Expression of the HPV16E7 oncoprotein by thymic epithelium is accompanied by disrupted T cell maturation and a failure of the thymus to involute with age

Transgenic mice expressing the E7 protein of HPV16 from the keratin 14 promoter demonstrate increasing thymic hypertrophy with age. This hypertrophy is associated with increased absolute numbers of all thymocyte types, and with increased cortical and medullary cellularity. In the thymic medulla, increased compartmentalization of the major thymic stromal cell types and expansion of thymic epithelial cell population is observed. Neither an increased rate of immature thymocyte division nor a decreased rate of immature thymocyte death was able to account for the observed hypertrophy. Thymocytes with reduced levels of expression of CD4 and/or CD8 were more abundant in transgenic (tg) mice and became increasingly more so with age. These thymic SP and DP populations with reduced levels of CD4 and/or CD8 markers had a lower rate of apoptosis in the tg than in the non-tg mice. The rate of export of mature thymocytes to peripheral lymphoid organs was less in tg animals relative to the pool of available mature cells, particularly for the increasingly abundant CD4lo population. We therefore suggest that mature thymocytes that would normally die in the thymus gradually accumulated in E7 transgenic animals, perhaps as a consequence of exposure to a hypertrophied E7-expressing thymic epithelium or to factors secreted by this expanded thymic stromal cell population. The K14E7 transgenic mouse thus provides a unique model to study effects of the thymic epithelial cell compartment on thymus development and involution.

Effect of aldosterone antagonism on myocardial dysfunction in hypertensive patients with diastolic heart failure

Background - Specific treatments targeting the pathophysiology of hypertensive heart disease are lacking. As aldosterone has been implicated in the genesis of myocardial fibrosis, hypertrophy, and dysfunction, we sought to determine the effects of aldosterone antagonism on myocardial function in hypertensive patients with suspected diastolic heart failure by using sensitive quantitative echocardiographic techniques in a randomized, double-blinded, placebo-controlled study. Methods and Results - Thirty medically treated ambulatory hypertensive patients (19 women, age 62 +/- 6 years) with exertional dyspnea, ejection fraction >50%, and diastolic dysfunction (E/A 250m/sec) and without ischemia were randomized to spironolactone 25 mg/d or placebo for 6 months. Patients were overweight (31 +/- 5 kg/m(2)) with reduced treadmill exercise capacity (6.7 +/- 2.1 METS). Long-axis strain rate (SR), peak systolic strain, and cyclic variation of integrated backscatter (CVIB) were averaged from 6 walls in 3 standard apical views. Mean 24-hour ambulatory blood pressure at baseline (133 +/- 17/80 +/- 7mm Hg) did not change in either group. Values for SR, peak systolic strain, and CVIB were similar between groups at baseline and remained unchanged with placebo. Spironolactone therapy was associated with increases in SR (baseline: -1.57 +/- 0.46 s(-1) versus 6-months: -1.91 +/- 0.36 s(-1), P < 0.01), peak systolic strain (-20.3 &PLUSMN; 5.0% versus -26.9 &PLUSMN; 4.3%, P < 0.001), and CVIB (7.4 +/- 1.7dB versus 8.6 +/- 1.7 dB, P = 0.08). Each parameter was significantly greater in the spironolactone group compared with placebo at 6 months (P = 0.05, P = 0.02, and P = 0.02, respectively), and the increases remained significant after adjusting for baseline differences. The increase in strain was independent of changes in blood pressure with intervention. The spironolactone group also exhibited reduction in posterior wall thickness (P = 0.04) and a trend to reduced left atrial area (P = 0.09). Conclusions - Aldosterone antagonism improves myocardial function in hypertensive heart disease.

