Autocrine Action of IGF2 Regulates Adult β-Cell Mass and Function.

Insulin-like growth factor 2 (IGF2), produced and secreted by adult β-cells, functions as an autocrine activator of the β-cell insulin-like growth factor 1 receptor signaling pathway. Whether this autocrine activity of IGF2 plays a physiological role in β-cell and whole-body physiology is not known. Here, we studied mice with β-cell-specific inactivation of Igf2 (βIGF2KO mice) and assessed β-cell mass and function in aging, pregnancy, and acute induction of insulin resistance. We showed that glucose-stimulated insulin secretion (GSIS) was markedly reduced in old female βIGF2KO mice; glucose tolerance was, however, normal because of increased insulin sensitivity. While on a high-fat diet, both male and female βIGF2KO mice displayed lower GSIS compared with control mice, but reduced β-cell mass was observed only in female βIGF2KO mice. During pregnancy, there was no increase in β-cell proliferation and mass in βIGF2KO mice. Finally, β-cell mass expansion in response to acute induction of insulin resistance was lower in βIGF2KO mice than in control mice. Thus, the autocrine action of IGF2 regulates adult β-cell mass and function to preserve in vivo GSIS in aging and to adapt β-cell mass in response to metabolic stress, pregnancy hormones, and acute induction of insulin resistance.

Poka-yoke for mass customization

Producing high quality products and services is one of the key concerns in order to keep up with the competition in the global markets. Companies are putting a great effort on preventing customers having faulty products and services by any means. However, the total elimination of mistakes in manufacturing processes has always been a great challenge for quality management. In this thesis the applicability of poka-yoke methodology in reducing the number of quality failures in the case company has been studied. Poka-yoke stands for the mistake-proofing and is mainly developed for the purpose of eliminating human errors in manufacturing processes. Inspection techniques; judgment, informative and source inspection are in the core of this methodology. Mass customization and large configurability of products leads to situation where the root causes of quality problems may vary a lot. To study the effects of these factors extensive analysis of quality failures was conducted. Recommendations and proposals for further actions regarding problem solving processes and utilization of mistake-proofing methods were provided on the basis of the analysis.

Evaluation of steroidomics by liquid chromatography hyphenated to mass spectrometry as a powerful analytical strategy for measuring human steroid perturbations.

This review presents the evolution of steroid analytical techniques, including gas chromatography coupled to mass spectrometry (GC-MS), immunoassay (IA) and targeted liquid chromatography coupled to mass spectrometry (LC-MS), and it evaluates the potential of extended steroid profiles by a metabolomics-based approach, namely steroidomics. Steroids regulate essential biological functions including growth and reproduction, and perturbations of the steroid homeostasis can generate serious physiological issues; therefore, specific and sensitive methods have been developed to measure steroid concentrations. GC-MS measuring several steroids simultaneously was considered the first historical standard method for analysis. Steroids were then quantified by immunoassay, allowing a higher throughput; however, major drawbacks included the measurement of a single compound instead of a panel and cross-reactivity reactions. Targeted LC-MS methods with selected reaction monitoring (SRM) were then introduced for quantifying a small steroid subset without the problems of cross-reactivity. The next step was the integration of metabolomic approaches in the context of steroid analyses. As metabolomics tends to identify and quantify all the metabolites (i.e., the metabolome) in a specific system, appropriate strategies were proposed for discovering new biomarkers. Steroidomics, defined as the untargeted analysis of the steroid content in a sample, was implemented in several fields, including doping analysis, clinical studies, in vivo or in vitro toxicology assays, and more. This review discusses the current analytical methods for assessing steroid changes and compares them to steroidomics. Steroids, their pathways, their implications in diseases and the biological matrices in which they are analysed will first be described. Then, the different analytical strategies will be presented with a focus on their ability to obtain relevant information on the steroid pattern. The future technical requirements for improving steroid analysis will also be presented.

Persistent spatial clusters of high body mass index in a Swiss urban population as revealed by the 5-year GeoCoLaus longitudinal study.

