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

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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

GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways

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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.

Emotion Dysregulation and Adolescent Psychopathology: A Prospective Study

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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

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

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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.

Microglial Dysregulation in OCD, Tourette Syndrome, and PANDAS

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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.

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

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.

Hypoventilation improvement in an adult non-invasively ventilated patient with Rapid-onset Obesity with Hypothalamic Dysfunction Hypoventilation and Autonomic Dysregulation (ROHHAD).

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Graziani, Alessandro; Casalini, Pierpaolo; Mirici-Cappa, Federica; Pezzi, Giuseppe; Giuseppe Stefanini, Francesco

2016-01-01

Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is a rare disease of unknown etiology, characterized by rapid-onset obesity in young children, hypoventilation, hypothalamic and autonomic dysfunction. Patients between the ages of 2 and 4 present with hyperphagia and weight gain, followed by neuro-hormonal dysfunction and central hypoventilation months or years later. Cardiac arrest may represent the fatal complication of alveolar hypoventilation and early mechanical ventilation is essential for the patient's life. In this paper, we describe a 22-year-old patient with ROHHAD syndrome who had an acute respiratory failure during nocturnal non-invasive ventilation (NIV).

Dysregulated sexuality and high sexual desire: distinct constructs?

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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.

Dysregulations in circulating sphingolipids associate with disease activity indices in female patients with systemic lupus erythematosus: a cross-sectional study.

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Checa, A; Idborg, H; Zandian, A; Sar, D Garcia; Surowiec, I; Trygg, J; Svenungsson, E; Jakobsson, P-J; Nilsson, P; Gunnarsson, I; Wheelock, C E

2017-09-01

Objective The objective of this study was to investigate the association of clinical and renal disease activity with circulating sphingolipids in patients with systemic lupus erythematosus. Methods We used liquid chromatography tandem mass spectrometry to measure the levels of 27 sphingolipids in plasma from 107 female systemic lupus erythematosus patients and 23 controls selected using a design of experiment approach. We investigated the associations between sphingolipids and two disease activity indices, the Systemic Lupus Activity Measurement and the Systemic Lupus Erythematosus Disease Activity Index. Damage was scored according to the Systemic Lupus International Collaborating Clinics damage index. Renal activity was evaluated with the British Island Lupus Activity Group index. The effects of immunosuppressive treatment on sphingolipid levels were evaluated before and after treatment in 22 female systemic lupus erythematosus patients with active disease. Results Circulating sphingolipids from the ceramide and hexosylceramide families were increased, and sphingoid bases were decreased, in systemic lupus erythematosus patients compared to controls. The ratio of C 16:0 -ceramide to sphingosine-1-phosphate was the best discriminator between patients and controls, with an area under the receiver-operating curve of 0.77. The C 16:0 -ceramide to sphingosine-1-phosphate ratio was associated with ongoing disease activity according to the Systemic Lupus Activity Measurement and the Systemic Lupus Erythematosus Disease Activity Index, but not with accumulated damage according to the Systemic Lupus International Collaborating Clinics Damage Index. Levels of C 16:0 - and C 24:1 -hexosylceramides were able to discriminate patients with current versus inactive/no renal involvement. All dysregulated sphingolipids were normalized after immunosuppressive treatment. Conclusion We provide evidence that sphingolipids are dysregulated in systemic lupus erythematosus and associated

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

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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.

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

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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

Timing of birth: Parsimony favors strategic over dysregulated parturition.

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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.

Benchmarking pathway interaction network for colorectal cancer to identify dysregulated pathways

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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.

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

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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.

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

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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.

Effect of Methylphenidate on Emotional Dysregulation in Children With Attention-Deficit/Hyperactivity Disorder + Oppositional Defiant Disorder/Conduct Disorder.

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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.

Disruptive Mood Dysregulation Disorder

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... 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 ...

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.

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

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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.

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

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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.

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

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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.

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

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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.

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

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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.

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

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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.

Disordered eating and emotion dysregulation among adolescents and their parents.

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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.

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

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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.

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

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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.

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

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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.

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

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Liana C L Portugal

included cerebellum, sensory-motor and fronto-limbic areas.The combination of pattern regression models and neuroimaging can help to determine the severity of behavioral and emotional dysregulation in youth at different time points.

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

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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.

Proteome analysis of schizophrenia patients Wernicke's area reveals an energy metabolism dysregulation

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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.

Dysregulated Fear in Toddlerhood Predicts Kindergarten Social Withdrawal through Protective Parenting

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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…

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

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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.

FREQUENT SUBGRAPH MINING OF PERSONALIZED SIGNALING PATHWAY NETWORKS GROUPS PATIENTS WITH FREQUENTLY DYSREGULATED DISEASE PATHWAYS AND PREDICTS PROGNOSIS.

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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.

Dysregulation of Histone Acetyltransferases and Deacetylases in Cardiovascular Diseases

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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.

Dopamine dysregulation syndrome in Parkinson’s disease

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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.

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

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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.

Dopaminergic Dysregulation, Artistic Expressiveness, and Parkinson's Disease

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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

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

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

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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.

Mosaic epigenetic dysregulation of ectodermal cells in autism spectrum disorder.

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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

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

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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.

Dysregulated behaviors in bulimia nervosa: a case-control study

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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...

Dysregulated pH in Tumor Microenvironment Checkmates Cancer Therapy

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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.

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

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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

Delineating the psychic structure of substance abuse and addictions: should anxiety, mood and impulse-control dysregulation be included?

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Pani, Pier Paolo; Maremmani, Icro; Trogu, Emanuela; Gessa, Gian Luigi; Ruiz, Pedro; Akiskal, Hagop Souren

2010-05-01

Current "official" nosology (e.g. DSM IV) is largely limited to physical manifestations of addiction that can be objectively observed and are suited to the maintaining of an "atheoretical" perspective. However, addicted subjects display additional psychiatric symptoms that affect their well-being and social functioning and, in accordance with DSM IV, are typically relegated to the domain of psychiatric "comorbidity." We contend that the relationship of these psychiatric symptoms with addiction is very close, as demonstrated by the high frequency of association observed. We further assert that substance use may modify pre-existing psychic structures such as temperament and related subthreshold conditions and lead to addiction as a specific mental disorder, inclusive also of symptoms pertaining to mood/anxiety, or impulse-control dimensions. The present contribution addresses the weaknesses of the current DSM-based nosology of addiction-related mental comorbidity. We highlight the overlap of the biological substrates and the neurophysiology of addictive processes and psychiatric symptoms associated with addiction, and propose the inclusion of specific mood, anxiety, and impulse-control dimensions in the psychopathology of addictive processes. We postulate that addiction reaches beyond the mere result of drug-elicited effects on the brain and cannot be peremptorily equated only with the use of drugs despite the adverse consequences produced. We infer that mood, anxiety and impulse-control dysregulation is at the very core of both the origins and clinical manifestations of addiction and should be incorporated into the nosology of the same, emphasising how addiction is a relapsing chronic condition in which psychiatric manifestations play a crucial role. To conclude, addictionology cannot be severed from its psychopathological connotations, in view of the undeniable presence of symptoms, of their manifest contribution to the way addicted patients feel and behave, and to

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

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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.

