Measures of knee and gait function and radiographic severity of knee osteoarthritis - A cross-sectional study.

BACKGROUND: Pain reports show at most weak to moderate relationship with structural findings of knee osteoarthritis (OA). Less is known about the relationship between measures of knee and gait function and structural findings of knee OA. RESEARCH QUESTION: To test the hypothesis that patient-reported, performance-based and three-dimensional knee and gait measures can distinguish between individuals with varying degrees of radiographic knee OA severity. METHODS: To increase the spectrum of radiographic severity baseline data of individuals included in a cohort study and in a randomized controlled trial respectively were included in this cross-sectional study. Individuals completed the Knee injury and Osteoarthritis Outcome Score (KOOS), Single Limb Mini Squat (SLMS) test, and three-dimensional gait analysis. Radiographic severity was dichotomized into mild (Kellgren Lawrence (KL) 1-2) or severe (KL 3-4) knee OA. Proxies for medial knee joint loading were peak knee adduction moment (KAM) and KAM impulse, and summary measures of overall gait function were the Gait Deviation Index for kinematics (GDI) and kinetics (GDI-kinetic). Area under the receiver operating characteristic curves (AUC) and logistic regressions were used to evaluate whether KOOS-scores, SLMS test, peak KAM, KAM impulse, and GDI-scores could discriminate radiographic severity of knee OA. RESULTS: The sample (n = 115) consisted of 60% women, mean age 61 years (SD 8). Good discriminating abilities (AUC > 0.7) were demonstrated for all measures of knee function and gait, except for GDI and GDI-kinetic (0.62 and 0.36, respectively). Odds ratios from logistic regressions largely supported the AUC findings. SIGNIFICANCE: With the exception of gait summary measures, discriminating abilities were demonstrated by all measures of knee and gait function. Given the interest in interpreting OA as a multi-factorial disease, this information may assist researchers in selecting the most appropriate outcomes for biomechanical studies.

IL-10 signaling prevents gluten-dependent intraepithelial CD4+ cytotoxic T lymphocyte infiltration and epithelial damage in the small intestine.

Breach of tolerance to gluten leads to the chronic small intestinal enteropathy celiac disease. A key event in celiac disease development is gluten-dependent infiltration of activated cytotoxic intraepithelial lymphocytes (IELs), which cytolyze epithelial cells causing crypt hyperplasia and villous atrophy. The mechanisms leading to gluten-dependent small intestinal IEL infiltration and activation remain elusive. We have demonstrated that under homeostatic conditions in mice, gluten drives the differentiation of anti-inflammatory T cells producing large amounts of the immunosuppressive cytokine interleukin-10 (IL-10). Here we addressed whether this dominant IL-10 axis prevents gluten-dependent infiltration of activated cytotoxic IEL and subsequent small intestinal enteropathy. We demonstrate that IL-10 regulation prevents gluten-induced cytotoxic inflammatory IEL infiltration. In particular, IL-10 suppresses gluten-induced accumulation of a specialized population of cytotoxic CD4+CD8αα+ IEL (CD4+ CTL) expressing Tbx21, Ifng, and Il21, and a disparate non-cytolytic CD4+CD8α- IEL population expressing Il17a, Il21, and Il10. Concomitantly, IL-10 suppresses gluten-dependent small intestinal epithelial hyperproliferation and upregulation of stress-induced molecules on epithelial cells. Remarkably, frequencies of granzyme B+CD4+CD8α+ IEL are increased in pediatric celiac disease patient biopsies. These findings demonstrate that IL-10 is pivotal to prevent gluten-induced small intestinal inflammation and epithelial damage, and imply that CD4+ CTL are potential new players into these processes.

Deformation twinning and grain partitioning in a hexagonal close-packed magnesium alloy.

