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Inter-limb differences in Achilles tendon mechanical, material and morphological properties have previously been described in non-athletes and attributed to the preferential use of a given limb. Achilles tendon overuse tendon injury generally initiate unilaterally and alters triceps surae activation and Achilles tendon properties. The investigation of inter-limb differences in muscle activation and tendon properties may provide directions for injury prevention in habitual runners. In this study triceps surae and Achilles tendon properties were investigated bilaterally in habitual runners during unilateral maximal isometric contractions. Morphological, mechanical and material Achilles tendon properties were assessed using isokinetic dynamometry, motion capture and ultrasonography while triceps surae activation strategies were assessed using electromyography. Lower limb preference was assessed for inter-limb comparisons using the Waterloo questionnaire. Zero and one-dimensional statistical analysis and Cohen’s d were employed to investigate possible inter-limb differences. Inter-limb associations in Achilles tendon properties and intra-limb associations between triceps surae activations were assessed using Pearson’s correlation coefficients. No differences were observed between the preferred and non-preferred limb in terms of triceps surae muscle activation amplitude and Achilles tendon properties. However, intra-limb association among triceps surae activation ratios were not identical between limbs. Runners and triathletes present similar Achilles tendons properties between limbs, and thus initial observations of unilateral changes in the Achilles tendon properties might be used as a strategy to prevent the onset of overuse tendon injury. The non-similar associations within activation ratios between limbs should be further explored since triceps surae activation strategies may alter loading of the Achilles tendon.

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Background:Osteoarthritis (OA) is an age-related joint disease which provokes chronic pain and limits mobility. The disease progression is associated with inflammatory responses and cartilage degradation. Both chondrocytes, the only cell type present in cartilage, and macrophages from the synovium, play a major role in OA pathophysiology. Liraglutide is a Glucagon-Like Peptide-1 Receptor (GLP-1R) agonist widely prescribed for the treatment of type 2 diabetes. Interestingly, anti-inflammatory properties of the GLP-1 pathway have been reported in various diseases outside diabetes.Objectives:We evaluated the anti-inflammatory and anti-catabolic effects of Liraglutide in two in vitro models relevant to OA by evaluating surrogate markers of inflammation, cartilage matrix proteolysis and differentiation.Methods:Lipopolysaccharide (LPS)-stimulated murine Raw 264.7 macrophages were treated with 10 concentrations (6.6nM-3.4µM) of Liraglutide for 24h. Anti-inflammatory activity was evaluated by the production of nitric oxide (NO) and prostaglandin E2 (PGE2) using Griess reaction and ELISA, respectively. Interleukin 1β (IL-1β)-stimulated mouse articular chondrocytes were treated with Liraglutide (6.6nM-3.4µM) for 24h. Production of IL-6, matrix metalloproteinase-3 (MMP-3) and glycosaminoglycans (GAG) was measured by ELISA and GAG assay, respectively. RTqPCR analyses were performed with three selected concentrations of Liraglutide (13.3nM, 53.1nM and 1.7µM) on both cell types to assess the expression of a panel of genes related to inflammation (IL-6, TNF, iNOS), M1/M2 macrophage phenotype (MCP-1, CD38, ERG-2), catabolism (MMP-13, ADAMTS-5) and differentiation (Sox9, Col2a1, Acan).Results:Liraglutide induced a dose-dependent inhibition of the LPS-induced production of NO (IC50=45nM) and PGE2 (IC50=54nM) in macrophages. Moreover, IL-6 and TNF gene expressions were significantly and dose-dependently decreased in Raw 264.7 cells treated with Liraglutide compared to LPS alone. Interestingly, there was a significant dose-dependent reduction of MCP-1 and CD38 (M1 marker) gene expression in cells treated with the 3 doses of Liraglutide compared to LPS alone while we observed a dose-dependent increase of ERG-2 (M2 marker) gene expression induced by Liraglutide. Liraglutide significantly dose-dependently reduced the IL-1β-induced release of IL-6 (IC50=38nM), MMP-3 (IC50=56nM) and GAG (IC50=47nM) in chondrocytes. Additionally, Liraglutide treatment dose-dependently decreased the IL-1β-induced gene expression of iNOS, MMP-13 and ADAMTS-5. Finally, IL-1β decreased gene expression of Sox9, Col2a1 and Acan differentiation markers, which was rescued in a dose-dependent manner by Liraglutide (Table 1).Table 1.Gene expression results (fold change) in Raw 264.7 murine macrophages or mouse primary articular chondrocytesCell typeMarkersVehicleVehicleLiraglutide (nM)13.353.11700Macrophages- LPS+ LPSIL61.0±0.2*63.6±7.158.8±6.536.3±8.4*30.8±2.6*TNFα1.0±0.2*26.8±4.917.5±2.6*9.5±1.8*4.1±2.1*MCP11.1±0.6*91.7±11.267.8±4.3*47.3±6.1*25.1±5.5*CD381.1±0.6*103.5±22.373.2±12.3*44.6±8.9*17.4±3.3*ERG21.0±0.3*0.3±0.11.1±0.5*2.1±0.6*3.1±0.2*Chondrocytes- IL1β+ IL1βiNOS1.0±0.2*47.8±17.634.2±15.518.9±8.2*11.8±2.9*MMP131.0±0.2*9.8±2.07.6±1.04.6±0.7*2.5±0.4*ADAMTS51.2±0.82.7±0.62.0±0.61.6±0.31.1±0.2Sox91.0±0.1*0.4±0.20.4±0.20.6±0.00.7±0.2Col2a11.0±0.2*0.3±0.10.3±0.10.5±0.30.8±0.3*Acan1.2±0.8*0.2±0.10.1±0.00.5±0.1*0.7±0.2** pConclusion:A shift in M1/M2 macrophage phenotype and the inhibition of chondrocyte expression of several mediators involved in inflammation and cartilage degradation explain, at least in part, our previous results from rodent osteoarthritis models that showed an analgesic, anti-inflammatory and anti-degradative effect of Liraglutide. The fact that Liraglutide is already safely prescribed in another indication allows us to foresee a first trial in humans in the short term.Acknowledgements:All the people who contributed to the InOsteo project: the members of 4P-Pharma, INSERM UMRS_938 research team, SATT Lutech and Sorbonne UniversityDisclosure of Interests:Francis Berenbaum Consultant of: Boehringer, Bone Therapeutics, CellProthera, Expanscience, Galapagos, Gilead, GSK, Merck Sereno, MSD, Nordic, Novartis, Pfizer, Regulaxis, Roche, Sandoz, Sanofi, Servier, UCB, Peptinov, 4P Pharma, 4Moving Biotech, Grant/research support from: TRB Chemedica, Coralie Meurot Employee of: 4P-Pharma, Laure Sudre Employee of: 4P-Pharma, Keren Bismuth Employee of: 4P-Pharma, Revital Rattenbach Shareholder of: 4P-Pharma, Employee of: 4P-Pharma, Patrice Denefle Speakers bureau: 4P-Pharma, Consultant of: 4P-Pharma, Pierre Fabre, Mimetas, Employee of: 4P-Pharma, Celine Martin Employee of: 4P-Pharma, Claire Jacques: None declared

