Class-switzched B cells display response to therapeutic B-cell depletion in rheumatoid arthritis

Introduction Reconstitution of peripheral blood (PB) B cells after therapeutic depletion with the chimeric anti-CD20 antibody rituximab (RTX) mimics lymphatic ontogeny. In this situation, the repletion kinetics and migratory properties of distinct developmental B-cell stages and their correlation to disease activity might facilitate our understanding of innate and adaptive B-cell functions in rheumatoid arthritis (RA). Methods Thirty-five 'RTX-naïve' RA patients with active arthritis were treated after failure of tumour necrosis factor blockade in an open-label study with two infusions of 1,000 mg RTX. Prednisone dose was tapered according to clinical improvement from a median of 10 mg at baseline to 5 mg at 9 and 12 months. Conventional disease-modifying antirheumatic drugs were kept stable. Subsets of CD19+ B cells were assessed by flow cytometry according to their IgD and CD27 surface expression. Their absolute number and relative frequency in PB were followed every 3 months and were determined in parallel in synovial tissue (n = 3) or synovial fluid (n = 3) in the case of florid arthritis. Results Six of 35 patients fulfilled the European League Against Rheumatism criteria for moderate clinical response, and 19 others for good clinical response. All PB B-cell fractions decreased significantly in number (P < 0.001) after the first infusion. Disease activity developed independently of the total B-cell number. B-cell repopulation was dominated in quantity by CD27-IgD+ 'naïve' B cells. The low number of CD27+IgD- class-switched memory B cells (MemB) in the blood, together with sustained reduction of rheumatoid factor serum concentrations, correlated with good clinical response. Class-switched MemB were found accumulated in flaring joints. Conclusions The present data support the hypothesis that control of adaptive immune processes involving germinal centre-derived, antigen, and T-cell-dependently matured B cells is essential for successful RTX treatment.

A Physiological Controller for Turbodynamic Ventricular Assist Devices Based on a Measurement of the Left Ventricular Volume

The current article presents a novel physiological control algorithm for ventricular assist devices (VADs), which is inspired by the preload recruitable stroke work. This controller adapts the hydraulic power output of the VAD to the end-diastolic volume of the left ventricle. We tested this controller on a hybrid mock circulation where the left ventricular volume (LVV) is known, i.e., the problem of measuring the LVV is not addressed in the current article. Experiments were conducted to compare the response of the controller with the physiological and with the pathological circulation, with and without VAD support. A sensitivity analysis was performed to analyze the influence of the controller parameters and the influence of the quality of the LVV signal on the performance of the control algorithm. The results show that the controller induces a response similar to the physiological circulation and effectively prevents over- and underpumping, i.e., ventricular suction and backflow from the aorta to the left ventricle, respectively. The same results are obtained in the case of a disturbed LVV signal. The results presented in the current article motivate the development of a robust, long-term stable sensor to measure the LVV.

Region Specific Response of Intervertebral Disc Cells to Complex Dynamic Loading: An Organ Culture Study Using a Dynamic Torsion-Compression Bioreactor

The spine is routinely subjected to repetitive complex loading consisting of axial compression, torsion, flexion and extension. Mechanical loading is one of the important causes of spinal diseases, including disc herniation and disc degeneration. It is known that static and dynamic compression can lead to progressive disc degeneration, but little is known about the mechanobiology of the disc subjected to combined dynamic compression and torsion. Therefore, the purpose of this study was to compare the mechanobiology of the intervertebral disc when subjected to combined dynamic compression and axial torsion or pure dynamic compression or axial torsion using organ culture. We applied four different loading modalities 1. control: no loading (NL), 2. cyclic compression (CC), 3. cyclic torsion (CT), and 4. combined cyclic compression and torsion (CCT) on bovine caudal disc explants using our custom made dynamic loading bioreactor for disc organ culture. Loads were applied for 8 h/day and continued for 14 days, all at a physiological magnitude and frequency. Our results provided strong evidence that complex loading induced a stronger degree of disc degeneration compared to one degree of freedom loading. In the CCT group, less than 10\% nucleus pulposus (NP) cells survived the 14 days of loading, while cell viabilities were maintained above 70\% in the NP of all the other three groups and in the annulus fibrosus (AF) of all the groups. Gene expression analysis revealed a strong up-regulation in matrix genes and matrix remodeling genes in the AF of the CCT group. Cell apoptotic activity and glycosaminoglycan content were also quantified but there were no statistically significant differences found. Cell morphology in the NP of the CCT was changed, as shown by histological evaluation. Our results stress the importance of complex loading on the initiation and progression of disc degeneration.

