Interleukin (IL)–12 and IL-23 Are Key Cytokines for Immunity against Salmonella in Humans

Patients with inherited deficiency of the interleukin (IL)–12/IL-23–interferon (IFN)–g axis show increased susceptibility to invasive disease caused by the intramacrophage pathogens salmonellae and mycobacteria. We analyzed data on 154 patients with such deficiency. Significantly more patients with IL-12/IL-23–component deficiency had a history of salmonella disease than did those with IFN-g–component deficiency. Salmonella disease was typically severe, extraintestinal, and caused by nontyphoidal serovars. These findings strongly suggest that IL-12/IL-23 is a key cytokine for immunity against salmonella in humans and that IL-12/IL-23 mediates this protective effect partly through IFN-g–independent pathways. Investigation of the IL-12/IL-23–IFN-g axis should be considered in patients with invasive salmonella disease

Successful treatment of persistent postoperative air leaks following the placement of an endobronchial one-way valve

resection in pathological conditions of the lung involve a very large spectrum of available methods, from chest drainage and placement of Heimlich valves to surgical repair or pleural decortication. However, in some of these patients surgery may be contraindicated. This report describes an endobronchial approach to the control of marked and prolonged air leaks in four patients using a newly designed one-way airway valve (Pulmonx Corporation; Redwood City, Ca.USA) placed into the segmental bronchus that is the source of air leakage. As the device is a one-way inspiratory airway blocker, it can be used to control persistent air leaks while maintaining the drainage of mucus. This approach potentially provides an effective nonsurgical and minimally invasive alternative addition to the armamentarium of treatments for patients who suffer with persistent post-operative air leaks where other methods have failed or in frail patients who are categorised as a high surgical risk

A Task-based Support Architecture for Developing Point-of-care Clinical Decision Support Systems for the Emergency Department

Objectives: The purpose of this study was to create a task-based support architecture for developing clinical decision support systems (CDSSs) that assist physicians in making decisions at the point-of-care in the emergency department (ED). The backbone of the proposed architecture was established by a task-based emergency workflow model for a patient-physician encounter. Methods: The architecture was designed according to an agent-oriented paradigm. Specifically, we used the O-MaSE (Organization-based Multi-agent System Engineering) method that allows for iterative translation of functional requirements into architectural components (e.g., agents). The agent-oriented paradigm was extended with ontology-driven design to implement ontological models representing knowledge required by specific agents to operate. Results: The task-based architecture allows for the creation of a CDSS that is aligned with the task-based emergency workflow model. It facilitates decoupling of executable components (agents) from embedded domain knowledge (ontological models), thus supporting their interoperability, sharing, and reuse. The generic architecture was implemented as a pilot system, MET3-AE – a CDSS to help with the management of pediatric asthma exacerbation in the ED. The system was evaluated in a hospital ED. Conclusions: The architecture allows for the creation of a CDSS that integrates support for all tasks from the task-based emergency workflow model, and interacts with hospital information systems. Proposed architecture also allows for reusing and sharing system components and knowledge across disease-specific CDSSs

Design and synthesis of inhibitors of DC-sign mediated infections

DC-SIGN (Dendritic Cell-Specific ICAM-3 Grabbing Nonintegrin) is a C-type (Calcium dependent) lectin, expressed as homotetramers (presenting four copies of a Carbohydrate Recognition Domain (CRD) at the C-terminus) on the surface of immature Dendritic Cells. [1] Dendritic Cells (DCs) areone of the most important class of Antigen Presenting Cells (APCs). They recognize many pathogens through various receptors such as DC-SIGN. After recognition, the pathogen is internalized and DCs mature and migrate to lymph nodes.[2] Then, DCs relay the corresponding processing antigens as MHC complexes to naive T-cells, which differentiate allowing the appropriate immuno-reponse. Some of these pathogens, such as HIV, hijack this mechanism to infect the immune system: they are recognized by DCs but escape the processing pathway. Thus, they can remain “hidden” inside the dendritic cells for many days, being able to reach and infect their target T-cells. The main carbohydrate ligand recognized by DC-SIGN is the high mannose glycan (Man)9(GlcNAc)2 , also known as Man9, a branched oligosaccharide which is presented in multiple copies by several pathogen glycoproteins (gp120, GP1, …). Hence, multivalent mannose display should be an adequate strategy to interact with this lectin with high affinity. In vivo, mannosides are normally hydrolyzed by mannosidases: the use of a structural mimic in place of the natural sugar could avoid an easy degradation in a biological environment. The aim of this project is to design and prepare products that meet these requirements. So far we have demonstrated that the monovalent mimic 1 shown in Figure 1[3] interacts with DC-SIGN (using NMR) and inhibits the DC-SIGN mediated infection in a pseudo-typed Ebola virus model. Moreover, this molecule has been conjugated to a Boltorn-type, leading to neo-glycoconjugates that inhibit the binding of DC-SIGN to gp120 (envelope protein of HIV). In this communication we will report the synthesis of new monovalent inhibitors and the results of their binding assays by SPR. We will show also the synthesis of some multivalent compounds. Acknowledgments. This work was supported by Azioni Integrate Italia-Spagna (IT074ABCCM). [1] T. B. H. Geijtenbeek, , Y. van Kook, et al., Cell 2000, 100, 575-585. [2] Y. van Kooyk, T. B. H. Geijtenbeek, Nat. Rev. Immunol. 2003, 3, 697-709. [3] José J. Reina, Sara Sattin, Donatella Invernizzi, Silvia Mari, Lorena Martínez-Prats, Georges Tabarani, Franck Fieschi, Rafael Delgado, Pedro M. Nieto, Javier Rojo, Anna Bernardi, ChemMedChem , 2007, 2(7),1030-1036

OA011-03. Clusterin, a natural ligand of DC-SIGN present in human semen inhibits HIV capture and transmission by dendritic cells

International audiencen.

