Anti-inflammatory potential of ulvan.

Green seaweeds are a widespread group of marine macroalgae that could be regarded as biorenewable source of valuable compounds, in particular sulfated polysaccharides like ulvans with interesting biological properties. Among them, anti-inflammatory activity represents an interesting target, since ulvans could potentially avoid side effects of conventional therapies. However, a great variability in ulvan content, composition, structure and properties occurs depending on seaweed specie and growth and processing conditions. All these aspects should be carefully considered in order to have reproducible and well characterized products. This review presents some concise ideas on ulvan composition and general concepts on inflammation mechanisms. Then, the main focus is on the importance of adequate selection of extraction, depolymerization and purification technologies followed by an updated survey on anti-inflammatory properties of ulvans through modulation of different signaling pathways. The potential application in a number of diseases, with special emphasis on inflammaging, gut microbiota dysbiosis, wound repair, and metabolic diseases is also discussed. This multidisciplinary overview tries to present the potential of ulvans considering not only mechanistic, but also processing and applications aspects, trusting that it can aid in the development and application of this widely available and renewable resource as an efficient and versatile anti-inflammatory agent.

Study of hydrogen sulfide biosynthesis in synovial tissue from diabetes-associated osteoarthritis and its influence on macrophage phenotype and abundance

Type 2 diabetes (DB) is an independent risk factor for osteoarthritis (OA). However, the mechanisms underlying the connection between both diseases remain unclear. Synovial macrophages from OA patients with DB present a marked pro-inflammatory phenotype. Since hydrogen sulphide (H2S) has been previously described to be involved in macrophage polarization, in this study we examined H2S biosynthesis in synovial tissue from OA patients with DB, observing a reduction of H2S-synthetizing enzymes in this subset of individuals. To elucidate these findings, we detected that differentiated TPH-1 cells to macrophages exposed to high levels of glucose presented a lower expression of H2S-synthetizing enzymes and an increased inflammatory response to LPS, showing upregulated expression of markers associated with M1 phenotype (i.e., CD11c, CD86, iNOS, and IL-6) and reduced levels of those related to M2 fate (CD206 and CD163). The co-treatment of the cells with a slow-releasing H2S donor, GYY-4137, attenuated the expression of M1 markers, but failed to modulate the levels of M2 indicators. GYY-4137 also reduced HIF-1α expression and upregulated the protein levels of HO-1, suggesting their involvement in the anti-inflammatory effects of H2S induction. In addition, we observed that intraarticular administration of H2S donor attenuated synovial abundance of CD68+ cells, mainly macrophages, in an in vivo model of OA. Taken together, the findings of this study seem to reinforce the key role of H2S in the M1-like polarization of synovial macrophages associated to OA and specifically its metabolic phenotype, opening new therapeutic perspectives in the management of this pathology. (AU)

Mesenchymal Stem Cell Therapy in Traumatic Spinal Cord Injury: A Systematic Review.

Recovery from a traumatic spinal cord injury (TSCI) is challenging due to the limited regenerative capacity of the central nervous system to restore cells, myelin, and neural connections. Cell therapy, particularly with mesenchymal stem cells (MSCs), holds significant promise for TSCI treatment. This systematic review aims to analyze the efficacy, safety, and therapeutic potential of MSC-based cell therapies in TSCI. A comprehensive search of PUBMED and COCHRANE databases until February 2023 was conducted, combining terms such as "spinal cord injury," "stem cells," "stem cell therapy," "mesenchymal stem cells," and "traumatic spinal cord injury". Among the 53 studies initially identified, 22 (21 clinical trials and 1 case series) were included. Findings from these studies consistently demonstrate improvements in AIS (ASIA Impairment Scale) grades, sensory scores, and, to a lesser extent, motor scores. Meta-analyses further support these positive outcomes. MSC-based therapies have shown short- and medium-term safety, as indicated by the absence of significant adverse events within the studied timeframe. However, caution is required when drawing generalized recommendations due to the limited scientific evidence available. Further research is needed to elucidate the long-term safety and clinical implications of these advancements. Although significant progress has been made, particularly with MSC-based therapies, additional studies exploring other potential future therapies such as gene therapies, neurostimulation techniques, and tissue engineering approaches are essential for a comprehensive understanding of the evolving TSCI treatment landscape.

