Ionizing radiation has different biological effects according to dose and dose rate. In particular, the biological effect of low-dose radiation is unclear. Low-dose whole-body gamma irradiation ...activates immune responses in several ways. However, the effects and mechanism of low-dose radiation on allergic responses remain poorly understood. Previously, we reported that low-dose ionizing radiation inhibits mediator release in IgE-mediated RBL-2H3 mast cell activation. In this study, to have any physiological relevance, we investigated whether low-dose radiation inhibits allergic responses in activated human mast cells (HMC-1(5C6) and LAD2 cells), mouse models of passive cutaneous anaphylaxis and the late-phase cutaneous response. High-dose radiation induced cell death, but low-dose ionizing radiation of <0.5 Gy did not induce mast cell death. Low-dose ionizing radiation that did not induce cell death significantly suppressed mediator release from human mast cells (HMC-1(5C6) and LAD2 cells) that were activated by antigen-antibody reaction. To determine the inhibitory mechanism of mediator released by low-dose ionizing radiation, we examined the phosphorylation of intracellular signaling molecules such as Lyn, Syk, phospholipase Cγ, and protein kinase C, as well as the intracellular free Ca2+ concentration (Ca2+i). The phosphorylation of signaling molecules and Ca2+i following stimulation of FcεRI receptors was inhibited by low dose ionizing radiation. In agreement with its in vitro effect, ionizing radiation also significantly inhibited inflammatory cells infiltration, cytokine mRNA expression (TNF-α, IL-4, IL-13), and symptoms of passive cutaneous anaphylaxis reaction and the late-phase cutaneous response in anti-dinitrophenyl IgE-sensitized mice. These results indicate that ionizing radiation inhibits both mast cell-mediated immediate- and delayed-type allergic reactions in vivo and in vitro.
Homeostatic intestinal barrier function in vivo is regulated through the secretion of the mast cell‐specific serine protease chymase. In the present study, we employ in vitro model systems to ...delineate the molecular basis of chymase‐mediated regulation of intestinal epithelial barrier function. Chymase stimulation of intestinal epithelial cell monolayers induced a biphasic modification of barrier function. The early phase response occurred within 30 minutes and was dependent on the proteolytic activity of chymase and associated with degradation of the epithelial tight junction protein claudin‐5. The late phase response occurred 12–24 hours following chymase exposure, and was characterized by chymase‐induced protease‐activated receptor‐2 (PAR‐2) activation and matrix metalloproteinase (MMP)‐2 expression and activation. In vitro analysis shows chymase induced PAR‐2 activation and increased MAPK activity and MMP‐2 expression. PAR‐2 and MMP‐2 antagonism significantly attenuated the late‐phase response of chymase‐stimulated barrier dysfunction. Collectively, these results suggest a complex mast cell/chymase‐mediated biphasic regulation of intestinal epithelial barrier function. This work wassupported in part by Food Allergy Anaphylaxis Network and NIH R01AI073553‐01 (S.P.H).
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Disruption of the intestinal epithelial barrier has been proposed to be a central predisposing factor to intestinal diseases, however the molecular mechanisms involved in the ...maintenance of homeostatic intestinal epithelial barrier integrity has not been defined. We demonstrate a decrease in paracellular and transcellular intestinal permeability in mast cell (MC)‐deficient Kit
W‐sh/W‐sh
mice as compared to C57Bl/6 WT mice (paracellular Dextran‐FITC: 172.3 ± 35.3 vs 378.1 ± 54.3 ng/ml; p < 0.005; transcellular HRP: 0.0079 ± 0.0036 vs 1.1129 ± 0.4798 ng/ml; p < 0.05). We confirm MC involvement in homeostatic intestinal barrier function as reconstitution of bone marrow derived mast cells (BMMC's) into Kit
W‐sh/W‐sh
mice restored intestinal epithelial barrier integrity. Importantly, we identified that MC‐regulation of homeostatic intestinal barrier function was dependent on MC protease 4 (
mcpt4)
. Moreover,
mcpt‐4
−/−
mice intestinal epithelial barrier integrity was decreased as compared to WT mice (Dextran‐FITC: 115.3 ± 25.2 vs 378.1 ± 54.3 ng/ml; p < 0.005; HRP: 0.179 ± 0.1306 vs 1.1129 ± 0.4798 ng/ml; p < 0.05), to levels equivalent to that of Kit
W‐sh/W‐sh
mice. Furthermore, reconstitution of
mcpt4
−/−
BMMC's into Kit
W‐sh/W‐sh
mice did not restore intestinal epithelial barrier integrity. Collectively, our data demonstrates a critical role for MC's in the regulation of homeostatic intestinal barrier function.