Alarmins (also known as danger signals) are endogenous molecules that are released to the extracellular milieu after infection or tissue damage. Extracellular alarmins interact with specific receptors expressed by cells that are engaged in host defence to stimulate signalling pathways that result in initiation of innate and adaptive immune responses, triggering inflammation or tissue repair. Alarmins are considered to be markers of destructive processes that occur in degenerative joint diseases (primarily osteoarthritis (OA)) and chronic inflammatory joint diseases (such as rheumatoid arthritis, psoriatic arthritis and spondylarthropathy). In OA, high mobility group protein B1 (HMGB1) and S100 proteins, along with many other alarmins, are abundantly secreted by joint cells, promoting cartilage matrix catabolism, osteophyte formation, angiogenesis and hypertrophic differentiation. The involvement of alarmins in chronic inflammatory arthritides is suggested by their presence in serum at high levels in these conditions, and their expression within inflamed synovia and synovial fluid. S100 proteins, HMGB1, IL-33 and other endogenous molecules have deleterious effects on joints, and can recruit immune cells such as dendritic cells to inflamed synovia, initiating the adaptive immune response and perpetuating disease. Improving our understanding of the pathological mechanisms associated with these danger signals is important to enable the targeting of new therapeutic approaches for arthritis.

Previous studies have been limited to describe asymmetries during pedalling and suggest possible repercussion on performance and/or injury risks. However, few studies have presented strategies to mitigate asymmetries. The purpose of this study was to assess the effectiveness of a pedalling retraining intervention to reduce bilateral pedal force asymmetries. Twenty cyclists were assessed and 10 enrolled in a pedalling retraining method receiving visual and verbal feedback of pedal forces. The asymmetry index was computed for comparison of bilateral peak pedal forces and used during retraining (12 trials at 70% of peak power). Significantly larger asymmetry was observed for asymmetrical cyclists at the first three trials (P 0.01 and ES = 1.39), which was reduced when post-retraining was compared to measures from symmetrical cyclists (P = 0.69 and ES = 0.18). Cyclists with larger asymmetry (20%) in bilateral pedal forces reduce their asymmetries using sessions of pedalling retraining and achieve asymmetry indices similar to symmetrical cyclists.

