SummaryFimbriae mediate bacterial attachment to host cells and provide a mechanism for tissue attack. They activate a host response by delivery of microbial products such as lipopolysaccharide (LPS) or through direct fimbriae-dependent signalling mechanisms. By coupling to glycosphingolipid (GSL) receptors, P fimbriae trigger cytokine responses in CD14 negative host cells. Here we show that P fimbriae utilize the Toll-like receptor 4 (TLR4)-dependent pathway to trigger mucosal inflammation. Escherichia coli strains expressing P fimbriae as their only virulence factor stimulated chemokine and neutrophil responses in the urinary tract of TLR4 proficient mice, but TLR4 defective mice failed to respond to infection. Mucosal cells were CD14 negative but expressed several TLR species including TLR4, and TLR4 protein was detected. Infection with P fimbriated bacteria stimulated an increase in TLR4 mRNA levels. The activation signal did not involve the LPS-CD14 pathway and was independent of lipid A myristoylation, as shown by mutational inactivation of the msbB gene. Co-staining experiments revealed that TLR4 and the GSL receptors for P fimbriae co-localized in the cell membrane. The results demonstrate that P fimbriae activate epithelial cells by means of a TLR4-dependent signalling pathway, and suggest that GSL receptors for P fimbriae can recruit TLR4 as co-receptors.

SummaryFimbriae target bacteria to different mucosal surfaces and enhance the inflammatory response at these sites. Inflammation may be triggered by the fimbriae themselves or by fimbriae-dependent delivery of other host activating molecules such as lipopolysaccharide (LPS). Although LPS activates systemic inflammation through the CD14 and Toll-like receptor 4 (TLR4) pathways, mechanisms of epithelial cell activation by LPS are not well understood. These cells lack CD14 receptors and are unresponsive to pure LPS, but fimbriated Escherichia coli overcome this refractoriness and trigger epithelial cytokine responses. We now show that type 1 fimbriae can present an LPS-and TLR4-dependent signal to the CD14-negative epithelial cells. Human uroepithelial cells were shown to express TLR4, and type 1 fimbriated E. coli strains triggered an LPS-dependent response in those cells. A similar LPS-and fimbriaedependent response was observed in the urinary tract of TLR4-proficient mice, but not in TLR4-defective mice. The moderate inflammatory response in the TLR4-defective mice was fimbriae dependent but LPS independent. The results demonstrate that type 1 fimbriae present LPS to CD14-negative cells and that the TLR4 genotype determines this response despite the absence of CD14 on the target cells. The results illustrate how the host`sees' LPS and other microbial products not as purified molecules but as complexes, and that fimbriae determine the molecular context in which LPS is presented to host cells.

SummaryCells in the mucosal barrier are equipped to sense and respond to microbes in the lumen and translate this molecular information into signals that can reach local or distant sites. The interaction of P-®mbriated Escherichia coli with human uroepithelial cells is a model to study the molecular mechanism of epithelial cell activation by mucosal pathogens. Here, we examine the role of lipopolysaccharide (LPS) as a co-stimulatory molecule in epithelial cell activation by P-®mbriated E. coli. P-®mbriated clinical isolates or recombinant strains were shown to trigger a ®mbriae-dependent epithelial cell cytokine response. Mutational inactivation of the msbB sequences that control lipid A myristoylation drastically impaired monocyte stimulation but not epithelial responses to P-®mbriated bacteria. Polymyxin B or bactericidal/permeability increasing factor (BPI) neutralized the effects of lipid A in the monocyte assay, but did not reduce epithelial responses. Finally, isolated LPS of the smooth, rough and deep rough chemotypes were poor epithelial cell activators. The cells were shown to lack surface CD14 or CD14 mRNA as well as the CD14 co-receptor function and were also very poor LPS responders in the presence of human serum. These results demonstrate that epithelial cell responses to P-®mbriated E. coli are CD14 and LPS independent, and suggest that attaching pathogens can overcome the LPS unresponsiveness of epithelial cells by ®mbriae-dependent activation mechanisms.

A hidden curriculum: mapping cultural competency in a medical programme.Wachtler, Caroline; Troein, Margareta (2003). A hidden curriculum: mapping cultural competency in a medical programme. Medical Education, 37(10), 861-868. DOI: 10.1046861-868. DOI: 10. /j.1365861-868. DOI: 10. -2923861-868. DOI: 10. .2003 General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from the public portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.A hidden curriculum: mapping cultural competency in a medical programme Aim This study was performed in order to evaluate the current status of cultural competency training at a medical school in southern Sweden.Methods We used a multimethod approach to curriculum evaluation. We reviewed the published list of learning objectives for the medical programme, interviewed curriculum directors and individual teachers for each term about course content and carried out focus group interviews with students in all stages of the medical programme.Results Cultural competency is a present but mostly hidden part of the curriculum. We found learning objectives about cultural competency. Teachers reported a total of 25 instances of teaching that had culture or cultural competency as the main theme or 1 of many themes. Students reported few specific learning instances where cultural competency was the main theme. Students and teachers considered cultural competency training to be integrated into the medical programme. Cultural competency was not assessed.Conclusion This evaluation showed places in the curriculum where cultural competency is a present, absent or hidden part of the curriculum. The differences between the 3 perspectives on the curriculum lead us to propose curriculum changes. This study illustrates how triangulation with a multifactorial methodology leads to understanding of the current curriculum and changes for the future.

This study indicates that cultural difference is not treated in GPs consultation with immigrant patients. Learning about cultural difference's effect on mutual understanding between doctor and patient could improve GPs cross-cultural communication. Increased awareness of the culture the doctor brings to the consultation could facilitate management of cross-cultural consultations.