Six months methylphenidate treatment improves emotion dysregulation in adolescents with attention deficit/hyperactivity disorder: a prospective study

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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

Dysregulation of glucose metabolism since young adulthood increases the risk of cardiovascular diseases in patients with bipolar disorder

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Pao-Huan Chen

2017-12-01

Full Text Available Aging patients with bipolar disorder (BD are at a high risk of cardiovascular diseases (CVDs. However, few studies have directly examined the association between metabolic risks and CVDs in patients with BD across the lifespan. Therefore, the aim of this study was to determine lifetime metabolic risk factors for CVDs in patients with BD. We recruited BD-I patients who were more than 50 years old and had had at least one psychiatric hospitalization. Patients who had a cardiologist-confirmed CVD diagnosis (ICD-9 code 401–414 were assigned to the case group. Fifty-five cases were matched with 55 control patient without CVDs based on age and sex. Clinical data were obtained by retrospectively reviewing 30 years of hospital records. Compared to control subjects, a significantly higher proportion of cases had impaired fasting glucose between ages 31 and 40 (44.0% versus 17.4%, p = 0.046, diabetes mellitus between ages 41 and 50 (25.6% versus 8.6%, p = 0.054, and diabetes mellitus after age 51 (36.3% versus 12.7%, p = 0.005. No significant difference was found in overweight, obesity, or dyslipidemia. After adjusting for years of education, first episode as mania, and second generation antipsychotic use, lifetime diabetes mellitus remained a risk factor for CVDs (OR = 4.45, 95% CI = 1.89–10.66, p = 0.001. The findings suggest that glucose dysregulation across the adult age span is probably the major metabolic risk contributing to CVDs in patients with BD. Clinicians therefore have to notice the serum fasting glucose levels of BD patients since young adulthood.

Functional Dysregulation of CDC42 Causes Diverse Developmental Phenotypes.

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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.

Widespread dysregulation of MiRNAs by MYCN amplification and chromosomal imbalances in neuroblastoma: association of miRNA expression with survival.

LENUS (Irish Health Repository)

Bray, Isabella

2009-01-01

MiRNAs regulate gene expression at a post-transcriptional level and their dysregulation can play major roles in the pathogenesis of many different forms of cancer, including neuroblastoma, an often fatal paediatric cancer originating from precursor cells of the sympathetic nervous system. We have analyzed a set of neuroblastoma (n = 145) that is broadly representative of the genetic subtypes of this disease for miRNA expression (430 loci by stem-loop RT qPCR) and for DNA copy number alterations (array CGH) to assess miRNA involvement in disease pathogenesis. The tumors were stratified and then randomly split into a training set (n = 96) and a validation set (n = 49) for data analysis. Thirty-seven miRNAs were significantly over- or under-expressed in MYCN amplified tumors relative to MYCN single copy tumors, indicating a potential role for the MYCN transcription factor in either the direct or indirect dysregulation of these loci. In addition, we also determined that there was a highly significant correlation between miRNA expression levels and DNA copy number, indicating a role for large-scale genomic imbalances in the dysregulation of miRNA expression. In order to directly assess whether miRNA expression was predictive of clinical outcome, we used the Random Forest classifier to identify miRNAs that were most significantly associated with poor overall patient survival and developed a 15 miRNA signature that was predictive of overall survival with 72.7% sensitivity and 86.5% specificity in the validation set of tumors. We conclude that there is widespread dysregulation of miRNA expression in neuroblastoma tumors caused by both over-expression of the MYCN transcription factor and by large-scale chromosomal imbalances. MiRNA expression patterns are also predicative of clinical outcome, highlighting the potential for miRNA mediated diagnostics and therapeutics.

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

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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.

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

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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.

Behavioral evidence of emotion dysregulation in binge eaters.

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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.

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

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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).

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

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

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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.

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....

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

Quantitative assessment of metal dysregulation in β-thalassemia patients in comparison with healthy controls by ICP-MS and chemometric analyses.

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Farooq, Sabiha; Mazhar, Wardah; Siddiqui, Amna Jabbar; Ansari, Saqib Hussain; Musharraf, Syed Ghulam

2018-01-31

β-Thalassemia is one of the most common inherited disorders and is widely distributed throughout the world. Owing to severe deficiencies in red blood cell production, blood transfusion is required to correct anemia for normal growth and development but causes additional complications owing to iron overload. The aim of this study is to quantify the biometal dysregulations in β-thalassemia patients as compared with healthy controls. A total of 17 elements were analyzed in serum samples of β-thalassemia patients and healthy controls using ICP-MS followed by chemometric analyses. Out of these analyzed elements, 14 showed a significant difference between healthy and disease groups at p 3. A PLS-DA model revealed an excellent separation with 89.8% sensitivity and 97.2% specificity and the overall accuracy of the model was 92.2%. This metallomic study revealed that there is major difference in metallomic profiling of β-thalassemia patients specifically in Co, Mn, Ni, V and Ba, whereas the fold changes in Co, Mn, V and Ba were found to be greater than that in Fe, providing evidence that, in addition to Fe, other metals are also altered significantly and therefore chelation therapy for other metals may also needed in β-thalassemia patients. Copyright © 2018 John Wiley & Sons, Ltd.

Failure of Chemotherapy in Hepatocellular Carcinoma Due to Impaired and Dysregulated Primary Liver Drug Metabolizing Enzymes and Drug Transport Proteins: What to Do?

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Ul Islam, Salman; Ahmed, Muhammad Bilal; Shehzad, Adeeb; Ul-Islam, Mazhar; Lee, Young Sup

2018-05-28

Most of the drugs are metabolized in the liver by the action of drug metabolizing enzymes. In hepatocellular carcinoma (HCC), primary drug metabolizing enzymes are severely dysregulated, leading to failure of chemotherapy. Sorafenib is the only standard systemic drug available, but it still presents certain limitations, and much effort is required to understand who is responsive and who is refractory to the drug. Preventive and therapeutic approaches other than systemic chemotherapy include vaccination, chemoprevention, liver transplantation, surgical resection, and locoregional therapies. This review details the dysregulation of primary drug metabolizing enzymes and drug transport proteins of the liver in HCC and their influence on chemotherapeutic drugs. Furthermore, it emphasizes the adoption of safe alternative therapeutic strategies to chemotherapy. The future of HCC treatment should emphasize the understanding of resistance mechanisms and the finding of novel, safe, and efficacious therapeutic strategies, which will surely benefit patients affected by advanced HCC. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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

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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

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....

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

Altered B cell homeostasis and Toll-like receptor 9-driven response in patients affected by autoimmune polyglandular syndrome Type 1: Altered B cell phenotype and dysregulation of the B cell function in APECED patients.

Science.gov (United States)

Perri, Valentina; Gianchecchi, Elena; Scarpa, Riccardo; Valenzise, Mariella; Rosado, Maria Manuela; Giorda, Ezio; Crinò, Antonino; Cappa, Marco; Barollo, Susi; Garelli, Silvia; Betterle, Corrado; Fierabracci, Alessandra

2017-02-01

APECED is a T-cell mediated disease with increased frequencies of CD8+ effector and reduction of FoxP3+ T regulatory cells. Antibodies against affected organs and neutralizing to cytokines are found in the peripheral blood. The contribution of B cells to multiorgan autoimmunity in Aire-/- mice was reported opening perspectives on the utility of anti-B cell therapy. We aimed to analyse the B cell phenotype of APECED patients compared to age-matched controls. FACS analysis was conducted on PBMC in basal conditions and following CpG stimulation. Total B and switched memory (SM) B cells were reduced while IgM memory were increased in patients. In those having more than 15 years from the first clinical manifestation the defect included also mature and transitional B cells; total memory B cells were increased, while SM were unaffected. In patients with shorter disease duration, total B cells were unaltered while SM and IgM memory behaved as in the total group. A defective B cell proliferation was detected after 4day-stimulation. In conclusion APECED patients show, in addition to a significant alteration of the B cell phenotype, a dysregulation of the B cell function involving peripheral innate immune mechanisms particularly those with longer disease duration. Copyright © 2016 Elsevier GmbH. All rights reserved.

