Implante endoscópico de mioblastos autólogos en el tratamiento de la incontinencia urinaria de esfuerzo y evaluación de su eficacia en conejos sometidos a esfinterotomía / Endoscopic implantation of autologous myoblasts for stress urinary incontinence and evaluation of its efficacy in sphincterotomized rabbits

Introducción La incontinencia urinaria de esfuerzo (IUE) constituye uno de los problemas de salud con mayor impacto en la vida de las personas. El objetivo del presente trabajo fue desarrollar una terapia para IUE dentro de la ingeniería de tejidos mediante aislamiento y cultivo de mioblastos autólogos (MAC), su implante endoscópico y el estudio de su eficacia en un modelo de incontinencia por esfinterotomía desarrollado en conejos. Materiales y métodos Se utilizaron conejos Nueva Zelanda, machos, sanos. Los animales fueron primero sangrados para obtención del plasma pobre en plaquetas (PPP) y biopsiados para el aislamiento de mioblastos. Posesfinterotomía, fueron divididos en dos grupos: grupo tratado (representado por aquellos animales que recibieron MAC resuspendidos en PPP) y grupo control (representado por aquellos animales que recibieron solo PPP). Se utilizó el punto de presión de pérdida (LPP) para medir la continencia de ambos grupos en diferentes instancias. Los resultados se evaluaron con modelos de regresión lineal jerárquica. Se efectuaron también estudios histológicos sobre los esfínteres de los conejos una vez finalizado el seguimiento. Resultados No se observaron diferencias estadísticamente significativas entre los valores basales de LPP de cada grupo. Los valores posesfinterotomía de ambos grupos estuvieron por debajo del 50% del valor basal, condición necesaria para considerarlos sujetos incontinentes. Los valores posimplante del grupo tratado fueron superiores al 50% del valor basal, permitiendo suponer una recuperación de la continencia. Se observó una diferencia estadísticamente significativa en los valores de LPP entre los dos grupos de tratamiento (p=0,003). El estudio histológico en el grupo tratado reveló islas interconectadas formadas por fibras musculares, mientras que en el grupo control se observó tejido conectivo periférico a la luz de la uretra e infiltrado inflamatorio. Discusión y conclusiones ... (AU)

Introduction Stress urinary incontinence (SUI) is one of the health problems with more impact on patients’ lives. The aim of the present work was to develop a therapy for SUI using tissue engineering by isolation and culture of autologous myoblasts (CAM) followed by endoscopic implantation. We also evaluated the efficacy of this therapy in a rabbit model of incontinence after sphincterotomy. Materials and methods We used healthy male New Zealand rabbits. The animals were first bled to obtain platelet-poor plasma (PPP) and biopsied for myoblast isolation. Post-sphincterotomy, they were divided into two groups: the treatment group (including animals that received CAM resuspended in PPP) and the control group (including animals receiving only PPP). The leak-point pressure (LPP) was used to measure continence in both groups at different time points. The results were evaluated with hierarchical linear regression models. Histological evaluation of the rabbits’ sphincters was also performed at the end of follow-up. Results No statistically significant differences were observed between the baseline LPP values of each group. The post-sphincterotomy values of both groups were below 50% of the baseline value, which was a mandatory condition for incontinence. The post-implantation values of the treatment group were higher than 50% of the baseline value, which led us to assume continence recovery. A statistically significant difference was observed in the LPP values between the two treatment groups (p=0.003). Histological study revealed interconnected islands formed by muscle fibers in the treatment group, and connective tissue surrounding the urethral lumen and inflammatory infiltrate in the control group. Discussion and conclusions The implantation of CAM significantly improved LPP values in the treatment group, and the improvement remained throughout the evaluation period. ... (AU)

Endoscopic implantation of autologous myoblasts for stress urinary incontinence and evaluation of its efficacy in sphincterotomized rabbits.

INTRODUCTION: Stress urinary incontinence (SUI) is one of the health problems with more impact on patients' lives. The aim of the present work was to develop a therapy for SUI using tissue engineering by isolation and culture of autologous myoblasts (CAM) followed by endoscopic implantation. We also evaluated the efficacy of this therapy in a rabbit model of incontinence after sphincterotomy. MATERIALS AND METHODS: We used healthy male New Zealand rabbits. The animals were first bled to obtain platelet-poor plasma (PPP) and biopsied for myoblast isolation. Post-sphincterotomy, they were divided into two groups: the treatment group (including animals that received CAM resuspended in PPP) and the control group (including animals receiving only PPP). The leak-point pressure (LPP) was used to measure continence in both groups at different time points. The results were evaluated with hierarchical linear regression models. Histological evaluation of the rabbits' sphincters was also performed at the end of follow-up. RESULTS: No statistically significant differences were observed between the baseline LPP values of each group. The post-sphincterotomy values of both groups were below 50% of the baseline value, which was a mandatory condition for incontinence. The post-implantation values of the treatment group were higher than 50% of the baseline value, which led us to assume continence recovery. A statistically significant difference was observed in the LPP values between the two treatment groups (p=0.003). Histological study revealed interconnected islands formed by muscle fibers in the treatment group, and connective tissue surrounding the urethral lumen and inflammatory infiltrate in the control group. DISCUSSION AND CONCLUSIONS: The implantation of CAM significantly improved LPP values in the treatment group, and the improvement remained throughout the evaluation period. It may be associated with the consistency of the implant and its stability at the injection site. Longer follow-up studies and human clinical investigations are required to consider CAM implantation as an alternative treatment for stress urinary incontinence.

