Predicting Rates of Angular Correction After Hemiepiphysiodesis in Patients With X-Linked Hypophosphatemic Rickets.

PURPOSE: Patients with X-linked hypophosphatemic rickets (XLH) often develop coronal plane knee deformities despite medical treatment. Hemiepiphysiodesis is an effective way to correct coronal plane knee deformities in skeletally immature patients, but a full understanding of the rate of angular correction after hemiepiphysiodesis in XLH patients, compared with idiopathic cases is lacking. METHODS: We retrospectively reviewed charts of 24 XLH patients and 37 control patients without metabolic bone disease who underwent hemiepiphysiodesis. All patients were treated with standard-of-care medical therapy (SOC=active vitamin D and phosphate salt supplementation) in our clinical research center and had a minimum of 2-year follow-up after hemiepiphysiodesis. Demographic data as well as complications, repeat procedures, or recurrence/overcorrection were recorded. Standing lower extremity radiographs were evaluated before the surgical intervention and at subsequent hardware removal or skeletal maturity, whichever came first. Mean axis deviation, knee zone, mechanical lateral distal femoral angle (mLDFA), and medial proximal tibial angle were measured on each radiograph. The rate of angular correction was calculated as the change in mLDFA and medial proximal tibial angle over the duration of treatment. RESULTS: The magnitude of the initial deformity of the distal femur was greater in XLH patients as compared with control for varus (XLH mLDFA 97.7 +/- 4.9 vs. Control mLDFA 92.0 +/- 2.0 degrees) and valgus (XLH mLDFA 78.7 +/- 6.2 vs. Controls mLDFA 83.6 +/- 3.2 degrees). The rate of correction was dependent on age. When correcting for age, XLH patients corrected femoral deformity at a 15% to 36% slower rate than control patients for the mLDFA (>3 y growth remaining XLH 0.71 +/- 0.46 vs. control 0.84 +/- 0.27 degrees/month, <3 y growth remaining XLH 0.37 +/- 0.33 vs. control 0.58 +/- 0.41 degrees/month). No significant differences were seen in the rate of proximal tibia correction. XLH patients were less likely to end treatment in zone 1 (55.0% XLH vs. 77.8% control). XLH patients had longer treatment times than controls (19.5 +/- 10.7 vs. 12.6 +/- 7.0 mu, P value <0.001), a higher average number of secondary procedures than controls (1.33 +/- 1.44 vs. 0.62 +/- 0.92 number of procedures), a higher rate of overcorrection than controls (29.2% vs. 5.4%), and a higher rate of subsequent corrective osteotomy than controls (37.5% vs. 8.1%). There was no significant difference in the rate of complications between groups (8.3% vs. 5.4%). CONCLUSIONS: Patients with XLH undergoing hemiepiphysiodesis have a 15% to 36% slower rate of femoral deformity correction that results in longer treatment times, a higher likelihood to undergo more secondary procedures, and a lower likelihood to reach neutral mechanical alignment. SIGNIFICANCE: This study provides important information to guide the timing and treatment of patients with XLH and coronal plane knee deformities. In addition, results from this study can be educational for families and patients with respect to anticipated treatment times, success rates of the procedure, complication rate, and likelihood of needing repeat procedures.

A whole-joint histopathologic grading system for murine knee osteoarthritis.

This study aims to develop a comprehensive and easily executable histopathologic grading scheme for murine knee osteoarthritis (OA) using specific scoring criteria for both cartilage and periarticular changes, which may overcome important limitations of the existing grading systems. The new grading scheme was developed based on mouse knee OA models with observation periods up to 24 months of age (spontaneous OA) or 24-week post-injury (posttraumatic OA). Semi-quantitative assessments of the histopathologic OA changes were applied to all four quadrants per femorotibial joint for 50 joints (200 quadrants) using specific scoring criteria rather than mild to severe grades. Scoring elements per quadrant were as follows: cartilage lesion (0-7), osteophyte (0-3), subchondral bone change (0-3), synovitis (0-3), and ectopic periarticular soft-tissue chondrogenesis and ossification (0-3). The new histopathologic grading scheme had high intra- and interobserver reproducibility (correlation coefficients r > 0.95) across experienced and novice observers. Sensitivity and reliability analyses confirmed the ability of the new scheme to detect minimal but significant OA progression (p < 0.01) within a 2-week interval and to accurately identify tissue- and quadrant-specific OA severity within the joints. In conclusion, this study presents the first whole-joint histopathologic grading scheme for murine knee OA that covers all-stage osteoarthritic changes in all major joint tissues, including periarticular soft-tissue ossification that is not included in any of the existing OA grading systems. This reproducible scheme is easy to execute and sensitive to minimal OA progression without using computer software, suitable for quick OA severity assessments of the entire femorotibial joint.

Traumatic Arthrotomy.

