Cbl-b interacts with ubiquitinated proteins; differential functions of the UBA domains of c-Cbl and Cbl-b.

Cbl proteins are ubiquitin protein ligases, which ubiquitinate activated tyrosine kinases and target them for degradation. Both c-Cbl and Cbl-b have an ubiquitin associated (UBA) domain at their C-terminal end. We observed that high molecular weight ubiquitinated proteins constitutively coimmunoprecipitated with transfected and endogenous Cbl-b, but not c-Cbl.

Exercise based rehabilitation for heart failure.

Background: The prevalence of chronic heart failure is increasing, and increases with increasing age. Major symptoms include breathlessness and restricted activities of daily living due to reduced functional capacity, which in turn affects quality of life. Exercise training has been shown to be effective in patients with coronary heart disease and has been proposed as an intervention to improve exercise tolerance in patients with heart failure.

Circulating cytokines and chemokines in acute symptomatic parvovirus B19 infection: negative association between levels of pro-inflammatory cytokines and development of B19-associated arthritis.

The aim of the study was to characterise the profile and clinical correlates (arthritis, rash, and fatigue) of cytokines, chemokines, and other mediators in symptomatic acute parvovirus B19 infection. Serum was examined from cases of acute B19 infection (as defined by serum anti-B19 IgM positivity) (n = 84), and in normal persons (n = 43) for B19 markers (serum B19 antibodies and DNA), rheumatoid factor (RF), and antinuclear antibody (ANA). A panel of cytokines/chemokines was measured in duplicate using the Bioplex Protein Array system (BioRad Hemel Hempstead, UK).

Effects of carvedilol on left ventricular remodelling in chronic stable heart failure: a cardiovascular magnetic resonance study.

Background: The ability of beta blockers to improve left ventricular function has been demonstrated, but data on the effects on cardiac remodelling are limited.

Objective: To investigate, using cardiovascular magnetic resonance (CMR), the effects of carvedilol on left ventricular remodelling in patients with chronic stable heart failure and left ventricular systolic dysfunction caused by coronary artery disease.

Design: Randomised, double blind, placebo controlled study.

Haemoglobin predicts survival in patients with chronic heart failure: a substudy of the ELITE II trial.

Aims: The correction of anaemia in chronic heart failure (CHF) has been suggested to be associated with an improvement in symptoms and cardiac function. We aimed to investigate the relationship between the concentration of haemoglobin and survival in CHF.

Methods And Results: We analysed haemoglobin concentrations in 3044 patients recruited in the Evaluation of Losartan In The Elderly (ELITE II) trial.

Is central nervous system processing altered in patients with heart failure?

Aims: Breathlessness is a cardinal symptom of heart failure and the altered regulation of breathing is common. The contribution of abnormal central nervous system activity has not previously been investigated directly, although abnormal autonomic responses have been described. Our aim was to assess whether heart failure patients exhibit different patterns of regional brain activation after exercise stress.

Influence of pretreatment systolic blood pressure on the effect of carvedilol in patients with severe chronic heart failure: the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) study.

Objectives: We sought to evaluate the influence of pretreatment systolic blood pressure (SBP) on the efficacy and safety of carvedilol in patients with chronic heart failure (CHF).

Background: Although beta-blockers reduce the risk of death in CHF, there is little reported experience with these drugs in patients with a low pretreatment SBP, who may respond poorly to beta-blockade.

Methods: We studied 2,289 patients with severe CHF who participated in the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial.

Life-years gained from defibrillator implantation: markedly nonlinear increase during 3 years of follow-up and its implications.

Background: Although treatment benefit in randomized controlled trials of defibrillators is often summarized by the numbers of lives saved (absolute risk difference), this may not be a good representation of what matters most to patients, namely, the amount of life they should expect to gain from implantation. The estimate of gain in life-years may depend on duration of follow-up. In this study, we examine this dependency.

NT-proBNP in severe chronic heart failure: rationale, design and preliminary results of the COPERNICUS NT-proBNP substudy.

