Raft-based sphingomyelin interactions revealed by new fluorescent sphingomyelin analogs

Sphingomyelin (SM) has been proposed to form cholesterol-dependent raft domains and sphingolipid domains in the plasma membrane (PM). How SM contributes to the formation and function of these domains remains unknown, primarily because of the scarcity of suitable fluorescent SM analogs. We developed new fluorescent SM analogs by conjugating a hydrophilic fluorophore to the SM choline headgroup without eliminating its positive charge, via a hydrophilic nonaethylene glycol linker. The new analogs behaved similarly to the native SM in terms of their partitioning behaviors in artificial liquid order-disorder phase-separated membranes and detergent-resistant PM preparations. Single fluorescent molecule tracking in the live-cell PM revealed that they indirectly interact with each other in cholesterol- and sphingosine backbone–dependent manners, and that, for ∼10–50 ms, they undergo transient colocalization-codiffusion with a glycosylphosphatidylinositol (GPI)-anchored protein, CD59 (in monomers, transient-dimer rafts, and clusters), in CD59-oligomer size–, cholesterol-, and GPI anchoring–dependent manners. These results suggest that SM continually and rapidly exchanges between CD59-associated raft domains and the bulk PM

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Chronic hyperglycemia increases the risk of lateral epicondylitis: the Locomotive Syndrome and Health Outcome in Aizu Cohort Study (LOHAS)

Background: Although humeral epicondylitis is a common health problem, there have been no reports that describe its prevalence in Japanese general population, and relatively little is known about its etiology and associated risk factors. Questions/purposes: This study aimed to clarify the prevalence of humeral epicondilitis in Japanese general population, and investigate the associated risk factors using the data from a cross-sectional study of the Locomotive Syndrome and Health Outcome in Aizu Cohort Study (LOHAS). Methods: A total of 1, 777 participants who participated in health checkups conducted at rural area in Japan in 2010 were enrolled. The prevalence of lateral and medial epicondylitis was investigated. Logistic regression models were performed to examine the relationship between lateral epicondylitis and correlated factors such as occupational status, smoking and alcohol preferences, and medical characteristics. Results: The overall prevalence of lateral and medial epicondylitis was 2.5 % and 0.3 %, respectively. A shortened version of the disabilities of the arm, shoulder and hand (The QuickDASH) score was significantly higher in subjects with lateral epicondylitis than in those without (15.0 ± 12.7 vs 8.5 ± 11.1). Subjects with definite chronic hyperglycemia (HbA1c ≥ 6.5) showed a 3.37-times higher risk of lateral epicondylitis than those with favorable glycemic control (HbA1c < 5.5) (95 % confidence interval (CI) 1.16–8.56). Age and sex, as well as occupational status, smoking and alcohol preference, and other metabolic factors were not significantly related to higher risk of lateral epicondylitis. Conclusions: Lateral epicondylitis influences activities of daily living. Chronic hyperglycemia might be one of the risk factor for lateral epicondylitis. Clinical relevance: Chronic hyperglycemia is significantly associated with lateral epicondylitis

Different In Vitro-Generated MUTZ-3-Derived Dendritic Cell Types Secrete Dexosomes with Distinct Phenotypes and Antigen Presentation Potencies

Human dendritic cell (DC) dexosomes were evaluated for their function and preclinical validation for vaccines. Dexosomes are small DC-secreted vesicles that contain absorbing immune signals. Vaccine manufacturing requires a significant number of monocyte-derived DCs (Mo-DCs) from donor blood; thus, Mo-DC dexosomes are expected to serve as novel materials for cancer vaccination. In this study, we characterized a potential dexosome model using immature and mature MUTZ3-derived DCs (M-imIL-4-DC, M-imIFN-DC, M-mIL-4-DC, and M-mIFN-DC) and their dexosomes (M-imIL-4-Dex, M-imIFN-Dex, M-mIL4-Dex, and M-mIFN-Dex). Despite the lack of significant differences in viability, M-mIFN-DC showed a significantly higher level of yield and higher levels of maturation surface markers, such as CD86 and HLA-ABC, than M-mIL-4-DC. In addition, M-mIFN-Dex expressed a higher level of markers, such as HLA-ABC, than M-mIL-4-Dex. Furthermore, M-mIFN-Dex exhibited a higher level of antigen presentation potency, as evaluated using a MART-1 system, than either M-imIFN-Dex or M-mIL-4-Dex. We found that M-mIFN-Dex is one of the four types of MUTZ3-derived DCs that harbor potential immunogenicity, suggesting that DC dexosomes could be useful resources in cancer immunotherapy

