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.     

Negative priming in associative learning: Evidence from a serial-conditioning procedure.

Three experiments investigated the suggestion that a predicted or primed stimulus commands less processing and consequently elicits a weaker CR than a stimulus that is not primed. In each experiment rats received initial training in which the presentation of each of 2 serial compounds, A-X and B-Y, was followed by the delivery of food. Subsequently, X's capacity to elicit the CR, approaching the site of food delivery, was assessed when X was preceded by Stimulus A (i.e., primed) or was presented after Stimulus B. Stimulus X elicited a more vigorous response when it was presented after B than when it followed A. These results show that the ability of one event to elicit its CR is reduced if its presentation has been predicted by some other event. This negative priming effect supports one aspect of A. R. Wagner's (1981) model of Pavlovian conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Enhancing effect of natural killer cell stimulatory factor (NKSF/interleukin-12) on cell-mediated cytotoxicity against tumor-derived and virus-infected cells

Natural killer cell stimulatory factor (NKSF) or interleukin-12 (IL-12) is a heterodimeric cytokine with pleiomorphic effects on T and NK cells, including induction of lymphokine production, mitogenesis, and enhancement of spontaneous cytotoxic activity. Similarly to IL-2, NKSF/IL-12 enhances NK cell-mediated cytotoxicity within a few hours and independently from induced proliferation. This effect is independent from other induced cytokines, because it is not prevented by antibodies neutralizing interferon (IFN)-alpha, IFN-beta, IFN-gamma, IL-2 or tumor necrosis factor (TNF)-alpha and, unlike the induction of IFN-gamma production by peripheral blood lymphocytes, it does not require HLA class II-positive accessory cells. Enhanced cytotoxicity is accompanied by morphologic changes in NK cells, including a significant increase in the number of cytoplasmic granules. In addition to the previously described ability to enhance the cytotoxic activity of NK cells against tumor-derived target cells, NKSF/IL-12 is also a potent stimulator of cytotoxicity against virus-infected cells, either fibroblasts acutely infected with herpes viruses or T cell lines chronically infected with human immunodeficiency virus-1. NK cell-mediated antibody-dependent cytotoxicity or anti-CD16 antibody-redirected lysis is not significantly enhanced by NKSF/IL-12. However, the ability of resting peripheral blood T cells to mediate anti-CD3 antibody-redirected lysis is enhanced by 18-h incubation with NKSF/IL-12, indicating that this lymphokine can modulate the cytotoxic capability of both NK and T cells.     

Serum amyloid P component scintigraphy and turnover studies for diagnosis and quantitative monitoring of AA amyloidosis in juvenile rheumatoid arthritis

OBJECTIVE: To evaluate aspects of the natural history of AA amyloidosis complicating juvenile rheumatoid arthritis (JRA), and its response to therapy with chlorambucil. METHODS: Scintigraphy and 7-day turnover studies were performed in JRA patients with histologically proven (n = 35) or clinically suspected (n = 30) AA amyloidosis, following intravenous injection of 123I and 125I-labeled serum amyloid P component (SAP). Prospective monitoring studies were performed over 2-3 years in 20 patients with amyloidosis. All but 2 amyloidosis patients were treated with chlorambucil. RESULTS: Positive scanning results were obtained in all patients in whom imaging was performed within 12 years of positive biopsy findings of amyloid and in 5 patients with clinically suspected amyloidosis. Negative scanning results with normal SAP metabolism, indicating regression of amyloid, were obtained in 4 patients whose amyloidosis had been in full clinical remission for more than 12 years. Prospective monitoring studies in patients whose JRA-associated inflammatory activity was in remission demonstrated regression of amyloid in 8 patients and no substantial changes in 8 others; however, in 4 further patients with active inflammation, there was accumulation of amyloid. There was a very poor correlation between the amount of amyloid present at a particular site and the resultant organ dysfunction. CONCLUSION: Radiolabeled SAP scintigraphy and turnover studies are useful complementary tools in the diagnosis, screening, and quantitative monitoring of type AA amyloidosis in JRA. The amyloid deposits may progress and/or regress at different rates in different anatomic sites over short periods.     

