IL-21 receptor signalling partially mediates Th2-mediated allergic airway responses.

BACKGROUND: Interleukin-21 (IL-21) has been implicated in the development of Th2-mediated immune responses; however, the exact role it plays in allergic diseases is not well understood. OBJECTIVE: To elucidate the contribution of IL-21 receptor signalling to Th2-dependent immune responses in the lung. METHODS: We compared allergic airway responses in wild-type BALB/c and Il21r-deficient mice exposed to local airway challenge with house dust mite (HDM). RESULTS: We demonstrate that IL-21R-deficiency reduces HDM-driven airway hyperresponsiveness (AHR) with only partial effects on airway inflammation. Concomitant with the reduction in AHR in Il21r-deficient mice, significant suppression was observed in protein levels of the Th2 cytokines IL-4, and IL-13. In contrast, IL-21R-deficiency was associated with an increase in PBS- and allergen-driven IgE levels, while IgG1 and IgG2a levels were decreased. Moreover, our results suggest that IL-21 may contribute to AHR through its ability to both directly induce Th2 cell survival and to impair regulatory T-cell suppression of Th2 cytokine production. Importantly, we show that IL-21-positive cells are increased in the bronchial mucosa of asthmatics compared with non-asthmatics. CONCLUSION: These results suggest that IL-21 plays an important role in the allergic diathesis by enhancing Th2 cytokine production through multiple mechanisms including the suppression of Treg inhibitory effects on Th2 cell cytokine production.

PD-L2 modulates asthma severity by directly decreasing dendritic cell IL-12 production.

Studies examining the role of programmed death 1 (PD-1) ligand 2 (PD-L2)/PD-1 in asthma have yielded conflicting results. To clarify its role, we examined the PD-L2 expression in biopsies from human asthmatics and the lungs of aeroallergen-treated mice. PD-L2 expression in bronchial biopsies correlated with the severity of asthma. In mice, allergen exposure increased PD-L2 expression on pulmonary myeloid dendritic cells (DCs), and PD-L2 blockade diminished allergen-induced airway hyperresponsiveness (AHR). By contrast, PD-1 blockade had no impact, suggesting that PD-L2 promotes AHR in a PD-1-independent manner. Decreased AHR was associated with enhanced serum interleukin (IL)-12 p40, and in vitro stimulation of DCs with allergen and PD-L2-Fc reduced IL-12 p70 production, suggesting that PD-L2 inhibits allergen-driven IL-12 production. In our model, IL-12 did not diminish T helper type 2 responses but rather directly antagonized IL-13-inducible gene expression, highlighting a novel role for IL-12 in regulation of IL-13 signaling. Thus, allergen-driven enhancement of PD-L2 signaling through a PD-1-independent mechanism limits IL-12 secretion, exacerbating AHR.

AI in medical education--another grand challenge for medical informatics.

The potential benefits of artificial intelligence in medicine (AIM) were never realized as anticipated. This paper addresses ways in which such potential can be achieved. Recent discussions of this topic have proposed a stronger integration between AIM applications and health information systems, and emphasize computer guidelines to support the new health care paradigms of evidence-based medicine and cost-effectiveness. These proposals, however, promote the initial definition of AIM applications as being AI systems that can perform or aid in diagnoses. We challenge this traditional philosophy of AIM and propose a new approach aiming at empowering health care workers to become independent self-sufficient problem solvers and decision makers. Our philosophy is based on findings from a review of empirical research that examines the relationship between the health care personnel's level of knowledge and skills, their job satisfaction, and the quality of the health care they provide. This review supports addressing the quality of health care by empowering health care workers to reach their full potential. As an aid in this empowerment process we argue for reviving a long forgotten AIM research area, namely, AI based applications for medical education and training. There is a growing body of research in artificial intelligence in education that demonstrates that the use of artificial intelligence can enhance learning in numerous domains. By examining the strengths of these educational applications and the results from previous AIM research we derive a framework for empowering medical personnel and consequently raising the quality of health care through the use of advanced AI based technology.

Health care workers and their needs: the forgotten shadow of AIM research.

The field of AI in Medicine (AIM) seems to have accepted that decision support is, and will be, needed within most medical domains. As society calls for cost-effectiveness, and human expertise or expert guidance are not always available, decision support systems (DSSs) are proposed as the solutions. These solutions, however, do not necessarily correspond with the basic needs of their targeted users. We will show this through a review of the literature related to health care workers and the various factors that have an influence on their performances. Furthermore, we will use these empirical findings to argue that the AIM community must go beyond its decision support philosophy, whereby the gaps in human expertise are filled in by the computer. In the future, joint emphasis must be placed on decision support and the promotion towards independent and self-sufficient problem solving. In order to implement this paradigm change, the AIM community will have to incorporate findings from the research discipline of AI in Education.

Acetate production from hydrogen and [13C]carbon dioxide by the microflora of human feces.

Fecal suspensions from humans were incubated with 13CO2 and H2. The suspensions were from subjects who harbored 10(8) and 10(10) methanogens per g (dry weight) of feces, respectively, and from a subject who did not harbor methanogens. Quantitative nuclear magnetic resonance spectroscopy showed that acetate labeled in both the methyl and carboxyl groups was formed by suspensions from the subject without methanogens and the subject with the lower concentrations of methanogens. The amounts of labeled acetate formed were in agreement with the amounts expected based on measurements of H2 utilization. No labeled acetate was formed by suspensions from the subject with the higher concentrations of methanogens, and essentially all of the H2 used was accounted for by CH4 production. Suspensions from the subject with lower concentrations of methanogens produced both methane and acetate from H2 and CO2. The results indicate that reduction of CO2 to acetate may be a major pathway for microbial production of acetate in the human colon except when very high concentrations of methanogens (ca. 10(10) per g [dry weight] of feces) are present. Double-labeled acetate was also formed from H2 and 13CO2 by fecal suspensions from nonmethanogenic and moderately methanogenic rats.