Trajectories of perceived exertion and pain over a 12-week neuromuscular exercise program in patients with knee osteoarthritis.

BACKGROUND: Exercise programs rely on the overload principle, yet patients with knee osteoarthritis (OA) may not adequately progress exercises due to fear of exacerbating symptoms. OBJECTIVE: To describe trajectories for perceived exertion and exercise-induced knee pain during a neuromuscular exercise program for patients with knee OA. DESIGN: Participants with knee OA completed a 12-week neuromuscular exercise program consisting of weekly supervised sessions plus home exercises. During each supervised session, the Borg's rating of perceived exertion (RPE; 6 = no exertion, 20 = maximal exertion) and knee pain (pre, post, max) using Numeric Rating Scales (NRS; 0 = no pain, 10 = worst imaginable pain) were completed. Mean changes in RPE and pain from weeks 1-12 were calculated. Mixed effects regression was used to investigate trajectories over time (weeks) for RPE, and maximum pain (pre-to-max) and pain-change (pre-to-post) during exercise. RESULTS: 56 patients (95%) completed the program. From week 1-12, RPE increased by 2.6 (95%CI, 1.7 to 3.5), from 'somewhat hard' to 'very hard', while max pain decreased by 1.0 NRS (95%CI, 0.5 to 1.3) and pain-change decreased by 0.9 NRS (95%CI, 0.4 to 1.3). Linear mixed effects regression showed a quadratic increase for RPE over time until between weeks 9 and 10, then RPE plateaued. Maximum pain decreased linearly over time. Pain-change showed a quadratic decrease over time until approximately week 9, then pain-change plateaued. CONCLUSIONS: In patients with knee OA participating in a 12-week neuromuscular exercise program, perceived exertion during exercise progressed from 'somewhat hard' to 'very hard' at 9 weeks, while exercise-induced knee pain decreased. Patients were able to work harder while experiencing decreases rather than increases in pain.

Demonstration of Tokamak Discharge Shutdown with Shell Pellet Payload Impurity Dispersal.

The first rapid tokamak discharge shutdown using dispersive core payload deposition with shell pellets has been achieved in the DIII-D tokamak. Shell pellets are being investigated as a possible new path toward achieving tokamak disruption mitigation with both low conducted wall heat loads and slow current quench. Conventional disruption mitigation injects radiating impurities into the outer edge of the tokamak plasma, which tends to result in poor impurity assimilation and creates a strong edge cooling and outward heat flow, thus requiring undesirable high-Z impurities to achieve low conducted heat loads. The shell pellet technique aims to produce a hollow temperature profile by using a thin, low-ablation shell surrounding a dispersive payload, giving a greatly increased impurity ablation (and radiation) rate when the payload is released in the plasma core. This principle was demonstrated successfully using 3.6 mm outer diameter, 40 µm thickness diamond shells holding boron powder. The pellets caused rapid (<10 ms) discharge shutdown with low conducted divertor heat fluence (∼0.1 MJ/m^{2}). Confirmation of massive release of the boron powder payload into the plasma core was obtained spectroscopically. Some evidence for the formation of a hollow temperature profile during the shutdown was observed. These first results open a new avenue for disruption mitigation research, hopefully enabling development of highly effective methods of avoiding disruption wall damage in future reactor-scale tokamaks.

First Direct Observation of Runaway-Electron-Driven Whistler Waves in Tokamaks.

DIII-D experiments at low density (n_{e}∼10^{19} m^{-3}) have directly measured whistler waves in the 100-200 MHz range excited by multi-MeV runaway electrons. Whistler activity is correlated with runaway intensity (hard x-ray emission level), occurs in novel discrete frequency bands, and exhibits nonlinear limit-cycle-like behavior. The measured frequencies scale with the magnetic field strength and electron density as expected from the whistler dispersion relation. The modes are stabilized with increasing magnetic field, which is consistent with wave-particle resonance mechanisms. The mode amplitudes show intermittent time variations correlated with changes in the electron cyclotron emission that follow predator-prey cycles. These can be interpreted as wave-induced pitch angle scattering of moderate energy runaways. The tokamak runaway-whistler mechanisms have parallels to whistler phenomena in ionospheric plasmas. The observations also open new directions for the modeling and active control of runaway electrons in tokamaks.

