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INTRODUCTIONLittle is known about longitudinal decline in white matter (WM) microstructure and its associations with cognition in preclinical Alzheimer’s disease (AD).METHODSLongitudinal diffusion tensor imaging and neuropsychological testing from 50 older adults who subsequently developed mild cognitive impairment or dementia (subsequently impaired, SI) and 200 cognitively normal controls. Rates of WM decline were compared between groups using voxel-wise linear mixed-effects models. Associations between change in WM and cognition were examined.RESULTSSI had faster decline in fractional anisotropy (FA) in the right inferior fronto-occipital fasciculus (R.IFOF) and bilateral splenium of the corpus callosum. Decline in R.IFOF FA was related to decline in verbal memory, visuospatial ability, processing speed, and MMSE (p≤ 0.05). Decline in bilateral splenium FA was related to decline in verbal fluency, processing speed, and MMSE (p≤ 0.05).DISCUSSIONAccelerated regional WM decline is characteristic of preclinical AD and related to domain specific cognitive decline.

Background: The most common surgical technique in traumatic anterior shoulder instability is the arthroscopic Bankart repair, which has excellent short-term results. The long-term results of the arthroscopic Bankart repair are less frequently studied, with a high recurrence rate of 23% to 35%. The aim of this study was to evaluate the medium-term to long-term results of arthroscopic Bankart repair using suture anchors and to identify specific risk factors for recurrent instability.Methods: Included were 147 patients after traumatic anterior shoulder dislocation who underwent an arthroscopic Bankart repair. The primary outcome was recurrent instability, defined as dislocation or subluxation as perceived by the patients. The secondary outcome was subjective shoulder stability and function as well as quality of life, evaluated using the Western Ontario Shoulder Instability Index, the Simple Shoulder Test, and the 12-Item Short Form Health Survey. Prognostic factors for recurrent instability were analyzed.Results: Recurrent instability occurred in 22% of patients with a mean follow-up of 6.3 years. Survival at 5 and 10 years without recurrent instability was 79% and 78%, respectively (95% confidence interval, 72%-85% and 71%-85%, respectively). The Western Ontario Shoulder Instability Index score, the Simple Shoulder Test score, and the 12-item Short Form Physical Component Summary improved significantly in the nonrecurrence group (P Conclusion: We found an overall recurrent instability rate of 22% (dislocation or subluxation). Good long-term results were observed after arthroscopic Bankart repair in patients older than 20 years with 3 or more suture anchors used. (C) 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved.

Introduction The long head of biceps tendon is frequently involved in degenerative rotator cuff tears. Therefore, this study explored the clinical results of an isolated biceps tenotomy and identified prognostic factors for improvement in pain and function. Materials and methods Between 2008 and 2017, an arthroscopic isolated biceps tenotomy was performed on 64 patients with a degenerative rotator cuff tear (> 65 years). Primary outcome was patient-perceived improvement in pain and function. Potential prognostic factors for improvement in pain and function were identified. Results A perceived improvement in pain was reported in 78% of the patients at three months after surgery and in 75% at a mean follow-up of 4.2 years (1–7 years; n = 55). A perceived improvement in function was observed in 49% of patients at three months and in 76% of patients at follow-up. Patients with a preoperatively normal acromiohumeral distance (> 10 mm) reported an improvement in pain and function significantly more often. Retraction of the supraspinatus tendon Patte 3 was significantly associated with worse functional outcome. Conclusions A biceps tenotomy can be a reliable treatment option for patients with symptomatic degenerative cuff tears who fail conservative treatment and have a normal acromiohumeral distance (> 10 mm).

Background Several surgical reconstructive options are available to treat massive rotator cuff tears (MRCTs). The rotator cable has an important function and we evaluated the clinical result after arthroscopic reconstruction of the rotator cable with an autograft tendon. Methods A prospective pilot study was performed with inclusion of four patients, average age of 64 years, with an irreparable MRCT. The patients underwent an arthroscopic reconstruction of the rotator cable with the use of the long head of biceps tendon autograft, except for one which was reconstructed with a hamstring tendon. Pre- and postsurgically, the Constant-Murley Score (CMS), Western Ontario Rotator Cuff Index (WORC), Simple Shoulder Test (SST), visual analog scale (VAS) scores, and an MRI was performed. Clinical results of the study group were compared with clinical results of comparable cohort of patients with a MRCT, treated non-operatively with physiotherapy. Results The CMS score increased after surgery in three of the four patients. The improvement of CMS score was comparable to the improvement of the CMS score encountered in a comparable cohort. The MRI at 12 months follow-up showed that the reconstructed rotator cable was disintegrated in all patients and the rotator cuff was detached and retracted. Conclusions In our pilot study, arthroscopic reconstruction of the rotator cable using a tendon autograft failed over time and showed no clinical benefit in comparison to the non-operative treatment with physiotherapy. Trial registration The regional Medical Ethical Committee (Zwolle) gave approval at 14th of October 2016 and assigned no. 16.06100.