Pervasive deformation twinning in magnesium greatly affects its strength and formability. The local stress fields associated with twinning play a key role on deformation behavior and fracture but are extremely difficult to characterize experimentally. In this study, we perform synchrotron experiments with differential-aperture X-ray microscopy to measure the 3D stress fields in the vicinity of a twin with a spatial resolution of 0.5 micrometer. The measured local stress field aids to identify the sequence of events involved with twinning. We find that the selected grain deforms elastically before twinning, and the twin formation splits the grain into two non-interacting domains. Under further straining one domain of the grain continued to deform elastically, whereas the other domain deforms plastically by prismatic slip. This heterogeneous deformation behavior may be mediated by the surrounding medium and it is likely to lead to asymmetric twin growth.

One year effectiveness of neuromuscular exercise compared with instruction in analgesic use on knee function in patients with early knee osteoarthritis: the EXERPHARMA randomized trial.

OBJECTIVE: To test long-term effectiveness of neuromuscular exercise (NEMEX) with instructions in optimized pharmacological treatment (PHARMA) on activities of daily living (ADL) in patients with early knee osteoarthritis. DESIGN: 12-months follow-up from a randomized controlled trial. Participants with mild-to-moderate medial tibiofemoral knee osteoarthritis were randomly allocated to 8 weeks NEMEX or PHARMA. The primary outcome measure was the ADL-subscale of the Knee Injury and Osteoarthritis Outcome Score (KOOS). Secondary outcome measures included the other four KOOS-subscales, the University of California Activity Score (UCLA) and the European Quality of Life-5 Dimensions. RESULTS: Ninety-three patients (57% women, 58 ± 8 years, body mass index 27 ± 4 kg/m2) were randomized to NEMEX (n = 47) or PHARMA group (n = 46) with data from 85% being available at 12-months follow-up. Good compliance was achieved for 49% of the participants in NEMEX (≥12 sessions) and 7% in PHARMA (half the daily dose of acetaminophen/NSAIDs ≥ 28 days). Within-group improvements in NEMEX were considered to be clinically relevant (≥10 points) for all KOOS-subscales, except Sport/Rec whereas, no between-groups difference in the primary outcome KOOS ADL (3.6 [-2.1 to 9.2]; P = 0.216) was observed. For KOOS Symptoms, a statistically significant difference of 7.6 points (2.6-12.7; P = 0.004) was observed in favor of NEMEX with 47% improving ≥10 points. CONCLUSIONS: No difference in improvement in difficulty with ADL was observed. NEMEX improved knee symptoms to a greater extent with half of patients reporting clinically relevant improvements. CLINICALTRIALS. GOV IDENTIFIER: NCT01638962 (July 3, 2012). ETHICAL COMMITTEE: S-20110153.

TGFßR signalling controls CD103+CD11b+ dendritic cell development in the intestine.

CD103+CD11b+ dendritic cells (DCs) are unique to the intestine, but the factors governing their differentiation are unclear. Here we show that transforming growth factor receptor 1 (TGFßR1) has an indispensable, cell intrinsic role in the development of these cells. Deletion of Tgfbr1 results in markedly fewer intestinal CD103+CD11b+ DCs and a reciprocal increase in the CD103-CD11b+ dendritic cell subset. Transcriptional profiling identifies markers that define the CD103+CD11b+ DC lineage, including CD101, TREM1 and Siglec-F, and shows that the absence of CD103+CD11b+ DCs in CD11c-Cre.Tgfbr1 fl/fl mice reflects defective differentiation from CD103-CD11b+ intermediaries, rather than an isolated loss of CD103 expression. The defect in CD103+CD11b+ DCs is accompanied by reduced generation of antigen-specific, inducible FoxP3+ regulatory T cells in vitro and in vivo, and by reduced numbers of endogenous Th17 cells in the intestinal mucosa. Thus, TGFßR1-mediated signalling may explain the tissue-specific development of these unique DCs.Developmental cues for the different dendritic cell (DC) subsets in the intestine are yet to be defined. Here the authors show that TGFßR1 signalling is needed for development of CD103+CD11b+ intestinal DCs from CD103-CD11b+ cells and that they contribute to the generation of Th17 and regulatory T cells.