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.

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.

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

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.

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.

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

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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.

Identifying microRNA/mRNA dysregulations in ovarian cancer.

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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

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

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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.

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

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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

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.

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...

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

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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.

Deletion of Fanca or Fancd2 dysregulates Treg in mice

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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

Deletion of Fanca or Fancd2 dysregulates Treg in mice.

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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.

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

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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

Dysregulated Functions of Lung Macrophage Populations in COPD.

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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.

Dysregulated Functions of Lung Macrophage Populations in COPD

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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

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

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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.

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

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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

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD): a case with additional features and review of the literature.

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Chew, H B; Ngu, L H; Keng, W T

2011-03-01

A rare syndrome of rapid-onset obesity with hypothalamic dysfunction, hypoventilation and autonomic dysregulation (ROHHAD) has been recently described. We report the first patient with this syndrome in Southeast Asia and review reported cases to date. Our patient was good health with normal development until the age of 2. He then developed hyperphagic obesity, hypersomnolence, seizures, alveolar hypoventilation, central hypothyroidism, sodium and water dysregulation, gastrointestinal dysmotility, strabismus, disordered temperature and irregular heart rate, altered sweating, delayed puberty, mental retardation and recurrent respiratory tract infections. The cardiomyopathy with heart failure and abnormal cerebral spinal fluid (CSF) neurotransmitter analysis present in our patient have not been reported previously. Tumours of the sympathetic nervous system are known to be associated with this syndrome but had not been found in our patient at the time of reporting. We highlight the difficulty of achieving the diagnosis of ROHHAD syndrome and its overlap with other well-established disease entities. The mortality and morbidity resulting from the high incidence of cardiorespiratory arrest may be prevented by early ventilatory support.

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

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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.

Dissociative symptoms and neuroendocrine dysregulation in depression.

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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.

Dysregulation in level of goal and action identification across psychological disorders

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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

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-.

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

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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.

The primary vascular dysregulation syndrome: implications for eye diseases

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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

Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer's disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels.

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Ruiz, Henry H; Chi, Tiffany; Shin, Andrew C; Lindtner, Claudia; Hsieh, Wilson; Ehrlich, Michelle; Gandy, Sam; Buettner, Christoph

2016-08-01

Epidemiologic studies have demonstrated an association between diabetes and dementia. Insulin signaling within the brain, in particular within the hypothalamus regulates carbohydrate, lipid, and branched chain amino acid (BCAA) metabolism in peripheral organs such as the liver and adipose tissue. We hypothesized that cerebral amyloidosis impairs central nervous system control of metabolism through disruption of insulin signaling in the hypothalamus, which dysregulates glucose and BCAA homeostasis resulting in increased susceptibility to diabetes. We examined whether APP/PS1 mice exhibit increased susceptibility to aging or high-fat diet (HFD)-induced metabolic impairment using metabolic phenotyping and insulin-signaling studies. APP/PS1 mice were more susceptible to high-fat feeding and aging-induced metabolic dysregulation including disrupted BCAA homeostasis and exhibited impaired hypothalamic insulin signaling. Our data suggest that AD pathology increases susceptibility to diabetes due to impaired hypothalamic insulin signaling, and that plasma BCAA levels could serve as a biomarker of hypothalamic insulin action in patients with AD. Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

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

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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.

Impulsivity in borderline personality disorder: a matter of disturbed impulse control or a facet of emotional dysregulation?

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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.

Low frequency of bipolar disorder, dopamine dysregulation syndrome, and punding in Brazilian patients with Parkinson's disease Baixa frequência de transtorno bipolar, síndrome de desregulação dopaminérgica e punding em pacientes brasileiros com doença de Parkinson

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Arthur Kummer

2010-03-01

Full Text Available OBJECTIVE: To investigate the frequency of bipolar disorder, dopamine dysregulation syndrome and punding in Parkinson's disease patients from a Brazilian movement disorders clinic. METHOD: One hundred patients underwent a comprehensive psychiatric examination composed of MINI-plus and specific questionnaires to investigate dopamine dysregulation syndrome and punding. RESULTS: We identified, respectively, one and five Parkinson's disease patients with bipolar disorder type I and type II. All manic/hypomanic episodes occurred before Parkinson's disease onset. No patient was identified with dopamine dysregulation syndrome or punding. CONCLUSION: The frequency of manic/hypomanic episodes seems to decrease with Parkinson's disease onset, and local environmental factors (e.g. drug availability may be responsible for the low frequency of dopamine dysregulation syndrome and punding in Brazilian Parkinson's disease patients.OBJETIVO: Investigar a frequência de transtorno bipolar, síndrome de desregulação dopaminérgica e punding em pacientes com doença de Parkinson de uma clínica de movimentos anormais no Brasil. MÉTODO: Cem pacientes foram submetidos à avaliação psiquiátrica composta pelo MINI-Plus e questionários específicos para investigar síndrome de desregulação dopaminérgica e punding. RESULTADOS: Identificamos, respectivamente, um e cinco pacientes com transtorno bipolar tipo I e tipo II. Todos os episódios maníacos/hipomaníacos ocorreram antes do início da doença de Parkinson. Nenhum paciente foi identificado com síndrome de desregulação dopaminérgica ou punding. CONCLUSÃO: A frequência de episódios maníacos/ hipomaníacos parece declinar com o início da doença de Parkinson. Fatores ambientais locais (p.ex.: disponibilidade de drogas podem ser responsáveis pela baixa frequência de síndrome de desregulação dopaminérgica e punding em pacientes brasileiros com doença de Parkinson.

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.

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.;

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

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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.

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

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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.

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

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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

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

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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).

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

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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…

Quantification of cell-free DNA in blood plasma and DNA damage degree in lymphocytes to evaluate dysregulation of apoptosis in schizophrenia patients.

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Ershova, E S; Jestkova, E M; Chestkov, I V; Porokhovnik, L N; Izevskaya, V L; Kutsev, S I; Veiko, N N; Shmarina, G; Dolgikh, O; Kostyuk, S V

2017-04-01

Oxidative DNA damage has been proposed as one of the causes of schizophrenia (SZ), and post mortem data indicate a dysregulation of apoptosis in SZ patients. To evaluate apoptosis in vivo we quantified the concentration of plasma cell-free DNA (cfDNA index, determined using fluorescence), the levels of 8-oxodG in cfDNA (immunoassay) and lymphocytes (FL1-8-oxodG index, flow cytometry) of male patients with acute psychotic disorders: paranoid SZ (total N = 58), schizophreniform (N = 11) and alcohol-induced (N = 14) psychotic disorder, and 30 healthy males. CfDNA in SZ (N = 58) does not change compared with controls. In SZ patients. Elevated levels of 8-oxodG were found in cfDNA (N = 58) and lymphocytes (n = 45). The main sources of cfDNA are dying cells with oxidized DNA. Thus, the cfDNA/FL1-8-oxodG ratio shows the level of apoptosis in damaged cells. Two subgroups were identified among the SZ patients (n = 45). For SZ-1 (31%) and SZ-2 (69%) median values of cfDNA/FL1-8-oxodG index are related as 1:6 (p DNA in the patient's body tissues and may be a contributing cause of acute psychotic disorder. Copyright © 2016 Elsevier Ltd. All rights reserved.

