Carvedilol protects better against vascular events than metoprolol in heart failure: results from COMET.

OBJECTIVES: We explored whether vascular protection by carvedilol could contribute to its superior effects in the treatment of heart failure (HF) compared with metoprolol tartrate in the COMET (Carvedilol Or Metoprolol European Trial) study. BACKGROUND: Full adrenergic blockade by carvedilol and additional (e.g., antioxidative) properties may lead to vascular protection relative to beta-1 blockade alone, and contribute to its efficacy in HF treatment. METHODS: Three thousand twenty-nine patients with HF due to ischemic (51%) or idiopathic cardiomyopathy (44%) were randomized double-blind to carvedilol (n = 1,511) or metoprolol (n = 1,518) and followed for 58 months. Vascular end points were cardiovascular death, stroke, stroke death, myocardial infarction (MI), and unstable angina. RESULTS: The effect of carvedilol on cardiovascular death improved consistently in subgroups with prespecified baseline variables. Myocardial infarctions were reported in 69 carvedilol and 94 metoprolol patients (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.52 to 0.97, p = 0.03). Cardiovascular death or nonfatal MI combined were reduced by 19% in carvedilol (HR 0.81, 95% CI 0.72 to 0.92, p = 0.0009 vs. metoprolol). Unstable angina was reported as an adverse event in 56 carvedilol and in 77 metoprolol patients (HR 0.71, 95% CI 0.501 to 0.998, p = 0.049). A stroke occurred in 65 carvedilol and 80 metoprolol patients (HR 0.79, 95% CI 0.57 to 1.10). Stroke or MI combined occurred in 130 carvedilol and 168 metoprolol patients (HR 0.75, 95% CI 0.60 to 0.95, p = 0.015), and fatal MI or fatal stroke occurred in 34 carvedilol and in 72 metoprolol patients (HR 0.46, 95% CI 0.31 to 0.69, p = 0.0002). Death after a nonfatal MI or stroke occurred in 61 of 124 carvedilol and in 106 of 160 metoprolol patients (HR 0.66, 95% CI 0.48 to 0.90, p = 0.0086). CONCLUSIONS: Carvedilol improves vascular outcomes better than metoprolol. These results suggest a ubiquitous protective effect of carvedilol against major vascular events.     

Reiter's syndrome

A retrospective evaluation of 83 patients with Reiter's syndrome (RS) and 166 comparison arthritis patients was conducted in order to assess the preliminary criteria for definite RS. Data analysis was based on the statement that Reiter's syndrome consists of an episode of peripheral arthritis of more than 1 month duration occurring in association with urethritis and/or cervicitis. During the initial episode of RS, 70 of the 83 RS patients satisfied the criteria, yielding a sensitivity of 84.3%.     

Localization of seed protein genes on flow-sorted field bean chromosomes

Chromosomes from reconstructed field bean (Vicia faba L.) karyotypes were flow-sorted and the DNA was used for the physical localization of seed storage and nonstorage (USP) protein genes using PCR with sequence specific primers. The data were confirmed and refined by using DNA of microisolated chromosomes of other karyotypes as the target for PCR. The specificity of the PCR products was proved by restrictase digestion into fragments of predicted length or by reamplification using nested primers. The genes are located within defined regions of chromosome I (USP=unknown seedprotein genes), II (vicilin genes, legumin B3 genes), III (legumin B4 genes), IV (pseudogenes 1) and V (legumin A genes and pseudogenes 1). Except for the pseudogene derived from the sequence of legumin B4 gene, all members of each gene family are located in one chromosome region exclusively. This approach proved to be useful for localizing genes that cannot be mapped genetically (due to the lack of allelic variants) and might be applied to integrate physical and genetic maps.     

Development of murine ischemic cardiomyopathy is associated with a transient inflammatory reaction and depends on reactive oxygen species

We examined the effects of daily repetitive brief (15 min) myocardial ischemia and reperfusion (I/R) in WT C57BL6 and extracellular superoxide dismutase (EC-SOD)-overexpressing mice. In the absence of myocardial necrosis, I/R resulted in persistent fibrosis in ischemic areas of C57/BL6 mice associated with persistent global and segmental anterior wall dysfunction. The I/R protocol induced chemokines (peak 3 days) followed sequentially by infiltration of macrophages and myofibroblasts (5 days). Fibrosis peaked at 7 days and was stable at 28 days despite regression of the chemokine and cellular response. Discontinuation of I/R at 7 or 28 days led to regression of fibrosis and ventricular dysfunction. In contrast, the EC-SOD mice developed markedly less chemokine induction, cell response, and fibrosis, with no ventricular dysfunction. Reversible fibrosis and ventricular dysfunction are features of human hibernating myocardium. The reduction of the cellular and functional response in EC-SOD mice suggests a role for reactive O(2) in the pathogenesis of ischemic cardiomyopathy.     