The effect of instruction in analgesic use compared with neuromuscular exercise on knee-joint load in patients with knee osteoarthritis: a randomized, single-blind, controlled trial.

OBJECTIVE: To investigate the effect of a neuro-muscular exercise (NEMEX) therapy program compared with instructions in optimized analgesics and anti-inflammatory drug use (PHARMA), on measures of knee-joint load in people with mild to moderate knee osteoarthritis (OA). We hypothesized that knee joint loading during walking would be reduced by NEMEX and potentially increased by PHARMA. DESIGN: Single-blind, randomized controlled trial (RCT) comparing NEMEX therapy twice a week with PHARMA. Participants with mild-to-moderate medial tibiofemoral knee OA were randomly allocated (1:1) to one of two 8-week treatments. Primary outcome was change in knee load during walking (Knee Index, a composite score from all three planes based on 3D movement analysis) after 8 weeks of intervention. Secondary outcomes were frontal plane peak knee adduction moment (KAM), Knee Injury and Osteoarthritis Outcome Scores (KOOS) and functional performance tests. RESULTS: Ninety three participants (57% women, 58 ± 8 years with a body mass index [BMI] of 27 ± 4 kg/m2 (mean ± standard deviation [SD])) were randomized to NEMEX group (n = 47) or PHARMA (n = 46); data from 44 (94%) and 41 (89%) participants respectively, were available at follow-up. 49% of the participants in NEMEX and only 7% in PHARMA demonstrated good compliance. We found no difference in the primary outcome as evaluated by the Knee Index -0.07 [-0.17; 0.04] Nm/%BW HT. Secondary outcomes largely supported this finding. CONCLUSIONS: We found no difference in the primary outcome; knee joint load change during walking from a NEMEX program vs information on the recommended use of analgesics and anti-inflammatory drugs. ClinicalTrials.gov Identifier: NCT01638962 (July 3, 2012). Ethical Committee: S-20110153.

Self-reported quality care for knee osteoarthritis: comparisons across Denmark, Norway, Portugal and the UK.

OBJECTIVES: To assess and compare patient perceived quality of osteoarthritis (OA) management in primary healthcare in Denmark, Norway, Portugal and the UK. METHODS: Participants consulting with clinical signs and symptoms of knee OA were identified in 30 general practices and invited to complete a cross-sectional survey including quality indicators (QI) for OA care. A QI was considered as eligible if the participant had checked 'Yes' or 'No', and as achieved if the participant had checked 'Yes' to the indicator. The median percentage (with IQR and range) of eligible QIs achieved by country was determined and compared in negative binominal regression analysis. Achievement of individual QIs by country was determined and compared using logistic regression analyses. RESULTS: A total of 354 participants self-reported QI achievement. The median percentage of eligible QIs achieved (checked 'Yes') was 48% (IQR 28%, 64%; range 0-100%) for the total sample with relatively similar medians across three of four countries. Achievement rates on individual QIs showed a large variation ranging from 11% (referral to services for losing weight) to 67% (information about the importance of exercise) with significant differences in achievement rates between the countries. CONCLUSIONS: The results indicated a potential for improvement in OA care in all four countries, but for somewhat different aspects of OA care. By exploring these differences and comparing healthcare services, ideas may be generated on how the quality might be improved across nations. Larger studies are needed to confirm and further explore the findings.

Aldara-induced psoriasis-like skin inflammation: isolation and characterization of cutaneous dendritic cells and innate lymphocytes.

