Dobutamine stress echocardiography: Prevalence of a nonischemic response in a low-risk population

The problems of population referral bias in the calculation of specificity in diagnostic testing for coronary artery disease have been previously described. Previous studies investigating the sensitivity and specificity of dobutamine stress echocardiography (DSE) have been subject to pretest and posttest referral biases, largely as a result of the requirement for coronary arteriography. This study determines the normalcy rate for DSE by examining a population at statistically low risk for coronary artery disease. The probability of significant coronary artery disease was determined for 828 consecutive patients referred for DSE at the University of Michigan, and groups were identified with <10% and <5% probability of disease. Four of 72 patients (5.6%) with a normal baseline echocardiogram and a probability of coronary artery disease of <10%, and three of 38 (7.9%) with a probability of <5% were found to have an abnormal DSE, yielding normalcy rates of 94.4% and 92.1%, respectively. The area of abnormality involved the posterior circulation in three of four patients (75%). This study demonstrates that DSE has a normalcy rate of 92% to 94% and is an accurate test for excluding the presence of significant coronary artery disease.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30826/1/0000488.pd

Usefulness of an accelerated transoesophageal stress echocardiography in the preoperative evaluation of high risk severely obese subjects awaiting bariatric surgery

<p>Abstract</p> <p>Background</p> <p>Severe obesity is associated with an increased risk of coronary artery disease (CAD). Bariatric surgery is an effective procedure for long term weight management as well as reduction of comorbidities. Preoperative evaluation of cardiac operative risk may often be necessary but unfortunately standard imaging techniques are often suboptimal in these subjects. The purpose of this study was to demonstrate the feasibility, safety and utility of transesophageal dobutamine stress echocardiography (TE-DSE) using an adapted accelerated dobutamine infusion protocol in severely obese subjects with comorbidities being evaluated for bariatric surgery for assessing the presence of myocardial ischemia.</p> <p>Methods</p> <p>Subjects with severe obesity [body mass index (BMI) >40 kg/m²] with known or suspected CAD and being evaluated for bariatric surgery were recruited.</p> <p>Results</p> <p>Twenty subjects (9M/11F), aged 50 ± 8 years (mean ± SD), weighing 141 ± 21 kg and with a BMI of 50 ± 5 kg/m²were enrolled in the study and underwent a TE-DSE. The accelerated dobutamine infusion protocol used was well tolerated. Eighteen (90%) subjects reached their target heart rate with a mean intubation time of 13 ± 4 minutes. Mean dobutamine dose was 31.5 ± 9.9 ug/kg/min while mean atropine dose was 0.5 ± 0.3 mg. TE-DSE was well tolerated by all subjects without complications including no significant arrhythmia, hypotension or reduction in blood arterial saturation. Two subjects had abnormal TE-DSE suggestive of myocardial ischemia. All patients underwent bariatric surgery with no documented cardiovascular complications.</p> <p>Conclusions</p> <p>TE-DSE using an accelerated infusion protocol is a safe and well tolerated imaging technique for the evaluation of suspected myocardial ischemia and cardiac operative risk in severely obese patients awaiting bariatric surgery. Moreover, the absence of myocardial ischemia on TE-DSE correlates well with a low operative risk of cardiac event.</p

Structural and functional interactions between six-transmembrane mu-opioid receptors and beta(2)-adrenoreceptors modulate opioid signaling

The primary molecular target for clinically used opioids is the mu-opioid receptor (MOR). Besides the major seven-transmembrane (7TM) receptors, the MOR gene codes for alternatively spliced six-transmembrane (6TM) isoforms, the biological and clinical significance of which remains unclear. Here, we show that the otherwise exclusively intracellular localized 6TM-MOR translocates to the plasma membrane upon coexpression with beta(2)-adrenergic receptors (beta(2)-ARs) through an interaction with the fifth and sixth helices of beta(2)-AR. Coexpression of the two receptors in BE(2)-C neuroblastoma cells potentiates calcium responses to a 6TM-MOR ligand, and this calcium response is completely blocked by a selective beta(2)-antagonist in BE(2)-C cells, and in trigeminal and dorsal root ganglia. Co-administration of 6TM-MOR and beta(2)-AR ligands leads to substantial analgesic synergy and completely reverses opioid-induced hyperalgesia in rodent behavioral models. Together, our results provide evidence that the heterodimerization of 6TM-MOR with beta(2)-AR underlies a molecular mechanism for 6TM cellular signaling, presenting a unique functional responses to opioids. This signaling pathway may contribute to the hyperalgesic effects of opioids that can be efficiently blocked by beta(2)-AR antagonists, providing a new avenue for opioid therapy.Peer reviewe