Background:Osteoarthritis (OA) is a degenerative joint disease affecting millions of individuals worldwide. Its development has been reported to be associated with cartilage degradation and inflammatory responses leading to pain, swelling and reduced function. Although OA is a disorder of the whole joint, the progressive destruction of cartilage extracellular matrix is considered as its hallmark. To date, approved OA treatments are only symptomatic. Therefore, there is an urgent need to explore disease-modifying OA drugs (DMOADs) that can mitigate, stop, or even reverse the development of OA.Objectives:In this context, the objective of this study was to assess the effect of liraglutide, a Glucagon-Like-Peptide 1 Receptor (GLP-1R) agonist approved for type 2 diabetes, on chondrogenesis, catabolism/inflammation and cartilage protection inin vitroandin vivopreclinical models of OA.Methods:The capacity of liraglutide to induce chondrogenesis was evaluated using primary human mesenchymal stem cells (hMSCs). Alcian blue staining was used to assess differentiation of hMSC into chondrocyte spheroids. IL-1β-stimulated mouse articular chondrocytes were treated with different concentrations of liraglutide for 24h. Production of matrix metalloproteinase MMP-13, prostaglandin E2 (PGE2) and nitrite was measured by ELISA and Griess reaction, respectively. Exendin 9-39, a GLP-1R antagonist, was used to confirm target engagement in thein vitroexperiments. Intra-articular (IA) injections of liraglutide or vehicle were performed in the type II collagenase rat model. Histopathological analyses (OARSI scores1) were conducted blindly by one investigator.Results:Liraglutide induced the differentiation of hMSCs into chondrocytes. Indeed, 21 days after differentiation initiation, 5/6 and 4/6 alcian-blue positive spheroids were observed for 10 and 100nM liraglutide, respectively, versus 0/6 for vehicle. Liraglutide significantly reduced dose-dependently the IL-1β-induced production of PGE2 (5808±178 for vehicle vs 4560±140, 2933±171 and 2365±85 pg/ml for liraglutide 10, 100 and 500nM, respectively, p≤0.001), nitrite (24.9±0.4 for vehicle vs 20.9±1.5, 19.1±0.9 and 16.5±0.5 µM for liraglutide 10, 100 and 500nM, respectively, p≤0.001) and MMP-13 (686±9 for vehicle vs 553±3, 402±5 and 297±8 pg/ml for liraglutide 10, 100 and 500nM, respectively, p≤0.001) in murine chondrocytes. Effects of liraglutide were GLP-1R dependent since exendin 9-39 significantly counteracted both chondrogenesis and inflammation/catabolism markers expression. Histological assessment of rat collagenase-injected knee joint revealed a significant (p≤0.05) decrease of the total joint score in the IA Liraglutide treated group (8±4) compared to vehicle (11±4).Conclusion:Liraglutide induced chondrogenesis, decreased metalloproteinase and inflammatory mediators production by chondrocytes and protected cartilage inin vitroandin vivopreclinical OA models, opening the way for repositioning this drug as a potential DMOAD.References:[1]Osteoarthritis Cartilage. 2010 Oct;18 Suppl 3:S24-34Acknowledgments:All the people who contributed to the InOsteo project: the members of 4P-Pharma, INSERM UMR S938 research team, SATT Lutech and Sorbonne UniversityDisclosure of Interests:Francis Berenbaum Grant/research support from: TRB Chemedica (through institution), MSD (through institution), Pfizer (through institution), Consultant of: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Bone Therapeutics, Regulaxis, Peptinov, 4P Pharma, Paid instructor for: Sandoz, Speakers bureau: Novartis, MSD, Pfizer, Lilly, UCB, Abbvie, Roche, Servier, Sanofi-Aventis, Flexion Therapeutics, Expanscience, GSK, Biogen, Nordic, Sandoz, Regeneron, Gilead, Sandoz, Coralie Meurot Employee of: 4P-Pharma, Jerome Breton Employee of: 4P-Pharma, Laure Sudre: None declared, Carole Bougault: None declared, Revital Rattenbach Shareholder of: 4P-Pharma, Employee of: 4P-Pharma, Celine Martin Employee of: 4P-Pharma, Claire Jacques: None declared

In a common compressive sensing (CS) formulation, limited Discrete Fourier Transform samples of a signal allow someone to reconstruct it by using an optimization procedure provided that certain well-known conditions hold. However, the frequencies in the Discrete Fourier Transform correspond to equally spaced samples of the continuous frequency domain, and the other possible frequency distributions are not usually considered in compressive sensing. This paper presents an irregular sampling of the normalized frequencies of the Discrete Fourier Transform which converges to an equidistributed sequence. This is done by taking the sequence of the fractional parts of the successive multiples of the golden number. That sequence was considered in applications in computer graphics and in magnetic resonance imaging [1], [2]. We also show that sub-matrices of the Discrete Fourier Transform with frequencies corresponding to fractional parts of multiples of the golden number produce signal-to-error ratios almost as high as the equally spaced counterpart. In addition, we show that the proposed irregular sampling converges faster to a uniform distribution in the range (0, 1). Thus, it reduces the discrepancy of pairwise distances of consecutive elements in the frequency sampling.

Context:Unassisted single-leg cycling should be replaced by assisted single-leg cycling, given that this last approach has potential to mimic joint kinetics and kinematics from double-leg cycling. However, there is need to test if assisting devices during pedaling effectively replicate joint forces and torque from double-leg cycling.Objectives:To compare double-leg, single-leg assisted, and unassisted cycling in terms of lower-limb kinetics and kinematics.Design:Cross-sectional crossover.Setting:Laboratory.Participants:14 healthy nonathletes.Interventions:Two double-leg cycling trials (240 ± 23 W) and 2 single-leg trials (120 ± 11 W) at 90 rpm were performed for 2 min using a bicycle attached to a cycle trainer. Measurements of pedal force and joint kinematics of participants’ right lower limb were performed during double- and single-leg trials. For the single-leg assisted trial, a custom-made adaptor was used to attach 10 kg of weight to the contralateral crank.Main Outcome Measures:Peak hip, knee, and ankle torques (flexors and extensors) along with knee-flexion angle and peak patellofemoral compressive force.Results:Reduced peak hip-extensor torque (10%) and increased peak knee-flexor torque (157%) were observed at the single-leg assisted cycling compared with the double-leg cycling. No differences were found for peak patellofemoral compressive force or knee-flexion angle comparing double-leg with single-leg assisted cycling. However, single-leg unassisted cycling resulted in larger peak patellofemoral compressive force (28%) and lower knee-flexion angle (3%) than double-leg cycling.Conclusions:These results suggest that although single-leg assisted cycling differs for joint torques, it replicates knee loads from double-leg cycling.

Peer review of research articles is a core part of our scholarly communication system. In spite of its importance, the status and purpose of peer review is often contested. What is its role in our modern digital research and communications infrastructure? Does it perform to the high standards with which it is generally regarded? Studies of peer review have shown that it is prone to bias and abuse in numerous dimensions, frequently unreliable, and can fail to detect even fraudulent research. With the advent of Web technologies, we are now witnessing a phase of innovation and experimentation in our approaches to peer review. These developments prompted us to examine emerging models of peer review from a range of disciplines and venues, and to ask how they might address some of the issues with our current systems of peer review. We examine the functionality of a range of social Web platforms, and compare these with the traits underlying a viable peer review system: quality control, quantified performance metrics as engagement incentives, and certification and reputation. Ideally, any new systems will demonstrate that they out-perform current models while avoiding as many of the biases of existing systems as possible. We conclude that there is considerable scope for new peer review initiatives to be developed, each with their own potential issues and advantages. We also propose a novel hybrid platform model that, at least partially, resolves many of the technical and social issues associated with peer review, and can potentially disrupt the entire scholarly communication system. Success for any such development relies on reaching a critical threshold of research community engagement with both the process and the platform, and therefore cannot be achieved without a significant change of incentives in research environments.