Psoriasis is a chronic auto-inflammatory skin disease of unknown etiology affecting millions of people worldwide. Dissecting the cellular networks and molecular signals promoting the development of psoriasis critically depends on appropriate animal models. Topical application of Aldara cream containing the Toll-like receptor (TLR)7-ligand Imiquimod induces skin inflammation and pathology in mice closely resembling plaque-type psoriasis in humans. The particular power of the Aldara model lies in examining the early events during psoriatic plaque formation, which is difficult to achieve in patients. Hence, recent reports using this model have challenged currently prevailing concepts concerning the pathophysiology of psoriasis. Here, we describe the induction and phenotype of Aldara-mediated dermatitis in mice and, in particular, analysis of the inflammatory cell infiltrate using flow cytometry.

Genetic fuzzy system predicting contractile reactivity patterns of small arteries.

Monitoring of physiological surrogate end points in drug development generates dynamic time-domain data reflecting the state of the biological system. Conventional data analysis often reduces the information in these data by extracting specific data points, thereby discarding potentially useful information. We developed a genetic fuzzy system (GFS) algorithm that is capable of learning all information in time-domain physiological data. Data on isometric force development of isolated small arteries were used as a framework for developing and optimizing a GFS. GFS performance was improved by several strategies. Results show that optimized fuzzy systems (OFSs) predict contractile reactivity of arteries accurately. In addition, OFSs identified significant differences that were undetectable using conventional analysis in the responses of arteries between groups. We concluded that OFSs may be used in clustering or classification tasks as aids in the objective identification or prediction of dynamic physiological behavior.

Elastic moduli inheritance and the weakest link in bulk metallic glasses.

We show that a variety of bulk metallic glasses (BMGs) inherit their Young's modulus and shear modulus from the solvent components. This is attributed to preferential straining of locally solvent-rich configurations among tightly bonded atomic clusters, which constitute the weakest link in an amorphous structure. This aspect of inhomogeneous deformation, also revealed by our in situ neutron diffraction studies of an elastically deformed BMG, suggests a rubberlike viscoelastic behavior due to a hierarchy of atomic bonds in BMGs.

Design, implementation, and testing of a cryogenic loading capability on an engineering neutron diffractometer.

A novel capability was designed, implemented, and tested for in situ neutron diffraction measurements during loading at cryogenic temperatures on the spectrometer for materials research at temperature and stress at Los Alamos National Laboratory. This capability allowed for the application of dynamic compressive forces of up to 250 kN on standard samples controlled at temperatures between 300 and 90 K. The approach comprised of cooling thermally isolated compression platens that in turn conductively cooled the sample in an aluminum vacuum chamber which was nominally transparent to the incident and diffracted neutrons. The cooling/heat rate and final temperature were controlled by regulating the flow of liquid nitrogen in channels inside the platens that were connected through bellows to the mechanical actuator of the load frame and by heaters placed on the platens. Various performance parameters of this system are reported here. The system was used to investigate deformation in Ni-Ti-Fe shape memory alloys at cryogenic temperatures and preliminary results are presented.

Atomic-scale structure and stability of the square root(31) x square root(31)R9 degrees surface of Al2O3(0001).

Through the interplay of noncontact atomic force microscopy studies and density functional theory calculations, an atomistic model for the Al2O3(0001)-square root(31) x square root(31)R9 degrees surface reconstruction is revealed. The surface is found to consist of an Al adlayer on the Al2O3 substrate, and the driving force for the formation of the reconstruction is related to a detailed balance between strain in the adlayer and the preference for Al atoms to be located on distinct substrate sites.

Deformation crossover: from nano- to mesoscale.

In situ synchrotron and neutron diffraction were used to study deformation mechanisms in Ni over a broad range of grain sizes. The experimental data show that unlike in coarse-grained metals, where the deformation is dominated by dislocation slip, plastic deformation in nanocrystalline Ni is mediated by grain-boundary activities, as evidenced by the lack of intergranular strain and texture development. For ultrafine-grained Ni, although dislocation slip is an active deformation mechanism, deformation twinning also plays an important role, whose propensity increases with the grain size.

Nuclear translocation of endonuclease G in degenerating neurons after permanent middle cerebral artery occlusion in mice.