Changes in biomechanical risk factors for knee osteoarthritis and their association with 5-year clinically important improvement after limb realignment surgery.

OBJECTIVE: To evaluate 5-year outcomes after lower limb realignment and test the hypothesis that surgery-induced changes in selected biomechanical risk factors for medial knee osteoarthritis (OA) are associated with clinically important improvements. DESIGN: We prospectively evaluated patient-reported outcomes, full-limb standing radiographs and gait biomechanics before, 6 months (surgery-induced change) and 5 years after medial opening wedge high tibial osteotomy (HTO) in 170 patients (46.4 ± 8.9 years, 135 males) with knee OA and varus alignment. Logistic regression tested the associations of 6-month changes in mechanical axis angle and knee adduction moment with achieving an increase of ≥10 points in the Knee injury and Osteoarthritis Outcome Score (KOOS)4 at 5 years, with and without adjusting for covariates. Gait data were also compared to existing data from healthy controls. RESULTS: Mean 5-year changes (95% confidence interval (CI)) were: KOOS4: +14.2 (10.8, 17.6); mechanical axis angle: +8.21° (7.58, 8.83); knee adduction moment: -1.49 %BW*Ht (-1.35, -1.63). The postoperative knee adduction moments were typically lower than values for healthy controls. When divided into quartiles, although all strata improved significantly, patients with reductions in knee adduction moment of 1.14-1.74 %BW*Ht (neither largest nor smallest changes) had highest 5-year KOOS4 scores. The 6-month change in knee adduction moment (odds ratios (OR) = 0.38; 95% CI: 0.22, 0.67), preoperative KOOS4 (OR = 0.96; 95% CI: 0.94, 0.99) and preoperative medial tibiofemoral narrowing grade (OR = 0.62; 95% CI: 0.37, 1.00) were negatively associated with having a 5-year clinically important improvement (C-statistic = 0.70). CONCLUSIONS: Substantial improvements in biomechanical risk factors and patient-reported outcomes are observed 5 years after medial opening wedge HTO. The surgery-induced change in load distribution during walking is significantly associated with long-term clinically important improvement.

Spatiotemporal Evolution of Runaway Electron Momentum Distributions in Tokamaks.

Novel spatial, temporal, and energetically resolved measurements of bremsstrahlung hard-x-ray (HXR) emission from runaway electron (RE) populations in tokamaks reveal nonmonotonic RE distribution functions whose properties depend on the interplay of electric field acceleration with collisional and synchrotron damping. Measurements are consistent with theoretical predictions of momentum-space attractors that accumulate runaway electrons. RE distribution functions are measured to shift to a higher energy when the synchrotron force is reduced by decreasing the toroidal magnetic field strength. Increasing the collisional damping by increasing the electron density (at a fixed magnetic and electric field) reduces the energy of the nonmonotonic feature and reduces the HXR growth rate at all energies. Higher-energy HXR growth rates extrapolate to zero at the expected threshold electric field for RE sustainment, while low-energy REs are anomalously lost. The compilation of HXR emission from different sight lines into the plasma yields energy and pitch-angle-resolved RE distributions and demonstrates increasing pitch-angle and radial gradients with energy.

Anatomical alignment, but not goniometry, predicts femorotibial cartilage loss as well as mechanical alignment: data from the Osteoarthritis Initiative.

