A European multicentre, placebo-controlled supplementation study with alpha-tocopherol, carotene-rich palm oil, lutein or lycopene: analysis of serum responses

Increased levels of oxidative stress have been implicated in tissue damage and the development of chronic diseases, and dietary antioxidants may reduce the risk of oxidative tissue damage. As part of a European multicentre project, several studies were undertaken with the aim of testing whether the consumption of foods rich in carotenoids reduces oxidative damage to human tissue components. We describe here the serum response of carotenoids and tocopherols upon supplementation with carotenoids from natural extracts (alpha-carotene+beta-carotene, lutein or lycopene; 15 mg/day) and/or with alpha-tocopherol (100 mg/day) in a multicentre, placebo-controlled intervention study in 400 healthy male and female volunteers, aged 25-45 years, from five European regions (France, Northern Ireland, Republic of Ireland, The Netherlands and Spain). Supplementation with alpha-tocopherol increased serum alpha-tocopherol levels, while producing a marked decrease in serum gamma-tocopherol. Supplementation with alpha- + beta-carotene (carotene-rich palm oil) resulted in 14-fold and 5-fold increases respectively in serum levels of these carotenoids. Supplementation with lutein (from marigold extracts) elevated serum lutein (approx. 5-fold), zeaxanthin (approx. doubled) and ketocarotenoids (although these were not present in the supplement), whereas lycopene supplementation (from tomato paste) resulted in a 2-fold increase in serum lycopene. The isomer distributions of beta-carotene and lycopene in serum remained constant regardless of the isomer composition in the capsules. In Spanish volunteers, additional data showed that the serum response to carotenoid supplementation reached a plateau after 4 weeks, and no significant side effects (except carotenodermia) or changes in biochemical or haematological indices were observed throughout the study. This part of the study describes dose-time responses, isomer distribution, subject variability and side effects during supplementation with the major dietary carotenoids in healthy subjects.     

Identification and characterization of an endogenous chemotactic ligand specific for FPRL2

Chemotaxis of dendritic cells (DCs) and monocytes is a key step in the initiation of an adequate immune response. Formyl peptide receptor (FPR) and FPR-like receptor (FPRL)1, two G protein-coupled receptors belonging to the FPR family, play an essential role in host defense mechanisms against bacterial infection and in the regulation of inflammatory reactions. FPRL2, the third member of this structural family of chemoattractant receptors, is characterized by its specific expression on monocytes and DCs. Here, we present the isolation from a spleen extract and the functional characterization of F2L, a novel chemoattractant peptide acting specifically through FPRL2. F2L is an acetylated amino-terminal peptide derived from the cleavage of the human heme-binding protein, an intracellular tetrapyrolle-binding protein. The peptide binds and activates FPRL2 in the low nanomolar range, which triggers intracellular calcium release, inhibition of cAMP accumulation, and phosphorylation of extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases through the G(i) class of heterotrimeric G proteins. When tested on monocytes and monocyte-derived DCs, F2L promotes calcium mobilization and chemotaxis. Therefore, F2L appears as a new natural chemoattractant peptide for DCs and monocytes, and the first potent and specific agonist of FPRL2.     

Circulating regulatory anti-T cell receptor antibodies in patients with myasthenia gravis

Serum anti-T cell receptor (TCR) Ab's are involved in immune regulation directed against pathogenic T cells in experimental models of autoimmune diseases. Our identification of a dominant T cell population expressing the Vbeta5.1 TCR gene (TCRBV5-1), which is responsible for the production of pathogenic anti-acetylcholine receptor (AChR) autoantibodies in HLA-DR3 patients with early-onset myasthenia gravis (EOMG), prompted us to explore the occurrence, reactivity, and regulatory role of anti-TCR Ab's in EOMG patients and disease controls with clearly defined other autoantibodies. In the absence of prior vaccination against the TCR, EOMG patients had elevated anti-Vbeta5.1 Ab's of the IgG class. This increase was restricted largely to EOMG cases with HLA-DR3 and with less severe disease, and it predicted clinical improvement in follow-up studies. EOMG patient sera containing anti-TCR Ab's bound specifically the native TCR on intact Vbeta5.1-expressing cells and specifically inhibited the proliferation and IFN-gamma production of purified Vbeta5.1-expressing cells to alloantigens in mixed lymphocyte reaction and the proliferation of a Vbeta5.1-expressing T cell clone to an AChR peptide, indicating a regulatory function for these Ab's. This evidence of spontaneously active anti-Vbeta5.1 Ab's in EOMG patients suggests dynamic protective immune regulation directed against the excess of pathogenic Vbeta5.1-expressing T cells. Though not sufficient to prevent a chronic, exacerbated autoimmune process, it might be boosted using a TCR peptide as vaccine.     

