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Metastatic disease is the major cause of breast cancer–related death and despite many advances, current therapies are rarely curative. Tumor cell migration and invasion require actin cytoskeletal reorganization to endow cells with capacity to disseminate and initiate the formation of secondary tumors. However, it is still unclear how these migratory cells colonize distant tissues to form macrometastases. The E6-associated protein, E6AP, acts both as an E3 ubiquitin-protein ligase and as a coactivator of steroid hormone receptors. We report that E6AP suppresses breast cancer invasiveness, colonization, and metastasis in mice, and in breast cancer patients, loss of E6AP associates with poor prognosis, particularly for basal breast cancer. E6AP regulates actin cytoskeletal remodeling via regulation of Rho GTPases, acting as a negative regulator of ECT2, a GEF required for activation of Rho GTPases. E6AP promotes ubiquitination and proteasomal degradation of ECT2 for which high expression predicts poor prognosis in breast cancer patients. We conclude that E6AP suppresses breast cancer metastasis by regulating actin cytoskeleton remodeling through the control of ECT2 and Rho GTPase activity. These findings establish E6AP as a novel suppressor of metastasis and provide a compelling rationale for inhibition of ECT2 as a therapeutic approach for patients with metastatic breast cancer. Cancer Res; 76(14); 4236–48. ©2016 AACR.

The aim of this study is to estimate the relative displacement between the spindle nose and the clamping vice in a rotary transfer machine due to temperature variations. The study was focused on the relative displacements caused by temperature variations produced by two heat sources: the environment around the machine and the three-axis computer numerical control station during the duty cycle. Regarding the last point, an analytical model was developed, in order to account for different thermal sources inside the three-axis module (e.g., ball-screws, rolling bearings, and guideways friction heat, as well as heat generation in the motor). The complete numerical model was calibrated and successfully validated. A comparison was run between numerical results and experimental data in the framework of trials involving a newly developed transfer machine. Finally, the complete model, considering the combination of both the heat sources, has made it possible to estimate spindle nose-clamp relative displacement during a typical working day, highlighting that the radial displacement risks affecting seriously the accuracy of a workpiece.

Objectives Venipuncture is one of the most frequently performed painful procedures in children. The aim of this study was to investigate the effectiveness of 2 analgesic strategies for venipuncture in children in a specific setting like a blood-drawing center. Methods This was a prospective randomized controlled trial. It was conducted in the blood-drawing center of a tertiary level children's hospital in Italy, between November 2014 and February 2015. Eligible patients were children aged from 4 to 12 years referred to the blood-drawing center for venipuncture. Enrolled children were randomized to be distracted by Buzzy device or by playing with a handheld computer. The procedural pain was measured with the faces pain scale-revised by children aged from 4 to 7 years and with a numerical rating scale by children aged from 8 to 12 years. Results Two hundred children with a median age of 8 years were enrolled in the study. The self-reported procedural pain was not statistically different between the Buzzy group and the handheld computer group: median (interquartile range) = 3.0 (1.0-4.8) and 2.0 (1.0-4.8), respectively (P = 0.72). Children reported significant pain in 25% of cases with both distraction strategies. The procedural success rate at the first attempt was not significantly different in the 2 groups. Conclusions Analgesia provided by Buzzy or by a handheld computer was not significantly different in children undergoing venipuncture in a blood-drawing center, with the great proportion of them reporting no or mild pain during procedure.