Endonuclease G (EndoG) is a mitochondrial enzyme, known to be involved in caspase-independent cell death following translocation to the cellular nucleus. Nuclear translocation of EndoG has been observed in the ischemic area following transient occlusion of the middle cerebral artery (MCA) in mice, but not after permanent MCA occlusion. In this study we investigated the cellular and temporal expression of EndoG in infarcted cortex during the first 24 h after permanent MCA occlusion in mice, using immunohistochemistry, quantitative rt-PCR and cell specific immunoflourescence markers. EndoG translocated from the cytoplasm to the nucleus as early as 4 h and with a significant increase in the number of EndoG positive nuclei at 12 and 24 h after MCA occlusion. Nuclear translocation of EndoG was observed in degenerating NeuN positive neurons that were evenly distributed throughout the developing infarct. Translocation of EndoG was supported by unaltered EndoG mRNA levels. EndoG was neither expressed in GFAP positive astrocytes nor in CD11b positive microglia/macrophages. In contrast, CD11b positive microglia, but not infiltrating CD11b positive bone marrow-derived macrophages, were shown to express activated caspase-3. The translocation of EndoG to the nucleus of neurons in the infarct implicates EndoG in ischemic neuronal degeneration after permanent MCA occlusion in mice. Increased knowledge about EndoG involvement in ischemic neuronal cell death in mice might offer a promise to control processes involved in neuronal cell death pathways in stroke.

Microglia and macrophages express tumor necrosis factor receptor p75 following middle cerebral artery occlusion in mice.

The proinflammatory and potential neurotoxic cytokine tumor necrosis factor (TNF) is produced by activated CNS resident microglia and infiltrating blood-borne macrophages in infarct and peri-infarct areas following induction of focal cerebral ischemia. Here, we investigated the expression of the TNF receptors, TNF-p55R and TNF-p75R, from 1 to 10 days following permanent occlusion of the middle cerebral artery in mice. Using quantitative polymerase chain reaction (PCR), we observed that the relative level of TNF-p55R mRNA was significantly increased at 1-2 days and TNF-p75R mRNA was significantly increased at 1-10 days following arterial occlusion, reaching peak values at 5 days, when microglial-macrophage CD11b mRNA expression was also increased. In comparison, the relative level of TNF mRNA was significantly increased from 1 to 5 days, with peak levels 1 day after arterial occlusion. In situ hybridization revealed mRNA expression of both receptors in predominantly microglial- and macrophage-like cells in the peri-infarct and subsequently in the infarct, and being most marked from 1 to 5 days. Using green fluorescent protein-bone marrow chimeric mice, we confirmed that TNF-p75R was expressed in resident microglia and blood-borne macrophages located in the peri-infarct and infarct 1 and 5 days after arterial occlusion, which was supported by Western blotting. The data show that increased expression of the TNF-p75 receptor following induction of focal cerebral ischemia in mice can be attributed to expression in activated microglial cells and blood-borne macrophages.

A quantitative in situ hybridization and polymerase chain reaction study of microglial-macrophage expression of interleukin-1beta mRNA following permanent middle cerebral artery occlusion in mice.

