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Sample records for c5a enhances dysregulated

  1. C5a enhances dysregulated inflammatory and angiogenic responses to malaria in vitro: potential implications for placental malaria.

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    Andrea Conroy

    Full Text Available Placental malaria (PM is a leading cause of maternal and infant mortality. Although the accumulation of parasitized erythrocytes (PEs and monocytes within the placenta is thought to contribute to the pathophysiology of PM, the molecular mechanisms underlying PM remain unclear. Based on the hypothesis that excessive complement activation may contribute to PM, in particular generation of the potent inflammatory peptide C5a, we investigated the role of C5a in the pathogenesis of PM in vitro and in vivo.Using primary human monocytes, the interaction between C5a and malaria in vitro was assessed. CSA- and CD36-binding PEs induced activation of C5 in the presence of human serum. Plasmodium falciparum GPI (pfGPI enhanced C5a receptor expression (CD88 on monocytes, and the co-incubation of monocytes with C5a and pfGPI resulted in the synergistic induction of cytokines (IL-6, TNF, IL-1beta, and IL-10, chemokines (IL-8, MCP-1, MIP1alpha, MIP1beta and the anti-angiogenic factor sFlt-1 in a time and dose-dependent manner. This dysregulated response was abrogated by C5a receptor blockade. To assess the potential role of C5a in PM, C5a plasma levels were measured in malaria-exposed primigravid women in western Kenya. Compared to pregnant women without malaria, C5a levels were significantly elevated in women with PM.These results suggest that C5a may contribute to the pathogenesis of PM by inducing dysregulated inflammatory and angiogenic responses that impair placental function.

  2. Complement C5a-C5aR interaction enhances MAPK signaling pathway activities to mediate renal injury in trichloroethylene sensitized BALB/c mice.

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    Zhang, Jia-xiang; Zha, Wan-sheng; Ye, Liang-ping; Wang, Feng; Wang, Hui; Shen, Tong; Wu, Chang-hao; Zhu, Qi-xing

    2016-02-01

    We have previously shown complement activation as a possible mechanism for trichloroethylene (TCE) sensitization, leading to multi-organ damage including the kidneys. In particular, excessive deposition of C5 and C5b-9-the membrane attack complex, which can generate significant tissue damage, was observed in the kidney tissue after TCE sensitization. The present study tested the hypothesis that anaphylatoxin C5a binding to its receptor C5aR mediates renal injury in TCE-sensitized BALB/c mice. BALB/c mice were sensitized through skin challenge with TCE, with or without pretreatment by the C5aR antagonist W54011. Kidney histopathology and the renal functional test were performed to assess renal injury, and immunohistochemistry and fluorescent labeling were carried out to assess C5a and C5aR expressions. TCE sensitization up-regulated C5a and C5aR expressions in kidney tissue, generated inflammatory infiltration, renal tubule damage, glomerular hypercellularity and impaired renal function. Antagonist pretreatment blocked C5a binding to C5aR and attenuated TCE-induced tissue damage and renal dysfunction. TCE sensitization also caused the deposition of major pro-inflammatory cytokines IL-2, TNF-α and IFN-γ in the kidney tissue (P < 0.05); this was accompanied by increased expression of P-p38, P-ERK and P-JNK proteins (P < 0.05). Pretreatment with the C5aR antagonist attenuated the increase of expression of P-p38, P-ERK and P-JNK proteins (P < 0.05) and also consistently reduced the TCE sensitization-induced increase of IL-2, TNF-α and IFN-γ (P < 0.05). These data identify C5a binding to C5aR, MAP kinase activation, and inflammatory cytokine release as a novel mechanism for complement-mediated renal injury by sensitization with TCE or other environmental chemicals. Copyright © 2015 John Wiley & Sons, Ltd.

  3. Estrogen enhances expression of the complement C5a receptor and the C5a-agonist evoked calcium influx in hormone secreting neurons of the hypothalamus.

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    Farkas, Imre; Varju, Patricia; Szabo, Emese; Hrabovszky, Erik; Okada, Noriko; Okada, Hidechika; Liposits, Zsolt

    2008-01-01

    In the present study we examined presence of the complement C5a receptor (C5aR) in hypothalamic neurosecretory neurons of the rodent brain and effect of estrogen on C5aR expression. Whole cell patch clamp measurements revealed that magnocellular neurons in the supraoptic and paraventricular nuclei of hypothalamic slices of the rats responded to the C5aR-agonist PL37-MAP peptide with calcium ion current pulses. Gonadotropin-releasing hormone (GnRH) producing neurons in slices of the preoptic area of the mice also reacted to the peptide treatment with inward calcium current. PL37-MAP was able to evoke the inward ion current of GnRH neurons in slices from ovariectomized animals. The amplitude of the inward pulses became higher in slices obtained from 17beta-estradiol (E2) substituted mice. Calcium imaging experiments demonstrated that PL37-MAP increased the intracellular calcium content in the culture of the GnRH-producing GT1-7 cell line in a concentration-dependent manner. Calcium imaging also showed that E2 pretreatment elevated the PL37-MAP evoked increase of the intracellular calcium content in the GT1-7 cells. The estrogen receptor blocker Faslodex in the medium prevented the E2-evoked increase of the PL37-MAP-triggered elevation of the intracellular calcium content in the GT1-7 cells demonstrating that the effect of E2 might be related to the presence of estrogen receptor. Real-time PCR experiments revealed that E2 increased the expression of C5aR mRNA in GT1-7 neurons, suggesting that an increased C5aR synthesis could be involved in the estrogenic modulation of calcium response. These data indicate that hypothalamic neuroendocrine neurons can integrate immune and neuroendocrine functions. Our results may serve a better understanding of the inflammatory and neurodegeneratory diseases of the hypothalamus and the related neuroendocrine and autonomic compensatory responses.

  4. Synergistic enhancement of chemokine generation and lung injury by C5a or the membrane attack complex of complement

    DEFF Research Database (Denmark)

    Czermak, B J; Lentsch, A B; Bless, N M

    1999-01-01

    demonstrated synergistic production of C-X-C (macrophage inflammatory protein-2 and cytokine-induced neutrophil chemoattractant) and C-C (macrophage inflammatory protein-1alpha and monocyte chemoattractant-1) chemokines. In the absence of the costimulus, C5a or MAC did not induce chemokine generation....... In in vivo studies, C5a and MAC alone caused limited or no intrapulmonary generation of chemokines, but in the presence of a costimulus (IgG immune complexes) C5a and MAC caused synergistic intrapulmonary generation of C-X-C and C-C chemokines but not of tumor necrosis factor alpha. Under these conditions...... increased neutrophil accumulation occurred, as did lung injury. These observations suggest that C5a and MAC function synergistically with a costimulus to enhance chemokine generation and the intensity of the lung inflammatory response....

  5. IFN-γ-producing NKT cells exacerbate sepsis by enhancing C5a generation via IL-10-mediated inhibition of CD55 expression on neutrophils.

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    Kim, Ji Hyung; Oh, Sae Jin; Ahn, Sehee; Chung, Doo Hyun

    2014-07-01

    A role for NKT cells has been implicated in sepsis, but the mechanism by which NKT cells contribute to sepsis remains unclear. Here, we examined WT and NKT-cell-deficient mice of C57BL/6 background during cecal ligation and puncture-induced sepsis. The levels of C5a, IFN-γ, and IL-10 were higher in the serum and peritoneal fluid of WT mice than in those of CD1d(-/-) mice, while the mortality rate was lower in CD1d(-/-) mice than in WT mice. C5a blockade decreased mortality of WT mice during sepsis, whereas it did not alter that of CD1d(-/-) mice. As assessed by intracellular staining, NKT cells expressed IFN-γ, while neutrophils expressed IL-10. Upon coculture, IL-10-deficient NKT cells enhanced IL-10 production by WT, but not IFN-γR-deficient, neutrophils. Meanwhile, CD1d(-/-) mice exhibited high CD55 expression on neutrophils during sepsis, whereas those cells from WT mice expressed minimal levels of CD55. Recombinant IL-10 administration into CD1d(-/-) mice reduced CD55 expression on neutrophils. Furthermore, adoptive transfer of sorted WT, but not IFN-γ-deficient, NKT cells into CD1d(-/-) mice suppressed CD55 expression on neutrophils, but increased IL-10 and C5a levels. Taken together, IFN-γ-producing NKT cells enhance C5a generation via IL-10-mediated inhibition of CD55 expression on neutrophils, thereby exacerbating sepsis. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  6. Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism

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    Jurian Schuijers

    2018-04-01

    Full Text Available Summary: Transcriptional dysregulation of the MYC oncogene is among the most frequent events in aggressive tumor cells, and this is generally accomplished by acquisition of a super-enhancer somewhere within the 2.8 Mb TAD where MYC resides. We find that these diverse cancer-specific super-enhancers, differing in size and location, interact with the MYC gene through a common and conserved CTCF binding site located 2 kb upstream of the MYC promoter. Genetic perturbation of this enhancer-docking site in tumor cells reduces CTCF binding, super-enhancer interaction, MYC gene expression, and cell proliferation. CTCF binding is highly sensitive to DNA methylation, and this enhancer-docking site, which is hypomethylated in diverse cancers, can be inactivated through epigenetic editing with dCas9-DNMT. Similar enhancer-docking sites occur at other genes, including genes with prominent roles in multiple cancers, suggesting a mechanism by which tumor cell oncogenes can generally hijack enhancers. These results provide insights into mechanisms that allow a single target gene to be regulated by diverse enhancer elements in different cell types. : Schuijers et al. show that a conserved CTCF site at the promoter of the MYC oncogene plays an important role in enhancer-promoter looping with tumor-specific super-enhancers. Perturbation of this site provides a potential therapeutic vulnerability. Keywords: gene regulation, super-enhancers, chromosome structure, enhancer docking

  7. Transcriptional Dysregulation of MYC Reveals Common Enhancer-Docking Mechanism.

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    Schuijers, Jurian; Manteiga, John Colonnese; Weintraub, Abraham Selby; Day, Daniel Sindt; Zamudio, Alicia Viridiana; Hnisz, Denes; Lee, Tong Ihn; Young, Richard Allen

    2018-04-10

    Transcriptional dysregulation of the MYC oncogene is among the most frequent events in aggressive tumor cells, and this is generally accomplished by acquisition of a super-enhancer somewhere within the 2.8 Mb TAD where MYC resides. We find that these diverse cancer-specific super-enhancers, differing in size and location, interact with the MYC gene through a common and conserved CTCF binding site located 2 kb upstream of the MYC promoter. Genetic perturbation of this enhancer-docking site in tumor cells reduces CTCF binding, super-enhancer interaction, MYC gene expression, and cell proliferation. CTCF binding is highly sensitive to DNA methylation, and this enhancer-docking site, which is hypomethylated in diverse cancers, can be inactivated through epigenetic editing with dCas9-DNMT. Similar enhancer-docking sites occur at other genes, including genes with prominent roles in multiple cancers, suggesting a mechanism by which tumor cell oncogenes can generally hijack enhancers. These results provide insights into mechanisms that allow a single target gene to be regulated by diverse enhancer elements in different cell types. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

  8. C5a receptor (CD88) blockade protects against MPO-ANCA GN.

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    Xiao, Hong; Dairaghi, Daniel J; Powers, Jay P; Ertl, Linda S; Baumgart, Trageen; Wang, Yu; Seitz, Lisa C; Penfold, Mark E T; Gan, Lin; Hu, Peiqi; Lu, Bao; Gerard, Norma P; Gerard, Craig; Schall, Thomas J; Jaen, Juan C; Falk, Ronald J; Jennette, J Charles

    2014-02-01

    Necrotizing and crescentic GN (NCGN) with a paucity of glomerular immunoglobulin deposits is associated with ANCA. The most common ANCA target antigens are myeloperoxidase (MPO) and proteinase 3. In a manner that requires activation of the alternative complement pathway, passive transfer of antibodies to mouse MPO (anti-MPO) induces a mouse model of ANCA NCGN that closely mimics human disease. Here, we confirm the importance of C5aR/CD88 in the mediation of anti-MPO-induced NCGN and report that C6 is not required. We further demonstrate that deficiency of C5a-like receptor (C5L2) has the reverse effect of C5aR/CD88 deficiency and results in more severe disease, indicating that C5aR/CD88 engagement enhances inflammation and C5L2 engagement suppresses inflammation. Oral administration of CCX168, a small molecule antagonist of human C5aR/CD88, ameliorated anti-MPO-induced NCGN in mice expressing human C5aR/CD88. These observations suggest that blockade of C5aR/CD88 might have therapeutic benefit in patients with ANCA-associated vasculitis and GN.

  9. Respiratory syncytial virus infection enhances Pseudomonas aeruginosa biofilm growth through dysregulation of nutritional immunity.

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    Hendricks, Matthew R; Lashua, Lauren P; Fischer, Douglas K; Flitter, Becca A; Eichinger, Katherine M; Durbin, Joan E; Sarkar, Saumendra N; Coyne, Carolyn B; Empey, Kerry M; Bomberger, Jennifer M

    2016-02-09

    Clinical observations link respiratory virus infection and Pseudomonas aeruginosa colonization in chronic lung disease, including cystic fibrosis (CF) and chronic obstructive pulmonary disease. The development of P. aeruginosa into highly antibiotic-resistant biofilm communities promotes airway colonization and accounts for disease progression in patients. Although clinical studies show a strong correlation between CF patients' acquisition of chronic P. aeruginosa infections and respiratory virus infection, little is known about the mechanism by which chronic P. aeruginosa infections are initiated in the host. Using a coculture model to study the formation of bacterial biofilm formation associated with the airway epithelium, we show that respiratory viral infections and the induction of antiviral interferons promote robust secondary P. aeruginosa biofilm formation. We report that the induction of antiviral IFN signaling in response to respiratory syncytial virus (RSV) infection induces bacterial biofilm formation through a mechanism of dysregulated iron homeostasis of the airway epithelium. Moreover, increased apical release of the host iron-binding protein transferrin during RSV infection promotes P. aeruginosa biofilm development in vitro and in vivo. Thus, nutritional immunity pathways that are disrupted during respiratory viral infection create an environment that favors secondary bacterial infection and may provide previously unidentified targets to combat bacterial biofilm formation.

  10. Dysregulated IER3 Expression is Associated with Enhanced Apoptosis in Titin-Based Dilated Cardiomyopathy

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    Qifeng Zhou

    2017-03-01

    Full Text Available Apoptosis (type I programmed cell death of cardiomyocytes is a major process that plays a role in the progression of heart failure. The early response gene IER3 regulates apoptosis in a wide variety of cells and organs. However, its role in heart failure is largely unknown. Here, we investigate the role of IER3 in an inducible heart failure mouse model. Heart failure was induced in a mouse model that imitates a human titin truncation mutation we found in a patient with dilated cardiomyopathy (DCM. Transferase dUTP nick end labeling (TUNEL and ssDNA stainings showed induction of apoptosis in titin-deficient cardiomyocytes during heart failure development, while IER3 response was dysregulated. Chromatin immunoprecipitation and knock-down experiments revealed that IER3 proteins target the promotors of anti-apoptotic genes and act as an anti-apoptotic factor in cardiomyocytes. Its expression is blunted during heart failure development in a titin-deficient mouse model. Targeting the IER3 pathway to reduce cardiac apoptosis might be an effective therapeutic strategy to combat heart failure.

  11. Protective effects of C5a blockade in sepsis

    DEFF Research Database (Denmark)

    Czermak, B J; Sarma, V; Pierson, C L

    1999-01-01

    in vitro had greatly reduced production of H2O2, which is known to be essential for the bactericidal function of neutrophils. In contrast, when companion CLP rats were treated with IgG antibody against C5a, survival rates were significantly improved, levels of bacteremia were considerably reduced...

  12. HSV neutralization by the microbicidal candidate C5A

    NARCIS (Netherlands)

    de Witte, L.; Bobardt, M.D.; Chatterji, U.; van Loenen, F.B.; Verjans, G.M.G.M.; Geijtenbeek, T.B.H.; Gallay, P.A.

    2011-01-01

    Genital herpes is a major risk factor in acquiring human immunodeficiency virus type-1 (HIV-1) infection and is caused by both Herpes Simplex virus type 1 (HSV-1) and HSV-2. The amphipathic peptide C5A, derived from the non-structural hepatitis C virus (HCV) protein 5A, was shown to prevent HIV-1

  13. HSV neutralization by the microbicidal candidate C5A

    NARCIS (Netherlands)

    L. de Witte (Lot); M.D. Bobardt (Michael); U. Chatterji (Udayan); F.B. van Loenen (Freek); G.M.G.M. Verjans (George); T.B.H. Geijtenbeek (Teunis); P.A. Gallay (Philippe)

    2011-01-01

    textabstractGenital herpes is a major risk factor in acquiring human immunodeficiency virus type-1 (HIV-1) infection and is caused by both Herpes Simplex virus type 1 (HSV-1) and HSV-2. The amphipathic peptide C5A, derived from the non-structural hepatitis C virus (HCV) protein 5A, was shown to

  14. Remote memories are enhanced by COMT activity through dysregulation of the endocannabinoid system in the prefrontal cortex.

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    Scheggia, D; Zamberletti, E; Realini, N; Mereu, M; Contarini, G; Ferretti, V; Managò, F; Margiani, G; Brunoro, R; Rubino, T; De Luca, M A; Piomelli, D; Parolaro, D; Papaleo, F

    2018-04-01

    The prefrontal cortex (PFC) is a crucial hub for the flexible modulation of recent memories (executive functions) as well as for the stable organization of remote memories. Dopamine in the PFC is implicated in both these processes and genetic variants affecting its neurotransmission might control the unique balance between cognitive stability and flexibility present in each individual. Functional genetic variants in the catechol-O-methyltransferase (COMT) gene result in a different catabolism of dopamine in the PFC. However, despite the established role played by COMT genetic variation in executive functions, its impact on remote memory formation and recall is still poorly explored. Here we report that transgenic mice overexpressing the human COMT-Val gene (COMT-Val-tg) present exaggerated remote memories (>50 days) while having unaltered recent memories (remote memories as silencing COMT Val overexpression starting from 30 days after the initial aversive conditioning normalized remote memories. COMT genetic overactivity produced a selective overdrive of the endocannabinoid system within the PFC, but not in the striatum and hippocampus, which was associated with enhanced remote memories. Indeed, acute pharmacological blockade of CB1 receptors was sufficient to rescue the altered remote memory recall in COMT-Val-tg mice and increased PFC dopamine levels. These results demonstrate that COMT genetic variations modulate the retrieval of remote memories through the dysregulation of the endocannabinoid system in the PFC.

  15. C5a and C5aR are elevated in joints of rheumatoid and psoriatic arthritis patients, and C5aR blockade attenuates leukocyte migration to synovial fluid

    DEFF Research Database (Denmark)

    Hornum, Lars; Hansen, Anker Jon; Tornehave, Ditte

    2017-01-01

    synovial fluid was significantly inhibited by anti-C5aR. The data support that the C5a-C5aR axis may be driving the infiltration of inflammatory cells into the synovial fluid and synovium in both rheumatoid and psoriatic arthritis, and suggest that C5a or C5aR may be a promising treatment target in both...... a Boyden chamber. Appropriate statistical tests were applied for comparisons. C5aR+ cells were detected in most rheumatoid arthritis, in all psoriatic arthritis, but not in non-inflammatory control synovia. C5aR+ cells were primarily neutrophils and macrophages. C5aR+ macrophages were mainly found...

  16. Dysregulated miR34a/diacylglycerol kinase ζ interaction enhances T-cell activation in acquired aplastic anemia.

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    Sun, Yuan-Xin; Li, Hui; Feng, Qi; Li, Xin; Yu, Ying-Yi; Zhou, Li-Wei; Gao, Yan; Li, Guo-Sheng; Ren, Juan; Ma, Chun-Hong; Gao, Cheng-Jiang; Peng, Jun

    2017-01-24

    Acquired aplastic anemia is an idiopathic paradigm of human bone marrow failure syndrome, which involves active destruction of hematopoietic stem cells and progenitors by cytotoxic T cells in the bone marrow. Aberrant expression of microRNAs in T cells has been shown to lead to development of certain autoimmune diseases. In the present study, we performed a microarray analysis of miRNA expression in bone marrow CD3+ T cells from patients with aplastic anemia and healthy controls. Overexpression of miR34a and underexpression of its target gene diacylglycerol kinase (DGK) ζ in bone marrow mononuclear cells were validated in 41 patients and associated with the severity of aplastic anemia. Further, the level of miR34a was higher in naïve T cells from patients than from controls. The role of miR34a and DGKζ in aplastic anemia was investigated in a murine model of immune-mediated bone marrow failure using miR34a-/- mice. After T-cell receptor stimulation in vitro, lymph node T cells from miR34a-/- mice demonstrated reduced activation and proliferation accompanied with a less profound down-regulation of DGKζ expression and decreased ERK phosphorylation compared to those from wild-type C57BL6 control mice. Infusion of 5 × 106 miR34a-/- lymph node T cells into sublethally irradiated CB6F1 recipients led to increased Lin-Sca1+CD117+ cells and less vigorous expansion of CD8+ T cells than injection of same number of wild-type lymph node cells. Our study demonstrates that the miR34a/DGKζ dysregulation enhances T-cell activation in aplastic anemia and targeting miR34a may represent a novel molecular therapeutic approach for patients with aplastic anemia.

  17. The C5a/C5aR1 axis controls the development of experimental allergic asthma independent of LysM-expressing pulmonary immune cells.

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    Anna V Wiese

    Full Text Available C5a regulates the development of maladaptive immune responses in allergic asthma mainly through the activation of C5a receptor 1 (C5aR1. Yet, the cell types and the mechanisms underlying this regulation are ill-defined. Recently, we described increased C5aR1 expression in lung tissue eosinophils but decreased expression in airway and pulmonary macrophages as well as in pulmonary CD11b+ conventional dendritic cells (cDCs and monocyte-derived DCs (moDCs during the allergic effector phase using a floxed green fluorescent protein (GFP-C5aR1 knock-in mouse. Here, we determined the role of C5aR1 signaling in neutrophils, moDCs and macrophages for the pulmonary recruitment of such cells and the importance of C5aR1-mediated activation of LysM-expressing cells for the development of allergic asthma. We used LysM-C5aR1 KO mice with a specific deletion of C5aR1 in LysMCre-expressing cells and confirmed the specific deletion of C5aR1 in neutrophils, macrophages and moDCs in the airways and/or the lung tissue. We found that alveolar macrophage numbers were significantly increased in LysM-C5aR1 KO mice. Induction of ovalbumin (OVA-driven experimental allergic asthma in GFP-C5aR1fl/fl and LysM-C5aR1 KO mice resulted in strong but similar airway resistance, mucus production and Th2/Th17 cytokine production. In contrast, the number of airway but not of pulmonary neutrophils was lower in LysM-C5aR1 KO as compared with GFP-C5aR1fl/fl mice. The recruitment of macrophages, cDCs, moDCs, T cells and type 2 innate lymphoid cells was not altered in LysM-C5aR1 KO mice. Our findings demonstrate that C5aR1 is critical for steady state control of alveolar macrophage numbers and the transition of neutrophils from the lung into the airways in OVA-driven allergic asthma. However, C5aR1 activation of LysM-expressing cells plays a surprisingly minor role in the recruitment and activation of such cells and the development of the allergic phenotype in OVA-driven experimental

  18. Pre-existing neutralizing antibody mitigates B cell dysregulation and enhances the Env-specific antibody response in SHIV-infected rhesus macaques.

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    Juan Pablo Jaworski

    Full Text Available Our central hypothesis is that protection against HIV infection will be powerfully influenced by the magnitude and quality of the B cell response. Although sterilizing immunity, mediated by pre-formed abundant and potent antibodies is the ultimate goal for B cell-targeted HIV vaccine strategies, scenarios that fall short of this may still confer beneficial defenses against viremia and disease progression. We evaluated the impact of sub-sterilizing pre-existing neutralizing antibody on the B cell response to SHIV infection. Adult male rhesus macaques received passive transfer of a sub-sterilizing amount of polyclonal neutralizing immunoglobulin (Ig purified from previously infected animals (SHIVIG or control Ig prior to intra-rectal challenge with SHIVSF162P4 and extensive longitudinal sampling was performed. SHIVIG treated animals exhibited significantly reduced viral load and increased de novo Env-specific plasma antibody. Dysregulation of the B cell profile was grossly apparent soon after infection in untreated animals; exemplified by a ≈50% decrease in total B cells in the blood evident 2-3 weeks post-infection which was not apparent in SHIVIG treated animals. IgD+CD5+CD21+ B cells phenotypically similar to marginal zone-like B cells were highly sensitive to SHIV infection, becoming significantly decreased as early as 3 days post-infection in control animals, while being maintained in SHIVIG treated animals, and were highly correlated with the induction of Env-specific plasma antibody. These results suggest that B cell dysregulation during the early stages of infection likely contributes to suboptimal Env-specific B cell and antibody responses, and strategies that limit this dysregulation may enhance the host's ability to eliminate HIV.

  19. Sequence-specific assignments in the 1H NMR spectrum of the human inflammatory protein C5a

    International Nuclear Information System (INIS)

    Zuiderweg, E.R.P.; Mollison, K.W.; Henkin, J.; Carter, G.W.

    1988-01-01

    Full sequence-specific assignments for the 1 H NMR lines of the backbone protons of the human complement factor C5a are described and documented. The results were obtained by largely following the methodology developed by Wuethrich et al. Assignments for the majority of the amino acid side chain protons were obtained by using a comparison of double- and triple-quantum-filtered two-dimensional correlated experiments together with the analysis of relayed coherence transfer spectra. The assignments provide the basis for the determination of the thus far unknown three-dimensional structure of C5a from nuclear Overhauser enhancement distance constraints

  20. Differential contribution of complement receptor C5aR in myeloid and non-myeloid cells in chronic ethanol-induced liver injury in mice.

    Science.gov (United States)

    McCullough, Rebecca L; McMullen, Megan R; Das, Dola; Roychowdhury, Sanjoy; Strainic, Michael G; Medof, M Edward; Nagy, Laura E

    2016-07-01

    Complement is implicated in the development of alcoholic liver disease. C3 and C5 contribute to ethanol-induced liver injury; however, the role of C5a receptor (C5aR) on myeloid and non-myeloid cells to progression of injury is not known. C57BL/6 (WT), global C5aR-/-, myeloid-specific C5aR-/-, and non-myeloid-specific C5aR-/- mice were fed a Lieber-DeCarli diet (32%kcal EtOH) for 25 days. Cultured hepatocytes were challenged with ethanol, TNFα, and C5a. Chronic ethanol feeding increased expression of pro-inflammatory mediators in livers of WT mice; this response was completely blunted in C5aR-/- mice. However, C5aR-/- mice were not protected from other measures of hepatocellular damage, including ethanol-induced increases in hepatic triglycerides, plasma alanine aminotransferase and hepatocyte apoptosis. CYP2E1 and 4-hydroxynonenal protein adducts were induced in WT and C5aR-/- mice. Myeloid-specific C5aR-/- mice were protected from ethanol-induced increases in hepatic TNFα, whereas non-myeloid-specific C5aR-/- displayed increased hepatocyte apoptosis and inflammation after chronic ethanol feeding. In cultured hepatocytes, cytotoxicity induced by challenge with ethanol and TNFα was completely eliminated by treatment with C5a in cells from WT, but not C5aR-/- mice. Further, treatment with C5a enhanced activation of pro-survival signal AKT in hepatocytes challenged with ethanol and TNFα. Taken together, these data reveal a differential role for C5aR during ethanol-induced liver inflammation and injury, with C5aR on myeloid cells contributing to ethanol-induced inflammatory cytokine expression, while non-myeloid C5aR protects hepatocytes from death after chronic ethanol feeding. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Complement C5a receptor antagonism by protamine and poly-L-Arg on human leukocytes.

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    Olsen, U B; Selmer, J; Kahl, J U

    1988-01-01

    It is shown that protamine selectively and dose-dependently inhibits complement C5a-induced leukocyte responses such as histamine release from basophils, chemiluminescence and beta-glucuronidase release from neutrophils. Protamine produces parallel rightward displacements of the C5a dose-response curves. The inhibitory capacity of the polypeptide is reversible and disappears following repeated washing of exposed cells. In neutrophils poly-L-Arg similarly and specifically antagonizes C5a-induced chemiluminescence and enzyme release. This polymer alone, however, degranulates basophils and neutrophils, leading to histamine and enzyme release, respectively. It is concluded that on human neutrophils the arginine-rich polycations protamine and poly-L-Arg exhibit a competitive C5a receptor antagonism. In addition, protamine inhibits the C5a receptors on basophils. It is hypothesized that molecular conformations of the arginine-rich polycations might bind reversibly to, and block negatively charged groups at the C5a-receptor sites.

  2. Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway.

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    Chloë R McDonald

    2015-09-01

    Full Text Available The in utero environment profoundly impacts childhood neurodevelopment and behaviour. A substantial proportion of pregnancies in Africa are at risk of malaria in pregnancy (MIP however the impact of in utero exposure to MIP on fetal neurodevelopment is unknown. Complement activation, in particular C5a, may contribute to neuropathology and adverse outcomes during MIP. We used an experimental model of MIP and standardized neurocognitive testing, MRI, micro-CT and HPLC analysis of neurotransmitter levels, to test the hypothesis that in utero exposure to malaria alters neurodevelopment through a C5a-C5aR dependent pathway. We show that malaria-exposed offspring have persistent neurocognitive deficits in memory and affective-like behaviour compared to unexposed controls. These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches. Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.

  3. C5a receptor deficiency alters energy utilization and fat storage.

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    Christian Roy

    Full Text Available To investigate the impact of whole body C5a receptor (C5aR deficiency on energy metabolism and fat storage.Male wildtype (WT and C5aR knockout (C5aRKO mice were fed a low fat (CHOW or a high fat high sucrose diet-induced obesity (DIO diet for 14 weeks. Body weight and food intake were measured weekly. Indirect calorimetry, dietary fatload clearance, insulin and glucose tolerance tests were also evaluated. Liver, muscle and adipose tissue mRNA gene expression were measured by RT-PCR.At week one and 12, C5aRKO mice on DIO had increased oxygen consumption. After 12 weeks, although food intake was comparable, C5aRKO mice had lower body weight (-7% CHOW, -12% DIO as well as smaller gonadal (-38% CHOW, -36% DIO and inguinal (-29% CHOW, -30% DIO fat pads than their WT counterparts. Conversely, in WT mice, C5aR was upregulated in DIO vs CHOW diets in gonadal adipose tissue, muscle and liver, while C5L2 mRNA expression was lower in C5aRKO on both diet. Furthermore, blood analysis showed lower plasma triglyceride and non-esterified fatty acid levels in both C5aRKO groups, with faster postprandial triglyceride clearance after a fatload. Additionally, C5aRKO mice showed lower CD36 expression in gonadal and muscle on both diets, while DGAT1 expression was higher in gonadal (CHOW and liver (CHOW and DIO and PPARγ was increased in muscle and liver.These observations point towards a role (either direct or indirect for C5aR in energy expenditure and fat storage, suggesting a dual role for C5aR in metabolism as well as in immunity.

  4. The complement anaphylatoxin C5a receptor contributes to obese adipose tissue inflammation and insulin resistance.

    Science.gov (United States)

    Phieler, Julia; Chung, Kyoung-Jin; Chatzigeorgiou, Antonios; Klotzsche-von Ameln, Anne; Garcia-Martin, Ruben; Sprott, David; Moisidou, Maria; Tzanavari, Theodora; Ludwig, Barbara; Baraban, Elena; Ehrhart-Bornstein, Monika; Bornstein, Stefan R; Mziaut, Hassan; Solimena, Michele; Karalis, Katia P; Economopoulou, Matina; Lambris, John D; Chavakis, Triantafyllos

    2013-10-15

    Obese adipose tissue (AT) inflammation contributes critically to development of insulin resistance. The complement anaphylatoxin C5a receptor (C5aR) has been implicated in inflammatory processes and as regulator of macrophage activation and polarization. However, the role of C5aR in obesity and AT inflammation has not been addressed. We engaged the model of diet-induced obesity and found that expression of C5aR was significantly upregulated in the obese AT, compared with lean AT. In addition, C5a was present in obese AT in the proximity of macrophage-rich crownlike structures. C5aR-sufficient and -deficient mice were fed a high-fat diet (HFD) or a normal diet (ND). C5aR deficiency was associated with increased AT weight upon ND feeding in males, but not in females, and with increased adipocyte size upon ND and HFD conditions in males. However, obese C5aR(-/-) mice displayed improved systemic and AT insulin sensitivity. Improved AT insulin sensitivity in C5aR(-/-) mice was associated with reduced accumulation of total and proinflammatory M1 macrophages in the obese AT, increased expression of IL-10, and decreased AT fibrosis. In contrast, no difference in β cell mass was observed owing to C5aR deficiency under an HFD. These results suggest that C5aR contributes to macrophage accumulation and M1 polarization in the obese AT and thereby to AT dysfunction and development of AT insulin resistance.

  5. C5a binding to human polymorphonuclear leukocyte plasma membrane (PMNLM) receptors

    International Nuclear Information System (INIS)

    Conway, R.G.; Mollison, K.W.; Carter, G.W.; Lane, B.

    1986-01-01

    Previous investigations of the C5a receptor have been performed using intact human PMNL. To circumvent some of the potential problems with such whole cell assays (e.g. internalization or metabolism of radioligand) the authors have developed a PMNLM binding assay. Human PMNLM were prepared by nitrogen cavitation and Percoll gradient centrifugation. Specific binding of [ 125 I]C5a to PMNLM was: high affinity, K/sub D/ = 0.6 nM; saturable, B/sub max/ = 8.7 pmol/mg protein; and reversible. Kinetic measurements agree with the K/sub D/ value obtained by Scatchard analysis. Furthermore, the binding activity of C5a correlates with biological activity as measured by myeloperoxidase release from human PMNL. Human serum C5a and recombinant C5a bind with similar affinities when measured by competition or direct binding and label the same number of sites in human PMNLM. The nonhydrolyzable GTP analog, GppNHp, induces a low affinity state of the C5a receptor (4-6 fold shift in K/sub D/) with little effect on B/sub max/. In summary, the criteria have been satisfied for identification of a biologically relevant C5a binding site in human PMNLM. Regulation of the C5a receptor and its membrane transduction mechanism(s) appears to involve guanyl nucleotides, as has been found for other chemoattractant receptors

  6. Critical role for complement receptor C5aR2 in the pathogenesis of renal ischemia-reperfusion injury

    NARCIS (Netherlands)

    Poppelaars, Felix; van Werkhoven, Maaike B; Kotimaa, Juha; Veldhuis, Zwanida J; Ausema, Albertina; Broeren, Stefan G M; Damman, Jeffrey; Hempel, Julia C.; Leuvenink, Henri G D; Daha, Mohamed R; van Son, Willem J; van Kooten, Cees; van Os, Ronald P; Hillebrands, Jan-Luuk; Seelen, Marc A

    The complement system, and specifically C5a, is involved in renal ischemia-reperfusion (IR) injury. The 2 receptors for complement anaphylatoxin C5a (C5aR1 and C5aR2) are expressed on leukocytes as well as on renal epithelium. Extensive evidence shows that C5aR1 inhibition protects kidneys from IR

  7. Reconsidering Emotion Dysregulation.

    Science.gov (United States)

    D'Agostino, Alessandra; Covanti, Serena; Rossi Monti, Mario; Starcevic, Vladan

    2017-12-01

    This article aims to review the concept of emotion dysregulation, focusing on issues related to its definition, meanings and role in psychiatric disorders. Articles on emotion dysregulation published until May 2016 were identified through electronic database searches. Although there is no agreement about the definition of emotion dysregulation, the following five overlapping, not mutually exclusive dimensions of emotion dysregulation were identified: decreased emotional awareness, inadequate emotional reactivity, intense experience and expression of emotions, emotional rigidity and cognitive reappraisal difficulty. These dimensions characterise a number of psychiatric disorders in various proportions, with borderline personality disorder and eating disorders seemingly more affected than other conditions. The present review contributes to the literature by identifying the key components of emotion dysregulation and by showing how these permeate various forms of psychopathology. It also makes suggestions for improving research endeavours. Better understanding of the various dimensions of emotion dysregulation will have implications for clinical practice. Future research needs to address emotion dysregulation in all its multifaceted complexity so that it becomes clearer what the concept encompasses.

  8. Disruptive Mood Dysregulation Disorder

    Science.gov (United States)

    ... Application Process Managing Grants Clinical Research Training Small Business Research Labs at NIMH Labs at NIMH Home Research ... Chat on Disruptive Mood Dysregulation Disorder (Archived Transcript) Research and ... Journal Articles: References and abstracts from MEDLINE/PubMed (National ...

  9. Deletion of the complement C5a receptor alleviates the severity of acute pneumococcal otitis media following influenza A virus infection in mice.

    Directory of Open Access Journals (Sweden)

    Hua Hua Tong

    Full Text Available There is considerable evidence that influenza A virus (IAV promotes adherence, colonization, and superinfection by S. pneumoniae (Spn and contributes to the pathogenesis of otitis media (OM. The complement system is a critical innate immune defense against both pathogens. To assess the role of the complement system in the host defense and the pathogenesis of acute pneumococcal OM following IAV infection, we employed a well-established transtympanically-induced mouse model of acute pneumococcal OM. We found that antecedent IAV infection enhanced the severity of acute pneumococcal OM. Mice deficient in complement C1qa (C1qa-/- or factor B (Bf -/- exhibited delayed viral and bacterial clearance from the middle ear and developed significant mucosal damage in the eustachian tube and middle ear. This indicates that both the classical and alternative complement pathways are critical for the oto-immune defense against acute pneumococcal OM following influenza infection. We also found that Spn increased complement activation following IAV infection. This was characterized by sustained increased levels of anaphylatoxins C3a and C5a in serum and middle ear lavage samples. In contrast, mice deficient in the complement C5a receptor (C5aR demonstrated enhanced bacterial clearance and reduced severity of OM. Our data support the concept that C5a-C5aR interactions play a significant role in the pathogenesis of acute pneumococcal OM following IAV infection. It is possible that targeting the C5a-C5aR axis might prove useful in attenuating acute pneumococcal OM in patients with influenza infection.

  10. A Novel Role for C5a in B-1 Cell Homeostasis

    Directory of Open Access Journals (Sweden)

    Katharina Bröker

    2018-02-01

    Full Text Available B-1 cells constitute a unique subpopulation of lymphocytes residing mainly in body cavities like the peritoneal cavity (PerC but are also found in spleen and bone marrow (BM. As innate-like B cells, they mediate first line immune defense through low-affinity natural IgM (nIgM antibodies. PerC B-1 cells can egress to the spleen and differentiate into nIgM antibody-secreting plasma cells that recognize conserved exogenous and endogenous cellular structures. Homing to and homeostasis within the PerC are regulated by the chemokine CXCL13 released by PerC macrophages and stroma cells. However, the exact mechanisms underlying the regulation of CXCL13 and B-1 homeostasis are not fully explored. B-1 cells play important roles in the inflammatory response to infection, autoimmunity, ischemia/reperfusion injury, obesity, and atherosclerosis. Remarkably, this list of inflammatory entities has a strong overlap with diseases that are regulated by complement suggesting a link between B-1 cells and the complement system. Interestingly, up to now, no data exist regarding the role of complement in B-1 cell biology. Here, we demonstrate for the first time that C5a regulates B-1 cell steady-state dynamics within the peritoneum, the spleen, and the BM. We found decreased B-1a cell numbers in the peritoneum and the spleen of C5aR1−/− mice associated with increased B1-a and B1-b numbers in the spleen and high serum titers of nIgM antibodies directed against phosphorylcholine and several pneumococcal polysaccharides. Similarly, peritoneal B-1a cells were decreased in the peritoneum and splenic B-1a and B-1b cells were increased in C5aR2−/− mice. The decrease in peritoneal B-1 cell numbers was associated with decreased peritoneal CXCL13 levels in C5aR1−/− and C5aR2−/− mice. In search for mechanisms, we found that combined TLR2 and IL-10 receptor activation in PerC macrophages induced strong CXCL13 production, which was significantly reduced in cells

  11. C5a Receptor (CD88) Blockade Protects against MPO-ANCA GN

    OpenAIRE

    Xiao, Hong; Dairaghi, Daniel J.; Powers, Jay P.; Ertl, Linda S.; Baumgart, Trageen; Wang, Yu; Seitz, Lisa C.; Penfold, Mark E.T.; Gan, Lin; Hu, Peiqi; Lu, Bao; Gerard, Norma P.; Gerard, Craig; Schall, Thomas J.; Jaen, Juan C.

    2013-01-01

    Necrotizing and crescentic GN (NCGN) with a paucity of glomerular immunoglobulin deposits is associated with ANCA. The most common ANCA target antigens are myeloperoxidase (MPO) and proteinase 3. In a manner that requires activation of the alternative complement pathway, passive transfer of antibodies to mouse MPO (anti-MPO) induces a mouse model of ANCA NCGN that closely mimics human disease. Here, we confirm the importance of C5aR/CD88 in the mediation of anti-MPO–induced NCGN and report th...

  12. Cloning, expression, cellular distribution, and role in chemotaxis of a C5a receptor in rainbow trout: the first identification of a C5a receptor in a nonmammalian species

    Science.gov (United States)

    Boshra, Hani; Li, Jun; Peters, Rodney; Hansen, John; Matlapudi, Anjan; Sunyer, J. Oriol

    2004-01-01

    C3a, C4a, and C5a anaphylatoxins generated during complement activation play a key role in inflammation. C5a is the most potent of the three anaphylatoxins in eliciting biological responses. The effects of C5a are mediated by its binding to C5a receptor (C5aR, CD88). To date, C5aR has only been identified and cloned in mammalian species, and its evolutionary history remains ill-defined. To gain insights into the evolution, conserved structural domains, and functions of C5aR, we have cloned and characterized a C5aR in rainbow trout, a teleost fish. The isolated cDNA encoded a 350-aa protein that showed the highest sequence similarity to C5aR from other species. Genomic analysis revealed the presence of one continuous exon encoding the entire open reading frame. Northern blot analysis showed significant expression of the trout C5a receptor (TC5aR) message in PBLs and kidney. Flow cytometric analysis showed that two Abs generated against two different areas of the extracellular N-terminal region of TC5aR positively stained the same leukocyte populations from PBLs. B lymphocytes and granulocytes comprised the majority of cells recognized by the anti-TC5aR. More importantly, these Abs inhibited chemotaxis of PBLs toward a chemoattractant fraction purified from complement-activated trout serum. Our data suggest that the split between C5aR and C3aR from a common ancestral molecule occurred before the emergence of teleost fish. Moreover, we demonstrate that the overall structure of C5aR as well as its role in chemotaxis have remained conserved for >300 million years.

  13. CYP4F18-Deficient Neutrophils Exhibit Increased Chemotaxis to Complement Component C5a

    Directory of Open Access Journals (Sweden)

    Rachel Vaivoda

    2015-01-01

    Full Text Available CYP4Fs were first identified as enzymes that catalyze hydroxylation of leukotriene B4 (LTB4. CYP4F18 has an unusual expression in neutrophils and was predicted to play a role in regulating LTB4-dependent inflammation. We compared chemotaxis of wild-type and Cyp4f18 knockout neutrophils using an in vitro assay. There was no significant difference in the chemotactic response to LTB4, but the response to complement component C5a increased 1.9–2.25-fold in knockout cells compared to wild-type (P < 0.01. This increase was still observed when neutrophils were treated with inhibitors of eicosanoid synthesis. There were no changes in expression of other CYP4 enzymes in knockout neutrophils that might compensate for loss of CYP4F18 or lead to differences in activity. A mouse model of dextran sodium sulfate colitis was used to investigate the consequences of increased C5a-dependent chemotaxis in vivo, but there was no significant difference in weight loss, disease activity, or colonic tissue myeloperoxidase between wild-type and Cyp4f18 knockout mice. This study demonstrates the limitations of inferring CYP4F function based on an ability to use LTB4 as a substrate, points to expanding roles for CYP4F enzymes in immune regulation, and underscores the in vivo challenges of CYP knockout studies.

  14. Heteronuclear three-dimensional NMR spectroscopy of the inflammatory protein C5a

    International Nuclear Information System (INIS)

    Zuiderweg, E.R.P.; Fesik, S.W.

    1989-01-01

    The utility of three-dimensional heteronuclear NMR spectroscopy for the assignment of 1 H and 15 N resonances of the inflammatory protein C5a (MW 8500), uniformly labeled with 15 N, is demonstrated at a protein concentration of 0.7 mM. It is shown that dramatic simplification of the 2D nuclear Overhauser effect spectrum (NOESY) is obtained by editing with respect to the frequency of the 15 N heteronucleus in a third dimension. The improved resolution in the 3D experiment largely facilitates the assignment of protein NMR spectra and allows for the determination of distance constraints from otherwise overlapping NOE cross peaks for purposes of 3D structure determination. The results show that 15 N heteronuclear 3D NMR can facilitate the structure determination of small proteins and promises to be a useful tool for the study of larger systems that cannot be studied by conventional 2D NMR techniques

  15. Heteronuclear three-dimensional NMR spectroscopy of the inflammatory protein C5a

    Energy Technology Data Exchange (ETDEWEB)

    Zuiderweg, E.R.P.; Fesik, S.W. (Abbott Laboratories, Abbott Park, IL (USA))

    1989-03-21

    The utility of three-dimensional heteronuclear NMR spectroscopy for the assignment of {sup 1}H and {sup 15}N resonances of the inflammatory protein C5a (MW 8500), uniformly labeled with {sup 15}N, is demonstrated at a protein concentration of 0.7 mM. It is shown that dramatic simplification of the 2D nuclear Overhauser effect spectrum (NOESY) is obtained by editing with respect to the frequency of the {sup 15}N heteronucleus in a third dimension. The improved resolution in the 3D experiment largely facilitates the assignment of protein NMR spectra and allows for the determination of distance constraints from otherwise overlapping NOE cross peaks for purposes of 3D structure determination. The results show that {sup 15}N heteronuclear 3D NMR can facilitate the structure determination of small proteins and promises to be a useful tool for the study of larger systems that cannot be studied by conventional 2D NMR techniques.

  16. Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis.

    Science.gov (United States)

    Jayne, David R W; Bruchfeld, Annette N; Harper, Lorraine; Schaier, Matthias; Venning, Michael C; Hamilton, Patrick; Burst, Volker; Grundmann, Franziska; Jadoul, Michel; Szombati, István; Tesař, Vladimír; Segelmark, Mårten; Potarca, Antonia; Schall, Thomas J; Bekker, Pirow

    2017-09-01

    Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, -4.3% to 37.1%; P =0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, -11.0% to 32.9%; P =0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis. Copyright © 2017 by the American Society of Nephrology.

  17. Identification and characterization of NDT 9513727 [N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a novel, orally bioavailable C5a receptor inverse agonist.

    Science.gov (United States)

    Brodbeck, Robbin M; Cortright, Daniel N; Kieltyka, Andrzej P; Yu, Jianying; Baltazar, Carolyn O; Buck, Marianne E; Meade, Robin; Maynard, George D; Thurkauf, Andrew; Chien, Du-Shieng; Hutchison, Alan J; Krause, James E

    2008-12-01

    The complement system represents an innate immune mechanism of host defense that has three effector arms, the C3a receptor, the C5a receptor (C5aR), and the membrane attack complex. Because of its inflammatory and immune-enhancing properties, the biological activity of C5a and its classical receptor have been widely studied. Because specific antagonism of the C5aR could have therapeutic benefit without affecting the protective immune response, the C5aR continues to be a promising target for pharmaceutical research. The lack of specific, potent and orally bioavailable small-molecule antagonists has limited the clinical investigation of the C5aR. We report the discovery of NDT 9513727 [N,N-bis(1,3-benzodioxol-5-ylmethyl)-1-butyl-2,4-diphenyl-1H-imidazole-5-methanamine], a small-molecule, orally bioavailable, selective, and potent inverse agonist of the human C5aR. NDT 9513727 was discovered based on the integrated use of in vitro affinity and functional assays in conjunction with medicinal chemistry. NDT 9513727 inhibited C5a-stimulated responses, including guanosine 5'-3-O-(thio)triphosphate binding, Ca(2+) mobilization, oxidative burst, degranulation, cell surface CD11b expression and chemotaxis in various cell types with IC(50)s from 1.1 to 9.2 nM, respectively. In C5a competition radioligand binding experiments, NDT 9513727 exhibited an IC(50) of 11.6 nM. NDT 9513727 effectively inhibited C5a-induced neutropenia in gerbil and cynomolgus macaque in vivo. The findings suggest that NDT 9513727 may be a promising new entity for the treatment of human inflammatory diseases.

  18. Purification of the active C5a receptor from human polymorphonuclear leukocytes as a receptor - G sub i complex

    Energy Technology Data Exchange (ETDEWEB)

    Rollins, T.E.; Siciliano, S.; Kobayashi, S.; Cianciarulo, D.N.; Bonilla-Argudo, V.; Collier, K.; Springer, M.S. (Merck Sharp and Dohme Research Lab., Rahway, NJ (United States))

    1991-02-01

    The authors have isolated, in an active state, the C5a receptor from human polymorphonuclear leukocytes. The purification was achieved in a single step using a C5a affinity column in which the C5a molecule was coupled to the resin through its N terminus. The purified receptor, like the crude solubilized molecule, exhibited a single class of high-affinity binding sites with a K{sub d} of 30 pM. Further, the binding of C5a retained its sensitivity to guanine nucleotides, implying that the purified receptor contained a guanine nucleotide-binding protein (G protein). SDS/PAGE revealed the presence of three polypeptides with molecular masses of 42, 40, and 36 kDa, which were determined to be the C5a-binding subunit and the {alpha} and {beta} subunits of G{sub i}, respectively. The 36- and 40-kDa polypeptides were identified by immunoblotting and by the ability of pertussis toxin to ADP-ribosylate the 40-kDa molecule. These results confirm their earlier hypothesis that the receptor exists as a complex with a G protein in the presence or absence of C5a. The tight coupling between the receptor and G protein should make possible the identification of the G protein(s) involved in the transduction pathways used by C5a to produce its many biological effects.

  19. Purification of the active C5a receptor from human polymorphonuclear leukocytes as a receptor - Gi complex

    International Nuclear Information System (INIS)

    Rollins, T.E.; Siciliano, S.; Kobayashi, S.; Cianciarulo, D.N.; Bonilla-Argudo, V.; Collier, K.; Springer, M.S.

    1991-01-01

    The authors have isolated, in an active state, the C5a receptor from human polymorphonuclear leukocytes. The purification was achieved in a single step using a C5a affinity column in which the C5a molecule was coupled to the resin through its N terminus. The purified receptor, like the crude solubilized molecule, exhibited a single class of high-affinity binding sites with a K d of 30 pM. Further, the binding of C5a retained its sensitivity to guanine nucleotides, implying that the purified receptor contained a guanine nucleotide-binding protein (G protein). SDS/PAGE revealed the presence of three polypeptides with molecular masses of 42, 40, and 36 kDa, which were determined to be the C5a-binding subunit and the α and β subunits of G i , respectively. The 36- and 40-kDa polypeptides were identified by immunoblotting and by the ability of pertussis toxin to ADP-ribosylate the 40-kDa molecule. These results confirm their earlier hypothesis that the receptor exists as a complex with a G protein in the presence or absence of C5a. The tight coupling between the receptor and G protein should make possible the identification of the G protein(s) involved in the transduction pathways used by C5a to produce its many biological effects

  20. Propiconazole-enhanced hepatic cell proliferation is associated with dysregulation of the cholesterol biosynthesis pathway leading to activation of Erk1/2 through Ras farnesylation

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, Lynea A.; Moore, Tanya; Nesnow, Stephen, E-mail: nesnow.stephen@epa.gov

    2012-04-15

    Propiconazole is a mouse hepatotumorigenic fungicide designed to inhibit CYP51, a key enzyme in the biosynthesis of ergosterol in fungi and is widely used in agriculture to prevent fungal growth. Metabolomic studies in mice revealed that propiconazole increased levels of hepatic cholesterol metabolites and bile acids, and transcriptomic studies revealed that genes within the cholesterol biosynthesis, cholesterol metabolism and bile acid biosyntheses pathways were up-regulated. Hepatic cell proliferation was also increased by propiconazole. AML12 immortalized hepatocytes were used to study propiconazole's effects on cell proliferation focusing on the dysregulation of cholesterol biosynthesis and resulting effects on Ras farnesylation and Erk1/2 activation as a primary pathway. Mevalonate, a key intermediate in the cholesterol biosynthesis pathway, increases cell proliferation in several cancer cell lines and tumors in vivo and serves as the precursor for isoprenoids (e.g. farnesyl pyrophosphate) which are crucial in the farnesylation of the Ras protein by farnesyl transferase. Farnesylation targets Ras to the cell membrane where it is involved in signal transduction, including the mitogen-activated protein kinase (MAPK) pathway. In our studies, mevalonic acid lactone (MVAL), a source of mevalonic acid, increased cell proliferation in AML12 cells which was reduced by farnesyl transferase inhibitors (L-744,832 or manumycin) or simvastatin, an HMG-CoA reductase inhibitor, indicating that this cell system responded to alterations in the cholesterol biosynthesis pathway. Cell proliferation in AML12 cells was increased by propiconazole which was reversed by co-incubation with L-744,832 or simvastatin. Increasing concentrations of exogenous cholesterol muted the proliferative effects of propiconazole and the inhibitory effects of L-733,832, results ascribed to reduced stimulation of the endogenous cholesterol biosynthesis pathway. Western blot analysis of subcellular

  1. C5a regulates IL-12+ DC migration to induce pathogenic Th1 and Th17 cells in sepsis.

    Directory of Open Access Journals (Sweden)

    Ning Ma

    Full Text Available OBJECTIVE: It is well known that complement system C5a is excessively activated during the onset of sepsis. However, it is unclear whether C5a can regulate dentritic cells (DCs to stimulate adaptive immune cells such as Th1 and Th17 in sepsis. METHODS: Sepsis was induced by cecal ligation and puncture (CLP. CLP-induced sepsis was treated with anti-C5a or IL-12. IL-12(+DC, IFNγ(+Th1, and IL-17(+Th17 cells were analyzed by flow cytometry. IL-12 was measured by ELISA. RESULTS: Our studies here showed that C5a induced IL-12(+DC cell migration from the peritoneal cavity to peripheral blood and lymph nodes. Furthermore, IL-12(+DC cells induced the expansion of pathogenic IFNγ(+Th1 and IL-17(+Th17 cells in peripheral blood and lymph nodes. Moreover, IL-12, secreted by DC cells in the peritoneal cavity, is an important factor that prevents the development of sepsis. CONCLUSION: Our data suggests that C5a regulates IL-12(+DC cell migration to induce pathogenic Th1 and Th17 cells in sepsis.

  2. Association of Immune and Metabolic Receptors C5aR and C5L2 with Adiposity in Women

    Science.gov (United States)

    Rezvani, Reza; Gupta, Abhishek; Marceau, Picard; Tchernof, André

    2014-01-01

    Adipose tissue receptors C5aR and C5L2 and their heterodimerization/functionality and interaction with ligands C5a and acylation stimulating protein (ASP) have been evaluated in cell and rodent studies. Their contribution to obesity factors in humans remains unclear. We hypothesized that C5a receptors, classically required for host defense, are also associated with adiposity. Anthropometry and fasting blood parameters were measured in 136 women divided by body mass index (BMI): normal/overweight (≤30 kg/m2; n = 34), obese I (≤45 kg/m2; n = 33), obese II (≤51 kg/m2; n = 33), and obese III (≤80 kg/m2; n = 36). Subcutaneous and omental adipose tissue C5aR and C5L2 expression were analysed. C5L2 expression was comparable between subcutaneous and omental across all BMI groups. Plasma ASP and ASP/omental C5L2 expression increased with BMI (P correlations between C5L2/C5aR and waist circumference, HDL-C, and adiponectin. Tissue and BMI differences in receptors and ligands, particularly in omental, suggest relationship to metabolic disturbances and highlight adipose-immune interactions. PMID:24523571

  3. Indomethacin inhibits the increased airway responsiveness to histamine following inhalation of C5a des Arg in rabbits.

    Science.gov (United States)

    Berend, N; Armour, C L; Black, J L

    1986-08-01

    It has been shown that inhalation of C5a des Arg increases rabbit airway responsiveness to histamine and that this is associated with an influx of neutrophils into the airway walls. This study was undertaken to see if the augmented response to histamine can be blocked by the cyclo-oxygenase inhibitor indomethacin. Spontaneously breathing, anesthetised rabbits were studied in a volume displacement plethysmograph and pulmonary resistance (R1) was measured using the electrical subtraction technique. Histamine does response curves (HDR) were generated by measuring R1 after serial nubulisation of saline and histamine (1, 3, 10, 30 and 100 mg/ml). Aerosols of either saline or C5a des Arg (1.5 ug/ml) were then inhaled by the animals over a time period of 2 min. An HDR was then repeated 4 hours later. In 9 rabbits the inhalation of C5a des Arg resulted in an upward shift of the repeat HDR: the area under the HDR was significantly greater than under the first HDR (p less than 0.05). In 6 rabbits the repeat HDR 4 hours after saline was shifted downwards (N.S.) indicating some degree of tachyphylaxis. When rabbits were pretreated with indomethacin (5 mg/kg i.v.) the repeat HDR following either C5a des Arg (n = 7) or saline (n = 6) were also shifted downwards i.e., the increased airway responsiveness noted after C5a des Arg was abolished. There was no significant difference in baseline saline R1 during the first or second HDR in any group. These results suggest that the increased airway responsiveness following nebulisation of C5a des Arg may be due to release from neutrophils of products of the cyclo-oxygenase pathway.

  4. Compromised neutrophil function and severe bovine E.coli mastitis: is C5a the missing link?

    Science.gov (United States)

    Around the periparturient period and during early lactation dairy cows have an elevated risk for clinical mastitis. The severity of Gram-negative infections during these periods has been correlated with reduced neutrophil functions. In this review we focus on the potential role of C5a in the develop...

  5. Tissue Destruction in Bullous Pemphigoid Can Be Complement Independent and May Be Mitigated by C5aR2

    Directory of Open Access Journals (Sweden)

    Christian M. Karsten

    2018-03-01

    Full Text Available Bullous pemphigoid (BP, the most frequent autoimmune bullous disorder, is a paradigmatic autoantibody-mediated disease associated with autoantibodies against BP180 (type XVII collagen, Col17. Several animal models have been developed that reflect important clinical and immunological features of human BP. Complement activation has been described as a prerequisite for blister formation, however, the recent finding that skin lesions can be induced by anti-Col17 F(ab′2 fragments indicates complement-independent mechanisms to contribute to blister formation in BP. Here, C5−/− mice injected with anti-Col17 IgG showed a reduction of skin lesions by about 50% associated with significantly less skin-infiltrating neutrophils compared to wild-type mice. Reduction of skin lesions and neutrophil infiltration was seen independently of the employed anti-Col17 IgG dose. Further, C5ar1−/− mice were protected from disease development, whereas the extent of skin lesions was increased in C5ar2−/− animals. Pharmacological inhibition of C5a receptor 1 (C5aR1 by PMX53 led to reduced disease activity when applied in a prophylactic setting. In contrast, PMX-53 treatment had no effect when first skin lesions had already developed. While C5aR1 was critically involved in neutrophil migration in vitro, its role for Col17-anti-Col17 IgG immune complex-mediated release of reactive oxygen species from neutrophils was less pronounced. Our data demonstrate that complement-dependent and -independent mechanisms coexist in anti-Col17-autoantibody-mediated tissue destruction. C5aR1 and C5aR2 seem to play opposing roles in this process with C5aR1 exerting its primary effect in recruiting inflammatory cells to the skin during the early phase of the disease. Further studies are required to fully understand the role of C5aR2 in autoantibody-mediated skin inflammation.

  6. Disordered eating and emotion dysregulation among adolescents and their parents.

    Science.gov (United States)

    Hansson, Erika; Daukantaité, Daiva; Johnsson, Per

    2017-04-04

    Research on the relationships between adolescent and parental disordered eating (DE) and emotion dysregulation is scarce. Thus, the aim of this study was to explore whether mothers' and fathers' own DE, as measured by SCOFF questionnaire, and emotion dysregulation, as measured by the difficulties in emotion regulation scale (DERS), were associated with their daughters' or sons' DE and emotion dysregulation. Furthermore, the importance of shared family meals and possible parent-related predictors of adolescent DE were explored. The total sample comprised 1,265 adolescents (M age  = 16.19, SD = 1.21; age range 13.5-19 years, 54.5% female) whose parents had received a self-report questionnaire via mail. Of these, 235 adolescents (18.6% of the total sample) whose parents completed the questionnaire were used in the analyses. Parents' responses were matched and compared with those of their child. Adolescent girls showed greater levels of DE overall than did their parents. Furthermore, DE was associated with emotion dysregulation among both adolescents and parents. Adolescent and parental emotion dysregulation was associated, although there were gender differences in the specifics of this relationship. The frequency of shared dinner meals was the only variable that was associated to DE and emotion dysregulation among adolescents, while parental eating disorder was the only variable that enhanced the probability of adolescent DE. The present study contributes to the literature by demonstrating that there are significant associations between parents and their adolescent children in terms of DE, emotion dysregulation, and shared family meals. Future studies should break down these relationships among mothers, fathers, girls, and boys to further clarify the specific associational, and possibly predictive, directions.

  7. Roles for C-X-C chemokines and C5a in lung injury after hindlimb ischemia-reperfusion

    DEFF Research Database (Denmark)

    Bless, N M; Warner, R L; Padgaonkar, V A

    1999-01-01

    We evaluated the roles of the C-X-C chemokines cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) as well as the complement activation product C5a in development of lung injury after hindlimb ischemia-reperfusion in rats. During reperfusion, CD11b...... and CD18, but not CD11a, were upregulated on neutrophils [bronchoalveolar lavage (BAL) and blood] and lung macrophages. BAL levels of CINC and MIP-2 were increased during the ischemic and reperfusion periods. Treatment with either anti-CINC or anti-MIP-2 IgG significantly reduced lung vascular......, 58, and 23%, respectively (P MIP-2 as well as the complement activation product C5a are required for lung neutrophil recruitment and full induction of lung injury after hindlimb ischemia-reperfusion in rats....

  8. Treatment with the C5a receptor antagonist ADC-1004 reduces myocardial infarction in a porcine ischemia-reperfusion model

    Directory of Open Access Journals (Sweden)

    Arheden Håkan

    2010-09-01

    Full Text Available Abstract Background Polymorphonuclear neutrophils, stimulated by the activated complement factor C5a, have been implicated in cardiac ischemia/reperfusion injury. ADC-1004 is a competitive C5a receptor antagonist that has been shown to inhibit complement related neutrophil activation. ADC-1004 shields the neutrophils from C5a activation before they enter the reperfused area, which could be a mechanistic advantage compared to previous C5a directed reperfusion therapies. We investigated if treatment with ADC-1004, according to a clinically applicable protocol, would reduce infarct size and microvascular obstruction in a large animal myocardial infarct model. Methods In anesthetized pigs (42-53 kg, a percutaneous coronary intervention balloon was inflated in the left anterior descending artery for 40 minutes, followed by 4 hours of reperfusion. Twenty minutes after balloon inflation the pigs were randomized to an intravenous bolus administration of ADC-1004 (175 mg, n = 8 or saline (9 mg/ml, n = 8. Area at risk (AAR was evaluated by ex vivo SPECT. Infarct size and microvascular obstruction were evaluated by ex vivo MRI. The observers were blinded to the treatment at randomization and analysis. Results ADC-1004 treatment reduced infarct size by 21% (ADC-1004: 58.3 ± 3.4 vs control: 74.1 ± 2.9%AAR, p = 0.007. Microvascular obstruction was similar between the groups (ADC-1004: 2.2 ± 1.2 vs control: 5.3 ± 2.5%AAR, p = 0.23. The mean plasma concentration of ADC-1004 was 83 ± 8 nM at sacrifice. There were no significant differences between the groups with respect to heart rate, mean arterial pressure, cardiac output and blood-gas data. Conclusions ADC-1004 treatment reduces myocardial ischemia-reperfusion injury and represents a novel treatment strategy of myocardial infarct with potential clinical applicability.

  9. Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists

    Science.gov (United States)

    Seow, Vernon; Lim, Junxian; Cotterell, Adam J.; Yau, Mei-Kwan; Xu, Weijun; Lohman, Rink-Jan; Kok, W. Mei; Stoermer, Martin J.; Sweet, Matthew J.; Reid, Robert C.; Suen, Jacky Y.; Fairlie, David P.

    2016-04-01

    Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory protein complement C5a that activates immune cells and promotes disease. Three equipotent antagonists (3D53, W54011, JJ47) of inflammatory responses to C5a (3nM) were compared for drug-likeness, receptor affinity and antagonist potency in human macrophages, and anti-inflammatory efficacy in rats. Only the least drug-like antagonist (3D53) maintained potency in cells against higher C5a concentrations and had a much longer duration of action (t1/2 ~ 20 h) than W54011 or JJ47 (t1/2 ~ 1-3 h) in inhibiting macrophage responses. The unusually long residence time of 3D53 on its receptor was mechanistically probed by molecular dynamics simulations, which revealed long-lasting interactions that trap the antagonist within the receptor. Despite negligible oral bioavailability, 3D53 was much more orally efficacious than W54011 or JJ47 in preventing repeated agonist insults to induce rat paw oedema over 24 h. Thus, residence time on a receptor can trump drug-likeness in determining efficacy, even oral efficacy, of pharmacological agents.

  10. Molecular characterization of the gerbil C5a receptor and identification of a transmembrane domain V amino acid that is crucial for small molecule antagonist interaction.

    Science.gov (United States)

    Waters, Stephen M; Brodbeck, Robbin M; Steflik, Jeremy; Yu, Jianying; Baltazar, Carolyn; Peck, Amy E; Severance, Daniel; Zhang, Lu Yan; Currie, Kevin; Chenard, Bertrand L; Hutchison, Alan J; Maynard, George; Krause, James E

    2005-12-09

    Anaphylatoxin C5a is a potent inflammatory mediator associated with pathogenesis and progression of several inflammation-associated disorders. Small molecule C5a receptor (C5aR) antagonist development is hampered by species-specific receptor biology and the associated inability to use standard rat and mouse in vivo models. Gerbil is one rodent species reportedly responsive to small molecule C5aR antagonists with human C5aR affinity. We report the identification of the gerbil C5aR cDNA using a degenerate primer PCR cloning strategy. The nucleotide sequence revealed an open reading frame encoding a 347-amino acid protein. The cloned receptor (expressed in Sf9 cells) bound recombinant human C5a with nanomolar affinity. Alignment of the gerbil C5aR sequence with those from other species showed that a Trp residue in transmembrane domain V is the only transmembrane domain amino acid unique to small molecule C5aR antagonist-responsive species (i.e. gerbil, human, and non-human primate). Site-directed mutagenesis was used to generate human and mouse C5aRs with a residue exchange of this Trp residue. Mutation of Trp to Leu in human C5aR completely eliminated small molecule antagonist-receptor interaction. In contrast, mutation of Leu to Trp in mouse C5aR enabled small molecule antagonist-receptor interaction. This crucial Trp residue is located deeper within transmembrane domain V than residues reportedly involved in C5a- and cyclic peptide C5a antagonist-receptor interaction, suggesting a novel interaction site(s) for small molecule antagonists. These data provide insight into the basis for small molecule antagonist species selectivity and further define sites critical for C5aR activation and function.

  11. Relationship of Circulating C5a and Complement Factor H Levels With Disease Control in Pregnant Women With Asthma.

    Science.gov (United States)

    Bohács, Anikó; Bikov, András; Ivancsó, István; Czaller, Ibolya; Böcskei, Renáta; Müller, Veronika; Rigó, János; Losonczy, György; Tamási, Lilla

    2016-04-01

    Asthma often complicates pregnancy and represents a risk of serious pregnancy complications. The complement system contributes to asthma pathogenesis and is up-regulated in healthy gestation as well. The anaphylatoxin C5a has a major pro-inflammatory role, and the complement factor H is a main soluble regulator protein both in asthma and during pregnancy; however, peripheral levels of these complement factors and their relationship to disease control have not yet been evaluated in pregnant subjects with asthma. The present study aimed to investigate circulating C5a and complement factor H levels in asthma (non-pregnant subjects with asthma; n = 19) and in pregnancy with asthma (pregnant subjects with asthma; n = 22), compared with healthy non-pregnant (n = 21) and healthy pregnant women (n = 13) and to test their relationship to clinical parameters of asthma (lung function, airway inflammation, and symptoms). Circulating C5a levels were higher in the pregnant asthma subject group compared with the healthy non-pregnant, healthy pregnant, and non-pregnant asthma groups: median 2.629 (interquartile range [IQR] 2.257-3.052) ng/mL versus 1.84 (IQR 1.576-2.563), 1.783 (IQR 0.6064-2.786), and 2.024 (IQR 1.232-2.615) ng/mL, respectively (P = .02 in all cases). C5a correlated negatively with FEV1 (r = -0.44, P = .039) and FVC values (r = -0.64, P = .001) in the pregnant asthma group and positively with fraction of exhaled nitric oxide levels in the non-pregnant asthma group (n = 12, r = 0.78, P = .004). Complement factor H levels were elevated in both the healthy pregnant and pregnant asthma subject groups compared with the healthy non-pregnant group (median 1,082 [IQR 734.9-1,224] and 910.7 [IQR 614.5-1076] μg/mL vs. 559.7 [IQR 388.7-783.1] μg/mL, P = .002 and P = .004, respectively) but not in the pregnant asthma group compared with the non-pregnant asthma group (median 687.4 [IQR 441.6-947.6] μg/mL, P = .10). Asthma during pregnancy increases the circulating level of

  12. Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury.

    Science.gov (United States)

    Bosmann, Markus; Grailer, Jamison J; Ruemmler, Robert; Russkamp, Norman F; Zetoune, Firas S; Sarma, J Vidya; Standiford, Theodore J; Ward, Peter A

    2013-12-01

    We investigated how complement activation promotes tissue injury and organ dysfunction during acute inflammation. Three models of acute lung injury (ALI) induced by LPS, IgG immune complexes, or C5a were used in C57BL/6 mice, all models requiring availability of both C5a receptors (C5aR and C5L2) for full development of ALI. Ligation of C5aR and C5L2 with C5a triggered the appearance of histones (H3 and H4) in bronchoalveolar lavage fluid (BALF). BALF from humans with ALI contained H4 histone. Histones were absent in control BALF from healthy volunteers. In mice with ALI, in vivo neutralization of H4 with IgG antibody reduced the intensity of ALI. Neutrophil depletion in mice with ALI markedly reduced H4 presence in BALF and was highly protective. The direct lung damaging effects of extracellular histones were demonstrated by airway administration of histones into mice and rats (Sprague-Dawley), which resulted in ALI that was C5a receptor-independent, and associated with intense inflammation, PMN accumulation, damage/destruction of alveolar epithelial cells, together with release into lung of cytokines/chemokines. High-resolution magnetic resonance imaging demonstrated lung damage, edema and consolidation in histone-injured lungs. These studies confirm the destructive C5a-dependent effects in lung linked to appearance of extracellular histones.

  13. Dysregulated metabolism contributes to oncogenesis

    Science.gov (United States)

    Hirschey, Matthew D.; DeBerardinis, Ralph J.; Diehl, Anna Mae E.; Drew, Janice E.; Frezza, Christian; Green, Michelle F.; Jones, Lee W.; Ko, Young H.; Le, Anne; Lea, Michael A.; Locasale, Jason W.; Longo, Valter D.; Lyssiotis, Costas A.; McDonnell, Eoin; Mehrmohamadi, Mahya; Michelotti, Gregory; Muralidhar, Vinayak; Murphy, Michael P.; Pedersen, Peter L.; Poore, Brad; Raffaghello, Lizzia; Rathmell, Jeffrey C.; Sivanand, Sharanya; Vander Heiden, Matthew G.; Wellen, Kathryn E.

    2015-01-01

    Cancer is a disease characterized by unrestrained cellular proliferation. In order to sustain growth, cancer cells undergo a complex metabolic rearrangement characterized by changes in metabolic pathways involved in energy production and biosynthetic processes. The relevance of the metabolic transformation of cancer cells has been recently included in the updated version of the review “Hallmarks of Cancer”, where the dysregulation of cellular metabolism was included as an emerging hallmark. While several lines of evidence suggest that metabolic rewiring is orchestrated by the concerted action of oncogenes and tumor suppressor genes, in some circumstances altered metabolism can play a primary role in oncogenesis. Recently, mutations of cytosolic and mitochondrial enzymes involved in key metabolic pathways have been associated with hereditary and sporadic forms of cancer. Together, these results suggest that aberrant metabolism, once seen just as an epiphenomenon of oncogenic reprogramming, plays a key role in oncogenesis with the power to control both genetic and epigenetic events in cells. In this review, we discuss the relationship between metabolism and cancer, as part of a larger effort to identify a broad-spectrum of therapeutic approaches. We focus on major alterations in nutrient metabolism and the emerging link between metabolism and epigenetics. Finally, we discuss potential strategies to manipulate metabolism in cancer and tradeoffs that should be considered. More research on the suite of metabolic alterations in cancer holds the potential to discover novel approaches to treat it. PMID:26454069

  14. Complement component C5a Promotes Expression of IL-22 and IL-17 from Human T cells and its Implication in Age-related Macular Degeneration

    Directory of Open Access Journals (Sweden)

    Klein Michael L

    2011-07-01

    Full Text Available Abstract Background Age related macular degeneration (AMD is the leading cause of irreversible blindness in elderly populations worldwide. Inflammation, among many factors, has been suggested to play an important role in AMD pathogenesis. Recent studies have demonstrated a strong genetic association between AMD and complement factor H (CFH, the down-regulatory factor of complement activation. Elevated levels of complement activating molecules including complement component 5a (C5a have been found in the serum of AMD patients. Our aim is to study whether C5a can impact human T cells and its implication in AMD. Methods Human peripheral blood mononuclear cells (PBMCs were isolated from the blood of exudative form of AMD patients using a Ficoll gradient centrifugation protocol. Intracellular staining and enzyme-linked immunosorbent assays were used to measure protein expression. Apoptotic cells were detected by staining of cells with the annexin-V and TUNEL technology and analyzed by a FACS Caliber flow cytometer. SNP genotyping was analyzed by TaqMan genotyping assay using the Real-time PCR system 7500. Results We show that C5a promotes interleukin (IL-22 and IL-17 expression by human CD4+ T cells. This effect is dependent on B7, IL-1β and IL-6 expression from monocytes. We have also found that C5a could protect human CD4+ cells from undergoing apoptosis. Importantly, consistent with a role of C5a in promoting IL-22 and IL-17 expression, significant elevation in IL-22 and IL-17 levels was found in AMD patients as compared to non-AMD controls. Conclusions Our results support the notion that C5a may be one of the factors contributing to the elevated serum IL-22 and IL-17 levels in AMD patients. The possible involvement of IL-22 and IL-17 in the inflammation that contributes to AMD may herald a new approach to treat AMD.

  15. Investigating multiple dysregulated pathways in rheumatoid arthritis ...

    Indian Academy of Sciences (India)

    Xian-Dong Song

    2018-03-09

    Mar 9, 2018 ... 5Department of Kidney Internal Medicine, Hongqi Hospital of ... on the gene expression profile, pathway data, and PPI information. ... controls. These 10 dysregulated pathways might be potential ... a significant burden on the healthcare systems (Yamada ... The risk of adverse effects and expensive treat-.

  16. Disruptive mood dysregulation disorder: current insights

    Directory of Open Access Journals (Sweden)

    Baweja R

    2016-08-01

    Full Text Available Raman Baweja, Susan D Mayes, Usman Hameed, James G Waxmonsky Department of Psychiatry, Penn State University College of Medicine, Hershey, PA, USA Abstract: Disruptive mood dysregulation disorder (DMDD was introduced as a new diagnostic entity under the category of depressive disorders in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5. It was included in DSM-5 primarily to address concerns about the misdiagnosis and consequent overtreatment of bipolar disorder in children and adolescents. DMDD does provide a home for a large percentage of referred children with severe persistent irritability that did not fit well into any DSM, Fourth Edition (DSM-IV diagnostic category. However, it has been a controversial addition to the DSM-5 due to lack of published validity studies, leading to questions about its validity as a distinct disorder. In this article, the authors discuss the diagnostic criteria, assessment, epidemiology, criticism of the diagnosis, and pathophysiology, as well as treatment and future directions for DMDD. They also review the literature on severe mood dysregulation, as described by the National Institute of Mental Health, as the scientific support for DMDD is based primarily on studies of severe mood dysregulation. Keywords: disruptive mood dysregulation disorder, persistent irritability, temper outbursts 

  17. Treatment with anti-C5aR mAb leads to early-onset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model

    DEFF Research Database (Denmark)

    Atkinson, Sara Marie; Nansen, Anneline; Usher, Pernille A.

    2015-01-01

    Blockade of the complement cascade at the C5a/C5a receptor (C5aR)-axis is believed to be an attractive treatment avenue in rheumatoid arthritis (RA). However, the effects of such interventions during the early phases of arthritis remain to be clarified. In this study we use the murine delayed-typ...

