Impulse oscillometry identifies peripheral airway dysfunction in children with adenosine deaminase deficiency.

Adenosine deaminase-deficient severe combined immunodeficiency (ADA-SCID) is characterized by impaired T-, B- and NK-cell function. Affected children, in addition to early onset of infections, manifest non-immunologic symptoms including pulmonary dysfunction likely attributable to elevated systemic adenosine levels. Lung disease assessment has primarily employed repetitive radiography and effort-dependent functional studies. Through impulse oscillometry (IOS), which is effort-independent, we prospectively obtained objective measures of lung dysfunction in 10 children with ADA-SCID. These results support the use of IOS in the identification and monitoring of lung function abnormalities in children with primary immunodeficiencies

The phosphoinositide 3-kinase-dependent activation of Btk is required for optimal eicosanoid production and generation of reactive oxygen species in antigen-stimulated mast cells

Activated mast cells are a major source of the eicosanoids PGD(2) and leukotriene C(4) (LTC(4)), which contribute to allergic responses. These eicosanoids are produced following the ERK1/2-dependent activation of cytosolic phospholipase A(2), thus liberating arachidonic acid, which is subsequently metabolized by the actions of 5-lipoxygenase and cyclooxygenase to form LTC(4) and PGD(2), respectively. These pathways also generate reactive oxygen species (ROS), which have been proposed to contribute to FcepsilonRI-mediated signaling in mast cells. In this study, we demonstrate that, in addition to ERK1/2-dependent pathways, ERK1/2-independent pathways also regulate FcepsilonRI-mediated eicosanoid and ROS production in mast cells. A role for the Tec kinase Btk in the ERK1/2-independent regulatory pathway was revealed by the significantly attenuated FcepsilonRI-dependent PGD(2), LTC(4), and ROS production in bone marrow-derived mast cells of Btk(-/-) mice. The FcepsilonRI-dependent activation of Btk and eicosanoid and ROS generation in bone marrow-derived mast cells and human mast cells were similarly blocked by the PI3K inhibitors, Wortmannin and LY294002, indicating that Btk-regulated eicosanoid and ROS production occurs downstream of PI3K. In contrast to ERK1/2, the PI3K/Btk pathway does not regulate cytosolic phospholipase A(2) phosphorylation but rather appears to regulate the generation of ROS, LTC(4), and PGD(2) by contributing to the necessary Ca(2+) signal for the production of these molecules. These data demonstrate that strategies to decrease mast cell production of ROS and eicosanoids would have to target both ERK1/2- and PI3K/Btk-dependent pathways

Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis

Neoplastic accumulation of mast cells in systemic mastocytosis (SM) associates with activating mutations in the receptor tyrosine kinase KIT. Constitutive activation of tyrosine kinase oncogenes has been linked to imbalances in oxidant/antioxidant mechanisms in other myeloproliferative disorders. However, the impact of KIT mutations on the redox status in SM and the potential therapeutic implications are not well understood. Here, we examined the regulation of reactive oxygen species (ROS) and of the antioxidant protein DJ-1 (PARK-7), which increases with cancer progression and acts to lessen oxidative damage to malignant cells, in relationship with SM severity. ROS levels were increased in both indolent (ISM) and aggressive variants of the disease (ASM). However, while DJ-1 levels were reduced in ISM with lower mast cell burden, they rose in ISM with higher mast cell burden and were significantly elevated in patients with ASM. Studies on mast cell lines revealed that activating KIT mutations induced constant ROS production and consequent DJ-1 oxidation and degradation that could explain the reduced levels of DJ-1 in the ISM population, while IL-6, a cytokine that increases with disease severity, caused a counteracting transcriptional induction of DJ-1 which would protect malignant mast cells from oxidative damage. A mouse model of mastocytosis recapitulated the biphasic changes in DJ-1 and the escalating IL-6, ROS and DJ-1 levels as mast cells accumulate, findings which were reversed with anti-IL-6 receptor blocking antibody. Our findings provide evidence of increased ROS and a biphasic regulation of the antioxidant DJ-1 in variants of SM and implicate IL-6 in DJ-1 induction and expansion of mast cells with KIT mutations. We propose consideration of IL-6 blockade as a potential adjunctive therapy in the treatment of patients with advanced mastocytosis, as it would reduce DJ-1 levels making mutation-positive mast cells vulnerable to oxidative damage

Seasonality of Holocene hydroclimate in the Eastern Mediterranean reconstructed using the oxygen isotope composition of carbonates and diatoms from Lake Nar, central Turkey

A positive shift in the oxygen isotope composition (δ18O) of lake carbonates in the Eastern Mediterranean from the early to late Holocene is usually interpreted as a change to drier (reduced P/E) conditions. However, it has also been suggested that changes in the seasonality of precipitation could explain these trends. Here, Holocene records of δ18O from both carbonates and diatom silica, from Lake Nar in central Turkey, provide insights into palaeoseasonality. We show how Δδ18Olakewater (the difference between spring and summer reconstructed δ18Olakewater) was minimal in the early Holocene and for most of the last millennium, but was greater at other times. For example, between ~4,100-1,600 years BP we suggest that increased Δδ18Olakewater could have been the result of relatively more spring/summer evaporation, amplified by a decline in lake level. In terms of change in annual mean δ18O, isotope mass balance modelling shows that this can be influenced by changes in seasonal P/E as well as inter-annual P/E, but lake level falls inferred from other proxies confirm there was a mid Holocene transition to drier climatic conditions in central Turkey