Technology enhanced assessment in complex collaborative settings

Building upon discussions by the Assessment Working Group at EDUsummIT 2013, this article reviews recent developments in technology enabled assessments of collaborative problem solving in order to point out where computerised assessments are particularly useful (and where non-computerised assessments need to be retained or developed) while assuring that the purposes and designs are transparent and empowering for teachers and learners. Technology enabled assessments of higher order critical thinking in a collaborative social context can provide data about the actions, communications and products created by a learner in a designed task space. Principled assessment design is required in order for such a space to provide trustworthy evidence of learning, and the design must incorporate and take account of the engagement of the audiences for the assessment as well as vary with the purposes and contexts of the assessment. Technology enhanced assessment enables in-depth unobtrusive documentation or ‘quiet assessment’ of the many layers and dynamics of authentic performance and allows greater flexibility and dynamic interactions in and among the design features. Most important for assessment FOR learning, are interactive features that allow the learner to turn up or down the intensity, amount and sharpness of the information needed for self-absorption and adoption of the feedback. Most important in assessment OF learning, are features that compare the learner with external standards of performance. Most important in assessment AS learning, are features that allow multiple performances and a wide array of affordances for authentic action, communication and the production of artefacts

Caveolae protect endothelial cells from membrane rupture during increased cardiac output.

Caveolae are strikingly abundant in endothelial cells, yet the physiological functions of caveolae in endothelium and other tissues remain incompletely understood. Previous studies suggest a mechanoprotective role, but whether this is relevant under the mechanical forces experienced by endothelial cells in vivo is unclear. In this study we have sought to determine whether endothelial caveolae disassemble under increased hemodynamic forces, and whether caveolae help prevent acute rupture of the plasma membrane under these conditions. Experiments in cultured cells established biochemical assays for disassembly of caveolar protein complexes, and assays for acute loss of plasma membrane integrity. In vivo, we demonstrate that caveolae in endothelial cells of the lung and cardiac muscle disassemble in response to acute increases in cardiac output. Electron microscopy and two-photon imaging reveal that the plasma membrane of microvascular endothelial cells in caveolin 1(-/-) mice is much more susceptible to acute rupture when cardiac output is increased. These data imply that mechanoprotection through disassembly of caveolae is important for endothelial function in vivo

The Influence of Transcription Factor Competition on the Relationship between Occupancy and Affinity

Transcription factors (TFs) are proteins that bind to specific sites on the DNA and regulate gene activity. Identifying where TF molecules bind and how much time they spend on their target sites is key to understanding transcriptional regulation. It is usually assumed that the free energy of binding of a TF to the DNA (the affinity of the site) is highly correlated to the amount of time the TF remains bound (the occupancy of the site). However, knowing the binding energy is not sufficient to infer actual binding site occupancy. This mismatch between the occupancy predicted by the affinity and the observed occupancy may be caused by various factors, such as TF abundance, competition between TFs or the arrangement of the sites on the DNA. We investigated the relationship between the affinity of a TF for a set of binding sites and their occupancy. In particular, we considered the case of the transcription factor lac repressor (lacI) in E.coli, and performed stochastic simulations of the TF dynamics on the DNA for various combinations of lacI abundance and competing TFs that contribute to macromolecular crowding. We also investigated the relationship of site occupancy and the information content of position weight matrices (PWMs) used to represent binding sites. Our results showed that for medium and high affinity sites, TF competition does not play a significant role for genomic occupancy except in cases when the abundance of the TF is significantly increased, or when the PWM displays relatively low information content. Nevertheless, for medium and low affinity sites, an increase in TF abundance (for both cognate and non-cognate molecules) leads to an increase in occupancy at several sites. © 2013 Zabet et al