Neurobiology of dysregulated motivational systems in drug addiction

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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

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 ...

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

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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.

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

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Norona, A N; Baker, B L

2017-02-01

Emotion regulation has been identified as a robust predictor of adaptive functioning across a variety of domains (Aldao et al. ). Furthermore, research examining early predictors of competence and deficits in ER suggests that factors internal to the individual (e.g. neuroregulatory reactivity, behavioural traits and cognitive ability) and external to the individual (e.g. caregiving styles and explicit ER training) contribute to the development of ER (Calkins ). Many studies have focused on internal sources or external sources; however, few have studied them simultaneously within one model, especially in studies examining children with developmental delays (DD). Here, we addressed this specific research gap and examined the contributions of one internal factor and one external factor on emotion dysregulation outcomes in middle childhood. Specifically, our current study used structural equation modelling (SEM) to examine prospective, predictive relationships between DD status, positive parenting at age 4 years and child emotion dysregulation at age 7 years. Participants were 151 families in the Collaborative Family Study, a longitudinal study of young children with and without DD. A positive parenting factor was composed of sensitivity and scaffolding scores from mother-child interactions at home and in the research centre at child age 4 years. A child dysregulation factor was composed of a dysregulation code from mother-child interactions and a parent-report measure of ER and lability/negativity at age 7 years. Finally, we tested the hypothesis that positive parenting would mediate the relationship between DD and child dysregulation. Mothers of children with DD exhibited fewer sensitive and scaffolding behaviours compared with mothers of typically developing children, and children with DD were more dysregulated on all measures of ER. SEM revealed that both DD status and early positive parenting predicted emotion dysregulation in middle childhood. Furthermore

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

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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.

Dimensions of Emotion Dysregulation in Anorexia Nervosa and Bulimia Nervosa: A Conceptual Review of the Empirical Literature

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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

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

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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.

Nocturnal Anxiety in a Youth with Rapid-onset Obesity, Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD).

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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.

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

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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.

The emotion dysregulation inventory: Psychometric properties and item response theory calibration in an autism spectrum disorder sample.

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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

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....

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

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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.

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

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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.

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

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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.

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

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

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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.

Dysregulated metabolism contributes to oncogenesis

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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

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.

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

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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.

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

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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…

Dysregulation of endothelial colony-forming cell function by a negative feedback loop of circulating miR-146a and -146b in cardiovascular disease patients.

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Ting-Yu Chang

Full Text Available Functional impairment of endothelial colony-forming cells (ECFCs, a specific cell lineage of endothelial progenitor cells (EPCs is highly associated with the severity of coronary artery disease (CAD, the most common type of cardiovascular disease (CVD. Emerging evidence show that circulating microRNAs (miRNAs in CAD patients' body fluid hold a great potential as biomarkers. However, our knowledge of the role of circulating miRNA in regulating the function of ECFCs and the progression of CAD is still in its infancy. We showed that when ECFCs from healthy volunteers were incubated with conditioned medium or purified exosomes of cultured CAD ECFCs, the secretory factors from CAD ECFCs dysregulated migration and tube formation ability of healthy ECFCs. It is known that exosomes influence the physiology of recipient cells by introducing RNAs including miRNAs. By using small RNA sequencing (smRNA-seq, we deciphered the circulating miRNome in the plasma of healthy individual and CAD patients, and found that the plasma miRNA spectrum from CAD patients was significantly different from that of healthy control. Interestingly, smRNA-seq of both healthy and CAD ECFCs showed that twelve miRNAs that had a higher expression in the plasma of CAD patients also showed higher expression in CAD ECFCs when compared with healthy control. This result suggests that these miRNAs may be involved in the regulation of ECFC functions. For identification of potential mRNA targets of the differentially expressed miRNA in CAD patients, cDNA microarray analysis was performed to identify the angiogenesis-related genes that were down-regulated in CAD ECFCs and Pearson's correlation were used to identify miRNAs that were negatively correlated with the identified angiogenesis-related genes. RT-qPCR analysis of the five miRNAs that negatively correlated with the down-regulated angiogenesis-related genes in plasma and ECFC of CAD patients showed miR-146a-5p and miR-146b-5p up

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

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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.

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.

Dysregulation of RNA Mediated Gene Expression in Motor Neuron Diseases.

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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.

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

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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

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

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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.

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

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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.

Main and interactive effects of emotion dysregulation and HIV symptom severity on quality of life among persons living with HIV/AIDS.

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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.

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

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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.

microRNA-128a dysregulation in transgenic Huntington’s disease monkeys

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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

The Pathogenesis and Treatment of Emotion Dysregulation in Borderline Personality Disorder

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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.

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

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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.

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

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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.

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

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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.

Does school mobility place elementary school children at risk for lower math achievement? The mediating role of cognitive dysregulation.

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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).

Does School Mobility Place Elementary School Children at Risk for Lower Math Achievement? The Mediating Role of Cognitive Dysregulation

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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

Role of innate and drug-induced dysregulation of brain stress and arousal systems in addiction: Focus on corticotropin-releasing factor, nociceptin/orphanin FQ, and orexin/hypocretin

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Martin-Fardon, Rémi; Zorrilla, Eric P.; Ciccocioppo, Roberto; Weiss, Friedbert

2010-01-01

Stress-like symptoms are an integral part of acute and protracted drug withdrawal, and several lines of evidence have shown that dysregulation of brain stress systems, including the extrahypothalamic corticotropin-releasing factor (CRF) system, following long-term drug use is of major importance in maintaining drug and alcohol addiction. Recently, two other neuropeptide systems have attracted interest, the nociceptin/orphanin FQ (N/OFQ) and orexin/hypocretin (Orx/Hcrt) systems. N/OFQ participates in a wide range of physiological responses, and the hypothalamic Orx/Hcrt system helps regulate several physiological processes, including feeding, energy metabolism, and arousal. Moreover, these two systems have been suggested to participate in psychiatric disorders, including anxiety and drug addiction. Dysregulation of these systems by chronic drug exposure has been hypothesized to play a role in the maintenance of addiction and dependence. Recent evidence demonstrated that interactions between CRF-N/OFQ and CRF-Orx/Hcrt systems may be functionally relevant for the control of stress-related addictive behavior. The present review discusses recent findings that support the hypotheses of the participation and dysregulation of these systems in drug addiction and evaluates the current understanding of interactions among these stress-regulatory peptides. PMID:20026088

Small intestinal bacterial overgrowth in patients with systemic sclerosis

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Saara Rawn

2017-01-01

Full Text Available Small intestinal bacterial overgrowth (SIBO is common in patients with systemic sclerosis (SSc yet often goes underrecognized in clinical practice. In patients with SSc, untreated SIBO may result in marked morbidity and possible mortality. The pathogenesis of SIBO is multifactorial and relates to immune dysregulation, vasculopathy, and dysmotility. This article reviews various diagnostic approaches and therapeutic options for SIBO. Treatment modalities mainly include prokinetics, probiotics, and antibiotics.

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

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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.

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

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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.

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

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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

Gender moderates the relationship between attachment insecurities and emotion dysregulation

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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

Dissecting microRNA dysregulation in age-related macular degeneration: new targets for eye gene therapy.

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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.

