Mild exercise expedites joint clearance and slows joint degradation in a joint instability model of osteoarthritis in male rats.

OBJECTIVE: Exercise remains a hallmark treatment for post-traumatic osteoarthritis (PTOA) and may maintain joint homeostasis in part by clearing inflammatory cytokines, cells, and particles. It remains largely unknown whether exercise-induced joint clearance can provide therapeutic relief of PTOA. In this study, we hypothesized that exercise could slow the progression of preclinical PTOA in part by enhancing knee joint clearance. DESIGN: Surgical medial meniscal transection was used to induce PTOA in 3-month-old male Lewis rats. A sham surgery was used as a control. Mild treadmill walking was introduced 3 weeks post-surgery and maintained to 6 weeks post-surgery. Gait and isometric muscle torque were measured at the study endpoint. Near-infrared imaging tracked how exercise altered lymphatic and venous knee joint clearance during discrete time points of PTOA progression. RESULTS: Exercise mitigated joint degradation associated with PTOA by preserving glycosaminoglycan content and reducing osteophyte volume (effect size (95% Confidence Interval (CI)); 1.74 (0.71-2.26)). PTOA increased hind step widths (0.57 (0.18-0.95) cm), but exercise corrected this gait dysfunction (0.54 (0.16-0.93) cm), potentially indicating pain relief. Venous, but not lymphatic, clearance was quicker 1-, 3-, and 6-weeks post-surgery compared to baseline. The mild treadmill walking protocol expedited lymphatic clearance rate in moderate PTOA (3.39 (0.20-6.59) hrs), suggesting exercise may play a critical role in restoring joint homeostasis. CONCLUSIONS: We conclude that mild exercise has the potential to slow disease progression in part by expediting joint clearance in moderate PTOA.

Gait assessment in a female rat Sprague Dawley model of disc-associated low back pain.

PURPOSE: Gait disturbances are common in human low back pain (LBP) patients, suggesting potential applicability to rodent LBP models. This study aims to assess the influence of disc-associated LBP on gait in female Sprague Dawley rats and explore the utility of the open-source Gait Analysis Instrumentation and Technology Optimized for Rodents (GAITOR) suite as a potential alternative tool for spontaneous pain assessment in a previously established LBP model. MATERIALS AND METHODS: Disc degeneration was surgically induced using a one-level disc scrape injury method, and microcomputed tomography was used to assess disc volume loss. After disc injury, axial hypersensitivity was evaluated using the grip strength assay, and an open field test was used to detect spontaneous pain-like behavior. RESULTS: Results demonstrated that injured animals exhibit a significant loss in disc volume and reduced grip strength. Open field test did not detect significant differences in distance traveled between sham and injured animals. Concurrently, animals with injured discs did not display significant gait abnormalities in stance time imbalance, temporal symmetry, spatial symmetry, step width, stride length, and duty factor compared to sham. However, comparisons with reference values of normal gait reported in prior literature reveal that injured animals exhibit mild deviations in forelimb and hindlimb stance time imbalance, forelimb temporal symmetry, and hindlimb spatial symmetry at some time points. CONCLUSIONS: This study concludes that the disc injury may have very mild effects on gait in female rats within 9 weeks post-injury and recommends future in depth dynamic gait analysis and longer studies beyond 9 weeks to potentially detect gait.

Temporal lobe injury with middle fossa approach to intracanalicular vestibular schwannomas: a systematic review.

There are several surgical approaches for vestibular schwannoma (VS) resection. However, management has gradually shifted from microsurgical resection, toward surveillance and radiosurgery. One of the arguments against microsurgery via the middle fossa approach (MFA) is the risk of temporal lobe retraction injury or sequelae. Here, we sought to evaluate the incidence of temporal lobe retraction injury or sequela from a MFA via a systematic review of the existing literature. This systematic review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Relevant studies reporting temporal lobe injury or sequela during MFA for VS were identified. Data was aggregated and subsequently analyzed to evaluate the incidence of temporal lobe injury. 22 studies were included for statistical analysis, encompassing 1522 patients that underwent VS resection via MFA. The overall rate of temporal lobe sequelae from this approach was 0.7%. The rate of CSF leak was 5.9%. The rate of wound infection was 0.6%. Meningitis occurred in 1.6% of patients. With the MFA, 92% of patients had good facial outcomes, and 54.9% had hearing preservation. Our series and literature review support that temporal lobe retraction injury or sequelae is an infrequent complication from an MFA for intracanalicular VS resection.