PURPOSE: To evaluate the potential differences in non-target embolization and vessel microsphere filling of a reflux-control microcatheter (RCM) compared to a standard end-hole microcatheter (SEHM) in a swine model. MATERIALS AND METHODS: Radiopaque microspheres were injected with both RCM and SEHM (2.4-Fr and 2.7-Fr) in the kidneys of a preclinical swine model. Transarterial renal embolization procedures with RCM or SEHM were performed in both kidneys of 14 pigs. Renal arteries were selectively embolized with an automated injection protocol of radio-opaque microspheres. Ex-vivo X-ray microtomography images of the kidneys were utilized to evaluate the embolization by quantification of the deposition of injected microspheres in the target vs. the non-target area of injection. X-ray microtomography images were blindly analyzed by five interventional radiologists. The degree of vessel filling and the non-target embolization were quantified using a scale from 1 to 5 for each parameter. An analysis of variance was used to compare the paired scores. RESULTS: Total volumes of radio-opaque microspheres injected were similar for RCM (11.5±3.6 [SD] mL; range: 6-17mL) and SEHM (10.6±5.2 [SD] mL; range: 4-19mL) (P=0.38). The voxels enhanced ratio in the target (T) vs. non-target (NT) areas was greater with RCM (T=98.3% vs. NT=1.7%) than with SEHM (T=89% vs. NT=11%) but the difference was not significant (P=0.30). The total score blindly given by the five interventional radiologists was significantly different between RCM (12.3±2.1 [SD]; range: 6-15) and the standard catheter (11.3±2.5 [SD]; range: 4-15) (P=0.0073), with a significant decrease of non-target embolization for RCM (3.8±1.3 [SD]; range: 3.5-4.2) compared to SEHM (3.2±1.5 [SD]; range: 2.9-3.5) (P=0.014). CONCLUSION: In an animal model, RCM microcatheters reduce the risk of non-target embolization from 11% to 1.7%, increasing the delivery of microspheres of 98% to the target vessels, compared to SEHM microcatheters. ispartof: DIAGNOSTIC AND INTERVENTIONAL IMAGING vol:102 issue:10 pages:641-648 ispartof: location:France status: published

Les torsades de pointes correspondent à un type particulier de tachycardie ventriculaire, associée à un allongement de l’intervalle QT. C’est un événement indésirable grave, mettant en péril la vie du patient. Des facteurs, tels que l’hypokaliémie, la bradycardie et certains médicaments, amplifient le risque de survenue de TDP. Or, plus d’une centaine de molécules commercialisées en France sont concernées.Malgré une fréquence d’apparition de torsades de pointes iatrogènes a priori mineures, ces dernières sont la plupart du temps contre-indiquées et leur impact clinique potentiel reste majeur. L’étude des médicaments fréquemment impliqués et la mise en place d’outils pratiques peut permettre au pharmacien de proposer des alternatives adaptées, contribuant ainsi à la prévention de ce risque iatrogène.

Depuis plusieurs années, les associations de consommateurs lancent régulièrement des alertes concernant la présence d’ingrédients potentiellement nocifs dans les produits cosmétiques, ce qui pousse les consommateurs à se soucier de plus en plus de la composition de ces produits.Les particularités de la peau du nourrisson, qui le rendent plus vulnérable aux toxicités potentielles de ces ingrédients, entraînent une vigilance accrue de la part des parents, soucieux du bien-être de leur enfant.A travers une étude analytique de la composition de différents produits cosmétiques destinés aux nourrissons ainsi que des résultats obtenus par ces produits sur différentes applications qui analysent la composition des produits cosmétiques, cet ouvrage permet de mettre en lumière les différences considérables de notation entre les différentes applications, dues notamment à une différence sur les critères pris en compte dans cette notation.

Nanodispersions of pristine single-wall carbon nanohorns (i.e., p-SWCNHs) and oxidized-SWCNHs (i.e.; o-SWCNHs) were used to modify screen printed electrode (SPE). p-SWCNHs and o-SWCNHs were fully characterized by using several analytical techniques, as: HR-TEM (High Resolution-Transmission Electron Microscopy), FE-SEM/EDX (Field Emission-Scanning Electron Microscopy/Energy Dispersive X-ray Analysis), Raman spectroscopy, thermogravimetric analysis, differential thermal analysis (DTA), and the Brunauer-Emmett-Teller (BET) method. The chemically modified SPEs were also characterized with Cyclic Voltammetry (CV), using several different electro-active targets. In all cases, p-SWCNHs showed better performances than those obtained for o-SWCNHs as well as with respect to conventional Glassy Carbon (GC) electrodes, in terms of peak currents, significant shift at lower redox-potential ranges and enhanced heterogeneous apparent kinetic constants.

