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1. Synovial fluid lubricin increases in spontaneous canine cruciate ligament rupture

   https://doi.org/10.1038/s41598-020-73270-2  

   Wang, Yuyan ; Gludish, David W. ; Hayashi, Kei ; Todhunter, Rory J. ; Krotscheck, Ursula ; Johnson, Philippa J. ; Cummings, Bethany P. ; Su, Jin ; Reesink, Heidi L. ( October 2020 , Scientific Reports)

   Lubricin is an important boundary lubricant and chondroprotective glycoprotein in synovial fluid. Both increased and decreased synovial fluid lubricin concentrations have been reported in experimental post-traumatic osteoarthritis (PTOA) animal models and in naturally occurring joint injuries in humans and animals, with no consensus about how lubricin is altered in different species or injury types. Increased synovial fluid lubricin has been observed following intra-articular fracture in humans and horses and in human late-stage osteoarthritis; however, it is unknown how synovial lubricin is affected by knee-destabilizing injuries in large animals. Spontaneous rupture of cranial cruciate ligament (RCCL), the anterior cruciate ligament equivalent in quadrupeds, is a common injury in dogs often accompanied by OA. Here, clinical records, radiographs, and synovial fluid samples from 30 dogs that sustained RCCL and 9 clinically healthy dogs were analyzed. Synovial fluid lubricin concentrations were nearly 16-fold greater in RCCL joints as compared to control joints, while IL-2, IL-6, IL-8, and TNF-α concentrations did not differ between groups. Synovial fluid lubricin concentrations were correlated with the presence of radiographic OA and were elevated in three animals sustaining RCCL injury prior to the radiographic manifestation of OA, indicating that lubricin may be a potential biomarker for early joint injury.

    

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2. Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis

   https://doi.org/10.1002/advs.202202720  

   McBride, David A. ; Kerr, Matthew D. ; Johnson, Wade T. ; Nguyen, Anders ; Zoccheddu, Martina ; Yao, Mina ; Prideaux, Edward B. ; Dorn, Nicholas C. ; Wang, Wei ; Svensson, Mattias N. D. ; et al ( March 2023 , Advanced Science)

   Disease modifying antirheumatic drugs (DMARDs) have improved the prognosis of autoimmune inflammatory arthritides but a large fraction of patients display partial or nonresponsiveness to front‐line DMARDs. Here, an immunoregulatory approach based on sustained joint‐localized release of all‐trans retinoic acid (ATRA), which modulates local immune activation and enhances disease‐protective T cells and leads to systemic disease control is reported. ATRA imprints a unique chromatin landscape in T cells, which is associated with an enhancement in the differentiation of naïve T cells into anti‐inflammatory regulatory T cells (T_reg) and suppression of T_regdestabilization. Sustained release poly‐(lactic‐co‐glycolic) acid (PLGA)‐based biodegradable microparticles encapsulating ATRA (PLGA‐ATRA MP) are retained in arthritic mouse joints after intra‐articular (IA) injection. IA PLGA‐ATRA MP enhance migratory T_regwhich in turn reduce inflammation and modify disease in injected and uninjected joints, a phenotype that is also reproduced by IA injection of T_reg. PLGA‐ATRA MP reduce proteoglycan loss and bone erosions in the SKG and collagen‐induced arthritis mouse models of autoimmune arthritis. Strikingly, systemic disease modulation by PLGA‐ATRA MP is not associated with generalized immune suppression. PLGA‐ATRA MP have the potential to be developed as a disease modifying agent for autoimmune arthritis.

    

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3. GdDO3NI Enhanced Magnetic Resonance Imaging Allows Imaging of Hypoxia After Brain Injury

   https://doi.org/10.1002/jmri.27912  

   Moghadas, Babak ; Bharadwaj, Vimala N. ; Tobey, John P. ; Tian, Yanqing ; Stabenfeldt, Sarah E. ; Kodibagkar, Vikram D. ( September 2021 , Journal of Magnetic Resonance Imaging)

   Brain tissue hypoxia is a common consequence of traumatic brain injury (TBI) due to the rupture of blood vessels during impact and it correlates with poor outcome. The current magnetic resonance imaging (MRI) techniques are unable to provide a direct map of tissue hypoxia.

   To investigate whether GdDO3NI, a nitroimidazole‐based T₁MRI contrast agent allows imaging hypoxia in the injured brain after experimental TBI.

   Prospective.

   TBI‐induced mice (controlled cortical impact model) were intravenously injected with either conventional T₁agent (gadoteridol) or GdDO3NI at 0.3 mmol/kg dose (n = 5 for each cohort) along with pimonidazole (60 mg/kg) at 1 hour postinjury and imaged for 3 hours following which they were euthanized.

   7 T/T₂‐weighted spin echo and T₁‐weighted gradient echo.

   Injured animals were imaged with T₂‐weighted spin‐echo sequence to estimate the extent of the injury. The mice were then imaged precontrast and postcontrast using a T₁‐weighted gradient‐echo sequence for 3 hours postcontrast. Regions of interests were drawn on the brain injury region, the contralateral brain as well as on the cheek muscle region for comparison of contrast kinetics. Brains were harvested immediately post‐imaging for immunohistochemical analysis.