Measurement of the vascular input function in mice for DCE-MRI

DCE-MRI is an important technique in the study of small animal cancer models because its sensitivity to vascular changes opens the possibility of quantitative assessment of early therapeutic response. However, extraction of physiologically descriptive parameters from DCE-MRI data relies upon measurement of the vascular input function (VIF), which represents the contrast agent concentration time course in the blood plasma. This is difficult in small animal models due to artifacts associated with partial volume, inflow enhancement, and the limited temporal resolution achievable with MR imaging. In this work, the development of a suite of techniques for high temporal resolution, artifact resistant measurement of the VIF in mice is described. One obstacle in VIF measurement is inflow enhancement, which decreases the sensitivity of the MR signal to the presence of contrast agent. Because the traditional techniques used to suppress inflow enhancement degrade the achievable spatiotemporal resolution of the pulse sequence, improvements can be achieved by reducing the time required for the suppression. Thus, a novel RF pulse which provides spatial presaturation contemporaneously with the RF excitation was implemented and evaluated. This maximizes the achievable temporal resolution by removing the additional RF and gradient pulses typically required for suppression of inflow enhancement. A second challenge is achieving the temporal resolution required for accurate characterization of the VIF, which exceeds what can be achieved with conventional imaging techniques while maintaining adequate spatial resolution and tumor coverage. Thus, an anatomically constrained reconstruction strategy was developed that allows for sampling of the VIF at extremely high acceleration factors, permitting capture of the initial pass of the contrast agent in mice. Simulation, phantom, and in vivo validation of all components were performed. Finally, the two components were used to perform VIF measurement in the murine heart. An in vivo study of the VIF reproducibility was performed, and an improvement in the measured injection-to-injection variation was observed. This will lead to improvements in the reliability of quantitative DCE-MRI measurements and increase their sensitivity.

Intracranial EEG reveals a time- and frequency-specific role for the right inferior frontal gyrus and primary motor cortex in stopping initiated responses.

Inappropriate response tendencies may be stopped via a specific fronto/basal ganglia/primary motor cortical network. We sought to characterize the functional role of two regions in this putative stopping network, the right inferior frontal gyrus (IFG) and the primary motor cortex (M1), using electocorticography from subdural electrodes in four patients while they performed a stop-signal task. On each trial, a motor response was initiated, and on a minority of trials a stop signal instructed the patient to try to stop the response. For each patient, there was a greater right IFG response in the beta frequency band ( approximately 16 Hz) for successful versus unsuccessful stop trials. This finding adds to evidence for a functional network for stopping because changes in beta frequency activity have also been observed in the basal ganglia in association with behavioral stopping. In addition, the right IFG response occurred 100-250 ms after the stop signal, a time range consistent with a putative inhibitory control process rather than with stop-signal processing or feedback regarding success. A downstream target of inhibitory control is M1. In each patient, there was alpha/beta band desynchronization in M1 for stop trials. However, the degree of desynchronization in M1 was less for successfully than unsuccessfully stopped trials. This reduced desynchronization on successful stop trials could relate to increased GABA inhibition in M1. Together with other findings, the results suggest that behavioral stopping is implemented via synchronized activity in the beta frequency band in a right IFG/basal ganglia network, with downstream effects on M1.

Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent

There is established clinical evidence for differences in drug response, cure rates and survival outcomes between different ethnic populations, but the causes are poorly understood. Differences in frequencies of functional genetic variants in key drug response and metabolism genes may significantly influence drug response differences in different populations. To assess this, we genotyped 1330 individuals of African (n=372) and European (n=958) descent for 4535 single-nucleotide polymorphisms in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Important and remarkable differences in the distribution of genetic variants were observed between Africans and Europeans and among the African populations. These could translate into significant differences in drug efficacy and safety profiles, and also in the required dose to achieve the desired therapeutic effect in different populations. Our data points to the need for population-specific genetic variation in personalizing medicine and care.