In this study, we discuss the portfolio, also known as learning folder. It exist several types among different supports. Its principal objective is to trace the learnings and the students’ progress by the successive addition of their production in one or more disciplines. In this research waged in PE on 3rd grade students, we measure the impact that can have the presentation portfolio and the assessment portfolio on the learnings. Regarding on the results achieved, we can admit the students who keep a portfolio have a better awareness of progress achieved in PE. But, it is the students who profit of an assessment portfolio who have a progress rate superior to them who keep a presentation portfolio and well superior to them who don’t keep it. With the assessment portfolio, the student may therefore become aware of his progress and better integrate the criteria which make him succeed.; Nous traitons dans cet écrit du portfolio, également appelé dossier d’apprentissage. Il en existe plusieurs types selon différents supports. Il a pour objectif principal de retracer les apprentissages et les progressions des élèves par l’ajout successif de leurs productions dans une ou plusieurs disciplines. Dans cette recherche menée en EPS sur des élèves de 3e, nous mesurons l’impact que peuvent avoir le portfolio de présentation et le portfolio d’évaluation sur les apprentissages. Au regard des résultats obtenus, nous pouvons admettre que les élèves disposant d’un portfolio ont une meilleure conscience des progrès réalisés en EPS. Mais ce sont les élèves bénéficiant d’un portfolio d’évaluation qui ont un taux de progression supérieur à ceux disposant d’un portfolio de présentation et bien supérieur à ceux n’en disposant pas. Avec le portfolio d’évaluation, l’élève prend donc conscience de ses progrès et intègre mieux les critères lui permettant d’être en réussite.

Intracellular serpins are proposed to inactivate proteases released from lysosome-related organelles into the host cell interior, preventing cell death. Serpinb9 opposes the immune cytotoxic protease, granzyme B, and in a number of settings protects cells against granzyme B-mediated cell death. Using a knockout mouse line engineered to express green fluorescent protein under the serpbinb9 promoter, we demonstrate that serpinb9 is vital for host survival during Ectromelia virus infection by maintaining both mature natural killer NK) cells, and activated CD8+ T cells. Serpinb9 expression parallels granzyme B expression within both populations during infection. Maturing serpinb9-null NK cells exhibit higher levels of granzyme B-mediated apoptosis during infection; hence there are fewer mature NK cells, and these cells also have lower cytotoxic potential. Thus the serpinb9-granzyme B axis is important for homeostasis of both major cytotoxic effector cell populations.

Serpinb9 (Sb9, also called Spi6) is an intracellular inhibitor of granzyme B (grB) that protects cytotoxic lymphocytes from grB-mediated death. In addition, Sb9 is also expressed in accessory immune cells, including dendritic cells (DCs), although its role is debated. Recently, we have demonstrated that Sb9 plays a grB-independent role in cross-presentation of antigens by CD8+ DCs. Here, using a mouse line expressing green fluorescent protein knocked in under the control of the Sb9 promoter, we demonstrate that Sb9 expression is highest in those tissue-resident and migratory DC subsets capable of cross-presentation. Further, we show that CD8+ DCs can be divided into two subsets based on Sb9 expression, and that only the subset expressing higher levels of Sb9 is capable of cross-presentation. These findings add support for role for Sb9 cross-presentation, and indicate that high Sb9 expression is a novel marker of cross-presentation capable DCs.

The dynamic in vivo profiling of lactate is of uppermost importance in both neuroenergetics and neuroprotection fields, considering its central suspected role as a metabolic and signaling molecule. For this purpose, we implemented proton magnetic resonance spectroscopy (1H-MRS) directly on brain microdialysate to monitor online the fluctuation of lactate contents during neuronal stimulation. Brain activation was obtained by right whisker stimulation of rats, which leads to the activation of the left barrel cortex area in which the microdialysis probe was implanted. The experimental protocol relies on the use of dedicated and sensitive home-made NMR microcoil able to perform lactate NMR profiling at submillimolar concentration. The MRS measurements of extracellular lactate concentration were performed inside a pre-clinical MRI scanner allowing simultaneous visualization of the correct location of the microprobe by MRI and detection of metabolites contained in the microdialysis by MRS. A 40% increase in lactate concentration was measured during whisker stimulation in the corresponding barrel cortex. This combination of microdialysis with online MRS/MRI provides a new approach to follow in vivo lactate fluctuations, and can be further implemented in physio-pathological conditions to get new insights on the role of lactate in brain metabolism and signaling.