Patellar tendon shortening may occur following patellofemoral joint replacement (PFJR). We hypothesized that patellar tendon shortening results in unfavourable patient-reported outcomes (PROs). The aim of this study was to determine the effect of patellar tendon shortening following PFJR on PROs. In this substudy of a prospective cohort study, a total of 108 patients with isolated patellofemoral osteoarthritis underwent 124 patellofemoral joint replacements. We measured both patellar tendon length and length of the patella on pre-operative radiographs, and on radiographs acquired at eight weeks and at one year post-operative. More than 10% decrease in patellar tendon length relative to the pre-operative patellar tendon length was defined as patellar tendon shortening. Clinical outcomes were assessed using the knee-specific KOOS questionnaire (Knee Injury and Osteoarthritis Outcome Score). Repeated measures ANOVA was used to analyze for differences in change from baseline KOOS subscales between patients with and patients without patellar tendon shortening. A complete series of standardized pre-operative, eight weeks and one year post-operative radiographs was available for 87 knees in 82 patients. At eight weeks, 16 of 87 knees (18%) showed patellar tendon length shortening, and 27 of 87 knees (31%) at one year. We found no statistically significant relation between patellar tendon length shortening and change from baseline KOOS subscales at one year follow-up (pain p = 0.29, symptoms p = 0.56, ADL p = 0.23, sport or recreation p = 0.22, knee-related quality of life (QOL) p = 0.15). Patellar tendon length shortening following PFJR occurs in 31% of knees at one year, and does not result in inferior PROs.

Release of growth factors while simultaneously maintaining their full biological activity over a period of days to weeks is an important issue in controlled drug delivery and in tissue engineering. In addition, the selected strategy to immobilize growth factors largely determines their biological activity. Silica surfaces derivatized with glycidyloxy propyl trimethoxysilane and poly(glycidyl methacrylate) brushes yielded epoxide-functionalized surfaces onto which human bone morphogenetic protein-6 (hBMP-6) was immobilized giving stable secondary amine bonds. The biological activity of hBMP-6 was unleashed by hydrolysis of the surface siloxane and ester bonds. We demonstrate that this type of labile bonding strategy can be applied to biomaterial surfaces with relatively simple and biocompatible chemistry, such as siloxane, ester, and imine bonds. Our data indicates that the use of differential hydrolytically labile linkers is a versatile method for functionalization of biomaterials with a variety of growth factors providing control over their biological activity.

Reproducible identification of white matter tracts across subjects is essential for the study of structural connectivity of the human brain. The key challenges are anatomical differences between subjects and human rater subjectivity in labeling. Labeling white matter regions of interest presents many challenges due to the need to integrate both local and global information. Clearly communicating the human/manual processes to capture this information is cumbersome, yet essential to lay a solid foundation for comprehensive atlases. The state-of-the-art for white matter atlas is the single population-averaged Johns Hopkins Eve atlas. A critical bottleneck with the Eve atlas framework is that manual labeling time is extensive and peripheral white matter regions are conservatively labeled. In this work, we developed protocols that will facilitate manual virtual dissection of white matter pathways, with the goals to be anatomically accurate, intuitive, reproducible, and act as an initial stage to build an amenable knowledge base of neuroanatomical regions. We analyzed reproducibility of the fiber bundles and variability of human raters using DICE correlation coefficient, intraclass correlation coefficient, and root mean squared error. The protocols at their initial stage have shown promising results on both typical 3T research acquisition Baltimore Longitudinal Study of Aging and high-acquisition quality Human Connectome Project datasets. The TractEM manual labeling protocols allow for reconstruction of reproducible subject-specific fiber bundles across the brain. The protocols and sample results have been made available in open source to improve generalizability and reliability in collaboration.