BACKGROUND: Non-specific adaptation from training can elicit similar muscle volume and muscle activation between cyclists and triathletes which differ in comparison to non-athletes. OBJECTIVE: To compare muscle volume, muscle activation and pedal forces of cyclists, triathletes and non-athletes. METHODS: Twelve cyclists, ten triathletes and twelve non-athletes performed an incremental test to determine their maximal power output (POMAX). Quadriceps and triceps surae volume were estimated from ultrasound images taken at rest, while pedal forces and muscle activation were recorded at POMAX at 90 rpm. RESULTS: Quadriceps volume was larger in cyclists (∼22%, p < 0.04) and triathletes (∼40%, p < 0.01) compared to nonathletes. Higher activation of rectus femoris (∼55%, p = 0.01) and tibialis anterior (∼88%, p = 0.01) were observed for triathletes compared to non-athletes at the first quarter of the pedaling cycle. Triathletes also showed higher activation for tibialis anterior than cyclists (∼68%, p = 0.03) at the first quarter. Non-athletes applied greater force on the pedal compared to triathletes at the first quarter (∼42%, p < 0.01). Pedal force effectiveness was higher for athletes (37–44%, p < 0.02) compared to nonathletes at the fourth quarter. CONCLUSIONS: Similar muscle volume and muscle activation between cyclists and triathletes may be related to a similar training volume supporting differences relative to non-athletes.

The paper analyzes the performance of a hospital system using a holistic and multidisciplinary approach. Data on impacts to the hospital system were collected using a standardized survey tool. A fault-tree analysis method is adopted to assess the functionality of critical hospital services based on three main contributing factors: staff, structure, and stuff. Damage to utility networks and to nonstructural components was found to have the most significant effect on hospital functionality. The functional curve is integrated over time to estimate the resilience of the regional acute-care hospital with and without the redistribution of its major services. The ability of the hospital network to offer redundancies in services after the earthquake increased the resilience of the Christchurch Hospital by 12%. The resilience method can be used to assess future performance of hospitals, and to quantify the effectiveness of seismic retrofits, hospital safety legislation, and new seismic preparedness strategies.

To evaluate the relationship of plasma endothelin-1 (ET-1) levels, a marker of endothelial dysfunction, and urinary albumin excretion in patients with type 2 diabetes mellitus (DM).Cross-sectional study was conducted in 279 patients (132 males, mean age: 58.7+/-11.0 years, mean DM duration: 11.3+/-8.1 years). Urinary albumin excretion, ET-1, and insulin were measured. Insulin sensitivity was estimated by homeostasis model assessment (HOMA-ir) index.ET-1 was associated with urinary albumin excretion after controlling for age, gender, body mass index, blood pressure, HbA1c test, and total cholesterol (R=0.436; adjusted R(2)=0.190, P0.01). Furthermore, there was a progressive increase in plasma ET-1 levels from patients with normoalbuminuria (n=187, 0.92+/-0.50pg/ml), microalbuminuria (n=68, 1.13+/-0.52pg/ml) to macroalbuminuria (n=24, 1.93+/-1.10pg/ml, P0.01).There is an independent association of plasma ET-1 levels with urinary albumin excretion. In addition, plasma ET-1 levels started to increase in the normal values of urinary albumin excretion suggesting that in patients with type 2 DM endothelial dysfunction is already present, in urinary albumin excretion values considered normal.

The safety of building occupants during and immediately after disasters, such as a major earthquake, is highly dependent on the way in which people interact with the damaged physical environment. While there are extensive studies on evacuation from undamaged structures and on structural behavior under seismic and other hazards, research on the influence of building damage on human evacuation behavior is limited. This study presents a framework by which models for buildings and human behavior can be coupled to analyze the dynamic influences of building damage on the evacuation process. The framework combines nonlinear dynamic finite-element modeling of structures, probabilistic modeling of damage, and agent-based modeling of human occupants to investigate the behavior of people as they interact with each other and with their dynamically-deteriorating environment as they attempt to evacuate the building. A case study is presented for a typical three-story commercial office building subjected to the ground motions of the 1994 Northridge, California earthquake. By using exit flow rates and other measures related to evacuation time histories as the outcomes of interest, it is shown how the proposed framework can be used as a tool to enhance building design and to develop recommendations for improved evacuation strategies. An important future extension of the work is expanding the framework for multiple buildings for community-wide models of postdisaster behavior.

