Effect of platelet-rich plasma injections versus placebo on pain and quality of life in patients with hip osteoarthritis: A double-blind, randomized clinical trial.

Objectives: This study aims to compare the efficacy of intra-articular platelet-rich plasma (PRP) injections over a saline placebo in terms of reduction of pain and impact on quality of life among patients with hip osteoarthritis. Patients and methods: A total of 60 patients (29 males, 31 females, mean age: 57.9±7.3 years; range, 47 to 69 years) with known hip osteoarthritis of Kellgren-Lawrance (KL) Grades 2/3 were randomized into placebo (n=30) and PRP groups (n=30) between June 2014 and June 2015. Both groups received intra-articular injections into the hip joint under ultrasound guidance for three consecutive weeks. The patients were followed for six months, and pain reduction was assessed using the Visual Analog Scale (VAS), Western Ontario and McMaster Universities Arthritis Index (WOMAC) questionnaire, and Short Form Health Survey-36 (SF-36). Results: Intra-articular PRP treatment showed no advantage over a saline placebo in terms of VAS scores during activity. Both groups showed a significant improvement in VAS activity scores at one and six months. The placebo group showed improvements in VAS resting scores, whereas the PRP group did not. Both groups showed no improvement in WOMAC-total scores. Both groups showed no significant improvement across most SF-36 domains with the exception of improved physical role functioning at one month and general health at one and six months in the placebo group. Conclusion: Intra-articular injections of PRP show no significant difference compared to a saline placebo over a period of six months on pain, function, and quality of life scores in patients with hip osteoarthritis.

Paving the cowpath in research within pure mathematics: A medium level model based on text driven variations.

In this paper we show how simple text-driven variations of given statements in mathematics can lead to interesting new problems and push forward a whole theory around simple initial questions. We exemplify this in two cases. Case 1 deals with problem-posing activities suitable for pupils and case 2 is a rational reconstruction of the organisation of mathematical knowledge within problems of graph colorings. Mathematicians learn to systematically look for subsequent problems around a given problem. We argue that this toy-model captures a nontrivial part of professional mathematical research within the pure fields and conjecture that it even grasps high level developments in mathematics. By doing this, we implicitly encourage a very simplistic view on criteria, so to speak a "cowpath" approach to progress in mathematics. The term "cowpath" is borrowed from architecture and software design, where it is commonly used. While we can contemplate which pathways are ideal, we may also just plant grass and see where people choose to walk. Those pathways are also self-enforcing, since we are less hesitant to walk on those rather than criss-cross the landscape.

Targeting the blood-brain barrier disruption in hypertension by ALK5/TGF-Β type I receptor inhibitor SB-431542 and dynamin inhibitor dynasore.

INTRODUCTION: In this study, we aimed to target two molecules, transforming growth factor-beta (TGF-ß) and dynamin to explore their roles in blood-brain barrier (BBB) disruption in hypertension. METHODS: For this purpose, angiotensin (ANG) II-induced hypertensive mice were treated with SB-431542, an inhibitor of the ALK5/TGF-ß type I receptor, and dynasore, an inhibitor of dynamin. Albumin-Alexa fluor 594 was used to assess BBB permeability. The alterations in the expression of claudin-5, caveolin (Cav)-1, glucose transporter (Glut)-1, and SMAD4 in the cerebral cortex and the hippocampus were evaluated by quantification of immunofluorescence staining intensity. RESULTS: ANG II infusion increased BBB permeability to albumin-Alexa fluor 594 which was reduced by SB-431542 (P < 0.01), but not by dynasore. In hypertensive animals treated with dynasore, claudin-5 immunofluorescence intensity increased in the cerebral cortex and hippocampus while it decreased in the cerebral cortex of SB-431542 treated hypertensive mice (P < 0.01). Both dynasore and SB-431542 prevented the increased Cav-1 immunofluorescence intensity in the cerebral cortex and hippocampus of hypertensive animals (P < 0.01). SB-431542 and dynasore decreased Glut-1 immunofluorescence intensity in the cerebral cortex and hippocampus of mice receiving ANG II (P < 0.01). SB-431542 increased SMAD4 immunofluorescence intensity in the cerebral cortex of hypertensive animals, while in the hippocampus a significant decrease was noted by both SB-431542 and dynasore (P < 0.01). CONCLUSION: Our data suggest that inhibition of the TGFß type I receptor prevents BBB disruption under hypertensive conditions. These results emphasize the therapeutic potential of targeting TGFß signaling as a novel treatment modality to protect the brain of hypertensive patients.

Extracellular vesicles derived from bone marrow mesenchymal stem cells enhance myelin maintenance after cortical injury in aged rhesus monkeys.

Cortical injury, such as stroke, causes neurotoxic cascades that lead to rapid death and/or damage to neurons and glia. Axonal and myelin damage in particular, are critical factors that lead to neuronal dysfunction and impair recovery of function after injury. These factors can be exacerbated in the aged brain where white matter damage is prevalent. Therapies that can ameliorate myelin damage and promote repair by targeting oligodendroglia, the cells that produce and maintain myelin, may facilitate recovery after injury, especially in the aged brain where these processes are already compromised. We previously reported that a novel therapeutic, Mesenchymal Stem Cell derived extracellular vesicles (MSC-EVs), administered intravenously at both 24 h and 14 days after cortical injury, reduced microgliosis (Go et al. 2019), reduced neuronal pathology (Medalla et al. 2020), and improved motor recovery (Moore et al. 2019) in aged female rhesus monkeys. Here, we evaluated the effect of MSC-EV treatment on changes in oligodendrocyte maturation and associated myelin markers in the sublesional white matter using immunohistochemistry, confocal microscopy, stereology, qRT-PCR, and ELISA. Compared to vehicle control monkeys, EV-treated monkeys showed a reduction in the density of damaged oligodendrocytes. Further, EV-treatment was associated with enhanced myelin maintenance, evidenced by upregulation of myelin-related genes and increases in actively myelinating oligodendrocytes in sublesional white matter. These changes in myelination correlate with the rate of motor recovery, suggesting that improved myelin maintenance facilitates this recovery. Overall, our results suggest that EVs act on oligodendrocytes to support myelination and improves functional recovery after injury in the aged brain. SIGNIFICANCE: We previously reported that EVs facilitate recovery of function after cortical injury in the aged monkey brain, while also reducing neuronal pathology (Medalla et al. 2020) and microgliosis (Go et al. 2019). However, the effect of injury and EVs on oligodendrocytes and myelination has not been characterized in the primate brain (Dewar et al. 1999; Sozmen et al. 2012; Zhang et al. 2013). In the present study, we assessed changes in myelination after cortical injury in aged monkeys. Our results show, for the first time, that MSC-EVs support recovery of function after cortical injury by enhancing myelin maintenance in the aged primate brain.