Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise

AbstractOBJECTIVESThe aim of the study was to test the hypothesis that angiotensin II (Ang II) blockade would improve exercise tolerance in patients with diastolic dysfunction and a marked increase in systolic blood pressure (SBP) during exercise.BACKGROUNDDiastolic dysfunction may be exacerbated during exercise, especially if there is a marked increase in SBP. Angiotensin II may contribute to the hypertensive response to exercise and impair diastolic performance.METHODSWe performed a randomized, double-blind, placebo-controlled, crossover study of two weeks of losartan (50 mg q.d.) on exercise tolerance and quality of life. The subjects were 20 patients, mean age 64 ± 10 years with normal left ventricular systolic function (EF >50%), no ischemia on stress echocardiogram, mitral flow velocity E/A <1, normal resting SBP (<150 mm Hg), and a hypertensive response to exercise (SBP >200 mm Hg). Exercise echocardiograms (Modified Bruce Protocol) and the Minnesota Living With Heart Failure questionnaire were administered at baseline, and after each two-week treatment period, separated by a two-week washout period.RESULTSResting blood pressure (BP) was unaltered by placebo or losartan. During control, patients were able to exercise for 11.3 ± 2.5 (mean ± SD) min, with a peak exercise SBP of 226 ± 24 mm Hg. After two weeks of losartan, baseline BP was unaltered, but peak SBP during exercise decreased to 193 ± 27 mm Hg (p < 0.05 vs. baseline and placebo), and exercise time increased to 12.3 ± 2.6 min (p < 0.05 vs. baseline and placebo). With placebo, there was no improvement in exercise duration (11.0 ± 2.0 min) or peak exercise SBP (217 ± 26 mm Hg). Quality of life improved with losartan (18 ± 22, p < 0.05) compared to placebo (22 ± 26).CONCLUSIONSIn patients with Doppler evidence of diastolic dysfunction at rest and a hypertensive response to exercise, Ang II receptor blockade blunts the hypertensive response to exercise, increases exercise tolerance and improves quality of life

Toward Eclipse Mapping of Hot Jupiters

Recent Spitzer infrared measurements of hot Jupiter eclipses suggest that eclipse mapping techniques could be used to spatially resolve the day-side photospheric emission of these planets using partial occultations. As a first step in this direction, we simulate ingress/egress lightcurves for the three brightest known eclipsing hot Jupiters and evaluate the degree to which parameterized photospheric emission models can be distinguished from each other with repeated, noisy eclipse measurements. We find that the photometric accuracy of Spitzer is insufficient to use this tool effectively. On the other hand, the level of photospheric details that could be probed with a few JWST eclipse measurements could greatly inform hot Jupiter atmospheric modeling efforts. A JWST program focused on non-parametric eclipse map inversions for hot Jupiters should be actively considered.Comment: 32 pages, 6 figures, 3 tables, accepted for publication in Ap

ABCC5, ERCC2, XPA and XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines

BACKGROUND: Although 40–50% of non-small cell lung cancer (NSCLC) tumors respond to cisplatin chemotherapy, there currently is no way to prospectively identify potential responders. The purpose of this study was to determine whether transcript abundance (TA) levels of twelve selected DNA repair or multi-drug resistance genes (LIG1, ERCC2, ERCC3, DDIT3, ABCC1, ABCC4, ABCC5, ABCC10, GTF2H2, XPA, XPC and XRCC1) were associated with cisplatin chemoresistance and could therefore contribute to the development of a predictive marker. Standardized RT (StaRT)-PCR, was employed to assess these genes in a set of NSCLC cell lines with a previously published range of sensitivity to cisplatin. Data were obtained in the form of target gene molecules relative to 10(6 )β-actin (ACTB) molecules. To cancel the effect of ACTB variation among the different cell lines individual gene expression values were incorporated into ratios of one gene to another. Each two-gene ratio was compared as a single variable to chemoresistance for each of eight NSCLC cell lines using multiple regression. In an effort to validate these results, six additional lines then were evaluated. RESULTS: Following validation, single variable models best correlated with chemoresistance (p < 0.001), were ERCC2/XPC, ABCC5/GTF2H2, ERCC2/GTF2H2, XPA/XPC and XRCC1/XPC. All single variable models were examined hierarchically to achieve two variable models. The two variable model with the highest correlation was (ABCC5/GTF2H2, ERCC2/GTF2H2) with an R(2 )value of 0.96 (p < 0.001). CONCLUSION: These results provide markers suitable for assessment of small fine needle aspirate biopsies in an effort to prospectively identify cisplatin resistant tumors

