Yap regulates skeletal muscle fatty acid oxidation and adiposity in metabolic disease.

Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.

Neuropathic pain in end-stage hip and knee osteoarthritis: differential associations with patient-reported pain at rest and pain on activity.

OBJECTIVE: We investigated whether pain at rest and pain on activity were differentially associated with neuropathic pain scores in individuals with end-stage hip and knee OA. DESIGN: Study participants were 843 patients with hip or knee OA scheduled for total joint arthroplasty. In pre-surgery questionnaires, measures of socio-demographics, health status, medication use, neuropathic pain (painDETECT), pain at rest and pain on activity (WOMAC pain items), depression (HADS) and pain catastrophizing (PCS) were collected. Multivariable linear regression models were estimated for men and women separately to examine the association between neuropathic pain scores (outcome) and study measures, entered in blocks. RESULTS: Sample mean age was 65.1 years (SD: 9.6); 57.1% were women. Mean painDETECT scores were significantly higher (P ≤Ö¹ 0.001) for women (11.2 ± 6.6 out of 38) than men (9.3 ± 7.0), with 35.6% of women and 27.7% of men meeting cut-offs for possible or likely neuropathic pain. In the final regression model for women, the coefficients for both types of pain were statistically significant, although the coefficient for pain at rest was 1.6 times greater than that for pain on activity. For men, only pain at rest was significantly associated with neuropathic pain scores. CONCLUSIONS: Findings support that possible neuropathic pain is experienced by a notable proportion of patients with end-stage hip and knee OA and is more strongly associated with pain at rest than pain on activity, particularly in men. Clinical presentation of pain at rest may warrant more thorough evaluation for potential neuropathic pain and have implications for appropriate pain management.

The Hippo pathway effector YAP is a critical regulator of skeletal muscle fibre size.

The Yes-associated protein (YAP) is a core effector of the Hippo pathway, which regulates proliferation and apoptosis in organ development. YAP function has been extensively characterized in epithelial cells and tissues, but its function in adult skeletal muscle remains poorly defined. Here we show that YAP positively regulates basal skeletal muscle mass and protein synthesis. Mechanistically, we show that YAP regulates muscle mass via interaction with TEAD transcription factors. Furthermore, YAP abundance and activity in muscles is increased following injury or degeneration of motor nerves, as a process to mitigate neurogenic muscle atrophy. Our findings highlight an essential role for YAP as a positive regulator of skeletal muscle size. Further investigation of interventions that promote YAP activity in skeletal muscle might aid the development of therapeutics to combat muscle wasting and neuromuscular disorders.

Postoperative improvement in health-related quality of life: a national comparison of surgical treatment for focal (one- to two-level) lumbar spinal stenosis compared with total joint arthroplasty for osteoarthritis.

BACKGROUND CONTEXT: The results of single-center studies have shown that surgical intervention for lumbar spinal stenosis yielded comparable health-related quality of life (HRQoL) improvement to total joint arthroplasty (TJA). Whether these results are generalizable to routine clinical practice in Canada is unknown. PURPOSE: The primary purpose of this equivalence study was to compare the relative improvement in physical HRQoL after surgery for focal lumbar spinal stenosis (FLSS) compared with TJA for hip and knee osteoarthritis (OA) across six Canadian centers. STUDY DESIGN/SETTING: A Canadian multicenter ambispective cohort study. PATIENT SAMPLE: A cohort of 371 primary one- to two-level spinal decompression (n=214 with instrumented fusion) for FLSS (n=179 with degenerative lumbar spondylolisthesis [DLS]) was compared with a cohort of primary total hip (n=156) and knee (n=208) arthroplasty for OA. OUTCOME MEASURES: The primary outcome was the change in preoperative to 2-year postoperative 36-Item Short Form Health Survey Physical Component Summary (PCS) score as reflected by the number of patients reaching minimal clinically important difference (MCID) and substantial clinical benefit (SCB). METHODS: Univariate analyses were conducted to identify baseline differences and factors that were significantly related to outcomes at 2 years. Multivariable regression modeling was used as our primary analysis to compare outcomes between groups. RESULTS: The mean age (years) and percent females for the spine, hip, and knee groups were 63.3/58.5, 66.0/46.9, and 65.8/64.3, respectively. All three groups experienced significant improvement of baseline PCS (p<.001). Multivariate analyses, adjusting for baseline differences (age, gender, baseline Mental Component Summary score, baseline PCS), demonstrated no significant differences in PCS outcome between spinal surgery and arthroplasty (combined hip and knee cohorts) patients with an odds ratio of 0.80 (95% confidence interval [CI], 0.57-1.11; p=.17) and 0.79 (95% CI, 0.58-1.09; p=.15) for achieving MCID or SCB, respectively. In subgroup analysis, spine and knee outcomes were not significantly different, with hip arthroplasty superior to both (p<.0001). CONCLUSIONS: Significant improvement in physical HRQoL after surgical treatment of FLSS (including DLS) is consistently achieved nationally. Our overall results demonstrate that a comparable number of patients can expect to achieve MCID and SCB 2 years after surgical intervention for FLSS and total knee arthroplasty.