Background: Neither profiles nor prognostic value of cardiac N-terminal proBNP (NT-proBNP) have been prospectively evaluated in a sufficient number of patients with severe chronic heart failure (CHF) treated with carvedilol or placebo.

Methods: Baseline and follow-up plasma concentrations of NT-proBNP were measured in the European part of the COPERNICUS Trial. This study enrolled patients with an ejection fraction <25% and symptoms of CHF at rest or on minimal exertion, equally randomized to placebo or carvedilol.

The epidemiological enigma of heart failure with preserved systolic function.

Background: Current epidemiological evidence suggests that the prevalence of preserved systolic function in patients with heart failure varies widely from 13 to 74%. This inconsistency suggests a lack of consensus as to what this condition really is and how it has been characterised for epidemiological studies.

Aims: In this review, we summarise and discuss the current understanding of the epidemiology of heart failure with preserved systolic function and the challenges that this raises.

Meta-analyses of mortality and morbidity effects of an angiotensin receptor blocker in patients with chronic heart failure already receiving an ACE inhibitor (alone or with a beta-blocker).

Background: While treatment with either angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) is clearly superior to placebo in the treatment of heart failure patients, controversy still surrounds the effects of ARBs in patients already receiving an ACEi. Even more controversial is the wisdom of administering ARBs in patients already on an ACEi and beta-blocker.

Methods: We present meta-analyses of the available randomised controlled trials to date (October 2003) of angiotensin II receptor antagonists versus placebo in patients with symptomatic chronic heart failure in which both groups received ACEi.

N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines.

The majority of ovarian cancer cells are resistant to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Subtoxic concentrations of the semisynthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) enhanced TRAIL-mediated apoptosis in ovarian cancer cell lines but not in immortalized nontumorigenic ovarian epithelial cells. The enhancement of TRAIL-mediated apoptosis by 4HPR was not due to changes in the levels of proteins known to modulate TRAIL sensitivity.

Differential contribution of dead space ventilation and low arterial pCO2 to exercise hyperpnea in patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

In chronic heart failure (CHF), the abnormally large ventilatory response to exercise (VE/VCO(2) slope) has 2 conceptual elements: the requirement of restraining arterial partial pressure of carbon dioxide (pCO(2)) from increasing (because of an increased ratio between increased physiologic dead space and tidal volume [VD/VT]) and the depression of arterial pCO(2) by further increased ventilation, which necessarily implies an important non-carbon dioxide stimulus to ventilation. We aimed to assess the contribution of these 2 factors in determining the elevated VE/VCO(2) slope in CHF. Thirty patients with CHF underwent cardiopulmonary exercise testing (age 65 +/- 11 years, left ventricular ejection fraction 34 +/- 15%, peak oxygen uptake 15.

Exercise training meta-analysis of trials in patients with chronic heart failure (ExTraMATCH).

Objective: To determine the effect of exercise training on survival in patients with heart failure due to left ventricular systolic dysfunction.

Design: Collaborative meta-analysis. Inclusion criteria Randomised parallel group controlled trials of exercise training for at least eight weeks with individual patient data on survival for at least three months.

The relationship between cholesterol and survival in patients with chronic heart failure.

Objectives: We sought to describe the relationship between cholesterol and survival in patients with chronic heart failure (CHF).

Background: Increasing lipoprotein levels are a cardiovascular risk factor. In patients with CHF, the prognostic value of endogenous lipoproteins is not fully clarified.

Ventricular long axis function is predictive of outcome in patients with chronic heart failure secondary to non-ischemic dilated cardiomyopathy.

Background: Ventricular long axis function has recently been proved to be of prognostic value in patients with heart failure. However, it remains unclear whether it can provide additional independent information over that provided by conventionally used LVEF or functional status. We conducted this study to address this issue, and to determine the prognostic importance of sequential change in long axis function over time in patients with idiopathic DCM.