BACKGROUND: Psychological symptoms are frequently present in patients scheduled for shoulder surgery. The perception of functional disability, activity level and pain in the shoulder is negatively influenced by psychological symptoms, which leads to higher scores of the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire. The aim of this study was to determine the influence of psychological symptoms on the minimal clinically important difference (MCID) of the DASH score in patients after shoulder surgery.METHODS: In this prospective longitudinal cohort study, 176 patients were included. Group 1 (32 patients) had symptoms of psychological disorders before and after surgery; group 2 had no symptoms of psychological disorders (110 patients). In the remaining patients (34 patients), psychological disorders changed after surgery. Clinical outcome was measured with the change of DASH score and anchor questions for perceived improvement of pain and function after surgery. Symptoms of psychological disorders were identified with the Four-Dimensional Symptom Questionnaire. An anchor-based mean change score technique was used to determine the MCID of the DASH score.RESULTS: DASH scores before and 12 months after shoulder surgery were significantly higher in patients with symptoms of psychological disorders; change of DASH score was not different between the two groups. The MCID of the DASH score was 13.0 [SD 20.7] in the group with symptoms of psychological disorders and 12.7 [SD 17.6] in the group with no symptoms of psychological disorders. We observed no difference (p = 0.559) in the MCID between the group with and the group without symptoms of psychological disorders.CONCLUSION: Symptoms of psychological disorders had a negative effect on the DASH score but no influence on the MCID of the DASH score. The DASH score could be used in future studies to assess the influence of psychological factors on the clinical outcome of treatment.

Background: A magnetic resonance imaging Oil RI) scan of the shoulder can have added value in diagnosing symptomatic osteoarthiitis of the acromioclavicular (AC) joint. Specific MRI signs have been recognized but not analyzed extensively before. This study aims to identify predictive MRI signs in patients with symptomatic AC osteoarthritis.Methods: The MRI scans of 70 patients with symptomatic AC osteoarthritis were compared with those of 70 patients with subacromial pain syndrome and no clinical signs of symptomatic AC osteoarthritis. Seven variables were evaluated on the MRI scans of the AC joint joint space narrowing, inferior osteophytes, joint effusion, osteolysis, hone marrow edema, impression on the supraspinatus, and inferior joint distension. Logistic regression analysis of these variables was performed.Results: The presence of inferior osteophytes, bone marrow edema, impression on the supraspinatus, and inferior joint distension was individually associated with symptomatic AC osteoarthritis. Bone marrow edema was observed only in patients with symptomatic AC osteoarthritis. Multivariate analysis showed a significant association between inferior joint distension, as well as impression on the supraspinatus muscle, and symptomatic AC osteoarthritis. The area under the receiver operating characteristic curve in the multivariate logistic model was 0.839 (95% confidence interval, 0.771 to 0.907). Interobserver and intraohserver variability showed good to excellent is values (range, 0.68 to 0.88).Conclusion: We identified predictive MRI signs in patients with symptomatic AC osteoarthritis. These findings, including bone marrow edema, inferior joint distension, and impression on the supraspinatus muscle, showed good discriminative ability. They are practical and easy to use and can assist the physician in diagnosing symptomatic AC osteoarthritis. (C) 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved.

Hypoxia has been shown to be important for maintaining cartilage homeostasis as well as for inducing chondrogenic differentiation. Ensuring low oxygen levels during in vitro culture is difficult, therefore we assessed the chondro-inductive capabilities of the hypoxia-mimicking agent O-phenanthroline, which is also known as a non-specific matrix metalloproteinase (MMP) inhibitor. We found that O-phenanthroline reduced the expression of MMP3 and MMP13 mRNA levels during chondrogenic differentiation of human chondrocytes (hChs), as well as after TNFα/IL-1β exposure in an explant model. Interestingly, O-phenanthroline significantly inhibited matrix degradation in a TNFα/IL-1β-dependent model of cartilage degeneration when compared to control and natural hypoxia (2.5% O2 ). O-Phenanthroline had limited ability to improve the chondrogenic differentiation or matrix deposition in the chondrogenic pellet model. Additionally, O-phenanthroline alleviated MMP-induced cartilage degradation without affecting chondrogenesis in the explant culture. The data presented in this study indicate that the inhibitory effect of O-phenanthroline on MMP expression is dominant over the hypoxia-mimicking effect. Copyright © 2014 John Wiley & Sons, Ltd.