  18. Dual Functions of the C5a Receptor as a Connector for the K562 Erythroblast-Like Cell-THP-1 Macrophage-Like Cell Island and as a Sensor for the Differentiation of the K562 Erythroblast-Like Cell during Haemin-Induced Erythropoiesis

    Directory of Open Access Journals (Sweden)

    Hiroshi Nishiura

    2012-01-01

    Full Text Available The transcriptional nuclear factor binding to the Y box of human leukocyte antigen genes (NF-Y for the C5a receptor (C5aR gene is active in erythroblasts. However, the roles of the C5aR in erythropoiesis are unclear. We have previously demonstrated that apoptotic cell-derived ribosomal protein S19 (RP S19 oligomers exhibit extraribosomal functions in promoting monocyte chemotaxis and proapoptosis via the C5aR without receptor internalisation. In contrast to the extraribosomal functions of the RP S19, a proapoptotic signal in pro-EBs, which is caused by mutations in the RP S19 gene, is associated with the inherited erythroblastopenia, Diamond-Blackfan anaemia. In this study, we detected C5aR expression and RP S19 oligomer generation in human erythroleukemia K562 cells during haemin-induced erythropoiesis. Under monocell culture conditions, the differentiation into K562 erythrocyte-like cells was enhanced following the overexpression of Wild-type RP S19. Conversely, the differentiation was repressed following the overexpression of mutant RP S19. An RP S19 oligomer inhibitor and a C5aR inhibitor blocked the association of the K562 basophilic EB-like cells and the THP-1 macrophage-like cells under coculture conditions. When bound to RP S19 oligomers, the C5aR may exhibit dual functions as a connector for the EB-macrophage island and as a sensor for EB differentiation in the bone marrow.

  19. Exercise Training Attenuates the Dysregulated Expression of Adipokines and Oxidative Stress in White Adipose Tissue

    Directory of Open Access Journals (Sweden)

    Takuya Sakurai

    2017-01-01

    Full Text Available Obesity-induced inflammatory changes in white adipose tissue (WAT, which caused dysregulated expression of inflammation-related adipokines involving tumor necrosis factor-α and monocyte chemoattractant protein-1, contribute to the development of insulin resistance. Moreover, current literature reports state that WAT generates reactive oxygen species (ROS, and the enhanced production of ROS in obese WAT has been closely associated with the dysregulated expression of adipokines in WAT. Therefore, the reduction in excess WAT and oxidative stress that results from obesity is thought to be one of the important strategies in preventing and improving lifestyle-related diseases. Exercise training (TR not only brings about a decrease in WAT mass but also attenuates obesity-induced dysregulated expression of the adipokines in WAT. Furthermore, some reports indicate that TR affects the generation of oxidative stress in WAT. This review outlines the impact of TR on the expression of inflammation-related adipokines and oxidative stress in WAT.

  20. Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes.

    Science.gov (United States)

    Martinelli, Simone; Krumbach, Oliver H F; Pantaleoni, Francesca; Coppola, Simona; Amin, Ehsan; Pannone, Luca; Nouri, Kazem; Farina, Luciapia; Dvorsky, Radovan; Lepri, Francesca; Buchholzer, Marcel; Konopatzki, Raphael; Walsh, Laurence; Payne, Katelyn; Pierpont, Mary Ella; Vergano, Samantha Schrier; Langley, Katherine G; Larsen, Douglas; Farwell, Kelly D; Tang, Sha; Mroske, Cameron; Gallotta, Ivan; Di Schiavi, Elia; Della Monica, Matteo; Lugli, Licia; Rossi, Cesare; Seri, Marco; Cocchi, Guido; Henderson, Lindsay; Baskin, Berivan; Alders, Mariëlle; Mendoza-Londono, Roberto; Dupuis, Lucie; Nickerson, Deborah A; Chong, Jessica X; Meeks, Naomi; Brown, Kathleen; Causey, Tahnee; Cho, Megan T; Demuth, Stephanie; Digilio, Maria Cristina; Gelb, Bruce D; Bamshad, Michael J; Zenker, Martin; Ahmadian, Mohammad Reza; Hennekam, Raoul C; Tartaglia, Marco; Mirzaa, Ghayda M

    2018-01-17

    Exome sequencing has markedly enhanced the discovery of genes implicated in Mendelian disorders, particularly for individuals in whom a known clinical entity could not be assigned. This has led to the recognition that phenotypic heterogeneity resulting from allelic mutations occurs more commonly than previously appreciated. Here, we report that missense variants in CDC42, a gene encoding a small GTPase functioning as an intracellular signaling node, underlie a clinically heterogeneous group of phenotypes characterized by variable growth dysregulation, facial dysmorphism, and neurodevelopmental, immunological, and hematological anomalies, including a phenotype resembling Noonan syndrome, a developmental disorder caused by dysregulated RAS signaling. In silico, in vitro, and in vivo analyses demonstrate that mutations variably perturb CDC42 function by altering the switch between the active and inactive states of the GTPase and/or affecting CDC42 interaction with effectors, and differentially disturb cellular and developmental processes. These findings reveal the remarkably variable impact that dominantly acting CDC42 mutations have on cell function and development, creating challenges in syndrome definition, and exemplify the importance of functional profiling for syndrome recognition and delineation. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  1. BCAA Metabolism and Insulin Sensitivity - Dysregulated by Metabolic Status?

    Science.gov (United States)

    Gannon, Nicholas P; Schnuck, Jamie K; Vaughan, Roger A

    2018-03-01

    Branched-chain amino acids (BCAAs) appear to influence several synthetic and catabolic cellular signaling cascades leading to altered phenotypes in mammals. BCAAs are most notably known to increase protein synthesis through modulating protein translation, explaining their appeal to resistance and endurance athletes for muscle hypertrophy, expedited recovery, and preservation of lean body mass. In addition to anabolic effects, BCAAs may increase mitochondrial content in skeletal muscle and adipocytes, possibly enhancing oxidative capacity. However, elevated circulating BCAA levels have been correlated with severity of insulin resistance. It is hypothesized that elevated circulating BCAAs observed in insulin resistance may result from dysregulated BCAA degradation. This review summarizes original reports that investigated the ability of BCAAs to alter glucose uptake in consequential cell types and experimental models. The review also discusses the interplay of BCAAs with other metabolic factors, and the role of excess lipid (and possibly energy excess) in the dysregulation of BCAA catabolism. Lastly, this article provides a working hypothesis of the mechanism(s) by which lipids may contribute to altered BCAA catabolism, which often accompanies metabolic disease. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Endocrine Dysregulation in Anorexia Nervosa Update

    Science.gov (United States)

    2011-01-01

    Context: Anorexia nervosa is a primary psychiatric disorder with serious endocrine consequences, including dysregulation of the gonadal, adrenal, and GH axes, and severe bone loss. This Update reviews recent advances in the understanding of the endocrine dysregulation observed in this state of chronic starvation, as well as the mechanisms underlying the disease itself. Evidence Acquisition: Findings of this update are based on a PubMed search and the author's knowledge of this field. Evidence Synthesis: Recent studies have provided insights into the mechanisms underlying endocrine dysregulation in states of chronic starvation as well as the etiology of anorexia nervosa itself. This includes a more complex understanding of the pathophysiologic bases of hypogonadism, hypercortisolemia, GH resistance, appetite regulation, and bone loss. Nevertheless, the etiology of the disease remains largely unknown, and effective therapies for the endocrine complications and for the disease itself are lacking. Conclusions: Despite significant progress in the field, further research is needed to elucidate the mechanisms underlying the development of anorexia nervosa and its endocrine complications. Such investigations promise to yield important advances in the therapeutic approach to this disease as well as to the understanding of the regulation of endocrine function, skeletal biology, and appetite regulation. PMID:21976742

  3. Epigenetic Dysregulation in Laryngeal Squamous Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Thian-Sze Wong

    2012-01-01

    Full Text Available Laryngeal carcinoma is a common head and neck cancer with poor prognosis. Patients with laryngeal carcinoma usually present late leading to the reduced treatment efficacy and high rate of recurrence. Despite the advance in the use of molecular markers for monitoring human cancers in the past decades, there are still no reliable markers for use to screen laryngeal carcinoma and follow the patients after treatment. Epigenetics emerged as an important field in understanding the biology of the human malignancies. Epigenetic alterations refer to the dysregulation of gene, which do not involve the alterations of the DNA sequence. Major epigenetic changes including methylation imbalance, histone modification, and small RNA dysregulation could play a role in the development of human malignancies. Global epigenetic change is now regarded as a molecular signature of cancer. The characteristics and behavior of a cancer could be predicted based on the specific epigenetic pattern. We here provide a review on the understanding of epigenetic dysregulation in laryngeal carcinoma. Further knowledge on the initiation and progression of laryngeal carcinoma at epigenetic level could promote the translation of the knowledge to clinical use.

  4. CFH Y402H polymorphism and the complement activation product C5a: effects on NF-κB activation and inflammasome gene regulation.

    Science.gov (United States)

    Cao, Sijia; Wang, Jay Ching Chieh; Gao, Jiangyuan; Wong, Matthew; To, Elliott; White, Valerie A; Cui, Jing Z; Matsubara, Joanne A

    2016-05-01

    The Y402H polymorphism in the complement factor H (CFH) gene is an important risk factor for age-related macular degeneration (AMD). Complement activation products and proinflammatory cytokines are associated with this polymorphism at the systemic level, but less is known of the associations in the outer retina of the genotyped eye. Here we investigate complement activation products and their role in nuclear factor (NF)-κB activation and gene expression of the NLRP3 inflammasome pathway. Postmortem donor eyes were genotyped for the CFH Y402H polymorphism and assessed for complement C3a, C5a, interleukin (IL)-18 and tumour necrosis factor (TNF)-α. ARPE19 cells were stimulated basolaterally with C5a or TNF-α in polarised cultures. NF-κB activation was assessed with a reporter cell line. Gene expression of inflammasome-related (NLRP3, caspase-1, IL-1β and IL-18) and classic inflammatory (IL-6 and IL-8) genes was studied. The distribution of inflammasome products, IL-1β and IL-18, was studied in postmortem donor eyes with AMD pathologies. Eyes with the homozygous at-risk variant demonstrated higher levels of C5a, IL-18 and TNF-α in Bruch's membrane and choroid. C5a promoted NF-κB activation and upregulation of IL-18 in polarised ARPE19. TNF-α promoted NF-κB activation and gene expression of caspase-1, IL-1β, IL-18, IL-6 and IL-8, but downregulated NLRP3. In eyes with geographic atrophy, strong immunoreactivity was observed for inflammasome products IL-1β and IL-18 compared with age-matched controls. The at-risk polymorphism of the CFH Y402H may contribute to AMD disease process through increased complement and NF-κB activation, and the upregulation of IL-18, a product of inflammasome activation. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  5. The effects of early positive parenting and developmental delay status on child emotion dysregulation.

    Science.gov (United States)

    Norona, A N; Baker, B L

    2017-02-01

    , findings provided support for our hypothesis that early positive parenting mediated the relationship between DD and dysregulation. This work enhances our understanding of the development of ER across childhood and how endogenous child factors (DD status) and exogenous family factors (positive parenting) affect this process. Our findings provide clear implications for early intervention programmes for children with DD. Because of the predictive relationships between (a) developmental status and ER and (b) parenting and ER, the results imply that sensitive parenting behaviours should be specifically targeted in parent interventions for children with DD. © 2016 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

  6. Emotion Dysregulation and Adolescent Psychopathology: A Prospective Study

    Science.gov (United States)

    Hatzenbuehler, Mark L.; Nolen-Hoeksema, Susan

    2011-01-01

    Background Emotion regulation deficits have been consistently linked to psychopathology in cross-sectional studies. However, the direction of the relationship between emotion regulation and psychopathology is unclear. This study examined the longitudinal and reciprocal relationships between emotion regulation deficits and psychopathology in adolescents. Methods Emotion dysregulation and symptomatology (depression, anxiety, aggressive behavior, and eating pathology) were assessed in a large, diverse sample of adolescents (N = 1,065) at two time points separated by seven months. Structural equation modeling was used to examine the longitudinal and reciprocal relationships between emotion dysregulation and symptoms of psychopathology. Results The three distinct emotion processes examined here (emotional understanding, dysregulated expression of sadness and anger, and ruminative responses to distress) formed a unitary latent emotion dysregulation factor. Emotion dysregulation predicted increases in anxiety symptoms, aggressive behavior, and eating pathology after controlling for baseline symptoms but did not predict depressive symptoms. In contrast, none of the four types of psychopathology predicted increases in emotion dysregulation after controlling for baseline emotion dysregulation. Conclusions Emotion dysregulation appears to be an important transdiagnostic factor that increases risk for a wide range of psychopathology outcomes in adolescence. These results suggest targets for preventive interventions during this developmental period of risk. PMID:21718967

  7. How Parkinsonian Toxins Dysregulate the Autophagy Machinery

    Directory of Open Access Journals (Sweden)

    Ruben K. Dagda

    2013-11-01

    Full Text Available Since their discovery, Parkinsonian toxins (6-hydroxydopamine, MPP+, paraquat, and rotenone have been widely employed as in vivo and in vitro chemical models of Parkinson’s disease (PD. Alterations in mitochondrial homeostasis, protein quality control pathways, and more recently, autophagy/mitophagy have been implicated in neurotoxin models of PD. Here, we highlight the molecular mechanisms by which different PD toxins dysregulate autophagy/mitophagy and how alterations of these pathways play beneficial or detrimental roles in dopamine neurons. The convergent and divergent effects of PD toxins on mitochondrial function and autophagy/mitophagy are also discussed in this review. Furthermore, we propose new diagnostic tools and discuss how pharmacological modulators of autophagy/mitophagy can be developed as disease-modifying treatments for PD. Finally, we discuss the critical need to identify endogenous and synthetic forms of PD toxins and develop efficient health preventive programs to mitigate the risk of developing PD.

  8. Steroid dysregulation and stomatodynia (burning mouth syndrome).

    Science.gov (United States)

    Woda, Alain; Dao, Thuan; Gremeau-Richard, Christelle

    2009-01-01

    Stomatodynia ( burning mouth syndrome) is characterized by a spontaneous, continuous burning pain felt in the oral mucosa typically of anxiodepressive menopausal women. Because there is no obvious organic cause, it is considered a nonspecific pain. This Focus Article proposes a hypothesis based on the following pathophysiological cascade: chronic anxiety or post traumatic stress leads to a dysregulation of the adrenal production of steroids. One consequence is a decreased or modified production of some major precursors for the neuroactive steroid synthesis occurring in the skin, mucosa, and nervous system. At menopause, the drastic fall of the other main precursor supply , the gonadal steroids, leads to a brisk alteration of the production of neuroactive steroids. This results in neurodegenerative alterations of small nerves fibers of the oral mucosa and /or some brain areas involved in oral somatic sensations. These neuropathic changes become irreversible and precipitate the burning pain, dysgeusia, and xerostomia associated with stomatodynia, which all involve thin nerve fibers.

  9. Dissociative symptoms and neuroendocrine dysregulation in depression.

    Science.gov (United States)

    Bob, Petr; Fedor-Freybergh, Peter; Jasova, Denisa; Bizik, Gustav; Susta, Marek; Pavlat, Josef; Zima, Tomas; Benakova, Hana; Raboch, Jiri

    2008-10-01

    Dissociative symptoms are traditionally attributed to psychological stressors that produce dissociated memories related to stressful life events. Dissociative disorders and dissociative symptoms including psychogenic amnesia, fugue, dissociative identity-disorder, depersonalization, derealization and other symptoms or syndromes have been reported as an epidemic psychiatric condition that may be coexistent with various psychiatric diagnoses such as depression, schizophrenia, borderline personality disorder or anxiety disorders. According to recent findings also the somatic components of dissociation may occur and influence brain, autonomic and neuroendocrine functions. At this time there are only few studies examining neuroendocrine response related to dissociative symptoms that suggest significant dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis. The aim of the present study is to perform examination of HPA axis functioning indexed by basal cortisol and prolactin and test their relationship to psychic and somatoform dissociative symptoms. Basal cortisol and prolactin and psychic and somatoform dissociative symptoms were assessed in 40 consecutive inpatients with diagnosis of unipolar depression mean age 43.37 (SD=12.21). The results show that prolactin and cortisol as indices of HPA axis functioning manifest significant relationship to dissociative symptoms. Main results represent highly significant correlations obtained by simple regression between psychic dissociative symptoms (DES) and serum prolactin (R=0.55, p=0.00027), and between somatoform dissociation (SDQ-20) and serum cortisol (R=-0.38, p=0.015). These results indicate relationship between HPA-axis reactivity and dissociative symptoms in unipolar depressive patients that could reflect passive coping behavior and disengagement.

  10. Confabulation: Developing the 'emotion dysregulation' hypothesis.

    Science.gov (United States)

    Turnbull, Oliver H; Salas, Christian E

    2017-02-01

    Confabulations offer unique opportunities for establishing the neurobiological basis of delusional thinking. As regards causal factors, a review of the confabulation literature suggests that neither amnesia nor executive impairment can be the sole (or perhaps even the primary) cause of all delusional beliefs - though they may act in concert with other factors. A key perspective in the modern literature is that many delusions have an emotionally positive or 'wishful' element, that may serve to modulate or manage emotional experience. Some authors have referred to this perspective as the 'emotion dysregulation' hypothesis. In this article we review the theoretical underpinnings of this approach, and develop the idea by suggesting that the positive aspects of confabulatory states may have a role in perpetuating the imbalance between cognitive control and emotion. We draw on existing evidence from fields outside neuropsychology, to argue for three main causal factors: that positive emotions are related to more global or schematic forms of cognitive processing; that positive emotions influence the accuracy of memory recollection; and that positive emotions make people more susceptible to false memories. These findings suggest that the emotions that we want to feel (or do not want to feel) can influence the way we reconstruct past experiences and generate a sense of self - a proposition that bears on a unified theory of delusional belief states. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

  11. Dopaminergic Dysregulation, Artistic Expressiveness, and Parkinson's Disease

    Science.gov (United States)

    López-Pousa, S.; Lombardía-Fernández, C.; Olmo, J. Garre; Monserrat-Vila, S.; Vilalta-Franch, J.; Calvó-Perxas, L.

    2012-01-01

    Background The most frequent behavioral manifestations in Parkinson's disease (PD) are attributed to the dopaminergic dysregulation syndrome (DDS), which is considered to be secondary to the iatrogenic effects of the drugs that replace dopamine. Over the past few years some cases of patients improving their creative abilities after starting treatment with dopaminergic pharmaceuticals have been reported. These effects have not been clearly associated to DDS, but a relationship has been pointed out. Methods Case study of a patient with PD. The evolution of her paintings along medication changes and disease advance has been analyzed. Results The patient showed a compulsive increase of pictorial production after the diagnosis of PD was made. She made her best paintings when treated with cabergolide, and while painting, she reported a feeling of well-being, with loss of awareness of the disease and reduction of physical limitations. Conclusions Dopaminergic antagonists (DA) trigger a dopaminergic dysfunction that alters artistic creativity in patients having a predisposition for it. The development of these skills might be due to the dopaminergic overstimulation due to the therapy with DA, which causes a neurophysiological alteration that globally determines DDS. PMID:23185168

  12. The Child Behavior Checklist Dysregulation Profile in Preschool Children: A Broad Dysregulation Syndrome.

    Science.gov (United States)

    Geeraerts, Sanne Barbara; Deutz, Marike Hester Francisca; Deković, Maja; Bunte, Tessa; Schoemaker, Kim; Espy, Kimberly Andrews; Prinzie, Peter; van Baar, Anneloes; Matthys, Walter

    2015-07-01

    Children with concurrent impairments in regulating affect, behavior, and cognition can be identified with the Anxious/Depressed, Aggressive Behavior, and Attention Problems scales (or AAA scales) of the Child Behavior Checklist (CBCL). Jointly, these scales form the Dysregulation Profile (DP). Despite persuasive evidence that DP is a marker for severe developmental problems, no consensus exists on the preferred conceptualization and operationalization of DP in preschool years. We addressed this concern by testing and validating the factor structure of DP in a group of predominantly clinically referred preschool children. Participants were 247 children (195 boys and 52 girls), aged 3.5 to 5.5 years. Children were assessed at baseline and 18 months later, using parent and teacher reports, a clinical interview with parents, behavioral observations, and neuropsychological tasks. Confirmatory factor analysis showed that a bifactor model, with a general DP factor and 3 specific factors representing the AAA scales, fitted the data better than a second-order model and a one-factor model for both parent-reported and teacher-reported child problem behavior. Criterion validity analyses showed that the DP factor was concurrently and longitudinally associated with markers of dysregulation and clinically relevant criteria, whereas the specific factors representing the AAA scales were more differentially related to those criteria. DP is best conceptualized as a broad syndrome of dysregulation that exists in addition to the specific syndromes as represented by the AAA scales. Implications for researchers and clinicians are discussed. Copyright © 2015 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

  13. Transcriptional dysregulation causes altered modulation of inhibition by haloperidol.

    Science.gov (United States)

    Brady, Lillian J; Bartley, Aundrea F; Li, Qin; McMeekin, Laura J; Hablitz, John J; Cowell, Rita M; Dobrunz, Lynn E

    2016-12-01

    Many neuropsychiatric and neurodevelopmental disorders such as schizophrenia and autism involve interneuron transcriptional dysregulation. The transcriptional coactivator PGC-1α regulates gene expression in GABAergic interneurons, which are important for regulating hippocampal network activity. Genetic deletion of PGC-1α causes a decrease in parvalbumin expression, similar to what is observed in schizophrenia postmortem tissue. Our lab has previously shown that PGC-1α -/- mice have enhanced GABAergic inhibition onto CA1 pyramidal cells, which increases the inhibition/excitation (I/E) ratio, alters hippocampal circuit function, and impairs hippocampal dependent behavior. The typical antipsychotic haloperidol, a dopamine receptor antagonist with selectivity for D2-like receptors, has previously been shown to increase excitation in the CA1 region of hippocampus. We therefore tested whether haloperidol could normalize the I/E balance in CA1 of PGC-1α -/- mice, potentially improving circuit function and behavior. Surprisingly, we discovered instead that interneuron transcriptional dysregulation caused by loss of PGC-1α alters the effects of haloperidol on hippocampal synaptic transmission and circuit function. Acute administration of haloperidol causes disinhibition in CA1 and decreases the I/E ratio onto CA1 pyramidal cells in slices from PGC-1α +/+ mice, but not PGC-1α -/- mice. The spread of activity in CA1, assessed by voltage sensitive dye imaging, is increased by haloperidol in slices from PGC-1α +/+ mice; however haloperidol decreases the spread of activity in slices from PGC-1α -/- mice. Haloperidol increased the power of hippocampal gamma oscillation in slices from PGC-1α +/+ mice but reduced the power of gamma oscillations in slices from PGC-1α -/- mice. Nest construction, an innate hippocampal-dependent behavior, is inhibited by haloperidol in PGC-1α +/+ mice, but not in PGC-1α -/- mice, which already have impaired nest building. The effects of

  14. Gender moderates the relationship between attachment insecurities and emotion dysregulation

    NARCIS (Netherlands)

    Velotti, P.; D’Aguanno, M.; de Campora, G.; di Francescantonio, S.; Garofalo, C.; Giromini, L.; Petrocchi, C.; Terrasi, M.; Zavattini, G.C.

    2016-01-01

    The relation between attachment styles and emotion regulation is well documented, and emotion dysregulation is considered characteristic of individuals with insecure attachment styles. Although gender differences in emotion regulation have often been reported, it is not clear whether the association

  15. Dysregulated behaviors in bulimia nervosa: a case-control study

    OpenAIRE

    Gonçalves, Sónia; Machado, Bárbara Freire Brito César; Martins, C.; Brandão, Isabel; Torres, António Roma; Machado, Paulo P. P.

    2014-01-01

    Background: Bulimia nervosa (BN) is often related to self-control difficulties and to dysregulated behaviours. This study aimed to evaluate the frequency of self-injurious behaviour, suicide attempts, and other dysregulated behaviours in BN, using two control groups (a healthy group and a general psychiatric group), and also to examine the association between these behaviours and alleged sexual abuse in BN.Method: Women (N = 233) aged between 13 and 38 years old were evaluated using a semi-st...

  16. Emotion Dysregulation Mediates Between Childhood Emotional Abuse and Motives for Substance Use.

    Science.gov (United States)

    Barahmand, Usha; Khazaee, Ali; Hashjin, Goudarz Sadeghi

    2016-12-01

    The purpose of this study is to assess the relative mediating effects of impulsivity and emotion dysregulation in the relationship between childhood maltreatment and motives for opiate use. Seventy four adolescent users of Tramadol, a synthetic opiate, were recruited from a boot camp for de-addiction and rehabilitation services for the study. Data were collected between May, 2014 and November, 2014. Participants completed assessments of childhood abuse history, difficulties regulating emotions, impulsiveness and motives for substance use as well as a socio-demographic information sheet. The results of the current study indicate that types of abuse may be associated with particular outcomes and can inform treatment planning for substance users. Findings from bootstrap mediator analyses indicated that emotion dysregulation, but not impulsiveness, mediated the relationship between childhood emotional abuse and expansion and enhancement motives for substance use. The current study provides preliminary evidence that difficulties regulating emotions may function as a mechanism linking prior childhood experiences of emotional abuse to subsequent motives for substance use. Clinical implications of these findings suggest that targeting emotion dysregulation problems may be an effective adjunct in the treatment of childhood emotional abuse adolescent victims at risk for substance use. Published by Elsevier Inc.

  17. Complement Receptors C5aR and C5L2 Are Associated with Metabolic Profile, Sex Hormones, and Liver Enzymes in Obese Women Pre- and Postbariatric Surgery

    Directory of Open Access Journals (Sweden)

    Reza Rezvani

    2014-01-01

    Full Text Available Objective. Obesity is associated with metabolic dysfunction with sex differences and chronic, low-grade inflammation. We proposed that hepatic expression of immune complement C3 related receptors (C3aR, C5aR, and C5L2 would be associated with pre- or postmenopausal status and metabolic profile in severely obese women. We hypothesized that C5L2/C5aR ratio, potentially influencing the ASP/C5L2 metabolic versus C5a/C5aR immune response, would predict metabolic profiles after weight loss surgery. Materials and Methods. Fasting plasma (hormone, lipid, and enzyme analysis and liver biopsies (RT-PCR gene expression were obtained from 91 women during surgery. Results. Hepatic C5L2 mRNA expression was elevated in pre- versus postmenopausal women (P<0.01 and correlated positively with circulating estradiol, estrone, ApoB, ApoA1, ApoA1/B, waist circumference, age, and LDL-C (all P<0.05. While plasma ASP was lower in pre- versus postmenopausal women (P<0.01, the hepatic C5L2/C5aR mRNA ratio was increased (P<0.001 and correlated positively with estrone (P<0.01 and estradiol (P<0.001 and negatively with circulating ApoB and liver enzymes ALT, AST, and GGT (all P<0.05. Over 12 months postoperatively, liver enzymes in low C5L2/C5aR mRNA ratio group remained higher (ALP and ALT, P<0.05, AST and GGT, P<0.001 2-way-ANOVA. Conclusion. C5L2-C5aR association with other mediators including estrogens may contribute to hepatic metabolic and inflammatory function.

  18. Emotion dysregulation and social competence: stability, change and predictive power.

    Science.gov (United States)

    Berkovits, L D; Baker, B L

    2014-08-01

    Social difficulties are closely linked to emotion dysregulation among children with typical development (TD). Children with developmental delays (DD) are at risk for poor social outcomes, but the relationship between social and emotional development within this population is not well understood. The current study examines the extent to which emotion dysregulation is related to social problems across middle childhood among children with TD or DD. Children with TD (IQ ≥ 85, n = 113) and children with DD (IQ ≤ 75, n = 61) participated in a longitudinal study. Annual assessments were completed at ages 7, 8 and 9 years. At each assessment, mothers reported on children's emotion dysregulation, and both mothers and teachers reported on children's social difficulties. Children with DD had higher levels of emotion dysregulation and social problems at each age than those with TD. Emotion dysregulation and social problems were significantly positively correlated within both TD and DD groups using mother report of social problems, and within the TD group using teacher report of social problems. Among children with TD, emotion dysregulation consistently predicted change in social problems from one year to the next. However, among children with DD, emotion dysregulation offered no unique prediction value above and beyond current social problems. Results suggested that the influence of emotion regulation abilities on social development may be a less salient pathway for children with DD. These children may have more influences, beyond emotion regulation, on their social behaviour, highlighting the importance of directly targeting social skill deficits among children with DD in order to ameliorate their social difficulties. © 2013 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

  19. Dysregulated sexuality and high sexual desire: distinct constructs?

    Science.gov (United States)

    Winters, Jason; Christoff, Kalina; Gorzalka, Boris B

    2010-10-01

    The literature on dysregulated sexuality, whether theoretical, clinical or empirical, has failed to differentiate the construct from high sexual desire. In this study, we tested three hypotheses which addressed this issue. A sample of 6458 men and 7938 women, some of whom had sought treatment for sexual compulsivity, addiction or impulsivity, completed an online survey comprised of various sexuality measures. Men and women who reported having sought treatment scored significantly higher on measures of dysregulated sexuality and sexual desire. For men, women, and those who had sought treatment, dysregulated sexuality was associated with increased sexual desire. Confirmatory factor analysis supported a one-factor model, indicating that, in both male and female participants, dysregulated sexuality and sexual desire variables loaded onto a single underlying factor. The results of this study suggest that dysregulated sexuality, as currently conceptualized, labelled, and measured, may simply be a marker of high sexual desire and the distress associated with managing a high degree of sexual thoughts, feelings, and needs.

  20. Dysregulation of Macrophage Activation Profiles by Engineered Nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Kodali, Vamsi; Littke, Matthew H.; Tilton, Susan C.; Teeguarden, Justin G.; Shi, Liang; Frevert, Charles W.; Wang, Wei; Pounds, Joel G.; Thrall, Brian D.

    2013-08-27

    Although the potential human health impacts from exposure to engineered nanoparticles (ENPs) are uncertain, past epidemiological studies have established correlations between exposure to ambient air pollution particulates and the incidence of pneumonia and lung infections. Using amorphous silica and superparamagnetic iron oxide (SPIO) as model high production volume ENPs, we examined how macrophage activation by bacterial lipopolysaccharide (LPS) or the lung pathogen Streptococcus pneumoniae is altered by ENP pretreatment. Neither silica nor SPIO treatment elicited direct cytotoxic or pro-inflammatory effects in bone marrow-derived macrophages. However, pretreatment of macrophages with SPIO caused extensive reprogramming of nearly 500 genes regulated in response to LPS challenge, hallmarked by exaggerated activation of oxidative stress response pathways and suppressed activation of both pro- and anti-inflammatory pathways. Silica pretreatment altered regulation of only 67 genes, but there was strong correlation with gene sets affected by SPIO. Macrophages exposed to SPIO displayed a phenotype suggesting an impaired ability to transition from an M1 to M2-like activation state, characterized by suppressed IL-10 induction, enhanced TNFα production, and diminished phagocytic activity toward S. pneumoniae. Studies in macrophages deficient in scavenger receptor A (SR-A) showed SR-A participates in cell uptake of both the ENPs and S. pneumonia and co-regulates the anti-inflammatory IL-10 pathway. Thus, mechanisms for dysregulation of innate immunity exist by virtue that common receptor recognition pathways are used by some ENPs and pathogenic bacteria, although the extent of transcriptional reprogramming of macrophage function depends on the physicochemical properties of the ENP after internalization. Our results also illustrate that biological effects of ENPs may be indirectly manifested only after challenging normal cell function. Finally, nanotoxicology screening

  1. Dysregulation of Autophagy Contributes to Anal Carcinogenesis.

    Directory of Open Access Journals (Sweden)

    Evie H Carchman

    . With the development of low-grade dysplasia in the K14E6/E7 mice, there was an increase in both punctate LC3β and p62 expression while EM revealed increased autophagosomes without evidence of autophagolysosomes. These observations are consistent with autophagy being inhibited at a later stage in the autophagic process. In contrast, in high-grade dysplasia and SCC in the DMBA-treated K14E6/E7 mice, there were decreased levels of p62 with a continued increase in punctate LC3β expression by IF, while autophagolysosomes were seen on EM, consistent with the process of autophagy proceeded to completion. Similar findings, including histological grade dependent changes in LC3β and p62 expression, were noted with human samples upon analysis of IF. Finally, with pharmacologic inhibition of autophagy in DMBA-treated, nontrangenic FVB/N mice, there was a significant increase in anal cancer development similar to that observed in DMBA- treated K14E6/E7 mice.Autophagic dysregulation is noted early on in HPV-associated anal carcinogenesis (low-grade dysplasia, with normalization of the autophagic process arising in late stages of HPV-associated anal carcinogenesis (high-grade dysplasia and invasive carcinoma.

  2. Emotion Dysregulation Mediates the Relation between Mindfulness and Rejection Sensitivity.

    Science.gov (United States)

    Velotti, Patrizia; Garofalo, Carlo; Bizzi, Fabiola

    2015-09-01

    The role of rejection sensitivity (RS; the tendency to anxiously expect, readily perceive, and overreact to implied or overt interpersonal rejection) in psychopathology has mainly been studied with regard to borderline personality disorder (BPD). In the present study, we first sought to extend previous evidence of heightened RS in a clinical group with psychiatric disorders other than BPD, when compared with a community sample. Then, we tested whether emotion dysregulation and mindfulness were associated with RS in both sample, further hypothesizing that emotion dysregulation would mediate the relation between mindfulness deficits and RS. We adopted a cross-sectional design involving 191 psychiatric patients and 277 community participants (total N=468). All participants completed the Rejection Sensitivity Questionnaire, the Five Facet Mindfulness Questionnaire, and the Difficulties in Emotion Regulation Scale. Our hypotheses were supported, with psychiatric patients reporting greater levels of rejection sensitivity and emotion dysregulation, and lower level of mindfulness. Mindfulness deficits and emotion dysregulation explained a significant amount of variance in RS, in both samples. Finally, bootstrap analyses revealed that mindfulness deficits played an indirect effect on RS through the mediating role of emotion dysregulation. In particular, two different patterns emerged. Among psychiatric patients, an impairment in the ability to assume a non-judgmental stance towards own thoughts and feelings was related to RS through the mediation of limited access to emotion regulation strategies. Conversely, in the community sample, overall emotion dysregulation mediated the effect of lack of attention and awareness for present activities and experience on RS. Longitudinal studies could help in delineating etiological models of RS, and the joint role of deficits in mindfulness and emotion regulation should inform treatment programs.

  3. Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder.

    Directory of Open Access Journals (Sweden)

    Esther R Berko

    Full Text Available DNA mutational events are increasingly being identified in autism spectrum disorder (ASD, but the potential additional role of dysregulation of the epigenome in the pathogenesis of the condition remains unclear. The epigenome is of interest as a possible mediator of environmental effects during development, encoding a cellular memory reflected by altered function of progeny cells. Advanced maternal age (AMA is associated with an increased risk of having a child with ASD for reasons that are not understood. To explore whether AMA involves covert aneuploidy or epigenetic dysregulation leading to ASD in the offspring, we tested a homogeneous ectodermal cell type from 47 individuals with ASD compared with 48 typically developing (TD controls born to mothers of ≥35 years, using a quantitative genome-wide DNA methylation assay. We show that DNA methylation patterns are dysregulated in ectodermal cells in these individuals, having accounted for confounding effects due to subject age, sex and ancestral haplotype. We did not find mosaic aneuploidy or copy number variability to occur at differentially-methylated regions in these subjects. Of note, the loci with distinctive DNA methylation were found at genes expressed in the brain and encoding protein products significantly enriched for interactions with those produced by known ASD-causing genes, representing a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms. The results indicate the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD. The epigenetic dysregulation observed in these ASD subjects born to older mothers may be associated with aging parental gametes, environmental influences during embryogenesis or could be the consequence of mutations of the chromatin regulatory genes increasingly implicated in ASD. The results indicate that epigenetic dysregulatory mechanisms may complement

  4. Staphylococcal enterotoxins stimulate lymphoma-associated immune dysregulation

    DEFF Research Database (Denmark)

    Krejsgaard, Thorbjørn Frej; Willerslev-Olsen, Andreas; Lindahl, Lise Maria

    2014-01-01

    a cascade of events involving cell-cell and asymmetric cytokine interactions between malignant and benign T cells, which stimulated the malignant T cells to express high levels of IL-10. Much evidence supports that malignant activation of the Stat3/IL-10 axis plays a key role in driving the immune...... dysregulation and severe immunodeficiency that characteristically develops in CTCL patients. The present findings thereby establish a novel link between SEs and immune dysregulation in CTCL strengthening the rationale for antibiotic treatment of colonized patients with severe or progressive disease....

  5. DEGAS: de novo discovery of dysregulated pathways in human diseases.

    Directory of Open Access Journals (Sweden)

    Igor Ulitsky

    Full Text Available BACKGROUND: Molecular studies of the human disease transcriptome typically involve a search for genes whose expression is significantly dysregulated in sick individuals compared to healthy controls. Recent studies have found that only a small number of the genes in human disease-related pathways show consistent dysregulation in sick individuals. However, those studies found that some pathway genes are affected in most sick individuals, but genes can differ among individuals. While a pathway is usually defined as a set of genes known to share a specific function, pathway boundaries are frequently difficult to assign, and methods that rely on such definition cannot discover novel pathways. Protein interaction networks can potentially be used to overcome these problems. METHODOLOGY/PRINCIPAL FINDINGS: We present DEGAS (DysrEgulated Gene set Analysis via Subnetworks, a method for identifying connected gene subnetworks significantly enriched for genes that are dysregulated in specimens of a disease. We applied DEGAS to seven human diseases and obtained statistically significant results that appear to home in on compact pathways enriched with hallmarks of the diseases. In Parkinson's disease, we provide novel evidence for involvement of mRNA splicing, cell proliferation, and the 14-3-3 complex in the disease progression. DEGAS is available as part of the MATISSE software package (http://acgt.cs.tau.ac.il/matisse. CONCLUSIONS/SIGNIFICANCE: The subnetworks identified by DEGAS can provide a signature of the disease potentially useful for diagnosis, pinpoint possible pathways affected by the disease, and suggest targets for drug intervention.

  6. Emotion dysregulation and interpersonal problems : The role of defensiveness

    NARCIS (Netherlands)

    Garofalo, C.; Velotti, Patrizia; Zavattini, Giulio Cesare; Kosson, D.S.

    2017-01-01

    Despite evidence that individual differences in defensiveness (typically measured with social desirability scales) may affect associations among self-report measures, little is known about the impact of defensiveness in the well-established relations between self-report emotion dysregulation and

  7. The Mediating Role of Cognitive Flexibility, Shame and Emotion Dysregulation Between Neuroticism and Depression

    Directory of Open Access Journals (Sweden)

    Majid Zarei

    2018-03-01

    Discussion: These findings suggest that for student depression, emotion dysregulation might be important and future intervention works can examine the effects of targeting emotion dysregulation among university students with high levels of neuroticism and/or depression.

  8. Dysregulated pH in Tumor Microenvironment Checkmates Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Jaleh Barar

    2013-12-01

    Full Text Available Introduction: The dysregulation of pH by cancerous cells of solid tumors is able to create a unique milieu that is in favor of progression, invasion and metastasis as well as chemo-/immuno-resistance traits of solid tumors. Bioelements involved in pH dysregulation provide new set of oncotargets, inhibition of which may result in better clinical outcome. Methods: To study the impacts of pH dysregulation, we investigated the tumor development and progression in relation with Warburg effect, glycolysis and formation of aberrant tumor microenvironment. Results: The upregulation of glucose transporter GLUT-1 and several enzymes involve in glycolysis exacerbates this phenomenon. The accumulation of lactic acids in cancer cells provokes upregulation of several transport machineries (MCT-1, NHE-1, CA IX and H+ pump V-ATPase resulting in reinforced efflux of proton into extracellular fluid. This deviant event makes pH to be settled at 7.4 and 6.6 respectively in cancer cells cytoplasm and extracellular fluid within the tumor microenvironment, which in return triggers secretion of lysosomal components (various enzymes in acidic milieu with pH 5 into cytoplasm. All these anomalous phenomena make tumor microenvironment (TME to be exposed to cocktail of various enzymes with acidic pH, upon which extracellular matrix (ECM can be remodeled and even deformed, resulting in emergence of a complex viscose TME with high interstitial fluid pressure. Conclusion: It seems that pH dysregulation is able to remodel various physiologic functions and make solid tumors to become much more invasive and metastatic. It also can cause undesired resistance to chemotherapy and immunotherapy. Hence, cancer therapy needs to be reinforced using specific inhibitors of bioelements involved in pH dysregulation of TME in solid tumors.

  9. Design of music player based on MCU STC12C5A60S2%一种基于51单片机的音乐播放器的设计

    Institute of Scientific and Technical Information of China (English)

    何谐; 唐大权; 张淑廷; 陈雪

    2014-01-01

    The hardware design method of the music player based on MCU STC12C5A60S2 is introduced in this paper. The program design of the music player based on principle of FAT32 file system is studied. In the music player, MCU STC12C5A60S2 is taken as a main controller,SD card as a memory medium of music files and VS1003 chip as a decoder unit. When the player is running,MCU STC12C5A60S2 reads the music file from the SD card and continuously transfers data flow to VS1003 for decoding. In the meantime,the OLED liquid crystal display shows the message of the music in real time. The tested results from experiments show the music player can play the music files in multiple formats fluently if the player is connected with ear phone.%主要介绍一种基于51单片机的音乐播放器的硬件设计方法,并研究在FAT32文件系统下音乐播放器的程序设计。该音乐播放器采用STC12C5A60S2单片机为主控制器,SD卡作为音乐文件的存储介质,VS1003芯片作为解码器。STC12C5A60S2单片机从 SD卡中读取音乐文件,并不断将数据流传送至VS1003解码,最后连接耳机播放,同时STC12C5A60S2连接OLED液晶显示屏实时显示音乐播放信息。实验表明,该音乐播放器连接耳机能流畅播放多种格式的音乐文件。

  10. Human cytomegalovirus infection dysregulates the canonical Wnt/β-catenin signaling pathway.

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    Magdalena Angelova

    Full Text Available Human Cytomegalovirus (HCMV is a ubiquitous herpesvirus that currently infects a large percentage of the world population. Although usually asymptomatic in healthy individuals, HCMV infection during pregnancy may cause spontaneous abortions, premature delivery, or permanent neurological disabilities in infants infected in utero. During infection, the virus exerts control over a multitude of host signaling pathways. Wnt/β-catenin signaling, an essential pathway involved in cell cycle control, differentiation, embryonic development, placentation and metastasis, is frequently dysregulated by viruses. How HCMV infection affects this critical pathway is not currently known. In this study, we demonstrate that HCMV dysregulates Wnt/β-catenin signaling in dermal fibroblasts and human placental extravillous trophoblasts. Infection inhibits Wnt-induced transcriptional activity of β-catenin and expression of β-catenin target genes in these cells. HCMV infection leads to β-catenin protein accumulation in a discrete juxtanuclear region. Levels of β-catenin in membrane-associated and cytosolic pools, as well as nuclear β-catenin, are reduced after infection; while transcription of the β-catenin gene is unchanged, suggesting enhanced degradation. Given the critical role of Wnt/β-catenin signaling in cellular processes, these findings represent a novel and important mechanism whereby HCMV disrupts normal cellular function.

  11. The detrimental effects of emotional process dysregulation on decision making in substance dependence

    Directory of Open Access Journals (Sweden)

    Anna eMurphy

    2012-11-01

    Full Text Available Substance dependence is complex and multifactorial, with many distinct pathways involved in both the development and subsequent maintenance of addictive behaviours. Various cognitive mechanisms have been implicated, including impulsivity, compulsivity and impaired decision-making. These mechanisms are modulated by emotional processes, resulting in increased likelihood of initial drug use, sustained substance dependence, and increased relapse during periods of abstinence. Emotional traits, such as sensation seeking, are risk factors for substance use, and chronic drug use can result in further emotional dysregulation via effects on reward, motivation and stress systems. We will explore theories of hyper and hypo sensitivity of the brain reward systems that may underpin motivational abnormalities and anhedonia. Disturbances in these systems contribute to the biasing of emotional processing toward cues related to drug use at the expense of natural rewards, which serves to maintain addictive behaviour, via enhanced drug craving. We will additionally focus on the sensitization of the brain stress systems that result in negative affect states that continue into protracted abstinence that is may lead to compulsive drug taking. We will explore how these emotional dysregulations impact upon decision-making controlled by goal-directed and habitual action selections systems, and, in combination with a failure of prefrontal inhibitory control, mediate maladaptive decision-making observed in substance dependent individuals such that they continue drug use in spite of negative consequences. An understanding of the emotional impacts on cognition in substance dependent individuals may guide the development of more effective therapeutic interventions.

  12. Does epigenetic dysregulation of pancreatic islets contribute to impaired insulin secretion and type 2 diabetes?

    Science.gov (United States)

    Dayeh, Tasnim; Ling, Charlotte

    2015-10-01

    β cell dysfunction is central to the development and progression of type 2 diabetes (T2D). T2D develops when β cells are not able to compensate for the increasing demand for insulin caused by insulin resistance. Epigenetic modifications play an important role in establishing and maintaining β cell identity and function in physiological conditions. On the other hand, epigenetic dysregulation can cause a loss of β cell identity, which is characterized by reduced expression of genes that are important for β cell function, ectopic expression of genes that are not supposed to be expressed in β cells, and loss of genetic imprinting. Consequently, this may lead to β cell dysfunction and impaired insulin secretion. Risk factors that can cause epigenetic dysregulation include parental obesity, an adverse intrauterine environment, hyperglycemia, lipotoxicity, aging, physical inactivity, and mitochondrial dysfunction. These risk factors can affect the epigenome at different time points throughout the lifetime of an individual and even before an individual is conceived. The plasticity of the epigenome enables it to change in response to environmental factors such as diet and exercise, and also makes the epigenome a good target for epigenetic drugs that may be used to enhance insulin secretion and potentially treat diabetes.

  13. Disorders of dysregulated signal traffic through the RAS-MAPK pathway: phenotypic spectrum and molecular mechanisms.

    Science.gov (United States)

    Tartaglia, Marco; Gelb, Bruce D

    2010-12-01

    RAS GTPases control a major signaling network implicated in several cellular functions, including cell fate determination, proliferation, survival, differentiation, migration, and senescence. Within this network, signal flow through the RAF-MEK-ERK pathway-the first identified mitogen-associated protein kinase (MAPK) cascade-mediates early and late developmental processes controlling morphology determination, organogenesis, synaptic plasticity, and growth. Signaling through the RAS-MAPK cascade is tightly controlled; and its enhanced activation represents a well-known event in oncogenesis. Unexpectedly, in the past few years, inherited dysregulation of this pathway has been recognized as the cause underlying a group of clinically related disorders sharing facial dysmorphism, cardiac defects, reduced postnatal growth, ectodermal anomalies, variable cognitive deficits, and susceptibility to certain malignancies as major features. These disorders are caused by heterozygosity for mutations in genes encoding RAS proteins, regulators of RAS function, modulators of RAS interaction with effectors, or downstream signal transducers. Here, we provide an overview of the phenotypic spectrum associated with germline mutations perturbing RAS-MAPK signaling, the unpredicted molecular mechanisms converging toward the dysregulation of this signaling cascade, and major genotype-phenotype correlations. © 2010 New York Academy of Sciences.

  14. The detrimental effects of emotional process dysregulation on decision-making in substance dependence

    Science.gov (United States)

    Murphy, Anna; Taylor, Eleanor; Elliott, Rebecca

    2012-01-01

    Substance dependence is complex and multifactorial, with many distinct pathways involved in both the development and subsequent maintenance of addictive behaviors. Various cognitive mechanisms have been implicated, including impulsivity, compulsivity, and impaired decision-making. These mechanisms are modulated by emotional processes, resulting in increased likelihood of initial drug use, sustained substance dependence, and increased relapse during periods of abstinence. Emotional traits, such as sensation-seeking, are risk factors for substance use, and chronic drug use can result in further emotional dysregulation via effects on reward, motivation, and stress systems. We will explore theories of hyper and hypo sensitivity of the brain reward systems that may underpin motivational abnormalities and anhedonia. Disturbances in these systems contribute to the biasing of emotional processing toward cues related to drug use at the expense of natural rewards, which serves to maintain addictive behavior, via enhanced drug craving. We will additionally focus on the sensitization of the brain stress systems that result in negative affect states that continue into protracted abstinence that is may lead to compulsive drug-taking. We will explore how these emotional dysregulations impact upon decision-making controlled by goal-directed and habitual action selections systems, and, in combination with a failure of prefrontal inhibitory control, mediate maladaptive decision-making observed in substance dependent individuals such that they continue drug use in spite of negative consequences. An understanding of the emotional impacts on cognition in substance dependent individuals may guide the development of more effective therapeutic interventions. PMID:23162443

  15. Pediatric Obesity-Related Asthma: The Role of Metabolic Dysregulation.

    Science.gov (United States)

    Vijayakanthi, Nandini; Greally, John M; Rastogi, Deepa

    2016-05-01

    The burden of obesity-related asthma among children, particularly among ethnic minorities, necessitates an improved understanding of the underlying disease mechanisms. Although obesity is an independent risk factor for asthma, not all obese children develop asthma. Several recent studies have elucidated mechanisms, including the role of diet, sedentary lifestyle, mechanical fat load, and adiposity-mediated inflammation that may underlie the obese asthma pathophysiology. Here, we review these recent studies and emerging scientific evidence that suggest metabolic dysregulation may play a role in pediatric obesity-related asthma. We also review the genetic and epigenetic factors that may underlie susceptibility to metabolic dysregulation and associated pulmonary morbidity among children. Lastly, we identify knowledge gaps that need further exploration to better define pathways that will allow development of primary preventive strategies for obesity-related asthma in children. Copyright © 2016 by the American Academy of Pediatrics.

  16. Timing of birth: Parsimony favors strategic over dysregulated parturition.

    Science.gov (United States)

    Catalano, Ralph; Goodman, Julia; Margerison-Zilko, Claire; Falconi, April; Gemmill, Alison; Karasek, Deborah; Anderson, Elizabeth

    2016-01-01

    The "dysregulated parturition" narrative posits that the human stress response includes a cascade of hormones that "dysregulates" and accelerates parturition but provides questionable utility as a guide to understand or prevent preterm birth. We offer and test a "strategic parturition" narrative that not only predicts the excess preterm births that dysregulated parturition predicts but also makes testable, sex-specific predictions of the effect of stressful environments on the timing of birth among term pregnancies. We use interrupted time-series modeling of cohorts conceived over 101 months to test for lengthening of early term male gestations in stressed population. We use an event widely reported to have stressed Americans and to have increased the incidence of low birth weight and fetal death across the country-the terrorist attacks of September 2001. We tested the hypothesis that the odds of male infants conceived in December 2000 (i.e., at term in September 2001) being born early as opposed to full term fell below the value expected from those conceived in the 50 prior and 50 following months. We found that term male gestations exposed to the terrorist attacks exhibited 4% lower likelihood of early, as opposed to full or late, term birth. Strategic parturition explains observed data for which the dysregulated parturition narrative offers no prediction-the timing of birth among gestations stressed at term. Our narrative may help explain why findings from studies examining associations between population- and/or individual-level stressors and preterm birth are generally mixed. © 2015 Wiley Periodicals, Inc.

  17. The primary vascular dysregulation syndrome: implications for eye diseases

    Science.gov (United States)

    2013-01-01

    Vascular dysregulation refers to the regulation of blood flow that is not adapted to the needs of the respective tissue. We distinguish primary vascular dysregulation (PVD, formerly called vasospastic syndrome) and secondary vascular dysregulation (SVD). Subjects with PVD tend to have cold extremities, low blood pressure, reduced feeling of thirst, altered drug sensitivity, increased pain sensitivity, prolonged sleep onset time, altered gene expression in the lymphocytes, signs of oxidative stress, slightly increased endothelin-1 plasma level, low body mass index and often diffuse and fluctuating visual field defects. Coldness, emotional or mechanical stress and starving can provoke symptoms. Virtually all organs, particularly the eye, can be involved. In subjects with PVD, retinal vessels are stiffer and more irregular, and both neurovascular coupling and autoregulation capacity are reduced while retinal venous pressure is often increased. Subjects with PVD have increased risk for normal-tension glaucoma, optic nerve compartment syndrome, central serous choroidopathy, Susac syndrome, retinal artery and vein occlusions and anterior ischaemic neuropathy without atherosclerosis. Further characteristics are their weaker blood–brain and blood-retinal barriers and the higher prevalence of optic disc haemorrhages and activated astrocytes. Subjects with PVD tend to suffer more often from tinnitus, muscle cramps, migraine with aura and silent myocardial ischaemic and are at greater risk for altitude sickness. While the main cause of vascular dysregulation is vascular endotheliopathy, dysfunction of the autonomic nervous system is also involved. In contrast, SVD occurs in the context of other diseases such as multiple sclerosis, retrobulbar neuritis, rheumatoid arthritis, fibromyalgia and giant cell arteritis. Taking into consideration the high prevalence of PVD in the population and potentially linked pathologies, in the current article, the authors provide

  18. Behavioral evidence of emotion dysregulation in binge eaters.

    Science.gov (United States)

    Eichen, Dawn M; Chen, Eunice; Boutelle, Kerri N; McCloskey, Michael S

    2017-04-01

    Binge eating is the most common disordered eating symptom and can lead to the development of obesity. Previous self-report research has supported the hypothesis that individuals who binge eat report greater levels of general emotion dysregulation, which may facilitate binge-eating behavior. However, to date, no study has experimentally tested the relation between binge eating history and in-vivo emotion dysregulation. To do this, a sample of female college students who either endorsed binge eating (n = 40) or denied the presence of any eating pathology (n = 47) completed the Difficulties with Emotion Regulation Scale (DERS) and a behavioral distress tolerance task (the Paced Auditory Serial Addition Task-Computer: PASAT-C) known to induce negative affect and distress. The binge eating group was 2.96 times more likely to quit the PASAT-C early (χ 2  = 5.04, p = 0.025) and reported greater irritability (F(1,84) = 7.09 p = 0.009) and frustration (F(1,84) = 5.00, p = 0.028) after completing the PASAT-C than controls, controlling for initial levels of these emotions. Furthermore, across the entire sample, quitting early was associated with greater emotion dysregulation on the DERS (r pb  = 0.342, p < 0.01). This study is the first to demonstrate that individuals who binge eat show in-vivo emotional dysregulation on a laboratory task. Future studies should examine the PASAT-C to determine its potential clinical utility for individuals with or at risk of developing binge eating. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS

    Directory of Open Access Journals (Sweden)

    Luciana Frick

    2016-01-01

    Full Text Available There is accumulating evidence that immune dysregulation contributes to the pathophysiology of obsessive-compulsive disorder (OCD, Tourette syndrome, and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS. The mechanistic details of this pathophysiology, however, remain unclear. Here we focus on one particular component of the immune system: microglia, the brain’s resident immune cells. The role of microglia in neurodegenerative diseases has been understood in terms of classic, inflammatory activation, which may be both a consequence and a cause of neuronal damage. In OCD and Tourette syndrome, which are not characterized by frank neural degeneration, the potential role of microglial dysregulation is much less clear. Here we review the evidence for a neuroinflammatory etiology and microglial dysregulation in OCD, Tourette syndrome, and PANDAS. We also explore new hypotheses as to the potential contributions of microglial abnormalities to pathophysiology, beyond neuroinflammation, including failures in neuroprotection, lack of support for neuronal survival, and abnormalities in synaptic pruning. Recent advances in neuroimaging and animal model work are creating new opportunities to elucidate these issues.

  20. Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS

    Science.gov (United States)

    2016-01-01

    There is accumulating evidence that immune dysregulation contributes to the pathophysiology of obsessive-compulsive disorder (OCD), Tourette syndrome, and Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS). The mechanistic details of this pathophysiology, however, remain unclear. Here we focus on one particular component of the immune system: microglia, the brain's resident immune cells. The role of microglia in neurodegenerative diseases has been understood in terms of classic, inflammatory activation, which may be both a consequence and a cause of neuronal damage. In OCD and Tourette syndrome, which are not characterized by frank neural degeneration, the potential role of microglial dysregulation is much less clear. Here we review the evidence for a neuroinflammatory etiology and microglial dysregulation in OCD, Tourette syndrome, and PANDAS. We also explore new hypotheses as to the potential contributions of microglial abnormalities to pathophysiology, beyond neuroinflammation, including failures in neuroprotection, lack of support for neuronal survival, and abnormalities in synaptic pruning. Recent advances in neuroimaging and animal model work are creating new opportunities to elucidate these issues. PMID:28053994

  1. Enhanced

    Directory of Open Access Journals (Sweden)

    Martin I. Bayala

    2014-06-01

    Full Text Available Land Surface Temperature (LST is a key parameter in the energy balance model. However, the spatial resolution of the retrieved LST from sensors with high temporal resolution is not accurate enough to be used in local-scale studies. To explore the LST–Normalised Difference Vegetation Index relationship potential and obtain thermal images with high spatial resolution, six enhanced image sharpening techniques were assessed: the disaggregation procedure for radiometric surface temperatures (TsHARP, the Dry Edge Quadratic Function, the Difference of Edges (Ts∗DL and three models supported by the relationship of surface temperature and water stress of vegetation (Normalised Difference Water Index, Normalised Difference Infrared Index and Soil wetness index. Energy Balance Station data and in situ measurements were used to validate the enhanced LST images over a mixed agricultural landscape in the sub-humid Pampean Region of Argentina (PRA, during 2006–2010. Landsat Thematic Mapper (TM and Moderate Resolution Imaging Spectroradiometer (EOS-MODIS thermal datasets were assessed for different spatial resolutions (e.g., 960, 720 and 240 m and the performances were compared with global and local TsHARP procedures. Results suggest that the Ts∗DL technique is the most adequate for simulating LST to high spatial resolution over the heterogeneous landscape of a sub-humid region, showing an average root mean square error of less than 1 K.

  2. Infant and toddler crying, sleeping and feeding problems and trajectories of dysregulated behavior across childhood.

    Science.gov (United States)

    Winsper, Catherine; Wolke, Dieter

    2014-01-01

    Infant and toddler regulatory problems (RPs) including crying, sleeping and feeding, are a frequent concern for parents and have been associated with negative behavioral outcomes in early and middle childhood. Uncertain is whether infant and toddler RPs predict stable, trait-like dysregulated behavior across childhood. We addressed this gap in the literature using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). RPs at 6, 15-18, & 24-30 months and childhood dysregulated behavior at 4, 7, 8, & 9.5 years were assessed using mother report. Latent Class Growth Analysis (LCGA) indicated that trajectories of childhood dysregulated behavior were stable over time. All single RPs (i.e., crying, sleeping & feeding problems) were significantly associated with childhood dysregulated behavior. For example, crying problems at 6 months after controlling for confounders (Odds Ratios; 95% Confidence Intervals): Moderate dysregulated behavior: OR = 1.50, 95% CI [1.09 to 2.06], high dysregulated behavior: OR = 2.13, 95% CI [1.49 to 3.05] and very high dysregulated behavior: OR = 2.85, 95% CI [1.64 to 4.94]. Multiple RPs were especially strongly associated with dysregulated behavior. For example, the RP composite at 15-18 months: 1 RP, very high dysregulated behavior: OR = 2.79, 95% CI [2.17 to 3.57], 2 RPs, very high dysregulated behavior: OR = 3.46, 95% CI [2.38 to 5.01], 3 RPs, very high dysregulated behavior: OR = 12.57, 95% CI [6.38 to 24.74]. These findings suggest that RPs in infants and toddlers predict stable dysregulated behavior trajectories across childhood. Interventions for early RPs could help prevent the development of chronic, highly dysregulated behavior.

  3. Emotion dysregulation and peer drinking norms uniquely predict alcohol-related problems via motives.

    Science.gov (United States)

    Simons, Raluca M; Hahn, Austin M; Simons, Jeffrey S; Murase, Hanako

    2017-08-01

    This study examined the relationships between emotion dysregulation, peer drinking norms, drinking motives, and alcohol-related outcomes among 435 college students. We examined the mediating roles of drinking motives when predicting alcohol consumption and related problems from the subscales of the Difficulties in Emotion Regulation Scale (DERS; Gratz and Roemer, 2004) via negative and positive reinforcement models. First, we hypothesized that individuals who lack in emotion regulation strategies or have difficulties in accepting negative emotions are more likely to drink to cope. Additionally, we hypothesized that individuals who act impulsively or become distracted when upset as well as those with higher peer drinking norms are more likely to drink for social and enhancement motives. The results of the path model indicated that limited access to emotion regulation strategies significantly predicted alcohol-related problems via both depression and anxiety coping motives, but did not predict alcohol consumption. Nonacceptance of emotional responses was not significantly associated with coping motives. Impulsivity had a significant direct relationship with alcohol problems. Difficulty in engaging in goal-directed behaviors predicted both enhancement and social motives, but only enhancement motives in turn predicted consumption. Norms indirectly predicted problems via enhancement motives and consumption. The results indicated that using alcohol to reduce negative or to increase positive emotions increases alcohol consumption and alcohol-related problems. Overall, results advance our understanding of the mechanisms of increased alcohol use and problems among college students. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Redox Dysregulation in the Pathophysiology of Schizophrenia and Bipolar Disorder

    DEFF Research Database (Denmark)

    Kulak, Anita; Steullet, Pascal; Cabungcal, Jan-Harry

    2013-01-01

    Abstract Significance: Schizophrenia (SZ) and bipolar disorder (BD) are classified as two distinct diseases. However, accumulating evidence shows that both disorders share genetic, pathological, and epidemiological characteristics. Based on genetic and functional findings, redox dysregulation due...... abnormal prefrontal levels of glutathione (GSH), the major cellular redox regulator and antioxidant. Here we review experimental data from rodent models demonstrating that permanent as well as transient GSH deficit results in behavioral, morphological, electrophysiological, and neurochemical alterations...... hypofunction, elevated glutamate levels, impairment of parvalbumin GABA interneurons, abnormal neuronal synchronization, altered dopamine neurotransmission, and deficient myelination. Critical Issues: Treatment with the GSH precursor and antioxidant N-acetylcysteine normalizes some of those deficits in mice...

  5. The dysregulated cluster in personality profiling research: Longitudinal stability and associations with bulimic behaviors and correlates

    Science.gov (United States)

    Slane, Jennifer D.; Klump, Kelly L.; Donnellan, M. Brent; McGue, Matthew; Iacono, William G.

    2013-01-01

    Among cluster analytic studies of the personality profiles associated with bulimia nervosa, a group of individuals characterized by emotional lability and behavioral dysregulation (i.e., a dysregulated cluster) has emerged most consistently. However, previous studies have all been cross-sectional and mostly used clinical samples. This study aimed to replicate associations between the dysregulated personality cluster and bulimic symptoms and related characteristics using a longitudinal, population-based sample. Participants were females assessed at ages 17 and 25 from the Minnesota Twin Family Study, clustered based on their personality traits. The Dysregulated cluster was successfully identified at both time points and was more stable across time than either the Resilient or Sensation Seeking clusters. Rates of bulimic symptoms and related behaviors (e.g., alcohol use problems) were also highest in the dysregulated group. Findings suggest that the dysregulated cluster is a relatively stable and robust profile that is associated with bulimic symptoms. PMID:23398096

  6. A Positive Affective Neuroendocrinology (PANE Approach to Reward and Behavioral Dysregulation

    Directory of Open Access Journals (Sweden)

    Keith eWelker

    2015-07-01

    Full Text Available Emerging lines of research suggest that both testosterone and maladaptive reward processing can modulate behavioral dysregulation. Yet to date, no integrative account has been provided that systematically explains neuroendocrine function, dysregulation of reward, and behavioral dysregulation in a unified perspective. This is particularly important given specific neuroendocrine systems are potential mechanisms underlying and giving rise to reward-relevant behaviors. In this review, we propose a forward thinking approach to study the mechanisms of reward and behavioral dysregulation from a positive affective neuroendocrinology (PANE perspective. This approach holds that testosterone increases reward processing, which increases the likelihood of behavioral dysregulation. Additionally, the PANE framework holds that reward processing mediates the effects of testosterone on behavioral dysregulation. We also explore sources of potential sex differences and the roles of age, cortisol, and individual differences within the PANE framework. Finally, we discuss future prospects for research questions and methodology in the emerging field of affective neuroendocrinology.

  7. Rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation (ROHHAD syndrome): A case report and literature review.

    Science.gov (United States)

    Ibáñez-Micó, S; Marcos Oltra, A M; de Murcia Lemauviel, S; Ruiz Pruneda, R; Martínez Ferrández, C; Domingo Jiménez, R

    ROHHAD syndrome (rapid-onset obesity with hypothalamic dysregulation, hypoventilation, and autonomic dysregulation) is a rare and complex disease, presenting in previously healthy children at the age of 2-4 years. Up to 40% of cases are associated with neural crest tumours. We present the case of a 2-year-old girl with symptoms of rapidly progressing obesity, who a few months later developed hypothalamic dysfunction with severe electrolyte imbalance, behaviour disorder, hypoventilation, and severe autonomic dysregulation, among other symptoms. Although the pathophysiology of this syndrome remains unclear, an autoimmune hypothesis has been proposed for ROHHAD. Therefore, after obtaining a limited response to intravenous immunoglobulins, we decided to test the response to a high dose cyclophosphamide (low dose was not effective either). Unfortunately our patient experienced many severe complications (among them central pontine myelinolysis, from which the patient recovered, and failure to wean from the ventilator requiring tracheostomy and long term ventilation) that required a prolonged ICU stay. Although her behaviour improved, our patient unfortunately died suddenly at home at the age of 5 due to respiratory pathology. ROHHAD syndrome is a rare and little-known disease which requires a multidisciplinary approach because it involves complex symptoms and multiple organ system involvement. Alveolar hypoventilation should be identified early and appropriate treatment should be started promptly for the best possible outcome. Immunomodulatory treatment with immunoglobulins, cyclophosphamide, or rituximab has previously resulted in symptom improvement in some cases. Because of the low incidence of the syndrome, multi-centre studies must be carried out in order to gather more accurate information about ROHHAD pathophysiology and design an appropriate therapeutic approach. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All

  8. The impact of attachment security and emotion dysregulation on anxiety in children and adolescents

    DEFF Research Database (Denmark)

    Bender, Patrick K.; Sømhovd, Mikael; Pons, Francisco

    2015-01-01

    Theoretical views and empirical findings suggest interrelations among attachment security, emotion dysregulation and anxiety in childhood and adolescence. However, the associations among the three constructs have rarely been investigated in children, and no study has yet addressed...... to anxiety and that emotion dysregulation would help explain the association between attachment security and anxiety. Results showed that more securely attached youths reported less emotion dysregulation and that youths who had fewer emotion regulation difficulties experienced less anxiety. The association...... between attachment security and anxiety was mediated by emotion dysregulation. The model was confirmed for both children and adolescents. Findings are discussed with respect to theoretical implications, as well as future directions....

  9. Deletion of Fanca or Fancd2 dysregulates Treg in mice

    Science.gov (United States)

    Du, Wei; Erden, Ozlem; Wilson, Andrew; Sipple, Jared M.; Schick, Jonathan; Mehta, Parinda; Myers, Kasiani C.; Steinbrecher, Kris A.; Davies, Stella M.

    2014-01-01

    Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and leukemia. Recent studies demonstrate variable immune defects in FA. However, the cause for FA immunodeficiency is unknown. Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (Tregs), shown functionally as exacerbation of graft-vs-host disease (GVHD) in mice. Recipient mice of Fanca−/− or Fancd2−/− BM chimeras exhibited severe acute GVHD after allogeneic BM transplantation (BMT). T cells from Fanca−/− or Fancd2−/− mice induced higher GVHD lethality than those from wild-type (WT) littermates. FA Tregs possessed lower proliferative suppression potential compared with WT Tregs, as demonstrated by in vitro proliferation assay and BMT. Analysis of CD25+Foxp3+ Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 target gene expression. Additionally, CD25+Foxp3+ Tregs of Fanca−/− or Fancd2−/− mice were less efficient in suppressing the production of GVHD-associated inflammatory cytokines. Consistently, aberrant NF-κB activity was observed in infiltrated T cells from FA GVHD mice. Conditional deletion of p65 in FA Tregs decreased GVHD mortality. Our study uncovers an essential role for FA proteins in maintaining Treg homeostasis, possibly explaining, at least in part, the immune deficiency reported in some FA patients. PMID:24501220

  10. [Stress and autonomic dysregulation in patients with fibromyalgia syndrome].

    Science.gov (United States)

    Friederich, H-C; Schellberg, D; Mueller, K; Bieber, C; Zipfel, S; Eich, W

    2005-06-01

    The aim of the present study was to evaluate to what extent the orthostatic dysregulation of FMS patients can be attributed primarily to reduced baroreceptor-mediated activation of the sympathetic nervous system and whether a hyporeactive sympathetic nervous system can also be confirmed for mental stress. A total of 28 patients with primary FMS were examined and compared with 15 healthy subjects. Diagnostic investigations of the autonomic nervous system were based on measuring HRV in frequency range and assessing spontaneous baroreflex sensitivity (sBRS) under mental stress and passive orthostatism. Both under orthostatic and mental stress FMS patients exhibited reduced activation of the sympathetic nervous system as measured by the spectral power of HRV in the low-frequency range and the mean arterial blood pressure or heart rate. The present study provided no indications for dysregulation of sBRS. The results obtained confirm the hypothesis of a hyporeactive stress system in FMS patients for both peripherally and centrally mediated stimulation of the sympathetic nervous system.

  11. Cytosine methylation dysregulation in neonates following intrauterine growth restriction.

    Directory of Open Access Journals (Sweden)

    Francine Einstein

    2010-01-01

    Full Text Available Perturbations of the intrauterine environment can affect fetal development during critical periods of plasticity, and can increase susceptibility to a number of age-related diseases (e.g., type 2 diabetes mellitus; T2DM, manifesting as late as decades later. We hypothesized that this biological memory is mediated by permanent alterations of the epigenome in stem cell populations, and focused our studies specifically on DNA methylation in CD34+ hematopoietic stem and progenitor cells from cord blood from neonates with intrauterine growth restriction (IUGR and control subjects.Our epigenomic assays utilized a two-stage design involving genome-wide discovery followed by quantitative, single-locus validation. We found that changes in cytosine methylation occur in response to IUGR of moderate degree and involving a restricted number of loci. We also identify specific loci that are targeted for dysregulation of DNA methylation, in particular the hepatocyte nuclear factor 4alpha (HNF4A gene, a well-known diabetes candidate gene not previously associated with growth restriction in utero, and other loci encoding HNF4A-interacting proteins.Our results give insights into the potential contribution of epigenomic dysregulation in mediating the long-term consequences of IUGR, and demonstrate the value of this approach to studies of the fetal origin of adult disease.

  12. Cytosine Methylation Dysregulation in Neonates Following Intrauterine Growth Restriction

    Science.gov (United States)

    Bhagat, Tushar D.; Fazzari, Melissa J.; Verma, Amit; Barzilai, Nir; Greally, John M.

    2010-01-01

    Background Perturbations of the intrauterine environment can affect fetal development during critical periods of plasticity, and can increase susceptibility to a number of age-related diseases (e.g., type 2 diabetes mellitus; T2DM), manifesting as late as decades later. We hypothesized that this biological memory is mediated by permanent alterations of the epigenome in stem cell populations, and focused our studies specifically on DNA methylation in CD34+ hematopoietic stem and progenitor cells from cord blood from neonates with intrauterine growth restriction (IUGR) and control subjects. Methods and Findings Our epigenomic assays utilized a two-stage design involving genome-wide discovery followed by quantitative, single-locus validation. We found that changes in cytosine methylation occur in response to IUGR of moderate degree and involving a restricted number of loci. We also identify specific loci that are targeted for dysregulation of DNA methylation, in particular the hepatocyte nuclear factor 4α (HNF4A) gene, a well-known diabetes candidate gene not previously associated with growth restriction in utero, and other loci encoding HNF4A-interacting proteins. Conclusions Our results give insights into the potential contribution of epigenomic dysregulation in mediating the long-term consequences of IUGR, and demonstrate the value of this approach to studies of the fetal origin of adult disease. PMID:20126273

  13. Transcriptional dysregulation in NIPBL and cohesin mutant human cells.

    Directory of Open Access Journals (Sweden)

    Jinglan Liu

    2009-05-01

    Full Text Available Cohesin regulates sister chromatid cohesion during the mitotic cell cycle with Nipped-B-Like (NIPBL facilitating its loading and unloading. In addition to this canonical role, cohesin has also been demonstrated to play a critical role in regulation of gene expression in nondividing cells. Heterozygous mutations in the cohesin regulator NIPBL or cohesin structural components SMC1A and SMC3 result in the multisystem developmental disorder Cornelia de Lange Syndrome (CdLS. Genome-wide assessment of transcription in 16 mutant cell lines from severely affected CdLS probands has identified a unique profile of dysregulated gene expression that was validated in an additional 101 samples and correlates with phenotypic severity. This profile could serve as a diagnostic and classification tool. Cohesin binding analysis demonstrates a preference for intergenic regions suggesting a cis-regulatory function mimicking that of a boundary/insulator interacting protein. However, the binding sites are enriched within the promoter regions of the dysregulated genes and are significantly decreased in CdLS proband, indicating an alternative role of cohesin as a transcription factor.

  14. Targeting emotion dysregulation in the treatment of self-injury.

    Science.gov (United States)

    Gratz, Kim L

    2007-11-01

    Clinically useful definitions of emotion regulation with respect to deliberate self-harm (referred to here as self-injury) focus on adaptive ways of responding to emotional distress rather than on the control of emotions or dampening of emotional arousal. According to one such definition, emotion regulation is a multifaceted construct involving a) the awareness, understanding, and acceptance of emotions; b) ability to engage in goal-directed behaviors, and inhibit impulsive behaviors, when experiencing negative emotions; c) the flexible use of situationally appropriate strategies to modulate the intensity and/or duration of emotional responses rather than to eliminate emotions entirely; and d) willingness to experience negative emotions as part of pursuing meaningful activities in life (Gratz & Roemer, 2004). This article addresses the role of emotion dysregulation in self-injury and discusses two treatments for self-injury that explicitly focus on increasing emotion regulation. These treatments are based on the premise that the reduction of emotion dysregulation will decrease the need for maladaptive behaviors that function to regulate emotions, such as self-injury. A case illustration describing how one of these treatments (an acceptance-based, emotion regulation group therapy) is used to treat self-injury is provided.

  15. Deletion of Fanca or Fancd2 dysregulates Treg in mice.

    Science.gov (United States)

    Du, Wei; Erden, Ozlem; Wilson, Andrew; Sipple, Jared M; Schick, Jonathan; Mehta, Parinda; Myers, Kasiani C; Steinbrecher, Kris A; Davies, Stella M; Pang, Qishen

    2014-03-20

    Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and leukemia. Recent studies demonstrate variable immune defects in FA. However, the cause for FA immunodeficiency is unknown. Here we report that deletion of Fanca or Fancd2 dysregulates the suppressive activity of regulatory T cells (Tregs), shown functionally as exacerbation of graft-vs-host disease (GVHD) in mice. Recipient mice of Fanca(-/-) or Fancd2(-/-) BM chimeras exhibited severe acute GVHD after allogeneic BM transplantation (BMT). T cells from Fanca(-/-) or Fancd2(-/-) mice induced higher GVHD lethality than those from wild-type (WT) littermates. FA Tregs possessed lower proliferative suppression potential compared with WT Tregs, as demonstrated by in vitro proliferation assay and BMT. Analysis of CD25(+)Foxp3(+) Tregs indicated that loss of Fanca or Fancd2 dysregulated Foxp3 target gene expression. Additionally, CD25(+)Foxp3(+) Tregs of Fanca(-/-) or Fancd2(-/-) mice were less efficient in suppressing the production of GVHD-associated inflammatory cytokines. Consistently, aberrant NF-κB activity was observed in infiltrated T cells from FA GVHD mice. Conditional deletion of p65 in FA Tregs decreased GVHD mortality. Our study uncovers an essential role for FA proteins in maintaining Treg homeostasis, possibly explaining, at least in part, the immune deficiency reported in some FA patients.

  16. Lifetime Sexual Victimization and Poor Risk Perception: Does Emotion Dysregulation Account for the Links?

    Science.gov (United States)

    Walsh, Kate; DiLillo, David; Messman-Moore, Terri L.

    2012-01-01

    The present study examined whether and which facets of emotion dysregulation serve an intervening role in the association between prior victimization and risk perception in an analogue sexual assault vignette. Participants were 714 university women who completed self-report measures of sexual victimization, emotion dysregulation, and a…

  17. Neurobiology of dysregulated motivational systems in drug addiction

    Science.gov (United States)

    Edwards, Scott; Koob, George F

    2010-01-01

    The progression from recreational drug use to drug addiction impacts multiple neurobiological processes and can be conceptualized as a transition from positive to negative reinforcement mechanisms driving both drug-taking and drug-seeking behaviors. Neurobiological mechanisms for negative reinforcement, defined as drug taking that alleviates a negative emotional state, involve changes in the brain reward system and recruitment of brain stress (or antireward) systems within forebrain structures, including the extended amygdala. These systems are hypothesized to be dysregulated by excessive drug intake and to contribute to allostatic changes in reinforcement mechanisms associated with addiction. Points of intersection between positive and negative motivational circuitry may further drive the compulsivity of drug addiction but also provide a rich neurobiological substrate for therapeutic intervention. PMID:20563312

  18. Understanding periviable birth: A microeconomic alternative to the dysregulation narrative.

    Science.gov (United States)

    Catalano, Ralph; Bruckner, Tim; Avalos, Lyndsay A; Stewart, Holly; Karasek, Deborah; Kariv, Shachar; Gemmill, Alison; Saxton, Katherine; Casey, Joan

    2017-12-12

    Periviable infants (i.e., those born in the 20th through 26th weeks of gestation) suffer much morbidity and approximately half die in the first year of life. Attempts to explain and predict these births disproportionately invoke a "dysregulation" narrative. Research inspired by this narrative has not led to efficacious interventions. The clinical community has, therefore, urged novel approaches to the problem. We aim to provoke debate by offering the theory, inferred from microeconomics, that risk tolerant women carry, without cognitive involvement, high risk fetuses farther into pregnancy than do other women. These extended high-risk pregnancies historically ended in stillbirth but modern obstetric practices now convert a fraction to periviable births. We argue that this theory deserves testing because it suggests inexpensive and noninvasive screening for pregnancies that might benefit from the costly and invasive interventions clinical research will likely devise. Copyright © 2017. Published by Elsevier Ltd.

