A Functional Polymorphism Downstream of Vitamin A Regulator Gene CYP26B1 Is Associated with Hand Osteoarthritis.

While genetic analyses have revealed ~100 risk loci associated with osteoarthritis (OA), only eight have been linked to hand OA. Besides, these studies were performed in predominantly European and Caucasian ancestries. Here, we conducted a genome-wide association study in the Han Chinese population to identify genetic variations associated with the disease. We recruited a total of 1136 individuals (n = 420 hand OA-affected; n = 716 unaffected control subjects) of Han Chinese ancestry. We carried out genotyping using Axiom Asia Precisi on Medicine Research Array, and we employed the RegulomeDB database and RoadMap DNase I Hypersensitivity Sites annotations to further narrow down our potential candidate variants. Genetic variants identified were tested in the Geisinger's hand OA cohort selected from the Geisinger MyCode community health initiative (MyCode®). We also performed a luciferase reporter assay to confirm the potential impact of top candidate single-nucleotide polymorphisms (SNPs) on hand OA. We identified six associated SNPs (p-value = 6.76 × 10-7-7.31 × 10-6) clustered at 2p13.2 downstream of the CYP26B1 gene. The strongest association signal identified was rs883313 (p-value = 6.76 × 10-7, odds ratio (OR) = 1.76), followed by rs12713768 (p-value = 1.36 × 10-6, OR = 1.74), near or within the enhancer region closest to the CYP26B1 gene. Our findings showed that the major risk-conferring CC haplotype of SNPs rs12713768 and rs10208040 [strong linkage disequilibrium (LD); D' = 1, r2 = 0.651] drives 18.9% of enhancer expression activity. Our findings highlight that the SNP rs12713768 is associated with susceptibility to and severity of hand OA in the Han Chinese population and that the suggested retinoic acid signaling pathway may play an important role in its pathogenesis.

A patient with postpolio syndrome developed cauda equina syndrome after neuraxial anesthesia: A case report.

Combined spinal anesthesia and postoperative epidural analgesia is widely used in orthopedic surgery. Uncommon but serious neurologic complications of neuraxial anesthesia (NA) include direct trauma during needle or catheter insertion, central nervous system infections, and neurotoxicity of local anesthetics. Cauda equina syndrome (CES) is a rare complication after NA but can result in severe neurologic deterioration that may require surgical intervention. We present a case of a 69-year-old woman with postpolio syndrome who developed CES after combined spinal anesthesia and postoperative epidural analgesia. Perioperative observations and follow-up examinations, including magnetic resonance imaging, revealed no evidence of direct needle- or catheter-induced trauma, spinal hematoma, spinal ischemia, intraneural anesthetic injection, or infection. We speculate that CES symptoms were observed because of enhanced sensitivity to a combination of regional anesthetic technique-related microtrauma and neurotoxicity of bupivacaine and ropivacaine. Thus, practitioners should be aware that patients with preexisting neurologic diseases may be at increased risk for CES after NA.

Placement-induced effects on high tibial osteotomized construct - biomechanical tests and finite-element analyses.

