Immunology taught by lung dendritic cells.

Dendritic cells (DCs) are leukocytes specialised in the uptake, processing, and presentation of antigen and fundamental in regulating both innate and adaptive immune functions. They are mainly localised at the interface between body surfaces and the environment, continuously scrutinising incoming antigen for the potential threat it may represent to the organism. In the respiratory tract, DCs constitute a tightly enmeshed network, with the most prominent populations localised in the epithelium of the conducting airways and lung parenchyma. Their unique localisation enables them to continuously assess inhaled antigen, either inducing tolerance to inoffensive substances, or initiating immunity against a potentially harmful pathogen. This immunological homeostasis requires stringent control mechanisms to protect the vital and fragile gaseous exchange barrier from unrestrained and damaging inflammation, or an exaggerated immune response to an innocuous allergen, such as in allergic asthma. During DC activation, there is upregulation of co-stimulatory molecules and maturation markers, enabling DC to activate naïve T cells. This activation is accompanied by chemokine and cytokine release that not only serves to amplify innate immune response, but also determines the type of effector T cell population generated. An increasing body of recent literature provides evidence that different DC subpopulations, such as myeloid DC (mDC) and plasmacytoid DC (pDC) in the lungs occupy a key position at the crossroads between tolerance and immunity. This review aims to provide the clinician and researcher with a summary of the latest insights into DC-mediated pulmonary immune regulation and its relevance for developing novel therapeutic strategies for various disease conditions such as infection, asthma, COPD, and fibrotic lung disease.

Biological markers of alcohol consumption in alcoholised drivers: Comparison of capillary electrophoresis (CZE CDT) and a direct immunoassay (N Latex CDT) with the traditional method of anion-exchange chromatography-immunoturbidimetry (%CDT TIA).

Objectives: The aim of this study was to compare specificity and sensitivity of different biological markers that can be used in a forensic field to identify potentially dangerous drivers because of their alcohol habits. Methods: We studied 280 Swiss drivers after driving while under the alcohol influence. 33 were excluded for not having CDT N results, 247 were included (218 men (88%) and 29 women (12%). Mean age was 42,4 (SD:12, min: 20 max: 76). The evaluation of the alcohol consumption concerned the month before the CDT test and was considered as such after the interview: Heavy drinkers (>3 drinks per day): 60 (32.7%), < 3 drinks per day and moderate: 127 (51.4%) 114 (46.5%), abstinent: 60 (24.3%) 51 (21%). Alcohol intake was monitored by structured interviews, self-reported drinking habits and the C-Audit questionnaire as well as information provided by their family and general practitioner. Consumption was quantified in terms of standard drinks, which contain approximately 10 grams of pure alcohol (Ref. WHO). Results: comparison between moderate (less or equal to 3 drinks per day) and excessive drinkers (more than 3 drinks) Marker ROC area 95% CI cut-off sensitivity specificity CDT TIA 0.852 0.786-0917 2.6* 0.93 LR+1.43 0.35 LR-0.192 CDT N latex 0.875 0.821-0.930 2.5* 0.66 LR+ 6.93 0.90 LR- 0.369 Asialo+disialo-tf 0.881 0.826-0.936 1.2* 0.78 LR+4.07 0.80 LR-0.268 1.7° 0.66 LR+8.9 0.93 LR-0.360 GGT 0.659 0.580-0.737 85* 0.37 LR+2.14 0.83 LR-0.764 * cut-off point suggested by the manufacturer ° cut-off point suggested by our laboratory Conclusion: With the cut-off point established by the manufacturer, CDT TIA performed poorly in term of specificity. N latex CDT and CZE CDT were better, especially if a 1.7 cut-off is used with CZE

Towards equivalent health care of prisoners: European soft law and public health policy in Geneva.

Prisoners have a right to health care and to be protected against inhumane and degrading treatment. Health care personnel and public policy makers play a central role in the protection of these rights and in the pursuit of public health goals. This article examines the legal framework for prison medicine in the canton of Geneva, Switzerland and provides examples of this framework that has shaped prisoners' medical care, including preventive measures. Geneva constitutes an intriguing example of how the Council of Europe standards concerning prison medicine have acquired a legal role in a Swiss canton. Learning how these factors have influenced implementation of prison medicine standards in Geneva may be helpful to public health managers elsewhere and encourage the use of similar strategies.

Identification of the biosynthetic gene cluster for the Pseudomonas aeruginosa antimetabolite L-2-amino-4-methoxy-trans-3-butenoic acid.