OBJECTIVE: To determine how frontal plane lower limb alignment obtained using a new femorotibial angle (FTA) measurement and non-radiographic handheld goniometry, predict femorotibial cartilage thickness loss in varus and valgus knees, compared with the gold standard mechanical axis (hip-knee-ankle [HKA]). METHODS: 934 Osteoarthritis (OA) Initiative knees with radiographic OA had the above alignment measures and 3T knee MRIs acquired. The new FTA measure was compared to the gold standard, with and without adjusting FTA for the sex-specific varus shift. Changes in medial (MFTC) and lateral femorotibial (LFTC) cartilage thickness were quantified over 1-year and 2-years. Adjusted odds ratios (adjORs) were used to compare how the different alignment measures predict medial and lateral cartilage loss in varus and valgus knees. RESULTS: Pearson correlation coefficients between 2-year MFTC/LFTC cartilage loss and alignment measures were small to moderate, and were similar for FTA (r = 0.28/-0.30) and for HKA (r = 0.28/-0.29). Using the adjusted FTA measure, varus and valgus predicted MFTC progression (adjOR = 3.73) and LFTC progression (adjOR = 2.55) as well as HKA (adjOR = 3.16 and 2.31) over 1-year, and this relationship was also observed over 2-years. Goniometry was a weak predictor for MFTC and LFTC progression (adjOR1-year = 1.65 and 1.71; adjOR2-year = 0.68 and 1.24). CONCLUSIONS: After adjustment, the new FTA measure obtained from short (fixed-flexion) knee films was as good as the gold standard in predicting medial and lateral cartilage loss over 1- or 2-years, without need for obtaining long-limb radiographs for determining the mechanical axis. Goniometry and non-adjusted FTA measures, in contrast, were poor predictors of cartilage loss.

Biomechanical effects of valgus knee bracing: a systematic review and meta-analysis.

To review and synthesize the biomechanical effects of valgus knee bracing for patients with medial knee osteoarthritis (OA). Electronic databases were searched from their inception to May 2014. Two reviewers independently determined study eligibility, rated study quality and extracted data. Where possible, data were combined into meta-analyses and pooled estimates with 95% confidence intervals (CI) for standardized mean differences (SMD) were calculated. Thirty studies were included with 478 subjects tested while using a valgus knee brace. Various biomechanical methods suggested valgus braces can decrease direct measures of medial knee compressive force, indirect measures representing the mediolateral distribution of load across the knee, quadriceps/hamstring and quadriceps/gastrocnemius co-contraction ratios, and increase medial joint space during gait. Meta-analysis from 17 studies suggested a statistically significant decrease in the external knee adduction moment (KAM) during walking, with a moderate-to-high effect size (SMD = 0.61; 95% CI: 0.39, 0.83; P < 0.001). Meta-regression identified a near-significant association for the KAM effect size and duration of brace use only (ß, -0.01; 95% CI: -0.03, 0.0001; P = 0.06); with longer durations of brace use associated with smaller treatment effects. Minor complications were commonly reported during brace use and included slipping, discomfort and poor fit, blisters and skin irritation. Systematic review and meta-analysis suggests valgus knee braces can alter knee joint loads through a combination of mechanisms, with moderate-to-high effect sizes in biomechanical outcomes.

Observation of a multimode plasma response and its relationship to density pumpout and edge-localized mode suppression.

Density pumpout and edge-localized mode (ELM) suppression by applied n=2 magnetic fields in low-collisionality DIII-D plasmas are shown to be correlated with the magnitude of the plasma response driven on the high-field side (HFS) of the magnetic axis but not the low-field side (LFS) midplane. These distinct responses are a direct measurement of a multimodal magnetic plasma response, with each structure preferentially excited by a different n=2 applied spectrum and preferentially detected on the LFS or HFS. Ideal and resistive magneto-hydrodynamic (MHD) calculations find that the LFS measurement is primarily sensitive to the excitation of stable kink modes, while the HFS measurement is primarily sensitive to resonant currents (whether fully shielding or partially penetrated). The resonant currents are themselves strongly modified by kink excitation, with the optimal applied field pitch for pumpout and ELM suppression significantly differing from equilibrium field alignment.

Pedestal bifurcation and resonant field penetration at the threshold of edge-localized mode suppression in the DIII-D Tokamak.

Rapid bifurcations in the plasma response to slowly varying n=2 magnetic fields are observed as the plasma transitions into and out of edge-localized mode (ELM) suppression. The rapid transition to ELM suppression is characterized by an increase in the toroidal rotation and a reduction in the electron pressure gradient at the top of the pedestal that reduces the perpendicular electron flow there to near zero. These events occur simultaneously with an increase in the inner-wall magnetic response. These observations are consistent with strong resonant field penetration of n=2 fields at the onset of ELM suppression, based on extended MHD simulations using measured plasma profiles. Spontaneous transitions into (and out of) ELM suppression with a static applied n=2 field indicate competing mechanisms of screening and penetration of resonant fields near threshold conditions. Magnetic measurements reveal evidence for the unlocking and rotation of tearinglike structures as the plasma transitions out of ELM suppression.

