The use of B-type natriuretic peptide in the management of patients with diabetes and acute dyspnoea

Aims/hypothesis: The aim of this study was to determine the impact of measurement of B-type natriuretic peptide (BNP) levels on the management of patients with diabetes presenting with acute dyspnoea. Methods: This study evaluated the subgroup of 103 patients with diabetes included in the B-type Natriuretic Peptide for Acute Shortness of Breath Evaluation (BASEL) study (n=452). Patients were randomly assigned to a diagnostic strategy with (n=47, BNP group) or without (n=56, control group) the use of BNP levels assessed by a rapid bedside assay. Time to discharge and total cost of treatment were recorded as the primary endpoints. Results: Although similar with regard to age and sex, patients with diabetes more often had pre-existing cardiovascular and renal disease and heart failure as the cause of acute dyspnoea compared with patients without diabetes. In addition, medical and economic outcomes were worse in patients with diabetes. The use of BNP levels significantly reduced time to discharge (median 9days [interquartile range (IQR) 2-16] in the BNP group vs 13days [IQR 8-22] in the control group; p=0.016). At 30days, the diabetic patients in the BNP group had spent significantly fewer days in hospital compared with the diabetic patients in the control group (9days [IQR 2-19] vs 16days [IQR 8-24], respectively; p=0.008). Total treatment costs at 30days were US$5,705 (IQR 2,285-9,137) in the BNP group and US$7,420 (IQR 4,194-11,966) in the control group (p=0.036). Conclusions/interpretation: The results of this study indicate that measurement of BNP levels improves the management of patients with diabetes presenting with acute dyspnoe

Coronary artery disease and outcome in acute congestive heart failure

OBJECTIVES: To quantify the prognostic impact of coronary artery disease (CAD) on patients with acute heart failure (HF). DESIGN: Prospective cohort study of 217 consecutive patients presenting with acute HF to the emergency department. Treatment, hospitalisation, the use of revascularisation procedures, and survival were observed during follow up of up to three years. RESULTS: CAD was present in 153 patients (71%). Patients with and without CAD were similar with respect to age and sex. Although adequate HF treatment was initiated more rapidly among patients with CAD, their initial outcomes including hospitalisation rate, time to discharge, and total treatment cost were significantly worse. Moreover, despite higher use of angiotensin converting enzyme inhibitors and β blockers during follow up, patients with CAD had a significantly lower survival rate. Cumulative survival at 720 days was 48.7% of patients with CAD as compared with 76.4% of patients without CAD (p  =  0.0004). In Cox regression analysis the presence of CAD increased the risk of death by more than 250% (hazard ratio 2.57, 95% confidence interval 1.50 to 4.39, p  =  0.001). This strong association persisted after multivariate adjustments. The use of coronary angiography and coronary revascularisation procedures was low, both at initial presentation and during follow up. CONCLUSION: CAD is a strong and independent predictor of mortality among patients with acute HF. Whether, for example, less restrictive use of revascularisation procedures in this elderly HF population can improve the outcome for patients with CAD warrants further study

Morpholino Antisense Oligonucleotide-Mediated Gene Knockdown During Thymocyte Development Reveals Role for Runx3 Transcription Factor in CD4 Silencing During Development of CD4^-/CD8⁺ Thymocytes

During thymic T cell development, immature CD4+/CD8+ thymocytes develop into either CD4+/CD8- helper or CD4-/CD8+ CTLs. The molecular mechanisms governing the complex selection and differentiation steps during thymic T cell development are not well understood. Here we developed a novel approach to investigate gene function during thymocyte development. We transfected ex vivo isolated immature thymocytes with gene-specific morpholino antisense oligonucleotides and induced differentiation in cell or organ cultures. A morpholino oligonucleotide specific for CD8α strongly reduces CD8 expression. To our knowledge, this is the first demonstrated gene knockdown by morpholino oligonucleotides in primary lymphocytes. Using this approach, we show here that the transcription factor Runx3 is involved in silencing of CD4 expression during CD8 T cell differentiation. Runx3 protein expression appears late in thymocyte differentiation and is confined to mature CD8 single-positive thymocytes, whereas Runx3 mRNA is transcribed in mature CD4 and CD8 thymocytes. Therefore, Runx3 protein expression is regulated at a post-transcriptional level. The knockdown of Runx3 protein expression through morpholino oligonucleotides inhibited the development of CD4-/CD8+ T cells. Instead, mature cells with a CD4+/CD8+ phenotype accumulated. Potential Runx binding sites were identified in the CD4 gene silencer element, which are bound by Runx protein in EMSAs. Mutagenesis of potential Runx binding sites in the CD4 gene silencer abolished silencing activity in a reporter gene assay, indicating that Runx3 is involved in CD4 gene silencing. The experimental approach developed here should be valuable for the functional analysis of other candidate genes in T cell differentiation