Studies of the renin angiotensin system in the human vasculature

The work presented in this thesis concentrates on the local generation of AII. Preliminary experiments using wire myography were performed in human resistance arteries from normal subjects, obtained by subcutaneous gluteal at biopsy. In these vessels, AI stimulated a contractile repose that was dependent on activation of the AII type 1 receptor (ATIR). Thus, conversion of AI to AII can occur within the vasculature. This conversion was resistant to inhibition of ACE with enalaprilat in human tissue. In contrast, AI responses in rabbit arteries were almost completely inhibited by enalaprilat. Further investigation demonstrated that the combination of enalaprilat and the chymase inhibitor, chymostatin (but neither agent alone), inhibited the response to AI in human resistance arteries. Thus, a dual pathway for AII generation exists in human arteries, probably mediated by ACE and chymase. Since the significance of non-ACE AII generation may be greatest in patients taking ACE-inhibitors, further studies were conducted on resistance arteries from patients with chronic heart failure (CHF) who were receiving such medication, compared to patients with coronary heart disease (CHD). In patients with CHD a similar dual pathway to that observed in normal volunteers appeared to be present. However, in arteries from patients with CHF, the contribution of chymase to AII generation - as inferred from the effect of inhibiting ACE - appeared to be less. Thus, the activity of the enzymes responsible for AII generation may be modulated by either the syndrome, or its treatment

The imprints of primordial non-gaussianities on large-scale structure: scale dependent bias and abundance of virialized objects

We study the effect of primordial nongaussianity on large-scale structure, focusing upon the most massive virialized objects. Using analytic arguments and N-body simulations, we calculate the mass function and clustering of dark matter halos across a range of redshifts and levels of nongaussianity. We propose a simple fitting function for the mass function valid across the entire range of our simulations. We find pronounced effects of nongaussianity on the clustering of dark matter halos, leading to strongly scale-dependent bias. This suggests that the large-scale clustering of rare objects may provide a sensitive probe of primordial nongaussianity. We very roughly estimate that upcoming surveys can constrain nongaussianity at the level |fNL| <~ 10, competitive with forecasted constraints from the microwave background.Comment: 16 pages, color figures, revtex4. v2: added references and an equation. submitted to PRD. v3: simplified derivation, additional reference

Probing Dark Energy Using Its Density Instead of Its Equation of State

The variation of dark energy density with redshift, $\rho_X(z)$, provides a critical clue to the nature of dark energy. Since $\rho_X(z)$ depends on the dark energy equation of state $w_X(z)$ through an integral, $\rho_X(z)$ can be constrained more tightly than $w_X(z)$ given the same observational data. We demonstrate this explicitly using current type Ia supernova (SN Ia) data [the Tonry/Barris sample], together with the Cosmic Microwave Background (CMB) shift parameter from CMB data (WMAP, CBI, and ACBAR), and the large scale structure (LSS) growth factor from 2dF galaxy survey data. We assume a flat universe, and use Markov Chain Monte Carlo (MCMC) technique in our analysis. We find that, while $w_X(z)$ extracted from current data is consistent with a cosmological constant at 68% C.L., $\rho_X(z)$ (which has far smaller uncertainties) is not. Our results clearly show the advantage of using $\rho_X(z)$, instead of $w_X(z)$, to probe dark energy.Comment: One color figure showing w_X(z) versus rho_X(z), reconstructed model-independently from data. Submitte

Bayesian power-spectrum inference for Large Scale Structure data

We describe an exact, flexible, and computationally efficient algorithm for a joint estimation of the large-scale structure and its power-spectrum, building on a Gibbs sampling framework and present its implementation ARES (Algorithm for REconstruction and Sampling). ARES is designed to reconstruct the 3D power-spectrum together with the underlying dark matter density field in a Bayesian framework, under the reasonable assumption that the long wavelength Fourier components are Gaussian distributed. As a result ARES does not only provide a single estimate but samples from the joint posterior of the power-spectrum and density field conditional on a set of observations. This enables us to calculate any desired statistical summary, in particular we are able to provide joint uncertainty estimates. We apply our method to mock catalogs, with highly structured observational masks and selection functions, in order to demonstrate its ability to reconstruct the power-spectrum from real data sets, while fully accounting for any mask induced mode coupling.Comment: 25 pages, 15 figure

Haemoglobin mass and running time trial performance after recombinant human erythropoietin administration in trained men