The work aimed at developing a novel MRI-based theranostic protocol for improving the anticancer efficacy of a Doxil-like liposomal formulation. The goal was achieved stimulating the intratumor release of the drug from the nanocarrier and favoring its diffusion in the lesion by the sequential application of low-intensity pulsed ultrasound. The protocol was tested on mice bearing a syngeneic breast cancer model. The combination of acoustic waves with different characteristics allowed for: i) the release of the drug and the co-encapsulated MRI agent (Gadoteridol) from the liposomes in the vessels of the tumor region, and ii) the extravasation of the released material, as well as intact liposomes, in the tumor stroma. The MR-T1 contrast enhancement measured in the tumor reported on the delivery and US-triggered release of Doxorubicin. The developed protocol resulted in a marked increase in the intratumor drug concentration that, in turn, led to the complete regression of the lesion. The protocol has a good clinical translatability because all the components of the theranostic agent (Doxorubicin, liposomes, Gadoteridol) are approved for human use.

International audience; The dynamic in vivo profiling of lactate is of uppermost importance in both neuroenergetics and neuroprotection fields, considering its central suspected role as a metabolic and signaling molecule. For this purpose, we implemented proton magnetic resonance spectroscopy (1 H-MRS) directly on brain microdialysate to monitor online the fluctuation of lactate contents during neuronal stimulation. Brain activation was obtained by right whisker stimulation of rats, which leads to the activation of the left barrel cortex area in which the microdialysis probe was implanted. The experimental protocol relies on the use of dedicated and sensitive home-made NMR microcoil able to perform lactate NMR profiling at submillimolar concentration. The MRS measurements of extracellular lactate concentration were performed inside a pre-clinical MRI scanner allowing simultaneous visualization of the correct location of the microprobe by MRI and detection of metabolites contained in the microdialysis by MRS. A 40% increase in lactate concentration was measured during whisker stimulation in the corresponding barrel cortex. This combination of microdialysis with online MRS/MRI provides a new approach to follow in vivo lactate fluctuations, and can be further implemented in physio-pathological conditions to get new insights on the role of lactate in brain metabolism and signaling.

Liver in vitro systems that allow reliable prediction of major human in vivo metabolic pathways have a significant impact in drug screening and drug metabolism research. In the present study, a novel porous scaffold composed of alginate was prepared by employing a gas-in-liquid foaming approach. Galactose residues were introduced on scaffold surfaces to promote cell adhesion and to enhance liver specific functions of the entrapped HepG2/C3A cells. Hepatoma cells in the gal-alginate scaffold showed higher levels of liver specific products (albumin and urea) and were more responsive to specific inducers (e.g. dexamethasone) and inhibitors (e.g. ketoconazole) of the CYP3A4 system than in conventional monolayer culture. HepG2/C3A cells were also more efficient in terms of rapid elimination of testosterone, used as a model substance, at rates comparable to those of in vivo excretion. In addition, an improvement in metabolism of testosterone, in terms of phase II metabolite formation, was also observed when the more differentiated HepaRG cells were used. Together the data suggest that hepatocyte/gas templated alginate-systems provide an innovative high throughput platform for in vitro drug metabolism and drug-drug interaction studies, with broad fields of application, and might provide a valid tool for minimizing animal use in preclinical testing of human relevance.

Barbed sutures have unidirectional circumferential shallow barbs, which distribute tension throughout the wound and close wound securely without the need to tie knots.We compare two different methods of wound closure in elective plastic surgical cases: barbed 3/0 V-Loc™180 suture and smooth 3/0 Maxon™ sutures, both polyglyconate monofilament synthetic absorbable sutures. We assessed the aesthetic long-term results with a minimum two year follow up.This is a prospective, randomized controlled study with internal control. A single surgeon performed all cases. Patients who underwent elective operations that involved long wound closure were enrolled in the study. Each patient acted as their own internal control with half their wound being sutured with 3/0 V-Loc™180 barbed suture and the other half with smooth 3/0 Maxon™ deep dermal sutures and then a subcuticular skin closure. In both groups, the superficial fascial system was closed with 1 Vicryl interrupted sutures on both sides. Long-term cosmesis was evaluated using the modified Hollander cosmesis score by review of standardized postoperative photographs by 9 blinded plastic surgeons and specialist registrars.The study reports on 33 female patients. The time taken for wound closure was significantly reduced using the barbed suture (p 0.001). There was no difference in the complication ratio in either group. Two-year aesthetic outcome was significantly superior when using the barbed suture (p = 0.0075).Barbed sutures closure of long wounds is faster and produces a better long-term aesthetic outcome than smooth sutures.