OBJECTIVE: Body mass index (BMI) may cluster in space among adults and be spatially dependent. Whether and how BMI clusters evolve over time in a population is currently unknown. We aimed to determine the spatial dependence of BMI and its 5-year evolution in a Swiss general adult urban population, taking into account the neighbourhood-level and individual-level characteristics. DESIGN: Cohort study. SETTING: Swiss general urban population. PARTICIPANTS: 6481 georeferenced individuals from the CoLaus cohort at baseline (age range 35-74 years, period=2003-2006) and 4460 at follow-up (period=2009-2012). OUTCOME MEASURES: Body weight and height were measured by trained healthcare professionals with participants standing without shoes in light indoor clothing. BMI was calculated as weight (kg) divided by height squared (m(2)). Participants were geocoded using their postal address (geographic coordinates of the place of residence). Getis-Ord Gi statistic was used to measure the spatial dependence of BMI values at baseline and its evolution at follow-up. RESULTS: BMI was not randomly distributed across the city. At baseline and at follow-up, significant clusters of high versus low BMIs were identified and remained stable during the two periods. These clusters were meaningfully attenuated after adjustment for neighbourhood-level income but not individual-level characteristics. Similar results were observed among participants who showed a significant weight gain. CONCLUSIONS: To the best of our knowledge, this is the first study to report longitudinal changes in BMI clusters in adults from a general population. Spatial clusters of high BMI persisted over a 5-year period and were mainly influenced by neighbourhood-level income.

Rapid analysis of multiclass antibiotic residues and some of their metabolites in hospital, urban wastewater and river water by ultra-highperformance liquid chromatography coupled to quadrupole-linear ion trap tandem mass spectrometry

The present work describes the development of a fast and robust analytical method for the determination of 53 antibiotic residues, covering various chemical groups and some of their metabolites, in environmental matrices that are considered important sources of antibiotic pollution, namely hospital and urban wastewaters, as well as in river waters. The method is based on automated off-line solid phase extraction (SPE) followed by ultra-high-performance liquid chromatography coupled to quadrupole linear ion trap tandem mass spectrometry (UHPLC–QqLIT). For unequivocal identification and confirmation, and in order to fulfill EU guidelines, two selected reaction monitoring (SRM) transitions per compound are monitored (the most intense one is used for quantification and the second one for confirmation). Quantification of target antibiotics is performed by the internal standard approach, using one isotopically labeled compound for each chemical group, in order to correct matrix effects. The main advantages of the method are automation and speed-up of sample preparation, by the reduction of extraction volumes for all matrices, the fast separation of a wide spectrum of antibiotics by using ultra-high-performance liquid chromatography, its sensitivity (limits of detection in the low ng/L range) and selectivity (due to the use of tandem mass spectrometry) The inclusion of β-lactam antibiotics (penicillins and cephalosporins), which are compounds difficult to analyze in multi-residue methods due to their instability in water matrices, and some antibiotics metabolites are other important benefits of the method developed. As part of the validation procedure, the method developed was applied to the analysis of antibiotics residues in hospital, urban influent and effluent wastewaters as well as in river water samples

The Coordinated Radio and Infrared Survey for High-mass Star Formation. II. Source Catalog

The CORNISH project is the highest resolution radio continuum survey of the Galactic plane to date. It is the 5 GHz radio continuum part of a series of multi-wavelength surveys that focus on the northern GLIMPSE region (10° < l < 65°), observed by the Spitzer satellite in the mid-infrared. Observations with the Very Large Array in B and BnA configurations have yielded a 1.''5 resolution Stokes I map with a root mean square noise level better than 0.4 mJy beam 1. Here we describe the data-processing methods and data characteristics, and present a new, uniform catalog of compact radio emission. This includes an implementation of automatic deconvolution that provides much more reliable imaging than standard CLEANing. A rigorous investigation of the noise characteristics and reliability of source detection has been carried out. We show that the survey is optimized to detect emission on size scales up to 14'' and for unresolved sources the catalog is more than 90% complete at a flux density of 3.9 mJy. We have detected 3062 sources above a 7σ detection limit and present their ensemble properties. The catalog is highly reliable away from regions containing poorly sampled extended emission, which comprise less than 2% of the survey area. Imaging problems have been mitigated by down-weighting the shortest spacings and potential artifacts flagged via a rigorous manual inspection with reference to the Spitzer infrared data. We present images of the most common source types found: H II regions, planetary nebulae, and radio galaxies. The CORNISH data and catalog are available online at http://cornish.leeds.ac.uk.

Normal values for pancreatic stone protein in different age groups.