Distinguishing closely related amyloid precursors using an RNA aptamer

Although amyloid fibrils assembled in vitro commonly involve a single protein, fibrils formed in vivo can contain multiple protein sequences. The amyloidogenic protein human ?2-microglobulin (h?2m) can co-polymerize with its N-terminally truncated variant (?N6) in vitro to form hetero-polymeric fibrils that differ from their homo-polymeric counterparts. Discrimination between the different assembly precursors, for example by binding of a biomolecule to one species in a mixture of conformers, offers an opportunity to alter the course of co-assembly and the properties of the fibrils formed. Here, using h?2m and its amyloidogenic counterpart, ??6, we describe selection of a 2'F-modified RNA aptamer able to distinguish between these very similar proteins. SELEX with a N30 RNA pool yielded an aptamer (B6) that binds h?2m with an EC50 of ?200 nM. NMR spectroscopy was used to assign the (1)H-(15)N HSQC spectrum of the B6-h?2m complex, revealing that the aptamer binds to the face of h?2m containing the A, B, E, and D ?-strands. In contrast, binding of B6 to ?N6 is weak and less specific. Kinetic analysis of the effect of B6 on co-polymerization of h?2m and ?N6 revealed that the aptamer alters the kinetics of co-polymerization of the two proteins. The results reveal the potential of RNA aptamers as tools for elucidating the mechanisms of co-assembly in amyloid formation and as reagents able to discriminate between very similar protein conformers with different amyloid propensity

Logistic regression models for short sequences of correlated binary variables possessing first-order Markov dependence.

In this dissertation we consider a first-order Markov dependence model for a short sequence of correlated Bernoulli random variables. Specifically, we offer logistic regression models with first-order Markov dependency, using preceding responses as covariates. We develop maximum likelihood and Bayesian methods for inference using these models, and compare them in simulation studies. We develop methods for obtaining informative priors for the Bayesian models, including a modified conditional means prior approach, which we refer to as the Markov dependent priors approach. Due to the implicit dependence of transition probabilities on the value of the marginal probability, elicitation of priors for transition probabilities from experts is problematic. With our approach, however, we can induce priors on regression coefficients from prior distributions on the marginal probability and the transition probabilities. We also give details for constructing informative priors when historical data is available, using power priors. Finally, we considered sample size determination for first-order Markov dependence probabilities using the Bayesian two-priors method

The diagnostic accuracy of preoperative CT scanning in the evaluation of pituitary prolactinomas. AJNR

patients (26 women and nine men) who had coronal CT scans of the sella turcica for suspected ACTH-secreting pituitary adenoma underwent transsphenoidal exploration. The CT examinations were performed with a fourth-generation EMI scanner (CT 7070). The reports of the preoperative CT examinations were compared with the findings at transsphenoidal exploration; in cases with negative CT scans, the decision to operate was based on biochemical evidence of Cushing&apos;s disease. In 27 patients, distinct adenomas were found at surgery; in the eight others, total hypophysectomy (four cases) or resection of the central core of the pituitary gland (four cases) was performed. Three patients had macroadenomas, all of which had been identified correctly on preoperative CT scan. Among the 24 microadenomas «10 mm diameter), 14 had been correctly identified on preoperative CT scan while 10 were found in patients with negative scans. The CT examinations in these 35 patients showed probable adenomas in 20 cases, of which 17 (85%) were confirmed at surgery. In the other three cases (15%), adenomas were not found . Among the 15 patients with negative CT scans, 10 (66.6%) had distinct adenomas found at surgery. Coronal CT scans for ACTH-secreting adenomas had a sensitivity of 63%, a specificity of 62.5% , and an overall accuracy rate of 62.8%. Thus, in our experience, CT scanning with current stateof-the-art equipment has poor diagnostic accuracy in Cushing&apos;s disease. The possible reasons for this are that most of the adenomas in this series were microadenomas less than 6 mm in diameter, and that ACTH microadenomas probably show almost the same degree of enhancement with contrast medium as the surrounding normal pituitary tissue. In recent years, high-resolution CT of the sella turcica has almost completely replaced all other imaging techniques in the investigation of abnormalities of the pituitary gland. However, there is scant information about the diagnostic accuracy of this procedure, especially in regard to the identification of adenomas in Cushing&apos;s disease Subjects and Methods The patients included in this study had been referred for CT of the sella turcica because of clinical and biochemical evidence of pituitary-dependent cortisol hypersecretion. The CT examinations were performed with a fourth-generation scanner (EMI CT 7070). The patients were placed on the scanner couch in the prone position with the neck hyperextended. The scanner gantry was angled 90 0 to a line connecting the outer canthus of the eye to the external auditory meatus (canthomeatalline) in order to obtain direct coronal views . Technical factors were chosen so as to optimize image quality and contrast resolution whi le confining the examination time to a reasonable duration: 120 kVp, 80-99 mA, scan time 3 or 6 sec, slice width 3-5 mm (5 mm slice width was only used for the three macroadenomas , which appeared obvious on the initial plain scans), slice overlap 1 mm , sca