Binay Kumar Singh, Amit Kumar, Sharath Chandra
et al.
Aim: Peripheral neuropathy is a frequent but often under-recognized extra-articular manifestation of rheumatoid arthritis (RA), frequently linked to chronic systemic inflammation. The neutrophil-to-lymphocyte ratio (NLR) has emerged as a simple marker of systemic inflammatory burden. This study aimed to investigate the association between NLR and peripheral neuropathy in RA. Methods: This cross-sectional study included 230 RA patients. Peripheral neuropathy was identified through clinical evaluation and nerve conduction studies. Demographic and clinical data, serological status, disease activity [28-joint Disease Activity Score (DAS28)], inflammatory markers, and complete blood counts were obtained. NLR was calculated from absolute neutrophil and lymphocyte counts. Multivariable logistic regression was used to identify factors associated with peripheral neuropathy. Discriminatory performance of NLR was evaluated using receiver operating characteristic (ROC) curve analysis. Results: Peripheral neuropathy was present in 93 of 230 patients (40.4%). Patients with neuropathy exhibited significantly higher NLR compared with those without neuropathy (median 3.8 vs. 2.3; P < 0.001). In multivariable logistic regression adjusting for age, disease duration, disease activity (DAS28), C-reactive protein (CRP), serological status, and glucocorticoid use, elevated NLR remained independently associated with the presence of peripheral neuropathy [adjusted odds ratio (OR) = 1.92, 95% confidence interval (CI): 1.48–2.49; P < 0.001]. Other factors significantly associated with neuropathy included older age, longer disease duration, higher DAS28, and seropositive status. CRP and glucocorticoid use were not significantly associated with neuropathy in the adjusted model. In the overall cohort, the model including NLR demonstrated significantly improved discrimination for peripheral neuropathy compared with the base model without NLR, with the area under the ROC curve (AUC) increasing from 0.75 (95% CI: 0.69–0.81) to 0.83 (95% CI: 0.77–0.89) after including NLR (P < 0.001). Conclusions: Elevated NLR is independently associated with the presence of peripheral neuropathy in RA after adjustment for major confounders, and it demonstrates incremental discriminatory value for distinguishing neuropathy status in RA.
Thomas P. Leahy, Ashley K. Fung, Stephanie N. Weiss
et al.
AbstractThe small leucine‐rich proteoglycans, decorin and biglycan, are minor components of the tendon extracellular matrix that regulate fibrillogenesis and matrix assembly. Our study objective was to define the temporal roles of decorin and biglycan during tendon healing using inducible knockout mice to include genetic knockdown at specific phases of healing: time of injury, the proliferative phase, and the remodeling phase. We hypothesized that knockdown of decorin or biglycan would adversely affect tendon healing, and that by prescribing the timing of knockdown, we could elucidate the temporal roles of these proteins during healing. Contrary to our hypothesis, decorin knockdown did not affect tendon healing. However, when biglycan was knocked down, either alone or coupled with decorin, tendon modulus was increased relative to wild‐type mice, and this finding was consistent among all induction timepoints. At 6 weeks postinjury, we observed increased expression of genes associated with the extracellular matrix and growth factor signaling in the biglycan knockdown and compound decorin–biglycan knockdown tendons. Interestingly, these groups demonstrated opposing trends in gene expression as a function of knockdown‐induction timepoint, highlighting distinct temporal roles for decorin and biglycan. In summary, this study finds that biglycan plays multiple functions throughout tendon healing, with the most impactful, detrimental role likely occurring during late‐stage healing. Statement of clinical importance: This study helps to define the molecular factors that regulate tendon healing, which may aid in the development of new clinical therapies.
Eisuke Ochi, Alice Barrington, Michelle Wehling‐Henricks
et al.
AbstractMuscle growth is influenced by changes in the mechanical environment that affect the expression of genes that regulate myogenesis. We tested whether the hormone Klotho could influence the response of muscle to mechanical loading. Applying mechanical loads to myoblasts in vitro increased RNA encoding transcription factors that are expressed in activated myoblasts (Myod) and in myogenic cells that have initiated terminal differentiation (Myog). However, application of Klotho to myoblasts prevented the loading‐induced activation of Myog without affecting loading‐induced activation of Myod. This indicates that elevated Klotho inhibits mechanically‐induced differentiation of myogenic cells. Elevated Klotho also reduced the transcription of genes encoding proteins involved in the canonical Wnt pathway or their target genes (Wnt9a, Wnt10a, Ccnd1). Because the canonical Wnt pathway promotes differentiation of myogenic cells, these findings indicate that Klotho inhibits the differentiation of myogenic cells experiencing mechanical loading. We then tested whether these effects of Klotho occurred in muscles of mice experiencing high‐intensity interval training (HIIT) by comparing wild‐type mice and klotho transgenic mice. The expression of a klotho transgene combined with HIIT synergized to tremendously elevate numbers of Pax7+ satellite cells and activated MyoD+ cells. However, transgene expression prevented the increase in myogenin+ cells caused by HIIT in wild‐type mice. Furthermore, transgene expression diminished the HIIT‐induced activation of the canonical Wnt pathway in Pax7+ satellite cells. Collectively, these findings show that Klotho inhibits loading‐ or exercise‐induced activation of muscle differentiation and indicate a new mechanism through which the responses of muscle to the mechanical environment are regulated.