BACKGROUND: High tibial osteotomy (HTO) with a medially opening wedge has been used to treat osteoarthritic knees. However, the osteotomized tibia becomes a highly unstable structure and necessitates the use of plate and screws to stabilize the medial opening and enhance bone healing. A T-shaped plate (e.g. TomoFix) with locking screws has been extensively used as a stabilizer of the HTO wedge. From the biomechanical viewpoint, however, the different plate sites and support bases of the HTO plate should affect the load-transferring path and wedge-stabilizing ability of the HTO construct. This study uses biomechanical tests and finite-element analyses to evaluate the placement- and base-induced effects of the HTO plates on construct performance. METHODS: Test-grade synthetic tibiae are chosen as the standard specimens of the static tests. A medial wedge is created for each specimen and stabilized by three plate variations: hybrid use of T- and I-shaped plates (TIP), anteriorly placed TomoFix (APT), and medially placed TomoFix (MPT). There are five tests for each variation. The failure loads of the three constructs are measured and used as the load references of the fatigue finite-element analysis. The residual life after two hundred thousand cycles is predicted for all variations. RESULTS: The testing results show no occurrence of implant back-out and breakage under all variations. However, the wedge fracture consistently occurs at the opening tip for the APT and MPT and the medially resected plateau for the TIP, respectively. The testing results reveal that both failure load and wedge stiffness of the TIP are the highest, followed by the MPT, while those of the APT are the least (P < 0.05). The fatigue analyses predict comparable values of residual life for the TIP and MPT and the highest value of damage accumulation for the APT. Both experimental and numerical tests show the biomechanical disadvantage of the APT than their counterparts. However, the TIP construct without locking screws shows the highest stress at the plate-screw interfaces. CONCLUSIONS: This study demonstrates the significant effect of placement site and support base on the construct behaviors. The TIP provides a wider base for supporting the HTO wedge even without the use of locking screws, thus significantly enhancing construct stiffness and suppressing wedge fracture. Compared to the APT, the MPT shows performance more comparable to that of the TIP. If a single plate and a smaller incision are considered, the MPT is recommended as the better alternative for stabilizing the medial HTO wedge.

Biomechanical effects of plate area and locking screw on medial open tibial osteotomy.

Medial open high tibial osteotomy (HTO) has been used to treat osteoarthritis of the medial compartment of the knee. However, weaker plate strength, unstable plate/screw junction and improper surgery technique are highly related to the HTO outcomes. Two π-shape plates were designed and eight variations (two supporting area × four locking stiffness) were compared by finite-element method. The computed tomography-based tibia was reconstructed and both wedge micromotion and implant stresses were chosen as the comparison indices. The construct was subjected to surgical and physiological loads. The medial-posterior region is the most loaded region and the load through the posterior leg is about four times that through the anterior leg. This indicates that the two-leg design can form a force-couple mechanism to effectively reduce the implant stresses. The use of locking screws significantly decrease the screw and hole stresses. However, the extending plate reduces the stresses of screws and holes above the wedge but makes the distal screws and holes much stressed. Wedge micromotion is affected by extending plate rather than locking screw. Three factors contribute to effective stabilisation of unstable HTO wedge: (1) intimate tibia-plate contact at medial-posterior regions, (2) sufficient rigidity at plate-screw junctions and (3) effective moment-balancing design at distal tibia-plate interfaces.

Transcriptional upregulation of DDR2 by ATF4 facilitates osteoblastic differentiation through p38 MAPK-mediated Runx2 activation.

Deficiency of the collagen receptor discoidin domain receptor tyrosine kinase (DDR2) in mice and humans results in dwarfism and short limbs, of which the mechanism remains unknown. Here we report that DDR2 is a key regulator of osteoblast differentiation. DDR2 mRNA expression was increased at an early stage of induced osteoblast differentiation. In the subchondral bone of human osteoarthritic knee, DDR2 was detected in osteoblastic cells. In mouse embryos, DDR2 expression was found from E11 to E15, preceding osteocalcin (OCN) and coinciding with Runx2 expression. Activating transcription factor 4 (ATF4) enhanced DDR2 mRNA expression, and knockdown of ATF4 expression delayed DDR2 induction during osteoblast differentiation. A CCAAT/enhancer binding protein (C/EBP) binding site at -1150 bp in the DDR2 promoter was required for ATF4-mediated DDR2 activation. C/EBPß bound to and cooperated with ATF4 in stimulating DDR2 transcription; accordingly, the ATF4 mutants deficient of C/EBPß binding were incapable of transactivating DDR2. Overexpression of DDR2 increased osteoblast-specific gene expression. Conversely, knockdown of DDR2 suppressed osteogenic marker gene expression and matrix mineralization during the induced osteogenesis. The stimulation of p38 MAPK by DDR2 was required for DDR2-induced activation of Runx2 and OCN promoters. Together our findings uncover a pathway in which ATF4, by binding to C/EBPß transcriptionally upregulates DDR2 expression, and DDR2, in turn, activates Runx2 through p38 MAPK to promote osteoblast differentiation.

