The Endogenous Th17 Response in NO<inf>2</inf>-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated. © 2013 Martin et al

T-cell and serological responses to Erp, an exported Mycobacterium tuberculosis protein, in tuberculosis patients and healthy individuals

<p>Abstract</p> <p>Background</p> <p>The identification of antigens able to differentiate tuberculosis (TB) disease from TB infection would be valuable. Cellular and humoral immune responses to Erp (Exported repetitive protein) – a recently identified <it>M. tuberculosis </it>protein – have not yet been investigated in humans and may contribute to this aim.</p> <p>Methods</p> <p>We analyzed the cellular and humoral immune responses to Erp, ESAT-6, Ag85B and PPD in TB patients, in BCG⁺individuals without infection, BCG⁺individuals with latent TB infection (LTBI) and BCG^-controls. We used lymphoproliferation, ELISpot IFN-γ, cytokine production assays and detection of specific human antibodies against recombinant <it>M. tuberculosis </it>proteins.</p> <p>Results</p> <p>We included 22 TB patients, 9 BCG⁺individuals without TB infection, 7 LTBI and 7 BCG^-controls. Erp-specific T cell counts were higher in LTBI than in the other groups. Erp-specific T cell counts were higher in LTBI subjects than TB patients (median positive frequency of 211 SFC/10⁶PBMC (range 118–2000) for LTBI subjects compared to 80 SFC/10⁶PBMC (range 50–191), p = 0.019); responses to PPD and ESAT-6 antigens did not differ between these groups. IFN-γ secretion after Erp stimulation differed between TB patients and LTBI subjects (p = 0.02). Moreover, LTBI subjects but not TB patients or healthy subjects produced IgG3 against Erp.</p> <p>Conclusion</p> <p>The frequencies of IFN-γ-producing specific T cells, the IFN-γ secretion and the production of IgG3 after Erp stimulation are higher in LTBI subjects than in TB patients, whereas PPD and ESAT-6 are not.</p

Near-infrared spectroscopy as a predictor of clinical deterioration: a case report of two infants with duct-dependent congenital heart disease

Background: Some infants with congenital heart disease are at risk of in-hospital cardiac arrest. To better foresee cardiac arrest in infants with congenital heart disease, it might be useful to continuously assess end-organ perfusion. Near-infrared spectroscopy is a non-invasive method to continuously assess multisite regional tissue oxygen saturation. Case presentation: We report on two infants with duct-dependent congenital heart disease who demonstrated a gradual change in cerebral and/or renal tissue oxygen saturation before cardiopulmonary resuscitation was required. In both cases, other clinical parameters such as heart rate, arterial oxygen saturation and blood pressure did not indicate that deterioration was imminent. Conclusions: These two cases demonstrate that near-infrared spectroscopy might contribute to detecting a deteriorating clinical condition and might therefore be helpful in averting cardiopulmonary collapse and need for resuscitation in infants with congenital heart disease

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

The effect of acute exercise on glycogen synthesis rate in obese subjects studied by 13C MRS

In obesity, insulin-stimulated glucose uptake in skeletal muscle is decreased. We investigated whether the stimulatory effect of acute exercise on glucose uptake and subsequent glycogen synthesis was normal. The study was performed on 18 healthy volunteers, 9 obese (BMI = 32.6 ± 1.2 kg/m2, mean ± SEM) and 9 lean (BMI = 22.0 ± 0.9 kg/m2), matched for age and gender. All participants underwent a euglycemic hyperinsulinemic clamp, showing reduced glucose uptake in the obese group (P = 0.01), during which they performed a short intense local exercise (single-legged toe lifting). Dynamic glucose incorporation into glycogen in the gastrocnemius muscle before and after exercise was assessed by 13C magnetic resonance spectroscopy combined with infusion of [1-13C]glucose. Blood flow was measured to investigate its potential contribution to glucose uptake. Before exercise, glycogen synthesis rate tended to be lower in obese subjects compared with lean (78 ± 14 vs. 132 ± 24 μmol/kg muscle/min; P = 0.07). Exercise induced highly significant rises in glycogen synthesis rates in both groups, but the increase in obese subjects was reduced compared with lean (112 ± 15 vs. 186 ± 27 μmol/kg muscle/min; P = 0.03), although the relative increase was similar (184 ± 35 vs. 202 ± 51%; P = 0.78). After exercise, blood flow increased equally in both groups, without a temporal relationship with the rate of glycogen synthesis. In conclusion, this study shows a stimulatory effect of a short bout of acute exercise on insulin-induced glycogen synthesis rate that is reduced in absolute values but similar in percentages in obese subjects. These results suggest a shared pathway between insulin- and exercise-induced glucose uptake and subsequent glycogen synthesis

