Citations

ATR is an apical kinase in one of the DNA-damage induced checkpoint pathways. Despite the development of inhibitors of kinases structurally related to ATR, as well as inhibitors of the ATR substrate Chk1, no ATR inhibitors have yet been developed. Here we review the effects of ATR downregulation in cancer cells and discuss the potential for development of ATR inhibitors for clinical use.

Abstract Obesity and black race have been associated with excess risk of multiple myeloma. The association of obesity with monoclonal gammopathy of undetermined significance (MGUS) is unknown. Further, it is not known whether the increased risk of multiple myeloma and MGUS in blacks is related to socioeconomic status, genetic susceptibility, or both. We screened 1000 black and 996 white women (range, 40-79 years) of similar socioeconomic status for MGUS; the aim of the study was to assess MGUS risk in relation to obesity and race. A total of 39 (3.9%) blacks and 21 (2.1%) whites had MGUS. On multivariate analysis, obesity (odds ratio [OR] = 1.8; P = .04), black race (OR = 1.8; P = .04), and increasing age (> 55 vs < 43 years; OR = 2.5; P = .03) were independently associated with an excess risk of MGUS. Our findings support the hypothesis that obesity is etiologically linked to myelomagenesis. The 2-fold excess of MGUS among blacks compared with whites of similar socioeconomic status supports a role for susceptibility genes in MGUS.

Computational fluid dynamics (CFD) studies provide a valuable tool for evaluating the role of hemodynamics in vascular diseases such as cerebral aneurysms and atherosclerosis. However, such models necessarily only include isolated segments of the vasculature. In this work, we evaluate the influence of geometric approximations in vascular anatomy on hemodynamics in elastase induced saccular aneurysms in rabbits. One representative high aspect ratio (AR—height/neck width) aneurysm and one low AR aneurysm were created at the origin of the right common carotid artery in two New Zealand white rabbits. Three-dimensional (3D) reconstructions of the aneurysm and surrounding arteries were created using 3D rotational angiographic data. Five models with varying extents of neighboring vasculature were created for both the high and low AR cases. A reference model included the aneurysm sac, left common carotid artery (LCCA), aortic arch, and downstream trifurcation/quadrification. Three-dimensional, pulsatile CFD studies were performed and streamlines, wall shear stress (WSS), oscillatory shear index, and cross sectional velocity were compared between the models. The influence of the vascular domain on intra-aneurysmal hemodynamics varied between the low and high AR cases. For the high AR case, even a simple model including only the aneurysm, a small section of neighboring vasculature, and simple extensions captured the main features of the steamline and WSS distribution predicted by the reference model. However, the WSS distribution in the low AR case was more strongly influenced by the extent of vasculature. In particular, it was necessary to include the downstream quadrification and upstream LCCA to obtain good predictions of WSS. The findings in this work demonstrate the accuracy of CFD results can be compromised if insufficient neighboring vessels are included in studies of hemodynamics in elastase induced rabbit aneurysms. Consideration of aspect ratio, hemodynamic parameters of interest, and acceptable magnitude of error when selecting the vascular domain will increase reliability of the results while decreasing computational time.

Health promotion programs may target a variety of behaviors including weight loss, exercise, stress, nutrition, or other risk factors. Comparing the outcomes of diverse programs is hampered by the absence of a common metric. Overall self-rated health has been used as a health outcome measure in population studies and in some primary care studies, but its potential use to monitor the outcomes of health programs is unexplored. The purpose of this study was to compare the outcomes of 4 health promotion programs using change in overall self-rated health as a common metric. Program-specific metrics used were weight change, change in minutes of exercise, change in stress management activities, and change in healthy nutrition practices. We found that, although all of our lifestyle interventions positively affected the program-specific metrics, only the weight loss and exercise programs showed improvement in specific metrics correlated with improvements in overall self-rated health. ( Population Health Management 2010;13:91–95)