Global gene expression profiling displays a network of dysregulated genes in non-atherosclerotic arterial tissue from patients with type 2 diabetes

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Skov Vibe

2012-02-01

Full Text Available Abstract Background Generalized arterial alterations, such as endothelial dysfunction, medial matrix accumulations, and calcifications are associated with type 2 diabetes (T2D. These changes may render the vessel wall more susceptible to injury; however, the molecular characteristics of such diffuse pre-atherosclerotic changes in diabetes are only superficially known. Methods To identify the molecular alterations of the generalized arterial disease in T2D, DNA microarrays were applied to examine gene expression changes in normal-appearing, non-atherosclerotic arterial tissue from 10 diabetic and 11 age-matched non-diabetic men scheduled for a coronary by-pass operation. Gene expression changes were integrated with GO-Elite, GSEA, and Cytoscape to identify significant biological pathways and networks. Results Global pathway analysis revealed differential expression of gene-sets representing matrix metabolism, triglyceride synthesis, inflammation, insulin signaling, and apoptosis. The network analysis showed a significant cluster of dysregulated genes coding for both intra- and extra-cellular proteins associated with vascular cell functions together with genes related to insulin signaling and matrix remodeling. Conclusions Our results identify pathways and networks involved in the diffuse vasculopathy present in non-atherosclerotic arterial tissue in patients with T2D and confirmed previously observed mRNA-alterations. These abnormalities may play a role for the arterial response to injury and putatively for the accelerated atherogenesis among patients with diabetes.

Markers of impaired motor and cognitive volition in Parkinson's disease: Correlates of dopamine dysregulation syndrome, impulse control disorder, and dyskinesias.

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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.

Transcriptional dysregulation in NIPBL and cohesin mutant human cells.

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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.

Genome Wide Expression Profiling of Cancer Cell Lines Cultured in Microgravity Reveals Significant Dysregulation of Cell Cycle and MicroRNA Gene Networks.

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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.

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

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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.

Dysregulation of striatal projection neurons in Parkinson's disease.

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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.

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

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

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

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

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

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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.

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

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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.

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

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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.

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

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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.

Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors

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Zuurbier, Linda; Gutierrez, Alejandro; Mullighan, Charles G.; Canté-Barrett, Kirsten; Gevaert, A. Olivier; de Rooi, Johan; Li, Yunlei; Smits, Willem K.; Buijs-Gladdines, Jessica G.C.A.M.; Sonneveld, Edwin; Look, A. Thomas; Horstmann, Martin; Pieters, Rob; Meijerink, Jules P.P.

2014-01-01

Three distinct immature T-cell acute lymphoblastic leukemia entities have been described including cases that express an early T-cell precursor immunophenotype or expression profile, immature MEF2C-dysregulated T-cell acute lymphoblastic leukemia cluster cases based on gene expression analysis (immature cluster) and cases that retain non-rearranged TRG@ loci. Early T-cell precursor acute lymphoblastic leukemia cases exclusively overlap with immature cluster samples based on the expression of early T-cell precursor acute lymphoblastic leukemia signature genes, indicating that both are featuring a single disease entity. Patients lacking TRG@ rearrangements represent only 40% of immature cluster cases, but no further evidence was found to suggest that cases with absence of bi-allelic TRG@ deletions reflect a distinct and even more immature disease entity. Immature cluster/early T-cell precursor acute lymphoblastic leukemia cases are strongly enriched for genes expressed in hematopoietic stem cells as well as genes expressed in normal early thymocyte progenitor or double negative-2A T-cell subsets. Identification of early T-cell precursor acute lymphoblastic leukemia cases solely by defined immunophenotypic criteria strongly underestimates the number of cases that have a corresponding gene signature. However, early T-cell precursor acute lymphoblastic leukemia samples correlate best with a CD1 negative, CD4 and CD8 double negative immunophenotype with expression of CD34 and/or myeloid markers CD13 or CD33. Unlike various other studies, immature cluster/early T-cell precursor acute lymphoblastic leukemia patients treated on the COALL-97 protocol did not have an overall inferior outcome, and demonstrated equal sensitivity levels to most conventional therapeutic drugs compared to other pediatric T-cell acute lymphoblastic leukemia patients. PMID:23975177

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) ...

Targeting emotion dysregulation in the treatment of self-injury.

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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.

BCAA Metabolism and Insulin Sensitivity - Dysregulated by Metabolic Status?

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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.

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

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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…

Further Evidence that Severe Scores in the Aggression/Anxiety-Depression/Attention Subscales of Child Behavior Checklist (Severe Dysregulation Profile) Can Screen for Bipolar Disorder Symptomatology: A Conditional Probability Analysis

Science.gov (United States)

Uchida, Mai; Faraone, Stephen V; Martelon, MaryKate; Kenworthy, Tara; Woodworth, K Yvonne; Spencer, Thomas; Wozniak, Janet; Biederman, Joseph

2014-01-01

Background Previous work shows that children with high scores (2 SD, combined score ≥ 210) on the Attention Problems, Aggressive Behavior, and Anxious-Depressed (A-A-A) subscales of the Child Behavior Checklist (CBCL) are more likely than other children to meet criteria for bipolar (BP)-I disorder. However, the utility of this profile as a screening tool has remained unclear. Methods We compared 140 patients with pediatric BP-I disorder, 83 with attention deficit hyperactivity disorder (ADHD), and 114 control subjects. We defined the CBCL-Severe Dysregulation profile as an aggregate cutoff score of ≥ 210 on the A-A-A scales. Patients were assessed with structured diagnostic interviews and functional measures. Results Patients with BP-I disorder were significantly more likely than both control subjects (Odds Ratio [OR]: 173.2; 95% Confidence Interval [CI], 21.2 to 1413.8; P < 0.001) and those with ADHD (OR: 14.6; 95% CI, 6.2 to 34.3; P < 0.001) to have a positive CBCL-Severe Dysregulation profile. Receiver Operating Characteristics analyses showed that the area under the curve for this profile comparing children with BP-I disorder against control subjects and those with ADHD was 99% and 85%, respectively. The corresponding positive predictive values for this profile were 99% and 92% with false positive rates of < 0.2% and 8% for the comparisons with control subjects and patients with ADHD, respectively. Limitations Non-clinician raters administered structured diagnostic interviews, and the sample was referred and largely Caucasian. Conclusions The CBCL-Severe Dysregulation profile can be useful as a screen for BP-I disorder in children in clinical practice. PMID:24882182

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

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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.

Cytokine Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, and ω-3 PUFAs.

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Leoncini, Silvia; De Felice, Claudio; Signorini, Cinzia; Zollo, Gloria; Cortelazzo, Alessio; Durand, Thierry; Galano, Jean-Marie; Guerranti, Roberto; Rossi, Marcello; Ciccoli, Lucia; Hayek, Joussef

2015-01-01

An involvement of the immune system has been suggested in Rett syndrome (RTT), a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2) or, more rarely, cyclin-dependent kinase-like 5 (CDKL5). To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg) response, as well as chemokines, were investigated in MECP2- (MECP2-RTT) (n = 16) and CDKL5-Rett syndrome (CDKL5-RTT) (n = 8), before and after ω-3 polyunsaturated fatty acids (PUFAs) supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. In MECP2-RTT, a Th2-shifted balance was evidenced, whereas in CDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4) were upregulated. In MECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced in CDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system.

Cytokine Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, and ω-3 PUFAs

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Silvia Leoncini

2015-01-01

Full Text Available An involvement of the immune system has been suggested in Rett syndrome (RTT, a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2 or, more rarely, cyclin-dependent kinase-like 5 (CDKL5. To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg response, as well as chemokines, were investigated in MECP2- (MECP2-RTT (n=16 and CDKL5-Rett syndrome (CDKL5-RTT (n=8, before and after ω-3 polyunsaturated fatty acids (PUFAs supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. In MECP2-RTT, a Th2-shifted balance was evidenced, whereas in CDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4 were upregulated. In MECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced in CDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system.

