INTRA-DUODENAL RELEASE OF A BITTER COMPOUND DECREASES CALORIC INTAKE IN HEALTHY VOLUNTEERS

Background and aim: α-gustducin and bitter taste receptors (T2R) are expressed both in the oral cavity and in the gastrointestinal (GI) tract. Experimental data showed that bitter tastants induce the release of gut hormones from enteroendocrine cells in the gut, suggesting a possible role of bitter taste receptors in the control of food intake and GI functions. We aimed to test the effects of a bitter taste receptor agonist on food intake and GI feelings. Material and methods: We enrolled 19 healthy subjects (9 males, age 27±7, BMI 24±6) in a double-blind placebo controlled study. Each subject randomly received an acid-resistant capsule containing placebo or 18 mg of quinine HCl. 60 minutes after capsule administration, the subjects underwent to an ad libitum test, until the maximum satiation. Meal test was composed by white bread, cheese and meat cream (89 kcal/portion: 50% carbohydrate, 31% fat, 19% protein). Caloric intake, meal duration and satiation levels, scored on a Visual Analogue Scale (VAS) were calculated at the end of the meal test. A questionnaire assessing GI sensations (bloating, fullness, nausea, epigastric discomfort and hunger) was administered before and at the end of the test. Data (mean ± SD) were compared by using paired t test. Results: No oral bitter sensation or side effects was observed both with quinine HCland placebo. No significant differences in terms of GI sensations and hunger feelings were observed between the two sessions of the study. The amount of calories ingested was significantly lower when subjects received quinine HCl than placebo (564±262 vs 667±278 kcal; p=0.02). Conversely, quinine HCl did not affect the meal duration (14.4±4.2 vs 16.6±4.6 min; p=NS) and the satiationintensity (82 vs 82 mm; p=NS). Conclusions: The intra-duodenal release of a bitter compound significantly decreases caloric intake in an ad libitum test meal without affecting GI sensations and hunger feeling. As the bitter compound does not influence meal duration, we hypothesize that quinine HCl decreases the caloric intake by affecting the rate of meal portions consumption. Evaluation of gut hormones kinetics and studies with other bitter taste receptor agonist are needed to establish the role of gastrointestinal bitter taste receptor in the control of food intak

CHRONIC CONSTIPATION IS A RISK FACTOR FOR METABOLIC SYNDROME

Background and aim: A recent epidemiologic survey in the U.S. provides indirect evidence that constipation is a risk factor for cardiovascular disease in postmenopausal females. To characterize the related factors involved in and to further analyse if this assumption also applies to an Italian population, we studied the impact of chronic constipation on ischemic cardiopathy and predisposing risk factors in a large population of female patients in a primary care setting. Material and methods: We retrospectively evaluated 754 female patients (mean age 46±20 years) on data file of a primary care setting. All subjects requiring medical referral for constipation were screened and presence of chronic constipation was confirmed by standardized questionnaires. The presence of clinical and/or instrumental diagnosis of ischemic cardiopathy, metabolic syndrome, diabetes and blood hypertension was scored in patients with and without chronic constipation. In all patients the consumption of drugs potentially delaying colonic transit (calcium channel blockers and beta blockers) was recorded. Patients on opioid or analgesic treatment were excluded. Results: The overall prevalence of chronic constipation was 9.4% (71/754) with the age being similar in patients with and without constipation (46±19 vs. 51±22, p=NS). The prevalence of metabolic syndrome was significantly higher in subjects with chronic constipation (5/66 vs 16/667, OR=3.1, 95% CI 1.1–8.9, p=0.03). Conversely, prevalence of diabetes, blood hypertension, ischemic cardiopathy was similar in patients with and without constipation (59/624 vs 10/61; 204/478 vs 28/43; 46/637 vs 6/65, respectively p= all NS). No significant difference was also observed as far as calcium channel blockers (64/619 vs 9/62) and beta blockers (81/602 vs 9/62) consumption in patients with or without constipation respectively. Conclusions: We showed that chronic constipation is a risk factor for metabolic syndrome in female patients. Although we did not find any significant association between chronic constipation and ischemic cardiopathy, our findings support the hypothesis that constipation may act as cardiovascular risk factor. Whether this association is dependent on dietary or hormonal factors deserves further investigation