Study of hydrogen sulfide biosynthesis in synovial tissue from diabetes-associated osteoarthritis and its influence on macrophage phenotype and abundance.

Type 2 diabetes (DB) is an independent risk factor for osteoarthritis (OA). However, the mechanisms underlying the connection between both diseases remain unclear. Synovial macrophages from OA patients with DB present a marked pro-inflammatory phenotype. Since hydrogen sulphide (H2S) has been previously described to be involved in macrophage polarization, in this study we examined H2S biosynthesis in synovial tissue from OA patients with DB, observing a reduction of H2S-synthetizing enzymes in this subset of individuals. To elucidate these findings, we detected that differentiated TPH-1 cells to macrophages exposed to high levels of glucose presented a lower expression of H2S-synthetizing enzymes and an increased inflammatory response to LPS, showing upregulated expression of markers associated with M1 phenotype (i.e., CD11c, CD86, iNOS, and IL-6) and reduced levels of those related to M2 fate (CD206 and CD163). The co-treatment of the cells with a slow-releasing H2S donor, GYY-4137, attenuated the expression of M1 markers, but failed to modulate the levels of M2 indicators. GYY-4137 also reduced HIF-1α expression and upregulated the protein levels of HO-1, suggesting their involvement in the anti-inflammatory effects of H2S induction. In addition, we observed that intraarticular administration of H2S donor attenuated synovial abundance of CD68+ cells, mainly macrophages, in an in vivo model of OA. Taken together, the findings of this study seem to reinforce the key role of H2S in the M1-like polarization of synovial macrophages associated to OA and specifically its metabolic phenotype, opening new therapeutic perspectives in the management of this pathology.

Relevance of the Extraction Stage on the Anti-Inflammatory Action of Fucoidans.

The anti-inflammatory action of fucoidans is well known, based on both in vitro and some in vivo studies. The other biological properties of these compounds, their lack of toxicity, and the possibility of obtaining them from a widely distributed and renewable source, makes them attractive novel bioactives. However, fucoidans' heterogeneity and variability in composition, structure, and properties depending on seaweed species, biotic and abiotic factors and processing conditions, especially during extraction and purification stages, make it difficult for standardization. A review of the available technologies, including those based on intensification strategies, and their influence on fucoidan composition, structure, and anti-inflammatory potential of crude extracts and fractions is presented.

Prognostic value of early magnetic resonance imaging in the morbidity and mortality of traumatic spinal cord injury.

OBJECTIVE: To assess in individuals with traumatic spinal cord injury (TSCI) the relationship between mortality and need for ICU and early magnetic resonance imaging (MRI), analyzing spinal parenchymal alterations, disruption of vertebral ligaments (DVL) and spinal cord compression (SCC). DESIGN: Retrospective study. SETTING: Third-level hospital, Spinal Cord Injury Unit and ICU. PATIENTS: Individuals with acute TSCI between 2010 and 2019. INTERVENTION: Analysis of MRI performed in the first 72 h. VARIABLES OF INTEREST: Admission to ICU and mortality. RESULTS: 269 cases collected. The pattern that demonstrated higher mortality was cord hemorrhage (16.7%) for 12.5% ​​of single-level edema and 6.5% of multilevel edema (p = 0.125). The same happened with ICU admissions: 69.0% in hemorrhage, 60.2% in multilevel edema and 46.3% in short edema (p = 0.018). Analyzing CCM, mortality was 13.4% with 59.2% of ICU admissions, for 2.2% and 42.2% of individuals without cord compression (p = 0.020 and p = 0.003). The figures of death and ICU admission among cord injuries with DVL were 15.0% and 67.3%, for 6.2% and 44.4% of the individuals without DLV (p < 0.001 and p = 0.013). CONCLUSIONS: The presence of spinal cord hemorrhage, SCC and DVL was associated with a higher admission in ICU. A significant increase in mortality was observed in cases with SCC and DVL.

Evaluation of the prognostic value of extra-parenchymal changes in traumatic spinal cord injury, assessed by magnetic resonance imaging.

