The malaria parasite has an obligate calcium requirement for normal intracellular growth and invasion of host erythrocytes. Calmodulin (CaM) is a vital calciumdependent protein present in eukaryotes. We found by radioimmunoassay that free parasites contain CaM. Schizontinfected erythrocytes had CaM levels of 23.3 ± 2.7 ng per 106 cells compared to normals (11.2 ±

No abstract

Plasmodium falciparum in culture grows optimally at 3% oxygen. Oxygen levels down to 0.5% still support growth, but anaerobic conditions do not. These findings, and the absence of the Krebs cycle in Plasmodium, suggested that in this organism oxygen may not function in electron transport but rather may act through metalloprotein oxygenases. Tetraethylthiuram disulfide (Antabuse, disulfiram) and its reduction product diethyldithiocarbamate inhibit many metalloprotein oxygenases and have a lipid/H20 partition coefficient and high binding constant for metal ions, favoring selective toxicity to the malaria parasite. These compounds exhibited active antimalarial effects in vitro in concentrations down to 0.1 ,g/ml, the lowest level tested. Tetraethylthiuram disulfide at a level as low as 1 pg/ml inhibited parasite glycolysis with no effect on glycolysis of normal erythrocytes. Erythrocytes pretreated with this drug at 10 pg/ml did not support growth of the parasite.Plasmodium falciparum, when cultured in vitro (1), has been shown to be a microaerophile, growing best at 3% 02 but tolerating 02 levels as low as 0.5% without appreciable reduction in multiplication rates (2). However, there does appear to be a critical level of 02 below which the parasite will not survive, in contrast to true anaerobic forms of life. It has been known for some time that the malaria parasite does not use the Krebs cycle to degrade its glucose completely to CO2 and H20 but instead excretes organic end products (3,4). This suggests that the parasite may depend on reactions involving oxygenases and hydroxylases in which 02 is a chemical reactant (5). These oxidations are catalyzed by oxidase enzymes or enzyme systems that activate the 02 and oxidize the substrate. Oxidases are often metalloproteins, containing metals such as iron, copper, or molybdenum, and are present in microorganisms, plants, and animals (6). Therefore, we felt, first, that a chelating agent with activity against such metalloproteins might have selective toxicity to malaria parasites without interference with the cellular metabolism of the host tissues. One type of agent emerges from the rest with high probability of achieving this objective, the dialkyldithiocarbamates and their dimers, the thiuram disulfides. Diethyldithiocarbamate (DDC) is a chelating agent with proven inhibitory activity against many of these enzymes (7). There is no sharp distinction among the alkyl dithiocarbamoyl compounds, and they can be transformed into each other in nutrient solutions (8). Dimethyldithiocarbamate is strongly fungotoxic, particularly to fungi with obligatory aerobic metabolism. Fortunately, higher plants and vertebrate animals possessing an obligatory aerobic type of metabolism show little or no response to these substances (7, 9, 10). The diethyl derivative (Antabuse, disulfiram) is even lesis toxic to mammals (11), and, in clinical trials, single doses of up to 6 g and daily doses of 0.25-0.60 g for several months produced noThe publication costs of this article were d...

There were no significant differences in healing outcome between collagen and hydrocolloid. Collagen was more expensive and offered no major benefits to patients otherwise eligible for hydrocolloid treatment.

Discharge software with CPOE did not affect readmissions, emergency department visits, or adverse events after discharge. Future studies should assess other endpoints such as patient perceptions or physician perceptions to see if discharge software has value.