RNA interference (RNAi) has recently emerged as a specific and efficient method to silence gene expression in mammalian cells either by transfection of short interfering RNAs (siRNAs; ref. 1) or, more recently, by transcription of short hairpin RNAs (shRNAs) from expression vectors and retroviruses. But the resistance of important cell types to transduction by these approaches, both in vitro and in vivo, has limited the use of RNAi. Here we describe a lentiviral system for delivery of shRNAs into cycling and non-cycling mammalian cells, stem cells, zygotes and their differentiated progeny. We show that lentivirus-delivered shRNAs are capable of specific, highly stable and functional silencing of gene expression in a variety of cell types and also in transgenic mice. Our lentiviral vectors should permit rapid and efficient analysis of gene function in primary human and animal cells and tissues and generation of animals that show reduced expression of specific genes. They may also provide new approaches for gene therapy.

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Helicobacter hepaticus is a naturally occurring pathogen of mice and has been used to develop models of chronic hepatitis , liver cancer , and , more recently , inflammatory bowel disease , in selected mouse strains. A/JCr mice are particularly susceptible to H. hepaticus-induced hepatitis and subsequent development of liver neoplasms , whereas C57BL/6 mice are resistant. In this study , we inoculated nine AXB recombinant inbred (RI) mouse strains , derived from A/J and C57BL/6 mice , with H. hepaticus to determine the genetic basis of resistance to Helicobacterinduced liver disease. Mice were surveyed 14 months after inoculation by culture and PCR for H. hepaticus colonization of the liver and cecum , and microscopic morphometric evaluations of the liver were performed to quantify and correlate the severity of inflammation , apoptosis , and proliferation. Analysis of variance of hepatic inflammation demonstrated significant variation among the RI strains (P < 0.0001), and the strain distribution pattern suggested a multigenic basis of disease resistance. Quantitative trait analysis using linear regression suggested possible linkage to loci on mouse chromosome 19. Hepatocellular and biliary epithelial apoptosis and proliferation indices , including proliferation of oval cells, were markedly increased and correlated with severity of inflammation. Prevalence of hepatic neoplasia was also increased in susceptible RI strains. These findings demonstrate a genetic basis for susceptibility to Helicobacter-induced disease and provide insight into its pathogenesis. (Am J Pathol 1999, 155:571-582)Helicobacter hepaticus is a well-described, naturally occurring pathogen of mice that causes chronic hepatitis and cancer and has been used as a model for the study of both hepatic carcinogenesis and the biology of Helicobacter-induced gastrointestinal disease. Like Helicobacter pylori, the organism is a gram-negative, ureasepositive, helical bacterium that is transmitted through fecal-oral contamination and results in chronic immune cell stimulation, inflammation, and neoplasia in susceptible animals.1-3 In A/J mice, infection causes severe hepatitis and the eventual development of preneoplastic altered foci, hyperplasia, adenoma, and carcinoma in the liver. In contrast, C57BL/6 mice infected with H. hepaticus are highly resistant to the development of disease and have minimal or no liver lesions.2 As with H. pylori-induced gastritis in people, the particular host factors in A/J and C57BL/6 mice that alter the pathogenesis and severity of disease expression after infection with H. hepaticus are poorly understood. Several studies have implicated an imbalance or dysregulation in immunity in response to the bacteria similar to that seen in H. pylori gastritis. [3][4][5][6]

The extent of systemic exposure following external therapeutic administration of permethrin is very low compared with doses used for preclinical toxicity studies, and elimination is virtually complete after 1 week. These data provide the pharmacokinetic basis for the clinical safety of topical permethrin.

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This article reviews some philosophical aspects of probability and describes how probability logic can give precise meanings to the concepts of inductive support, corroboration, refutation, and related notions, as well as provide a foundation for logically sound statistical inference. Probability logic also provides a basis for recognizing prior distributions as an integral component of statistical analysis, rather than the current misleading practice of pretending that statistics applied to observational data are objective. This basis is important, because the use of realistic priors in a statistical analysis can yield more stringent tests of hypotheses and more accurate estimates than conventional procedures.

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