The disciplining of self-help: Doing self-help the Norwegian way.

We explore how Norwegian self-help groups are defined and managed to create a particular form of health system governmentality. Self-help groups are typically framed as therapeutic communities where participants define the agenda creating a space where open and equal interaction can produce individual learning and personal growth. In Norway, however, self-help groups are managed in a way that integrates them in to the health system but insulates them from clinical medicine; an approach that disciplines participants to act in a particular way in relation to the health system. We draw on the analysis of 1456 pages of public documents and websites from the National Nodal Point for Self-Help (NPSH), the organisation that manages self-help groups, and central government including individual testimonies from participants published between 2006 and 2014. We argue, drawing on Foucault, that self-help premised on lay-leadership and self-determination is at odds with the centrally defined regulation apparent in the model adopted in Norway and an example of disciplining that reinforces health system governmentality and serves the interests of the medical profession and the state. Further we propose that this illustrates the contestation between the pastoral power of medics, the National Nodal Point for Self-Help and the Ministry of Health. Our analysis of Norwegian self-help as a mechanism to create a particular form of health system governmentality helps explain the expansion of self-help and self-management within developed health systems and provides an explanation for why self-help within health systems, is typically situated adjacent to, rather than integrated into, clinical medicine.

Identification of discrete epitopes of Ro52p200 and association with fetal cardiac conduction system manifestations in a rodent model.

Congenital heart block (CHB) is a potentially lethal condition characterized by a third-degree atrioventricular block (AVB). Despite anti-Ro52 antibodies being detected in nearly 90% of mothers of affected children, CHB occurs in only 1-2% of anti-Ro/Sjögren's-syndrome-related antigen A (SSA) autoantibody-positive pregnancies. Maternal antibodies have been suggested to bind molecules crucial to fetal cardiac function; however, it remains unknown whether a single antibody profile associates with CHB or whether several specificities and cross-reactive targets exist. Here, we aimed to define further the reactivity profile of CHB-associated antibodies towards Ro52p200 (amino acid 200-239). We first analysed reactivity of a monoclonal anti-Ro52 antibody shown to induce AVB in rats (7.8C7) and of sera from anti-Ro52p200 antibody-positive mothers of children with CHB towards a panel of modified Ro52p200 peptides, and subsequently evaluated their potential to induce AVB in rats upon transfer during gestation. We observed that CHB maternal sera displayed a homogeneous reactivity profile targeting preferentially the C-terminal part of Ro52p200, in contrast to 7.8C7 that specifically bound the p200 N-terminal end. In particular, amino acid D233 appeared crucial to maternal antibody reactivity towards p200. Despite low to absent reactivity towards rat p200 and different binding profiles towards mutated rat peptides indicating recognition of different epitopes within Ro52p200, immunoglobulin (Ig)G purified from two mothers of children with CHB could induce AVB in rats. Our findings support the hypothesis that several fine antibody specificities and cross-targets may exist and contribute to CHB development in anti-Ro52 antibody-positive pregnancies.

Reaching 1 m deep on Mars: the Icebreaker drill.

The future exploration of Mars will require access to the subsurface, along with acquisition of samples for scientific analysis and ground-truthing of water ice and mineral reserves for in situ resource utilization. The Icebreaker drill is an integral part of the Icebreaker mission concept to search for life in ice-rich regions on Mars. Since the mission targets Mars Special Regions as defined by the Committee on Space Research (COSPAR), the drill has to meet the appropriate cleanliness standards as requested by NASA's Planetary Protection Office. In addition, the Icebreaker mission carries life-detection instruments; and in turn, the drill and sample delivery system have to meet stringent contamination requirements to prevent false positives. This paper reports on the development and testing of the Icebreaker drill, a 1 m class rotary-percussive drill and triple redundant sample delivery system. The drill acquires subsurface samples in short, approximately 10 cm bites, which makes the sampling system robust and prevents thawing and phase changes in the target materials. Autonomous drilling, sample acquisition, and sample transfer have been successfully demonstrated in Mars analog environments in the Arctic and the Antarctic Dry Valleys, as well as in a Mars environmental chamber. In all environments, the drill has been shown to perform at the "1-1-100-100" level; that is, it drilled to 1 m depth in approximately 1 hour with less than 100 N weight on bit and approximately 100 W of power. The drilled substrate varied and included pure ice, ice-rich regolith with and without rocks and with and without 2% perchlorate, and whole rocks. The drill is currently at a Technology Readiness Level (TRL) of 5. The next-generation Icebreaker drill weighs 10 kg, which is representative of the flightlike model at TRL 5/6.

