Comparison of the effect of valsartan and lisinopril on autonomic nervous system activity in chronic heart failure.

Background: In chronic heart failure (CHF), the derangement of autonomic nervous system activity has a deep impact on the progression of the disease. It has been demonstrated that modulation of the renin-angiotensin aldosterone system (RAAS) increases autonomic control of heart rate and reduces adrenergic activity. We sought to evaluate, in CHF, the different effects of an ACE inhibitor (lisinopril) and of an AT1 receptor antagonist (valsartan) on heart rate variability, baroreflex sensitivity and norepinephrine plasma levels.

Low levels of endogenous oxidative damage cluster levels in unirradiated viral and human DNAs.

Ionizing radiation induces bistranded DNA damage clusters-two or more oxidized bases, abasic, sites or strand breaks on opposing strands within a few helical turns-but it is not known if clusters are also formed in unirradiated DNA in solution or in unirradiated cultured human cells. The frequencies of endogenous oxidized purine clusters (recognized by Escherichia coli Fpg protein), oxidized pyrimidine clusters (recognized by Nth protein), and abasic clusters (cleavage by Nfo protein) were determined using quantitative gel electrophoresis, electronic imaging, and number average length analysis. Methods of DNA isolation and storage were found to affect cluster levels significantly.

Allelic variants of natriuretic peptide receptor genes are associated with family history of hypertension and cardiovascular phenotype.

Objective: Abnormalities in the natriuretic peptide system could play a key role in the genesis of hypertension. We evaluated the associations between a family history of hypertension, cardiovascular phenotype and allelic variants of Npr1 and Npr3, two candidate genes that codify for natriuretic peptide receptors.

Methods: We genotyped 45 young normotensive subjects (19 males, 26.

Enhanced reflex response to baroreceptor deactivation in subjects with tilt-induced syncope.

Objectives: We sought to evaluate whether changes in resting baroreflex control of heart rate are a distinctive feature of healthy subjects with a history of syncope prone to a positive tilt-test response.

Background: The mechanisms involved in the pathogenesis of vasovagal syncope (VVS) are still poorly understood; in particular, the contribution of arterial baroreflex control of heart rate is matter of discussion.

Methods: A passive tilt-table test was performed in 312 consecutive, otherwise healthy subjects (age 36 +/- 15 years) with unexplained syncope and 100 control subjects.

Mechanisms of block of muscle type CLC chloride channels (Review).

CLC proteins are a nine-member gene family of Cl- channels that have diverse roles in the plasma membrane and in intracellular organelles. The recent structure determination of bacterial CLC homologues by Dutzler et al. was a breakthrough for the structure-function analysis of CLC channels.

Cardiac resynchronization therapy tailored by echocardiographic evaluation of ventricular asynchrony.

Objectives: The value of interventricular and intraventricular echocardiographic asynchrony parameters in predicting reverse remodeling after cardiac resynchronization therapy (CRT) was investigated.

Background: Cardiac resynchronization therapy has been suggested as a promising strategy in patients with severe heart failure and left bundle branch block (LBBB), but the entity of benefit is variable and no criteria are yet available to predict which patients will gain.

Methods: Interventricular and intraventricular mechanical asynchrony was evaluated in 20 patients (8 men and 12 women, 63 +/- 10 years) with advanced heart failure caused by ischemic (n = 4) or nonischemic dilated cardiomyopathy (n = 16) and LBBB (QRS duration of at least 140 ms) using echocardiographic Doppler measurements.

Molecular requisites for drug binding to muscle CLC-1 and renal CLC-K channel revealed by the use of phenoxy-alkyl derivatives of 2-(p-chlorophenoxy)propionic acid.

CLC channels are a gene family of Cl(-) channels that serve a variety of functions, several of which are involved in genetic diseases. Few specific ligands of CLC channels are known that could be useful as pharmacological tools or potential drugs. We synthesized various derivatives of 2-(p-chlorophenoxy)propionic acid, the S(-)-enantiomer of which is a specific blocker of the muscle channel CLC-1.

Shortened head-up tilting test guided by systolic pressure reductions in neurocardiogenic syncope.

Background: Asymptomatic reductions in arterial pressure have been reported to occur before the onset of tilt-induced syncope. We investigated the predictive value of these reductions for a positive tilt result.

Methods And Results: In a first study, 238 consecutive healthy subjects with unexplained syncope underwent a passive tilt table test.

Whole-body bioelectrical impedance analysis in patients with chronic heart failure: reproducibility of the method and effects of body side.

Background: Fluid imbalance and malnutrition have an important role in the clinical setting of chronic heart failure (CHF). Recently, tetrapolar bioelectrical impedance analysis has been suggested as an attractive method which may be used in the clinical assessment of the body composition. The aim of this study was to determine the effects of body side on whole bioelectrical impedance analysis parameters and test-retest reliability, prior to its use in a large cohort of patients.

Depression but not anxiety influences the autonomic control of heart rate after myocardial infarction.

Aims: It has been previously hypothesized that the adverse outcome observed in depressed patients after myocardial infarction might be due to an imbalance in autonomic nervous system activity. The aim of this study was to define the role of depressive and anxious symptoms in influencing autonomic control of heart rate after myocardial infarction.

Methods And Results: The SD of RR intervals, baroreflex sensitivity, and depression and anxiety (Zung's scales) were assessed before discharge in 103 patients with acute myocardial infarction; 32 were found to be depressed.