Variation in transcriptional regulation of cyclin dependent kinase inhibitor p21(waf1/cip1 )among human bronchogenic carcinomas

BACKGROUND: Cell proliferation control depends in part on the carefully ordered regulation of transcription factors. The p53 homolog p73, contributes to this control by directly upregulating the cyclin dependent kinase inhibitor, p21(waf1/cip1). E2F1, an inducer of cell proliferation, directly upregulates p73 and in some systems upregulates p21 directly. Because of its central role in controlling cell proliferation, upregulation of p21 has been explored as a modality for treating bronchogenic carcinoma (BC). Improved understanding of p21 transcriptional regulation will facilitate identification of BC tissues that are responsive to p21-directed therapies. Toward this goal, we investigated the role that E2F1 and p73 each play in the transcriptional regulation of p21. RESULTS: Among BC samples (N = 21) p21 transcript abundance (TA) levels varied over two orders of magnitude with values ranging from 400 to 120,000 (in units of molecules/10(6 )molecules β-actin). The p21 values in many BC were high compared to those observed in normal bronchial epithelial cells (BEC) (N = 18). Among all BC samples, there was no correlation between E2F1 and p21 TA but there was positive correlation between E2F1 and p73α (p < 0.001) TA. Among BC cell lines with inactivated p53 and wild type p73 (N = 7) there was positive correlation between p73α and p21 TA (p < 0.05). Additionally, in a BC cell line in which both p53 and p73 were inactivated (H1155), E2F1 TA level was high (50,000), but p21 TA level was low (470). Transiently expressed exogenous p73α in the BC cell line Calu-1, was associated with a significant (p < 0.05) 90% increase in p21 TA and a 20% reduction in E2F1 TA. siRNA mediated reduction of p73 TA in the N417 BC cell line was associated with a significant reduction in p21 TA level (p < 0.01). CONCLUSION: p21 TA levels vary considerably among BC patients which may be attributable to 1) genetic alterations in Rb and p53 and 2) variation in TA levels of upstream transcription factors E2F1 and p73. Here we provide evidence that p73 upregulates p21 TA in BC tissues and upregulated p21 TA may result from E2F1 upregulation of p73 but not from E2F1 directly

CO\u3csub\u3e2\u3c/sub\u3e-Fixing One-Carbon Metabolism in a Cellulose-Degrading Bacterium \u3cem\u3eClostridium thermocellum\u3c/em\u3e

Clostridium thermocellum can ferment cellulosic biomass to formate and other end products, including CO2. This organism lacks formate dehydrogenase (Fdh), which catalyzes the reduction of CO2 to formate. However, feeding the bacterium 13C-bicarbonate and cellobiose followed by NMR analysis showed the production of 13C-formate in C. thermocellum culture, indicating the presence of an uncharacterized pathway capable of converting CO2 to formate. Combining genomic and experimental data, we demonstrated that the conversion of CO2 to formate serves as a CO2 entry point into the reductive one-carbon (C1) metabolism, and internalizes CO2 via two biochemical reactions: the reversed pyruvate: ferredoxin oxidoreductase (rPFOR), which incorporates CO2 using acetyl-CoA as a substrate and generates pyruvate, and pyruvate- formate lyase (PFL) converting pyruvate to formate and acetyl-CoA. We analyzed the labeling patterns of proteinogenic amino acids in individual deletions of all five putative PFOR mutants and in a PFL deletion mutant. We identified two enzymes acting as rPFOR, confirmed the dual activities of rPFOR and PFL crucial for CO2 uptake, and provided physical evidence of a distinct in vivo “rPFOR-PFL shunt” to reduce CO2 to formate while circumventing the lack of Fdh. Such a pathway precedes CO2 fixation via the reductive C1 metabolic pathway in C. thermocellum. These findings demonstrated the metabolic versatility of C. thermocellum, which is thought of as primarily a cellulosic heterotroph but is shown here to be endowed with the ability to fix CO2 as well