Recommendations for the analysis of rodent gait data to evaluate osteoarthritis treatments.

Behavioral assays of animal pain and disability can increase the clinical relevance of a preclinical study. However, pain and symptoms are difficult to measure in preclinical models. Because animals often alter their movement patterns to reduce or avoid joint pain, gait analysis can be an important tool for quantifying OA-related symptoms in rodents. Technologies to measure rodent gait continue to advance and have been the focus of prior reviews. Regardless of the techniques used, the analysis of rodent gait data can be complex due to multiple confounding variables. The goal of this review is to discuss recent advances in the understanding of OA-related gait changes and provide recommendations on the analysis of gait data. Recent studies suggest OA-affected animals reduce vertical loading through their injured limb while walking, indicating dynamic ground reaction forces are important data to collect when possible. Moreover, gait data analysis depends on accurately measuring and accounting for the confounding effects of velocity and other covariates (such as animal size) when interpreting shifts in various gait parameters. Herein, we discuss different statistical techniques to account for covariates and interpret gait shifts. In particular, this review will discuss residualization and linear mixed effects models, including how both techniques can account for inter- and intra-animal variability and the effects of velocity. Furthermore, this review discusses future considerations for using rodent gait analysis, while highlighting the intricacies of gait analysis as a tool to measure joint function and behavioral outcomes.

Apoptosis-Decellularized Peripheral Nerve Scaffold Allows Regeneration across Nerve Gap.

Peripheral nerve injury results in loss of motor and sensory function distal to the nerve injury and is often permanent in nerve gaps longer than 5 cm. Autologous nerve grafts (nerve autografts) utilize patients' own nerve tissue from another part of their body to repair the defect and are the gold standard in care. However, there is a limited autologous tissue supply, size mismatch between donor nerve and injured nerve, and morbidity at the site of nerve donation. Decellularized cadaveric nerve tissue alleviates some of these limitations and has demonstrated success clinically. We previously developed an alternative apoptosis-assisted decellularization process for nerve tissue. This new process may result in an ideal scaffold for peripheral nerve regeneration by gently removing cells and antigens while preserving delicate topographical cues. In addition, the apoptosis-assisted process requires less active processing time and is inexpensive. This study examines the utility of apoptosis-decellularized peripheral nerve scaffolds compared to detergent-decellularized peripheral nerve scaffolds and isograft controls in a rat nerve gap model. Results indicate that, at 8 weeks post-injury, apoptosis-decellularized peripheral nerve scaffolds perform similarly to detergent-decellularized and isograft controls in both functional (muscle weight recovery, gait analysis) and histological measures (neurofilament staining, macrophage infiltration). These new apoptosis-decellularized scaffolds hold great promise to provide a less expensive scaffold for nerve injury repair, with the potential to improve nerve regeneration and functional outcomes compared to current detergent-decellularized scaffolds.

Neuromodulation as a Potential Disease-Modifying Therapy for Osteoarthritis.

PURPOSE OF REVIEW: The following review discusses the therapeutic potential of targeting the autonomic nervous system (ANS) for osteoarthritis (OA) treatment and encourages the field to consider the candidacy of bioelectronic medicine as a novel OA treatment strategy. RECENT FINDINGS: The study of OA pathogenesis has focused on changes occurring at the joint level. As such, treatments for OA have been aimed at the local joint environment, intending to resolve local inflammation and decrease pain. However, OA pathogenesis has shown to be more than joint wear and tear. Specifically, OA-related peripheral and central sensitization can prompt neuroplastic changes in the nervous system beyond the articular joint. These neuroplastic changes may alter physiologic systems, like the neuroimmune axis. In this way, OA and related comorbidities may share roots in the form of altered neuroimmune communication and autonomic dysfunction. ANS modulation may be able to modify OA pathogenesis or reduce the impact of OA comorbidities. Moreover, blocking chronic nociceptive drive from the joint may help to prevent maladaptive nervous system plasticity in OA.

The response of money market funds to the COVID-19 pandemic.