Synoptic assessment of coastal total alkalinity through community science.

Comprehensive sampling of the carbonate system in estuaries and coastal waters can be difficult and expensive because of the complex and heterogeneous nature of near-shore environments. We show that sample collection by community science programs is a viable strategy for expanding estuarine carbonate system monitoring and prioritizing regions for more targeted assessment. 'Shell Day' was a single-day regional water monitoring event coordinating coastal carbonate chemistry observations by 59 community science programs and seven research institutions in the northeastern United States, in which 410 total alkalinity (TA) samples from 86 stations were collected. Field replicates collected at both low and high tides had a mean standard deviation between replicates of 3.6 ± 0.3 µmol kg-1 (σ mean ± SE, n = 145) or 0.20 ± 0.02%. This level of precision demonstrates that with adequate protocols for sample collection, handling, storage, and analysis, community science programs are able to collect TA samples leading to high-quality analyses and data. Despite correlations between salinity, temperature, and TA observed at multiple spatial scales, empirical predictions of TA had relatively high root mean square error >48 µmol kg-1. Additionally, ten stations displayed tidal variability in TA that was not likely driven by low TA freshwater inputs. As such, TA cannot be predicted accurately from salinity using a single relationship across the northeastern US region, though predictions may be viable at more localized scales where consistent freshwater and seawater endmembers can be defined. There was a high degree of geographic heterogeneity in both mean and tidal variability in TA, and this single-day snapshot sampling identified three patterns driving variation in TA, with certain locations exhibiting increased risk of acidification. The success of Shell Day implies that similar community science based events could be conducted in other regions to not only expand understanding of the coastal carbonate system, but also provide a way to inventory monitoring assets, build partnerships with stakeholders, and expand education and outreach to a broader constituency.

Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers.

BACKGROUND: Metaplastic breast cancer (MBC) is a rare form of breast cancer characterized by an aggressive clinical presentation, with a poor response to standard chemotherapy. MBCs are typically triple-negative breast cancers (TNBCs), frequently with alterations to genes of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. The objective of this study was to determine the response to PI3K and MAPK pathway inhibitors in patient-derived xenografts (PDXs) of MBCs with targetable alterations. METHODS: We compared survival between triple-negative MBCs and other histological subtypes, in a clinical cohort of 323 TNBC patients. PDX models were established from primary breast tumors classified as MBC. PI3K-AKT-mTOR and RTK-MAPK pathway alterations were detected by targeted next-generation sequencing (NGS) and analyses of copy number alterations. Activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways was analyzed with reverse-phase protein arrays (RPPA). PDXs carrying an activating mutation of PIK3CA and genomic changes to the RTK-MAPK signaling pathways were treated with a combination consisting of a PI3K inhibitor and a MEK inhibitor. RESULTS: In our clinical cohort, the patients with MBC had a worse prognosis than those with other histological subtypes. We established nine metaplastic TNBC PDXs. Three had a pathogenic mutation of PIK3CA and additional alterations to genes associated with RTK-MAPK signaling. The MBC PDXs expressed typical EMT and stem cell genes and were of the mesenchymal or mesenchymal stem-like TNBC subtypes. On histological analysis, MBC PDXs presented squamous or chondroid differentiation. RPPA analysis showed activation of the PI3K-AKT-mTOR and RTK-MAPK signaling pathways. In vivo, the combination of PI3K and MAPK inhibitors displayed marked antitumor activity in PDXs carrying genomic alterations of PIK3CA, AKT1, BRAF, and FGFR4. CONCLUSION: The treatment of metaplastic breast cancer PDXs by activation of the PI3K-AKT-mTOR and RTK-MAPK pathways at the genomic and protein levels with a combination of PI3K and MEK inhibitors resulted in tumor regression in mutated models and may therefore be of interest for therapeutic purposes.

Excellent results of large-diameter ceramic-on-ceramic bearings in total hip arthroplasty: Is Squeaking Related to Head Size.