IntroductionTotal knee replacement (TKR) for osteoarthritis results in a satisfactory outcome in the majority of patients, although up to one in five patients may be dissatisfied with the outcome. Persistent pain is a main contributor to patient dissatisfaction, and femoral and tibial component malrotation have been identified as a potential cause for both persistent pain and patellofemoral problems. Based on the assumption that component malrotation is the causative factor for persistent pain, early revision for patients with symptomatic malrotated components has been advocated in the literature. However, convincing evidence that component malrotation indeed results in less than optimal outcomes is lacking. This study aims to assess the relation between knee prosthesis component rotation and patient-reported outcomes in a large group of patients and to determine the range of femoral, tibial and combined rotation that results in the best clinical outcomes.Methods and analysisIn this single-centre, prospective observational cohort study, a total of 500 patients will undergo TKR. All patients will have a 3D-CT assessment of femoral and tibial component rotation within 8 weeks after surgery. Outcome measures will include the Oxford Knee Score, the Knee Injury and Osteoarthritis Outcome Score, EQ-5D, visual analogue scale for pain, the American Knee Society Score and the knee joint range of motion. We will assess the relation between femoral, tibial and combined component rotation and patient-reported outcome measures at 8 weeks and 1 year of follow-up, and we will determine the range of femoral, tibial and combined rotation that results in the best clinical outcomes.Ethics and disseminationEthical approval for this study has been granted by the Isala Hospital ethics committee. The results will be published in a peer-reviewed journal and presented at relevant meetings.Trial registration numberNL7635.

A supramolecular strategy is presented for the assembly of growth factors employing His(6)-tagged single-domain antibodies (VHH). A combination of orthogonal supramolecular interactions of beta-cyclodextrin (beta CD)adamantyl (Ad) hostguest and N-nitrilotriacetic acid (NTA)histidine (His) interactions was employed to generate reversible and homogeneous layers of growth factors. A single-domain antibody VHH fragment was identified to bind to the human bone morphogenetic protein-6 (hBMP6) growth factor and could be recombinantly expressed in E. coli. The VHH fragment was equipped with a C-terminal hexahistidine (His(6)) tether to facilitate the assembly on beta CD surfaces using a linker that contains an Ad group to bind to the beta CD receptors and an NTA moiety to interact with the His(6)-tag upon cocomplexation of Ni2+ ions. After exploring the thermodynamic and kinetic stability of the VHH assemblies on beta CD surfaces using a variety of experimental techniques including microcontact printing (mu CP), surface plasmon resonance (SPR), microscale thermophoresis (MST), and theoretical models for determining the thermodynamic behavior of the system, hBMP6 was assembled onto the VHH-functionalized surfaces. After analyzing the immobilized hBMP6 using immunostaining, the biological activity of hBMP6 was demonstrated in cell differentiation experiments. Early osteogenic differentiation was analyzed in terms of alkaline phosphatase (ALP) activity of KS483-4C3 mouse progenitor cells, and the results indicated that the reversibly immobilized growth factors were functionally delivered to the cells. In conclusion, the supramolecular strategy used here offers the necessary affinity, reversibility, and temporal control to promote biological function of the growth factors that were delivered by this strategy.

Strategies to generate platforms combining tissue targeting and regeneration properties are in great demand in the regenerative medicine field. Here we employ an approach to directly visualize the immobilization of cysteine-terminated peptides on a novel fluorogenic surface. Peptides with relevant biological properties, CLPLGNSH and CLRGRYW, were synthesized to function as peptide binders to transforming growth factor (TGF)-β1 and collagen type II (CII). The selective immobilization of the peptides was directly detected using a fluorogenic surface. Adhered proteins were confined to patterns of these peptides matching with the fluorogenic areas. These results show that the fluorogenic signal can be used to detect the chemo-selective immobilization of non-fluorescent biomolecules and to correlate the cell response with the patterned peptides. After analyzing the sequence specificity and cross-reactivity of the binding of TGF-β1 and CII to the respective peptide regions employing immunofluorescence assays, both peptides were co-immobilized in a step-wise process as detected by the fluorogenic surface. TGF-β1 and CII could be self-sorted from a mixture in a regio-selective manner resulting in a bi-functional protein platform. Surfaces of CLPLGNSH pre-loaded with TGF-β1 showed excellent bioactivity in combination with human articular chondrocytes (HACs) and stimulated expression of chondrogenic markers.