A generative-oriented model-driven design environment for customizable video surveillance systems

To tackle the growing complexity and huge demand for tailored domestic video surveillance systems along with a high demanding time-to-market expectation, engineers at IVV Automação, LDAa are exploiting video surveillance domain as families of systems that can be developed following a pay-as-you-go fashion rather than developing an ex-nihilo new product. Several and different new functionalities are required for each new product’s hardware platforms (e.g., ranging from mobile phone, PDA to desktop PC) and operating systems (e.g., flavors of Linux, Windows and MAC OS X). Some of these functionalities have special economical constraints of development time and memory footprint. To better accommodate all the above listing requirements, a model-driven generative software development paradigm supported by mainstream tools is proposed to offer a significant leverage in hiding commonalities and configuring variabilities across families of video surveillance products while maintaining the new product quality.This work was funded through the Competitive Factors Operational Program COMPETE and through national funds though the Science and Technology Foundation - FCT, within the project: FCOMP-01-0124-FEDER-022674. This work was developed in cooperation with IVV Automation; all support and means provided by the company is acknowledged

Tissue Microenvironments Define and Get Reinforced by Macrophage Phenotypes in Homeostasis or during Inflammation, Repair and Fibrosis

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Base

Computational Prediction of Host-Parasite Protein Interactions between P. falciparum and H. sapiens

To obtain candidates of interactions between proteins of the malaria parasite Plasmodium falciparum and the human host, homologous and conserved interactions were inferred from various sources of interaction data. Such candidate interactions were assessed by applying a machine learning approach and further filtered according to expression and molecular characteristics, enabling involved proteins to indeed interact. The analysis of predicted interactions indicated that parasite proteins predominantly target central proteins to take control of a human host cell. Furthermore, parasite proteins utilized their protein repertoire in a combinatorial manner, providing a broad connection to host cellular processes. In particular, several prominent pathways of signaling and regulation proteins were predicted to interact with parasite chaperones. Such a result suggests an important role of remodeling proteins in the interaction interface between the human host and the parasite. Identification of such molecular strategies that allow the parasite to take control of the host has the potential to deepen our understanding of the parasite specific remodeling processes of the host cell and illuminate new avenues of disease intervention

Key Science Goals for the Next-Generation Event Horizon Telescope

The Event Horizon Telescope (EHT) has led to the first images of a supermassive black hole, revealing the central compact objects in the elliptical galaxy M87 and the Milky Way. Proposed upgrades to this array through the next-generation EHT (ngEHT) program would sharply improve the angular resolution, dynamic range, and temporal coverage of the existing EHT observations. These improvements will uniquely enable a wealth of transformative new discoveries related to black hole science, extending from event-horizon-scale studies of strong gravity to studies of explosive transients to the cosmological growth and influence of supermassive black holes. Here, we present the key science goals for the ngEHT and their associated instrument requirements, both of which have been formulated through a multi-year international effort involving hundreds of scientists worldwide

Multistep Ion Channel Remodeling and Lethal Arrhythmia Precede Heart Failure in a Mouse Model of Inherited Dilated Cardiomyopathy

Background: Patients with inherited dilated cardiomyopathy (DCM) frequently die with severe heart failure (HF) or die suddenly with arrhythmias, although these symptoms are not always observed at birth. It remains unclear how and when HF and arrhythmogenic changes develop in these DCM mutation carriers. In order to address this issue, properties of the myocardium and underlying gene expressions were studied using a knock-in mouse model of human inherited DCM caused by a deletion mutation DK210 in cardiac troponinT. Methodology/Principal Findings: By 1 month, DCM mice had already enlarged hearts, but showed no symptoms of HF and a much lower mortality than at 2 months or later. At around 2 months, some would die suddenly with no clear symptoms of HF, whereas at 3 months, many of the survivors showed evident symptoms of HF. In isolated left ventricular myocardium (LV) from 2 month-mice, spontaneous activity frequently occurred and action potential duration (APD) was prolonged. Transient outward (Ito) and ultrarapid delayed rectifier K + (IKur) currents were significantly reduced in DCM myocytes. Correspondingly, down-regulation of Kv4.2, Kv1.5 and KChIP2 was evident in mRNA and protein levels. In LVs at 3-months, more frequent spontaneous activity, greater prolongation of APD and further down-regulation in above K + channels were observed. At 1 month, in contrast, infrequent spontaneous activity and down-regulation of Kv4.2, but not Kv1.5 or KChIP2, were observed

