High-Tech Methods of Cytokine Imbalance Correction in Intervertebral Disc Degeneration.

An important mechanism for the development of intervertebral disc degeneration (IDD) is an imbalance between anti-inflammatory and pro-inflammatory cytokines. Therapeutic and non-therapeutic approaches for cytokine imbalance correction in IDD either do not give the expected result, or give a short period of time. This explains the relevance of high-tech medical care, which is part of specialized care and includes the use of new resource-intensive methods of treatment with proven effectiveness. The aim of the review is to update knowledge about new high-tech methods based on cytokine imbalance correction in IDD. It demonstrates promise of new approaches to IDD management in patients resistant to previously used therapies, including: cell therapy (stem cell implantation, implantation of autologous cultured cells, and tissue engineering); genetic technologies (gene modifications, microRNA, and molecular inducers of IDD); technologies for influencing the inflammatory cascade in intervertebral discs mediated by abnormal activation of inflammasomes; senolytics; exosomal therapy; and other factors (hypoxia-induced factors; lysyl oxidase; corticostatin; etc.).

Association of the ACTN3 Gene's Single-Nucleotide Variant Rs1815739 (R577X) with Sports Qualification and Competitive Distance in Caucasian Athletes of the Southern Urals.

An elite athlete's status is associated with a multifactorial phenotype depending on many environmental and genetic factors. Of course, the peculiarities of the structure and function of skeletal muscles are among the most important characteristics in the context of athletic performance. PURPOSE: To study the associations of SNV rs1815739 (C577T or R577X) allelic variants and genotypes of the ACTN3 gene with qualification and competitive distance in Caucasian athletes of the Southern Urals. METHODS: A total of 126 people of European origin who lived in the Southern Urals region took part in this study. The first group included 76 cyclical sports athletes (speed skating, running disciplines in track-and-field): SD (short distances) subgroup-40 sprinters (mean 22.1 ± 2.4 y.o.); LD (long distances) subgroup-36 stayer athletes (mean 22.6 ± 2.7 y.o.). The control group consisted of 50 healthy nonathletes (mean 21.4 ± 2.7 y.o.). We used the Step One Real-Time PCR System (Applied Biosystems, USA) device for real-time polymerase chain reaction. RESULTS: The frequency of the major allele R was significantly higher in the SD subgroup compared to the control subgroup (80% vs. 64%; p-value = 0.04). However, we did not find any significant differences in the frequency of the R allele between the athletes of the SD subgroup and the LD subgroup (80% vs. 59.7%, respectively; p-value > 0.05). The frequency of the X allele was lower in the SD subgroup compared to the LD subgroup (20% vs. 40.3%; p-value = 0.03). The frequency of homozygous genotype RR was higher in the SD subgroup compared to the control group (60.0% vs. 34%; p-value = 0.04). The R allele was associated with competitive distance in the SD group athletes compared to those of the control group (OR = 2.45 (95% CI: 1.02-5.87)). The X allele was associated with competitive distance in the LD subgroup compared to the SD subgroup (OR = 2.7 (95% CI: 1.09-6.68)). CONCLUSIONS: Multiplicative and additive inheritance models demonstrated that high athletic performance for sprinters was associated with the homozygous dominant genotype 577RR in cyclical sports athletes of Caucasian origin in the Southern Urals.

Molecular Basic of Pharmacotherapy of Cytokine Imbalance as a Component of Intervertebral Disc Degeneration Treatment.

Intervertebral disc degeneration (IDD) and associated conditions are an important problem in modern medicine. The onset of IDD may be in childhood and adolescence in patients with a genetic predisposition. With age, IDD progresses, leading to spondylosis, spondylarthrosis, herniated disc, spinal canal stenosis. One of the leading mechanisms in the development of IDD and chronic back pain is an imbalance between pro-inflammatory and anti-inflammatory cytokines. However, classical therapeutic strategies for correcting cytokine imbalance in IDD do not give the expected response in more than half of the cases. The purpose of this review is to update knowledge about new and promising therapeutic strategies based on the correction of the molecular mechanisms of cytokine imbalance in patients with IDD. This review demonstrates that knowledge of the molecular mechanisms of the imbalance between pro-inflammatory and anti-inflammatory cytokines may be a new key to finding more effective drugs for the treatment of IDD in the setting of acute and chronic inflammation.

Amyotrophic Lateral Sclerosis Mimic Syndrome in a 24-Year-Old Man with Chiari 1 Malformation and Syringomyelia: A Clinical Case.

Chiari 1 Malformation (CM1) is classically defined as a caudal displacement of the cerebellar tonsils through the foramen magnum into the spinal cord. Modern imaging techniques and experimental studies disclose a different etiology for the development of CM1, but the main etiology factor is a structural defect in the skull as a deformity or partial reduction, which push down the lower part of the brain and cause the cerebellum to compress into the spinal canal. CM1 is classified as a rare disease. CM1 can present with a wide variety of symptoms, also non-specific, with consequent controversies on diagnosis and surgical decision-making, particularly in asymptomatic or minimally symptomatic. Other disorders, such as syringomyelia (Syr), hydrocephalus, and craniocervical instability can be associated at the time of the diagnosis or appear secondarily. Therefore, CM1-related Syr is defined as a single or multiple fluid-filled cavities within the spinal cord and/or the bulb. A rare CM1-related disorder is syndrome of lateral amyotrophic sclerosis (ALS mimic syndrome). We present a unique clinical case of ALS mimic syndrome in a young man with CM1 and a huge singular syringomyelic cyst with a length from segment C2 to Th12. At the same time, the clinical picture showed upper hypotonic-atrophic paraparesis in the absence of motor disorders in the lower extremities. Interestingly, this patient did not have a disorder of superficial and deep types of sensitivity. This made it difficult to diagnose CM1. For a long time, the patient's symptoms were regarded as a manifestation of ALS, as an independent neurological disease, and not as a related disorder of CM1. Surgical treatment for CM1 was not effective, but it allowed to stabilize the course of CM1-related ALS mimic syndrome over the next two years.

