The innate immune system in drosophila and mammals senses the invasion of microorganisms using the family of Toll receptors, stimulation of which initiates a range of host defense mechanisms. In drosophila antimicrobial responses rely on two signaling pathways: the Toll pathway and the IMD pathway. In mammals there are at least 10 members of the Toll-like receptor (TLR) family that recognize specific components conserved among microorganisms. Activation of the TLRs leads not only to the induction of inflammatory responses but also to the development of antigen-specific adaptive immunity. The TLR-induced inflammatory response is dependent on a common signaling pathway that is mediated by the adaptor molecule MyD88. However, there is evidence for additional pathways that mediate TLR ligand-specific biological responses.

Toll-like receptors.

Escherichia coli is the predominant nonpathogenic facultative flora of the human intestine. Some E. coli strains, however, have developed the ability to cause disease of the gastrointestinal, urinary, or central nervous system in even the most robust human hosts. Diarrheagenic strains of E. coli can be divided into at least six different categories with corresponding distinct pathogenic schemes. Taken together, these organisms probably represent the most common cause of pediatric diarrhea worldwide. Several distinct clinical syndromes accompany infection with diarrheagenic E. coli categories, including traveler’s diarrhea (enterotoxigenic E. coli), hemorrhagic colitis and hemolytic-uremic syndrome (enterohemorrhagic E. coli), persistent diarrhea (enteroaggregative E. coli), and watery diarrhea of infants (enteropathogenic E. coli). This review discusses the current level of understanding of the pathogenesis of the diarrheagenic E. coli strains and describes how their pathogenic schemes underlie the clinical manifestations, diagnostic approach, and epidemiologic investigation of these important pathogens.

Diarrheagenic Escherichia coli

Few microorganisms are as versatile as Escherichia coli. An important member of the normal intestinal microflora of humans and other mammals, E. coli has also been widely exploited as a cloning host in recombinant DNA technology. But E. coli is more than just a laboratory workhorse or harmless intestinal inhabitant; it can also be a highly versatile, and frequently deadly, pathogen. Several different E. coli strains cause diverse intestinal and extraintestinal diseases by means of virulence factors that affect a wide range of cellular processes.

Pathogenic Escherichia coli

Unlike eukaryotes, which evolve principally through the modification of existing genetic information, bacteria have obtained a significant proportion of their genetic diversity through the acquisition of sequences from distantly related organisms. Horizontal gene transfer produces extremely dynamic genomes in which substantial amounts of DNA are introduced into and deleted from the chromosome. These lateral transfers have effectively changed the ecological and pathogenic character of bacterial species.

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Lateral gene transfer and the nature of bacterial innovation

The invention relates to transgenic non-human animals capable of producing heterologous antibodies and methods for producing human sequence antibodies which bind to human antigens with substantial affinity.

Transgenic non-human animals capable of producing heterologous antibodies

The murine response to lipopolysaccharide (LPS) or endotoxin is determined by the allelic form of the Lps gene carried by the host (1,2). Mice that are homozygous for the defective Lps d allele, such as C3H/HeJ (HeJ) animals, respond to only high doses of endotoxin, whereas mice that are homozygous or heterozygous for the normal Lps n allele, e.g., C3H/HeN (HeN) mice, react to low-dose challenge. Thus, HeJ mice are insensitive to quantities of LPS that elicit mitogenic, inflammatory, hemopoietic, or lethal effects in HeN mice (3–10). Furthermore, the nature of the cellular influx into the peritoneum of LPS-inoculated HeN and HeJ mice differs. Low doses of LPS (1–10 pg) induce an early polymorphonuclear (PMN) increase, followed by a rapid rise in macrophages and macrophage colony-forming cells in the HeJ peritoneal cavity (7,11,12). By contrast, a relatively small PMN infiltrate is evident in the HeN peritoneal inflammatory response, and the onset of the macrophage influx is delayed compared to the HeJ response.

Inflammatory response of LPS-hyporesponsive and LPS-responsive mice to challenge with Gram-negative bacteria Salmonella typhimurium and Klebsiella pneumoniae.

Learning lessons for automated vehicle design: Using systems thinking to analyse and compare automation-related accidents across transport domains

INTRODUCTION In August, 2011, the F. Edward Hebert School of Medicine extensively revised its four year curriculum, focusing on the theme of “Molecules to Military Medicine.” Since most civilian medical schools undergoing a major curricular reform typically allow three to seven years for full implementation, the fact that its revision was designed and implemented in two years, was itself a momentous achievement. As such, this report will describe some of the key innovations associated with the new curriculum, followed by a summary of some of the leadership lessons that may help guide other programs considering similar types of curricular revision.

Academic Change Management: Leadership Lessons From Curricular Reform

When inbred or outbred mice are challenged with Salmonella typhimurium, they develop a disease which is similar in its pathogenesis to typhoid fever in man. Whether the animals ultimately survive the infection depends on the virulence of the bacterial strain, the route of challenge, and the genetic constitution of the mice. Although mice of some inbred strains and many outbred strains survive parenteral inoculation with up to 10,000 virulent salmonellae, mice of other inbred strains invariably succumb to low-dose (< 10 bacteria) challenge. Several distinct host genes have been identified which regulate this differential susceptibility to murine typhoid. Some of these genes act early in the course of the disease (Ity, Lps, and the C3HeB/FeJ gene), and mice that express the, susceptibility allele at any one of these loci (e.g., Ity S or Lps d ) usually die by day 10 of infection with a virulent strain of S. typhimurium (Plant and Glynn 1976; Hormaeche 1979; O’Brien et al. 1980, O’Brien and Rosenstreich 1983).

Alison D. O'Brien

Papers

Inflammatory response of LPS-hyporesponsive and LPS-responsive mice to challenge with Gram-negative bacteria Salmonella typhimurium and Klebsiella pneumoniae.

Learning lessons for automated vehicle design: Using systems thinking to analyse and compare automation-related accidents across transport domains

Academic Change Management: Leadership Lessons From Curricular Reform

Susceptibility of Mus musculus musculus (Czech I) mice to Salmonella typhimurium infection.

Using patient dependency to calculate staffing needs in A&E