Cardiosphere-Derived Cells Improve Function in the Infarcted Rat Heart for at Least 16 Weeks – an MRI Study

Aims Endogenous cardiac progenitor cells, expanded from explants via cardiosphere formation, present a promising cell source to prevent heart failure following myocardial infarction. Here we used cine-magnetic resonance imaging (MRI) to track administered cardiosphere-derived cells (CDCs) and to measure changes in cardiac function over four months in the infarcted rat heart. Methods and Results CDCs, cultured from neonatal rat heart, comprised a heterogeneous population including cells expressing the mesenchymal markers CD90 and CD105, the stem cell marker c-kit and the pluripotency markers Sox2, Oct3/4 and Klf-4. CDCs (2×106) expressing green fluorescent protein (GFP+) were labelled with fluorescent micron-sized particles of iron oxide (MPIO). Labelled cells were administered to the infarcted rat hearts (n = 7) by intramyocardial injection immediately following reperfusion, then by systemic infusion (4×106) 2 days later. A control group (n = 7) was administered cell medium. MR hypointensities caused by the MPIOs were detected at all times and GFP+ cells containing MPIO particles were identified in tissue slices at 16 weeks. At two days after infarction, cardiac function was similar between groups. By 6 weeks, ejection fractions in control hearts had significantly decreased (47±2%), but this was not evident in CDC-treated hearts (56±3%). The significantly higher ejection fractions in the CDC-treated group were maintained for a further 10 weeks. In addition, CDC-treated rat hearts had significantly increased capillary density in the peri-infarct region and lower infarct sizes. MPIO-labelled cells also expressed cardiac troponin I, von Willebrand factor and smooth muscle actin, suggesting their differentiation along the cardiomyocyte lineage and the formation of new blood vessels. Conclusions CDCs were retained in the infarcted rat heart for 16 weeks and improved cardiac function

Alternatively Activated Mononuclear Phagocytes from the Skin Site of Infection and the Impact of IL-4Rα Signalling on CD4+T Cell Survival in Draining Lymph Nodes after Repeated Exposure to Schistosoma mansoni Cercariae

In a murine model of repeated exposure of the skin to infective Schistosoma mansoni cercariae, events leading to the priming of CD4 cells in the skin draining lymph nodes were examined. The dermal exudate cell (DEC) population recovered from repeatedly (4x) exposed skin contained an influx of mononuclear phagocytes comprising three distinct populations according to their differential expression of F4/80 and MHC-II. As determined by gene expression analysis, all three DEC populations (F4/80-MHC-IIhigh, F4/80+MHC-IIhigh, F4/80+MHC-IIint) exhibited major up-regulation of genes associated with alternative activation. The gene encoding RELMα (hallmark of alternatively activated cells) was highly up-regulated in all three DEC populations. However, in 4x infected mice deficient in RELMα, there was no change in the extent of inflammation at the skin infection site compared to 4x infected wild-type cohorts, nor was there a difference in the abundance of different mononuclear phagocyte DEC populations. The absence of RELMα resulted in greater numbers of CD4+ cells in the skin draining lymph nodes (sdLN) of 4x infected mice, although they remained hypo-responsive. Using mice deficient for IL-4Rα, in which alternative activation is compromised, we show that after repeated schistosome infection, levels of regulatory IL-10 in the skin were reduced, accompanied by increased numbers of MHC-IIhigh cells and CD4+ T cells in the skin. There were also increased numbers of CD4+ T cells in the sdLN in the absence of IL-4Rα compared to cells from singly infected mice. Although their ability to proliferate was still compromised, increased cellularity of sdLN from 4x IL-4RαKO mice correlated with reduced expression of Fas/FasL, resulting in decreased apoptosis and cell death but increased numbers of viable CD4+ T cells. This study highlights a mechanism through which IL-4Rα may regulate the immune system through the induction of IL-10 and regulation of Fas/FasL mediated cell death