IL-1R1/MyD88 signaling and the inflammasome are essential in pulmonary inflammation and fibrosis in mice

The molecular mechanisms of acute lung injury resulting in inflammation and fibrosis are not well established. Here we investigate the roles of the IL-1 receptor 1 (IL-1R1) and the common adaptor for Toll/IL-1R signal transduction, MyD88, in this process using a murine model of acute pulmonary injury. Bleomycin insult results in expression of neutrophil and lymphocyte chemotactic factors, chronic inflammation, remodeling, and fibrosis. We demonstrate that these end points were attenuated in the lungs of IL-1R1– and MyD88-deficient mice. Further, in bone marrow chimera experiments, bleomycin-induced inflammation required primarily MyD88 signaling from radioresistant resident cells. Exogenous rIL-1β recapitulated a high degree of bleomycin-induced lung pathology, and specific blockade of IL-1R1 by IL-1 receptor antagonist dramatically reduced bleomycin-induced inflammation. Finally, we found that lung IL-1β production and inflammation in response to bleomycin required ASC, an inflammasome adaptor molecule. In conclusion, bleomycin-induced lung pathology required the inflammasome and IL-1R1/MyD88 signaling, and IL-1 represented a critical effector of pathology and therapeutic target of chronic lung inflammation and fibrosis.     

Functional MRI with active, fully implanted, deep brain stimulation systems: safety and experimental confounds

We investigated safety issues and potential experimental confounds when performing functional magnetic resonance imaging (fMRI) investigations in human subjects with fully implanted, active, deep brain stimulation (DBS) systems. Measurements of temperature and induced voltage were performed in an in vitro arrangement simulating bilateral DBS during magnetic resonance imaging (MRI) using head transmit coils in both 1.5 and 3.0 T MRI systems. For MRI sequences typical of an fMRI study with coil-averaged specific absorption rates (SARs) less than 0.4 W/kg, no MRI-induced temperature change greater than the measurement sensitivity (0.1 degrees C) was detected at 1.5 T, and at 3 T temperature elevations were less than 0.5 degrees C, i.e. within safe limits. For the purposes of demonstration, MRI pulse sequences with SARs of 1.45 W/kg and 2.34 W/kg (at 1.5 T and 3 T, respectively) were prescribed and elicited temperature increases (>1 degrees C) greater than those considered safe for human subjects. Temperature increases were independent of the presence or absence of active stimulator pulsing. At both field strengths during echo planar MRI, the perturbations of DBS equipment performance were sufficiently slight, and temperature increases sufficiently low to suggest that thermal or electromagnetically mediated experimental confounds to fMRI with DBS are unlikely. We conclude that fMRI studies performed in subjects with subcutaneously implanted DBS units can be both safe and free from DBS-specific experimental confounds. Furthermore, fMRI in subjects with fully implanted rather than externalized DBS stimulator units may offer a significant safety advantage. Further studies are required to determine the safety of MRI with DBS for other MRI systems, transmit coil configurations and DBS arrangements.     

Simultaneous EEG-Correlated Ictal fMRI

The ability to continuously acquire simultaneous EEG and fMRI data during seizures presents a formidable challenge both clinically and technically. Published ictal fMRI reports have so far been unable to benefit from simultaneous electrographic recordings and remain largely assumptive. Unique findings from a Continuous EEG-correlated fMRI experiment are presented in which a focal subclinical seizure was captured in its entirety. For the first time dynamic and biphasic Blood Oxygen Level Dependent (BOLD) signal changes are shown using statistical parametric mapping time-locked to the ictal EEG activity localizing seizure generation and propagation sites, with millimeter resolution, to electroclinically concordant gray matter structures. Though presently of limited clinical applicability, a new avenue is opened for further research.     

Revealing tacit knowledge used by experienced health professionals for interprofessional collaboration

ABSTRACT

With the current interest in interprofessional collaboration in health care as a response to ever-increasing complexity of health issues and scarcity of resources, many higher education institutions are developing interprofessional education (IPE) programs. However, there has been little empirical work on what. With the current interest for interprofessional collaboration in health care ever-increasing knowledge and skills are required to work collaboratively between health professions. We have undertaken to describe interprofessional collaboration as a practice largely underpinned by tacit knowledge acquired by experienced clinicians. Clinicians from all health professions in a large francophone university in Eastern Canada were invited to participate in explicitation interviews. Explicitation interviews require participants to freely recall an interprofessional collaboration event (e.g., team meeting or joint care delivery) and describe specific actions they personally enacted. An experienced health professional encounters many interprofessional situations over time; the actions they describe reflect their personal theories about the practice. Hence, it is highly probable that they use them frequently when working with colleagues in clinical settings. Unveiled tacit knowledge was divided into four themes: the importance of a sense of belonging to a team, the imperative to meet face-to-face, the practice of soliciting the working hypotheses of colleagues, and the art of summarizing meeting discussions.