Response of B-type natriuretic pepticle to exercise in hypertensive patients with suspected diastolic heart failure: Correlation with cardiac function, hemodynamics, and workload

Background Diastolic heart failure (DHF) is characterized by dyspnea due to increased left ventricular (LV) filling pressures during stress. We sought the relationship of exercise-induced increases in B-type natriuretic peptide (BNP) to LV filling pressures and parameters of cardiovascular performance in suspected DHF. Methods Twenty-six treated hypertensive patients with suspected DHF (exertional dyspnea, LV ejection fraction >50%, and diastolic dysfunction) underwent maximal exercise echocardiography using the Bruce protocol. BNP, transmitral Doppler, and tissue Doppler for systolic (So) and early (Ea) and late (Aa) diastolic mitral annular velocities were obtained at rest and peak stress. LV filling pressures were estimated with E/Ea ratios. Results Resting BNP correlated with resting pulse pressure (r=0.45, P=0.02). Maximal exercise performance (4.6 +/- 2.5min) was limited by dyspnea. Blood pressure increased with exercise (from 143 +/- 19/88 +/- 8 to 191 +/- 22/90 +/- 10 mm Hg); 13 patients (50%) had a hypertensive response. Peak exercise BNP correlated with peak transmitral E velocity (r = 0.41, P <.05) and peak heart rate (r = -0.40, P <.05). BNP increased with exercise (from 48 57 to 74 97 pg/mL, P =.007), and the increment of BNP with exercise was associated with maximal workload and peak exercise So, Ea, and Aa (P <.01 for all). Filling pressures, approximated by lateral E/Ea ratio, increased with exercise (7.7 +/- 2.0 to 10.0 +/- 4.8, P <.01). BNP was higher in patients with possibly elevated filling pressures at peak exercise (E/Ea >10) compared to those with normal pressures (123 +/- 124 vs 45 +/- 71 pg/mL, P =.027). Conclusions Augmentation of BNP with exercise in hypertensive patients with suspected DHF is associated with better exercise capacity, LV systolic and diastolic function, and left atrial function. Peak exercise BNP levels may identify exercise-induced elevation of filling pressures in DHF.

National survey of the prevalence, incidence, primary care burden, and treatment of heart failure in Scotland

Objective: To examine the epidemiology, primary care burden, and treatment of heart failure in Scotland, UK. Design: Cross sectional data from primary care practices participating in the Scottish continuous morbidity recording scheme between 1 April 1999 and 31 March 2000. Setting: 53 primary care practices ( 307 741 patients). Subjects: 2186 adult patients with heart failure. Results: The prevalence of heart failure in Scotland was 7.1 in 1000, increasing with age to 90.1 in 1000 among patients greater than or equal to 85 years. The incidence of heart failure was 2.0 in 1000, increasing with age to 22.4 in 1000 among patients greater than or equal to 85 years. For older patients, consultation rates for heart failure equalled or exceeded those for angina and hypertension. Respiratory tract infection was the most common comorbidity leading to consultation. Among men, 23% were prescribed a beta blocker, 11% spironolactone, and 46% an angiotensin converting enzyme inhibitor. The corresponding figures for women were 20% (p = 0.29 versus men), 7% (p = 0.02), and 34% (p < 0.001). Among patients, 75 years 26% were prescribed a β blocker, 11% spironolactone, and 50% an angiotensin converting enzyme inhibitor. The corresponding figures for patients &GE; 75 years were 19% (p = 0.04 versus patients < 75), 7% (p = 0.04), and 33% (p < 0.001). Conclusions: Heart failure is a common condition, especially with advancing age. In the elderly, the community burden of heart failure is at least as great as that of angina or hypertension. The high rate of concomitant respiratory tract infection emphasises the need for strategies to immunise patients with heart failure against influenza and pneumococcal infection. Drugs proven to improve survival in heart failure are used less frequently for elderly patients and women.

Effects of a nurse-led, clinic and home-based intervention on recurrent hospital use in chronic heart failure

Background: Few studies have examined the potential benefits of specialist nurse-led programs of care involving home and clinic-based follow-up to optimise the post-discharge management of chronic heart failure (CHF). Objective: To determine the effectiveness of a hybrid program of clinic plus home-based intervention (C+HBI) in reducing recurrent hospitalisation in CHF patients. Methods: CHF patients with evidence of left ventricular systolic dysfunction admitted to two hospitals in Northern England were assigned to a C+HBI lasting 6 months post-discharge (n=58) or to usual, post-discharge care (UC: n=48) via a cluster randomization protocol. The co-primary endpoints were death or unplanned readmission (event-free survival) and rate of recurrent, all-cause readmission within 6 months of hospital discharge. Results: During study follow-up, more UC patients had an unplanned readmission for any cause (44% vs. 22%: P=0.0191 OR 1.95 95% CI 1.10-3.48) whilst 7 (15%) versus 5 (9%) UC and C+HBI patients, respectively, died (P=NS). Overall, 15 (26%) C+HBI versus 21 (44%) UC patients experienced a primary endpoint. C+HBI was associated with a non-significant, 45% reduction in the risk of death or readmission when adjusting for potential confounders (RR 0.55, 95% CI 0.28-1.08: P=0.08). Overall, C+HBI patients accumulated significantly fewer unplanned readmissions (15 vs. 45: P