Summary Background In 2000, world leaders agreed on the Millennium Development Goals (MDGs). MDG 4 called for a two-thirds reduction in the under-5 mortality rate between 1990 and 2015. We aimed to ...estimate levels and trends in under-5 mortality for 195 countries from 1990 to 2015 to assess MDG 4 achievement and then intended to project how various post-2015 targets and observed rates of change will affect the burden of under-5 deaths from 2016 to 2030. Methods We updated the UN Inter-agency Group for Child Mortality Estimation (UN IGME) database with 5700 country-year datapoints. As of July, 2015, the database contains about 17 000 country-year datapoints for mortality of children younger than 5 years for 195 countries, and includes all available nationally-representative data from vital registration systems, population censuses, household surveys, and sample registration systems. We used these data to generate estimates, with uncertainty intervals, of under-5 (age 0–4 years) mortality using a Bayesian B-spline bias-reduction model (B3 model). This model includes a data model to adjust for systematic biases associated with different types of data sources. To provide insights into the global and regional burden of under-5 deaths associated with post-2015 targets, we constructed five scenario-based projections for under-5 mortality from 2016 to 2030 and estimated national, regional, and global under-5 mortality rates up to 2030 for each scenario. Results The global under-5 mortality rate has fallen from 90·6 deaths per 1000 livebirths (90% uncertainty interval 89·3–92·2) in 1990 to 42·5 (40·9–45·6) in 2015. During the same period, the annual number of under-5 deaths worldwide dropped from 12·7 million (12·6 million–13·0 million) to 5·9 million (5·7 million–6·4 million). The global under-5 mortality rate reduced by 53% (50–55%) in the past 25 years and therefore missed the MDG 4 target. Based on point estimates, two regions—east Asia and the Pacific, and Latin America and the Caribbean—achieved the MDG 4 target. 62 countries achieved the MDG 4 target, of which 24 were low-income and lower-middle income countries. Between 2016 and 2030, 94·4 million children are projected to die before the age of 5 years if the 2015 mortality rate remains constant in each country, and 68·8 million would die if each country continues to reduce its mortality rate at the pace estimated from 2000 to 2015. If all countries achieve the Sustainable Development Goal of an under-5 mortality rate of 25 or fewer deaths per 1000 livebirths by 2030, we project 56·0 million deaths by 2030. About two-thirds of all sub-Saharan African countries need to accelerate progress to achieve this target. Interpretation Despite substantial progress in reducing child mortality, concerted efforts remain necessary to avoid preventable under-5 deaths in the coming years and to accelerate progress in improving child survival further. Urgent actions are needed most in the regions and countries with high under-5 mortality rates, particularly those in sub-Saharan Africa and south Asia. Funding None.
Tropical cyclones play an increasingly important role in shaping ecosystems. Understanding and generalizing their responses is challenging because of meteorological variability among storms and its ...interaction with ecosystems. We present a research framework designed to compare tropical cyclone effects within and across ecosystems that: a) uses a disaggregating approach that measures the responses of individual ecosystem components, b) links the response of ecosystem components at fine temporal scales to meteorology and antecedent conditions, and c) examines responses of ecosystem using a resistance–resilience perspective by quantifying the magnitude of change and recovery time. We demonstrate the utility of the framework using three examples of ecosystem response: gross primary productivity, stream biogeochemical export, and organismal abundances. Finally, we present the case for a network of sentinel sites with consistent monitoring to measure and compare ecosystem responses to cyclones across the United States, which could help improve coastal ecosystem resilience.