AIMS: This study reports the mid-term results of total hip arthroplasty (THA) performed using a monoblock acetabular component with a large-diameter head (LDH) ceramic-on-ceramic (CoC) bearing. PATIENTS AND METHODS: Of the 276 hips (246 patients) included in this study, 264 (96%) were reviewed at a mean of 67 months (48 to 79) postoperatively. Procedures were performed with a mini posterior approach. Clinical and radiological outcomes were recorded at regular intervals. A noise assessment questionnaire was completed at last follow-up. RESULTS: There were four re-operations (1%) including one early revision for insufficient primary fixation (0.4%). No hip dislocation was reported. The mean University of California, Los Angeles (UCLA) activity score, 12-Item Short-Form Health Survey (SF-12) Mental Component Summary (MCS) score, SF-12 Physical Component Summary (PCS) score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and Forgotten Joint Score (FJS) were 6.6 (2 to 10), 52.8 (25.5 to 65.7), 53.0 (27.2 to 66.5), 7.7 (0 to 63), and 88.5 (23 to 100), respectively. No signs of loosening or osteolysis were observed on radiological review. The incidence of squeaking was 23% (n = 51/225). Squeaking was significantly associated with larger head diameter (p < 0.001), younger age (p < 0.001), higher SF-12 PCS (p < 0.001), and UCLA scores (p < 0.001). Squeaking did not affect patient satisfaction, with 100% of the squeaking hips satisfied with the surgery. CONCLUSION: LDH CoC THAs have demonstrated excellent functional outcomes at medium-term follow-up, with very low revision rate and no dislocations. The high incidence of squeaking did not affect patient satisfaction or function. LDH CoC with a monoblock acetabular component has the potential to provide long term implant survivorship with unrestricted activity, while avoiding implant impingement, liner fracture at insertion, and hip instability. Cite this article: Bone Joint J 2018;100-B:1434-41.

Kinematic TKA using navigation: Surgical technique and initial results.

BACKGROUND: Kinematic alignment for total knee arthroplasty (TKA) may be one way of improving outcomes. Previous studies have either used patient-specific instrumentation, which adds cost, or standard instrumentation, which provides no intraoperative feedback on resection alignment. HYPOTHESIS: To determine if computer navigation could reproduce native patient anatomy and simplify ligament balance during TKA whilst giving satisfactory improvements in functional scores at early follow-up. MATERIALS AND METHODS: Computer navigation was used for kinematic distal femoral and proximal tibial cuts in 100 consecutive and unselected TKAs. Resections were modified only if measured angles fell outside a pre-defined safe range of combined coronal orientation within±3 degrees of neutral and/or independent femoral or tibial cuts within±5 degrees. Pre- and postoperative measurements of the hip-knee-ankle (HKA) angle, the lateral distal femoral angle (LDFA) and the medial proximal tibial angle (MPTA) were taken using long-leg standing radiographs. Clinical evaluation was with the WOMAC and KOOS scales. RESULTS: Mean follow-up was 2.4 years (range 1.0-3.7, SD 0.8). The mean pre-op LDFA was 2.1 degrees valgus (9.2 valgus to 3.7 varus, SD 2.5) and 1.8 degrees valgus post-op (5.7 valgus to 4.2 varus, SD 2.0) (P=0.41). The mean pre-op MPTA was 3.0 degrees varus (10.6 valgus to 10.2 varus, SD 3.2) and 2.4 degrees varus post-op (4.0 valgus to 6.8 varus, SD 2.2) (P=0.03). The mean WOMAC score improved from 49.4 (29-85, SD 12.8) to 24.7 (0-73, SD 16.5) (P<0.001) and the mean KOOS score from 37.1 (7.2-77.2, SD 13.0) to 65.1 (26.8-100, SD 16) (P<0.001). Five knees (5%) required additional ligament release, four with valgus OA and one with varus OA. Two knees (2%) required lateral retinacular release for patellar tracking. DISCUSSION: Computer navigation for kinematic TKA provides the operating surgeon with full control and feedback at each step, whilst also allowing partial correction of more extreme anatomy that might be unsuitable for recreation during TKA. This technique helps to preserve ligament isometry and produces satisfactory improvements in functional scores. LEVEL OF EVIDENCE: IV (retrospective case series review).

A randomised trial of all-polyethylene and metal-backed tibial components in unicompartmental arthroplasty of the knee.

This randomised trial evaluated the outcome of a single design of unicompartmental arthroplasty of the knee (UKA) with either a cemented all-polyethylene or a metal-backed modular tibial component. A total of 63 knees in 45 patients (17 male, 28 female) were included, 27 in the all-polyethylene group and 36 in the metal-backed group. The mean age was 57.9 years (39.6 to 76.9). At a mean follow-up of 6.4 years (5 to 9.9), 11 all-polyethylene components (41%) were revised (at a mean of 5.8 years; 1.4 to 8.0) post-operatively and two metal-backed components were revised (at one and five years). One revision in both groups was for unexplained pain, one in the metal-backed group was for progression of osteoarthritis. The others in the all-polyethylene group were for aseptic loosening. The survivorship at seven years calculated by the Kaplan-Meier method for the all-polyethylene group was 56.5% (95% CI 31.9 to 75.2, number at risk 7) and for the metal-backed group was 93.8% (95% CI 77.3 to 98.4, number at risk 16) This difference was statistically significant (p < 0.001). At the most recent follow-up, significantly better mean Western Ontario and McMaster Universities Arthritis Index Scores were found in the all-polyethylene group (13.4 vs 23.0, p = 0.03) but there was no difference in the mean Knee injury and Osteoarthritis Outcome scores (68.8; 41.4 to 99.0 vs 62.6; 24.0 to 100.0), p = 0.36). There were no significant differences for range of movement (p = 0.36) or satisfaction (p = 0.23). This randomised study demonstrates that all-polyethylene components in this design of fixed bearing UKA had unsatisfactory results with significantly higher rates of failure before ten years compared with the metal-back components.

