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Unicompartmental knee replacement: Does the macroscopic status of the anterior cruciate ligament affect outcome?
PURPOSE: ACL damage is associated with progression of arthritis and whilst in the population undergoing joint replacement in the majority of cases the ACL is intact there is a wide spectrum of ACL disease. This study investigated whether the macroscopic status of the ACL affected functional outcome or survival following UKR. METHODS: The macroscopic status of the ACL was recorded in 820 cemented Oxford UKRs implanted by two surgeons for the recommended indications. The ACL was considered functionally normal in the setting of anteromedial tibial wear and macroscopically the ACL visually appeared normal or had synovial damage or longitudinal splits. The patients were followed up independently with a mean follow-up of 10.3years (range 5.3 to 16.6). RESULTS: More marked ACL macroscopic damage was significantly associated with increasing age, male gender and a more extensive anteromedial tibial defect. Patients with more ACL damage had a significantly lower pre-operative AKSS Objective Score, however no difference in AKSS-Functional or OKS was detected between groups. At 10years no difference in functional outcome or activity level was found between groups. Compared to those with a macroscopically normal ACL at 10years a significantly greater improvement from baseline OKS score was seen in patients with macroscopic ACL abnormalities. At 15years no difference in implant survival, or failure mechanism, was detected between groups. CONCLUSION: The macroscopic status of the ACL does not affect long term functional outcomes or implant survival and in the setting of an intact ACL macroscopic status is not a contraindication to mobile bearing UKR. LEVEL OF EVIDENCE: Level IV.
Increased generation of Foxp3(+) regulatory T cells by manipulating antigen presentation in the thymus.
Regulatory T-cell (Treg) selection in the thymus is essential to prevent autoimmune diseases. Although important rules for Treg selection have been established, there is controversy regarding the degree of self-reactivity displayed by T-cell receptors expressed by Treg cells. In this study we have developed a model of autoimmune skin inflammation, to determine key parameters in the generation of skin-reactive Treg cells in the thymus (tTreg). tTreg development is predominantly AIRE dependent, with an AIRE-independent component. Without the knowledge of antigen recognized by skin-reactive Treg cells, we are able to enhance skin-specific tTreg cell generation using three approaches. First, we increase medullary thymic epithelial cells by using mice lacking osteoprotegerin or by adding TRANCE (RANKL, Tnfsf11). Second, we inject intrathymically peripheral dendritic cells from skin-draining sites. Finally, we inject skin tissue lysates intrathymically. These findings have implications for enhancing the generation of organ-specific Treg cells in autoimmune diseases.
Perivascular Arrest of CD8+ T Cells Is a Signature of Experimental Cerebral Malaria.
There is significant evidence that brain-infiltrating CD8+ T cells play a central role in the development of experimental cerebral malaria (ECM) during Plasmodium berghei ANKA infection of C57BL/6 mice. However, the mechanisms through which they mediate their pathogenic activity during malaria infection remain poorly understood. Utilizing intravital two-photon microscopy combined with detailed ex vivo flow cytometric analysis, we show that brain-infiltrating T cells accumulate within the perivascular spaces of brains of mice infected with both ECM-inducing (P. berghei ANKA) and non-inducing (P. berghei NK65) infections. However, perivascular T cells displayed an arrested behavior specifically during P. berghei ANKA infection, despite the brain-accumulating CD8+ T cells exhibiting comparable activation phenotypes during both infections. We observed T cells forming long-term cognate interactions with CX3CR1-bearing antigen presenting cells within the brains during P. berghei ANKA infection, but abrogation of this interaction by targeted depletion of the APC cells failed to prevent ECM development. Pathogenic CD8+ T cells were found to colocalize with rare apoptotic cells expressing CD31, a marker of endothelial cells, within the brain during ECM. However, cellular apoptosis was a rare event and did not result in loss of cerebral vasculature or correspond with the extensive disruption to its integrity observed during ECM. In summary, our data show that the arrest of T cells in the perivascular compartments of the brain is a unique signature of ECM-inducing malaria infection and implies an important role for this event in the development of the ECM-syndrome.
High-Throughput Mechanobiology Screening Platform Using Micro- and Nanotopography.
We herein demonstrate the first 96-well plate platform to screen effects of micro- and nanotopographies on cell growth and proliferation. Existing high-throughput platforms test a limited number of factors and are not fully compatible with multiple types of testing and assays. This platform is compatible with high-throughput liquid handling, high-resolution imaging, and all multiwell plate-based instrumentation. We use the platform to screen for topographies and drug-topography combinations that have short- and long-term effects on T cell activation and proliferation. We coated nanofabricated "trench-grid" surfaces with anti-CD3 and anti-CD28 antibodies to activate T cells and assayed for interleukin 2 (IL-2) cytokine production. IL-2 secretion was enhanced at 200 nm trench width and >2.3 μm grating pitch; however, the secretion was suppressed at 100 nm width and <0.5 μm pitch. The enhancement on 200 nm grid trench was further amplified with the addition of blebbistatin to reduce contractility. The 200 nm grid pattern was found to triple the number of T cells in long-term expansion, a result with direct clinical applicability in adoptive immunotherapy.
