Comparison of drug and cell-based delivery: engineered adult mesenchymal stem cells expressing soluble tumor necrosis factor receptor II prevent arthritis in mouse and rat animal models

Rheumatoid arthritis (RA) is a systemic autoimmune disease with unknown etiology where tumor necrosis factor-alpha (TNFα) plays a critical role. Etanercept®, the biologic drug form of soluble tumor necrosis factor receptor-II (sTNFRII) is used to treat RA based on the rational that sTNFRII binds TNFα and blocks inflammation. We compared and benchmarked sTNFRII protein delivery from genetically engineered mesenchymal stem cells (MSCs) to Etanercept®. Blocking TNFα-dependent ICAM-1 surface expression on transduced human MSCs and culture media inhibition of nitric oxide production from ΤΝFα−treated bovine chondrocytes showed functionality of the sTNFRII construction. Implanted TNFRII-transduced MSCs removed mouse serum circulating TNFα generated from either implanted TNFα expressing cells or lipopolysaccharide (LPS) induction better than Etanercept® (TNFα, 100%; IL1α, 90%; and IL6, 60% within 6 hrs.), suggesting faster clearance of the sTNFR:TNFα complex from the animals. In vivo efficacy of sTNFRII-transduced MSCs was illustrated in two (immune-deficient and immune-competent) arthritic rodent models. In the BalbC/SCID mouse antibody-induced arthritis (AbIA) model, intramuscular injection of sTNFR transduced human MSCs reduced joint inflammation by 90% compared to untransduced human MSCs; in the antigen-induced arthritis (AIA) Fisher rat model, both sTNFR transduced rat MSCs and Etanercept® inhibited joint inflammation by 30%. In vitro chondrogenesis assays showed the ability of TNFα and IL1α, but not IFNγ to inhibit human MSC differentiation to chondrocytes, illustrating an additional negative role for inflammatory cytokines in joint repair. The data supports the utility of human MSCs as therapeutic gene delivery vehicles and their potential used in alleviating inflammation within the arthritic joint

Peripheral quantitative computed tomography (pQCT) reveals low bone mineral density in adolescents with motor difficulties

© 2015, International Osteoporosis Foundation and National Osteoporosis Foundation. Summary: This is the first reported study to describe local bone mineral density, assess parameters of fracture risk and report history of fractures in adolescents with motor difficulties. Motor difficulties evidenced by poor coordination in adolescence should be considered a new risk factor for below-average bone strength and structure and fracture risk. Introduction: Adolescents with motor difficulties are characterised by poor coordination and low levels of physical activity and fitness. It is possible these deficits translate into below-average bone strength and structure. The objectives of this study were to describe local bone mineral density (BMD), assess parameters of fracture risk (stress–strain index, SSI) and report history of fractures in this group. Methods: Thirty-three adolescents (13 females), mean age of 14.3 (SD = 1.5) years, with motor difficulties underwent peripheral quantitative computed tomography (pQCT) measurements at proximal (66 %) and distal (4 %) sites of the non-dominant radius (R4 and R66) and tibia (T4 and T66). One sample t test was used to compare Z-scores for total BMD, trabecular density, cortical density and stress strain index (SSI) against standardized norms. Results: Significant differences were present at R4 total density mean Z-score = -0.85 (SD = 0.7, p < 0.001), R66 cortical density mean Z-score = -0.74 (SD = 1.97, p = 0.038), R66 SSI mean Z-score = -1.00 (SD = 1.08, p < 0.001) and T66 SSI mean Z-score = -0.70 (SD = 1.15, p < 0.001). There was a higher incidence of fractures (26.9 %) compared to the normal population (3–9 %). Conclusions: Motor difficulties in adolescence should be considered a risk factor for below-average bone strength and structure and fracture risk. Strategies are needed to improve bone health in this high-risk-group

Optimizing Detection of Major Depression Among Patients with Coronary Artery Disease Using the Patient Health Questionnaire: Data from the Heart and Soul Study

BACKGROUND: Clinical guidelines recommend depression screening in patients with coronary artery disease (CAD), but how to accomplish this is unclear. OBJECTIVE: We evaluated the test characteristics of the two-item Patient Health Questionnaire (PHQ-2), the nine-item Patient Health Questionnaire (PHQ-9), and a two-step screening approach (PHQ-2 then PHQ-9 if positive on PHQ-2), compared with the Computerized Diagnostic Interview Schedule (C-DIS) for major depression. We also evaluated a “PHQ diagnosis ” of depression, requiring five of nine symptoms “more than half the days, ” compared with the C-DIS. DESIGN: Cross-sectional study of 1,024 outpatients with CAD

Bone mineral density and cardiovascular risk factors in postmenopausal women with coronary artery disease

It has been suggested that osteoporosis and coronary artery disease (CAD) have overlapping pathophysiological mechanisms and related risk factors. The aim of this study was to investigate the association between several traditional cardiovascular risk factors and measures of bone mineral density (BMD) in postmenopausal women with and without clinically significant CAD defined angiographically. A case-control study was undertaken of 180 postmenopausal women (aged between 48 and 88 years) who were recruited from King Abdulaziz University Hospital, Saudi Arabia. Study subjects underwent dual-energy x-ray absorptiometry and coronary angiography. The presence of hypertension, diabetes, dyslipidemia, obesity, smoking and physical activity was identified from clinical examination and history. Demographic, anthropometric and biochemical characteristics were measured. Univariate and multivariate analyses were employed to explore the relationships between cardiovascular risk factors, including BMD, and the presence of CAD. CAD patients were more likely to have a lower BMD and T-score at the femoral neck than those without CAD (P<0.05). Significant differences were found between the groups for fasting lipid profile, fasting blood glucose and anthropometric measures (P<0.05). Conditional logistic regression showed that 3 risk factors were significantly related with the presence of CAD: high-density lipoprotein-cholesterol (odds ratio, OR: 0.226, 95% confidence interval, CI: 0.062-0.826), fasting plasma glucose (OR: 1.154, 95% CI: 1.042-1.278) and femoral neck T-score (OR: 0.545, 95% CI: 0.374-0.794). This study suggests an association of low BMD and elevated CAD risk. Nevertheless, additional longitudinal studies are needed to determine the temporal sequence of this association