronic gastritis is a chronic polyetiological inflammatory-dystrophic disease of the gastric mucosa with impaired cell regeneration and progressive atrophy of the gastric epithelium. The consequences of the disease are damage to the surface layer of the epithelium and glandular apparatus of the gastric mucosa and the development of inflammatory processes in them. Depending on the etiological factor, the inflammatory process may be limited to the superficial epithelium of the mucous membrane or spread to the entire thickness of the glandular apparatus and even the muscular layer. The main symptoms of gastritis are pain and dyspeptic disorders. Patients complain of heartburn, belching sour, feeling of pressure, burning, distension in the epigastric region, constipation, rarely - vomiting. Usually dyspeptic disorders appear during the exacerbation of the disease. Appetite usually does not change, however at the expressed frustration of function of a stomach and a duodenum can amplify or decrease - up to full (short-term) loss. The analysis of modern approaches to physical therapy of patients with chronic gastritis indicates a lack of attention to this issue. The program of physical therapy for children 7-10 years old with chronic gastritis during the hospital period includes: therapeutic physical training, therapeutic massage, physiotherapy and diet therapy.

Clinical manifestations and diagnosis of keratoconus. Treatment of iatrogenic keratoconus

Keratoconus is a dystrophic disease of the cornea, when it is thinned with the formation of a conus-like protrusion (protrusion of the cornea). This disease belongs to the group of keratectasia, it has a multifactorial nature and occurs in approximately 25 % of all corneal pathologies. The disease can be either primary, which is based on dystrophic changes in the cornea, or secondary, which develops against the background of prenatal keratitis. Keratoconus of iatrogenic origin, which develops as a result of refractive eye microsurgery, has become widespread during the last 20 years. Most often primary keratoconus manifests during puberty, progresses to 30–40 years, after which its development slows down. An early clinical manifestation of this corneal pathology is a progressive decrease in visual acuity, development of double vision (binocular diplopia) with the development of a strong headache against this background. Monocular polyopia — images and symbols with multiple contours — develops subsequently. Severe dry eyes, itching, photophobia appear in advanced stages. Diagnosis of keratoconus in some cases can be a significant difficulty, since the use of conventional research methods only allow to suspect refractive errors in the form of myopia or astigmatism. It is necessary to take into account the impossibility of correcting visual impairment using conventional methods — glasses or contact lenses — to make correct diagnosis. As a rule, diagnosis of keratoconus requires use of expanded spectrum of instrumental research methods.

UNDERWATER TRACTION THERAPY FOR THE TREATMENT OF LUMBAR BACK PAIN: THE ACHIEVEMENTS AND CONTRADICTIONS (A LITERATURE REVIEW)

At present, degenerative dystrophic disease of intervertebral disks and lumbar back pain associated with this condition constitute a most serious medical, social and economic problem. This article was designed to consider underwater spine traction as a drug-free treatment for low back pain. The literature review includes the historical milestones and current concepts of traction therapy. The paper includes the analysis of the long-established clinical notions having the influence on the evaluation of the effectiveness of the treatment and proposes the new up-to-date approach to the investigation of the pathological condition being condidered and the method for its therapy.

Multifunctional ion transport properties of human SLC4A11: comparison of the SLC4A11-B and SLC4A11-C variants

Congenital hereditary endothelial dystrophy (CHED), Harboyan syndrome (CHED with progressive sensorineural deafness), and potentially a subset of individuals with late-onset Fuchs' endothelial corneal dystrophy are caused by mutations in the SLC4A11 gene that results in corneal endothelial cell abnormalities. Originally classified as a borate transporter, the function of SLC4A11 as a transport protein remains poorly understood. Elucidating the transport function(s) of SLC4A11 is needed to better understand how its loss results in the aforementioned posterior corneal dystrophic disease processes. Quantitative PCR experiments demonstrated that, of the three known human NH2-terminal variants, SLC4A11-C is the major transcript expressed in human corneal endothelium. We studied the expression pattern of the three variants in mammalian HEK-293 cells and demonstrated that the SLC4A11-B and SLC4A11-C variants are plasma membrane proteins, whereas SLC4A11-A is localized intracellularly. SLC4A11-B and SLC4A11-C were shown to be multifunctional ion transporters capable of transporting H+ equivalents in both a Na+-independent and Na+-coupled mode. In both transport modes, SLC4A11-C H+ flux was significantly greater than SLC4A11-B. In the presence of ammonia, SLC4A11-B and SLC4A11-C generated inward currents that were comparable in magnitude. Chimera SLC4A11-C-NH2-terminus-SLC4A11-B experiments demonstrated that the SLC4A11-C NH2-terminus functions as an autoactivating domain, enhancing Na+-independent and Na+-coupled H+ flux without significantly affecting the electrogenic NH3-H( n)+ cotransport mode. All three modes of transport were significantly impaired in the presence of the CHED causing p.R109H (SLC4A11-C numbering) mutation. These complex ion transport properties need to be addressed in the context of corneal endothelial disease processes caused by mutations in SLC4A11.

Method of Diagnostics the Severity Level of Degenerative and Dystrophic Disease of the Spine in the Patients

Diagnostic research can be used to diagnose the severity level of degenerative and dystrophic disease of the spine (DSP) in the patients. The authors analyzed the results of the examination of 60 patients suffering from DSP. Inclusion criteria patients in the study were that they have verified DSP. Diagnoses of diseases in the patients were clinically verified and by means of neuro-imaging methods: X-ray study of the spine and magnetic resonance imaging of the spine. Criterion for exclusion from the study was the absence of DSP. The age of the patients of the 1st group was 61,1±8,3 years, the age of the patients of the 2nd group 2 was 58,1±10,9 years. Method to diagnose the severity of the current verified DSP in patients differs in that the discriminant function D. was calculated using discriminant analysis. If the value of D>0, then the patients have DSP with diskogenic disorders, if D<0 – the patients have DSP without hernia formations of intervertebral disks. Discriminant function: D=6,029×P+0,292×G-3,709×psevdoparal+0,088×ascending-0,691×TT+2,550×CDBVofVBP+1,537×HDL-4,9. Neurological study of the patients with DSP is insufficient for the study of pathogenetic mechanisms of formation of neurological disorders. A great role in patients with these diseases plays the formation of violations of production of antioxidants, hypercholesterolemia, coagulographic disorders of the blood plasma.