A major population of mucosal memory CD4⁺ T cells, coexpressing IL-18Rα and DR3, display innate lymphocyte functionality

Mucosal tissues contain large numbers of memory CD4(+) T cells that, through T-cell receptor-dependent interactions with antigen-presenting cells, are believed to have a key role in barrier defense and maintenance of tissue integrity. Here we identify a major subset of memory CD4(+) T cells at barrier surfaces that coexpress interleukin-18 receptor alpha (IL-18Rα) and death receptor-3 (DR3), and display innate lymphocyte functionality. The cytokines IL-15 or the DR3 ligand tumor necrosis factor (TNF)-like cytokine 1A (TL1a) induced memory IL-18Rα(+)DR3(+)CD4(+) T cells to produce interferon-γ, TNF-α, IL-6, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-22 in the presence of IL-12/IL-18. TL1a synergized with IL-15 to enhance this response, while suppressing IL-15-induced IL-10 production. TL1a- and IL-15-mediated cytokine induction required the presence of IL-18, whereas induction of IL-5, IL-13, GM-CSF, and IL-22 was IL-12 independent. IL-18Rα(+)DR3(+)CD4(+) T cells with similar functionality were present in human skin, nasal polyps, and, in particular, the intestine, where in chronic inflammation they localized with IL-18-producing cells in lymphoid aggregates. Collectively, these results suggest that human memory IL-18Rα(+)DR3(+) CD4(+) T cells may contribute to antigen-independent innate responses at barrier surfaces.Mucosal Immunology advance online publication, 1 October 2014; doi:10.1038/mi.2014.87

Lymphocyte and monocyte flow cytometry immunophenotyping as a diagnostic tool in uncharacteristic inflammatory disorders

<p>Abstract</p> <p>Background</p> <p>Patients with uncharacteristic inflammatory symptoms such as long-standing fatigue or pain, or a prolonged fever, constitute a diagnostic and therapeutic challenge. The aim of the present study was to determine if an extended immunophenotyping of lymphocytes and monocytes including activation markers can define disease-specific patterns, and thus provide valuable diagnostic information for these patients.</p> <p>Methods</p> <p>Whole blood from patients with gram-negative bacteraemia, neuroborreliosis, tuberculosis, acute mononucleosis, influenza or a mixed connective tissue disorders, as diagnosed by routine culture and serology techniques was analysed for lymphocyte and monocyte cell surface markers using a no-wash, no-lyse protocol for multi-colour flow cytometry method. The immunophenotyping included the activation markers HLA-DR and CD40. Plasma levels of soluble TNF alpha receptors were analysed by ELISA.</p> <p>Results</p> <p>An informative pattern was obtained by combining two of the analysed parameters: (i), the fractions of HLA-DR-expressing CD4+ T cells and CD8+ T cells, respectively, and (ii), the level of CD40 on CD14+ CD16- monocytes. Patients infected with gram-negative bacteria or EBV showed a marked increase in monocyte CD40, while this effect was less pronounced for tuberculosis, borrelia and influenza. The bacterial agents could be distinguished from the viral agents by the T cell result; CD4+ T cells reacting in bacterial infection, and the CD8+ T cells dominating for the viruses. Patients with mixed connective tissue disorders also showed increased activation, but with similar engagement of CD4+ and CD8+ T cells. Analysis of soluble TNF alpha receptors was less informative due to a large inter-individual variation.</p> <p>Conclusion</p> <p>Immunophenotyping including the combination of the fractions of HLA-DR expressing T cell subpopulations with the level of CD40 on monocytes produces an informative pattern, differentiating between infections of bacterial and viral origin. Furthermore, a quantitative analysis of these parameters revealed the novel finding of characteristic patterns indicating a subacute bacterial infection, such as borreliosis or tuberculosis, or a mixed connective tissue disorder. The employed flow cytometric method is suitable for clinical diagnostic laboratories, and may help in the assessment of patients with uncharacteristic inflammatory symptoms.</p

Restricted Isometries for Partial Random Circulant Matrices

In the theory of compressed sensing, restricted isometry analysis has become a standard tool for studying how efficiently a measurement matrix acquires information about sparse and compressible signals. Many recovery algorithms are known to succeed when the restricted isometry constants of the sampling matrix are small. Many potential applications of compressed sensing involve a data-acquisition process that proceeds by convolution with a random pulse followed by (nonrandom) subsampling. At present, the theoretical analysis of this measurement technique is lacking. This paper demonstrates that the $s$th order restricted isometry constant is small when the number $m$ of samples satisfies $m \gtrsim (s \log n)^{3/2}$, where $n$ is the length of the pulse. This bound improves on previous estimates, which exhibit quadratic scaling

How to optimise drug study design: pharmacokinetics and pharmacodynamics studies introduced to paediatricians

