47 research outputs found
Gene- and cell-based therapy of muscle system hereditary disorders: State-of-art
Genetic disorders primarily affecting skeletal muscles can be caused by dysfunction of more than 30 genes. To date there is no effective etiotropic and pathogenetic treatment of such disorders. Investigators focus on search for new therapeutic agents based on gene and cell technologies, small molecules as well. There are numerous preclinical and several dozens of clinical studies in the world. Unfortunately tested technologies did not lead to significant advance in treatment of patients with such disorders. At the same time resulting data allow to determine the most feasible directions of future development combining of genome correction methods with cell delivery of corrected genome to skeletal muscles. This review is intended to give general information about etiology of skeletal muscles genetic disorders, the main directions of biotechnological development and results of the clinical studies
Effects of autologous gingiva-derived cells with myogenic potential on regeneration of skeletal muscle
In our recent studies we found for the first time the ability of human multipotent mesenchymal stromal cells (MSCs) derived from alveolar gingiva (alveolar mucosa) to differentiate into myogenic direction. The aim of the present study was to evaluate the effects of autologous gingiva-derived MSCs with myogenic potential on the regeneration of muscular tissue after mechanical damage. The study was conducted on 11 male rabbits. Biopsy of alveolar gingiva was performed at each animal before experiment for autologous MSCs obtainment. Cultures of MSCs were induced in vitro into myogenic direction. To model the damage, the medial heads of the gastrocnemius muscles were intersected on both pelvic limbs of the rabbit. Injection of autologous MSCs was performed on the seventh day after injury into the damaged muscle of one of the extremities, while equal volume of saline (control) was injected into the muscle of the contralateral limb. The animals were sacrificed on 0, 21, and 35 days after the administration of cells. MSCs transplantation led to significant reduction of the area of muscle damage. Immunohistochemical analysis revealed earlier increase in the proportion of MyoD- and myogenin-positive cells, as well as decrease in the expression of Ki-67 in damaged tissue, in experimental group compared to the control. Autologous cells did not significantly affect the composition of muscle fibers. Significant decrease in the proportion of fibrous tissue was also observed in the experimental group. The results indicate the effectiveness of autologous alveolar gingiva-derived MSCs for treatment of mechanical damage of muscle tissue. Local administration of cells accelerated reparative regeneration and prevented fibrosis
SAFETY AND EFFECTIVENESS OF INTRAARTICULAR ADMINISTRATION OF ADIPOSE-DERIVED STROMAL VASCULAR FRACTION FOR TREATMENT OF KNEE ARTICULAR CARTILAGE DEGENERATIVE DAMAGE: PRELIMINARY RESULTS OF A CLINICAL TRIAL
The incidence of knee osteoarthritis tends to increase every year and constitutes more than 83% of overall OA morbidity. Moreover, the OA morbidity among younger patients is also increasing. However, currently available treatment methods do not provide quite satisfactory outcomes.Purpose of the study – to evaluate safety and efficacy of intraarticular introduction of autologous adipose-derived stromal vascular fraction for treatment of knee osteoarthritis.Material and methods. By the moment of writing the present report, 28 patients were included into the study. All patients underwent tumescent liposuction under local anesthesia. The stromal vascular fraction was isolated from lipoaspirate within 1,5 hours after harvesting and subsequently injected into the articular cavity. Follow-up period was 6 months after injections. The authors report on efficacy data of 10 patients who completed the study according to protocol and safety data of all 28 patients. Efficacy was evaluated basing on laboratory assessments and patient’s subjective assessment by validated questionnaires.Results. Neither adverse reactions no adverse events were observed. Significant decrease of pain severity by VAS was noted in one week after injection and pain score continued decreasing during the whole follow up period. The increase of KOOS score was noted starting on the fifth week after injection. KSS part 1 score increased in 8 weeks, KSS part 2 score — in 6 months after injection. Physical health, assessed with SF-36 questionnaire significantly improved in 2 and 6 months after the procedure. There was a clear trend towards improvement of mental health.Conclusion. Preliminary results of clinical study suggest intraarticular injection of autologous adipose-derived stromal vascular fraction to be a safe and efficient method of the treatment of knee osteoarthritis
Lineage Regulators Direct BMP and Wnt Pathways to Cell-Specific Programs during Differentiation and Regeneration
SummaryBMP and Wnt signaling pathways control essential cellular responses through activation of the transcription factors SMAD (BMP) and TCF (Wnt). Here, we show that regeneration of hematopoietic lineages following acute injury depends on the activation of each of these signaling pathways to induce expression of key blood genes. Both SMAD1 and TCF7L2 co-occupy sites with master regulators adjacent to hematopoietic genes. In addition, both SMAD1 and TCF7L2 follow the binding of the predominant lineage regulator during differentiation from multipotent hematopoietic progenitor cells to erythroid cells. Furthermore, induction of the myeloid lineage regulator C/EBPα in erythroid cells shifts binding of SMAD1 to sites newly occupied by C/EBPα, whereas expression of the erythroid regulator GATA1 directs SMAD1 loss on nonerythroid targets. We conclude that the regenerative response mediated by BMP and Wnt signaling pathways is coupled with the lineage master regulators to control the gene programs defining cellular identity