Michael B. Berger, Paul Slosar, Zvi Schwartz
et al.
The use of metallic and polymeric materials for implants has been increasing over the past decade. This trend can be attributed to a variety of factors including a significant increase in basic science research focused on implant material characteristics and how various surface modifications may stimulate osseointegration and, ultimately, fusion. There are many interbody fusion devices and dental implants commercially available; however, detailed information about their surface properties, and the effects that various materials and surface modifications may have on osteogenesis, is lacking in the literature. While the concept of bone-implant osseointegration is a relatively recent addition to the spine fusion literature, there is a comparatively large body of literature related to dental implants. The purpose of this article is to summarize the science of surface modified bone-facing implants, focusing on biomimetic material chemistry and topography of titanium implants, to promote a better understanding of how these characteristics may impact bone formation and osseointegration. This manuscript has the following aspects: highlights the role of titanium and its alloys as potent osteoconductive bioactive materials; explores the importance of biomimetic surface topography at the macro-, micro- and nano-scale; summarizes how material surface design can influence osteogenesis and immune responses in vitro; focuses on the kinds of surface modifications that play a role in the process. Biomimetic surface modifications can be varied across many clinically available biomaterials, and the literature supports the hypothesis that those biomaterial surfaces that exhibit physical properties of bone resorption pits, such as roughness and complex hierarchical structures at the submicron and nanoscale, are more effective in supporting osteoblast differentiation in vitro and osteogenesis in vivo.
AbstractSkeletal muscle mass is regulated through coordinated activation of multiple signaling pathways. TAK1 signalosome has been found to be activated in various conditions of muscle atrophy and hypertrophy. However, the role and mechanisms by which TAK1 regulates skeletal muscle mass remain less understood. Here, we demonstrate that supraphysiological activation of TAK1 in skeletal muscle of adult mice stimulates translational machinery, protein synthesis, and myofiber growth. TAK1 causes phosphorylation of elongation initiation factor 4E (eIF4E) independent of mTOR. Inactivation of TAK1 disrupts neuromuscular junction morphology and causes deregulation of Smad signaling. Using genetic approaches, we demonstrate that TAK1 prevents excessive loss of muscle mass during denervation. TAK1 favors the nuclear translocation of Smad4 and cytoplasmic retention of Smad6. TAK1 is also required for the phosphorylation of eIF4E in denervated skeletal muscle. Collectively, our results demonstrate that TAK1 supports skeletal muscle growth and prevents neurogenic muscle atrophy in adult mice.
Elena Losina, Shuang Song, Gordon P. Bensen
et al.
ObjectiveTo determine the prevalence of chronic and occasional opioid use and identify risk factors of opioid use among persons with knee osteoarthritis (OA).MethodsWe used the Medicare Current Beneficiary Survey to select a knee OA cohort. We obtained data on demographics characteristics, marital status, comorbidities, insurance, and prescription medication coverage from survey data and linked Medicare claims. We included all prescribed medication records classified as opioid under the First Databank therapeutic antiarthritics or analgesics categories. We stratified individuals with knee OA into 3 opioid use groups: 1) nonusers (0 prescriptions/year), 2) occasional users (1–5 prescriptions/year), and 3) chronic users (6+ prescriptions/year). We built multivariable logistic regression models using a generalized estimating equation to determine correlates of chronic opioid use.ResultsAmong 3,549 Medicare beneficiaries with knee OA and a mean ± SD age of 78 ± 7 years, 68% were female, 9% were chronic users, and 21% used opioids occasionally. Multivariable analysis showed that non‐Hispanic ethnicity (odds ratio [OR] 4.8, 95% confidence interval [95% CI] 2.2–10.2), divorced status (vs. married; OR 2.3, 95% CI 1.5–3.5), Medicaid eligibility (OR 1.9, 95% CI 1.3–2.7), depression (OR 1.9, 95% CI 1.5–2.5), chronic obstructive pulmonary disease (OR 1.9, 95% CI 1.4–2.5), and inability to walk without assistive devices (vs. no difficulty walking; OR 2.4, 95% CI 1.5–3.7) were independently associated with chronic opioid use.ConclusionA total of 9% of persons with knee OA use opioids chronically. Efforts to find nonopioid regimens for treating knee OA pain should be tailored to patients at high risk for chronic use.