Increased prefrontal activity and reduced motor cortex activity during imagined eccentric compared to concentric muscle actions.

In this study we used functional magnetic resonance imaging (fMRI) to examine differences in recruited brain regions during the concentric and the eccentric phase of an imagined maximum resistance training task of the elbow flexors in healthy young subjects. The results showed that during the eccentric phase, pre-frontal cortex (BA44) bilaterally was recruited when contrasted to the concentric phase. During the concentric phase, however, the motor and pre-motor cortex (BA 4/6) was recruited when contrasted to the eccentric phase. Interestingly, the brain activity of this region was reduced, when compared to the mean activity of the session, during the eccentric phase. Thus, the neural mechanisms governing imagined concentric and eccentric contractions appear to differ. We propose that the recruitment of the pre-frontal cortex is due to an increased demand of regulating force during the eccentric phase. Moreover, it is possible that the inability to fully activate a muscle during eccentric contractions may partly be explained by a reduction of activity in the motor and pre-motor cortex.

Frontier electronic structures of Ru(tcterpy)(NCS)3 and Ru(dcbpy)2(NCS)2: a photoelectron spectroscopy study.

The frontier electronic structures of Ru(tcterpy)(NCS)3 [black dye (BD)] and Ru(dcbpy)2(NCS)(2) (N719) have been investigated by photoelectron spectroscopy (PES), X-ray absorption spectroscopy (XAS) and resonant photoelectron spectroscopy (RPES). N1s XAS has been used to probe the nitrogen contribution in the unoccupied density of states, and PES, together with RPES over the N1s edge, has been used to delineate the character of the occupied density of states. The experimental findings of the frontier electron structure are compared to calculations of the partial density of states for the nitrogens in the different ligands (NCS and terpyridine/bipyridine) and for Ru4d. The result indicates large similarities between the two complexes. Specifically, the valence level spectra show two well separated structures at low binding energy. The experimental results indicate that the outermost structure in the valence region largely has a Ru4d character but with a substantial character also from the NCS ligand. Interestingly, the second lowest structure also has a significant Ru4d character mixed into the structure otherwise dominated by NCS. Comparing the two complexes the BD valence structures lowest in binding energy contains a large contribution from the NCS ligands but almost no contribution from the terpyridine ligands, while for N719 also some contribution from the bipyridine ligands is mixed into the energy levels.

New Alzheimer's disease locus on chromosome 8.

BACKGROUND: Family history is one of the most consistent risk factors for dementia. Therefore, analysis of families with a distinct inheritance pattern of disease can be a powerful approach for the identification of previously unknown disease genes. OBJECTIVE: To map susceptibility regions for Alzheimer's disease. METHODS: A complete genome scan with 369 microsatellite markers was carried out in 12 extended families collected in Sweden. Age at disease onset ranged from 53 to 78 years, but in 10 of the families there was at least one member with age at onset of < or =65 years. Mutations in known early-onset Alzheimer's disease susceptibility genes have been excluded. All people were genotyped for APOE, but no clear linkage with the epsilon4 allele was observed. RESULTS: Although no common disease locus could be found in all families, in two families an extended haplotype was identified on chromosome 8q shared by all affected members. In one of the families, a non-parametric multimarker logarithm of the odds (LOD) score of 4.2 (p = 0.004) was obtained and analysis based on a dominant model showed a parametric LOD score of 2.4 for this region. All six affected members of this family shared a haplotype of 10 markers spanning about 40 cM. Three affected members in another family also shared a haplotype in the same region. CONCLUSION: On the basis of our data, we propose the existence of a dominantly acting Alzheimer's disease susceptibility locus on chromosome 8.

Electronic and molecular surface structure of Ru(tcterpy)(NCS)3 and Ru(dcbpy)2(NCS)2 adsorbed from solution onto nanostructured TiO2: a photoelectron spectroscopy study.