Evaluation of periarticular traumatic wounds for joint penetration is a common clinical concern for orthopaedic surgeons. Wounds that violate the joint capsule can result in deep infection and sepsis. Understanding the anatomic landmarks and capsular extensions of the major joints is key to proper evaluation. Initial evaluation of periarticular wounds includes thorough examination of the wound and plain radiographs. Historically, the saline load test has been the diagnostic test of choice for assessing traumatic arthrotomy; however, CT has recently been shown to have excellent sensitivity and specificity for detecting open knee joint injuries. Current treatment of traumatic arthrotomy includes intravenous antibiotics and surgical irrigation and débridement. Future areas of research must focus on further validation of CT evaluation and its use in other major joints, standardizing antibiotic treatment, and further delineating the role of nonsurgical management in minor injuries.

Primary Arthrodesis for Diabetic Ankle Fractures.

BACKGROUND: Treatment of ankle fractures in patients with diabetes is associated with increased complication rates. Ankle arthrodesis is considered a salvage procedure after failed ankle fracture fixation, yet primary ankle arthrodesis has been proposed as a treatment option for patients with significant diabetes-related complications. To date, the characteristics of patients who undergo primary ankle arthrodesis and the associated outcomes have not been described. METHODS: A retrospective review was performed of 13 patients with diabetes who underwent primary arthrodesis for traumatic ankle fracture. Patient demographics were characterized in addition to their diabetes complications, Adelaide Fracture in the Diabetic Ankle (AFDA) score, and fracture type. Outcomes assessed included reoperation rates, infection rates, wound complications, nonunion/malunion, amputation, and development of Charcot arthropathy postoperatively. RESULTS: Patients who underwent primary arthrodesis had high rates of diabetes complications, average AFDA scores of 6.4, and high rates of severe injuries, including 38.5% open fractures and 69.2% fracture dislocations. The overall complication rate for primary arthrodesis of ankle fractures in diabetes patients was more than 75% in this cohort. Complications included a 38.5% reoperation rate, 38.5% infection rate, 53.8% wound complication rate, and 23.1% amputation rate. Despite a high nonunion rate at the attempted fusion sites, 89.9% of fractures healed and patients had a stable extremity. CONCLUSION: This review is the first to characterize the epidemiology and complications of diabetes patients undergoing primary ankle arthrodesis for ankle fractures. In this cohort, patients with multiple diabetic complications and severe injuries underwent primary arthrodesis, which led to an overall high complication rate. Further research is needed to determine the appropriate treatment option for these high-risk patients, and tibiotalocalcaneal stabilization without arthrodesis may be beneficial. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Pseudotumor from Metal-on-Metal Total Hip Arthroplasty Causing Unilateral Leg Edema: Case Presentation and Literature Review.

Metal-on-metal (MoM) total hip arthroplasty (THA) can be associated with adverse metal reactions, including pseudotumors. This case report describes a 58-year-old female with an MoM THA-related pseudotumor that caused unilateral leg edema from compression of her external iliac vein. After thorough preoperative workup to rule out infection and deep vein thrombosis and consultation with a vascular surgeon, the patient underwent revision THA and excision of her pseudotumor. She had complete resolution of her swelling at 4 years after surgery. Review of all available case reports for this rare complication revealed that almost all patients were female. All patients underwent revision THA, with resolution of their symptoms. Literature review demonstrates that women are disproportionally affected by complications associated with MoM THA. We recommend close monitoring of patients with MoM THA, particularly women, for development of adverse metal reactions.

Deletion of the insulin receptor in sensory neurons increases pancreatic insulin levels.

Insulin is known to have neurotrophic properties and loss of insulin support to sensory neurons may contribute to peripheral diabetic neuropathy (PDN). Here, genetically-modified mice were generated in which peripheral sensory neurons lacked the insulin receptor (SNIRKO mice) to determine whether disrupted sensory neuron insulin signaling plays a crucial role in the development of PDN and whether SNIRKO mice develop symptoms of PDN due to reduced insulin neurotrophic support. Our results revealed that SNIRKO mice were euglycemic and never displayed significant changes in a wide range of sensorimotor behaviors, nerve conduction velocity or intraepidermal nerve fiber density. However, SNIRKO mice displayed elevated serum insulin levels, glucose intolerance, and increased insulin content in the islets of Langerhans of the pancreas. These results contribute to the growing idea that sensory innervation of pancreatic islets is key to regulating islet function and that a negative feedback loop of sensory neuron insulin signaling keeps this regulation in balance. Our results suggest that a loss of insulin receptors in sensory neurons does not lead to peripheral nerve dysfunction. The SNIRKO mice will be a powerful tool to investigate sensory neuron insulin signaling and may give a unique insight into the role that sensory neurons play in modifying islet physiology.

Increased FNDC5 is associated with insulin resistance in high fat-fed mice.

