Receptor mediated targeting of liposomes

The targeting of liposomes to cells and the delivery of the liposomal contents into the cells have been investigated using either α-melanocyte stimulating hormone or Ricin-B-chain as ligands for promoting the binding of liposomes to cells. α-melanocyte stimulating hormone has been conjugated to liposomes and to Ricin-A-chain via the Lys₁₁ residue without significant loss of biological activity. The resulting conjugates were found to bind to Bl6 melanoma cells which express receptors for the hormone. Hormone targeted ricin was shown to be toxic to the cells, indicating receptor mediated internalisation of the conjugate. The hormone targeted liposomes however were unable to mediate the delivery of cytotoxic levels of methotrexate. Ricin-B-chain, a lectin which mediates membrane translocation of the toxic ricin-A-chain, was examined for its applicability for targeting of liposomes to cells. This lectin was shown to promote the binding of liposomes to cells and to mediate the delivery of cytotoxic concentrations of methotrexate. Further evidence of functional ricin-B-chain mediated intracellular delivery of the liposomal contents was shown by liposome mediated transformation of cells, and delivery of nuclease into the cell resultin in digestion of genomic DNA. The study demonstrates that α-melanocyte stimulating hormone is unsuitable as a ligand by which to achieve delivery of large quantities of material into cells, although cell-specific targeting can be achieved. Ricin-B-chain is however ideally suited for this task, though is less cell-specific. This finding may be of use in studies in which investigators wish to achieve intracellular delivery of compounds

A comparison of methods for treatment selection in seamless phase II/III clinical trials incorporating information on short-term endpoints

In an adaptive seamless phase II/III clinical trial interim analysis data are used for treatment selection, enabling resources to be focussed on comparison of more effective treatment(s) with a control. In this paper we compare two methods recently proposed to enable use of short-term endpoint data for decision-making at the interim analysis. The comparison focusses on the power and the probability of correctly identifying the most promising treatment. We show that the choice of method depends on how well short-term data predict the best treatment, which may be measured by the correlation between treatment effects on short-term and long-term endpoints

A COMPARATIVE MAPPING OF ENZYMES INVOLVED IN HEXOSEMONOPHOSPHATE SHUNT AND CITRIC ACID CYCLE IN THE BRAIN *

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66082/1/j.1471-4159.1963.tb05042.x.pd

A QUANTITATIVE MAPPING OF ALKALINE PHOSPHATASE IN THE BRAIN OF THE RHESUS MONKEY *

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65477/1/j.1471-4159.1966.tb07513.x.pd

An enzyme histochemical study of torpedoes and dendritic swellings in the cerebellum

In 8 cases, the following enzymes were studied in the dendritic swellings and torpedoes of Purkinje cells of cerebellum: succinic dehydrogenase, cytochrome oxidase, lactic dehydrogenase, NAD-diaphorase, alkaline phosphatase, acid phosphatase, acetyl cholinesterase and nonspecific cholinesterase. Activity of the oxidative enzymes was always extremely high in the dendritic swellings, but varied greatly among cases in the torpedoes; 4 cases showed very weak activity of oxidative enzymes in torpedoes, while 4 other cases showed an intense reaction. Dendritic swellings and torpedoes exhibited no alkaline phosphatase, acetyl cholinesterase, or nonspecific cholinesterase activity. In Dendritenanschwellungen und Torpedos der Purkinje-Zellen des Kleinhirns von 8 Fällen wurden die folgenden Enzyme untersucht: Bernsteinsäure-Dehydrogenase, Cytochrom-Oxidase, Milchsäure-Dehydrogenase, NAD-Diaphorase, alkalische Phosphatase, saure Phosphatase, Acetylcholinesterase und unspezifische Cholinesterase. Die Aktivität der oxidativen Enzyme war in den Dendritenanschwellungen immer sehr hoch, in den Torpedos aber von Fall zu Fall sehr unterschiedlich: 4 Fälle zeigten nur sehr geringe Aktivität, die 4 anderen jedoch eine sehr intensive Reaktion. Die Dendritenanschwellungen und Torpedos zeigten keine Aktivität der alkalischen Phosphatase, Acetylcholinesterase oder unspezifischen Cholinesterase.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47226/1/401_2004_Article_BF00687526.pd