Molecular Occupancy of Nanodot Arrays.
Single-molecule nanodot arrays, in which a biomolecule of choice (protein, nucleic acid, etc.) is bound to a metallic nanoparticle on a solid substrate, are becoming an increasingly important tool in the study of biomolecular and cellular interactions. We have developed an on-chip measurement protocol to monitor and control the molecular occupancy of nanodots. Arrays of widely spaced nanodots and nanodot clusters were fabricated on glass surfaces by nanolithography and functionalized with fluorescently labeled proteins. The molecular occupancy was determined by monitoring individual fluorophore bleaching events, while accounting for fluorescence quenching effects. We found that the occupancy can be interpreted as a packing problem, and depends on nanodot size and binding ligand concentration, where the latter is easily adjusted to compensate the flexibility of dimension control in nanofabrication. The results are scalable with nanodot cluster size, extending to large area close packed arrays. As an example, the nanoarray platform was used to probe the geometric requirement of T-cell activation at the single-molecule level.
Size-dependent protein segregation at membrane interfaces.
Membrane interfaces formed at cell-cell junctions are associated with characteristic patterns of membrane protein organization, such as E-cadherin enrichment in epithelial junctional complexes and CD45 exclusion from the signaling foci of immunological synapses. To isolate the role of protein size in these processes, we reconstituted membrane interfaces in vitro using giant unilamellar vesicles decorated with synthetic binding and non-binding proteins. We show that size differences between binding and non-binding proteins can dramatically alter their organization at membrane interfaces in the absence of active contributions from the cytoskeleton, with as little as a ~5 nm increase in non-binding protein size driving its exclusion from the interface. Combining in vitro measurements with Monte Carlo simulations, we find that non-binding protein exclusion is also influenced by lateral crowding, binding protein affinity, and thermally-driven membrane height fluctuations that transiently limit access to the interface. This simple, sensitive, and highly effective means of passively segregating proteins has implications for signaling at cell-cell junctions and protein sorting at intracellular contact points between membrane-bound organelles.
The influence of cemented femoral stem choice on the incidence of revision for periprosthetic fracture after primary total hip arthroplasty: an analysis of national joint registry data.
AIMS: Periprosthetic fracture (PF) after primary total hip arthroplasty (THA) is an uncommon but potentially devastating complication. This study aims to investigate the influence of cemented stem designs on the risk of needing a revision for a PF. PATIENTS AND METHODS: We analysed data on 257 202 primary THAs with cemented stems and 390 linked first revisions for PF recorded in the National Joint Registry (NJR) of England, Wales and Northern Ireland to determine if a cemented femoral stem brand was associated with the risk of having revision for a PF after primary THA. All cemented femoral stem brands with more than 10 000 primary operations recorded in the NJR were identified. The four most commonly used cemented femoral stems were the Exeter V40 (n = 146 409), CPT (n = 24 300), C-Stem (n = 15 113) and Charnley (n = 20 182). We compared the revision risk ratios due to PF amongst the stems using a Poisson regression model adjusting for patient factors. Compared with the Exeter V40, the age, gender and ASA grade adjusted revision rate ratio was 3.89 for the cemented CPT stem (95% confidence interval (CI) 3.07 to 4.93), 0.89 for the C-Stem (95% CI 0.57 to 1.41) and 0.41 for the Charnley stem (95% CI 0.24 to 0.70). CONCLUSIONS: The limitations of the study include incomplete data capture, analysis of only PF requiring revision and that observation does not imply causality. Nevertheless, this study demonstrates that the choice of a cemented stem may influence the risk of revision for PF. Cite this article: Bone Joint J 2016;98-B:1347-54.
Immune dysregulation in patients with PTEN hamartoma tumor syndrome: Analysis of FOXP3 regulatory T cells.
