Economic analysis of fertilizer options for maize production in Tanzania

United States Agency for International Developmen

Comparison of the Tolvaptan Versus Furosemide-Based Diuretic Regimes in Patients Hospitalized for Heart Failure with Hyponatremia (AQUA-AHF)

Hyponatremia is associated with worse longitudinal outcomes, and recently, poorer diuretic response in patients hospitalized for heart failure (HF). Whether tolvaptan monotherapy is a viable alternative to intravenous loop diuretics for decongestive therapy has not been tested. This study prospectively compared the efficacy and safety of a tolvaptan-based versus furosemide-based diuretic regimen on short-term outcomes in hyponatremic acute HF patients. Prospective, randomized, open-label, parallel-group, pilot study comparing a tolvaptan-based versus conventional continuous infusion furosemide-based regimen. Thirty-three subjects requiring hospitalization for acute HF with evidence of volume overload, and a serum sodium < 135 mEq/L within 48h of presentation were randomized to tolvaptan 30mg PO once daily or furosemide 5mg/h IV for the initial 24h, after which treatments could be escalated if required. Primary efficacy and safety endpoints were mean urine output and mean change in GFR at 24h post randomization. Additional endpoints included net fluid balance, changes in laboratory markers (electrolytes, cystatin C, NT-proBNP, plasma renin), weight, and dyspnea up to 96h post-randomization. Tolvaptan subjects were less often male (61 vs 93%) and had lower LVEF (24 vs 33%). Age, home diuretic dose, baseline serum sodium and vitals were not different. Four subjects in each group required study drug dose escalation (median daily dose throughout was tolvaptan 30mg and furosemide 120mg). Urine output and net fluid balance was not significantly different between tolvaptan or furosemide groups at 24h or any subsequent time point up to 96h. GFR tended to increase with tolvaptan, whereas it decreased with furosemide. Cystatin C improved at 24h with tolvaptan and the % change was significant compared to furosemide (-6.4±11.8 vs 4.1±17.2 % change, p=0.036). No significant between group differences were seen at 24h or study drug discontinuation/96h for NT-proBNP or PRA. As expected, serum sodium and potassium increased with tolvaptan compared to furosemide. Proportion with self-reported dyspnea that was moderately or markedly better at 24h was not different between groups (44% tolvaptan vs 27% furosemide, p=0.469). No major adverse events occurred. Diuresis with tolvaptan was similarly effective compared to intravenous furosemide for acute HF. Tolvaptan was associated with signals for improved renal and electrolyte safety, however the clinical significance needs to be tested in a larger study

Cardiac-Specific Gene Expression Facilitated by an Enhanced Myosin Light Chain Promoter

Background: Adenoviral gene transfer has been shown to be effective in cardiac myocytes in vitro and in vivo. A major limitation of myocardial gene therapy is the extracardiac transgene expression. Methods: To minimize extracardiac gene expression, we have constructed a tissue-specific promoter for cardiac gene transfer, namely, the 250-bp fragment of the myosin light chain-2v (MLC-2v) gene, which is known to be expressed in a tissue-specific manner in ventricular myocardium followed by a luciferase (luc) reporter gene (Ad.4 × MLC250.Luc). Rat cardiomyocytes, liver and kidney cells were infected with Ad.4 × MLC.Luc or control vectors. For in vivo testing, Ad.4 × MLC250.Luc was injected into the myocardium or in the liver of rats. Kinetics of promoter activity were monitored over 8 days using a cooled CCD camera. Results: In vitro: By infecting hepatic versus cardiomyocyte cells, we found that the promoter specificity ratio (luc activity in cardiomyocytes per liver cells) was 20.4 versus 0.9 (Ad.4 × MLC250.Luc vs. Ad.CMV). In vivo: Ad.4 × MLC250.Luc significantly reduced luc activity in liver (38.4-fold), lung (16.1-fold), and kidney (21.8-fold) versus Ad.CMV (p = .01); whereas activity in the heart was only 3.8-fold decreased. The gene expression rate of cardiomyocytes versus hepatocytes was 7:1 (Ad.4 × MLC.Luc) versus 1:1.4 (Ad.CMV.Luc). Discussion: This new vector may be useful to validate therapeutic approaches in animal disease models and offers the perspective for selective expression of therapeutic genes in the diseased heart

Tolvaptan vs. furosemide-based diuretic regimens in patients hospitalized for heart failure with hyponatremia (AQUA-AHF)

Aims Hyponatremia is associated with poorer outcomes and diuretic response in patients hospitalized for heart failure. This study compared a tolvaptan-based vs. furosemide-based diuretic regimen on short-term clinical responses in hyponatremic acute heart failure. Methods and results Prospective, randomized, open-label, parallel-group, single-centre study comparing oral tolvaptan vs. continuous infusion furosemide. Thirty-three subjects requiring hospitalization for acute congestive heart failure, and a serum sodium < 135 mmol/L, were randomized to tolvaptan 30 mg orally daily or furosemide 5 mg/h intravenously for initial 24 h, after which treatments could be escalated. Median daily dose throughout was tolvaptan 30 mg and furosemide 120 mg, with four subjects in each group requiring dose escalation. Urine output and net fluid balance were not different between groups at 24 h or subsequent time points up to 96 h. Changes in estimated glomerular filtration rate were comparable. Cystatin C improved at 24 h with tolvaptan compared with furosemide (-6.4 +/- 11.8 vs. 4.1 +/- 17.2% change,P = 0.036), but the effect was transient. No significant between group differences were seen for NT-proBNP, plasma renin activity, or urinary neutrophil gelatinase-associated lipocalin:Cr. Serum sodium, as well as copeptin levels, increased with tolvaptan compared with furosemide. Conclusions Oral tolvaptan was associated with similar, but not superior, diuresis compared with intravenous furosemide for acute heart failure with concomitant hyponatremia

Cardiac-Specific Gene Expression Facilitated by an Enhanced Myosin Light Chain Promoter

Background: Adenoviral gene transfer has been shown to be effective in cardiac myocytes in vitro and in vivo. A major limitation of myocardial gene therapy is the extracardiac transgene expression. Methods: To minimize extracardiac gene expression, we have constructed a tissue-specific promoter for cardiac gene transfer, namely, the 250-bp fragment of the myosin light chain-2v (MLC-2v) gene, which is known to be expressed in a tissue-specific manner in ventricular myocardium followed by a luciferase (luc) reporter gene (Ad.4 × MLC 250 .Luc). Rat cardiomyocytes, liver and kidney cells were infected with Ad.4 × MLC.Luc or control vectors. For in vivo testing, Ad.4 × MLC 250 .Luc was injected into the myocardium or in the liver of rats. Kinetics of promoter activity were monitored over 8 days using a cooled CCD camera. Results: In vitro: By infecting hepatic versus cardiomyocyte cells, we found that the promoter specificity ratio (luc activity in cardiomyocytes per liver cells) was 20.4 versus 0.9 (Ad.4 × MLC 250 .Luc vs. Ad.CMV). In vivo: Ad.4 × MLC 250 .Luc significantly reduced luc activity in liver (38.4-fold), lung (16.1-fold), and kidney (21.8-fold) versus Ad.CMV ( p = .01); whereas activity in the heart was only 3.8-fold decreased. The gene expression rate of cardiomyocytes versus hepatocytes was 7:1 (Ad.4 × MLC.Luc) versus 1:1.4 (Ad.CMV.Luc). Discussion: This new vector may be useful to validate therapeutic approaches in animal disease models and offers the perspective for selective expression of therapeutic genes in the diseased heart