Osteoarthritis year in review 2014: mechanics--basic and clinical studies in osteoarthritis.

The purpose of this review was to highlight recent research in mechanics and osteoarthritis (OA) by summarizing results from selected studies spanning basic and clinical research methods. Databases were searched from January 2013 through to March 2014. Working in pairs, reviewers selected 67 studies categorized into four themes--mechanobiology, ambulatory mechanics, biomechanical interventions and mechanical risk factors. Novel developments in mechanobiology included the identification of cell signaling pathways that mediated cellular responses to loading of articular cartilage. Studies in ambulatory mechanics included an increased focus on instrumented knee implants and progress in computational models, both emphasizing the importance of muscular contributions to load. Several proposed biomechanical interventions (e.g., shoe insoles and knee braces) produced variable changes in external knee joint moments during walking, while meta-analysis of randomized clinical trials did not support the use of lateral wedge insoles for decreasing pain. Results from high quality randomized trials suggested diet with or without exercise decreased indicators of knee joint load during walking, whereas similar effects from exercise alone were not detected with the measures used. Data from longitudinal cohorts suggested mechanical alignment was a risk factor for incidence and progression of OA, with the mechanism involving damage to the meniscus. In combination, the basic and clinical studies highlight the importance of considering multiple contributors to joint loading that can evoke both protective and damaging responses. Although challenges clearly exist, future studies should strive to integrate basic and clinical research methods to gain a greater understanding of the interactions among mechanical factors in OA and to develop improved preventive and therapeutic strategies.

SBS-managed high-peak-power nanosecond-pulse fiber-based master oscillator power amplifier.

We report on a compactly packaged Yb-doped fiber-based laser architecture featuring an actively pulse controlled, single-longitudinal-mode seeder and multistage amplifier chain terminated by a "folded" rod-type photonic crystal fiber. In this laser source, stimulated Brillouin scattering (SBS) is the power-limiting factor, but is managed by phase modulating the seeder with a pseudo-random noise signal. Pulse energy/peak power of ~2 mJ/1.5 MW at 10 kHz repetition rate are thus obtained within ~1.55 ns pulses of peak spectral brightness >20 kW cm(-2) sr(-1) Hz(-1).

Reduction of edge-localized mode intensity using high-repetition-rate pellet injection in tokamak H-mode plasmas.

High repetition rate injection of deuterium pellets from the low-field side (LFS) of the DIII-D tokamak is shown to trigger high-frequency edge-localized modes (ELMs) at up to 12× the low natural ELM frequency in H-mode deuterium plasmas designed to match the ITER baseline configuration in shape, normalized beta, and input power just above the H-mode threshold. The pellet size, velocity, and injection location were chosen to limit penetration to the outer 10% of the plasma. The resulting perturbations to the plasma density and energy confinement time are thus minimal (<10%). The triggered ELMs occur at much lower normalized pedestal pressure than the natural ELMs, suggesting that the pellet injection excites a localized high-n instability. Triggered ELMs produce up to 12× lower energy and particle fluxes to the divertor, and result in a strong decrease in plasma core impurity density. These results show for the first time that shallow, LFS pellet injection can dramatically accelerate the ELM cycle and reduce ELM energy fluxes on plasma facing components, and is a viable technique for real-time control of ELMs in ITER.

Experimental investigation of the role of fluid turbulent stresses and edge plasma flows for intrinsic rotation generation in DIII-D H-mode plasmas.

The first measurements of turbulent stresses and flows inside the separatrix of a tokamak H-mode plasma are reported, using a reciprocating multitip Langmuir probe at the DIII-D tokamak. A strong co-current rotation layer at the separatrix is found to precede intrinsic rotation development in the core. The measured fluid turbulent stresses transport toroidal momentum outward against the velocity gradient and thus try to sustain the edge layer. However, large kinetic stresses must exist to explain the net inward momentum transport leading to co-current core plasma rotation. The importance of such kinetic stresses is corroborated by the success of a simple orbit loss model, representing a purely kinetic mechanism, in the prediction of features of the edge corotation layer.

Alignment, body mass and their interaction on dynamic knee joint load in patients with knee osteoarthritis.