Is mortality from heart failure increasing in Australia? An analysis of official data on mortality for 1997-2003

Objective To assess whether trends in mortality from heart failure(HF) in Australia are due to a change in awareness of the condition or real changes in its epidemiology. Methods We carried out a retrospective analysis of official data on national mortality data between 1997 and 2003. A death was attributed to HF if the death certificate mentioned HF as either the underlying cause of death (UCD) or among the contributory factors. Findings From a total of 907 242 deaths, heart failure was coded as the UCD for 29 341 (3.2%) and was mentioned anywhere on the death certificate in 135 268 (14.9%). Between 1997 and 2003, there were decreases in the absolute numbers of deaths and in the age-specific and age-standardized mortality rates for HF either as UCD or mentioned anywhere for both sexes. HF was mentioned for 24.6% and 17.8% of deaths attributed to ischaemic heart disease and circulatory disease, respectively, and these proportions remained unchanged over the period of study. In addition, HF as UCD accounted for 8.3% of deaths attributed to circulatory disease and this did not change materially from 1997 to 2003. Conclusion The decline in mortality from HF measured as either number of deaths or rate probably reflects a real change in the epidemiology of HF. Population-based studies are required to determine accurately the contributions of changes in incidence, survival and demographic factors to the evolving epidemiology of HF.

Predicting residue-wise contact orders in proteins by support vector regression

Background: The residue-wise contact order (RWCO) describes the sequence separations between the residues of interest and its contacting residues in a protein sequence. It is a new kind of one-dimensional protein structure that represents the extent of long-range contacts and is considered as a generalization of contact order. Together with secondary structure, accessible surface area, the B factor, and contact number, RWCO provides comprehensive and indispensable important information to reconstructing the protein three-dimensional structure from a set of one-dimensional structural properties. Accurately predicting RWCO values could have many important applications in protein three-dimensional structure prediction and protein folding rate prediction, and give deep insights into protein sequence-structure relationships. Results: We developed a novel approach to predict residue-wise contact order values in proteins based on support vector regression (SVR), starting from primary amino acid sequences. We explored seven different sequence encoding schemes to examine their effects on the prediction performance, including local sequence in the form of PSI-BLAST profiles, local sequence plus amino acid composition, local sequence plus molecular weight, local sequence plus secondary structure predicted by PSIPRED, local sequence plus molecular weight and amino acid composition, local sequence plus molecular weight and predicted secondary structure, and local sequence plus molecular weight, amino acid composition and predicted secondary structure. When using local sequences with multiple sequence alignments in the form of PSI-BLAST profiles, we could predict the RWCO distribution with a Pearson correlation coefficient (CC) between the predicted and observed RWCO values of 0.55, and root mean square error (RMSE) of 0.82, based on a well-defined dataset with 680 protein sequences. Moreover, by incorporating global features such as molecular weight and amino acid composition we could further improve the prediction performance with the CC to 0.57 and an RMSE of 0.79. In addition, combining the predicted secondary structure by PSIPRED was found to significantly improve the prediction performance and could yield the best prediction accuracy with a CC of 0.60 and RMSE of 0.78, which provided at least comparable performance compared with the other existing methods. Conclusion: The SVR method shows a prediction performance competitive with or at least comparable to the previously developed linear regression-based methods for predicting RWCO values. In contrast to support vector classification (SVC), SVR is very good at estimating the raw value profiles of the samples. The successful application of the SVR approach in this study reinforces the fact that support vector regression is a powerful tool in extracting the protein sequence-structure relationship and in estimating the protein structural profiles from amino acid sequences.

Measurement of strain and strain rate by echocardiography - Ready for prime time?

