Protein Replacement Therapy and Gene Transfer in Canine Models of Hemophilia A, Hemophilia B, von Willebrand Disease, and Factor VII Deficiency

Dogs with hemophilia A, hemophilia B, von Willebrand disease (VWD), and factor VII deficiency faithfully recapitulate the severe bleeding phenotype that occurs in humans with these disorders. The first rational approach to diagnosing these bleeding disorders became possible with the development of reliable assays in the 1940s through research that used these dogs. For the next 60 years, treatment consisted of replacement of the associated missing or dysfunctional protein, first with plasma-derived products and subsequently with recombinant products. Research has consistently shown that replacement products that are safe and efficacious in these dogs prove to be safe and efficacious in humans. But these highly effective products require repeated administration and are limited in supply and expensive; in addition, plasma-derived products have transmitted bloodborne pathogens. Recombinant proteins have all but eliminated inadvertent transmission of bloodborne pathogens, but the other limitations persist. Thus, gene therapy is an attractive alternative strategy in these monogenic disorders and has been actively pursued since the early 1990s. To date, several modalities of gene transfer in canine hemophilia have proven to be safe, produced easily detectable levels of transgene products in plasma that have persisted for years in association with reduced bleeding, and correctly predicted the vector dose required in a human hemophilia B liver-based trial. Very recently, however, researchers have identified an immune response to adeno-associated viral gene transfer vector capsid proteins in a human liver-based trial that was not present in preclinical testing in rodents, dogs, or nonhuman primates. This article provides a review of the strengths and limitations of canine hemophilia, VWD, and factor VII deficiency models and of their historical and current role in the development of improved therapy for humans with these inherited bleeding disorders

Status report on solid control in leachates

Sludge pretreatment will involve some combination of washing and leaching with sodium hydroxide solutions to remove soluble salts and amphoteric material such as alumina. It is of paramount importance to prevent gelation and uncontrolled solid formation in tanks, transfer lines, and process equipment. An evaluation of results of washing and caustic leaching indicates that washing is more effective in dissolving sludge solids than subsequent sodium hydroxide treatment. Only aluminum and chromium were removed more effectively by caustic leaching than by water washing

Conventional and Dense Gas Techniques for the Production of Liposomes: A Review

The aim of this review paper is to compare the potential of various techniques developed for production of homogenous, stable liposomes. Traditional techniques, such as Bangham, detergent depletion, ether/ethanol injection, reverse-phase evaporation and emulsion methods, were compared with the recent advanced techniques developed for liposome formation. The major hurdles for scaling up the traditional methods are the consumption of large quantities of volatile organic solvent, the stability and homogeneity of the liposomal product, as well as the lengthy multiple steps involved. The new methods have been designed to alleviate the current issues for liposome formulation. Dense gas liposome techniques are still in their infancy, however they have remarkable advantages in reducing the use of organic solvents, providing fast, single-stage production and producing stable, uniform liposomes. Techniques such as the membrane contactor and heating methods are also promising as they eliminate the use of organic solvent, however high temperature is still required for processing

Hydraulic Performance and Gas Behavior of a Tall Crystalline Silicotitanate Ion-Exchange Column

Crystalline silicotitanate (CST) sorbent is one of several technologies being evaluated by the Savannah River Site (SRS) for removing cesium from high-level tank-waste supernatant. As currently envisioned, three large 5-ft-diam, 20-ft-high ion-exchange columns will be operated in series at a superficial velocity of 4.1 cm/min. The CST will be subjected to a high radiation field from the sorbed cesium. The tests described in this work were conducted to evaluate column hydraulics, to identify changes in the CST particles during operation, to explore how radiolytic gases generated during operation behave, and to demonstrate sluicing of CST into and out of columns