No Difference in the Rates of Unplanned Return to the Operating Room Between Magnetically Controlled Growing Rods and Traditional Growth Friendly Surgery for Children With Cerebral Palsy.

BACKGROUND: Early-onset scoliosis (EOS) is common in children with cerebral palsy (CP). The effectiveness of magnetically controlled growing rods (MCGR) and the risk for unplanned return to the operating room (UPROR) remain to be studied in this patient population. The primary outcome of this study was to examine the frequency of UPROR between MCGRs as compared with traditional growth friendly (TGF) surgeries for children with EOS secondary to CP. METHODS: Patients with EOS secondary to CP were prospectively identified from an international database, with data retrospectively analyzed. Scoliosis, kyphosis, T1-S1, and T1-T12 height were measured preoperation, immediate postoperation, and at minimum 2-year follow-up. The risk and etiology of UPRORs were compared between MCGR and TGF. RESULTS: Of the 120 patients that met inclusion criteria, 86 received TGF (age 7.5±0. 1.8 y; mean follow-up 7.0±2.9 y) and 34 received MCGR (age 7.1±2.2 y, mean follow-up 2.8±0.0.5 y). Compared with TGF, MCGR resulted in significant improvements in maintenance of scoliosis (P=0.007). At final follow-up, UPRORs were 8 of 34 patients (24%) for MCGR and 37 of 86 patients (43%) for TGF (P=0.05). To minimize the influence of follow-up period, UPRORs within the first 2 years postoperation were evaluated: MCGR (7 of 34 patients, 21%) versus TGF (20 of 86 patients, 23%; P=0.75). Within the first 2 years, etiology of UPROR as a percentage of all patients per group were deep infection (13% TGF, 6% MCGR), implant failure/migration (12% TGF, 9% MCGR), dehiscence (4% TGF, 3% MCGR), and superficial infection (4% TGF, 3% MCGR). The most common etiology of UPROR for TGF was deep infection and for MCGR was implant failure/migration. CONCLUSION: For patients with EOS secondary to CP, there was no difference in the risk of UPROR within the first 2 years postoperatively whether treated with TGF surgery or with MCGRs (23% TGF, 21% MCGR). LEVEL OF EVIDENCE: Level III-retrospective cohort, therapeutic study.

Recent developments in emerging therapeutic targets of osteoarthritis.

PURPOSE OF REVIEW: Despite the tremendous individual suffering and socioeconomic burden caused by osteoarthritis, there are currently no effective disease-modifying treatment options. This is in part because of our incomplete understanding of osteoarthritis disease mechanism. This review summarizes recent developments in therapeutic targets identified from surgical animal models of osteoarthritis that provide novel insight into osteoarthritis pathology and possess potential for progression into preclinical studies. RECENT FINDINGS: Several candidate pathways and processes that have been identified include chondrocyte autophagy, growth factor signaling, inflammation, and nociceptive signaling. Major strategies that possess therapeutic potential at the cellular level include inhibiting autophagy suppression and decreasing reactive oxygen species (ROS) production. Cartilage anabolism and prevention of cartilage degradation has been shown to result from growth factor signaling modulation, such as TGF-ß, TGF-α, and FGF; however, the results are context-dependent and require further investigation. Pain assessment studies in rodent surgical models have demonstrated potential in employing anti-NGF strategies for minimizing osteoarthritis-associated pain. SUMMARY: Studies of potential therapeutic targets in osteoarthritis using animal surgical models are helping to elucidate osteoarthritis pathology and propel therapeutics development. Further studies should continue to elucidate pathological mechanisms and therapeutic targets in various joint tissues to improve overall joint health.

Chondrocyte hypertrophy in skeletal development, growth, and disease.