To use single-leg cycling training for varying populations, it is important to understand whether a counterweight attached to the contralateral crank during single-leg cycling drills replicates the effects of the opposite leg in the ipsilateral leg. Therefore, we compared single-leg assisted cycling using a counterweight on the contralateral crank for joint kinetics, kinematics, and lower-limb muscle activation. Fourteen healthy nonathletes performed 2 bilateral cycling trials (240 ± 23 W and 90 ± 2 rpm) and 2 single-leg trials (120 ± 11 W and 90 ± 2 rpm) for measurements of pedal force, joint kinematics, and muscle activation of their right lower limb. For 1 single-leg trial, a custom-made adaptor was used to attach 10 kg of weight to the contralateral leg. Total force applied on the pedal, pedal force effectiveness, the mean joint angles and range of motion, mechanical work at the crank, hip, knee, and ankle joints, electromyography, pedaling cadence, and right crank mechanical work were assessed. Biceps femoris (87%), vastus lateralis (15%), rectus femoris (57%), tibialis anterior (57%), and gastrocnemius medialis (12%) activations were larger in the single-leg assisted trial compared with the bilateral trial. Lower total pedal force (17%) and increased index of effectiveness (16%) also indicate mechanical differences in single-leg cycling using a counterweight on the contralateral crank than conventional bilateral cycling. Single-leg assisted training should be used with caution because of potential differences in muscle recruitment and pedaling kinetics compared with bilateral cycling.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used drugs for the treatment of inflammatory disease and have a chemopreventive effect in a variety of tumors. Several studies have demonstrated unequivocally that certain NSAIDs cause antiproliferative effects independent of cyclooxygenase (COX) activity. In this study, we investigated the effect of chemically unrelated NSAIDs in the proliferation of glioma cell lines and the possible mechanisms involved in indomethacin-mediated inhibition of proliferation in glioma cells lines. The glioma cell lines were treated with NSAIDs and proliferation was measured by cell counting. Indomethacin, acetaminophen, sulindac sulfide and NS-398 (N-[2-cyclohexyloxy)-4-nitrophenyl]methane-sulfonamide) induced a time- and concentration-dependent inhibition of C6 rat glioma cell proliferation. The inhibition of COX by chemically unrelated NSAIDs leads to inhibition of rat and human glioma cell proliferation. The tetrazolium reduction assay (MTT) indicated a reduction in cell viability induced by indomethacin. None of the NSAIDs tested induced caspase-3/7 activation, assayed with a fluorigenic substrate. The indomethacin-induced inhibition of C6 cells proliferation was abrogated by the use of the c-Src inhibitor, PP2 and the MEK inhibitor, PD 098059, suggesting COX-independent mechanisms. Indomethacin decreased the percentage of cells in the S phase, with relative increases in the G0/G1 and/or the G2/M phase. NSAIDs may be clinically important for pharmacological intervention in gliomas.

Neurofibromatosis type 1 (NF1) is the most common of all the phakomatoses. It is an autosomal dominant disorder, with about 50% of patients being new mutations. NF1 is diagnosed based on the presence of well established diagnostic criteria. Prominent cutaneous manifestations include cafe-au-lait spots, freckling and cutaneous neurofibromas. CNS lesions are frequent and imaging is valuable for diagnosis, treatment and follow-up of patients. Tumors of the central nervous system are frequent. Optic nerve glioma usually affects younger patients with clinical symptoms in one third of cases. MRI shows fusiform enlargement with variable enhancement of the optic nerve. These tumors are usually non-aggressive with good prognosis. Other gliomas and astrocytomas can occur as well, usually midline in location, that also generally have good prognosis. Non-tumoral white matter lesions, referred as unidentified bright objects or UBO's, are frequently observed, typically in the basal ganglia and posterior fossa structures. These lesions are usually seen during childhood and they typically diminish with age. The distinction between UBO's and other tumors may be difficult to achieve at imaging, and a malignant evolution may very rarely be observed. Patients with NF1 may have hydrocephalus and dural sac anomalies leading to meningocele formation. Neurofibromas and plexiform neurofibromas involve peripheral nerves and nerve sheaths. Plexiform neurofibromas may cause radicular symptoms. They more frequently involve the lumbosacral plexus. Neurofibromas are homogeneous oval shaped tumors that may extend into the spinal canal. Neurofibrosarcoma is the main cause of death of NF1 patients less than 40 years of age. It may develop de novo or from sarcomatous degeneration of a pre-existing plexiform neurofibroma. It should be suspected in patients with new onset of symptoms or patients with changing symptoms. At imaging, it is characterized by a large heterogeneous tumor invading adjacent structures. Osseous lesions have been described including progressive thoracic scoliosis, vertebral anomalies (posterior scalloping is very suggestive), long bones anomalies with frequent bowing of the tibia, sometimes resulting in pseudarthrosis, and rib anomalies with ribbon ribs. Vascular lesions may occur resulting in arterial hypertension and aneurysm formation.

Neuroimaging, particularly MR imaging, plays a major role for the diagnosis of many acute toxic encephalopathies. Toxic disorders are related to drugs (immunosuppressive agents, chemotherapeutic agents, anti-epileptic drugs, heroin...), to metals (lead, manganese, mercury...), and to industrial and environmental chemicals (solvent, carbon monoxide...). MR imaging with diffusion and perfusion imaging provides information regarding brain lesions induced by the toxic agents (vasogenic edema, cytotoxic edema, infarction, hemorrhage, demyelination...).

2009 H1N1 pandemic influenza (A(H1N1)pdm09) virus infected large numbers of people worldwide. Recent studies suggest infection with A(H1N1)pdm09 virus elicited cross-reactive anti-hemagglutinin (HA) memory B cell response to conserved regions of HA. However, the breadth and magnitude of cross-reactive immunity in children and adults following A(H1N1)pdm09 infection are unknown. Methods: We investigated serum anti-HA immunity to a number of group-1 and -2 viruses in children and adults using hemagglutination inhibition (HAI), enzyme-linked immunosorbent assay and virus neutralization assay. Results: Applying hemagglutination inhibition (HAI) titres?40 against A(H1N1)pdm09 as threshold of sero-positivity, we observed significantly higher levels of anti-HA antibodies to a number of virus subtypes, including those neutralizing H5N1, in subjects with HAI titre?40 than those with HAI

We report on 2 cases of kerions in children: one of them was located on the pubis, an exceptional location; the second one was located on the scalp and presented like multiple abscess of the scalp, for which surgical drainage was performed. In both cases, Trichophyton mentagrophytes was involved. This dermatophyte is zoophilic, contrary to the dermatophytes usually involved in tinea capitis, which could explain the poor adaptation of the dermatophyte to the human host, who would therefore react by generating a severe inflammatory reaction. Antifungal drugs are recommended for the treatment of kerions, especially griseofuline for 6 to 8 weeks. The value of oral steroids and surgery continues to be debated.