Influence of the stem fixation scenario on load transfer in a hip resurfacing arthroplasty with a biomimetic stem.

Finite element (FE) analysis is a widely used tool for extensive preclinical testing of orthopaedic implants such as hip resurfacing femoral components, including evaluation of different stem fixation scenarios (cementation vs osseointegration, etc.). Most FE models use surface-to-surface contact elements to model the load-bearing interfaces that connect bone, cement and implant and neglect the mechanical effects of phenomena such as residual stresses from bone cement curing. The objective of the current study is to evaluate and quantify the effect of different stem fixation scenarios and related phenomena such as residual stresses from bone cement curing. Four models of a previously clinically available implant (Durom) were used to model different stem fixation scenarios of a new biomimetic stem: a cemented stem, a frictional stem, a partially and completely bonded stem, with and without residual stresses from bone cement curing. For the frictional stem, stem-bone micromotions were increased from 0% to 61% of the available surface subjected to micromotions between 10 and 40µm with the inclusion of residual stresses from bone cement curing. Bonding the stem, even partially, increased stress in the implant at the stem-head junction. Complete bonding of the stem decreased bone strain at step tip, at the cost of increased strain shielding when compared with the frictional stem and partially bonded stem. The increase of micromotions and changes in bone strain highlighted the influence of interfacial conditions on load transfer, and the need for a better modeling method, one capable of assessing the effect of phenomena such as interdigitation and residual stresses from bone cement curing.

Bone remodeling in the resurfaced femoral head: effect of cement mantle thickness and interface characteristics.

Metal-on-metal hip resurfacing prostheses were re-introduced during the last 10-15 years. These prostheses have the potential to better restore normal function with limited activity restriction, being an option for younger and more active patients. Resurfacing procedures have demonstrated high failure rates in national registers [1,2]. Multiple factors may affect early and long-term HR performance. The influence of femoral cement mantle thickness and different interface characteristics between the prosthesis components on the long-term performance of resurfacing prostheses is still unknown. In the present work, a model was used to predict bone remodeling with different mantle thicknesses and interface characteristics. A very thin cement mantle (0.25mm) increased bone resorption at the superior femoral head, while greater thickness (1 or 3mm) had a lesser effect. In all cases, bone apposition was predicted around the stem and at the stem tip. Bone formation and resorption were observed clinically in good agreement with the predictions calculated in simulations. Computed results showed that 1-mm cement mantle thickness combined with a bonded bone-cement interface and a debonded implant-cement interface was an appropriate configuration. Bone remodeling results and computed equivalent strains were correlated. In conclusion, we have been able to demonstrate the importance of choosing an adequate cement mantle thickness. Additionally, computational studies should consider realistic interface characteristics between the components in order to perform simulations closer to reality.

Metal-on-metal hip resurfacing compared with 28-mm diameter metal-on-metal total hip replacement: a randomised study with six to nine years' follow-up.

A total of 219 hips in 192 patients aged between 18 and 65 years were randomised to 28-mm metal-on-metal uncemented total hip replacements (THRs, 107 hips) or hybrid hip resurfacing (HR, 112 hips). At a mean follow-up of eight years (6.6 to 9.3) there was no significant difference between the THR and HR groups regarding rate of revision (4.0% (4 of 99) vs 5.8% (6 of 104), p = 0.569) or re-operation rates without revision (5.1% (5 of 99) vs 2.9% (3 of 104), p = 0.428). In the THR group one recurrent dislocation, two late deep infections and one peri-prosthetic fracture required revision, whereas in the HR group five patients underwent revision for femoral head loosening and one for adverse reaction to metal debris. The mean University of California, Los Angeles activity scores were significantly higher in HR (7.5 (sd 1.7) vs 6.9 (sd 1.7), p = 0.035), but similar mean Western Ontario and McMaster Universities Osteoarthritis Index scores were obtained (5.8 (sd 9.5) in HR vs 5.1 (sd 8.9) in THR, p = 0.615) at the last follow-up. Osteolysis was found in 30 of 81 THR patients (37.4%), mostly in the proximal femur, compared with two of 83 HR patients (2.4%) (p < 0.001). At five years the mean metal ion levels were < 2.5 µg/l for cobalt and chromium in both groups; only titanium was significantly higher in the HR group (p = 0.001). Although revision rates and functional scores were similar in both groups at mid-term, long-term survival analysis is necessary to determine whether one procedure is more advantageous than the other.