   One‐way analysis of variance and two‐samplet‐tests were performed with aP < 0.05 was considered statistically significant.

   GdDO3NI retention in the injury region at 2.5–3 hours post‐injection was significantly higher compared to gadoteridol (mean retention fraction 63.95% ± 27.43% vs. 20.68% ± 7.43% for gadoteridol at 3 hours) while it rapidly cleared out of the muscle region. Pimonidazole staining confirmed the presence of hypoxia in both gadoteridol and GdDO3NI cohorts, and the later cohort showed good agreement with MRI contrast enhancement.

   GdDO3NI was successfully shown to visualize hypoxia in the brain post‐TBI using T₁‐weighted MRI at 2.5–3 hours postcontrast.

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4. Using an Arthrometer to Quantify Ankle Laxity: An Infographic Summary

   https://doi.org/10.1177/19417381221147511  

   Gulick, Dawn T. ( January 2023 , Sports Health: A Multidisciplinary Approach)

   Lateral ankle sprains are a common musculoskeletal injury. The anterior talofibular ligament (ATFL) is the primary ligament involved and is assessed via an anterior drawer test. Clinically assessing joint laxity has been a subjective task. Evaluating both magnitude of translation and quality of the endfeel has presented challenges. Until recently, a reliable and valid arthrometer to test joints other than the knee has not been available. The Mobil-Aider arthrometer has undergone bench testing for validity, reliability testing in healthy persons, and most recently the testing of participants for pathology. A summary of these studies is available in the Online Supplement . The goal of this study was to determine the ability of the arthrometer to objectively identify the anterior translation of the ankle and the relationship to the clinical diagnosis. The participant was evaluated by a physician and magnitude of ankle sprain was determined. An arthrometer was used to perform an anterior drawer test (uninjured before injured, 3 measures each) in the prone position. Both clinicians were blinded to the data of the other. There were 30 participants, 10 per group (uninjured, 1° sprain, 2° sprain). Mann-Whitney U testing found significant differences between the control and grade 1 ankle sprain groups ( P < .001), the control and grade 2 ankle sprain groups ( P < .001), and the grade 1 and grade 2 ankle sprain groups ( P = .004). There was ± 0.31 mm difference in anterior translation between healthy ankles, whereas there was 1.11 mm and 2.16 mm difference between ankles in grade 1 and grade 2 sprains, respectively. The anterior drawer test is the gold standard for clinical ATFL testing, but the subjective nature of this test poses challenges. Technology is available to assess ankle joint laxity and enhance the objectivity of patient assessment and throughout the recovery process. An arthrometer is a valuable tool in quantifying orthopaedic examination.

    

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5. Collagen Fibril Abnormalities in Human and Mice Abdominal Aortic Aneurysm

   Jones, B. ; Tonniges, J. R. ; Debsk, A.i ; Albert, B. ; Yeung, D. A. ; Gadde, N. ; Mahajan, A. ; Sharma, N. ; Calomeni, E. P. ; Go, M. ; et al ( August 2020 , Biomedical Engineering Society 2020 Annual Meeting)

   null (Ed.)

   Introduction: Vascular diseases like abdominal aortic aneurysms (AAA) are characterized by a drastic remodeling of the vessel wall, accompanied with changes in the elastin and collagen content. At the macromolecular level, the elastin fibers in AAA have been reported to undergo significant structural alterations. While the undulations (waviness) of the collagen fibers is also reduced in AAA, very little is understood about changes in the collagen fibril at the sub-fiber level in AAA as well as in other vascular pathologies. Materials and Methods: In this study we investigated structural changes in collagen fibrils in human AAA tissue extracted at the time of vascular surgery and in aorta extracted from angiotensin II (AngII) infused ApoE−/− mouse model of AAA. Collagen fibril structure was examined using transmission electron microscopy and atomic force microscopy. Images were analyzed to ascertain length and depth of D-periodicity, fibril diameter and fibril curvature. Tissues were also stained using collagen hybridizing peptide (CHP) and analyzed using fluorescent microscopy and second harmonic generation (SHG) microscopy to locate regions of healthy and degraded collagen. Results: Abnormal collagen fibrils with compromised D-periodic banding were observed in the excised human tissue and in remodeled regions of AAA in AngII infused mice (Figure 1). These abnormal fibrils were characterized by statistically significant reduction in depths of D-periods and an increased curvature of collagen fibrils. These features were more pronounced in human AAA as compared to murine samples. Additionally, regions of abnormal collagen were located within the remodeled areas of AAA tissue and were distinct from healthy collagen regions as ascertained using CHP staining and SHG (Figure 1). Thoracic aorta from Ang II-infused mice, abdominal aorta from saline-infused mice, and abdominal aorta from non-AAA human controls did not contain abnormal collagen fibrils. Conclusions: The structural alterations in abnormal collagen fibrils appear similar to those reported for collagen fibrils subjected to mechanical overload or chronic inflammation in other tissues. Detection of abnormal collagen could be utilized to better understand the functional properties of the underlying extracellular matrix in vascular as well as other pathologies. 

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