Multidimensional reference regions for IGF-I, IGFBP-2 and IGFBP-3 concentrations in serum of healthy adults.

Context: The insulin-like growth factor (IGF) system exerts many effects on the growth and differentiation of both normal and malignant cells. The serum concentrations of insulin-like growth factor I (S-IGF-I), insulin-like growth factor-binding protein 2 (S-IGFBP-2) and insulin-like growth factor-binding protein 3 (S-IGFBP-3) and their inter-relations may differ in certain disease states from those seen in healthy individuals.

Objective: To estimate age-, gender- and body mass index (BMI)-specific univariate, bivariate and trivariate 95% reference regions for these components in healthy adults and present indices that will facilitate interpretation of patient observations in relation to these reference regions.

Beyond the sarcomere: CSRP3 mutations cause hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a frequent genetic cardiac disease and the most common cause of sudden cardiac death in young individuals. Most of the currently known HCM disease genes encode sarcomeric proteins. Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations.

A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a heterogeneous autosomal dominant cardiac disorder with a prevalence of 1 in 500. Over 450 different pathogenic mutations in at least 16 genes have been identified so far. The large allelic and genetic heterogeneity of HCM requires high-throughput, rapid, and affordable mutation detection technologies to efficiently integrate molecular screening into clinical practice.

Dysfunction of dysferlin-deficient hearts.

Mutations in the gene encoding dysferlin cause limb-girdle muscular dystrophy 2B (LGMD2B), a disorder that is believed to spare the heart. We observed dilated cardiomyopathy in two out of seven LGMD2B patients and cardiac abnormalities in three others. Cardiac biopsies showed that dysferlin was completely absent from the sarcolemma and appeared to be trapped within the cardiomyocytes.

Expression of the protein phosphatase 1 inhibitor KEPI is downregulated in breast cancer cell lines and tissues and involved in the regulation of the tumor suppressor EGR1 via the MEK-ERK pathway.

KEPI is a protein kinase C-potentiated inhibitory protein for type 1 Ser/Thr protein phosphatases. We found no or reduced expression of KEPI in breast cancer cell lines, breast tumors and metastases in comparison to normal breast cell lines and tissues, respectively. KEPI protein expression and ubiquitous localization was detected with a newly generated antibody.

A systematic meta-analysis of the efficacy and heterogeneity of disease management programs in congestive heart failure.

Background: We sought to systematically combine the evidence on efficacy of disease management programs (DMPs) in the treatment of congestive heart failure (CHF), to identify and explain heterogeneity of results from prior studies of DMPs, and to assess potential publication bias from these studies.

Methods And Results: We conducted a systematic literature search on randomized clinical trials investigating the effect of DMPs on CHF outcomes and performed meta-analyses and meta-regressions comparing DMPs and standard care for mortality and rehospitalization. We included 36 studies from 13 different countries (with data from 8341 patients).

Asymmetric dimethylarginine is an independent risk factor for coronary heart disease: results from the multicenter Coronary Artery Risk Determination investigating the Influence of ADMA Concentration (CARDIAC) study.

Background: Asymmetric dimethylarginine (ADMA) plasma levels have been shown to be elevated in diseases related to endothelial dysfunction such as hypertension, hyperlipidemia, diabetes mellitus, and others. It has been shown that ADMA predicts cardiovascular mortality in patients who have coronary heart disease (CHD). However, the question whether ADMA is an independent risk factor for CHD still remains unresolved.

Gene expression analysis of human tissue from patients with cardiomyopathies: a new tool for guiding therapies in the future?

The complete sequencing of the human genome led to the development of a number of new molecular technologies. DNA microarrays represent an exciting new tool for gene expression analysis in human tissue. Measurements of the expressions of many thousands of genes in parallel is possible now.

Increased susceptibility to complement attack due to down-regulation of decay-accelerating factor/CD55 in dysferlin-deficient muscular dystrophy.

Dysferlin is expressed in skeletal and cardiac muscles. However, dysferlin deficiency results in skeletal muscle weakness, but spares the heart. We compared intraindividual mRNA expression profiles of cardiac and skeletal muscle in dysferlin-deficient SJL/J mice and found down-regulation of the complement inhibitor, decay-accelerating factor/CD55, in skeletal muscle only.

[Familial dilated cardiomyopathy].