Coupling computer-interpretable guidelines with a drug-database through a web-based system – The PRESGUID project

BACKGROUND: Clinical Practice Guidelines (CPGs) available today are not extensively used due to lack of proper integration into clinical settings, knowledge-related information resources, and lack of decision support at the point of care in a particular clinical context. OBJECTIVE: The PRESGUID project (PREScription and GUIDelines) aims to improve the assistance provided by guidelines. The project proposes an online service enabling physicians to consult computerized CPGs linked to drug databases for easier integration into the healthcare process. METHODS: Computable CPGs are structured as decision trees and coded in XML format. Recommendations related to drug classes are tagged with ATC codes. We use a mapping module to enhance computerized guidelines coupling with a drug database, which contains detailed information about each usable specific medication. In this way, therapeutic recommendations are backed up with current and up-to-date information from the database. RESULTS: Two authoritative CPGs, originally diffused as static textual documents, have been implemented to validate the computerization process and to illustrate the usefulness of the resulting automated CPGs and their coupling with a drug database. We discuss the advantages of this approach for practitioners and the implications for both guideline developers and drug database providers. Other CPGs will be implemented and evaluated in real conditions by clinicians working in different health institutions

Deeply Virtual Compton Scattering off the neutron

The present experiment exploits the interference between the Deeply Virtual Compton Scattering (DVCS) and the Bethe-Heitler processes to extract the imaginary part of DVCS amplitudes on the neutron and on the deuteron from the helicity-dependent D$({\vec e},e'\gamma)X$ cross section measured at $Q^2$=1.9 GeV$^2$ and $x_B$=0.36. We extract a linear combination of generalized parton distributions (GPDs) particularly sensitive to $E_q$, the least constrained GPD. A model dependent constraint on the contribution of the up and down quarks to the nucleon spin is deduced.Comment: Published in Phys. Rev. Let

The E00-110 experiment in Jefferson Lab's Hall A: Deeply Virtual Compton Scattering off the Proton at 6 GeV

We present final results on the photon electroproduction ($\vec{e}p\rightarrow ep\gamma$) cross section in the deeply virtual Compton scattering (DVCS) regime and the valence quark region from Jefferson Lab experiment E00-110. Results from an analysis of a subset of these data were published before, but the analysis has been improved which is described here at length, together with details on the experimental setup. Furthermore, additional data have been analyzed resulting in photon electroproduction cross sections at new kinematic settings, for a total of 588 experimental bins. Results of the $Q^2$- and $x_B$-dependences of both the helicity-dependent and helicity-independent cross sections are discussed. The $Q^2$-dependence illustrates the dominance of the twist-2 handbag amplitude in the kinematics of the experiment, as previously noted. Thanks to the excellent accuracy of this high luminosity experiment, it becomes clear that the unpolarized cross section shows a significant deviation from the Bethe-Heitler process in our kinematics, compatible with a large contribution from the leading twist-2 DVCS$^2$ term to the photon electroproduction cross section. The necessity to include higher-twist corrections in order to fully reproduce the shape of the data is also discussed. The DVCS cross sections in this paper represent the final set of experimental results from E00-110, superseding the previous publication.Comment: 48 pages, 32 figure

Scaling Tests of the Cross Section for Deeply Virtual Compton Scattering

We present the first measurements of the \vec{e}p->epg cross section in the deeply virtual Compton scattering (DVCS) regime and the valence quark region. The Q^2 dependence (from 1.5 to 2.3 GeV^2) of the helicity-dependent cross section indicates the twist-2 dominance of DVCS, proving that generalized parton distributions (GPDs) are accessible to experiment at moderate Q^2. The helicity-independent cross section is also measured at Q^2=2.3 GeV^2. We present the first model-independent measurement of linear combinations of GPDs and GPD integrals up to the twist-3 approximation.Comment: 5 pages, 4 figures, 2 tables. Text shortened for publication. References added. One figure remove

Exclusive Neutral Pion Electroproduction in the Deeply Virtual Regime

We present measurements of the ep->ep pi^0 cross section extracted at two values of four-momentum transfer Q^2=1.9 GeV^2 and Q^2=2.3 GeV^2 at Jefferson Lab Hall A. The kinematic range allows to study the evolution of the extracted hadronic tensor as a function of Q^2 and W. Results will be confronted with Regge inspired calculations and GPD predictions. An intepretation of our data within the framework of semi-inclusive deep inelastic scattering has also been attempted