Wind waves in sea ice of the western Arctic and a global coupled wave-ice model.

The retreat of Arctic sea ice is enabling increased ocean wave activity at the sea ice edge, yet the interactions between surface waves and sea ice are not fully understood. Here, we examine in situ observations of wave spectra spanning 2012-2021 in the western Arctic marginal ice zone (MIZ). Swells exceeding 30 cm are rarely observed beyond 100 km inside the MIZ. However, local wind waves are observed in patches of open water amid partial ice cover during the summer. These local waves remain fetch-limited between ice floes with heights less than 1 m. To investigate these waves at climate scales, we conduct experiments varying wave attenuation and generation in ice with a global model including coupled interactions between waves and sea ice. A weak high-frequency attenuation rate is required to simulate the local waves in observations. The choices of attenuation scheme and wind input in ice have a remarkable impact on the extent of wave activity across ice-covered oceans, particularly in the Antarctic. As well as demonstrating the need for stronger constraints on wave attenuation, our results suggest that further attention should be directed towards locally generated wind waves and their role in sea ice evolution. This article is part of the theme issue 'Theory, modelling and observations of marginal ice zone dynamics: multidisciplinary perspectives and outlooks'.

Pharmacological characterization of GLPG1972/S201086, a potent and selective small-molecule inhibitor of ADAMTS5.

OBJECTIVE: A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) is a key enzyme in degradation of cartilage in osteoarthritis (OA). We report the pharmacological characterization of GLPG1972/S201086, a new, potent and selective small-molecule ADAMTS5 inhibitor. METHODS: Potency and selectivity of GLPG1972/S201086 for ADAMTS5 were determined using fluorescently labeled peptide substrates. Inhibitory effects of GLPG1972/S201086 on interleukin-1α-stimulated glycosaminoglycan release in mouse femoral head cartilage explants and on interleukin-1ß-stimulated release of an ADAMTS5-derived aggrecan neoepitope (quantified with ELISA) in human articular cartilage explants were determined. In the destabilization of the medial meniscus (DMM) mouse and menisectomized (MNX) rat models, effects of oral GLPG1972/S201086 on relevant OA histological and histomorphometric parameters were evaluated. RESULTS: GLPG1972/S201086 inhibited human and rat ADAMTS5 (IC50 ± SD: 19 ± 2 nM and <23 ± 1 nM, respectively), with 8-fold selectivity over ADAMTS4, and 60->5,000-fold selectivity over other related proteases in humans. GLPG1972/S201086 dose-dependently inhibited cytokine-stimulated aggrenolysis in mouse and human cartilage explants (100% at 20 µM and 10 µM, respectively). In DMM mice, GLPG1972/S201086 (30-120 mg/kg b.i.d) vs vehicle reduced femorotibial cartilage proteoglycan loss (23-37%), cartilage structural damage (23-39%) and subchondral bone sclerosis (21-36%). In MNX rats, GLPG1972/S201086 (10-50 mg/kg b.i.d) vs vehicle reduced cartilage damage (OARSI score reduction, 6-23%), and decreased proteoglycan loss (∼27%) and subchondral bone sclerosis (77-110%). CONCLUSIONS: GLPG1972/S201086 is a potent, selective and orally available ADAMTS5 inhibitor, demonstrating significant protective efficacy on both cartilage and subchondral bone in two relevant in vivo preclinical OA models.

Pituitary metastasis: From pathology to clinical and radiological considerations.

PURPOSE: A review of the literature with respect to pituitary metastases (PM) with clinical and radiological considerations are summarized to facilitate clinical decision making in the management of PM METHODS: A review of literature associated with PM and tumour to tumour metastases in the English literature was reviewed and summarized RESULTS: Pituitary metastases account for 1.0-3.6% of all surgically treated pituitary lesions. Often identified in parallel with extensive disseminated disease, once diagnosed, the prognosis is generally poor, although survival is highly heterogeneous and dependent on the primary tumor histology. Within this anatomical region is also the observation of tumor-to-tumor metastases and collision tumours. Both the tumor macro- and microenvironment play central roles to the progression of disease with distinctive radiological features that may suggest a metastatic sellar lesion as opposed to a primary pituitary lesion. Surgical resection is the first line of therapy followed by adjuvant chemoradiotherapy and endocrinological evaluation for hormonal supplementation CONCLUSION: PMs are relatively rare but important oncological entities representing disseminated disease in the majority of cases. Careful consideration of the relevant clinical history and radiological features can aid the clinician differentiate between a metastatic lesion to the pituitary region and a primary pituitary tumor. While surgical resection is first line therapy, stereotactic radiosurgery in carefully selected patients is emerging as a viable alternative.

