Fluid structural analysis of urine flow in a stented ureter

Many urologists are currently studying new designs of ureteral stents to improve the quality of their operations and the subsequent recovery of the patient. In order to help during this design process, many computational models have been developed to simulate the behaviour of different biological tissues and provide a realistic computational environment to evaluate the stents. However, due to the high complexity of the involved tissues, they usually introduce simplifications to make these models less computationally demanding. In this study, the interaction between urine flow and a double-J stented ureter with a simplified geometry has been analysed.The Fluid-Structure Interaction (FSI) of urine and the ureteral wall was studied using three models for the solid domain: Mooney-Rivlin, Yeoh, and Ogden. The ureter was assumed to be quasi-incompressible and isotropic. Data obtained in previous studies fromex vivo and in vivo mechanical characterization of different ureters were used to fit thementioned models.The results show that the interaction between the stented ureter and urine is negligible. Therefore, we can conclude that this type of models does not need to include the FSI and could be solved quite accurately assuming that the ureter is a rigid body and, thus, using the more simple Computational Fluid Dynamics (CFD) approach

Characterization of microRNA expression profiles in normal and osteoarthritic human chondrocytes

[Abstract] Background. Osteoarthritis (OA) is a multifactorial disease characterized by destruction of the articular cartilage due to environmental, mechanical and genetic components. The genetics of OA is complex and is not completely understood. Recent works have demonstrated the importance of microRNAs (miRNAs) in cartilage function. MiRNAs are a class of small noncoding RNAs that regulate gene expression and are involved in different cellular process: apoptosis, proliferation, development, glucose and lipid metabolism. The aim of this study was to identify and characterize the expression profile of miRNAs in normal and OA chondrocytes and to determine their role in the OA. Methods. Chondrocytes were moved to aggregate culture and evaluated using histological and qPCR techniques. miRNAs were isolated and analyzed using the Agilent Human miRNA Microarray. Results. Of the 723 miRNAs analyzed, 7 miRNAs showed a statistically significant differential expression. Amongst these 7 human miRNAs, 1 was up-regulated in OA chondrocytes (hsa-miR-483-5p) and 6 were up-regulated in normal chondrocytes (hsa-miR-149*, hsa-miR-582-3p, hsa-miR-1227, hsa-miR-634, hsa-miR-576-5p and hsa-miR-641). These profiling results were validated by the detection of some selected miRNAs by qPCR. In silico analyses predicted that key molecular pathways potentially altered by the miRNAs differentially expressed in normal and OA chondrocytes include TGF-beta, Wnt, Erb and mTOR signalling; all of them implicated in the development, maintenance and destruction of articular cartilage. Conclusions. We have identified 7 miRNAs differentially expressed in OA and normal chondrocytes. Our potential miRNA target predictions and the signalling cascades altered by the differentially expressed miRNAs supports the potential involvement of the detected miRNAs in OA pathology. Due to the importance of miRNA in mediating the translation of target mRNA into protein, the identification of these miRNAs differentially expressed in normal and OA chondrocyte micropellets could have important diagnostic and therapeutic potential. Further studies are needed to know the function of these miRNAs, including the search of their target mRNA genes, which could lead to the development of novel therapeutic strategies for the OA treatment.Instituto de Salud Carlos III; CIBER BBN CB06-01-004

Reduced Levels of H₂S in Diabetes-Associated Osteoarthritis Are Linked to Hyperglycaemia, Nrf-2/HO-1 Signalling Downregulation and Chondrocyte Dysfunction