Association of Single-Nucleotide Polymorphisms Rs2779249 (chr17:26128581 C>A) and Rs rs2297518 (chr17: chr17:27769571 G>A) of the NOS2 Gene with Tension-Type Headache and Arterial Hypertension Overlap Syndrome in Eastern Siberia.

Inducible nitric oxide (NO) synthase (iNOS), encoded by the NOS2 gene, promotes the generation of high levels of NO to combat harmful environmental influences in a wide range of cells. iNOS can cause adverse effects, such as falling blood pressure, if overexpressed. Thus, according to some data, this enzyme is an important precursor of arterial hypertension (AH) and tension-type headache (TTH), which are the most common multifactorial diseases in adults. The purpose of this study was to investigate the association of rs2779249 (chr17:26128581 C>A) and rs2297518 (chr17: chr17:27769571 G>A) of the NOS2 gene with TTH and AH overlap syndrome (OS) in Caucasians in Eastern Siberia. The sample size was 91 participants: the first group-30 patients with OS; the second group-30 patients AH; and the third group-31 healthy volunteers. RT-PCR was used for the determination of alleles and genotypes of the SNPs rs2779249 and rs2297518 of the NOS2 gene in all groups of participants. We showed that the frequency of allele A was significantly higher among patients with AH compared with healthy volunteers (p-value < 0.05). The frequency of the heterozygous genotype CA of rs2779249 was higher in the first group vs. the control (p-value = 0.03), and in the second group vs. the control (p-value = 0.045). The frequency of the heterozygous genotype GA of rs2297518 was higher in the first group vs. the control (p-value = 0.035), and in the second group vs. the control (p-value = 0.001). The allele A of rs2779249 was associated with OS (OR = 3.17 [95% CI: 1.31-7.67], p-value = 0.009) and AH (OR = 2.94 [95% CI: 1.21-7.15], p-value = 0.015) risks compared with the control. The minor allele A of rs2297518 was associated with OS (OR = 4.0 [95% CI: 0.96-16.61], p-value = 0.035) and AH (OR = 8.17 [95% CI: 2.03-32.79], p-value = 0.001) risks compared with the control. Therefore, our pilot study demonstrated that the SNPs rs2779249 and rs229718 of the NOS2 gene could be promising genetic biomarkers for this OS risk in Caucasians from Eastern Siberia.

New Genetic Biomarkers of the Overlap Syndrome Tension-Type Headache and Arterial Hypertension.

BACKGROUND: Nitric oxide (NO) is an important autocrine and paracrine signaling molecule that plays a crucial role in cardiovascular physiology and pathology regulation. NO is an important molecule involved in regulation of cerebral and extra cerebral cranial blood flow and arterial diameters. Reduced bioavailability of NO in the endothelium is an important precursor for impaired vasodilation and arterial hypertension (AH). Furthermore, NO is involved in nociceptive processing. A NO-induced biphasic response with immediate and a delayed headache is typical for chronic tension-type headaches (TTH) in humans. The aim was to study the association of allelic variants and genotypes of the single nucleotide variant (SNV) rs3782218 of the NOS1 gene with the TTH and AH overlap syndrome development in middle age adults. MATERIALS AND METHODS: We observed 91 Caucasian participants who resided in Krasnoyarsk city: group 1 (TTH and AH overlap syndrome)-30 patients; group 2 (AH without headache)-30 patients; group 3 (control)-31 healthy volunteers. The diagnosis of AH was based on criteria of the European Society of Cardiology and the European Society of Hypertension (2018) и criteria of the Russian Society of Cardiology (2020). Diagnosis of TTH was based on criteria of the International Classification of Headache Disorders (2018). Real-time polymerase chain reaction was used for the determination of allelic variants and genotypes of the SNV rs3782218 of the NOS1 gene in all groups of participants. RESULTS: The frequency of the minor allele T of rs3782218 was statistically significantly higher by 16.7 times in group 1 (TTH and AH) compared to group 3 (control): 26.7% versus 1.6%, respectively (p-value = 0.000065) and 3.2 times higher in group 1 (TTH and AH) compared to group 2 (AH without headache): 26.7% versus 8.3%, respectively (p-value = 0.008). The frequency of the heterozygous (CT) genotype was statistically significantly higher in group 1 (TTH and AH) compared to group 3 (control): 40.0% versus 3.2% (p-value = 0.000454) and in group 1 (TTH and AH) compared to group 2 (AH without headache): 40.0% versus 16.7% (p-value = 0.045). The minor allele T was statistically significantly associated with a high risk of developing the TTH and AH overlap syndrome compared with the controls (odds ratio (OR) = 22.2 (95% confidential interval (CI): 2.8-173.5)) and compared with AH without headache (OR = 4.0 (95% CI: 1.4-11.8)). Although the frequency of the minor allele T was 5.2 times higher in group 2 (AH without headache) compared with group 3 (control), there were not statistically significantly differences (p-value = 0.086). CONCLUSION: Thus, the minor allele T of rs3782218 of the NOS1 gene is an important genetic biomarker for a high risk of developing the TTH and AH overlap syndrome in hypertensive patients.