Pathology-pain relationships in different osteoarthritis animal model phenotypes: it matters what you measure, when you measure, and how you got there.

OBJECTIVE: To determine whether osteoarthritis (OA) pain characteristics and mechanistic pathways in pre-clinical models are phenotype-specific. DESIGN: Male 11-week-old C57BL6 mice had unilateral medial-meniscal-destabilization (DMM) or antigen-induced-arthritis (AIA), vs sham-surgery/immunised-controls (Sham/Im-CT). Pain behaviour (allodynia, mechanical- and thermal-hyperalgesia, hindlimb static weight-bearing, stride-length) and lumbar dorsal root ganglia (DRG) gene-expression were measured at baseline, day-3, week-1/-2/-4/-8/-16, and pain-behaviour:gene-expression:joint-pathology associations investigated. RESULTS: DMM and AIA induced structural OA defined by progressively increasing cartilage erosion, subchondral bone sclerosis and osteophyte size and maturation. All pain-behaviours were modified, with model-specific differences in severity and temporal pattern. Tactile allodynia developed acutely in both models and persisted to week-16. During early-OA (wk4-8) there was; reduced right hindlimb weight-bearing in AIA; thermal-hyperalgesia and reduced stride-length in DMM. During chronic-OA (wk12-16); mechanical-hyperalgesia and reduced right hindlimb weight-bearing were observed in DMM only. There were no associations in either model between different pain-behaviour outcomes. A coordinated DRG-expression profile was observed in sham and Im-CT for all 11 genes tested, but not in AIA and DMM. At wk-16 despite equivalent joint pathology, changes in DRG-expression (Calca, Trpa1, Trpv1, Trpv4) were observed only in DMM. In AIA mechanical-hyperalgesia was associated with Trpv1 (r = -0.79) and Il1b (r = 0.53). In DMM stride-length was associated with Calca, Tac1, Trpv1, Trpv2, Trpv4 and Adamts5 (r = 0.4-0.57). DRG gene-expression change was correlated with subchondral-bone sclerosis in DMM, and cartilage damage in AIA. Positive pain-behaviour:joint-pathology associations were only present in AIA - for synovitis, subchondral-bone resorption, chondrocyte-hypertrophy and cartilage damage. CONCLUSION: Pain and peripheral sensory neuronal responses are OA-phenotype-specific with distinct pathology:pain-outcome:molecular-mechanism relationships.

Differential patterns of pathology in and interaction between joint tissues in long-term osteoarthritis with different initiating causes: phenotype matters.

OBJECTIVE: To determine if osteoarthritis (OA) progression and joint tissue-pathology associations link specific animal models to different human OA phenotypes. DESIGN: Male 11-week-old C57BL6 mice had unilateral medial-meniscal-destabilization (DMM) or antigen-induced-arthritis (AIA). Joint tissue histopathology was scored day-3 to week-16. Tissue-pathology associations (corrected for time and at week-16) were determined by partial correlation coefficients, and odds ratios (OR) calculated for likelihood of cartilage damage and joint inflammation by ordinal-logistic-regression. RESULTS: Despite distinct temporal patterns of progression, by week-16 joint-wide OA pathology in DMM and AIA was equivalent. Significant pathology associations common to both models included: osteophyte size and maturity (r > 0.4); subchondral bone (SCB) sclerosis and osteophyte maturity (r > 0.25); cartilage erosion and chondrocyte hypertrophy/apoptosis (r > 0.4), SCB sclerosis (r > 0.26), osteophyte size (r > 0.3), and maturity (r > 0.32). DMM-specific associations were between cartilage proteoglycan loss and structural damage (r = 0.56), osteophyte maturity (r = 0.49), size (r = 0.45), and SCB sclerosis (r = 0.28). AIA-specific associations were between SCB sclerosis and chondrocyte hypertrophy/apoptosis (r = 0.40) and osteophyte size (r = 0.37); and synovitis with cartilage structural damage (r = 0.18). No tissue-pathology associations were common to both models at week-16. Increased likelihood of cartilage structural damage was associated with: chondrocyte hypertrophy/apoptosis (OR>1.7), and osteophyte size (OR>2.3) in both models; SCB sclerosis (OR = 2.0) and proteoglycan loss (OR = 2.4) in DMM; and synovitis (OR = 1.2) in AIA. Joint inflammation was associated positively with cartilage proteoglycan loss (OR = 1.4) and inversely with osteophyte size (OR = 0.21) in AIA only. CONCLUSION: This study highlights the importance of defining OA-models by initiating mechanisms and progression, not just end-stage joint-tissue pathology.

