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

"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

Health-Related Quality of Life in patients with Parkinson's disease A systematic review based on the ICF model

Neurological Motor Disorder

Clinical observational gait analysis to evaluate improvement of balance during gait with vibrotactile biofeedback

Background and Purpose. This study explores the effect of vibrotactile biofeedback on gait in 20 patients with bilateral vestibular areflexia using observational gait analysis to score individual balance. Methods.A tilt sensor mounted on the head or trunk is used to detect head or body tilt and activates, via a microprocessor, 12 equally distributed vibrators placed around the waist. Two positions of the tilt sensor were evaluated besides no biofeedback in three different gait velocity tasks (slow/fast tandem gait, normal gait on foam) resulting in nine different randomized conditions. Biofeedback activated versus inactivated was compared. Twenty patients (10 males, 10 females, age 39-77 years) with a bilateral vestibular areflexia or severe bilateral vestibular hyporeflexia, severe balance problems and frequent falls participated in this study. Results.Significant improvements in balance during gait were shown in our patients using biofeedback and sensor on the trunk. Only two patients showed a significant individual gait improvement with the biofeedback system, but in the majority of our patients, it increased confidence and a feeling of balance. Conclusion.This study indicates the feasibility of vibrotactile biofeedback for vestibular rehabilitation and to improve balance during gait. © 2011 John Wiley & Sons, Ltd

Effect of calendar age on physical performance: A comparison of standard clinical measures with instrumented measures in middle-aged to older adults

Background: Decline in physical performance is highly prevalent during aging. Identification of sensitive markers of age-related changes in physical performance is important for early detection, development of therapeutic strategies and insight into underlying mechanisms. We studied the association of calendar age and familial longevity with standard clinical and instrumented measures of physical performance in a cohort of healthy middle-aged to older adults. Methods: Cross-sectional analysis within the Leiden Longevity Study consisting of offspring of nonagenarian siblings and their partners (n = 300, mean age (SD) 65.3 (6.7) years). Standard clinical measures were 25-meter walking speed and total duration of the chair stand test (CST). Instrumented measures were determined using a body fixed sensor. Dependence of physical performance on calendar age and familial longevity (offspring versus partner status) was analyzed using linear and logistic regression, respectively, adjusted for gender and height. Results: Higher calendar age was associated with slower walking speed and longer duration of the CST (standardized β (95% CI) -.024 (-.042; -.006) and .035 (.014;.056), respectively). Instrumented measures showed similar effect sizes with strongest associations for gait stability and symmetry in mediolateral direction and for the extension and flexion phase of sit-to-stand and stand-to-sit transfers, respectively. No differences were observed between offspring of nonagenarian siblings and their partners. Conclusions: Standard clinical and instrumented measures of physical performance are associated with similar effect size to age-related changes in physical performance observable from middle age. The potential added value of instrumented measures for understanding underlying mechanisms requires further attention

Is the Assessment of 5 Meters of Gait with a Single Body-Fixed-Sensor Enough to Recognize Idiopathic Parkinson's Disease-Associated Gait?

Quantitative assessment of gait in patients with Parkinson's disease (PD) is an important step in addressing motor symptoms and improving clinical management. Based on the assessment of only 5 meters of gait with a single body-fixed-sensor placed on the lower back, this study presents a method for the identification of step-by-step kinematic parameters in 14 healthy controls and in 28 patients at early-to-moderate stages of idiopathic PD. Differences between groups in step-by-step kinematic parameters were evaluated to understand gait impairments in the PD group. Moreover, a discriminant model between groups was built from a subset of significant and independent parameters and based on a 10-fold cross-validated model. The discriminant model correctly classified a total of 89.5% participants with four kinematic parameters. The sensitivity of the model was 95.8% and the specificity 78.6%. The results indicate that the proposed method permitted to reasonably recognize idiopathic PD-associated gait from 5-m walking assessments. This motivates further investigation on the clinical utility of short episodes of gait assessment with body-fixed-sensors

Phosphoinositide phosphatase SHIP-1 regulates apoptosis induced by edelfosine, Fas ligation and DNA damage in mouse lymphoma cells

International audienceS49 mouse lymphoma cells undergo apoptosis in response to the alkyl-lysophospholipid (ALP) edelfosine, Fas/CD95 ligand (FasL) and DNA damage. Cells made resistant to ALP (S49AR) are defective in sphingomyelin synthesis and ALP uptake, and also have acquired resistance to FasL and DNA damage. However, these cells can be resensitized following prolonged culturing in the absence of ALP. The resistant cells show sustained ERK/Akt activity, consistent with enhanced survival signalling. In search of a common mediator of the observed cross-resistance, we found that S49AR cells lacked the PtdIns(3,4,5)P3 phosphatase SHIP-1, a known regulator of the Akt survival pathway. Resensitization of the S49AR cells restored SHIP-1 expression as well as phosphoinositide and sphingomyelin levels. Knockdown of SHIP-1 mimicked the S49AR phenotype in terms of apoptosis cross-resistance, sphingomyelin deficiency and altered phosphoinositide levels. Collectively, our results suggest that SHIP-1 collaborates with sphingomyelin synthase to regulate lymphoma cell death irrespective of the nature of the apoptotic stimulus