Strain and strain rate (SR) are measures of deformation that are basic descriptors of both the nature and the function of cardiac tissue. These properties may now be measured using either Doppler or two-dimensional ultrasound techniques. Although these measurements are feasible in routine clinical echocardiography, their acquisition and analysis nonetheless presents a number of technical challenges and complexities. Echocardiographic strain and SR imaging has been applied to the assessment of resting ventricular function, the assessment of myocardial viability using low-dose dobutamine infusion, and stress testing for ischemia. Resting function assessment has been applied in both the left and the fight ventricles, and may prove particularly valuable for identifying myocardial diseases and following up the treatment response. Although the evidence base is limited, SR imaging seems to be feasible and effective for the assessment of myocardial viability. The use of the technique for the detection of ischemia during stress echocardiography is technically challenging and likely to evolve further. The clinical availability of strain and SR measurement may offer a solution to the ongoing need for quantification of regional and global cardiac function. Nonetheless, these techniques are susceptible to artifact, and further technical development is necessary.

Cardiac contributions to exercise training responses in patients with chronic heart failure: A strain imaging study

The improvement of exercise capacity due to exercise training in heart failure has been associated with peripheral adaptation, but the contribution of cardiac responses is less clear. We sought the extent to which the improvement of functional capacity in patients undergoing exercise training for heart failure was related to myocardial performance. Thirty-seven patients (35 men, age 64 +/- 11) with symptomatic heart failure and left ventricular ejection fraction

Recent changes in heart failure hospitalisations in Australia

Aim: To assess trends in admissions of patients with heart failure (HF) to all hospitals in Australia between 1996-1997 and 2003-2004. Methods and results: We carried out a retrospective analysis of the official population-based National Hospital Morbidity Data in Australia. Although the absolute number of separations with a principal diagnosis of HF remained stable, the age- and sex-standardized separation rate for HF recorded as principal diagnosis decreased from 2.0 per 1000 population in 1996-1997 to 1.6 per 1000 population in 2003-2004. The corresponding values for HF recorded in any diagnostic position were 7.7 and 4.7 per 1000 population. Men had higher in-hospital mortality than women (8.9% versus 8.1%,p < 0.001) and also a larger decrease in this measure over the study period (21.9% versus 14.4%). While the geometric mean length of stay for HF as principal diagnosis fell from 5.4 days in 1996-1997 to 4.9 days in 2003-2004, the proportion of bed-days related to such diagnoses relative to total bed days attributed to circulatory diseases increased from 12.8% to 13.7% (p < 0.001). Conclusion: There were no increase in number of admissions involving HF and standardized rates of hospital separations with HF fell in Australia between 1996 and 2004. The explanation for the observed declines in in-hospital case fatality and the separation rates should be sought in whole-of-community studies. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Anisotropic viscous models of large-deformation Mohr-Coulomb failure

We have developed a way to represent Mohr-Coulomb failure within a mantle-convection fluid dynamics code. We use a viscous model of deformation with an orthotropic viscoplasticity (a different viscosity is used for pure shear to that used for simple shear) to define a prefered plane for slip to occur given the local stress field. The simple-shear viscosity and the deformation can then be iterated to ensure that the yield criterion is always satisfied. We again assume the Boussinesq approximation, neglecting any effect of dilatancy on the stress field. An additional criterion is required to ensure that deformation occurs along the plane aligned with maximum shear strain-rate rather than the perpendicular plane, which is formally equivalent in any symmetric formulation. We also allow for strain-weakening of the material. The material can remember both the accumulated failure history and the direction of failure. We have included this capacity in a Lagrangian-integration-point finite element code and show a number of examples of extension and compression of a crustal block with a Mohr-Coulomb failure criterion. The formulation itself is general and applies to 2- and 3-dimensional problems.

Prediction of functional capacity in chronic heart failure patients using myocardial tissue Doppler