Most of our bones form through the process of endochondral ossification, which is tightly regulated by the activity of the cartilage growth plate. Chondrocyte maturation through the various stages of growth plate physiology ultimately results in hypertrophy. Chondrocyte hypertrophy is an essential contributor to longitudinal bone growth, but recent data suggest that these cells also play fundamental roles in signaling to other skeletal cells, thus coordinating endochondral ossification. On the other hand, ectopic hypertrophy of articular chondrocytes has been implicated in the pathogenesis of osteoarthritis. Thus, a better understanding of the processes that control chondrocyte hypertrophy in the growth plate as well as in articular cartilage is required for improved management of both skeletal growth disorders and osteoarthritis. This review summarizes recent findings on the regulation of hypertrophic chondrocyte differentiation, the cellular mechanisms involved in hypertrophy, and the role of chondrocyte hypertrophy in skeletal physiology and pathophysiology.

Autoimmune epididymoorchitis is essential to the pathogenesis of male-specific spondylarthritis in HLA-B27-transgenic rats.

OBJECTIVE: Male rats transgenic for HLA-B27 and human ß(2) -microglobulin (hß(2) m) spontaneously develop epididymoorchitis (EO) preceding the development of spondylarthritis (SpA). In the specific B27/hß(2) m-transgenic rat cross-strain (21-3 × 382-2)F(1) , only the males develop SpA, and neither sex develops gut inflammation. This study was undertaken to determine whether EO and SpA in male (21-3 × 382-2)F(1) rats are causally related. In addition, the primary characteristics of EO in this rat arthritis model were assessed. METHODS: Male B27/hß(2) m-transgenic (21-3 × 382-2)F(1) rats underwent bilateral, unilateral, or sham epididymoorchiectomy between ages 36 and 125 days. The castrated rats were given testosterone replacement. Alternatively, the 21-3 and 283-2 transgene loci were crossed with a transgene inducing aspermatogenesis. Rats were observed for the development of EO, arthritis, and spondylitis. RESULTS: In unmanipulated transgenic rats, inflammation was first evident in the ductuli efferentes (DE; ducts linking the rete testis to epididymis) as early as age 30 days. The inflammation was initially neutrophilic, and later became granulomatous. Antisperm and anti-testis cell antibodies appeared in the rat serum after age 70 days. Cells infiltrating the testes were predominantly CD4+ T cells and CD68+ or CD163+ macrophages. Quantitative polymerase chain reaction of the DE, epididymis, and testis showed elevations in the levels of interferon-γ, interleukin-10 (IL-10), and IL-17A. In addition, levels of IL-12A, IL-22, IL-23A, and IL-23 receptor were found to be elevated in the DE. Remarkably, castration of the rats before age 91 days completely prevented the subsequent onset of arthritis and spondylitis, as did transgene-induced azospermia. CONCLUSION: Autoimmune EO develops spontaneously in HLA-B27/hß(2) m-transgenic (21-3 × 283-2)F(1) rats at age 30 days, the age when antigen-positive meiotic germ cells first exit the testis. Persistent testicular inflammation and/or antigenic stimulation are essential prerequisites for the subsequent development of SpA. Thus, dysregulated innate immunity at immune-privileged sites may be an essential mechanism triggering the onset of SpA.

Unmet need in the treatment of polymyalgia rheumatica and giant cell arteritis.

For decades, aside from prednisone and the occasional use of immune suppressive drugs such as methotrexate, there was little to offer patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). However, there is a great interest in various steroid sparing treatments in both these conditions. This paper aims to provide an overview of our current knowledge of PMR and GCA, examining their similarities and distinctions in terms of clinical presentation, diagnosis, and treatment, with emphasis placed on reviewing recent and ongoing research efforts on emerging treatment. Multiple recent and ongoing clinical trials are demonstrating new therapeutics that will provide benefit and contribute to the evolution of clinical guidelines and standard of care for patients with GCA and/or PMR.

A Na+/K+ ATPase Pump Regulates Chondrocyte Differentiation and Bone Length Variation in Mice.