Differential cell reaction upon Toll-like receptor 4 and 9 activation in human alveolar and lung interstitial macrophages

BACKGROUND: Investigations on pulmonary macrophages (M&#934;) mostly focus on alveolar M&#934; (AM) as a well-defined cell population. Characteristics of M&#934; in the interstitium, referred to as lung interstitial M&#934; (IM), are rather ill-defined. In this study we therefore aimed to elucidate differences between AM and IM obtained from human lung tissue. METHODS: Human AM and IM were isolated from human non-tumor lung tissue from patients undergoing lung resection. Cell morphology was visualized using either light, electron or confocal microscopy. Phagocytic activity was analyzed by flow cytometry as well as confocal microscopy. Surface marker expression was measured by flow cytometry. Toll-like receptor (TLR) expression patterns as well as cytokine expression upon TLR4 or TLR9 stimulation were assessed by real time RT-PCR and cytokine protein production was measured using a fluorescent bead-based immunoassay. RESULTS: IM were found to be smaller and morphologically more heterogeneous than AM, whereas phagocytic activity was similar in both cell types. HLA-DR expression was markedly higher in IM compared to AM. Although analysis of TLR expression profiles revealed no differences between the two cell populations, AM and IM clearly varied in cell reaction upon activation. Both M&#934; populations were markedly activated by LPS as well as DNA isolated from attenuated mycobacterial strains (M. bovis H37Ra and BCG). Whereas AM expressed higher amounts of inflammatory cytokines upon activation, IM were more efficient in producing immunoregulatory cytokines, such as IL10, IL1ra, and IL6.CONCLUSION: AM appear to be more effective as a non-specific first line of defence against inhaled pathogens, whereas IM show a more pronounced regulatory function. These dissimilarities should be taken into consideration in future studies on the role of human lung M&#934; in the inflammatory response

Quick Minds Slowed Down: Effects of Rotation and Stimulus Category on the Attentional Blink

BACKGROUND: Most people show a remarkable deficit to report the second of two targets when presented in close temporal succession, reflecting an attentional restriction known as the 'attentional blink' (AB). However, there are large individual differences in the magnitude of the effect, with some people showing no such attentional restrictions. METHODOLOGY/PRINCIPAL FINDINGS: Here we present behavioral and electrophysiological evidence suggesting that these 'non-blinkers' can use alphanumeric category information to select targets at an early processing stage. When such information was unavailable and target selection could only be based on information that is processed relatively late (rotation), even non-blinkers show a substantial AB. Electrophysiologically, in non-blinkers this resulted in enhanced distractor-related prefrontal brain activity, as well as delayed target-related occipito-parietal activity (P3). CONCLUSION/SIGNIFICANCE: These findings shed new light on possible strategic mechanisms that may underlie individual differences in AB magnitude and provide intriguing clues as to how temporal restrictions as reflected in the AB can be overcome

GPs' perspectives of type 2 diabetes patients' adherence to treatment: A qualitative analysis of barriers and solutions