Motile response patterns and ultrastructural observations of the isolated outer hair cell

The tonotopic organization of the mammalian cochlea is accompanied by structural gradients which include the somatic lengths of outer hair cells (OHCs). These receptors rest upon the vibrating portion of the basilar membrane and have been reported to exhibit motile responses following chemical and electrical stimulation. These movements were examined in detail in this dissertation. It was found that isolated OHCs cultured in vitro respond to chemical depolarization with slow tonic movements, and to electrical waveforms with bi-directional, frequency following movements extending from DC to at least 10 kHz.^ Slow contractions were also elicited following electrical stimulation, bath incubation in carbachol (a cholinergic agonist), and increases in extracellular K+ concentration as little as 50 mM.^ Isolated OHCs display anatomical features which are remarkable when contrasted with those prepared from intact receptor organs. A complex structure located between the cuticular plate and the nuclear membrane was consistently observed and was examined by serial cross-sections which revealed a network of non-membrane bound densities. This corresponded to a granular complex seen at the light microscope level. The complex was composed of dense regions of organelles, striated structures embedded within the core, and a circumferential network of microtubules residing in the peri-nuclear portion of the cell. In cells which had lost their nuclear attachment to the terminal synaptic body, the granular complex could be made to contract without effecting any change in cellular length, implying that the complex may be the driving force behind certain aspects of the motile response.^ Most cells displayed movements which revealed asymmetries analogous to those reported for OHC receptor potentials in vivo. The contraction phase (for longer cells) was shown to have a small time constant (approximately 400 microseconds) and saturated with limited displacements. The expansion phase had time constants as large as 1.3 milliseconds but yielded displacements as much as 60 percent larger than those seen for contractions.^ Additional waveform characteristics seen in the in vivo response could be emulated either by biasing the cell's resting length with either direct current, triggering contractions via large electrical displacements, or incubation with depolarizing compounds.^ Alternatively, short (20-30 um) cells revealed more linear response characteristics to the probe stimulus. Partial saturation was achieved and revealed a DC component which was opposite in polarity to that seen in longer cells. (Abstract shortened with permission of author.) ^

Nonviolent factors: Variables associated with ethnic violence, and factors which are associated with nonviolent response to grievances toward members of other ethnic groups

Ethnic violence appears to be the major source of violence in the world. Ethnic hostilities are potentially all-pervasive because most countries in the world are multi-ethnic. Public health's focus on violence documents its increasing role in this issue.^ The present study is based on a secondary analysis of a dataset of responses by 272 individuals from four ethnic groups (Anglo, African, Mexican, and Vietnamese Americans) who answered questions regarding variables related to ethnic violence from a general questionnaire which was distributed to ethnically diverse purposive, nonprobability, self-selected groups of individuals in Houston, Texas, in 1993.^ One goal was psychometric: learning about issues in analysis of datasets with modest numbers, comparison of two approaches to dealing with missing observations not missing at random (conducting analysis on two datasets), transformation analysis of continuous variables for logistic regression, and logistic regression diagnostics.^ Regarding the psychometric goal, it was concluded that measurement model analysis was not possible with a relatively small dataset with nonnormal variables, such as Likert-scaled variables; therefore, exploratory factor analysis was used. The two approaches to dealing with missing values resulted in comparable findings. Transformation analysis suggested that the continuous variables were in the correct scale, and diagnostics that the model fit was adequate.^ The substantive portion of the analysis included the testing of four hypotheses. Hypothesis One proposed that attitudes/efficacy regarding alternative approaches to resolving grievances from the general questionnaire represented underlying factors: nonpunitive social norms and strategies for addressing grievances--using the political system, organizing protests, using the system to punish offenders, and personal mediation. Evidence was found to support all but one factor, nonpunitive social norms.^ Hypothesis Two proposed that the factor variables and the other independent variables--jail, grievance, male, young, and membership in a particular ethnic group--were associated with (non)violence. Jail, grievance, and not using the political system to address grievances were associated with a greater likelihood of intergroup violence.^ No evidence was found to support Hypotheses Three and Four, which proposed that grievance and ethnic group membership would interact with other variables (i.e., age, gender, etc.) to produce variant levels of subgroup (non)violence.^ The generalizability of the results of this study are constrained by the purposive self-selected nature of the sample and small sample size (n = 272).^ Suggestions for future research include incorporating other possible variables or factors predictive of intergroup violence in models of the kind tested here, and the development and evaluation of interventions that promote electoral and nonelectoral political participation as means of reducing interethnic conflict. ^