Durom hip resurfacing system: retrospective study of 644 cases with an average follow-up of 34 months.

INTRODUCTION: The performance of second-generation metal-on-metal bearings has led to the reintroduction of hip resurfacing. The goal of this multicentre study was to evaluate the short-term radiological and clinical outcomes with the Durom hip resurfacing system. HYPOTHESIS: The Durom hip-resurfacing system will have similar results to other hip resurfacing systems and traditional hip arthroplasty implants. MATERIALS AND METHODS: In the four participating centers, 580 patients (406 men, 174 women) and 644 hips were included. The average patient age was 48 years (range 16-77). A posterolateral surgical approach was used in 357 cases; a Hardinge-type approach was used in 182 cases and a Rottinger-type approach in 105. RESULTS: After an average follow-up of 34 months, 31 hips (4.8%) had been revised. The reasons for revision were the following: 10 (1.6%) neck fracture (seven with Rottinger operative approach, one with Hardinge approach and one with posterolateral approach); 12 (1.9%) femoral loosening (four with lateral approach and eight with posterolateral approach); four (0.6%) acetabular cup migration; three (0.5%) unexplained pain; one (0.2%) adverse reaction to metal debris; one (0.2%) infection. Four hips (0.6%) dislocated but without recurrence - all were operated using the Hardinge approach. The 613 hips that were not operated on again had satisfactory clinical results; the Merle d'Aubigné score was 17.2 (range 12-18) and the WOMAC score was 91 (range 20-100). The five-year survival rate was 91% (95% CI: 87-94%). Based on radiographs, the average cup inclination was 44.4° (range 30 to 70°). The femoral offset was reduced by an average of 2.4mm (-31 to 23 mm) and the leg length had increased by an average of 0.8mm (-15 to 19 mm) relative to the other side, which was prosthesis-free. None of the non-revised implants showed any signs of loosening. DISCUSSION: This multicentre evaluation revealed that the Durom revision rate was slightly higher than the rate with other hip resurfacing systems and traditional total hip arthroplasty. Although the Durom system displayed excellent tribological performance, the differences relative to other implants may be attributed to the challenges associated with impaction, related to the geometry and design of the cup, and to precarious primary fixation. The choice of surgical exposure and implantation technique was an important factor in the survival of the implant. LEVEL OF PROOF: Level IV - Retrospective study.

The influence of uncemented femoral stem length and design on its primary stability: a finite element analysis.

One of the crucial factors for short- and long-term clinical success of total hip arthroplasty cementless implants is primary stability. Indeed, motion at the bone-implant interface above 40 µm leads to partial bone ingrowth, while motion exceeding 150 µm completely inhibits bone ingrowth. The aim of this study was to investigate the effect of two cementless femoral stem designs with different lengths on the primary stability. A finite element model of a composite Sawbones(®) fourth generation, implanted with five lengths of the straight prosthesis design and four lengths of the curved prosthesis design, was loaded with hip joint and abductor forces representing two physiological activities: fast walking and stair climbing. We found that reducing the straight stem length from 146 to 54 mm increased the average micromotion from 17 to 52 µm during fast walking, while the peak value increased from 42 to 104 µm. With the curved stem, reducing length from 105 to 54 mm increased the average micromotion from 10 to 29 µm, while the peak value increased from 37 to 101 µm. Similar findings are obtained for stair climbing for both stems. Although the present study showed that femoral stem length as well as stem design directly influences its primary stability, for the two femoral stems tested, length could be reduced substantially without compromising the primary stability. With the aim of minimising surgical invasiveness, newer femoral stem design and currently well performing stems might be used with a reduced length without compromising primary stability and hence, long-term survivorship.

Prox1 suppresses the proliferation of neuroblastoma cells via a dual action in p27-Kip1 and Cdc25A.

Neuroblastoma is a pediatric tumor that originates from precursor cells of the sympathetic nervous system with less than 40% long-term survival in children diagnosed with high-risk disease. These clinical observations underscore the need for novel insights in the mechanisms of malignant transformation and progression. Accordingly, it was recently reported that Prox1, a homeobox transcription regulator, is expressed in higher levels in human neuroblastoma with favorable prognosis. Consistently, we have recently shown that Prox1 exerts a strong antiproliferative effect on neural precursor cells during embryonic development. Thus, Prox1 is a candidate gene with a critical role in suppressing malignant neuroblastoma transformation. Here, we provide evidence that Prox1 strongly suppresses the proliferation of mouse and human neuroblastoma cell lines and blocks the growth of neuroblastoma tumors in SCID mice. Conversely, short hairpin RNA (shRNA) -mediated knockdown of basal Prox1 expression significantly induces proliferation, genomic instability and the ability of neuroblastoma cells to form tumors. Mechanistically, analysis of an inducible Prox1-overexpressing Neuro2A cell line indicates that Prox1 is sufficient to suppress CyclinD1, CyclinA and CyclinB1, consistent with a role in cell cycle arrest. Surprisingly, Prox1 strongly induces CyclinE1 expression in the same system despite its action on blocking cell cycle progression, which could account for the context dependent oncogenic function of Prox1. Most importantly, Prox1 was sufficient to decrease Cdc25A and induce p27-Kip1, but not p21-Cip1 or p53. By alleviating the Prox1 action in Cdc25A and p27-Kip1 expression, we were able to rescue its effect on cell cycle arrest. Together these data suggest that Prox1 negatively regulates neuroblastoma carcinogenesis through suppression of Cdc25A and induction of p27-Kip1 to counteract CyclinE1 overexpression and block cell cycle progression. Furthermore, these observations render Prox1 a candidate target for the treatment of neuroblastoma tumors.