OBJECTIVES: To analyze the relationship between neurological progression following traumatic spinal cord injury and Spinal Cord Compression (SCC) and Spinal Ligamentous Injury (LI) by magnetic resonance imaging. DESIGN: Retrospective observational study. SETTING: Spinal Cord Injury Unit (A Coruña, Spain). PARTICIPANTS: Patients were admitted for traumatic spinal cord injury between January 2010 and December 2018 with a magnetic resonance imaging examination performed during the acute phase. INTERVENTION: Evaluation of SCC and LI by magnetic resonance imaging. OUTCOME MEASURES: Comparisons between neurological examination at admission and discharge were made, assessing ASIA Impairment Scale (AIS) grade and motor score. RESULTS: Data from 296 patients were collected. A relationship between SCC and LI and complete injuries were found (P < 0.001). Improvement of the AIS grade was observed in 31.6% of patients with SCC and 31.3% with LI versus 42.7% and 37.8% of subjects without these complications, respectively. Regarding motor score, patients with SCC had lower mean values at the beginning (46.9 ± 26.8 versus 61.1 ± 29.9 in the control group, P < 0.001), as well as less improvement when assessed by the percentage of change (35.1 ± 37.5% versus 49.4 ± 38.1% in the control group, P = 0.010). Similar results were obtained in cases with LI: mean motor score at admission was 45.9 ± 26.7 versus 54.9 ± 29.4 in the control group (P = 0.014) and the percentage of change was 28.5 ± 37.1% in comparison to 46.0 ± 37.5% (P = 0.001) in the controls. CONCLUSIONS: There is a relationship between SCC and LI and complete spinal cord injury. This patient population has lower possibilities of improving their AIS grade and motor score.

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

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.

Antifibrotic effect of brown algae-derived fucoidans on osteoarthritic fibroblast-like synoviocytes.

Synovial fibrosis is a pathological process which contributes to joint pain and stiffness in several musculoskeletal disorders. Fucoidans, sulfated polysaccharides found in brown algae, have recently emerged as promising therapeutic agents. Despite the increasing amount of evidence suggesting the protective role of fucoidans in different experimental approaches of human fibrotic disorders, the effect of these sulfated polysaccharides on synovial fibrosis has not been investigated yet. By an in vitro experimental approach in fibroblast-like synoviocytes, we detected that fucoidans inhibit their differentiation into myofibroblasts with tumor cell-like characteristics and restore apoptosis. Composition and structure of fucoidan appear to be critical for the detected activity. Furthermore, protective effects of these sulfated polysaccharides are mediated by upregulation of nitric oxide production and modulation of TGF-ß/smad pathway. Altogether, our results support the use of fucoidans as therapeutic compounds in the treatment of the fibrotic processes involved in rheumatic pathologies.

Neurological recovery after traumatic spinal cord injury: prognostic value of magnetic resonance.

STUDY DESIGN: Retrospective observational study. OBJECTIVES: Assess the relationship between Magnetic Resonance (MR) image patterns and neurological recovery in patients with Traumatic Spinal Cord Injury (TSCI). SETTING: Spinal cord injury unit in Spain. METHODS: Patients admitted for acute TSCI between January 2010 and December 2018 with a MR exam performed in the acute phase were selected. Five patterns were established: normal, single-level edema, multilevel edema, hemorrhage, and spinal cord transection. Comparisons between the ASIA Injury Severity (AIS) score and Motor Index (MI) at admission and at discharge were made. RESULTS: Collected 296 patients. Normal and cord transection patterns were excluded due to the low number of cases. Single-level edema pattern was primarily observed in cases with incomplete injuries, hemorrhage pattern in complete injuries, and multilevel edema pattern at similar percentages in complete and incomplete lesions. Improvement of the AIS score was found in 40.9% of single-level edema, 20.2% of multilevel edema, and 19.0% of hemorrhage (p = 0.042) patterns. By excluding the AIS grade D from the analyses, the figures increased to 70.3%, 52.2%, and 19.4% respectively (p < 0.001). This significant relationship was confirmed by multivariate analysis, although it was not as relevant as the examination according to ASIA-ISCoS performed at admission (p = 0.005 vs p < 0.001). Mean variation of the MI was also significantly different (p < 0.001) between the three groups: 22.6 ± 21.4 for single-level edema, 16.9 ± 21.1 for multilevel edema, and 4.5 ± 8.4 for hemorrhage. CONCLUSION: MR injury patterns observed at the acute phase are associated with the possibility of improvement of the AIS score and MI.

A pilot randomized controlled trial of aquatic-based activities in a group occupational therapy program for adults living with serious mental illness in Spain.