As medical providers seek new ways to control costs, online visits have begun to receive serious consideration. The purpose of this study was to compare the odds of being a cost outlier during a 6-month period after either an online visit or a standard drop-in visit in a conventional medical office setting. Medical records of primary care patients (both adults and children) seen in a large group practice in Minnesota in 2008 were analyzed for this study. Two groups of patients were studied: those who had an online visit ( N = 390) and a comparison group who had regular office care for same-day, acute visits ( N = 376). Case types were classified as either complex or common, with common being defined as treatment for pinkeye, sore throat, viral illness, bronchitis, or cough. Outliers were defined as patients for whom standard costs exceeded the 75 th percentile during a 6-month period after the index visit. Multiple logistic regression analysis was used to adjust for differences between groups. The percentage of online visitors who were cost outliers was 21.2 (versus 28.5 in the standard visit group). Median standard costs were $161 for online visits and $219 for same-day acute visits. The adjusted odds of being a cost outlier was lower for the online visit group than for the standard visit group (odds ratio [OR] 0.52, 95% confidence interval [95% CI] 0.35–0.77) after adjusting for number of visits in the previous 6 months, age, sex, and case type. Outpatient visits in the previous 6 months were positively related to outlier status (OR 1.23, 95% CI 1.17–1.29). Online visits appeared to reduce medical costs for patients during a 6-month period after the visit. ( Population Health Management 2010;13:59–63)

Object The authors previously reported the development of the Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for measuring dopamine and suggested that this technology may be useful for evaluating deep brain stimulation–related neuromodulatory effects on neurotransmitter systems. The WINCS supports fast-scan cyclic voltammetry (FSCV) at a carbon-fiber microelectrode (CFM) for real-time, spatially resolved neurotransmitter measurements. The FSCV parameters used to establish WINCS dopamine measurements are not suitable for serotonin, a neurotransmitter implicated in depression, because they lead to CFM fouling and a loss of sensitivity. Here, the authors incorporate into WINCS a previously described N-shaped waveform applied at a high scan rate to establish wireless serotonin monitoring. Methods Optimized for the detection of serotonin, FSCV consisted of an N-shaped waveform scanned linearly from a resting potential of +0.2 to +1.0 V, then to −0.1 V and back to +0.2 V, at a rate of 1000 V/second. Proof-of-principle tests included flow injection analysis and electrically evoked serotonin release in the dorsal raphe nucleus of rat brain slices. Results Flow cell injection analysis demonstrated that the N waveform, applied at a scan rate of 1000 V/second, significantly reduced serotonin fouling of the CFM, relative to that observed with FSCV parameters for dopamine. In brain slices, WINCS reliably detected subsecond serotonin release in the dorsal raphe nucleus evoked by local high-frequency stimulation. Conclusions The authors found that WINCS supported high-fidelity wireless serotonin monitoring by FSCV at a CFM. In the future such measurements of serotonin in large animal models and in humans may help to establish the mechanism of deep brain stimulation for psychiatric disease.

Measurements of dynamic force-length behavior of maximally activated strips of smooth muscle during oscillatory length changes show that force decreases well below the isometric force during the shortening phase of the oscillation. The magnitude of the decrease depends on the rate of shortening; for slower shortening, the decrease is smaller and force is larger. Modeling of expiratory flow, based on these data, predicts that vital capacity in constricted lungs depends on the rate of expiration. In maximally constricted lungs, forced vital capacity (FVC) is predicted to be 16% smaller than control, and vital capacity for a very slow expiration (SVC), 31% less than control. These predictions were tested by measuring FVC and SVC in constricted normal subjects. In the first group of 9 subjects, four maneuvers were made following the delivery of two doses of methacholine in the order: SVC, FVC, FVC, SVC. In a second group of 11 subjects, two maneuvers were performed at each dose in the order: FVC, SVC. At the highest dose of methacholine, FVC for both trials in group 1 and for the one trial in group 2 were all ∼13% less than control, a slightly smaller decrease than predicted. SVC for the 1st trial in group 1 was 27% less than control, also slightly smaller than predicted. The difference between FVC and SVC for this trial, 13%, was close to the predicted difference of 15%. However, SVC for the 2nd trial in group 1 (preceded by 3 vital capacity maneuvers) and for group 2 (preceded by 1) were no different from FVC. We conclude that vital capacity in constricted lungs depends on the dynamic force-length properties of smooth muscle and that the history dependence of the dynamic properties of smooth muscle is more complicated than has been inferred from oscillatory force-length behavior.