Practising the Space Between: Embodying Belief as an Evangelical Anglican Student

This article explores the formation of British evangelical university students as believers. Drawing on ethnographic fieldwork conducted with a conservative evangelical Anglican congregation in London, I describe how students in this church come to embody a highly cognitive, word-based mode of belief through particular material practices. As they learn to identify themselves as believers, practices of reflexivity and accountability enable them to develop a sense of narrative coherence in their lives that allows them to negotiate tensions that arise from their participation in church and broader social structures. I demonstrate that propositional belief – in contexts where it becomes an identity marker – is bound up with relational practices of belief, such that distinctions between “belief in” and “belief that” are necessarily blurred in the lives of young evangelicals

Mapping the G-structures and supersymmetric vacua of five-dimensional N=4 supergravity

We classify the supersymmetric vacua of N=4, d=5 supergravity in terms of G-structures. We identify three classes of solutions: with R^3, SU(2) and generic SO(4) structure. Using the Killing spinor equations, we fully characterize the first two classes and partially solve the latter. With the N=4 graviton multiplet decomposed in terms of N=2 multiplets: the graviton, vector and gravitino multiplets, we obtain new supersymmetric solutions corresponding to turning on fields in the gravitino multiplet. These vacua are described in terms of an SO(5) vector sigma-model coupled with gravity, in three or four dimensions. A new feature of these N=4 vacua, which is not seen from an N=2 point of view, is the possibility for preserving more exotic fractions of supersymmetry. We give a few concrete examples of these new supersymmetric (albeit singular) solutions. Additionally, we show how by truncating the N=4, d=5 set of fields to minimal supergravity coupled with one vector multiplet we recover the known two-charge solutions.Comment: 31 pages, late

Signature of the Simplicial Supermetric

We investigate the signature of the Lund-Regge metric on spaces of simplicial three-geometries which are important in some formulations of quantum gravity. Tetrahedra can be joined together to make a three-dimensional piecewise linear manifold. A metric on this manifold is specified by assigning a flat metric to the interior of the tetrahedra and values to their squared edge-lengths. The subset of the space of squared edge-lengths obeying triangle and analogous inequalities is simplicial configuration space. We derive the Lund-Regge metric on simplicial configuration space and show how it provides the shortest distance between simplicial three-geometries among all choices of gauge inside the simplices for defining this metric (Regge gauge freedom). We show analytically that there is always at least one physical timelike direction in simplicial configuration space and provide a lower bound on the number of spacelike directions. We show that in the neighborhood of points in this space corresponding to flat metrics there are spacelike directions corresponding to gauge freedom in assigning the edge-lengths. We evaluate the signature numerically for the simplicial configuration spaces based on some simple triangulations of the three-sphere (S^3) and three-torus (T^3). For the surface of a four-simplex triangulation of S^3 we find one timelike direction and all the rest spacelike over all of the simplicial configuration space. For the triangulation of T^3 around flat space we find degeneracies in the simplicial supermetric as well as a few gauge modes corresponding to a positive eigenvalue. Moreover, we have determined that some of the negative eigenvalues are physical, i.e. the corresponding eigenvectors are not generators of diffeomorphisms. We compare our results with the known properties of continuum superspace.Comment: 24 pages, RevTeX, 4 eps Figures. Submitted to Classical Quantum Gravit