Material properties of subchondral bone from patients with osteoporosis or osteoarthritis by microindentation testing and electron probe microanalysis.

Cancellous bone from patients with osteoarthritis (OA) has a reduced material density and appears to be undermineralized. It is hypothesized that this will result in a reduction in the mechanical stiffness and strength of the bone matrix. In this study, bone was obtained from superior and inferior sites, subjected to relatively high and low loads, respectively, from human femoral heads retrieved after surgery for osteoporotic hip fracture (OP), or for hip arthroplasty due to OA.

Global impairment of cardiac autonomic nervous activity late after the Fontan operation.

Background: Atrial tachyarrhythmia is a common cause of morbidity and mortality in patients with univentricular physiology undergoing the Fontan operation. We examined cardiac autonomic nervous activity, a predictor of arrhythmia and sudden death in other cardiovascular disease, in patients late after the Fontan operation, employing heart rate variability (HRV) and baroreflex sensitivity.

Methods And Results: We measured HRV and baroreflex sensitivity in 22 consecutive patients (8 male, age 26+/-9 years) who had undergone the Fontan operation 13+/-6 years previously, and 22 age- and sex-matched healthy controls.

A model for amyloid fibril formation in immunoglobulin light chains based on comparison of amyloidogenic and benign proteins and specific antibody binding.

In an attempt to understand the mechanism of amyloid fibril formation in light chain amyloidosis, the properties of amyloidogenic (SMA) and benign (LEN) immunoglobulin light chain variable domains (VL) were compared. The conformations of LEN and SMA were measured using secondary and tertiary structural probes over the pH range from 2 and 8. At all pH values, LEN was more stable than SMA.

The relationship between age and production of tumour necrosis factor-alpha in healthy volunteers and patients with chronic heart failure.

Background: Ageing is associated with an altered immune response. Elevated plasma levels of tumour necrosis factor-alpha (TNF-alpha) are present in patients with advanced chronic heart failure (CHF). However, the relationship between age and the immune response in CHF is unknown.

Reproducibility of the measurement of the muscle ergoreflex activity in chronic heart failure.

Background: A causative role for symptom generation in heart failure has been attributed to overactive muscle afferents, metaboreflex and mechanoreflex. We examined the reproducibility of the methods commonly used to assess these reflexes.

Material And Methods: Twelve stable heart failure patients (62.

Haemoglobin concentration and prognosis in new cases of heart failure.

Anaemia is common in severe chronic heart failure and is reported to be a predictor of death. We investigated 552 patients (median age 76 years, range 29-95; 54% men [n=296]), in whom the duration of heart failure was sufficiently short that it would be unlikely to affect haemoglobin concentrations. By contrast with studies in established chronic heart failure, haemoglobin was not independently associated with prognosis when age and serum creatinine concentration were included in the analysis.

Variability of phase shift between blood pressure and heart rate fluctuations: a marker of short-term circulation control.

Background: We postulated that the variability of the phase shift between blood pressure and heart rate fluctuation near the frequency of 0.10 Hz might be useful in assessing autonomic circulatory control.

Methods And Results: We tested this hypothesis in 4 groups of subjects: 28 young, healthy individuals; 13 elderly healthy individuals; 25 patients with coronary heart disease; and 19 patients with a planned or implanted cardioverter-defibrillator (ICD recipients).

Elevated circulating levels of inflammatory cytokines and bacterial endotoxin in adults with congenital heart disease.

Chronic heart failure is a state of immune activation, and endotoxin is a potential trigger for cytokine production. Our aim was to study whether immune activation and endotoxemia occur in adults with congenital heart disease. We prospectively measured tumor necrosis factor (TNF)-alpha, soluble TNF receptors (sTNFR-1, sTNFR-2), interleukin-6, interleukin-10, endotoxin, and soluble CD14 levels in 52 consecutive adults with congenital heart disease (age 34 +/- 2 years [mean +/- SEM]) and 18 healthy controls (age 31 +/- 1 years).