Joint perception after hip or knee replacement surgery.

INTRODUCTION: Knee and hip arthroplasties are recognized as being effective. However, subjects with a prosthetic joint rarely report returned sensation comparable to their native joint. HYPOTHESIS: Joint perception by patients following hip joint replacement is better than following knee replacement and in both cases this perception is directly related to the clinical results measured with currently validated scores. PATIENTS AND METHODS: Patient joint perception in prosthetic reconstruction was evaluated in 347 patients, 46 who underwent unicompartmental knee arthroplasty (UKA), 119 tricompartmental knee arthroplasty (TKA), 93 hip resurfacing (HR), and 89 total hip arthroplasty (THA). The subjects' joint perception, their satisfaction, and the WOMAC clinical score were recorded and compared. RESULTS: Joint perception was significantly worse for knee arthroplasties (TKA and UKA) compared to hip arthroplasties (THA or HR) (P<0.001). The WOMAC score was also significantly less favorable for knee arthroplasties than for hip arthroplasties (P<0.0001). However, there was no significant difference for the clinical scores between TKA and UKA as well as between HR and THA. Joint perception was strongly correlated with the WOMAC score for all groups (R(2)=0.951). DISCUSSION: No difference was found after more conservative surgeries such as HR or UKA compared to traditional arthroplasty procedures (THA or TKA). Demonstrating inferior results in comparison to the hip, knee arthroplasties deserve particular attention and can still be improved. The assessment of joint perception used in this study can be considered a valuable clinical tool that is strongly correlated to validated, but more complex to apply, clinical scores.

Anisotropic bone remodeling of a biomimetic metal-on-metal hip resurfacing implant.

Hip resurfacing (HR) is a highly attractive option for young and active patients. Some surgeons have advocated cementing the metaphyseal stem of the femoral component to improve fixation and survivorship of HR. However, extending component fixation to the metaphysis may promote femoral head strain shielding, which in turn may reduce survival of the femoral component. Replacing the metallic metaphyseal stem by a composite material with bone-matching properties could help to alleviate this phenomenon. This study uses finite element analysis to examine the strain state in the femoral head for three types of implant fixation: an unfixed metallic stem, an osseointegrated biomimetic stem and a cemented metallic stem. Bone remodeling is also simulated to evaluate long-term bone resorption due to strain shielding. Results show that the unfixed stem causes strain shielding in the femoral head, and that cementing the stem increases strain shielding. The biomimetic stem does not eliminate the strain shielding effect, but reduces it significantly versus the metallic cemented version. The current finite element study suggests that an osseointegrated metaphyseal stem made of biomimetic material in hip resurfacing implants could become an interesting alternative when fixation extension is desired.

Radiographic changes of the femoral neck after total hip resurfacing.