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....

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...

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

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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…

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

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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…

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

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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.

Power spectrum scale invariance identifies prefrontal dysregulation in paranoid schizophrenia.

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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.

Cytosine methylation dysregulation in neonates following intrauterine growth restriction.

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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.

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

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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.

Anesthesia in a pediatric patient with ROHADD syndrome.

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Esparza Isasa, E; Palomero Rodríguez, M A; Acebedo Bambaren, I; Medrano Viñas, C; Gil Mayo, D; Domínguez Pérez, F; Pestaña Lagunas, D

2018-05-01

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome is a rare entity that is characterised by its onset in healthy children at 2-4 years of age. It is a complex syndrome that includes, among other symptoms, rapid weight gain with hyperphagia, hypothalamic dysfunction, central hypoventilation, and autonomic dysregulation. The case is presented of a 10-year-old boy with a diagnosis of ROHHAD syndrome undergoing insertion of a port-a-cath under general anaesthesia, who developed complications during the anaesthetic procedure related to his illness. The peri-operative management of these patients represents a challenge for the anaesthetist, given the involvement of multiple systems and the frequent respiratory comorbidities associated with them. A summary is presented of some of the implications and anaesthetic considerations that must be taken into account in the management of these patients. Copyright © 2018 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

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

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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

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

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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.

In Search of HPA Axis Dysregulation in Child and Adolescent Depression

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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…

Diabetes mellitus and impaired glucose tolerance in patients with schizophrenia, before and after antipsychotic treatment

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Rayees Ahmad Wani

2015-01-01

Full Text Available Background: Treatment with antipsychotics increases the risk of developing diabetes in patients of schizophrenia but this diabetogenic potential of different antipsychotics seems to be different. Moreover, there may be an independent link between schizophrenia and diabetes. So we plan to study the prevalence of glucose dysregulation in patients of schizophrenia before and after treatment with various antipsychotics. Materials and Methods: Fifty patients (32 males and 18 females diagnosed with schizophrenia were evaluated for glucose dysregulation using oral glucose tolerance test, initially (drug naive and after antipsychotic treatment. Age- and sex-matched healthy volunteer group of 50 subjects (35 males and 15 females was taken for comparison. Results were interpreted using American Diabetic Association criteria. Results: Though the glycemic status of the patient group was comparable with healthy controls initially but antipsychotic treatment was associated with glucose dysregulation. For first 6 weeks the antipsychotic (olanzapine, risperidone, haloperidol and aripiprazole-induced glucose dysregulation was comparable, which was seen to be maximum with the olanzapine-treated group at the end of this study, 14 weeks. Conclusion: We conclude that antipsychotic treatment of nondiabetic drug naive schizophrenia patients was associated with adverse effects on glucose regulation. For initial 6 weeks the antipsychotic-induced glucose dysregulation was comparable, which was seen to be maximum with olanzapine at the end of study, i.e. 14 weeks. Keeping this at the back of mind we can stabilize a patient initially with a more effective drug, olanzapine, and later on shift to one with less metabolic side effects.

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

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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

Major depressive disorder and generalized anxiety disorder show different autonomic dysregulations revealed by heart-rate variability analysis in first-onset drug-naïve patients without comorbidity.

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Shinba, Toshikazu

2017-02-01

The aim of the present study was to examine whether depression and anxiety disorder manifest different autonomic dysregulations using heart-rate variability (HRV) and heart rate (HR) measurements. HRV and HR were recorded both at rest and during task execution (random-number generation) in first-onset drug-naïve patients with major depressive disorder (MDD, n = 14) and generalized anxiety disorder (GAD, n = 11) as well as in healthy controls (n = 41). The patients showed no comorbidity of depression and anxiety disorder. GAD patients did not exhibit panic or phobic symptoms at the time of measurement. Following power spectrum analysis of HR trend, the high- (HF) and low-frequency (LF) components, the sum (LF + HF), and the LF/HF ratio were compared among the groups. In the MDD patients, as previously reported, HF was low and the LF/HF ratio was high during the initial-rest condition, and HF was less reactive to the task. In contrast, GAD patients showed significantly high HF, although autonomic reactivity was not impaired. The results indicate that baseline autonomic activity and its reactivity to behavioral changes are different between MDD and GAD in the early stage of illness. High parasympathetic tone in GAD may reflect responses of the parasympathetic system to anxiety. MDD is accompanied by an autonomic shift toward sympathetic activation and a reduced reactivity to task. © 2016 The Authors. Psychiatry and Clinical Neurosciences © 2016 Japanese Society of Psychiatry and Neurology.

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,

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

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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.

Subcorneal Pustular Dermatosis: A Case Report of a Patient with Diffuse Scleroderma

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Fatemeh Mokhtari

2018-01-01

Full Text Available Subcorneal pustular dermatosis (SPD or Sneddon-Wilkinson disease is a rare, benign, chronic, sterile pustular eruption which is associated with various systemic diseases including immunoglobinopathies, neoplasms, and autoimmune disorders. This paper reports a case of SPD in a patient with diffuse scleroderma in a 37-year-old woman. The hypothesis that immune dysregulation may play a role in the pathogenesis of SPD was supposed by the coexistence of diffuse scleroderma and SPD in our patient.

Onco-GPCR signaling and dysregulated expression of microRNAs in human cancer.

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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.

A Pilot Trial of Mindfulness Meditation Training for ADHD in Adulthood: Impact on Core Symptoms, Executive Functioning, and Emotion Dysregulation.

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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.

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.

Multiple mechanisms of MYCN dysregulation in Wilms tumour

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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

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

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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

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

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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

Cytosine Methylation Dysregulation in Neonates Following Intrauterine Growth Restriction

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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

Potential Therapeutic Effects of Meditation for Treating Affective Dysregulation

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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.

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

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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…

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

miR2Pathway: A Novel Analytical Method to Discover MicroRNA-mediated Dysregulated Pathways Involved in Hepatocellular Carcinoma.

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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.

Mild KCC2 hypofunction causes inconspicuous chloride dysregulation that degrades neural coding

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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.

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

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

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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.

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

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

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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.

Behavioral and Neural Sustained Attention Deficits in Disruptive Mood Dysregulation Disorder and Attention-Deficit/Hyperactivity Disorder.

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Pagliaccio, David; Wiggins, Jillian Lee; Adleman, Nancy E; Curhan, Alexa; Zhang, Susan; Towbin, Kenneth E; Brotman, Melissa A; Pine, Daniel S; Leibenluft, Ellen

2017-05-01

Disruptive mood dysregulation disorder (DMDD), characterized by severe irritability, and attention-deficit/hyperactivity disorder (ADHD) are highly comorbid. This is the first study to characterize neural and behavioral similarities and differences in attentional functioning across these disorders. Twenty-seven healthy volunteers, 31 patients with DMDD, and 25 patients with ADHD (8 to 18 years old) completed a functional magnetic resonance imaging attention task. Group differences in intra-subject variability in reaction time (RT) were examined. The present functional magnetic resonance imaging analytic approach precisely quantified trial-wise associations between RT and brain activity. Group differences manifested in the relation between RT and brain activity (all regions: p  2.54, partial eta-squared [η p 2 ] > 0.06). Patients with DMDD showed specific alterations in the right paracentral lobule, superior parietal lobule, fusiform gyrus, and cerebellar culmen. In contrast, patients with DMDD and those with ADHD exhibited blunted compensatory increases in activity on long RT trials. In addition, youth with DMDD exhibited increased activity in the postcentral gyrus, medial frontal gyrus, and cerebellar tonsil and declive (all regions: p  2.46, η p 2 > 0.06). Groups in the imaging sample did not differ significantly in intra-subject variability in RT (F 2,79  = 2.664, p = .076, η p 2  = 0.063), although intra-subject variability in RT was significantly increased in youth with DMDD and ADHD when including those not meeting strict motion and accuracy criteria for imaging analysis (F 2,96  = 4.283, p = .017, η p 2  = 0.083). Patients with DMDD exhibited specific alterations in the relation between pre-stimulus brain activity and RT. Patients with DMDD and those with ADHD exhibited similar blunting of compensatory neural activity in frontal, parietal, and other regions. In addition, patients with DMDD showed increased RT variability compared with healthy