PREDICTIVE VARIABLES FOR WEIGHT CHANGE 2 YEARS FOLLOWING PARTICIPATION IN A WEIGHT LOSS INTERVENTION PROGRAM

A historical prospective study was designed to assess the man weight status of subjects who participated in a behavioral weight reduction program in 1983 and to determine whether there was an association between the dependent variable weight change and any of 31 independent variables after a 2 year follow-up period. Data was obtained by abstracting the subjects records and from a follow-up questionnaire administered 2 years following program participation. Five hundred nine subjects (386 females and 123 males) of 1460 subjects who participated in the program, completed and returned the questionnaire. Results showed that mean weight was significantly different (p < 0.001) between the measurement at baseline and after a 2 year follow-up period. The mean weight loss of the group was 5.8 pounds, 10.7 pounds for males and 4.2 pounds for females after a 2 year follow-up period. A total of 63.9% of the group, 69.9% of males and 61.9% of females were still below their initial weight after the 2 year follow-up period. Sixteen of the 31 variables assessed utilizing bivariate analyses were found to be significantly (p (LESSTHEQ) 0.05) associated with weight change after a 2 year follow-up period. These variables were then entered into a multivariate linear regression model. A total of 37.9% of the variance of the dependent variable, weight change, was accounted for by all 16 variables. Eight of these variables were found to be significantly (p (LESSTHEQ) 0.05) predictive of weight change in the stepwise multivariate process accounting for 37.1% of the variance. These variables included: Two baseline variables (percent over ideal body weight at enrollment and occupation) and six follow-up variables (feeling in control of eating habits, percent of body weight lost during treatment, frequency of weight measurement, physical activity, eating in response to emotions, and number of pounds of weight gain needed to resume a diet). It was concluded that a greater amount of emphasis should be placed on the six follow-up variables by clinicians involved in the treatment of obesity, and by the subjects themselves to enhance their chances of success at long-term weight loss. ^

EVOLUTION OF DOMINANCE UNDER FREQUENCY-DEPENDENT INTRASPECIFIC COMPETITION IN AN ASSORTATIVELY MATING POPULATION

We study the evolution of higher levels of dominance as a response to negative frequency-dependent selection. In contrast to previous studies, we focus on the effect of assortative mating on the evolution of dominance under frequency-dependent intraspecific competition. We analyze a two-locus two-allele model, in which the primary locus has a major effect on a quantitative trait that is under a mixture of frequency-independent stabilizing selection, density-dependent selection, and frequency-dependent selection caused by intraspecific competition for a continuum of resources. The second (modifier) locus determines the degree of dominance at the trait level. Additionally, the population mates assortatively with respect to similarities in the ecological trait. Our analysis shows that the parameter region in which dominance can be established decreases if small levels of assortment are introduced. In addition, the degree of dominance that can be established also decreases. In contrast, if assortment is intermediate, sexual selection for extreme types can be established, which leads to evolution of higher levels of dominance than under random mating. For modifiers with large effects, intermediate levels of assortative mating are most favorable for the evolution of dominance. For large modifiers, the speed of fixation can even be higher for intermediate levels of assortative mating than for random mating.

Jet energy measurement with the ATLAS detector in proton-proton collisions at sqrt(s) = 7 TeV

The jet energy scale (JES) and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of sqrt(s) = 7 TeV corresponding to an integrated luminosity of 38 inverse pb. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0.4 or R=0.6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pt > 20 GeV and pseudorapidities eta<4.5. The JES systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams. The JES uncertainty is less than 2.5% in the central calorimeter region (eta<0.8) for jets with 60 < pt < 800 GeV, and is maximally 14% for pt < 30 GeV in the most forward region 3.2 50 GeV after a dedicated correction for this effect. The JES is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pt, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pt jets recoiling against a high-pt jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, providing an improved jet energy resolution and a reduced flavour dependence of the jet response. The JES systematic uncertainty determined from a combination of in situ techniques are consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pt jets.

Frequency of and predictors for withholding patient safety concerns among oncology staff: a survey study.

Speaking up about patient safety is vital to avoid errors reaching the patient and to improve a culture of safety. This study investigated the prevalence of non-speaking up despite concerns for safety and aimed to identify predictors for withholding voice among healthcare professionals (HCPs) in oncology. A self-administered questionnaire assessed safety concerns, speaking up beliefs and behaviours among nurses and doctors from nine oncology departments. Multiple regression analysis was used to identify predictors for withholding safety concerns. A total of 1013 HCPs returned the completed survey (response rate 65%). Safety concerns were common among responders. Fifty-four per cent reported to recognise their colleagues making potentially harmful errors at least sometimes. A majority of responders reported at least some episodes of withholding concerns about patient safety. Thirty-seven per cent said they remained silent at least once when they had information that might have helped prevent an incident. Respondents believed that a high level of interpersonal, communication and coping skills are necessary to speak up about patient safety issues at their workplace. Higher levels of perceived advocacy for patient safety and psychological safety significantly decreased the frequency of withholding voice. Remaining silent about safety concerns is a common phenomenon in oncology. Improved strategies are needed to support staff in effective communication and make cancer care safer.

Suppressing versus releasing a habit: frequency-dependent effects of prefrontal transcranial magnetic stimulation.