L-2-amino-4-methoxy-trans-3-butenoic acid (AMB) is a potent antibiotic and toxin produced by Pseudomonas aeruginosa. Using a novel biochemical assay combined with site-directed mutagenesis in strain PAO1, we have identified a five-gene cluster specifying AMB biosynthesis, probably involving a thiotemplate mechanism. Overexpression of this cluster in strain PA7, a natural AMB-negative isolate, led to AMB overproduction.

The structural nature of perceptual experiences

Intuitively, we think of perception as providing us with direct cognitive access to physical objects and their properties. But this common sense picture of perception becomes problematic when we notice that perception is not always veridical. In fact, reflection on illusions and hallucinations seems to indicate that perception cannot be what it intuitively appears to be. This clash between intuition and reflection is what generates the puzzle of perception. The task and enterprise of unravelling this puzzle took, and still takes, centre stage in the philosophy of perception. The goal of my dissertation is to make a contribution to this enterprise by formulating and defending a new structural approach to perception and perceptual consciousness. The argument for my structural approach is developed in several steps. Firstly, I develop an empirically inspired causal argument against naïve and direct realist conceptions of perceptual consciousness. Basically, the argument says that perception and hallucination can have the same proximal causes and must thus belong to the same mental kind. I emphasise that this insight gives us good reasons to abandon what we are instinctively driven to believe - namely that perception is directly about the outside physical world. The causal argument essentially highlights that the information that the subject acquires in perceiving a worldly object is always indirect. To put it another way, the argument shows that what we, as perceivers, are immediately aware of, is not an aspect of the world but an aspect of our sensory response to it. A view like this is traditionally known as a Representative Theory of Perception. As a second step, emphasis is put on the task of defending and promoting a new structural version of the Representative Theory of Perception; one that is immune to some major objections that have been standardly levelled at other Representative Theories of Perception. As part of this defence and promotion, I argue that it is only the structural features of perceptual experiences that are fit to represent the empirical world. This line of thought is backed up by a detailed study of the intriguing phenomenon of synaesthesia. More precisely, I concentrate on empirical cases of synaesthetic experiences and argue that some of them provide support for a structural approach to perception. The general picture that emerges in this dissertation is a new perspective on perceptual consciousness that is structural through and through.

Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study.

BACKGROUND: The quality of colon cleansing is a major determinant of quality of colonoscopy. To our knowledge, the impact of bowel preparation on the quality of colonoscopy has not been assessed prospectively in a large multicenter study. Therefore, this study assessed the factors that determine colon-cleansing quality and the impact of cleansing quality on the technical performance and diagnostic yield of colonoscopy. METHODS: Twenty-one centers from 11 countries participated in this prospective observational study. Colon-cleansing quality was assessed on a 5-point scale and was categorized on 3 levels. The clinical indication for colonoscopy, diagnoses, and technical parameters related to colonoscopy were recorded. RESULTS: A total of 5832 patients were included in the study (48.7% men, mean age 57.6 [15.9] years). Cleansing quality was lower in elderly patients and in patients in the hospital. Procedures in poorly prepared patients were longer, more difficult, and more often incomplete. The detection of polyps of any size depended on cleansing quality: odds ratio (OR) 1.73: 95% confidence interval (CI)[1.28, 2.36] for intermediate-quality compared with low-quality preparation; and OR 1.46: 95% CI[1.11, 1.93] for high-quality compared with low-quality preparation. For polyps >10 mm in size, corresponding ORs were 1.0 for low-quality cleansing, OR 1.83: 95% CI[1.11, 3.05] for intermediate-quality cleansing, and OR 1.72: 95% CI[1.11, 2.67] for high-quality cleansing. Cancers were not detected less frequently in the case of poor preparation. CONCLUSIONS: Cleansing quality critically determines quality, difficulty, speed, and completeness of colonoscopy, and is lower in hospitalized patients and patients with higher levels of comorbid conditions. The proportion of patients who undergo polypectomy increases with higher cleansing quality, whereas colon cancer detection does not seem to critically depend on the quality of bowel preparation.