  19. Dysregulation of RNA Mediated Gene Expression in Motor Neuron Diseases.

    Science.gov (United States)

    Gonçalves, Inês do Carmo G; Rehorst, Wiebke A; Kye, Min Jeong

    2016-01-01

    Recent findings indicate an important role for RNA-mediated gene expression in motor neuron diseases, including ALS (amyotrophic lateral sclerosis) and SMA (spinal muscular atrophy). ALS, also known as Lou Gehrig's disease, is an adult-onset progressive neurodegenerative disorder, whereby SMA or "children's Lou Gehrig's disease" is considered a pediatric neurodevelopmental disorder. Despite the difference in genetic causes, both ALS and SMA share common phenotypes; dysfunction/loss of motor neurons that eventually leads to muscle weakness and atrophy. With advanced techniques in molecular genetics and cell biology, current data suggest that these two distinct motor neuron diseases share more than phenotypes; ALS and SMA have similar cellular pathological mechanisms including mitochondrial dysfunction, oxidative stress and dysregulation in RNA-mediated gene expression. Here, we will discuss the current findings on these two diseases with specific focus on RNA-mediated gene regulation including miRNA expression, pre-mRNA processing and RNA binding proteins.

  20. Getting too sweet: galectin-1 dysregulation in gestational diabetes mellitus.

    Science.gov (United States)

    Blois, Sandra M; Gueuvoghlanian-Silva, Barbara Y; Tirado-González, Irene; Torloni, Maria R; Freitag, Nancy; Mattar, Rosiane; Conrad, Melanie L; Unverdorben, Laura; Barrientos, Gabriela; Knabl, Julia; Toldi, Gergely; Molvarec, Attila; Rose, Matthias; Markert, Udo R; Jeschke, Udo; Daher, Silvia

    2014-07-01

    Galectin-1 (gal-1) is a prototype carbohydrate-binding protein, whose dysregulation is associated with adverse pregnancy outcomes such as spontaneous abortion and pre-eclampsia. Furthermore, it is known that faulty gal-1 protein production or gene regulation can be caused by single-nucleotide polymorphisms in the LGALS1 gene. Gestational diabetes mellitus (GDM) is also an adverse pregnancy outcome and the most common metabolic disorder during gestation. However, gal-1 expression patterns during GDM remain largely unknown. Our aims were to define local and peripheral gal-1 expression patterns during pregnancy, and to investigate LGALS1 gene polymorphisms in GDM patients. Circulating gal-1 levels were determined by ELISA in GDM patients and normal pregnant controls, and LGALS1 gene polymorphisms were assessed for association with GDM. Placental tissues were collected from control and GDM term pregnancies to evaluate local gal-1 expression by immunofluorescence. Our results show that GDM is associated with a failure to increase circulating gal-1 levels during the second and third trimester, as well as overexpression of gal-1 in placental tissue. Additionally, the LGALS1 polymorphism rs4820294 was associated with the development of GDM. In pregnancies complicated by GDM, we observed gal-1 dysregulation both locally in the placenta and peripherally in the circulation. Furthermore, the association between the LGALS1 polymorphism and GDM may indicate a genetic contribution to this adverse pregnancy outcome. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  1. MicroRNA regulation and dysregulation in epilepsy

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    Danyella Barbosa Dogini

    2013-10-01

    Full Text Available Epilepsy, one of the most frequent neurological disorders, represents a group of diseases that have in common the clinical occurrence of seizures. The pathogenesis of different types of epilepsy involves many important biological pathways; some of which have been shown to be regulated by microRNAs (miRNAs. In this paper, we will critically review relevant studies regarding the role of miRNAs in epilepsy. Overall, the most common type of epilepsy in the adult population is temporal lobe epilepsy (TLE, and the form associated with mesial temporal sclerosis (MTS, called mesial TLE, is particularly relevant due to the high frequency of resistance to clinical treatment. There are several target studies, as well few genome-wide miRNA expression profiling studies reporting abnormal miRNA expression in tissue with MTS, both in patients and in animal models. Overall, these studies show a fine correlation between miRNA regulation/dysregulation and inflammation, seizure-induced neuronal death and other relevant biological pathways. Furthermore, expression of many miRNAs is dynamically regulated during neurogenesis and its dysregulation may play a role in the process of cerebral corticogenesis leading to malformations of cortical development (MCD, which represent one of the major causes of drug-resistant epilepsy. In addition, there are reports of miRNAs involved in cell proliferation, fate specification and neuronal maturation and these processes are tightly linked to the pathogenesis of MCD. Large-scale analyzes of miRNA expression in animal models with induced status epilepticus have demonstrated changes in a selected group of miRNAs thought to be involved in the regulation of cell death, synaptic reorganization, neuroinflammation and neural excitability. In addition, knocking-down specific miRNAs in these animals have demonstrated that this may consist in a promising therapeutic intervention.

  2. Moderate exercise ameliorates dysregulated hippocampal glycometabolism and memory function in a rat model of type 2 diabetes.

    Science.gov (United States)

    Shima, Takeru; Matsui, Takashi; Jesmin, Subrina; Okamoto, Masahiro; Soya, Mariko; Inoue, Koshiro; Liu, Yu-Fan; Torres-Aleman, Ignacio; McEwen, Bruce S; Soya, Hideaki

    2017-03-01

    Type 2 diabetes is likely to be an independent risk factor for hippocampal-based memory dysfunction, although this complication has yet to be investigated in detail. As dysregulated glycometabolism in peripheral tissues is a key symptom of type 2 diabetes, it is hypothesised that diabetes-mediated memory dysfunction is also caused by hippocampal glycometabolic dysfunction. If so, such dysfunction should also be ameliorated with moderate exercise by normalising hippocampal glycometabolism, since 4 weeks of moderate exercise enhances memory function and local hippocampal glycogen levels in normal animals. The hippocampal glycometabolism in OLETF rats (model of human type 2 diabetes) was assessed and, subsequently, the effects of exercise on memory function and hippocampal glycometabolism were investigated. OLETF rats, which have memory dysfunction, exhibited higher levels of glycogen in the hippocampus than did control rats, and breakdown of hippocampal glycogen with a single bout of exercise remained unimpaired. However, OLETF rats expressed lower levels of hippocampal monocarboxylate transporter 2 (MCT2, a transporter for lactate to neurons). Four weeks of moderate exercise improved spatial memory accompanied by further increase in hippocampal glycogen levels and restoration of MCT2 expression independent of neurotrophic factor and clinical symptoms in OLETF rats. Our findings are the first to describe detailed profiles of glycometabolism in the type 2 diabetic hippocampus and to show that 4 weeks of moderate exercise improves memory dysfunction in type 2 diabetes via amelioration of dysregulated hippocampal glycometabolism. Dysregulated hippocampal lactate-transport-related glycometabolism is a possible aetiology of type-2-diabetes-mediated memory dysfunction.

  3. Mitochondrial Calcium Dysregulation Contributes to Dendrite Degeneration Mediated by PD/LBD-Associated LRRK2 Mutants.

    Science.gov (United States)

    Verma, Manish; Callio, Jason; Otero, P Anthony; Sekler, Israel; Wills, Zachary P; Chu, Charleen T

    2017-11-15

    Mutations in leucine-rich repeat kinase 2 (LRRK2) contribute to development of late-onset familial Parkinson's disease (PD), with clinical features of motor and cognitive dysfunction indistinguishable from sporadic PD. Calcium dysregulation plays an important role in PD pathogenesis, but the mechanisms of neurodegeneration remain unclear. Recent reports indicate enhanced excitatory neurotransmission in cortical neurons expressing mutant LRRK2, which occurs before the well-characterized phenotype of dendritic shortening. As mitochondria play a major role in the rapid buffering of cytosolic calcium, we hypothesized that altered mitochondrial calcium handling contributes to dendritic retraction elicited by the LRRK2-G2019S and -R1441C mutations. In primary mouse cortical neurons, we observed increased depolarization-induced mitochondrial calcium uptake. We found that expression of mutant LRRK2 elicited transcriptional upregulation of the mitochondrial calcium uniporter (MCU) and the mitochondrial calcium uptake 1 protein (MICU1) with no change in levels of the mitochondrial calcium antiporter NCLX. Elevated MCU and MICU1 were also observed in LRRK2-mutated patient fibroblasts, along with increased mitochondrial calcium uptake, and in postmortem brains of sporadic PD/PDD patients of both sexes. Transcriptional upregulation of MCU and MICU1 was caused by activation of the ERK1/2 (MAPK3/1) pathway. Inhibiting ERK1/2 conferred protection against mutant LRRK2-induced neurite shortening. Pharmacological inhibitors or RNAi knockdown of MCU attenuated mitochondrial calcium uptake and dendritic/neuritic shortening elicited by mutant LRRK2, whereas expression of a constitutively active mutant of NCLX that enhances calcium export from mitochondria was neuroprotective. These data suggest that an increased susceptibility to mitochondrial calcium dysregulation contributes to dendritic injury in mutant LRRK2 pathogenesis. SIGNIFICANCE STATEMENT Cognitive dysfunction and dementia are

  4. Identifying microRNA/mRNA dysregulations in ovarian cancer.

    Science.gov (United States)

    Miles, Gregory D; Seiler, Michael; Rodriguez, Lorna; Rajagopal, Gunaretnam; Bhanot, Gyan

    2012-03-27

    MicroRNAs are a class of noncoding RNA molecules that co-regulate the expression of multiple genes via mRNA transcript degradation or translation inhibition. Since they often target entire pathways, they may be better drug targets than genes or proteins. MicroRNAs are known to be dysregulated in many tumours and associated with aggressive or poor prognosis phenotypes. Since they regulate mRNA in a tissue specific manner, their functional mRNA targets are poorly understood. In previous work, we developed a method to identify direct mRNA targets of microRNA using patient matched microRNA/mRNA expression data using an anti-correlation signature. This method, applied to clear cell Renal Cell Carcinoma (ccRCC), revealed many new regulatory pathways compromised in ccRCC. In the present paper, we apply this method to identify dysregulated microRNA/mRNA mechanisms in ovarian cancer using data from The Cancer Genome Atlas (TCGA). TCGA Microarray data was normalized and samples whose class labels (tumour or normal) were ambiguous with respect to consensus ensemble K-Means clustering were removed. Significantly anti-correlated and correlated genes/microRNA differentially expressed between tumour and normal samples were identified. TargetScan was used to identify gene targets of microRNA. We identified novel microRNA/mRNA mechanisms in ovarian cancer. For example, the expression level of RAD51AP1 was found to be strongly anti-correlated with the expression of hsa-miR-140-3p, which was significantly down-regulated in the tumour samples. The anti-correlation signature was present separately in the tumour and normal samples, suggesting a direct causal dysregulation of RAD51AP1 by hsa-miR-140-3p in the ovary. Other pairs of potentially biological relevance include: hsa-miR-145/E2F3, hsa-miR-139-5p/TOP2A, and hsa-miR-133a/GCLC. We also identified sets of positively correlated microRNA/mRNA pairs that are most likely result from indirect regulatory mechanisms. Our findings identify

  5. Pediatric emotional dysregulation and behavioral disruptiveness treated with hypnosis: a time-series design.

    Science.gov (United States)

    Iglesias, Alex; Iglesias, Adam

    2014-01-01

    A case of pediatric oppositional defiant disorder (ODD) with concomitant emotional dysregulation and secondary behavioral disruptiveness was treated with hypnosis by means of the hypnotic hold, a method adapted by the authors. An A-B-A-B time-series design with multiple replications was employed to measure the relationship of the hypnotic treatment to the dependent measure: episodes of emotional dysregulation with accompanying behavioral disruptiveness. The findings indicated a statistically significant relationship between the degree of change from phase to phase and the treatment. Follow-up at 6 months indicated a significant reduction of the frequency of targeted episodes of emotional dysregulation and behavioral disruptiveness at home.

  6. Dysregulated Functions of Lung Macrophage Populations in COPD.

    Science.gov (United States)

    Kapellos, Theodore S; Bassler, Kevin; Aschenbrenner, Anna C; Fujii, Wataru; Schultze, Joachim L

    2018-01-01

    Chronic obstructive pulmonary disease (COPD) is a diverse respiratory disease characterised by bronchiolitis, small airway obstruction, and emphysema. Innate immune cells play a pivotal role in the disease's progression, and in particular, lung macrophages exploit their prevalence and strategic localisation to orchestrate immune responses. To date, alveolar and interstitial resident macrophages as well as blood monocytes have been described in the lungs of patients with COPD contributing to disease pathology by changes in their functional repertoire. In this review, we summarise recent evidence from human studies and work with animal models of COPD with regard to altered functions of each of these myeloid cell populations. We primarily focus on the dysregulated capacity of alveolar macrophages to secrete proinflammatory mediators and proteases, induce oxidative stress, engulf microbes and apoptotic cells, and express surface and intracellular markers in patients with COPD. In addition, we discuss the differences in the responses between alveolar macrophages and interstitial macrophages/monocytes in the disease and propose how the field should advance to better understand the implications of lung macrophage functions in COPD.

  7. Dysregulation of Histone Acetyltransferases and Deacetylases in Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Yonggang Wang

    2014-01-01

    Full Text Available Cardiovascular disease (CVD remains a leading cause of mortality worldwide despite advances in its prevention and management. A comprehensive understanding of factors which contribute to CVD is required in order to develop more effective treatment options. Dysregulation of epigenetic posttranscriptional modifications of histones in chromatin is thought to be associated with the pathology of many disease models, including CVD. Histone acetyltransferases (HATs and deacetylases (HDACs are regulators of histone lysine acetylation. Recent studies have implicated a fundamental role of reversible protein acetylation in the regulation of CVDs such as hypertension, pulmonary hypertension, diabetic cardiomyopathy, coronary artery disease, arrhythmia, and heart failure. This reversible acetylation is governed by enzymes that HATs add or HDACs remove acetyl groups respectively. New evidence has revealed that histone acetylation regulators blunt cardiovascular and related disease states in certain cellular processes including myocyte hypertrophy, apoptosis, fibrosis, oxidative stress, and inflammation. The accumulating evidence of the detrimental role of histone acetylation in cardiac disease combined with the cardioprotective role of histone acetylation regulators suggests that the use of histone acetylation regulators may serve as a novel approach to treating the millions of patients afflicted by cardiac diseases worldwide.

  8. Iron dysregulation combined with aging prevents sepsis-induced apoptosis.

    Science.gov (United States)

    Javadi, Pardis; Buchman, Timothy G; Stromberg, Paul E; Turnbull, Isaiah R; Vyas, Dinesh; Hotchkiss, Richard S; Karl, Irene E; Coopersmith, Craig M

    2005-09-01

    Sepsis, iron loading, and aging cause independent increases in gut epithelial and splenic apoptosis. It is unknown how their combination will affect apoptosis and systemic cytokine levels. Hfe-/- mice (a murine homologue of hemochromatosis) abnormally accumulate iron in their tissues. Aged (24-26 months) or mature (16-18 months) Hfe-/- mice and wild type (WT) littermates were subjected to cecal ligation and puncture (CLP) or sham laparotomy. Intestine, spleen, and blood were harvested 24 h later and assessed for apoptosis and cytokine levels. Gut epithelial and splenic apoptosis were low in both aged septic and sham Hfe-/- mice, regardless of the amount of iron in their diet. Mature septic WT mice had increased apoptosis compared to age-matched sham WT mice. Mature septic Hfe-/- mice had similar levels of intestinal cell death to age-matched septic WT mice but higher levels of splenic apoptosis. Apoptosis was significantly lower in septic aged Hfe-/- mice than septic mature Hfe-/- animals. Interleukin-6 was elevated in septic aged Hfe-/- mice compared to sham mice. Although sepsis, chronic iron dysregulation, and aging each increase gut and splenic apoptosis, their combination yields cell death levels similar to sham animals despite the fact that aged Hfe-/- mice are able to mount an inflammatory response following CLP and mature Hfe-/- mice have elevated sepsis-induced apoptosis. Combining sepsis with two risk factors that ordinarily increase cell death and increase mortality in CLP yields an apoptotic response that could not have been predicted based upon each element in isolation.

  9. Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency

    Directory of Open Access Journals (Sweden)

    Kavya Reddy

    2016-03-01

    Full Text Available Attenuated auto-lysosomal system has been associated with Alzheimer disease (AD, yet all underlying molecular mechanisms leading to this impairment are unknown. We show that the amino acid sensing of mechanistic target of rapamycin complex 1 (mTORC1 is dysregulated in cells deficient in presenilin, a protein associated with AD. In these cells, mTORC1 is constitutively tethered to lysosomal membranes, unresponsive to starvation, and inhibitory to TFEB-mediated clearance due to a reduction in Sestrin2 expression. Normalization of Sestrin2 levels through overexpression or elevation of nuclear calcium rescued mTORC1 tethering and initiated clearance. While CLEAR network attenuation in vivo results in buildup of amyloid, phospho-Tau, and neurodegeneration, presenilin-knockout fibroblasts and iPSC-derived AD human neurons fail to effectively initiate autophagy. These results propose an altered mechanism for nutrient sensing in presenilin deficiency and underline an importance of clearance pathways in the onset of AD.

  10. Potential Therapeutic Effects of Meditation for Treating Affective Dysregulation

    Directory of Open Access Journals (Sweden)

    Natalie T. Y. Leung

    2014-01-01

    Full Text Available Affective dysregulation is at the root of many psychopathologies, including stress induced disorders, anxiety disorders, and depression. The root of these disorders appears to be an attenuated, top-down cognitive control from the prefrontal cortices over the maladaptive subcortical emotional processing. A form of mental training, long-term meditation practice can trigger meditation-specific neuroplastic changes in the brain regions underlying cognitive control and affective regulation, suggesting that meditation can act as a kind of mental exercise to foster affective regulation and possibly a cost-effective intervention in mood disorders. Increasing research has suggested that the cultivation of awareness and acceptance along with a nonjudgmental attitude via meditation promotes adaptive affective regulation. This review examined the concepts of affective regulation and meditation and discussed behavioral and neural evidence of the potential clinical application of meditation. Lately, there has been a growing trend toward incorporating the “mindfulness” component into existing psychotherapeutic treatment. Promising results have been observed thus far. Future studies may consider exploring the possibility of integrating the element of “compassion” into current psychotherapeutic approaches.

  11. Influenza virus induces apoptosis via BAD-mediated mitochondrial dysregulation.

    Science.gov (United States)

    Tran, Anh T; Cortens, John P; Du, Qiujiang; Wilkins, John A; Coombs, Kevin M

    2013-01-01

    Influenza virus infection results in host cell death and major tissue damage. Specific components of the apoptotic pathway, a signaling cascade that ultimately leads to cell death, are implicated in promoting influenza virus replication. BAD is a cell death regulator that constitutes a critical control point in the intrinsic apoptosis pathway, which occurs through the dysregulation of mitochondrial outer membrane permeabilization and the subsequent activation of downstream apoptogenic factors. Here we report a novel proviral role for the proapoptotic protein BAD in influenza virus replication. We show that influenza virus-induced cytopathology and cell death are considerably inhibited in BAD knockdown cells and that both virus replication and viral protein production are dramatically reduced, which suggests that virus-induced apoptosis is BAD dependent. Our data showed that influenza viruses induced phosphorylation of BAD at residues S112 and S136 in a temporal manner. Viral infection also induced BAD cleavage, late in the viral life cycle, to a truncated form that is reportedly a more potent inducer of apoptosis. We further demonstrate that knockdown of BAD resulted in reduced cytochrome c release and suppression of the intrinsic apoptotic pathway during influenza virus replication, as seen by an inhibition of caspases-3, caspase-7, and procyclic acidic repetitive protein (PARP) cleavage. Our data indicate that influenza viruses carefully modulate the activation of the apoptotic pathway that is dependent on the regulatory function of BAD and that failure of apoptosis activation resulted in unproductive viral replication.

  12. Multiple mechanisms of MYCN dysregulation in Wilms tumour

    Science.gov (United States)

    Williams, Richard D.; Chagtai, Tasnim; Alcaide-German, Marisa; Apps, John; Wegert, Jenny; Popov, Sergey; Vujanic, Gordan; van Tinteren, Harm; van den Heuvel-Eibrink, Marry M.; Kool, Marcel; de Kraker, Jan; Gisselsson, David; Graf, Norbert; Gessler, Manfred; Pritchard-Jones, Kathy

    2015-01-01

    Genomic gain of the proto-oncogene transcription factor gene MYCN is associated with poor prognosis in several childhood cancers. Here we present a comprehensive copy number analysis of MYCN in Wilms tumour (WT), demonstrating that gain of this gene is associated with anaplasia and with poorer relapse-free and overall survival, independent of histology. Using whole exome and gene-specific sequencing, together with methylation and expression profiling, we show that MYCN is targeted by other mechanisms, including a recurrent somatic mutation, P44L, and specific DNA hypomethylation events associated with MYCN overexpression in tumours with high risk histologies. We describe parallel evolution of genomic copy number gain and point mutation of MYCN in the contralateral tumours of a remarkable bilateral case in which independent contralateral mutations of TP53 also evolve over time. We report a second bilateral case in which MYCN gain is a germline aberration. Our results suggest a significant role for MYCN dysregulation in the molecular biology of Wilms tumour. We conclude that MYCN gain is prognostically significant, and suggest that the novel P44L somatic variant is likely to be an activating mutation. PMID:25749049

  13. Dysregulation of striatal projection neurons in Parkinson's disease.

    Science.gov (United States)

    Beck, Goichi; Singh, Arun; Papa, Stella M

    2018-03-01

    The loss of nigrostriatal dopamine (DA) is the primary cause of motor dysfunction in Parkinson's disease (PD), but the underlying striatal mechanisms remain unclear. In spite of abundant literature portraying structural, biochemical and plasticity changes of striatal projection neurons (SPNs), in the past there has been a data vacuum from the natural human disease and its close model in non-human primates. Recently, single-cell recordings in advanced parkinsonian primates have generated new insights into the altered function of SPNs. Currently, there are also human data that provide direct evidence of profoundly dysregulated SPN activity in PD. Here, we review primate recordings that are impacting our understanding of the striatal dysfunction after DA loss, particularly through the analysis of physiologic correlates of parkinsonian motor behaviors. In contrast to recordings in rodents, data obtained in primates and patients demonstrate similar major abnormalities of the spontaneous SPN firing in the alert parkinsonian state. Furthermore, these studies also show altered SPN responses to DA replacement in the advanced parkinsonian state. Clearly, there is yet much to learn about the striatal discharges in PD, but studies using primate models are contributing unique information to advance our understanding of pathophysiologic mechanisms.

  14. Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime.

    Science.gov (United States)

    McBrayer, MaryKate; Nixon, Ralph A

    2013-12-01

    Early-onset FAD (familial Alzheimer's disease) is caused by mutations of PS1 (presenilin 1), PS2 (presenilin 2) and APP (amyloid precursor protein). Beyond the effects of PS1 mutations on proteolytic functions of the γ-secretase complex, mutant or deficient PS1 disrupts lysosomal function and Ca2+ homoeostasis, both of which are considered strong pathogenic factors in FAD. Loss of PS1 function compromises assembly and proton-pumping activity of the vacuolar-ATPase on lysosomes, leading to defective lysosomal acidification and marked impairment of autophagy. Additional dysregulation of cellular Ca2+ by mutant PS1 in FAD has been ascribed to altered ion channels in the endoplasmic reticulum; however, rich stores of Ca2+ in lysosomes are also abnormally released in PS1-deficient cells secondary to the lysosomal acidification defect. The resultant rise in cytosolic Ca2+ activates Ca2+-dependent enzymes, contributing substantially to calpain overactivation that is a final common pathway leading to neurofibrillary degeneration in all forms of AD (Alzheimer's disease). In the present review, we discuss the close inter-relationships among deficits of lysosomal function, autophagy and Ca2+ homoeostasis as a pathogenic process in PS1-related FAD and their relevance to sporadic AD.

  15. [Pain and emotional dysregulation: Cellular memory due to pain].

    Science.gov (United States)

    Narita, Minoru; Watanabe, Moe; Hamada, Yusuke; Tamura, Hideki; Ikegami, Daigo; Kuzumaki, Naoko; Igarashi, Katsuhide

    2015-08-01

    Genetic factors are involved in determinants for the risk of psychiatric disorders, and neurological and neurodegenerative diseases. Chronic pain stimuli and intense pain have effects at a cellular and/or gene expression level, and will eventually induce "cellular memory due to pain", which means that tissue damage, even if only transient, can elicit epigenetically abnormal transcription/translation and post-translational modification in related cells depending on the degree or kind of injury or associated conditions. Such cell memory/transformation due to pain can cause an abnormality in a fundamental intracellular response, such as a change in the three-dimensional structure of DNA, transcription, or translation. On the other hand, pain is a multidimensional experience with sensory-discriminative and motivational-affective components. Recent human brain imaging studies have examined differences in activity in the nucleus accumbens between controls and patients with chronic pain, and have revealed that the nucleus accumbens plays a role in predicting the value of a noxious stimulus and its offset, and in the consequent changes in the motivational state. In this review, we provide a very brief overview of a comprehensive understanding of chronic pain associated with emotional dysregulation due to transcriptional regulation, epigenetic modification and miRNA regulation.

  16. Dopamine dysregulation syndrome in Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    A V Nikitina

    2013-01-01

    Full Text Available Dopamine dysregulation syndrome (DDS is an iatrogenic disease developing during dopaminergic therapy. According to the data available in the literature, DDS develops in 3-4% of the Parkinson’s disease (PD cases. DDS in PD is frequently accompanied by other impulse control disorders (ICD: punding, compulsive shopping, hypersexuality, overeating. 246 patients with PD, of whom 16 (6.4% were found to have DDS, were examined. The patients’ age was 64±7.4 years. Women (n = 10 more often developed DDS than men (n = 6. The patients mainly suffered from the mixed form of the disease. Stages III and IV were diagnosed in 72 and 22%, respectively. The duration of PD was 12+2.6 years. In the PD patients with DDS, the quality-of-life indicators ranged from 19.8 to 90% (54+20.1%. The equivalent dose of levodopa is 1323.4+299 mg/day. DDS was concurrent with other types of ICD in 4 patients: panding in 2, compulsive shopping and punding in 1, and punding and hypersexuality. The doses of levodopa were corrected in patients receiving high doses of dopaminergic drugs. In the patients with DDS concurrent with punding or hypersexuality, the dose of dopaminergic receptor agonists was gradually reduced and subsequently discontinued.

  17. Dysregulated Functions of Lung Macrophage Populations in COPD

    Science.gov (United States)

    Bassler, Kevin; Aschenbrenner, Anna C.

    2018-01-01

    Chronic obstructive pulmonary disease (COPD) is a diverse respiratory disease characterised by bronchiolitis, small airway obstruction, and emphysema. Innate immune cells play a pivotal role in the disease's progression, and in particular, lung macrophages exploit their prevalence and strategic localisation to orchestrate immune responses. To date, alveolar and interstitial resident macrophages as well as blood monocytes have been described in the lungs of patients with COPD contributing to disease pathology by changes in their functional repertoire. In this review, we summarise recent evidence from human studies and work with animal models of COPD with regard to altered functions of each of these myeloid cell populations. We primarily focus on the dysregulated capacity of alveolar macrophages to secrete proinflammatory mediators and proteases, induce oxidative stress, engulf microbes and apoptotic cells, and express surface and intracellular markers in patients with COPD. In addition, we discuss the differences in the responses between alveolar macrophages and interstitial macrophages/monocytes in the disease and propose how the field should advance to better understand the implications of lung macrophage functions in COPD. PMID:29670919

  18. Role of Melanin in Melanocyte Dysregulation of Reactive Oxygen Species

    Directory of Open Access Journals (Sweden)

    Noah C. Jenkins

    2013-01-01

    Full Text Available We have recently reported a potential alternative tumor suppressor function for p16 relating to its capacity to regulate oxidative stress and observed that oxidative dysregulation in p16-depleted cells was most profound in melanocytes, compared to keratinocytes or fibroblasts. Moreover, in the absence of p16 depletion or exogenous oxidative insult, melanocytes exhibited significantly higher basal levels of reactive oxygen species (ROS than these other epidermal cell types. Given the role of oxidative stress in melanoma development, we speculated that this increased susceptibility of melanocytes to oxidative stress (and greater reliance on p16 for suppression of ROS may explain why genetic compromise of p16 is more commonly associated with predisposition to melanoma rather than other cancers. Here we show that the presence of melanin accounts for this differential oxidative stress in normal and p16-depleted melanocytes. Thus the presence of melanin in the skin appears to be a double-edged sword: it protects melanocytes as well as neighboring keratinocytes in the skin through its capacity to absorb UV radiation, but its synthesis in melanocytes results in higher levels of intracellular ROS that may increase melanoma susceptibility.

  19. Systematic identification of core transcription factors mediating dysregulated links bridging inflammatory bowel diseases and colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Yun Xiao

    Full Text Available Accumulating evidence shows a tight link between inflammation and cancer. However, comprehensive identification of pivotal transcription factors (i.e., core TFs mediating the dysregulated links remains challenging, mainly due to a lack of samples that can effectively reflect the connections between inflammation and tumorigenesis. Here, we constructed a series of TF-mediated regulatory networks from a large compendium of expression profiling of normal colonic tissues, inflammatory bowel diseases (IBDs and colorectal cancer (CRC, which contains 1201 samples in total, and then proposed a network-based approach to characterize potential links bridging inflammation and cancer. For this purpose, we computed significantly dysregulated relationships between inflammation and their linked cancer networks, and then 24 core TFs with their dysregulated genes were identified. Collectively, our approach provides us with quite important insight into inflammation-associated tumorigenesis in colorectal cancer, which could also be applied to identify functionally dysregulated relationships mediating the links between other different disease phenotypes.

  20. Depressive Symptoms, Emotion Dysregulation, and Bulimic Symptoms in Youth With Type 1 Diabetes

    Science.gov (United States)

    Young-Hyman, Deborah L.; Peterson, Claire M.; Fischer, Sarah; Markowitz, Jessica T.; Muir, Andrew B.; Laffel, Lori M.

    2016-01-01

    This study evaluated the associations between depressive symptoms, emotion dysregulation and bulimic symptoms in youth with type 1 diabetes (T1D) in the context of the diagnosis and treatment of T1D. Study participants were 103 youth in 2 distinct groups: newly diagnosed (New) or transitioning to pump therapy (continuous subcutaneous insulin infusion [CSII]; “Pump”), who completed questionnaires regarding symptoms of depression, emotion dysregulation, and bulimia. Glycemic control (A1c), height, weight, and questionnaires were evaluated within 10 days of diagnosis (n = 58) or at education/clinic visit before starting insulin utilizing CSII (n = 45). In the newly diagnosed group, only depression accounted for significant variance in bulimia scores (β = .47, P symptoms and emotion dysregulation were associated with greater bulimic symptoms. Depressive symptoms and emotion dysregulation, an indicator of poor coping/behavioral control, could help explain adoption of disordered eating behaviors in youth with T1D who are transitioning to pump therapy. PMID:27137457

  1. NASA 14 Day Undersea Missions: A Short-Duration Spaceflight Analog for Immune System Dysregulation?

    Science.gov (United States)

    Crucian, B. E.; Stowe, R. P.; Mehta, S. K.; Chouker, A.; Feuerecker, M.; Quiriarte, H.; Pierson, D. L.; Sams, C. F.

    2011-01-01

    This poster paper reviews the use of 14 day undersea missions as a possible analog for short duration spaceflight for the study of immune system dysregulation. Sixteen subjects from the the NASA Extreme Enviro nment Mission Operations (NEEMO) 12, 13 and 14 missions were studied for immune system dysregulation. The assays that are presented in this poster are the Virleukocyte subsets, the T Cell functions, and the intracellular/secreted cytokine profiles. Other assays were performed, but are not included in this presntation.

  2. Does Emotion Dysregulation Mediate the Association Between Sluggish Cognitive Tempo and College Students' Social Impairment?

    Science.gov (United States)

    Flannery, Andrew J; Becker, Stephen P; Luebbe, Aaron M

    2016-09-01

    Studies demonstrate an association between sluggish cognitive tempo (SCT) and social impairment, although no studies have tested possible mechanisms of this association. This study aimed to (a) examine SCT in relation to college students' social functioning; (b) test if SCT is significantly associated with emotion dysregulation beyond depressive, anxious, and ADHD symptoms; and (c) test if emotion dysregulation mediates the association between SCT symptoms and social impairment. College students (N = 158) completed measures of psychopathology symptoms, emotion dysregulation, and social functioning. Participants with elevated SCT (12%) had higher ADHD, depressive, and anxious symptoms in addition to poorer emotion regulation and social adjustment than participants without elevated SCT. Above and beyond other psychopathologies, SCT was significantly associated with social impairment but not general interpersonal functioning. SCT was also associated with emotion dysregulation, even after accounting for the expectedly strong association between depression and emotion dysregulation. Further analyses supported emotion dysregulation as a mediator of the association between SCT and social impairment. These findings are important for theoretical models of SCT and underscore the need for additional, longitudinal research. © The Author(s) 2014.

  3. Dysregulated autophagy contributes to podocyte damage in Fabry's disease.

    Directory of Open Access Journals (Sweden)

    Max C Liebau

    Full Text Available Fabry's disease results from an inborn error of glycosphingolipid metabolism that is due to deficiency of the lysosomal hydrolase α-galactosidase A. This X-linked defect results in the accumulation of enzyme substrates with terminally α-glycosidically bound galactose, mainly the neutral glycosphingolipid Globotriaosylceramide (Gb3 in various tissues, including the kidneys. Although end-stage renal disease is one of the most common causes of death in hemizygous males with Fabry's disease, the pathophysiology leading to proteinuria, hematuria, hypertension, and kidney failure is not well understood. Histological studies suggest that the accumulation of Gb3 in podocytes plays an important role in the pathogenesis of glomerular damage. However, due to the lack of appropriate animal or cellular models, podocyte damage in Fabry's disease could not be directly studied yet. As murine models are insufficient, a human model is needed. Here, we developed a human podocyte model of Fabry's disease by combining RNA interference technology with lentiviral transduction of human podocytes. Knockdown of α-galactosidase A expression resulted in diminished enzymatic activity and slowly progressive accumulation of intracellular Gb3. Interestingly, these changes were accompanied by an increase in autophagosomes as indicated by an increased abundance of LC3-II and a loss of mTOR kinase activity, a negative regulator of the autophagic machinery. These data suggest that dysregulated autophagy in α-galactosidase A-deficient podocytes may be the result of deficient mTOR kinase activity. This finding links the lysosomal enzymatic defect in Fabry's disease to deregulated autophagy pathways and provides a promising new direction for further studies on the pathomechanism of glomerular injury in Fabry patients.

  4. Dysregulated physiological stress systems and accelerated cellular aging.

    Science.gov (United States)

    Révész, Dóra; Verhoeven, Josine E; Milaneschi, Yuri; de Geus, Eco J C N; Wolkowitz, Owen M; Penninx, Brenda W J H

    2014-06-01

    Exposure to chronic stressors is associated with accelerated biological aging as indicated by reduced leukocyte telomere length (LTL). This impact could be because of chronic overactivation of the body's physiological stress systems. This study examined the associations between LTL and the immune system, hypothalamic-pituitary-adrenal axis and autonomic nervous system. LTL was assessed in 2936 adults from the Netherlands Study of Depression and Anxiety. Inflammation markers (interleukin-6, c-reactive protein, tumor necrosis factor-alpha), hypothalamic-pituitary-adrenal-axis indicators (salivary cortisol awakening curve [area under the curve indicators, with respect to the ground and increase], evening levels, 0.5 mg dexamethasone cortisol suppression ratio), and autonomic nervous system measures (heart rate, respiratory sinus arrhythmia, pre-ejection period) were determined. Linear regression analyses were performed and adjusted for sociodemographic, lifestyle and clinical factors. Shorter LTL was significantly associated with higher c-reactive protein, interleukin-6, area under the curve with respect to increase, and heart rate. A cumulative index score was calculated based on the number of highest tertiles of these 4 stress markers. LTL demonstrated a significant gradient within subjects ranging from having zero (5528 base pairs) to having 4 elevated stress markers (5371 base pairs, p for trend = 0.002), corresponding to a difference of 10 years of accelerated biological aging. Contrary to the expectations, shorter LTL was also associated with longer pre-ejection period, indicating lower sympathetic tone. This large-scale study showed that inflammation, high awakening cortisol response, and increased heart rate are associated with shorter LTL, especially when they are dysregulated cumulatively. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. Angiogenesis dysregulation in term asphyxiated newborns treated with hypothermia.

    Directory of Open Access Journals (Sweden)

    Henna Shaikh

    Full Text Available Neonatal encephalopathy following birth asphyxia is a major predictor of long-term neurological impairment. Therapeutic hypothermia is currently the standard of care to prevent brain injury in asphyxiated newborns but is not protective in all cases. More robust and versatile treatment options are needed. Angiogenesis is a demonstrated therapeutic target in adult stroke. However, no systematic study examines the expression of angiogenesis-related markers following birth asphyxia in human newborns.This study aimed to evaluate the expression of angiogenesis-related protein markers in asphyxiated newborns developing and not developing brain injury compared to healthy control newborns.Twelve asphyxiated newborns treated with hypothermia were prospectively enrolled; six developed eventual brain injury and six did not. Four healthy control newborns were also included. We used Rules-Based Medicine multi-analyte profiling and protein array technologies to study the plasma concentration of 49 angiogenesis-related proteins. Mean protein concentrations were compared between each group of newborns.Compared to healthy newborns, asphyxiated newborns not developing brain injury showed up-regulation of pro-angiogenic proteins, including fatty acid binding protein-4, glucose-6-phosphate isomerase, neuropilin-1, and receptor tyrosine-protein kinase erbB-3; this up-regulation was not evident in asphyxiated newborns eventually developing brain injury. Also, asphyxiated newborns developing brain injury showed a decreased expression of anti-angiogenic proteins, including insulin-growth factor binding proteins -1, -4, and -6, compared to healthy newborns.These findings suggest that angiogenesis pathways are dysregulated following birth asphyxia and are putatively involved in brain injury pathology and recovery.

  6. Angiogenesis Dysregulation in Term Asphyxiated Newborns Treated with Hypothermia

    Science.gov (United States)

    Shaikh, Henna; Boudes, Elodie; Khoja, Zehra; Shevell, Michael; Wintermark, Pia

    2015-01-01

    Background Neonatal encephalopathy following birth asphyxia is a major predictor of long-term neurological impairment. Therapeutic hypothermia is currently the standard of care to prevent brain injury in asphyxiated newborns but is not protective in all cases. More robust and versatile treatment options are needed. Angiogenesis is a demonstrated therapeutic target in adult stroke. However, no systematic study examines the expression of angiogenesis-related markers following birth asphyxia in human newborns. Objective This study aimed to evaluate the expression of angiogenesis-related protein markers in asphyxiated newborns developing and not developing brain injury compared to healthy control newborns. Design/Methods Twelve asphyxiated newborns treated with hypothermia were prospectively enrolled; six developed eventual brain injury and six did not. Four healthy control newborns were also included. We used Rules-Based Medicine multi-analyte profiling and protein array technologies to study the plasma concentration of 49 angiogenesis-related proteins. Mean protein concentrations were compared between each group of newborns. Results Compared to healthy newborns, asphyxiated newborns not developing brain injury showed up-regulation of pro-angiogenic proteins, including fatty acid binding protein-4, glucose-6-phosphate isomerase, neuropilin-1, and receptor tyrosine-protein kinase erbB-3; this up-regulation was not evident in asphyxiated newborns eventually developing brain injury. Also, asphyxiated newborns developing brain injury showed a decreased expression of anti-angiogenic proteins, including insulin-growth factor binding proteins -1, -4, and -6, compared to healthy newborns. Conclusions These findings suggest that angiogenesis pathways are dysregulated following birth asphyxia and are putatively involved in brain injury pathology and recovery. PMID:25996847

  7. Power spectrum scale invariance identifies prefrontal dysregulation in paranoid schizophrenia.

    Science.gov (United States)

    Radulescu, Anca R; Rubin, Denis; Strey, Helmut H; Mujica-Parodi, Lilianne R

    2012-07-01

    Theory and experimental evidence suggest that complex living systems function close to the boundary of chaos, with erroneous organization to an improper dynamical range (too stiff or chaotic) underlying system-wide dysregulation and disease. We hypothesized that erroneous organization might therefore also characterize paranoid schizophrenia, via optimization abnormalities in the prefrontal-limbic circuit regulating emotion. To test this, we acquired fMRI scans from 35 subjects (N = 9 patients with paranoid schizophrenia and N = 26 healthy controls), while they viewed affect-valent stimuli. To quantify dynamic regulation, we analyzed the power spectrum scale invariance (PSSI) of fMRI time-courses and computed the geometry of time-delay (Poincaré) maps, a measure of variability. Patients and controls showed distinct PSSI in two clusters (k(1) : Z = 4.3215, P = 0.00002 and k(2) : Z = 3.9441, P = 0.00008), localized to the orbitofrontal/medial prefrontal cortex (Brodmann Area 10), represented by β close to white noise in patients (β ≈ 0) and in the pink noise range in controls (β ≈ -1). Interpreting the meaning of PSSI differences, the Poincaré maps indicated less variability in patients than controls (Z = -1.9437, P = 0.05 for k(1) ; Z = -2.5099, P = 0.01 for k(2) ). That the dynamics identified Brodmann Area 10 is consistent with previous schizophrenia research, which implicates this area in deficits of working memory, executive functioning, emotional regulation and underlying biological abnormalities in synaptic (glutamatergic) transmission. Our results additionally cohere with a large body of work finding pink noise to be the normal range of central function at the synaptic, cellular, and small network levels, and suggest that patients show less supple responsivity of this region. Copyright © 2011 Wiley-Liss, Inc.

  8. Differential risk for late adolescent conduct problems and mood dysregulation among children with early externalizing behavior problems.

    Science.gov (United States)

    Okado, Yuko; Bierman, Karen L

    2015-05-01

    To investigate the differential emergence of antisocial behaviors and mood dysregulation among children with externalizing problems, the present study prospectively followed 317 high-risk children with early externalizing problems from school entry (ages 5-7) to late adolescence (ages 17-19). Latent class analysis conducted on their conduct and mood symptoms in late adolescence revealed three distinct patterns of symptoms, characterized by: 1) criminal offenses, conduct disorder symptoms, and elevated anger ("conduct problems"), 2) elevated anger, dysphoric mood, and suicidal ideation ("mood dysregulation"), and 3) low levels of severe conduct and mood symptoms. A diathesis-stress model predicting the first two outcomes was tested. Elevated overt aggression at school entry uniquely predicted conduct problems in late adolescence, whereas elevated emotion dysregulation at school entry uniquely predicted mood dysregulation in late adolescence. Experiences of low parental warmth and peer rejection in middle childhood moderated the link between early emotion dysregulation and later mood dysregulation but did not moderate the link between early overt aggression and later conduct problems. Thus, among children with early externalizing behavior problems, increased risk for later antisocial behavior or mood dysfunction may be identifiable in early childhood based on levels of overt aggression and emotion dysregulation. For children with early emotion dysregulation, however, increased risk for mood dysregulation characterized by anger, dysphoric mood, and suicidality--possibly indicative of disruptive mood dysregulation disorder--emerges only in the presence of low parental warmth and/or peer rejection during middle childhood.

  9. The cost of empathy: Parent-adolescent conflict predicts emotion dysregulation for highly empathic youth.

    Science.gov (United States)

    Van Lissa, Caspar J; Hawk, Skyler T; Koot, Hans M; Branje, Susan; Meeus, Wim H J

    2017-09-01

    Empathy plays a key role in maintaining close relationships and promoting prosocial conflict resolution. However, research has not addressed the potential emotional cost of adolescents' high empathy, particularly when relationships are characterized by more frequent conflict. The present 6-year longitudinal study (N = 467) investigated whether conflict with parents predicted emotion dysregulation more strongly for high-empathy adolescents than for lower-empathy adolescents. Emotion dysregulation was operationalized at both the experiential level, using mood diary data collected for 3 weeks each year, and at the dispositional level, using annual self-report measures. In line with predictions, we found that more frequent adolescent-parent conflict predicted greater day-to-day mood variability and dispositional difficulties in emotion regulation for high-empathy adolescents, but not for average- and low-empathy adolescents. Mood variability and difficulties in emotion regulation, in turn, also predicted increased conflict with parents. These links were not moderated by empathy. Moreover, our research allowed for a novel investigation of the interplay between experiential and dispositional emotion dysregulation. Day-to-day mood variability predicted increasing dispositional difficulties in emotion regulation over time, which suggests that experiential dysregulation becomes consolidated into dispositional difficulties in emotion regulation. Moderated mediation analyses revealed that, for high-empathy adolescents, conflict was a driver of this dysregulation consolidation process. Finally, emotion dysregulation played a role in overtime conflict maintenance for high-empathy adolescents. This suggests that, through emotion dysregulation, high empathy may paradoxically also contribute to maintaining negative adolescent-parent interactions. Our research indicates that high empathy comes at a cost when adolescent-parent relationships are characterized by greater negativity

  10. Genetically enhanced asynapsis of autosomal chromatin promotes transcriptional dysregulation and meiotic failure

    Czech Academy of Sciences Publication Activity Database

    Homolka, David; Jansa, Petr; Forejt, Jiří

    2012-01-01

    Roč. 121, č. 1 (2012), s. 91-104 ISSN 0009-5915 R&D Projects: GA MŠk(CZ) LD11079 Institutional research plan: CEZ:AV0Z50520514 Keywords : meiotic silencing of unsynapsed chromatin * meiotic sex chromosome inactivation * autosomal translocation Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.340, year: 2012

  11. Optimal Versus Realized Trajectories of Physiological Dysregulation in Aging and Their Relation to Sex-Specific Mortality Risk

    DEFF Research Database (Denmark)

    Arbeev, Konstantin G; Cohen, Alan A; Arbeeva, Liubov S

    2016-01-01

    dysregulation is related to different aging-related characteristics such as decline in stress resistance and adaptive capacity (which typically are not observed in the data and thus can be analyzed only indirectly), and, ultimately, to estimate how such dynamic relationships increase mortality risk with age. We...... substantial sex differences in these processes, with women becoming dysregulated more quickly but with men showing a much greater sensitivity to dysregulation in terms of mortality risk....

  12. Emotional dysregulation and anxiety control in the psychopathological mechanism underlying drive for thinness

    Directory of Open Access Journals (Sweden)

    Francesca eFiore

    2014-04-01

    Full Text Available Emotional dysregulation is a process which consists in mitigating, intensifying or maintaining a given emotion and is the trigger for some psychological disorders. Research has shown that a anxiety control plays an important role in emotional expression and regulation and, in addition, for anorexia nervosa and, more in general, in drive for thinness. Scientific literature suggests that in anorexia nervosa there is a core of emotional dysregulation and anxiety control. The aim of this study is to explore the roles of emotional dysregulation and anxiety control as independent or third variables in a mediational regression model related to drive for thinness. 154 clinical individuals with anorexia participated in the study and all completed a set of self-report questionnaires: eating disorders inventory version 3 (EDI-3, DERS, and the anxiety control questionnaire (ACQ. The data confirmed a mediational model in which the relation between emotional dysregulation and drive for thinness is mediated by anxiety control. The current study partially supports a clinical model in which emotional dysregulation is a distal factor in eating disorders while the mediator variable anxiety control is a proximal factor in the psychopathological process underlying it.

  13. Developmental delay and emotion dysregulation: Predicting parent-child conflict across early to middle childhood

    Science.gov (United States)

    Marquis, Willa A.; Noroña, Amanda N.; Baker, Bruce L.

    2016-01-01

    Cumulative risk research has increased understanding of how multiple risk factors impact various socioemotional and interpersonal outcomes across the life span. However, little is known about risk factors for parent-child conflict early in development, where identifying predictors of change could be highly salient for intervention. Given their established association with parent-child conflict, child developmental delay (DD) and emotion dysregulation were examined as predictors of change in conflict across early to middle childhood (ages 3 to 7 years). Participants (n=211) were part of a longitudinal study examining the development of psychopathology in children with or without DD. Level of parent-child conflict was derived from naturalistic home observations, while child dysregulation was measured using an adapted CBCL-Emotion Dysregulation Index. PROCESS was used to examine the conditional interactive effects of delay status (typically developing, DD) and dysregulation on change in conflict from child ages 3 to 5 and 5 to 7 years. Across both of these timeframes, parent-child conflict increased only for families of children with both DD and high dysregulation, providing support for an interactive risk model of parent-child conflict. Findings are considered in the context of developmental transitions, and implications for intervention are discussed. PMID:28054804

  14. Understanding the connection between self-esteem and aggression: The mediating role of emotion dysregulation.

    Science.gov (United States)

    Garofalo, Carlo; Holden, Christopher J; Zeigler-Hill, Virgil; Velotti, Patrizia

    2016-01-01

    The purpose of the present study was to extend previous knowledge concerning the link between self-esteem and aggression by examining the mediating role of emotion dysregulation among offenders and community participants. A sample of 153 incarcerated violent offenders and a community sample of 197 individuals completed self-report measures of self-esteem level, emotion dysregulation, and trait aggression. Offenders reported lower levels of self-esteem than community participants, as well as greater levels of emotional nonacceptance and hostility. Bootstrapping analyses were performed to test whether emotion dysregulation mediated the association between self-esteem level and aggression. In the offender sample, mediation models were significant for three of the four aspects of trait aggression that were considered. Emotion dysregulation fully mediated the links that low self-esteem had with physical aggression, anger, and hostility. The same pattern (with the addition of full mediation for verbal aggression) was confirmed in the community sample. Our findings suggest that emotion dysregulation may play an important role in the connection between low self-esteem and aggression. Alternative models of the associations among these variables were tested and discussed. As a whole, the present results are consistent with those of other studies and suggest that it may be beneficial to include emotion regulation modules as part of prevention and treatment programs for violent offenders. © 2015 Wiley Periodicals, Inc.

  15. Dysregulated Pathway Identification of Alzheimer's Disease Based on Internal Correlation Analysis of Genes and Pathways.

    Science.gov (United States)

    Kong, Wei; Mou, Xiaoyang; Di, Benteng; Deng, Jin; Zhong, Ruxing; Wang, Shuaiqun

    2017-11-20

    Dysregulated pathway identification is an important task which can gain insight into the underlying biological processes of disease. Current pathway-identification methods focus on a set of co-expression genes and single pathways and ignore the correlation between genes and pathways. The method proposed in this study, takes into account the internal correlations not only between genes but also pathways to identifying dysregulated pathways related to Alzheimer's disease (AD), the most common form of dementia. In order to find the significantly differential genes for AD, mutual information (MI) is used to measure interdependencies between genes other than expression valves. Then, by integrating the topology information from KEGG, the significant pathways involved in the feature genes are identified. Next, the distance correlation (DC) is applied to measure the pairwise pathway crosstalks since DC has the advantage of detecting nonlinear correlations when compared to Pearson correlation. Finally, the pathway pairs with significantly different correlations between normal and AD samples are known as dysregulated pathways. The molecular biology analysis demonstrated that many dysregulated pathways related to AD pathogenesis have been discovered successfully by the internal correlation detection. Furthermore, the insights of the dysregulated pathways in the development and deterioration of AD will help to find new effective target genes and provide important theoretical guidance for drug design. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  16. SI-SHY: Dysregulated Fear in Toddlerhood Predicts Kindergarten Social Withdrawal through Protective Parenting.

    Science.gov (United States)

    Kiel, Elizabeth J; Buss, Kristin A

    2014-05-01

    Two recent advances in the study of fearful temperament (behavioral inhibition) include the validation of dysregulated fear as a temperamental construct that more specifically predicts later social withdrawal and anxiety, and the use of conceptual and statistical models that place parenting as a mechanism of development from temperament to these outcomes. The current study further advances these areas by examining whether protective parenting mediated the relation between dysregulated fear in toddlerhood and social withdrawal in kindergarten. Participants included 93 toddlers and their mothers, who engaged in laboratory tasks assessing traditional fearful temperament, dysregulated fear, and protective parenting. When children reached kindergarten, they returned to the laboratory for a multimethod assessment of social withdrawal. Results confirmed the hypothesis that dysregulated fear predicted social withdrawal through protective parenting, and this occurred above and beyond the effect of traditional fearful temperament. These findings bolster support for the use of dysregulated fear as a temperamental construct related to, but perhaps more discerning of risk than traditionally measured fearful temperament/behavioral inhibition and highlight the importance of transactional influences between the individual and the caregiving environment in the development of social withdrawal.

  17. PTSD, emotion dysregulation, and dissociative symptoms in a highly traumatized sample

    Science.gov (United States)

    Powers, Abigail; Cross, Dorthie; Fani, Negar; Bradley, Bekh

    2015-01-01

    Exposure to multiple traumas has been shown to result in many negative mental health outcomes, including posttraumatic stress disorder (PTSD). Dissociation, which involves disruptions in memory, identity, and perceptions, may be a component of PTSD, particularly among individuals who have experienced childhood trauma. Emotion regulation difficulties are also strongly associated with childhood trauma and emotion dysregulation may be a particularly important factor to consider in the development and maintenance of dissociative symptoms. The goal of the present study was to determine whether emotion dysregulation mediated the relationship between PTSD symptoms and dissociation in a sample of 154 (80% female, 97% African-American) adults recruited from a public, urban hospital. PTSD was measured using the Clinician Administered PTSD Scale, emotion dysregulation was measured using the Difficulties in Emotion Regulation Scale, and dissociation was measured using the Multiscale Dissociation Inventory. A linear regression analysis showed that both PTSD and emotion dysregulation were statistically significant predictors of dissociation even after controlling for trauma exposure. Alexithymia and an inability to use emotion regulation strategies in particular were predictive of dissociation above and beyond other predictor variables. Using bootstrapping techniques, we found that overall emotion dyregulation partially mediated the effect of PTSD symptoms on dissociative symptoms. Our results suggest that emotion dysregulation may be important in understanding the relation between PTSD and dissociative symptoms. Treatment approaches may consider a focus on training in emotional understanding and the development of adaptive regulation strategies as a way to address dissociative symptoms in PTSD patients. PMID:25573648

  18. Emotion dysregulation mediates the relationship between child maltreatment and psychopathology: A structural equation model.

    Science.gov (United States)

    Jennissen, Simone; Holl, Julia; Mai, Hannah; Wolff, Sebastian; Barnow, Sven

    2016-12-01

    The present study investigated the mediating effects of emotion dysregulation on the relationship between child maltreatment and psychopathology. An adult sample (N=701) from diverse backgrounds of psychopathology completed the Childhood Trauma Questionnaire (CTQ), the Difficulties in Emotion Regulation Scale (DERS), the Brief Symptom Inventory (BSI), and the negative affect subscale of the Positive and Negative Affect Schedule (PANAS) in a cross-sectional online survey. Correlational analyses showed that all types of child maltreatment were uniformly associated with emotion dysregulation, and dimensions of emotion dysregulation were strongly related to psychopathology. Limited access to strategies for emotion regulation emerged as the most powerful predictor. Structural equation modeling analyses revealed that emotion dysregulation partially mediated the relationship between child maltreatment and psychopathology, even after controlling for shared variance with negative affect. These findings emphasize the importance of emotion dysregulation as a possible mediating mechanism in the association between child maltreatment and later psychopathology. Additionally, interventions targeting specific emotion regulation strategies may be effective to reduce psychopathology in victims of child maltreatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. SI-SHY: Dysregulated Fear in Toddlerhood Predicts Kindergarten Social Withdrawal through Protective Parenting

    Science.gov (United States)

    Kiel, Elizabeth J.; Buss, Kristin A.

    2014-01-01

    Two recent advances in the study of fearful temperament (behavioral inhibition) include the validation of dysregulated fear as a temperamental construct that more specifically predicts later social withdrawal and anxiety, and the use of conceptual and statistical models that place parenting as a mechanism of development from temperament to these outcomes. The current study further advances these areas by examining whether protective parenting mediated the relation between dysregulated fear in toddlerhood and social withdrawal in kindergarten. Participants included 93 toddlers and their mothers, who engaged in laboratory tasks assessing traditional fearful temperament, dysregulated fear, and protective parenting. When children reached kindergarten, they returned to the laboratory for a multimethod assessment of social withdrawal. Results confirmed the hypothesis that dysregulated fear predicted social withdrawal through protective parenting, and this occurred above and beyond the effect of traditional fearful temperament. These findings bolster support for the use of dysregulated fear as a temperamental construct related to, but perhaps more discerning of risk than traditionally measured fearful temperament/behavioral inhibition and highlight the importance of transactional influences between the individual and the caregiving environment in the development of social withdrawal. PMID:25242893

  20. Developmental delay and emotion dysregulation: Predicting parent-child conflict across early to middle childhood.

    Science.gov (United States)

    Marquis, Willa A; Noroña, Amanda N; Baker, Bruce L

    2017-04-01

    Cumulative risk research has increased understanding of how multiple risk factors impact various socioemotional and interpersonal outcomes across the life span. However, little is known about risk factors for parent-child conflict early in development, where identifying predictors of change could be highly salient for intervention. Given their established association with parent-child conflict, child developmental delay (DD) and emotion dysregulation were examined as predictors of change in conflict across early to middle childhood (ages 3 to 7 years). Participants (n = 211) were part of a longitudinal study examining the development of psychopathology in children with or without DD. Level of parent-child conflict was derived from naturalistic home observations, whereas child dysregulation was measured using an adapted CBCL-Emotion Dysregulation Index. PROCESS was used to examine the conditional interactive effects of delay status (typically developing, DD) and dysregulation on change in conflict from child ages 3 to 5 and 5 to 7 years. Across both of these timeframes, parent-child conflict increased only for families of children with both DD and high dysregulation, providing support for an interactive risk model of parent-child conflict. Findings are considered in the context of developmental transitions, and implications for intervention are discussed. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  1. A cleanroom sleeping environment's impact on markers of oxidative stress, immune dysregulation, and behavior in children with autism spectrum disorders.

    Science.gov (United States)

    Faber, Scott; Zinn, Gregory M; Boggess, Andrew; Fahrenholz, Timothy; Kern, John C; Kingston, H M Skip

    2015-03-19

    An emerging paradigm suggests children with autism display a unique pattern of environmental, genetic, and epigenetic triggers that make them susceptible to developing dysfunctional heavy metal and chemical detoxification systems. These abnormalities could be caused by alterations in the methylation, sulfation, and metalloprotein pathways. This study sought to evaluate the physiological and behavioral effects of children with autism sleeping in an International Organization for Standardization Class 5 cleanroom. Ten children with autism, ages 3-12, slept in a cleanroom for two weeks to evaluate changes in toxin levels, oxidative stress, immune dysregulation, and behavior. Before and after the children slept in the cleanroom, samples of blood and hair and rating scale scores were obtained to assess these changes. Five children significantly lowered their concentration of oxidized glutathione, a biomarker of oxidative stress. The younger cohort, age 5 and under, showed significantly greater mean decreases in two markers of immune dysregulation, CD3% and CD4%, than the older cohort. Changes in serum magnesium, influencing neuronal regulation, correlated negatively while changes in serum iron, affecting oxygenation of tissues, correlated positively with age. Changes in serum benzene and PCB 28 concentrations showed significant negative correlations with age. The younger children demonstrated significant improvements on behavioral rating scales compared to the older children. In a younger pair of identical twins, one twin showed significantly greater improvements in 4 out of 5 markers of oxidative stress, which corresponded with better overall behavioral rating scale scores than the other twin. Younger children who slept in the cleanroom altered elemental levels, decreased immune dysregulation, and improved behavioral rating scales, suggesting that their detoxification metabolism was briefly enhanced. The older children displayed a worsening in behavioral rating scale

  2. Sexual victimization, fear of sexual powerlessness, and cognitive emotion dysregulation as barriers to sexual assertiveness in college women.

    Science.gov (United States)

    Zerubavel, Noga; Messman-Moore, Terri L

    2013-12-01

    The current study examined sexual victimization and two barriers to young women's sexual assertiveness: fear of sexual powerlessness and cognitive emotion dysregulation. College women (N = 499) responded to surveys and indicated that fear of sexual powerlessness and, to a lesser extent, cognitive emotion dysregulation were barriers to sexual assertiveness. Compared with nonvictims, sexually victimized women had greater problems with sexual assertiveness, fear of sexual powerlessness, and cognitive emotion dysregulation. Among victims, fear of sexual powerlessness and emotion dysregulation interacted to impede sexual assertiveness. Findings support targeting identified barriers in interventions to improve sexual assertiveness and reduce risk for unwanted sexual experiences and sexual victimization.

  3. Alcohol-related biases in selective attention and action tendency make distinct contributions to dysregulated drinking behaviour.

    Science.gov (United States)

    Sharbanee, Jason M; Stritzke, Werner G K; Wiers, Reinout W; MacLeod, Colin

    2013-10-01

    To assess whether alcohol-related biases in selective-attention and action tendency uniquely or concurrently predict the ability to regulate alcohol consumption. Two groups of undergraduate social drinkers (total n = 55) who differed in their ability to regulate their alcohol consumption completed a novel Selective-Attention/Action-Tendency Task (SA/ATT), which assessed separately alcohol-related biases in selective attention and action tendency. University of Western Australia, Australia. Dysregulated drinking was operationalized as a self-reported high level of alcohol consumption on the Alcohol Consumption Questionnaire, and a high desire to reduce consumption on the Brief Readiness to Change Algorithm. Selective attention and action tendency were assessed using the SA/ATT, working memory was assessed using the operation-span task and participant characteristics were assessed using the Alcohol Use Disorders Identification Test (AUDIT) and Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES). Results indicated that (i) there was no significant association between alcohol-related biases in selective attention and action tendency, r = 0.16, P = 0.274, and (ii) biases towards alcohol, in both selective attention, β = 1.01, odds ratio = 2.74, P = 0.022, and action tendency, β = 1.24, odds ratio = 3.45, P = 0.015, predicted independent variance in dysregulated-drinker status. Biases in selective attention and action tendency appear to be distinct mechanisms that contribute independently to difficulty regulating alcohol consumption. Treatment components that could be combined to target both mechanisms could enhance treatment outcomes for alcohol-use disorders. © 2013 Society for the Study of Addiction.

  4. Environmental pollutants and dysregulation of male puberty--a comparison among species.

    Science.gov (United States)

    Magnusson, Ulf; Ljungvall, Karl

    2014-04-01

    The scientific literature on altered onset of puberty predominantly involves studies on females. This paper reviews current knowledge on the role of environmental pollutants in dysregulation of male puberty in humans, laboratory rodents and farm animals. The methods used to determine the onset of puberty are well developed in humans and farm animals, and standardized across studies in humans. In laboratory rodents standardized external morphological endpoints are used. There is an increasing weight of evidence from epidemiological studies in humans, as well as from experiments in animals, indicating that environmental pollutants dysregulate puberty in males. Most data are from studies on "classical" persistent environmental pollutants. Assessing the effect of multichemical environmental pollution on dysregulation of puberty in humans is more challenging; further solid epidemiological data would likely contribute most to our understanding, especially if combined with systematically collected field-data from selected wildlife. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  5. Self-Concept Clarity and Emotion Dysregulation in Nonsuicidal Self-Injury.

    Science.gov (United States)

    Lear, Mary K; Pepper, Carolyn M

    2016-12-01

    Recent research has linked identity instability with engagement in nonsuicidal self-injury (NSSI; Claes, Luyckx, & Bijttebier, 2014; Claes et al., 2015). This study examined the relationship between self-concept clarity (SCC), an index of identity stability, and NSSI in a sample of 147 college students, using a cross-sectional survey design. The relationship between SCC and emotion dysregulation in NSSI severity was also examined. SCC was significantly negatively associated with NSSI engagement, as well as NSSI frequency and versatility, above negative affect or age. SCC fully accounted for the variance originally explained by emotion dysregulation in NSSI versatility. NSSI frequency was not significantly predicted by emotion regulation, but self-concept clarity reached marginal significance. These findings provide preliminary support for identity instability as a contributing factor to a relationship between emotion dysregulation and NSSI severity. Possible explanations and future research directions are discussed.

  6. The Relationship Between Emotion Dysregulation and Impulsive Aggression in Veterans With Posttraumatic Stress Disorder Symptoms.

    Science.gov (United States)

    Miles, Shannon R; Menefee, Deleene S; Wanner, Jill; Teten Tharp, Andra; Kent, Thomas A

    2016-06-01

    While Veterans in general are no more dangerous than the civilian population, Veterans with posttraumatic stress disorder (PTSD) have stronger associations with anger and hostility and certain forms of aggression, such as intimate partner violence, than civilians with PTSD. This is alarming because up to 21% of Veterans seeking Veterans Affairs (VA) health care are diagnosed with PTSD. Emotion regulation difficulties (emotion dysregulation) are also related to increased PTSD symptom severity and may play a role in aggressive behavior. Because the predominant form of aggression in PTSD appears to be the impulsive subtype, the authors sought to clarify the relationship between PTSD, emotion dysregulation, and impulsive aggression. We examined how emotion dysregulation influenced impulsive aggression in a Veteran sample (N = 479) seeking treatment for trauma sequelae. All Veterans completed measures that assessed demographic information, emotion dysregulation, aggression frequency and subtype, and PTSD symptoms. Men generally reported more aggression than women. The emotion dysregulation, aggression, and PTSD measures were significantly correlated. Two cross-sectional mediation models showed emotion dysregulation fully accounted for the relationship between PTSD and impulsive aggression (indirect path for men: b = .07, SE = .026, bias-correct and accelerated confidence interval [BCa CI] = [0.02, 0.13]; indirect path for women: b = .08, SE = .022, BCa CI = [0.05, 0.13]). PTSD can increase negative emotions yet does not always lead to aggressive behaviors. The ability to regulate emotions may be pivotal to inhibiting aggression in those with PTSD. PTSD interventions may benefit from augmentation with emotion regulation skills training. © The Author(s) 2015.

  7. Immune System Dysregulation and Herpesvirus Reactivation Persist During Long-Duration Spaceflight

    Science.gov (United States)

    Crucian, B. E.; Mehta, S.; Stowe, R. P.; Uchakin, P.; Quiriarte, H.; Pierson, D.; Sams, C. F.

    2011-01-01

    This poster presentation reviews a study that is designed to address immune system dysregulation and the risk to crewmembers in long duration exploration class missions. This study will address these objectives: (1) Determine the status of adaptive immunity physiological stress, viral immunity, latent herpesvirus reactivation in astronauts during 6 month missions to the International Space Station; (2) determine the clinical risk related to immune dysregulation for exploration class spaceflight; and (3) determine an appropriate monitoring strategy for spaceflight-associated immune dysfunction that could be used for the evaluation of countermeasures. The study anticipates 17 subjects, and for this presentation, (midpoint study data) 10 subjects are reviewed.

  8. The role of social support on emotion dysregulation and Internet addiction among Chinese adolescents: A structural equation model.

    Science.gov (United States)

    Mo, Phoenix K H; Chan, Virginia W Y; Chan, Samuel W; Lau, Joseph T F

    2018-07-01

    Internet addiction is prevalent among adolescents and is associated with various negative outcomes. Relatively few studies examined the role of emotion dysregulation and social support on Internet addiction in this population. The present examined the association between emotion dysregulation, social support, and Internet addiction among junior secondary school students in Hong Kong. The mediating role of emotion dysregulation and Internet use on the relationship between social support and Internet addiction and the gender difference in such association were also tested. A total of 862 junior secondary school students (grade 7 to 8) from 4 schools completed a cross-sectional survey. 10.9% scored above the cut-off for Internet addiction based on the Chen Internet Addiction Scale. Results from structural equation modeling revealed that social support was negatively related to emotion dysregulation and Internet usage, which in turn, were positively related to Internet addiction. Results from multi-group analysis by gender showed that the relationship between social support and emotion dysregulation, Internet usage, and Internet addiction, and those between emotion dysregulation and Internet addiction and between Internet usage and Internet addiction were stronger among female participants. Emotion dysregulation is a potential risk factor while social support is a potential protective factor for Internet addiction. The role of social support on emotion dysregulation and Internet addiction were stronger among female students. Gender-sensitive interventions on Internet Addiction for adolescents are warranted, such interventions should increase social support and improve emotion regulation. Copyright © 2018. Published by Elsevier Ltd.

  9. Dysregulation of the autonomic nervous system and its association with the presence and intensity of chronic widespread pain

    NARCIS (Netherlands)

    Barakat, A.; Vogelzangs, N.; Licht, C.M.M.; Geenen, R.; Macfarlane, G.J.; de Geus, E.J.C.; Smit, J.H.; Penninx, B.W.J.H.; Dekker, J.

    2012-01-01

    Objective To test the hypotheses that dysregulation of the autonomic nervous system (ANS) is associated with the presence of chronic widespread pain (CWP), and that dysregulation of the ANS is associated with higher pain intensity in CWP. Methods Cross-sectional data were obtained from 1,574

  10. Dysregulation of the Autonomic Nervous System and Its Association With the Presence and Intensity of Chronic Widespread Pain

    NARCIS (Netherlands)

    Barakat, Ansam; Vogelzangs, Nicole; Licht, Carmilla M. M.; Geenen, Rinie; Macfarlane, Gary J.; de Geus, Eco J. C.; Smit, Johannes H.; Penninx, Brenda W. J. H.; Dekker, Joost

    Objective. To test the hypotheses that dysregulation of the autonomic nervous system (ANS) is associated with the presence of chronic widespread pain (CWP), and that dysregulation of the ANS is associated with higher pain intensity in CWP. Methods. Cross-sectional data were obtained from 1,574

  11. Integrating Dialectical Behavior Therapy and Cognitive-Behavioral Couple Therapy: A Couples Skills Group for Emotion Dysregulation

    Science.gov (United States)

    Kirby, Jennifer S.; Baucom, Donald H.

    2007-01-01

    Given the reciprocal influences of emotion dysregulation and relationship functioning, it is important to target such emotional difficulties within an interpersonal context. Treating emotion dysregulation within intimate relationships can offer valuable opportunities for both emotional and relationship difficulties to be addressed. This paper…

  12. Family enmeshment, adolescent emotional dysregulation, and the moderating role of gender.

    Science.gov (United States)

    Kivisto, Katherine Little; Welsh, Deborah P; Darling, Nancy; Culpepper, Christi L

    2015-08-01

    Enmeshment plays a key role in many families' dysfunctional interactions and may be especially detrimental for adolescents. Sixty-four adolescents completed ratings of family enmeshment, perceived distress tolerance, an interpersonal challenge task, and mood ratings before and immediately after the task. Before and during the challenge task, adolescents' respiratory sinus arrhythmia (an indicator of cardiac vagal tone) was recorded. Associations were tested between adolescents' perceptions of family enmeshment and 3 aspects of adolescent emotional dysregulation. Adolescents who perceived higher family enmeshment also demonstrated greater emotional dysregulation in several domains: negative global appraisals of distress tolerance, stronger increase in subjective negative mood from baseline to postchallenge, lower baseline vagal tone, and vagal augmentation during the challenge task. Gender differences also emerged, such that girls reported more negative distress appraisals overall and enmeshed boys showed greater emotional dysregulation across analyses. Findings are discussed in terms of how clinicians may dynamically assess and treat enmeshment and emotional dysregulation in families with male and female adolescents. (c) 2015 APA, all rights reserved).

  13. Emotion Dysregulation and Anxiety in Adults with ASD: Does Social Motivation Play a Role?

    Science.gov (United States)

    Swain, Deanna; Scarpa, Angela; White, Susan; Laugeson, Elizabeth

    2015-01-01

    Young adults with ASD and no intellectual impairment are more likely to exhibit clinical levels of anxiety than typically developing peers (DSM-5, American Psychiatric Association, 2013). This study tests a mechanistic model in which anxiety culminates via emotion dysregulation and social motivation. Adults with ASD (49 males, 20 females)…

  14. Emotion regulation and aggression : The incremental contribution of alexithymia, impulsivity, and emotion dysregulation facets

    NARCIS (Netherlands)

    Garofalo, C.; Velotti, Patrizia; Zavattini, Giulio Cesare

    2018-01-01

    Objective: Prior research has long emphasized the role of alexithymia and impulsivity to explain aggressive tendencies. Recently, a growing body of research seems to support the relevance of the broader construct of emotion dysregulation to understand aggression. The present study was the first to

  15. In Search of HPA Axis Dysregulation in Child and Adolescent Depression

    Science.gov (United States)

    Guerry, John D.; Hastings, Paul D.

    2011-01-01

    Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in adults with major depressive disorder is among the most consistent and robust biological findings in psychiatry. Given the importance of the adolescent transition to the development and recurrence of depressive phenomena over the lifespan, it is important to have an integrative…

  16. Investigating multiple dysregulated pathways in rheumatoid arthritis based on pathway interaction network.

    Science.gov (United States)

    Song, Xian-Dong; Song, Xian-Xu; Liu, Gui-Bo; Ren, Chun-Hui; Sun, Yuan-Bo; Liu, Ke-Xin; Liu, Bo; Liang, Shuang; Zhu, Zhu

    2018-03-01

    The traditional methods of identifying biomarkers in rheumatoid arthritis (RA) have focussed on the differentially expressed pathways or individual pathways, which however, neglect the interactions between pathways. To better understand the pathogenesis of RA, we aimed to identify dysregulated pathway sets using a pathway interaction network (PIN), which considered interactions among pathways. Firstly, RA-related gene expression profile data, protein-protein interactions (PPI) data and pathway data were taken up from the corresponding databases. Secondly, principal component analysis method was used to calculate the pathway activity of each of the pathway, and then a seed pathway was identified using data gleaned from the pathway activity. A PIN was then constructed based on the gene expression profile, pathway data, and PPI information. Finally, the dysregulated pathways were extracted from the PIN based on the seed pathway using the method of support vector machines and an area under the curve (AUC) index. The PIN comprised of a total of 854 pathways and 1064 pathway interactions. The greatest change in the activity score between RA and control samples was observed in the pathway of epigenetic regulation of gene expression, which was extracted and regarded as the seed pathway. Starting with this seed pathway, one maximum pathway set containing 10 dysregulated pathways was extracted from the PIN, having an AUC of 0.8249, and the result indicated that this pathway set could distinguish RA from the controls. These 10 dysregulated pathways might be potential biomarkers for RA diagnosis and treatment in the future.

  17. Adverse Childhood Experiences and Disordered Gambling: Assessing the Mediating Role of Emotion Dysregulation.

    Science.gov (United States)

    Poole, Julia C; Kim, Hyoun S; Dobson, Keith S; Hodgins, David C

    2017-12-01

    Adverse childhood experiences (ACEs), such as sexual and physical abuse, have been established as risk factors for the development of disordered gambling. The underlying mechanism by which ACEs influence disordered gambling, however, remains unknown. The aims of the present research were to comprehensively investigate ten types of childhood adversity and their relationships to disordered gambling in adulthood, and to test whether emotion dysregulation mediated the relationship between ACEs and disordered gambling. A sample of community gamblers (N = 414) completed self-report measures of ACEs, emotion dysregulation, and gambling severity. Results revealed a significant association between all but one type (physical abuse) of ACEs and disordered gambling. Further, the results highlighted the cumulative impact of ACEs on gambling. Specifically, individuals who experienced three or more types of ACEs were more than three times as likely to report disordered gambling as compared to individuals with no history of childhood adversity. Importantly, as hypothesized, emotion dysregulation mediated the relationship between ACEs and disordered gambling. Findings from this research describe the association between ACEs and gambling and indicate a causal link between childhood adversity and disordered gambling. Results suggest that treatment initiatives may do well to address both ACEs and emotion dysregulation in the treatment of problem gambling.

  18. The Impact of Alexithymia on Emotion Dysregulation in Anorexia Nervosa and Bulimia Nervosa over Time.

    Science.gov (United States)

    Brown, Tiffany A; Avery, Jade C; Jones, Michelle D; Anderson, Leslie K; Wierenga, Christina E; Kaye, Walter H

    2018-03-01

    Research supports that anorexia nervosa-restricting subtype (AN-R) and bulimia nervosa (BN) are associated with emotion regulation difficulties and alexithymia. However, the impact of diagnosis on the relationship between these constructs is less well understood. The purpose of the present study was to examine whether eating disorder diagnosis moderated the association between admission alexithymia and emotion regulation through discharge. Adult patients with AN-R (n = 54) and BN (n = 60) completed assessments at treatment admission and discharge from a partial hospital program. Eating disorder diagnosis moderated the association between admission alexithymia levels and change in global emotion dysregulation, impulse control difficulties and access to emotion regulation strategies. At higher levels of admission alexithymia, there were no differences between AN-R and BN on emotion dysregulation, whereas at lower levels of alexithymia, AN-R patients demonstrated lower levels of emotion dysregulation. Results imply that difficulties with alexithymia appear to have a greater impact on emotion dysregulation for AN-R patients. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association. Copyright © 2017 John Wiley & Sons, Ltd and Eating Disorders Association.

  19. Just Breathe: The Effects of Emotional Dysregulation and Test Anxiety on GPA

    Science.gov (United States)

    Hartman, Samantha D.; Wasieleski, David T.; Whatley, Mark A.

    2017-01-01

    College is considered to be one of the most evaluative and stressful times during a student's academic career. A student's inability to regulate emotions may be correlated with an increased level of test anxiety. Previous research has indicated significant relationships between emotional dysregulation and generalized anxiety disorders (e.g.,…

  20. Pediatric Bipolar Disorder versus Severe Mood Dysregulation: Risk for Manic Episodes on Follow-Up

    Science.gov (United States)

    Stringaris, Argyris; Baroni, Argelinda; Haimm, Caroline; Brotman, Melissa; Lowe, Catherine H.; Myers, Frances; Rustgi, Eileen; Wheeler, Wanda; Kayser, Reilly; Towbin, Kenneth; Leibenluft, Ellen

    2010-01-01

    Objective: An important question in pediatric bipolar research is whether marked nonepisodic irritability is a manifestation of bipolar disorder in youth. This study tests the hypothesis that youth with severe mood dysregulation (SMD), a category created for the purpose of studying children presenting with severe nonepisodic irritability, will be…

  1. Differentiating Bipolar Disorder--Not Otherwise Specified and Severe Mood Dysregulation

    Science.gov (United States)

    Towbin, Kenneth; Axelson, David; Leibenluft, Ellen; Birmaher, Boris

    2013-01-01

    Objective: Bipolar disorder--not otherwise specified (BP-NOS) and severe mood dysregulation (SMD) are severe mood disorders that were defined to address questions about the diagnosis of bipolar disorder (BD) in youth. SMD and BP-NOS are distinct phenotypes that differ in clinical presentation and longitudinal course. The purpose of this review is…

  2. Neural Correlates of Reversal Learning in Severe Mood Dysregulation and Pediatric Bipolar Disorder

    Science.gov (United States)

    Adleman, Nancy E.; Kayser, Reilly; Dickstein, Daniel; Blair, R. James R.; Pine, Daniel; Leibenluft, Ellen

    2011-01-01

    Objective: Outcome and family history data differentiate children with severe mood dysregulation (SMD), a syndrome characterized by chronic irritability, from children with "classic" episodic bipolar disorder (BD). Nevertheless, the presence of cognitive inflexibility in SMD and BD highlights the need to delineate neurophysiologic similarities and…

  3. Dysregulated Fear in Toddlerhood Predicts Kindergarten Social Withdrawal through Protective Parenting

    Science.gov (United States)

    Kiel, Elizabeth J.; Buss, Kristin A.