The element specificity of photoelectron spectroscopy (PES) has been used to compare the electronic and molecular structure of the dyes Ru(tcterpy)(NCS)3 (BD) and Ru(dcbpy)2(NCS)2 adsorbed from solution onto nanostructured TiO2. Ru(dcbpy)2(NCS)2 was investigated in its acid (N3) and in its 2-fold deprotonated form (N719) having tetrabutylammonium (TBA+) as counterions. A comparison of the O1s spectra for the dyes indicates that the interactions through the carboxylate groups with the TiO2 surface are very similar for the dyes. However, we observe that some of the dye molecules also interact through the NCS groups when adsorbed at the TiO2 surface. Comparing the N719 and the N3 molecule, the fraction of NCS groups interacting through the sulfur atoms is smaller for N719 than for N3. We also note that the counterion TBA+ is coadsorbed with the N719 and BD molecules although the amount was smaller than expected from the molecular formulas. Comparing the valence levels for the dyes adsorbed on TiO2, the position of the highest occupied electronic energy level is similar for N3 and N719, while that for BD is lower by 0.25 eV relative to that of the other complexes.

Phenotypes indicating cytolytic properties of Borrelia-specific interferon-gamma secreting cells in chronic Lyme neuroborreliosis.

The immuno-pathogenetic mechanisms underlying chronic Lyme neuroborreliosis are mainly unknown. Human Borrelia burgdorferi (Bb) infection is associated with Bb-specific secretion of interferon-gamma (IFN-gamma), which may be important for the elimination of Bb, but this may also cause tissue injury. In order to increase the understanding of the pathogenic mechanisms in chronic neuroborreliosis, we investigated which cell types that secrete IFN-gamma. Blood mononuclear cells from 13 patients with neuroborreliosis and/or acrodermatitis chronicum atrophicans were stimulated with Bb antigen and the phenotypes of the induced IFN-gamma-secreting cells were analyzed with three different approaches. Cells expressing CD8 or TCRgammadelta, which both have cytolytic properties, were the main phenotypes of IFN-gamma-secreting cells, indicating that tissue injury in chronic neuroborreliosis may be mediated by cytotoxic cells.

Subacute hyponatraemia after transurethral resection of the prostate.

We present a case of subacute hyponatraemia which developed 3 days after a transurethral resection of the prostate. Symptoms consisted of nausea, vomiting and headache. Release of vasopressin due to excessive surgical bleeding, combined with liberal oral and intravenous administration of sodium-free fluids, was considered to be the cause.

Escherichia coli P fimbriae utilize the Toll-like receptor 4 pathway for cell activation.

Fimbriae 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.

Type 1 fimbriae deliver an LPS- and TLR4-dependent activation signal to CD14-negative cells.

Fimbriae 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 fimbriae-dependent 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.

The 'innate' host response protects and damages the infected urinary tract.

Symptoms of infection and tissue pathology are caused by the host response; not by the microbe per se. The same response is also critical for the defence and is needed to clear infection. It is therefore essential to understand how the host response is activated and to identify the critical effector mechanisms of the defence. We have studied these issues in the urinary tract infection (UTI) model. The symptoms of UTI and the host defence both rely on the so-called 'innate' immune system, making this one of the best characterized human disease models of 'innate immunity. We discuss the critical molecular events that determine whether the host response will be activated by P-fimbriated uropathogenic Escherichia coli as well as factors determining whether the patient develops acute pyelonephritis or asymptomatic bacteriuria. We will describe the glycoconjugate receptors used by the P-fimbriated bacteria adhering to host tissues, the recruitment of TLR4 co-receptors and the signalling pathways that allow progression to symptomatic disease, and discuss how these mechanisms are altered in asymptomatic carriers, presenting the possible genetic basis for unresponsiveness. We have shown that neutrophils are the critical effectors of the host defence and that neutrophil dysfunctions lead to acute pyelonephritis and renal scarring. Here we discuss the mechanisms of neutrophil-mediated, chemokine receptor (CXCR1)-dependent clearance, and the defect in interleukin-8 receptor homolog knock-out (IL-8Rh KO) mice and describe the data linking low CXCR1 expression to recurrent pyelonephritis in man, as well as the information on the genetic basis for low CXCR1 expression in affected patients. Finally, the mechanisms of renal scarring in IL8Rh KO mice will be discussed in relation to human disease. Our studies hold the promise to provide a molecular and genetic explanation for disease susceptibility in some patients with UTI and to offer more precise tools for the diagnosis and therapy of these infections.

P fimbriae-dependent, lipopolysaccharide-independent activation of epithelial cytokine responses.

Cells 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-fimbriated 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-fimbriated E. coli. P-fimbriated clinical isolates or recombinant strains were shown to trigger a fimbriae-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-fimbriated 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-fimbriated E. coli are CD14 and LPS independent, and suggest that attaching pathogens can overcome the LPS unresponsiveness of epithelial cells by fimbriae-dependent activation mechanisms.

