A comparison of skin-test responses using antigen from Leishmania donovani and a lizard trypanosome

261 individuals were skin tested with leishmanin from Leishmania donovani and with an antigen from a lizard trypanosome isolated in an area endemic for kala-azar in Ethiopia. 83 of the 261 responded positively, with indurations of 5 mm or greater, to one antigen but negatively to the other, and 42 reacted positively to both.Among the Afar people of the Awash valley in north-eastern Ethiopia and the Nyangatom people of south-western Ethiopia, positive response to both antigens was high, though many individuals responded to one antigen but not the other. Both these groups live as cattle pasturalists, a predominantly male occupation, in areas where known vectors of kala-azar as well as lizard-feeding sandflies exist. Among the Anuak and Suri people, who live in areas of south-western Ethiopia infested with tsetse flies, the lizard trypanosome antigen gave a markedly higher skin test positivity than did the leishmanin antigen. This suggests that the lizard trypanosome may give artificially high results in other immunological tests of exposure to trypanosomiasis in areas where lizard trypanosomes and man-biting sandflies co-exist with mammalian trypanosomes transmitted by Glossina.     

Potent inhibition of human folylpolyglutamate synthetase by a phosphinic acid mimic of the tetrahedral reaction intermediate

A phosphorous-containing pseudopeptide folate analog (Valiaeva et al., J Org Chem 2001;66:5146-54) was designed to mimic the tetrahedral intermediate formed in the ATP-dependent reaction catalyzed by folylpolyglutamate synthetase (FPGS). This analog, methotrexate-phosphinate (MTX-phosphinate; 4-amino-4-deoxy-10-methylpteroyl-L-Glu-gamma-[psi(P(O)(OH)-CH(2))]glutarate), is a highly potent (K(is), 3.1+/-0.5 nM), competitive inhibitor of recombinant human cytosolic FPGS. Within experimental limits, FPGS inhibition was not time-dependent, and preincubation of FPGS, inhibitor, and ATP did not potentiate the inhibition. These results suggest that slow phosphorylation to produce a more potent inhibitor form is not involved. MTX-phosphinate was not growth inhibitory to human CCRF-CEM leukemia cells at 1 microM (70-fold above the concentration of MTX giving 50% growth inhibition), probably because of poor transport. Because of its exceedingly high potency as an FPGS inhibitor, MTX-phosphinate represents a lead structure from which cell-permeable analogs may be developed to test the hypothesis that FPGS inhibition is therapeutically efficacious.     

Differential behavioral responses to cocaine are associated with dynamics of mesolimbic dopamine proteins in Lewis and Fischer 344 rats

Differential behavioral and biochemical responses to drugs of abuse may reflect genetic makeup as suggested by studies of inbred Lewis (LEW) and Fischer 344 (F344) rats. We investigated locomotor activity, stereotypy signs, and levels of specific proteins in the nucleus accumbens (NAc) and ventral tegmental area (VTA) in these strains at baseline and following chronic administration of cocaine (30 mg/kg/day for 14 days). Using Western blot analysis, we replicated our previous findings of baseline strain differences and found lower levels of DeltaFosB immunoreactivity in NAc of F344 vs. LEW rats. F344 rats showed greater baseline locomotor activity, sniffing, and grooming compared to LEW rats. Chronic cocaine increased DeltaFosB levels in NAc in both strains, whereas adaptations in other proteins were induced in F344 rats only. These included reduced levels of tyrosine hydroxylase (TH) in NAc and increased TH and glial fibrillary acidic protein (GFAP) immunoreactivity in VTA. Chronic cocaine led to greater increases in overall stereotypy in F344 vs. LEW rats and decreased exploratory behaviors in LEW rats. Opposing effects by strain were seen in locomotor activity. Whereas F344 rats showed higher initial activity levels that decreased with cocaine exposure (tolerance), LEW rats showed increased activity over days (sensitization) with no strain differences seen at 14 days. Further, conditioned locomotor activation to vehicle injections was greater in F344 vs. LEW rats. These results suggest that behavioral responsiveness to chronic cocaine exposure may reflect dynamics of mesolimbic dopamine protein levels and demonstrate the role of genetic background in responsiveness to cocaine.     

Experimental intrahepatic portacaval anastomosis: use of expandable Gianturco stents

Original Gianturco expandable stents and their modifications were used to create an experimental intrahepatic portacaval anastomosis (EIPCA) in 30 young domestic swine without portal hypertension. The study focused on the design of a suitable stent, the technique of its application, and the evaluation of short-term patency of the EIPCA. A stent with a 2.5-cm-long body and wire skirts on both ends was most suitable for EIPCA creation. Well-positioned stents shunted most of the portal blood in the inferior vena cava circulation and remained patent for 4-6 weeks. Ingrowth of liver parenchyma and abundant proliferation of the intima and connective tissue inside the stent lumen in these rapidly growing animals gradually decreased EIPCA patency, and thrombus formation with diminished blood flow closed them completely.