[Abstract] Different findings indicate that type 2 diabetes is an independent risk factor for osteoarthritis (OA). However, the mechanisms underlying the connection between both diseases remain unclear. Changes in the balance of hydrogen sulphide (H₂S) are thought to play an important role in the pathogenesis of diabetes and its complications, although its role is still controversial. In this study, we examined the modulation of H₂S levels in serum and chondrocytes from OA diabetic (DB) and non-diabetic (non-DB) patients and in cells under glucose stress, in order to elucidate whether impairment in H₂S-mediated signalling could participate in the onset of DB-related OA. Here, we identified a reduction in H₂S synthesis in the cartilage from OA-DB patients and in cells under glucose stress, which is associated with hyperglycaemia-mediated dysregulation of chondrocyte metabolism. In addition, our results indicate that H₂S is an inductor of the Nrf-2/HO-1 signalling pathway in cartilage, but is also a downstream target of Nrf-2 transcriptional activity. Thereby, impairment of the H₂S/Nrf-2 axis under glucose stress or DB triggers chondrocyte catabolic responses, favouring the disruption of cartilage homeostasis that characterizes OA pathology. Finally, our findings highlight the benefits of the use of exogeneous sources of H₂S in the treatment of DB-OA patients, and warrant future clinical studies.This research was funded by grant PI19/01206 from the Fondo de Investigación Sanitaria, integrated in the National Plan for Scientific Program, Development, and Technological Innovation 2013–2016 and funded by the Instituto de Salud Carlos III (ISCIII)-General Subdirection of Assessment and Promotion of Research-European Regional Development Fund (FEDER) “A way of making Europe”, and also by grants ED431B 2020/55 (Grupos con Potencial de Crecemento 2020) and IN607A 2021/7 (Grupos de Referencia Competitiva) from Xunta de Galicia. The study was also supported by the Biomedical Research Network Centre (CIBER), an initiative of ISCIII. C.V.-G. thanks Xunta de Galicia for his postdoctoral contract (grant number ED481D 2017/023)Xunta de Galicia; ED431B 2020/55Xunta de Galicia; IN607A 2021/7Xunta de Galicia; ED481D 2017/02

One-year, efficacy and safety open label study, with a single injection of a new hyaluronan for knee OA: the SOYA trial

[Abstract] Purpose. To assess the efficacy and safety of a single injection of a new formulation of hyaluronic acid (MPS-HA2%) in patients with symptomatic knee osteoarthritis after 12 months’ follow-up. Patients and Methods. Prospective, single-arm, multicentre, open-label, 12-month follow-up study. Patients with Kellgren–Lawrence (KL) 2–3 and visual analogue scale (VAS) pain scores of ≥40–< 80 mm received a single injection of MPS-HA2%. The primary outcome was the reduction in VAS pain scores from baseline, and the secondary outcomes were the Western Ontario and McMaster (WOMAC) Universities Osteoarthritis Index, the minimum clinically important improvement (MCII), and patient and investigator global assessments (PGA, IGA) measured on 5-point Likert scale. Adverse events were recorded throughout the study for safety purposes. Results. A total of 101 patients (mean age: 68 years; 74% female; and 78% overweight) were included. The mean reduction in pain at 12 months was 37.7%; the total WOMAC score improved by 36.5% and the pain, stiffness and physical function subscores returned improvements of 32.1%, 34.1% and 32.7%, respectively (p=0.0001 with respect to baseline). At 12 months, a statistically significant 62.2% of patients obtained an improvement equal to or greater than the MCII. The mean PGA score at baseline was 2.44 and 1.46 at 12 months (p<0.05), and the mean IGA scores at equivalent timepoints were 2.29 and 1.48 (p<0.05). Fourteen patients received a second injection at the 6-month follow-up visit. Eight patients reported a total of 12 treatment-related adverse events that were local, non-serious and of mild-to-moderate intensity. Conclusion. With just a single intra-articular injection, this not controlled trial suggests that MPS-HA2% is effective 12 months after the procedure in most cases. Patient tolerability and safety were both optimal (NCT03852914)

Effect of balneotherapy in sulfurous water on an in vivo murine model of osteoarthritis

[Abstract] Osteoarthritis (OA) is a chronic joint disease that results in progressive cartilage destruction and subsequently joint dysfunction. Growing evidence indicates beneficial impact of balneological interventions in OA; however, their mechanisms of action are still unclear. Here, we evaluate the effect of balneotherapy in sulfurous water in an OA experimental model. Experimental OA was induced in Wistar rats by transection of the medial collateral ligament and removal of the medial meniscus of the left knee. Animals were randomized into three groups: non-treated (control) and balneotherapy using sulfurous water (SW) or tap water (TW). Macroscopic evaluation was performed, as well as evaluation of pain levels and analysis of motor function by rotarod test. Histopathological changes in articular cartilage and synovium were also evaluated. The presence of matrix metalloproteinase-13 (MMP-13) and oxidative damage markers was assessed by immunohistochemistry. Joint destabilization induced joint thickening, loss of joint flexion, and increased levels of pain. At day 40, animals from SW group presented lower pain levels than those from control group. Experimental OA also affected motor function. Balneotherapy in sulfur-rich water significantly improved joint mobility in relation to that in tap water. Besides, we observed that cartilage deterioration was lower in SW group than in the other two groups. Likewise, SW group showed reduced levels of MMP-13 in the cartilage. Conversely, we failed to observe any modulation on synovial inflammation. Finally, balneotherapy in sulfurous water diminished the presence of oxidative damage markers. Our results suggest the beneficial effect of balneotherapy in sulfur-rich water on an experimental model of OA, showing a reduced cartilage destruction and oxidative damage. Thus, these findings support the use of balneotherapy as a non-pharmacological treatment in OA.Instituto de Salud Carlos III; PI16/02124Xunta de Galicia; AGRUP2015/05 CICA-INIBICXunta de Galicia; IN607A 2017/11(GPC

