High-resolution magnetic resonance imaging quantitatively detects individual pancreatic islets.

OBJECTIVE-We studied whether manganese-enhanced high-field magnetic resonance (MR) imaging (MEHFMRI) could quantitatively detect individual islets in situ and in vivo and evaluate changes in a model of experimental diabetes.RESEARCH DESIGN AND METHODS-Whole pancreata from untreated (n = 3), MnCl(2) and glucose-injected mice (n = 6), and mice injected with either streptozotocin (STZ; n = 4) or citrate buffer (n = 4) were imaged ex vivo for unambiguous evaluation of islets. Exteriorized pancreata of MnCl(2) and glucose-injected mice (n = 6) were imaged in vivo to directly visualize the gland and minimize movements. In all cases, MR images were acquired in a 14.1 Testa scanner and correlated with the corresponding (immuno)histological sections.RESULTS-In ex vivo experiments, MEHFMRI distinguished different pancreatic tissues and evaluated the relative abundance of islets in the pancreata of normoglycemic mice. MEHFMRI also detected a significant decrease in the numerical and volume density of islets in STZ-injected mice. However, in the latter measurements the loss of beta-cells was undervalued under the conditions tested. The experiments on the externalized pancreata confirmed that MEHFMRI could visualize native individual islets in living, anesthetized mice.CONCLUSIONS-Data show that MEHFMRI quantitatively visualizes individual islets in the intact mouse pancreas, both ex vivo and in vivo. Diabetes 60:2853-2860, 2011

Seroprevalence of hepatitis e virus in domestic pigs and wild boars in Switzerland.

Hepatitis E is considered an emerging human viral disease in industrialized countries. Studies from Switzerland report a human seroprevalence of hepatitis E virus (HEV) of 2.6-21%, a range lower than in adjacent European countries. The aim of this study was to determine whether HEV seroprevalence in domestic pigs and wild boars is also lower in Switzerland and whether it is increasing and thus indicating that this zoonotic viral infection is emerging. Serum samples collected from 2,001 pigs in 2006 and 2011 and from 303 wild boars from 2008 to 2012 were analysed by ELISA for the presence of HEV-specific antibodies. Overall HEV seroprevalence was 58.1% in domestic pigs and 12.5% in wild boars. Prevalence in domestic pigs was significantly higher in 2006 than in 2011. In conclusion, HEV seroprevalence in domestic pigs and wild boars in Switzerland is comparable with the seroprevalence in other countries and not increasing. Therefore, prevalence of HEV in humans must be related to other factors than prevalence in pigs or wild boars.

Quality assurance in the 22991 EORTC ROG trial in localized prostate cancer: dummy run and individual case review.

INTRODUCTION: EORTC trial 22991 was designed to evaluate the addition of concomitant and adjuvant short-term hormonal treatments to curative radiotherapy in terms of disease-free survival for patients with intermediate risk localized prostate cancer. In order to assess the compliance to the 3D conformal radiotherapy protocol guidelines, all participating centres were requested to participate in a dummy run procedure. An individual case review was performed for the largest recruiting centres as well. MATERIALS AND METHODS: CT-data of an eligible prostate cancer patient were sent to 30 centres including a description of the clinical case. The investigator was requested to delineate the volumes of interest and to perform treatment planning according to the protocol. Thereafter, the investigators of the 12 most actively recruiting centres were requested to provide data on five randomly selected patients for an individual case review. RESULTS: Volume delineation varied significantly between investigators. Dose constraints for organs at risk (rectum, bladder, hips) were difficult to meet. In the individual case review, no major protocol deviations were observed, but a number of dose reporting problems were documented for centres using IMRT. CONCLUSIONS: Overall, results of this quality assurance program were satisfactory. The efficacy of the combination of a dummy run procedure with an individual case review is confirmed in this study, as none of the evaluated patient files harboured a major protocol deviation. Quality assurance remains a very important tool in radiotherapy to increase the reliability of the trial results. Special attention should be given when designing quality assurance programs for more complex irradiation techniques.