Influence of gender and family history of hypertension on autonomic control of heart rate, diastolic function and brain natriuretic peptide.

Objective: To verify in a unitary view whether autonomic control of heart rate and cardiac structure and function are modified early in offspring of hypertensive families.

Methods And Results: We selected 87 age- and sex-matched young normotensive subjects with (n = 45) and without (n = 42) a family history of hypertension who underwent evaluations of arterial pressure, time-domain parameters of autonomic heart rate control (24-h ECG monitoring), spectral baroreflex sensitivity, left ventricular geometry and function (echo-Doppler) and plasma brain natriuretic peptide levels (BNP). The group with a family history of hypertension significantly differed from their counterparts for systolic pressure (119 +/- 11 versus 114 +/- 9 mmHg, P< 0.

pRB and p107 have distinct effects when expressed in pRB-deficient tumor cells at physiologically relevant levels.

A key difference among the three structurally similar pRB family members is that only pRB is a tumor suppressor. Identification of distinctive functional differences between pRB and p107/p130 therefore holds promise for a better understanding of the tumor suppression mechanisms of pRB. Enigmatically, pRB and p107 have been shown to have indistinguishable growth suppression activities when studied in the pRB-deficient Saos-2 cell system.

Age effect on phase relations between respiratory oscillations of the RR interval and systolic pressure.

Spectral analysis may allow the evaluation of (baroreflex) gain and phase between the RR interval and systolic pressure oscillations synchronous with respiration but, unlike baroreflex gain, the determinants of phase are not completely understood. We evaluated the correlates of spectral phase in 92 healthy subjects (44 men) aged 10-80 years. To do so, the cardiorespiratory signals during paced breathing at 16 breaths/min were continuously recorded and analyzed.

Influence of hydrophilic and lipophilic beta-blockers on heart rate, ventricular repolarization and their interrelationship in normal subjects.

Background: It has been hypothesized that hydrophilic and lipophilic beta-blockers have different antiarrhythmic properties because only the latter seem to reduce the rate of sudden death in post-myocardial infarction patients as well as animal models which seem to be independent of their effect on autonomic nervous system modulation. The aim of this study was to evaluate the different effects of a hydrophilic (nadolol) and lipophilic (metoprolol) beta-blocker on ventricular repolarization in normal subjects.

Methods: Seventeen normal subjects entered this randomized, single-blind cross-over study designed to compare the effects of nadolol (80 mg/day) and slow-release metoprolol (200 mg/day) on dynamic ventricular repolarization.

DP1 phosphorylation in multimeric complexes: weaker interaction with cyclin A through the E2F1 cyclin A binding domain leads to more efficient phosphorylation than stronger interaction through the p107 cyclin A binding domain.

Stable enzyme-substrate interaction has been recognized as a major mechanism underlying the substrate preferences of cyclin-dependent kinases (Cdks). To learn the relationship between stability of physical association and efficiency of phosphorylation, we studied DP1 phosphorylation by cyclin A-Cdk2 in multiprotein complexes. When DP1 was connected to cyclin A-Cdk2 through E2F4 and p107, its phosphorylation was very inefficient, although its association with cyclin A-Cdk2 was stable.

Mouse Sin3A interacts with and can functionally substitute for the amino-terminal repression of the Myc antagonist Mxi1.

Mxi1 is a basic region helix-loop-helix leucine zipper (bHLH/LZ) protein that, in association with Max, antagonizes Myc oncogenic activities. A possible mechanistic basis for Mxi1-mediated repression was provided by the recent demonstration that the repressive potential of Mxi1 correlates with its ability to physically associate with mSin3B, one of two mammalian homologues of the yeast transcriptional repressor SIN3. Here, we sought to characterize more fully the physical properties of the second homologue, mSin3A and to determine whether the recruitment of mSin3A by Mxi1 is indeed required for anti-Myc activity.

An amino-terminal domain of Mxi1 mediates anti-Myc oncogenic activity and interacts with a homolog of the yeast transcriptional repressor SIN3.

Documented interactions among members of the Myc superfamily support a yin-yang model for the regulation of Myc-responsive genes in which transactivation-competent Myc-Max heterodimers are opposed by repressive Mxi1-Max or Mad-Max complexes. Analysis of mouse mxi1 has led to the identification of two mxi1 transcript forms possessing open reading frames that differ in their capacity to encode a short amino-terminal alpha-helical domain. The presence of this segment dramatically augments the suppressive potential of Mxi1 and allows for association with a mammalian protein that is structurally homologous to the yeast transcriptional repressor SIN3.

Homologous sequences in adenovirus E1A and human papillomavirus E7 proteins mediate interaction with the same set of cellular proteins.

Studies of adenovirus E1A oncoprotein mutants suggest that the association of E1A with the retinoblastoma protein (pRB) is necessary for E1A-mediated transformation. Mutational analysis of E1A indicates that two regions of pRB are required for E1A to form stable complexes with the retinoblastoma protein. In addition to pRB binding, these regions are necessary for E1A association with several other cellular proteins, including p130, p107, cyclin A, and p33cdk2.

Adenovirus E1A makes two distinct contacts with the retinoblastoma protein.

Two regions near the amino terminus of the adenovirus E1A protein, which were first identified by sequence conservation among various adenovirus serotypes, have been shown by genetic studies to be essential for E1A-mediated transformation. These same regions are also required for interaction with a number of cellular proteins, including the retinoblastoma protein (pRB). Using synthetic peptides corresponding to portions of these conserved regions, we show that each region can bind independently to pRB.