Prehospital Period in Patients with COVID-19: Cardiovascular Comorbidity and Pharmacotherapy During the First Epidemic Wave (Hospital Registry Data)
Aim. Based on the data from the register of patients with COVID-19 and community-acquired pneumonia (CAP), analyze the duration of the prehospital period, cardiovascular comorbidity and the quality of prehospital pharmacotherapy of concomitant cardiovascular diseases (CVD).Material and methods. Patients were included to the study which admitted to the FSBI "NMHC named after N.I. Pirogov" of the Ministry of Health of the Russian Federation with a suspected or confirmed diagnosis of COVID-19 and/or CAP. The data for prehospital therapy, information from medical histories and a patients’survey in the hospital or by telephone contact 1-2 weeks after discharge were study. The duration of the prehospital stage was determined from the date of the appearance of clinical symptoms of coronavirus infection to the date of hospitalization.Results. The average age of the patients (n=1130; 579 [51.2%] men and 551 [48.8%] women) was 57.5±12.8 years. The prehospital stage was 7 (5,0; 10,0) days and did not differ significantly in patients with the presence and absence of CVD, but was significantly less in the deceased than in the surviving patients, as well as in those who required artificial lung ventilation (ALV). 583 (51.6%) patients had at least one CVD. Cardiovascular comorbidity was registered in 222 (42.7%) patients with hypertension, 210 (95.5%) patients with coronary heart disease (CHD), 104 (91.2%) patients with atrial fibrillation (AF). The inclusion of non-cardiac chronic diseases in the analysis led to an increase in the total proportion of patients with concomitant diseases to 65.8%. Approximately a quarter of hypertensive patients did not receive antihypertensive therapy, a low proportion of patients receiving antiplatelet agents and statins for CHD was revealed – 53% and 31.8%, respectively, anticoagulants for AF – 50.9%.Conclusion. The period from the onset of symptoms to hospitalization was significantly shorter in the deceased than in the surviving patients, as well as in those who required ALV. The proportion of people with a history of at least one CVD was about half of the entire cohort of patients. In patients with CVD before COVID-19 disease, a low frequencies of prescribing antihypertensive drugs, statins, antiplatelet agents and anticoagulants (in patients with AF) were recorded at the prehospital stage
Distributed Dynamical Computation in Neural Circuits with Propagating Coherent Activity Patterns
Activity in neural circuits is spatiotemporally organized. Its spatial organization consists of multiple, localized coherent patterns, or patchy clusters. These patterns propagate across the circuits over time. This type of collective behavior has ubiquitously been observed, both in spontaneous activity and evoked responses; its function, however, has remained unclear. We construct a spatially extended, spiking neural circuit that generates emergent spatiotemporal activity patterns, thereby capturing some of the complexities of the patterns observed empirically. We elucidate what kind of fundamental function these patterns can serve by showing how they process information. As self-sustained objects, localized coherent patterns can signal information by propagating across the neural circuit. Computational operations occur when these emergent patterns interact, or collide with each other. The ongoing behaviors of these patterns naturally embody both distributed, parallel computation and cascaded logical operations. Such distributed computations enable the system to work in an inherently flexible and efficient way. Our work leads us to propose that propagating coherent activity patterns are the underlying primitives with which neural circuits carry out distributed dynamical computation
Hematopoietic Stem Cell Development Is Dependent on Blood Flow
SummaryDuring vertebrate embryogenesis, hematopoietic stem cells (HSCs) arise in the aorta-gonads-mesonephros (AGM) region. We report here that blood flow is a conserved regulator of HSC formation. In zebrafish, chemical blood flow modulators regulated HSC development, and silent heart (sih) embryos, lacking a heartbeat and blood circulation, exhibited severely reduced HSCs. Flow-modifying compounds primarily affected HSC induction after the onset of heartbeat; however, nitric oxide (NO) donors regulated HSC number even when treatment occurred before the initiation of circulation, and rescued HSCs in sih mutants. Morpholino knockdown of nos1 (nnos/enos) blocked HSC development, and its requirement was shown to be cell autonomous. In the mouse, Nos3 (eNos) was expressed in HSCs in the AGM. Intrauterine Nos inhibition or embryonic Nos3 deficiency resulted in a reduction of hematopoietic clusters and transplantable murine HSCs. This work links blood flow to AGM hematopoiesis and identifies NO as a conserved downstream regulator of HSC development
Modelling human choices: MADeM and decision‑making
Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)