Transmitted resistance to antiretroviral drugs in acute and early HIV-1 infection has been well documented, although overall trends vary depending on geography and cohort characteristics. To describe ...the changing pattern of transmitted drug-resistant HIV-1 in a well-defined cohort in New York City, a total of 361 patients with acute or recent HIV-1 infection were prospectively studied over a decade (1995-2004) with respect to HIV-1 genotypes and longitudinal T-cell subsets and HIV-1 RNA levels. The prevalence of overall transmitted resistance changed from 13.2% to 24.1% (P = 0.11) during the periods 1995 to 1998 and 2003 to 2004. Nonnucleoside reverse transcriptase inhibitor resistance prevalence increased significantly from 2.6% to 13.4% (P = 0.007) during the same periods, whereas prevalence of multidrug-resistant virus shifted from 2.6% to 9.8% (P = 0.07) but did not achieve statistical significance. A comparable immunologic and virologic response of appropriately treated individuals was observed regardless of viral drug susceptibility status, suggesting that initial combination therapy guided by baseline resistance testing in the case of acute and early infection may result in a favorable treatment response even in the case of a drug-resistant virus. These data have important implications for selection of empiric first-line regimens for treatment of acutely infected antiretroviral-naive individuals and reinforce the need for baseline resistance testing in acute and early HIV-1 infection.
ABSTRACT
Acute mesenteric ischemia is associated with high morbidity and mortality. In recent studies, we found that the intestine is an important source of matrix metalloproteinase (MMP)8 during ...intestinal injury. We hypothesized that genetic ablation or pharmacological inhibition of MMP8 would reduce intestinal injury in mice subjected to intestinal ischemia–reperfusion (I/R) injury. Male mice aged 8–12 wk were subjected to intestinal I/R injury by transient occlusion of the superior mesenteric artery for 30 min. MMP8 was inhibited by genetic and pharmacological approaches. In vivo10th and 90th percentiles study endpoints included several functional, histological, and biochemical assays. Intestinal sections were assessed for barrier function and expression of tight junction proteins. I/R injury led to increased intestinal and systemic expression of MMP8. This increase was associated with increased intestinal neutrophil infiltration, epithelial injury, and permeability. I/R injury was associated with increased systemic inflammation and weight loss. These parameters were ameliorated by inhibiting MMP8. I/R injury caused a loss of the tight junction protein claudin‐3, which was ameliorated by genetic ablation of MMP8. MMP8 plays an important role in intestinal I/R injury through mechanisms involving increased inflammation and loss of claudin‐3. Inhibition of MMP8 is a potential therapeutic strategy in this setting.—Daly, M. C., Atkinson, S. J., Varisco, B.M., Klingbeil L., Hake, P., Lahni, P., Piraino, G., Wu, D., Hogan, S. P., Zingarelli, B., Wong, H.R. Role of matrix metalloproteinase‐8 as a mediator of injury in intestinal ischemia and reperfusion. FASEB J. 30, 3453–3460 (2016). www.fasebj.org
Idiopathic membranous nephropathy remains the leading cause of nephrotic syndrome in Caucasian adults. Immunosuppressive therapy with cyclosporine (CSA) is often successful in reducing proteinuria, ...but its use is associated with a high relapse rate. Rituximab, a monoclonal antibody that specifically targets CD20 on the surface of B-cells, is effective in achieving a complete remission of proteinuria in patients with idiopathic membranous nephropathy. However, whether rituximab is as effective as CSA in inducing and maintaining complete or partial remission of proteinuria in these patients is unknown. The membranous nephropathy trial of rituximab (MENTOR) hypothesizes that B-cell targeting with rituximab is non-inferior to CSA in inducing long-term remission of proteinuria.
Patients with idiopathic membranous nephropathy, proteinuria ≥5 g/24 h, and a minimum of 3 months of Angiotensin-II blockade will be randomized into a 12-month treatment period with i.v. rituximab, 1,000 mg (2 infusions, 14 days apart; repeated at 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months) or oral CSA 3.5-5 mg/kg/day for 6 months (continued for another 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months). The efficacy of treatment will be assessed by the remission status (based on changes in proteinuria) at 24 months from randomization. Patient safety will be assessed via collection of adverse event data and evaluation of pre- and posttreatment laboratory data. At the 6-month post-randomization visit, patients who have been randomized to either CSA or rituximab but who do not have a reduction in proteinuria ≥25% (confirmed on repeat measurements within 2 weeks) will be considered treatment failures and exit the study.
This study will test for the first time whether treatment with rituximab is non-inferior to CSA in inducing long-term remission (complete or partial) of proteinuria in patients with idiopathic membranous nephropathy.
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