The Covid-19 Pandemic has increased the attention paid to money market funds. Using Covid-19 cases and a measure of lockdowns, shutdowns, etc., we analyze if money market fund investors and managers responded to the intensity of the pandemic. We ask whether or not the Federal Reserve implementation of the Money Market Mutual Fund Liquidity Facility (MMLF) had an effect on market participant behavior. We find that institutional prime investors responded significantly to the MMLF. Fund managers responded to the intensity of the pandemic but largely ignored the reduction in uncertainty created by the implementation of the MMLF.

Autonomic Nervous System Dysregulation and Osteoarthritis Pain: Mechanisms, Measurement, and Future Outlook.

PURPOSE OF REVIEW: The autonomic nervous system is an important regulator of stress responses and exhibits functional changes in chronic pain states. This review discusses potential overlap among autonomic dysregulation, osteoarthritis (OA) progression, and chronic pain. From this foundation, we then discuss preclinical to clinical research opportunities to close gaps in our knowledge of autonomic dysregulation and OA. Finally, we consider the potential to generate new therapies for OA pain via modulation of the autonomic nervous system. RECENT FINDINGS: Recent reviews provide a framework for the autonomic nervous system in OA progression; however, research is still limited on the topic. In other chronic pain states, functional overlaps between the central autonomic network and pain processing centers in the brain suggest relationships between concomitant dysregulation of the two systems. Non-pharmacological therapeutics, such as vagus nerve stimulation, mindfulness-based meditation, and exercise, have shown promise in alleviating painful symptoms of joint diseases, and these interventions may be partially mediated through the autonomic nervous system. The autonomic nervous system appears to be dysregulated in OA progression, and further research on rebalancing autonomic function may lead to novel therapeutic strategies for treating OA pain.

A Novel Device for the Quantification of Synovial Fluid Viscosity Via Magnetic Deflection.

Changes in synovial fluid viscosity may be used to detect joint disease; however, methods to evaluate these changes at the point-of-care are currently rudimentary. Previously, we demonstrated that magnetic particle translation through static synovial fluid could serve as a surrogate marker of synovial fluid mechanics. In this work, we examine the magnetic deflection of a stream of particles flowing through a stream of synovial fluid and relate this deflection to changes in fluid mechanics. First, a flow device was designed, where a stream of magnetic particles flows along with synovial fluid. As the particle stream approaches and passes a fixed permanent magnet, the particle stream deflects. Conceptually, as the synovial fluid viscosity decreases, the deflection of the particle stream should increase due to a decreased drag force opposing the force magnetization. To assess this concept, particle deflection was first measured in Newtonian glycerol solutions of known varying viscosity under different flow conditions. Next, the device was used to test bovine synovial fluid viscosity, which had been progressively degraded using ultrasonication. A strong correlation was observed between the deflection of the magnetic particles and the viscosity of the glycerol solutions (R2 = 0.987) and the amount of ultrasonic degradation of synovial fluid (R2 = 0.7045). In the future, the principle of particle deflection may be used to design point-of-care quantification of synovial fluid mechanics, as the assessment does not require particles to be separated from the fluid for quantification and could be conducted under simple flow conditions.

Diagnosing hereditary cancer predisposition in men with prostate cancer.

PURPOSE: We describe the pathogenic variant spectrum and identify predictors of positive results among men referred for clinical genetic testing for prostate cancer. METHODS: One thousand eight hundred twelve men with prostate cancer underwent clinical multigene panel testing between April 2012 and September 2017. Stepwise logistic regression determined the most reliable predictors of positive results among clinical variables reported on test requisition forms. RESULTS: A yield of 9.4-12.1% was observed among men with no prior genetic testing. In this group, the positive rate of BRCA1 and BRCA2 was 4.6%; the positive rate for the mismatch repair genes was 2.8%. Increasing Gleason score (odds ratio [OR] 1.19; 95% confidence interval [CI] 0.97-1.45); personal history of breast or pancreatic cancer (OR 3.62; 95% CI 1.37-9.46); family history of breast, ovarian, or pancreatic cancer (OR 2.32 95% CI 1.48-3.65); and family history of Lynch syndrome-associated cancers (OR 1.97; 95% CI 1.23-3.15) were predictors of positive results. CONCLUSION: These results support multigene panel testing as the primary genetic testing approach for hereditary prostate cancer and are supportive of recommendations for consideration of germline testing in men with prostate cancer. Expanding the criteria for genetic testing should be considered as many pathogenic variants are actionable for treatment of advanced prostate cancer.