The Pituitary Tumors and Their Tumor-Specific Microenvironment.

Pituitary tumors develop within a macroenvironment and microenvironment that favor their overall survival. Given the pituitary gland's unique anatomic, histological, and physiological properties, the role of the TME in the pituitary tumors is central. This chapter summarizes the body of literature investigating the role of each component of the TME in relation to tumors of the pituitary and its intimate association with tumorigenesis, maintenance, and progression.

Factors affecting knee abduction during weight-bearing activities in individuals with anterior cruciate ligament reconstruction.

OBJECTIVE: To investigate if muscle strength and muscle activation patterns are associated with increased knee abduction during two functional tasks, commonly used in rehabilitation for individuals with anterior cruciate ligament reconstruction (ACLR). DESIGN: Cross-sectional study. SETTING: Laboratory. PARTICIPANTS: 24 women and 29 men approximately 7 months after ACLR. MAIN OUTCOME MEASURES: Isometric peak torque of the trunk and lower extremity muscles were determined during maximal voluntary contractions. Trunk and lower extremity average muscle activation amplitude and peak knee abduction were evaluated during the single-leg squat (SLS) and the single-leg hop for distance (SLHD) for the injured side. Separate backward regressions were performed for men and women. RESULTS: In women, lower knee flexion and extension strength were associated with greater peak knee abduction during the SLS (B = 4.63-18.26, p ≤ 0.036); lower knee flexion strength and iliocostalis activation on the non-injured side were associated with greater peak knee abduction during the SLHD (B = 0.60-20.48, p ≤ 0.043). No associations between muscle function and peak knee abduction were found in men. CONCLUSIONS: Muscle function may contribute differently to knee abduction in men and women after ACLR. This should be considered when designing rehabilitation programs to reduce knee abduction in these patients.

Attributes of Bio-Oss® and Moa-Bone® graft materials in a pilot study using the sheep maxillary sinus model.

BACKGROUND AND OBJECTIVE: The aim of this pilot study was to characterize surface morphology and to evaluate resorption and osseous healing of two deproteinated bovine bone graft materials after sinus grafting in a large animal model. MATERIAL AND METHODS: Surfaces of a novel particulate bovine bone graft, Moa-Bone® were compared with Bio-Oss® using scanning electron microscopy. Six sheep then had maxillary sinus grafting bilaterally, covered with BioGide® . Grafted maxillae were harvested after 4, 6 and 12 weeks. Healing was described for half of each site using resin-embedded ground sections. For the other half, paraffin-embedded sections were examined using tartrate resistant acid phosphatase staining for osteoclast activity, runt-related transcription factor2 immunohistochemistry for pre-osteoblasts and osteoblasts and proliferating cell nuclear antigen for proliferative cells. RESULTS: Moa-Bone® had a smoother, more porous fibrous structure with minimal globular particles compared with Bio-Oss® . After 4 weeks, woven bone formed on both grafts and the Moa-Bone® particles also showed signs of resorption. After 12 weeks, Moa-Bone® continued to be resorbed, however Bio-Oss® did not; both grafts were surrounded by maturing lamellar bone. Moa-Bone® was associated with earlier evidence of runt-related transcription factor 2-positive cells. Moa-Bone® but not Bio-Oss® was associated with strong tartrate resistant acid phosphatase-positive osteoclasts on the graft surface within resorption lacunae at both 4 and 6 weeks post-grafting. CONCLUSION: Both materials supported osseous healing and maturation without inflammation. Moa-Bone® showed marked osteoclast activity after 4 and 6 weeks and demonstrated positive attributes for grafting, if complete remodeling of the graft within the site is desired. Further optimization of Moa-Bone® for maxillofacial applications is warranted.