(Young Investigator Award) Trabecular Bone Score Helps Classifying Women At Risk Of Fracture Prospectively In The Ofely Study

Introduction: To determine the metabolic effect of teriparatide (TPTD) on bone, 99mTc-MDP skeletal plasma clearance was measured in postmenopausal women with osteoporosis treated with TPTD 20 μg/day. Methods: Ten postmenopausal women with osteoporosis had radionuclide bone scans at baseline, 3, and 18 months after starting TPTD 20 μg/day and after 6 months off therapy. Participants were injected with 600 MBq 99mTc- MDP and whole body bone scans acquired at 10 min, 1, 2, 3, and 4 h. Multiple blood samples were taken between 5 min and 4 h and free 99mTc-MDP measured using ultrafiltration. 99mTc-MDP plasma clearance (Kbone) was evaluated using the Patlak plot method. Regional differences in Kbone were studied by measuring the whole skeleton and subregions. Serum procollagen type I Nterminal propeptide (PINP), bone-specific alkaline phosphatase (BSAP), and urinary N-terminal telopeptide (NTX) were measured at each visit.Discussion: The median increase from baseline in whole skeleton Kbone was 22% (P=0.004) at 3 months and 34% (P= 0.002) at 18 months, decreasing to 0.7% after 6 months off therapy. In subregions, Kbone value increases were statistically significant at 3 months and in all subregions except the pelvis at 18 months. After 6 months off therapy, subregional Kbone values also returned toward baseline. Bone markers increases from baseline were statistically significant at 3 and 18 months (BSAP, 15% and 36%; PINP, 137% and 192%; NTX, 109% and 125%). After 6 months off therapy, PINP and NTX values had declined, though remained above baseline (BSAP, −3%; PINP, 43%; NTX, 56%). Increased Kbone values in the whole body and lower extremities were correlated with increases in most bone markers at 3 and 18 months. Increased skeletal uptake of 99mTc-MDP during treatment with TPTD is indicative of increased bone formation and is supported by increases in bone turnover markers.Conclusion: Changes in Kbone and skeletal uptake measured by radionuclide bone scans in patients taking TPTD are the result of metabolic activity of the drug. These data may provide physicians with useful insights when interpreting bone scan results in this population.

Importance of IL28B gene polymorphisms in hepatitis C virus genotype 2 and 3 infected patients.

BACKGROUND & AIMS: Genetic variation in the interleukin 28B (IL28B) gene has been associated with the response to interferon-alfa/ribavirin therapy in hepatitis C virus (HCV) genotype 1-infected patients. The importance of three IL28B single nucleotide polymorphisms (rs8099917, rs12980275 and rs12979860) for HCV genotype 2/3-infected patients is unknown. METHODS: In patients with chronic hepatitis C genotype 2/3 (n=267), IL28B host genotypes (rs8099917, rs12980275 and rs12979860) were analyzed for associations with sustained virologic response (SVR) to antiviral therapy with (pegylated) interferon-alfa and ribavirin and with respect to epidemiological, biochemical, and virological parameters. For comparison, hepatitis C genotype 1 patients (n=378) and healthy controls (n=200) were included. RESULTS: The rs12979860 CC genotype, lower age, and genotype 2 were significantly associated with SVR in HCV genotype 2/3-infected patients (p=0.01, p=0.03 and p=0.03, respectively). No association was observed for rs8099917 and rs12980275. In addition, an SVR in patients with rapid virologic response (RVR) was associated with the rs12979860 CC genotype (p=0.05), while for non-RVR no association was found. Furthermore, a significant association with a higher baseline viral load was observed for all three IL28B genotypes in genotype 1/2/3-infected patients. Finally, increasing frequencies of the rs12979860 CC genotypes were observed in genotype 1- (33.9%), genotype 3- (38.9%), and genotype 2-infected (51.9%) patients in comparison with healthy controls (49.0%) (p<0.01). CONCLUSIONS: In genotype 2/3-infected patients, rs12979860 was significantly associated with SVR. The frequency of the rs12979860 CC genotype is lower in HCV genotype 1 vs. genotype 2/3 patients. All major IL28B genotypes are associated with HCV-RNA concentration.

Inflammation and TCR Signal Strength Determine the Breadth of the T Cell Response in a Bim-Dependent Manner.

Generating a diverse T cell memory population through vaccination is a promising strategy to overcome pathogen epitope variability and tolerance to tumor Ags. The effector and memory pool becomes broad in TCR diversity by recruiting high- and low-affinity T cells. We wanted to determine which factors dictate whether a memory T cell pool has a broad versus focused repertoire. We find that inflammation increases the magnitude of low- and high-affinity T cell responses equally well, arguing against a synergistic effect of TCR and inflammatory signals on T cell expansion. We dissect the differential effects of TCR signal strength and inflammation and demonstrate that they control effector T cell survival in a bim-dependent manner. Importantly, bim-dependent cell death is overcome with a high Ag dose in the context of an inflammatory environment. Our data define the framework for the generation of a broad T cell memory pool to inform future vaccine design.