The development of new non-invasive diagnostic and therapeutic approaches is of paramount importance in order to improve the outcome of patients with glioblastoma (GBM). In this work we investigated a completely non-invasive pre-clinical protocol to effectively target and detect brain tumors through the orotracheal route, using ultra-small nanoparticles (USRPs) and MRI. A mouse model of GBM was developed. In vivo MRI acquisitions were performed before and after intravenous or orotracheal administration of the nanoparticles to identify and segment the tumor. The accumulation of the nanoparticles in neoplastic lesions was assessed ex vivo through fluorescence microscopy. Before the administration of contrast agents, MR images allowed the identification of the presence of abnormal brain tissue in 73% of animals. After orotracheal or intravenous administration of USRPs, in all the mice an excellent co-localization of the position of the tumor with MRI and histology was observed. The elimination time of the USRPs from the tumor after the orotracheal administration was approximately 70% longer compared with intravenous injection. MRI and USRPs were shown to be powerful imaging tools able to detect, quantify and longitudinally monitor the development of GBMs. The absence of ionizing radiation and high resolution of MRI, along with the complete non-invasiveness and good reproducibility of the proposed protocol, make this technique potentially translatable to humans. To our knowledge, this is the first time that the advantages of a needle-free orotracheal administration route have been demonstrated for the investigation of the pathomorphological changes due to GBMs.

This paper presents a Multi-satellite Data Analysis and Simulator Tool (MDAST), developed with the original goal to support the science requirements of a Martian 3-Unit CubeSat mission profile named Bleeping Interplanetary Radiation Determination Yo-yo (BIRDY). MDAST was firstly designed and tested by taking into account the positions, attitudes, instruments field of view and energetic particles flux measurements from four spacecrafts (ACE, MSL, STEREO A, and STEREO B). Secondly, the simulated positions, attitudes and instrument field of view from the BIRDY CubeSat have been adapted for input. And finally, this tool can be used for data analysis of the measurements from the four spacecrafts mentioned above so as to simulate the instrument trajectory and observation capabilities of the BIRDY CubeSat. The onset, peak and end time of a solar particle event is specifically defined and identified with this tool. It is not only useful for the BIRDY mission but also for analyzing data from the four satellites aforementioned and can be utilized for other space weather missions with further customization.

The accurate characterization and description of the vascular network of a cancer lesion is of paramount importance in clinical practice and cancer research in order to improve diagnostic accuracy or to assess the effectiveness of a treatment. The aim of this study was to show the effectiveness of liposomes as an ultrasound contrast agent to describe the 3-D vascular architecture of a tumor. Eight C57BL/6 mice grafted with syngeneic B16-F10 murine melanoma cells were injected with a bolus of 1,2-Distearoyl-sn-glycero-3-phosphocoline (DSPC)-based non-targeted liposomes and with a bolus of microbubbles. 3-D contrast-enhanced images of the tumor lesions were acquired in three conditions: pre-contrast, after the injection of microbubbles, and after the injection of liposomes. By using a previously developed reconstruction and characterization image processing technique, we obtained the 3-D representation of the vascular architecture in these three conditions. Six descriptive parameters of these networks were also computed: the number of vascular trees (NT), the vascular density (VD), the number of branches, the 2-D curvature measure, the number of vascular flexes of the vessels, and the 3-D curvature. Results showed that all the vascular descriptors obtained by liposome-based images were statistically equal to those obtained by using microbubbles, except the VD which was found to be lower for liposome images. All the six descriptors computed in pre-contrast conditions had values that were statistically lower than those computed in presence of contrast, both for liposomes and microbubbles. Liposomes have already been used in cancer therapy for the selective ultrasound-mediated delivery of drugs. This work demonstrated their effectiveness also as vascular diagnostic contrast agents, therefore proving that liposomes can be used as efficient “theranostic” ( i.e. therapeutic + diagnostic) ultrasound probes.

Aim Needle-related procedures can be painful for children, and distraction provides ideal pain relief in blood-drawing centres. This study assessed the effectiveness of playing a computer game during venipuncture, compared with low-tech distraction by a nurse. Methods We conducted this prospective, randomised controlled trial at the blood-drawing centre of a tertiary-level children's hospital in Italy. Half of the 200 children played Angry Birds on a hand-held computer while the other half were distracted by a second, specifically trained nurse who sang to them, read a book, blew bubbles or played with puppets. Pain was measured using a faces pain scale for children aged 4–7 years and a numeric scale for children aged 8–13 years. Results The 200 children had a median age of eight years. Children reported significant pain in 16 cases (16%) in the hand-held computer distraction group and in 15 cases (15%) in the nurse-led low-tech distraction group (p = 0.85). The procedural success rate at the first attempt was not different in the two groups. Conclusion Playing a game on a hand-held computer meant that only one in six children reported pain during venipuncture, but it was not superior to being distracted by nurses.