Neural correlates of working memory in children and adolescents with agenesis of the corpus callosum: An fMRI study.

The ability to temporarily maintain relevant information in mind in the presence of interference or distracting information, also called working memory (WM), is critical for higher cognitive functions and cognitive development. In typically developing (TD) children, WM is underpinned by a fronto-parietal network of interacting left and right brain regions. Developmental absence (agenesis) of the corpus callosum (AgCC) is a congenital brain malformation resulting from disruption of corpus callosum formation. This study aims to investigate functional organisation of WM in children and adolescents with AgCC using functional magnetic resonance imaging (fMRI). Nine children with AgCC and a comparison group of sixteen TD children aged 8-17 years completed an fMRI WM paradigm designed to enable investigation of different WM processes, i.e., encoding, maintenance and retrieval. We found that AgCC children recruited globally similar brain regions as the TD comparison group during the WM task, despite significant disparity in brain development, i.e., bilateral occipito-frontal activations during verbal encoding, and bilateral fronto-parietal executive control network during retrieval. However, compared to their TD peers, children with AgCC seemed less able to engage lateralised brain systems specialised for particular memory material (i.e. less supramarginal activations for verbal material and less fusiform activations for face processing) and particular memory process (i.e. absence of right-predominant activations during retrieval). Group differences in the pattern of activation might also reflect different cognitive strategies to cope with competition in processing resources with different susceptibility to concurrent tasks (verbal vs visual), such as differential recruitment of associative visual areas and executive prefrontal regions in the AgCC compared with the TD group depending on the concurrent task completed during maintenance. This study provides a first step towards a better understanding of functional brain networks underlying higher cognitive functions in children with AgCC.

Utility of circulating serum miRNAs as biomarkers of early cartilage degeneration in animal models of post-traumatic osteoarthritis and inflammatory arthritis.

OBJECTIVE: The purpose of this study was to determine if serum microRNA (miRNA) signatures were biomarkers of early cartilage degeneration in preclinical mouse models of post-traumatic osteoarthritis (OA) and inflammatory arthritis. METHODS: Cartilage degeneration was induced in 10-12 week old male C57BL6 mice by destabilization of the medial meniscus (DMM) or intra-articular injection of methylated-bovine-serum-albumin (AIA), with sham-operated or saline-injected control animals (n = 6/treatment/time). Total serum RNA and knee joints were isolated at 1, 4 and 16 weeks post-induction. Cartilage degeneration was scored histologically. Serum miRNA expression profiling was performed using Agilent microarrays and validated by qPCR. RESULTS: DMM-operated and AIA mice had characteristic cartilage degeneration (proteoglycan loss, chondrocyte hypertrophy, structural damage), that increased significantly with time compared with controls, and with distinct temporal differences between arthritis models. However, expression profiling revealed no statistically significant dysregulation of serum miRNAs between AIA vs saline-injected or DMM vs sham-operated control mice at the critical early disease stages. The inability to detect DMM or AIA serum miRNA signatures compared with controls was not due to the insensitivity of the expression profiling approach since significant changes were observed in miRNA expression between the arthritis models and between time points. CONCLUSION: While distinct patterns of progressive cartilage degradation were induced in the arthritis models, we were unable to identify any serum miRNAs that were significantly dysregulated in early stages of disease compared with controls. This suggests circulating serum miRNAs may not be useful as cartilage biomarkers in distinguishing the early or progressive stages of arthritis cartilage degeneration.

Considerations for the design and execution of protocols for animal research and treatment to improve reproducibility and standardization: "DEPART well-prepared and ARRIVE safely".