Constructing a small modular stellarator in Latin America

https://www.scopus.com/inward/record.url?eid=2-s2.0-84938118149&partnerID=40&md5=1d385f1e177901beaf6f30228abdd67bThis paper aims at briefly describing the design and construction issues of the stellarator of Costa Rica 1 (SCR-1). The SCR-1 is a small modular stellarator for magnetic confinement of plasma developed by the Plasma Laboratory for Fusion Energy and Applications of the Instituto Tecnológico de Costa Rica (ITCR). SCR-1 will be a 2-field period small modular stellarator with an aspect ratio > 4.4; low shear configuration with core and edge rotational transform equal to 0.32 and 0.28; it will hold plasma in a 6061-T6 aluminum torus shaped vacuum vessel with an minor plasma radius 54.11 mm, a volume of 13.76 liters (0.01 m3), and major radius R = 238 mm. Plasma will be confined in the volume by on axis magnetic field 43.8 mT generated by 12 modular coils with 6 turns each, carrying a current of 767.8 A per turn providing a total toroidal field (TF) current of 4.6 kA-turn per coil. The coils will be supplied by a bank of cell batteries of 120 V. Typical length of the plasma pulse will be between 4 s to 10 s. The SCR-1 plasmas will be heated by ECH second harmonic at 2.45 GHz with a plasma density cut-off value of 7.45 × 1016 m-3. Two magnetrons with a maximum output power of 2 kW and 3 kW will be used. © Published under licence by IOP Publishing Ltd.Ad Astra Rocket Company,Instituto Tecnologico de Costa Rica,International Atomic Energy Agency (IAEA),Universidad Nacional de Costa Ric

Long-term effects of hydrogen sulfide on the anabolic-catabolic balance of articular cartilage in vitro

[Abstract] Healthy cartilage maintenance relies on an equilibrium among the anabolic and catabolic processes in chondrocytes. With the onset of osteoarthritis (OA), increased interleukin (IL)-1β levels induce an inhibition of the synthesis of extracellular matrix (ECM) proteins, as well as an increase in proteases. This eventually leads to a predominance of the catabolic phenotype and the progressive loss of articular cartilage. Hydrogen sulfide (H2S) is a small gaseous molecule recognized as the third endogenous gasotransmitter. When administered exogenously, it has shown anti-inflammatory and anti-catabolic properties in several in vitro and in vivo models. Here, OA cartilage disks were co-cultured in vitro with IL-1β (5 ng/ml) and NaSH or GYY4137 (200 or 1000 μM) for 21 days. The ability of these two H2S-producing compounds to avoid long term extracellular matrix (ECM) destruction was evaluated. We used a glycosaminoglycan (GAG) quantification kit histology and immunohistochemistry (IHC) to evaluate matrix proteins degradation and matrix metalloproteinases (MMP) abundance. Through the GAGs quantification assay, safranin O (S-O) and toluidine blue (TB) stains, and keratan/chondroitin sulfate (KS/ChS) IHCs it was shown that co-stimulation with H2S-forming reagents effectively avoided GAGs destruction. Both Masson's trichrome (MT) stain and collagen (col) type II IHC, as well as aggrecan (agg) IHC demonstrated that not only were these proteins protected but even promoted, their abundance being higher than in the basal condition. Further, stains also demonstrated that positivity in the inter-territorial and intra-cellular for the different matrix components were rescued, suggesting that NaSH and GYY4137 might also have pro-anabolic effects. In addition, a clear protective effect against the increased MMPs levels was seen, since increased MMP3 and 13 levels were subsequently reduced with the co-stimulation with sulfide compounds. In general, GYY4137 was more effective than NaSH, and increasing the dose improved the results. This study demonstrates that H2S anti-catabolic effects, which had been previously proven in short-term (24–48 h) in vitro cellular models, are maintained over time directly in OA cartilage tissue.Instituto de Salud Carlos III; PI12/0032