OBJECTIVES: In children, there is often lack of sufficient information concerning the pharmacokinetics (PK) and pharmacodynamics (PD) of a study drug to support dose selection and effective evaluation of efficacy in a randomised clinical trial (RCT). Therefore, one should consider the relevance of relatively small PKPD studies, which can provide the appropriate data to optimise the design of an RCT. METHODS: Based on the experience of experts collaborating in the EU-funded Global Research in Paediatrics consortium, we aimed to inform clinician-scientists working with children on the design of investigator-initiated PKPD studies. KEY FINDINGS: The importance of the identification of an optimal dose for the paediatric population is explained, followed by the differences and similarities of dose-ranging and efficacy studies. The input of clinical pharmacologists with modelling expertise is essential for an efficient dose-finding study. CONCLUSIONS: The emergence of new laboratory techniques and statistical tools allows for the collection and analysis of sparse and unbalanced data, enabling the implementation of (observational) PKPD studies in the paediatric clinic. Understanding of the principles and methods discussed in this study is essential to improve the quality of paediatric PKPD investigations, and to prevent the conduct of paediatric RCTs that fail because of inadequate dosing

The person-centred approach to an ageing society

Modern care is often based on investigations such as laboratory markers and imaging - for example, X-ray or ultrasound. The results contribute to a diagnosis and, if judged necessary, treatment is initiated. This diseased-oriented approach is the prevailing mode of management in modern medicine. In contrast, person-centered care (PCC) takes the point of departure from each person\ub4s subjective experience of illness and its impact on daily life. A patient is considered as a person with emotions and feelings. PCC is considered present within clinical care according to a definition articulated by the Centre for Person Centred Care at the University of Gothenburg (GPCC) when three core components are present: elicitation of a detailed patient narrative; formulated partnership between caregiver and patient and documentation of the partnership in the patient record. Accordingly, when there is an illness requiring care and the person is attended using these components, PCC is being applied. In most situations today, PCC is not applied in terms of the narrative and is not fully elicited or the partnership and/or the documentation are not included. It is proposed that the challenge to Society arising from changing demographics can be addressed by implementing PCC and creating an alternative to existing healthcare. The importance and benefits of such an approach on a wider scale is not yet clear as research has been limited to date. Studies in selected patient populations (heart failure and hip fractures), however, have shown promising results. As the population ages, there will be a dramatic increase in healthcare consumption. Even with technological developments, there will be a need for tremendous resources to be dedicated to care. A new organization and attitude from healthcare policymakers and providers above and beyond the present model appears required in order to respond to this demand. As part of such change, person-centred care, with the interaction between healthcare providers and the person of the patient, can facilitate, compensate and develop more effective healthcare services for the future

Plant-Derived Polysaccharide Supplements Inhibit Dextran Sulfate Sodium-Induced Colitis in the Rat

Several plant-derived polysaccharides have been shown to have anti-inflammatory activity in animal models. Ambrotose complex and Advanced Ambrotose are dietary supplements that include aloe vera gel, arabinogalactan, fucoidan, and rice starch, all of which have shown such activity. This study was designed to evaluate these formulations against dextran sulfate sodium (DSS)-induced colitis in rats and to confirm their short-term safety after 14 days of daily dosing. Rats were dosed daily orally with vehicle, Ambrotose or Advanced Ambrotose. On day six groups of rats received tap water or 5% Dextran Sulfate sodium. Ambrotose and Advanced Ambrotose significantly lowered the disease scores and partially prevented the shortening of colon length. An increase in monocyte count was induced by dextran sulfate sodium and inhibited by Ambrotose and Advanced Ambrotose. There were no observable adverse effects after 14-day daily doses. The mechanism of action of the formulations against DSS-induced colitis may be related to its effect on monocyte count

Versterking van ketenondernemerschap in de agrosector; Advies ten behoeve van 'Partners voor Ondernemerschap

Om te komen tot ketens die als geheel responsiever, ondernemender, duurzamer, efficiënter en flexibeler zijn is een integrale aanpak nodig met de volgende drie elementen: Versterking van het ondernemerschap in de primaire land- en tuinbouw; Versterking van het ondernemerschap en ondernemendheid bij medewerkers, waaronder erfbetreders en bestuurders in andere ketenschakels; Versterking van integraal ketenondernemerschap. Met name voor directie- en bestuursleden in de agribusiness is een 'out of the box'-aanpak van wezenlijk belang. Daarnaast wordt aanbevolen de competenties en vaardigheden van de (overige) medewerkers, met name van erfbetreders/ relatiebeheerders, regelmatig te toetsen en te ontwikkelen

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium

Background:Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. Methods:Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. Results:Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95 confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. Conclusion:Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2. © 2014 Cancer Research UK