Construction of a Resting High Fidelity ECG "SuperScore" for Management and Screening of Heart Disease

Resting conventional ECG is notoriously insensitive for detecting coronary artery disease (CAD) and only nominally useful in screening for cardiomyopathy (CM). Similarly, conventional exercise stress test ECG is both time- and labor-consuming and its accuracy in identifying CAD is suboptimal for use in population screening. We retrospectively investigated the accuracy of several advanced resting electrocardiographic (ECG) parameters, both alone and in combination, for detecting CAD and cardiomyopathy (CM)

Peer Effects in Drug Use and Sex Among College Students

Past research suggests that congregating delinquent youth increases their likelihood of problem behavior. We test for analogous peer effects in the drug use and sexual behavior of male ( n = 279) and female ( n = 435) college students, using data on the characteristics of first-year roommates to whom they were randomly assigned. We find that males who reported binge drinking in high school drink much more in college if assigned a roommate who also binge drank in high school than if assigned a nonbinge-drinking roommate. No such multiplier effect is observed for females, nor are multiplier effects observed for marijuana use or sexual behavior for either males or females. Students who did not engage in these behaviors in high school do not appear to be affected by their roommates’ high school behavior.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44594/1/10802_2005_Article_3576.pd

A Systems Approach for Tumor Pharmacokinetics

Recent advances in genome inspired target discovery, small molecule screens, development of biological and nanotechnology have led to the introduction of a myriad of new differently sized agents into the clinic. The differences in small and large molecule delivery are becoming increasingly important in combination therapies as well as the use of drugs that modify the physiology of tumors such as anti-angiogenic treatment. The complexity of targeting has led to the development of mathematical models to facilitate understanding, but unfortunately, these studies are often only applicable to a particular molecule, making pharmacokinetic comparisons difficult. Here we develop and describe a framework for categorizing primary pharmacokinetics of drugs in tumors. For modeling purposes, we define drugs not by their mechanism of action but rather their rate-limiting step of delivery. Our simulations account for variations in perfusion, vascularization, interstitial transport, and non-linear local binding and metabolism. Based on a comparison of the fundamental rates determining uptake, drugs were classified into four categories depending on whether uptake is limited by blood flow, extravasation, interstitial diffusion, or local binding and metabolism. Simulations comparing small molecule versus macromolecular drugs show a sharp difference in distribution, which has implications for multi-drug therapies. The tissue-level distribution differs widely in tumors for small molecules versus macromolecular biologic drugs, and this should be considered in the design of agents and treatments. An example using antibodies in mouse xenografts illustrates the different in vivo behavior. This type of transport analysis can be used to aid in model development, experimental data analysis, and imaging and therapeutic agent design.National Institutes of Health (U.S.) (grant T32 CA079443

Human GLI3 Intragenic Conserved Non-Coding Sequences Are Tissue-Specific Enhancers

The zinc-finger transcription factor GLI3 is a key regulator of development, acting as a primary transducer of Sonic hedgehog (SHH) signaling in a combinatorial context dependent fashion controlling multiple patterning steps in different tissues/organs. A tight temporal and spatial control of gene expression is indispensable, however, cis-acting sequence elements regulating GLI3 expression have not yet been reported. We show that 11 ancient genomic DNA signatures, conserved from the pufferfish Takifugu (Fugu) rubripes to man, are distributed throughout the introns of human GLI3. They map within larger conserved non-coding elements (CNEs) that are found in the tetrapod lineage. Full length CNEs transiently transfected into human cell cultures acted as cell type specific enhancers of gene transcription. The regulatory potential of these elements is conserved and was exploited to direct tissue specific expression of a reporter gene in zebrafish embryos. Assays of deletion constructs revealed that the human-Fugu conserved sequences within the GLI3 intronic CNEs were essential but not sufficient for full-scale transcriptional activation. The enhancer activity of the CNEs is determined by a combinatorial effect of a core sequence conserved between human and teleosts (Fugu) and flanking tetrapod-specific sequences, suggesting that successive clustering of sequences with regulatory potential around an ancient, highly conserved nucleus might be a possible mechanism for the evolution of cis-acting regulatory elements

The development and validation of the pictorial motivation scale in physical activity

The purpose of the present research was to report the validation of the pictorial motivation scale in English. This scale is designed for adolescents and adults with an intellectual disability who are unable to independently read a questionnaire. The scale has a picture and phrase depicting 16 items related to participation in sport and physical activity; four for each of the following subscales, intrinsic motivation, self-determined extrinsic motivation, non self-determined extrinsic motivation, and amotivation. Phase 1 of the research describes the formal translation of the scale from French to English. Results from three studies conducted with Special Olympians (Phase 2) and adolescents in a special school (Phases 3 and 4) provided support for the internal consistency, test–retest reliability, and factorial and construct validity of the scale. Overall, the scale would appear to be sufficiently reliable and valid to warrant its continued use and further development