Dilated cardiomyopathy (DCM) is the most frequent form of primary myocardial diseases and the third most common cause of heart failure. Clinically, DCM is characterized by a progressive course of ventricular dilatation and systolic dysfunction. The life expectancy is limited and varies according to the underlying etiology with a median survival time of about 5 years after diagnosis.

Prevalence of cardiac beta-myosin heavy chain gene mutations in patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a frequent, autosomal-dominant cardiac disease and manifests predominantly as left ventricular hypertrophy. Mutations in the cardiac beta-myosin heavy chain gene (MYH7) are responsible for the disease in about 30% of cases where mutations were identified. We clinically evaluated a large group of 147 consecutive HCM patients from three cardiology centers in Germany, Poland, and Kyrgyzstan according to the same protocol.

Returning hypertrophy after surgery in a patient with hypertrophic cardiomyopathy caused by a myosin-binding protein C mutation.

We report a 13-year follow-up of a patient who underwent both myectomy and septal ablation due to hypertrophic cardiomyopathy caused by a cardiac myosin-binding protein C gene mutation. After myectomy the patient again developed significant septal hypertrophy at the operated septal area with a need for a second interventional therapy. This exceptional case underscores the remarkable ability of the heart muscle to show a continuous hypertrophic process over many years.

Decreased interactions of mutant muscle LIM protein (MLP) with N-RAP and alpha-actinin and their implication for hypertrophic cardiomyopathy.

Previous work has shown that mutations in muscle LIM protein (MLP) can cause hypertrophic cardiomyopathy (HCM). In order to gain an insight into the molecular basis of the disease phenotype, we analysed the binding characteristics of wild-type MLP and of the (C58G) mutant MLP that causes hypertrophic cardiomyopathy. We show that MLP can form a ternary complex with two of its previously documented myofibrillar ligand proteins, N-RAP and alpha-actinin, which indicates the presence of distinct, non-overlapping binding sites.

Effects of ACE gene insertion/deletion polymorphism on response to spironolactone in patients with chronic heart failure.

Background: Angiotensin-converting enzyme (ACE) is involved in the pathophysiology of chronic heart failure, and its activity is determined in part by a polymorphism of the ACE gene. We hypothesized that the benefits of spironolactone, which inhibits downstream elements of ACE-mediated abnormalities, may depend on ACE genotype.

Methods: We randomly assigned 93 chronic heart failure patients to treatment with spironolactone (n = 47) or to a control group (n = 46) and followed them for 12 months.

Reference levels of insulin-like growth factor I in the serum of healthy adults: comparison of four immunoassays.

The measurement of insulin-like growth factor-I (IGF-I) has become an essential tool for diagnosing growth hormone deficiency and acromegaly, as well as for monitoring the efficacy of treatment in these disorders. The latter aspect gains significance in the light of epidemiological studies which indicate a relationship between IGF-I levels and the incidence of certain malignancies. We aimed to evaluate the performance of widely implemented IGF-I assays by testing four representative, commercially available immunoassays.

Expression profiling of human idiopathic dilated cardiomyopathy.

Objective: To investigate the global changes accompanying human dilated cardiomyopathy (DCM) we performed a large-scale expression screen using myocardial biopsies from a group of DCM patients with moderate heart failure. By hierarchical clustering and functional annotation of the deregulated genes we examined extensive changes in the cellular and molecular processes associated to DCM.

Methods: The expression profiles were obtained using a whole genome covering library (UniGene RZPD1) comprising 30336 cDNA clones and amplified RNA from myocardiac biopsies from 10 DCM patients in comparison to tissue samples from four non-failing, healthy donors.

Uric acid and survival in chronic heart failure: validation and application in metabolic, functional, and hemodynamic staging.

Background: Serum uric acid (UA) could be a valid prognostic marker and useful for metabolic, hemodynamic, and functional (MFH) staging in chronic heart failure (CHF).

Methods And Results: For the derivation study, 112 patients with CHF (age 59+/-12 years, peak oxygen consumption [Vo2] 17+/-7 mL/kg per minute) were recruited. In separate studies, we validated the prognostic value of UA (n=182) and investigated the relationship between MFH score and the decision to list patients for heart transplantation (n=120).

Mutations in the human muscle LIM protein gene in families with hypertrophic cardiomyopathy.

Background: Muscle LIM protein (MLP) is an essential nuclear regulator of myogenic differentiation. Additionally, it may act as an integrator of protein assembly of the actin-based cytoskeleton. MLP-knockout mice develop a marked cardiac hypertrophy reaction and dilated cardiomyopathy (DCM).