    2014-01-01

    Two recent advances in the study of fearful temperament (behavioural inhibition) include the validation of dysregulated fear as a temperamental construct that more specifically predicts later social withdrawal and anxiety, and the use of conceptual and statistical models that place parenting as a mechanism of development from temperament to these…

  4. Severe Affective and Behavioural Dysregulation Is Associated with Significant Psychosocial Adversity and Impairment

    Science.gov (United States)

    Jucksch, Viola; Salbach-Andrae, Harriet; Lenz, Klaus; Goth, Kirstin; Dopfner, Manfred; Poustka, Fritz; Freitag, Christine M.; Lehmkuhl, Gerd; Lehmkuhl, Ulrike; Holtmann, Martin

    2011-01-01

    Background: Recently, a highly heritable behavioral phenotype of simultaneous deviance on the Anxious/Depressed, Attention Problems, and Aggressive Behavior syndrome scales has been identified on the Child Behavior Checklist (CBCL-Dysregulation Profile, CBCL-DP). This study aims to investigate psychosocial adversity and impairment of the CBCL-DP.…

  5. Dysregulation of the mitosis-meiosis switch in testicular carcinoma in situ

    DEFF Research Database (Denmark)

    Jørgensen, Anne; Nielsen, John E; Almstrup, Kristian

    2013-01-01

    , except in spermatocytic seminoma (not derived from CIS). In conclusion, this study indicates that meiosis signalling is dysregulated in CIS cells and that a key regulator of the mitosis-meiosis switch, DMRT1, is expressed in 'early-stage' CIS cells but is down-regulated with further invasive...

  6. A novel statistical approach shows evidence for multi-system physiological dysregulation during aging.

    Science.gov (United States)

    Cohen, Alan A; Milot, Emmanuel; Yong, Jian; Seplaki, Christopher L; Fülöp, Tamàs; Bandeen-Roche, Karen; Fried, Linda P

    2013-03-01

    Previous studies have identified many biomarkers that are associated with aging and related outcomes, but the relevance of these markers for underlying processes and their relationship to hypothesized systemic dysregulation is not clear. We address this gap by presenting a novel method for measuring dysregulation via the joint distribution of multiple biomarkers and assessing associations of dysregulation with age and mortality. Using longitudinal data from the Women's Health and Aging Study, we selected a 14-marker subset from 63 blood measures: those that diverged from the baseline population mean with age. For the 14 markers and all combinatorial sub-subsets we calculated a multivariate distance called the Mahalanobis distance (MHBD) for all observations, indicating how "strange" each individual's biomarker profile was relative to the baseline population mean. In most models, MHBD correlated positively with age, MHBD increased within individuals over time, and higher MHBD predicted higher risk of subsequent mortality. Predictive power increased as more variables were incorporated into the calculation of MHBD. Biomarkers from multiple systems were implicated. These results support hypotheses of simultaneous dysregulation in multiple systems and confirm the need for longitudinal, multivariate approaches to understanding biomarkers in aging. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  7. Parental Interpersonal Sensitivity and Youth Social Problems: A Mediational Role for Child Emotion Dysregulation

    Science.gov (United States)

    Suveg, Cynthia; Jacob, Marni L.; Payne, Mary

    2010-01-01

    We examined the relations between parental interpersonal sensitivity and youth social problems and explored the mediational role of child emotion dysregulation. Mothers (N = 42; M age = 39.38) and fathers (N = 41; M age = 39.38) of youth aged 7-12 (N = 42; M age = 9.12) completed measures of their own interpersonal sensitivity and reported on…

  8. Aldosterone dysregulation with aging predicts renal vascular function and cardiovascular risk.

    Science.gov (United States)

    Brown, Jenifer M; Underwood, Patricia C; Ferri, Claudio; Hopkins, Paul N; Williams, Gordon H; Adler, Gail K; Vaidya, Anand

    2014-06-01

    Aging and abnormal aldosterone regulation are both associated with vascular disease. We hypothesized that aldosterone dysregulation influences the age-related risk of renal vascular and cardiovascular disease. We conducted an analysis of 562 subjects who underwent detailed investigations under conditions of liberal and restricted dietary sodium intake (1124 visits) in the General Clinical Research Center. Aldosterone regulation was characterized by the ratio of maximal suppression to stimulation (supine serum aldosterone on a liberal sodium diet divided by the same measure on a restricted sodium diet). We previously demonstrated that higher levels of this Sodium-modulated Aldosterone Suppression-Stimulation Index (SASSI) indicate greater aldosterone dysregulation. Renal plasma flow (RPF) was determined via p-aminohippurate clearance to assess basal renal hemodynamics and the renal vascular responses to dietary sodium manipulation and angiotensin II infusion. Cardiovascular risk was calculated using the Framingham Risk Score. In univariate linear regression, older age (β=-4.60; Page and SASSI, where the inverse relationship between SASSI and RPF was most apparent with older age (Page may interact to mediate renal vascular disease. Our findings suggest that the combination of aldosterone dysregulation and renal vascular dysfunction could additively increase the risk of future cardiovascular outcomes; therefore, aldosterone dysregulation may represent a modifiable mechanism of age-related vascular disease.

  9. Understanding the connection between self-esteem and aggression : The mediating role of emotion dysregulation

    NARCIS (Netherlands)

    Garofalo, C.; Holden, C.J.; Zeigler-Hill, V.; Velotti, P.

    2016-01-01

    The purpose of the present study was to extend previous knowledge concerning the link between self-esteem and aggression by examining the mediating role of emotion dysregulation among offenders and community participants. A sample of 153 incarcerated violent offenders and a community sample of 197

  10. Initial Development of a Measure of Emotional Dysregulation for Individuals with Cluster B Personality Disorders

    Science.gov (United States)

    Newhill, Christina E.; Mulvey, Edward P.; Pilkonis, Paul A.

    2004-01-01

    Individuals with DSM-IV Cluster B personality disorders are at particular risk of violence toward self or others. Emotional dysregulation is likely to be a factor in such incidents and is a central issue addressed in therapies with personality-disordered individuals. This article reports findings from a study that developed an original 18-item…

  11. Adult Outcomes of Childhood Dysregulation: A 14-Year Follow-up Study

    Science.gov (United States)

    Althoff, Robert R.; Verhulst, Frank C.; Rettew, David C.; Hudziak, James J.; van der Ende, Jan

    2010-01-01

    Objective: Using a general population sample, the adult outcomes of children who presented with severe problems with self-regulation defined as being concurrently rated highly on attention problems, aggressive behavior, and anxious-depression on the Child Behavior Checklist-Dysregulation Profile (CBCL-DP) were examined. Method: Two thousand…

  12. The Impact of Attachment Security and Emotion Dysregulation on Anxiety in Children and Adolescents

    Science.gov (United States)

    Bender, Patrick K.; Sømhovd, Mikael; Pons, Francisco; Reinholdt-Dunne, Marie L.; Esbjørn, Barbara H.

    2015-01-01

    Theoretical views and empirical findings suggest interrelations among attachment security, emotion dysregulation and anxiety in childhood and adolescence. However, the associations among the three constructs have rarely been investigated in children, and no study has yet addressed these associations in adolescence. The aim of the present study was…

  13. Pathway Interaction Network Analysis Identifies Dysregulated Pathways in Human Monocytes Infected by Listeria monocytogenes

    Directory of Open Access Journals (Sweden)

    Wufeng Fan

    2017-01-01

    Full Text Available In our study, we aimed to extract dysregulated pathways in human monocytes infected by Listeria monocytogenes (LM based on pathway interaction network (PIN which presented the functional dependency between pathways. After genes were aligned to the pathways, principal component analysis (PCA was used to calculate the pathway activity for each pathway, followed by detecting seed pathway. A PIN was constructed based on gene expression profile, protein-protein interactions (PPIs, and cellular pathways. Identifying dysregulated pathways from the PIN was performed relying on seed pathway and classification accuracy. To evaluate whether the PIN method was feasible or not, we compared the introduced method with standard network centrality measures. The pathway of RNA polymerase II pretranscription events was selected as the seed pathway. Taking this seed pathway as start, one pathway set (9 dysregulated pathways with AUC score of 1.00 was identified. Among the 5 hub pathways obtained using standard network centrality measures, 4 pathways were the common ones between the two methods. RNA polymerase II transcription and DNA replication owned a higher number of pathway genes and DEGs. These dysregulated pathways work together to influence the progression of LM infection, and they will be available as biomarkers to diagnose LM infection.

  14. Childhood trauma and eating psychopathology: a mediating role for dissociation and emotion dysregulation?

    Science.gov (United States)

    Moulton, Stuart J; Newman, Emily; Power, Kevin; Swanson, Vivien; Day, Kenny

    2015-01-01

    The present study examined the relationship between different forms of childhood trauma and eating psychopathology using a multiple mediation model that included emotion dysregulation and dissociation as hypothesised mediators. 142 female undergraduate psychology students studying at two British Universities participated in this cross-sectional study. Participants completed measures of childhood trauma (emotional abuse, physical abuse, sexual abuse, emotional neglect and physical neglect), eating psychopathology, dissociation and emotion dysregulation. Multiple mediation analysis was conducted to investigate the study's proposed model. Results revealed that the multiple mediation model significantly predicted eating psychopathology. Additionally, both emotion dysregulation and dissociation were found to be significant mediators between childhood trauma and eating psychopathology. A specific indirect effect was observed between childhood emotional abuse and eating psychopathology through emotion dysregulation. Findings support previous research linking childhood trauma to eating psychopathology. They indicate that multiple forms of childhood trauma should be assessed for individuals with eating disorders. The possible maintaining role of emotion regulation processes should also be considered in the treatment of eating disorders. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Transmission of Neglect in Substance Abuse Families: The Role of Child Dysregulation and Parental SUD.

    Science.gov (United States)

    Dunn, Marija G.; Mezzich, Ada; Janiszewski, Susan; Kirisci, Levent; Tarter, Ralph E.

    2001-01-01

    Paternal and maternal models of transmission of child neglect were tested separately in offspring of men with a substance use disorder (SUD). Child dysregulation was independently related to neglect severity. SUD in the mother directly correlated with severity of neglectful parenting. (Contains 51 references and 2 tables.) (GCP)

  16. Cortisol Predicts Behavioral Dysregulation and Length of Stay among Children Admitted for Psychiatric Inpatient Treatment

    Science.gov (United States)

    Luebbe, Aaron M.; Elledge, L. Christian; Kiel, Elizabeth J.; Stoppelbein, Laura

    2012-01-01

    Individual differences in behavioral regulation system (BRS) and stress response system (SRS) functioning may reflect greater biological sensitivity to context. The current study tested whether children's cortisol, a measure of the SRS, was related to observed dysregulated behavior, an indicator of the BRS, in a sample of children admitted for…

  17. A Novel Group Therapy for Children with ADHD and Severe Mood Dysregulation

    Science.gov (United States)

    Waxmonsky, James G.; Wymbs, Fran A.; Pariseau, Meaghan E.; Belin, Peter J.; Waschbusch, Daniel A.; Babocsai, Lysett; Fabiano, Gregory A.; Akinnusi, Opeolowa O.; Haak, Jenifer L.; Pelham, William E.

    2013-01-01

    Objective: No psychosocial treatments have been developed for children with ADHD and severe mood dysregulation (SMD) despite the significant prevalence and morbidity of this combination. Therefore, the authors developed a novel treatment program for children with ADHD and SMD. Method: The novel therapy program integrates components of…

  18. Disruptive Mood Dysregulation Disorder Symptoms by Age in Autism, ADHD, and General Population Samples

    Science.gov (United States)

    Mayes, Susan Dickerson; Kokotovich, Cari; Mathiowetz, Christine; Baweja, Raman; Calhoun, Susan L.; Waxmonsky, James

    2017-01-01

    Disruptive mood dysregulation disorder (DMDD) is a controversial "DSM-5" diagnosis. It is not known how DMDD symptoms vary by age and if differences are similar for autism, ADHD, and general population samples. Our study analyzed the two DMDD symptoms (irritable-angry mood and temper outbursts) in 1,827 children with autism or ADHD (with…

  19. Genome-Wide Association Study of the Child Behavior Checklist Dysregulation Profile

    Science.gov (United States)

    Mick, Eric; McGough, James; Loo, Sandra; Doyle, Alysa E.; Wozniak, Janet; Wilens, Timothy E.; Smalley, Susan; McCracken, James; Biederman, Joseph; Faraone, Stephen V.

    2011-01-01

    Objective: A potentially useful tool for understanding the distribution and determinants of emotional dysregulation in children is a Child Behavior Checklist profile, comprising the Attention Problems, Anxious/Depressed, and Aggressive Behavior clinical subscales (CBCL-DP). The CBCL-DP indexes a heritable trait that increases susceptibility for…

  20. Metabolic dysregulation and interventions in type 2 diabetes mellitus and HIV-lipodystrophy

    NARCIS (Netherlands)

    Wijk, J.P.H. van

    2005-01-01

    The focus of this thesis is on two aspects of metabolic dysregulation, type 2 diabetes mellitus and HIV-lipodystrophy, and the effects of insulin-sensitizing agents. Thiazolidinediones (TZDs) have received increasing attenttion for the treatment of hyperglycemia in type 2 diabetes. Currently,

  1. PTSD Symptoms, Emotion Dysregulation, and Alcohol-Related Consequences Among College Students With a Trauma History.

    Science.gov (United States)

    Tripp, Jessica C; McDevitt-Murphy, Meghan E; Avery, Megan L; Bracken, Katherine L

    2015-01-01

    Posttraumatic stress disorder (PTSD), alcohol use, and alcohol-related consequences have been linked to emotion dysregulation. Sex differences exist in both emotion regulation dimensions and alcohol use patterns. This investigation examined facets of emotion dysregulation as potential mediators of the relationship between PTSD symptoms and alcohol-related consequences and whether differences may exist across sexes. Participants were 240 college students with a trauma history who reported using alcohol within the past three months and completed measures of PTSD symptoms, emotion dysregulation, alcohol consumption, alcohol-related consequences, and negative affect. The six facets of emotion dysregulation were examined as mediators of the relationship between PTSD symptoms and alcohol-related consequences in the full sample and by sex. There were differences in sexes on several variables, with women reporting higher PTSD scores and lack of emotional awareness. Men reported significantly more drinks per week in a typical week and a heavy week. There were significant associations between the variables for the full sample, with PTSD showing associations with five facets of emotion dysregulation subscales: impulse control difficulties when upset, difficulties engaging in goal-directed behavior, nonacceptance of emotional responses, lack of emotional clarity, and limited access to emotion regulation strategies. Alcohol-related consequences were associated with four aspects of emotion dysregulation: impulse control difficulties when upset, difficulties engaging in goal-directed behavior, nonacceptance of emotional responses, and limited access to emotion regulation strategies. Two aspects of emotion regulation, impulse control difficulties and difficulties engaging in goal directed behavior, mediated the relationship between PTSD symptoms and alcohol-related consequences in the full sample, even after adjusting for the effects of negative affect. When examined separately by

  2. Dysregulation of coronary microvascular reactivity in asymptomatic patients with type 2 diabetes mellitus

    Energy Technology Data Exchange (ETDEWEB)

    Momose, Mitsuru; Neverve, Jodi; Nekolla, Stephan G.; Schwaiger, Markus; Bengel, Frank M. [Nuklearmedizinische Klinik und Poliklinik der Technischen Universitaet Muenchen, Klinikum rechts der Isar, Ismaninger Strasse 22, 81675 Munich (Germany); Abletshauser, Claudia [Department of Medicine, Novartis Pharma GmbH, Nuernberg (Germany); Schnell, Oliver; Standl, Eberhard [Institut fuer Diabetesforschung, Munich (Germany)

    2002-12-01

    In diabetic patients, a number of studies have suggested an impairment of vascular reactivity in response to vasodilatory stimuli. The pattern of dysregulation at the coronary microcirculatory level, however, has not been clearly defined. Thus, it was the aim of this study to characterise coronary microvascular function non-invasively in a homogeneous group of asymptomatic type 2 diabetic patients. In 46 patients with type 2 diabetes, myocardial blood flow (MBF) was quantified at baseline, in response to cold pressor test (CPT) and during adenosine-mediated vasodilation using positron emission tomography and nitrogen-13 ammonia. None of the patients had been treated with insulin, and none had symptoms of cardiac disease. Decreased MBF during CPT, indicating microvascular dysregulation, was observed in 16 patients (CPT-), while 30 patients demonstrated increased MBF during CPT (CPT+). Response to CPT was mildly, but significantly correlated with response to adenosine (r=0.44, P=0.0035). There was no difference in HbA1c, serum lipid levels or serum endothelial markers between the groups. Microvascular dysregulation in the CPT- group was associated with elevated baseline MBF (P<0.0001), reduced baseline vascular resistance (P=0.0026) and an abnormal increase in resistance during CPT (P=0.0002). In conclusion, coronary microvascular dysregulation is present in approximately one-third of asymptomatic, non-insulin-treated type 2 diabetic patients. Elevated baseline blood flow and reduced microvascular resistance at rest are characteristics of this dysregulation. These data suggest a state of activation of endothelial-dependent vasodilation at baseline which appears to limit the flow response to stress conditions. (orig.)

  3. Can Emotional and Behavioral Dysregulation in Youth Be Decoded from Functional Neuroimaging?

    Directory of Open Access Journals (Sweden)

    Liana C L Portugal

    Full Text Available High comorbidity among pediatric disorders characterized by behavioral and emotional dysregulation poses problems for diagnosis and treatment, and suggests that these disorders may be better conceptualized as dimensions of abnormal behaviors. Furthermore, identifying neuroimaging biomarkers related to dimensional measures of behavior may provide targets to guide individualized treatment. We aimed to use functional neuroimaging and pattern regression techniques to determine whether patterns of brain activity could accurately decode individual-level severity on a dimensional scale measuring behavioural and emotional dysregulation at two different time points.A sample of fifty-seven youth (mean age: 14.5 years; 32 males was selected from a multi-site study of youth with parent-reported behavioral and emotional dysregulation. Participants performed a block-design reward paradigm during functional Magnetic Resonance Imaging (fMRI. Pattern regression analyses consisted of Relevance Vector Regression (RVR and two cross-validation strategies implemented in the Pattern Recognition for Neuroimaging toolbox (PRoNTo. Medication was treated as a binary confounding variable. Decoded and actual clinical scores were compared using Pearson's correlation coefficient (r and mean squared error (MSE to evaluate the models. Permutation test was applied to estimate significance levels.Relevance Vector Regression identified patterns of neural activity associated with symptoms of behavioral and emotional dysregulation at the initial study screen and close to the fMRI scanning session. The correlation and the mean squared error between actual and decoded symptoms were significant at the initial study screen and close to the fMRI scanning session. However, after controlling for potential medication effects, results remained significant only for decoding symptoms at the initial study screen. Neural regions with the highest contribution to the pattern regression model

  4. Benchmarking pathway interaction network for colorectal cancer to identify dysregulated pathways

    Directory of Open Access Journals (Sweden)

    Q. Wang

    Full Text Available Different pathways act synergistically to participate in many biological processes. Thus, the purpose of our study was to extract dysregulated pathways to investigate the pathogenesis of colorectal cancer (CRC based on the functional dependency among pathways. Protein-protein interaction (PPI information and pathway data were retrieved from STRING and Reactome databases, respectively. After genes were aligned to the pathways, each pathway activity was calculated using the principal component analysis (PCA method, and the seed pathway was discovered. Subsequently, we constructed the pathway interaction network (PIN, where each node represented a biological pathway based on gene expression profile, PPI data, as well as pathways. Dysregulated pathways were then selected from the PIN according to classification performance and seed pathway. A PIN including 11,960 interactions was constructed to identify dysregulated pathways. Interestingly, the interaction of mRNA splicing and mRNA splicing-major pathway had the highest score of 719.8167. Maximum change of the activity score between CRC and normal samples appeared in the pathway of DNA replication, which was selected as the seed pathway. Starting with this seed pathway, a pathway set containing 30 dysregulated pathways was obtained with an area under the curve score of 0.8598. The pathway of mRNA splicing, mRNA splicing-major pathway, and RNA polymerase I had the maximum genes of 107. Moreover, we found that these 30 pathways had crosstalks with each other. The results suggest that these dysregulated pathways might be used as biomarkers to diagnose CRC.

  5. Maternal control and early child dysregulation: Moderating roles of ethnicity and child delay status.

    Science.gov (United States)

    Caplan, B; Baker, B L

    2017-02-01

    Maternal controlling behaviour has been found to influence child development, particularly in behavioural and emotional regulation. Given the higher rates of interfering parent control found in mothers of children with developmental delays (DD) and Latina mothers, their children could be at increased risk for behavioural and emotional dysregulation. While studies generally support this increased risk for children with DD, findings for Latino children are mixed and often attributed to cultural models of child rearing. The present study sought to determine the moderating roles of child DD and mother ethnicity in determining the relationships between two types of parent control (supportive directiveness and interference) and child dysregulation over time. The present study, involving 178 3-year old children with DD (n = 80) or typical development (n = 98), examined observed parent control (directive versus interfering) of Latina and Anglo mothers as it relates to change in preschool child dysregulation over 2 years. Interfering parent control was greater for children with DD and also for Latino mothers. Supportive directive parenting generally related to relatively greater decline in child behaviour and emotion dysregulation over time, while interfering parenting generally related to less decline in child behaviour dysregulation over time. In Anglo but not Latino families, these relationships tended to vary as a function of child disability. Parent directives that support, rather than deter, ongoing child activity may promote positive regulatory development. These results particularly hold for children with DD and Latino families, and have implications for parenting practices and intervention. © 2016 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

  6. Emotion dysregulation and dyadic conflict in depressed and typical adolescents: Evaluating concordance across psychophysiological and observational measures

    Science.gov (United States)

    Crowell, Sheila E.; Baucom, Brian R.; Yaptangco, Mona; Bride, Daniel; Hsiao, Ray; McCauley, Elizabeth; Beauchaine, Theodore P.

    2014-01-01

    Many depressed adolescents experience difficulty regulating their emotions. These emotion regulation difficulties appear to emerge in part from socialization processes within families and then generalize to other contexts. However, emotion dysregulation is typically assessed within the individual, rather than in the social relationships that shape and maintain dysregulation. In this study, we evaluated concordance of physiological and observational measures of emotion dysregulation during interpersonal conflict, using a multilevel actor-partner interdependence model (APIM). Participants were 75 mother-daughter dyads, including 50 depressed adolescents with or without a history of self-injury, and 25 typically developing controls. Behavior dysregulation was operationalized as observed aversiveness during a conflict discussion, and physiological dysregulation was indexed by respiratory sinus arrhythmia (RSA). Results revealed different patterns of concordance for control versus depressed participants. Controls evidenced a concordant partner (between-person) effect, and showed increased physiological regulation during minutes when their partner was more aversive. In contrast, clinical dyad members displayed a concordant actor (within-person) effect, becoming simultaneously physiologically and behaviorally dysregulated. Results inform current understanding of emotion dysregulation across multiple levels of analysis. PMID:24607894

  7. Emotion dysregulation and dyadic conflict in depressed and typical adolescents: evaluating concordance across psychophysiological and observational measures.

    Science.gov (United States)

    Crowell, Sheila E; Baucom, Brian R; Yaptangco, Mona; Bride, Daniel; Hsiao, Ray; McCauley, Elizabeth; Beauchaine, Theodore P

    2014-04-01

    Many depressed adolescents experience difficulty in regulating their emotions. These emotion regulation difficulties appear to emerge in part from socialization processes within families and then generalize to other contexts. However, emotion dysregulation is typically assessed within the individual, rather than in the social relationships that shape and maintain dysregulation. In this study, we evaluated concordance of physiological and observational measures of emotion dysregulation during interpersonal conflict, using a multilevel actor-partner interdependence model (APIM). Participants were 75 mother-daughter dyads, including 50 depressed adolescents with or without a history of self-injury, and 25 typically developing controls. Behavior dysregulation was operationalized as observed aversiveness during a conflict discussion, and physiological dysregulation was indexed by respiratory sinus arrhythmia (RSA). Results revealed different patterns of concordance for control versus depressed participants. Controls evidenced a concordant partner (between-person) effect, and showed increased physiological regulation during minutes when their partner was more aversive. In contrast, clinical dyad members displayed a concordant actor (within-person) effect, becoming simultaneously physiologically and behaviorally dysregulated. Results inform current understanding of emotion dysregulation across multiple levels of analysis. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Dysregulated proinflammatory and fibrogenic phenotype of fibroblasts in cystic fibrosis.

    Directory of Open Access Journals (Sweden)

    François Huaux

    Full Text Available Morbi-mortality in cystic fibrosis (CF is mainly related to chronic lung infection and inflammation, uncontrolled tissue rearrangements and fibrosis, and yet the underlying mechanisms remain largely unknown. We evaluated inflammatory and fibrosis responses to bleomycin in F508del homozygous and wild-type mice, and phenotype of fibroblasts explanted from mouse lungs and skin. The effect of vardenafil, a cGMP-specific phosphodiesterase type 5 inhibitor, was tested in vivo and in culture. Responses of proinflammatory and fibrotic markers to bleomycin were enhanced in lungs and skin of CF mice and were prevented by treatment with vardenafil. Purified lung and skin fibroblasts from CF mice proliferated and differentiated into myofibroblasts more prominently and displayed higher sensitivity to growth factors than those recovered from wild-type littermates. Under inflammatory stimulation, mRNA and protein expression of proinflammatory mediators were higher in CF than in wild-type fibroblasts, in which CFTR expression reached similar levels to those observed in other non-epithelial cells, such as macrophages. Increased proinflammatory responses in CF fibroblasts were reduced by half with submicromolar concentrations of vardenafil. Proinflammatory and fibrogenic functions of fibroblasts are upregulated in CF and are reduced by vardenafil. This study provides compelling new support for targeting cGMP signaling pathway in CF pharmacotherapy.

  9. The herpes simplex virus-induced demise of keratinocytes is associated with a dysregulated pattern of p63 expression.

    Science.gov (United States)

    Megyeri, Klára; Orosz, László; Kormos, Bernadett; Pásztor, Katalin; Seprényi, György; Ocsovszki, Imre; Mándi, Yvette; Bata-Csörgo, Zsuzsanna; Kemény, Lajos

    2009-01-01

    p63 plays a pivotal role in the development and maintenance of stratified epithelial tissues. In an effort to gain insight into the pathogenic mechanisms of skin infections caused by HSV-1 and HSV-2, we determined the patterns of p63 expression in primary keratinocytes and in the HaCaT cell line. The levels of DeltaNp63alpha and a 50kDa p73 isoform were decreased, Bax-alpha remained unaffected, while the expressions of the Bax-beta, TAp63gamma and a 44.5kDa p73 isoform were highly increased in both HSV-1-infected HaCaT cells and primary keratinocytes. In contrast, in response to HSV-2 infection the levels of DeltaNp63alpha, a 50kDa p73 isoform and a 44.5kDa p73 protein were decreased, Bax-alpha and TAp63gamma remained unaffected, while the expression of Bax-beta was slightly increased. The knockdown of TAp63 expression enhanced the viability of HSV-1-infected cells. Thus, HSV-1 and HSV-2 modulate the patterns of p63 and Bax expression in a serotype-specific manner. The dysregulated pattern of p63 expression observed in HSV-infected keratinocytes may comprise part of a mechanism by which these viruses perturb the functions of keratinocytes and lead to their demise.

  10. Lamotrigine use in patients with binge eating and purging, significant affect dysregulation, and poor impulse control.

    Science.gov (United States)

    Trunko, Mary Ellen; Schwartz, Terry A; Marzola, Enrica; Klein, Angela S; Kaye, Walter H

    2014-04-01

    Some patients with symptoms of binge eating and purging are successfully treated with specific serotonin reuptake inhibitors (SSRIs), but others experience only partial or no benefit. Significant affect dysregulation and poor impulse control may be characteristics that limit responsiveness. We report on the treatment of five patients with bulimia nervosa (BN), anorexia nervosa-binge/purge type (AN-B/P) or eating disorder not otherwise specified (EDNOS), using the anticonvulsant lamotrigine after inadequate response to SSRIs. Following addition of lamotrigine to an antidepressant in four cases, and switch from an antidepressant to lamotrigine in one case, patients experienced substantial improvement in mood reactivity and instability, impulsive drives and behaviors, and eating-disordered symptoms. These findings raise the possibility that lamotrigine, either as monotherapy or as an augmenting agent to antidepressants, may be useful in patients who binge eat and purge, and have significant affect dysregulation with poor impulse control. Copyright © 2013 Wiley Periodicals, Inc.

  11. Chronic complex dissociative disorders and borderline personality disorder: disorders of emotion dysregulation?

    Science.gov (United States)

    Brand, Bethany L; Lanius, Ruth A

    2014-01-01

    Emotion dysregulation is a core feature of chronic complex dissociative disorders (DD), as it is for borderline personality disorder (BPD). Chronic complex DD include dissociative identity disorder (DID) and the most common form of dissociative disorder not otherwise specified (DDNOS, type 1), now known as Other Specified Dissociative Disorders (OSDD, type 1). BPD is a common comorbid disorder with DD, although preliminary research indicates the disorders have some distinguishing features as well as considerable overlap. This article focuses on the epidemiology, clinical presentation, psychological profile, treatment, and neurobiology of chronic complex DD with emphasis placed on the role of emotion dysregulation in each of these areas. Trauma experts conceptualize borderline symptoms as often being trauma based, as are chronic complex DD. We review the preliminary research that compares DD to BPD in the hopes that this will stimulate additional comparative research.

  12. Dysregulated miR-183 inhibits migration in breast cancer cells.

    LENUS (Irish Health Repository)

    Lowery, Aoife J

    2010-01-01

    The involvement of miRNAs in the regulation of fundamental cellular functions has placed them at the fore of ongoing investigations into the processes underlying carcinogenesis. MiRNA expression patterns have been shown to be dysregulated in numerous human malignancies, including breast cancer, suggesting their probable involvement as novel classes of oncogenes or tumour suppressor genes. The identification of differentially expressed miRNAs and elucidation of their functional roles may provide insight into the complex and diverse molecular mechanisms of tumorigenesis. MiR-183 is located on chromosome 7q32 and is part of a miRNA family which are dysregulated in numerous cancers. The aims of this study were to further examine the expression and functional role of miR-183 in breast cancer.

  13. Immune System Dysregulation, Viral Reactivation and Stress During Short-Duration Space Flight

    Science.gov (United States)

    Crucian, Brian; Mehta, Satish; Stowe, Raymond; Uchakin, Peter; Quiriarte, Heather; Pierson, Duane; Sams, Clarence

    2010-01-01

    This slide presentation reviews a study that was conducted to ascertain if the immune system dysregulation, viral reactivation and stress from short duration space flight were a result of the stress of landing and readjustment to gravity. The objectives of the study were to replace several recent immune studies with one comprehensive study that will include in-flight sampling; address lack of in-flight data: (i.e., determine the in-flight status of immunity, physiological stress, viral immunity/reactivation); determine the clinical risk related to immune dysregulation for exploration class spaceflight; and determine the appropriate monitoring strategy for spaceflight-associated immune dysfunction, that could be used for the evaluation of countermeasures.

  14. Mild KCC2 hypofunction causes inconspicuous chloride dysregulation that degrades neural coding

    Directory of Open Access Journals (Sweden)

    Nicolas eDoyon

    2016-01-01

    Full Text Available Disinhibition caused by Cl- dysregulation is implicated in several neurological disorders. This form of disinhibition, which stems primarily from impaired Cl- extrusion through the co-transporter KCC2, is typically identified by a depolarizing shift in GABA reversal potential (EGABA. Here we show, using computer simulations, that intracellular [Cl-] exhibits exaggerated fluctuations during transient Cl- loads and recovers more slowly to baseline when KCC2 level is even modestly reduced. Using information theory and signal detection theory, we show that increased Cl- lability and settling time degrade neural coding. Importantly, these deleterious effects manifest after less KCC2 reduction than needed to produce the gross changes in EGABA required for detection by most experiments, which assess KCC2 function under weak Cl- load conditions. By demonstrating the existence and functional consequences of occult Cl- dysregulation, these results suggest that modest KCC2 hypofunction plays a greater role in neurological disorders than previously believed.

  15. The Pathogenesis and Treatment of Emotion Dysregulation in Borderline Personality Disorder

    Directory of Open Access Journals (Sweden)

    Andreas Laddis

    2015-01-01

    Full Text Available Uncontrollable emotional lability and impulsivity are a paramount phenomenon of Borderline Personality Disorder (BPD. This paper aims to review theories that entertain emotion dysregulation as the core deficit of BPD and a key factor in the etiology of BPD, in order, then, to propose the author’s own theory, which arguably transcends certain limitations of the earlier ones. The author asserts that his psychodynamic theory explains the symptoms of BPD more thoroughly and it inspires a more parsimonious interpretation of brain imaging findings. In closing, the author draws implications of the proposed theory for clinical practice. He reports an efficacy study for treatment of emotion dysregulation based on that theory.

  16. Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) Syndrome: A Case Report

    OpenAIRE

    Bagheri; Pourbakhtyaran; Talebi Kiasari; Taherkhanchi; Salarian; Sadeghi

    2016-01-01

    Introduction Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation (ROHHAD) is a rare disease. To date, there have been only few reported cases of ROHHAD syndrome. Case Presentation We report a 5-year-old- Iranian girl who had normal growth and development until her 4th year of life. At that time, the patient developed weight gain, constipation, coldness in the extremities, and hyperhidros...

  17. Dysregulation of angiopoietins is associated with placental malaria and low birth weight.

    Directory of Open Access Journals (Sweden)

    Karlee L Silver

    Full Text Available BACKGROUND: Placental malaria (PM is associated with adverse pregnancy outcomes including low birth weight (LBW. However, the precise mechanisms by which PM induces LBW are poorly defined. Based on the essential role of angiopoietin (ANG-1 and -2 in normal placental vascular development, we hypothesized that PM may result in the dysregulation of angiopoietins and thereby contribute to LBW outcomes. METHODS AND FINDINGS: In a mouse model of PM, we show that Plasmodium berghei ANKA infection of pregnant mice resulted in dysregulated angiopoietin levels and fetal growth restriction. PM lead to decreased ANG-1, increased ANG-2, and an elevated ratio of ANG-2/ANG-1 in the placenta and the serum. These observations were extended to malaria-exposed pregnant women: In a study of primigravid women prospectively followed over the course of pregnancy, Plasmodium falciparum infection was associated with a decrease in maternal plasma ANG-1 levels (P = 0.031 and an increase in the ANG-2:ANG-1 ratio (P = 0.048. ANG-1 levels recovered with successful treatment of peripheral parasitemia (P = 0.010. In a cross-sectional study of primigravidae at delivery, angiopoietin dysregulation was associated with PM (P = 0.002 and LBW (P = 0.041. Women with PM who delivered LBW infants had increased ANG-2:ANG-1 ratios (P = 0.002 compared to uninfected women delivering normal birth weight infants. CONCLUSIONS: These data support the hypothesis that dysregulation of angiopoietins is associated with PM and LBW outcomes, and suggest that ANG-1 and ANG-2 levels may be clinically informative biomarkers to identify P. falciparum-infected mothers at risk of LBW deliveries.

  18. Emotion Dysregulation and Anxiety in Adults with ASD: Does Social Motivation Play a Role?

    OpenAIRE

    Swain, Deanna; Scarpa-Friedman, Angela; White, Susan; Laugeson, Elizabeth

    2015-01-01

    Young adults with ASD and no intellectual impairment are more likely to exhibit clinical levels of anxiety than typically developing peers (DSM-5, American Psychiatric Association, 2013). This study tests a mechanistic model in which anxiety culminates via emotion dysregulation and social motivation. Adults with ASD (49 males, 20 females) completed self-report measures on emotion regulation, caregivers completed measures on ASD severity and both on social anxiety. Results indicated that emoti...

  19. Cell cycle pathway dysregulation in human keratinocytes during chronic exposure to low arsenite.

    Science.gov (United States)

    Al-Eryani, Laila; Waigel, Sabine; Jala, Venkatakrishna; Jenkins, Samantha F; States, J Christopher

    2017-09-15

    Arsenic is naturally prevalent in the earth's crust and widely distributed in air and water. Chronic low arsenic exposure is associated with several cancers in vivo, including skin cancer, and with transformation in vitro of cell lines including immortalized human keratinocytes (HaCaT). Arsenic also is associated with cell cycle dysregulation at different exposure levels in multiple cell lines. In this work, we analyzed gene expression in HaCaT cells to gain an understanding of gene expression changes contributing to transformation at an early time point. HaCaT cells were exposed to 0 or 100nM NaAsO 2 for 7weeks. Total RNA was purified and analyzed by microarray hybridization. Differential expression with fold change≥|1.5| and p-value≤0.05 was determined using Partek Genomic Suite™ and pathway and network analyses using MetaCore™ software (FDR≤0.05). Cell cycle analysis was performed using flow cytometry. 644 mRNAs were differentially expressed. Cell cycle/cell cycle regulation pathways predominated in the list of dysregulated pathways. Genes involved in replication origin licensing were enriched in the network. Cell cycle assay analysis showed an increase in G2/M compartment in arsenite-exposed cells. Arsenite exposure induced differential gene expression indicating dysregulation of cell cycle control, which was confirmed by cell cycle analysis. The results suggest that cell cycle dysregulation is an early event in transformation manifested in cells unable to transit G2/M efficiently. Further study at later time points will reveal additional changes in gene expression related to transformation processes. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Dysregulation of the unfolded protein response in db/db mice with diet induced steatohepatitis

    OpenAIRE

    Rinella, Mary E.; Siddiqui, M. Shaddab; Gardikiotes, Konstantina; Gottstein, Jeanne; Elias, Marc; Green, Richard M.

    2011-01-01

    In humans with non-alcoholic fatty liver, diabetes is associated with more advanced disease. We have previously shown that diabetic db/db mice are highly susceptible to methionine choline deficient diet (MCD) induced hepatic injury. Since activation of the unfolded protein response (UPR) is an important adaptive cellular mechanism in diabetes, obesity and fatty liver, we hypothesized that dysregulation of the UPR may partially explain how diabetes could promote liver injury.

  1. Blood Glucose and Insulin Concentrations after Octreotide Administration in Horses With Insulin Dysregulation

    OpenAIRE

    Frank, N.; Hermida, P.; Sanchez?Londo?o, A.; Singh, R.; Gradil, C.M.; Uricchio, C.K.

    2017-01-01

    Background Octreotide is a somatostatin analog that suppresses insulin secretion. Hypothesis We hypothesized that octreotide would suppress insulin concentrations in horses and that normal (N) horses and those with insulin dysregulation (ID) would differ significantly in their plasma glucose and insulin responses to administration of octreotide. Animals Twelve horses, N = 5, ID = 7. Methods Prospective study. An oral sugar test was performed to assign horses to N and ID groups. Octreotide (1....

  2. Dysregulation of type 2 innate lymphoid cells and TH2 cells impairs pollutant-induced allergic airway responses.

    Science.gov (United States)

    De Grove, Katrien C; Provoost, Sharen; Hendriks, Rudi W; McKenzie, Andrew N J; Seys, Leen J M; Kumar, Smitha; Maes, Tania; Brusselle, Guy G; Joos, Guy F

    2017-01-01

    Although the prominent role of T H 2 cells in type 2 immune responses is well established, the newly identified type 2 innate lymphoid cells (ILC2s) can also contribute to orchestration of allergic responses. Several experimental and epidemiologic studies have provided evidence that allergen-induced airway responses can be further enhanced on exposure to environmental pollutants, such as diesel exhaust particles (DEPs). However, the components and pathways responsible remain incompletely known. We sought to investigate the relative contribution of ILC2 and adaptive T H 2 cell responses in a murine model of DEP-enhanced allergic airway inflammation. Wild-type, Gata-3 +/nlslacZ (Gata-3-haploinsufficient), RAR-related orphan receptor α (RORα) fl/fl IL7R Cre (ILC2-deficient), and recombination-activating gene (Rag) 2 -/- mice were challenged with saline, DEPs, or house dust mite (HDM) or DEP+HDM. Airway hyperresponsiveness, as well as inflammation, and intracellular cytokine expression in ILC2s and T H 2 cells in the bronchoalveolar lavage fluid and lung tissue were assessed. Concomitant DEP+HDM exposure significantly enhanced allergic airway inflammation, as characterized by increased airway eosinophilia, goblet cell metaplasia, accumulation of ILC2s and T H 2 cells, type 2 cytokine production, and airway hyperresponsiveness compared with sole DEPs or HDM. Reduced Gata-3 expression decreased the number of functional ILC2s and T H 2 cells in DEP+HDM-exposed mice, resulting in an impaired DEP-enhanced allergic airway inflammation. Interestingly, although the DEP-enhanced allergic inflammation was marginally reduced in ILC2-deficient mice that received combined DEP+HDM, it was abolished in DEP+HDM-exposed Rag2 -/- mice. These data indicate that dysregulation of ILC2s and T H 2 cells attenuates DEP-enhanced allergic airway inflammation. In addition, a crucial role for the adaptive immune system was shown on concomitant DEP+HDM exposure. Copyright © 2016 American

  3. Cross-population validation of statistical distance as a measure of physiological dysregulation during aging.

    Science.gov (United States)

    Cohen, Alan A; Milot, Emmanuel; Li, Qing; Legault, Véronique; Fried, Linda P; Ferrucci, Luigi

    2014-09-01

    Measuring physiological dysregulation during aging could be a key tool both to understand underlying aging mechanisms and to predict clinical outcomes in patients. However, most existing indices are either circular or hard to interpret biologically. Recently, we showed that statistical distance of 14 common blood biomarkers (a measure of how strange an individual's biomarker profile is) was associated with age and mortality in the WHAS II data set, validating its use as a measure of physiological dysregulation. Here, we extend the analyses to other data sets (WHAS I and InCHIANTI) to assess the stability of the measure across populations. We found that the statistical criteria used to determine the original 14 biomarkers produced diverging results across populations; in other words, had we started with a different data set, we would have chosen a different set of markers. Nonetheless, the same 14 markers (or the subset of 12 available for InCHIANTI) produced highly similar predictions of age and mortality. We include analyses of all combinatorial subsets of the markers and show that results do not depend much on biomarker choice or data set, but that more markers produce a stronger signal. We conclude that statistical distance as a measure of physiological dysregulation is stable across populations in Europe and North America. Copyright © 2014 Elsevier Inc. All rights reserved.

  4. Adult attachment, emotion dysregulation, and symptoms of depression and generalized anxiety disorder.

    Science.gov (United States)

    Marganska, Anna; Gallagher, Michelle; Miranda, Regina

    2013-01-01

    Differences in attachment style have been linked to both emotion regulation and psychological functioning, but the emotion regulatory mechanism through which attachment style might impact symptoms of depression and anxiety is unclear. The present study examined the explanatory role of emotion dysregulation in the relation between adult attachment style and symptoms of depression and generalized anxiety disorder (GAD) in a sample of 284 adults. Secure attachment was associated with lower depression and GAD symptoms and lower emotion dysregulation, whereas insecure attachment styles were generally associated with higher depression and GAD scores and higher emotion dysregulation. Perceived inability to generate effective emotion regulation strategies mediated the relation between insecure attachment and both depression and GAD symptoms. Nonacceptance of negative emotions and inability to control impulsive behaviors emerged as additional mediators of the relation between insecure attachment styles and GAD symptoms. The differential contribution of attachment style and emotion regulation to the prediction of depression and GAD symptoms may reflect differences in vulnerability to depression and GAD. © 2013 American Orthopsychiatric Association.

  5. Social exposure and emotion dysregulation: Main effects in relation to nonsuicidal self-injury.

    Science.gov (United States)

    Zelkowitz, Rachel L; Porter, Andrew C; Heiman, Ellen R; Cole, David A

    2017-10-01

    We examined the relation of interpersonal and media exposure to nonsuicidal self-injury (NSSI) among 340 university students in the southeastern United States (73.5% female, M age = 19.38 years, SD = 1.15). We also assessed interactions and main effects of each exposure and emotion dysregulation in relation to NSSI, testing the social learning hypothesis of NSSI. Most participants endorsed medium to high levels of exposure to NSSI via media sources. More than one-third of participants were somewhat or very familiar with someone who engaged in NSSI. Almost half reported occasional or frequent conversations about NSSI. Both exposure forms were significantly related to NSSI history. However, hurdle regression analyses revealed that interpersonal exposure and emotion dysregulation, but not media exposure, were significantly associated with NSSI history and frequency. We did not find evidence for an emotion dysregulation-by-interpersonal-exposure interaction. We discuss implications for theoretical models of NSSI, limitations, and future directions. Copyright © 2017. Published by Elsevier Ltd.

  6. Immune System Dysregulation and Latent Herpesvirus Reactivation During Winterover at Concordia Station, Dome C, Antarctica

    Science.gov (United States)

    Crucian, B. E.; Feuerecker, M.; Salam, A. P.; Rybka, A.; Stowe, R. P.; Morrels, M.; Meta, S. K.; Quiriarte, H.; Quintens, Roel; Thieme, U.; hide

    2011-01-01

    Immune system dysregulation occurs during spaceflight and consists of altered peripheral leukocyte distribution, reductions in immunocyte function and altered cytokine production profiles. Causes may include stress, confinement, isolation, and disrupted circadian rhythms. All of these factors may be replicated to some degree in terrestrial environments. NASA is currently evaluating the potential for a ground-based analog for immune dysregulation, which would have utility for mechanistic investigations and countermeasures evaluation. For ground-based space physiology research, the choice of terrestrial analog must carefully match the system of interest. Antarctica winter-over, consisting of prolonged durations in an extreme/dangerous environment, station-based habitation, isolation and disrupted circadian rhythms, is potentially a good ground-analog for spaceflight-associated immune dysregulation. Of all Antarctica bases, the French-Italian Concordia Station, may be the most appropriate to replicate spaceflight/exploration conditions. Concordia is an interior base located in harsh environmental conditions, and has been constructed to house small, international crews in a station-environment similar to what should be experienced by deep space astronauts. The ESA-NASA CHOICE study assessed innate and adaptive immunity, viral reactivation and stress factors during Concordia winterover deployment. The study was conducted over two winterover missions in 2009 and 2010. Final study data from NASA participation in these missions will be presented.

  7. Antireward, compulsivity, and addiction: seminal contributions of Dr. Athina Markou to motivational dysregulation in addiction.

    Science.gov (United States)

    Koob, George F

    2017-05-01

    Addiction is defined as a chronically relapsing disorder characterized by compulsive drug seeking that is hypothesized to derive from multiple sources of motivational dysregulation. Dr. Athina Markou made seminal contributions to our understanding of the neurobiology of addiction with her studies on the dysregulation of reward function using animal models with construct validity. Repeated overstimulation of the reward systems with drugs of abuse decreases reward function, characterized by brain stimulation reward and presumbably reflecting dysphoria-like states. The construct of negative reinforcement, defined as drug taking that alleviates a negative emotional state that is created by drug abstinence, is particularly relevant as a driving force in both the withdrawal/negative affect and preoccupation/anticipation stages of the addiction cycle. The negative emotional state that drives such negative reinforcement is hypothesized to derive from the dysregulation of key neurochemical circuits that drive incentive-salience/reward systems (dopamine, opioid peptides) in the ventral striatum and from the recruitment of brain stress systems (corticotropin-releasing factor, dynorphin) within the extended amygdala. As drug taking becomes compulsive-like, the factors that motivate behavior are hypothesized to shift to drug-seeking behavior that is driven not only by positive reinforcement but also by negative reinforcement. This shift in motivation is hypothesized to reflect the allostatic misregulation of hedonic tone such that drug taking makes the hedonic negative emotional state worse during the process of seeking temporary relief with compulsive drug taking.

  8. The child behavior checklist dysregulation profile predicts adolescent DSM-5 pathological personality traits 4 years later.

    Science.gov (United States)

    De Caluwé, Elien; Decuyper, Mieke; De Clercq, Barbara

    2013-07-01

    Emotional dysregulation in childhood has been associated with various forms of later psychopathology, although no studies have investigated the personality related adolescent outcomes associated with early emotional dysregulation. The present study uses a typological approach to examine how the child behavior checklist-dysregulation profile (CBCL-DP) predicts DSM-5 pathological personality traits (as measured with the personality inventory for the diagnostic and statistical manual of mental disorders 5 or PID-5 by Krueger et al. (Psychol Med 2012)) across a time span of 4 years in a sample of 243 children aged 8-14 years (57.2 % girls). The results showed that children assigned to the CBCL-DP class are at risk for elevated scores on a wide range of DSM-5 personality pathology features, including higher scores on hostility, risk taking, deceitfulness, callousness, grandiosity, irresponsibility, impulsivity and manipulativeness. These results are discussed in the context of identifying early manifestations of persistent regulation problems, because of their enduring impact on a child's personality development.

  9. Cardiac mTORC1 Dysregulation Impacts Stress Adaptation and Survival in Huntington’s Disease

    Directory of Open Access Journals (Sweden)

    Daniel D. Child

    2018-04-01

    Full Text Available Summary: Huntington’s disease (HD is a dominantly inherited neurological disorder caused by CAG-repeat expansion in exon 1 of Huntingtin (HTT. But in addition to the neurological disease, mutant HTT (mHTT, which is ubiquitously expressed, impairs other organ systems. Indeed, epidemiological and animal model studies suggest higher incidence of and mortality from heart disease in HD. Here, we show that the protein complex mTORC1 is dysregulated in two HD mouse models through a mechanism that requires intrinsic mHTT expression. Moreover, restoring cardiac mTORC1 activity with constitutively active Rheb prevents mortality and relieves the mHTT-induced block to hypertrophic adaptation to cardiac stress. Finally, we show that chronic mTORC1 dysregulation is due in part to mislocalization of endogenous Rheb. These data provide insight into the increased cardiac-related mortality of HD patients, with cardiac mHTT expression inhibiting mTORC1 activity, limiting heart growth, and decreasing the heart’s ability to compensate to chronic stress. : Child et al. demonstrate that mTORC1 dysregulation is a key molecular mechanism in the Huntington’s disease (HD heart phenotype. Impaired cardiac mTORC1 activity in HD mouse models requires intrinsic mHTT expression and explains the limited adaptation to cardiac stress. Keywords: Huntington’s disease, heart, mTOR, Rheb

  10. Metacognitions or distress intolerance: The mediating role in the relationship between emotional dysregulation and problematic internet use.

    Science.gov (United States)

    Akbari, Mehdi

    2017-12-01

    Given the relevance of problematic Internet use (PIU) to everyday life, its relationship to emotional dysregulation and the importance of metacognitions and distress intolerance in process and intermediaries research, this study examined which of metacognitions and distress intolerance acts as an intermediary between emotional dysregulation and PIU. In the current study, 413 undergraduate students from the University of Tehran, Iran (202 females; mean age = 20.13) voluntarily completed a questionnaire package which included the Internet Addiction Test (IAT), Difficulties in Emotion Regulation Scale (DERS), Metacognitions Questionnaire 30 (MCQ-30(, and Distress Tolerance Scale (DTS). The data were then analyzed using structural equation modeling by LISREL software. Significant correlations were found between PIU and emotional dysregulation and both distress intolerance and metacognitions ( P  intolerance. Also, these findings emphasize that distress intolerance has a more significant mediating role than metacognition in the relationship between emotional dysregulation and PIU.

  11. Longitudinal pathways from early maternal depression to children's dysregulated representations: a moderated mediation analysis of harsh parenting and gender.

    Science.gov (United States)

    Martoccio, Tiffany L; Brophy-Herb, Holly E; Maupin, Angela N; Robinson, Joann L

    2016-01-01

    There is some evidence linking maternal depression, harsh parenting, and children's internal representations of attachment, yet, longitudinal examinations of these relationships and differences in the developmental pathways between boys and girls are lacking. Moderated mediation growth curves were employed to examine harsh parenting as a mechanism underlying the link between maternal depression and children's dysregulated representations using a nationally-representative, economically-vulnerable sample of mothers and their children (n = 575; 49% boys, 51% girls). Dysregulation representations were measured using the MacArthur Story Stem Battery at five years of age (M = 5.14, SD = 0.29). Harsh parenting mediated the association between early maternal depression and dysregulated representations for girls. Though initial harsh parenting was a significant mediator for boys, a stronger direct effect of maternal depression to dysregulated representations emerged over time. Results are discussed in terms of their implications for intervention efforts aimed at promoting early supportive parenting.

  12. Dialectical behavior therapy skills use and emotion dysregulation in personality disorders and psychopathy: a community self-report study.

    Science.gov (United States)

    Neacsiu, Andrada D; Tkachuck, Mathew A

    2016-01-01

    Emotion dysregulation is a critical transdiagnostic mental health problem that needs to be further examined in personality disorders (PDs). The current study examined dialectical behavior therapy (DBT) skills use, emotion dysregulation, and dysfunctional coping among adults who endorsed symptoms of cluster B PDs and psychopathy. We hypothesized that skills taught in DBT and emotion dysregulation are useful for adults with PDs other than borderline personality disorder (BPD). Using a self-report questionnaire, we examined these constructs in three groups of community adults: those who reported symptoms consistent with borderline personality disorder (BPD; N = 29), those who reported symptoms consistent with any other cluster B PD (N = 22), and those with no reported cluster B PD symptoms (N = 77) as measured by the Personality Diagnostic Questionnaire-4 + . Both PD groups reported higher emotion dysregulation and dysfunctional coping when compared to the no PD group. Only the BPD group had significantly lower DBT skills use. DBT skills use was found to be a significant predictor of cluster B psychopathology but only before accounting for emotion dysregulation. When added to the regression model, emotion dysregulation was found to be a significant predictor of cluster B psychopathology but DBT skills use no longer had a significant effect. Across all groups, DBT skills use deficits and maladaptive coping, but not emotion dysregulation, predicted different facets of psychopathy. Emotion dysregulation and use of maladaptive coping are problems in cluster B PDs, outside of BPD, but not in psychopathy. Inability to use DBT skills may be unique to BPD. Because this study relied exclusively on self-report, this data is preliminary and warrants further investigation.

  13. Anxiety among adults with a history of childhood adversity: Psychological resilience moderates the indirect effect of emotion dysregulation.

    Science.gov (United States)

    Poole, Julia C; Dobson, Keith S; Pusch, Dennis

    2017-08-01

    Adverse childhood experiences (ACEs) have been widely identified as risk factors for increased symptoms of anxiety across the lifespan. Little is known, however, about the processes by which ACEs set the stage for increased symptoms of anxiety in adulthood. The current study evaluated whether emotion dysregulation and psychological resilience influence the association between ACEs and symptoms of anxiety. A sample of adult primary care patients (N=4006) completed self-report measures related to ACEs, symptoms of anxiety, emotion dysregulation, and psychological resilience. A moderated mediation analysis showed that emotion dysregulation mediated the association between ACEs and anxiety symptoms, and that the strength of this effect varied as a function of psychological resilience. Specifically, the influence of ACEs on emotional dysregulation was stronger among individuals with low levels of psychological resilience than among those with high levels of psychological resilience. These findings remained significant when controlling for a range of sociodemographic variables in the model. Cross-sectional designs preclude inferences about causality and self-report data may be susceptible to reporting biases. Other psychological variables that may be relevant to the current results, such as protective factors in childhood, were not assessed. These results have implications for the conceptualization of ACEs, emotion dysregulation, and psychological resilience in etiological models of anxiety. They also highlight the relevance of ACEs, emotion dysregulation, and psychological resilience to the detection, treatment, and prevention of anxiety disorders. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Negative parental attribution and emotional dysregulation in Chinese early adolescents: Harsh fathering and harsh mothering as potential mediators.

    Science.gov (United States)

    Wang, Mingzhong; Wang, Jing

    2018-04-21

    The current study examined the potential mediating roles of harsh fathering and harsh mothering in the association between negative parental attribution and emotional dysregulation in Chinese adolescents and explored the moderating role of child gender on this indirect association. 864 students (367 girls, mean age = 13.55 years) with their parents were recruited as participants from two middle schools in Shandong Province, People's Republic of China. The results demonstrated that both harsh fathering and harsh mothering could partially mediate the association between negative maternal attribution and child emotional dysregulation, whereas only harsh fathering could partially mediate the association between negative paternal attribution and child emotional dysregulation. Moreover, we found the moderating role of child gender only for the association between harsh fathering and child emotional dysregulation, in that harsh fathering could be associated with higher levels of emotional dysregulation in girls. These results shed light on efforts to prevent harsh parenting and child emotional dysregulation. Copyright © 2018 Elsevier Ltd. All rights reserved.

  15. Dysregulated left inferior parietal activity in schizophrenia and depression: functional connectivity and characterization

    Directory of Open Access Journals (Sweden)

    Veronika I. Müller

    2013-06-01

    Full Text Available The inferior parietal cortex (IPC is a heterogeneous region that is known to be involved in a multitude of diverse different tasks and processes, though its contribution to these often-complex functions is yet poorly understood. In a previous study we demonstrated that patients with depression failed to deactivate the left IPC during processing of congruent audiovisual information. We now found the same dysregulation (same region and condition in schizophrenia. By using task-independent (resting state and task-dependent (MACM analyses we aimed at characterizing this particular region with regard to its connectivity and function. Across both approaches, results revealed functional connectivity of the left inferior parietal seed region with bilateral IPC, precuneus and posterior cingulate cortex (PrC/PCC, medial orbitofrontal cortex (mOFC, left middle frontal (MFG as well as inferior frontal (IFG gyrus. Network-level functional characterization further revealed that on the one hand, all interconnected regions are part of a network involved in memory processes. On the other hand, sub-networks are formed when emotion, language, social cognition and reasoning processes are required. Thus, the IPC-region that is dysregulated in both depression and schizophrenia is functionally connected to a network of regions which, depending on task demands may form sub-networks. These results therefore indicate that dysregulation of left IPC in depression and schizophrenia might not only be connected to deficits in audiovisual integration, but is possibly also associated to impaired memory and deficits in emotion processing in these patient groups.

  16. Dysregulation of chemokine receptor expression and function in leukocytes from ALS patients.

    Science.gov (United States)

    Perner, Caroline; Perner, Florian; Stubendorff, Beatrice; Förster, Martin; Witte, Otto W; Heidel, Florian H; Prell, Tino; Grosskreutz, Julian

    2018-03-28

    Amyotrophic lateral sclerosis (ALS) is rapidly progressive adult-onset motor neuron disease characterized by the neurodegeneration of both upper and lower motor neurons in the cortex and the spinal cord; the majority of patients succumb to respiratory failure. Although the etiology is not yet fully understood, there is compelling evidence that ALS is a multi-systemic disorder, with peripheral inflammation critically contributing to the disease process. However, the full extent and nature of this immunological dysregulation remains to be established, particularly within circulating blood cells. Therefore, the aim of the present study was to identify dysregulated inflammatory molecules in peripheral blood cells of ALS patients and analyze for functional consequences of the observed findings. To this end, we employed flow cytometry-based screening to quantify the surface expression of major chemokine receptors and integrins. A significantly increased expression of CXCR3, CXCR4, CCL2, and CCL5 was observed on T cells in ALS patients compared to healthy controls. Intriguingly, the expression was even more pronounced in patients with a slow progressive phenotype. To further investigate the functional consequences of this altered surface expression, we used a modified Boyden chamber assay to measure chemotaxis in ALS patient-derived lymphocytes. Interestingly, chemoattraction with the CXCR3-Ligand IP10 led to upregulated migratory behavior of ALS lymphocytes compared to healthy controls. Taken together, our data provides evidence for a functional dysregulation of IP10-directed chemotaxis in peripheral blood cells in ALS patients. However, whether the chemokine itself or its receptor CXCR3, or both, could serve as potential therapeutic targets in ALS requires further investigations.

  17. Early life adversity potentiates the effects of later life stress on cumulative physiological dysregulation

    DEFF Research Database (Denmark)

    Dich, Nadya; Hansen, Åse Marie; Avlund, Kirsten

    2015-01-01

    tested this hypothesis by investigating whether experience of stressful events and circumstances (SEC) in childhood or adolescence amplified the effect of adulthood SEC on physiological dysregulation (allostatic load, AL) in later midlife. Design: Observational data were used in the present study....... Physiological functioning was measured in later midlife (participants' age ranged from 49 to 63). Both childhood/adolescence and adulthood SEC were reported retrospectively on the same occasion. Methods: Participants were 5,309 Danish men and women from Copenhagen Ageing and Midlife Biobank. SEC included socio......: The results provide further insight into the mechanisms behind the "biological embedding" of childhood stress....

  18. Metabogenic and Nutriceutical Approaches to Address Energy Dysregulation and Skeletal Muscle Wasting in Duchenne Muscular Dystrophy

    Directory of Open Access Journals (Sweden)

    Emma Rybalka

    2015-11-01

    Full Text Available Duchenne Muscular Dystrophy (DMD is a fatal genetic muscle wasting disease with no current cure. A prominent, yet poorly treated feature of dystrophic muscle is the dysregulation of energy homeostasis which may be associated with intrinsic defects in key energy systems and promote muscle wasting. As such, supplementative nutriceuticals that target and augment the bioenergetical expansion of the metabolic pathways involved in cellular energy production have been widely investigated for their therapeutic efficacy in the treatment of DMD. We describe the metabolic nuances of dystrophin-deficient skeletal muscle and review the potential of various metabogenic and nutriceutical compounds to ameliorate the pathological and clinical progression of the disease.

  19. Aetiological pathways to Borderline Personality Disorder symptoms in early adolescence: childhood dysregulated behaviour, maladaptive parenting and bully victimisation.

    Science.gov (United States)

    Winsper, Catherine; Hall, James; Strauss, Vicky Y; Wolke, Dieter

    2017-01-01

    Developmental theories for the aetiology of Borderline Personality Disorder (BPD) suggest that both individual features (e.g., childhood dysregulated behaviour) and negative environmental experiences (e.g., maladaptive parenting, peer victimisation) may lead to the development of BPD symptoms during adolescence. Few prospective studies have examined potential aetiological pathways involving these two factors. We addressed this gap in the literature using data from the Avon Longitudinal Study of Parents and Children (ALSPAC). We assessed mother-reported childhood dysregulated behaviour at 4, 7 and 8 years using the Strengths and Difficulties Questionnaire (SDQ); maladaptive parenting (maternal hitting, punishment, and hostility) at 8 to 9 years; and bully victimisation (child and mother report) at 8, 9 and 10 years. BPD symptoms were assessed at 11 years using the UK Childhood Interview for DSM-IV BPD. Control variables included adolescent depression (assessed with the Short Moods and Feelings Questionnaire-SMFQ) and psychotic symptoms (assessed with the Psychosis-Like Symptoms Interview-PLIKS) at 11 to 14 years, and mother's exposure to family adversity during pregnancy (assessed with the Family Adversity Scale-FAI). In unadjusted logistic regression analyses, childhood dysregulated behaviour and all environmental risk factors (i.e., family adversity, maladaptive parenting, and bully victimisation) were significantly associated with BPD symptoms at 11 years. Within structural equation modelling controlling for all associations simultaneously, family adversity and male sex significantly predicted dysregulated behaviour across childhood, while bully victimisation significantly predicted BPD, depression, and psychotic symptoms. Children displaying dysregulated behaviour across childhood were significantly more likely to experience maladaptive parenting (β = 0.075, p  bullying (β = 0.097, p  < 0.001). While significant indirect associations

  20. The Relationship between Childhood Maltreatment and Emotional Dysregulation in Self Mutilation: An Investigation among Substance Dependent Patients.

    Science.gov (United States)

    Karagöz, Başak; Dağ, İhsan

    2015-03-01

    The present study aims to examine the role of emotion dysregulation and childhood maltreatment in self mutilation (SM) of substance dependent patients. Specifically, the present study examined whether emotion dysregulation and its dimensions, and childhood maltreatment and its dimensions were associated with SM. The relationship between emotion dysregulation and childhood maltreatment was also investigated. The sample of study consisted of 55 alcohol dependent and 24 opiate dependent patients (n=79). Substance dependence was diagnosed by means of the Structured Clinical Interview for DSM-IV-TR (SCID-I), Turkish version. Childhood Trauma Questionnaire (CTQ) and Difficulties in Emotion Regulation Scale (DERS) were used. Findings indicated that substance dependents with SM and without SM were differentiated in terms of overall emotion dysregulation. Results also suggest the relevance of three specific dimensions of emotion dysregulation to SM: Difficulties engaging in goal-directed behaviors when experiencing negative emotions, difficulties controlling impulsive behaviors when experiencing negative emotions, and limited access to effective emotion regulation strategies. These dimensions were predicted from childhood emotional maltreatment and neglect. It is also revealed that substance dependents with SM had higher points than those without SM on emotional childhood maltreatment and neglect, physical childhood maltreatment. Results were supported by the literature suggested that self-mutilation functions as a emotional regulation strategy. Findings also suggested that self- mutilation is related to early relationships take place in family environment in which individuals grow up.

  1. Posttraumatic stress and emotion dysregulation: Relationships with smoking to reduce negative affect and barriers to smoking cessation.

    Science.gov (United States)

    Short, Nicole A; Oglesby, Mary E; Raines, Amanda M; Zvolensky, Michael J; Schmidt, Norman B

    2015-08-01

    Many cigarette smokers have experienced a traumatic event, and elevated posttraumatic stress symptoms (PTSS) are associated with increased smoking levels. Previous research has found that elevated PTSS are associated with smoking to cope with negative affect, and it has been posited that perceptions of being unable to cope with the consequences of smoking cessation interfere with smoking cessation in this population. However, the mechanism of the relationship between PTSS and these smoking maintenance factors (i.e., smoking to reduce negative affect and barriers to cessation) has not been established. Emotion dysregulation is one potential mechanism as it is associated with PTSS as well as addictive behavior aimed at avoiding and reducing negative emotional states. We cross-sectionally tested the hypotheses that 1) PTSS and emotion dysregulation would be incrementally associated with smoking to reduce negative affect and barriers to cessation, and 2) that emotion dysregulation would mediate the relationships between PTSS, smoking to reduce negative affect, and barriers to cessation among a community sample of trauma-exposed individuals presenting for smoking cessation treatment (N=315). Results demonstrated that elevated PTSS were associated with increased smoking to reduce negative affect and barriers to cessation, and that emotion dysregulation mediated these relationships. These findings provide evidence of a mechanism between PTSS and psychological smoking maintenance factors, and suggest that emotion dysregulation may be a useful target for smoking cessation interventions among trauma-exposed individuals. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Hypoxia dysregulates the production of adiponectin and plasminogen activator inhibitor-1 independent of reactive oxygen species in adipocytes

    International Nuclear Information System (INIS)

    Chen Baoying; Lam, Karen S.L.; Wang Yu; Wu Donghai; Lam, Michael C.; Shen Jiangang; Wong Laiching; Hoo, Ruby L.C.; Zhang Jialiang; Xu Aimin

    2006-01-01

    Low plasma levels of adiponectin (hypoadiponectinemia) and elevated circulating concentrations of plasminogen activator inhibitor (PAI)-1 are causally associated with obesity-related insulin resistance and cardiovascular disease. However, the mechanism that mediates the aberrant production of these two adipokines in obesity remains poorly understood. In this study, we investigated the effects of hypoxia and reactive oxygen species (ROS) on production of adiponectin and PAI-1 in 3T3-L1 adipocytes. Quantitative PCR and immunoassays showed that ambient hypoxia markedly suppressed adiponectin mRNA expression and its protein secretion, and increased PAI-1 production in mature adipocytes. Dimethyloxallyl glycine, a stabilizer of hypoxia-inducible factor 1α (HIF-1α), mimicked the hypoxia-mediated modulations of these two adipokines. Hypoxia caused a modest elevation of ROS in adipocytes. However, ablation of intracellular ROS by antioxidants failed to alleviate hypoxia-induced aberrant production of adiponectin and PAI-1. On the other hand, the antioxidants could reverse hydrogen peroxide (H 2 O 2 )-induced dysregulation of adiponectin and PAI-1 production. H 2 O 2 treatment decreased the expression levels of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein (C/EBPα), but had no effect on HIF-1α, whereas hypoxia stabilized HIF-1α and decreased expression of C/EBPα, but not PPARγ. Taken together, these data suggest that hypoxia and ROS decrease adiponectin production and augment PAI-1 expression in adipocytes via distinct signaling pathways. These effects may contribute to hypoadiponectinemia and elevated PAI-1 levels in obesity, type 2 diabetes, and cardiovascular diseases

  3. Comprehensive analysis of differential co-expression patterns reveal transcriptional dysregulation mechanism and identify novel prognostic lncRNAs in esophageal squamous cell carcinoma

    Directory of Open Access Journals (Sweden)

    Li Z

    2017-06-01

    , which were differentially co-expressed with the two lncRNAs, might also have the predictive capacity. Our findings will enhance the understanding of ESCC transcriptional dysregulation from a view of cross-link of lncRNA and mRNA, and the two-lncRNA combination may serve as a novel prognostic biomarker for clinical applications of ESCC. Keywords: ESCC, differential co-expression analysis, differential regulation analysis, dysregulation, lncRNA, prognostic biomarker

  4. Dysregulation of heat shock protein 27 expression in oral tongue squamous cell carcinoma

    International Nuclear Information System (INIS)

    Wang, Anxun; Liu, Xiqiang; Sheng, Shihu; Ye, Hui; Peng, Tingsheng; Shi, Fei; Crowe, David L; Zhou, Xiaofeng

    2009-01-01

    Recent proteomic studies identified Hsp27 as a highly over-expressed protein in oral squamous cell carcinoma (OSCC). Clinical studies that attempted to evaluate the prognostic values of Hsp27 yielded inconsistent results, which may be due to inclusion of OSCC cases from multiple anatomic sites. In this study, to determine the utility of Hsp27 for prognosis, we focused on oral tongue SCC (OTSCC), one of the most aggressive forms of OSCC. Archival clinical samples of 15 normal oral tongue mucosa, 31 dysplastic lesions, 80 primary OTSCC, and 32 lymph node metastases were examined for Hsp27 expression by immunohistochemistry (IHC). Statistical analyses were carried out to assess the prognostic value of Hsp27 expression for patients with this disease. Dysregulation of Hsp27 expression was observed in dysplastic lesions, primary OTSCC, and lymph node metastases, and appears to be associated with disease progression. Statistical analysis revealed that the reduced Hsp27 expression in primary tumor tissue was associated with poor differentiation. Furthermore, the higher expression of Hsp27 was correlated with better overall survival. Our study confirmed that the dysregulation of Hsp27 expression is a frequent event during the progression of OTSCC. The expression of Hsp27 appears to be an independent prognostic marker for patients with this disease

  5. Negative reinforcement eating expectancies, emotion dysregulation, and symptoms of bulimia nervosa.

    Science.gov (United States)

    Hayaki, Jumi

    2009-09-01

    Research suggests that emotion dysregulation or difficulties in the modulation of emotional experience constitute risk for eating disorders. Recent work has also highlighted the role of certain eating-related cognitions, specifically expectations of negative emotional reinforcement from eating, in the development of disturbed eating patterns. However, it is unclear whether these expectancies are merely a dimension of a general inability to regulate emotions effectively or rather a unique cognitive-affective risk factor for the development of an eating disorder. This study examines the unique contribution of eating expectancies to symptoms of bulimia nervosa (BN) after controlling for two dimensions of emotion dysregulation (alexithymia and experiential avoidance) previously implicated in the phenomenology of eating disorders. Participants were 115 undergraduate women who self-reported demographics, alexithymia, experiential avoidance, eating expectancies, and symptoms of BN. Eating expectancies uniquely contributed 12.4% of the variance in symptoms of BN, F(2, 108) = 11.74, p symptoms of BN. These results suggest that individuals who expect eating to provide emotional relief may be especially susceptible to disordered eating. Findings are discussed in terms of emotional risk models and clinical interventions for BN.

  6. Meta-Analysis of Multiple Sclerosis Microarray Data Reveals Dysregulation in RNA Splicing Regulatory Genes

    Directory of Open Access Journals (Sweden)

    Elvezia Maria Paraboschi

    2015-09-01

    Full Text Available Abnormalities in RNA metabolism and alternative splicing (AS are emerging as important players in complex disease phenotypes. In particular, accumulating evidence suggests the existence of pathogenic links between multiple sclerosis (MS and altered AS, including functional studies showing that an imbalance in alternatively-spliced isoforms may contribute to disease etiology. Here, we tested whether the altered expression of AS-related genes represents a MS-specific signature. A comprehensive comparative analysis of gene expression profiles of publicly-available microarray datasets (190 MS cases, 182 controls, followed by gene-ontology enrichment analysis, highlighted a significant enrichment for differentially-expressed genes involved in RNA metabolism/AS. In detail, a total of 17 genes were found to be differentially expressed in MS in multiple datasets, with CELF1 being dysregulated in five out of seven studies. We confirmed CELF1 downregulation in MS (p = 0.0015 by real-time RT-PCRs on RNA extracted from blood cells of 30 cases and 30 controls. As a proof of concept, we experimentally verified the unbalance in alternatively-spliced isoforms in MS of the NFAT5 gene, a putative CELF1 target. In conclusion, for the first time we provide evidence of a consistent dysregulation of splicing-related genes in MS and we discuss its possible implications in modulating specific AS events in MS susceptibility genes.

  7. Mindfulness and Modification Therapy for Behavioral Dysregulation: A Comparison Trial Focused on Substance Use and Aggression.

    Science.gov (United States)

    Wupperman, Peggilee; Cohen, Mia Gintoft; Haller, Deborah L; Flom, Peter; Litt, Lisa C; Rounsaville, Bruce J

    2015-10-01

    Disorders of behavioral dysregulation often involve more than one dsyregulated behavior (e.g., drug abuse and aggression, alcohol abuse and gambling). The high co-occurrence suggests the need of a transdiagnostic treatment that can be customized to target multiple specific behaviors. The current pilot study compared a 20-week, individual transdiagnostic therapy (mindfulness and modification therapy [MMT]) versus treatment as usual (TAU) in targeting alcohol problems, drug use, physical aggression, and verbal aggression in self-referred women. Assessments were administered at baseline, post-intervention, and 2-month follow-up. Wilcoxon signed-ranked tests and multilevel modeling showed that MMT (n = 13) displayed (a) significant and large decreases in alcohol/drug use, physical aggression, and verbal aggression; (b) significantly greater decreases in alcohol/drug use and physical aggression than did TAU (n = 8); and (c) minimal-to-no deterioration of effects at follow-up. Both conditions showed significant decreases in verbal aggression, with no statistically significant difference between conditions. MMT also displayed greater improvements in mindfulness. Preliminary findings support the feasibility and efficacy of MMT in decreasing multiple dysregulated behaviors. © 2015 Wiley Periodicals, Inc.

  8. Early Dysregulation of Cell Adhesion and Extracellular Matrix Pathways in Breast Cancer Progression

    Science.gov (United States)

    Emery, Lyndsey A.; Tripathi, Anusri; King, Chialin; Kavanah, Maureen; Mendez, Jane; Stone, Michael D.; de las Morenas, Antonio; Sebastiani, Paola; Rosenberg, Carol L.

    2009-01-01

    Proliferative breast lesions, such as simple ductal hyperplasia (SH) and atypical ductal hyperplasia (ADH), are candidate precursors to ductal carcinoma in situ (DCIS) and invasive cancer. To better understand the relationship of breast lesions to more advanced disease, we used microdissection and DNA microarrays to profile the gene expression of patient-matched histologically normal (HN), ADH, and DCIS from 12 patients with estrogen receptor positive sporadic breast cancer. SH were profiled from a subset of cases. We found 837 differentially expressed genes between DCIS-HN and 447 between ADH-HN, with >90% of the ADH-HN genes also present among the DCIS-HN genes. Only 61 genes were identified between ADH-DCIS. Expression differences were reproduced in an independent cohort of patient-matched lesions by quantitative real-time PCR. Many breast cancer-related genes and pathways were dysregulated in ADH and maintained in DCIS. Particularly, cell adhesion and extracellular matrix interactions were overrepresented. Focal adhesion was the top pathway in each gene set. We conclude that ADH and DCIS share highly similar gene expression and are distinct from HN. In contrast, SH appear more similar to HN. These data provide genetic evidence that ADH (but not SH) are often precursors to cancer and suggest cancer-related genetic changes, particularly adhesion and extracellular matrix pathways, are dysregulated before invasion and even before malignancy is apparent. These findings could lead to novel risk stratification, prevention, and treatment approaches. PMID:19700746

  9. Commingling effect of gynoid and android fat patterns on cardiometabolic dysregulation in normal weight American adults.

