Mechanism of human immunodeficiency virus type 1 localization in CD4-negative thymocytes: differentiation from a CD4-positive precursor allows productive infection

Human immunodeficiency virus (HIV) infection of the thymus could have profound effects on development of the immune response, particularly in children. We and others have established that in addition to infecting and depleting CD4-bearing thymocytes, functional HIV proviruses are found in thymocytes lacking surface CD4 expression. Using in vitro thymocyte cultures, we show that neither HIV-mediated down regulation of CD4 nor CD4-independent infection contributes to the localization of HIV in cells lacking the primary virus receptor. Rather, infection of a CD4-positive precursor cell (CD4 positive/CD8 positive) with subsequent differentiation into a mature CD4-negative phenotype results in productively infected CD4-negative cells. This novel mechanism may contribute to pathogenesis by distributing viral sequences into functional subsets of T cells typically refractory to HIV infection and could account for the presence of viral DNA in CD8-positive lymphocytes recently observed in patients.     

Autoimmune hemolytic anemia and posthepatitis-C liver cirrhosis

Here we are presenting the case of a 70-years-old woman who has hepatic cirrhosis anti-HCV and insulin-dependent diabetes mellitus, without relevant epidemiologic ascendants or previous transfusions and HBV, HIV negatives. On admission to our hospital she showed signs of autoimmune hemolytic anaemia (AHA) which was confirmed by positive direct Coombs test and an improvement in blood test after corticoid treatment. Having discarded other possible causes such as drugs infectious diseases or essential mixed cryoglobulinemia (CME), we put forward the possible association between AHA and infection by HCV, where AHA was an extrahepatic immunological manifestation of HCV. This fact has never been brought to light in previous medical literature.     

Novel NMDA antagonists: replacement of the pyridinium ring of 6,11-ethanobenzo[b]quinolizinium cations with heteroisoquinolinium cations

Replacement of the pyridinium ring of 6,11-ethanobenzo[b]quinolizinium cations with thiazolium (4a and 4b) and N-methylimidazolium (4c and 4d) resulted in equipotent compounds in the [3H]TCP binding assay. The corresponding N-methyl-1,2,4-triazolium analogs were less potent in this assay. The thiazolium derivative 4b, with a Ki = 2.9 nM, is being evaluated as a possible neuroprotective N-methyl-D-aspartic acid (NMDA) antagonist.     

Analysis of the roles of antilipopolysaccharide and anti-cholera toxin immunoglobulin A (IgA) antibodies in protection against Vibrio cholerae and cholera toxin by use of monoclonal IgA antibodies in vivo

Secretory immunoglobulin A (IgA) antibodies (sIgA) directed against cholera toxin (CT) and surface components of Vibrio cholerae are associated with protection against cholera, but the relative importance of specific sIgAs in protection is unknown. A monoclonal IgA directed against the V. cholerae lipopolysaccharide (LPS), secreted into the intestines of neonatal mice bearing hybridoma tumors, was previously shown to provide protection against a lethal oral dose of 10(7) V. cholerae cells. We show here that a single oral dose of 5 to 50 micrograms of the monoclonal anti-LPS IgA, given within 2 h before V. cholerae challenge, protected neonatal mice against challenge. In contrast, an oral dose of 80 micrograms of monoclonal IgA directed against CT B subunit (CTB) failed to protect against V. cholerae challenge. A total of 80 micrograms of monoclonal anti-CTB IgA given orally protected neonatal mice from a lethal (5-micrograms) oral dose of CT. Secretion of the same anti-CTB IgA antibodies into the intestines of mice bearing IgA hybridoma backpack tumors, however, failed to protect against lethal oral doses of either CT (5 micrograms) or V. cholerae (10(7) cells). Furthermore, monoclonal anti-CTB IgA, either delivered orally or secreted onto mucosal surfaces in mice bearing hybridoma tumors, did not significantly enhance protection over that provided by oral anti-LPS IgA alone. These results demonstrate that anti-LPS sIgA is much more effective than anti-CT IgA in prevention of V. cholerae-induced diarrheal disease.     

An approach for treating the hepatobiliary disease of cystic fibrosis by somatic gene transfer

Cystic fibrosis (CF) is an inherited disease of epithelial cell ion transport that is associated with pathology in multiple organ systems, including lung, pancreas, and liver. As treatment of the pulmonary manifestations of CF has improved, management of CF liver disease has become increasingly important in adult patients. This report describes an approach for treating CF liver disease by somatic gene transfer. In situ hybridization and immunocytochemistry analysis of rat liver sections indicated that the endogenous CFTR (cystic fibrosis transmembrane conductance regulator) gene is primarily expressed in the intrahepatic biliary epithelial cells. To specifically target recombinant genes to the biliary epithelium in vivo, recombinant adenoviruses expressing lacZ or human CFTR were infused retrograde into the biliary tract through the common bile duct. Conditions were established for achieving recombinant gene expression in virtually all cells of the intrahepatic bile ducts in vivo. Expression persisted in the smaller bile ducts for the duration of the experiment, which was 21 days. These studies suggest that it may be feasible to prevent CF liver disease by genetically reconstituting CFTR expression in the biliary tract, using an approach that is clinically feasible.     

Mitochondrial DNA haplotype frequencies in natural and experimental populations of Drosophila subobscura

The evolution of Drosophila subobscura mitochondrial DNA has been studied in experimental populations, founded with flies from a natural population from Esporles (Majorca, Balearic Islands, Spain). This population, like other European ones, is characterized by the presence of two very common (>96%) mitochondrial haplotypes (called I and II) and rare and endemic haplotypes that appear at very low frequencies. There is no statistical evidence of positive Darwinian selection acting on the mitochondrial DNA variants according to Tajima's neutrality test. Two experimental populations, with one replicate each, were established with flies having a heterogeneous nuclear genetic background, which was representative of the composition of the natural population. Both populations were started with the two most frequent mitochondrial haplotypes, but at different initial frequencies. After 13 to 16 generations, haplotype II reached fixation in three cages and its frequency was 0.89 by generation 25 in the fourth cage. Random drift can be rejected as the force responsible for the observed changes in haplotype frequencies. There is not only statistical evidence of a linear trend favoring a mtDNA (haploid) fitness effect, but also of a significant nonlinear deviation that could be due to a nuclear component.