Cardio-Protection Afforded by Β-Blockade Is Maintained During Resistance Exercise

Objectives Whether or not the cardio-protective effect of β-adrenergic blockade is retained during resistance exercise has not been systematically evaluated. Therefore the purpose of this study was to measure selected cardiorespiratory responses to isometric exercise involving hand-gripping, single-leg extension, or double-leg dead-lift, under placebo (control), β1-selective (atenolol), and non-selective (propranolol) adrenergic blockade conditions. Design Eleven young male adults were evaluated in a randomized, double-blinded, repeated measures study design and performed all three exercise modalities at 30% of maximal voluntary contraction under placebo, atenolol and propranolol conditions. Methods Heart rate, systolic and diastolic blood pressure, rate-pressure product, oxygen uptake, cardiac output, stroke volume and total peripheral resistance were directly measured or calculated at rest and during the third minute of each of the three exercise modes. Results Irrespective of drug condition, a graded pressor response was observed going from rest to exercise so that rest \u3c handgrip \u3c leg extension \u3c dead-lift for heart rate, systolic and diastolic blood pressures, rate-pressure product and oxygen uptake (p \u3c 0.05 for all). Cardiac output only increased with the dead-lift mode of exercise (p \u3c 0.01). Importantly β-adrenergic blockade with either atenolol or propranolol similarly attenuated the rise in heart rate, and systolic blood pressure; thus rate-pressure product demonstrated a mode-of-exercise by drug interaction effect (p \u3c 0.001) with the greatest reductions seen with the dead-lift procedure. Conclusions The findings indicate that cardio-protection afforded by selective or non-selective β-blockade at rest is preserved during isometric exercise and even enhanced once heart rate increases above 100 beats min−1

Do “one-size” employment policies fit all young workers? Heterogeneity in work attribute preferences among the Millennial generation

There has been a stream of research that explores how the present generation of workers (i.e., Millennials) may be different from previous generations (e.g., Baby Boomers and Gen Xers). This line of research often considers Millennials as homogeneous and concludes any differences to be “generational effects.” However, it is unlikely for a generation, which spans almost 20 years, to be uniformly homogeneous with respect to their work values and attitudes. Findings on generational differences conducted in the United States are also often generalized to other countries, ignoring the potential for national influences. In this regard, we apply a multi-method approach using three samples to demonstrate that there are differences within the Millennial generation that affect work values, preferences for work/life balance, and attraction to employer attributes. Specifically, we focus on the heterogeneity resulting from differences in age, gender, relationship status, and nationality. Our results suggest that Millennials are not as homogeneous as we assumed, and this can limit the effectiveness of managerial policies designed to improve individual and work outcomes for an entire generation of workers. Our study demonstrates that it is important for us to understand how individual, relational, and contextual factors may contribute to the heterogeneity within a generation

Multimodality PET/MRI agents targeted to activated macrophages

The recent emergence of multimodality imaging, particularly the combination of PET and MRI, has led to excitement over the prospect of improving detection of disease. Iron oxide nanoparticles have become a popular platform for the fabrication of PET/MRI probes owing to their advantages of high MRI detection sensitivity, biocompatibility, and biodegradability. In this article, we report the synthesis of dextran-coated iron oxide nanoparticles (DIO) labeled with the positron emitter ^(64)Cu to generate a PET/MRI probe, and modified with maleic anhydride to increase the negative surface charge. The modified nanoparticulate PET/MRI probe (MDIO-^(64)Cu-DOTA) bears repetitive anionic charges on the surface that facilitate recognition by scavenger receptor type A (SR-A), a ligand receptor found on activated macrophages but not on normal vessel walls. MDIO-^(64)Cu-DOTA has an average iron oxide core size of 7–8 nm, an average hydrodynamic diameter of 62.7 nm, an r_1 relaxivity of 16.8 mM^(−1) s^(−1), and an r_2 relaxivity of 83.9 mM^(−1) s^(−1) (37 °C, 1.4 T). Cell studies confirmed that the probe was nontoxic and was specifically taken up by macrophages via SR-A. In comparison with the nonmodified analog, the accumulation of MDIO in macrophages was substantially improved. These characteristics demonstrate the promise of MDIO-^(64)Cu-DOTA for identification of vulnerable atherosclerotic plaques via the targeting of macrophages

Spacetime Emergence and General Covariance Transmutation

Spacetime emergence refers to the notion that classical spacetime "emerges" as an approximate macroscopic entity from a non-spatio-temporal structure present in a more complete theory of interacting fundamental constituents. In this article, we propose a novel mechanism involving the "soldering" of internal and external spaces for the emergence of spacetime and the twin transmutation of general covariance. In the context of string theory, this mechanism points to a critical four dimensional spacetime background.Comment: 11 pages, v2: version to appear in MPL

Compositionality, stochasticity and cooperativity in dynamic models of gene regulation

We present an approach for constructing dynamic models for the simulation of gene regulatory networks from simple computational elements. Each element is called a ``gene gate'' and defines an input/output-relationship corresponding to the binding and production of transcription factors. The proposed reaction kinetics of the gene gates can be mapped onto stochastic processes and the standard ode-description. While the ode-approach requires fixing the system's topology before its correct implementation, expressing them in stochastic pi-calculus leads to a fully compositional scheme: network elements become autonomous and only the input/output relationships fix their wiring. The modularity of our approach allows to pass easily from a basic first-level description to refined models which capture more details of the biological system. As an illustrative application we present the stochastic repressilator, an artificial cellular clock, which oscillates readily without any cooperative effects.Comment: 15 pages, 8 figures. Accepted by the HFSP journal (13/09/07

