Wnt2 accelerates cardiac myocyte differentiation from ES-cell derived mesodermal cells via non-canonical pathway

The efficient induction of cardiomyocyte differentiation from embryonic stem (ES) cells is crucial for cardiac regenerative medicine. Although Wnts play important roles in cardiac development, complex questions remain as to when, how and what types of Wnts are involved in cardiogenesis. We found that Wnt2 was strongly up-regulated during cardiomyocyte differentiation from ES cells. Therefore, we investigated when and how Wnt2 acts in cardiogenesis during ES cell differentiation. Wnt2 was strongly expressed in the early developing murine heart. We applied this embryonic Wnt2 expression pattern to ES cell differentiation, to elucidate Wnt2 function in cardiomyocyte differentiation. Wnt2 knockdown revealed that intrinsic Wnt2 was essential for efficient cardiomyocyte differentiation from ES cells. Moreover, exogenous Wnt2 increased cardiomyocyte differentiation from ES cells. Interestingly, the effects on cardiogenesis of intrinsic Wnt2 knockdown and exogenous Wnt2 addition were temporally restricted. During cardiomyocyte differentiation from ES cells, Wnt2 didn't activate canonical Wnt pathway but utilizes JNK/AP-1 pathway which is required for cardiomyocyte differentiation from ES cells. Therefore we conclude that Wnt2 plays strong positive stage-specific role in cardiogenesis through non-canonical Wnt pathway in murine ES cells.     

Is a composite score of physical performance measures more useful than usual gait speed alone in assessing functional status?

Overall physical performance can be represented by a composite score that is derived from upper and lower extremity performance measures. We aimed to identify whether composite scores of performance measures, particularly the lower extremity performance (LEP) score, upper extremity performance (UEP) score, and an overall score, are more accurate than usual gait speed (UGS) for assessing a wide range of functional status. We conducted a cross-sectional analysis on data from 701 community-dwelling older women (mean age 74.3 years). Trained testers measured UGS and the seven tests included in the composite scores. Using self-reported questionnaires, we assessed multiphasic functional status: physical function, higher-level functional capacity, mobility limitation, activities of daily living (ADLs), and falls. We compared the areas under the receiver operating characteristic curves (AUCs) of UGS with LEP, UEP, and overall scores for each status. We found no significant differences between the AUCs of UGS and LEP score for each status. The UEP score had significantly smaller AUCs for low physical function (0.73) and mobility limitation (0.78) than UGS alone (0.81 and 0.85, respectively), and the differences were substantial. Although the overall score had significantly greater AUCs for low higher-level functional capacity (0.83) and ADLs disability (0.83) than UGS alone (0.78 and 0.80, respectively), the differences were only 3-5%. The UGS should not be regarded solely as a measure of lower extremity function; this single test may represent overall physical performance. The UGS alone, which can be measured quickly and easily, suffice for assessing a wide range of functional status in older women.     

AAV8 vector expressing IL24 efficiently suppresses tumor growth mediated by specific mechanisms in MLL/AF4-positive ALL model mice

Mixed-lineage leukemia (MLL)/AF4-positive acute lymphoblastic leukemia (ALL) is a common type of leukemia in infants, which is associated with a high relapse rate and poor prognosis. IL24 selectively induces apoptosis in cancer cells and exerts immunomodulatory and antiangiogenic effects. We examined the effects of adeno-associated virus type 8 (AAV8) vector-mediated muscle-directed systemic gene therapy in MLL/AF4-positive ALL using IL24. In a series of in vitro studies, we examined the effects of AAV8-IL24-transduced C2C12 cell-conditioned medium. We also examined the effects of AAV8-IL24 in MLL/AF4 transgenic mice. The results revealed the effects of AAV8-IL24 in MLL/AF4-positive ALL both in vitro and in vivo. With regard to the mechanism of therapy using AAV8-IL24 in MLL/AF4-positive ALL, we demonstrated the antiangiogenicity and effects on the ER stress pathway and unreported pathways through inhibition of S100A6 and HOXA9, which is specific to MLL/AF4-positive ALL. Inhibition of S100A6 by IL24 was dependent on TNF-α and induced acetylation of p53 followed by activation of the caspase 8-caspase 3 apoptotic pathway. Inhibition of HOXA9 by IL24, which was independent of TNF-α, induced MEIS1 activation followed by activation of the caspase 8-caspase 3 apoptotic pathway. Thus, gene therapy using AAV8-IL24 is a promising treatment for MLL/AF4-positive ALL.     

Russell body gastritis

A 63-year-old woman who presented with chest and back pain underwent an upper gastrointestinal endoscopy which revealed elevated legion in the antrum mucosa. Histologic examinations of gastric biopsies were showing monoclonal proliferation plasma cells containing Russell bodies. Differential diagnosis from B-cell lymphoma and plasmacytoma is difficult, because of monoclonality. Molecular analyses of immunoglobulin heavy chain (IgH) gene demonstrated that gene rearrangement was negative. Thus, diagnosis of Russell body gastritis was made. The Giemsa stains were also showing infection of Helicobacter pylori (H.pylori). After eradication therapy for H.pylori, follow-up upper gastrointestinal endoscopy was performed. She then recovered.     

Moderate-to-vigorous physical activity and the risk of stroke recurrence in patients with a history of minor ischemic stroke in Japan: a retrospective analysis

Background: Physical activity (PA) is beneficial for stroke prevention; in particular, moderate-to-vigorous physical activity (MVPA). However, few studies have investigated its relationship with recurrent ischemic stroke (RIS).

Objectives: To clarify the relationship between MVPA and RIS and the burden of risk factors after a first-ever ischemic stroke.

Methods: A total of 45 outpatients (mean age 67.1 ± 10.2 years) who had previously experienced a transient ischemic attack or a minor non-cardioembolic ischemic stroke at a single hospital in Japan (mean 6.4 ± 4.2 years previously), were enrolled between March and June 2016. All patients wore an accelerometer around their hips for 10 days, and their percentage body fat (%BF) and visceral fat level (VFL) were measured by bioelectrical impedance. Retrospective information about the history of RIS and risk factors (blood pressure, lipoprotein cholesterol and estimated glomerular filtration rate) were extracted from the clinical records. Binary logistic regression models were used to estimate the relevance of the RIS history to MVPA and potential risk factors such as sociodemographic and clinical variables (obesity, smoking and hypertension).

Results: RIS occurred in 9 patients; they had significantly higher VFL (p = 0.007) and %BF (p = 0.007) values and lower MVPA (p = 0.011) values than patients without recurrence. A multivariate analysis of these factors indicated that age, VFL and MVPA were signi?cant independent predictors of RIS.

Conclusions: Patients with a history of mild ischemic stroke had low MVPA and high VFL values, which together may be a risk factor for RIS.