Liver Fibrosis in HCV Monoinfected and HIV/HCV Coinfected Patients: Dysregulation of Matrix Metalloproteinases (MMPs and Their Tissue Inhibitors TIMPs and Effect of HCV Protease Inhibitors

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Tiziana Latronico

2016-03-01

Full Text Available An imbalance between matrix metalloproteinases (MMPs and tissue inhibitors of metalloproteinases (TIMPs may contribute to liver fibrosis in patients with hepatitis C (HCV infection. We measured the circulating levels of different MMPs and TIMPs in HCV monoinfected and HIV/HCV coinfected patients and evaluated the potential for anti-HCV therapy to modulate MMP and TIMP levels in HCV subjects. We analyzed 83 plasma samples from 16 HCV monoinfected patients undergoing dual or triple anti-HCV therapy, 15 HIV/HCV coinfected patients with undetectable HIV load, and 10 healthy donors (HD. Levels of MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, MMP-10, TIMP-1, and TIMP-2 were measured by a SearchLight Multiplex Immunoassay Kit. MMP-2 and MMP-9 were the highest expressed MMPs among all the analyzed samples and their levels significantly increased in HCV monoinfected and HIV/HCV coinfected subjects compared to HD. TIMP-1 levels were significantly higher in HCV and HIV/HCV subjects compared to HD and were correlated with liver stiffness. These findings raise the possibility of using circulating TIMP-1 as a non-invasive marker of liver fibrosis in HCV infection. A longitudinal study demonstrated that MMP-9 levels significantly decreased (40% reduction from baseline in patients receiving dual as well as triple direct-acting antivirals (DAA anti-HCV therapy, which had no effect on MMP-2, TIMP-1, and TIMP-2. As the dysregulation of MMP-2 and MMP-9 may reflect inflammatory processes in the liver, the decrease of MMP-9 following HCV protease inhibitor treatment suggests a positive effect on the reduction of liver inflammation.

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

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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.,…

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

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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.

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

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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.

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

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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.

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

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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…

[Renal patient's diet: Can fish be included?].

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Castro González, M I; Maafs Rodríguez, A G; Galindo Gómez, C

2012-01-01

Medical and nutritional treatment for renal disease, now a major public health issue, is highly complicated. Nutritional therapy must seek to retard renal dysfunction, maintain an optimal nutritional status and prevent the development of underlying pathologies. To analyze ten fish species to identify those that, because of their low phosphorus content, high biological value protein and elevated n-3 fatty acids EPA and DHA, could be included in renal patient's diet. The following fish species (Litte tunny, Red drum, Spotted eagleray, Escolar, Swordfish, Big-scale pomfret, Cortez flounder, Largemouth blackbass, Periche mojarra, Florida Pompano) were analyzed according to the AOAC and Keller techniques to determine their protein, phosphorus, sodium, potassium, cholesterol, vitamins D(3) and E, and n-3 EPA+DHA content. These results were used to calculate relations between nutrients. The protein in the analyzed species ranged from 16.5 g/100 g of fillet (Largemouth black bass) to 27.2 g/100 g (Red drum); the lowest phosphorus value was 28.6 mg/100 g (Periche mojarra) and the highest 216.3 mg/100 g (Spotted eagle ray). 80% of the fish presented > 100 mg EPA + DHA in 100 g of fillet. By its Phosphorus/gProtein ratio, Escolar and Swordfish could not be included in the renal diet; Little tunny, Escolar, Big-scale pomfret, Largemouth black-bass, Periche mojarra and Florida Pompano presented a lower Phosphorus/EPA + DHA ratio. Florida pompano is the most recommended specie for renal patients, due to its optimal nutrient relations. However, all analyzed species, except Escolar and Swordfish, could be included in renal diets.

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

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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.

Dysregulated mitophagy and mitochondrial organization in optic atrophy due to OPA1 mutations.

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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

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

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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.

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.

Angiogenesis Dysregulation in Term Asphyxiated Newborns Treated with Hypothermia

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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

Angiogenesis dysregulation in term asphyxiated newborns treated with hypothermia.

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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.

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

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Li Z

2017-06-01

Full Text Available Zhen Li,1 Qianlan Yao,1 Songjian Zhao,1 Yin Wang,2,3 Yixue Li,1,4 Zhen Wang4 1School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 2Shanghai Center for Bioinformation Technology, Shanghai Academy of Science and Technology, 3Collaborative Innovation Center for Genetics and Development, Fudan University, 4Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, People’s Republic of China Abstract: Esophageal squamous cell carcinoma (ESCC is one of the most common malignancies worldwide and occurs at a relatively high frequency in People’s Republic of China. However, the molecular mechanism underlying ESCC is still unclear. In this study, the mRNA and long non-coding RNA (lncRNA expression profiles of ESCC were downloaded from the Gene Expression Omnibus database, and then differential co-expression analysis was used to reveal the altered co-expression relationship of gene pairs in ESCC tumors. A total of 3,709 mRNAs and 923 lncRNAs were differentially co-expressed between normal and tumor tissues, and we found that most of the gene pairs lost associations in the tumor tissues. The differential regulatory networking approach deciphered that transcriptional dysregulation was ubiquitous in ESCC, and most of the differentially regulated links were modulated by 37 TFs. Our study also found that two novel lncRNAs (ADAMTS9-AS1 and AP000696.2 might be essential in the development of ectoderm and epithelial cells, which could significantly stratify ESCC patients into high-risk and low-risk groups, and were much better than traditional clinical tumor markers. Further inspection of two risk groups showed that the changes in TF-target regulation in the high-risk patients were significantly higher than those in the low-risk patients. In addition, four signal transduction-related DCmRNAs (ERBB3, ENSA, KCNK7, MFSD5

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.

Effects of intranasal oxytocin on the attentional bias to emotional stimuli in patients with bulimia nervosa.

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Kim, Youl-Ri; Eom, Jin-Sup; Leppanen, Jenni; Leslie, Monica; Treasure, Janet

2018-05-01

Bulimia nervosa (BN) is characterized by binge eating and emotional dysregulation including increased negative affectivity (anger, anxiety). The aim of this study was to examine the effect of oxytocin on attentional processes towards anger in patients with BN. The study design consisted of a double-blind, placebo-controlled within-subject crossover, single dose experiment. Sixty-four women (31 patients with BN and 33 healthy comparisons) completed self-reported measures to evaluate emotional difficulties and were administered a single dose of intranasal oxytocin (40IU) or placebo followed by a visual probe detection task to examine attentional orienting to angry or happy faces. Patients with BN reported higher emotional dysregulation and more difficulties in controlling anger compared to the healthy comparison group. Patients with BN and the healthy women exhibited similar attentional bias to angry faces in the placebo condition. Intranasal oxytocin reduced the attentional bias towards angry faces in both the BN patients and the healthy women. We found that a single dose of oxytocin reduced vigilance towards angry faces in patients with BN as well as healthy women. The results showed that patients with BN are not different from healthy women in terms of vigilance towards threat. Copyright © 2018 Elsevier Ltd. All rights reserved.