Hypoxia has been shown to be important for maintaining cartilage homeostasis as well as for inducing chondrogenic differentiation. Ensuring low oxygen levels during in vitro culture is difficult, therefore we assessed the chondro-inductive capabilities of the hypoxia-mimicking agent O-phenanthroline, which is also known as a non-specific matrix metalloproteinase (MMP) inhibitor. We found that O-phenanthroline reduced the expression of MMP3 and MMP13 mRNA levels during chondrogenic differentiation of human chondrocytes (hChs), as well as after TNFα/IL-1β exposure in an explant model. Interestingly, O-phenanthroline significantly inhibited matrix degradation in a TNFα/IL-1β-dependent model of cartilage degeneration when compared to control and natural hypoxia (2.5% O

Arthritis research & therapy 15(5), R126 (2013). doi:10.1186/ar4306, Published by BioMed Central, London

In adult articular cartilage, the extracellular matrix is maintained by a balance between the degradation and the synthesis of matrix components. Chondrocytes that sparsely reside in the matrix and rarely proliferate are the key cellular mediators for cartilage homeostasis. There are indications for the involvement of the WNT signaling pathway in maintaining articular cartilage. Various WNTs are involved in the subsequent stages of chondrocyte differentiation during development, and deregulation of WNT signaling was observed in cartilage degeneration. Even though gene expression and protein synthesis can be activated upon injury, articular cartilage has a limited ability of self-repair and efforts to regenerate articular cartilage have so far not been successful. Because WNT signaling was found to be involved in the development and maintenance of cartilage as well as in the degeneration of cartilage, interfering with this pathway might contribute to improving cartilage regeneration. However, most of the studies on elucidating the role of WNT signaling in these processes were conducted using in vitro or in vivo animal models. Discrepancies have been found in the role of WNT signaling between chondrocytes of mouse and human origin, and extrapolation of results from mouse models to the human situation remains a challenge. Elucidation of detailed WNT signaling functions will provide knowledge to improve cartilage regeneration.

Introduction In this study, we tested the ability of small molecule inhibitors of WNT/β-catenin signaling to block interleukin 1β (IL-1β)- and tumor necrosis factor α (TNFα)-induced cartilage degradation. Proinflammatory cytokines such as IL-1β and TNFα are potent inducers of cartilage degradation by upregulating matrix metalloproteinase (MMP) expression and activity. Because WNT/β-catenin signaling was found to be involved in IL-1β- and TNFα-induced upregulation of MMP activity, we hypothesized that inhibition of WNT/β-catenin signaling might block IL-1β- and TNFα-induced cartilage degradation. We tested the effect of small molecules that block the interaction between β-catenin and TCF/Lef transcription factors on IL-1β- and TNFα-induced cartilage degradation in mouse fetal metatarsals. Methods We used mouse fetal metatarsals treated with IL-1β and TNFα as an ex vivo model for cytokine-induced cartilage degradation. Metatarsals were treated with IL-1β and TNFα in combination with the small molecules PKF115-584, PKF118-310 and CGP049090 at different concentrations and then harvested them for histological and gene expression analysis. Results We found that IL-1β- and TNFα-induced cartilage degradation in mouse fetal metatarsals was blocked by inhibiting WNT/β-catenin signaling using small molecule PKF115-584 and partially using CGP049090 dose-dependently. In addition, we found that PKF115-584 blocked IL-1β- and TNFα-induced MMP mRNA expression, but did not reverse the inhibitory effect of IL-1β on the expression of cartilage anabolic genes. Conclusion In this study, we show that inhibition of WNT/β-catenin signaling by small molecules can effectively prevent IL-1β- and TNFα-induced cartilage degradation by blocking MMP expression and activity. Furthermore, we elucidate the involvement of WNT/β-catenin signaling in IL-1β- and TNFα-induced cartilage degradation.

Approximate formulas that yield the resonance amplitude of symmetric two‐junction interferometers have been derived using step‐by‐step linearizations and approximations based on physical arguments. The resonance amplitude is found to strongly depend on the device Q. It increases as Q increases, reaches a peak, and subsequently decreases again. In the low‐Q region, the resonance step is very broad and largely independent of rapid changes in device current. This is not the case in the high‐Q region where the resonance amplitude increases with decreasing device current rise time. In the range of validity of the approximations, the results were compared to computer solutions, and reasonable agreement was found for arbitrarily chosen test cases. Although derived for two‐junction interferometers, the results can be extended directly to certain symmetric three‐junction interferometers.

Resonance dc structures are experimentally investigated in two‐junction interferometers in which the device Q is adjusted to low values with an external resistor connected across the main device inductance. The measurements agree well with the results of a recent analytic theory of interferometer resonances and show that practical interferometer devices with low and adjustable resonance amplitudes can be built.