The genetic and developmental mechanisms involved in limb formation are relatively well documented, but how these mechanisms are modulated by changes in chondrocyte physiology to produce differences in limb bone length remains unclear. Here, we used high throughput RNA sequencing (RNAseq) to probe the developmental genetic basis of variation in limb bone length in Longshanks, a mouse model of experimental evolution. We find that increased tibia length in Longshanks is associated with altered expression of a few key endochondral ossification genes such as Npr3, Dlk1, Sox9, and Sfrp1, as well reduced expression of Fxyd2, a facultative subunit of the cell membrane-bound Na+/K+ ATPase pump (NKA). Next, using murine tibia and cell cultures, we show a dynamic role for NKA in chondrocyte differentiation and in bone length regulation. Specifically, we show that pharmacological inhibition of NKA disrupts chondrocyte differentiation, by upregulating expression of mesenchymal stem cell markers (Prrx1, Serpina3n), downregulation of chondrogenesis marker Sox9, and altered expression of extracellular matrix genes (e.g., collagens) associated with proliferative and hypertrophic chondrocytes. Together, Longshanks and in vitro data suggest a broader developmental and evolutionary role of NKA in regulating limb length diversity.

Liver X Receptor activation regulates genes involved in lipid homeostasis in developing chondrocytes.

Objective: Osteoarthritis (OA) is the most common type of arthritis and causes debilitating symptoms and decreased quality of life. A better understanding of the molecular mechanisms maintaining cartilage health is needed for developing novel therapeutic strategies. Liver X Receptors (LXRs) are nuclear receptors that have been previously shown to protect against OA. To better understand the regulatory mechanisms behind this effect, we systematically examined LXR's effects on growth plate chondrocyte gene expression. Methods: Primary chondrocytes isolated from the long bones of E15.5 mice were treated with the specific LXR agonist, GW3965, and RNA was isolated for Affymetrix microarrays. Bioinformatics analyses were performed using Gene Ontology (GO) and KEGG pathway analysis. Immunohistochemistry was conducted to examine protein localization of LXR and identified targets in GW3965-treated E15.5 tibiae compared to control. Results: LXR activation in primary growth plate chondrocytes resulted in differential regulations of various genes involved in lipid metabolism. This pattern was compared to LXR activation in immature murine articular chondrocytes (IMACs), which revealed similar roles in lipid homeostasis. Immunohistochemical analysis of LXR and its identified targets Abca1 and Srebf1 revealed preferential protein localization to pre-hypertrophic and resting chondrocytes in GW3965-treated tibial growth plates compared to controls. Conclusion: Our findings show for the first time that LXR activation alters expression of lipid metabolism genes in growth plate chondrocytes, in part through activation of molecules responsible for cellular cholesterol efflux. This provides insight into potential mechanisms through which LXR regulates cellular metabolism to alter chondrocyte behavior and phenotype.

The Impact of a Rotating Elective on Medical Students' Perception of Radiation Oncology.