[This article][1] ([1][2]) has been retracted at the request of the editors. Following an institutional review by Peter MacCallum Cancer Center (Victoria, Australia), the primary affiliation for several of the authors, it was not possible to confidently identify and assign the primary datasets to

SummaryA case of onychomycosis caused by Trichosporon mucoides in a man with diabetes is presented. The infection was characterized by a brown–black pigmentation of the nail plates and subungual hyperkeratosis of the first three toes of both feet. Onychogryphosis was also visible on the third left toe. Direct microscopic examinations revealed wide and septate hyphae and spores. Three cultures on Sabouraud–gentamicin–chloramphenicol 2 agar and chromID Candida agar produced white, creamy, and smooth colonies that were judged to be morphologically typical of T. mucoides. Microscopic examinations of the colonies showed arthroconidia and blastoconidia. The urease test was positive. A sugar assimilation test on yeast nitrogen base agar showed assimilation of galactitol, sorbitol, and arabinitol. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) confirmed the diagnosis of T. mucoides infection. The patient was treated with topical urea and oral itraconazole. Three months later, a mild improvement was observed. The patient was subsequently lost to follow-up.

Benign symmetrical lipomatosis (Madelung's disease) is a rare condition of unclear aetiology characterized by numerous, unencapsulated lipomatous deposits. The only effective treatment is by surgical intervention; however, there is no consensus in the optimal approach. We present the case of a patient who required staged, multi-modality treatment to achieve disease quiescence. The case highlights the usefulness of magnetic resonance imaging as a tool for assessment as well as preoperative planning.

Despite the increasing attention to university-industry technology transfer, limited emphasis has been posed on how the university offices in charge of this task organize themselves to grow. University Technology Transfer Offices (UTTOs) can grow internally, e.g. expanding their staff, or externally, e.g. pooling resources among different UTTOs creating new organizational structures. In this paper we study the latter. Exploiting the opportunity of a specific technology transfer policy introduced in Italy, we develop six in-depth case-studies, encompassing twenty UTTOs. We identify three organizational structures that are adopted by UTTOs to achieve external growth. In discussing antecedents, advantages and disadvantages of each organizational structure, we derive implications for UTTOs' managers and policy makers.

PURPOSE:This study is aimed at demonstrating the in vivo potential of Gd(III)-loaded glucan particles (Gd-GPs) as magnetic resonance imaging (MRI)-positive agents for labeling and tracking phagocytic cells. PROCEDURE:GPs were obtained from Saccharomyces cerevisae and loaded with the water-insoluble complex Gd-DOTAMA(C18)2. The uptake kinetics of Gd-GPs by murine macrophages was studied in vitro and the internalization mechanism was assessed by competition assays. The in vivo performance of Gd-GPs was tested at 7.05T on a mouse model of acute liver inflammation. RESULTS:The minimum number of Gd-GPs-labeled J774.A1 macrophages detected in vitro by MRI was ca. 300 cells/μl of agar, which is the lowest number ever reported for cells labeled with a positive T1 agent. Intravenous injection of macrophages labeled with Gd-GPs in a mouse model of liver inflammation enabled the MRI visualization of the cellular infiltration in the diseased area. CONCLUSIONS:Gd-GPs represent a promising platform for tracking macrophages by MRI as a T1 alternative to the golden standard T2-based iron oxide particles.