The skin is a metabolically active organ expressing biotransformation enzymes able to metabolize both endogenous molecules and xenobiotics. We investigated the impact of metabolism on the delivery of testosterone through the skin with an ex vivo pig ear skin system as an alternative model for human skin. Penetration, absorption and metabolic capabilities were investigated up to 72 h after application of [14C]-testosterone doses of 50-800 nmol on either fresh or frozen skin, with the latter model being metabolically inactive. Testosterone absorption and metabolite production were monitored by radio-HPLC and gas chromatography-mass spectrometry. Testosterone absorption through frozen skin was much lower, irrespective of the dose of testosterone applied, compared to fresh skin. Using fresh skin samples, >95% of the radioactivity recovered in culture media, as well as the skin itself, corresponded to metabolites. These results were compared with the metabolic data obtained from other in vitro systems (liver and skin microsomes). The present work leads to the conclusion that most of the enzymatic activities expressed in liver fractions are also expressed in pig and human skin. The metabolic activity of the skin can modulate the biological activity of pharmaceuticals (and xenobiotics). Consequently, it can also greatly affect transdermal drug delivery.

This paper presents a standardized methodology to analyze the impact of disasters on the functionality of healthcare systems post-disaster. The methodology to collect loss-of-function data was developed in 2010 and tested after the Bio-Bio, Baja California, and Christchurch earthquakes of 2010 and 2011. The survey tool collects field data on the performance of critical building systems and infrastructure, assesses the impact of system and infrastructure failure on the ability of hospitals to keep functioning, and provides data that can enhance existing and future tools to assess the performance of healthcare facilities. These survey tools can be used by other reconnaissance teams to collect data from both the healthcare and engineering perspectives, as well as an event tree which links the two perspectives together. This multi-disciplinary approach, involving engineers, epidemiologists, and health and emergency managers, is necessary to properly analyze how structural and non-structural damage disrupts essential services provided by hospitals.

Purpose IL-8 and its murine equivalent keratinocyte chemoattractant (Kc), chemokines produced by chondrocytes, contribute to the pathophysiology of osteoarthritis. However, the mechanisms leading to their production are poorly known. We aimed to investigate whether mechanical (compression), inflammatory (IL-1β) and metabolic (visfatin) stresses may induce the release of Kc when applied on murine cartilage. Methods Mouse cartilage explants were subjected to intermittent compression for 4, 6 and 24 h. Primary cultures of immature murine articular chondrocytes were obtained by enzymatic digestion of articular cartilage from 6-days-old newborns mice. The effect of compression, IL-1β (10, 50, 100 pg/mL) and of visfatin (5 μg/mL) on the release of Kc was assessed by ELISA. IL-8 levels in conditioned media from human OA joint tissues (cartilage or synovium) were also assessed. Results In comparison with non-compressed explants, loading increased Kc release of 3.2-, 1.9- and 2.0-fold at 4, 6 and 24 h respectively ( P n = 9). IL-1β triggered an increase of Kc release by primary cultured chondrocytes of 4.1-, 15.5- and 35.2-fold at 10, 50 and 100 pg/mL of IL-1β respectively ( P n = 4). Likewise, visfatin (5 μg/mL) induced an increase in Kc release of 56.5 ± 25.2 fold ( P = 0.002, n = 6). IL-8 was released in conditioned media by synovium as well as by cartilage. Conclusion We show for the first time that IL-8/Kc is highly responsive to mechanical, inflammatory and metabolic stresses, strengthening the hypothesis that IL-8/Kc could be added to the cytokines which may have a deleterious impact in osteoarthritis.

Joint Bone Spine - In Press.Proof corrected by the author Available online since jeudi 16 fevrier 2012

The influence of optical pumping and detection rates on the cesium beam frequency standard is evaluated. It is shown that pumping and detection parameters have a large impact on cavity-phase-dependent and second-order Doppler effect frequency shifts. A supplementary parameter is needed in order to evaluate the error budget of the optical operated clock. Variations in the pumping conditions, such as laser intensity, should be avoided since they will be converted into frequency fluctuations. >

This study addresses development and validation of a composite multifactorial pain scale (CPS) in an experimental equine model of acute orthopaedic pain. Eighteen horses were allocated to control (sedation with/without epidural analgesia - mixture of morphine, ropivacaine, detomidine and ketamine) and experimental groups: amphotericin-B injection in the tarsocrural joint induced pain and analgesia was either i.v. phenylbutazone administered post-induction of synovitis, or pre-emptive epidural mixture, or a pre-emptive combination of the 2. Inter- and intra-observer reproducibility was good (0.8

The development of rate equations with coherence in which the effects of laser spectrum wings and linewidth are included is discussed. The optical pumping efficiencies are evaluated in the cesium ground state hyperfine levels when two lasers pumping schemes are used under different conditions of polarization, tuning, laser linewidth, and power densities. It is also found that the effect of coherence is important when one laser is sigma polarized in the two-laser optical pumping schemes. Thus it is preferable to avoid sigma polarization in order to have a better optical pumping efficiency. >

An outline is given of a method and a tool developed to ensure permanent software quality evaluation and to create an experience database for future quality assurance tasks. The authors mainly focus on the benefits of using such a tool and its evolution in an industrial environment for global quality assurance of multisite large-scale software projects. >

Based on the Geneva clinical practice to prevent and treat delirium, a review of the Swiss literature on this topic allows us to stress the key points concerning this frequent geriatric syndrome. Emergency admissions, post surgery periods as well as nursing home admissions are key risk events precipitating the onset of delirious episodes. A careful screening and the use of validated diagnostic tools allow reducing both the incidence of delirium as well as the nursing team workload. Swiss non-pharmacologic as well as pharmacologic approaches are carefully described.

