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

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

Markedly impaired bilateral coordination of gait in post-stroke patients: Is this deficit distinct from asymmetry? A cohort study.

Contains fulltext : 97098.pdf (publisher's version ) (Open Access)BACKGROUND: Multiple aspects of gait are typically impaired post-stroke. Asymmetric gait is common as a consequence of unilateral brain lesions. The relationship between the resulting asymmetric gait and impairments in the ability to properly coordinate the reciprocal stepping activation of the legs is not clear. The objective of this exploratory study is to quantify the effects of hemiparesis on two putatively independent aspects of the bilateral coordination of gait to gain insight into mechanisms and their relationship and to assess their potential as clinical markers. METHODS: Twelve ambulatory stroke patients and age-matched healthy adults wore a tri-axial piezo-resistive accelerometer and walked back and forth along a straight path in a hall at a comfortable walking speed during 2 minutes. Gait speed, gait asymmetry (GA), and aspects of the bilateral coordination of gait (BCG) were determined. Bilateral coordination measures included the left-right stepping phase for each stride phii, consistency in the phase generation phi_CV, accuracy in the phase generation phi_ABS, and Phase Coordination Index (PCI), a combination of accuracy and consistency of the phase generation. RESULTS: Group differences (p < 0.001) were observed for gait speed (1.1 +/- 0.1 versus 1.7 +/- 0.1 m/sec for patients and controls, respectively), GA (26.3 +/- 5.6 versus 5.5 +/- 1.2, correspondingly) and PCI (19.5 +/- 2.3 versus 6.2 +/- 1.0, correspondingly). A significant correlation between GA and PCI was seen in the stroke patients (r = 0.94; p < 0.001), but not in the controls. CONCLUSIONS: In ambulatory post-stroke patients, two gait coordination properties, GA and PCI, are markedly impaired. Although these features are not related to each other in healthy controls, they are strongly related in stroke patients, which is a novel finding. A measurement approach based on body-fixed sensors apparently may provide sensitive markers that can be used for clinical assessment and for enhancing rehabilitation targeting in post-stroke patients

The validity of assessing temporal events, sub-phases and trunk kinematics of the sit-to-walk movement in older adults using a single inertial sensor

The aim of this study was to develop a method to identify temporal events, sub-phases and trunk kinematics of the sit-to-walk (STW) using a single inertial sensor (IS) worn at the lower back and to determine the validity of this method. Twenty-seven healthy older adults performed a STW movement, which started from sitting in a chair and included walking 3 m.Participants[U+05F3] movements were recorded with the IS, a reference measurement system consisting of an optical motion capture system (3 markers on the IS and one on each foot) and on-off switches located in the seat of the chair.Using the data from the IS and the reference measurement systems, the following signals and variables were calculated and compared: 3D IS motion (accelerations, velocities, displacements and angles), temporal events (start of trunk movement, seat-off, end of trunk flexion phase, end of trunk rising phase and gait initiation) and trunk kinematics (flexion range, maximum flexion velocity, maximum forward velocity and forward velocity during seat-off and at first heel-strike and maximum vertical velocity and vertical velocity at first heel-strike).For most variables acceptable differences (RMSE<10%) were found between IS and reference measurement systems, except for sideways displacements and non-sagittal plane rotations. Furthermore, good results were found for temporal event detection, with ICC values for all variables being 0.988 or higher. With exception of the vertical velocity at heel-strike agreement for trunk kinematics was high, with ICC values being 0.867 or higher

Salient and placebo vibrotactile feedback are equally effective in reducing sway in bilateral vestibular loss patients

This study explores the effect of vibrotactile biofeedback on body sway in stance in patients with severe bilateral vestibular losses in a placebo-controlled study. A tilt sensor mounted on the head or trunk is used to detect head or body tilt and activates via a microprocessor 12 small vibrators that are placed around the waist with a mutual distance of 30°. Two positions of the tilt sensor (head and trunk) and three types of biofeedback (normal, full and random) were evaluated, besides no biofeedback. Body sway during stance was assessed in 10 patients with bilateral vestibular areflexia and performance was scored in the seven different conditions. Inter-individual and test-retest variability without biofeedback was assessed in 10 additional patients with bilateral vestibular areflexia. In six patients no significant change in body swaypath was observed using biofeedback. In four patients body swaypath decreased significantly using biofeedback and sensor on the head in all three activation modes, whereas with sensor on the trunk only one patient showed a significant improvement in swaypath in all three activation modes. The patients rated the functionality of the AVBF system and its effect on balance on average 6.5 on a scale from 0 to 10. Thus, body sway improved in 4 out of 10 patients using biofeedback, but the improvement with true biofeedback was only observed in those subjects where an improvement was present in placebo mode as well. The improvement was, at least partially, caused by other effects than biofeedback, like training, increased self-confidence or alertness

A correlation study of objective functionality and WOMAC in total knee arthroplasty

Function studies after total knee arthroplasty (TKA) generally use either self-reported instruments or objective quantitative measurements of walking activities, but it is unclear how objective factors influence self-reports. This retrospective multicenter study assessed the impact of objective variables on subjective self-reported functional outcome after TKA in 128 patients at a mean of 41 months after TKA. Self-reported disability was measured by the Western Ontario and McMaster University (WOMAC) scale, and the quality of walking and representative daily activities were determined objectively by the DynaPort knee test. Objective assessment was found to be a poor predictor of WOMAC abnormality, with correlations of 0.343, 0.246, and 0.269 with WOMAC function, stiffness, and pain, respectively. The results of WOMAC are thus strongly influenced by factors other than quantitative parameters of the lower extremity. These findings provide support for including an objective assessment of activities of daily living together with a subjective self-report

"Can do" versus "do do": A Novel Concept to Better Understand Physical Functioning in Patients with Chronic Obstructive Pulmonary Disease

Contains fulltext : 203249.pdf (publisher's version ) (Open Access)10 p