BACKGROUND: Patients with heterozygous germline mutations in phosphatase and tensin homolog deleted on chromosome 10 (PTEN) experience autoimmunity and lymphoid hyperplasia. OBJECTIVES: Because regulation of the phosphoinositide 3-kinase (PI3K) pathway is critical for maintaining regulatory T (Treg) cell functions, we investigate Treg cells in patients with heterozygous germline PTEN mutations (PTEN hamartoma tumor syndrome [PHTS]). METHODS: Patients with PHTS were assessed for immunologic conditions, lymphocyte subsets, forkhead box P3 (FOXP3)+ Treg cell levels, and phenotype. To determine the functional importance of phosphatases that control the PI3K pathway, we assessed Treg cell induction in vitro, mitochondrial depolarization, and recruitment of PTEN to the immunologic synapse. RESULTS: Autoimmunity and peripheral lymphoid hyperplasia were found in 43% of 79 patients with PHTS. Immune dysregulation in patients with PHTS included lymphopenia, CD4+ T-cell reduction, and changes in T- and B-cell subsets. Although total CD4+FOXP3+ Treg cell numbers are reduced, frequencies are maintained in the blood and intestine. Despite pathogenic PTEN mutations, the FOXP3+ T cells are phenotypically normal. We show that the phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP) downstream of PTEN is highly expressed in normal human Treg cells and provides complementary phosphatase activity. PHLPP is indispensable for the differentiation of induced Treg cells in vitro and Treg cell mitochondrial fitness. PTEN and PHLPP form a phosphatase network that is polarized at the immunologic synapse. CONCLUSION: Heterozygous loss of function of PTEN in human subjects has a significant effect on T- and B-cell immunity. Assembly of the PTEN-PHLPP phosphatase network allows coordinated phosphatase activities at the site of T-cell receptor activation, which is important for limiting PI3K hyperactivation in Treg cells despite PTEN haploinsufficiency.
A computer-aided tracking and motion analysis with ultrasound (CAT & MAUS) system for the description of hip joint kinematics.
PURPOSE: Investigation of joint kinematics contributes to developing a better understanding of musculoskeletal conditions. However, the most commonly used optoelectronic motion analysis systems cannot determine the movements of underlying bone landmarks with high accuracy because of soft tissue artefacts. The aim of this paper was to present a computer-aided measurement system to track the underlying bone anatomy in a 3D global coordinate frame and describe hip joint kinematics of ten healthy volunteers during gait. METHODS: We have developed a measurement tool with an image-based computer-aided post-processing pipeline for automatic bone segmentation in ultrasound (US) images and a globally optimal 3D surface-to-surface registration method to quantify hip joint movements. The segmentation algorithm exploits US intensity profiles, including information about the integrated backscattering, acoustic shadows, and local phase features. A global optimization method is applied based on the traditional iterative closest point registration algorithm, which is robust to initialization. The International Society of Biomechanics recommended joint kinematics descriptor has been adapted to calculate the joint kinematics. RESULTS: The developed system prototype has been validated with a ball-joint femoral phantom and tested in vivo with 10 volunteers. The maximum Euclidean distance error of the automatic bone segmentation is less than 2 pixels (approximately 0.2 mm). The maximum absolute rotation angle error is less than [Formula: see text]. CONCLUSION: This computer-aided tracking and motion analysis with ultrasound (CAT & MAUS) system shows the feasibility of describing hip joint kinematics for clinical investigation and diagnosis using an image-based solution.
Lateral osteophytes do not represent a contraindication to medial unicompartmental knee arthroplasty: a 15-year follow-up.
PURPOSE: Lateral osteophytes have been reported to be associated with lateral compartment disease and as such it is unclear whether medial unicompartmental knee arthroplasty should be performed if these are present. METHODS: Using the OARSI classification system, 0 (no osteophyte) to 3 (large osteophyte), radiographs from a series of cemented meniscal-bearing unicompartmental knee arthroplasty implanted in the setting of full-thickness lateral cartilage where lateral osteophytes were not considered a contraindication were identified and factors associated with the presence and size of lateral osteophytes, and their impact on clinical outcomes and implant survival were assessed. RESULTS: Pre-operative radiographs from 458 knees (392 patients), independently followed up for a mean 10.5 years (range 5.3-16.6), were assessed. Lateral osteophytes were present in 62 % of knees with 18 % scored as Grade 3. Inter-observer reliability was good (kappa = 0.70). The presence and size of lateral osteophytes was associated with younger age at joint replacement (p = 0.01) and increasing BMI (p = 0.01). No association was seen with gender, pre-operative status, assessed using the Oxford Knee Score (OKS), American Knee Society (AKSS) Objective or Functional Score, Tegner activity score, or size of medial tibial lesion. Subgroup analysis of Grade 3 Osteophytes revealed that these were associated with a greater degree of macroscopic ACL damage. At 10 years there was no difference in function (n.s.), and at 15 years no difference in implant survival or mechanism of failure between groups (n.s.). Subgroup analysis of Grade 3 osteophytes found no significant difference in functional outcome at 10 years or implant survival at 15 years. CONCLUSION: The presence of lateral osteophytes is not a contraindication to medial meniscal-bearing unicompartmental knee arthroplasty. The clinical relevance of this study is that it highlights the importance of an appropriate pre-operative assessment of the lateral compartment as in the setting of full-thickness cartilage at operation lateral osteophytes do not compromise long-term functional outcome or implant survival. LEVEL OF EVIDENCE: IV.