    Science.gov (United States)

    Okosun, I S; Seale, J P; Lyn, R

    2015-05-18

    To determine the independent and commingling effect of android and gynoid percent fat (measured using Dual Energy X-Ray Absorptiometry) on cardiometabolic dysregulation in normal weight American adults. The 2005-2006 data (n=1802) from the United States National Health and Nutritional Examination Surveys (NHANES) were used in this study. Associations of android percent fat, gynoid percent fat and their joint occurrence with risks of cardiometabolic risk factors were estimated using prevalence odds ratios from logistic regression analyses. Android-gynoid percent fat ratio was more highly correlated with cardiometabolic dysregulation than android percent fat, gynoid percent fat or body mass index. Commingling of android and gynoid adiposities was associated with much greater odds of cardiometabolic risk factors than either android or gynoid adiposities. Commingling of android and gynoid adiposities was associated with 1.75 (95% confidence interval (CI)=1.42-2.93), 1.48 (95% CI=1.32-1.91), 1.61 (95% CI=1.50-1.89), 3.56 (95% CI=2.91-4.11) and 1.86 (95% CI=1.49-1.96) increased odds of elevated glucose, elevated blood pressure, elevated low-density lipoprotein-cholesterol, elevated triglyceride and low high-density lipoprotein-cholesterol, respectively. Normal weight subjects who present with both android and gynoid adiposities should be advised of the associated health risks. Both android and gynoid fat accumulations should be considered in developing public health strategies for reducing cardiometabolic disease risk in normal weight subjects.

  10. No miR quirk: dysregulation of microRNAs in pancreatic ductal adenocarcinoma.

    Science.gov (United States)

    Cheung, Philip Y; Szafranska-Schwarzbach, Anna E; Schlageter, Annette M; Andruss, Bernard F; Weiss, Glen J

    2012-01-01

    MicroRNAs are post-transcriptional regulators of gene expression with tissue-specific expression profiles. Dysregulation of microRNAs has been shown to play a role in carcinogenesis. Although progress has been made in the diagnosis and treatment of many cancers, pancreatic cancer remains an intractable public health problem, causing 6.58% of cancer deaths despite making up less than 3% of cancer diagnoses in the United States. No screening, diagnostic or imaging techniques exist with the sensitivity to detect pancreatic cancer in its early, operable stages. Risk factors include numerous inherited syndromes, diabetes mellitus, and hepatitis C virus infection. Here we review the literature regarding dysregulation of microRNA expression in native pancreas, pancreatic ductal adenocarcinoma (the dominant form of pancreatic cancer), and its risk factors to illuminate the biology and progression of this disease. We explore promising evidence for the use of microRNAs as prognostic and diagnostic tools, and discuss emerging reports on microRNA therapeutics.

  11. Dysregulation in level of goal and action identification across psychological disorders

    Science.gov (United States)

    Watkins, Edward

    2011-01-01

    Goals, events, and actions can be mentally represented within a hierarchical framework that ranges from more abstract to more concrete levels of identification. A more abstract level of identification involves general, superordinate, and decontextualized mental representations that convey the meaning of goals, events, and actions, “why” an action is performed, and its purpose, ends, and consequences. A more concrete level of identification involves specific and subordinate mental representations that include contextual details of goals, events, and actions, and the specific “how” details of an action. This review considers three lines of evidence for considering that dysregulation of level of goal/action identification may be a transdiagnostic process. First, there is evidence that different levels of identification have distinct functional consequences and that in non-clinical samples level of goal/action identification appears to be regulated in a flexible and adaptive way to match the level of goal/action identification to circumstances. Second, there is evidence that level of goal/action identification causally influences symptoms and processes involved in psychological disorders, including emotional response, repetitive thought, impulsivity, problem solving and procrastination. Third, there is evidence that the level of goal/action identification is biased and/or dysregulated in certain psychological disorders, with a bias towards more abstract identification for negative events in depression, GAD, PTSD, and social anxiety. PMID:20579789

  12. Dopamine dysregulation hypothesis: the common basis for motivational anhedonia in major depressive disorder and schizophrenia?

    Science.gov (United States)

    Szczypiński, Jan Józef; Gola, Mateusz

    2018-03-24

    Abnormalities in reward processing are crucial symptoms of major depressive disorder (MDD) and schizophrenia (SCH). Recent neuroscientific findings regarding MDD have led to conclusions about two different symptoms related to reward processing: motivational and consummatory anhedonia, corresponding, respectively, to impaired motivation to obtain rewards ('wanting'), and diminished satisfaction from consuming them ('liking'). One can ask: which of these is common for MDD and SCH. In our review of the latest neuroscientific studies, we show that MDD and SCH do not share consummatory anhedonia, as SCH patients usually have unaltered liking. Therefore, we investigated whether motivational anhedonia is the common symptom across MDD and SCH. With regard to the similarities and differences between the neural mechanisms of MDD and SCH, here we expand the current knowledge of motivation deficits and present the common underlying mechanism of motivational anhedonia - the dopamine dysregulation hypothesis - stating that any prolonged dysregulation in tonic dopamine signaling that exceeds the given equilibrium can lead to striatal dysfunction and motivational anhedonia. The implications for further research and treatment of MDD and SCH are also discussed.

  13. Preoccupied Attachment and Emotional Dysregulation: Specific Aspects of Borderline Personality Disorder or General Dimensions of Personality Pathology?

    Science.gov (United States)

    Scott, Lori N.; Kim, Yookyung; Nolf, Kimberly A.; Hallquist, Michael N.; Wright, Aidan G.C.; Stepp, Stephanie D.; Morse, Jennifer Q.; Pilkonis, Paul A.

    2013-01-01

    Emotional dysregulation and impaired attachment are seen by many clinical researchers as central aspects of borderline personality disorder (BPD). Alternatively, these constructs may represent general impairments in personality that are nonspecific to BPD. Using multitrait-multimethod models, we examined the strength of associations among preoccupied attachment, difficulties with emotion regulation, BPD features, and features of two other personality disorders (i.e., antisocial and avoidant) in a combined psychiatric outpatient and community sample of adults. Results suggested that preoccupied attachment and difficulties with emotion regulation shared strong positive associations with each other and with each of the selected personality disorders. However, preoccupied attachment and emotional dysregulation were more strongly related to BPD features than to features of other personality disorders. Our findings suggest that although impairments in relational and emotional domains may underlie personality pathology in general, preoccupied attachment and emotional dysregulation also have specificity for understanding core difficulties in those with BPD. PMID:23586934

  14. Preoccupied attachment and emotional dysregulation: specific aspects of borderline personality disorder or general dimensions of personality pathology?

    Science.gov (United States)

    Scott, Lori N; Kim, Yookyung; Nolf, Kimberly A; Hallquist, Michael N; Wright, Aidan G C; Stepp, Stephanie D; Morse, Jennifer Q; Pilkonis, Paul A

    2013-08-01

    Emotional dysregulation and impaired attachment are seen by many clinical researchers as central aspects of borderline personality disorder (BPD). Alternatively, these constructs may represent general impairments in personality that are nonspecific to BPD. Using multitraitmultimethod models, the authors examined the strength of associations among preoccupied attachment, difficulties with emotion regulation, BPD features, and features of two other personality disorders (i.e., antisocial and avoidant) in a combined psychiatric outpatient and community sample of adults. Results suggested that preoccupied attachment and difficulties with emotion regulation shared strong positive associations with each other and with each of the selected personality disorders. However, preoccupied attachment and emotional dysregulation were more strongly related to BPD features than to features of other personality disorders. Findings suggest that although impairments in relational and emotional domains may underlie personality pathology in general, preoccupied attachment and emotional dysregulation also have specificity for understanding core difficulties in those with BPD.

  15. Weight-Related Correlates of Psychological Dysregulation in Adolescent and Young Adult (AYA) Females with Severe Obesity

    Science.gov (United States)

    Gowey, Marissa A.; Reiter-Purtill, Jennifer; Becnel, Jennifer; Peugh, James; Mitchell, James E.; Zeller, Meg H.

    2016-01-01

    Objective Severe obesity is the fastest growing pediatric subgroup of excess weight levels. Psychological dysregulation (i.e., impairments in regulating cognitive, emotional, and/or behavioral processes) has been associated with obesity and poorer weight loss outcomes. The present study explored associations of dysregulation with weight-related variables among adolescent and young adult (AYA) females with severe obesity. Methods Fifty-four AYA females with severe obesity (MBMI=48.71 kg/m2; Mage=18.29, R=15–21 years; 59.3% White) completed self-report measures of psychological dysregulation and weight-related constructs including meal patterns, problematic eating behaviors, and body and weight dissatisfaction, as non-surgical comparison participants in a multi-site study of adolescent bariatric surgery outcomes. Pearson and bivariate correlations were conducted and stratified by age group to analyze associations between dysregulation subscales (affective, behavioral, cognitive) and weight-related variables. Results Breakfast was the most frequently skipped meal (consumed 3–4 times/week). Eating out was common (4–5 times/week) and mostly occurred at fast-food restaurants. Evening hyperphagia (61.11%) and eating in the absence of hunger (37.04%) were commonly endorsed, while unplanned eating (29.63%), a sense of loss of control over eating (22.22%), eating beyond satiety (22.22%), night eating (12.96%), and binge eating (11.11%) were less common. Almost half of the sample endorsed extreme weight dissatisfaction. Dysregulation was associated with most weight-related attitudes and behaviors of interest in young adults but select patterns emerged for adolescents. Conclusions Higher levels of psychological dysregulation are associated with greater BMI, problematic eating patterns and behaviors, and body dissatisfaction in AYA females with severe obesity. These findings have implications for developing novel intervention strategies for severe obesity in AYAs that may

  16. Dysregulation of gene expression within the peroxisome proliferator activated receptor pathway in morbidly obese patients.

    Science.gov (United States)

    Hindle, A Katharine; Koury, Jadd; McCaffrey, Tim; Fu, Sidney W; Brody, Fred

    2009-06-01

    The causes of obesity are multifactorial but may include dysregulation of a family of related genes, such as the peroxisome proliferator activated receptor gamma (PPARgamma). When activated, the PPARgamma pathway promotes lipid metabolism. This study used microarray technology to evaluate differential gene expression profiles in obese patients undergoing bariatric surgery. The study enrolled six morbidly obese patients with a body mass index (BMI) exceeding 35 and four nonobese individuals. Blood samples were stabilized in PaxGene tubes (PreAnalytiX), and total RNA was extracted. Next, 100 ng of total RNA was amplified and labeled using the Ovation RNA Amplification System V2 with the Ovation whole-blood reagent (NuGen) before it was hybridized to an Affymetrix (Santa Clara, CA) focus array containing more than 8,500 verified genes. The data were analyzed using an analysis of variance (ANOVA) (p < 0.05) in the GeneSpring program, and potential pathways were identified with the Ingenuity program. Real-time quantitative reverse transcriptase-polymerase chain reaction was used to validate the array data. A total of 97 upregulated genes and 125 downregulated genes were identified. More than a 1.5-fold change was identified between the morbidly obese patients and the control subjects for a cluster of dysregulated genes involving pathways regulating cell metabolism and lipid formation. Specifically, the PPARgamma pathway showed a plethora of dysregulated genes including tumor necrosis factor-alpha (TNFalpha). In morbidly obese patients, TNFalpha expression was increased (upregulated) 1.6-fold. These findings were confirmed using quantitative polymerase chain reaction with a 2.8-fold change. Microarrays are a powerful tool for identifying biomarkers indicating morbid obesity by analyzing differential gene expression profiles. This study confirms the association of PPARgamma with morbid obesity. Also, these findings in blood support previous work documented in tissue

  17. Investigating the role of dimensions of UPPS-P model of impulsivity and age increasing in men’s emotion dysregulation

    Directory of Open Access Journals (Sweden)

    Hashem Jebraeili

    2018-04-01

    Results: The findings showed that there were significant coloration between all dimensions of impulsivity, with the exception of sensation seeking, and age with emotion dysregulation. Results of regression analysis showed that dimensions of impulsivity and age have significant role in prediction of emotion dysregulation and explain 47 percent of total variance of it (F=40.67, P

  18. Attention Biases Towards and Away from Threat Mark the Relation between Early Dysregulated Fear and the Later Emergence of Social Withdrawal.

    Science.gov (United States)

    Morales, Santiago; Pérez-Edgar, Koraly E; Buss, Kristin A

    2015-08-01

    Fearful temperament, mostly studied as behavioral inhibition (BI), has been extensively associated with social withdrawal in childhood and the later emergence of anxiety disorders, especially social anxiety disorder (SAD). Recent studies have characterized a distinct type of fearful temperament marked by high levels of fear in low threat situations - labeled dysregulated fear. Dysregulated fear has been related to SAD over and above risks associated with BI. However, the mechanism by which dysregulated fear is related to SAD has not been studied. Cognitive mechanisms, such as attentional bias towards threat, may be a possible conduit. We examined differences in attentional bias towards threat in six-year-olds who displayed a pattern of dysregulated fear at age two (N = 23) compared with children who did not display dysregulated fear (N = 33). Moreover, we examined the concurrent relation between attentional bias and social withdrawal. Results indicated that children characterized by dysregulated fear showed a significant bias away from threat, and that this bias was significantly different from the children without dysregulated fear, who showed no significant bias. Moreover, attentional bias towards threat was positively related to social withdrawal only for the dysregulated fear group. These results are discussed in consideration of the existing knowledge of attentional bias to threat in the developmental and pediatric anxiety literatures, as well as recent studies that find important heterogeneity in attentional bias.

  19. The Dysregulation Profile in middle childhood and adolescence across reporters: factor structure, measurement invariance, and links with self-harm and suicidal ideation

    NARCIS (Netherlands)

    M.H.F. Deutz (Marike); S.B. Geeraert (Sanne Barbara); A.L. Van Baar (Anneloes); M. Deković (Maja); P.J. Prinzie (Peter)

    2016-01-01

    textabstractRecently, a phenotype of severe dysregulation, the Dysregulation Profile (DP), has been identified. DP consists of elevated scores on the Anxious/Depressed (AD), Aggressive Behavior (AGG) and Attention Problems (AP) scales of the Child Behavior Checklist (CBCL), Teacher Report Form

  20. The Dysregulation Profile in middle childhood and adolescence across reporters: factor structure, measurement invariance, and links with self-harm and suicidal ideation

    NARCIS (Netherlands)

    Deutz, Marike; Geeraerts, Sanne; van Baar, Anneloes; Dekovic, Maja; Prinzie, Peter

    2016-01-01

    Recently, a phenotype of severe dysregulation, the Dysregulation Profile (DP), has been identified. DP consists of elevated scores on the Anxious/Depressed (AD), Aggressive Behavior (AGG) and Attention Problems (AP) scales of the Child Behavior Checklist (CBCL), Teacher Report Form (TRF), or Youth

  1. The role of central noradrenergic dysregulation in anxiety disorders: evidence from clinical studies.

    Science.gov (United States)

    Kalk, N J; Nutt, D J; Lingford-Hughes, A R

    2011-01-01

    The nature of the noradrenergic dysregulation in clinical anxiety disorders remains unclear. In panic disorder, the predominant view has been that central noradrenergic neuronal networks and/or the sympathetic nervous system was normal in patients at rest, but hyper-reactive to specific stimuli, for example carbon dioxide. These ideas have been extended to other anxiety disorders, which share with panic disorder characteristic subjective anxiety and physiological symptoms of excess sympathetic activity. For example, Generalized Anxiety Disorder is characterized by chronic free-floating anxiety, muscle tension, palpitation and insomnia. It has been proposed that there is chronic central hypersecretion of noradrenaline in Generalized Anxiety Disorder, with consequent hyporesponsiveness of central post-synaptic receptors. With regards to other disorders, it has been suggested that there is noradrenergic involvement or derangement, but a more specific hypothesis has not been enunciated. This paper reviews the evidence for noradrenergic dysfunction in anxiety disorders, derived from indirect measures of noradrenergic function in clinical populations.

  2. An Emerging Role for Long Non-Coding RNA Dysregulation in Neurological Disorders

    Directory of Open Access Journals (Sweden)

    Elio Scarpini

    2013-10-01

    Full Text Available A novel class of transcripts, long non coding RNAs (lncRNAs, has recently emerged as key players in several biological processes, including dosage compensation, genomic imprinting, chromatin regulation, embryonic development and segmentation, stem cell pluripotency, cell fate determination and potentially many other biological processes, which still are to be elucidated. LncRNAs are pervasively transcribed in the genome and several lines of evidence correlate dysregulation of different lncRNAs to human diseases including neurological disorders. Although their mechanisms of action are yet to be fully elucidated, evidence suggests lncRNA contributions to the pathogenesis of a number of diseases. In this review, the current state of knowledge linking lncRNAs to different neurological disorders is discussed and potential future directions are considered.

  3. An Emerging Role for Long Non-Coding RNA Dysregulation in Neurological Disorders

    Science.gov (United States)

    Fenoglio, Chiara; Ridolfi, Elisa; Galimberti, Daniela; Scarpini, Elio

    2013-01-01

    A novel class of transcripts, long non coding RNAs (lncRNAs), has recently emerged as key players in several biological processes, including dosage compensation, genomic imprinting, chromatin regulation, embryonic development and segmentation, stem cell pluripotency, cell fate determination and potentially many other biological processes, which still are to be elucidated. LncRNAs are pervasively transcribed in the genome and several lines of evidence correlate dysregulation of different lncRNAs to human diseases including neurological disorders. Although their mechanisms of action are yet to be fully elucidated, evidence suggests lncRNA contributions to the pathogenesis of a number of diseases. In this review, the current state of knowledge linking lncRNAs to different neurological disorders is discussed and potential future directions are considered. PMID:24129177

  4. Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation

    Science.gov (United States)

    Chang, Hsiang-Yu; Hou, Shin-Chen; Way, Tzong-Der; Wong, Chi-Huey; Wang, I.-Fan

    2013-11-01

    Conformational disorders are involved in various neurodegenerative diseases. Reactive oxygen species (ROS) are the major contributors to neurodegenerative disease; however, ROS that affect the structural changes in misfolded disease proteins have yet to be well characterized. Here we demonstrate that the intrinsic propensity of TDP-43 to aggregate drives the assembly of TDP-43-positive stress granules and soluble toxic TDP-43 oligomers in response to a ROS insult via a disulfide crosslinking-independent mechanism. Notably, ROS-induced TDP-43 protein assembly correlates with the dynamics of certain TDP-43-associated chaperones. The heat-shock protein (HSP)-90 inhibitor 17-AAG prevents ROS-induced TDP-43 aggregation, alters the type of TDP-43 multimers and reduces the severity of pathological TDP-43 inclusions. In summary, our study suggests that a common mechanism could be involved in the pathogenesis of conformational diseases that result from HSP dysregulation.

  5. Successful treatment of dopamine dysregulation syndrome with dopamine D2 partial agonist antipsychotic drug

    Directory of Open Access Journals (Sweden)

    Mizushima Jin

    2012-07-01

    Full Text Available Abstract Dopamine dysregulation syndrome (DDS consists of a series of complications such as compulsive use of dopaminergic medications, aggressive or hypomanic behaviors during excessive use, and withdrawal states characterized by dysphoria and anxiety, caused by long-term dopaminergic treatment in patients with Parkinson’s disease (PD. Although several ways to manage DDS have been suggested, there has been no established treatment that can manage DDS without deterioration of motor symptoms. In this article, we present a case of PD in whom the administration of the dopamine D2 partial agonistic antipsychotic drug aripiprazole improved DDS symptoms such as craving and compulsive behavior without worsening of motor symptoms. Considering the profile of this drug as a partial agonist at D2 receptors, it is possible that it exerts its therapeutic effect on DDS by modulating the dysfunctional dopamine system.

  6. The Einstein Center for Epigenomics: studying the role of epigenomic dysregulation in human disease.

    Science.gov (United States)

    McLellan, Andrew S; Dubin, Robert A; Jing, Qiang; Maqbool, Shahina B; Olea, Raul; Westby, Gael; Broin, Pilib Ó; Fazzari, Melissa J; Zheng, Deyou; Suzuki, Masako; Greally, John M

    2009-10-01

    There is increasing interest in the role of epigenetic and transcriptional dysregulation in the pathogenesis of a range of human diseases, not just in the best-studied example of cancer. It is, however, quite difficult for an individual investigator to perform these studies, as they involve genome-wide molecular assays combined with sophisticated computational analytical approaches of very large datasets that may be generated from various resources and technologies. In 2008, the Albert Einstein College of Medicine in New York, USA established a Center for Epigenomics to facilitate the research programs of its investigators, providing shared resources for genome-wide assays and for data analysis. As a result, several avenues of research are now expanding, with cancer epigenomics being complemented by studies of the epigenomics of infectious disease and a neuroepigenomics program.

  7. Genetic Association of Major Depression With Atypical Features and Obesity-Related Immunometabolic Dysregulations

    DEFF Research Database (Denmark)

    Milaneschi, Yuri; Lamers, Femke; Peyrot, Wouter J

    2017-01-01

    Importance: The association between major depressive disorder (MDD) and obesity may stem from shared immunometabolic mechanisms particularly evident in MDD with atypical features, characterized by increased appetite and/or weight (A/W) during an active episode. Objective: To determine whether...... subgroups of patients with MDD stratified according to the A/W criterion had a different degree of genetic overlap with obesity-related traits (body mass index [BMI] and levels of C-reactive protein [CRP] and leptin). Design, Setting, and Patients: This multicenter study assembled genome-wide genotypic...... between atypical depressive symptoms and obesity-related traits may arise from shared pathophysiologic mechanisms in patients with MDD. Development of treatments effectively targeting immunometabolic dysregulations may benefit patients with depression and obesity, both syndromes with important disability....

  8. Polyvagal Theory and developmental psychopathology: emotion dysregulation and conduct problems from preschool to adolescence.

    Science.gov (United States)

    Beauchaine, Theodore P; Gatzke-Kopp, Lisa; Mead, Hilary K

    2007-02-01

    In science, theories lend coherence to vast amounts of descriptive information. However, current diagnostic approaches in psychopathology are primarily atheoretical, emphasizing description over etiological mechanisms. We describe the importance of Polyvagal Theory toward understanding the etiology of emotion dysregulation, a hallmark of psychopathology. When combined with theories of social reinforcement and motivation, Polyvagal Theory specifies etiological mechanisms through which distinct patterns of psychopathology emerge. In this paper, we summarize three studies evaluating autonomic nervous system functioning in children with conduct problems, ages 4-18. At all age ranges, these children exhibit attenuated sympathetic nervous system responses to reward, suggesting deficiencies in approach motivation. By middle school, this reward insensitivity is met with inadequate vagal modulation of cardiac output, suggesting additional deficiencies in emotion regulation. We propose a biosocial developmental model of conduct problems in which inherited impulsivity is amplified through social reinforcement of emotional lability. Implications for early intervention are discussed.

  9. Narrative representations of caregivers and emotion dysregulation as predictors of maltreated children's rejection by peers.

    Science.gov (United States)

    Shields, A; Ryan, R M; Cicchetti, D

    2001-05-01

    This study examined whether maltreated children were more likely than nonmaltreated children to develop poor-quality representations of caregivers and whether these representations predicted children's rejection by peers. A narrative task assessing representations of mothers and fathers was administered to 76 maltreated and 45 nonmaltreated boys and girls (8-12 years old). Maltreated children's representations were more negative/constricted and less positive/coherent than those of nonmaltreated children. Maladaptive representations were associated with emotion dysregulation, aggression, and peer rejection, whereas positive/coherent representations were related to prosocial behavior and peer preference. Representations mediated maltreatment's effects on peer rejection in part by undermining emotion regulation. Findings suggest that representations of caregivers serve an important regulatory function in the peer relationships of at-risk children.

  10. Pancreatic Islet Protein Complexes and Their Dysregulation in Type 2 Diabetes

    DEFF Research Database (Denmark)

    Pedersen, Helle Krogh; Gudmundsdottir, Valborg; Brunak, Søren

    2017-01-01

    Type 2 diabetes (T2D) is a complex disease that involves multiple genes. Numerous risk loci have already been associated with T2D, although many susceptibility genes remain to be identified given heritability estimates. Systems biology approaches hold potential for discovering novel T2D genes...... by considering their biological context, such as tissue-specific protein interaction partners. Pancreatic islets are a key T2D tissue and many of the known genetic risk variants lead to impaired islet function, hence a better understanding of the islet-specific dysregulation in the disease-state is essential...... to unveil the full potential of person-specific profiles. Here we identify 3,692 overlapping pancreatic islet protein complexes (containing 10,805 genes) by integrating islet gene and protein expression data with protein interactions. We found 24 of these complexes to be significantly enriched for genes...

  11. Dysregulation of Cell Death and Its Epigenetic Mechanisms in Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Haijing Wu

    2016-12-01

    Full Text Available Systemic lupus erythematosus (SLE is a systemic autoimmune disease involving multiple organs and tissues, which is characterized by the presence of excessive anti-nuclear autoantibodies. The pathogenesis of SLE has been intensively studied but remains far from clear. Increasing evidence has shown that the genetic susceptibilities and environmental factors-induced abnormalities in immune cells, dysregulation of apoptosis, and defects in the clearance of apoptotic materials contribute to the development of SLE. As the main source of auto-antigens, aberrant cell death may play a critical role in the pathogenesis of SLE. In this review, we summarize up-to-date research progress on different levels of cell death—including increasing rate of apoptosis, necrosis, autophagy and defects in clearance of dying cells—and discuss the possible underlying mechanisms, especially epigenetic modifications, which may provide new insight in the potential development of therapeutic strategies for SLE.

  12. Polyvagal Theory and Developmental Psychopathology: Emotion Dysregulation and Conduct Problems from Preschool to Adolescence

    Science.gov (United States)

    Beauchaine, Theodore P.; Gatzke-Kopp, Lisa; Mead, Hilary K.

    2007-01-01

    In science, theories lend coherence to vast amounts of descriptive information. However, current diagnostic approaches in psychopathology are primarily atheoretical, emphasizing description over etiological mechanisms. We describe the importance of Polyvagal Theory toward understanding the etiology of emotion dysregulation, a hallmark of psychopathology. When combined with theories of social reinforcement and motivation, Polyvagal Theory specifies etiological mechanisms through which distinct patterns of psychopathology emerge. In this paper, we summarize three studies evaluating autonomic nervous system functioning in children with conduct problems, ages 4-18. At all age ranges, these children exhibit attenuated sympathetic nervous system responses to reward, suggesting deficiencies in approach motivation. By middle school, this reward insensitivity is met with inadequate vagal modulation of cardiac output, suggesting additional deficiencies in emotion regulation. We propose a biosocial developmental model of conduct problems in which inherited impulsivity is amplified through social reinforcement of emotional lability. Implications for early intervention are discussed. PMID:17045726

  13. Interactions of the gasotransmitters contribute to microvascular tone (dysregulation in the preterm neonate.

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    Rebecca M Dyson

    Full Text Available Hydrogen sulphide (H2S, nitric oxide (NO, and carbon monoxide (CO are involved in transitional microvascular tone dysregulation in the preterm infant; however there is conflicting evidence on the interaction of these gasotransmitters, and their overall contribution to the microcirculation in newborns is not known. The aim of this study was to measure the levels of all 3 gasotransmitters, characterise their interrelationships and elucidate their combined effects on microvascular blood flow.90 preterm neonates were studied at 24h postnatal age. Microvascular studies were performed by laser Doppler. Arterial COHb levels (a measure of CO were determined through co-oximetry. NO was measured as nitrate and nitrite in urine. H2S was measured as thiosulphate by liquid chromatography. Relationships between levels of the gasotransmitters and microvascular blood flow were assessed through partial correlation controlling for the influence of gestational age. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow and derive a theoretical model of their interactions.No relationship was observed between NO and CO (p = 0.18, r = 0.18. A positive relationship between NO and H2S (p = 0.008, r = 0.28 and an inverse relationship between CO and H2S (p = 0.01, r = -0.33 exists. Structural equation modelling was used to examine the combination of these effects on microvascular blood flow. The model with the best fit is presented.The relationships between NO and H2S, and CO and H2S may be of importance in the preterm newborn, particularly as NO levels in males are associated with higher H2S levels and higher microvascular blood flow and CO in females appears to convey protection against vascular dysregulation. Here we present a theoretical model of these interactions and their overall effects on microvascular flow in the preterm newborn, upon which future mechanistic studies may be based.

  14. Sleep and Physiological Dysregulation: A Closer Look at Sleep Intraindividual Variability.

    Science.gov (United States)

    Bei, Bei; Seeman, Teresa E; Carroll, Judith E; Wiley, Joshua F

    2017-09-01

    Variable daily sleep (ie, higher intraindividual variability; IIV) is associated with negative health consequences, but potential physiological mechanisms are poorly understood. This study examined how the IIV of sleep timing, duration, and quality is associated with physiological dysregulation, with diurnal cortisol trajectories as a proximal outcome and allostatic load (AL) as a multisystem distal outcome. Participants are 436 adults (Mage ± standard deviation = 54.1 ± 11.7, 60.3% women) from the Midlife in the United States study. Sleep was objectively assessed using 7-day actigraphy. Diurnal cortisol was measured via saliva samples (four/day for 4 consecutive days). AL was measured using 23 biomarkers from seven systems (inflammatory, hypothalamic-pituitary-adrenal axis, metabolic glucose and lipid, cardiovascular, parasympathetic, sympathetic) using a validated bifactor model. Linear and quadratic effects of sleep IIV were estimated using a validated Bayesian model. Controlling for covariates, more variable sleep timing (p = .04 for risetime, p = .097 for bedtime) and total sleep time (TST; p = .02), but not mean sleep variables, were associated with flatter cortisol diurnal slope. More variable sleep onset latency and wake after sleep onset, later average bedtime, and shorter TST were associated with higher AL adjusting for age and sex (p-values sleep patterns were associated with blunted diurnal cortisol trajectories but not with higher multisystem physiological dysregulation. The associations between sleep IIV and overall health are likely complex, including multiple biopsychosocial determinants and require further investigation. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

  15. The Impact of Age-Related Dysregulation of the Angiotensin System on Mitochondrial Redox Balance

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    Ramya eVajapey

    2014-11-01

    Full Text Available Aging is associated with the accumulation of various deleterious changes in cells. According to the free radical and mitochondrial theory of aging, mitochondria initiate most of the deleterious changes in aging and govern life span. The failure of mitochondrial reduction-oxidation (redox homeostasis and the formation of excessive free radicals are tightly linked to dysregulation in the Renin Angiotensin System (RAS. A main rate-controlling step in RAS is renin, an enzyme that hydrolyzes angiotensinogen to generate angiotensin I. Angiotensin I is further converted to Angiotensin II (Ang II by angiotensin-converting enzyme (ACE. Ang II binds with equal affinity to two main angiotensin receptors—type 1 (AT1R and type 2 (AT2R. The binding of Ang II to AT1R activates NADPH oxidase, which leads to increased generation of cytoplasmic reactive oxygen species (ROS. This Ang II-AT1R–NADPH-ROS signal triggers the opening of mitochondrial KATP channels and mitochondrial ROS production in a positive feedback loop. Furthermore, RAS has been implicated in the decrease of many of ROS scavenging enzymes, thereby leading to detrimental levels of free radicals in the cell.AT2R is less understood, but evidence supports an anti-oxidative and mitochondria-protective function for AT2R. The overlap between age related changes in RAS and mitochondria, and the consequences of this overlap on age-related diseases are quite complex. RAS dysregulation has been implicated in many pathological conditions due to its contribution to mitochondrial dysfunction. Decreased age-related, renal and cardiac mitochondrial dysfunction was seen in patients treated with angiotensin receptor blockers. The aim of this review is to: (a report the most recent information elucidating the role of RAS in mitochondrial redox hemostasis and (b discuss the effect of age-related activation of RAS on generation of free radicals.

  16. Dysregulation of chemo-cytokine production in schizophrenic patients versus healthy controls

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    Di Giannantonio Massimo

    2011-01-01

    Full Text Available Abstract Background The exact cause of schizophrenia is not known, although several aetiological theories have been proposed for the disease, including developmental or neurodegenerative processes, neurotransmitter abnormalities, viral infection and immune dysfunction or autoimmune mechanisms. Growing evidence suggests that specific cytokines and chemokines play a role in signalling the brain to produce neurochemical, neuroendocrine, neuroimmune and behavioural changes. A relationship between inflammation and schizophrenia was supported by abnormal cytokines production, abnormal concentrations of cytokines and cytokine receptors in the blood and cerebrospinal fluid in schizophrenia. Since the neuropathology of schizophrenia has recently been reported to be closely associated with microglial activation we aimed to determined whether spontaneous or LPS-induced peripheral blood mononuclear cell chemokines and cytokines production is dysregulated in schizophrenic patients compared to healthy subjects. We enrolled 51 untreated first-episode schizophrenics (SC and 40 healthy subjects (HC and the levels of MCP-1, MIP-1α, IL-8, IL-18, IFN-γ and RANTES were determined by Elisa method in cell-free supernatants of PBMC cultures. Results In the simultaneous quantification we found significantly higher levels of constitutively and LPS-induced MCP-1, MIP-1α, IL-8 and IL-18, and lower RANTES and IFNγ levels released by PBMC of SC patients compared with HC. In ten SC patients receiving therapy with risperidone, olanzapine or clozapine basal and LPS-induced production of RANTES and IL-18 was increased, while both basal and LPS-induced MCP-1 production was decreased. No statistically significant differences were detected in serum levels after therapy. Conclusion The observation that in schizophrenic patients the PBMC production of selected chemo-cytokines is dysregulated reinforces the hypothesis that the peripheral cyto-chemokine network is involved in the

  17. How dysregulated colonic crypt dynamics cause stem cell overpopulation and initiate colon cancer.

    Science.gov (United States)

    Boman, Bruce M; Fields, Jeremy Z; Cavanaugh, Kenneth L; Guetter, Arthur; Runquist, Olaf A

    2008-05-01

    Based on investigation of the earliest colonic tissue alteration in familial adenomatous polyposis (FAP) patients, we present the hypothesis that initiation of colorectal cancer by adenomatous polyposis coli (APC) mutation is mediated by dysregulation of two cellular mechanisms. One involves differentiation, which normally decreases the proportion (proliferative fraction) of colonic crypt cells that can proliferate; the other is a cell cycle mechanism that simultaneously increases the probability that proliferative cells are in S phase. In normal crypts, stem cells (SC) at the crypt bottom generate rapidly proliferating cells, which undergo differentiation while migrating up the crypt. Our modeling of normal crypts suggests that these transitions are mediated by mechanisms that regulate proliferative fraction and S-phase probability. In FAP crypts, the population of rapidly proliferating cells is shifted upwards, as indicated by the labeling index (LI; i.e., crypt distribution of cells in S phase). Our analysis of FAP indicates that these transitions are delayed because the proliferative fraction and S-phase probability change more slowly as a function of crypt level. This leads to expansion of the proliferative cell population, including a subpopulation that has a low frequency of S-phase cells. We previously reported that crypt SC overpopulation explains the LI shift. Here, we determine that SCs (or cells having high stemness) are proliferative cells with a low probability of being in S phase. Thus, dysregulation of mechanisms that control proliferative fraction and S-phase probability explains how APC mutations induce SC overpopulation at the crypt bottom, shift the rapidly proliferating cell population upwards, and initiate colon tumorigenesis.

  18. Cocaine withdrawal causes delayed dysregulation of stress genes in the hippocampus.

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    M Julia García-Fuster

    Full Text Available Relapse, even following an extended period of withdrawal, is a major challenge in substance abuse management. Delayed neurobiological effects of the drug during prolonged withdrawal likely contribute to sustained vulnerability to relapse. Stress is a major trigger of relapse, and the hippocampus regulates the magnitude and duration of stress responses. Recent work has implicated hippocampal plasticity in various aspects of substance abuse. We asked whether changes in stress regulatory mechanisms in the hippocampus may participate in the neuroadaptations that occur during prolonged withdrawal. We therefore examined changes in the rat stress system during the course of withdrawal from extended daily access (5-hours of cocaine self-administration, an animal model of addiction. Tissue was collected at 1, 14 and 28 days of withdrawal. Plasma corticosterone levels were determined and corticosteroid receptors (GR, MR, MR/GR mRNA ratios and expression of other stress-related molecules (HSP90AA1 and HSP90AB1 mRNA were measured in hippocampal subfields using in situ hybridization. Results showed a delayed emergence of dysregulation of stress genes in the posterior hippocampus following 28 days of cocaine withdrawal. This included increased GR mRNA in DG and CA3, increased MR and HSP90AA1 mRNA in DG, and decreased MR/GR mRNA ratio in DG and CA1. Corticosterone levels progressively decreased during the course of withdrawal, were normalized following 28 days of withdrawal, and were correlated negatively with GR and positively with MR/GR mRNA ratio in DG. These results suggest a role for the posterior hippocampus in the neuroadaptations that occur during prolonged withdrawal, and point to a signaling partner of GR, HSP90AA1, as a novel dysregulated target during cocaine withdrawal. These delayed neurobiological effects of extended cocaine exposure likely contribute to sustained vulnerability to relapse.

  19. Specific mixing facilitates the comparative quantification of phosphorylation sites with significant dysregulations

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Jing [Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R& A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Xu, Bo [Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R& A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023 (China); Liu, Zheyi; Dong, Mingming; Mao, Jiawei; Zhou, Ye; Chen, Jin [Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R& A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023 (China); University of Chinese Academy of Sciences, Beijing 100049 (China); Wang, Fangjun, E-mail: wangfj@dicp.ac.cn [Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R& A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023 (China); Zou, Hanfa [Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R& A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian 116023 (China)

    2017-01-15

    Mass spectrometry (MS) based quantitative analyses of proteome and proteome post-translational modifications (PTMs) play more and more important roles in biological, pharmaceutical and clinical studies. However, it is still a big challenge to accurately quantify the proteins or proteins PTM sites with extreme relative abundances in comparative protein samples, such as the significantly dysregulated ones. Herein, a novel quantification strategy, Mixing at Specific Ratio (MaSR) before isotope labeling, had been developed to improve the quantification accuracy and coverage of extreme proteins and protein phosphorylation sites. Briefly, the comparative protein samples were firstly mixed together at specific ratios of 9:1 and 1:9 (w/w), followed with mass differentiate light and heavy isotope labeling, respectively. The extreme proteins and protein phosphorylation sites, even if the newly expressed or disappeared ones, could be accurately quantified due to all of the proteins' relative abundances had been adjusted to 2 orders of magnitude (1/9-9) by this strategy. The number of quantified phosphorylation sites with more than 20 folds changes was improved about 10 times in comparative quantification of pervanadate stimulated phosphoproteome of HeLa cells, and 134 newly generated and 21 disappeared phosphorylation sites were solely quantified by the MaSR strategy. The significantly up-regulated phosphorylation sites were mainly involved in the key phosphoproteins regulating the insulin-related pathways, such as PI3K-AKT and RAS-MAPK pathways. Therefore, the MaSR strategy exhibits as a promising way in elucidating the biological processes with significant dysregulations. - Highlights: • All the proteins' relative abundances were adjusted into 2 orders of magnitude (1/9-9). • The quantification accuracy and coverage of extreme proteins and protein phosphorylation sites had been improved. • The newly expressed or disappeared proteins and protein

  20. Peripheral effects of FAAH deficiency on fuel and energy homeostasis: role of dysregulated lysine acetylation.

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    Bhavapriya Vaitheesvaran

    Full Text Available FAAH (fatty acid amide hydrolase, primarily expressed in the liver, hydrolyzes the endocannabinoids fatty acid ethanolamides (FAA. Human FAAH gene mutations are associated with increased body weight and obesity. In our present study, using targeted metabolite and lipid profiling, and new global acetylome profiling methodologies, we examined the role of the liver on fuel and energy homeostasis in whole body FAAH(-/- mice.FAAH(-/- mice exhibit altered energy homeostasis demonstrated by decreased oxygen consumption (Indirect calorimetry. FAAH(-/- mice are hyperinsulinemic and have adipose, skeletal and hepatic insulin resistance as indicated by stable isotope phenotyping (SIPHEN. Fed state skeletal muscle and liver triglyceride levels was increased 2-3 fold, while glycogen was decreased 42% and 57% respectively. Hepatic cholesterol synthesis was decreased 22% in FAAH(-/- mice. Dysregulated hepatic FAAH(-/- lysine acetylation was consistent with their metabolite profiling. Fasted to fed increases in hepatic FAAH(-/- acetyl-CoA (85%, p<0.01 corresponded to similar increases in citrate levels (45%. Altered FAAH(-/- mitochondrial malate dehydrogenase (MDH2 acetylation, which can affect the malate aspartate shuttle, was consistent with our observation of a 25% decrease in fed malate and aspartate levels. Decreased fasted but not fed dihydroxyacetone-P and glycerol-3-P levels in FAAH(-/- mice was consistent with a compensating contribution from decreased acetylation of fed FAAH(-/- aldolase B. Fed FAAH(-/- alcohol dehydrogenase (ADH acetylation was also decreased.Whole body FAAH deletion contributes to a pre-diabetic phenotype by mechanisms resulting in impairment of hepatic glucose and lipid metabolism. FAAH(-/- mice had altered hepatic lysine acetylation, the pattern sharing similarities with acetylation changes reported with chronic alcohol treatment. Dysregulated hepatic lysine acetylation seen with impaired FAA hydrolysis could support the liver

  1. Evidence for widespread dysregulation of circadian clock progression in human cancer

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    Jarrod Shilts

    2018-01-01

    Full Text Available The ubiquitous daily rhythms in mammalian physiology are guided by progression of the circadian clock. In mice, systemic disruption of the clock can promote tumor growth. In vitro, multiple oncogenes can disrupt the clock. However, due to the difficulties of studying circadian rhythms in solid tissues in humans, whether the clock is disrupted within human tumors has remained unknown. We sought to determine the state of the circadian clock in human cancer using publicly available transcriptome data. We developed a method, called the clock correlation distance (CCD, to infer circadian clock progression in a group of samples based on the co-expression of 12 clock genes. Our method can be applied to modestly sized datasets in which samples are not labeled with time of day and coverage of the circadian cycle is incomplete. We used the method to define a signature of clock gene co-expression in healthy mouse organs, then validated the signature in healthy human tissues. By then comparing human tumor and non-tumor samples from twenty datasets of a range of cancer types, we discovered that clock gene co-expression in tumors is consistently perturbed. Subsequent analysis of data from clock gene knockouts in mice suggested that perturbed clock gene co-expression in human cancer is not caused solely by the inactivation of clock genes. Furthermore, focusing on lung cancer, we found that human lung tumors showed systematic changes in expression in a large set of genes previously inferred to be rhythmic in healthy lung. Our findings suggest that clock progression is dysregulated in many solid human cancers and that this dysregulation could have broad effects on circadian physiology within tumors. In addition, our approach opens the door to using publicly available data to infer circadian clock progression in a multitude of human phenotypes.

  2. Autoimmune dysregulation and purine metabolism in adenosine deaminase (ADA-deficiency

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    Aisha Vanessa Sauer

    2012-08-01

    Full Text Available Genetic defects in the adenosine deaminase (ADA gene are among the most common causes for severe combined immunodeficiency (SCID. ADA-SCID patients suffer from lymphopenia, severely impaired cellular and humoral immunity, failure to thrive and recurrent infections. Currently available therapeutic options for this otherwise fatal disorder include bone marrow transplantation (BMT, enzyme replacement therapy with bovine ADA (PEG-ADA or hematopoietic stem cell gene therapy (HSC-GT. Although varying degrees of immune reconstitution can be achieved by these treatments, breakdown of tolerance is a major concern in ADA-SCID. Immune dysregulation such as autoimmune hypothyroidism, diabetes mellitus, hemolytic anemia, and immune thrombocytopenia are frequently observed in milder forms of the disease. However, several reports document similar complications also in patients on long-term PEG-ADA and after BMT or GT treatment.A skewed repertoire and decreased immune functions have been implicated in autoimmunity observed in certain B-cell and/or T-cell immunodeficiencies, but it remains unclear to what extent specific mechanisms of tolerance are affected in ADA deficiency. Herein we provide an overview about ADA-SCID and the autoimmune manifestations reported in these patients before and after treatment. We also assess the value of the ADA-deficient mouse model as a useful tool to study both immune and metabolic disease mechanisms. With focus on regulatory T and B cells we discuss the lymphocyte subpopulations particularly prone to contribute to the loss of self-tolerance and onset of autoimmunity in ADA deficiency. Moreover we address which aspects of immune dysregulation are specifically related to alterations in purine metabolism caused by the lack of ADA and the subsequent accumulation of metabolites with immunomodulatory properties.

  3. FGF-23 dysregulates calcium homeostasis and electrophysiological properties in HL-1 atrial cells.

    Science.gov (United States)

    Kao, Yu-Hsun; Chen, Yao-Chang; Lin, Yung-Kuo; Shiu, Rong-Jie; Chao, Tze-Fan; Chen, Shih-Ann; Chen, Yi-Jen

    2014-08-01

    Fibroblast growth factor (FGF)-23 is a key regulator of phosphate homeostasis. Higher FGF-23 levels are correlated with poor outcomes in cardiovascular diseases. FGF-23 can produce cardiac hypertrophy and increase intracellular calcium, which can change cardiac electrical activity. However, it is not clear whether FGF-23 possesses arrhythmogenic potential through calcium dysregulation. Therefore, the purposes of this study were to evaluate the electrophysiological effects of FGF-23 and identify the underlying mechanisms. Patch clamp, confocal microscope with Fluo-4 fluorescence, and Western blot analyses were used to evaluate the electrophysiological characteristics, calcium homeostasis and calcium regulatory proteins in HL-1 atrial myocytes with and without FGF-23 (10 and 25 ng/mL) incubation for 24 h. FGF-23 (25 ng/mL) increased L-type calcium currents, calcium transient and sarcoplasmic reticulum Ca(2+) contents in HL-1 cells. FGF-23 (25 ng/mL)-treated cells (n = 14) had greater incidences (57%, 17% and 15%, P calcium/calmodulin-dependent protein kinase IIδ and phospholamban (PLB) at threonine 17 but had similar phosphorylation extents of PLB at serine 16, total PLB and sarcoplasmic reticulum Ca(2+) -ATPase protein. Moreover, the FGF receptor inhibitor (PD173074, 10 nM), calmodulin inhibitor (W7, 5 μM) and phospholipase C inhibitor (U73122, 1 μM) attenuated the effects of FGF-23 on calcium/calmodulin-dependent protein kinase II phosphorylation. FGF-23 increases HL-1 cells arrhythmogenesis with calcium dysregulation through modulating calcium-handling proteins. © 2014 Stichting European Society for Clinical Investigation Journal Foundation.

  4. From the Bottom-Up: Chemotherapy and Gut-Brain Axis Dysregulation.

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    Bajic, Juliana E; Johnston, Ian N; Howarth, Gordon S; Hutchinson, Mark R

    2018-01-01

    The central nervous system and gastrointestinal tract form the primary targets of chemotherapy-induced toxicities. Symptoms associated with damage to these regions have been clinically termed chemotherapy-induced cognitive impairment and mucositis. Whilst extensive literature outlines the complex etiology of each pathology, to date neither chemotherapy-induced side-effect has considered the potential impact of one on the pathogenesis of the other disorder. This is surprising considering the close bidirectional relationship shared between each organ; the gut-brain axis. There are complex multiple pathways linking the gut to the brain and vice versa in both normal physiological function and disease. For instance, psychological and social factors influence motility and digestive function, symptom perception, and behaviors associated with illness and pathological outcomes. On the other hand, visceral pain affects central nociception pathways, mood and behavior. Recent interest highlights the influence of functional gut disorders, such as inflammatory bowel diseases and irritable bowel syndrome in the development of central comorbidities. Gut-brain axis dysfunction and microbiota dysbiosis have served as key portals in understanding the potential mechanisms associated with these functional gut disorders and their effects on cognition. In this review we will present the role gut-brain axis dysregulation plays in the chemotherapy setting, highlighting peripheral-to-central immune signaling mechanisms and their contribution to neuroimmunological changes associated with chemotherapy exposure. Here, we hypothesize that dysregulation of the gut-brain axis plays a major role in the intestinal, psychological and neurological complications following chemotherapy. We pay particular attention to evidence surrounding microbiota dysbiosis, the role of intestinal permeability, damage to nerves of the enteric and peripheral nervous systems and vagal and humoral mediated changes.

  5. Exposure to Violence, Posttraumatic Stress Symptoms, and Borderline Personality Pathology Among Adolescents in Residential Psychiatric Treatment: The Influence of Emotion Dysregulation.

    Science.gov (United States)

    Buckholdt, Kelly E; Weiss, Nicole H; Young, John; Gratz, Kim L

    2015-12-01

    Exposure to violence during adolescence is a highly prevalent phenomenon associated with a range of deleterious outcomes. Theoretical literature suggests that emotion dysregulation is one consequence of exposure to violence associated with the manifestation of posttraumatic stress symptoms (PTSS) and borderline personality (BP) pathology. Thus, the goal of the present study was to examine the mediating role of emotion dysregulation in the relation between exposure to violence and both PTSS and BP pathology in a sample of 144 adolescents (age 10- to 17-years; 51% male; 55% African American) admitted to a psychiatric residential treatment center. Exposure to violence was associated with greater emotion dysregulation, which, in turn, was associated with greater PTSS and BP pathology. Furthermore, emotion dysregulation mediated the associations between exposure to violence and both PTSS and BP pathology. Findings suggest the importance of assessing and treating emotion dysregulation among violence-exposed adolescents in psychiatric residential treatment.

  6. Emotion dysregulation mediates the relationship between trauma exposure, post-migration living difficulties and psychological outcomes in traumatized refugees.

    Science.gov (United States)

    Nickerson, Angela; Bryant, Richard A; Schnyder, Ulrich; Schick, Matthis; Mueller, Julia; Morina, Naser

    2015-03-01

    While emotion dysregulation represents an important mechanism underpinning psychological responses to trauma, little research has investigated this in refugees. In the current study, we examined the mediating role of emotion dysregulation in the relationship between refugee experiences (trauma and living difficulties) and psychological outcomes. Participants were 134 traumatized treatment-seeking refugees who completed measures indexing trauma exposure, post-migration living difficulties, difficulties in emotion regulation, posttraumatic stress disorder, depression, and explosive anger. Findings revealed distinctive patterns of emotion dysregulation associated with each of these psychological disorders. Results also indicated that emotion regulation difficulties mediated the association between both trauma and psychological symptoms, and living difficulties and psychological symptoms. Limitations include a cross-sectional design and the use of measures that had not been validated across all cultural groups in this study. These findings underscore the key role of emotion dysregulation in psychological responses of refugees, and highlight potential directions for treatment interventions for traumatized refugees. Copyright © 2014 Elsevier B.V. All rights reserved.

  7. A novel dysregulated pathway-identification analysis based on global influence of within-pathway effects and crosstalk between pathways

    Science.gov (United States)

    Han, Junwei; Li, Chunquan; Yang, Haixiu; Xu, Yanjun; Zhang, Chunlong; Ma, Jiquan; Shi, Xinrui; Liu, Wei; Shang, Desi; Yao, Qianlan; Zhang, Yunpeng; Su, Fei; Feng, Li; Li, Xia

    2015-01-01

    Identifying dysregulated pathways from high-throughput experimental data in order to infer underlying biological insights is an important task. Current pathway-identification methods focus on single pathways in isolation; however, consideration of crosstalk between pathways could improve our understanding of alterations in biological states. We propose a novel method of pathway analysis based on global influence (PAGI) to identify dysregulated pathways, by considering both within-pathway effects and crosstalk between pathways. We constructed a global gene–gene network based on the relationships among genes extracted from a pathway database. We then evaluated the extent of differential expression for each gene, and mapped them to the global network. The random walk with restart algorithm was used to calculate the extent of genes affected by global influence. Finally, we used cumulative distribution functions to determine the significance values of the dysregulated pathways. We applied the PAGI method to five cancer microarray datasets, and compared our results with gene set enrichment analysis and five other methods. Based on these analyses, we demonstrated that PAGI can effectively identify dysregulated pathways associated with cancer, with strong reproducibility and robustness. We implemented PAGI using the freely available R-based and Web-based tools (http://bioinfo.hrbmu.edu.cn/PAGI). PMID:25551156

  8. Trajectories of depressive symptoms in foster youth transitioning into adulthood: the roles of emotion dysregulation and PTSD.

    Science.gov (United States)

    Valdez, Christine E; Bailey, Brenda E; Santuzzi, Alecia M; Lilly, Michelle M

    2014-01-01

    Foster youth often experience considerable adversity both in and out of foster care, including histories of abuse and/or neglect, and further stressors within the foster system. These adverse experiences often occur at key developmental periods that can compromise emotional functioning and lead to posttraumatic symptomatology, including posttraumatic stress disorder (PTSD) and emotion dysregulation. In the face of difficult histories and ongoing mental health challenges, youth transitioning into adulthood may be particularly vulnerable to increases in depressive symptoms. We explored the trajectory of depressive symptoms in foster youth from age 17 to 19 using a piecewise linear growth model, examining the effects of PTSD and emotion dysregulation on youth's depressive symptoms over time. Results revealed depressive symptoms decreased from age 17 to 18 but increased from 18 to 19. PTSD and emotion dysregulation predicted greater baseline depressive symptoms and decreases in symptoms from age 17 to 18, whereas only PTSD predicted increases in depressive symptoms from 18 to 19. Females reported higher levels of depressive symptoms compared to males. Additionally, emotion dysregulation was a stronger predictor of depressive symptoms for females than males. Implications for service delivery for foster youth transitioning into adulthood are discussed. © The Author(s) 2014.

  9. Soluble CD93 Is Involved in Metabolic Dysregulation but Does Not Influence Carotid Intima-Media Thickness

    NARCIS (Netherlands)

    Strawbridge, Rona J.; Hilding, Agneta; Silveira, Angela; Osterholm, Cecilia; Sennblad, Bengt; McLeod, Olga; Tsikrika, Panagiota; Foroogh, Fariba; Tremoli, Elena; Baldassarre, Damiano; Veglia, Fabrizio; Rauramaa, Rainer; Smit, Andries J.; Giral, Phillipe; Kurl, Sudhir; Mannarino, Elmo; Grossi, Enzo; Syvanen, Ann-Christine; Humphries, Steve E.; de Faire, Ulf; Ostenson, Claes-Goran; Maegdefessel, Lars; Hamsten, Anders; Backlund, Alexandra

    2016-01-01

    Type 2 diabetes and cardiovascular disease are complex disorders involving metabolic and inflammatory mechanisms. Here we investigated whether sCD93, a group XIV c-type lectin of the endosialin family, plays a role in metabolic dysregulation or carotid intima-media thickness (IMT). Although no

  10. Contextual Risk, Maternal Negative Emotionality, and the Negative Emotion Dysregulation of Preschool Children from Economically Disadvantaged Families

    Science.gov (United States)

    Brown, Eleanor D.; Ackerman, Brian P.

    2011-01-01

    Research Findings: This study examined relations between contextual risk, maternal negative emotionality, and preschool teacher reports of the negative emotion dysregulation of children from economically disadvantaged families. Contextual risk was represented by cumulative indexes of family and neighborhood adversity. The results showed a direct…

  11. Moderate voluntary exercise attenuates the metabolic syndrome in melanocortin-4 receptor-deficient rats showing central dopaminergic dysregulation

    Directory of Open Access Journals (Sweden)

    Silvana Obici

    2015-10-01

    Conclusions: Central dopamine dysregulation during VWR reinforces the link between MC4R function and molecular and behavioral responding to rewards. The data also suggest that exercise can be a successful lifestyle intervention in MC4R-haploinsufficient individuals despite reduced positive reinforcement during exercise training.

  12. Dysregulation of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages: An individual participant meta-analysis

    NARCIS (Netherlands)

    Gardner, M.P.; Lightman, S.; Sayer, A.A.; Cooper, C.; Cooper, R.; Deeg, D.J.H.; Ebrahim, S.; Gallacher, J.; Kivimaki, M.; Kumari, M.; Kuh, D; Martin, R.M.; Peeters, G.; Ben-Shlomoa, Y.

    2013-01-01

    The association between functioning of the hypothalamic pituitary adrenal (HPA) axis and physical performance at older ages remains poorly understood. We carried out meta-analyses to test the hypothesis that dysregulation of the HPA axis, as indexed by patterns of diurnal cortisol release, is

  13. Correspondence between Physiological and Self-Report Measures of Emotion Dysregulation: A Longitudinal Investigation of Youth with and without Psychopathology

    Science.gov (United States)

    Vasilev, Christina A.; Crowell, Sheila E.; Beauchaine, Theodore P.; Mead, Hilary K.; Gatzke-Kopp, Lisa M.

    2009-01-01

    Background: Several theoretical perspectives suggest that emotion dysregulation is a predisposing risk factor for many psychiatric disorders. Yet despite a rapidly evolving literature, difficulties with emotion regulation (ER) are often measured inconsistently across studies, with little regard to whether different approaches capture the same…

  14. [Is emotional dysregulation a component of attention-deficit/hyperactivity disorder (ADHD)?].

    Science.gov (United States)

    Villemonteix, T; Purper-Ouakil, D; Romo, L

    2015-04-01

    the ventral striatum. Morphological alterations of the amygdala have also been reported in previous structural studies in children with ADHD. Emotional lability can result from different neurobiological mechanisms. In particular, bottom-up and top-down processes can be opposed. Bottom-up related emotional dysregulation involves an increased emotional reactivity, and is thought to be linked to the automatic evaluative activity of the amygdala. Top-down mechanisms are associated with the regulation of such activity, and rely on a prefrontal network including the lateral prefrontal cortex, the anterior cingulate cortex and the orbitofrontal cortex. Since various neuropsychological impairments and alterations in multiple brain networks have been implicated in the etiology of ADHD, contemporary models emphasize its neuropsychological heterogeneity. It is therefore likely that some but not all children with ADHD will exhibit neurobiological alterations in circuits dedicated to emotional regulation, possibly at different levels. Future research will have to identify the different causal pathways and to decide whether emotional lability represents a criterion to subtype ADHD diagnoses. Emotional dysregulation is now known to play a causal role regarding ADHD symptomatology. Along with executive functioning, reaction time variability and potentially delay aversion, emotional dysregulation should therefore be included in future theoretical models of ADHD, as well as in clinical practice when identifying the major impairments in this diagnostic group and when deciding therapeutic strategies. Copyright © 2014 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

  15. NASA 14 Day Undersea Missions: A Short-Duration Spaceflight Analog for Immune System Dysregulation

    Science.gov (United States)

    Crucian, B. E.; Stowe, R. P.; Mehta, S. K.; Quiriarte, H.; Pierson, D. L.; Sams, C. F.

    2010-01-01

    BACKGROUND Spaceflight-associated immune dysregulation (SAID) occurs during spaceflight and may represent specific clinical risks for exploration-class missions. An appropriate ground analog for spaceflight-associated immune dysregulation would offer a platform for ground-evaluation of various potential countermeasures. This study evaluated the NASA Undersea Mission Operations ( NEEMO ), consisting of 14 day undersea deployment at the Aquarius station, as an analog for SAID. Sixteen Aquanauts from missions NEEMO-12, 13 and 14 participated in the study. RESULTS Mid-mission alterations leukocyte distribution occurred, including granulocytosis and elevations in central-memory CD8+ T-cells. General T cell function was reduced during NEEMO missions in roughly 50% of subjects. Secreted cytokines profiles were evaluated following whole blood stimulation with CD3/CD28 (T cells) or LPS (monocytes). T cell production of IFNg, IL-5, IL-10, IL-2, TNFa and IL-6 were all reduced before and during the mission. Conversely, monocyte production of TNFa, IL-10, IL-6, IL-1b and IL-8 were elevated during mission, moreso at the MD-14 timepoint. Antibodies to Epstein-Barr virus (EBV) viral capsid antigen and early antigen were increased in approximately 40% of the subjects. Changes in EBV tetramer-positive CD8+ T-cells exhibited a variable pattern. Antibodies against Cytomegalovirus (CMV) were marginally increased during the mission. Herpesvirus reactivation was determined by PCR. EBV viral load was generally elevated at L-6. Higher levels of salivary EBV were found during the NEEMO mission than before and after as well as than the healthy controls. No VZV or CMV was found in any pre, during and after NEEMO mission or control samples. Plasma cortisol was elevated at L-6. CONCLUSION Unfortunately, L-6 may be too near to mission start to be an appropriate baseline measurement. The general immune changes in leukocyte distribution, T cell function, cytokine production, virus specific

  16. Weight-related correlates of psychological dysregulation in adolescent and young adult (AYA) females with severe obesity.

    Science.gov (United States)

    Gowey, Marissa A; Reiter-Purtill, Jennifer; Becnel, Jennifer; Peugh, James; Mitchell, James E; Zeller, Meg H

    2016-04-01

    Severe obesity is the fastest growing pediatric subgroup of excess weight levels. Psychological dysregulation (i.e., impairments in regulating cognitive, emotional, and/or behavioral processes) has been associated with obesity and poorer weight loss outcomes. The present study explored associations of dysregulation with weight-related variables among adolescent and young adult (AYA) females with severe obesity. Fifty-four AYA females with severe obesity (MBMI = 48.71 kg/m(2); Mage = 18.29, R = 15-21 years; 59.3% White) completed self-report measures of psychological dysregulation and weight-related constructs including meal patterns, problematic eating behaviors, and body and weight dissatisfaction, as non-surgical comparison participants in a multi-site study of adolescent bariatric surgery outcomes. Pearson and bivariate correlations were conducted and stratified by age group to analyze associations between dysregulation subscales (affective, behavioral, cognitive) and weight-related variables. Breakfast was the most frequently skipped meal (consumed 3-4 times/week). Eating out was common (4-5 times/week) and mostly occurred at fast-food restaurants. Evening hyperphagia (61.11%) and eating in the absence of hunger (37.04%) were commonly endorsed, while unplanned eating (29.63%), a sense of loss of control over eating (22.22%), eating beyond satiety (22.22%), night eating (12.96%), and binge eating (11.11%) were less common. Almost half of the sample endorsed extreme weight dissatisfaction. Dysregulation was associated with most weight-related attitudes and behaviors of interest in young adults but select patterns emerged for adolescents. Higher levels of psychological dysregulation are associated with greater BMI, problematic eating patterns and behaviors, and body dissatisfaction in AYA females with severe obesity. These findings have implications for developing novel intervention strategies for severe obesity in AYAs that may have a multidimensional

  17. MicroRNA function and dysregulation in bone tumors: the evidence to date

    International Nuclear Information System (INIS)

    Nugent, Mary

    2014-01-01

    Micro ribonucleic acids (miRNAs) are small non-coding RNA segments that have a role in the regulation of normal cellular development and proliferation including normal osteogenesis. They exert their effects through inhibition of specific target genes at the post-transcriptional level. Many miRNAs have altered expression levels in cancer (either increased or decreased depending on the specific miRNA). Altered miRNA expression profiles have been identified in several malignancies including primary bone tumors such as osteosarcoma and Ewing’s sarcoma. It is thought that they may function as tumor suppressor genes or oncogenes and hence when dysregulated contribute to the initiation and progression of malignancy. miRNAs are also thought to have a role in the development of bone metastases in other malignancies. In addition, evidence increasingly suggests that miRNAs may play a part in determining the response to chemotherapy in the treatment of osteosarcoma. These molecules are readily detectable in tissues, both fresh and formalin fixed paraffin embedded and, more recently, in blood. Although there are fewer published studies regarding circulating miRNA profiles, they appear to reflect changes in tissue expression. Thus miRNAs may serve as potential indicators of disease presence but more importantly, may have a role in disease characterization or as potential therapeutic targets. This review gives a brief overview of miRNA biochemistry and explores the evidence to date implicating these small molecules in the pathogenesis of bone tumors

  18. Dysregulation of glucose metabolism even in Chinese PCOS women with normal glucose tolerance.

    Science.gov (United States)

    Li, Weiping; Li, Qifu

    2012-01-01

    To clarify the necessity of improving glucose metabolism in polycystic ovary syndrome (PCOS) women as early as possible, 111 PCOS women with normal glucose tolerance and 92 healthy age-matched controls were recruited to investigate glucose levels distribution, insulin sensitivity and β cell function. 91 PCOS women and 33 controls underwent hyperinsulinemic-euglycemic clamp to assess their insulin sensitivity, which was expressed as M value. β cell function was estimated by homeostatic model assessment (HOMA)-β index after adjusting insulin sensitivity (HOMA-βad index). Compared with lean controls, lean PCOS women had similar fasting plasma glucose (FPG), higher postprandial plasma glucose (PPG) (6.03±1.05 vs. 5.44±0.97 mmol/L, PPCOS women had higher levels of both FPG (5.24±0.58 vs. 4.90±0.39, PPCOS women separately, and the cutoff of BMI indicating impaired β cell function of PCOS women was 25.545kg/m². In conclusion, insulin resistance and dysregulation of glucose metabolism were common in Chinese PCOS women with normal glucose tolerance. BMI ≥ 25.545kg/m² indicated impaired β cell function in PCOS women with normal glucose tolerance.

  19. Repeated verum but not placebo acupuncture normalizes connectivity in brain regions dysregulated in chronic pain

    Directory of Open Access Journals (Sweden)

    Natalia Egorova

    2015-01-01

    Full Text Available Acupuncture, an ancient East Asian therapy, is aimed at rectifying the imbalance within the body caused by disease. Studies evaluating the efficacy of acupuncture with neuroimaging tend to concentrate on brain regions within the pain matrix, associated with acute pain. We, however, focused on the effect of repeated acupuncture treatment specifically on brain regions known to support functions dysregulated in chronic pain disorders. Transition to chronic pain is associated with increased attention to pain, emotional rumination, nociceptive memory and avoidance learning, resulting in brain connectivity changes, specifically affecting the periaqueductal gray (PAG, medial frontal cortex (MFC and bilateral hippocampus (Hpc. We demonstrate that the PAG–MFC and PAG–Hpc connectivity in patients with chronic pain due to knee osteoarthritis indeed correlates with clinical severity scores and further show that verum acupuncture-induced improvement in pain scores (compared to sham is related to the modulation of PAG–MFC and PAG–Hpc connectivity in the predicted direction. This study shows that repeated verum acupuncture might act by restoring the balance in the connectivity of the key pain brain regions, altering pain-related attention and memory.

  20. Into the Fourth Dimension: Dysregulation of Genome Architecture in Aging and Alzheimer's Disease.

    Science.gov (United States)

    Winick-Ng, Warren; Rylett, R Jane

    2018-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by synapse dysfunction and cognitive impairment. Understanding the development and progression of AD is challenging, as the disease is highly complex and multifactorial. Both environmental and genetic factors play a role in AD pathogenesis, highlighted by observations of complex DNA modifications at the single gene level, and by new evidence that also implicates changes in genome architecture in AD patients. The four-dimensional structure of chromatin in space and time is essential for context-dependent regulation of gene expression in post-mitotic neurons. Dysregulation of epigenetic processes have been observed in the aging brain and in patients with AD, though there is not yet agreement on the impact of these changes on transcription. New evidence shows that proteins involved in genome organization have altered expression and localization in the AD brain, suggesting that the genomic landscape may play a critical role in the development of AD. This review discusses the role of the chromatin organizers and epigenetic modifiers in post-mitotic cells, the aging brain, and in the development and progression of AD. How these new insights can be used to help determine disease risk and inform treatment strategies will also be discussed.

  1. International differences in the links between obesity and physiological dysregulation: the United States, England, and Taiwan.

    Science.gov (United States)

    Vasunilashorn, Sarinnapha; Kim, Jung Ki; Crimmins, Eileen M

    2013-01-01

    Excess weight has generally been associated with adverse health outcomes; however, the link between overweight and health outcomes may vary with socioeconomic, cultural, and epidemiological conditions. We examine associations of weight with indicators of biological risk in three nationally representative populations: the US National Health and Nutrition Examination Survey, the English Longitudinal Study of Ageing, and the Social Environment and Biomarkers of Aging Study in Taiwan. Indicators of biological risk were compared for obese (defined using body mass index (BMI) and waist circumference) and normal weight individuals aged 54+. Generally, obesity in England was associated with elevated risk for more markers examined; obese Americans also had elevated risks except that they did not have elevated blood pressure (BP). Including waist circumference in our consideration of BMI indicated different links between obesity and waist size across countries; we found higher physiological dysregulation among those with high waist but normal BMI compared to those with normal waist and normal BMI. Americans had the highest levels of biological risk in all weight/waist groups. Cross-country variation in biological risk associated with obesity may reflect differences in health behaviors, lifestyle, medication use, and culture.

  2. International Differences in the Links between Obesity and Physiological Dysregulation: The United States, England, and Taiwan

    Directory of Open Access Journals (Sweden)

    Sarinnapha Vasunilashorn

    2013-01-01

    Full Text Available Excess weight has generally been associated with adverse health outcomes; however, the link between overweight and health outcomes may vary with socioeconomic, cultural, and epidemiological conditions. We examine associations of weight with indicators of biological risk in three nationally representative populations: the US National Health and Nutrition Examination Survey, the English Longitudinal Study of Ageing, and the Social Environment and Biomarkers of Aging Study in Taiwan. Indicators of biological risk were compared for obese (defined using body mass index (BMI and waist circumference and normal weight individuals aged 54+. Generally, obesity in England was associated with elevated risk for more markers examined; obese Americans also had elevated risks except that they did not have elevated blood pressure (BP. Including waist circumference in our consideration of BMI indicated different links between obesity and waist size across countries; we found higher physiological dysregulation among those with high waist but normal BMI compared to those with normal waist and normal BMI. Americans had the highest levels of biological risk in all weight/waist groups. Cross-country variation in biological risk associated with obesity may reflect differences in health behaviors, lifestyle, medication use, and culture.

  3. Dysregulated homeostasis of target tissues or autoantigens - A novel principle in autoimmunity.

    Science.gov (United States)

    Petersen, Frank; Yue, Xiaoyang; Riemekasten, Gabriela; Yu, Xinhua

    2017-06-01

    Monogenic autoimmune disorders provide a powerful tool for our understanding of the principles of autoimmunity due to the obvious impact of a single gene on the disease. So far, approximately 100 single gene defects causing murine monogenic autoimmune disorders have been reported and the functional characterization of these genes will provide significant progress in understanding the nature of autoimmunity. According to their function, genes leading to monogenic autoimmune disorders can be categorized into two groups. An expectable first group contains genes involved in the homeostasis of the immune system, including homeostasis of immune organs and immune cells. Intriguingly, the second group consists of genes functionally involved in the homeostasis of target tissues or autoantigens. According to our novel hypothesis, we propose that autoimmunity represents a consequence of a dysregulated homeostasis of the immune system and/or its targets including autoantigens and target tissues. In this review we refer to both aspects of homeostasis in autoimmunity with a highlight on the role of the homeostasis of target tissues and autoantigens. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Relating the bipolar spectrum to dysregulation of behavioural activation: a perspective from dynamical modelling.

    Directory of Open Access Journals (Sweden)

    Arno Steinacher

    Full Text Available Bipolar Disorders affect a substantial minority of the population and result in significant personal, social and economic costs. Understanding of the causes of, and consequently the most effective interventions for, this condition is an area requiring development. Drawing upon theories of Bipolar Disorder that propose the condition to be underpinned by dysregulation of systems governing behavioural activation or approach motivation, we present a mathematical model of the regulation of behavioural activation. The model is informed by non-linear, dynamical principles and as such proposes that the transition from "non-bipolar" to "bipolar" diagnostic status corresponds to a switch from mono- to multistability of behavioural activation level, rather than an increase in oscillation of mood. Consistent with descriptions of the behavioural activation or approach system in the literature, auto-activation and auto-inhibitory feedback is inherent within our model. Comparison between our model and empirical, observational data reveals that by increasing the non-linearity dimension in our model, important features of Bipolar Spectrum disorders are reproduced. Analysis from stochastic simulation of the system reveals the role of noise in behavioural activation regulation and indicates that an increase of nonlinearity promotes noise to jump scales from small fluctuations of activation levels to longer lasting, but less variable episodes. We conclude that further research is required to relate parameters of our model to key behavioural and biological variables observed in Bipolar Disorder.

  5. Cortisol dysregulation: the bidirectional link between stress, depression, and type 2 diabetes mellitus.

    Science.gov (United States)

    Joseph, Joshua J; Golden, Sherita H

    2017-03-01

    Controversy exists over the role of stress and depression in the pathophysiology of type 2 diabetes mellitus. Depression has been shown to increase the risk for progressive insulin resistance and incident type 2 diabetes mellitus in multiple studies, whereas the association of stress with diabetes is less clear, owing to differences in study designs and in forms and ascertainment of stress. The biological systems involved in adaptation that mediate the link between stress and physiological functions include the hypothalamic-pituitary-adrenal (HPA) axis and the autonomic nervous and immune systems. The HPA axis is a tightly regulated system that represents one of the body's mechanisms for responding to acute and chronic stress. Depression is associated with cross-sectional and longitudinal alterations in the diurnal cortisol curve, including a blunted cortisol awakening response and flattening of the diurnal cortisol curve. Flattening of the diurnal cortisol curve is also associated with insulin resistance and type 2 diabetes mellitus. In this article, we review and summarize the evidence supporting HPA axis dysregulation as an important biological link between stress, depression, and type 2 diabetes mellitus. © 2016 New York Academy of Sciences.

  6. Maternal physiological dysregulation while parenting poses risk for infant attachment disorganization and behavior problems.

    Science.gov (United States)

    Leerkes, Esther M; Su, Jinni; Calkins, Susan D; O'Brien, Marion; Supple, Andrew J

    2017-02-01

    The extent to which indices of maternal physiological arousal (skin conductance augmentation) and regulation (vagal withdrawal) while parenting predict infant attachment disorganization and behavior problems directly or indirectly via maternal sensitivity was examined in a sample of 259 mothers and their infants. Two covariates, maternal self-reported emotional risk and Adult Attachment Interview attachment coherence were assessed prenatally. Mothers' physiological arousal and regulation were measured during parenting tasks when infants were 6 months old. Maternal sensitivity was observed during distress-eliciting tasks when infants were 6 and 14 months old, and an average sensitivity score was calculated. Attachment disorganization was observed during the Strange Situation when infants were 14 months old, and mothers reported on infants' behavior problems when infants were 27 months old. Over and above covariates, mothers' arousal and regulation while parenting interacted to predict infant attachment disorganization and behavior problems such that maternal arousal was associated with higher attachment disorganization and behavior problems when maternal regulation was low but not when maternal regulation was high. This effect was direct and not explained by maternal sensitivity. The results suggest that maternal physiological dysregulation while parenting places infants at risk for psychopathology.

  7. Dysregulation of TIM-3-galectin-9 pathway in the cystic fibrosis airways.

    LENUS (Irish Health Repository)

    Vega-Carrascal, Isabel

    2012-02-01

    The T-cell Ig and mucin domain-containing molecules (TIMs) have emerged as promising therapeutic targets to correct abnormal immune function in several autoimmune and chronic inflammatory conditions. It has been reported that proinflammatory cytokine dysregulation and neutrophil-dominated inflammation are the main causes of morbidity in cystic fibrosis (CF). However, the role of TIM receptors in CF has not been investigated. In this study, we demonstrated that TIM-3 is constitutively overexpressed in the human CF airway, suggesting a link between CF transmembrane conductance regulator (CFTR) function and TIM-3 expression. Blockade of CFTR function with the CFTR inhibitor-172 induced an upregulation of TIM-3 and its ligand galectin-9 in normal bronchial epithelial cells. We also established that TIM-3 serves as a functional receptor in bronchial epithelial cells, and physiologically relevant concentrations of galectin-9 induced TIM-3 phosphorylation, resulting in increased IL-8 production. In addition, we have demonstrated that both TIM-3 and galectin-9 undergo rapid proteolytic degradation in the CF lung, primarily because of neutrophil elastase and proteinase-3 activity. Our results suggest a novel intrinsic defect that may contribute to the neutrophil-dominated immune response in the CF airways.

  8. Dysregulation of TIM-3-galectin-9 pathway in the cystic fibrosis airways.

    LENUS (Irish Health Repository)

    Vega-Carrascal, Isabel

    2011-03-01

    The T-cell Ig and mucin domain-containing molecules (TIMs) have emerged as promising therapeutic targets to correct abnormal immune function in several autoimmune and chronic inflammatory conditions. It has been reported that proinflammatory cytokine dysregulation and neutrophil-dominated inflammation are the main causes of morbidity in cystic fibrosis (CF). However, the role of TIM receptors in CF has not been investigated. In this study, we demonstrated that TIM-3 is constitutively overexpressed in the human CF airway, suggesting a link between CF transmembrane conductance regulator (CFTR) function and TIM-3 expression. Blockade of CFTR function with the CFTR inhibitor-172 induced an upregulation of TIM-3 and its ligand galectin-9 in normal bronchial epithelial cells. We also established that TIM-3 serves as a functional receptor in bronchial epithelial cells, and physiologically relevant concentrations of galectin-9 induced TIM-3 phosphorylation, resulting in increased IL-8 production. In addition, we have demonstrated that both TIM-3 and galectin-9 undergo rapid proteolytic degradation in the CF lung, primarily because of neutrophil elastase and proteinase-3 activity. Our results suggest a novel intrinsic defect that may contribute to the neutrophil-dominated immune response in the CF airways.

  9. MicroRNA dysregulation as a prognostic biomarker in colorectal cancer

    International Nuclear Information System (INIS)

    Dong, Yujuan; Yu, Jun; Ng, Simon SM

    2014-01-01

    Colorectal cancer (CRC) is one of the most potentially curable cancers, yet it remains the fourth most common overall cause of cancer death worldwide. The identification of robust molecular prognostic biomarkers can refine the conventional tumor–node–metastasis staging system, avoid understaging of tumor, and help pinpoint patients with early-stage CRC who may benefit from aggressive treatments. Recently, epigenetic studies have provided new molecular evidence to better categorize the CRC subtypes and predict clinical outcomes. In this review, we summarize recent findings concerning the prognostic potential of microRNAs (miRNAs) in CRC. We first discuss the prognostic value of three tissue miRNAs (miR-21-5p, miR-29-3p, miR-148-3p) that have been examined in multiple studies. We also summarize the dysregulation of miRNA processing machinery DICER in CRC and its association with risk for mortality. We also reviewe the potential application of miRNA-associated single-nucleotide polymorphisms as prognostic biomarkers for CRC, especially the miRNA-associated polymorphism in the KRAS gene. Last but not least, we discuss the microsatellite instability-related miRNA candidates. Among all these candidates, miR-21-5p is the most promising prognostic marker, yet further prospective validation studies are required before it can go into clinical usage

  10. Dysregulation of protease and protease inhibitors in a mouse model of human pelvic organ prolapse.

    Directory of Open Access Journals (Sweden)

    Madhusudhan Budatha

    Full Text Available Mice deficient for the fibulin-5 gene (Fbln5(-/- develop pelvic organ prolapse (POP due to compromised elastic fibers and upregulation of matrix metalloprotease (MMP-9. Here, we used casein zymography, inhibitor profiling, affinity pull-down, and mass spectrometry to discover additional protease upregulated in the vaginal wall of Fbln5(-/- mice, herein named V1 (25 kDa. V1 was a serine protease with trypsin-like activity similar to protease, serine (PRSS 3, a major extrapancreatic trypsinogen, was optimum at pH 8.0, and predominantly detected in estrogenized vaginal epithelium of Fbln5(-/- mice. PRSS3 was (a localized in epithelial secretions, (b detected in media of vaginal organ culture from both Fbln5(-/- and wild type mice, and (c cleaved fibulin-5 in vitro. Expression of two serine protease inhibitors [Serpina1a (α1-antitrypsin and Elafin] was dysregulated in Fbln5(-/- epithelium. Finally, we confirmed that PRSS3 was expressed in human vaginal epithelium and that SERPINA1 and Elafin were downregulated in vaginal tissues from women with POP. These data collectively suggest that the balance between proteases and their inhibitors contributes to support of the pelvic organs in humans and mice.