Interleukin-1beta (IL-1beta) is known to play a central role in ischemia-induced brain damage in rodents. In comparison to the rat, however, the available data on the cellular synthesis of IL-1beta mRNA and protein in the mouse are very limited. Here, we report on the time profile, the topography and the quantitative, cellular expression of IL-1beta mRNA in mice subjected to permanent occlusion of the distal middle cerebral artery (MCA). The in situ hybridization analysis showed that IL-1beta mRNA was expressed during the first post-surgical hour in a small number of high-expressing macrophage-like cells, located in cortical layers I and II of the future infarct. At 2 h, a significant number of faintly labeled IL-1beta mRNA-expressing cells had appeared in the developing peri-infarct, and the number remained constant at 4 h and 6 h, when the hybridization signal began to distribute to the cellular processes. Quantitative PCR performed on whole hemispheres showed a significant 20-fold increase in the relative level of IL-1beta mRNA at 12 h and a highly significant 42-fold increase at 24 h, at which time single IL-1beta mRNA-expressing cells were supplemented by aggregates and perivascular infiltrates of intensely labeled IL-1beta mRNA-expressing cells. Immunohistochemistry and double immunohistochemical stainings in addition to combined in situ hybridization, confirmed that the intensely labeled IL-1beta mRNA-expressing and IL-1beta protein synthesizing cells predominantly were glial fibrillary acidic protein-immunonegative, macrophage associated antigen-1-immunopositive microglia-macrophages. By day 5 there was a dramatic decline in the relative level of IL-1beta mRNA in the ischemic hemisphere. In summary, the data provide evidence that permanent occlusion of the distal MCA in mice results in expression of IL-1beta mRNA and IL-1beta synthesis in spatially and temporally segregated subpopulations of microglia and macrophages.

Five mouse homologues of the human dendritic cell C-type lectin, DC-SIGN.

DC-SIGN, a human C-type lectin, is expressed on the surface of dendritic cells (DC), while a closely related human gene, DC-SIGNR or L-SIGN, is found on sinusoidal endothelial cells of liver and lymph node. Both DC-SIGN and DC-SIGNR/L-SIGN can bind ICAM-3 and HIV gp120, and transmit HIV to susceptible cells in trans. Here, we report the cloning of five mouse genes homologous to human DC-SIGN and DC-SIGNR/L-SIGN. Only one gene, named mouse DC-SIGN, is highly expressed in DC, and is not found in a panel of mouse macrophage and lymphocyte cell lines. The other four genes, named mouse SIGNR1 (SIGN-Related gene 1), SIGNR2, SIGNR3 and SIGNR4, are expressed at lower levels in various cells according to RT-PCR and Northern blot analyses on RNA. All the genes of mouse DC-SIGN and SIGNRs map to adjacent regions of chromosome 8 A1.2-1.3. However, like human DC-SIGN, only the mouse DC-SIGN gene is closely juxtaposed to the CD23 gene, while the other four SIGNR genes are located close to each other in a neighboring region. mRNAs of mouse DC-SIGN and three SIGNR genes encode type II transmembrane proteins (DC-SIGN, 238 amino acids; SIGNR1, 325 amino acids; SIGNR3, 237 amino acids; SIGNR4, 208 amino acids), but the SIGNR2 gene only encodes a carbohydrate recognition domain (CRD) without a cytosolic domain and a transmembrane domain (SIGNR2, 178 amino acids). Amino acid sequence similarities between the CRD of human DC-SIGN and the mouse homologues are 67% for DC-SIGN, 69% for SIGNR1, 65% for SIGNR2, 68% for SIGNR3 and 70% for SIGNR4 respectively. However, the membrane proximal neck domains in the mouse genes are much shorter than their counterparts in human DC-SIGN and DC-SIGNR/L-SIGN. This family of mouse C-type lectins is therefore complex, but only one of the new genes, DC-SIGN, is juxtaposed to CD23 and is expressed at high levels in DC.

Fluorescence EXAFS for the in situ study on the state of promoters in catalysis.

The fluorescence EXAFS (FLEXAFS) technique has been combined with an in situ cell and on-line gas analysis. For this purpose a seven-element silicon drift detector has been used, which has high count rate capabilities and can be operated at room temperature. The potential of this technique is shown by the study of the state of copper promoter atoms in Fe-Cr based high temperature shift (HTS) catalysts. The FLEXAFS measurements revealed that Cu (0.17-1.5 wt%) is present in the metallic state under working conditions of the catalysts but easily re-oxidizes upon air exposure. The reduction behaviour of copper depends strongly on the copper concentration and the pre-treatment, i.e. if the catalysts have been calcined or used in the HTS reaction. For used catalysts, a Cu(I) phase was detected as intermediate during reduction. Its stability was especially high at low copper concentration.