Establishment of home care patient support system: Okayama Central Hospital experience

We established a system to serve aged and disabled people within their neighborhood area. This system consists of visiting nursing service and an institutional care unit, both of which were directed by a managing bureau called the “Life assistance bureau”. This bureau investigates the needs of patients, negotiates with the government, supervises members and is authorized to plan budget and personnel affairs. Activities in one representative case handled by this bureau are reported

Low testosterone levels, depressive symptoms, and falls in older men: a cross-sectional study.

While several studies have cited a potential association between testosterone deficiency and risk of falls among community-dwelling older men, evidence for such an association is conflicting. Depressive symptoms, which occasionally accompany testosterone deficiency but which are often neglected as associated symptoms, may actually provoke falls independent of or jointly with testosterone deficiency. We examined the association between testosterone levels, depressive symptoms, and falls, and assessed the joint effect of testosterone levels and depressive symptoms on falls among older men.Data for this cross-sectional study were obtained from 869 men aged over 60 years who participated in health check-ups conducted in 2010 from 2 Japanese municipalities. Salivary testosterone (sT) levels were measured using an enzyme-linked immunosorbent assay, and depressive symptoms were assessed via the short form of the Center for Epidemiologic Studies Depression Scale. Self-reported "any fall" over the 1-month period. Among the total of 482 participants analyzed (median age, 70 years), 10.8% reported any fall. On comparison between 90th percentile sT levels and lower levels, our logistic regression model with restricted cubic splines showed that lower sT levels were associated with an increased likelihood of suffering any fall after adjustment for sociodemographic characteristics, comorbidities, and mobility function. For example, 5th percentile sT was associated with any fall [adjusted odds ratio (OR), 4.23; 95% confidence interval (CI), 1.66–10.8]. Depressive symptoms were also strongly associated with any fall [adjusted OR, 3.49 (95% CI, 1.52–8.04)]. We noted no apparent interaction of sT and depressive symptoms with falls (P = .079), suggesting that the joint effect of testosterone deficiency and depressive symptoms on falls was multiplicative. Indeed, compared with a combination of 90th percentile sT values and no depressive symptoms, adjusted OR for any fall in a combination involving 5th percentile sT and depressive symptoms was 14.8-fold (95% CI, 3.76–58.0). Our findings indicated that both relatively low testosterone levels and presence of depressive symptoms were independently associated with falls among older men. Causality of these associations should be confirmed in future prospective studies

Viscosity Estimation of a Suspension with Rigid Spheres in Circular Microchannels Using Particle Tracking Velocimetry

Suspension flows are ubiquitous in industry and nature. Therefore, it is important to understand the rheological properties of a suspension. The key to understanding the mechanism of suspension rheology is considering changes in its microstructure. It is difficult to evaluate the influence of change in the microstructure on the rheological properties affected by the macroscopic flow field for non-colloidal particles. In this study, we propose a new method to evaluate the changes in both the microstructure and rheological properties of a suspension using particle tracking velocimetry (PTV) and a power-law fluid model. Dilute suspension (0.38%) flows with fluorescent particles in a microchannel with a circular cross section were measured under low Reynolds number conditions (Re &asymp; 10&minus;4). Furthermore, the distribution of suspended particles in the radial direction was obtained from the measured images. Based on the power-law index and dependence of relative viscosity on the shear rate, we observed that the non-Newtonian properties of the suspension showed shear-thinning. This method will be useful in revealing the relationship between microstructural changes in a suspension and its rheology