A Novel Dimeric Inhibitor Targeting Beta2GPI in Beta2GPI/Antibody Complexes Implicated in Antiphospholipid Syndrome

Background: b2GPI is a major antigen for autoantibodies associated with antiphospholipid syndrome (APS), an autoimmune disease characterized by thrombosis and recurrent pregnancy loss. Only the dimeric form of b2GPI generated by anti-b2GPI antibodies is pathologically important, in contrast to monomeric b2GPI which is abundant in plasma. Principal Findings: We created a dimeric inhibitor, A1-A1, to selectively target b2GPI in b2GPI/antibody complexes. To make this inhibitor, we isolated the first ligand-binding module from ApoER2 (A1) and connected two A1 modules with a flexible linker. A1-A1 interferes with two pathologically important interactions in APS, the binding of b2GPI/antibody complexes with anionic phospholipids and ApoER2. We compared the efficiency of A1-A1 to monomeric A1 for inhibition of the binding of b2GPI/antibody complexes to anionic phospholipids. We tested the inhibition of b2GPI present in human serum, b2GPI purified from human plasma and the individual domain V of b2GPI. We demonstrated that when b2GPI/antibody complexes are formed, A1-A1 is much more effective than A1 in inhibition of the binding of b2GPI to cardiolipin, regardless of the source of b2GPI. Similarly, A1-A1 strongly inhibits the binding of dimerized domain V of b2GPI to cardiolipin compared to the monomeric A1 inhibitor. In the absence of anti-b2GPI antibodies, both A1-A1 and A1 only weakly inhibit the binding of pathologically inactive monomeric b2GPI to cardiolipin. Conclusions: Our results suggest that the approach of using a dimeric inhibitor to block b2GPI in the pathologica

FLAIR* to visualize veins in white matter lesions: A new tool for the diagnosis of multiple sclerosis?

Royal College of Radiologists (pump priming grant to RJPS). MEM is partly funded (20%) by the Barts and the London National Institute for Health Research Cardiovascular Biomedical Research Unit. Additional study support provided by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, USA

Frequent sputum production is associated with disturbed night's rest and impaired sleep quality in patients with COPD

Purpose In this study, we measured night's rest parameters measured with an accelerometer and sleep quality in mild to very severe patients with COPD. Furthermore, our aim was to investigate the association between night's rest parameters and clinical variables and the association between sleep quality and quality of life or health status. Methods Mild to very severe COPD patients were recruited from general practitioners and outpatient clinics of general hospitals to participate in a cross-sectional study on physical activity in patients with COPD. A total of 103 patients (mean age 65 years, 67 % male) wore the accelerometer during night's rest for at least four nights and were included in the analyses. Results No significant associations were found between objectively measured body movements during night's rest or subjective sleep quality and lung function, dyspnoea severity, body composition and physical activity during the day. Patients with frequent sputum production during the day had a higher number of sitting transitions during the night (5.3 vs 4.3 sitting transitions) and more frequently got out of bed compared to patients who hardly ever produced sputum during the day (1.0 vs 0.8 times per night). Furthermore, these patients also reported worse sleep quality (Pittsburgh sleep quality index (PSQI) score 4 vs 3). Conclusions Our results indicate that objectively measured body movements during night's rest like body postures and transitions are not related to sleep quality in patients with COPD. We did find an association between frequent sputum production and disturbances during night's rest and sleep quality. Future studies should investigate whether the treatment of mucus hypersecretion leads to improved night's rest

Decrease of thalamic gray matter following limb amputation

Modern neuroscience has elucidated general mechanisms underlying the functional plasticity of the adult mammalian brain after limb deafferentation. However, little is known about possible structural alterations following amputation and chronic loss of afferent input in humans. Using voxel-based morphometry (VBM), based on high-resolution magnetic resonance images, we investigated the brain structure of 28 volunteers with unilateral limb amputation and compared them to healthy controls. Subjects with limb amputation exhibited a decrease in gray matter of the posterolateral thalamus contralateral to the side of the amputation. The thalamic gray matter differences were positively correlated with the time span after the amputation but not with the frequency or magnitude of coexisting phantom pain. Phantom limb pain was unrelated to thalamic structural variations, but was positively correlated to a decrease in brain areas related to the processing of pain. No gray matter increase was detected. The unilateral thalamic differences may reflect a structural correlate of the loss of afferent input as a secondary change following deafferentation

Sparse Signal Recovery from Fixed Low-Rank Subspace via Compressive Measurement

This paper designs and evaluates a variant of CoSaMP algorithm, for recovering the sparse signal s from the compressive measurement  given a fixed low-rank subspace spanned by U. Instead of firstly recovering the full vector then separating the sparse part from the structured dense part, the proposed algorithm directly works on the compressive measurement to do the separation. We investigate the performance of the algorithm on both simulated data and video compressive sensing. The results show that for a fixed low-rank subspace and truly sparse signal the proposed algorithm could successfully recover the signal only from a few compressive sensing (CS) measurements, and it performs better than ordinary CoSaMP when the sparse signal is corrupted by additional Gaussian noise

Minimal correlation between physical exercise capacity and daily activity in patients with intermittent claudication

Background Walking capacity measured by a treadmill test (TT) reflects the patient's maximal capacity in a controlled setting and is part of the physical exercise capacity (PEC). Daily physical activity (PA) is defined as the total of actively freely produced movements per day. A lower PA level has been increasingly recognized as a strong predictor of increased morbidity and mortality in patients with intermittent claudication (IC). Recent insights suggested that an increased PEC does not automatically lead to an increase in daily PA. However, the precise relation between PEC and PA in patients with IC is still unclear. Methods A cross-sectional study was conducted to assess the association between several PEC outcomes and PA in a general IC population. PEC was determined by well-established tests (Gardner-Skinner TT, a physical performance battery, a timed up-and-go test, and a 6-minute walk test distance). PA was obtained during 7 consecutive days using a triaxial accelerometer (Dynaport MoveMonitor; McRoberts BV, The Hague, The Netherlands). Five PA components (lying, sitting, standing, shuffling, and locomotion) and four parameters (total duration, number of periods, mean duration per period, and mean movement intensity per period) were analysed. Correlation coefficients between PEC and PA components were calculated. Results Data of 46 patients were available for analysis. Patients were sedentary (sitting and lying) during 81% of the day and were physically active (standing, shuffling, and locomotion) for the remaining 19% of the time. Correlations between PEC outcomes and PA ranged from very weak (0.025) to moderate (0.663). Moderate correlations (as therefore assumed to be relevant) were only found for outcomes of both the TT and 6-minute walk test and the locomotion components of PA. For instance, functional claudication distance (measured by TT) and number of steps per day correlated reasonably well (Spearman correlation ρ = 0.663; P <.01). Conclusions Exercise capacity and PA correlate minimally in patients with IC. PA may be preferred as a novel outcome measure and future treatment target in patients with IC