Tolerability of extended duration intravenous milrinone in patients hospitalized for advanced heart failure and the usefulness of uptitration of oral angiotensin-converting enzyme inhibitors.

Milrinone is a phosphodiesterase inhibitor that has been shown to improve hemodynamic parameters in patients with class III to IV heart failure when administered intravenously for < or =48 hours. This study examines the tolerability of long-term intravenous milrinone therapy and assesses its utility in allowing upward titration of oral vasodilator agents. A retrospective review of hospital records identified 63 patients who underwent hemodynamic monitoring and received intravenous milrinone for >24 hours in a critical care setting. Hemodynamics and medications were recorded before and after 24 hours of milrinone therapy. Additional medications, as well as any adverse events, were recorded throughout milrinone therapy. The mean dose of milrinone was 0.43 +/- 0.10 microg/kg/min, with a mean duration of 12 +/- 15 days (range 1 to 70). Therapy was continued for >48 hours in 89% of patients. After 24 hours of milrinone therapy, patients exhibited significant improvements in pulmonary artery pressures, pulmonary capillary wedge pressures, and cardiac index. When compared with baseline, significantly more patients received angiotensin-converting enzyme (ACE) inhibitors after 24 hours of milrinone and at the end of milrinone therapy (67% vs 86%, p <0.01). Likewise, significantly more patients also received oral hydralazine and/or nitrates at the end of milrinone therapy (38% vs 65%, p <0.01) when compared with baseline. The mean doses of most oral medications at the 3 time periods were similar. The ACE inhibitor dose was significantly higher at the end of milrinone therapy when compared with baseline, and hydralazine dose was significantly higher at the end of therapy when compared with 24 hours. Few adverse effects were noted, with only 10% of patients experiencing symptomatic ventricular tachycardia and 2 patients with significant hypotension requiring discontinuation of the drug. The adverse events were similar in the group of patients who received milrinone for > or =7 days compared with the entire cohort. Milrinone was well tolerated over the long term in a controlled inpatient setting, and allowed uptitration of oral vasodilator therapy.

Treatment of hepatic veno-occlusive disease with low-dose tissue plasminogen activator: impact on coagulation profile.

An 18-year-old white male developed severe hepatic veno-occlusive disease (VOD) during an autologous bone marrow transplant for primary refractory nodular sclerosing Hodgkin's disease. As a result of VOD-induced hepatic dysfunction, coagulation studies revealed depression of vitamin K dependent procoagulant factor VII. Intravenous recombinant tissue plasminogen activator 20 mg over h on 4 consecutive days and continuous heparin infusion (1000 unit bolus followed by 150 units/kg/day) resulted in rapid reversal of the VOD syndrome. During treatment, procoagulant factors II, VII, IX and X levels increased indicating the return of hepatic synthesizing capacity. Factor V levels, which were elevated pre-therapy, also rose dramatically. Plasma antigen levels of protein C, a natural anticoagulant, remained severely depressed. No clinical evidence of bleeding and only minimal systemic fibrinolysis was noted. Despite concerns regarding the use of lytic therapy in a thrombocytopenic post-BMT patient, serial measurements of coagulation parameters during severe VOD suggested that low dose rt-PA improved portions of the systemic hemostatic profile.

[Immunodetection of RNA-dependent RNA polymerase from turnip yellow luteovirus using monoclonal antibodies]. / Immunodetektsiia RNK-zavisimoi RNK-polimerazy virusa zheltukhi turnepsa s pomoshch'iu monokonal'nykh antitel.

Monoclonal antibodies (MAs) to the RNA-dependent RNA polymerase from turnip yellow luteovirus (TYV) were prepared using a recombinant protein as immunogen and were shown to be directed to C-terminal part of the viral replicase. These MAs were found to interact with a 70-kDa protein found in extracts from TYV-infected plants. Our result is the first successful attempt at detecting the RNA-dependent RNA polymerase of a luteovirus in infected plant extracts. We also found that the protein is not processed further and its accumulation and content in the infected plant obey a definite dynamics during the infection. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 1; see also http://www.maik.ru.

Contributions of the extracellular and cytoplasmic domains of platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31) in regulating cell-cell localization.

PECAM-1/CD31, a vascular cell adhesion/signaling molecule that has been implicated in a number of vascular functions (including angiogenesis and the transmigration of leukocytes through endothelium) is highly enriched at the cell-cell borders of adjacent endothelial cells. To identify the mechanisms responsible for this localization, a series of PECAM-1 mutants and chimeric PECAM-1 molecules were transfected into non-PECAM-expressing cells and the ability of the constructs to move to cell-cell borders of adjacent cells was determined using immunohistochemistry and confocal microscopy. Although neither the extracellular domain, by itself, nor the cytoplasmic domain, by itself, was sufficient to direct cell-cell localization, the combination of the extracellular and transmembrane domains with a small group of highly charged amino acids in a membrane proximal region of the cytoplasmic domain was sufficient to direct efficient localization of the molecule to cell-cell borders. Importantly, only constructs that supported PECAM-1 mediated adhesion localized to cell-cell borders. Our data are consistent with a 'diffusion trapping' model in which movement of PECAM-1 in the cell membrane occurs relatively freely until the 'stablized' extracellular domain of the molecule encounters its ligand on an adjacent cell. When this occurs, the complex is 'captured' at the cell-cell interface leading to localization at cell-cell borders.