FNDC5/irisin, has recently been identified as a novel protein that stimulates the "browning" of white adipose by inducing thermogenesis via increased uncoupling protein 1 (UCP1). We tested the hypothesis that high fat diet-induced prediabetic mice would exhibit increased FNDC5 and this effect would be attenuated by chronic exercise. C57BL/6 mice were randomized into three groups for the 4 week intervention: Standard diet (Std, n = 12), High fat diet (HF, n = 14), or High fat diet and free access to a running wheel (HFEX, n = 14). Body weight, glucose, insulin, and the homeostatic model assessment of insulin resistance (HOMA-IR) were greater in HF compared to Std and HFEX after the 4 week intervention. In support of our hypothesis, FNDC5 was higher in HF in both skeletal muscle and adipose compared to Std and was lower in adipose only in HFEX compared to HF mice. Following the same pattern, PGC-1α was significantly higher in HF compared to Std in skeletal muscle and significantly lower in HFEX compared to HF in adipose. UCP1 was significantly lower in HFEX versus Std (in skeletal muscle) and versus HF (in adipose). HOMA-IR was significantly correlated with FNDC5 protein levels in adipose. Increased FNDC5 in adipose and skeletal muscle may be a compensatory mechanism to offset high fat diet-induced weight gain and insulin resistance by increasing energy expenditure.

A Role for Insulin in Diabetic Neuropathy.

The peripheral nervous system is one of several organ systems that are profoundly affected in diabetes. The longstanding view is that insulin does not have a major role in modulating neuronal function in both central and peripheral nervous systems is now being challenged. In the setting of insulin deficiency or excess insulin, it is logical to propose that insulin dysregulation can contribute to neuropathic changes in sensory neurons. This is particularly important as sensory nerve damage associated with prediabetes, type 1 and type 2 diabetes is so prevalent. Here, we discuss the current experimental literature related to insulin's role as a potential neurotrophic factor in peripheral nerve function, as well as the possibility that insulin deficiency plays a role in diabetic neuropathy. In addition, we discuss how sensory neurons in the peripheral nervous system respond to insulin similar to other insulin-sensitive tissues. Moreover, studies now suggest that sensory neurons can also become insulin resistant like other tissues. Collectively, emerging studies are revealing that insulin signaling pathways are active contributors to sensory nerve modulation, and this review highlights this novel activity and should provide new insight into insulin's role in both peripheral and central nervous system diseases.

Peripheral nervous system insulin resistance in ob/ob mice.

BACKGROUND: A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy. Neuronal insulin resistance is associated with several neurological disorders and recent evidence has indicated that dorsal root ganglion (DRG) neurons in primary culture display altered insulin signaling, yet in vivo results are lacking. Here, experiments were performed to test the hypothesis that the PNS of insulin-resistant mice displays altered insulin signal transduction in vivo. For these studies, nondiabetic control and type 2 diabetic ob/ob mice were challenged with an intrathecal injection of insulin or insulin-like growth factor 1 (IGF-1) and downstream signaling was evaluated in the DRG and sciatic nerve using Western blot analysis. RESULTS: The results indicate that insulin signaling abnormalities documented in other "insulin sensitive" tissues (i.e. muscle, fat, liver) of ob/ob mice are also present in the PNS. A robust increase in Akt activation was observed with insulin and IGF-1 stimulation in nondiabetic mice in both the sciatic nerve and DRG; however this response was blunted in both tissues from ob/ob mice. The results also suggest that upregulated JNK activation and reduced insulin receptor expression could be contributory mechanisms of PNS insulin resistance within sensory neurons. CONCLUSIONS: These findings contribute to the growing body of evidence that alterations in insulin signaling occur in the PNS and may be a key factor in the pathogenesis of diabetic neuropathy.

In vivo peripheral nervous system insulin signaling.

Alterations in peripheral nervous system (PNS) insulin support may contribute to diabetic neuropathy (DN); yet, PNS insulin signaling is not fully defined. Here, we investigated in vivo insulin signaling in the PNS and compared the insulin responsiveness to that of muscle, liver, and adipose. Non-diabetic mice were administered increasing doses of insulin to define a dose-response relationship between insulin and Akt activation in the dorsal root ganglion (DRG) and sciatic nerve. Resulting EC50 doses were used to characterize the PNS insulin signaling time course and make comparisons between insulin signaling in the PNS and other peripheral tissues (i.e., muscle, liver, and adipose). The results demonstrate that the PNS is responsive to insulin and that differences in insulin signaling pathway activation exist between PNS compartments. At a therapeutically relevant dose, Akt was activated in the muscle, liver, and adipose at 30 min, correlating with the changes in blood glucose levels. Interestingly, the sciatic nerve showed a similar signaling profile as insulin-sensitive tissues; however, there was not a comparable activation in the DRG or spinal cord. These results present new evidence regarding PNS insulin signaling pathways in vivo and provide a baseline for studies investigating the contribution of disrupted PNS insulin signaling to DN pathogenesis.