The effects of age on the severity of joint damage and intra-articular inflammation following a simulated medial meniscus injury in 3, 6, and 9 month old male rats.

Purpose: Aging is a known risk factor for osteoarthritis (OA). Several transgenic rodent models have been used to investigate the effects of accelerated or delayed aging in articular joints. However, age-effects on the progression of post-traumatic OA are less frequently evaluated. The objective of this study is to evaluate how animal age affects the severity of intra-articular inflammation and joint damage in the rat medial collateral ligament plus medial meniscus transection (MCLT+MMT) model of knee OA.Methods: Forty-eight, male Lewis rats were aged to 3, 6, or 9 months old. At each age, eight rats received either an MCLT+MMT surgery or a skin-incision. At 2 months post-surgery, intra-articular evidence of CTXII, IL1ß, IL6, TNFα, and IFNγ was evaluated using a multiplex magnetic capture technique, and histological evidence of OA was assessed via a quantitative histological scoring technique.Results: Elevated levels of CTXII and IL6 were found in MCLT+MMT knees relative to skin-incision and contralateral controls; however, animal age did not affect the severity of joint inflammation. Conversely, histological investigation of cartilage damage showed larger cartilage lesion areas, greater width of affected cartilage, and more evidence of hypertrophic cartilage damage in MCLT+MMT knees with age.Conclusions: These data indicate the severity of cartilage damage subsequent to MCLT+MMT surgery is related to the rat's age at the time of injury. However, despite greater levels of cartilage damage, the level of intra-articular inflammation was not necessarily affected in 3, 6, and 9 month old male rats.

Use of magnetic capture to identify elevated levels of CCL2 following intra-articular injection of monoiodoacetate in rats.

PURPOSE: Synovial fluid biomarkers help evaluate osteoarthritis (OA) development. Magnetic capture, our new magnetic nanoparticle-based technology, has proven to be effective for determining extracellular matrix fragment levels in two rat OA models. Here, the feasibility of magnetic capture for detecting monocyte chemoattractant protein-1 (MCP-1 or CCL2) is demonstrated after intra-articular injection of monoiodoacetate (MIA) in the rat knee. METHODS: Forty-eight male Lewis rats received a right hind limb, intra-articular injection of MIA (1 mg in 25 µl of saline) or 25 µl of saline. Magnetic capture and lavage were performed at 7 days after injection (n = 6 per treatment per procedure), with magnetic capture additionally performed at 14 and 28 days post-injection (n = 6 per treatment per time point). CCL2 was also assessed in serum. RESULTS: Serum CCL2 levels revealed no difference between MIA and saline animals (p = 0.0851). In contrast, magnetic capture and lavage detected a significant increase of CCL2 in the MIA-injected knee, with the MIA-injected knee having elevated CCL2 compared to contralateral and saline-injected knees (p = 0.00016 (contralateral) and p = 0.00016 (saline) for magnetic capture; p = 0.00023 (contralateral) and p = 0.00049 (saline) for lavage). CONCLUSIONS: Magnetic capture of CCL2 was successfully developed and applied to determine levels of CCL2 in a rat knee. Magnetic capture detected a statistically significant increase of CCL2 in MIA-injected knees compared to controls, and CCL2 levels stayed relatively stable from week 1 through week 4 post-MIA injection.

The relationship of inter-implant time and hearing outcomes for bilateral cochlear implants.