A tale of two lakes: a multi-proxy comparison of Lateglacial and Holocene environmental change in Cappadocia, Turkey

Individual palaeoenvironmental records represent a combination of regional-scale (e.g. climatic) and site-specific local factors. Here we compare multiple climate proxies from two nearby maar lake records, assuming that common signals are due to regional-scale forcing. A new core sequence from Nar Lake in Turkey is dated by varves and U–Th to the last 13.8 ka. Markedly dry periods during the Lateglacial stadial, at 4.3–3.7 and at 3.2–2.6 ka BP, are associated with peaks in Mg/dolomite, positive δ18O, elevated diatom-inferred electrical conductivity, an absence of laminated sediments and low Quercus/chenopod ratios. Wet phases occurred during the early–mid Holocene and 1.5–0.6 ka BP, characterized by negative δ18O, calcite precipitation, high Ca/Sr ratios, a high percentage of planktonic diatoms, laminated sediments and high Quercus/chenopod ratios. Comparison with the record from nearby Eski Acıgöl shows good overall correspondence for many proxies, especially for δ18O. Differences are related to basin infilling and lake ontogeny at Eski Acıgöl, which consequently fails to register climatic changes during the last 2 ka, and to increased flux of lithogenic elements into Nar Lake during the last 2.6 ka, not primarily climatic in origin. In attempting to separate a regional signal from site-specific ‘noise’, two lakes may therefore be better than one

Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal

Activation of tissue mast cells (MCs) and their abnormal growth and accumulation in various organs are typically found in primary MC disorders also referred to as mastocytosis. However, increasing numbers of patients are now being informed that their clinical findings are due to MC activation (MCA) that is neither associated with mastocytosis nor with a defined allergic or inflammatory reaction. In other patients with MCA, MCs appear to be clonal cells, but criteria for diagnosing mastocytosis are not met. A working conference was organized in 2010 with the aim to define criteria for diagnosing MCA and related disorders, and to propose a global unifying classification of all MC disorders and pathologic MC reactions. This classification includes three types of `MCA syndromes' (MCASs), namely primary MCAS, secondary MCAS and idiopathic MCAS. MCA is now defined by robust and generally applicable criteria, including (1) typical clinical symptoms, (2) a substantial transient increase in serum total tryptase level or an increase in other MC-derived mediators, such as histamine or prostaglandin D 2, or their urinary metabolites, and (3) a response of clinical symptoms to agents that attenuate the production or activities of MC mediators. These criteria should assist in the identification and diagnosis of patients with MCAS, and in avoiding misdiagnoses or overinterpretation of clinical symptoms in daily practice. Moreover, the MCAS concept should stimulate research in order to identify and exploit new molecular mechanisms and therapeutic targets. Copyright (C) 2011 S. Karger AG, Base

Tracking the hydro-climatic signal from lake to sediment: a field study from central Turkey

Palaeo-hydrological interpretations of lake sediment proxies can benefit from a robust understanding of the modern lake environment. In this study, we use Nar Gölü, a non-outlet, monomictic maar lake in central Turkey, as a field site for a natural experiment using observations and measurements over a 17-year monitoring period (1997–2014). We compare lake water and sediment trap data to isotopic, chemical and biotic proxies preserved in its varved sediments. Nar Gölü underwent a 3 m lake-level fall between 2000 and 2010. δ18Olakewater is correlated with this lake-level fall, responding to the change in water balance. Endogenic carbonate is shown to precipitate in isotopic equilibrium with lake water and there is a strong relationship between δ18Olakewater and δ18Ocarbonate, which suggests the water balance signal is accurately recorded in the sediment isotope record. Over the same period, sedimentary diatom assemblages also responded, and conductivity inferred from diatoms showed a rise. Shifts in carbonate mineralogy and elemental chemistry in the sediment record through this decade were also recorded. Intra-annual changes in δ18Olakewater and lake water chemistry are used to demonstrate the seasonal variability of the system and the influence this may have on the interpretation of δ18Ocarbonate. We use these relationships to help interpret the sedimentary record of changing lake hydrology over the last 1725 years. Nar Gölü has provided an opportunity to test critically the chain of connection from present to past, and its sedimentary record offers an archive of decadal- to centennial-scale hydro-climatic chang

Activation of transglutaminase and production of protein-bound gamma-glutamylhistamine in stimulated mouse mast cells

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The ingenious mast cell: Contemporary insights into mast cell behavior and function

Mast cells are (in)famous for their role in allergic diseases, but the physiological and pathophysiological roles of this ingenious cell are still not fully understood. Mast cells are important for homeostasis and surveillance of the human system, recognizing both endogenous and exogenous agents, which induce release of a variety of mediators acting on both immune and non-immune cells, including nerve cells, fibroblasts, endothelial cells, smooth muscle cells, and epithelial cells. During recent years, clinical and experimental studies on human mast cells, as well as experiments using animal models, have resulted in many discoveries that help decipher the function of mast cells in health and disease. In this review, we focus particularly on new insights into mast cell biology, with a focus on mast cell development, recruitment, heterogeneity, and reactivity. We also highlight the development in our understanding of mast cell-driven diseases and discuss the development of novel strategies to treat such conditions