Relations between post-mortem alterations and glycolytic metabolism in the brain

Certain post-mortem alterations of brain tissue result from the continuation of anaerobic glycolysis in the presence of abolished tissue oxidation. Experimental incubation of cerebellar tissue from rats in glucose or in glucose-6-phosphate in the presence of cyanide resulted in klasmatodendrosis of astrocytes and marked edematous changes, particularly in the neuroglia of the Purkinje layer. The presence of glycolysis was indicated by a drop in pH of the incubation medium. The tissue changes were indistinguishable from post-mortem alterations in human material. Blocking of glycolysis during the incubation eliminated the experimental tissue changes. The distribution of post-mortem changes depended on the normal cytochemical organization of a given region; regions which normally showed large aggregations of neuroglia cells with weak activity of oxidative enzymes showed strongest glycolytic tissue alterations. There was exidently no sharp border line between normal tissue glycolysis and post-mortem alterations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32354/1/0000425.pd

The Reconstruction Problem in Microdosimetry

A generalised formulation of microdosimetry clarifies the linkages between the spatial distribution of energy deposits, their proximity function, and the specific energy. The role of the proximity function suggest that it may replace, for various purposes, the inchoate distribution. The Fourier transform of the proximity function is the product of the Fourier transform of the inchoate distribution with its conjugate. This operation causes the loss of phase information, and the reconstruction problem - the reconstruction of the inchoate distribution from its proximity function - can, therefore, not be resolved by a mere deconvolution. For any finite point pattern one can, however, show that its proximity function permits, in principle, the reconstruction. Numerical examples with 2-dimensional patterns of up to 30 points have consistently led to unique solutions, apart from reflections. While there is a finite algorithm, it is readily seen that the number of steps becomes excessive when the number of points in the pattern increases. The reconstruction problem can, thus, be solved in principle but not necessarily in practice. A more general approach must thus be based on numerical optimisation. The algorithm starts with an assumed initial point pattern and utilises a suitable measure for the difference between its proximity function and that of the original pattern. Minimising this difference can lead to the original or to a similar pattern. With simple algorithms one obtains convergence only for patterns of few points; but improved optimisation methods are likely to provide more general solutions

Thermal aspects of the smelting of iron ore in reconstructed South African Iron Age furnaces

SYNOPSIS A study was made of the smelting process in two experimental furnaces patterned on Iron Age furnaces excavated at Melville Koppies Nature Reserve, Johannesburg. In a number of smelting experiments, the influences of air supply, temperature, time of operation, fuel consumption, and other operational factors were investigated. Metallurgical and metallographic aspects of the furnace operation and smelting products are discussed, and the experiments are compared with similar research work conducted in Europe and Africa. SAMEVATTING Daar is 'n studie gemaak van die smeltproses in twee eksperimentele oonde wat gebou is volgens die patroon van oonde uit die Ystertydperk wat in die Natuurreservaat Melville Koppies, Johannesburg, uitgegrawe is. Die invloed van die lugtoevoer, temperatuur, bewerktyd, brandstofverbruik en ander bedryfsaspekte is in 'n aantal smelteksperimente ondersoek. Die metallurgiese en metallografiese aspekte van die oondbedryf en smeltprodukte word bespreek, en die eksperimente word vergelyk met deeglike navorsingswerk wat in Europa en Afrika gedoen is. Introduction The work described in this paper is a continuation of the archaeo-metallurgical investigations undertaken over the past ten years at the Archaeological Research Unit of the University of the Witwatersrandl-3. One of the previous studies on the correlation of slag characteristics and operational furnace temperatures had led to the conclusion that further work in this field, based on smelting experiments, would be desirable3. The present paper reports on such experiments, and on the results obtained by temperature measurements in furnaces and by the construction of temperature profiles. Since slag is the principal, and often the only, preserved material from ancient smelting sites, various methods were investigated by which information on the thermal characteristics of the smelting process could be obtained from samples of slag: chemical/physical analysis, phase-diagram studies, determination of liquidus temperatures, and metallographic examinations. In addition, the problem of preheating ofthe air injected into such furnaces was investigated