OBJECTIVE: To review the factors in experimental design that contribute to poor translation of pre-clinical research to therapies for patients with osteoarthritis (OA) and how this might be improved. METHODS: Narrative review of the literature, and evaluation of the different stages of design conduct and analysis of studies using animal models of OA to define specific issues that might reduce quality of evidence and how this can be minimised. RESULTS: Preventing bias and improving experimental rigour and reporting are important modifiable factors to improve translation from pre-clinical animal models to successful clinical trials of therapeutic agents. Despite publication and adoption by many journals of guidelines such as Animals in Research: Reporting In Vivo Experiments (ARRIVE), experimental animal studies published in leading rheumatology journals are still deficient in their reporting. In part, this may be caused by researchers first consulting these guidelines after the completion of experiments, at the time of publication. This review discusses factors that can (1) bias the outcome of experimental studies using animal models of osteoarthritis or (2) alter the quality of evidence for translation. We propose a checklist to consult prior to starting experiments; in the Design and Execution of Protocols for Animal Research and Treatment (DEPART). CONCLUSIONS: Following DEPART during the design phase will enable completion of the ARRIVE checklist at the time of publication, and thus improve the quality of evidence for inclusion of experimental animal research in meta-analyses and systematic reviews: "DEPART well-prepared and ARRIVE safely".

Visuospatial working memory in very preterm and term born children--impact of age and performance.

Working memory is crucial for meeting the challenges of daily life and performing academic tasks, such as reading or arithmetic. Very preterm born children are at risk of low working memory capacity. The aim of this study was to examine the visuospatial working memory network of school-aged preterm children and to determine the effect of age and performance on the neural working memory network. Working memory was assessed in 41 very preterm born children and 36 term born controls (aged 7-12 years) using functional magnetic resonance imaging (fMRI) and neuropsychological assessment. While preterm children and controls showed equal working memory performance, preterm children showed less involvement of the right middle frontal gyrus, but higher fMRI activation in superior frontal regions than controls. The younger and low-performing preterm children presented an atypical working memory network whereas the older high-performing preterm children recruited a working memory network similar to the controls. Results suggest that younger and low-performing preterm children show signs of less neural efficiency in frontal brain areas. With increasing age and performance, compensational mechanisms seem to occur, so that in preterm children, the typical visuospatial working memory network is established by the age of 12 years.

First demonstration of resolution of an infundibulum by direct treatment of the arterial wall with Pipeline flow-diverting stent.

INTRODUCTION: Infundibula are symmetrical funnel-shaped widening, measuring more than 3 mm at its base with the branch artery arising from its apex. The pathological significance of this entity remains controversial. Although a relatively common appearance in otherwise normal angiograms, they have occasionally been described to progress into saccular aneurysms or directly rupture. METHODS/RESULTS: We describe the first case of a disappearing infundibulum after a flow diverting stent was deployed across the infundibulum during the treatment of an adjacent aneurysm. CONCLUSIONS: We concur in the view that infundibula are at least pre-pathological lesions that may in certain circumstances require consideration for treatment. Our case for the first time offers a potential treatment option for such situations.

Incidence of post-intubation subglottic stenosis in children: prospective study.

OBJECTIVE: To evaluate the incidence of subglottic stenosis in children undergoing endotracheal intubation. METHODS: Children in the paediatric intensive care unit of a tertiary care hospital were considered eligible for inclusion if they received endotracheal intubation for more than 24 hours. After extubation, children underwent flexible fibre-optic nasolaryngoscopy. Based on this first evaluation, they were divided into two groups: 'acute normal', with mild laryngeal alterations or normal findings; and 'acute alterations', with moderate to severe laryngeal alterations. Further laryngoscopic follow up (7-10 days later) was undertaken for those children in the acute normal group who developed symptoms during follow up (after discharge from the intensive care unit), and for all children in the acute alterations group. Children were then classified into two final groups: 'normal final examination', with no chronic changes; and 'subglottic stenosis'. RESULTS: We included 123 children. The incidence of subglottic stenosis was 11.38 per cent (95 per cent confidence interval, 6.63-17.94 per cent). All the children who developed subglottic stenosis had had moderate to severe alterations immediately after extubation. CONCLUSION: This incidence of subglottic stenosis is quite high and needs further investigation to identify risk factors.

Low circulating protein C levels are associated with lower leg ulcers in patients with diabetes.