Although aquatic-based interventions are increasingly used in the psychiatric rehabilitation services, the effects of this type of community program as an adjuvant therapy for psychosocial problems of people with serious mental illness (SMI) have been under-explored. This research evaluated the feasibility and outcomes of an occupational therapy program consisting of aquatic-based activities (AA-OT program) in the community in Spain. This study is the first randomized controlled trial (RCT) on this topic. This pilot trial was conducted with a sample of 16 adults with SMI who were randomly allocated to the AA-OT program plus treatment as usual or treatment as usual alone (eight in each group). The AA-OT program included activation of daily living skills, warm-up, group activities/tasks, and relaxation. It consisted of two sessions per week over 12 weeks. Outcomes were evaluated at week 0 and 12. A total of 14 participants (87.5%) completed the trial. No adverse events or side-effects were noted. Comparisons between the two groups on change scores showed that participants in the intervention group showed significant improvements in several outcome measures: psychosocial problems (HoNOS), two health-related quality of life scales (SF-36: Physical Functioning and Mental Health), and performance of social activities (Activity and Social Relations scale). Satisfaction with the program was high. In conclusion, the results support the feasibility and potential benefits of this occupational therapy program. 12 weeks of aquatic-based activities in a group intervention may enhance the outcomes of psychiatric rehabilitation improving the severity of psychosocial problems, patient-reported health status, and social relations. This community-based program may be beneficial as a non-pharmacologic method in the illness management and recovery of people with SMI. The findings from this pilot trial need to be confirmed in a large, fully-powered RCT.

Study of fucoidans as natural biomolecules for therapeutical applications in osteoarthritis.

Osteoarthritis (OA) is the most prevalent articular chronic disease. Although, to date there is no cure for OA. Fucoidans, one of the main therapeutic components of brown algae, have emerged as promising molecules in OA treatment. However, the variability between fucoidans makes difficult the pursuit of the most suitable candidate to target specific pathological processes. By an in vitro experimental approach in chondrocytes and fibroblast-like synoviocytes, we observed that chemical composition of fucoidan, and specifically the phlorotannin content and the ratio sulfate:fucose, seems critically relevant for its biological activity. Nonetheless, other factors like concentration and molecular weight of the fucoidan may influence on its beneficial effects. Additionally, a cell-type dependent response was also detected. Thus, our results shed light on the potential use of fucoidans as natural molecules in the treatment of key pathological processes in the joint that favor the development of rheumatic disorders as OA.

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

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.

Is Myofascial Release Therapy Cost-Effective When Compared With Manual Therapy to Treat Workers' Mechanical Neck Pains?

OBJECTIVE: The aim of this study was to do a cost-benefit analysis of myofascial release therapy (MRT) compared to manual therapy (MT) for treating occupational mechanical neck pain. METHODS: Variables regarding the outcomes of the intervention were intensity of neck pain, cervical disability, quality of life, craniovertebral angle, and ranges of cervical motion. Costs were assessed based on a social perspective using diary costs. Between-groups differences in average cost, cost-effectiveness, and cost-utility ratios were assessed using bootstrap parametric techniques. The economic cost-benefit evaluation was with regard to an experimental parallel group study design. There were 59 participants. RESULTS: Myofascial released therapy showed significant improvement over MT for cervical mobility (side bending, rotation, and craniovertebral angle). The total cost of MRT was approximately 20% less (-$519.81; 95% confidence interval, -$1193.67 to $100.31) than that of MT, although this was not statistically significant. Cost-effectiveness and cost-utility ratios showed that MRT could be associated with lower economic costs. CONCLUSION: With probabilities of 93.9% and 95.8%, MRT seems to be cost-effective for treating mechanical neck pain without the need to add any additional cost to obtain a better clinical benefit. Consequently, we believe it could be included in the clinical practice guidelines of different Spanish health care institutions.

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

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.

Hydrogen sulfide biosynthesis is impaired in the osteoarthritic joint.