INTRODUCTION: Significant femoral neck narrowing following hip resurfacing arthroplasty has been observed. Several factors contributing to the physiopathology of femoral neck narrowing have been suggested. The aim of this study was to evaluate the femoral neck radiographic changes observed after hip resurfacing at a minimum follow-up period of 5 years and to determine their causes. PATIENTS AND METHODS: We conducted a prospective study of 57 hip resurfacing arthroplasties performed in 53 patients (30 men, 23 women) of mean age 49.2 years (32-65) at surgery. These patients were clinically reviewed (inguinal pain during walking, WOMAC and UCLA scores) at 2 years and radiographically examined at 1, 2 and 5 postoperative years. The accuracy of our computer-aided measurement method was 1mm. Measurement of femoral neck to implant ratio was performed to assess the amount of neck thinning at the femoral neck-implant junction (N/H) and midway between the implant and the inter-trochanteric line (N(1/2)H) on an AP radiograph. Neck-thinning greater than 10% was considered as significant. Any other radiographic morphologic change in the femoral neck was investigated. Metallic ion concentration in blood was measured. A uni- and multivariate analysis was performed to determine the correlation with radiographic changes. RESULTS: In one third of the patients, femoral neck narrowing was greater than 1mm at 2 and 5 postoperative years. Such result corresponds to a mean decrease in neck to implant ratio (N/H) of 5.9% (range, 2.3 to 9.4) at 2 years and 8.3% (range, 2.5 to 23.8) at 5 years. At 5 postoperative years, an overall neck thinning greater than 10% was reported in 3 patients (with a 10- to 17-% increase in femoral neck narrowing between the 2nd and the 5th postoperative year). In one case, neck thinning was associated with fracture of the femoral stem managed with revision surgery during which femoral neck necrosis was confirmed. Neck thinning was, in these cases, circumferential to the neck-implant junction. There was no significant negative impact on clinical scores and no relationship could be established between neck thinning and factors such as BMI or patient activity. Moreover, neck thinning greater than 10% was reported in two cases after 2 postoperative years through the appearance of a localized femoral neck notching which was absent in the postoperative period, secondary to a femoroacetabular impingement. DISCUSSION-CONCLUSION: Femoral neck narrowing used to be a common phenomenon after HR when polyethylene acetabular bearings were implanted thus inducing osteolysis secondary to PE wear debris. The incidence of such phenomenon has decreased but still occurs after HR when using a metal-on-metal bearing surface. It has an early occurence but stabilizes after 2 postoperative years. Changes in mechanical stress distribution in the neck region after hip resurfacing have been hypothesized to be a cause of neck thinning. Other aetiologies may be suggested. An overall evolutive femoral neck narrowing after 2 postoperative years should raise the suspicion of necrosis leading to a risk of loosening, fracture or implant failure. Therefore, radiographic monitoring should be conducted. The presence of femoral neck notching secondary to femoroacetabular impingement represents a differential diagnosis which conservative treatment is advocated in the absence of any associated symptoms.

Metal ion release from bearing wear and corrosion with 28 mm and large-diameter metal-on-metal bearing articulations: a follow-up study.

We have updated our previous randomised controlled trial comparing release of chromium (Cr) and cobalt (Co) ions and included levels of titanium (Ti) ions. We have compared the findings from 28 mm metal-on-metal total hip replacement, performed using titanium CLS/Spotorno femoral components and titanium AlloFit acetabular components with Metasul bearings, with Durom hip resurfacing using a Metasul articulation or bearing and a titanium plasma-sprayed coating for fixation of the acetabular component. Although significantly higher blood ion levels of Cr and Co were observed at three months in the resurfaced group than in total hip replacement, no significant difference was found at two years post-operatively for Cr, 1.58 microg/L and 1.62 microg/L respectively (p = 0.819) and for Co, 0.67 microg/L and 0.94 microg/L respectively (p = 0.207). A steady state was reached at one year in the resurfaced group and after three months in the total hip replacement group. Interestingly, Ti, which is not part of the bearing surfaces with its release resulting from metal corrosion, had significantly elevated ion levels after implantation in both groups. The hip resurfacing group had significantly higher Ti levels than the total hip replacement group for all periods of follow-up. At two years the mean blood levels of Ti ions were 1.87 microg/L in hip resurfacing and and 1.30 microg/L in total hip replacement (p = 0.001). The study confirms even with different bearing diameters and clearances, hip replacement and 28 mm metal-on-metal total hip replacement produced similar Cr and Co metal ion levels in this randomised controlled trial study design, but apart from wear on bearing surfaces, passive corrosion of exposed metallic surfaces is a factor which influences ion concentrations. Ti plasma spray coating the acetabular components for hip resurfacing produces significantly higher release of Ti than Ti grit-blasted surfaces in total hip replacement.

[Hip resurfacing: current state of knowledge]. / Resurfaçage de hanche: état actuel des connaissances.

SUMMARY: The tribologic quality of metal-on-metal bearings has enabled a second generation of hip resurfacing techniques. Compared with a conventional hip prosthesis, this type of arthroplasty has many advantages: sparing femoral (and acetabular) bone stock, preservation of hip joint biomechanics (femoral offset, leg length), better recovery for high-level sports activities, easier revision, less risk of dislocation, less risk of extension to the shaft in the event of osteolysis. Hip resurfacing can thus be considered as true "minimally invasive bone surgery". There are however specific complications of resurfacing, including femoral neck fracture and collapse of the femoral head. All of the conventional approaches can be used for hip resurfacing procedures, but a precise operative technique is mandatory. The key to success is a proper position of the femoral piece. Certain biomechanical rules for implantation are required in order to limit the cam effect, spare femoral bone, and maintain harmonious loading. Hip resurfacing can be indicated for young and/or active subjects for whom restoration of hip biomechanics offers a real advantage over conventional hip arthroplasty. The mid-term results have been encouraging, both clinically and radiographically.

The differential expression of osteoprotegerin (OPG) and receptor activator of nuclear factor kappaB ligand (RANKL) in human osteoarthritic subchondral bone osteoblasts is an indicator of the metabolic state of these disease cells.