Survival and clinical function of cemented and uncemented prostheses in total knee replacement: a meta-analysis.

Using meta-analysis we compared the survival and clinical outcomes of cemented and uncemented techniques in primary total knee replacement. We reviewed randomised controlled trials and observational studies comparing cemented and uncemented fixation. Our primary outcome was survival of the implant free of aseptic loosening. Our secondary outcome was joint function as measured by the Knee Society score. We identified 15 studies that met our final eligibility criteria. The combined odds ratio for failure of the implant due to aseptic loosening for the uncemented group was 4.2 (95% confidence interval (CI) 2.7 to 6.5) (p < 0.0001). Subgroup analysis of data only from randomised controlled trials showed no differences between the groups for odds of aseptic loosening (odds ratio 1.9, 95% CI 0.55 to 6.40, p = 0.314). The weighted mean difference for the Knee Society score was 0.005 (95% CI -0.26 to 0.26) (p = 0.972). There was improved survival of the cemented compared to uncemented implants, with no statistically significant difference in the mean Knee Society score between groups for all pooled data.

The effect of a tibial baseplate undersurface peripheral lip on cement penetration in total knee arthroplasty.

Many total knee arthroplasty (TKA) tibial baseplates have a peripheral lip or cement pocket theoretically to increase cement penetration by decreasing edge escape of the cement squeeze film on baseplate impaction. We reviewed 177 consecutive TKAs (89 nonlipped and 87 lipped baseplates) performed by a single surgeon, using the same third-generation tibial cementation techniques. Cement penetration patterns of the lateral 12 mm of proximal tibia were examined by a semiautomatic computerized digital image analysis technique. Penetration in the lipped baseplate was double that of the nonlipped baseplate at the component's lateral edge (P<.05) and continued to be statistically significantly greater to 4 mm from edge. From 5 to 7 mm, the difference was no longer statistically significant, and from 8 to 12 mm, the penetration was equal.

The effect of freezing and intraosseous fluid on the stiffness behavior of canine trabecular bone.

The effect of disrupting the intraosseous fluid compartment and freezing on the mechanical stiffness of trabecular bone in intact canine femoral head specimens was investigated. Twenty-four skeletally mature dogs were divided into two groups. Twelve paired fresh femora were tested and 12 paired femora were tested after freezing at -20 degrees C. The intact femoral head specimens were subjected to a load of physiologic magnitude, and then the stiffness of the underlying trabecular bone was determined in intact femora, in drilled femora with a disrupted intraosseous fluid compartment, and subsequently after refilling the compartment with fluid. Drilling of the femoral head and disrupting its bony fluid compartment resulted in a 40% decrease in stiffness (P<.001). This effect was seen only with fresh specimens and not frozen specimens. Refilling the bony compartment with fluid restored the stiffness of the fresh femoral head. These results demonstrate the mechanical properties of trabecular bone in canine femoral head specimens in vitro are affected by intraosseous fluid and freezing. Removal of the intraosseous fluid decreases the mechanical stiffness of canine trabecular bone, and freezing the specimens appears to alter the intraosseous fluid compartment behavior. It is necessary to gain a better understanding of the dynamic mechanical properties of intact bone to improve the existing analytical and experimental mechanical bone models. The effect of intraosseous fluid and freezing should be considered in these models.

Patient factors affecting autologous and allogeneic blood transfusion rates in total hip arthroplasty.

Factors that place patients undergoing total hip arthroplasty (THA) at increased risk of receiving an allogeneic or autologous blood transfusion may aid in determining which patients should predonate blood. The records of 354 consecutive patients undergoing THA were retrospectively reviewed to determine patient factors related to transfusion requirement. The risk of transfusion requirement was most strongly correlated with low preoperative hemoglobin level, but also with older age, higher American Society of Anesthesiologists physical status rating, female sex, cemented arthroplasty, and revision surgery. These patients were also least likely to predonate blood, likely because of their comorbid status.