Intraarticular Administration Effect of Hydrogen Sulfide on an In Vivo Rat Model of Osteoarthritis

[Abstract] Osteoarthritis (OA) is the most common articular chronic disease. However, its current treatment is limited and mostly symptomatic. Hydrogen sulfide (H2S) is an endogenous gas with recognized physiological activities. The purpose here was to evaluate the effects of the intraarticular administration of a slow-releasing H2S compound (GYY-4137) on an OA experimental model. OA was induced in Wistar rats by the transection of medial collateral ligament and the removal of the medial meniscus of the left joint. The animals were randomized into three groups: non-treated and intraarticularly injected with saline or GYY-4137. Joint destabilization induced articular thickening (≈5% increment), the loss of joint mobility and flexion (≈12-degree angle), and increased levels of pain (≈1.5 points on a scale of 0 to 3). Animals treated with GYY-4137 presented improved motor function of the joint, as well as lower pain levels (≈75% recovery). We also observed that cartilage deterioration was attenuated in the GYY-4137 group (≈30% compared with the saline group). Likewise, these animals showed a reduced presence of pro-inflammatory mediators (cyclooxygenase-2, inducible nitric oxide synthase, and metalloproteinase-13) and lower oxidative damage in the cartilage. The increment of the nuclear factor-erythroid 2-related factor 2 (Nrf-2) levels and Nrf-2-regulated gene expression (≈30%) in the GYY-4137 group seem to be underlying its chondroprotective effects. Our results suggest the beneficial impact of the intraarticular administration of H2S on experimental OA, showing a reduced cartilage destruction and oxidative damage, and supporting the use of slow H2S-producing molecules as a complementary treatment in OA.Instituto de Salud Carlos III; PI16/02124Xunta de Galicia; AGRUP2015/05 CICA-INIBICXunta de Galicia; IN607A 2017/1

mtDNA variability determines spontaneous joint aging damage in a conplastic mouse model.

Mitochondria and mtDNA variations contribute to specific aspects of the aging process. Here, we aimed to investigate the influence of mtDNA variation on joint damage in a model of aging using conplastic mice. A conplastic (BL/6NZB) mouse strain was developed with the C57BL/6JOlaHsd nuclear genome and NZB/OlaHsd mtDNA, for comparison with the original C57BL/6JOlaHsd strain (BL/6C57). Conplastic (BL/6NZB) and BL/6C57 mice were sacrificed at 25, 75, and 90 weeks of age. Hind knee joints were processed for histological analysis and joint pathology graded using the Mankin scoring system. By immunohistochemistry, cartilage expression of markers of autophagy (LC3, Beclin-1, and P62) and markers of senescence (MMP13, beta-Galactosidase, and p16) and proliferation (Ki67) were analyzed. We also measured the expression of 8-oxo-dG and cleaved caspase-3. Conplastic (BL/6NZB) mice presented lower Mankin scores at 25, 75, and 90 weeks of age, higher expression of LC3 and Beclin-1 and lower of P62 in cartilage than the original strain. Moreover, the downregulation of MMP13, beta-Galactosidase, and p16 was detected in cartilage from conplastic (BL/6NZB) mice, whereas higher Ki67 levels were detected in these mice. Finally, control BL/6C57 mice showed higher cartilage expression of 8-oxo-dG and cleaved caspase-3 than conplastic (BL/6NZB) mice. This study demonstrates that mtDNA genetic manipulation ameliorates joint aging damage in a conplastic mouse model, suggesting that mtDNA variability is a prognostic factor for aging-related osteoarthritis (OA) and that modulation of mitochondrial oxidative phosphorylation (OXPHOS) could be a novel therapeutic target for treating OA associated with aging.This work was supported by grants from Fondo de Investigación Sanitaria (PI16/02124, PI19/01206 and RETIC-RIER-RD16/0012/0002) integrated in the National Plan for Scientific Program, Development and Technological Innovation 2013–2016, and funded by the ISCIII-General Subdirection of Assessment and Promotion of Research-European Regional Development Fund (FEDER) “A way of making Europe”, by Grant IN607A2021/07 from GAIN, Xunta de Galicia (F.J.B.) and by CIBERFES-ISCIII, MINECO: SAF2015-65633-R, RTI2018-099357-BI00, and HFSP (RGP0016/2018) to J.A.E.S