OBJECTIVE: We previously reported that human OA subchondral bone osteoblasts could be discriminated into two subpopulations identified by their levels of endogenous production (low [L] or high [H]) of PGE(2). Here, we investigated the OPG and RANKL expression levels, the histologic analysis of the subchondral bone as well as the osteoclast differentiation effect of osteoblasts on normal and both OA subpopulations (L and H), and further examined on the L OA osteoblasts the modulation of bone remodelling factors on the OPG and RANKL levels, as well as on the resorption activity. METHODS: Gene expression was determined using real-time PCR, PGE2 and OPG levels by specific ELISA, and membranous RANKL by flow cytometry. Histological observation of the subchondral bone was performed on human knee specimens. Osteoclast differentiation and formation was assayed by using the pre-osteoclastic cell line RAW 264.7. OPG and RANKL modulation on L OA osteoblasts was monitored following treatment with osteotropic factors, and the resorption activity was studied by the co-culture of differentiated PBMC/osteoblasts. RESULTS: Human OA subchondral bone osteoblasts expressed less OPG than normal. Compared to normal, RANKL gene expression levels were increased in L OA and decreased in H OA cells. The OPG/RANKL mRNA ratio was significantly diminished in L OA compared to normal or H OA (p<0.02, p<0.03), and markedly increased in H OA compared to normal. Inhibition of endogenous PGE(2) levels by indomethacin markedly decreased the ratio of OPG/RANKL on the H OA. In contrast to H OA osteoblasts, L OA cells induced a significantly higher level of osteoclast differentiation and formation (p<0.05). Histological analysis showed a reduced subchondral bone on the L OA and an increased bone mass on the H OA compared to normal. Treatment of L OA osteoblasts with osteotropic factors revealed that the OPG/RANKL mRNA expression ratio was significantly reduced by vitamin D(3) and significantly increased by TNF-alpha, PTH and PGE(2), while IL-1Beta demonstrated no effect. OPG protein levels showed similar profiles. No true effect was noted on membranous RANKL upon treatment with IL-1Beta, PGE(2) and PTH, but a significant increase was observed with vitamin D3 and TNF-alpha. The resorption activity of the L OA cells was significantly inhibited by all treatments except IL-1Beta, with maximum effect observed with vitamin D(3) and PGE(2). CONCLUSION: OPG and RANKL levels, and consequently the OPG/RANKL ratio, differed according to human OA subchondral bone osteoblast classification; it is decreased in L and increased in H OA. These findings, in addition to those showing that L OA osteoblasts have a reduced subchondral bone mass and induce a higher level of osteoclast differentiation, strongly suggest that the metabolic state of the L OA osteoblasts favours bone resorption.

[Return to sport after hip resurfacing or total hip arthroplasty: a randomized study]. / Activités sportives après resurfaçage et prothèse totale de hanche : une étude prospective randomisée.

PURPOSE OF THE STUDY: Since component wear of the prosthetic metal-polyethylene bearing is directly related to the level of patient activity, it would be logical, for patients with a total hip arthroplasty, to advise against long-term participation in activities with repeated movements The purpose of this prospective randomized study was to compare the type, intensity and frequency of sports activities performed after resurfacing hip arthroplasty (RH) or total hip arthroplasty (THA) using a metal-on-metal bearing. MATERIAL AND METHODS: This study concerned 205 hips, including 152 with a unilateral hip arthroplasty (71 THA and 81 RH). Three clinical scores were used: an overall activity score, the University of California, Los Angeles (UCLA) score and the Western Ontario McMaster Osteoarthritis Index (WOMAC) score, as well as patient satisfaction, return to sports activities (using a visual analog scale [VAS]) and frequency of factors limiting activity. Patients completed a questionnaire to determine the type, intensity and frequency of sports activities practiced pre- and postoperatively. RESULTS: The mean overall activity score immediately before surgery was not statistically different between the two groups (p=0.111). One year after surgery, the score was 17.9 in the RH group and 12.4 in the THA group (p=0.001). At last follow-up, the mean WOMAC score was 8.1 (range 0-73, S.D. 13.1) in the RH group and 9.8 (range 0-41, S.D. 10.9) in the THA group (p=0.409). The mean UCLA score was 7.17 in the RH group (range 2-10, S.D. 1.90) and 6.75 in the THA group (range 2-10, S.D. 1.71) (p=0.174). The mean satisfaction with return to sports activities as assessed on the VAS was 7.78 in the RH group and 7.43 in the THA group (p=0.313). DISCUSSION: The results of this study demonstrate that the degree and intensity of postoperative sports activities are greater in the RH group than in the THA group, although this difference was less pronounced than expected. The excellent joint stability after RH (big head effect) could be one of the main factors favoring a high activity level compared to conventional THA, by limiting the episodes of dislocation and increasing the suction effect between the joint components. It is nevertheless difficult to ascertain the long-term effect of intense sports activity on the fixation of osteo-integrated implants (cups) and cemented components (femoral stem).