The Effect of Iron and Erythropoietin Treatment on the A1C of Patients With Diabetes and Chronic Kidney Disease

OBJECTIVE - To examine the effect of intravenous iron and erythropoietin-stimulating agents (ESAs) on glycemic control and A1C of patients with diabetes and chronic kidney disease (CKD). RESEARCH DESIGN AND METHODS- This was a prospective study of patients with type 2 diabetes and CKD stage IIIB or IV undergoing intravenous iron (group A) and/or ESA (group B). Full blood profiles were determined over the study period. Glycemic control was monitored using A1C, seven-point daily glucose three times weekly, and continuous glucose monitoring (CGM). RESULTS - There were 15 patients in both group A and group B. Mean A1C (95% CI) values fell in both groups (7.40% [6.60-8.19] to 6.96% [6.27-7.25] , P < 0.01, with intravenous iron and 7.31% [6.42-8.54] to 6.63% [6.03-7.36] , P = 0.013, ESA). There was no change in mean blood glucose in group A (9.55 mmol/l [8.20-10.90] vs. 9.71 mmol/l [8.29-11.13] , P = 0.07) and in group B (8.72 mmol/l [7.31-10.12] vs. 8.78 mmol/l [7.47-9.99] , P=0.61) over the study period. Hemoglobin and hematocrit values significantly increased following both treatments. There was no linear relationship found between the change in A1C values and the rise of hemoglobin following either treatment. CONCLUSIONS - Both iron and ESA cause a significant fall in A1C values without a change to glycemic control in patients with diabetes and CKD. At the present time, regular capillary glucose measurements and the concurrent use of CGM remain the best alternative measurements of glycemic control in this patient group

Serial Diffusion MRI to Monitor and Model Treatment Response of the Targeted Nanotherapy CRLX101

Purpose: Targeted nanotherapies are being developed to improve tumor drug delivery and enhance therapeutic response. Techniques that can predict response will facilitate clinical translation and may help define optimal treatment strategies. We evaluated the efficacy of diffusion-weighted magnetic resonance imaging to monitor early response to CRLX101 (a cyclodextrin-based polymer particle containing the DNA topoisomerase I inhibitor camptothecin) nanotherapy (formerly IT-101), and explored its potential as a therapeutic response predictor using a mechanistic model of tumor cell proliferation. Experimental Design: Diffusion MRI was serially conducted following CRLX101 administration in a mouse lymphoma model. Apparent diffusion coefficients (ADCs) extracted from the data were used as treatment response biomarkers. Animals treated with irinotecan (CPT-11) and saline were imaged for comparison. ADC data were also input into a mathematical model of tumor growth. Histological analysis using cleaved-caspase 3, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling, Ki-67, and hematoxylin and eosin (H&E) were conducted on tumor samples for correlation with imaging results. Results: CRLX101-treated tumors at day 2, 4, and 7 posttreatment exhibited changes in mean ADC = 16 ± 9%, 24 ± 10%, 49 ± 17%, and size (TV) = −5 ± 3%, −30 ± 4%, and −45 ± 13%, respectively. Both parameters were statistically greater than controls [p(ADC) ≤ 0.02, and p(TV) ≤ 0.01 at day 4 and 7], and noticeably greater than CPT-11–treated tumors (ADC = 5 ± 5%, 14 ± 7%, and 18 ± 6%; TV = −15 ± 5%, −22 ± 13%, and −26 ± 8%). Model-derived parameters for cell proliferation obtained using ADC data distinguished CRLX101-treated tumors from controls (P = 0.02). Conclusions: Temporal changes in ADC specified early CRLX101 treatment response and could be used to model image-derived cell proliferation rates following treatment. Comparisons of targeted and nontargeted treatments highlight the utility of noninvasive imaging and modeling to evaluate, monitor, and predict responses to targeted nanotherapeutics

ROCKETSHIP: a flexible and modular software tool for the planning, processing and analysis of dynamic MRI studies

Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a promising technique to characterize pathology and evaluate treatment response. However, analysis of DCE-MRI data is complex and benefits from concurrent analysis of multiple kinetic models and parameters. Few software tools are currently available that specifically focuses on DCE-MRI analysis with multiple kinetic models. Here, we developed ROCKETSHIP, an open-source, flexible and modular software for DCE-MRI analysis. ROCKETSHIP incorporates analyses with multiple kinetic models, including data-driven nested model analysis. Results: ROCKETSHIP was implemented using the MATLAB programming language. Robustness of the software to provide reliable fits using multiple kinetic models is demonstrated using simulated data. Simulations also demonstrate the utility of the data-driven nested model analysis. Applicability of ROCKETSHIP for both preclinical and clinical studies is shown using DCE-MRI studies of the human brain and a murine tumor model. Conclusion: A DCE-MRI software suite was implemented and tested using simulations. Its applicability to both preclinical and clinical datasets is shown. ROCKETSHIP was designed to be easily accessible for the beginner, but flexible enough for changes or additions to be made by the advanced user as well. The availability of a flexible analysis tool will aid future studies using DCE-MRI