Background As Radiation Oncology (RO) is a field with limited exposure in undergraduate medical education curricula, the information sources used to form students' perception of the field can have a substantial impact on whether students decide to pursue experiences in RO. Furthermore, the effects of a single elective experience in RO can strongly influence career decisions as it may serve as the only experience for students to gain an understanding of RO as a specialty. This study analyzes which information sources students use and most strongly value when forming their perception of RO both before and after participating in the program, while also analyzing changes in the perception of various speciality-related factors associated with RO. Methods To address underrepresented specialties, the Pre-clerkship Residency Exploration Program (PREP) was developed to provide students exposure to RO and 13 other specialties through half-day clinical rotations, simulations, skills sessions, and panel discussions. A total of 37 participants completed both "Pre-program" and "Post-program" surveys to evaluate which information sources they use and value most when forming their perception of RO, and student perception of career factors associated with RO was assessed. Results Students reported that Pre-program information sources of RO were based on Lectures (35 students, 94.6%) and Preceptors (18 students, 48.7%). Post-program responses indicated that the greatest sources of information used were from Preceptors (36 students, 97.3%) and Residents (34 students, 91.9%), with the greatest increase being found in interactions with Residents for gaining specialty information (78% increase). Students most highly valued Preceptors, Residents, and Lectures as information sources when forming their perception of RO. Pre-program, students had the greatest positive perception of RO with respect to Income Potential (mean: 3.76/5.00 ± 0.87), Intellectual Challenge (mean: 3.90/5.00 ± 0.94), and Research Opportunities (mean: 3.86/5.00 ± 0.83) while most negatively assessing the factors of Flexibility (mean: 2.69/5.00 ± 0.93) and Level of Stress (mean: 2.93/5.00 ± 0.94). Conclusions Student perception of a medical specialty is a factor that may influence student elective choice and career decisions. Through participating in PREP, significant positive increases were found in students' perception of RO in the areas of Flexibility, Patient Population, Competitiveness of the Specialty, Quality of the Working Environment, and Levels of Stress. This study highlights which information sources students value the most when forming their perception of RO and the impact a single elective experience has on improving student perception of the field. RO-based programs and lectures can be better designed using this information to introduce students to this specialty.

Nuclear receptors as potential drug targets in osteoarthritis.

Osteoarthritis is amongst the major causes of disability worldwide, but no medications that can slow or stop progression of this disorder have been identified. Recent evidence suggests roles for a variety of members of the nuclear receptor family of ligand-activated transcription factors in various forms of osteoarthritis. Since nuclear receptors are amongst the major classes of drug targets, these studies suggest that modulators of nuclear receptor activity might provide novel strategies to treat osteoarthritis. This review focuses on recent advances in our understanding of the role of nuclear receptors in osteoarthritis onset and progression, as well as their therapeutic implications. Future studies should continue to examine the possible roles of additional nuclear receptors in the pathophysiology of different types of osteoarthritis.

Nuclear receptors regulate lipid metabolism and oxidative stress markers in chondrocytes.

Joint homeostasis failure can result in osteoarthritis (OA). Currently, there are no treatments to alter disease progression in OA, but targeting early changes in cellular behavior has great potential. Recent data show that nuclear receptors contribute to the pathogenesis of OA and could be viable therapeutic targets, but their molecular mechanisms in cartilage are incompletely understood. This study examines global changes in gene expression after treatment with agonists for four nuclear receptor implicated in OA (LXR, PPARδ, PPARγ, and RXR). Murine articular chondrocytes were treated with agonists for LXR, PPARδ, PPARγ, or RXR and underwent microarray, qPCR, and cellular lipid analyses to evaluate changes in gene expression and lipid profile. Immunohistochemistry was conducted to compare two differentially expressed targets (Txnip, Gsta4) in control and cartilage-specific PPARδ knockout mice subjected to surgical destabilization of the medial meniscus (DMM). Nuclear receptor agonists induced different gene expression profiles with many responses affecting lipid metabolism. LXR activation downregulated gene expression of proteases involved in OA, whereas RXR agonism decreased expression of ECM components and increased expression of Mmp13. Functional assays indicate increases in cell triglyceride accumulation after PPARγ, LXR, and RXR agonism but a decrease after PPARδ agonism. PPARδ and RXR downregulate the antioxidant Gsta4, and PPARδ upregulates Txnip. Wild-type, but not PPARδ-deficient mice, display increased staining for Txnip after DMM. Collectively, these data demonstrate that nuclear receptor activation in chondrocytes primarily affects lipid metabolism. In the case of PPARδ, this change might lead to increased oxidative stress, possibly contributing to OA-associated changes. KEY MESSAGE: Nuclear receptors regulate metabolic genes in chondrocytes. Nuclear receptors affect triglyceride levels. PPARδ mediates regulation of oxidative stress markers. Nuclear receptors are promising therapeutic targets for osteoarthritis.