  11. Lack of the Lysosomal Membrane Protein, GLMP, in Mice Results in Metabolic Dysregulation in Liver.

    Directory of Open Access Journals (Sweden)

    Xiang Yi Kong

    Full Text Available Ablation of glycosylated lysosomal membrane protein (GLMP, formerly known as NCU-G1 has been shown to cause chronic liver injury which progresses into liver fibrosis in mice. Both lysosomal dysfunction and chronic liver injury can cause metabolic dysregulation. Glmp gt/gt mice (formerly known as Ncu-g1gt/gt mice were studied between 3 weeks and 9 months of age. Body weight gain and feed efficiency of Glmp gt/gt mice were comparable to wild type siblings, only at the age of 9 months the Glmp gt/gt siblings had significantly reduced body weight. Reduced size of epididymal fat pads was accompanied by hepatosplenomegaly in Glmp gt/gt mice. Blood analysis revealed reduced levels of blood glucose, circulating triacylglycerol and non-esterified fatty acids in Glmp gt/gt mice. Increased flux of glucose, increased de novo lipogenesis and lipid accumulation were detected in Glmp gt/gt primary hepatocytes, as well as elevated triacylglycerol levels in Glmp gt/gt liver homogenates, compared to hepatocytes and liver from wild type mice. Gene expression analysis showed an increased expression of genes involved in fatty acid uptake and lipogenesis in Glmp gt/gt liver compared to wild type. Our findings are in agreement with the metabolic alterations observed in other mouse models lacking lysosomal proteins, and with alterations characteristic for advanced chronic liver injury.

  12. Allostatic dysregulation of natural reward processing in prescription opioid misuse: autonomic and attentional evidence.

    Science.gov (United States)

    Garland, Eric L; Froeliger, Brett; Howard, Matthew O

    2015-02-01

    Chronic pain patients who misuse prescription opioids may suffer from allostatic dysregulation of natural reward processing. Hence, this study examined whether prescription opioid misusers with chronic pain (n=72) evidenced decreased natural reward responsiveness relative to non-misusers with chronic pain (n=26). Subjects completed a dot probe task containing pain-related, opioid-related, and natural reward stimuli while attentional bias (AB) scores and heart rate variability (HRV) responses were assessed. Compared to non-misusers, misusers evidenced significantly more attenuated HRV responses to opioid, pain, and natural reward cues presented during the dot probe task. These significant between-groups differences in HRV were largest during attention to natural reward cues, but became non-significant in a sensitivity analysis controlling for opioid dosing. In addition, non-misusers evidenced an AB toward natural reward cues, whereas misusers did not. Findings suggest that opioid misusers exhibit attentional and autonomic deficits during reward processing. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Stress management at the worksite: reversal of symptoms profile and cardiovascular dysregulation.

    Science.gov (United States)

    Lucini, Daniela; Riva, Silvano; Pizzinelli, Paolo; Pagani, Massimo

    2007-02-01

    Work stress may increase cardiovascular risk either indirectly, by inducing unhealthy life styles, or directly, by affecting the autonomic nervous system and arterial pressure. We hypothesized that, before any apparent sign of disease, work-related stress is already accompanied by alterations of RR variability profile and that a simple onsite stress management program based on cognitive restructuring and relaxation training could reduce the level of stress symptoms, revert stress-related autonomic nervous system dysregulation, and lower arterial pressure. We compared 91 white-collar workers, enrolled at a time of work downsizing (hence, in a stress condition), with 79 healthy control subjects. Psychological profiles were assessed by questionnaires and autonomic nervous system regulation by spectral analysis of RR variability. We also tested a simple onsite stress management program (cognitive restructuring and relaxation training) in a subgroup of workers compared with a sham subgroup (sham program). Workers presented an elevated level of stress-related symptoms and an altered variability profile as compared with control subjects (low-frequency component of RR variability was, respectively, 65.2+/-2 versus 55.3+/-2 normalized units; Pstress management program, which also slightly lowered systolic arterial pressure. No changes were observed in the sham program group. This noninvasive study indicates that work stress is associated with unpleasant symptoms and with an altered autonomic profile and suggests that a stress management program could be implemented at the worksite, with possible preventive advantages for hypertension.

  14. MicroRNA function and dysregulation in bone tumors: the evidence to date.

    LENUS (Irish Health Repository)

    Nugent, Mary

    2014-01-01

    Micro ribonucleic acids (miRNAs) are small non-coding RNA segments that have a role in the regulation of normal cellular development and proliferation including normal osteogenesis. They exert their effects through inhibition of specific target genes at the post-transcriptional level. Many miRNAs have altered expression levels in cancer (either increased or decreased depending on the specific miRNA). Altered miRNA expression profiles have been identified in several malignancies including primary bone tumors such as osteosarcoma and Ewing\\'s sarcoma. It is thought that they may function as tumor suppressor genes or oncogenes and hence when dysregulated contribute to the initiation and progression of malignancy. miRNAs are also thought to have a role in the development of bone metastases in other malignancies. In addition, evidence increasingly suggests that miRNAs may play a part in determining the response to chemotherapy in the treatment of osteosarcoma. These molecules are readily detectable in tissues, both fresh and formalin fixed paraffin embedded and, more recently, in blood. Although there are fewer published studies regarding circulating miRNA profiles, they appear to reflect changes in tissue expression. Thus miRNAs may serve as potential indicators of disease presence but more importantly, may have a role in disease characterization or as potential therapeutic targets. This review gives a brief overview of miRNA biochemistry and explores the evidence to date implicating these small molecules in the pathogenesis of bone tumors.

  15. High fructose corn syrup induces metabolic dysregulation and altered dopamine signaling in the absence of obesity.

    Science.gov (United States)

    Meyers, Allison M; Mourra, Devry; Beeler, Jeff A

    2017-01-01

    The contribution of high fructose corn syrup (HFCS) to metabolic disorder and obesity, independent of high fat, energy-rich diets, is controversial. While high-fat diets are widely accepted as a rodent model of diet-induced obesity (DIO) and metabolic disorder, the value of HFCS alone as a rodent model of DIO is unclear. Impaired dopamine function is associated with obesity and high fat diet, but the effect of HFCS on the dopamine system has not been investigated. The objective of this study was to test the effect of HFCS on weight gain, glucose regulation, and evoked dopamine release using fast-scan cyclic voltammetry. Mice (C57BL/6) received either water or 10% HFCS solution in combination with ad libitum chow for 15 weeks. HFCS consumption with chow diet did not induce weight gain compared to water, chow-only controls but did induce glucose dysregulation and reduced evoked dopamine release in the dorsolateral striatum. These data show that HFCS can contribute to metabolic disorder and altered dopamine function independent of weight gain and high-fat diets.

  16. High fructose corn syrup induces metabolic dysregulation and altered dopamine signaling in the absence of obesity.

    Directory of Open Access Journals (Sweden)

    Allison M Meyers

    Full Text Available The contribution of high fructose corn syrup (HFCS to metabolic disorder and obesity, independent of high fat, energy-rich diets, is controversial. While high-fat diets are widely accepted as a rodent model of diet-induced obesity (DIO and metabolic disorder, the value of HFCS alone as a rodent model of DIO is unclear. Impaired dopamine function is associated with obesity and high fat diet, but the effect of HFCS on the dopamine system has not been investigated. The objective of this study was to test the effect of HFCS on weight gain, glucose regulation, and evoked dopamine release using fast-scan cyclic voltammetry. Mice (C57BL/6 received either water or 10% HFCS solution in combination with ad libitum chow for 15 weeks. HFCS consumption with chow diet did not induce weight gain compared to water, chow-only controls but did induce glucose dysregulation and reduced evoked dopamine release in the dorsolateral striatum. These data show that HFCS can contribute to metabolic disorder and altered dopamine function independent of weight gain and high-fat diets.

  17. Psychogenic and neural visual-cue response in PD dopamine dysregulation syndrome.

    Science.gov (United States)

    Loane, Clare; Wu, Kit; O'Sullivan, Sean S; Lawrence, Andrew D; Woodhead, Zoe; Lees, Andrew J; Piccini, Paola; Politis, Marios

    2015-11-01

    Dopamine dysregulation syndrome (DDS) in Parkinson's disease (PD) patients refers to the compulsive use of dopaminergic replacement therapy and has serious psycho-social consequences. Mechanisms underlying DDS are not clear although has been linked to dysfunctional brain reward networks. With fMRI, we investigate behavioral and neural response to drug-cues in six PD DDS patients and 12 PD control patients in both the ON and OFF medication state. Behavioral measures of liking, wanting and subjectively 'feeling ON medication' were also collected. Behaviorally, PD DDS patients feel less ON and want their drugs more at baseline compared to PD controls. Following drug-cue exposure, PD DDS patients feel significantly more ON medication, which correlates with significant increases in reward related regions. The results demonstrate that exposure to drug-cues increases the subjective feeling of being 'ON' medication which corresponds to dysfunctional activation in reward related regions in PD DDS patients. These findings should be extended in future studies. Visual stimuli being sufficient to elicit behavioral response through neuroadaptations could have direct implications to the management of addictive behavior. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Brain Hypoactivation, Autonomic Nervous System Dysregulation, and Gonadal Hormones in Depression: A Preliminary Study

    Science.gov (United States)

    Holsen, Laura M.; Lee, Jong-Hwan; Spaeth, Sarah B.; Ogden, Lauren A.; Klibanski, Anne; Whitfield-Gabrieli, Susan; Sloan, Richard P.; Goldstein, Jill M.

    2012-01-01

    The comorbidity of major depressive disorder (MDD) and cardiovascular disease (CVD) is among the 10th leading cause of morbidity and mortality worldwide. Thus, understanding the co-occurrence of these disorders will have major public health significance. MDD is associated with an abnormal stress response, manifested in brain circuitry deficits, gonadal dysfunction, and autonomic nervous system (ANS) dysregulation. Contribution of the relationships between these systems to the pathophysiology of MDD is not well understood. The objective of this preliminary study was to investigate, in parallel, relationships between HPG-axis functioning, stress response circuitry activation, and parasympathetic reactivity in healthy controls and women with MDD. Using fMRI with pulse oximetry [from which we calculated the high frequency (HF) component of R-R interval variability (HF-RRV), a measure of parasympathetic modulation] and hormone data, we studied eight women with recurrent MDD in remission and six controls during a stress response paradigm. We demonstrated that hypoactivations of hypothalamus, amygdala, hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and subgenual ACC were associated with lower parasympathetic cardiac modulation in MDD women. Estradiol and progesterone attenuated group differences in the effect of HF-RRV on hypoactivation in the amygdala, hippocampus, ACC, and OFC in MDD women. Findings have implications for understanding the relationship between mood, arousal, heart regulation, and gonadal hormones, and may provide insights into MDD and CVD risk comorbidity. PMID:22395084

  19. Dysregulation of hepatic microRNA expression profiles with Clonorchis sinensis infection.

    Science.gov (United States)

    Han, Su; Tang, Qiaoran; Lu, Xi; Chen, Rui; Li, Yihong; Shu, Jing; Zhang, Xiaoli; Cao, Jianping

    2016-11-30

    Clonorchiasis remains an important zoonotic parasitic disease worldwide. The molecular mechanisms of host-parasite interaction are not fully understood. Non-coding microRNAs (miRNAs) are considered to be key regulators in parasitic diseases. The regulation of miRNAs and host micro-environment may be involved in clonorchiasis, and require further investigation. MiRNA microarray technology and bioinformatic analysis were used to investigate the regulatory mechanisms of host miRNA and to compare miRNA expression profiles in the liver tissues of control and Clonorchis sinensis (C. sinensis)-infected rats. A total of eight miRNAs were downregulated and two were upregulated, which showed differentially altered expression profiles in the liver tissue of C. sinensis-infected rats. Further analysis of the differentially expressed miRNAs revealed that many important signal pathways were triggered after infection with C. sinensis, which were related to clonorchiasis pathogenesis, such as cell apoptosis and inflammation, as well as genes involved in signal transduction mechanisms, such as pathways in cancer and the Wnt and Mitogen-activated protein kinases (MAPK) signaling pathways. The present study revealed that the miRNA expression profiles of the host were changed by C. sinensis infection. This dysregulation in miRNA expression may contribute to the etiology and pathophysiology of clonorchiasis. These results also provide new insights into the regulatory mechanisms of miRNAs in clonorchiasis, which may present potential targets for future C. sinensis control strategies.

  20. Dysregulation of C-X-C motif ligand 10 during aging and association with cognitive performance.

    Science.gov (United States)

    Bradburn, Steven; McPhee, Jamie; Bagley, Liam; Carroll, Michael; Slevin, Mark; Al-Shanti, Nasser; Barnouin, Yoann; Hogrel, Jean-Yves; Pääsuke, Mati; Gapeyeva, Helena; Maier, Andrea; Sipilä, Sarianna; Narici, Marco; Robinson, Andrew; Mann, David; Payton, Antony; Pendleton, Neil; Butler-Browne, Gillian; Murgatroyd, Chris

    2018-03-01

    Chronic low-grade inflammation during aging (inflammaging) is associated with cognitive decline and neurodegeneration; however, the mechanisms underlying inflammaging are unclear. We studied a population (n = 361) of healthy young and old adults from the MyoAge cohort. Peripheral levels of C-X-C motif chemokine ligand 10 (CXCL10) was found to be higher in older adults, compared with young, and negatively associated with working memory performance. This coincided with an age-related reduction in blood DNA methylation at specific CpGs within the CXCL10 gene promoter. In vitro analysis supported the role of DNA methylation in regulating CXCL10 transcription. A polymorphism (rs56061981) that altered methylation at one of these CpG sites further associated with working memory performance in 2 independent aging cohorts. Studying prefrontal cortex samples, we found higher CXCL10 protein levels in those with Alzheimer's disease, compared with aged controls. These findings support the association of peripheral inflammation, as demonstrated by CXCL10, in aging and cognitive decline. We reveal age-related epigenetic and genetic factors which contribute to the dysregulation of CXCL10. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  1. Friction-Induced Mitochondrial Dysregulation Contributes to Joint Deterioration in Prg4 Knockout Mice

    Directory of Open Access Journals (Sweden)

    Kimberly A. Waller

    2017-06-01

    Full Text Available Deficiency of PRG4 (lubricin, the boundary lubricant in mammalian joints, contributes to increased joint friction accompanied by superficial and upper intermediate zone chondrocyte caspase-3 activation, as shown in lubricin-null (Prg4−/− mice. Caspase-3 activity appears to be reversible upon the restitution of Prg4 either endogenously in vivo, in a gene trap mouse, or as an applied lubricant in vitro. In this study we show that intra-articular injection of human PRG4 in vivo in Prg4−/− mice prevented caspase-3 activation in superficial zone chondrocytes and was associated with a modest decrease in whole joint friction measured ex vivo using a joint pendulum method. Non-lubricated Prg4−/− mouse cartilage shows caspase cascade activation caused by mitochondrial dysregulation, and significantly higher levels of peroxynitrite (ONOO− and −OH and superoxide (O−2 compared to Prg4+/+ and Prg4+/− cartilage. Enzymatic activity levels of caspase 8 across Prg4 mutant mice were not significantly different, indicating no extrinsic apoptosis pathway activation. Western blots showed caspase-3 and 9 activation in Prg4−/− tissue extracts, and the appearance of nitrosylated Cys163 in the active cleft of caspase-3 which inhibits its enzymatic activity. These findings are relevant to patients at risk for arthrosis, from camptodactyl-arthropathy-coxa vara-pericarditis (CACP syndrome and transient lubricin insufficiency due to trauma and inflammation.

  2. Convergent dysregulation of frontal cortical cognitive and reward systems in eating disorders.

    Science.gov (United States)

    Stefano, George B; Ptáček, Radek; Kuželová, Hana; Mantione, Kirk J; Raboch, Jiří; Papezova, Hana; Kream, Richard M

    2013-05-10

    A substantive literature has drawn a compelling case for the functional involvement of mesolimbic/prefrontal cortical neural reward systems in normative control of eating and in the etiology and persistence of severe eating disorders that affect diverse human populations. Presently, we provide a short review that develops an equally compelling case for the importance of dysregulated frontal cortical cognitive neural networks acting in concert with regional reward systems in the regulation of complex eating behaviors and in the presentation of complex pathophysiological symptoms associated with major eating disorders. Our goal is to highlight working models of major eating disorders that incorporate complementary approaches to elucidate functionally interactive neural circuits defined by their regulatory neurochemical phenotypes. Importantly, we also review evidence-based linkages between widely studied psychiatric and neurodegenerative syndromes (e.g., autism spectrum disorders and Parkinson's disease) and co-morbid eating disorders to elucidate basic mechanisms involving dopaminergic transmission and its regulation by endogenously expressed morphine in these same cortical regions.

  3. The Development and Course of Bipolar Spectrum Disorders: An Integrated Reward and Circadian Rhythm Dysregulation Model

    Science.gov (United States)

    Alloy, Lauren B.; Nusslock, Robin; Boland, Elaine M.

    2014-01-01

    In this article, we present and review the evidence for two major biopsychosocial theories of the onset and course of bipolar spectrum disorders (BSDs) that integrate behavioral, environmental, and neurobiological mechanisms: the reward hypersensitivity and the social and circadian rhythm disruption models. We describe the clinical features, spectrum, age of onset, and course of BSDs. We then discuss research designs relevant to demonstrating whether a hypothesized mechanism represents a correlate, vulnerability, or predictor of the course of BSDs, as well as important methodological issues. We next present the reward hypersensitivity model of BSD, followed by the social/circadian rhythm disruption model of BSD. For each model, we review evidence regarding whether the proposed underlying mechanism is associated with BSDs, provides vulnerability to the onset of BSDs, and predicts the course of BSDs. We then present a new integrated reward/circadian rhythm (RCR) dysregulation model of BSD and discuss how the RCR model explains the symptoms, onset, and course of BSDs. We end with recommendations for future research directions. PMID:25581235

  4. Relating the bipolar spectrum to dysregulation of behavioural activation: a perspective from dynamical modelling.

    Science.gov (United States)

    Steinacher, Arno; Wright, Kim A

    2013-01-01

    Bipolar Disorders affect a substantial minority of the population and result in significant personal, social and economic costs. Understanding of the causes of, and consequently the most effective interventions for, this condition is an area requiring development. Drawing upon theories of Bipolar Disorder that propose the condition to be underpinned by dysregulation of systems governing behavioural activation or approach motivation, we present a mathematical model of the regulation of behavioural activation. The model is informed by non-linear, dynamical principles and as such proposes that the transition from "non-bipolar" to "bipolar" diagnostic status corresponds to a switch from mono- to multistability of behavioural activation level, rather than an increase in oscillation of mood. Consistent with descriptions of the behavioural activation or approach system in the literature, auto-activation and auto-inhibitory feedback is inherent within our model. Comparison between our model and empirical, observational data reveals that by increasing the non-linearity dimension in our model, important features of Bipolar Spectrum disorders are reproduced. Analysis from stochastic simulation of the system reveals the role of noise in behavioural activation regulation and indicates that an increase of nonlinearity promotes noise to jump scales from small fluctuations of activation levels to longer lasting, but less variable episodes. We conclude that further research is required to relate parameters of our model to key behavioural and biological variables observed in Bipolar Disorder.

  5. A reinforcement sensitivity model of affective and behavioral dysregulation in marijuana use and associated problems.

    Science.gov (United States)

    Emery, Noah N; Simons, Jeffrey S

    2017-08-01

    This study tested a model linking sensitivity to punishment (SP) and reward (SR) to marijuana use and problems via affect lability and poor control. A 6-month prospective design was used in a sample of 2,270 young-adults (64% female). The hypothesized SP × SR interaction did not predict affect lability or poor control, but did predict use likelihood at baseline. At low levels of SR, SP was associated with an increased likelihood of abstaining, which was attenuated as SR increased. SP and SR displayed positive main effects on both affect lability and poor control. Affect lability and poor control, in turn, mediated effects on the marijuana outcomes. Poor control predicted both increased marijuana use and, controlling for use level, greater intensity of problems. Affect lability predicted greater intensity of problems, but was not associated with use level. There were few prospective effects. SR consistently predicted greater marijuana use and problems. SP however, exhibited both risk and protective pathways. Results indicate that SP is associated with a decreased likelihood of marijuana use. However, once use is initiated SP is associated with increased risk of problems, in part, due to its effects on both affect and behavioral dysregulation. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  6. Inflammation and ER Stress Downregulate BDH2 Expression and Dysregulate Intracellular Iron in Macrophages

    Directory of Open Access Journals (Sweden)

    Susu M. Zughaier

    2014-01-01

    Full Text Available Macrophages play a very important role in host defense and in iron homeostasis by engulfing senescent red blood cells and recycling iron. Hepcidin is the master iron regulating hormone that limits dietary iron absorption from the gut and limits iron egress from macrophages. Upon infection macrophages retain iron to limit its bioavailability which limits bacterial growth. Recently, a short chain butyrate dehydrogenase type 2 (BDH2 protein was reported to contain an iron responsive element and to mediate cellular iron trafficking by catalyzing the synthesis of the mammalian siderophore that binds labile iron; therefore, BDH2 plays a crucial role in intracellular iron homeostasis. However, BDH2 expression and regulation in macrophages have not yet been described. Here we show that LPS-induced inflammation combined with ER stress led to massive BDH2 downregulation, increased the expression of ER stress markers, upregulated hepcidin expression, downregulated ferroportin expression, caused iron retention in macrophages, and dysregulated cytokine release from macrophages. We also show that ER stress combined with inflammation synergistically upregulated the expression of the iron carrier protein NGAL and the stress-inducible heme degrading enzyme heme oxygenase-1 (HO-1 leading to iron liberation. This is the first report to show that inflammation and ER stress downregulate the expression of BDH2 in human THP-1 macrophages.

  7. Epigenetic dysregulation underlies radiation-induced transgenerational genome instability in vivo

    International Nuclear Information System (INIS)

    Koturbash, Igor; Baker, Mike; Loree, Jonathan; Kutanzi, Kristy; Hudson, Darryl; Pogribny, Igor; Sedelnikova, Olga; Bonner, William; Kovalchuk, Olga

    2006-01-01

    Purpose: Although modern cancer radiation therapy has led to increased patient survival rates, the risk of radiation treatment-related complications is becoming a growing problem. Among various complications, radiation also poses a threat to the progeny of exposed parents. It causes transgenerational genome instability that is linked to transgenerational carcinogenesis. Although the occurrence of transgenerational genome instability, which manifests as elevated delayed and nontargeted mutation, has been well documented, the mechanisms by which it arises remain obscure. We hypothesized that epigenetic alterations may play a pivotal role in the molecular etiology of transgenerational genome instability. Methods and Materials: We studied the levels of cytosine DNA methylation in somatic tissues of unexposed offspring upon maternal, paternal, or combined parental exposure. Results: We observed a significant loss of global cytosine DNA methylation in the thymus tissue of the offspring upon combined parental exposure. The loss of DNA methylation was paralleled by a significant decrease in the levels of maintenance (DNMT1) and de novo methyltransferases DNMT3a and 3b and methyl-CpG-binding protein MeCP2. Along with profound changes in DNA methylation, we noted a significant accumulation of DNA strand breaks in thymus, which is a radiation carcinogenesis target organ. Conclusions: The observed changes were indicative of a profound epigenetic dysregulation in the offspring, which in turn could lead to genome destabilization and possibly could serve as precursor for transgenerational carcinogenesis. Future studies are clearly needed to address the cellular and carcinogenic repercussions of those changes

  8. Onco-GPCR signaling and dysregulated expression of microRNAs in human cancer.

    Science.gov (United States)

    Nohata, Nijiro; Goto, Yusuke; Gutkind, J Silvio

    2017-01-01

    The G-protein-coupled receptor (GPCR) family is the largest family of cell-surface receptors involved in signal transduction. Aberrant expression of GPCRs and G proteins are frequently associated with prevalent human diseases, including cancer. In fact, GPCRs represent the therapeutic targets of more than a quarter of the clinical drugs currently on the market. MiRNAs (miRNAs) are also aberrantly expressed in many human cancers, and they have significant roles in the initiation, development and metastasis of human malignancies. Recent studies have revealed that dysregulation of miRNAs and their target genes expression are associated with cancer progression. The emerging information suggests that miRNAs play an important role in the fine tuning of many signaling pathways, including GPCR signaling. We summarize our current knowledge of the individual functions of miRNAs regulated by GPCRs and GPCR signaling-associated molecules, and miRNAs that regulate the expression and activity of GPCRs, their endogenous ligands and their coupled heterotrimeric G proteins in human cancer.

  9. Proteome analysis of schizophrenia patients Wernicke's area reveals an energy metabolism dysregulation

    Directory of Open Access Journals (Sweden)

    Marangoni Sérgio

    2009-04-01

    Full Text Available Abstract Background Schizophrenia is likely to be a consequence of DNA alterations that, together with environmental factors, will lead to protein expression differences and the ultimate establishment of the illness. The superior temporal gyrus is implicated in schizophrenia and executes functions such as the processing of speech, language skills and sound processing. Methods We performed an individual comparative proteome analysis using two-dimensional gel electrophoresis of 9 schizophrenia and 6 healthy control patients' left posterior superior temporal gyrus (Wernicke's area – BA22p identifying by mass spectrometry several protein expression alterations that could be related to the disease. Results Our analysis revealed 11 downregulated and 14 upregulated proteins, most of them related to energy metabolism. Whereas many of the identified proteins have been previously implicated in schizophrenia, such as fructose-bisphosphate aldolase C, creatine kinase and neuron-specific enolase, new putative disease markers were also identified such as dihydrolipoyl dehydrogenase, tropomyosin 3, breast cancer metastasis-suppressor 1, heterogeneous nuclear ribonucleoproteins C1/C2 and phosphate carrier protein, mitochondrial precursor. Besides, the differential expression of peroxiredoxin 6 (PRDX6 and glial fibrillary acidic protein (GFAP were confirmed by western blot in schizophrenia prefrontal cortex. Conclusion Our data supports a dysregulation of energy metabolism in schizophrenia as well as suggests new markers that may contribute to a better understanding of this complex disease.

  10. Placental adaptations to micronutrient dysregulation in the programming of chronic disease.

    Science.gov (United States)

    Hofstee, Pierre; McKeating, Daniel; Perkins, Anthony V; Cuffe, James S M

    2018-04-21

    Poor nutrition during pregnancy is known to impair foetal development and increase the risk of chronic disease in offspring. Both macronutrients and micronutrients are required for a healthy pregnancy although significantly less is understood about the role of micronutrients in the programming of chronic disease. This is despite the fact that modern calorie rich diets are often also deficient in key micronutrients. The importance of micronutrients in gestational disorders is clearly understood but how they impact long term disease in humans requires further investigation. In contrast, animal studies have demonstrated how diets high or low in specific micronutrients influence offspring physiology. Many of these studies highlight the importance of the placenta in determining disease risk. This review will explore the effects of individual vitamins, minerals and trace elements on offspring disease outcomes and discuss several key placental adaptations that are affected by multiple micronutrients. These placental adaptations include micronutrient induced dysregulation of oxidative stress, altered methyl donor availability and its impact on epigenetic mechanisms as well as endocrine dysfunction. Critical gaps in our current knowledge and the relative importance of different micronutrients at different gestational ages will also be highlighted. Finally, this review will discuss the need for further studies to characterise the micronutrient status of Australian women of reproductive age and correlate micronutrient status to placental adaptations, pregnancy complications and offspring disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  11. microRNA-128a dysregulation in transgenic Huntington’s disease monkeys

    Science.gov (United States)

    2014-01-01

    Background Huntington’s Disease (HD) is a progressive neurodegenerative disorder with a single causal mutation in the Huntingtin (HTT) gene. MicroRNAs (miRNAs) have recently been implicated as epigenetic regulators of neurological disorders, however, their role in HD pathogenesis is not well defined. Here we study transgenic HD monkeys (HD monkeys) to examine miRNA dysregulation in a primate model of the disease. Results In this report, 11 miRNAs were found to be significantly associated (P value monkeys. We further focused on one of those candidates, miR-128a, due to the corresponding disruption in humans and mice with HD as well as its intriguing lists of gene targets. miR-128a was downregulated in our HD monkey model by the time of birth. We then confirmed that miR-128a was also downregulated in the brains of pre-symptomatic and post-symptomatic HD patients. Additionally, our studies confirmed a panel of canonical HD signaling genes regulated by miR-128a, including HTT and Huntingtin Interaction Protein 1 (HIP1). Conclusion Our studies found that miR-128a may play a critical role in HD and could be a viable candidate as a therapeutic or biomarker of the disease. PMID:24929669

  12. Dysregulated autophagy in restrictive cardiomyopathy due to Pro209Leu mutation in BAG3.

    Science.gov (United States)

    Schänzer, A; Rupp, S; Gräf, S; Zengeler, D; Jux, C; Akintürk, H; Gulatz, L; Mazhari, N; Acker, T; Van Coster, R; Garvalov, B K; Hahn, A

    2018-03-01

    Myofibrillary myopathies (MFM) are hereditary myopathies histologically characterized by degeneration of myofibrils and aggregation of proteins in striated muscle. Cardiomyopathy is common in MFM but the pathophysiological mechanisms are not well understood. The BAG3-Pro209Leu mutation is associated with early onset MFM and severe restrictive cardiomyopathy (RCM), often necessitating heart transplantation during childhood. We report on a young male patient with a BAG3-Pro209Leu mutation who underwent heart transplantation at eight years of age. Detailed morphological analyses of the explanted heart tissue showed intracytoplasmic inclusions, aggregation of BAG3 and desmin, disintegration of myofibers and Z-disk alterations. The presence of undegraded autophagosomes, seen by electron microscopy, as well as increased levels of p62, LC3-I and WIPI1, detected by immunohistochemistry and western blot analyses, indicated a dysregulation of autophagy. Parkin and PINK1, proteins involved in mitophagy, were slightly increased whereas mitochondrial OXPHOS activities were not altered. These findings indicate that altered autophagy plays a role in the pathogenesis and rapid progression of RCM in MFM caused by the BAG3-Pro209Leu mutation, which could have implications for future therapeutic strategies. Copyright © 2018 Elsevier Inc. All rights reserved.

  13. Pancreatic Islet Protein Complexes and Their Dysregulation in Type 2 Diabetes

    DEFF Research Database (Denmark)

    Pedersen, Helle Krogh; Gudmundsdottir, Valborg; Brunak, Søren

    2017-01-01

    Type 2 diabetes (T2D) is a complex disease that involves multiple genes. Numerous risk loci have already been associated with T2D, although many susceptibility genes remain to be identified given heritability estimates. Systems biology approaches hold potential for discovering novel T2D genes by ...... starting point when evaluating an individual's alterations at the genome, transcriptome, or proteome level in relation to T2D in clinical settings.......Type 2 diabetes (T2D) is a complex disease that involves multiple genes. Numerous risk loci have already been associated with T2D, although many susceptibility genes remain to be identified given heritability estimates. Systems biology approaches hold potential for discovering novel T2D genes...... by considering their biological context, such as tissue-specific protein interaction partners. Pancreatic islets are a key T2D tissue and many of the known genetic risk variants lead to impaired islet function, hence a better understanding of the islet-specific dysregulation in the disease-state is essential...

  14. Emotional Dysregulation in Adults With Attention-Deficit/Hyperactivity Disorder-Validity, Predictability, Severity, and Comorbidity.

    Science.gov (United States)

    Corbisiero, Salvatore; Mörstedt, Beatrice; Bitto, Hannes; Stieglitz, Rolf-Dieter

    2017-01-01

    Attention-deficit/hyperactivity disorder (ADHD) is characterized by inattention, hyperactivity, and impulsivity. However, this triad might not be able to explain the complete spectrum of ADHD symptoms, as emotional dysregulation (ED) frequently seems to accompany the disorder. The aim of this study was to further understand the role of ED in adult ADHD. The sample comprised 393 adults with ADHD without or with comorbidity, and 121 adults without ADHD or any other mental disorder. Additionally, the sample focused on ED. The contribution of core symptoms and the effect of comorbidity on ED were tested and the predictive value of ED for the ADHD diagnosis itself analyzed. Finally, all subjects were categorized into groups-No ADHD, ADHD, and ADHD + ED-to analyze the differences in the severity of ADHD symptomatology in the three groups. ED levels were found to be elevated in patients with ADHD. The core symptoms affected ED, and the ADHD diagnosis was predicted by ED. The addition of ED to a regression model with the core symptoms was shown to improve the predictability of the ADHD diagnosis. The presence of ED proved to be an indicator of the severity of adult ADHD independent of a present comorbidity. ED is a significant symptom in adult patients with ADHD and appears to be associated with ADHD itself. Whilst the presence of other mental disorders intensifies symptoms of ED, ED seems not to manifest solely as a consequence of comorbidity. © 2016 Wiley Periodicals, Inc.

  15. DSM-5 intermittent explosive disorder: Relationship with Disruptive Mood Dysregulation Disorder.

    Science.gov (United States)

    Coccaro, Emil F

    2018-04-30

    This study was designed to estimate how many adults with DSM-5 Intermittent Explosive Disorder (IED) would also meet diagnostic criteria for Disruptive Mood Dysregulation Disorder (DMDD). This was done by examining how many individuals with IED would meet the DMDD criterion of being persistently angry in between impulsive aggressive outbursts. The first one-hundred study participants diagnosed with DSM-5 IED in our clinical research program were included in this study. Two questions were added to the IED module from the Structured Clinical Interview for DSM-5 Disorders (SCID) inquiring about the duration of anger in between impulsive aggressive outbursts in IED study participants. Data regarding aggression, impulsivity, anger expression, and related dysphoric variables were also collected. The proportion of time spent as angry in between impulsive aggressive outbursts was DSM-5 IED. Despite this, persistently-angry (i.e., angry >50% time in between outbursts) IED study participants displayed no differences from not-persistently-angry IED study participants in dysphoric and aggression/impulsivity related variables. These data indicate that inter-outburst anger in those with IED is relatively brief and that such individuals do not generally display the kind of persistent anger that is a diagnostic feature of DMDD. Copyright © 2018. Published by Elsevier Inc.

  16. Neural Correlates of Irritability in Disruptive Mood Dysregulation and Bipolar Disorders.

    Science.gov (United States)

    Wiggins, Jillian Lee; Brotman, Melissa A; Adleman, Nancy E; Kim, Pilyoung; Oakes, Allison H; Reynolds, Richard C; Chen, Gang; Pine, Daniel S; Leibenluft, Ellen

    2016-07-01

    Bipolar disorder and disruptive mood dysregulation disorder (DMDD) are clinically and pathophysiologically distinct, yet irritability can be a clinical feature of both illnesses. The authors examine whether the neural mechanisms mediating irritability differ between bipolar disorder and DMDD, using a face emotion labeling paradigm because such labeling is deficient in both patient groups. The authors hypothesized that during face emotion labeling, irritability would be associated with dysfunctional activation in the amygdala and other temporal and prefrontal regions in both disorders, but that the nature of these associations would differ between DMDD and bipolar disorder. During functional MRI acquisition, 71 youths (25 with DMDD, 24 with bipolar disorder, and 22 healthy youths) performed a labeling task with happy, fearful, and angry faces of varying emotional intensity. Participants with DMDD and bipolar disorder showed similar levels of irritability and did not differ from each other or from healthy youths in face emotion labeling accuracy. Irritability correlated with amygdala activity across all intensities for all emotions in the DMDD group; such correlation was present in the bipolar disorder group only for fearful faces. In the ventral visual stream, associations between neural activity and irritability were found more consistently in the DMDD group than in the bipolar disorder group, especially in response to ambiguous angry faces. These results suggest diagnostic specificity in the neural correlates of irritability, a symptom of both DMDD and bipolar disorder. Such evidence of distinct neural correlates suggests the need to evaluate different approaches to treating irritability in the two disorders.

  17. Serum proteomics reveals systemic dysregulation of innate immunity in type 1 diabetes

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Qibin; Fillmore, Thomas L.; Schepmoes, Athena A.; Clauss, Therese RW; Gritsenko, Marina A.; Mueller, Patricia W.; Rewers, Marian; Atkinson, Mark A.; Smith, Richard D.; Metz, Thomas O.

    2013-01-14

    Using global liquid chromatography-mass spectrometry (LC-MS)-based proteomics analyses, we identified 24 serum proteins significantly variant between those with type 1 diabetes and healthy controls. Functionally, these proteins represent innate immune responses, the activation cascade of complement, inflammatory responses and blood coagulation. Targeted verification analyses were performed on 52 surrogate peptides representing these proteins with serum samples from an antibody standardization program cohort of 100 healthy control and 50 type 1 diabetic subjects, and 16 peptides were verified having very good discriminating power, with areas under the receiver operator characteristic curve ≥ 0.8. Further validation with blinded serum samples from an independent cohort (10 healthy control and 10 type 1 diabetic) demonstrated that peptides from platelet basic protein and C1 inhibitor achieved both 100% sensitivity and 100% specificity for classification of samples. The disease specificity of these proteins was assessed using serum from 50 age matched type 2 diabetic individuals, and a subset of proteins, particularly C1 inhibitor were exceptionally good discriminators between these two forms of diabetes. The panel of biomarkers distinguishing those with type 1 diabetes from healthy control and type 2 diabetes suggests dysregulated innate immune responses may be associated with the development of this disorder.

  18. Pattern-recognition receptors: signaling pathways and dysregulation in canine chronic enteropathies-brief review.

    Science.gov (United States)

    Heilmann, Romy M; Allenspach, Karin

    2017-11-01

    Pattern-recognition receptors (PRRs) are expressed by innate immune cells and recognize pathogen-associated molecular patterns (PAMPs) as well as endogenous damage-associated molecular pattern (DAMP) molecules. With a large potential for synergism or convergence between their signaling pathways, PRRs orchestrate a complex interplay of cellular mediators and transcription factors, and thus play a central role in homeostasis and host defense. Aberrant activation of PRR signaling, mutations of the receptors and/or their downstream signaling molecules, and/or DAMP/PAMP complex-mediated receptor signaling can potentially lead to chronic auto-inflammatory diseases or development of cancer. PRR signaling pathways appear to also present an interesting new avenue for the modulation of inflammatory responses and to serve as potential novel therapeutic targets. Evidence for a dysregulation of the PRR toll-like receptor (TLR)2, TLR4, TLR5, and TLR9, nucleotide-binding oligomerization domain-containing protein (NOD)2, and the receptor of advanced glycation end products (RAGE) exists in dogs with chronic enteropathies. We describe the TLR, NOD2, and RAGE signaling pathways and evaluate the current veterinary literature-in comparison to human medicine-to determine the role of TLRs, NOD2, and RAGE in canine chronic enteropathies.

  19. Dysregulation of Brain Reward Systems in Eating Disorders: Neurochemical Information from Animal Models of Binge Eating, Bulimia Nervosa, and Anorexia Nervosa

    Science.gov (United States)

    Avena, Nicole M.; Bocarsly, Miriam E.

    2012-01-01

    Food intake is mediated, in part, through brain pathways for motivation and reinforcement. Dysregulation of these pathways may underlay some of the behaviors exhibited by patients with eating disorders. Research using animal models of eating disorders has greatly contributed to the detailed study of potential brain mechanisms that many underlie the causes or consequences of aberrant eating behaviors. This review focuses on neurochemical evidence of reward-related brain dysfunctions obtained through animal models of binge eating, bulimia nervosa, or anorexia nervosa. The findings suggest that alterations in dopamine (DA), acetylcholine (ACh) and opioid systems in reward-related brain areas occur in response to binge eating of palatable foods. Moreover, animal models of bulimia nervosa suggest that while bingeing on palatable food releases DA, purging attenuates the release of ACh that might otherwise signal satiety. Animal models of anorexia nervosa suggest that restricted access to food enhances the reinforcing effects of DA when the animal does eat. The activity-based anorexia model suggests alterations in mesolimbic DA and serotonin occur as a result of starvation coupled with excessive wheel running. These findings with animal models complement data obtained through neuroimaging and pharmacotherapy studies of clinical populations. Finally, information on the neurochemical consequences of the behaviors associated with these eating disorders will be useful in understanding these complex disorders and may inform future therapeutic approaches, as discussed here. PMID:22138162

  20. Increased radiosensitivity of HPV-positive head and neck cancer cell lines due to cell cycle dysregulation and induction of apoptosis

    International Nuclear Information System (INIS)

    Arenz, Andrea; Ziemann, Frank; Wittig, Andrea; Preising, Stefanie; Engenhart-Cabillic, Rita; Mayer, Christina; Wagner, Steffen; Klussmann, Jens-Peter; Wittekindt, Claus; Dreffke, Kirstin

    2014-01-01

    Human Papillomavirus (HPV)-related head and neck squamous cell carcinoma (HNSCC) respond favourably to radiotherapy as compared to HPV-unrelated HNSCC. We investigated DNA damage response in HPV-positive and HPV-negative HNSCC cell lines aiming to identify mechanisms, which illustrate reasons for the increased sensitivity of HPV-positive cancers of the oropharynx. Radiation response including clonogenic survival, apoptosis, DNA double-strand break (DSB) repair, and cell cycle redistribution in four HPV-positive (UM-SCC-47, UM-SCC-104, 93-VU-147T, UPCI:SCC152) and four HPV-negative (UD-SCC-1, UM-SCC-6, UM-SCC-11b, UT-SCC-33) cell lines was evaluated. HPV-positive cells were more radiosensitive (mean SF2: 0.198 range: 0.22-0.18) than HPV-negative cells (mean SF2: 0.34, range: 0.45-0.27; p = 0.010). Irradiated HPV-positive cell lines progressed faster through S-phase showing a more distinct accumulation in G2/M. The abnormal cell cycle checkpoint activation was accompanied by a more pronounced increase of cell death after x-irradiation and a higher number of residual and unreleased DSBs. The enhanced responsiveness of HPV-related HNSCC to radiotherapy might be caused by a higher cellular radiosensitivity due to cell cycle dysregulation and impaired DNA DSB repair. (orig.) [de

  1. Dysregulation of brain reward systems in eating disorders: neurochemical information from animal models of binge eating, bulimia nervosa, and anorexia nervosa.

    Science.gov (United States)

    Avena, Nicole M; Bocarsly, Miriam E

    2012-07-01

    Food intake is mediated, in part, through brain pathways for motivation and reinforcement. Dysregulation of these pathways may underlay some of the behaviors exhibited by patients with eating disorders. Research using animal models of eating disorders has greatly contributed to the detailed study of potential brain mechanisms that many underlie the causes or consequences of aberrant eating behaviors. This review focuses on neurochemical evidence of reward-related brain dysfunctions obtained through animal models of binge eating, bulimia nervosa, or anorexia nervosa. The findings suggest that alterations in dopamine (DA), acetylcholine (ACh) and opioid systems in reward-related brain areas occur in response to binge eating of palatable foods. Moreover, animal models of bulimia nervosa suggest that while bingeing on palatable food releases DA, purging attenuates the release of ACh that might otherwise signal satiety. Animal models of anorexia nervosa suggest that restricted access to food enhances the reinforcing effects of DA when the animal does eat. The activity-based anorexia model suggests alterations in mesolimbic DA and serotonin occur as a result of restricted eating coupled with excessive wheel running. These findings with animal models complement data obtained through neuroimaging and pharmacotherapy studies of clinical populations. Information on the neurochemical consequences of the behaviors associated with these eating disorders will be useful in understanding these complex disorders and may inform future therapeutic approaches, as discussed here. This article is part of a Special Issue entitled 'Central Control of Food Intake'. Copyright © 2011 Elsevier Ltd. All rights reserved.

  2. Impulsivity in borderline personality disorder: a matter of disturbed impulse control or a facet of emotional dysregulation?

    Science.gov (United States)

    Sebastian, Alexandra; Jacob, Gitta; Lieb, Klaus; Tüscher, Oliver

    2013-02-01

    Impulsivity is regarded as a clinical, diagnostic and pathophysiological hallmark of borderline personality disorder (BPD). Self-report measures of impulsivity consistently support the notion of higher impulsive traits in BPD patients as compared to healthy control subjects. Laboratory tests of impulsivity, i.e. neuropsychological tests of impulse control render weak and inconsistent results both across different cognitive components of impulse control and within the same cognitive component of impulse control. One important factor worsening impulsive behaviors and impulse control deficits in BPD is comorbid attention-deficit/hyperactivity disorder (ADHD). In addition, emotional dysregulation interacts with impulse control especially for BPD salient emotions. In sum, although basic mechanisms of impulse control seem not to be disturbed in BPD, clinically well observed impulsive behaviors may be explained by comorbid ADHD or may be the consequence of dysregulation of BPD salient emotions.

  3. Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD): exome sequencing of trios, monozygotic twins and tumours

    OpenAIRE

    Barclay, Sarah F.; Rand, Casey M.; Borch, Lauren A.; Nguyen, Lisa; Gray, Paul A.; Gibson, William T.; Wilson, Richard J. A.; Gordon, Paul M. K.; Aung, Zaw; Berry-Kravis, Elizabeth M.; Ize-Ludlow, Diego; Weese-Mayer, Debra E.; Bech-Hansen, N. Torben

    2015-01-01

    Background Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified. We searched for de novo coding mutations among a carefully-diagnosed and clinically homogeneous cohort of 35 ROHHAD patients. Methods We sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin ...

  4. Does school mobility place elementary school children at risk for lower math achievement? The mediating role of cognitive dysregulation.

    Science.gov (United States)

    Friedman-Krauss, Allison H; Raver, C Cybele

    2015-12-01

    Children growing up in poverty have a higher likelihood of exposure to multiple forms of adversity that jeopardize their chances of academic success. The current paper identifies school mobility, or changing schools, as 1 such poverty-related risk. Using a sample of low-income, predominantly ethnic-minority children (n = 381) in Chicago, this study tests the hypothesis that repeatedly changing schools during the 5-year period between Head Start (preschool) and third grade is a potent predictor of children's math achievement in fourth grade and that children's cognitive dysregulation serves as a mechanism through which school mobility may negatively affect children's math achievement. Hierarchical linear models controlling for baseline child and family characteristics (including children's early math and dysregulation measured during Head Start) revealed an inverse relation between the number of times low-income children changed schools between preschool and third grade and children's math achievement on state standardized tests in fourth grade. Furthermore, frequently changing schools (3 or 4 school changes over the same time period) was positively associated with teacher-reported cognitive dysregulation in third grade and negatively associated with children's math achievement in fourth grade. Evidence for the role of children's cognitive dysregulation as a partial statistical mediator was found for the relation between frequently changing schools and math achievement, even after accounting for baseline risk. Results are discussed in terms of school policies, practices, and intervention strategies to prevent the disruptive and potentially stressful experiences of school mobility for young, low-income children. (c) 2015 APA, all rights reserved).

  5. Quantitative proteomics reveals the mechanism and consequence of gliotoxin-mediated dysregulation of the methionine cycle in Aspergillus niger

    OpenAIRE

    Manzanares-Miralles, Lara; Bayram, Ozgur; Sarikaya-Bayram, Ozlem; Smith, Elizabeth B.; Dolan, Stephen K.; Jones, Gary W.; Doyle, Sean

    2016-01-01

    Gliotoxin (GT) is a redox-active metabolite, produced by Aspergillus fumigatus,which inhibits the growth of other fungi. Here we demonstrate how Aspergillus niger responds to GT exposure. Quantitative proteomics revealed that GT dysregulated the abundance of 378 proteins including those involved in methionine metabolism and induced de novo abundance of two S-adenosylmethionine (SAM)-dependent methyltransferases. Increased abundance of enzymes S-adenosylhomocysteinase (p = 0.0018) ...

  6. Does School Mobility Place Elementary School Children at Risk for Lower Math Achievement? The Mediating Role of Cognitive Dysregulation

    Science.gov (United States)

    Friedman-Krauss, Allison H.; Raver, C. Cybele

    2015-01-01

    Children growing up in poverty have a higher likelihood of exposure to multiple forms of adversity that jeopardize their chances of academic success. The current paper identifies school mobility, or changing schools, as 1 such poverty-related risk. Using a sample of low-income, predominantly ethnic-minority children (n = 381) in Chicago, this study tests the hypothesis that repeatedly changing schools during the 5-year period between Head Start (preschool) and third grade is a potent predictor of children’s math achievement in fourth grade and that children’s cognitive dysregulation serves as a mechanism through which school mobility may negatively affect children’s math achievement. Hierarchical linear models controlling for baseline child and family characteristics (including children’s early math and dysregulation measured during Head Start) revealed an inverse relation between the number of times low-income children changed schools between preschool and third grade and children’s math achievement on state standardized tests in fourth grade. Furthermore, frequently changing schools (3 or 4 school changes over the same time period) was positively associated with teacher-reported cognitive dysregulation in third grade and negatively associated with children’s math achievement in fourth grade. Evidence for the role of children’s cognitive dysregulation as a partial statistical mediator was found for the relation between frequently changing schools and math achievement, even after accounting for baseline risk. Results are discussed in terms of school policies, practices, and intervention strategies to prevent the disruptive and potentially stressful experiences of school mobility for young, low-income children. PMID:26436870

  7. Dysregulated RNA-Induced Silencing Complex (RISC) Assembly within CNS Corresponds with Abnormal miRNA Expression during Autoimmune Demyelination.

    Science.gov (United States)

    Lewkowicz, Przemysław; Cwiklińska, Hanna; Mycko, Marcin P; Cichalewska, Maria; Domowicz, Małgorzata; Lewkowicz, Natalia; Jurewicz, Anna; Selmaj, Krzysztof W

    2015-05-13

    MicroRNAs (miRNAs) associate with Argonaute (Ago), GW182, and FXR1 proteins to form RNA-induced silencing complexes (RISCs). RISCs represent a critical checkpoint in the regulation and bioavailability of miRNAs. Recent studies have revealed dysregulation of miRNAs in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE); however, the function of RISCs in EAE and MS is largely unknown. Here, we examined the expression of Ago, GW182, and FXR1 in CNS tissue, oligodendrocytes (OLs), brain-infiltrating T lymphocytes, and CD3(+)splenocytes (SCs) of EAE mic, and found that global RISC protein levels were significantly dysregulated. Specifically, Ago2 and FXR1 levels were decreased in OLs and brain-infiltrating T cells in EAE mice. Accordingly, assembly of Ago2/GW182/FXR1 complexes in EAE brain tissues was disrupted, as confirmed by immunoprecipitation experiments. In parallel with alterations in RISC complex content in OLs, we found downregulation of miRNAs essential for differentiation and survival of OLs and myelin synthesis. In brain-infiltrating T lymphocytes, aberrant RISC formation contributed to miRNA-dependent proinflammatory helper T-cell polarization. In CD3(+) SCs, we found increased expression of both Ago2 and FXR1 in EAE compared with nonimmunized mice. Therefore, our results demonstrate a gradient in expression of miRNA between primary activated T cells in the periphery and polarized CNS-infiltrating T cells. These results suggest that, in polarized autoreactive effector T cells, miRNA synthesis is inhibited in response to dysregulated RISC assembly, allowing these cells to maintain a highly specific proinflammatory program. Therefore, our findings may provide a mechanism that leads to miRNA dysregulation in EAE/MS. Copyright © 2015 the authors 0270-6474/15/357521-17$15.00/0.

  8. Dimensions of Emotion Dysregulation in Anorexia Nervosa and Bulimia Nervosa: A Conceptual Review of the Empirical Literature

    Science.gov (United States)

    Lavender, Jason M.; Wonderlich, Stephen A.; Engel, Scott G.; Gordon, Kathryn H.; Kaye, Walter H.; Mitchell, James E.

    2015-01-01

    Several existing conceptual models and psychological interventions address or emphasize the role of emotion dysregulation in eating disorders. The current article uses Gratz and Roemer’s (2004) multidimensional model of emotion regulation and dysregulation as a clinically relevant framework to review the extant literature on emotion dysregulation in anorexia nervosa (AN) and bulimia nervosa (BN). Specifically, the dimensions reviewed include: (1) the flexible use of adaptive and situationally appropriate strategies to modulate the duration and/or intensity of emotional responses, (2) the ability to successfully inhibit impulsive behavior and maintain goal-directed behavior in the context of emotional distress, (3) awareness, clarity, and acceptance of emotional states, and (4) the willingness to experience emotional distress in the pursuit of meaningful activities. The current review suggests that both AN and BN are characterized by broad emotion regulation deficits, with difficulties in emotion regulation across the four dimensions found to characterize both AN and BN, although a small number of more specific difficulties may distinguish the two disorders. The review concludes with a discussion of the clinical implications of the findings, as well as a summary of limitations of the existing empirical literature and suggestions for future research. PMID:26112760

  9. Effects of Food Additives on Immune Cells As Contributors to Body Weight Gain and Immune-Mediated Metabolic Dysregulation.

    Science.gov (United States)

    Paula Neto, Heitor A; Ausina, Priscila; Gomez, Lilian S; Leandro, João G B; Zancan, Patricia; Sola-Penna, Mauro

    2017-01-01

    Food additives are compounds used in order to improve food palatability, texture, and shelf life. Despite a significant effort to assure safety of use, toxicological analysis of these substances, generally, rely on their direct toxicity to target organs (liver and kidney) or their genotoxic effects. Much less attention is paid to the effects of these compounds on cells of the immune system. This is of relevance given that metabolic dysregulation and obesity have a strong immune-mediated component. Obese individuals present a state of chronic low-grade inflammation that contributes to the establishment of insulin resistance and other metabolic abnormalities known as the metabolic syndrome. Obesity and metabolic syndrome are currently recognized as worldwide epidemics that pose a profound socioeconomic impact and represent a concern to public health. Cells of the immune system contribute to both the maintenance of "lean homeostasis" and the metabolic dysregulation observed in obese individuals. Although much attention has been drawn in the past decades to obesity and metabolic syndrome as a result of ingesting highly processed food containing large amounts of fat and simple sugars, mounting evidence suggest that food additives may also be important contributors to metabolic derangement. Herein, we review pieces of evidence from the literature showing that food additives have relevant effects on cells of the immune system that could contribute to immune-mediated metabolic dysregulation. Considering their potential to predispose individuals to develop obesity and metabolic syndrome, their use should be taken with caution or maybe revisited.

  10. Dysregulated DNA Methyltransferase 3A Upregulates IGFBP5 to Suppress Trophoblast Cell Migration and Invasion in Preeclampsia.

    Science.gov (United States)

    Jia, Yuanhui; Li, Ting; Huang, Xiaojie; Xu, Xianghong; Zhou, Xinyao; Jia, Linyan; Zhu, Jingping; Xie, Dandan; Wang, Kai; Zhou, Qian; Jin, Liping; Zhang, Jiqin; Duan, Tao

    2017-02-01

    Preeclampsia is a unique multiple system disorder during human pregnancy, which affects ≈5% to 8% of pregnancies. Its risks and complications have become the major causes of maternal and fetal morbidity and mortality. Although abnormal placentation to which DNA methylation dysregulation is always linked is speculated to be one of the reasons causing preeclampsia, the underlying mechanisms still remain elusive to date. Here we revealed that aberrant DNA methyltransferase 3A (DNMT3A) plays a critical role in preeclampsia. Our results show that the expression and localization of DNMT3A are dysregulated in preeclamptic placenta. Moreover, knockdown of DNMT3A obviously inhibits trophoblast cell migration and invasion. Mechanistically, IGFBP5 (insulin-like growth factor-binding protein 5), known as a suppressor, is upregulated by decreased DNMT3A because of promoter hypomethylation. Importantly, IGFBP5 downregulation can rescue the defects caused by DNMT3A knockdown, thereby, consolidating the significance of IGFBP5 in the downstream of DNMT3A in trophoblast. Furthermore, we detected low promoter methylation and high protein expression of IGFBP5 in the clinical samples of preeclamptic placenta. Collectively, our study suggests that dysregulation of DNMT3A and IGFBP5 is relevant to preeclampsia. Thus, we propose that DNMT3A and IGFBP5 can serve as potential markers and targets for the clinical diagnosis and therapy of preeclampsia. © 2017 American Heart Association, Inc.

  11. Effect of Methylphenidate on Emotional Dysregulation in Children With Attention-Deficit/Hyperactivity Disorder + Oppositional Defiant Disorder/Conduct Disorder.

    Science.gov (United States)

    Kutlu, Ayse; Akyol Ardic, Ulku; Ercan, Eyup Sabri

    2017-04-01

    Emotional dysregulation (ED) is a frequent feature of attention-deficit/hyperactivity disorder (ADHD). It can be observed as a dysregulation profile or a deficient emotional self-regulation (DESR) profile. Oppositional defiant disorder/conduct disorder (ODD/CD) comorbidity is prevalent in ADHD and known to be related with ED. The first-line treatment of ADHD includes psychostimulants, but their effects on ED are not well studied. This study aimed to evaluate the outcomes of methylphenidate (MPH) treatment on ED in ADHD + ODD/CD cases. A total of 118 ADHD + ODD/CD patients with a mean age of 9.0 ± 1.9 years were treated with MPH for 1 year. Also, parents of cases were recruited for a parent-training program, which initiated after first month of MPH treatment. Symptom severity was assessed at baseline and 12th month by Turgay Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Based Child and Adolescent Behavior Disorders Screening and Rating Scale-Parent Form, Children Depression Inventory, Child Behavior Checklist 4-18 years, and Parental Acceptance and Rejection Questionnaire-Mother Form. Emotional dysregulation (DESR + DP) was present in 85.6% of cases. Conduct disorder was significantly higher in patients with DP, whereas ODD was significantly higher in the DESR and non-ED groups (P disorders as ODD and CD, which are comorbid with ADHD. The MPH treatment is effective on ED independently from other clinical determinants.

  12. Effects of Food Additives on Immune Cells As Contributors to Body Weight Gain and Immune-Mediated Metabolic Dysregulation

    Directory of Open Access Journals (Sweden)

    Heitor A. Paula Neto

    2017-11-01

    Full Text Available Food additives are compounds used in order to improve food palatability, texture, and shelf life. Despite a significant effort to assure safety of use, toxicological analysis of these substances, generally, rely on their direct toxicity to target organs (liver and kidney or their genotoxic effects. Much less attention is paid to the effects of these compounds on cells of the immune system. This is of relevance given that metabolic dysregulation and obesity have a strong immune-mediated component. Obese individuals present a state of chronic low-grade inflammation that contributes to the establishment of insulin resistance and other metabolic abnormalities known as the metabolic syndrome. Obesity and metabolic syndrome are currently recognized as worldwide epidemics that pose a profound socioeconomic impact and represent a concern to public health. Cells of the immune system contribute to both the maintenance of “lean homeostasis” and the metabolic dysregulation observed in obese individuals. Although much attention has been drawn in the past decades to obesity and metabolic syndrome as a result of ingesting highly processed food containing large amounts of fat and simple sugars, mounting evidence suggest that food additives may also be important contributors to metabolic derangement. Herein, we review pieces of evidence from the literature showing that food additives have relevant effects on cells of the immune system that could contribute to immune-mediated metabolic dysregulation. Considering their potential to predispose individuals to develop obesity and metabolic syndrome, their use should be taken with caution or maybe revisited.

  13. The Effectiveness of the Unified Protocol on Emotional Dysregulation and Cognitive Emotion Regulation Strategies in Patients with Psychosomatic Disorders

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    Mina Mazaheri

    2014-01-01

    Full Text Available Background: The unified treatment approach (UP is an emotion-focused cognitive-behavioral therapy in which the main object of treatment is emotional processes. The aim of the present research was to examine the effectiveness of The Unified Protocol (UP on emotional dysregulation and cognitive emotion regulation strategies in patients with psychosomatic disorders. Methods: Emotion-focused cognitive behavioral therapy (ECBT, a unified treatment, with 12 weekly group sessions of 2 hours, was presented to 14 patients with psychosomatic complaints at the Subspecialty Center of Psychiatry in Isfahan in 2013. Pre- and post-intervention assessments were done by means of the self-report tests of Difficulties in Emotion Regulation Scale (DERS and Cognitive Emotion Regulation Questionnaire (CERQ. Results: Significant reductions in post-test scores of total emotional dysregulation (P < 0.01 as well as the factors of non-acceptance (P < 0.05 and strategy (P < 0.01 were seen, while the other factors (goal, impulse, awareness, and clarity did not change. Moreover, a significant reduction was observed in the catastrophizing strategy score (P < 0.05, in comparison with other cognitive strategies. Conclusion: This pilot study including 14 patients with psychosomatic disorders indicates that the Unified treatment approach is an effective treatment in improvement of emotional dysregulation and in reduction of utilizing maladaptive cognitive strategies.

  14. GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways.

    Science.gov (United States)

    Guerenne, Laura; Beurlet, Stéphanie; Said, Mohamed; Gorombei, Petra; Le Pogam, Carole; Guidez, Fabien; de la Grange, Pierre; Omidvar, Nader; Vanneaux, Valérie; Mills, Ken; Mufti, Ghulam J; Sarda-Mantel, Laure; Noguera, Maria Elena; Pla, Marika; Fenaux, Pierre; Padua, Rose Ann; Chomienne, Christine; Krief, Patricia

    2016-01-27

    In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS) patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease. We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS) and acute myeloid leukemia (AML) post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively. Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples. These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study.

  15. GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways

    Directory of Open Access Journals (Sweden)

    Laura Guerenne

    2016-01-01

    Full Text Available Abstract Background In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease. Methods We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS and acute myeloid leukemia (AML post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively. Results Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples. Conclusions These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study.

  16. Prediction of Smoking, Alcohol, Drugs, and Psychoactive Drugs Abuse Based on Emotional Dysregulation and Child Abuse Experience in People with Borderline Personality Traits

    Directory of Open Access Journals (Sweden)

    M GannadiFarnood

    2014-12-01

    Full Text Available Objective: This research was an attempt to predict the tendency of people having borderline personality traits to smoking, drinking alcohol, and taking psychoactive drugs based on emotional dysregulation and child abuse. Method: This study employed a correlation method which is categorized in descriptive category. A sample including 600 male and female bachelor students of Tabriz University was selected by cluster sampling. Then, high risk behaviors scale, Emotional dysregulation Scale, Child abuse scale, and borderline personality scale (STB were distributed among this group. Findings: Stepwise multiple regression analysis suggested that emotional dysregulation and child abuse significantly predicted varying degrees of smoking, drug, and alcohol usage. Conclusion: The research findings suggest the basic role of initial biological vulnerability in terms of emotional regulation (dysregulation and invalidating family environment (child abuse in the prediction of catching the disorder of borderline personality traits and producing high riskbehaviorssuch as alcohol drink and drug usage.

  17. The emotion dysregulation inventory: Psychometric properties and item response theory calibration in an autism spectrum disorder sample.

    Science.gov (United States)

    Mazefsky, Carla A; Yu, Lan; White, Susan W; Siegel, Matthew; Pilkonis, Paul A

    2018-04-06

    Individuals with autism spectrum disorder (ASD) often present with prominent emotion dysregulation that requires treatment but can be difficult to measure. The Emotion Dysregulation Inventory (EDI) was created using methods developed by the Patient-Reported Outcomes Measurement Information System (PROMIS ® ) to capture observable indicators of poor emotion regulation. Caregivers of 1,755 youth with ASD completed 66 candidate EDI items, and the final 30 items were selected based on classical test theory and item response theory (IRT) analyses. The analyses identified two factors: (a) Reactivity, characterized by intense, rapidly escalating, sustained, and poorly regulated negative emotional reactions, and (b) Dysphoria, characterized by anhedonia, sadness, and nervousness. The final items did not show differential item functioning (DIF) based on gender, age, intellectual ability, or verbal ability. Because the final items were calibrated using IRT, even a small number of items offers high precision, minimizing respondent burden. IRT co-calibration of the EDI with related measures demonstrated its superiority in assessing the severity of emotion dysregulation with as few as seven items. Validity of the EDI was supported by expert review, its association with related constructs (e.g., anxiety and depression symptoms, aggression), higher scores in psychiatric inpatients with ASD compared to a community ASD sample, and demonstration of test-retest stability and sensitivity to change. In sum, the EDI provides an efficient and sensitive method to measure emotion dysregulation for clinical assessment, monitoring, and research in youth with ASD of any level of cognitive or verbal ability. Autism Res 2018. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. This paper describes a new measure of poor emotional control called the Emotion Dysregulation Inventory (EDI). Caregivers of 1,755 youth with ASD completed candidate items, and advanced statistical

  18. Acquired partial lipodystrophy and C3 glomerulopathy: Dysregulation of the complement system as a common mechanism

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    Fernando Corvillo

    2018-05-01

    Full Text Available The activation of the alternative pathway of the complement is involved in the development of several renal diseases, such as atypical haemolytic uraemic syndrome and C3 glomerulopathy. In C3 glomerulopathy, a high percentage of patients have circulating levels of the autoantibody called C3NeF, which causes systemic dysregulation of the complement system. In some cases, the presence of this antibody has been related with abnormalities of adipose tissue, causing acquired partial lipodystrophy (Barraquer–Simons syndrome. Acquired partial lipodystrophy is an extremely rare disorder affecting the distribution of subcutaneous adipose tissue and that mainly onsets during childhood. These patients, in addition to possibly presenting with all the metabolic disorders associated with the adipose tissue defect, present with C3 hypocomplementemia and C3NeF and 25% have developed C3 glomerulopathy. Although it has been known for some time how the dysregulation of the complement system affects the kidneys, it remains unknown how it exactly affects adipose tissue; nevertheless, the relationship is quite clear. In this paper, we describe the connection between the complement system with the biology of the adipose tissue and its pathogenesis reflected from acquired partial lipodystrophy. Resumen: La activación de la vía alternativa del complemento interviene en el desarrollo de varias enfermedades renales, como el síndrome hemolítico urémico atípico o la glomerulopatía C3. En esta última enfermedad un elevado porcentaje de los pacientes presentan niveles circulantes de un autoanticuerpo denominado C3NeF, causante de la desregulación del complemento a nivel sistémico. En ciertos casos, la presencia de este anticuerpo se asocia con alteraciones en el tejido adiposo, causando lipodistrofia parcial adquirida (síndrome de Barraquer-Simons, una enfermedad ultra-rara que afecta a la distribución del tejido adiposo subcutáneo y que comienza principalmente

  19. A whole-body mathematical model of cholesterol metabolism and its age-associated dysregulation

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    Mc Auley Mark T

    2012-10-01

    clearance of LDL-C gradually to 50% by age 65 years can result in an increase of LDL-C by as much as 116 mg/dL. Conclusions Our model clearly demonstrates that of the two putative mechanisms that have been implicated in the dysregulation of cholesterol metabolism with age, alterations to the removal rate of plasma LDL-C has the most significant impact on cholesterol metabolism and small changes to the number of hepatic LDL receptors can result in a significant rise in LDL-C. This first whole-body systems based model of cholesterol balance could potentially be used as a tool to further improve our understanding of whole-body cholesterol metabolism and its dysregulation with age. Furthermore, given further fine tuning the model may help to investigate potential dietary and lifestyle regimes that have the potential to mitigate the effects aging has on cholesterol metabolism.

  20. Rapid-onset obesity, hypoventilation, hypothalamic dysfunction, autonomic dysregulation and neuroendocrine tumor syndrome with a homogenous enlargement of the pituitary gland: a case report.

    Science.gov (United States)

    Aljabban, Lama; Kassab, Lina; Bakoura, Nour Alhuda; Alsalka, Mohammad Fayez; Maksoud, Ismaeil

    2016-11-22

    Rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome is a rare pediatric disorder with a variable sequence of clinical presentations, undefined etiology, and high risk of mortality. Our patient presented an unusual course of the disease accompanied by a homogenous mild enlargement of her pituitary gland with an intact pituitary-endocrine axis which, to the best of our knowledge, represents a new finding in rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome. We present a documented case of a 4 years and 8-month-old Syrian Arabic girl with a distinctive course of signs and symptoms of rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome accompanied by mature ganglioneuroma in her chest, a homogenous mild enlargement of her pituitary gland, generalized cortical brain atrophy, and seizures. Three months after her first marked symptoms were noted she had a sudden progression of severe respiratory distress that ended with her death. The findings of this case could increase our understanding of the pathogenetic mechanisms of rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation, and place more emphases on pediatricians to consider rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome whenever early rapid onset of obesity, associated with any malfunction, is observed in children. This knowledge could be lifesaving for children with rapid-onset obesity with hypoventilation, hypothalamic dysfunction, and autonomic dysregulation syndrome.

  1. Histone Deacetylase Inhibitor Alleviates the Neurodegenerative Phenotypes and Histone Dysregulation in Presenilins-Deficient Mice

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    Ting Cao

    2018-05-01

    Full Text Available Histone acetylation has been shown to play a crucial role in memory formation, and histone deacetylase (HDAC inhibitor sodium butyrate (NaB has been demonstrated to improve memory performance and rescue the neurodegeneration of several Alzheimer’s Disease (AD mouse models. The forebrain presenilin-1 and presenilin-2 conditional double knockout (cDKO mice showed memory impairment, forebrain degeneration, tau hyperphosphorylation and inflammation that closely mimics AD-like phenotypes. In this article, we have investigated the effects of systemic administration of NaB on neurodegenerative phenotypes in cDKO mice. We found that chronic NaB treatment significantly restored contextual memory but did not alter cued memory in cDKO mice while such an effect was not permanent after treatment withdrawal. We further revealed that NaB treatment did not rescue reduced synaptic numbers and cortical shrinkage in cDKO mice, but significantly increased the neurogenesis in subgranular zone of dentate gyrus (DG. We also observed that tau hyperphosphorylation and inflammation related protein glial fibrillary acidic protein (GFAP level were decreased in cDKO mice by NaB. Furthermore, GO and pathway analysis for the RNA-Seq data demonstrated that NaB treatment induced enrichment of transcripts associated with inflammation/immune processes and cytokine-cytokine receptor interactions. RT-PCR confirmed that NaB treatment inhibited the expression of inflammation related genes such as S100a9 and Ccl4 found upregulated in the brain of cDKO mice. Surprisingly, the level of brain histone acetylation in cDKO mice was dramatically increased and was decreased by the administration of NaB, which may reflect dysregulation of histone acetylation underlying memory impairment in cDKO mice. These results shed some lights on the possible molecular mechanisms of HDAC inhibitor in alleviating the neurodegenerative phenotypes of cDKO mice and provide a promising target for treating AD.

  2. Dysregulated CD46 shedding interferes with Th1-contraction in systemic lupus erythematosus.

    Science.gov (United States)

    Ellinghaus, Ursula; Cortini, Andrea; Pinder, Christopher L; Le Friec, Gaelle; Kemper, Claudia; Vyse, Timothy J

    2017-07-01

    IFN-γ-producing T helper 1 (Th1) cell responses mediate protection against infections but uncontrolled Th1 activity also contributes to a broad range of autoimmune diseases. Autocrine complement activation has recently emerged as key in the induction and contraction of human Th1 immunity: activation of the complement regulator CD46 and the C3aR expressed by CD4 + T cells via autocrine generated ligands C3b and C3a, respectively, are critical to IFN-γ production. Further, CD46-mediated signals also induce co-expression of immunosuppressive IL-10 in Th1 cells and transition into a (self)-regulating and contracting phase. In consequence, C3 or CD46-deficient patients suffer from recurrent infections while dysregulation of CD46 signaling contributes to Th1 hyperactivity in rheumatoid arthritis and multiple sclerosis. Here, we report a defect in CD46-regulated Th1 contraction in patients with systemic lupus erythematosus (SLE). We observed that MMP-9-mediated increased shedding of soluble CD46 by Th1 cells was associated with this defect and that inhibition of MMP-9 activity normalized release of soluble CD46 and restored Th1 contraction in patients' T cells. These data may deliver the first mechanistic explanation for the increased serum CD46 levels observed in SLE patients and indicate that targeting CD46-cleaving proteases could be a novel avenue to modulate Th1 responses. © 2017 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): Response to ventilatory challenges.

    Science.gov (United States)

    Carroll, Michael S; Patwari, Pallavi P; Kenny, Anna S; Brogadir, Cindy D; Stewart, Tracey M; Weese-Mayer, Debra E

    2015-12-01

    Hypoventilation is a defining feature of Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), a rare respiratory and autonomic disorder. This chronic hypoventilation has been explained as the result of dysfunctional chemosensory control circuits, possibly affecting peripheral afferent input, central integration, or efferent motor control. However, chemosensory function has never been quantified in a cohort of ROHHAD patients. Therefore, the purpose of this study was to assess the response to awake ventilatory challenge testing in children and adolescents with ROHHAD. The ventilatory, cardiovascular and cerebrovascular responses in 25 distinct comprehensive physiological recordings from seven unique ROHHAD patients to three different gas mixtures were analyzed at breath-to-breath and beat-to-beat resolution as absolute measures, as change from baseline, or with derived metrics. Physiologic measures were recorded during a 3-min baseline period of room air, a 3-min gas exposure (of 100% O2; 95% O2, 5% CO2; or 14% O2, 7% CO2 balanced with N2), and a 3-min recovery period. An additional hypoxic challenge was conducted which consisted of either five or seven tidal breaths of 100% N2. While ROHHAD cases showed a diminished VT and inspiratory drive response to hypoxic hypercapnia and absent behavioral awareness of the physiologic compromise, most ventilatory, cardiovascular, and cerebrovascular measures were similar to those of previously published controls using an identical protocol, suggesting a mild chemosensory deficit. Nonetheless, the high mortality rate, comorbidity and physiological fragility of patients with ROHHAD demand continued clinical vigilance. © 2015 Wiley Periodicals, Inc.

  4. Smoking before isometric exercise amplifies myocardial stress and dysregulates baroreceptor sensitivity and cerebral oxygenation.

    Science.gov (United States)

    Anyfanti, Panagiota; Triantafyllidou, Eleftheria; Papadopoulos, Stavros; Triantafyllou, Areti; Nikolaidis, Michalis G; Kyparos, Antonios; Vrabas, Ioannis S; Douma, Stella; Zafeiridis, Andreas; Dipla, Konstantina

    2017-06-01

    This crossover study examined whether acute cardiovascular responses, baroreceptor sensitivity (BRS), and brain oxygenation during isometric exercise are altered after cigarette smoking. Twelve young, habitual smokers randomly performed a smoking and a control protocol, during which participants smoked one cigarette (0.9 mg nicotine) or a sham cigarette, before exercise. Testing involved baseline, a 5-minute smoking, a 10-minute post-smoking rest, 3-minute handgrip exercise (30% maximum voluntary contraction), and recovery. Beat-to-beat blood pressure, heart rate (HR), and cerebral oxygenation (near infrared spectroscopy) were continuously monitored. Double-product, stroke volume (SV), cardiac output, systemic vascular resistance and BRS were assessed. During post-smoking rest, systolic or diastolic blood pressure (140.8 ± 12.1/87.0 ± 6.9 vs. 125.9 ± 7.1/77.3 ± 5.5 mm Hg), HR, and double product were higher in the smoking versus the control protocol, whereas BRS was lower (P exercise, smoking resulted in greater HR and double product (17,240 ± 3893 vs. 15,424 ± 3173 mm Hg·bpm) and lower BRS versus the control protocol (P smoking elicited a delayed return of brain oxygenation indices, lower BRS, and higher double product. Smoking a cigarette shortly before the exercise session amplifies myocardial stress and dysregulates autonomic function and cerebral oxygenation during exercise and recovery, even in young habitual smokers, perceived as free from long-term cardiovascular effects of smoking. Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

  5. HPA axis dysregulation, NR3C1 polymorphisms and glucocorticoid receptor isoforms imbalance in metabolic syndrome.

    Science.gov (United States)

    Martins, Clarissa Silva; Elias, Daniel; Colli, Leandro Machado; Couri, Carlos Eduardo; Souza, Manoel Carlos L A; Moreira, Ayrton C; Foss, Milton C; Elias, Lucila L K; de Castro, Margaret

    2017-03-01

    Metabolic syndrome (MetS) shares several similarities with hypercortisolism. To evaluate hypothalamic-pituitary-adrenal (HPA) axis sensitivity to dexamethasone (DEX), NR3C1 single nucleotide polymorphisms (SNPs), and expression of glucocorticoid receptor (GR) isoforms and cytokines in peripheral immune cells of MetS patients and controls. Prospective study with 40 MetS patients and 40 controls was conducted at the Ribeirão Preto Medical School University Hospital. Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5, and 1 mg of DEX given at 2300 h. In addition, p.N363S (rs6195), p.ER22/23EK (rs6189-6190), and BclI (rs41423247) SNPs were evaluated by quantitative polymerase chain reaction allelic discrimination. Exons 3 to 9 and exon/intron boundaries of NR3C1 were sequenced. GR isoforms and cytokines (IL1B, IL2, IL4, IL6, IL8, IL10, IFNγ, TNFα) expression were assessed by quantitative polymerase chain reaction. Plasma and salivary cortisol (nmol/L) after 1-mg DEX were higher in MetS patients compared with controls (PF: 70.2 ± 17.3 vs 37.9 ± 2.6, P = .02, and SF: 4.9 ± 1.7 vs 2.2 ± 0.3, P molecular mechanism of glucocorticoid resistance in MetS. Thus, HPA axis dysregulation might contribute to MetS pathogenesis. Copyright © 2016 John Wiley & Sons, Ltd.