OBJECTIVE: To examine the interaction and relative contributions of frontal plane alignment and body mass on dynamic knee joint loading in patients with knee osteoarthritis (OA). METHODS: We completed three-dimensional gait analyses and hip-to-ankle standing anteroposterior radiographs on 487 patients with knee OA referred to a tertiary care center specializing in orthopaedics. RESULTS: Using sequential (hierarchical) linear regression, the interaction term (mechanical axis anglexmass) contributed significantly (P<0.001) to a model (total adjusted R(2)=0.70) predicting the external knee adduction moment, that included mechanical axis angle (R(2)=0.37) and mass (R(2)=0.06) while controlling for age, sex, height, Kellgren and Lawrence grade, pain score during walking, gait speed, toe out angle and trunk lean (R(2)=0.25). When the sample was split into tertiles for mass, mechanical axis angle accounted for 32-54% of explained variance in knee adduction moment. In the tertile with greatest mass, results suggest a 3.2 N m increase in knee load for every 1 degrees increase in varus alignment. When split into tertiles for mechanical axis angle, mass accounted for 6-10% of explained variance in the knee adduction moment. In the tertile with the most varus alignment, results suggest a 0.4 N m increase in knee load for every 1 kg increase in mass. CONCLUSION: Our findings describe the interaction between alignment and body mass on dynamic knee joint loading, with the association between alignment and load highest in patients with the highest mass. Our findings also emphasize the role of malalignment on knee load at all levels of mass, and have implications for better understanding risk factors and intervention strategies for knee OA.

Resonant pedestal pressure reduction induced by a thermal transport enhancement due to stochastic magnetic boundary layers in high temperature plasmas.

Good alignment of the magnetic field line pitch angle with the mode structure of an external resonant magnetic perturbation (RMP) field is shown to induce modulation of the pedestal electron pressure p(e) in high confinement high rotation plasmas at the DIII-D tokamak with a shape similar to ITER, the next step tokamak experiment. This is caused by an edge safety factor q95 resonant enhancement of the thermal transport, while in contrast, the RMP induced particle pump out does not show a significant resonance. The measured p(e) reduction correlates to an increase in the modeled stochastic layer width during pitch angle variations matching results from resistive low rotation plasmas at the TEXTOR tokamak. These findings suggest a field line pitch angle resonant formation of a stochastic magnetic edge layer as an explanation for the q95 resonant character of type-I edge localized mode suppression by RMPs.

Psychophysical functions for perceived and remembered size.

Separate groups of people estimated the sizes of perceived or of remembered objects. In three independent experiments, both sets of data were well fit by power functions, and the exponent was reliably smaller by remembered than for perceived size.

Imaging divertor strike point splitting in RMP ELM suppression experiments in the DIII-D tokamak.

Fast visible imaging of the lower divertor from above is used to study the structure and dynamics of lobes induced by resonant magnetic perturbations (RMPs) in Edge-Localized Mode (ELM) suppression experiments in DIII-D. The best compromise between the amount of light and sharp imaging was obtained using emission at 601 nm from Fulcher band molecular deuterium. Multiple spatially resolved peaks in the D2 emission, taken as a proxy for the particle flux, are readily resolved during RMPs, in contrast to the heat flux measured by infrared cameras, which shows little spatial structure in ITER-like conditions. The 25 mm objective lens provides high spatial resolution (2-4 mm/pixel) from the centerpost to the outer shelf over 40° toroidally that overlaps the field of view of the IRTV that measures the divertor heat flux, allowing direct comparison in non-axisymmetric discharges. The image is coupled to a Phantom 7.3 camera using a Schott wound fiber bundle, providing high temporal resolution that allows the lobe dynamics to be resolved between ELMs and across ELM suppression onset. These measurements are used to study the heat and particle flux in 3D magnetic fields and to validate models for the plasma response to RMPs.

Granzyme B short-circuits the need for caspase 8 activity during granule-mediated cytotoxic T-lymphocyte killing by directly cleaving Bid.