Cementless acetabular fixation in total hip arthroplasty using polyglycolide-lactide screws: an in vivo canine study.

Bone ingrowth into cementless acetabular components was evaluated in a canine total hip arthroplasty model, comparing components initially stabilized with polyglycolide-lactide screws with those initially stabilized with titanium screws. The acetabular shell was anchored with 2 polyglycolide-lactide screws in 16 dogs and with 2 titanium screws in 12 dogs. The dogs were followed and sacrificed at 7 weeks, 14 weeks, 10 months, or 15 months. Histomorphometric analysis of bone ingrowth into the weight-bearing dome of the acetabular shell was conducted. No difference was detected in mean bone ingrowth into the acetabular shell comparing the 2 screw groups. The results of this study do not support a significant advantage to the use of biodegradable screws for the initial stabilization of cementless acetabular components in canine total hip arthroplasty.

Use of a polyglycolide lactide cement plug restrictor in total hip arthroplasty.

The use of a polyglycolide lactide cement plug restrictor in cemented femoral fixation during total hip arthroplasty was evaluated. Femoral cement pressurization was evaluated in vitro in a cadaveric model and the host response to polymer degradation was evaluated in vivo in a canine total hip arthroplasty model. Sixteen embalmed anatomic specimen femurs were prepared for cement femoral fixation. The intramedullary canal was plugged with either an ultrahigh molecular weight polyethylene cement plug restrictor or a polyglycolide lactide cement plug restrictor. Peak pressures in the proximal, mid, and distal portions of the cement mantle were recorded during cement insertion, cement pressurization, and implant insertion. There was no difference between the two plug groups in peak pressures throughout the cement mantle during cement insertion, pressurization, or implant insertion. Total hip arthroplasty using a cementless acetabular component and a cemented femoral stem was performed in 24 dogs. The femoral intramedullary canal was plugged with a polyethylene or a biodegradable cement plug restrictor. The dogs were sacrificed at 7 weeks, 10 months, or 15 months. Radiographically, no osteolytic lesions were seen around either plug type. Histomorphometrically, the polyglycolide lactide plugs appeared intact at 7 weeks and partially degraded by 10 and 15 months. In both plug groups, a mild fibrohistiocytic reaction with infiltration of fibrocytes, histocytes, and endothelial cells was seen. No osteolysis was observed. The results of the current study show that femoral cement pressurization can be attained in vitro using a biodegradable cement plug restrictor and that for as long as 15 months in the in vivo canine model there were no adverse reactions associated with use of these plugs compared with conventional ultrahigh molecular weight polyethylene plugs.

A randomized trial of hydroxyapatite coated prostheses in total hip arthroplasty.

In a prospective randomized trial, 62 consecutive primary cementless total hip arthroplasties in 55 patients were performed by one surgeon using either hydroxyapatite coated (35 hips) or nonhydroxyapatite coated femoral prostheses (27 hips). The dual tapered femoral stem had a Ti-6AI-4V plasma sprayed circumferential proximal porous coat applied to the proximal 1/3 of the stem. The middle 1/3 had a roughened blasted textured surface, and the distal 1/3 had a smooth surface. The hydroxyapatite coated femoral stems had an additional hydroxyapatite coating applied to the proximal porous coat with use of an air plasma process. The patients in the two groups were not significantly different regarding age (48.2 +/- 9.0 years hydroxyapatite group, 50.4 +/- 8.7 years control group), gender, Charnley class, or length of followup (4.4 +/- 0.7 years hydroxyapatite group, 4.9 +/- 1.0 years control group). Forty-nine patients (54 hips) were available for clinical followup, and 45 patients (50 hips) had radiographic followup. A minimum 3-year followup was recorded. To date, there have been no femoral prostheses failures. No femoral implant has migrated or subsided. Radiographically, the hydroxyapatite coated stems showed trends toward increased distal stem related cortical hypertrophy, increased cancellous condensation and less endosteal cavitation. Two nonhydroxyapatite coated stems had distal endosteal cavitation, whereas no hydroxyapatite coated stems did. There were two cases of acetabular osteolysis (revision in one) and two cases of acetabular cup migration (nonrevised), all occurring in the control group. The overall revision rate was 4%. There was no difference in Harris hip scores at 6 months (80.6 +/- 13.0 points hydroxyapatite group, 83.8 +/- 12.4 points control group) or at last followup (85.6 +/- 15.4 points hydroxyapatite group, 89.7 +/- 13.4 control group). The Harris hip pain scores also were not significantly different at 6 months or at last followup. Multiple linear regression analysis controlling for age, gender, and length of followup revealed no significant predictors of Harris hip or pain scores. The results of this study at an average of 4.6 years do not indicate a significant clinical advantage to the use of hydroxyapatite coated femoral prostheses in primary cementless total hip arthroplasty when judged by the criteria of Harris hip scores and femoral stem survivorship.