  6. Temporal associations between affective instability and dysregulated eating behavior in bulimia nervosa.

    Science.gov (United States)

    Berner, Laura A; Crosby, Ross D; Cao, Li; Engel, Scott G; Lavender, Jason M; Mitchell, James E; Wonderlich, Stephen A

    2017-09-01

    Prior research suggests that the construct of emotional instability may be salient to bulimia nervosa (BN), but no study to date has used ecological momentary assessment (EMA) to examine its temporal association with binge eating and purging. In the current study, 133 women with DSM-IV BN used portable digital devices to provide multiple daily negative affect (NA) and positive affect (PA) ratings and record eating disorder behaviors over 2 weeks. Two state-of-the art indices quantified affective instability: probability of acute change (PAC), which represents the likelihood of extreme affective increases, and mean squared successive difference (MSSD), which represents average change over successive recordings. For extreme affective change, results revealed that on bulimic behavior days, extreme NA increases were less likely after bulimic behaviors than before them, and extreme increases in PA were more likely after bulimic behaviors than during the same time period on non-bulimic behavior days. However, average NA instability (i.e., MSSD) was (a) greater on bulimic behavior days than non-bulimic behavior days, (b) greater after bulimic behaviors than during the same time period on non-bulimic behavior days, and (c) greater after bulimic behaviors than before them. Results lend support to the notion that bulimic behaviors are negatively reinforcing (i.e., via post-behavior acute affective changes), but also indicate that these behaviors may exacerbate overall affective dysregulation. These findings may improve understanding of BN maintenance and inform the development of novel interventions or refinement of existing treatments. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Dysregulation of long noncoding RNAs in mouse testes and spermatozoa after exposure to cadmium

    International Nuclear Information System (INIS)

    Gao, Fengxin; Zhang, Peng; Zhang, Hongyan; Zhang, Yunhui; Zhang, Yunwen; Hao, Qingyun; Zhang, Xiaoning

    2017-01-01

    There is increasing evidence that cadmium (Cd) exposure can cause male subfertility and even complete infertility in mammals. Long noncoding (lnc) RNAs are critical for spermatogenesis, and their dysregulation might lead to male infertility. However, whether they are involved in Cd-induced subfertility is unknown. Here we found that intraperitoneal exposure to Cd in mice led to male subfertility indicated by reductions in testicular sperm production and motility, and by abnormal morphology. Testicular and sperm RNAs were used to investigate lncRNA expression profiles by strand-specific RNA sequencing at the transcriptome level to help determine any RNA-related mechanisms in Cd-induced subfertility. The Cd-treated testes and spermatozoa exhibited aberrant expression profiles for lncRNAs and mRNAs. Of the lncRNAs, there were 139 with upregulated expression and 174 with downregulated expression in testes; in contrast, 685 were upregulated and 375 were downregulated in spermatozoa. For mRNA expression, 214 were upregulated and 226 were downregulated in testes; 272 were upregulated and 111 were downregulated in spermatozoa. Gene ontology and pathway analyses showed that the functions of differentially expressed lncRNA targets and mRNAs were closely linked with many processes involved in spermatogenesis. Additionally, many newly identified lncRNAs showed inducible expression, suggesting that they might be good candidate markers for Cd-induced male reproductive toxicity. This study provides a preliminary database for further exploring lncRNA-related mechnisms in male infertility induced by Cd. - Highlights: • LncRNA profiles were changed by Cd exposure in mouse testes and spermatozoa. • Differentially expressed lncRNA targets and mRNAs were linked with spermatogenesis. • Providing a database for exploring lncRNA-related mechnisms in male infertility. • LncRNA might be candidate markers for Cd-induced male reproductive toxicity.

  8. Tributyltin exposure at noncytotoxic doses dysregulates pancreatic β-cell function in vitro and in vivo.

    Science.gov (United States)

    Chen, Ya-Wen; Lan, Kuo-Cheng; Tsai, Jing-Ren; Weng, Te-I; Yang, Ching-Yao; Liu, Shing-Hwa

    2017-09-01

    Tributyltin (TBT) is an endocrine disruptor. TBT can be found in food and in human tissues and blood. Several animal studies revealed that organotins induced diabetes with decreased insulin secretion. The detailed effect and mechanism of TBT on pancreatic β-cell function still remain unclear. We investigated the effect and mechanism of TBT exposure at noncytotoxic doses relevant to human exposure on β-cell function in vitro and in vivo. The β-cell-derived RIN-m5F cells and pancreatic islets from mouse and human were treated with TBT (0.05-0.2 μM) for 0.5-4 h. Adult male mice were orally exposed to TBT (25 μg/kg/day) with or without antioxidant N-acetylcysteine (NAC) for 1-3 weeks. Assays for insulin secretion and glucose metabolism were carried out. Unlike previous studies, TBT at noncytotoxic concentrations significantly increased glucose-stimulated insulin secretion and intracellular Ca 2+ ([Ca 2+ ] i ) in β-cells. The reactive oxygen species (ROS) production and phosphorylation of protein kinase C (PKC-pan) and extracellular signal-regulated kinase (ERK)1/2 were also increased. These TBT-triggered effects could be reversed by antiestrogen ICI182780 and inhibitors of ROS, [Ca 2+ ] i , and PKC, but not ERK. Similarly, islets treated with TBT significantly increased glucose-stimulated insulin secretion, which could be reversed by ICI182780, NAC, and PKC inhibitor. Mice exposed to TBT for 3 weeks significantly increased blood glucose and plasma insulin and induced glucose intolerance and insulin resistance, which could be reversed by NAC. These findings suggest that low/noncytotoxic doses of TBT induce insulin dysregulation and disturb glucose homeostasis, which may be mediated through the estrogen receptor-regulated and/or oxidative stress-related signaling pathways.

  9. Humoral Dysregulation Associated with Increased Systemic Inflammation among Injection Heroin Users.

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    Michael S Piepenbrink

    Full Text Available Injection drug use is a growing major public health concern. Injection drug users (IDUs have a higher incidence of co-morbidities including HIV, Hepatitis, and other infections. An effective humoral response is critical for optimal homeostasis and protection from infection; however, the impact of injection heroin use on humoral immunity is poorly understood. We hypothesized that IDUs have altered B cell and antibody profiles.A comprehensive systems biology-based cross-sectional assessment of 130 peripheral blood B cell flow cytometry- and plasma- based features was performed on HIV-/Hepatitis C-, active heroin IDUs who participated in a syringe exchange program (n = 19 and healthy control subjects (n = 19. The IDU group had substantial polydrug use, with 89% reporting cocaine injection within the preceding month. IDUs exhibited a significant, 2-fold increase in total B cells compared to healthy subjects, which was associated with increased activated B cell subsets. Although plasma total IgG titers were similar between groups, IDUs had significantly higher IgG3 and IgG4, suggestive of chronic B cell activation. Total IgM was also increased in IDUs, as well as HIV Envelope-specific IgM, suggestive of increased HIV exposure. IDUs exhibited numerous features suggestive of systemic inflammation, including significantly increased plasma sCD40L, TNF-α, TGF-α, IL-8, and ceramide metabolites. Machine learning multivariate analysis distilled a set of 10 features that classified samples based on group with absolute accuracy.These results demonstrate broad alterations in the steady-state humoral profile of IDUs that are associated with increased systemic inflammation. Such dysregulation may impact the ability of IDUs to generate optimal responses to vaccination and infection, or lead to increased risk for inflammation-related co-morbidities, and should be considered when developing immune-based interventions for this growing population.

  10. Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis.

    Science.gov (United States)

    Amici, David R; Pinal-Fernandez, Iago; Mázala, Davi A G; Lloyd, Thomas E; Corse, Andrea M; Christopher-Stine, Lisa; Mammen, Andrew L; Chin, Eva R

    2017-03-22

    Sporadic inclusion body myositis (IBM) is the most common primary myopathy in the elderly, but its pathoetiology is still unclear. Perturbed myocellular calcium (Ca 2+ ) homeostasis can exacerbate many of the factors proposed to mediate muscle degeneration in IBM, such as mitochondrial dysfunction, protein aggregation, and endoplasmic reticulum stress. Ca 2+ dysregulation may plausibly be initiated in IBM by immune-mediated membrane damage and/or abnormally accumulating proteins, but no studies to date have investigated Ca 2+ regulation in IBM patients. We first investigated protein expression via immunoblot in muscle biopsies from IBM, dermatomyositis, and non-myositis control patients, identifying several differentially expressed Ca 2+ -regulatory proteins in IBM. Next, we investigated the Ca 2+ -signaling transcriptome by RNA-seq, finding 54 of 183 (29.5%) genes from an unbiased list differentially expressed in IBM vs. controls. Using an established statistical approach to relate genes with causal transcription networks, Ca 2+ abundance was considered a significant upstream regulator of observed whole-transcriptome changes. Post-hoc analyses of Ca 2+ -regulatory mRNA and protein data indicated a lower protein to transcript ratio in IBM vs. controls, which we hypothesized may relate to increased Ca 2+ -dependent proteolysis and decreased protein translation. Supporting this hypothesis, we observed robust (4-fold) elevation in the autolytic activation of a Ca 2+ -activated protease, calpain-1, as well as increased signaling for translational attenuation (eIF2a phosphorylation) downstream of the unfolded protein response. Finally, in IBM samples we observed mRNA and protein under-expression of calpain-3, the skeletal muscle-specific calpain, which broadly supports proper Ca 2+ homeostasis. Together, these data provide novel insight into mechanisms by which intracellular Ca 2+ regulation is perturbed in IBM and offer evidence of pathological downstream effects.

  11. Early life environmental and pharmacological stressors result in persistent dysregulations of the serotonergic system

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    Peiyan eWong

    2015-04-01

    Full Text Available Dysregulations in the brain serotonergic system and exposure to environmental stressors have been implicated in the development of major depressive disorder. Here, we investigate the interactions between the stress and serotonergic systems by characterizing the behavioral and biochemical effects of chronic stress applied during early-life or adulthood in wild type (WT mice and mice with deficient tryptophan hydroxylase 2 (TPH2 function. We showed that chronic mild stress applied in adulthood did not affect the behaviors and serotonin levels of WT and TPH2 knock-in (KI mice. Whereas, maternal separation (MS stress increased anxiety- and depressive-like behaviors of WT mice, with no detectable behavioral changes in TPH2 KI mice. Biochemically, we found that MS WT mice had reduced brain serotonin levels, which was attributed to increased expression of monoamine oxidase A (MAO A. The increased MAO A expression was detected in MS WT mice at 4 weeks old and adulthood. No change in TPH2 expression was detected. To determine whether a pharmacological stressor, dexamethasone (Dex, will result in similar biochemical results obtained from MS, we used an in vitro system, SH-SY5Y cells, and found that Dex treatment resulted in increased MAO A expression levels. We then treated WT mice with Dex for 5 days, either during postnatal days 7-11 or adulthood. Both groups of Dex treated WT mice had reduced basal corticosterone and glucocorticoid receptors expression levels. However, only Dex treatment during PND7-11 resulted in reduced serotonin levels and increased MAO A expression. Just as with MS WT mice, TPH2 expression in PND7-11 Dex-treated WT mice was unaffected. Taken together, our findings suggest that both environmental and pharmacological stressors affect the expression of MAO A, and not TPH2, when applied during the critical postnatal period. This leads to long-lasting perturbations in the serotonergic system, and results in anxiety- and depressive

  12. Child behavior checklist dysregulation profile in children with disruptive behavior disorders: A longitudinal study.

    Science.gov (United States)

    Masi, Gabriele; Pisano, Simone; Milone, Annarita; Muratori, Pietro

    2015-11-01

    A Child Behavior Checklist (CBCL) profile defined as Dysregulation Profile (DP) (scores 2 standard deviations or more in anxiety/depression, aggression, attention subscales) has been correlated to poor emotional and behavioral self-regulation. The clinical meaning and the prognostic implications of CBCL-DP are still debated, although it seems associated with severe psychopathology and poor adjustment. In the present study, we used the CBCL-DP score to examine the adolescent outcomes (psychiatric diagnosis, substance use, psychiatric hospitalization) in 80 referred children with disruptive behavior disorders -DBD- (Oppositional Defiant Disorder or conduct disorder), aged 8-9 years, 72 males (90%) and 8 females (10%), followed-up until the age of 14-15 years. Children with higher score on the CBCL-DP profile were at increased risk for presenting ADHD and mood disorders in adolescence. While ADHD in adolescence was predicted also by an ADHD diagnosis during childhood, CBCL-DP score was the only significant predictor of a mood disorder at 14-15 years. On the contrary, CBCL-DP score was not associated with a higher risk of conduct disorder, substance use and hospitalizations in adolescence. A cost-effective and reliable diagnostic measure such as the CBCL may be a part of the diagnostic procedure aimed to capture these at-risk children, to monitor their natural history up to adolescence, and to prevent the risk of a full-blown mood disorder. The small sample size and a selection bias of severe patients with DBD limit the generalization of the findings. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Autoimmunity and autoinflammation: A systems view on signaling pathway dysregulation profiles.

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    Arsen Arakelyan

    Full Text Available Autoinflammatory and autoimmune disorders are characterized by aberrant changes in innate and adaptive immunity that may lead from an initial inflammatory state to an organ specific damage. These disorders possess heterogeneity in terms of affected organs and clinical phenotypes. However, despite the differences in etiology and phenotypic variations, they share genetic associations, treatment responses and clinical manifestations. The mechanisms involved in their initiation and development remain poorly understood, however the existence of some clear similarities between autoimmune and autoinflammatory disorders indicates variable degrees of interaction between immune-related mechanisms.Our study aims at contributing to a holistic, pathway-centered view on the inflammatory condition of autoimmune and autoinflammatory diseases. We have evaluated similarities and specificities of pathway activity changes in twelve autoimmune and autoinflammatory disorders by performing meta-analysis of publicly available gene expression datasets generated from peripheral blood mononuclear cells, using a bioinformatics pipeline that integrates Self Organizing Maps and Pathway Signal Flow algorithms along with KEGG pathway topologies.The results reveal that clinically divergent disease groups share common pathway perturbation profiles. We identified pathways, similarly perturbed in all the studied diseases, such as PI3K-Akt, Toll-like receptor, and NF-kappa B signaling, that serve as integrators of signals guiding immune cell polarization, migration, growth, survival and differentiation. Further, two clusters of diseases were identified based on specifically dysregulated pathways: one gathering mostly autoimmune and the other mainly autoinflammatory diseases. Cluster separation was driven not only by apparent involvement of pathways implicated in adaptive immunity in one case, and inflammation in the other, but also by processes not explicitly related to immune

  14. Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX syndrome: a paradigm of immunodeficiency with autoimmunity

    Directory of Open Access Journals (Sweden)

    Federica eBarzaghi

    2012-07-01

    Full Text Available Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX syndrome is a rare monogenic primary immunodeficiency (PID due to mutations of FOXP3, a key transcription factor for naturally occurring (n regulatory T (Treg cells. The dysfunction of Treg cells is the main pathogenic event leading to the multi-organ autoimmunity that characterizes IPEX syndrome, a paradigm of genetically determined PID with autoimmunity. IPEX has a severe early onset and can become rapidly fatal within the first year of life regardless of the type and site of the mutation. The initial presenting symptoms are severe enteritis and/or type 1 diabetes mellitus, alone or in combination with eczema and elevated serum IgE. Other autoimmune symptoms, such as hypothyroidism, cytopenia, hepatitis, nephropathy, arthritis, and alopecia, can develop in patients who survive the initial acute phase.The current therapeutic options for IPEX patients are limited. Supportive and replacement therapies combined with pharmacological immunosuppression are required to control symptoms at onset. However, these procedures can allow only a reduction of the clinical manifestations without a permanent control of the disease. The only known effective cure for IPEX syndrome is haematopoietic stem cell transplantation, but it is always limited by the availability of a suitable donor and the lack of specific guidelines for bone marrow transplant in the context of this disease.This review aims to summarize the clinical histories and genomic mutations of the IPEX patients described in the literature to date. We will focus on the clinical and immunological features that allow differential diagnosis of IPEX syndrome and distinguish it from other PID with autoimmunity. The efficacy of the current therapies will be reviewed, and possible innovative approaches, based on the latest highlights of the pathogenesis to treat this severe primary autoimmune disease of childhood, will be discussed.

  15. Dysregulation of soluble epoxide hydrolase and lipidomic profiles in anorexia nervosa

    KAUST Repository

    Shih, P. B.

    2015-03-31

    Individuals with anorexia nervosa (AN) restrict eating and become emaciated. They tend to have an aversion to foods rich in fat. Because epoxide hydrolase 2 (EPHX2) was identified as a novel AN susceptibility gene, and because its protein product, soluble epoxide hydrolase (sEH), converts bioactive epoxides of polyunsaturated fatty acid (PUFA) to the corresponding diols, lipidomic and metabolomic targets of EPHX2 were assessed to evaluate the biological functions of EPHX2 and their role in AN. Epoxide substrates of sEH and associated oxylipins were measured in ill AN, recovered AN and gender- and race-matched controls. PUFA and oxylipin markers were tested as potential biomarkers for AN. Oxylipin ratios were calculated as proxy markers of in vivo sEH activity. Several free- and total PUFAs were associated with AN diagnosis and with AN recovery. AN displayed elevated n-3 PUFAs and may differ from controls in PUFA elongation and desaturation processes. Cytochrome P450 pathway oxylipins from arachidonic acid, linoleic acid, alpha-linolenic acid and docosahexaenoic acid PUFAs are associated with AN diagnosis. The diol:epoxide ratios suggest the sEH activity is higher in AN compared with controls. Multivariate analysis illustrates normalization of lipidomic profiles in recovered ANs. EPHX2 influences AN risk through in vivo interaction with dietary PUFAs. PUFA composition and concentrations as well as sEH activity may contribute to the pathogenesis and prognosis of AN. Our data support the involvement of EPHX2-associated lipidomic and oxylipin dysregulations in AN, and reveal their potential as biomarkers to assess responsiveness to future intervention or treatment.

  16. Dopamine Dysregulation Syndrome and other psychiatric problems in Parkinson’s Disease: Diagnosis and Treatment

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    Sibel Ertan

    2011-06-01

    Full Text Available In a small number of patients with Parkinson’s disease (PD, a series of behavioral disorders included within the spectrum of impulsive-compulsive disorders develop under the dopamine replacement therapy (DRT. These behaviors are grouped into three as “impulse control disorders (ICD” characterized by rewards-seeking behaviors, “punding” characterized by aimless, ritualist stereotypical repetative behaviors, and “dopamine dysregulation syndrome (DDS” characterized by drug overuse due to chemical addiction. The prevalance of DDS in PD was reported to be around 3-4%. Patients with DDS have an urge to increase their dopaminergic doses beyond their needs for parkinsonien symptoms. DDS is reported to be more common especially in patients with an early onset of disease, high doses of DRT, previous history of or current depression, history of alcohol or substance abuse, and in those having impulsive personality constantly seeking for a change or novelty. DDS is commonly observed in association with “punding” and ICD. The pathophysiology underlying these disorders is explained by specific mechanisms in addition to DRT. Dopamine is not only responsible in the control of the movement, but also plays an important role in the modulation of brain reward systems. The potential maladaptive dysfunction of the mesolimbic dopaminergic system underlies the pathogenesis of DDS. Although the most potent trigger of DDS in PD is known as L-dopa, subcutaneous apomorphine and oral dopamine agonists could also be responsible from the development of DDS. The patients and caregivers should be informed for these behavioral disorders that might emerge under DRT, the possible risk factors should be questioned before dopaminergic therapy, and the choice of drug should be made under these concerns. In patients with DDS, fast-acting DRT formulations should be avoided. In DDS cases associated with hypomaniac or psychotic episodes, treatment should made with

  17. Dopamine Dysregulation Syndrome and other psychiatric problems in Parkinson’s Disease: Diagnosis and Treatment

    Directory of Open Access Journals (Sweden)

    Sibel Ertan

    2011-06-01

    Full Text Available In a small number of patients with Parkinson’s disease (PD, a series of behavioral disorders included within the spectrum of impulsive-compulsive disorders develop under the dopamine replacement therapy (DRT. These behaviors are grouped into three as “impulse control disorders (ICD” characterized by rewards-seeking behaviors, “punding” characterized by aimless, ritualist stereotypical repetative behaviors, and “dopamine dysregulation syndrome (DDS” characterized by drug overuse due to chemical addiction. The prevalance of DDS in PD was reported to be around 3-4%. Patients with DDS have an urge to increase their dopaminergic doses beyond their needs for parkinsonien symptoms. DDS is reported to be more common especially in patients with an early onset of disease, high doses of DRT, previous history of or current depression, history of alcohol or substance abuse, and in those having impulsive personality constantly seeking for a change or novelty. DDS is commonly observed in association with “punding” and ICD. The pathophysiology underlying these disorders is explained by specific mechanisms in addition to DRT. Dopamine is not only responsible in the control of the movement, but also plays an important role in the modulation of brain reward systems. The potential maladaptive dysfunction of the mesolimbic dopaminergic system underlies the pathogenesis of DDS. Although the most potent trigger of DDS in PD is known as L-dopa, subcutaneous apomorphine and oral dopamine agonists could also be responsible from the development of DDS. The patients and caregivers should be informed for these behavioral disorders that might emerge under DRT, the possible risk factors should be questioned before dopaminergic therapy, and the choice of drug should be made under these concerns. In patients with DDS, fast-acting DRT formulations should be avoided. In DDS cases associated with hypomaniac or psychotic episodes, treatment should made with

  18. Emotional dysregulation in those with bipolar disorder, borderline personality disorder and their comorbid expression.

    Science.gov (United States)

    Bayes, Adam; Parker, Gordon; McClure, Georgia

    2016-11-01

    Differentiation of the bipolar disorders (BP) from a borderline personality disorder (BPD) can be challenging owing to shared features, with emotional dysregulation being the likely principal one. To assess differences in emotion regulation strategies in those with BP alone, BPD alone and those comorbid for both. We interviewed participants previously receiving a BP or BPD diagnosis, studying those who met DSM criteria for one or both conditions. The sample comprised 83 with bipolar disorder, 53 with BPD and 54 comorbid for both. Analyses established linear trends, with the greatest impairment in emotion regulation strategies in the comorbid group followed by the BPD group, and with the lowest in the BP group. Specific deficits in the comorbid group included impulsivity, difficulties with goal directed behaviour, and accessing strategies. A similar linear profile was quantified for maladaptive cognitive emotion regulation strategies, weighted to catastrophizing and rumination. Adaptive emotion regulation strategies were superior in the bipolar group, without significant differences observed between the comorbid and BPD groups. Reliance on self-report measures; combined BP I and II participants limits generalisability of results to each bipolar sub-type; use of DSM diagnoses risking artefactual comorbidity; while there was an over-representation of females in all groups. Differences in emotion regulation strategies advance differentiation of those with either BP or BPD, while we identify the specificity of differing strategies to each condition and their synergic effect in those comorbid for both conditions. Study findings should assist the development and application of targeted strategies for those with either or both conditions. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

  19. Association of dopamine gene variants, emotion dysregulation and ADHD in autism spectrum disorder.

    Science.gov (United States)

    Gadow, Kenneth D; Pinsonneault, Julia K; Perlman, Greg; Sadee, Wolfgang

    2014-07-01

    The aim of the present study was to evaluate the association of dopaminergic gene variants with emotion dysregulation (EMD) and attention-deficit/hyperactivity disorder (ADHD) symptoms in children with autism spectrum disorder (ASD). Three dopamine transporter gene (SLC6A3/DAT1) polymorphisms (intron8 5/6 VNTR, 3'-UTR 9/10 VNTR, rs27072 in the 3'-UTR) and one dopamine D2 receptor gene (DRD2) variant (rs2283265) were selected for genotyping based on à priori evidence of regulatory activity or, in the case of DAT1 9/10 VNTR, commonly reported associations with ADHD. A sample of 110 children with ASD was assessed with a rigorously validated DSM-IV-referenced rating scale. Global EMD severity (parents' ratings) was associated with DAT1 intron8 (ηp(2)=.063) and rs2283265 (ηp(2)=.044). Findings for DAT1 intron8 were also significant for two EMD subscales, generalized anxiety (ηp(2)=.065) and depression (ηp(2)=.059), and for DRD2 rs2283265, depression (ηp(2)=.053). DRD2 rs2283265 was associated with teachers' global ratings of ADHD (ηp(2)=.052). DAT1 intron8 was associated with parent-rated hyperactivity (ηp(2)=.045) and both DAT1 9/10 VNTR (ηp(2)=.105) and DRD2 rs2283265 (ηp(2)=.069) were associated with teacher-rated inattention. These findings suggest that dopaminergic gene polymorphisms may modulate EMD and ADHD symptoms in children with ASD but require replication with larger independent samples. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Emotional preferences and goals and emotion dysregulation in children with Asperger's syndrome and typically developing children.

    Science.gov (United States)

    López-Pérez, Belén; Ambrona, Tamara; Gummerum, Michaela

    2018-02-05

    Emotion goals lie at the heart of emotion regulation, as people have to first decide what emotions they want to feel before engaging in emotion regulation. Given that children with Asperger's syndrome (AS) are characterized by exhibiting difficulties in emotion regulation, studying whether they display similar or different emotion goals compared to typically developing (TD) children may provide insightful information. Thirty AS and 30 TD children (10-12 years) reported about their general (i.e., how they want to feel in general) and contextualized (i.e., how they want to feel when confronting vs. collaborating with someone) emotion goals, and about their difficulties in emotion regulation through questionnaires. Results showed that both groups did not differ in their general emotional goals and in their contextualized emotion goals for happiness for collaboration and anger for confrontation. AS children only differed from TD children in a higher preference for sadness for collaboration and happiness for confrontation. These emotion goals predicted their difficulties to engage in goal-directed behaviour. The obtained results support the need to further study emotion goals as an aspect of emotion dysregulation, namely the difficulties to engage in goal-directed behaviour when experiencing different emotions. AS and TD children did not differ in their general emotion goals. AS and TD children did not vary in their preferences for happiness for collaboration and anger for confrontation. AS children only differed in a higher preference for sadness for collaboration and happiness for confrontation. Understanding emotion goals might help practitioners to develop better interventions. © 2018 The British Psychological Society.

  1. Haematopoietic malignancies caused by dysregulation of a chromatin-binding PHD finger.

    Science.gov (United States)

    Wang, Gang G; Song, Jikui; Wang, Zhanxin; Dormann, Holger L; Casadio, Fabio; Li, Haitao; Luo, Jun-Li; Patel, Dinshaw J; Allis, C David

    2009-06-11

    Histone H3 lysine 4 methylation (H3K4me) has been proposed as a critical component in regulating gene expression, epigenetic states, and cellular identities1. The biological meaning of H3K4me is interpreted by conserved modules including plant homeodomain (PHD) fingers that recognize varied H3K4me states. The dysregulation of PHD fingers has been implicated in several human diseases, including cancers and immune or neurological disorders. Here we report that fusing an H3K4-trimethylation (H3K4me3)-binding PHD finger, such as the carboxy-terminal PHD finger of PHF23 or JARID1A (also known as KDM5A or RBBP2), to a common fusion partner nucleoporin-98 (NUP98) as identified in human leukaemias, generated potent oncoproteins that arrested haematopoietic differentiation and induced acute myeloid leukaemia in murine models. In these processes, a PHD finger that specifically recognizes H3K4me3/2 marks was essential for leukaemogenesis. Mutations in PHD fingers that abrogated H3K4me3 binding also abolished leukaemic transformation. NUP98-PHD fusion prevented the differentiation-associated removal of H3K4me3 at many loci encoding lineage-specific transcription factors (Hox(s), Gata3, Meis1, Eya1 and Pbx1), and enforced their active gene transcription in murine haematopoietic stem/progenitor cells. Mechanistically, NUP98-PHD fusions act as 'chromatin boundary factors', dominating over polycomb-mediated gene silencing to 'lock' developmentally critical loci into an active chromatin state (H3K4me3 with induced histone acetylation), a state that defined leukaemia stem cells. Collectively, our studies represent, to our knowledge, the first report that deregulation of the PHD finger, an 'effector' of specific histone modification, perturbs the epigenetic dynamics on developmentally critical loci, catastrophizes cellular fate decision-making, and even causes oncogenesis during mammalian development.

  2. Reading related white matter structures in adolescents are influenced more by dysregulation of emotion than behavior

    Directory of Open Access Journals (Sweden)

    Tzipi Horowitz-Kraus

    2017-01-01

    Full Text Available Mood disorders and behavioral are broad psychiatric diagnostic categories that have different symptoms and neurobiological mechanisms, but share some neurocognitive similarities, one of which is an elevated risk for reading deficit. Our aim was to determine the influence of mood versus behavioral dysregulation on reading ability and neural correlates supporting these skills in youth, using diffusion tensor imaging in 11- to 17-year-old children and youths with mood disorders or behavioral disorders and age-matched healthy controls. The three groups differed only in phonological processing and passage comprehension. Youth with mood disorders scored higher on the phonological test but had lower comprehension scores than children with behavioral disorders and controls; control participants scored the highest. Correlations between fractional anisotropy and phonological processing in the left Arcuate Fasciculus showed a significant difference between groups and were strongest in behavioral disorders, intermediate in mood disorders, and lowest in controls. Correlations between these measures in the left Inferior Longitudinal Fasciculus were significantly greater than in controls for mood but not for behavioral disorders. Youth with mood disorders share a deficit in the executive-limbic pathway (Arcuate Fasciculus with behavioral-disordered youth, suggesting reduced capacity for engaging frontal regions for phonological processing or passage comprehension tasks and increased reliance on the ventral tract (e.g., the Inferior Longitudinal Fasciculus. The low passage comprehension scores in mood disorder may result from engaging the left hemisphere. Neural pathways for reading differ mainly in executive-limbic circuitry. This new insight may aid clinicians in providing appropriate intervention for each disorder.

  3. Haploinsufficiency of BAZ1B contributes to Williams syndrome through transcriptional dysregulation of neurodevelopmental pathways.

    Science.gov (United States)

    Lalli, Matthew A; Jang, Jiwon; Park, Joo-Hye C; Wang, Yidi; Guzman, Elmer; Zhou, Hongjun; Audouard, Morgane; Bridges, Daniel; Tovar, Kenneth R; Papuc, Sorina M; Tutulan-Cunita, Andreea C; Huang, Yadong; Budisteanu, Magdalena; Arghir, Aurora; Kosik, Kenneth S

    2016-04-01

    Williams syndrome (WS) is a neurodevelopmental disorder caused by a genomic deletion of ∼28 genes that results in a cognitive and behavioral profile marked by overall intellectual impairment with relative strength in expressive language and hypersocial behavior. Advancements in protocols for neuron differentiation from induced pluripotent stem cells allowed us to elucidate the molecular circuitry underpinning the ontogeny of WS. In patient-derived stem cells and neurons, we determined the expression profile of the Williams-Beuren syndrome critical region-deleted genes and the genome-wide transcriptional consequences of the hemizygous genomic microdeletion at chromosome 7q11.23. Derived neurons displayed disease-relevant hallmarks and indicated novel aberrant pathways in WS neurons including over-activated Wnt signaling accompanying an incomplete neurogenic commitment. We show that haploinsufficiency of the ATP-dependent chromatin remodeler, BAZ1B, which is deleted in WS, significantly contributes to this differentiation defect. Chromatin-immunoprecipitation (ChIP-seq) revealed BAZ1B target gene functions are enriched for neurogenesis, neuron differentiation and disease-relevant phenotypes. BAZ1B haploinsufficiency caused widespread gene expression changes in neural progenitor cells, and together with BAZ1B ChIP-seq target genes, explained 42% of the transcriptional dysregulation in WS neurons. BAZ1B contributes to regulating the balance between neural precursor self-renewal and differentiation and the differentiation defect caused by BAZ1B haploinsufficiency can be rescued by mitigating over-active Wnt signaling in neural stem cells. Altogether, these results reveal a pivotal role for BAZ1B in neurodevelopment and implicate its haploinsufficiency as a likely contributor to the neurological phenotypes in WS. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. Blood Glucose and Insulin Concentrations after Octreotide Administration in Horses With Insulin Dysregulation.

    Science.gov (United States)

    Frank, N; Hermida, P; Sanchez-Londoño, A; Singh, R; Gradil, C M; Uricchio, C K

    2017-07-01

    Octreotide is a somatostatin analog that suppresses insulin secretion. We hypothesized that octreotide would suppress insulin concentrations in horses and that normal (N) horses and those with insulin dysregulation (ID) would differ significantly in their plasma glucose and insulin responses to administration of octreotide. Twelve horses, N = 5, ID = 7. Prospective study. An oral sugar test was performed to assign horses to N and ID groups. Octreotide (1.0 μg/kg IV) was then administered, and blood was collected at 0, 5, 10, 15, 20, 25, 30, 45, 60, 75, and 90 minute, and 2, 3, 4, 6, 8, 12, and 24 hour for measurement of glucose and insulin concentrations. Area under the curve (AUC) values were calculated. Mean AUC values for glucose and insulin did not differ between normal (n = 5) and ID (n = 7) groups after octreotide injection. Significant time (P glucose and insulin concentrations. A group × time interaction (P = .091) was detected for insulin concentrations after administration of octreotide, but the group (P = .33) effect was not significant. Octreotide suppresses insulin secretion, resulting in hyperglycemia, and then concentrations increase above baseline as glycemic control is restored. Our hypothesis that octreotide causes insulin concentrations to decrease in horses was supported, but differences between N and ID groups did not reach statistical significance when blood glucose and insulin responses were compared. The utility of an octreotide response test remains to be determined. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  5. Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations.

    Science.gov (United States)

    Liao, Chunyan; Ashley, Neil; Diot, Alan; Morten, Karl; Phadwal, Kanchan; Williams, Andrew; Fearnley, Ian; Rosser, Lyndon; Lowndes, Jo; Fratter, Carl; Ferguson, David J P; Vay, Laura; Quaghebeur, Gerardine; Moroni, Isabella; Bianchi, Stefania; Lamperti, Costanza; Downes, Susan M; Sitarz, Kamil S; Flannery, Padraig J; Carver, Janet; Dombi, Eszter; East, Daniel; Laura, Matilde; Reilly, Mary M; Mortiboys, Heather; Prevo, Remko; Campanella, Michelangelo; Daniels, Matthew J; Zeviani, Massimo; Yu-Wai-Man, Patrick; Simon, Anna Katharina; Votruba, Marcela; Poulton, Joanna

    2017-01-10

    To investigate mitophagy in 5 patients with severe dominantly inherited optic atrophy (DOA), caused by depletion of OPA1 (a protein that is essential for mitochondrial fusion), compared with healthy controls. Patients with severe DOA (DOA plus) had peripheral neuropathy, cognitive regression, and epilepsy in addition to loss of vision. We quantified mitophagy in dermal fibroblasts, using 2 high throughput imaging systems, by visualizing colocalization of mitochondrial fragments with engulfing autophagosomes. Fibroblasts from 3 biallelic OPA1(-/-) patients with severe DOA had increased mitochondrial fragmentation and mitochondrial DNA (mtDNA)-depleted cells due to decreased levels of OPA1 protein. Similarly, in siRNA-treated control fibroblasts, profound OPA1 knockdown caused mitochondrial fragmentation, loss of mtDNA, impaired mitochondrial function, and mitochondrial mislocalization. Compared to controls, basal mitophagy (abundance of autophagosomes colocalizing with mitochondria) was increased in (1) biallelic patients, (2) monoallelic patients with DOA plus, and (3) OPA1 siRNA-treated control cultures. Mitophagic flux was also increased. Genetic knockdown of the mitophagy protein ATG7 confirmed this by eliminating differences between patient and control fibroblasts. We demonstrated increased mitophagy and excessive mitochondrial fragmentation in primary human cultures associated with DOA plus due to biallelic OPA1 mutations. We previously found that increased mitophagy (mitochondrial recycling) was associated with visual loss in another mitochondrial optic neuropathy, Leber hereditary optic neuropathy (LHON). Combined with our LHON findings, this implicates excessive mitochondrial fragmentation, dysregulated mitophagy, and impaired response to energetic stress in the pathogenesis of mitochondrial optic neuropathies, potentially linked with mitochondrial mislocalization and mtDNA depletion. Copyright © 2016 The Author(s). Published by Wolters Kluwer Health, Inc

  6. Altered gene synchrony suggests a combined hormone-mediated dysregulated state in major depression.

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    Chris Gaiteri

    2010-04-01

    Full Text Available Coordinated gene transcript levels across tissues (denoted "gene synchrony" reflect converging influences of genetic, biochemical and environmental factors; hence they are informative of the biological state of an individual. So could brain gene synchrony also integrate the multiple factors engaged in neuropsychiatric disorders and reveal underlying pathologies? Using bootstrapped Pearson correlation for transcript levels for the same genes across distinct brain areas, we report robust gene transcript synchrony between the amygdala and cingulate cortex in the human postmortem brain of normal control subjects (n = 14; Control/Permutated data, p<0.000001. Coordinated expression was confirmed across distinct prefrontal cortex areas in a separate cohort (n = 19 subjects and affected different gene sets, potentially reflecting regional network- and function-dependent transcriptional programs. Genewise regional transcript coordination was independent of age-related changes and array technical parameters. Robust shifts in amygdala-cingulate gene synchrony were observed in subjects with major depressive disorder (MDD, denoted here "depression" (n = 14; MDD/Permutated data, p<0.000001, significantly affecting between 100 and 250 individual genes (10-30% false discovery rate. Biological networks and signal transduction pathways corresponding to the identified gene set suggested putative dysregulated functions for several hormone-type factors previously implicated in depression (insulin, interleukin-1, thyroid hormone, estradiol and glucocorticoids; p<0.01 for association with depression-related networks. In summary, we showed that coordinated gene expression across brain areas may represent a novel molecular probe for brain structure/function that is sensitive to disease condition, suggesting the presence of a distinct and integrated hormone-mediated corticolimbic homeostatic, although maladaptive and pathological, state in major depression.

  7. Effects of STN and GPi deep brain stimulation on impulse control disorders and dopamine dysregulation syndrome.

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    Sarah J Moum

    Full Text Available Impulse control disorders (ICDs and dopamine dysregulation syndrome (DDS are important behavioral problems that affect a subpopulation of patients with Parkinson's disease (PD and typically result in markedly diminished quality of life for patients and their caregivers. We aimed to investigate the effects of subthalamic nucleus (STN and internal globus pallidus (GPi deep brain stimulation (DBS on ICD/DDS frequency and dopaminergic medication usage.A retrospective chart review was performed on 159 individuals who underwent unilateral or bilateral PD DBS surgery in either STN or GPi. According to published criteria, pre- and post-operative records were reviewed to categorize patients both pre- and post-operatively as having ICD, DDS, both ICD and DDS, or neither ICD nor DDS. Group differences in patient demographics, clinical presentations, levodopa equivalent dose (LED, and change in diagnosis following unilateral/bilateral by brain target (STN or GPi DBS placement were examined.28 patients met diagnostic criteria for ICD or DDS pre- or post-operatively. ICD or DDS classification did not differ by GPi or STN target stimulation. There was no change in DDS diagnosis after unilateral or bilateral stimulation. For ICD, diagnosis resolved in 2 of 7 individuals after unilateral or bilateral DBS. Post-operative development of these syndromes was significant; 17 patients developed ICD diagnoses post-operatively with 2 patients with pre-operative ICD developing DDS post-operatively.Unilateral or bilateral DBS did not significantly treat DDS or ICD in our sample, even though a few cases of ICD resolved post-operatively. Rather, our study provides preliminary evidence that DDS and ICD diagnoses may emerge following DBS surgery.

  8. Persistent polar depletion of stratospheric ozone and emergent mechanisms of ultraviolet radiation-mediated health dysregulation.

    Science.gov (United States)

    Dugo, Mark A; Han, Fengxiang; Tchounwou, Paul B

    2012-01-01

    -mediated dysregulations of rhythmicity and homeostasis among animals, including humans.

  9. EphrinB1 expression is dysregulated and promotes oncogenic signaling in medulloblastoma.

    Science.gov (United States)

    McKinney, Nicole; Yuan, Liangping; Zhang, Hongying; Liu, Jingbo; Cho, Yoon-Jae; Rushing, Elisabeth; Schniederjan, Matthew; MacDonald, Tobey J

    2015-01-01

    Eph receptors and ephrin ligands are master regulators of oncogenic signaling required for proliferation, migration, and metastasis. Yet, Eph/ephrin expression and activity in medulloblastoma (MB), the most common malignant brain tumor of childhood, remains poorly defined. We hypothesized that Eph/ephrins are differentially expressed by sonic hedgehog (SHH) and non-SHH MB and that specific members contribute to the aggressive phenotype. Affymetrix gene expression profiling of 29 childhood MB, separated into SHH (N = 11) and non-SHH (N = 18), was performed followed by protein validation of selected Eph/ephrins in another 60 MB and two MB cell lines (DAOY, D556). Functional assays were performed using MB cells overexpressing or deleted for selected ephrins. We found EPHB4 and EFNA4 almost exclusively expressed by SHH MB, whereas EPHA2, EPHA8, EFNA1 and EFNA3 are predominantly expressed by non-SHH MB. The remaining family members, except EFNB1, are ubiquitously expressed by over 70-90 % MB, irrespective of subgroup. EFNB1 is the only member differentially expressed by 28 % of SHH and non-SHH MB. Corresponding protein expression for EphB/ephrinB1 and B2 was validated in MB. Only ephrinB2 was also detected in fetal cerebellum, indicating that EphB/ephrinB1 expression is MB-specific. EphrinB1 immunopositivity localizes to tumor cells within MB with the highest proliferative index. EphrinB1 overexpression promotes EphB activation, alters F-actin distribution and morphology, decreases adhesion, and significantly promotes proliferation. Either silencing or overexpression of ephrinB1 impairs migration. These results indicate that EphrinB1 is uniquely dysregulated in MB and promotes oncogenic responses in MB cells, implicating ephrinB1 as a potential target.

  10. Nonverbal intelligence in young children with dysregulation: the Generation R Study.

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    Basten, Maartje; van der Ende, Jan; Tiemeier, Henning; Althoff, Robert R; Rijlaarsdam, Jolien; Jaddoe, Vincent W V; Hofman, Albert; Hudziak, James J; Verhulst, Frank C; White, Tonya

    2014-11-01

    Children meeting the Child Behavior Checklist Dysregulation Profile (CBCL-DP) suffer from high levels of co-occurring internalizing and externalizing problems. Little is known about the cognitive abilities of these children with CBCL-DP. We examined the relationship between CBCL-DP and nonverbal intelligence. Parents of 6,131 children from a population-based birth cohort, aged 5 through 7 years, reported problem behavior on the CBCL/1.5-5. The CBCL-DP was derived using latent profile analysis on the CBCL/1.5-5 syndrome scales. Nonverbal intelligence was assessed using the Snijders Oomen Nonverbal Intelligence Test 2.5-7-Revised. We examined the relationship between CBCL-DP and nonverbal intelligence using linear regression. Analyses were adjusted for parental intelligence, parental psychiatric symptoms, socio-economic status, and perinatal factors. In a subsample with diagnostic interview data, we tested if the results were independent of the presence of attention deficit hyperactivity disorder (ADHD) or autism spectrum disorders (ASD). The results showed that children meeting the CBCL-DP (n = 110, 1.8%) had a 11.0 point lower nonverbal intelligence level than children without problems and 7.2-7.3 points lower nonverbal intelligence level than children meeting other profiles of problem behavior (all p values intelligence in children with CBCL-DP. In conclusion, we found that children with CBCL-DP have a considerable lower nonverbal intelligence score. The CBCL-DP and nonverbal intelligence may share a common neurodevelopmental etiology.

  11. Failure to Deliver and Translate-New Insights into RNA Dysregulation in ALS.

    Science.gov (United States)

    Coyne, Alyssa N; Zaepfel, Benjamin L; Zarnescu, Daniela C

    2017-01-01

    Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. The molecular mechanisms underlying disease pathogenesis remain largely unknown. Multiple genetic loci including genes involved in proteostasis and ribostasis have been linked to ALS providing key insights into the molecular mechanisms underlying disease. In particular, the identification of the RNA binding proteins TDP-43 and fused in sarcoma (FUS) as causative factors of ALS resulted in a paradigm shift centered on the study of RNA dysregulation as a major mechanism of disease. With wild-type TDP-43 pathology being found in ~97% of ALS cases and the identification of disease causing mutations within its sequence, TDP-43 has emerged as a prominent player in ALS. More recently, studies of the newly discovered C9orf72 repeat expansion are lending further support to the notion of defects in RNA metabolism as a key factor underlying ALS. RNA binding proteins are involved in all aspects of RNA metabolism ranging from splicing, transcription, transport, storage into RNA/protein granules, and translation. How these processes are affected by disease-associated mutations is just beginning to be understood. Considerable work has gone into the identification of splicing and transcription defects resulting from mutations in RNA binding proteins associated with disease. More recently, defects in RNA transport and translation have been shown to be involved in the pathomechanism of ALS. A central hypothesis in the field is that disease causing mutations lead to the persistence of RNA/protein complexes known as stress granules. Under times of prolonged cellular stress these granules sequester specific mRNAs preventing them from translation, and are thought to evolve into pathological aggregates. Here we will review recent efforts directed at understanding how altered RNA metabolism contributes to ALS pathogenesis.

  12. Mast cells dysregulate apoptotic and cell cycle genes in mucosal squamous cell carcinoma

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    Davis Paul

    2006-12-01

    Full Text Available Abstract Background Mucosal squamous cell carcinoma of the head and neck is a disease of high mortality and morbidity. Interactions between the squamous cell carcinoma and the host's local immunity, and how the latter contributes to the biological behavior of the tumor are unclear. In vivo studies have demonstrated sequential mast cell infiltration and degranulation during squamous cell carcinogenesis. The degree of mast cell activation correlates closely with distinct phases of hyperkeratosis, dysplasia, carcinoma in-situ and invasive carcinoma. However, the role of mast cells in carcinogenesis is unclear. Aim This study explores the effects of mast cells on the proliferation and gene expression profile of mucosal squamous cell carcinoma using human mast cell line (HMC-1 and human glossal squamous cell carcinoma cell line (SCC25. Methods HMC-1 and SCC25 were co-cultured in a two-compartment chamber, separated by a polycarbonate membrane. HMC-1 was stimulated to degranulate with calcium ionophore A23187. The experiments were done in quadruplicate. Negative controls were established where SCC25 were cultured alone without HMC-1. At 12, 24, 48 and 72 hours, proliferation and viability of SCC25 were assessed with MTT colorimetric assay. cDNA microarray was employed to study differential gene expression between co-cultured and control SCC25. Results HMC-1/SCC25 co-culture resulted in suppression of growth rate for SCC-25 (34% compared with 110% for the control by 72 hours, p Conclusion We show that mast cells have a direct inhibitory effect on the proliferation of mucosal squamous cell carcinoma in vitro by dysregulating key genes in apoptosis and cell cycle control.

  13. Disruptive Mood Dysregulation Disorder in a Community Mental Health Clinic: Prevalence, Comorbidity and Correlates.

    Science.gov (United States)

    Freeman, Andrew J; Youngstrom, Eric A; Youngstrom, Jennifer K; Findling, Robert L

    2016-03-01

    The revision of the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5) added a new diagnosis of disruptive mood dysregulation disorder (DMDD) to depressive disorders. This study examines the prevalence, comorbidity, and correlates of the new disorder, with a particular focus on its overlap with oppositional defiant disorder (ODD), with which DMDD shares core symptoms. Data were obtained from 597 youth 6-18 years of age who participated in a systematic assessment of symptoms offered to all intakes at a community mental health center (sample accrued from July 2003 to March 2008). Assessment included diagnostic, symptomatic, and functional measures. DMDD was diagnosed using a post-hoc definition from item-level ratings on the Schedule for Affective Disorders and Schizophrenia for School-Age Children that closely matches the DSM-5 definition. Caregivers rated youth on the Child Behavior Checklist. Approximately 31% of youth met the operational definition of DMDD, and 40% had Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) diagnoses of ODD. Youth with DMDD almost always had ODD (odds ratio [OR] = 53.84) and displayed higher rates of comorbidity with attention-deficit/hyperactivity disorder (ADHD) and conduct disorder than youth without DMDD. Caregivers of youth with DMDD reported more symptoms of aggressive behavior, rule-breaking, social problems, anxiety/depression, attention problems, and thought problems than all other youth without DMDD. Compared with youth with ODD, youth with DMDD were not significantly different in terms of categorical or dimensional approaches to comorbidity and impairment. The new diagnosis of DMDD might be common in community mental health clinics. Youth with DMDD displayed more severe symptoms and poorer functioning than youth without DMDD. However, DMDD almost entirely overlaps with ODD and youth with DMDD were not significantly different than youth with ODD. These findings raise concerns

  14. Caprine arthritis encephalitis virus dysregulates the expression of cytokines in macrophages.

    Science.gov (United States)

    Lechner, F; Machado, J; Bertoni, G; Seow, H F; Dobbelaere, D A; Peterhans, E

    1997-01-01

    Caprine arthritis encephalitis virus (CAEV) is a lentivirus of goats that leads to chronic mononuclear infiltration of various tissues, in particular, the radiocarpal joints. Cells of the monocyte/macrophage lineage are the major host cells of CAEV in vivo. We have shown that infection of cultured goat macrophages with CAEV results in an alteration of cytokine expression in vitro. Constitutive expression of interleukin 8 (IL-8) and monocyte chemoattractant protein 1 (MCP-1) was increased in infected macrophages, whereas transforming growth factor beta1 (TGF-beta1) mRNA was down-regulated. When macrophages were infected with a CAEV clone lacking the trans-acting nuclear regulatory gene tat, IL-8 and MCP-1 were also increased. No significant differences from cells infected with the wild-type clone were observed, suggesting that Tat is not required for the increased expression of IL-8 and MCP-1 in infected macrophages. Furthermore, infection with CAEV led to an altered pattern of cytokine expression in response to lipopolysaccharide (LPS), heat-killed Listeria monocytogenes plus gamma interferon, or fixed cells of Staphylococcus aureus Cowan I. In infected macrophages, tumor necrosis factor alpha, IL-1beta, IL-6, and IL-12 p40 mRNA expression was reduced in response to all stimuli tested whereas changes in expression of granulocyte-macrophage colony-stimulating factor depended on the stimulating agent. Electrophoretic mobility shift assays demonstrated that, in contrast to effects of human immunodeficiency virus infection of macrophages, CAEV infection had no effect on the level of constitutive nuclear factor-kappaB (NF-kappaB) activity or on the level of LPS-stimulated NF-kappaB activity, suggesting that NF-kappaB is not involved in altered regulation of cytokine expression in CAEV-infected cells. In contrast, activator protein 1 (AP-1) binding activity was decreased in infected macrophages. These data show that CAEV infection may result in a dysregulation of

  15. Brain-derived neurotrophic factor ameliorates brain stem cardiovascular dysregulation during experimental temporal lobe status epilepticus.

    Directory of Open Access Journals (Sweden)

    Ching-Yi Tsai

    Full Text Available BACKGROUND: Status epilepticus (SE is an acute, prolonged epileptic crisis with a mortality rate of 20-30%; the underlying mechanism is not completely understood. We assessed the hypothesis that brain stem cardiovascular dysregulation occurs during SE because of oxidative stress in rostral ventrolateral medulla (RVLM, a key nucleus of the baroreflex loop; to be ameliorated by brain-derived neurotrophic factor (BDNF via an antioxidant action. METHODOLOGY/PRINCIPAL FINDINGS: In a clinically relevant experimental model of temporal lobe SE (TLSE using Sprague-Dawley rats, sustained hippocampal seizure activity was accompanied by progressive hypotension that was preceded by a reduction in baroreflex-mediated sympathetic vasomotor tone; heart rate and baroreflex-mediated cardiac responses remained unaltered. Biochemical experiments further showed concurrent augmentation of superoxide anion, phosphorylated p47(phox subunit of NADPH oxidase and mRNA or protein levels of BDNF, tropomyosin receptor kinase B (TrkB, angiotensin AT1 receptor subtype (AT1R, nitric oxide synthase II (NOS II or peroxynitrite in RVLM. Whereas pretreatment by microinjection bilaterally into RVLM of a superoxide dismutase mimetic (tempol, a specific antagonist of NADPH oxidase (apocynin or an AT1R antagonist (losartan blunted significantly the augmented superoxide anion or phosphorylated p47(phox subunit in RVLM, hypotension and the reduced baroreflex-mediated sympathetic vasomotor tone during experimental TLSE, pretreatment with a recombinant human TrkB-Fc fusion protein or an antisense bdnf oligonucleotide significantly potentiated all those events, alongside peroxynitrite. However, none of the pretreatments affected the insignificant changes in heart rate and baroreflex-mediated cardiac responses. CONCLUSIONS/SIGNIFICANCE: We conclude that formation of peroxynitrite by a reaction between superoxide anion generated by NADPH oxidase in RVLM on activation by AT1R and NOS II

  16. Hypothalamic-pituitary-adrenal axis dysregulation and cortisol activity in obesity: A systematic review.

    Science.gov (United States)

    Incollingo Rodriguez, Angela C; Epel, Elissa S; White, Megan L; Standen, Erin C; Seckl, Jonathan R; Tomiyama, A Janet

    2015-12-01

    Although there is substantial evidence of differential hypothalamic-pituitary-adrenal (HPA) axis activity in both generalized and abdominal obesity, consistent trends in obesity-related HPA axis perturbations have yet to be identified. To systematically review the existing literature on HPA activity in obesity, identify possible explanations for inconsistencies in the literature, and suggest methodological improvements for future study. Included papers used Pubmed, Google Scholar, and the University of California Library search engines with search terms body mass index (BMI), waist-to-hip ratio (WHR), waist circumference, sagittal diameter, abdominal versus peripheral body fat distribution, body fat percentage, DEXA, abdominal obesity, and cortisol with terms awakening response, slope, total daily output, reactivity, feedback sensitivity, long-term output, and 11β-HSD expression. Empirical research papers were eligible provided that they included at least one type of obesity (general or abdominal), measured at least one relevant cortisol parameter, and a priori tested for a relationship between obesity and cortisol. A general pattern of findings emerged where greater abdominal fat is associated with greater responsivity of the HPA axis, reflected in morning awakening and acute stress reactivity, but some studies did show underresponsiveness. When examined in adipocytes, there is a clear upregulation of cortisol output (due to greater expression of 11β-HSD1), but in hepatic tissue this cortisol is downregulated. Overall obesity (BMI) appears to also be related to a hyperresponsive HPA axis in many but not all studies, such as when acute reactivity is examined. The reviewed literature contains numerous inconsistencies and contradictions in research methodologies, sample characteristics, and results, which partially precluded the development of clear and reliable patterns of dysregulation in each investigated cortisol parameter. The literature to date is

  17. Dynamic ligand modulation of EPO receptor pools, and dysregulation by polycythemia-associated EPOR alleles.

    Directory of Open Access Journals (Sweden)

    Seema Singh

    which mutated EPOR-T polycythemia alleles dysregulate the erythron. Notably, specific new tools also are characterized for studies of EPOR expression, activation, action and metabolism.

  18. Dysregulated gene expression in the primary osteoblasts and osteocytes isolated from hypophosphatemic Hyp mice.

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    Kazuaki Miyagawa

    Full Text Available Osteocytes express multiple genes involved in mineral metabolism including PHEX, FGF23, DMP1 and FAM20C. In Hyp mice, a murine model for X-linked hypophosphatemia (XLH, Phex deficiency results in the overproduction of FGF23 in osteocytes, which leads to hypophosphatemia and impaired vitamin D metabolism. In this study, to further clarify the abnormality in osteocytes of Hyp mice, we obtained detailed gene expression profiles in osteoblasts and osteocytes isolated from the long bones of 20-week-old Hyp mice and wild-type (WT control mice. The expression of Fgf23, Dmp1, and Fam20c was higher in osteocytic cells than in osteoblastic cells in both genotypes, and was up-regulated in Hyp cells. Interestingly, the up-regulation of these genes in Hyp bones began before birth. On the other hand, the expression of Slc20a1 encoding the sodium/phosphate (Na+/Pi co-transporter Pit1 was increased in osteoblasts and osteocytes from adult Hyp mice, but not in Hyp fetal bones. The direct effects of extracellular Pi and 1,25-dihydroxyvitamin D3 [1,25(OH2D3] on isolated osteoblastic and osteocytic cells were also investigated. Twenty-four-hour treatment with 10-8 M 1,25(OH2D3 increased the expression of Fgf23 in WT osteoblastic cells but not in osteocytic cells. Dmp1 expression in osteocytic cells was increased due to the 24-hour treatment with 10 mM Pi and was suppressed by 10-8 M 1,25(OH2D3 in WT osteocytic cells. We also found the up-regulation of the genes for FGF1, FGF2, their receptors, and Egr-1 which is a target of FGF signaling, in Hyp osteocytic cells, suggesting the activation of FGF/FGFR signaling. These results implicate the complex gene dysregulation in osteoblasts and osteocytes of Hyp mice, which might contribute to the pathogenesis.

  19. Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old age.

    Science.gov (United States)

    Ramos-Miguel, Alfredo; Jones, Andrea A; Sawada, Ken; Barr, Alasdair M; Bayer, Thomas A; Falkai, Peter; Leurgans, Sue E; Schneider, Julie A; Bennett, David A; Honer, William G

    2018-06-01

    variables were associated with different cognitive domains. In addition, linear mixed effect models of global cognitive decline estimated that both 150-kDa SNARE levels and CPLX1/CPLX2 ratio were associated with better cognition and less decline over time. The results are consistent with previous studies reporting that synapse dysfunction (i.e. dysplasticity) may be initiated early, and relatively independent of neuropathology-driven synapse loss. Frontotemporal dysregulation of the GABAergic/glutamatergic stimuli might be a target for future drug development. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. Dynamic Ligand Modulation of EPO Receptor Pools, and Dysregulation by Polycythemia-Associated EPOR Alleles

    Science.gov (United States)

    Singh, Seema; Verma, Rakesh; Pradeep, Anamika; Leu, Karen; Mortensen, R. Bruce; Young, Peter R.; Oyasu, Miho; Schatz, Peter J.; Green, Jennifer M.; Wojchowski, Don M.

    2012-01-01

    mutated EPOR-T polycythemia alleles dysregulate the erythron. Notably, specific new tools also are characterized for studies of EPOR expression, activation, action and metabolism. PMID:22253704

  1. SIRT1 inactivation induces inflammation through the dysregulation of autophagy in human THP-1 cells

    International Nuclear Information System (INIS)

    Takeda-Watanabe, Ai; Kitada, Munehiro; Kanasaki, Keizo; Koya, Daisuke

    2012-01-01

    Sirtinol-induced inflammation and NF-κB activation associated with p62/Sqstm1 accumulation. In summary, SIRT1 inactivation induces inflammation through NF-κB activation and dysregulates autophagy via nutrient-sensing pathways such as the mTOR and AMPK pathways, in THP-1 cells.

  2. SIRT1 inactivation induces inflammation through the dysregulation of autophagy in human THP-1 cells

    Energy Technology Data Exchange (ETDEWEB)

    Takeda-Watanabe, Ai; Kitada, Munehiro; Kanasaki, Keizo [Diabetology and Endocrinology, Kanazawa Medical University, Kahoku-Gun, Ishikawa (Japan); Koya, Daisuke, E-mail: koya0516@kanazawa-med.ac.jp [Diabetology and Endocrinology, Kanazawa Medical University, Kahoku-Gun, Ishikawa (Japan)

    2012-10-12

    is implicated in decreased 5 Prime -AMP activated kinase (AMPK) activation, leading to the impairment of autophagy. The mTOR inhibitor, rapamycin, abolishes Sirtinol-induced inflammation and NF-{kappa}B activation associated with p62/Sqstm1 accumulation. In summary, SIRT1 inactivation induces inflammation through NF-{kappa}B activation and dysregulates autophagy via nutrient-sensing pathways such as the mTOR and AMPK pathways, in THP-1 cells.

  3. Emotional dysregulation is a primary symptom in adult Attention-Deficit/Hyperactivity Disorder (ADHD).

    Science.gov (United States)

    Hirsch, Oliver; Chavanon, MiraLynn; Riechmann, Elke; Christiansen, Hanna

    2018-05-01

    Clinical observations suggest that adults have more diverse deficits than children with Attention Deficit/Hyperactivity Disorder (ADHD). These seem to entail difficulties with emotionality, self-concept and emotion regulation in particular, along with the cardinal symptoms of inattention, impulsivity, and hyperactivity for adult patients. Here, we probed a model that explicitly distinguished positive and negative affect, problems with self-concept and emotion regulation skills as distinct but correlating factors with the symptom domains of inattention, hyperactivity, and impulsivity. Participants were 213 newly diagnosed adults with ADHD (62.9% male, mean age 33.5 years). Symptoms were assessed via self-report on the Conners' Adult ADHD Rating Scales, a modified version of the Positive and Negative Affect Scale and the Emotion Regulation Skill Questionnaire. A confirmatory factor analysis with the R package lavaan, using a robust Maximum Likelihood estimator (MLR) for non-normal data, was conducted to test our new non-hierarchical 7-factor model. All calculated model-fit statistics revealed good model-fit (χ 2 /df ratio = 2.03, robust RMSEA = .07). The SRMR in our model reached .089, indicating an acceptable model fit. Factor loadings on the postulated factors had salient loadings ≥ .31 except for one item on the hyperactivity factor. Latent factor associations were especially salient between emotional dysregulation and problems with self-concept, and also partially with impulsivity/emotional lability. The three models of ADHD and emotion regulation as suggested by Shaw et al. (2014) could not be disentangled in this study, though the overall results support the model with shared neurocognitive deficits. Further, we did not separately analyze ADHD with or without comorbid disorders. As our sample of clinical cases with ADHD is highly comorbid (47.9%), other disorders than ADHD might account for the emotion regulation deficits, though a sensitivity

  4. Dysregulation of the ADAM17/Notch signalling pathways in endometriosis: from oxidative stress to fibrosis.

    Science.gov (United States)

    González-Foruria, Iñaki; Santulli, Pietro; Chouzenoux, Sandrine; Carmona, Francisco; Chapron, Charles; Batteux, Frédéric

    2017-07-01

    Is oxidative stress associated with the A disintegrin and metalloproteases (ADAM) metallopeptidase domain 17 (ADAM17)/Notch signalling pathway and fibrosis in the development of endometriosis? Oxidative stress is correlated with hyperactivation of the ADAM17/Notch signalling pathway and a consequent increase in fibrosis in patients with endometriosis. It is nowadays accepted that oxidative stress plays an important role in the onset and progression of endometriosis. Oxidative stress is able to induce the synthesis of some members of the 'ADAM' family, such as ADAM17. ADAM17/Notch signalling is dysregulated in other profibrotic and inflammatory diseases. This was a prospective laboratory study conducted in a tertiary-care university hospital between January 2011 and April 2013. We investigated non-pregnant, younger than 42-year-old patients (n = 202) during surgery for a benign gynaecological condition. After complete surgical exploration of the abdominopelvic cavity, 121 women with histologically proven endometriosis and 81 endometriosis-free control women were enrolled. Peritoneal fluid (PF) samples were obtained from all the study participants during surgery in order to detect advanced oxidation protein products (AOPPs) and metalloproteinase activity of ADAM17. Stromal cells from endometrial specimens (n = 8) were obtained from endometrium of control patients (Cs), and from eutopic (Es) and ectopic (Ps) endometrium of patients with deep infiltrating endometriosis (DIE) (n = 8). ADAM17, Notch and the fibrosis markers α-smooth muscle actin (α-SMA) and type-I collagen were assessed using immunoblotting in all the endometrial samples obtained. Additionally, fibrosis was assessed after using Notch cleavage inhibitors (DAPT and FLI-06). Notch and fibrosis were also evaluated after stimulation of stromal endometrial cells with ADAM17 purified protein, increasing concentrations of H2O2 and primary cell culture supernatants. Patients with DIE presented higher PF AOPP

  5. Nitric oxide dysregulation in the pathogenesis of preeclampsia among Ghanaian women

    Directory of Open Access Journals (Sweden)

    Adu-Bonsaffoh K

    2015-02-01

    early-onset disease. Conclusion: This study has determined a profound NO upregulation in PE evidenced by significant elevation of NO metabolite levels compared to normal pregnancy. This might be due to deranged endothelial function with dysregulated production of NO to restore the persistent hypertension characteristic of PE. Keywords: preeclampsia, endothelial dysfunction, nitric oxide, Griess reagent

  6. Effect of family structure and TPH2 G-703T on the stability of dysregulation profile throughout adolescence.

    Science.gov (United States)

    Nobile, Maria; Bianchi, Valentina; Monzani, Dario; Beri, Silvana; Bellina, Monica; Greco, Andrea; Colombo, Paola; Tesei, Alessandra; Caldirola, Daniela; Giorda, Roberto; Perna, Giampaolo; Molteni, Massimo

    2016-01-15

    Two different polymorphisms (TPH2 G-703T and 5-HTTLPR) involved in the serotonergic pathway have been reported to play a role, both alone and in interaction with the environment, in early and adult emotion regulation. As most of these studies are cross-sectional, we know little about the impact of these polymorphisms over time, particularly during adolescence. Because we were interested in the effects of these polymorphisms and environment (i.e., family structure) at different time-points on the emotional dysregulation profile, we performed a path analysis model in a general adolescent population sample of a five-year follow-up study. We found a high stability of Dysregulation Profile problems independently from the examined allelic variants. We also found that early family structure directly influences the levels of dysregulation problems in early adolescence, both alone and in interaction with TPH2, suggesting the presence of a gene-environment interaction effect. Furthermore, we found that in adolescents homozygous for the TPH2 G allele, the effect of the early family structure remains active during late adolescence, albeit mediated by earlier emotional problems. The high attrition rate, the use of only one source on behavioral problems of adolescents, and the focus on a single polymorphism in the investigated genes could limit the generalizability of the present results. These results suggest that early family structure could play a significant role in the development and maintenance of emotional and behavioral problems not only in early adolescence but also in late-adolescence, although this effect was mediated and moderated by behavioral and genetic variables. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Lack of Resilience Is Related to Stress-Related Sleep Reactivity, Hyperarousal, and Emotion Dysregulation in Insomnia Disorder.

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    Palagini, Laura; Moretto, Umberto; Novi, Martina; Masci, Isabella; Caruso, Danila; Drake, Christopher L; Riemann, Dieter

    2018-05-15

    According to the diathesis-stress model of insomnia, insomnia may develop in vulnerable individuals in response to stress. Resilience is a psychobiological factor that determines an individual's capacity to adapt successfully to stressful events and low resilience increases vulnerability for development of mental disorders. The aim was to explore resilience in subjects with insomnia and its relationship with the factors that contribute to its development and perpetuation. The study consisted of 58 subjects with Insomnia Disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and 38 good sleepers. Resilience Scale for Adults (RSA), Ford Insomnia Response to Stress Test (FIRST), Pre-sleep Arousal Scale (PSAS), and Difficulties in Emotion Regulation Scale (DERS) were administered while taking into account psychiatric symptoms. Differences in means between groups were assessed using t test or Mann-Whitney U /Wilcoxon test. Linear/multivariable regression analyses and mediation analyses were performed. Subjects with insomnia (24 females, mean age 49 ± 2.1 years) had lower RSA and higher FIRST, DERS, and PSAS scores than good sleepers (22 females, mean age 47.2 ± 1.2 years). After controlling for anxiety/depressive symptoms, low resilience correlated with high stress-related sleep reactivity ( P = .004), pre-sleep cognitive hyperarousal ( P = .01) and emotion dysregulation ( P = .01). Emotion dysregulation mediated the relationship between low resilience and cognitive hyperarousal (Z = 2.06, P = .03). Subjects with insomnia showed low resilience, which was related to high stress-related sleep reactivity, emotional dysregulation, and hyperarousal. If resilience helps to minimize the extent of pathogenesis in the developmental process, an early identification of vulnerable candidates should be useful for preventing insomnia development and maintenance. A commentary on this article appears in this issue on page 709. © 2018 American

  8. HPRT deficiency coordinately dysregulates canonical Wnt and presenilin-1 signaling: a neuro-developmental regulatory role for a housekeeping gene?

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    Tae Hyuk Kang

    2011-01-01

    Full Text Available We have used microarray-based methods of global gene expression together with quantitative PCR and Western blot analysis to identify dysregulation of genes and aberrant cellular processes in human fibroblasts and in SH-SY5Y neuroblastoma cells made HPRT-deficient by transduction with a retrovirus stably expressing an shRNA targeted against HPRT. Analysis of the microarray expression data by Gene ontology (GO and Gene Set Enrichment Analysis (GSEA as well as significant pathway analysis by GeneSpring GX10 and Panther Classification System reveal that HPRT deficiency is accompanied by aberrations in a variety of pathways known to regulate neurogenesis or to be implicated in neurodegenerative disease, including the canonical Wnt/β-catenin and the Alzheimer's disease/presenilin signaling pathways. Dysregulation of the Wnt/β-catenin pathway is confirmed by Western blot demonstration of cytosolic sequestration of β-catenin during in vitro differentiation of the SH-SY5Y cells toward the neuronal phenotype. We also demonstrate that two key transcription factor genes known to be regulated by Wnt signaling and to be vital for the generation and function of dopaminergic neurons; i.e., Lmx1a and Engrailed 1, are down-regulated in the HPRT knockdown SH-SY5Y cells. In addition to the Wnt signaling aberration, we found that expression of presenilin-1 shows severely aberrant expression in HPRT-deficient SH-SY5Y cells, reflected by marked deficiency of the 23 kDa C-terminal fragment of presenilin-1 in knockdown cells. Western blot analysis of primary fibroblast cultures from two LND patients also shows dysregulated presenilin-1 expression, including aberrant proteolytic processing of presenilin-1. These demonstrations of dysregulated Wnt signaling and presenilin-1 expression together with impaired expression of dopaminergic transcription factors reveal broad pleitropic neuro-regulatory defects played by HPRT expression and suggest new directions for

  9. Transcriptional dysregulation of γ-aminobutyric acid transporter in parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia.

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    Bitanihirwe, Byron K Y; Woo, Tsung-Ung W

    2014-12-30

    Parvalbumin (PV)-containing neurons are functionally compromised in schizophrenia. Using double in situ hybridization in postmortem human prefrontal cortex, we found that the messenger RNA (mRNA) for the γ-aminobutyric acid (GABA) transporter GAT-1 was undetectable in 22-41% of PV neurons in layers 3-4 in schizophrenia. In the remaining PV neurons with detectable GAT-1 mRNA, transcript expression was decreased by 26% in layer 3. Hence, the dysfunction of PV neurons involves the molecular dysregulation of presynaptic GABA reuptake. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  10. Dysregulation of Ca(v)1.4 channels disrupts the maturation of photoreceptor synaptic ribbons in congenital stationary night blindness type 2.

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    Liu, Xiaoni; Kerov, Vasily; Haeseleer, Françoise; Majumder, Anurima; Artemyev, Nikolai; Baker, Sheila A; Lee, Amy

    2013-01-01

    Mutations in the gene encoding Cav 1.4, CACNA1F, are associated with visual disorders including X-linked incomplete congenital stationary night blindness type 2 (CSNB2). In mice lacking Cav 1.4 channels, there are defects in the development of "ribbon" synapses formed between photoreceptors (PRs) and second-order neurons. However, many CSNB2 mutations disrupt the function rather than expression of Cav 1.4 channels. Whether defects in PR synapse development due to altered Cav 1.4 function are common features contributing to the pathogenesis of CSNB2 is unknown. To resolve this issue, we profiled changes in the subcellular distribution of Cav 1.4 channels and synapse morphology during development in wild-type (WT) mice and mouse models of CSNB2. Using Cav 1.4-selective antibodies, we found that Cav 1.4 channels associate with ribbon precursors early in development and are concentrated at both rod and cone PR synapses in the mature retina. In mouse models of CSNB2 in which the voltage-dependence of Cav 1.4 activation is either enhanced (Cav 1.4I756T) or inhibited (CaBP4 KO), the initial stages of PR synaptic ribbon formation are largely unaffected. However, after postnatal day 13, many PR ribbons retain the immature morphology. This synaptic abnormality corresponds in severity to the defect in synaptic transmission in the adult mutant mice, suggesting that lack of sufficient mature synapses contributes to vision impairment in Cav 1.4I756T and CaBP4 KO mice. Our results demonstrate the importance of proper Cav 1.4 function for efficient PR synapse maturation, and that dysregulation of Cav 1.4 channels in CSNB2 may have synaptopathic consequences.

  11. Food-intake dysregulation in type 2 diabetic Goto-Kakizaki rats: hypothesized role of dysfunctional brainstem thyrotropin-releasing hormone and impaired vagal output.

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    Zhao, K; Ao, Y; Harper, R M; Go, V L W; Yang, H

    2013-09-05

    Thyrotropin-releasing hormone (TRH), a neuropeptide contained in neural terminals innervating brainstem vagal motor neurons, enhances vagal outflow to modify multisystemic visceral functions and food intake. Type 2 diabetes (T2D) and obesity are accompanied by impaired vagal functioning. We examined the possibility that impaired brainstem TRH action may contribute to the vagal dysregulation of food intake in Goto-Kakizaki (GK) rats, a T2D model with hyperglycemia and impaired central vagal activation by TRH. Food intake induced by intracisternal injection of TRH analog was reduced significantly by 50% in GK rats, compared to Wistar rats. Similarly, natural food intake in the dark phase or food intake after an overnight fast was reduced by 56-81% in GK rats. Fasting (48h) and refeeding (2h)-associated changes in serum ghrelin, insulin, peptide YY, pancreatic polypeptide and leptin, and the concomitant changes in orexigenic or anorexigenic peptide expression in the brainstem and hypothalamus, all apparent in Wistar rats, were absent or markedly reduced in GK rats, with hormone release stimulated by vagal activation, such as ghrelin and pancreatic polypeptide, decreased substantially. Fasting-induced Fos expression accompanying endogenous brainstem TRH action decreased by 66% and 91%, respectively, in the nucleus tractus solitarius (NTS) and the dorsal motor nucleus of the vagus (DMV) in GK rats, compared to Wistar rats. Refeeding abolished fasting-induced Fos-expression in the NTS, while that in the DMV remained in Wistar but not GK rats. These findings indicate that dysfunctional brainstem TRH-elicited vagal impairment contributes to the disturbed food intake in T2D GK rats, and may provide a pathophysiological mechanism which prevents further weight gain in T2D and obesity. Published by Elsevier Ltd.

  12. Melatonin Reverses Fas, E2F-1 and Endoplasmic Reticulum Stress Mediated Apoptosis and Dysregulation of Autophagy Induced by the Herbicide Atrazine in Murine Splenocytes.

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    Shweta Sharma

    Full Text Available Exposure to the herbicide Atrazine (ATR can cause immunotoxicity, apart from other adverse consequences for animal and human health. We aimed at elucidating the apoptotic mechanisms involved in immunotoxicity of ATR and their attenuation by Melatonin (MEL. Young Swiss mice were divided into control, ATR and MEL+ATR groups based on daily (x14 intraperitoneal administration of the vehicle (normal saline, ATR (100 mg/kg body weight and MEL (20 mg/kg body weight with ATR. Isolated splenocytes were processed for detection of apoptosis by Annexin V-FITC and TUNEL assays, and endoplasmic reticulum (ER stress by immunostaining. Key proteins involved in apoptosis, ER stress and autophagy were quantified by immunoblotting. ATR treatment resulted in Fas-mediated activation of caspases 8 and 3 and inactivation of PARP1 which were inhibited significantly by co-treatment with MEL. MEL also attenuated the ATR-induced, p53 independent mitochondrial apoptosis through upregulation of E2F-1 and PUMA and suppression of their downstream target Bax. An excessive ER stress triggered by ATR through overexpression of ATF-6α, spliced XBP-1, CREB-2 and GADD153 signals was reversed by MEL. MEL also reversed the ATR-induced impairment of autophagy which was indicated by a decline in BECN-1, along with significant enhancement in LC3B-II and p62 expressions. Induction of mitochondrial apoptosis, ER stress and autophagy dysregulation provide a new insight into the mechanism of ATR immunotoxicity. The cytoprotective role of MEL, on the other hand, was defined by attenuation of ER stress, Fas-mediated and p53 independent mitochondria-mediated apoptosis as well as autophagy signals.

  13. Emotional dysregulation in borderline personality disorder and its influence on communication behavior and feelings in romantic relationships.

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    Miano, Annemarie; Grosselli, Luna; Roepke, Stefan; Dziobek, Isabel

    2017-08-01

    Dysfunction in romantic relationships constitutes one of the most burdensome symptoms of borderline personality disorder (BPD). The aim of this study was to ascertain how emotional dysregulation affects behavior and relationship related feelings of women with BPD in threatening conversations with their own romantic partner. Thirty couples in which the women were diagnosed with BPD and 34 healthy control (HC) couples were videotaped while discussing personally threatening (i.e., personal failure) and relationship-threatening (i.e., separation) themes. Third party raters evaluated stress and communication behaviors during the conversations. Relationship related feelings, i.e., closeness and relationship insecurity, were assessed by self-report. Overall, women with BPD were rated as more stressed in threatening situations than HC women and their partners, but not more stressed in relationship-threatening than personally threatening situations. A heightened stress response of women with BPD predicted more negative and less positive communication behaviors and a stronger decline in self-rated closeness to the partner compared to HC. Stress-induced increases in relationship insecurity were specific to women with BPD. Our results highlight the central role of emotional dysregulation in interpersonal dysfunctions of persons with BPD and the need to address individual emotion regulation strategies more explicitly in dyadic contexts. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. The Effects of Exercise Training on Obesity-Induced Dysregulated Expression of Adipokines in White Adipose Tissue

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    Takuya Sakurai

    2013-01-01

    Full Text Available Obesity is recognized as a risk factor for lifestyle-related diseases such as type 2 diabetes and cardiovascular disease. White adipose tissue (WAT is not only a static storage site for energy; it is also a dynamic tissue that is actively involved in metabolic reactions and produces humoral factors, such as leptin and adiponectin, which are collectively referred to as adipokines. Additionally, because there is much evidence that obesity-induced inflammatory changes in WAT, which is caused by dysregulated expression of inflammation-related adipokines involving tumor necrosis factor-α and monocyte chemoattractant protein 1, contribute to the development of insulin resistance, WAT has attracted special attention as an organ that causes diabetes and other lifestyle-related diseases. Exercise training (TR not only leads to a decrease in WAT mass but also attenuates obesity-induced dysregulated expression of the inflammation-related adipokines in WAT. Therefore, TR is widely used as a tool for preventing and improving lifestyle-related diseases. This review outlines the impact of TR on the expression and secretory response of adipokines in WAT.