PURPOSE: Determine the relationship between time elapsed between sequential bilateral cochlear implantation (BiCI) and speech intelligibility scores in post-lingually deafened adults. MATERIALS AND METHODS: Retrospective review of post-lingually deafened adults who received bilateral cochlear implants from January 1, 2011 to January 1, 2018 at an ambulatory tertiary referral center. RESULTS: 113 patients (226 cochlear implants) were initially reviewed, with 56 patients (112 implants) being included in the final analysis. Median inter-implant interval was 187.5 days (IQ range 54.25-346.5). Maximum interval was 1787 days. Mean age at first implant was 60.66 ± 13.37. Bilateral AzBio score in quiet and inter-implant interval showed no significant correlation (r = 0.034, p = 0.815). There was no significant difference in mean bilateral AzBio scores in quiet between the simultaneous and sequential implantation groups (p = 0.22). Similar non-significant results were seen when examining the correlation between AzBio Difference and inter-implant interval (r = -0.07, p = 0.66). No significant result between mean AzBio Difference of simultaneous and sequential implant recipients was found (p = 0.06). CONCLUSIONS: For the inter-implant intervals examined, there seems to be no significant decline in speech intelligibility scores for patients receiving sequential bilateral cochlear implants compared to simultaneously implanted patients. There was no significant correlation noted between increasing inter-implant intervals and speech intelligibility scores.

Family communication and patient distress after germline genetic testing in individuals with pancreatic ductal adenocarcinoma.

BACKGROUND: Germline genetic testing currently is recommended for patients with pancreatic ductal adenocarcinoma (PDAC). In the current study, the authors assessed how often results are communicated to first-degree relatives within 3 months and the emotional impact of testing on patients. METHODS: A total of 148 patients who were newly diagnosed with PDAC and who had undergone testing of 32 cancer susceptibility genes at 3 academic centers were selected; 71% participated. Subjects completed the Multidimensional Impact of Cancer Risk Assessment (MICRA) and a family communication survey. The results of both surveys were assessed at 3 months according to the genetic test result (positive, negative, or variant of unknown significance [VUS]) and whether a patient met criteria for genetic testing. RESULTS: A total of 99 patients completed the MICRA survey and 104 completed the family communication survey. The average age of the patients was 67 years, 47% were female, 29% had stage III/IV (AJCC 8th edition) disease, and 42% met genetic testing criteria. Approximately 80% of patients told at least 1 first-degree relative about their result. There was a trend toward greater disclosure among patients who tested positive (93% vs 77% for those with a VUS result [P = .149] and 74% for those who tested negative [P = .069]). Patients not meeting genetic testing criteria were less likely to disclose results (69% vs 93%; P = .003). MICRA scores did not differ by test result, age, stage of disease, or sex. CONCLUSIONS: The rate of result communication was high, although it was lower among patients who did not meet genetic testing criteria, those who tested negative, or those who had a VUS result. Testing-associated distress was similar across patient groups, and was comparable to that reported by other patients with cancer. Improved communication for all patients is crucial given the prognosis of PDAC, which limits time for disclosure.

Functional Measures of Grip Strength and Gait Remain Altered Long-term in a Rat Model of Post-traumatic Elbow Contracture.

Post-traumatic joint contracture (PTJC) is a debilitating condition, particularly in the elbow. Previously, we established an animal model of elbow PTJC quantifying passive post-mortem joint mechanics and histological changes temporally. These results showed persistent motion loss similar to what is experienced in humans. Functional assessment of PTJC in our model was not previously considered; however, these measures would provide a clinically relevant measure and would further validate our model by demonstrating persistently altered joint function. To this end, a custom bilateral grip strength device was developed, and a recently established open-source gait analysis system was used to quantify forelimb function in our unilateral injury model. In vivo joint function was shown to be altered long-term and never fully recover. Specifically, forelimb strength in the injured limbs showed persistent deficits at all time points; additionally, gait patterns remained imbalanced and asymmetric throughout the study (although a few gait parameters did return to near normal levels). A quantitative understanding of these longitudinal, functional disabilities further strengthens the clinical relevance of our rat PTJC model enabling assessment of the effectiveness of future interventions aimed at reducing or preventing PTJC.

Quantitative histological grading methods to assess subchondral bone and synovium changes subsequent to medial meniscus transection in the rat.