Combined clonotyping and gene signatures of individual tumor-reactive CD8 T-cells define their functional relevance following peptide vaccination in melanoma patients

Novel cancer vaccines are capableto efficiently induce and boost humantumor antigen specific T-cells. However,the properties of these CD8T-cells are only partially characterized.For in depth investigation ofT-cells following Melan-A/MART-1peptide vaccination in melanoma patients,we conducted a detailed prospectivestudy at the single cell level.We first sorted individual human naiveand effector CD8 T-cells from peripheralblood by flow cytometry, andtested a modified RT-PCR protocolincluding a global amplification ofexpressed mRNAs to obtain sufficientcDNAfromsingle cells.We successfullydetected the expression ofseveral specific genes of interest evendown to 106-fold dilution (equivalentto 10-5 cell). We then analyzed tumor-specific effector memory (EM)CD8T-cell subpopulations ex vivo, assingle cells from vaccinated melanomapatients. To elucidate the hallmarksof effective immunity the genesignatures were defined by a panel ofgenes related to effector functions(e.g. IFN-, granzyme B, perforin),and individual clonotypes were identifiedaccording to the expression ofdistinct T-cell receptors (TCR). Usingthis novel single cell analysis approach,we observed that T-cell differentiationis clonotype dependent,with a progressive restriction in TCRBV clonotype diversity from EMCD28pos to EMCD28neg subsets. However,the effector function gene imprintingis clonotype-independent,but dependent on differentiation,since it correlates with the subset oforigin (EMCD28pos or EMCD28neg). We also conducted a detailedcomparative analysis after vaccinationwith natural vs. analog Melan-Apeptide. We found that the peptideused for vaccination determines thefunctional outcome of individualT-cell clonotypes, with native peptideinducing more potent effector functions.Yet, selective clonotypic expansionwith differentiation was preservedregardless of the peptide usedfor vaccination. In summary, the exvivo single cell RT-PCR approach ishighly sensitive and efficient, andrepresents a reliable and powerfultool to refine our current view of molecularprocesses taking place duringT-cell differentiation.

I have faith in my thing, you know what I mean? Mixed method elements on individual investments on religious markets.

In contemporary society, religious signification and secular systems mix and influence each other. Holistic conceptions of a world in which man is integrated harmoniously with nature meet representations of a world run by an immanent God. On the market of the various systems, the individual goes from one system to another, following his immediate needs and expectations without necessarily leaving any marks in a meaningful long term system. This article presents the first results of an ongoing research in Switzerland on contemporary religion focusing on (new) paths of socialization of modern that individuals and the various (non-) belief systems that they simultaneously develop

Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies.

BACKGROUND: Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women. METHODS: Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression. FINDINGS: Breast cancer risk increased by a factor of 1·050 (95% CI 1·044-1·057; p<0·0001) for every year younger at menarche, and independently by a smaller amount (1·029, 1·025-1·032; p<0·0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1·43, 1·33-1·52, p<0·001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p<0·006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p<0·01 for both comparisons). INTERPRETATION: The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours. FUNDING: Cancer Research UK.

Profile of a serial killer: cellular and molecular approaches to study individual cytotoxic T-cells following therapeutic vaccination.

T-cell vaccination may prevent or treat cancer and infectious diseases, but further progress is required to increase clinical efficacy. Step-by-step improvements of T-cell vaccination in phase I/II clinical studies combined with very detailed analysis of T-cell responses at the single cell level are the strategy of choice for the identification of the most promising vaccine candidates for testing in subsequent large-scale phase III clinical trials. Major aims are to fully identify the most efficient T-cells in anticancer therapy, to characterize their TCRs, and to pinpoint the mechanisms of T-cell recruitment and function in well-defined clinical situations. Here we discuss novel strategies for the assessment of human T-cell responses, revealing in part unprecedented insight into T-cell biology and novel structural principles that govern TCR-pMHC recognition. Together, the described approaches advance our knowledge of T-cell mediated-protection from human diseases.

Impact of the C2/C6 ratio of high-molecular-weight hydroxyethyl starch on pharmacokinetics and blood coagulation in pigs