Food has always been a significant part of travel and tourism, and in recent years there has been a rise of awareness and interest in healthy food and nutrition and its connection to well-being. Implementation of healthy nutrition into health tourism is the object of research in this paper. The rise of the healthy food trends is accompanied by a rise of accessible information quantity, however this also including information of bad quality. But nonetheless, today’s tourist is very well informed about impacts of nutrition on health, and has specific needs and desires. A tourism product provider needs to be able to meet these needs and even exceed the tourists’ expectations, and therefore must be very well informed as well., Hrana je uvijek bila značajan dio turizma, a tijekom posljednjih godina je došlo do porasta interesa za zdravu hranu i prehranu i svijesti o povezanosti istih sa zdravljem čovjeka. Implementacija zdrave hrane u zdravstveni turizam je predmet istraživanja ovog rada. Porast trendova zdrave hrane je popraćeno rastom količine pristupačnih informacija, međutim to uključuje i informacije loše kvalitete. Bez obzira na to, današnji turist je vrlo dobro informiran o utjecaju prehrane na zdravlje, i ima specifične želje i potrebe. Pružatelj turističkog proizvoda mora biti sposoban zadovoljiti te želje i čak nadmašiti očekivanja turista, stoga mora također biti vrlo dobro informiran.

International audience

International audience; In order to study metabolic processes in animal models of diseases and in patients, microdialysis probes have evolved as powerful tools that are minimally invasive. However, analyses of microdialysate, performed remotely, do not provide real-time monitoring of microdialysate composition. Microdialysate solutions can theoretically be analyzed online inside a preclicinal or clinical MRI scanner using MRS techniques. Due to low NMR sensitivity, acquisitions of real-time NMR spectra on very small solution volumes (μL) with low metabolite concentrations (mM range) represent a major issue. To address this challenge we introduce the approach of combining a microdialysis probe with a custom-built magnetic resonance microprobe that allows for online metabolic analysis (1 H and 13 C) with high sensitivity under continuous flow conditions. This system is mounted inside an MRI scanner and allows performing simultaneously MRI experiments and rapid MRS metabolic analysis of the microdialysate. The feasibility of this approach is demonstrated by analyzing extracellular brain cancer cells (glioma) in vitro and brain metabolites in an animal model in vivo. We expect that our approach is readily translatable into clinical settings and can be used for a better and precise understanding of diseases linked to metabolic dysfunction.

Two novel Gd-based contrast agents (CAs) for the molecular imaging of matrix metalloproteinases (MMPs) were synthetized and characterized in vitro and in vivo. These probes were based on the PLG*LWAR peptide sequence, known to be hydrolyzed between Gly and Leu by a broad panel of MMPs. A Gd–DOTA chelate was conjugated to the N-terminal position through an amide bond, either directly to proline (compd Gd–K11) or through a hydrophilic spacer (compd Gd–K11N). Both CA were made strongly amphiphilic by conjugating an alkyl chain at the C-terminus of the peptide sequence. Gd–K11 and Gd–K11N have a good affinity for β-cyclodextrins (KD 310 and 670 µ m respectively) and for serum albumin (KD 350 and 90 µ m respectively), and can be efficiently cleaved in vitro at the expected site by MMP-2 and MMP-12. Upon MMP-dependent cleavage, the CAs lose the C-terminal tetrapeptide and the alkyl chain, thus undergoing to an amphiphilic-to-hydrophilic transformation that is expected to alter tissue pharmacokinetics. To prove this, Gd–K11 was systemically administered to mice bearing a subcutaneous B16.F10 melanoma, either pre-treated or not with the broad spectrum MMP inhibitor GM6001 (Ilomastat). The washout of the Gd-contrast enhancement in MR images was significantly faster for untreated subjects (displaying MMP activity) with respect to treated ones (MMP activity inhibited). The washout kinetics of Gd-contrast enhancement from the tumor microenvironment could be then interpreted in terms of the local activity of MMPs. Copyright © 2012 John Wiley & Sons, Ltd.

Age-related thymic involution causes a decreased output of thymocytes from the thymus, thereby resulting in impairment of T cell-mediated immunity. While alterations in the T cell and non-haematopoietic stromal compartments have been described, the effects of thymic involution on thymic dendritic cells (DC) are not clearly known. Thymic DC play an essential role in shaping T cell-mediated immune responses by deleting self-reactive thymocytes to establish central tolerance and by inducing regulatory T-cell (Treg) development. It is therefore important to assess the prevalence of and alterations to thymic DC with age, as this may impact on their function. We assessed the numbers and proportions of the three distinct subsets of thymic DC in ageing mice, and showed that these subsets are differentially regulated. This is expected as thymic DC subsets have different origins of development. We further assessed the responses of thymic DC in a regenerative environment, such as that induced by sex-steroid ablation (SSA), and clearly showed that, consistent with global thymus regrowth, all three DC populations increased in numbers and regained their relative proportions to thymocytes after an initial lag period. These findings are important for the clinical translation of thymic regenerative approaches, and indicate that SSA facilitates the maintenance of critical processes such as negative selection and Treg induction through promoting thymic DC regeneration.