BACKGROUND: Pancreatic stone protein (PSP) has been identified as a promising sepsis marker in adults, children and neonates. However, data on population-based reference values are lacking. This study aimed to establish age-specific reference values for PSP. METHODS: PSP was determined using a specific ELISA. PSP serum concentrations were determined in 372 healthy subjects including 217 neonates, 94 infants and children up to 16 years, and 61 adults. The adjacent categories method was used to determine which age categories had significantly different PSP concentrations. RESULTS: PSP circulating levels were not gender-dependent and ranged from 1.0 to 99.4 ng/ml with a median of 9.2 ng/ml. PSP increased significantly between the age categories, from a median of 2.6 ng/ml in very preterm newborns, to 6.3 ng/ml in term newborns, to 16.1 ng/ml in older children (p < 0.001). PSP levels were higher on postnatal day three compared to levels measured immediately post delivery (p < 0.001). Paired umbilical artery and umbilical vein samples were strongly correlated (p < 0.001). Simultaneously obtained capillary heel-prick versus venous samples showed a good level of agreement for PSP (Rho 0.89, bias 19 %). CONCLUSIONS: This study provides age-specific normal values that may be used to define cut-offs for future trials on PSP. We demonstrate an age-dependent increase of PSP from birth to childhood.

Insulin secretion in health and disease: nutrients dictate the pace.

NlmCategory="UNASSIGNED">Insulin is a key hormone controlling metabolic homeostasis. Loss or dysfunction of pancreatic β-cells lead to the release of insufficient insulin to cover the organism needs, promoting diabetes development. Since dietary nutrients influence the activity of β-cells, their inadequate intake, absorption and/or utilisation can be detrimental. This review will highlight the physiological and pathological effects of nutrients on insulin secretion and discuss the underlying mechanisms. Glucose uptake and metabolism in β-cells trigger insulin secretion. This effect of glucose is potentiated by amino acids and fatty acids, as well as by entero-endocrine hormones and neuropeptides released by the digestive tract in response to nutrients. Glucose controls also basal and compensatory β-cell proliferation and, along with fatty acids, regulates insulin biosynthesis. If in the short-term nutrients promote β-cell activities, chronic exposure to nutrients can be detrimental to β-cells and causes reduced insulin transcription, increased basal secretion and impaired insulin release in response to stimulatory glucose concentrations, with a consequent increase in diabetes risk. Likewise, suboptimal early-life nutrition (e.g. parental high-fat or low-protein diet) causes altered β-cell mass and function in adulthood. The mechanisms mediating nutrient-induced β-cell dysfunction include transcriptional, post-transcriptional and translational modifications of genes involved in insulin biosynthesis and secretion, carbohydrate and lipid metabolism, cell differentiation, proliferation and survival. Altered expression of these genes is partly caused by changes in non-coding RNA transcripts induced by unbalanced nutrient uptake. A better understanding of the mechanisms leading to β-cell dysfunction will be critical to improve treatment and find a cure for diabetes.

Sponge Mass Mortalities in a Warming Mediterranean Sea: Are Cyanobacteria-Harboring Species Worse Off?

Mass mortality events are increasing dramatically in all coastal marine environments. Determining the underlying causes of mass mortality events has proven difficult in the past because of the lack of prior quantitative data on populations and environmental variables. Four-year surveys of two shallow-water sponge species, Ircinia fasciculata and Sarcotragus spinosulum, were carried out in the western Mediterranean Sea. These surveys provided evidence of two severe sponge die-offs (total mortality ranging from 80 to 95% of specimens) occurring in the summers of 2008 and 2009. These events primarily affected I. fasciculata, which hosts both phototrophic and heterotrophic microsymbionts, while they did not affect S. spinosulum, which harbors only heterotrophic bacteria. We observed a significant positive correlation between the percentage of injured I. fasciculata specimens and exposure time to elevated temperature conditions in all populations, suggesting a key role of temperature in triggering mortality events. A comparative ultrastructural study of injured and healthy I. fasciculata specimens showed that cyanobacteria disappeared from injured specimens, which suggests that cyanobacterial decay could be involved in I. fasciculata mortality. A laboratory experiment confirmed that the cyanobacteria harbored by I. fasciculata displayed a significant reduction in photosynthetic efficiency in the highest temperature treatment. The sponge disease reported here led to a severe decrease in the abundance of the surveyed populations. It represents one of the most dramatic mass mortality events to date in the Mediterranean Sea

Identification of new transformation products during enzymatic treatment of tetracycline and erythromycin antibiotics at laboratory scale by an on-line turbulent flow liquid-chromatography coupled to a high resolution mass spectrometer LTQ-Orbitrap