Vitamin D, cardiovascular disease and mortality

A poor vitamin D status, i.e. low serum levels of 25-hydroxyvitamin D [25(OH)D], is common in the general population. This finding is of concern not only because of the classic vitamin D effects on musculoskeletal outcomes, but also because expression of the vitamin D receptor (VDR) and vitamin D metabolizing enzymes in the heart and blood vessels suggests a role of vitamin D in the cardiovascular system. VDR-knockout mice suffer from cardiovascular disease (CVD), and various experimental studies suggest cardiovascular protection by vitamin D, including antiatherosclerotic, anti-inflammatory and direct cardio-protective actions, beneficial effects on classic cardiovascular risk factors as well as suppression of parathyroid hormone (PTH) levels. In epidemiological studies, low levels of 25(OH)D are associated with increased risk of CVD and mortality. Data from randomized controlled trials (RCTs) are sparse and have partially, but not consistently, shown some beneficial effects of vitamin D supplementation on cardiovascular risk factors (e.g. arterial hypertension). We have insufficient data on vitamin D effects on cardiovascular events, but meta-analyses of RCTs indicate that vitamin D may modestly reduce all-cause mortality. Despite accumulating data suggesting that a sufficient vitamin D status may protect against CVD, we still must wait for results of large-scale RCTs before raising general recommendations for vitamin D in the prevention and treatment of CVD. In current clinical practice, the overall risks and costs of vitamin D supplementation should be weighed against the potential adverse consequences of untreated vitamin D deficiency.     

Peas,beans, and the Pythagorean theorem – the relevance of glucose‐6‐phosphate dehydrogenase deficiency in dermatology

Glucose‐6‐phosphate (G6PD) deficiency is a common disease characterized by acute hemolysis induced by oxidative stress. More than 400 million subjects throughout the world carry the hereditary enzyme defect with the highest prevalences in Africa, Asia, and the Mediterranean region. In individuals affected by the erythrocytic enzymatic disorder, besides infectious diseases and diet, acute hemolytic crisis can be triggered by numerous drugs frequently used for the treatment of dermatoses.Taking into account the increasing number of immigrants from geographic regions with high preva‐lences of G6PD deficiency, dermatologists should be alert to the presence of disease.     

Life chances after surgery of congenital heart disease: the influence of cardiac surgery on intergenerational social mobility. A comparison between patients and general population data.

BACKGROUND: To examine whether operated congenital heart disease (CHD) is setting preconditions for an active life by comparing intergenerational social mobility in patients with a population sample. DESIGN AND METHODS: The patient sample consisted of 314 females (42.1%) and males who underwent surgery for CHD (mean age at surgery 7.3 years, SD 7.8). According to the type of surgery, patients were classified as curative, reparative, or palliative. Consequently, the three groups reflect increasing severities of the initial heart defect. The mean age at examination was 26.9 years (7.6). Controls consisted of individuals who participated in the 2002 survey of the German Socio-Economic Panel. All individuals with complete sociodemographic information were included, and the final sample consisted of 4864 women (46.1%) and men (mean age 32.5 years, SD 7.2). RESULTS: Once having entered the labour market, intergenerational social mobility between patients and controls did not differ. For upward mobility respondents' social background was the key determinant; the respective standardized regression effect was beta=0.66. After dividing the study population, the social background turned out to having a slightly stronger effect in patients (beta=0.73) than in controls (beta=0.65). For downward mobility effects of the social background were smaller than for upward mobility (beta=0.19 in patients and beta=0.21 in controls). In economically active patients CHD severity did not determine social mobility. DISCUSSION: We conclude that a large proportion of patients could not or did not enter the labour market. Those who did experienced social mobility rates that are comparable with the general population.     