Osteoarthritis (OA) is the most common form of arthritis and it is a leading cause of disability in the elderly. Its complete etiology is not known although there are several metabolic, genetic, epigenetic, and local contributing factors involved. At the moment, there is no cure for this pathology and treatment alternatives to retard or stop its progression are intensively being sought. Hydrogen sulfide (H2S) is a small gaseous molecule and is present in sulfurous mineral waters as its active component. Data from recent clinical trials shows that balneotherapy (immersion in mineral and/or thermal waters from natural springs) in sulfurous waters can improve OA symptoms, in particular, pain and function. Yet, the underlying mechanisms are poorly known. Hydrogen sulfide is also considered, with NO and CO, an endogenous signaling gasotransmitter. It is synthesized endogenously with the help of three enzymes, cystathionine gamma-lyase (CTH), cystathionine beta-synthase (CBS), and 3-mercaptopyruvate sulfurtransferase (3-MPST). Here, the expression of these three enzymes was demonstrated by quantitative real-time polymerase chain reaction (qRT-PCR) and their protein abundance [by immunohistochemistry and Western blot (WB)] in human articular cartilage. No significant differences were found in CBS or CTH expression or abundance, but mRNA and protein levels of 3-MPST were significantly reduced in cartilage form OA donors. Also, the biosynthesis of H2S from OA cartilage, measured with a specific microelectrode, was significantly lower than in OA-free tissue. Yet, no differences were found in H2S concentration in serum from OA patients and OA-free donors. The current results suggest that reduced levels of the mitochondrial enzyme 3-MPST in OA cartilage might be, at least in part, responsible for a reduction in H2S biosynthesis in this tissue and that impaired H2S biosynthesis in the joint might be a contributing factor to OA. This could contribute to explain why exogenous supplementation of H2S, for instance with sulfurous thermal water, has positive effects in OA patients.

15-Deoxy-Δ-12, 14-prostaglandin J2 acts cooperatively with prednisolone to reduce TGF-ß-induced pro-fibrotic pathways in human osteoarthritis fibroblasts.

BACKGROUND/AIMS: Synovial fibrosis is a pathological process that is observed in several musculoskeletal disorders and characterized by the excessive deposition of extracellular matrix, as well as cell migration and proliferation. Despite the fact that glucocorticoids are widely employed in the treatment of rheumatic pathologies such as osteoarthritis (OA) and rheumatoid arthritis, the mechanisms by which glucocorticoids act in the joint and their impacts on pro-fibrotic pathways are still unclear. MATERIALS: Human OA synovial fibroblasts were obtained from knee and hip joints. Cells were treated with prednisolone (1 mM) or transforming growth factor-beta 1 (TGF-ß1) (10 ng/ml) for 1 and 7 days for quantification of RNA and protein expression (by real-time quantitative reverse transcription-PCR and western blot, respectively), 72 h for immunocytochemistry analysis, and 48 h for proliferation (by BrdU assay) and migration (by wound assay) studies. In addition, cells were preincubated with prednisolone and/or the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist 15-deoxy-Δ-12,14-prostaglandin J2 (15d-PGJ2) for 6 h before adding TGF-ß1. pSmad1/5, pSmad2 and ß-catenin levels were analyzed by Western blot. The activin receptor-like kinase-5 (ALK-5) inhibitor (SB-431542) was employed for the mechanistic assays. RESULTS: Prednisolone showed a predominant anti-fibrotic impact on fibroblast-like synoviocytes as it attenuated the spontaneous and TGF-ß-induced gene expression of pro-fibrotic markers. Prednisolone also reduced α-sma protein and type III collagen levels, as well as cell proliferation and migration after TGF-ß stimulation. However, prednisolone did not downregulate the gene expression of all the pro-fibrotic markers tested and did not restore the reduced PPAR-γ levels after TGF-ß stimulation. Interestingly, anti-fibrotic actions of the glucocorticoid were reinforced in the presence of the PPAR-γ agonist 15d-PGJ2. Combined pretreatment modulated Smad2/3 levels and, similar to the ALK-5 inhibitor, blocked ß-catenin accumulation elicited by TGF-ß. CONCLUSIONS: Prednisolone, along with 15d-PGJ2, modulates pro-fibrotic pathways activated by TGF-ß in synovial fibroblasts at least partially through the inhibition of ALK5/Smad2 signaling and subsequent ß-catenin accumulation. These findings shed light on the potential therapeutic effects of glucocorticoids treatment combined with a PPAR-γ agonist against synovial fibrosis, although future studies are warranted to further evaluate this concern.

Risks factors of mechanical ventilation in acute traumatic cervical spinal cord injured patients.