A 33-year-old patient with cranial epidural tuberculoma without history of tuberculosis is described. CT and MR imaging showed a lesion located on both sides of a right frontotemporal bone destruction with epidural extent. Except for a small necrotic core, the lesion enhanced intensely after contrast medium administration. Osteitis and subgaleal abscess were associated. The displaced dura mater delineated the epidural tuberculoma. Diagnosis was verified by histology and identification of Mycobacterium tuberculosis. After removal of the tuberculoma and combination therapy, there was a complete regression of abnormalities. Differential diagnoses are dural tuberculoma, focal tuberculous pachymeningitis and tuberculous epidural empyema.

Background Osteoarthritis (OA) is characterized by joint degeneration, leading to a progressive loss of articular cartilage in response to mechanical and biochemical factors. However, OA is a complex disease not limited to cartilage degeneration. Indeed, several experiments suggest that subchondral bone remodeling could initiate and/or contribute to cartilage loss in OA through a bone/cartilage interplay. Objectives We aimed to identify soluble mediators released by loaded osteoblasts/osteocytes that could induce the release of pro-catabolic factors by chondrocytes by using a novel and unique bone/cartilage communication model. Methods Murine experiments: Thanks to a three dimensional culture model, murine osteoblasts were submitted to compression in Biopress Flexercell plates. Conditioned media from compressed (CM) or uncompressed (UCM) osteoblasts were used to stimulate mouse articular chondrocytes. Then, soluble mediators released by compressed osteoblasts were identified by iTRAQ®, a differential secretomic analysis approach. Chondrocyte expression of metalloproteinases MMP-3, MMP-13 and cartilage extracellular matrix components type II collagen and aggrecan were assessed by RT-PCR, western blot analysis and ELISA. Immunodepletion and blocking antibody experiments were realized using mouse compressed conditioned media. Human experiments: OA tissue was obtained from patients undergoing total knee replacement. Subchondral bone and cartilage from tibial plateaus and femoral condyles were isolated, cut into small pieces, washed and incubated in culture medium. Conditioned media were then used to stimulate human articular chondrocytes. Results Media from compressed osteoblast (CM) strongly induced MMP-3 and -13 chondrocyte mRNA expression. Consistently, CM osteoblasts-derived media also significantly stimulated the releases of MMP-3 and -13 by chondrocytes. CM osteoblasts-derived media also affected cartilage matrix proteins expressions by downregulating type II collagen mRNA. So, the ability of soluble mediators released by loaded osteoblasts to induce a chondrocyte pro-catabolic phenotype was demonstrated. In order to identify osteoblast-derived soluble mediators responsible for this chondrocyte phenotype, osteoblast-derived conditioned media were analyzed by iTRAQ®. This sophisticated proteomic technique allowed identification of 105 proteins secreted by osteoblasts among which only 10% were upregulated in response to compression. Among them, secreted 14-3-3e (s14-3-3 e) dose-dependently induced the release of pro-catabolic factors (MMP-3, MMP-13) by mouse chondrocytes. s14-3-3e dramatically mimicked the effects of CM osteoblasts-derived media. MMP-3 and MMP-13 chondrocyte expressions were strongly inhibited by a s14-3-3 blocking antibody or by immunodepleting s14-3-3 when added into the CM osteoblasts-derived media. Furthermore, s14-3-3e was strongly released by human OA subchondral bone and paralleled with the increase of MMP-3 expression in these human samples. MMP-3 expression was dose-dependently stimulated by recombinant s14-3-3e in human OA chondrocytes. Conclusions We have identified s14-3-3e as a novel soluble mediator, critical in the communication between subchondral bone and cartilage, that opens new perspectives in the fields of biomarkers and therapeutical targets in osteoarthritis. Disclosure of Interest None Declared

Background Visfatin exerts a nicotinamide phosphoribosyltransferase (NAMPT) enzymatic activity, which is the rate-limiting stage in the salvage pathway of nicotinamide adenine dinucleotide (NAD) biosynthesis. NAD is involved in many biological processes including redox reactions, sirtuins activity and TNFαsynthesis (1). We have previously demonstrated the induction of prostaglandin E 2 release by visfatin-stimulated chondrocytes (2). Objectives i) Analyze the production and the enzymatic active conformation of visfatin/Nampt in human joint with osteoarthritis (OA), ii) Investigate its pro-inflammatory role on chondrocytes and osteoblasts, iii) Determine the involvement of the Nampt activity in the activation of those two cell types. Methods Human OA joint tissues (synovium, cartilage, subchondral bone) from patients undergoing total knee arthroplasty were frozen or incubated 24h in serum-free media. Visfatin/NAMPT conformation in OA synovial fluids, tissue media and extracts was evaluated by Immunoblot (IB). NAMPT/visfatin concentration in tissue media was measured by ELISA. NAMPT activity was assessed in OA synovium extracts using Cyclex colorimetric assay. Primary cultures of murine chondrocytes and osteoblasts were stimulated for 24h with recombinant visfatin/NAMPT (5 µg/mL) with or without APO866 (10nM), a pharmacologic inhibitor of NAMPT activity. mRNA and protein expression of IL-6, IL-8/Kc, MCP-1, VEGF TGFβ, Ihh, Runx2 and type X collagen was examined by qRT-PCR and ELISA. Results Human OA synovium, cartilage and subchondral bone all released visfatin/NAMPT (628±106, 152±46, 195±26 ng/g tissue, respectively) with significantly higher level for the synovium (p Image/graph Conclusions Visfatin/NAMPT is released by all OA tissues under a dimeric enzymatically active conformation and mostly by the synovium which displays a detectable NAMPT activity. The NAMPT activity of visfatin is involved in chondrocytes and osteoblasts activation. Thus, targeting its enzymatic activity with a compound like APO866 (being currently tested in hematological malignancies) may be a new therapeutic approach of OA. References Wang et al., Nature Structural & Molecular Biology, 2006; Gosset et al., Arthritis & Rheumatism, 2008 Acknowledgements Grant from the French Society of Rheumatology (SFR) Disclosure of Interest None Declared