AIM OF THE STUDY: The importance of the medial meniscus to knee health is demonstrated by studies which show meniscus injuries significantly increase the likelihood of developing osteoarthritis (OA), and knee OA can be modeled in rodents using simulated meniscus injuries. Traditionally, histological assessments of OA in these models have focused on damage to the articular cartilage; however, OA is now viewed as a disease of the entire joint as an organ system. The aim of this study was to develop quantitative histological measures of bone and synovial changes in a rat medial meniscus injury model of knee OA. MATERIALS AND METHODS: To initiate OA, a medial meniscus transection (MMT) and a medial collateral ligament transection (MCLT) were performed in 32 male Lewis rats (MMT group). MCLT alone served as the sham procedure in 32 additional rats (MCLT sham group). At weeks 1, 2, 4, and 6 post-surgery, histological assessment of subchondral bone and synovium was performed (n = 8 per group per time point). RESULTS: Trabecular bone area and the ossification width at the osteochondral interface increased in both the MMT and MCLT groups. Subintimal synovial cell morphology also changed in MMT and MCLT groups relative to naïve animals. CONCLUSIONS: OA affects the joint as an organ system, and quantifying changes throughout an entire joint can improve our understanding of the relationship between joint destruction and painful OA symptoms following meniscus injury.

Mechanical Integrity of a Decellularized and Laser Drilled Medial Meniscus.

Since the meniscus has limited capacity to self-repair, creating a long-lasting meniscus replacement may help reduce the incidence of osteoarthritis (OA) after meniscus damage. As a first step toward this goal, this study evaluated the mechanical integrity of a decellularized, laser drilled (LD) meniscus as a potential scaffold for meniscal engineering. To evaluate the decellularization process, 24 porcine menisci were processed such that one half remained native tissue, while the other half was decellularized in sodium dodecyl sulphate (SDS). To evaluate the laser drilling process, 24 additional menisci were decellularized, with one half remaining intact while the other half was LD. Decellularization did not affect the tensile properties, but had significant effects on the cyclic compressive hysteresis and unconfined compressive stress relaxation. Laser drilling decreased the Young's modulus and instantaneous stress during unconfined stress relaxation and the circumferential ultimate strength during tensile testing. However, the losses in mechanical integrity in the LD menisci were generally smaller than the variance observed between samples, and thus, the material properties for the LD tissue remained within a physiological range. In the future, optimization of laser drilling patterns may improve these material properties. Moreover, reseeding the construct with cells may further improve the mechanical properties prior to implantation. As such, this work serves as a proof of concept for generating decellularized, LD menisci scaffolds for the purposes of meniscal engineering.

Factors that influence physical function and emotional well-being among Medicare-Medicaid enrollees.

Dually enrolled Medicare-Medicaid older adults are a vulnerable population. We tested House's Conceptual Framework for Understanding Social Inequalities in Health and Aging in Medicare-Medicaid enrollees by examining the extent to which disparities indicators, which included race, age, gender, neighborhood poverty, education, income, exercise (e.g., walking), and physical activity (e.g., housework) influence physical function and emotional well-being. This secondary analysis included 337 Black (31%) and White (69%) older Medicare-Medicaid enrollees. Using path analysis, we determined that race, neighborhood poverty, education, and income did not influence physical function or emotional well-being. However, physical activity (e.g., housework) was associated with an increased self-report of physical function and emotional well-being of ß = .23, p < .001; ß = .17, p < .01, respectively. Future studies of factors that influence physical function and emotional well-being in this population should take into account health status indicators such as allostatic load, comorbidity, and perceived racism/discrimination.

Gait analysis methods for rodent models of osteoarthritis.

Patients with osteoarthritis (OA) primarily seek treatment due to pain and disability, yet the primary endpoints for rodent OA models tend to be histological measures of joint destruction. The discrepancy between clinical and preclinical evaluations is problematic, given that radiographic evidence of OA in humans does not always correlate to the severity of patient-reported symptoms. Recent advances in behavioral analyses have provided new methods to evaluate disease sequelae in rodents. Of particular relevance to rodent OA models are methods to assess rodent gait. While obvious differences exist between quadrupedal and bipedal gait sequences, the gait abnormalities seen in humans and in rodent OA models reflect similar compensatory behaviors that protect an injured limb from loading. The purpose of this review is to describe these compensations and current methods used to assess rodent gait characteristics, while detailing important considerations for the selection of gait analysis methods in rodent OA models.

Recurrent meningitis secondary to a petrous apex meningocele.

This case report describes a patient who was found to have a cerebrospinal fluid (CSF) leak originating from the petrous apex. The patient initially presented with multiple bouts of meningitis. The patient was treated surgically via a middle cranial fossa approach but presented five years later with recurrent meningitis and was found to have an osseous defect of the petrous apex which was not recognized prior to the initial surgery.