Surgeons' Accuracy in Achieving Their Desired Acetabular Component Orientation.
BACKGROUND: Wide variability in cup orientation has been reported. The aims of this study were to determine how accurate surgeons are at orientating the acetabular component and whether factors such as visual cues and the side of operating table improved accuracy. METHODS: A pelvic model was positioned in neutral alignment on an operating table and was prepared as in a posterior approach. Twenty-one surgeons (9 trainers and 12 trainees) were tasked with positioning an acetabular component in a series of target orientations. The orientation of the component was measured using stereophotogrammetry, and the difference between the achieved orientation and the target orientation was calculated. Tasks included stating the surgeon's preferred orientation and thereafter placing the cup in that orientation, reproducing visual cues (transverse acetabular ligament and alignment guide), altering orientation by 10°, and estimating orientation while on the assistant's side. RESULTS: The preferred inclination was 42° and the preferred anteversion was 21°. On average, surgeons decreased the inclination by 4° and increased the anteversion by 11° when tasked with replicating their desired orientation. The variability (defined as 2 standard deviations) in achieving a target orientation was 14°. The use of visual cues, such as the transverse acetabular ligament or the alignment guide, significantly improved accuracy to 1° for anteversion (p < 0.001) and -3° for inclination (p = 0.003). In addition, the use of an alignment guide reduced the variability by one-third. Trainees and trainers had similar accuracy and variability. There was greater variability in assessing cup inclination when standing on the assistant's side compared with the surgeon's side of the table, which has implications for training. CONCLUSIONS: Surgeons overestimate operative inclination and underestimate anteversion, which is of benefit, as this, on average, helps to achieve the desired radiographic cup orientation. Although the use of visual cues helps, conventional techniques result in a large variability in acetabular component orientation. New and better guides and methods for training need to be developed.
Maintenance of CD4 T cell fitness through regulation of Foxo1.
Foxo transcription factors play an essential role in regulating specialized lymphocyte functions and in maintaining T cell quiescence. Here, we used a system in which Foxo1 transcription-factor activity, which is normally terminated upon cell activation, cannot be silenced, and we show that enforcing Foxo1 activity disrupts homeostasis of CD4 conventional and regulatory T cells. Despite limiting cell metabolism, continued Foxo1 activity is associated with increased activation of the kinase Akt and a cell-intrinsic proliferative advantage; however, survival and cell division are decreased in a competitive setting or growth-factor-limiting conditions. Via control of expression of the transcription factor Myc and the IL-2 receptor β-chain, termination of Foxo1 signaling couples the increase in cellular cholesterol to biomass accumulation after activation, thereby facilitating immunological synapse formation and mTORC1 activity. These data reveal that Foxo1 regulates the integration of metabolic and mitogenic signals essential for T cell competitive fitness and the coordination of cell growth with cell division.
Age and Outcomes of Medial Meniscal-Bearing Unicompartmental Knee Arthroplasty.
BACKGROUND: National joint registries report increasing revision rates with decreasing patient age for all types of joint arthroplasty. This study aimed to explore the effect of age on function and revision risk in patients undergoing medial meniscal-bearing UKA. METHODS: A prospectively followed cohort of 1000 consecutive medial meniscal-bearing UKAs at a designer center was analyzed. All knees were implanted for recommended indications and had mean 10-year follow-up. Patients were grouped by age at surgery (<55, 55 to <65, 65 to <75, 75+). Oxford Knee Scores (OKS) were assessed at 5 and 10 years. Component-time revision incidence rates and Kaplan-Meier implant survival were calculated. RESULTS: Mean patient age at surgery was 66.6 years (range, 33-88). All age-groups had significant (P < .001) improvement in OKS over time, and at 5 years achieved a median OKS of 44. At 10 years, median OKS, from youngest group to eldest, were 44, 45, 42, and 39, with the eldest group having a significantly lower OKS (P < .01). Ten-year implant survival rates were 97%, 94%, 94%, and 93%, respectively, and was not significantly associated with age at UKA. CONCLUSION: Medial meniscal-bearing UKA provides good functional outcomes in all age-groups; however, in older patients (75+), the functional outcome deteriorated at 10 years presumably due to deteriorating health. Contrary to registry observations, the revision rate was not higher in younger patients. These results suggest that, with correct indications, patient age should not be considered a contraindication to medial meniscal-bearing UKA.