Cytotoxic T lymphocytes (CTL) can trigger an apoptotic signal through the Fas receptor or by the exocytosis of granzyme B and perforin. Caspase activation is an important component of both pathways. Granzyme B, a serine proteinase contained in granules, has been shown to proteolytically process and activate members of the caspase family in vitro. In order to gain an understanding of the contributions of caspases 8 and 3 during granule-induced apoptosis in intact cells, we have used target cells that either stably express the rabbitpox virus-encoded caspase inhibitor SPI-2 or are devoid of caspase 3. The overexpression of SPI-2 in target cells significantly inhibited DNA fragmentation, phosphatidylserine externalization, and mitochondrial disruption during Fas-mediated cell death. In contrast, SPI-2 expression in target cells provided no protection against granzyme-mediated apoptosis, mitochondrial collapse, or cytolysis, leading us to conclude that SPI-2-inhibited caspases are not an essential requirement for the granzyme pathway. Caspase 3-deficient MCF-7 cells were found to be resistant to CTL-mediated DNA fragmentation but not to CTL-mediated cytolysis and loss of the mitochondrial inner membrane potential. Furthermore, we demonstrate that granzyme B directly cleaves the proapoptotic molecule Bid, bypassing the need for caspase 8 activation of Bid. These results provide evidence for a two-pronged strategy for mediating target cell destruction and provide evidence of a direct link between granzyme B activity, Bid cleavage, and caspase 3 activation in whole cells.

Differences in the responsiveness of splenic, lymph node, and peripheral blood lymphoid cells to tumor membrane extracts.

The blastogenic response of normal spleen, lymph node, and peripheral blood lymphoid cells to tumor-associated antigens (TAA) derived from two syngeneic C57BL/6J tumors was measured by [3H]thymidine incorporation. Peripheral blood cells were responsive to TAA from B16 melanoma and from BW10232 mammary carcinoma at both a high (10(-1) to 10(-3) mg/ml) and a low (10(-5) to 10(-6) mg/ml) concentration of antigen. While peripheral blood cells always responded to TAA, spleen cells and lymph node cells did not. When spleen and lymph node cells did respond, they sometimes responded at different concentrations of TAA than did the peripheral blood cells. Spleen cells generally responded to "low" concentrations of TAA, while lymph node cells responded to "high" concentrati-ns of TAA. These data suggest two subpopulations of lymphoid cells capable of response to TA.. Spleen cells from mice bearing the BW10232 mammary carcinoma became responsive to BW10232 TAA at low concentrations of antigen. Lymph node cells became responsive at high concentrations of BW10232 antigen. The response of both subpopulations to BW10232 TAA was amplified in peripheral blood cells. Spleen cells were 30 times more responsive in the tumor bearer than in normal animals, while lymph node cells were only 3 times more responsive. It is shown that lymphoid cells taken from different areas or "lymphoid compartments" do not always show similar responses and should not be considered equivalent in evaluating immune responses to tumor cells.

Gene-specific differences in the aflatoxin B1 adduction of chicken erythrocyte chromatin.

Mature and immature chicken erythrocyte nuclei were treated with activated aflatoxin B1 (2,3-dichloroaflatoxin B1), producing covalently bound DNA adducts. This reaction produces alkali-labile sites in the DNA which can be identified by using a variation of the Maxam-Gilbert sequencing procedure. We determined the aflatoxin B1 accessibility of defined regions of the erythroid genome by using different specific probes and monitoring the disappearance of similar-sized fragments generated by restriction enzyme digestion. The genes studied were the erythroid-specific beta-globin and histone H5 genes, which are potentially active in mature erythroid nuclei and transcriptionally active in immature erythrocytes, and the vitellogenin and ovalbumin genes, which are both transcriptionally inactive in these cells. The beta-globin and histone H5 genes were more accessible than the repressed vitellogenin and ovalbumin genes to aflatoxin B1 modification in mature and immature erythroid chromatin. Micrococcal nuclease was used to probe the nucleosomal organization of active (beta-globin and histone H5) and repressed (vitellogenin and ovalbumin) genes in chicken erythrocytes. The vitellogenin and ovalbumin genes show a canonical nucleosome repeat pattern in mature and immature chicken erythrocyte nuclei. In contrast, the beta-globin and histone H5 genes lack a distinct nucleosomal repeat pattern in these cells. These results support the hypothesis that transcriptionally active genes are preferentially accessible to carcinogen modification because of their disrupted chromatin structure.