Total hip arthroplasty complicated by tuberculous infection.

The case of a 66-year-old woman with tuberculous infection complicating a total hip arthroplasty that had been performed 4 years previously for degenerative arthritis is reported. The patient had no prior history of exposure to tuberculosis and no evidence of skeletal or nonskeletal tuberculous infection. The need for a high index of suspicion when dealing with unexpected arthroplasty failure is emphasized. Tuberculous cultures are recommended in these cases prior to revision surgery.

Choosing the socket in total hip arthroplasty.

Significant improvements have been made in the long-term results of cemented femoral components, but there has been little improvement in the results of cemented acetabular components. Polyethylene wear debris has been proposed as the most important factor causing loosening of cemented acetabular components. Polyethylene thickness and femoral-head size affect the rate of acetabular wear and loosening. The early results of total hip arthroplasty with noncemented acetabular components are promising, and many feel that they represent the state of the art. The hemispheric components with a porous coating have proven superior to most of the screw ring designs. There are potential disadvantages with the use of screws to augment fixation of the hemispheric components, and recently it has become popular to under-ream the acetabulum and press-fit the oversized acetabular component without the use of screws.

The effect of the medial collar in total hip arthroplasty with porous-coated components inserted without cement. An in vivo canine study.

We performed an in vivo study in a canine model to compare the results of the use of a porous-coated collared femoral component with those of the use of a porous-coated collarless femoral component in total hip arthroplasties without cement. Our study focused on the comparative proximal strain pattern, bone ingrowth, and cortical porosity of the two types of prostheses. We used a trochanteric wire marker to measure subsidence. The use of the limb was assessed with gait analysis. Twelve weeks after the operation, the collarless components had significantly greater bone ingrowth proximally (p = 0.003) and were associated with significantly lower cortical porosity (p = 0.006). There were no differences between the groups with regard to either axial or hoop strain. While the group that had a collarless prosthesis had significantly less proximal-medial radiolucency (p = 0.03), there were no differences between the groups with regard to subsidence.

Fixation with biodegradable devices of acetabular components in a canine model.

Cementless total hip arthroplasty was performed in 13 dogs. The acetabular component was anchored with two biodegradable devices (polylactic acid) in seven dogs and with two titanium screws in six dogs. At 14 weeks, histomorphometric determinations of bony ingrowth into the porous coating of the acetabular weight bearing dome was 54.4% when fixed with the biodegradable devices and 58.9% when fixed with the titanium screws (no statistically significant difference; p = 0.556). At the sites of fixation, less bony ingrowth occurred with the biodegradable devices. The use of biodegradable devices in total hip arthroplasty should overcome the potential metal corrosion of titanium screws that can lead to polyethylene wear.

Femoral component offset. Its effect on strain in bone-cement.

The magnitude of the offset of the femoral prosthesis strongly influences the mechanics of the hip following a total hip arthroplasty. An increased offset increases the moment arm of the abductor muscles. This reduces the abductor force required for normal gait and, consequently, reduces the resultant force across the hip joint. These factors are advantageous. However, increased offset also increases the bending moment on the implant, which could adversely increase the strain in the medial cement mantle. To evaluate the relative advantages and disadvantages of these conflicting results of increasing the offset of the femoral component the authors measured in vitro in cadaver femora the effect of differing offsets of the femoral component on strain in the cement mantle. After testing the intact femora, the authors cemented femoral prostheses in place and quantified the abductor force, resultant force, and strain in the cement mantle under loading conditions simulating single limb stance at different femoral offset levels. The reduction in both abductor and resultant force was substantial with increased femoral component offset, but the strain in the cement of the proximal medial portion of the cement mantle was not significantly increased.

A comparison of the strength and stability of six techniques of cerclage wire fixation for fractures.

An in vitro comparison of six methods of cerclage wire fixation was performed using 1-mm-diameter stainless steel wire. A testing apparatus was designed to simulate the tensile forces on a cerclage wire around a femoral shaft fracture. The hairpin cerclage knot that we describe generated significantly higher initial compressive force (p < 0.001) and had significantly higher tensile strength (p < 0.02) compared with the other five methods.