BACKGROUND: The problem of poor compliance/adherence to prescribed treatments is very complex. Health professionals are rarely being asked how they handle the patient's (poor) therapy compliance/adherence. In this study, we examine explicitly the physicians' expectations of their diabetes patients' compliance/adherence. The objectives of our study were: (1) to elicit problems physicians encounter with type 2 diabetes patients' adherence to treatment recommendations; (2) to search for solutions and (3) to discover escape mechanisms in case of frustration. METHODS: In a descriptive qualitative study, we explored the thoughts and feelings of general practitioners (GPs) on patients' compliance/adherence. Forty interested GPs could be recruited for focus group participation. Five open ended questions were derived on the one hand from a similar qualitative study on compliance/adherence in patients living with type 2 diabetes and on the other hand from the results of a comprehensive review of recent literature on compliance/adherence. A well-trained diabetes nurse guided the GPs through the focus group sessions while an observer was attentive for non-verbal communication and interactions between participants. All focus groups were audio taped and transcribed for content analysis. Two researchers independently performed the initial coding. A first draft with results was sent to all participants for agreement on content and comprehensiveness. RESULTS: General practitioners experience problems with the patient's deficient knowledge and the fact they minimize the consequences of having and living with diabetes. It appears that great confidence in modern medical science does not stimulate many changes in life style. Doctors tend to be frustrated because their patients do not achieve the common Evidence Based Medicine (EBM) objectives, i.e. on health behavior and metabolic control. Relevant solutions, derived from qualitative studies, for better compliance/adherence seem to be communication, tailored and shared care. GPs felt that a structured consultation and follow-up in a multidisciplinary team might help to increase compliance/adherence. It was recognized that the GP's efforts do not always meet the patients' health expectations. This initiates GPs' frustration and leads to a paternalistic attitude, which may induce anxiety in the patient. GPs often assume that the best methods to increase compliance/adherence are shocking the patients, putting pressure on them and threatening to refer them to hospital. CONCLUSION: GPs identified a number of problems with compliance/adherence and suggested solutions to improve it. GPs need communication skills to cope with patients' expectations and evidence based goals in a tailored approach to diabetes care

Echinococcus granulosus Antigen B Structure: Subunit Composition and Oligomeric States

Antigen B (AgB) is the major secretory protein of the Echinococcus granulosus hydatid cyst, the causative agent of cystic hydatid disease. Structurally, AgB is a multisubunit protein formed by 8-kDa subunits, but it is not known which subunits are secreted by a single parasite (cyst) and how they interact in the formation of distinct AgB oligomeric states. Here, we investigated AgB subunit composition and oligomeric states in individual samples from bovine and human cysts. We identified AgB8/1, AgB8/2, AgB8/3 and AgB8/4 subunits in AgB oligomers of all samples analyzed. Quantitative and qualitative differences in the expression of AgB subunits were observed within and between samples. Using recombinant subunits as models, we showed that AgB subunits form distinct oligomeric states, with a rAgB8/3>rAgB8/2>rAgB8/1 maximum size relation. We also demonstrated by different experimental approaches that rAgB8/3 oligomers are more similar, both in size and morphology, to those observed for E. granulosus AgB. Overall, we provided experimental evidences that AgB is composed of different subunits within a single cyst, and that subunits have different abundances and oligomerization properties. These issues are important for the understanding of AgB expression and structure variations, and their impact for the host-parasite cross-talk

Family Businesses and Adaptation: A Dynamic Capabilities Approach

The main objective of this research was to propose a framework centred on the dynamic capabilities approach, and to be applied in the context of family businesses’ adaption to their changing business environment. Data were gathered through interviews with ten FBs operating in Western Australia. Based on the findings, the clusters of activities, sensing, seizing, and transforming emerged as key factors for firms’ adaptation, and were reinforced by firms’ open culture, signature processes, idiosyncratic knowledge, and valuable, rare, inimitable and non-substitutable attributes. Thus, the usefulness of the proposed framework was confirmed. Implications and future research opportunities are presented. © 2018, The Author(s)