STUDY DESIGN: Descriptive retrospective study. OBJECTIVES: To analyze risk factors associated with mechanical ventilation (MV) in cases of acute traumatic Cervical Spinal Cord Injury (tCSCI). SETTING: Unidad de Lesionados Medulares, Complejo Hospitalario Universitario A Coruña, in Galicia (Spain). METHODS: The study included patients with tCSCI who were hospitalized between January 2010 and December 2014. The following variables were analyzed: age, gender, etiology, neurological level, ASIA (American Spinal Injury Association) grade, associated injuries, injury severity score (ISS), ASIA motor score (AMS) at admission and mortality. RESULTS: A total of 146 patients met the study's inclusion criteria. The majority were men (74.7%) with mean age of 62.6 (s.d. ± 18.8) years. Sixty patients (41.1%) required MV. Mean age of ventilated vs. non-ventilated patients was 57.3 vs. 65.7. Men were more likely to require MV than women, ASIA grades A and B were also more likely to need MV than grades C and D, as well as patients with associated injuries. The AMS of patients receiving MV was lower than that of those who did not require MV (20.1 vs. 54.3). Moreover, the ISS was higher in patients receiving MV (31.2 vs. 13.4). An AMS ≤ 37 and an ISS ≥ 13 increased the risk of requiring MV by a factor of 11.98 and 7.28, respectively. CONCLUSIONS: Isolated factors associated with a greater risk of MV in tCSCI were: age, gender, ASIA grade, ISS and AMS. However, the only factor with a significant discriminatory ability to determine the need for MV was the AMS at admission.

The mitochondrial inhibitor oligomycin induces an inflammatory response in the rat knee joint.

BACKGROUND: Recent findings support a connection between mitochondrial dysfunction and activation of inflammatory pathways in articular cells. This study investigates in vivo in an acute model whether intra-articular administration of oligomycin, an inhibitor of mitochondrial function, induces an oxidative and inflammatory response in rat knee joints. METHODS: Oligomycin was injected into the rat left knee joint on days 0, 2, and 5 before joint tissues were obtained on day 6. The right knee joint served as control. Results were evaluated by macroscopy and histopathology and by measuring cellular and mitochondrial reactive oxygen species (ROS), 4-hydroxy-2-nonenal (4-HNE, a marker of lipid peroxidation), nuclear factor erythroid 2-related factor 2 (Nrf2), and CD68 (macrophages) and chemokine levels. The marker of mitochondrial mass COX-IV was also evaluated. RESULTS: The macroscopic findings showed significantly greater swelling in oligomycin-injected knees than in control knees. Likewise, the histological score of synovial damage was also increased significantly. Immunohistochemical studies showed high expression of IL-8, coinciding with a marked infiltration of polymorphonuclears and CD68+ cells in the synovium. Mitochondrial mass was increased in the synovium of oligomycin-injected joints, as well as cellular and mitochondrial ROS production, and 4-HNE. Relatedly, expression of the oxidative stress-related transcription factor Nrf2 was also increased. As expected, no histological differences were observed in the cartilage; however, cytokine-induced neutrophil chemoattractant-1 mRNA and protein expression were up-regulated in this tissue. CONCLUSIONS: Mitochondrial failure in the joint is able to reproduce the oxidative and inflammatory status observed in arthritic joints.

Hydrogen Sulfide and Inflammatory Joint Diseases.

BACKGROUND: Rheumatoid arthritis (RA) and osteoarthritis (OA) are widespread rheumatic diseases characterized by persistent inflammation and joint destruction. Hydrogen sulfide (H2S) is an endogenous gas with important physiologic functions in the brain, vasculature and other organs. Recent studies have found H2S to be a mediator in inflammatory joint diseases. OBJECTIVE: This review summarizes the recent literature in this area highlighting relevant developments. CONCLUSIONS: Several authors have found that H2S exhibited anti-inflammatory, anti-catabolic and/or anti-oxidant effects in rodent models of acute arthritis and in in vitro models using human synoviocytes and articular chondrocytes from RA and OA tissues. The earliest studies used fast-dissolving salts, such as NaSH, but GYY4137, which produces H2S more physiologically, shortly appeared. More recently still, new H2S-forming compounds that target mitochondria have been synthesized. These compounds open exciting opportunities for investigating the role of H2S in cell bioenergetics, typically altered in arthritides. Positive results have also been obtained when H2S is administered as a sulphurous water bath, an option meriting further study. These findings suggest that exogenous supplementation of H2S may provide a viable therapeutic option for these diseases, particularly in OA.