This work describes the formation of transformation products (TPs) by the enzymatic degradation at laboratory scale of two highly consumed antibiotics: tetracycline (Tc) and erythromycin (ERY). The analysis of the samples was carried out by a fast and simple method based on the novel configuration of the on-line turbulent flow system coupled to a hybrid linear ion trap – high resolution mass spectrometer. The method was optimized and validated for the complete analysis of ERY, Tc and their transformation products within 10 min without any other sample manipulation. Furthermore, the applicability of the on-line procedure was evaluated for 25 additional antibiotics, covering a wide range of chemical classes in different environmental waters with satisfactory quality parameters. Degradation rates obtained for Tc by laccase enzyme and ERY by EreB esterase enzyme without the presence of mediators were ∼78% and ∼50%, respectively. Concerning the identification of TPs, three suspected compounds for Tc and five of ERY have been proposed. In the case of Tc, the tentative molecular formulas with errors mass within 2 ppm have been based on the hypothesis of dehydroxylation, (bi)demethylation and oxidation of the rings A and C as major reactions. In contrast, the major TP detected for ERY has been identified as the “dehydration ERY-A”, with the same molecular formula of its parent compound. In addition, the evaluation of the antibiotic activity of the samples along the enzymatic treatments showed a decrease around 100% in both cases

Modelling body mass index and endometrial cancer risk in a pooled-analysis of three case-control studies.

OBJECTIVE: To quantify the relation between body mass index (BMI) and endometrial cancer risk, and to describe the shape of such a relation. DESIGN: Pooled analysis of three hospital-based case-control studies. SETTING: Italy and Switzerland. POPULATION: A total of 1449 women with endometrial cancer and 3811 controls. METHODS: Multivariate odds ratios (OR) and 95% confidence intervals (95% CI) were obtained from logistic regression models. The shape of the relation was determined using a class of flexible regression models. MAIN OUTCOME MEASURE: The relation of BMI with endometrial cancer. RESULTS: Compared with women with BMI 18.5 to <25 kg/m(2) , the odds ratio was 5.73 (95% CI 4.28-7.68) for women with a BMI ≥35 kg/m(2) . The odds ratios were 1.10 (95% CI 1.09-1.12) and 1.63 (95% CI 1.52-1.75) respectively for an increment of BMI of 1 and 5 units. The relation was stronger in never-users of oral contraceptives (OR 3.35, 95% CI 2.78-4.03, for BMI ≥30 versus <25 kg/m(2) ) than in users (OR 1.22, 95% CI 0.56-2.67), and in women with diabetes (OR 8.10, 95% CI 4.10-16.01, for BMI ≥30 versus <25 kg/m(2) ) than in those without diabetes (OR 2.95, 95% CI 2.44-3.56). The relation was best fitted by a cubic model, although after the exclusion of the 5% upper and lower tails, it was best fitted by a linear model. CONCLUSIONS: The results of this study confirm a role of elevated BMI in the aetiology of endometrial cancer and suggest that the risk in obese women increases in a cubic nonlinear fashion. The relation was stronger in never-users of oral contraceptives and in women with diabetes. TWEETABLE ABSTRACT: Risk of endometrial cancer increases with elevated body weight in a cubic nonlinear fashion.

Pancreatic adenocarcinoma: the impact of preneoplastic lesion pattern on survival.

Pancreatic adenocarcinoma is associated with a very poor prognosis, characterized with a 5-year survival rate of only 5%. Surgery is the only curative treatment for selected patients. Nevertheless, recurrence is very frequent. Identifying prognostic factors is thus warranted. Like numerous other tumors, adenocarcinomas are preceded by preneoplastic lesions. The role and the impact of these lesions remain unclear. This study aimed to assess the impact of the preneoplastic lesion pattern and histo-morphological features, on survival after pancreatic resection. Thirty-five patients who underwent pancreatic resection for pancreatic adenocarcinoma were identified from a prospective database of a single center, between 2003 and 2008. We considered demographics, tumor characteristics and type of treatment. The major outcome was survival. Analyzes were separated into two groups, according to the preneoplastic lesions: Pancreatic intraepithelial neoplasia (PanIN)-related carcinomas and intracanalar papillary mucinous neoplasia (IPMN)-related carcinomas. The former were more frequent, accounting for 63% (22/35). Moreover, they displayed more aggressive features, with a higher tumor stage (p = 0.01) and higher rate of positive lymph nodes (p = 0.019). Lymphatic (p = 0.009) and perinervous (p = 0.019) invasions were also more frequent. Survival was negatively influenced by PanIN preneoplastic lesions (p = 0.015), T3-4 tumor stage (p = 0.038), positive lymph nodes (p = 0.044), lymphatic (p = 0.019) and vascular (p = 0.029) invasions. Pancreatic adenocarcinoma displays different behavior according to its preneoplastic lesion. Indeed, PanIN-related adenocarcinoma showed more aggressive features and lower survival rate. Preneoplastic lesions may represent predictive factors for survival. Their role and predictive value should be investigated more thoroughly.