Anatomic reconstruction of neglected Achilles tendon rupture with autogenous peroneal longus tendon by EndoButton fixation.

BACKGROUND: Neglected or chronic rupture of the Achilles tendon usually needs a reconstruction procedure. Many graft sources have been reported for this procedure, such as a proximal V-Y gastrocnemius tendon flap, flexor hallucis longus tendon, fascia lata, plantaris tendon, synthetic materials, and peroneus brevis. However, how to fix the graft at the calcaneal site remains controversial. METHODS: An alternative technique to anatomically reconstruct the Achilles tendon using an autogenous peroneal longus tendon with EndoButton-CL fixation at the calcaneal site for treatment of a patient who had a chronic neglected rupture of the Achilles tendon is described. RESULTS: The patient was allowed to begin gentle exercise, such as swimming and cycling 12 weeks after surgery, and encouraged to augment rehabilitation of hindfoot eversion and ankle plantar flexion. The ankle plantar flexion and hindfoot eversion strength was not reduced after active rehabilitation in 2.5 years of follow-up. CONCLUSIONS: Our technique reuses two small central incisions, thus, preserving skin integrity as much as possible to reduce wound breakdown or infection. The management of chronic or neglected Achilles tendon rupture by autogenous peroneal longus tendon with EndoButton-CL fixation at the calcaneal site is an anatomic and safe, but technically demanding technique.

Septic arthritis caused by vancomycin-intermediate Staphylococcus aureus.

Four methicillin-resistant Staphylococcus aureus isolates were consecutively isolated from synovial fluid and a knee wound of a patient with septic arthritis. Determination of the MIC of vancomycin and population analysis confirmed these isolates as vancomycin-intermediate S. aureus (VISA). Results of this study also revealed that cell wall thickness and reduced susceptibility to Triton X-100 were characteristic features of VISA.

The nitric oxide donor glyceryl trinitrate increases subchondral bone sclerosis and cartilage degeneration following ovine meniscectomy.

AIM: To examine the effect of glyceryl trinitrate (GTN), a nitric oxide (NO) donor compound, on the concurrent progression of cartilage and subchondral bone changes in an ovine meniscectomy model of osteoarthritis (OA). METHODS: Bilateral lateral meniscectomy (MX) was performed on 12 ewes to induce OA. Six were treated with topical GTN (0.7mg/kg twice weekly) (MX+GTN). Six other sheep formed non-operated controls (NOC). After sacrifice at six months, the subchondral bone density (BMD) of the lateral and medial femoral condyles (LFC, MFC) and tibial plateau (LTP, MTP) was assessed by DEXA. Dynamic biomechanical testing was performed across the MTP and LTP. Histological sections from each region were scored qualitatively and the thickness of the subchondral bone plate (SCB) was determined by image analysis. RESULTS: MX+GTN displayed significantly greater SCB thickness relative to MX in the LFC (mean increase +88% and +42%, respectively) and the MFC. SCB BMD was 10-12% greater in MX+GTN relative to MX in the LFC, LTP and MTP. MX+GTN sheep also showed greater increases in some histopathology variables, greater central erosion of the LTP, and changes in dynamic stiffness (decreased) and phase lag (increased) in the outer zone of the LTP. CONCLUSIONS: Treatment with GTN significantly increased subchondral bone thickness and density during subchondral remodelling following meniscectomy. In addition, it slightly but significantly worsened degeneration of cartilage structure and function. These results suggest that clinical use of GTN may accelerate both cartilage degeneration and subchondral bone sclerosis if used in the presence of OA, and demonstrate that NO has the potential be an important mediator of the subchondral bone changes seen in OA.