Activated protein C (APC) promotes angiogenesis and reepithelialisation and accelerates healing of diabetic ulcers. The aim of this study was to determine the relationship between the incidence of lower leg ulcers and plasma levels of APC's precursor, protein C (PC), in diabetic patients. Patients with diabetes who had a lower leg ulcer(s) for >6 months (n = 36) were compared with age-, type of diabetes-, and sex-matched subjects with diabetes but without an ulcer (n = 36, controls). Total PC was assessed using a routine PC colorimetric assay. There was a significantly (P < 0.001) lower level of plasma PC in patients with ulcers (103.3 ± 22.7, mean ± SD) compared with control (127.1 ± 34.0) subjects, when corrected for age and matched for gender and type of diabetes. Ulcer type (neuropathic, ischaemic, or mixed) was not a significant covariate for plasma PC levels (P = 0.35). There was no correlation between PC levels and gender, type of diabetes, HbA1c, or C-reactive protein in either group. In summary, decreased circulating PC levels are associated with, and may predispose to, lower leg ulceration in patients with diabetes.

Comparison of gait and pathology outcomes of three meniscal procedures for induction of knee osteoarthritis in sheep.

OBJECTIVE(S): Meniscectomy (MX) of sheep induces a well-established animal model of human osteoarthritis (OA). This study compared the clinical (lameness) and pathological outcomes of unilateral, complete medial MX vs two less traumatic and more easily performed meniscal destabilisation procedures. METHODS: Four-year old wethers (n = 6/group) underwent sham operation, cranial pole release (CPR), mid-body transection (MBT) or total MX of the medial meniscus. Joints were assessed for gross pathology (cartilage erosion and osteophytes), histomorphometry, two histopathology scoring methods (modified Mankin-type and Pritzker score), and immunohistology for ADAMTS- and MMP-cleaved neoepitopes, at 12 weeks post-op. Ground reaction forces (GRFs) were determined by force plate in a subset (n = 4/group) at baseline, 2.5, 8, and 12 weeks post-op. RESULTS: Gross pathology scores of operated groups differed significantly from sham animals (P < 0.05) but not from each other, though qualitative differences were noted: CPR sheep developed more cranial and focal lesions, while MBT and MX joints showed more widespread lesions and osteophyte formation. Similarly, histopathology scores were significantly elevated vs sham but did not differ between operated groups at P < 0.05, except for a trend for lower tibial cartilage histopathology in MBT consistent with the immunohistologic pattern of reduced aggrecanase-cleavage neoepitope in that model. CPR sheep developed less femoral subchondral sclerosis, suggesting some residual biomechanical effect from the destabilised but intact meniscus. Few significant differences were noted between operated groups in force plate analyses, though gait abnormalities appeared to be least in CPR sheep, and most persistent (>12 weeks) in MBT animals. CONCLUSION: The well-validated ovine MX model and the simpler meniscal destabilisation procedures resulted in broadly similar joint pathology and lameness. Meniscal CPR or MBT, as easier and more clinically relevant procedures, may represent preferred models for the induction of OA and evaluation of potential disease-modifying therapies.

Time to diagnosis of paediatric posterior fossa tumours: an 11-year West of Scotland experience 2000-2011.

INTRODUCTION: Brain tumours are the most common solid childhood malignancy accounting for 20% of all paediatric cancers. Of these, posterior fossa tumours comprise approximately 60-70% of all brain tumours in children. Several studies have estimated the median pre-diagnostic interval (PSI) of paediatric brain tumours as approximately 60 days. OBJECTIVES: The objectives of this retrospective analysis were to (a) identify the common presenting symptoms of posterior fossa tumours, (b) determine the time interval from the first attributable symptom to the radiological diagnosis of a posterior fossa tumour, (c) compare the West of Scotland with other international centres and (d) identify which factors correlate with outcome for these children. MATERIALS AND METHODS: A retrospective case note review of 69 children diagnosed with posterior fossa tumours from January 2000 to September 2011. Of the 69 children diagnosed during this period, complete data were available for 66 children (M:F = 31:35, Mean age (SD): 7.50 + 4.53 years). Results. Nausea and vomiting (75.8%), headaches (63.6%) and incoordination (51.5%) were recorded as the most common presenting symptoms followed by lethargy (28.8%), cranial nerve palsy (25.8%) and diplopia (24.2%). Fifty-three of the sixty-six children (i.e., 80.3%) demonstrated radiological evidence of hydrocephalus on their initial scan. The majority of children were assessed by less than three specialists after a median PSI of 43.5 days. The only variable significantly associated with PSI was tumour grade (r = - 0.202, p = 0.036). Neither age at diagnosis, number of specialists seen, nor outcome was significantly correlated with PSI. The only factor associated with outcome was tumour grade (r = 0.337, p = 0.006). CONCLUSION: Despite recent reports indicating poor performance of the UK with respect to time to diagnosis of paediatric brain tumours, the present data indicate that the experience of this cohort is favourably comparable to international standards.

