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

A Quantitative Genetic Analysis of the Associations Among Language Skills, Peer Interactions, and Behavioral Problems in Childhood: Results From a Sample of Twins

A body of empirical research has revealed that there are associations among language skills, peer interactions, and behavioral problems in childhood. At the same time, however, there has been comparatively less research devoted to exploring the mutual unfolding of these factors over the first few years of life. The current study is designed to partially address this gap in the literature by examining how language skills, negative peer interactions, and behavioral problems are interrelated in a sample of twins drawn from the Early Childhood Longitudinal Study–Birth Cohort (ECLS-B). Employing a quantitative genetic framework, the results of the current study revealed that variance in language skills, negative peer interactions, and externalizing behavioral problems were all due to a combination of genetic and environmental factors. Bivariate Cholesky models indicated that most of the covariance among language skills, negative peer interactions, and externalizing behavioral problems was due to common genetic factors. Additional analyses using a modified DeFries–Fulker approach nested within a path model revealed a bidirectional association between negative peer interactions and externalizing behavioral problems, wherein there appeared to be feedback loops between the two. Implications of the results are discussed and avenues for future research are offered

Improving the Robustness of the Advanced LIGO Detectors to Earthquakes

Teleseismic, or distant, earthquakes regularly disrupt the operation of ground–based gravitational wave detectors such as Advanced LIGO. Here, we present EQ mode, a new global control scheme, consisting of an automated sequence of optimized control filters that reduces and coordinates the motion of the seismic isolation platforms during earthquakes. This, in turn, suppresses the differential motion of the interferometer arms with respect to one another, resulting in a reduction of DARM signal at frequencies below 100 mHz. Our method greatly improved the interferometers\u27 capability to remain operational during earthquakes, with ground velocities up to 3.9 μm s−1 rms in the beam direction, setting a new record for both detectors. This sets a milestone in seismic controls of the Advanced LIGO detectors\u27 ability to manage high ground motion induced by earthquakes, opening a path for further robust operation in other extreme environmental conditions

Do different depression phenotypes have different risks for recurrent coronary heart disease?

Although research has consistently established that depression and elevated depressive symptoms are associated with an increased risk of coronary heart disease (CHD) recurrence and mortality, clinical trials have failed to show that conventional depression interventions offset this risk. As depression is a complex and heterogeneous syndrome, we believe that examining simpler, or intermediary, phenotypes rather than one complex phenotype may allow better identification of those at particular risk of CHD recurrence and mortality. This approach may further contribute to the development of specific depression treatments that would improve medical outcomes. Although there are many possible intermediary phenotypes (IPs), specifiers and dimensions of depression, we will focus on only two when considering the relation between depression and risk of CHD recurrence and mortality: Incident Depression and Anhedonic Depression. Future research on IPs of depression is needed to clarify which are associated with the greatest risk for CHD recurrence and mortality and which, if any, are benign. Theoretical advances in depression phenotyping may also help elucidate the behavioural and biological mechanisms underlying the increased risk of CHD among patients with specific depression phenotypes. Finally, tests of depression interventions may be guided by this new theoretical approach

Sexual Orientation and Involvement in Nonviolent and Violent Delinquent Behaviors: Findings From the National Longitudinal Study of Adolescent to Adult Health

Abstract This study examined the association between sexual orientation and nonviolent and violent delinquency across the life course. We analyzed self-reported nonviolent and violent delinquency in a sample of heterosexual males (N = 5220-7023) and females (N = 5984-7875), bisexuals (N = 34-73), gay males (N = 145-189), and lesbians (N = 115-150) from the National Longitudinal Study of Adolescent to Adult Health (Add Health). The analyses revealed, in general, that bisexuals were the most delinquent of the sexual orientation categories for both males and females. Additional analyses revealed that heterosexual males reported significantly higher levels of both violent and nonviolent delinquency than gay males, whereas lesbians reported more involvement in nonviolent delinquency and, to a lesser extent, violent delinquency relative to heterosexual females. Analyses also revealed that lesbians reported significantly more delinquent behavior, particularly for nonviolent delinquency, than gay males. Future research should explore the mechanisms that account for these observed patterns and how they can be used to more fully understand the etiology of delinquency

Sister Mary Joseph's Nodule at a University Teaching Hospital in Northwestern Tanzania: A Retrospective Review of 34 cases.

Sister Mary Joseph's nodule is a metastatic tumor deposit in the umbilicus and often represents advanced intra-abdominal malignancy with dismal prognosis. There is a paucity of published data on this subject in our setting. This study was conducted to describe the clinicopathological presentation and treatment outcome of this condition in our environment and highlight challenges associated with the care of these patients, and to proffer solutions for improved outcome. This was a retrospective study of histologically confirmed cases of Sister Mary Joseph's nodule seen at Bugando Medical Centre between March 2003 and February 2013. Data collected were analyzed using descriptive statistics. A total of 34 patients were enrolled in the study. Males outnumbered females by a ratio of 1.4:1. The vast majority of patients (70.6%) presented with large umbilical nodule > 2 cm in size. The stomach (41.1%) was the most common location of the primary tumor. Adenocarcinoma (88.2%) was the most frequent histopathological type. Most of the primary tumors (52.9%) were poorly differentiated. As the disease was advanced and metastatic in all patients, only palliative therapy was offered. Out of 34 patients, 11 patients died in the hospital giving a mortality rate of 32.4%. Patients were followed up for 24 months. At the end of the follow-up period, 14(60.9%) patients were lost to follow-up and the remaining 9 (39.1%) patients died. Patients survived for a median period of 28 weeks (range, 2 to 64 weeks). The nodule recurred in 6 (26.1%) patients after complete excision. Sister Mary Joseph's nodule of the umbilicus is not rare in our environment and often represents manifestation of a variety of advanced intra-abdominal malignancies. The majority of the patients present at a late stage and many with distant metastases. The patient's survival is very short leading to a poor outcome. Early detection of primary cancer at an early stage may improve the prognosis

Boojums and the Shapes of Domains in Monolayer Films

Domains in Langmuir monolayers support a texture that is the two-dimensional version of the feature known as a boojum. Such a texture has a quantifiable effect on the shape of the domain with which it is associated. The most noticeable consequence is a cusp-like feature on the domain boundary. We report the results of an experimental and theoretical investigation of the shape of a domain in a Langmuir monolayer. A further aspect of the investigation is the study of the shape of a ``bubble'' of gas-like phase in such a monolayer. This structure supports a texture having the form of an inverse boojum. The distortion of a bubble resulting from this texture is also studied. The correspondence between theory and experiment, while not perfect, indicates that a qualitative understanding of the relationship between textures and domain shapes has been achieved.Comment: replaced with published version, 10 pages, 13 figures include

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