&lt;p&gt;Recombinant human erythropoietin (rHuEpo) increases haemoglobin mass (Hbmass) and maximal oxygen uptake (v˙ O2 max).&lt;/p&gt; &lt;p&gt;Purpose: This study defined the time course of changes in Hbmass, v˙ O2 max as well as running time trial performance following 4 weeks of rHuEpo administration to determine whether the laboratory observations would translate into actual improvements in running performance in the field.&lt;/p&gt; &lt;p&gt;Methods: 19 trained men received rHuEpo injections of 50 IUNkg21 body mass every two days for 4 weeks. Hbmass was determined weekly using the optimized carbon monoxide rebreathing method until 4 weeks after administration. v˙ O2 max and 3,000 m time trial performance were measured pre, post administration and at the end of the study.&lt;/p&gt; &lt;p&gt;Results: Relative to baseline, running performance significantly improved by ,6% after administration (10:3061:07 min:sec vs. 11:0861:15 min:sec, p,0.001) and remained significantly enhanced by ,3% 4 weeks after administration (10:4661:13 min:sec, p,0.001), while v˙ O2 max was also significantly increased post administration (60.765.8 mLNmin21Nkg21 vs. 56.066.2 mLNmin21Nkg21, p,0.001) and remained significantly increased 4 weeks after rHuEpo (58.065.6 mLNmin21Nkg21, p = 0.021). Hbmass was significantly increased at the end of administration compared to baseline (15.261.5 gNkg21 vs. 12.761.2 gNkg21, p,0.001). The rate of decrease in Hbmass toward baseline values post rHuEpo was similar to that of the increase during administration (20.53 gNkg21Nwk21, 95% confidence interval (CI) (20.68, 20.38) vs. 0.54 gNkg21Nwk21, CI (0.46, 0.63)) but Hbmass was still significantly elevated 4 weeks after administration compared to baseline (13.761.1 gNkg21, p&#60;0.001).&lt;/p&gt; &lt;p&gt;Conclusion: Running performance was improved following 4 weeks of rHuEpo and remained elevated 4 weeks after administration compared to baseline. These field performance effects coincided with rHuEpo-induced elevated v˙ O2 max and Hbmass.&lt;/p&gt

Limitations for health research with restricted data collection from UK primary care

Purpose UK primary care provides a rich data source for research. The impact of proposed data collection restrictions is unknown. This study aimed to assess the impact of restricting the scope of electronic health record (EHR) data collection on the ability to conduct research. The study estimated the consequences of restricted data collection on published Clinical Practice Research Datalink studies from high impact journals or referenced in clinical guidelines. Methods A structured form was used to systematically analyse the extent to which individual studies would have been possible using a database with data collection restrictions in place: (1) retrospective collection of specified diseases only; (2) retrospective collection restricted to a 6‐ or 12‐year period; (3) prospective and retrospective collection restricted to non‐sensitive data. Outcomes were categorised as unfeasible (not reproducible without major bias); compromised (feasible with design modification); or unaffected. Results Overall, 91% studies were compromised with all restrictions in place; 56% studies were unfeasible even with design modification. With restrictions on diseases alone, 74% studies were compromised; 51% were unfeasible. Restricting collection to 6/12 years had a major impact, with 67 and 22% of studies compromised, respectively. Restricting collection of sensitive data had a lesser but marked impact with 10% studies compromised. Conclusion EHR data collection restrictions can profoundly reduce the capacity for public health research that underpins evidence‐based medicine and clinical guidance. National initiatives seeking to collect EHRs should consider the implications of restricting data collection on the ability to address vital public health questions

Sensitivity and Insensitivity of Galaxy Cluster Surveys to New Physics

We study the implications and limitations of galaxy cluster surveys for constraining models of particle physics and gravity beyond the Standard Model. Flux limited cluster counts probe the history of large scale structure formation in the universe, and as such provide useful constraints on cosmological parameters. As a result of uncertainties in some aspects of cluster dynamics, cluster surveys are currently more useful for analyzing physics that would affect the formation of structure than physics that would modify the appearance of clusters. As an example we consider the Lambda-CDM cosmology and dimming mechanisms, such as photon-axion mixing.Comment: 24 pages, 8 eps figures. References added, discussion of scatter in relations between cluster observables lengthene

Star Formation and Feedback in Smoothed Particle Hydrodynamic Simulations--I. Isolated Galaxies

We present an analysis of star formation and feedback recipes appropriate for galactic smoothed particle hydrodynamics simulations. Using an isolated Milky Way-like galaxy, we constrain these recipes based on well-established observational results. Our star formation recipe is based on that of Katz (1992) with the additional inclusion of physically motivated supernova feedback recipes. We propose a new feedback recipe in which type II supernovae are modelled using an analytical treatment of blastwaves. With this feedback mechanism and a tuning of other star formation parameters, the star formation in our isolated Milky Way-like galaxy is constant and follows the slope and normalisation of the observed Schmidt law. In addition, we reproduce the low density cutoff and filamentary structure of star formation observed in disk galaxies. Our final recipe will enable better comparison of cosmological N-body simulations with observations.Comment: 18 pages, 22 figures, accepted to MNRAS, full resolution figures, more data, and movies at http://hpcc.astro.washington.edu/starformatio