Zonal differences in meniscus matrix turnover and cytokine response.

OBJECTIVE: To determine the mechanisms of meniscal degeneration and whether this varied zonally and from articular cartilage. DESIGN: Normal ovine menisci were dissected into inner and outer zones and along with cartilage cultured ±IL-1α and TNFα. Glycosaminoglycan (GAG) and collagen release, and gene expression were quantified. Aggrecan proteolysis was analysed by Western blotting with neoepitope-specific antibodies. Matrix metalloproteinase (MMP)2, MMP9 and MMP13 activity was evaluated by gelatin zymography or fluorogenic assay. RESULTS: Inner meniscus was more cartilaginous containing more GAG and expressing more ACAN and COL2A1 than outer zones. Higher expression of VCAN and ADAMTS4 in medial outer and both zones of the lateral meniscus reflected their embryologic origin from cells outside the cartilage anlagen. All meniscal regions released a greater % GAG in response to cytokines; only outer zones had cytokine-stimulated collagenolysis. Cytokine-induced aggrecanolysis was primarily due to increased ADAMTS cleavage in cartilage and inner menisci but MMPs in the outer menisci. Outer menisci always released more active MMP2 than other tissues and more active MMP13 in basal and TNF-stimulated cultures. Expression of ACAN, COL1A1 and COL2A1 was decreased by both cytokines in all tissues, while VCAN was increased by IL-1α in cartilage and inner menisci. Metalloproteinase expression was differentially regulated by IL-1α and TNFα: ADAMTS4, MMP1, MMP3 were upregulated more by IL-1α in inner zones whereas ADAMTS5, MMP13 and MMP9 were more upregulated by TNFα in outer zones. CONCLUSIONS: Meniscal degeneration mechanisms are zonally-dependent, and may contribute to the enzymatic burden in the joint.

Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis.

OBJECTIVES: To investigate the regulation of sclerostin (SOST) in osteoarthritis (OA) and its potential effects on articular cartilage degradation. METHODS: SOST and other Wnt-ß-catenin components were immuno-localised in osteochondral sections of surgically-induced OA in knees of sheep and mice, and human OA samples obtained at arthroplasty. Regulation of SOST mRNA and protein expression by ovine chondrocytes in response to interleukin-1α (IL-1α) or tumour necrosis factor-α (TNFα) was examined in explant cultures. The effect of 25 or 250 ng/ml recombinant SOST alone or in combination with IL-1α, on ovine articular cartilage explant aggrecan degradation, and chondrocyte gene expression of Wnt-ß-catenin pathway proteins, metalloproteinases and their inhibitors, and cartilage matrix proteins was quantified. RESULTS: Contrary to being an osteocyte-specific protein, SOST was expressed by articular chondrocytes, and mRNA levels were upregulated in vitro by IL-1α but not TNFα. Chondrocyte SOST staining was significantly increased only in the focal area of cartilage damage in surgically-induced OA in sheep and mice, as well as end-stage human OA. In contrast, osteocyte SOST was focally decreased in the subchondral bone in sheep OA in association with bone sclerosis. SOST was biologically active in chondrocytes, inhibiting Wnt-ß-catenin signalling and catabolic metalloproteinase [matrix metalloproteinases (MMP) and distintegrin and metalloproteinase with thrombospndin repeats (ADAMTS)] expression, but also decreasing mRNA levels of aggrecan, collagen II and tissue inhibitors of metalloproteinaes (TIMPs). Despite this mixed effect, SOST dose-dependently inhibited IL-1α-stimulated cartilage aggrecanolysis in vitro. CONCLUSIONS: These results implicate SOST in regulating the OA disease processes, but suggest opposing effects by promoting disease-associated subchondral bone sclerosis while inhibiting degradation of cartilage.