The science-industry interface: Correlation of time series of indicators and their spectra,and growth models in the nuclear fuels industry

This paper is the third in a series on the flows of influence at the interface between geoscience research and the exploration for and mining of nuclear fuels. It deals with the application of signal processing methods to research and industry indicators, with emphasis on time and frequency domain correlations and lags, and on growth modelling of the indicators using the special and general logistic models. The findings include the following: there was a strong interchange across the science-industry interface; quantitative methods can establish the degree of correlation and the time periods in which these correlations mainly reside; also the timing of decisions to initiate exploration and research can be specified in this case. A strategy of applying quantitative methods, history of science, and periodic analyses of the state of the industry to studies of science policy is suggested by this research.     

Excited-state-absorption cross sections and amplifier modeling inthe 1300-nm region for Nd-doped glasses

The performance of Nd³⁺-doped fibre amplifiers is limited by strong excited-state absorption (ESA) of the signal, and, even for fluorozirconate glasses, ESA prevents the important region below 1320 nm from being used. To quantify this limitation and explore alternative host materials, ESA and stimulated-emission cross sections have been measured for a representative group of glass compositions. These parameters have been used in an accurate fiber-amplifier model to provide the first quantitative comparisons of performance for Nd³⁺ -doped glasses in the 1300-nm band as a function of host     

Transgenic overproduction of islet amyloid polypeptide (amylin) is not sufficient for islet amyloid formation

Islet amyloid polypeptide forms islet amyloid deposits in non-insulin-dependent diabetes mellitus. We have generated transgenic mice which express human islet amyloid polypeptide in their pancreatic beta cells yet do not develop islet amyloid deposits despite producing levels of the amyloidogenic human peptide 2 - 3 fold higher than the native (mouse) peptide. To determine whether marked overproduction of islet amyloid polypeptide is a potential cause of islet amyloid formation, we increased expression of this transgene by producing homozygous transgenic animals and by making heterozygous mice experimentally insulin resistant with nicotinic acid. Pancreatic content of islet amyloid polypeptide-like immunoreactivity in homozygous and nicotinic acid-treated mice was 2-fold (25 +/- 7 fmol/microg; n = 6) and 3.5-fold (47 +/- 20 fmol/microg; n = 3) higher, respectively, than that of untreated heterozygous animals (13+/-2 fmol/microg; n = 11; both p < 0.05). Despite this marked increase in production of islet amyloid polypeptide, neither group of mice developed gross islet amyloid deposits even after 16 months of age. We conclude that overproduction of islet amyloid polypeptide, even as produced by extreme insulin resistance, is not in itself sufficient for islet amyloid formation.     

Seasonal variation in the role of grey squirrels as hosts of Ixodes ricinus, the tick vector of the Lyme disease spirochaete, in a British woodland

The partition of free fatty acids (FFA) to egg-phosphatidylcholine (egg-PC) and egg-phosphatidylethanolamine (egg-PE) vesicles was studied. Upon the addition of FFA to the suspension of vesicles, the pH of the aqueous phase changed depending on the length and saturation of the FFA hydrocarbon chain, as well as on the vesicle composition. The medium pH decreased faster if FFA was added to egg-PE as compared to egg-PC vesicles. The fluorescent free fatty acid indicator (ADIFAB) was used to measure the amount of FFA remaining in the aqueous phase. Most of the FFA added to the suspension of egg-PE vesicles remained in the aqueous phase, whereas in the presence of egg-PC vesicles the FFA partitioned preferentially into the lipid phase. The amount of FFA incorporated into the lipid bilayers was estimated by measuring the changes of pH at the lipid bilayer surface, using fluorescein-PE. At high surface concentrations of FFA, decreasing pH at the bilayer surface caused the protonation of FFA, and raised the pK of FFA at the bilayer surface from 5 to about 7. The partition of FFA in egg-PE vesicles was an order of magnitude lower than that in egg-PC vesicles. The incorporation amount was determined more by the molecular packing than by the nature of lipid headgroups, because steroylcaprioyl-PE, which preferred the bilayer structure, behaved more like egg-PC than egg-PE. Understanding FFA partition characteristics would help to interpret the hydrolysis measurements of phospholipids, and to explain many biological activities of FFA.