Meningococcal disease is particularly severe. The case-fatality rate is 7.78% in Europe and 10–14% in the USA. This paper reports the results of a sero-epidemiological study in Italy on meningitis due to Meningococcus C before the introduction of the monovalent conjugate vaccine. In 2003–2004, a total of 577 sera were collected in 17 of the 20 Italian Regions. Serum Bactericidal Assay (SBA) was performed by using rabbit complement serum according to standardized SBA. The results showed that the percentages of protected subjects decreased from 6 to 12 months of age, increased from 1 to 4 years, decreased again until the age of 8 years and from 13 to 16 years, and were particularly high in 9- and 17-year-old subjects. The geometric mean titre of bactericidal antibodies (SBAbs GMT) was low in subjects under 1 year of age, significantly increased in 1–9-year-old children and decreased in adolescents and young adults. Finally, in each one-year age-group, low levels of antibodies were observed in subjects under 1 year of age, in 10-year-old subjects and in 14–16-year-old adolescents. High titres were observed in 3-, 8-, 9- and 17-year-old subjects. Our results therefore indicate that meningococcus C has the highest probability of spreading among 1–4, 8–10 and 14–17-year-old subjects in Italy.

Central tolerance is established through negative selection of self-reactive thymocytes and the induction of T-regulatory cells (TRs). The role of thymic dendritic cells (TDCs) in these processes has not been clearly determined. In this study, we demonstrate thatin vivo, TDCs not only play a role in negative selection but in the induction of TRs. TDCs include two conventional dendritic cell (DC) subtypes, CD8loSirpαhi/+(CD8loSirpα+) and CD8hiSirpαlo/−(CD8loSirpα−), which have different origins. We found that the CD8hiSirpα+DCs represent a conventional DC subset that originates from the blood and migrates into the thymus. Moreover, we show that the CD8loSirpα+DCs demonstrate a superior capacity to induce TRsin vitro. Finally, using a thymic transplantation system, we demonstrate that the DCs in the periphery can migrate into the thymus, where they efficiently induce TRgeneration and negative selection.

A novel dendritic cell (DC)–restricted molecule, Clec9A, was identified by gene expression profiling of mouse DC subtypes. Based on sequence similarity, a human ortholog was identified. Clec9A encodes a type II membrane protein with a single extracellular C-type lectin domain. Both the mouse Clec9A and human CLEC9A were cloned and expressed, and monoclonal antibodies (mAbs) against each were generated. Surface staining revealed that Clec9A was selective for mouse DCs and was restricted to the CD8+ conventional DC and plasmacytoid DC subtypes. A subset of human blood DCs also expressed CLEC9A. A single injection of mice with a mAb against Clec9A, which targets antigens (Ags) to the DCs, produced a striking enhancement of antibody responses in the absence of added adjuvants or danger signals, even in mice lacking Toll-like receptor signaling pathways. Such targeting also enhanced CD4 and CD8 T-cell responses. Thus, Clec9A serves as a new marker to distinguish subtypes of both mouse and human DCs. Furthermore, targeting Ags to DCs with antibodies to Clec9A is a promising strategy to enhance the efficiency of vaccines, even in the absence of adjuvants.

A system for orbital object monitoring is analyzed, based on a mid-latitude and an equatorial observatory. The enhancements with respect to the use of a single telescope located at mid-latitude, for space debris detection and tracking are highlighted in terms of surveying volume, object identification, and orbital determination accuracy. The need to improve observation capabilities in monitoring and cataloguing such kinds of objects is constantly growing, due to the constant increase of operative satellites and space debris in both geostationary Earth orbit (GEO) and low Earth orbit (LEO) regions. After the considerations on the feasibility of the whole system, an overview of the observatories’ design is sketched, on the basis of previous Italian experience in space debris observation, and taking into account constraints imposed by the instrumentation. In particular the main characteristics of components, software for image analysis and observation methodologies are analyzed and a possible configuration is given, based on the ALMASCOPE observatory realized by the Space Robotics Group at the University of Bologna. This observatory was used for the 2010 test campaign carried out from the Broglio Space Center in Kenya.