Cytokine responses during mucosal infections: role in disease pathogenesis and host defence.

Mucosal pathogens use diverse and highly specific molecular mechanisms to activate mucosal inflammation. It may even be argued that their virulence depends on the inflammatory response that they induce. Some bacteria target epithelial cells and trigger them to produce inflammatory mediators but others cross the mucosa and activate macrophages or dendritic cells. Although systemic release of inflammatory mediators causes many symptoms and signs of infection, local chemokine production leads to the recruitment of inflammatory cells and lymphocytes that participate directly in the clearance of bacteria from mucosal sites. In this way, mucosal inflammation is a two-edged sword responsible for disease associated tissue destruction and crucial for the antimicrobial defence. Understanding of these pathways should create tools to enhance the defence and interfere with disease.

Sphingomyelin, glycosphingolipids and ceramide signalling in cells exposed to P-fimbriated Escherichia coli.

Uropathogenic Escherichia coli attach to epithelial cells through P fimbriae that bind Galalpha1-4Galbeta-oligosaccharide sequences in cell surface glycosphingolipids. The binding of P-fimbriated E. coli to uroepithelial cells causes the release of ceramide, activation of the ceramide signalling pathway and a cytokine response in the epithelial cells. The present study examined the molecular source of ceramide in human kidney A498 cells exposed to P-fimbriated E. coli. Agonists such as TNF-alpha and IL-1beta released ceramide from sphingomyelin by the activation of endogenous sphingomyelinases and hydrolysis of sphingomyelin, and triggered an IL-6 response. P-fimbriated E. coli caused a slight increase in endogenous sphingomyelinase activity, but there was no associated sphingomyelin hydrolysis. Instead, the concentration of galactose-containing glycolipids decreased. We propose that P-fimbriated E. coli differ from other activators of the ceramide pathway, in that release of ceramide is from receptor glycolipids and not from sphingomyelin. Receptor breakdown may be an efficient host defence strategy, as it reduces the concentration of cell surface receptors, releases soluble receptor analogues and activates an inflammatory response.

Bacterial attachment to uro-epithelial cells: mechanisms and consequences.

Microbial attachment to mucosal surfaces is a first step in mucosal infection. Specific interactions between microbial surface ligands and host receptors influence the distribution of microbes in their sites of infection. Adhesion has often been regarded as a sufficient end point, explaining tissue tropism and bacterial persistence at mucosal sites. Adherence, however, is also a virulence factor through which microbes gain access to host tissues, upset the integrity of the mucosal barrier, and cause disease. The induction of mucosal inflammation is one aspect of this process. Bacterial attachment to mucosal surfaces activates the production of pro-inflammatory cytokines that cause both local and systemic inflammation. Epithelial cells are one source of these cytokines. The binding of fimbrial lectins to epithelial cell receptors triggers transmembrane signaling events that upregulate cytokine-specific mRNA and increase cytokine secretion. P fimbriae that bind the globoseries of glycolipids cause the release of ceramides and activation of the ceramide signaling pathway which contributes to the IL-6 response. Spread of cytokines and other pro-inflammatory mediators from the local site contributes to the symptoms and signs of infection.

Bacterial adherence and mucosal cytokine responses. Receptors and transmembrane signaling.

By attaching to cells or secreted mucosal components, microbes are thought to avoid elimination by the flow of secretions that constantly wash mucosal surfaces. The attached state enhances their ability to trap nutrients and allows the bacteria to multiply more efficiently than do unattached bacterial cells. Attachment is therefore regarded as an end result in itself, and emphasis has been placed on the role of adherence for colonization of mucosal surfaces. Specific adherence was shown to be essential for the tissue tropism that is to guide microbes to their respective sites of colonization/infection. Attachment is not only a mechanism of tissue targeting but also a first step in the pathogenesis of many infections. The attaching bacteria engage in a "cross-talk" with the host cells through the mutual exchange of signals and responses. Enteropathogenic E. coli induce attaching and effacing lesions (Finley et al., this issue). Shigella and Listeria sp. invade the cells and cause actin polymerization (Sansonetti et al., this issue). This review describes the ability of bacteria to trigger mucosal inflammation through activation of cells in the mucosal lining. The results suggest that receptors for bacterial adhesins bind their ligands with a high degree of specificity and that ligand-receptor interactions trigger transmembrane signaling events that cause cell activation. Receptors for microbial ligands thus appear to fulfill also the same criteria as those used to define receptors for other classes of ligands such as hormones, growth factors, and cytokines.