When subjects are required to generate a random sequence of numbers they typically produce too many forward and backward 'counts' (e.g. 5-6, 4-3). This counting bias is interpreted as the consequence of an interference by overlearned tendencies to arrange numbers according to their natural order. Inhibition of such well-learned routines is known to rely on frontal lobe functioning. We examined differential effects of slow (1 Hz) and fast (10 Hz) repetitive transcranial magnetic stimulation (rTMS) over the left or right dorsolateral prefrontal cortex (DLPFC) on random number generation (RNG) performance. Eighteen healthy men performed an RNG task. Those subjects stimulated over the left DLPFC showed a frequency-dependent rTMS effect: counting bias was significantly reduced after the 1 Hz stimulation compared with baseline, but significantly exaggerated after the 10 Hz stimulation compared with 1 Hz stimulation. In contrast, the sequences of the subjects stimulated over the right DLPFC showed the well-known excess of counting in all conditions (i.e. baseline, 1 Hz and 10 Hz). These findings confirm the functional importance of specifically the left DLPFC in sequential response production and show, for the first time, that rTMS affects cognitive processing in a frequency-dependent manner.

The Career Satisfaction Scale in Context: A Test for Measurement Invariance Across Four Occupational Groups

This study analyzed the influence of the occupational context on the conceptualization of career satisfaction measured by the career satisfaction scale (CSS). In a large sample of N ¼ 729 highly educated professionals, a cross-occupational (i.e., physicians, economists, engineers, and teachers) measurement invariance analysis showed that the CSS was conceptualized according to occupational group membership, that is, 4 of the 5 items of the scale showed measurement noninvariance. More specifically, the relative importance, the response biases, and the reliabilities associated with different career satisfaction content domains measured by the CSS (i.e., achieved success, overall career goals, goals for advancement, goals for income, and goals for development of new skills) varied by occupational context. However, results of a comparison between manifest and latent mean differences between the occupational groups revealed that the observed measurement noninvariance did not affect the estimation of mean differences.

Glycemic Variability Is Associated with Frequency of Blood Glucose Testing and Bolus: Post Hoc Analysis Results from the ProAct Study

ntroduction: The ProAct study has shown that a pump switch to the Accu-Chek® Combo system (Roche Diagnostics Deutschland GmbH, Mannheim, Germany) in type 1 diabetes patients results in stable glycemic control with significant improvements in glycated hemoglobin (HbA1c) in patients with unsatisfactory baseline HbA1c and shorter pump usage time. Patients and Methods: In this post hoc analysis of the ProAct database, we investigated the glycemic control and glycemic variability at baseline by determination of several established parameters and scores (HbA1c, hypoglycemia frequency, J-score, Hypoglycemia and Hyperglycemia Indexes, and Index of Glycemic Control) in participants with different daily bolus and blood glucose measurement frequencies (less than four day, four or five per day, and more than five per day, in both cases). The data were derived from up to 299 patients (172 females, 127 males; age [mean±SD], 39.4±15.2 years; pump treatment duration, 7.0±5.2 years). Results: Participants with frequent glucose readings had better glycemic control than those with few readings (more than five readings per day vs. less than four readings per day: HbA1c, 7.2±1.1% vs. 8.0±0.9%; mean daily blood glucose, 151±22 mg/dL vs. 176±30 mg/dL; percentage of readings per month >300 mg/dL, 10±4% vs. 14±5%; percentage of readings in target range [80-180 mg/dL], 59% vs. 48% [P<0.05 in all cases]) and had a lower glycemic variability (J-score, 49±13 vs. 71±25 [P<0.05]; Hyperglycemia Index, 0.9±0.5 vs. 1.9±1.2 [P<0.05]; Index of Glycemic Control, 1.9±0.8 vs. 3.1±1.6 [P<0.05]; Hypoglycemia Index, 0.9±0.8 vs. 1.2±1.3 [not significant]). Frequent self-monitoring of blood glucose was associated with a higher number of bolus applications (6.1±2.2 boluses/day vs. 4.5±2.0 boluses/day [P<0.05]). Therefore, a similar but less pronounced effect on glycemic variability in favor of more daily bolus applications was observed (more than five vs. less than four bolues per day: J-score, 57±17 vs. 63±25 [not significant]; Hypoglycemia Index, 1.0±1.0 vs. 1.5±1.4 [P<0.05]; Hyperglycemia Index, 1.3±0.6 vs. 1.6±1.1 [not significant]; Index of Glycemic Control, 2.3±1.1 vs. 3.1±1.7 [P<0.05]). Conclusions: Pump users who perform frequent daily glucose readings have a better glycemic control with lower glycemic variability.