Background. Exercise therapy improves functional capacity in CHF, but selection and individualization of training would be helped by a simple non-invasive marker of peak VO2. Peak VO2 in these pts is difficult to predict without direct measurement, and LV ejection fraction is a poor predictor. Myocardial tissue velocities are less load-dependent, and may be predictive of the exercise response in CHF pts. We sought to use tissue velocity as a predictor of peak VO2 in CHF pts. Methods. Resting 2D-echocardiography and tissue Doppler imaging were performed in 182 CHF pts (159 male, age 62±10 years) before and after metabolic exercise testing. The majority of these patients (129, 71%) had an ischemic cardiomyopathy, with resting EF of 35±13% and a peak VO2 of 13.5±4.7 ml/kg/min. Results. Neither resting EF (r=0.15) nor peak EF (r=0.18, both p=NS) were correlated with peak VO2. However, peak VO2 correlated with peak systolic velocity in septal (Vss, r=0.31) and lateral walls (Vsl, r=0.26, both p=0.01). In a general linear model (r2 = 0.25), peak VO2 was calculated from the following equation: 9.6 + 0.68*Vss - 0.09*age + 0.06*maximum HR. This model proved to be a superior predictor of peak VO2 (r=0.51, p=0.01) than the standard prediction equations of Wasserman (r= -0.12, p=0.01). Conclusions. Resting tissue Doppler, age and maximum heart rate may be used to predict functional capacity in CHF patients. This may be of use in selecting and following the response to therapy, including for exercise training.

An anisotropic viscous representation of Mohr-Coulomb failure for use is modelling coupled mantle-continent dynamics

In mantle convection models it has become common to make use of a modified (pressure sensitive, Boussinesq) von Mises yield criterion to limit the maximum stress the lithosphere can support. This approach allows the viscous, cool thermal boundary layer to deform in a relatively plate-like mode even in a fully Eulerian representation. In large-scale models with embedded continental crust where the mobile boundary layer represents the oceanic lithosphere, the von Mises yield criterion for the oceans ensures that the continents experience a realistic broad-scale stress regime. In detailed models of crustal deformation it is, however, more appropriate to choose a Mohr-Coulomb yield criterion based upon the idea that frictional slip occurs on whichever one of many randomly oriented planes happens to be favorably oriented with respect to the stress field. As coupled crust/mantle models become more sophisticated it is important to be able to use whichever failure model is appropriate to a given part of the system. We have therefore developed a way to represent Mohr-Coulomb failure within a code which is suited to mantle convection problems coupled to large-scale crustal deformation. Our approach uses an orthotropic viscous rheology (a different viscosity for pure shear to that for simple shear) to define a prefered plane for slip to occur given the local stress field. The simple-shear viscosity and the deformation can then be iterated to ensure that the yield criterion is always satisfied. We again assume the Boussinesq approximation - neglecting any effect of dilatancy on the stress field. An additional criterion is required to ensure that deformation occurs along the plane aligned with maximum shear strain-rate rather than the perpendicular plane which is formally equivalent in any symmetric formulation. It is also important to allow strain-weakening of the material. The material should remember both the accumulated failure history and the direction of failure. We have included this capacity in a Lagrangian-Integration-point finite element code and will show a number of examples of extension and compression of a crustal block with a Mohr-Coulomb failure criterion, and comparisons between mantle convection models using the von Mises versus the Mohr-Coulomb yield criteria. The formulation itself is general and applies to 2D and 3D problems, although it is somewhat more complicated to identify the slip plane in 3D.

Post-Bretton Woods evidence on PPP under different exchange rate regimes

This article investigates the behaviour of exchange rates across different regimes for a post-Bretton Woods period. The exchange rate regime classification is based on the classification of Frankel et al. (2004) who condensed the 10 categories of exchange rate regimes reported by the International Monetary Fund (IMF) into three categories. Panel unitroot tests and panel cointegration are used to examine the Purchasing Power Parity (PPP) hypothesis. The latter test is used to check for both the weak and strong forms of PPP. The panel unit-root tests show no evidence of PPP and suggest there is no difference in the behaviour of exchange rates across different regimes. However, failure to detect PPP across any of the regimes could be due to structural breaks. This assumption is reinforced by the results of cointegration tests, which suggest that there exists at least a weak form of PPP for the different regimes. The evidence for strong PPP decreases as the exchange rate regime moves away from a flexible exchange rate regime.

All-fiber polarization locked vector soliton laser using carbon nanotubes

We report an all-fiber mode-locked erbium-doped fiber laser (EDFL) employing carbon nanotube (CNT) polymer composite film. By using only standard telecom grade components, without any complex polarization control elements in the laser cavity, we have demonstrated polarization locked vector solitons generation with duration of ~583fs , average power of ~3 mW (pulse energy of 118pJ ) at the repetition rate of ~25.7 MHz.