Rapport de synthèse : Contexte: l'hydroxyéthylamidon (HEA) est largement utilisé comme expanseur volémique en anesthésiologie et réanimation. Cependant, cette classe de produits perturbe le system de la coagulation. Des améliorations restent possibles dans le choix de la combinaison optimale de poids moléculaire, de degré de substitution en radicaux éthyle et de localisation de ces radicaux sur le squelette glucidique des polymères, afin d'optimiser leur efficacité et leur tolérance. L'HEA de poids moléculaire élevé et faiblement substitué n'affecte pas plus la coagulation sanguine que de l'HEA de bas poids moléculaire faiblement substitué. Nous examinons in vivo l'effet d'un abaissement du rapport C2/C6 sur les caractéristiques pharmacocinétiques et l'impact sur la coagulation sanguine d'un HEA de haut poids moléculaire faiblement substitué. Matériels et méthode: nous comparons dans une étude prospective, randomisée et parallèle l'HEA 650/0.42/2.8 avec l'HEA 650/0.42/5.6 auprès de 30 cochons. Avant, pendant et jusqu'à 630 minutes après une perfusion de 30 ml/kg d'HEA, des échantillons sanguins ont été collectés pour mesurer les concentrations d'HEA, les tests de coagulation plasmatique classiques et la coagulation sanguine par thrombélastographie (TEG®, Haemoscope Corporation, Niles, II, U.S.). Les paramètres pharmacocinétiques ont été estimés en adaptant un modèle à deux compartiments. Résultats: la constante d'élimination est de 0.009 ± 0.001 (min-1) pour l'HEA 650/0.42/2.8 et 0.007 ± 0.001 (min-1) pour l'HEA 650/0.42/5.6 (p<0.001); la surface sous la courbe de concentration est de 1374 ± 340 min*g/L pour l'HEA 650/0.42/2.8 et 1697 ± 411 min*g/L pour l'HEA 650/0.42/5.6 (p=0.026). Les concentrations mesurées d'HEA ne montrent pas de différence entre l'HEA 650/0.42/2.8 et l'HEA 650/0.42/5.6. Les deux solutions d'HEA affectent de façon identique la coagulation sanguine: l'index de coagulation thrombélastographique diminue pareillement à ta fin de la perfusion d'HEA 650/0.42/2.8 et d'HEA 650/0.42/5.6 (p=0.29). De même, le temps de thromboplastine partielle activée et le temps de prothrombine augmentent de manière similaire pour l'HEA 650/0.42/2.8 et l'HEA 650/0.42/5.6 (p=0.83). Conclusion: la réduction du rapport C2/C6 de l'HEA de poids moléculaire élevé et faiblement substitué aboutit à une élimination légèrement accélérée d'HEA. Cependant, elle ne modifie pas l'effet perturbateur sur la coagulation.

Subclinical hypothyroidism and the risk of coronary heart disease and mortality: an individual participant data analysis from nine prospective cohort studies

Texte intégral: http://www.springerlink.com/content/3q68180337551r47/fulltext.pdf

A general model to predict individual exposure to solar UV by using ambient irradiance data

Excessive exposure to solar ultraviolet (UV) is the main cause of skin cancer. Specific prevention should be further developed to target overexposed or highly vulnerable populations. A better characterisation of anatomical UV exposure patterns is however needed for specific prevention. To develop a regression model for predicting the UV exposure ratio (ER, ratio between the anatomical dose and the corresponding ground level dose) for each body site without requiring individual measurements. A 3D numeric model (SimUVEx) was used to compute ER for various body sites and postures. A multiple fractional polynomial regression analysis was performed to identify predictors of ER. The regression model used simulation data and its performance was tested on an independent data set. Two input variables were sufficient to explain ER: the cosine of the maximal daily solar zenith angle and the fraction of the sky visible from the body site. The regression model was in good agreement with the simulated data ER (R(2)=0.988). Relative errors up to +20% and -10% were found in daily doses predictions, whereas an average relative error of only 2.4% (-0.03% to 5.4%) was found in yearly dose predictions. The regression model predicts accurately ER and UV doses on the basis of readily available data such as global UV erythemal irradiance measured at ground surface stations or inferred from satellite information. It renders the development of exposure data on a wide temporal and geographical scale possible and opens broad perspectives for epidemiological studies and skin cancer prevention.

Comparison of four embolic materials for portal vein embolization: experimental study in pigs.

Different embolic materials for portal vein embolization (PVE) were evaluated. Twenty pigs received left and median PVE. Hydrophilic phosphorylcholine, N-butyl cyanoacrylate, hydrophilic gel, and polyvinyl alcohol (PVA) particles measuring either 50-150 microm or 700-900 microm were used in five pigs each. Portography and portal vein pressure measurement were performed before, immediately after PVE, and before being euthanized at day 7. Tissue wedges from embolized, and non-embolized liver were obtained for pathology. After complete embolization, recanalization occurred at 7 days in one gel and one 700-900 PVA embolization. Post-PVE increase in portal pressure was found in all groups (p = 0.01). The area of the hepatic lobules in non-embolized liver was larger than in the embolized liver in all groups (p = 0.001). The ratios of the areas between non-embolized/embolized livers were 1.65, 2.19, 1.57, and 1.32 for gel, NBCA, 50-150 PVA and 700-900 PVA, respectively; the ratios of fibrosis between the embolized and non-embolized livers were 1.37, 3.01, 3.49, and 2.11 for gel, NBCA, 50-150 PVA and 700-900 PVA, respectively. Hepatic lobules in non-embolized liver were significantly larger with NBCA than in other groups (p = 0.01). Fibrosis in embolized liver was significantly higher for NBCA and 50-150 PVA (p = 0.002). The most severe changes in embolized and non-embolized liver were induced by 50-150 PVA and NCBA PVE.