  15. Childhood traumatization by primary caretaker and affect dysregulation in patients with borderline personality disorder and somatoform disorder

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    Annemiek van Dijke

    2011-03-01

    Full Text Available Affect regulation is often compromised as a result of early life interpersonal traumatization and disruption in caregiving relationships like in situations where the caretaker is emotionally, sexually or physically abusing the child. Prior studies suggest a clear relationship between early childhood attachment-related psychological trauma and affect dysregulation. We evaluated the relationship of retrospectively recalled childhood traumatization by primary caretaker(s (TPC and affect dysregulation in 472 adult psychiatric patients diagnosed with borderline personality disorder (BPD, somatoform disorder (SoD, both BPD and SoD, or disorders other than BPD or SoD, using the Bermond-Vorst Alexithymia Questionnaire, the self-report version of the Structured Interview for Disorders of Extreme Stress, the Self-rating Inventory for Posttraumatic Stress Disorder (SRIP and the Traumatic Experiences Checklist. Almost two-thirds of participants reported having experienced childhood TPC, ranging from approximately 50% of patients with SoD or other psychiatric disorders to more than 75% of patients with comorbid BPD + SoD. Underregulation of affect was associated with emotional TPC and TPC occurring in developmental epoch 0–6 years. Over-regulation of affect was associated with physical TPC. Childhood trauma by a primary caretaker is prevalent among psychiatric patients, particularly those with BPD, and differentially associated with underand over-regulation of affect depending on the type of traumatic exposure.For the abstract or full text in other languages, please see Supplementary files under Reading Tools online

  16. Immune dysregulation and cognitive vulnerability in the aging brain: Interactions of microglia, IL-1β, BDNF and synaptic plasticity.

    Science.gov (United States)

    Patterson, Susan L

    2015-09-01

    Older individuals often experience declines in cognitive function after events (e.g. infection, or injury) that trigger activation of the immune system. This occurs at least in part because aging sensitizes the response of microglia (the brain's resident immune cells) to signals triggered by an immune challenge. In the aging brain, microglia respond to these signals by producing more pro-inflammatory cytokines (e.g. interleukin-1beta or IL-1β) and producing them for longer than microglia in younger brains. This exaggerated inflammatory response can compromise processes critical for optimal cognitive functioning. Interleukin-1β is central to the inflammatory response and is a key mediator and modulator of an array of associated biological functions; thus its production and release is usually very tightly regulated. This review will focus on the impact of dysregulated production of IL-1β on hippocampus dependent-memory systems and associated synaptic plasticity processes. The neurotrophin brain-derived neurotrophic factor (BNDF) helps to protect neurons from damage caused by infection or injury, and it plays a critical role in many of the same memory and hippocampal plasticity processes compromised by dysregulated production of IL-1β. This suggests that an exaggerated brain inflammatory response, arising from aging and a secondary immune challenge, may erode the capacity to provide the BDNF needed for memory-related plasticity processes at hippocampal synapses. This article is part of a Special Issue entitled 'Neuroimmunology and Synaptic Function'. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Abnormalities of thymic stroma may contribute to immune dysregulation in murine models of leaky severe combined immunodeficiency

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    Francesca eRucci

    2011-05-01

    Full Text Available Lymphostromal cross-talk in the thymus is essential to allow generation of a diversified repertoire of T lymphocytes and to prevent autoimmunity by self-reactive T cells. Hypomorphic mutations in genes that control T cell development have been associated with immunodeficiency and immune dysregulation both in humans and in mice. We have studied T cell development and thymic stroma architecture and maturation in two mouse models of leaky SCID, carrying hypomorphic mutations in Rag1 and Lig4 genes. Defective T cell development was associated with abnormalities of thymic architecture that predominantly affect the thymic medulla, with reduction of the pool of mature medullary thymic epithelial cells (mTECs. While the ability of mTECs to express Aire is preserved in mutant mice, the frequency of mature mTECs expressing Aire and tissue-specific antigens (TSAs is severely reduced. Similarly, the ability of CD4+ T cells to differentiate into Foxp3+ natural regulatory T cells is preserved in Rag1 and Lig4 mutant mice, but their number is greatly reduced. These data indicate that hypomorphic defects in T cell development may cause defective lymphostromal cross-talk and impinge on thymic stromal cells maturation, and thus favor immune dysregulation.

  18. A Pilot Trial of Mindfulness Meditation Training for ADHD in Adulthood: Impact on Core Symptoms, Executive Functioning, and Emotion Dysregulation.

    Science.gov (United States)

    Mitchell, John T; McIntyre, Elizabeth M; English, Joseph S; Dennis, Michelle F; Beckham, Jean C; Kollins, Scott H

    2017-11-01

    Mindfulness meditation training is garnering increasing empirical interest as an intervention for ADHD in adulthood, although no studies of mindfulness as a standalone treatment have included a sample composed entirely of adults with ADHD or a comparison group. The aim of this study was to assess the feasibility, acceptability, and preliminary efficacy of mindfulness meditation for ADHD, executive functioning (EF), and emotion dysregulation symptoms in an adult ADHD sample. Adults with ADHD were stratified by ADHD medication status and otherwise randomized into an 8-week group-based mindfulness treatment ( n = 11) or waitlist group ( n = 9). Treatment feasibility and acceptability were positive. In addition, self-reported ADHD and EF symptoms (assessed in the laboratory and ecological momentary assessment), clinician ratings of ADHD and EF symptoms, and self-reported emotion dysregulation improved for the treatment group relative to the waitlist group over time with large effect sizes. Improvement was not observed for EF tasks. Findings support preliminary treatment efficacy, though require larger trials.

  19. Cohesin Rad21 Mediates Loss of Heterozygosity and Is Upregulated via Wnt Promoting Transcriptional Dysregulation in Gastrointestinal Tumors

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    Huiling Xu

    2014-12-01

    Full Text Available Summary: Loss of heterozygosity (LOH of the adenomatous polyposis coli (APC gene triggers a series of molecular events leading to intestinal adenomagenesis. Haploinsufficiency of the cohesin Rad21 influences multiple initiating events in colorectal cancer (CRC. We identify Rad21 as a gatekeeper of LOH and a β-catenin target gene and provide evidence that Wnt pathway activation drives RAD21 expression in human CRC. Genome-wide analyses identified Rad21 as a key transcriptional regulator of critical CRC genes and long interspersed element (LINE-1 or L1 retrotransposons. Elevated RAD21 expression tracks with reactivation of L1 expression in human sporadic CRC, implicating cohesin-mediated L1 expression in global genomic instability and gene dysregulation in cancer. : Rad21 holds the cohesin complex together as part of its role in chromosome partitioning and DNA repair. Xu et al. identify Rad21 as a key mediator of Apc gene heterozygous loss, the event initiating intestinal tumorigenesis. The subsequent activation of the Wnt pathway further induces Rad21, global gene dysregulation, chromosome instability, and pervasive retrotransposon activation.

  20. FAS/FASL are dysregulated in chordoma and their loss-of-function impairs zebrafish notochord formation.

    Science.gov (United States)

    Ferrari, Luca; Pistocchi, Anna; Libera, Laura; Boari, Nicola; Mortini, Pietro; Bellipanni, Gianfranco; Giordano, Antonio; Cotelli, Franco; Riva, Paola

    2014-07-30

    Chordoma is a rare malignant tumor that recapitulates the notochord phenotype and is thought to derive from notochord remnants not correctly regressed during development. Apoptosis is necessary for the proper notochord development in vertebrates, and the apoptotic pathway mediated by Fas and Fasl has been demonstrated to be involved in notochord cells regression. This study was conducted to investigate the expression of FAS/FASL pathway in a cohort of skull base chordomas and to analyze the role of fas/fasl homologs in zebrafish notochord formation. FAS/FASL expression was found to be dysregulated in chordoma leading to inactivation of the downstream Caspases in the samples analyzed. Both fas and fasl were specifically expressed in zebrafish notochord sorted cells. fas and fasl loss-of-function mainly resulted in larvae with notochord multi-cell-layer jumps organization, larger vacuolated notochord cells, defects in the peri-notochordal sheath structure and in vertebral mineralization. Interestingly, we observed the persistent expression of ntla and col2a1a, the zebrafish homologs of the human T gene and COL2A1 respectively, which are specifically up-regulated in chordoma. These results demonstrate for the first time the dysregulation of FAS/FASL in chordoma and their role in notochord formation in the zebrafish model, suggesting their possible implication in chordoma onset.

  1. Normative development of the Child Behavior Checklist Dysregulation Profile from early childhood to adolescence: Associations with personality pathology.

    Science.gov (United States)

    Deutz, Marike H F; Vossen, Helen G M; De Haan, Amaranta D; Deković, Maja; Van Baar, Anneloes L; Prinzie, Peter

    2018-05-01

    The Dysregulation Profile (DP) is a broad indicator of concurrent affective, behavioral, and cognitive dysregulation, often measured with the anxious/depressed, aggressive behavior, and attention problems syndrome scales of the Child Behavior Checklist. Despite an expanding body of research on the DP, knowledge of the normative developmental course of the DP from early childhood to adolescence is lacking. Furthermore, although we know that the DP longitudinally predicts personality pathology, no research yet has examined whether next to the DP in early childhood, the rate of change of the DP across development predicts personality pathology. Therefore, using cohort-sequential latent growth modeling in a population-based sample (N = 668), we examined the normative developmental course of mother-reported DP from ages 4 to 17 years and its associations with a wide range of adolescent-reported personality pathology dimensions 3 years later. The results showed that the DP follows a nonlinear developmental course with a peak in early adolescence. The initial level of the DP at age 4 and, to a lesser extent, the rate of change in the DP predicted a range of personality pathology dimensions in late adolescence. The findings suggest that the DP is a broad developmental precursor of personality pathology in late adolescence.

  2. Upregulated GABA Inhibitory Function in ADHD Children with Child Behavior Checklist–Dysregulation Profile: 123I-Iomazenil SPECT Study

    Science.gov (United States)

    Nagamitsu, Shinichiro; Yamashita, Yushiro; Tanigawa, Hitoshi; Chiba, Hiromi; Kaida, Hayato; Ishibashi, Masatoshi; Kakuma, Tatsuyuki; Croarkin, Paul E.; Matsuishi, Toyojiro

    2015-01-01

    The child behavior checklist–dysregulation profile (CBCL–DP) refers to a pattern of elevated scores on the attention problems, aggression, and anxiety/depression subscales of the child behavior checklist. The aim of the present study was to investigate the potential role of GABA inhibitory neurons in children with attention deficit/hyperactivity disorder (ADHD) and dysregulation assessed with a dimensional measure. Brain single photon emission computed tomography (SPECT) was performed in 35 children with ADHD using 123I-iomazenil, which binds with high affinity to benzodiazepine receptors. Iomazenil binding activities were assessed with respect to the presence or absence of a threshold CBCL–DP (a score ≥210 for the sum of the three subscales: Attention Problems, Aggression, and Anxiety/Depression). We then attempted to identify which CBCL–DP subscale explained the most variance with respect to SPECT data, using “age,” “sex,” and “history of maltreatment” as covariates. Significantly higher iomazenil binding activity was seen in the posterior cingulate cortex (PCC) of ADHD children with a significant CBCL–DP. The Anxiety/Depression subscale on the CBCL had significant effects on higher iomazenil binding activity in the left superior frontal, middle frontal, and temporal regions, as well as in the PCC. The present brain SPECT findings suggest that GABAergic inhibitory neurons may play an important role in the neurobiology of the CBCL–DP, in children with ADHD. PMID:26082729

  3. Dissecting microRNA dysregulation in age-related macular degeneration: new targets for eye gene therapy.

    Science.gov (United States)

    Askou, Anne Louise; Alsing, Sidsel; Holmgaard, Andreas; Bek, Toke; Corydon, Thomas J

    2018-02-01

    MicroRNAs (miRNAs) are key regulators of gene expression in humans. Overexpression or depletion of individual miRNAs is associated with human disease. Current knowledge suggests that the retina is influenced by miRNAs and that dysregulation of miRNAs as well as alterations in components of the miRNA biogenesis machinery are involved in retinal diseases, including age-related macular degeneration (AMD). Furthermore, recent studies have indicated that the vitreous has a specific panel of circulating miRNAs and that this panel varies according to the specific pathological stress experienced by the retinal cells. MicroRNA (miRNA) profiling indicates subtype-specific miRNA profiles for late-stage AMD highlighting the importance of proper miRNA regulation in AMD. This review will describe the function of important miRNAs involved in inflammation, oxidative stress and pathological neovascularization, the key molecular mechanisms leading to AMD, and focus on dysregulated miRNAs as potential therapeutic targets in AMD. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  4. Calcineurin Dysregulation Underlies Spinal Cord Injury-Induced K+ Channel Dysfunction in DRG Neurons.

    Science.gov (United States)

    Zemel, Benjamin M; Muqeem, Tanziyah; Brown, Eric V; Goulão, Miguel; Urban, Mark W; Tymanskyj, Stephen R; Lepore, Angelo C; Covarrubias, Manuel

    2017-08-23

    Dysfunction of the fast-inactivating Kv3.4 potassium current in dorsal root ganglion (DRG) neurons contributes to the hyperexcitability associated with persistent pain induced by spinal cord injury (SCI). However, the underlying mechanism is not known. In light of our previous work demonstrating modulation of the Kv3.4 channel by phosphorylation, we investigated the role of the phosphatase calcineurin (CaN) using electrophysiological, molecular, and imaging approaches in adult female Sprague Dawley rats. Pharmacological inhibition of CaN in small-diameter DRG neurons slowed repolarization of the somatic action potential (AP) and attenuated the Kv3.4 current. Attenuated Kv3.4 currents also exhibited slowed inactivation. We observed similar effects on the recombinant Kv3.4 channel heterologously expressed in Chinese hamster ovary cells, supporting our findings in DRG neurons. Elucidating the molecular basis of these effects, mutation of four previously characterized serines within the Kv3.4 N-terminal inactivation domain eliminated the effects of CaN inhibition on the Kv3.4 current. SCI similarly induced concurrent Kv3.4 current attenuation and slowing of inactivation. Although there was little change in CaN expression and localization after injury, SCI induced upregulation of the native regulator of CaN 1 (RCAN1) in the DRG at the transcript and protein levels. Consistent with CaN inhibition resulting from RCAN1 upregulation, overexpression of RCAN1 in naive DRG neurons recapitulated the effects of pharmacological CaN inhibition on the Kv3.4 current and the AP. Overall, these results demonstrate a novel regulatory pathway that links CaN, RCAN1, and Kv3.4 in DRG neurons. Dysregulation of this pathway might underlie a peripheral mechanism of pain sensitization induced by SCI. SIGNIFICANCE STATEMENT Pain sensitization associated with spinal cord injury (SCI) involves poorly understood maladaptive modulation of neuronal excitability. Although central mechanisms have

  5. Identifying mRNA targets of microRNA dysregulated in cancer: with application to clear cell Renal Cell Carcinoma

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    Liou Louis S

    2010-04-01

    Full Text Available Abstract Background MicroRNA regulate mRNA levels in a tissue specific way, either by inducing degradation of the transcript or by inhibiting translation or transcription. Putative mRNA targets of microRNA identified from seed sequence matches are available in many databases. However, such matches have a high false positive rate and cannot identify tissue specificity of regulation. Results We describe a simple method to identify direct mRNA targets of microRNA dysregulated in cancers from expression level measurements in patient matched tumor/normal samples. The word "direct" is used here in a strict sense to: a represent mRNA which have an exact seed sequence match to the microRNA in their 3'UTR, b the seed sequence match is strictly conserved across mouse, human, rat and dog genomes, c the mRNA and microRNA expression levels can distinguish tumor from normal with high significance and d the microRNA/mRNA expression levels are strongly and significantly anti-correlated in tumor and/or normal samples. We apply and validate the method using clear cell Renal Cell Carcinoma (ccRCC and matched normal kidney samples, limiting our analysis to mRNA targets which undergo degradation of the mRNA transcript because of a perfect seed sequence match. Dysregulated microRNA and mRNA are first identified by comparing their expression levels in tumor vs normal samples. Putative dysregulated microRNA/mRNA pairs are identified from these using seed sequence matches, requiring that the seed sequence be conserved in human/dog/rat/mouse genomes. These are further pruned by requiring a strong anti-correlation signature in tumor and/or normal samples. The method revealed many new regulations in ccRCC. For instance, loss of miR-149, miR-200c and mir-141 causes gain of function of oncogenes (KCNMA1, LOX, VEGFA and SEMA6A respectively and increased levels of miR-142-3p, miR-185, mir-34a, miR-224, miR-21 cause loss of function of tumor suppressors LRRC2, PTPN13, SFRP1

  6. Dysregulation of endothelial colony-forming cell function by a negative feedback loop of circulating miR-146a and -146b in cardiovascular disease patients.

    Directory of Open Access Journals (Sweden)

    Ting-Yu Chang

    -regulation compared to healthy control. Knockdown of miR-146a-5p or miR-146b-5p in CAD ECFCs enhanced migration and tube formation activity in diseased ECFCs. Contrarily, overexpression of miR-146a-5p or miR-146b-5p in healthy ECFC repressed migration and tube formation in ECFCs. TargetScan analysis showed that miR-146a-5p and miR-146b-5p target many of the angiogenesis-related genes that were down-regulated in CAD ECFCs. Knockdown of miR-146a-5p or miR-146b-5p restores CAV1 and RHOJ levels in CAD ECFCs. Reporter assays confirmed the direct binding and repression of miR-146a-5p and miR-146b-5p to the 3'-UTR of mRNA of RHOJ, a positive regulator of angiogenic potential in endothelial cells. Consistently, RHOJ knockdown inhibited the migration and tube formation ability in ECFCs. Collectively, we discovered the dysregulation of miR-146a-5p/RHOJ and miR-146b-5p/RHOJ axis in the plasma and ECFCs of CAD patients that could be used as biomarkers or therapeutic targets for CAD and other angiogenesis-related diseases.

  7. Complement mediated renal inflammation induced by donor brain death : role of renal C5a-C5aR interaction

    NARCIS (Netherlands)

    van Werkhoven, M. B.; Damman, J.; van Dijk, M. C. R. F.; Daha, M. R.; de Jong, I. J.; Leliveld, A.; Krikke, C.; Leuvenink, H. G.; van Goor, H.; van Son, W. J.; Olinga, P.; Hillebrands, J. -L.; Seelen, M. A. J.

    Kidneys retrieved from brain-dead donors have impaired allograft function after transplantation compared to kidneys from living donors. Donor brain death (BD) triggers inflammatory responses, including both systemic and local complement activation. The mechanism by which systemic activated

  8. Typical patterns of disordered eating among Swedish adolescents: associations with emotion dysregulation, depression, and self-esteem.

    Science.gov (United States)

    Hansson, Erika; Daukantaitė, Daiva; Johnsson, Per

    2016-01-01

    Using the person-oriented approach, we determined the relationships between four indicators (restraint and eating, shape, and weight concerns) of disordered eating (DE), as measured by the self-reported Eating Disorders Examination Questionnaire (EDE-Q), to identify typical DE patterns. We then related these patterns to clinical EDE-Q cut-off scores and emotion dysregulation, depression, self-esteem, and two categories of DE behaviors (≥2 or ≤1 "yes" responses on the SCOFF questionnaire). Typical patterns of DE were identified in a community sample of 1,265 Swedish adolescents ( M age  = 16.19, SD  = 1.21; age range 13.5-19 years) using a cluster analysis. Separate analyses were performed for girls ( n  = 689) and boys ( n  = 576). The cluster analysis yielded a six-cluster solution for each gender. Four of the six clusters for girls and five for boys showed scores above the clinical cut-off on at least one of the four DE indicators. For girls, the two clusters that scored above the clinical cut-offs on all four DE indicators reported severe psychological problems, including high scores on emotion dysregulation and depression and low scores on self-esteem. In contrast, for boys, although two clusters reported above the clinical cut-off on all four indicators, only the cluster with exceedingly high scores on shape and weight concerns reported high emotion dysregulation and depression, and extremely low self-esteem. Furthermore, significantly more girls and boys in the most problematic DE clusters reported ≥2 "yes" responses on the SCOFF questionnaire (as opposed to ≤1 response), indicating clear signs of DE and severe psychological difficulties. We suspect that the various problematic DE patterns will require different paths back to a healthy diet. However, more research is needed to determine the developmental trajectories of these DE patterns and ensure more precise clinical cut-off scores, especially for boys. Comprehensive understanding

  9. Norepinephrine and Epinephrine Enhanced the Infectivity of Enterovirus 71.

    Directory of Open Access Journals (Sweden)

    Yu-Ting Liao

    Full Text Available Enterovirus 71 (EV71 infections may be associated with neurological complications, including brainstem encephalitis (BE. Severe EV71 BE may be complicated with autonomic nervous system (ANS dysregulation and/or pulmonary edema (PE. ANS dysregulation is related to the overactivation of the sympathetic nervous system, which results from catecholamine release.The aims of this study were to explore the effects of catecholamines on severe EV71 infection and to investigate the changes in the percentages of EV71-infected cells, virus titer, and cytokine production on the involvement of catecholamines.Plasma levels of norepinephrine (NE and epinephrine (EP in EV71-infected patients were measured using an enzyme-linked immunoassay. The expression of adrenergic receptors (ADRs on RD, A549, SK-N-SH, THP-1, Jurkat and human peripheral blood mononuclear cells (hPBMCs were detected using flow cytometry. The percentages of EV71-infected cells, virus titer, and cytokine production were investigated after treatment with NE and EP.The plasma levels of NE and EP were significantly higher in EV71-infected patients with ANS dysregulation and PE than in controls. Both α1A- and β2-ADRs were expressed on A549, RD, SK-N-SH, HL-60, THP-1, Jurkat cells and hPBMCs. NE treatment elevated the percentages of EV71-infected cells to 62.9% and 22.7% in THP-1 and Jurkat cells, respectively. Via treatment with EP, the percentages of EV71-infected cells were increased to 64.6% and 26.9% in THP-1 and Jurkat cells. The percentage of EV71-infected cells increased upon NE or EP treatment while the α- and β-blockers reduced the percentages of EV71-infected cells with NE or EP treatment. At least two-fold increase in virus titer was observed in EV71-infected A549, SK-N-SH and hPBMCs after treatment with NE or EP. IL-6 production was enhanced in EV71-infected hPBMCs at a concentration of 102 pg/mL NE.The plasma levels of NE and EP elevated in EV71-infected patients with ANS

  10. Norepinephrine and Epinephrine Enhanced the Infectivity of Enterovirus 71.

    Science.gov (United States)

    Liao, Yu-Ting; Wang, Shih-Min; Wang, Jen-Ren; Yu, Chun-Keung; Liu, Ching-Chuan

    2015-01-01

    Enterovirus 71 (EV71) infections may be associated with neurological complications, including brainstem encephalitis (BE). Severe EV71 BE may be complicated with autonomic nervous system (ANS) dysregulation and/or pulmonary edema (PE). ANS dysregulation is related to the overactivation of the sympathetic nervous system, which results from catecholamine release. The aims of this study were to explore the effects of catecholamines on severe EV71 infection and to investigate the changes in the percentages of EV71-infected cells, virus titer, and cytokine production on the involvement of catecholamines. Plasma levels of norepinephrine (NE) and epinephrine (EP) in EV71-infected patients were measured using an enzyme-linked immunoassay. The expression of adrenergic receptors (ADRs) on RD, A549, SK-N-SH, THP-1, Jurkat and human peripheral blood mononuclear cells (hPBMCs) were detected using flow cytometry. The percentages of EV71-infected cells, virus titer, and cytokine production were investigated after treatment with NE and EP. The plasma levels of NE and EP were significantly higher in EV71-infected patients with ANS dysregulation and PE than in controls. Both α1A- and β2-ADRs were expressed on A549, RD, SK-N-SH, HL-60, THP-1, Jurkat cells and hPBMCs. NE treatment elevated the percentages of EV71-infected cells to 62.9% and 22.7% in THP-1 and Jurkat cells, respectively. Via treatment with EP, the percentages of EV71-infected cells were increased to 64.6% and 26.9% in THP-1 and Jurkat cells. The percentage of EV71-infected cells increased upon NE or EP treatment while the α- and β-blockers reduced the percentages of EV71-infected cells with NE or EP treatment. At least two-fold increase in virus titer was observed in EV71-infected A549, SK-N-SH and hPBMCs after treatment with NE or EP. IL-6 production was enhanced in EV71-infected hPBMCs at a concentration of 102 pg/mL NE. The plasma levels of NE and EP elevated in EV71-infected patients with ANS dysregulation and

  11. Dysregulation of Neuronal Ca2+ Channel Linked to Heightened Sympathetic Phenotype in Prohypertensive States

    OpenAIRE

    Larsen, Hege E.; Bardsley, Emma N.; Lefkimmiatis, Konstantinos; Paterson, David J.

    2016-01-01

    Hypertension is associated with impaired nitric oxide (NO)–cyclic nucleotide (CN)-coupled intracellular calcium (Ca2+) homeostasis that enhances cardiac sympathetic neurotransmission. Because neuronal membrane Ca2+ currents are reduced by NO-activated S-nitrosylation, we tested whether CNs affect membrane channel conductance directly in neurons isolated from the stellate ganglia of spontaneously hypertensive rats (SHRs) and their normotensive controls. Using voltage-clamp and cAMP–protein kin...

  12. Alcohol, Adipose Tissue and Lipid Dysregulation

    Directory of Open Access Journals (Sweden)

    Jennifer L. Steiner

    2017-02-01

    Full Text Available Chronic alcohol consumption perturbs lipid metabolism as it increases adipose tissue lipolysis and leads to ectopic fat deposition within the liver and the development of alcoholic fatty liver disease. In addition to the recognition of the role of adipose tissue derived fatty acids in liver steatosis, alcohol also impacts other functions of adipose tissue and lipid metabolism. Lipid balance in response to long‐term alcohol intake favors adipose tissue loss and fatty acid efflux as lipolysis is upregulated and lipogenesis is either slightly decreased or unchanged. Study of the lipolytic and lipogenic pathways has identified several regulatory proteins modulated by alcohol that contribute to these effects. Glucose tolerance of adipose tissue is also impaired by chronic alcohol due to decreased glucose transporter‐4 availability at the membrane. As an endocrine organ, white adipose tissue (WAT releases several adipokines that are negatively modulated following chronic alcohol consumption including adiponectin, leptin, and resistin. When these effects are combined with the enhanced expression of inflammatory mediators that are induced by chronic alcohol, a proinflammatory state develops within WAT, contributing to the observed lipodystrophy. Lastly, while chronic alcohol intake may enhance thermogenesis of brown adipose tissue (BAT, definitive mechanistic evidence is currently lacking. Overall, both WAT and BAT depots are impacted by chronic alcohol intake and the resulting lipodystrophy contributes to fat accumulation in peripheral organs, thereby enhancing the pathological state accompanying chronic alcohol use disorder.

  13. Epigenetic dysregulation of interleukin 8 (CXCL8) hypersecretion in cystic fibrosis airway epithelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Poghosyan, Anna, E-mail: pannagos@yahoo.com; Patel, Jamie K.; Clifford, Rachel L.; Knox, Alan J., E-mail: alan.knox@nottingham.ac.uk

    2016-08-05

    Airway epithelial cells in cystic fibrosis (CF) overexpress Interleukin 8 (CXCL8) through poorly defined mechanisms. CXCL8 transcription is dependent on coordinated binding of CCAAT/enhancer binding protein (C/EBP)β, nuclear factor (NF)-κB, and activator protein (AP)-1 to the promoter. Here we show abnormal epigenetic regulation is responsible for CXCL8 overexpression in CF cells. Under basal conditions CF cells had increased bromodomain (Brd)3 and Brd4 recruitment and enhanced NF-κB and C/EBPβ binding to the CXCL8 promoter compared to non-CF cells due to trimethylation of histone H3 at lysine 4 (H3K4me3) and DNA hypomethylation at CpG6. IL-1β increased NF-κB, C/EBPβ and Brd4 binding. Furthermore, inhibitors of bromodomain and extra-terminal domain family (BET) proteins reduced CXCL8 production in CF cells suggesting a therapeutic target for the BET pathway. -- Highlights: •A regulatory mechanism of CXCL8 transcriptional control in CF airways is proposed. •There was an increased binding of NF-κB and C/EBPβ transcription factors. •There was enhanced recruitment of BET proteins to the CXCL8 promoter. •Epigenetic modifications are responsible for the aberrant CXCL8 transcription.

  14. Epigenetic dysregulation of interleukin 8 (CXCL8) hypersecretion in cystic fibrosis airway epithelial cells

    International Nuclear Information System (INIS)

    Poghosyan, Anna; Patel, Jamie K.; Clifford, Rachel L.; Knox, Alan J.

    2016-01-01

    Airway epithelial cells in cystic fibrosis (CF) overexpress Interleukin 8 (CXCL8) through poorly defined mechanisms. CXCL8 transcription is dependent on coordinated binding of CCAAT/enhancer binding protein (C/EBP)β, nuclear factor (NF)-κB, and activator protein (AP)-1 to the promoter. Here we show abnormal epigenetic regulation is responsible for CXCL8 overexpression in CF cells. Under basal conditions CF cells had increased bromodomain (Brd)3 and Brd4 recruitment and enhanced NF-κB and C/EBPβ binding to the CXCL8 promoter compared to non-CF cells due to trimethylation of histone H3 at lysine 4 (H3K4me3) and DNA hypomethylation at CpG6. IL-1β increased NF-κB, C/EBPβ and Brd4 binding. Furthermore, inhibitors of bromodomain and extra-terminal domain family (BET) proteins reduced CXCL8 production in CF cells suggesting a therapeutic target for the BET pathway. -- Highlights: •A regulatory mechanism of CXCL8 transcriptional control in CF airways is proposed. •There was an increased binding of NF-κB and C/EBPβ transcription factors. •There was enhanced recruitment of BET proteins to the CXCL8 promoter. •Epigenetic modifications are responsible for the aberrant CXCL8 transcription.

  15. Dysregulation of glycogen synthase COOH- and NH2-terminal phosphorylation by insulin in obesity and type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Højlund, Kurt; Birk, Jesper Bratz; Klein, Ditte Kjærsgaard

    2009-01-01

    Context: Insulin-stimulated glucose disposal is impaired in obesity and type 2 diabetes mellitus (T2DM) and is tightly linked to impaired skeletal muscle glucose uptake and storage. Impaired activation of glycogen synthase (GS) by insulin is a well-established defect in both obesity and T2DM....... The exaggerated insulin resistance in T2DM compared with obese subjects was not reflected by differences in site 3 phosphorylation but was accompanied by a significantly higher site 1b phosphorylation during insulin stimulation. Hyperphosphorylation of another Ca(2+)/calmodulin-dependent kinase-II target......, phospholamban-Thr17, was also evident in T2DM. Dephosphorylation of GS by phosphatase treatment fully restored GS activity in all groups. Conclusions: Dysregulation of GS phosphorylation plays a major role in impaired insulin regulation of GS in obesity and T2DM. In obesity, independent of T2DM...

  16. Dysregulation of TGFβ1 Activity in Cancer and Its Influence on the Quality of Anti-Tumor Immunity

    Directory of Open Access Journals (Sweden)

    Kristian M. Hargadon

    2016-08-01

    Full Text Available TGFβ1 is a pleiotropic cytokine that exhibits a variety of physiologic and immune regulatory functions. Although its influence on multiple cell types is critical for the regulation of numerous biologic processes in the host, dysregulation of both TGFβ1 expression and activity is frequently observed in cancer and contributes to various aspects of cancer progression. This review focuses on TGFβ1’s contribution to tumor immune suppression and escape, with emphasis on the influence of this regulatory cytokine on the differentiation and function of dendritic cells and T cells. Clinical trials targeting TGFβ1 in cancer patients are also reviewed, and strategies for future therapeutic interventions that build on our current understanding of immune regulation by TGFβ1 are discussed.

  17. Markers of impaired motor and cognitive volition in Parkinson's disease: Correlates of dopamine dysregulation syndrome, impulse control disorder, and dyskinesias.

    Science.gov (United States)

    Hinkle, Jared T; Perepezko, Kate; Rosenthal, Liana S; Mills, Kelly A; Pantelyat, Alexander; Mari, Zoltan; Tochen, Laura; Bang, Jee Yun; Gudavalli, Medha; Yoritomo, Nadine; Butala, Ankur; Bakker, Catherine C; Johnson, Vanessa; Moukheiber, Emile; Dawson, Ted M; Pontone, Gregory M

    2018-02-01

    Dopaminergic therapy in Parkinson's disease (PD) can be associated with both motoric (e.g., dyskinesias) and neuropsychiatric adverse effects. Examples of the latter include Dopamine Dysregulation Syndrome (DDS) and impulse control disorder (ICD), which are separate but related behavioral/psychiatric complications of treatment in PD. Dysregulation of volition characterizes both dyskinesias and DDS/ICD; thus, we analyzed potential disease-related correlates in a large PD cohort. We analyzed cross-sectional data from 654 participants collected through the NINDS Parkinson's Disease Biomarkers Program. DDS/ICD symptoms and dyskinesias were assessed using the Movement Disorders Society (revised) Unified Parkinson's Disease Rating Scale. Potential associated variables were selected from PD-validated or PD-specific scales of neuropsychiatric or motoric status. Multivariable models with DDS/ICD or dyskinesia presence outcomes were produced with backward stepwise regression to identify factors independently associated with DDS/ICD and/or dyskinesias. Fifty-three (8.1%) participants endorsed DDS and/or ICD symptoms and 150 (22.9%) were dyskinetic. In multivariable analysis, psychosis was independently associated with both dyskinesias (p = 0.006) and DDS/ICD (p < 0.001). Unpredictable motor fluctuations (p = 0.026) and depression (p = 0.023) were also associated with DDS/ICD; female sex (p = 0.025), low tremor score (p = 0.001) and high akinesia-rigidity score (p < 0.001) were associated with dyskinesias. Our findings suggest that psychosis may be an important marker of impaired volition across motor and cognitive domains. Unpredictable motor fluctuations, psychosis, and depression may together comprise a phenotypic profile of patients at increased risk for DDS/ICD. Similarly, dyskinetic PD patients should be closely monitored for psychotic symptoms and treated appropriately. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Aging-induced dysregulation of dicer1-dependent microRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells.

    Science.gov (United States)

    Ungvari, Zoltan; Tucsek, Zsuzsanna; Sosnowska, Danuta; Toth, Peter; Gautam, Tripti; Podlutsky, Andrej; Csiszar, Agnes; Losonczy, Gyorgy; Valcarcel-Ares, M Noa; Sonntag, William E; Csiszar, Anna

    2013-08-01

    Age-related impairment of angiogenesis is likely to play a central role in cerebromicrovascular rarefaction and development of vascular cognitive impairment, but the underlying mechanisms remain elusive. To test the hypothesis that dysregulation of Dicer1 (ribonuclease III, a key enzyme of the microRNA [miRNA] machinery) impairs endothelial angiogenic capacity in aging, primary cerebromicrovascular endothelial cells (CMVECs) were isolated from young (3 months old) and aged (24 months old) Fischer 344 × Brown Norway rats. We found an age-related downregulation of Dicer1 expression both in CMVECs and in small cerebral vessels isolated from aged rats. In aged CMVECs, Dicer1 expression was increased by treatment with polyethylene glycol-catalase. Compared with young cells, aged CMVECs exhibited altered miRNA expression profile, which was associated with impaired proliferation, adhesion to vitronectin, collagen and fibronectin, cellular migration (measured by a wound-healing assay using electric cell-substrate impedance sensing technology), and impaired ability to form capillary-like structures. Overexpression of Dicer1 in aged CMVECs partially restored miRNA expression profile and significantly improved angiogenic processes. In young CMVECs, downregulation of Dicer1 (siRNA) resulted in altered miRNA expression profile associated with impaired proliferation, adhesion, migration, and tube formation, mimicking the aging phenotype. Collectively, we found that Dicer1 is essential for normal endothelial angiogenic processes, suggesting that age-related dysregulation of Dicer1-dependent miRNA expression may be a potential mechanism underlying impaired angiogenesis and cerebromicrovascular rarefaction in aging.

  19. Decreased DGCR8 expression and miRNA dysregulation in individuals with 22q11.2 deletion syndrome.

    Directory of Open Access Journals (Sweden)

    Chantal Sellier

    Full Text Available Deletion of the 1.5-3 Mb region of chromosome 22 at locus 11.2 gives rise to the chromosome 22q11.2 deletion syndrome (22q11DS, also known as DiGeorge and Velocardiofacial Syndromes. It is the most common micro-deletion disorder in humans and one of the most common multiple malformation syndromes. The syndrome is characterized by a broad phenotype, whose characterization has expanded considerably within the last decade and includes many associated findings such as craniofacial anomalies (40%, conotruncal defects of the heart (CHD; 70-80%, hypocalcemia (20-60%, and a range of neurocognitive anomalies with high risk of schizophrenia, all with a broad phenotypic variability. These phenotypic features are believed to be the result of a change in the copy number or dosage of the genes located in the deleted region. Despite this relatively clear genetic etiology, very little is known about which genes modulate phenotypic variations in humans or if they are due to combinatorial effects of reduced dosage of multiple genes acting in concert. Here, we report on decreased expression levels of genes within the deletion region of chromosome 22, including DGCR8, in peripheral leukocytes derived from individuals with 22q11DS compared to healthy controls. Furthermore, we found dysregulated miRNA expression in individuals with 22q11DS, including miR-150, miR-194 and miR-185. We postulate this to be related to DGCR8 haploinsufficiency as DGCR8 regulates miRNA biogenesis. Importantly we demonstrate that the level of some miRNAs correlates with brain measures, CHD and thyroid abnormalities, suggesting that the dysregulated miRNAs may contribute to these phenotypes and/or represent relevant blood biomarkers of the disease in individuals with 22q11DS.

  20. Prenatal cadmium exposure dysregulates sonic hedgehog and Wnt/β-catenin signaling in the thymus resulting in altered thymocyte development

    International Nuclear Information System (INIS)

    Hanson, Miranda L.; Brundage, Kathleen M.; Schafer, Rosana; Tou, Janet C.; Barnett, John B.

    2010-01-01

    Cadmium (Cd) is both an environmental pollutant and a component of cigarette smoke. Although evidence demonstrates that adult exposure to Cd causes changes in the immune system, there are limited reports in the literature of immunomodulatory effects of prenatal exposure to Cd. The sonic hedgehog (Shh) and Wnt/β-catenin pathways are required for thymocyte maturation. Several studies have demonstrated that Cd exposure affects these pathways in different organ systems. This study was designed to investigate the effect of prenatal Cd exposure on thymocyte development, and to determine if these effects were linked to dysregulation of Shh and Wnt/β-catenin pathways. Pregnant C57Bl/6 mice were exposed to an environmentally relevant dose (10 ppm) of Cd throughout pregnancy and effects on the thymus were assessed on the day of birth. Thymocyte phenotype was determined by flow cytometry. A Gli:luciferase reporter cell line was used to measure Shh signaling. Transcription of target genes and translation of key components of both signaling pathways were assessed using real-time RT-PCR and western blot, respectively. Prenatal Cd exposure increased the number of CD4 + cells and a subpopulation of double-negative cells (DN; CD4 - CD8 - ), DN4 (CD44 - CD25 - ). Shh and Wnt/β-catenin signaling were both decreased in the thymus. Target genes of Shh (Patched1 and Gli1) and Wnt/β-catenin (c-fos, and c-myc) were affected differentially among thymocyte subpopulations. These findings suggest that prenatal exposure to Cd dysregulates two signaling pathways in the thymus, resulting in altered thymocyte development.

  1. Epigenetic mechanism of maternal post-traumatic stress disorder in delayed rat offspring development: dysregulation of methylation and gene expression.

    Science.gov (United States)

    Zhang, X G; Zhang, H; Liang, X L; Liu, Q; Wang, H Y; Cao, B; Cao, J; Liu, S; Long, Y J; Xie, W Y; Peng, D Z

    2016-08-19

    Maternal post-traumatic stress disorder (PTSD) increases the risk of adverse neurodevelopmental outcomes in the child. Epigenetic alternations may play an essential role in the negative effects of PTSD. This study was aimed to investigate the possible epigenetic alterations of maternal PTSD, which underpins the developmental and behavioral impact. 24 pregnant Sprague-Dawley (SD) rats were randomly grouped into PTSD and control groups. Open-field tests (OFTs), elevated pull maze (EPM) assays, gene expression profile chip tests, and methylated DNA immunoprecipitation sequencing (MeDIP-Seq) were performed on the offsprings 30 days after birth. The results showed that PTSD offsprings had lower body weights and OFT scores than control offsprings. Enzyme-linked immunosorbent assays showed that serotonin receptor (5-HT) and dopamine levels were significantly lower in PTSD offsprings than in control offsprings. In contrast, corticosterone levels were higher in the PTSD group than in the control group. In a comparison of the PTSD group versus the control group, 4,160 significantly differentially methylated loci containing 30,657 CpGs were identified; 2,487 genes, including 13 dysmethylated genes, were validated by gene expression profiling, showing a negative correlation between methylation and gene expression (R = -0.617, P = 0.043). In conclusion, maternal PTSD could delay the physical and behavioral development of offsprings, and the underlying mechanism could contribute to changes in neurotransmitters and gene expression, owing to dysregulation of whole-genome methylation. These findings could support further clinical research on appropriate interventions for maternal PTSD to prevent methylation dysregulation and developmental retardation.

  2. Using machine learning and surface reconstruction to accurately differentiate different trajectories of mood and energy dysregulation in youth.

    Science.gov (United States)

    Versace, Amelia; Sharma, Vinod; Bertocci, Michele A; Bebko, Genna; Iyengar, Satish; Dwojak, Amanda; Bonar, Lisa; Perlman, Susan B; Schirda, Claudiu; Travis, Michael; Gill, Mary Kay; Diwadkar, Vaibhav A; Sunshine, Jeffrey L; Holland, Scott K; Kowatch, Robert A; Birmaher, Boris; Axelson, David; Frazier, Thomas W; Arnold, L Eugene; Fristad, Mary A; Youngstrom, Eric A; Horwitz, Sarah M; Findling, Robert L; Phillips, Mary L

    2017-01-01

    Difficulty regulating positive mood and energy is a feature that cuts across different pediatric psychiatric disorders. Yet, little is known regarding the neural mechanisms underlying different developmental trajectories of positive mood and energy regulation in youth. Recent studies indicate that machine learning techniques can help elucidate the role of neuroimaging measures in classifying individual subjects by specific symptom trajectory. Cortical thickness measures were extracted in sixty-eight anatomical regions covering the entire brain in 115 participants from the Longitudinal Assessment of Manic Symptoms (LAMS) study and 31 healthy comparison youth (12.5 y/o;-Male/Female = 15/16;-IQ = 104;-Right/Left handedness = 24/5). Using a combination of trajectories analyses, surface reconstruction, and machine learning techniques, the present study aims to identify the extent to which measures of cortical thickness can accurately distinguish youth with higher (n = 18) from those with lower (n = 34) trajectories of manic-like behaviors in a large sample of LAMS youth (n = 115; 13.6 y/o; M/F = 68/47, IQ = 100.1, R/L = 108/7). Machine learning analyses revealed that widespread cortical thickening in portions of the left dorsolateral prefrontal cortex, right inferior and middle temporal gyrus, bilateral precuneus, and bilateral paracentral gyri and cortical thinning in portions of the right dorsolateral prefrontal cortex, left ventrolateral prefrontal cortex, and right parahippocampal gyrus accurately differentiate (Area Under Curve = 0.89;p = 0.03) youth with different (higher vs lower) trajectories of positive mood and energy dysregulation over a period up to 5years, as measured by the Parent General Behavior Inventory-10 Item Mania Scale. Our findings suggest that specific patterns of cortical thickness may reflect transdiagnostic neural mechanisms associated with different temporal trajectories of positive mood and energy dysregulation in youth. This approach has

  3. Using machine learning and surface reconstruction to accurately differentiate different trajectories of mood and energy dysregulation in youth.

    Directory of Open Access Journals (Sweden)

    Amelia Versace

    Full Text Available Difficulty regulating positive mood and energy is a feature that cuts across different pediatric psychiatric disorders. Yet, little is known regarding the neural mechanisms underlying different developmental trajectories of positive mood and energy regulation in youth. Recent studies indicate that machine learning techniques can help elucidate the role of neuroimaging measures in classifying individual subjects by specific symptom trajectory. Cortical thickness measures were extracted in sixty-eight anatomical regions covering the entire brain in 115 participants from the Longitudinal Assessment of Manic Symptoms (LAMS study and 31 healthy comparison youth (12.5 y/o;-Male/Female = 15/16;-IQ = 104;-Right/Left handedness = 24/5. Using a combination of trajectories analyses, surface reconstruction, and machine learning techniques, the present study aims to identify the extent to which measures of cortical thickness can accurately distinguish youth with higher (n = 18 from those with lower (n = 34 trajectories of manic-like behaviors in a large sample of LAMS youth (n = 115; 13.6 y/o; M/F = 68/47, IQ = 100.1, R/L = 108/7. Machine learning analyses revealed that widespread cortical thickening in portions of the left dorsolateral prefrontal cortex, right inferior and middle temporal gyrus, bilateral precuneus, and bilateral paracentral gyri and cortical thinning in portions of the right dorsolateral prefrontal cortex, left ventrolateral prefrontal cortex, and right parahippocampal gyrus accurately differentiate (Area Under Curve = 0.89;p = 0.03 youth with different (higher vs lower trajectories of positive mood and energy dysregulation over a period up to 5years, as measured by the Parent General Behavior Inventory-10 Item Mania Scale. Our findings suggest that specific patterns of cortical thickness may reflect transdiagnostic neural mechanisms associated with different temporal trajectories of positive mood and energy dysregulation in youth. This

  4. The microRNA effector RNA-induced silencing complex in hidradenitis suppurativa: a significant dysregulation within active inflammatory lesions.

    Science.gov (United States)

    Hessam, S; Sand, M; Skrygan, M; Bechara, Falk G

    2017-09-01

    Recently, we could show that the expression levels of the key regulators of the microRNA (miRNA) maturation and transport were dysregulated in inflamed hidradenitis suppurativa (HS) tissue (Heyam et al. in Wiley Interdiscip Rev RNA 6:271-289, 2015). The RNA-induced silencing complex (RISC) is the central element of the miRNA pathway and regulates miRNA formation and function. We investigated the expression of the RISC components, namely transactivation-responsive RNA-binding protein-1 (TRBP1), TRBP2, protein activator (PACT) of the interferon-induced protein kinase R, Argonaute RISC Catalytic Component-1 (AGO1) and Component-2 (AGO2), metadherin, and staphylococcal nuclease and Tudor domain-containing-1 (SND1) in inflamed HS tissue compared to healthy and psoriatic controls by real-time reverse transcription polymerase chain reaction. Expression levels of all investigated components were significantly lower in lesional HS skin (n = 18) compared to healthy controls (n = 10). TRBP1, PACT, AGO1, AGO2, and SND1 expression levels were significantly down-regulated in lesional HS skin compared to healthy-appearing perilesional skin (n = 7). TRBP2 and SND1 expression levels were significantly lower in healthy-appearing perilesional skin compared to healthy controls. In lesional HS skin, expression levels of PACT, AGO1, and AGO2 were significantly lower compared to psoriatic skin (n = 10). In summary, our data showed that all investigated components of RISC are dysregulated in the skin of HS patients, providing support for the hypothesis that miRNAs may have a pathological role in the inflammatory pathogenesis of HS.

  5. SHORT-TERM STRESS ENHANCES CELLULAR IMMUNITY AND INCREASES EARLY RESISTANCE TO SQUAMOUS CELL CARCINOMA

    OpenAIRE

    Dhabhar, Firdaus S.; Saul, Alison N.; Daugherty, Christine; Holmes, Tyson H.; Bouley, Donna M.; Oberyszyn, Tatiana M.

    2009-01-01

    In contrast to chronic/long-term stress that suppresses/dysregulates immune function, an acute/short-term fight-or-flight stress response experienced during immune activation can enhance innate and adaptive immunity. Moderate ultraviolet-B (UV) exposure provides a non-invasive system for studying the naturalistic emergence, progression and regression of squamous cell carcinoma (SCC). Because SCC is an immunoresponsive cancer, we hypothesized that short-term stress experienced before UV exposu...

  6. miRNA-21 is dysregulated in response to vein grafting in multiple models and genetic ablation in mice attenuates neointima formation

    NARCIS (Netherlands)

    McDonald, Robert A; White, Katie M; Wu, Junxi; Cooley, Brian C; Robertson, Keith E; Halliday, Crawford A; McClure, John D; Francis, Sheila; Lu, Ruifaug; Kennedy, Simon; George, Sarah J; Wan, Song; van Rooij, Eva; Baker, Andrew H

    AIMS: The long-term failure of autologous saphenous vein bypass grafts due to neointimal thickening is a major clinical burden. Identifying novel strategies to prevent neointimal thickening is important. Thus, this study aimed to identify microRNAs (miRNAs) that are dysregulated during neointimal

  7. Indoxyl Sulfate as a Mediator Involved in Dysregulation of Pulmonary Aquaporin-5 in Acute Lung Injury Caused by Acute Kidney Injury

    Directory of Open Access Journals (Sweden)

    Nozomi Yabuuchi

    2016-12-01

    Full Text Available High mortality of acute kidney injury (AKI is associated with acute lung injury (ALI, which is a typical complication of AKI. Although it is suggested that dysregulation of lung salt and water channels following AKI plays a pivotal role in ALI, the mechanism of its dysregulation has not been elucidated. Here, we examined the involvement of a typical oxidative stress-inducing uremic toxin, indoxyl sulfate (IS, in the dysregulation of the pulmonary predominant water channel, aquaporin 5 (AQP-5, in bilateral nephrectomy (BNx-induced AKI model rats. BNx evoked AKI with the increases in serum creatinine (SCr, blood urea nitrogen (BUN and serum IS levels and exhibited thickening of interstitial tissue in the lung. Administration of AST-120, clinically-used oral spherical adsorptive carbon beads, resulted in a significant decrease in serum IS level and thickening of interstitial tissue, which was accompanied with the decreases in IS accumulation in various tissues, especially lung. Interestingly, a significant decrease in AQP-5 expression of lung was observed in BNx rats. Moreover, the BNx-induced decrease in pulmonary AQP-5 protein expression was markedly restored by oral administration of AST-120. These results suggest that BNx-induced AKI causes dysregulation of pulmonary AQP-5 expression, in which IS could play a toxico-physiological role as a mediator involved in renopulmonary crosstalk.

  8. Heavy alcohol use, rather than alcohol dependence, is associated with dysregulation of the hypothalamic-pituitary-adrenal axis and the autonomic nervous system

    NARCIS (Netherlands)

    Boschloo, Lynn; Vogelzangs, Nicole; Licht, Carmilla M. M.; Vreeburg, Sophie A.; Smit, Johannes H.; van den Brink, Wim; Veltman, Dick J.; de Geus, Eco J. C.; Beekman, Aartjan T. F.; Penninx, Brenda W. J. H.

    2011-01-01

    Heavy alcohol use as well as alcohol dependence (AD) have been associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis and the autonomic nervous system (ANS). However, the relative contribution of alcohol use and AD is unclear. Baseline data were derived from 2947 persons of

  9. Depressive Symptoms, Emotion Dysregulation, and Bulimic Symptoms in Youth With Type 1 Diabetes: Varying Interactions at Diagnosis and During Transition to Insulin Pump Therapy.

    Science.gov (United States)

    Young-Hyman, Deborah L; Peterson, Claire M; Fischer, Sarah; Markowitz, Jessica T; Muir, Andrew B; Laffel, Lori M

    2016-07-01

    This study evaluated the associations between depressive symptoms, emotion dysregulation and bulimic symptoms in youth with type 1 diabetes (T1D) in the context of the diagnosis and treatment of T1D. Study participants were 103 youth in 2 distinct groups: newly diagnosed (New) or transitioning to pump therapy (continuous subcutaneous insulin infusion [CSII]; "Pump"), who completed questionnaires regarding symptoms of depression, emotion dysregulation, and bulimia. Glycemic control (A1c), height, weight, and questionnaires were evaluated within 10 days of diagnosis (n = 58) or at education/clinic visit before starting insulin utilizing CSII (n = 45). In the newly diagnosed group, only depression accounted for significant variance in bulimia scores (β = .47, P symptoms and emotion dysregulation were associated with greater bulimic symptoms. Depressive symptoms and emotion dysregulation, an indicator of poor coping/behavioral control, could help explain adoption of disordered eating behaviors in youth with T1D who are transitioning to pump therapy. © 2016 Diabetes Technology Society.

  10. miR2Pathway: A Novel Analytical Method to Discover MicroRNA-mediated Dysregulated Pathways Involved in Hepatocellular Carcinoma.

    Science.gov (United States)

    Li, Chaoxing; Dinu, Valentin

    2018-03-22

    MicroRNAs (miRNAs) are small, non-coding RNAs involved in the regulation of gene expression at a post-transcriptional level. Recent studies have shown miRNAs as key regulators of a variety of biological processes, such as proliferation, differentiation, apoptosis, metabolism, etc. Aberrantly expressed miRNAs influence individual gene expression level, but rewired miRNA-mRNA connections can influence the activity of biological pathways. Here, we define rewired miRNA-mRNA connections as the differential (rewiring) effects on the activity of biological pathways between hepatocellular carcinoma (HCC) and normal phenotypes. Our work presented here uses a PageRank-based approach to measure the degree of miRNA-mediated dysregulation of biological pathways between HCC and normal samples based on rewired miRNA-mRNA connections. In our study, we regard the degree of miRNA-mediated dysregulation of biological pathways as disease risk of biological pathways. Therefore, we propose a new method, miR2Pathway, to measure and rank the degree of miRNA-mediated dysregulation of biological pathways by measuring the total differential influence of miRNAs on the activity of pathways between HCC and normal states. miR2Pathway proposed here systematically shows the first evidence for a mechanism of biological pathways being dysregulated by rewired miRNA-mRNA connections, and provides new insight into exploring mechanisms behind HCC. Thus, miR2Pathway is a novel method to identify and rank miRNA-dysregulated pathways in HCC. Copyright © 2018. Published by Elsevier Inc.

  11. Main and interactive effects of emotion dysregulation and HIV symptom severity on quality of life among persons living with HIV/AIDS.

    Science.gov (United States)

    Brandt, Charles P; Jardin, Charles; Sharp, Carla; Lemaire, Chad; Zvolensky, Michael J

    2017-04-01

    HIV symptoms are associated with a poorer quality of life (QOL) among persons living with HIV/AIDS (PLWHA). Yet, there is little understanding of emotional factors that impact the relation between HIV symptom severity and QOL. The present study examined the main and interactive effects of emotion dysregulation and HIV symptom severity on multiple indices of QOL, including physical (impact of physical problems related to HIV), psychological (frequency of negative feelings), independence (necessity of medical treatment to function in daily life), social (feelings of acceptance), environmental (satisfaction with living conditions and medical care), and spiritual (fear of the future and death) among a sample of 74 PLWHA. Participants (72.9% male; mean age = 48.24, SD = 7.85) were recruited from AIDS Service Organizations in the United States. Results indicated that higher HIV symptom severity is significantly associated with lower physical and independence QOL, whereas higher emotion dysregulation is significantly associated with lower scores on all measured aspects of QOL. Additionally, results indicated that the interaction of emotion dysregulation and HIV symptom severity was significantly associated with both physical and environmental QOL. The form of the observed significant interactions indicated that HIV symptom severity was related to poorer QOL among those with lower (versus higher) emotion dysregulation. The present findings indicate that emotion dysregulation is related to QOL among PLWHA and may interact with HIV symptom severity to negatively impact certain aspects of QOL. Given the profound impact that HIV has on QOL, this finding is important in understanding these relations mechanistically, and may be important in the development of novel psychological treatment strategies.

  12. Genome Wide Expression Profiling of Cancer Cell Lines Cultured in Microgravity Reveals Significant Dysregulation of Cell Cycle and MicroRNA Gene Networks.

    Directory of Open Access Journals (Sweden)

    Prasanna Vidyasekar

    Full Text Available Zero gravity causes several changes in metabolic and functional aspects of the human body and experiments in space flight have demonstrated alterations in cancer growth and progression. This study reports the genome wide expression profiling of a colorectal cancer cell line-DLD-1, and a lymphoblast leukemic cell line-MOLT-4, under simulated microgravity in an effort to understand central processes and cellular functions that are dysregulated among both cell lines. Altered cell morphology, reduced cell viability and an aberrant cell cycle profile in comparison to their static controls were observed in both cell lines under microgravity. The process of cell cycle in DLD-1 cells was markedly affected with reduced viability, reduced colony forming ability, an apoptotic population and dysregulation of cell cycle genes, oncogenes, and cancer progression and prognostic markers. DNA microarray analysis revealed 1801 (upregulated and 2542 (downregulated genes (>2 fold in DLD-1 cultures under microgravity while MOLT-4 cultures differentially expressed 349 (upregulated and 444 (downregulated genes (>2 fold under microgravity. The loss in cell proliferative capacity was corroborated with the downregulation of the cell cycle process as demonstrated by functional clustering of DNA microarray data using gene ontology terms. The genome wide expression profile also showed significant dysregulation of post transcriptional gene silencing machinery and multiple microRNA host genes that are potential tumor suppressors and proto-oncogenes including MIR22HG, MIR17HG and MIR21HG. The MIR22HG, a tumor-suppressor gene was one of the highest upregulated genes in the microarray data showing a 4.4 log fold upregulation under microgravity. Real time PCR validated the dysregulation in the host gene by demonstrating a 4.18 log fold upregulation of the miR-22 microRNA. Microarray data also showed dysregulation of direct targets of miR-22, SP1, CDK6 and CCNA2.

  13. A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Justin R. Piro

    2012-06-01

    Full Text Available Although inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic, and persistent inflammation contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer's disease (AD. Whether anti-inflammatory approaches can be used to treat AD, however, is a major unanswered question. We recently demonstrated that monoacylglycerol lipase (MAGL hydrolyzes endocannabinoids to generate the primary arachidonic acid pool for neuroinflammatory prostaglandins. In this study, we show that genetic inactivation of MAGL attenuates neuroinflammation and lowers amyloid β levels and plaques in an AD mouse model. We also find that pharmacological blockade of MAGL recapitulates the cytokine-lowering effects through reduced prostaglandin production, rather than enhanced endocannabinoid signaling. Our findings thus reveal a role of MAGL in modulating neuroinflammation and amyloidosis in AD etiology and put forth MAGL inhibitors as a potential next-generation strategy for combating AD.

  14. Transcriptional dysregulation of 5-HT1A autoreceptors in mental illness

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    Albert Paul R

    2011-05-01

    Full Text Available Abstract The serotonin-1A (5-HT1A receptor is among the most abundant and widely distributed 5-HT receptors in the brain, but is also expressed on serotonin neurons as an autoreceptor where it plays a critical role in regulating the activity of the entire serotonin system. Over-expression of the 5-HT1A autoreceptor has been implicated in reducing serotonergic neurotransmission, and is associated with major depression and suicide. Extensive characterization of the transcriptional regulation of the 5-HT1A gene (HTR1A using cell culture systems has revealed a GC-rich "housekeeping" promoter that non-selectively drives its expression; this is flanked by a series of upstream repressor elements for REST, Freud-1/CC2D1A and Freud-2/CC2D1B factors that not only restrict its expression to neurons, but may also regulate the level of expression of 5-HT1A receptors in various subsets of neurons, including serotonergic neurons. A separate set of allele-specific factors, including Deaf1, Hes1 and Hes5 repress at the HTR1A C(-1019G (rs6295 polymorphism in serotonergic neurons in culture, as well as in vivo. Pet1, an obligatory enhancer for serotonergic differentiation, has been identified as a potent activator of 5-HT1A autoreceptor expression. Taken together, these results highlight an integrated regulation of 5-HT1A autoreceptors that differs in several aspects from regulation of post-synaptic 5-HT1A receptors, and could be selectively targeted to enhance serotonergic neurotransmission.

  15. Serum metabolomic profiling in acute alcoholic hepatitis identifies multiple dysregulated pathways.

    Science.gov (United States)

    Rachakonda, Vikrant; Gabbert, Charles; Raina, Amit; Bell, Lauren N; Cooper, Sara; Malik, Shahid; Behari, Jaideep

    2014-01-01

    While animal studies have implicated derangements of global energy homeostasis in the pathogenesis of acute alcoholic hepatitis (AAH), the relevance of these findings to the development of human AAH remains unclear. Using global, unbiased serum metabolomics analysis, we sought to characterize alterations in metabolic pathways associated with severe AAH and identify potential biomarkers for disease prognosis. This prospective, case-control study design included 25 patients with severe AAH and 25 ambulatory patients with alcoholic cirrhosis. Serum samples were collected within 24 hours of the index clinical encounter. Global, unbiased metabolomics profiling was performed. Patients were followed for 180 days after enrollment to determine survival. Levels of 234 biochemicals were altered in subjects with severe AAH. Random-forest analysis, principal component analysis, and integrated hierarchical clustering methods demonstrated that metabolomics profiles separated the two cohorts with 100% accuracy. Severe AAH was associated with enhanced triglyceride lipolysis, impaired mitochondrial fatty acid beta oxidation, and upregulated omega oxidation. Low levels of multiple lysolipids and related metabolites suggested decreased plasma membrane remodeling in severe AAH. While most measured bile acids were increased in severe AAH, low deoxycholate and glycodeoxycholate levels indicated intestinal dysbiosis. Several changes in substrate utilization for energy homeostasis were identified in severe AAH, including increased glucose consumption by the pentose phosphate pathway, altered tricarboxylic acid (TCA) cycle activity, and enhanced peptide catabolism. Finally, altered levels of small molecules related to glutathione metabolism and antioxidant vitamin depletion were observed in patients with severe AAH. Univariable logistic regression revealed 15 metabolites associated with 180-day survival in severe AAH. Severe AAH is characterized by a distinct metabolic phenotype spanning

  16. 27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP/GLUT4 system dysregulation

    Science.gov (United States)

    Mateos, Laura; Maioli, Silvia; Ali, Zeina; Gulyás, Balázs; Winblad, Bengt; Savitcheva, Irina

    2017-01-01

    Hypercholesterolemia is associated with cognitively deteriorated states. Here, we show that excess 27-hydroxycholesterol (27-OH), a cholesterol metabolite passing from the circulation into the brain, reduced in vivo brain glucose uptake, GLUT4 expression, and spatial memory. Furthermore, patients exhibiting higher 27-OH levels had reduced 18F-fluorodeoxyglucose uptake. This interplay between 27-OH and glucose uptake revealed the engagement of the insulin-regulated aminopeptidase (IRAP). 27-OH increased the levels and activity of IRAP, countered the IRAP antagonist angiotensin IV (AngIV)–mediated glucose uptake, and enhanced the levels of the AngIV-degrading enzyme aminopeptidase N (AP-N). These effects were mediated by liver X receptors. Our results reveal a molecular link between cholesterol, brain glucose, and the brain renin-angiotensin system, all of which are affected in some neurodegenerative diseases. Thus, reducing 27-OH levels or inhibiting AP-N maybe a useful strategy in the prevention of the altered glucose metabolism and memory decline in these disorders. PMID:28213512

  17. Excess ω-6 fatty acids influx in aging drives metabolic dysregulation, electrocardiographic alterations, and low-grade chronic inflammation.

    Science.gov (United States)

    Kain, Vasundhara; Ingle, Kevin A; Kachman, Maureen; Baum, Heidi; Shanmugam, Gobinath; Rajasekaran, Namakkal S; Young, Martin E; Halade, Ganesh V

    2018-02-01

    Maintaining a balance of ω-6 and ω-3 fatty acids is essential for cardiac health. Current ω-6 and ω-3 fatty acids in the American diet have shifted from the ideal ratio of 2:1 to almost 20:1; while there is a body of evidence that suggests the negative impact of such a shift in younger organisms, the underlying age-related metabolic signaling in response to the excess influx of ω-6 fatty acids is incompletely understood. In the present study, young (6 mo old) and aging (≥18 mo old) mice were fed for 2 mo with a ω-6-enriched diet. Excess intake of ω-6 enrichment decreased the total lean mass and increased nighttime carbohydrate utilization, with higher levels of cardiac cytokines indicating low-grade chronic inflammation. Dobutamine-induced stress tests displayed an increase in PR interval, a sign of an atrioventricular defect in ω-6-fed aging mice. Excess ω-6 fatty acid intake in aging mice showed decreased 12-lipoxygenase with a concomitant increase in 15-lipoxygenase levels, resulting in the generation of 15( S)-hydroxyeicosatetraenoic acid, whereas cyclooxygenase-1 and -2 generated prostaglandin E 2 , leukotriene B 4, and thromboxane B 2 . Furthermore, excessive ω-6 fatty acids led to dysregulated nuclear erythroid 2-related factor 2/antioxidant-responsive element in aging mice. Moreover, ω-6 fatty acid-mediated changes were profound in aging mice with respect to the eicosanoid profile while minimal changes were observed in the size and shape of cardiomyocytes. These findings provide compelling evidence that surplus consumption of ω-6 fatty acids, coupled with insufficient intake of ω-3 fatty acids, is linked to abnormal changes in ECG. These manifestations contribute to functional deficiencies and expansion of the inflammatory mediator milieu during later stages of aging. NEW & NOTEWORTHY Aging has a profound impact on the metabolism of fatty acids to maintain heart function. The excess influx of ω-6 fatty acids in aging perturbed

  18. Six months methylphenidate treatment improves emotion dysregulation in adolescents with attention deficit/hyperactivity disorder: a prospective study

    Directory of Open Access Journals (Sweden)

    Suzer Gamli I

    2018-05-01

    Full Text Available Ipek Suzer Gamli,1 Aysegul Yolga Tahiroglu2 1Sanliurfa Education and Research Hospital, Eyyubiye, Sanliurfa, Turkey; 2Child and Adolescent Psychiatry Department, Cukurova University School of Medicine, Saricam, Adana, Turkey Purpose: Individuals with attention deficit/hyperactivity disorder (ADHD may suffer from emotional dysregulation (ED, although this symptom is not listed among the diagnostic criteria. Methylphenidate (MPH is useful in reducing emotional symptoms in ADHD. The aim of the present study was to determine both psychosocial risk factors and presence of ED in adolescents with ADHD before and after MPH treatment. Participants and methods: Eighty-two patients aged 12–18 years with ADHD were included as participants. The Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children – Present and Lifetime, the Difficulties in Emotion Regulation Scale (DERS, sociodemographic form, and the Inventory of Statements About Self-Injury were administered. Results were compared before and after 6 months MPH treatment. Results: A significant improvement was detected on DERS for impulsivity (15.9±6.8 initial vs 14.2±6.5 final test, p<0.01 and total score (88.4±23.3 initial vs 82.4±2.7 final test, p<0.05 across all patients taking MPH regardless of subtype and sex. Despite treatment, a significant difference remained for impulsivity, strategies, and total score in patients with comorbid oppositional defiant disorder (ODD compared with those without ODD, but no difference was detected for conduct disorder comorbidity. In patients who self-harm, scores for goals, impulsivity, strategies, clarity, and total score were higher before treatment: furthermore, impulsivity and total score remained high after treatment. In maltreated patients, goals, impulsivity, strategies, and total scores were significantly higher before treatment; however, their symptoms were ameliorated after treatment with MPH. Conclusion: Individuals with

  19. Interleukin-6-deficient mice refractory to IgA dysregulation but not anorexia induction by vomitoxin (deoxynivalenol) ingestion.

    Science.gov (United States)

    Pestka, J J; Zhou, H R

    2000-07-01

    Dietary exposure to the trichothecene vomitoxin (VT) causes feed refusal and elevates IgA production in the mouse. Based on the observations that IL-6 can cause anorexia and promote IgA production and that gene expression of this cytokine is increased in vivo and ex vivo on VT exposure, we hypothesized that IL-6 is an essential cytokine in VT-induced feed refusal and IgA dysregulation. To test this hypothesis, the effects of dietary VT on feed intake, weight gain, serum IgA levels and kidney mesangial IgA deposition in an IL-6-"knockout" mouse (B6129-IL6(tmi Kopf)) were compared to those in both a corresponding "wildtype" (B6129F2) and a previously characterized "sentinel" strain (B6C3F1) that possess the intact gene for this cytokine. IL-6 deficiency did not alter the capacity of VT to cause feed refusal or impair weight gain. VT-fed B6129F2 and B6C3F1 mice had significantly higher serum IgA concentrations than did their corresponding controls fed clean diet, whereas significant differences were not observed between IL-6 KO mice fed VT or control diets. Kidneys taken from VT-fed wild-type and sentinel mice had significantly increased mesangial IgA deposition as compared to controls. While slight increases in mesangial IgA were observed in VT-fed IL-6 KO mice, mean fluorescence intensities were significantly less than that found in the corresponding wild-type and sentinel strains. IL-6 KO mice appeared to be less prone to the development of microscopic haematuria following VT exposure than were the corresponding wild-type and sentinel strains. In total, the results suggested that IL-6-deficient mice were refractory to VT-induced dysregulation of IgA production and development of IgA nephropathy, whereas chronic VT-mediated nutritional effects related to feed intake and weight gain were unaffected.

  20. FREQUENT SUBGRAPH MINING OF PERSONALIZED SIGNALING PATHWAY NETWORKS GROUPS PATIENTS WITH FREQUENTLY DYSREGULATED DISEASE PATHWAYS AND PREDICTS PROGNOSIS.

    Science.gov (United States)

    Durmaz, Arda; Henderson, Tim A D; Brubaker, Douglas; Bebek, Gurkan

    2017-01-01

    Large scale genomics studies have generated comprehensive molecular characterization of numerous cancer types. Subtypes for many tumor types have been established; however, these classifications are based on molecular characteristics of a small gene sets with limited power to detect dysregulation at the patient level. We hypothesize that frequent graph mining of pathways to gather pathways functionally relevant to tumors can characterize tumor types and provide opportunities for personalized therapies. In this study we present an integrative omics approach to group patients based on their altered pathway characteristics and show prognostic differences within breast cancer (p network-based classifier algorithms and showed that our unsupervised approach generates more robust and biologically relevant clustering whereas previous approaches failed to report specific functions for similar patient groups or classify patients into prognostic groups. These results could serve as a means to improve prognosis for future cancer patients, and to provide opportunities for improved treatment options and personalized interventions. The proposed novel graph mining approach is able to integrate PPI networks with gene expression in a biologically sound approach and cluster patients in to clinically distinct groups. We have utilized breast cancer and glioblastoma multiforme datasets from microarray and RNA-Seq platforms and identified disease mechanisms differentiating samples. Supplementary methods, figures, tables and code are available at https://github.com/bebeklab/dysprog.

  1. Orthostatic Dysregulation during Postural Change on the Dental Chair and Intraoperative Monitoring by Heart Rate Variability Analysis

    Directory of Open Access Journals (Sweden)

    Yukihiro Momota

    2014-01-01

    Full Text Available This is the first case report of orthostatic dysregulation (OD manifested during postural change on the dental chair and intraoperatively monitored by heart rate variability (HRV analysis. OD-associated autonomic dysfunction is induced by postural changes and easily leads to disturbance in circulatory dynamics; however, most dental practices have not yet realized the importance of managing OD. We measured autonomic activity in a patient with OD during dental therapy and assessed the clinical significance of HRV analysis for OD. The patient was a 17-year-old Japanese female. She was diagnosed with impacted wisdom teeth and had no previous history of a distinct systemic disease. A surgical procedure to extract the teeth was safely performed under both local anesthesia and sedation with nitrous oxide and midazolam. After the surgery, her postural change to sitting induced orthostatic hypotension. HRV variables showed parasympathetic dominance due to the upright position. Subsequently, her posture was returned to supine, and atropine sulfate administration for the immediate treatment of OD returned her blood pressure to normal levels. HRV variables showed relative sympathetic dominance due to an atropine-derived parasympathetic blockade. HRV analysis revealed OD-associated autonomic dysfunction and should become a standard tool for safe and secure dental management of OD.

  2. Myeloid Dysregulation in a Human Induced Pluripotent Stem Cell Model of PTPN11-Associated Juvenile Myelomonocytic Leukemia

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    Sonia Mulero-Navarro

    2015-10-01

    Full Text Available Somatic PTPN11 mutations cause juvenile myelomonocytic leukemia (JMML. Germline PTPN11 defects cause Noonan syndrome (NS, and specific inherited mutations cause NS/JMML. Here, we report that hematopoietic cells differentiated from human induced pluripotent stem cells (hiPSCs harboring NS/JMML-causing PTPN11 mutations recapitulated JMML features. hiPSC-derived NS/JMML myeloid cells exhibited increased signaling through STAT5 and upregulation of miR-223 and miR-15a. Similarly, miR-223 and miR-15a were upregulated in 11/19 JMML bone marrow mononuclear cells harboring PTPN11 mutations, but not those without PTPN11 defects. Reducing miR-223’s function in NS/JMML hiPSCs normalized myelogenesis. MicroRNA target gene expression levels were reduced in hiPSC-derived myeloid cells as well as in JMML cells with PTPN11 mutations. Thus, studying an inherited human cancer syndrome with hiPSCs illuminated early oncogenesis prior to the accumulation of secondary genomic alterations, enabling us to discover microRNA dysregulation, establishing a genotype-phenotype association for JMML and providing therapeutic targets.

  3. Nocturnal Anxiety in a Youth with Rapid-onset Obesity, Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD).

    Science.gov (United States)

    Grudnikoff, Eugene; Foley, Carmel; Poole, Claudette; Theodosiadis, Eva

    2013-08-01

    Behavioral and psychiatric disorders are common in youth with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD). We outline a rational approach to psychiatric treatment of a patient with a complex medical condition. We report the course of symptoms in a teen with ROHHAD, the inpatient treatment, and review current evidence for use of psychopharmacologic agents in youth with sleep and anxiety disturbances. A 14-year-old female began rapidly gaining weight as a preschooler, developed hormonal imbalance, and mixed sleep apnea. Consultation was requested after a month of ROHHAD exacerbation, with severe anxiety, insomnia, and auditory hallucinations. Olanzapine and citalopram were helpful in controlling the symptoms. Following discharge, the patient gained weight and olanzapine was discontinued. Lorazepam was started in coordination with pulmonary service. Relevant pharmacologic considerations included risk of respiratory suppression, history of paradoxical reaction to hypnotics, hepatic isoenzyme interactions and side effects of antipsychotics. Core symptoms of ROHHAD may precipitate psychiatric disorders. A systematic evidence-based approach to psychopharmacology is necessary in the setting of psychiatric consultation.

  4. Regulation and dysregulation of esophageal peristalsis by the integrated function of circular and longitudinal muscle layers in health and disease.

    Science.gov (United States)

    Mittal, Ravinder K

    2016-09-01

    Muscularis propria throughout the entire gastrointestinal tract including the esophagus is comprised of circular and longitudinal muscle layers. Based on the studies conducted in the colon and the small intestine, for more than a century, it has been debated whether the two muscle layers contract synchronously or reciprocally during the ascending contraction and descending relaxation of the peristaltic reflex. Recent studies in the esophagus and colon prove that the two muscle layers indeed contract and relax together in almost perfect synchrony during ascending contraction and descending relaxation of the peristaltic reflex, respectively. Studies in patients with various types of esophageal motor disorders reveal temporal disassociation between the circular and longitudinal muscle layers. We suggest that the discoordination between the two muscle layers plays a role in the genesis of esophageal symptoms, i.e., dysphagia and esophageal pain. Certain pathologies may selectively target one and not the other muscle layer, e.g., in eosinophilic esophagitis there is a selective dysfunction of the longitudinal muscle layer. In achalasia esophagus, swallows are accompanied by the strong contraction of the longitudinal muscle without circular muscle contraction. The possibility that the discoordination between two muscle layers plays a role in the genesis of esophageal symptoms, i.e., dysphagia and esophageal pain are discussed. The purpose of this review is to summarize the regulation and dysregulation of peristalsis by the coordinated and discoordinated function of circular and longitudinal muscle layers in health and diseased states.

  5. and Epigenetic Dysregulation in Diabetes-prone Bicongenic B6.NODC11bxC1tb Mice

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    Erin Garrigan

    2015-01-01

    Full Text Available In Type 1 diabetic (T1D human monocytes, STAT5 aberrantly binds to epigenetic regulatory sites of two proinflammatory genes, CSF2 (encoding granulocyte–macrophage colony-stimulating factor and PTGS2 (encoding prostaglandin synthase 2/cyclooxygenase 2. Bicongenic B6.NOD C11bxC1tb mice re-create this phenotype of T1D monocytes with only two nonobese diabetic (NOD Idd subloci (130.8 Mb–149.7 Mb, of Idd5 on Chr 1 and 32.08–53.85 Mb of Idd4.3 on Chr11 on C57BL/6 genetic background. These two Idd loci interact through STAT5 binding at upstream regulatory regions affecting Csf2 ( Chr 11 and Ptgs2 ( Chr 1 expression. B6.NODC11bxC1tb mice exhibited hyperglycemia and immune destruction of pancreatic islets between 8 and 30 weeks of age, with 12%–22% penetrance. Thus, B6