Theories of the pathogenesis of hepatic encephalopathy

The earliest hypothesis of the pathogenesis of HE implicated ammonia, although effects of appreciable concentrations of this neurotoxin did not resemble HE. Altered eurotransmission in the brain was suggested by similarities between increased GABA-mediated inhibitory neurotransmission and HE, specifically decreased consciousness and impaired motor function. Evidence of increased GABAergic tone in models of HE has accumulated; potential mechanisms include increased synaptic availability of GABA and accumulation of natural benzodiazepine receptor ligands with agonist properties. Pathophysiological concentrations of ammonia associated with HE, have the potential of enhancing GABAergic tone by mechanisms that involve its interactions with the GABAa receptor complex.     

Differential cytotoxicity of phospholipid analogues to pathogenic Acanthamoeba species and mammalian cells

OBJECTIVES: Previous studies have reported the ability of several phospholipid analogues to successfully inhibit the growth of Acanthamoeba species in vitro. This study tests further phospholipid analogues, either as free drug or in liposomal formulations, and unlike previous studies, examines their comparative toxicities to mammalian cells. METHODS: The relative cytotoxic activities of the phospholipid derivatives hexadecyl-PC, octadecyl-PC, elaidyl-PC, erucyl-PC and edelfosine, against Acanthamoeba castellanii, Acanthamoeba polyphaga and a rabbit corneal epithelial (RCE) cell line, was determined by the alamarBlue assay. Free and liposomal formulations were compared for hexadecyl-PC and elaidyl-PC. RESULTS: Both hexadecyl-PC and octadecyl-PC (IC50 values between 3.9 and 7.8 microM) demonstrated considerable activity against A. castellanii, as did elaidyl-PC (IC50 values between 15.6 and 31.25 microM). Both hexadecyl-PC and elaidyl-PC also proved effective against A. polyphaga (IC50 values between 15.6 and 31.25 and between 31.25 and 62.5 microM, respectively). In contrast, neither erucyl-PC nor edelfosine was inhibitory against either Acanthamoeba species. The growth of RCE cells was inhibited by octadecyl-PC, erucyl-PC and edelfosine (octadecyl-PC and erucyl-PC IC50 values between 7.8 and 15.6 microM and edelfosine IC50 values between 31.25 and 62.5 microM). Liposomal formulations of hexadecyl-PC and elaidyl-PC were less effective than free drug against both Acanthamoeba species. CONCLUSIONS: These results demonstrate that hexadecyl-PC has the highest therapeutic index and is the most promising for the treatment of acanthamoebiasis.     

Micafungin activity against Candida bloodstream isolates: effect of growth medium and susceptibility testing method

An excellent correlation between micafungin MICs were demonstrated against Candida bloodstream isolates (n = 200) by the Sensititre YeastOne and National Committee for Clinical Laboratory Standards M27-A2 methods. Use of antibiotic medium 3 (2%) dextrose improved micafungin activity and was not associated with paradoxical growth as noted with 3 Candida isolates tested using RPMI (2%) dextrose.     

Augmentation of post transplant immunity: antigen encounter at the time of hematopoietic stem cell transplantation enhances antigen-specific donor T-cell responses in the post transplant repertoire

After transplant, the immune system is reconstituted by cells derived from both hematopoietic stem cells and peripheral expansion from differentiated donor T cells. After transplant, immune function is poor despite transplantation of mature lymphocytes from immune-competent donors. We tested the hypothesis that early antigen encounter at the time of cell transplant would improve the desired donor T-cell responses. Two independent models of peptide-specific T-cell responses were studied. The model for CD4 cells employed T cells from transgenic (Tg) DO11.11 mice that constitutively express the T-cell receptor for the class II-restricted ovalbumin peptide 323-339. The model for CD8 cells employed non-Tg H2-Db-restricted T-cell responses to the influenza nucleoprotein peptide 366-374. As measured both functionally and by direct imaging of T cells using clonotypic reagents, encounter with specific antigen at the time of T-cell transplantation led to clonal expansion of donor T cells and preservation of donor T-cell function in the post transplant immune environment. Antigen-specific donor T-cell function was poor if antigen encounter was delayed or omitted. Severe parent>F1 graft-versus-host reactions blocked the effect of early antigen exposure. Vaccination of transplant recipients against microbial or leukemia antigens may be worthy of study.     

Rapid prenatal diagnosis of beta thalassemia using DNA amplification and nonradioactive probes

We used in vitro DNA amplification by the polymerase chain reaction and nonradioactive probes for prenatal diagnosis of beta thalassemia in Chinese from the Guangdong province. Exact molecular diagnoses were made in all 20 fetuses studied over a 6-month period. We conclude that this method of prenatal diagnosis for beta thalassemia is a viable approach in many parts of the world where this disease is common.