Caspase-9-dependent decrease of nuclear pore channel hydrophobicity is accompanied by nuclear envelope leakiness

Advances in nanomedicine require conceptual understanding of physiological processes. Apoptosis is a fundamental physiological process that is characterized, among other things, by an increased permeability of the nuclear envelope (NE). The latter is a tight transport barrier, known to restrict nuclear delivery rate of therapeutic nanoparticles. Therefore, an understanding of the underlying mechanism that leads to the breakdown of the barrier during apoptosis could stimulate the development of new approaches in gene therapy. We set out to elucidate this mechanism following induction of apoptosis on isolated cell nuclei. We tested the hypothesis whether caspases, mediators of apoptosis, trigger the NE leakiness at the level of the nuclear pore complexes (NPCs) using fluorescence techniques. As the permeability barrier inside the NPC channel is thought to be based on hydrophobic–hydrophobic protein interactions we further investigated the NPC channel hydrophobicity using atomic force microscopy. Caspase-9 was found to induce NE leakiness to large macromolecules. Leakiness was prevented by pretreatment of NPCs with an importin-β mutant, which irreversibly binds and thereby obstructs the NPC channel. Utilizing an ultra-sharp, hydrophobic atomic force microscope tip as a chemical nanosensor that reaches deep into the apoptotic NPC channel, a remarkable decrease of hydrophobic binding sites was detected therein. We conclude that caspase 9 gives rise to NE leakiness by perturbing the hydrophobicity-based barrier inside the NPC channel. This explains the high passive NE permeability in early apoptosis.From the Clinical EditorIn this study, biological processes taking place in the nucleus during the course of apoptosis have been monitored using atomic force microscopy-based nanosensors. The conclusion was that one of the caspases, caspase 9 perturbes the hydrophobicity-based barrier inside the nuclear pore complex channel causing nuclear envelope leakiness.     

Is the Ability index superior to the NYHA classification for assessing heart failure?

BACKGROUND: Heart failure (HF) is a major problem in the long-term follow-up of adolescents and adults with congenital heart disease (ACHD) after cardiac surgery. The functional status of ACHD may be assessed in terms of the NYHA classification or the Ability index (ABILITY). OBJECTIVE: The purpose of our study was to examine which of the two classification systems is more closely related to objectively defined HF. METHODS : NT-pro brain natriuretic peptide (N-BNP) and maximal oxygen uptake (VO(2max)) were measured in 360 consecutive ACHD patients. HF was defined as an elevated N-BNP level > or =100 pg/ml combined with a reduced VO(2max) < or =25 ml/kg/min. RESULTS: There were no significant differences between the NYHA and ABILITY in grading HF in these patients. In both classifications, the risk of HF increases continuously over the classes and grades from odds ratio (OR) 1 in NYHA I/ABILITY 1 to an OR=3.4 in NYHA II/ ABILITY 2 up to 11.6 or 5.4 (ns) in NYHA III/ABILITY 3. Thus in the highest scores HF is found in 70-77% of the patients. The fact that in NYHA class I and ABILITY grade 1, 15% and 19% of the patients exhibited HF according to the measured indices underscores the discrepancy between subjective and objective assessment of the individual patients condition. CONCLUSION: The NYHA classification and the Ability index take different approaches to the patients with congenital heart defects but are equally suitable for the judgement of HF in post surgical ACHD.     

Regulation by glucocorticoids of interferon gamma-induced HLA-DR antigen expression in cultured human orbital fibroblasts

OBJECTIVE: The purpose of this study was to determine whether glucocorticoids can block the induction of HLA-DR antigen expression by interferon gamma in human fibroblasts in culture. DESIGN AND PATIENTS: Confluent cultures of fibroblasts derived from the orbit or the skin of patients with Graves' ophthalmopathy or from normal subjects were treated with interferon gamma (100 U/ml) without or with graded concentrations of steroids. MEASUREMENTS: Cultures were analysed for HLA-DR expression using quantitative immunoblotting and indirect immunofluorescence. RESULTS: Glucocorticoids could block HLA-DR induction in a dose-dependent manner. At 10(-6) mol/l, the steroids dexamethasone and RU 28362 inhibited expression by 70% (P < 0.004) and 56% (P < 0.002) respectively. RU 38486, a glucocorticoid antagonist, could reverse the effect of both glucocorticoids, an action that was also dose dependent. At 10(-5) mol/l, RU 38486 blocked virtually the entire glucocorticoid effect. CONCLUSIONS: These results suggest that glucocorticoids can regulate HLA-DR induction by interferon gamma at physiological concentrations, an action which is stereospecific and mediated through the glucocorticoid receptor.