Purpose: Skeletogenesis and bone fracture healing involve endochondral ossification, a process during which cartilaginous primordia are gradually replaced by bone tissue. In line with a role for cyclooxygenase-2 (COX-2) in the endochondral ossification process, non-steroidal anti-inflammatory drugs (NSAIDs) were reported to negatively affect bone fracture healing due to impaired osteogenesis. However, a role for COX-2 activity in the chondrogenic phase of endochondral ossification has not been addressed before. Methods: The role of COX-2 was studied during chondrogenic differentiation of ATDC5 cells and rabbit periosteal explants. BMP-2 was used to increase hypertrophic differentiation and the NSAIDs NS398 and Celecoxib were applied to specifically inhibit COX-2 activity. Chondrogenic outcome was measured by gene- and protein expression analysis, and (immuno) histochemical stainings. For in vivo evidence skeletally immature NZW rabbits were treated with Celecoxib (10mg/kg) for 21 days. Growth plate development was analyzed by histochemistry. Results: Our data reveal essential cross-talk between COX-2 and BMP-2 during chondrocyte hypertrophic differentiation. BMP-2 mediated chondrocyte hypertrophy is associated with increased COX-2 expression and pharmacological inhibition of COX-2 activity decreased BMP-2 induced hypertrophic differentiation in independent chondrogenic models in vitro and ex vivo, while leaving chondrogenesis unaltered. Importantly, systemic inhibition of COX-2 activity in vivo resulted in significantly decreased growth plate thickness, which could be attributed to impaired chondrocyte hypertrophic differentiation. Conclusions: Our findings demonstrate that COX-2 is an important executing factor of BMP-2-induced chondrocyte hypertrophy in the context of endochondral ossification. These observations provide a novel etiological perspective on the adverse effects of NSAIDs on bone fracture healing and have important implications for the use of NSAIDs during endochondral skeletal development. In addition, our data provides a novel strategy to improve the outcome of cartilage regenerative medicine by decreasing the level of unwanted chondrocyte hypertrophy and ossification.

Two-laser optical pumping schemes show great promise for atom preparation since they can act as a nearly perfect state selector. This paper presents a new theoretical model to evaluate the pumping efficiency of two-laser pumping schemes, taking into account optical, ground and excited states hyperfine and Zeeman coherences, neighboring transitions, and fluctuating laser fields. The model is used to predict the optical pumping efficiency of two lasers with Lorentzian spectral profiles on a beam of cesium atoms. The particular laser intensities and linewidths that optimize the optical pumping efficiency and rate are calculated.

Increased levels of the chitinase 3-like protein human cartilage glycoprotein 39 (HC-gp39) have been demonstrated in synovial fluids of patients with rheumatoid or osteoarthritis. Recently, this protein has emerged as a potential growth factor for synovial cells and chondrocytes, but little is known about its role in differentiation. The transcription factor SOX-9 has been demonstrated to be a master regulator of the differentiation of mesenchymal cells into chondrocytes.

Forty-eight new uv lines have been observed and identified in the singly and doubly excited systems of C IV, and in C V. The beam-foil technique was used to excite the spectra and to measure radiative lifetimes for 16 levels. Good agreement is found with available theoretical predictions.

Since there are divergencies in the thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) in old age, and since a hypothalamopituitary dysfunction has been suggested in the elderly, we have studied the thyroid function and the TRH responsiveness of TSH and prolactin (PRL) in 56 euthyroid patients over 70 years old, grouped according to age (70-79, 80-89, 90 or more years) and sex. Results were compared to those of 15 postmenopausal women and 11 men. In the elderly patients there was a decrease in plasma tri-iodothyronine (T3) and an increase in reverse T3 (rT3) levels while thyroxine (T4), basal TSH and PRL levels remained normal. The mean TSH and PRL responses to TRH (250 micrograms i.v.) were reduced but there was no age effect within the elderly. Only a sex effect was detected, TSH and PRL responses being appreciably lowered in men. In eight patients without severe disease or malnutrition, the response of TSH was not significant. We conclude that despite an apparent euthyroid status, TSH and PRL responses are blunted in elderly patients, and more in men than in women. These data, consistent with a hypothetical hypothalamopituitary dysfunction, indicate the difficulties of thyroid status assessment in the elderly.

Behaviour of exogenous heparin was studied in 35 subjects after intravenous injection of 50 u/kg heparin : 10 healthy control adults, 8 control children with normal hemostatic system, 17 children with nephrotic syndrome without renal insufficiency. Blood samples were collected before injection and 15 min, 30 min, 60 min and 120 min later, for the following tests : APTT, thrombin time, automatised heparin assay using a chromogenic substrate (S-2238). Heparin behaviour was assessed by two criteria : recovery (plasma heparin level) 15 min after the injection ; halflife of recovered heparin. Results were compared with the following parameters : WBC and platelet count ; serum albumin and lipids ; plasma antithrombin III, α2 macroglobulin and fibrinogen ; histological findings when availableIn nephrotic children, mean heparin recovery was lower than in the control groups, very poor or even negligible in 9/17 cases. Heparin halflife was close to 37 min in most patients, shorter than in healthy controls (mean : 46 min), and dramatically decreased in 4 cases.No significant correlation was observed between the observed heparin behaviour and the considered parameters ; sensitivity to heparin was notably unrelated to plasma antithrombin III level. Insensitivity was observed in three patients with amyloidosis.