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

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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.…

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

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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.

Decreased DGCR8 expression and miRNA dysregulation in individuals with 22q11.2 deletion syndrome.

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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.

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

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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.

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.

Dysregulated CD46 shedding interferes with Th1-contraction in systemic lupus erythematosus.

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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.

Dysregulation of TGFβ1 Activity in Cancer and Its Influence on the Quality of Anti-Tumor Immunity

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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.

Complex phenotype of dyskeratosis congenita and mood dysregulation with novel homozygous RTEL1 and TPH1 variants.

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Ungar, Rachel A; Giri, Neelam; Pao, Maryland; Khincha, Payal P; Zhou, Weiyin; Alter, Blanche P; Savage, Sharon A

2018-06-01

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome caused by germline mutations in telomere biology genes. Patients have extremely short telomeres for their age and a complex phenotype including oral leukoplakia, abnormal skin pigmentation, and dysplastic nails in addition to bone marrow failure, pulmonary fibrosis, stenosis of the esophagus, lacrimal ducts and urethra, developmental anomalies, and high risk of cancer. We evaluated a patient with features of DC, mood dysregulation, diabetes, and lack of pubertal development. Family history was not available but genome-wide genotyping was consistent with consanguinity. Whole exome sequencing identified 82 variants of interest in 80 genes based on the following criteria: homozygous, <0.1% minor allele frequency in public and in-house databases, nonsynonymous, and predicted deleterious by multiple in silico prediction programs. Six genes were identified likely contributory to the clinical presentation. The cause of DC is likely due to homozygous splice site variants in regulator of telomere elongation helicase 1, a known DC and telomere biology gene. A homozygous, missense variant in tryptophan hydroxylase 1 may be clinically important as this gene encodes the rate limiting step in serotonin biosynthesis, a biologic pathway connected with mood disorders. Four additional genes (SCN4A, LRP4, GDAP1L1, and SPTBN5) had rare, missense homozygous variants that we speculate may contribute to portions of the clinical phenotype. This case illustrates the value of conducting detailed clinical and genomic evaluations on rare patients in order to identify new areas of research into the functional consequences of rare variants and their contribution to human disease. © 2018 Wiley Periodicals, Inc.

Treatment responses in adult depressive patients treated with ...

African Journals Online (AJOL)

with dexamethasone/corticotrophin-releasing hormone. Lina Zhang1*, Yanbo Chen2, ... Keywords: stress, depressive patients, hormonal response, hormonal dysregulation, sertraline, ..... interactions in depression: will cause inform cure. Mol.

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

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

Depressive Symptoms, Emotion Dysregulation, and Bulimic Symptoms in Youth With Type 1 Diabetes: Varying Interactions at Diagnosis and During Transition to Insulin Pump Therapy.

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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.

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

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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.

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

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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.

Typical patterns of disordered eating among Swedish adolescents: associations with emotion dysregulation, depression, and self-esteem.

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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

Patients with carcinoid syndrome exhibit symptoms of aggressive impulse dysregulation

NARCIS (Netherlands)

Russo, S; Boon, JC; Kema, IP; Willemse, PHB; den Boer, JA; Korf, J; de Vries, EGE

2004-01-01

Objective: Carcinoid tumors can produce excessive amounts of biogenic amines, notably serotonin. We assessed psychiatric symptoms in carcinoid patients and peripheral metabolism of tryptophan, the precursor of serotonin. Methods: Twenty consecutive patients with carcinoid syndrome underwent a

A splice donor mutation in NAA10 results in the dysregulation of the retinoic acid signaling pathway and causes Lenz microphthalmia syndrome

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Esmailpour, Taraneh; Riazifar, Hamidreza; Liu, Linan; Donkervoort, Sandra; Huang, Vincent H; Madaan, Shreshtha; Shoucri, Bassem M; Busch, Anke; Wu, Jie; Towbin, Alexander; Chadwick, Robert B; Sequeira, Adolfo; Vawter, Marquis P; Sun, Guoli; Johnston, Jennifer J; Biesecker, Leslie G; Kawaguchi, Riki; Sun, Hui; Kimonis, Virginia; Huang, Taosheng

2014-01-01

Introduction Lenz microphthalmia syndrome (LMS) is a genetically heterogeneous X-linked disorder characterised by microphthalmia/anophthalmia, skeletal abnormalities, genitourinary malformations, and anomalies of the digits, ears, and teeth. Intellectual disability and seizure disorders are seen in about 60% of affected males. To date, no gene has been identified for LMS in the microphthalmia syndrome 1 locus (MCOPS1). In this study, we aim to find the disease-causing gene for this condition. Methods and results Using exome sequencing in a family with three affected brothers, we identified a mutation in the intron 7 splice donor site (c.471+2T→A) of the N-acetyltransferase NAA10 gene. NAA10 has been previously shown to be mutated in patients with Ogden syndrome, which is clinically distinct from LMS. Linkage studies for this family mapped the disease locus to Xq27-Xq28, which was consistent with the locus of NAA10. The mutation co-segregated with the phenotype and cDNA analysis showed aberrant transcripts. Patient fibroblasts lacked expression of full length NAA10 protein and displayed cell proliferation defects. Expression array studies showed significant dysregulation of genes associated with genetic forms of anophthalmia such as BMP4, STRA6, and downstream targets of BCOR and the canonical WNT pathway. In particular, STRA6 is a retinol binding protein receptor that mediates cellular uptake of retinol/vitamin A and plays a major role in regulating the retinoic acid signalling pathway. A retinol uptake assay showed that retinol uptake was decreased in patient cells. Conclusions We conclude that the NAA10 mutation is the cause of LMS in this family, likely through the dysregulation of the retinoic acid signalling pathway. PMID:24431331

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

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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…

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

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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…

Plasma kynurenine and related measures in tic disorder patients

NARCIS (Netherlands)

Hoekstra, Pieter J.; Anderson, George M.; Troost, Pieter W.; Kallenberg, Cees G. M.; Minderaa, Ruud B.

Objective Increased plasma kynurenine has been reported in tic disorder patients, and this observation has been suggested to be indicative of immune dysregulation. In the present study, we examined plasma levels of kynurenine and related molecules in a group of tic disorder patients. Methods Plasma

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

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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)…

How Parkinsonian Toxins Dysregulate the Autophagy Machinery

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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.

Glutamate Receptors in the Central Nucleus of the Amygdala Mediate Cisplatin-Induced Malaise and Energy Balance Dysregulation through Direct Hindbrain Projections.

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Alhadeff, Amber L; Holland, Ruby A; Nelson, Alexandra; Grill, Harvey J; De Jonghe, Bart C

2015-08-05

Cisplatin chemotherapy is used commonly to treat a variety of cancers despite severe side effects such as nausea, vomiting, and anorexia that compromise quality of life and limit treatment adherence. The neural mechanisms mediating these side effects remain elusive despite decades of clinical use. Recent data highlight the dorsal vagal complex (DVC), lateral parabrachial nucleus (lPBN), and central nucleus of the amygdala (CeA) as potential sites of action in mediating the side effects of cisplatin. Here, results from immunohistochemical studies in rats identified a population of cisplatin-activated DVC neurons that project to the lPBN and a population of cisplatin-activated lPBN calcitonin gene-related peptide (CGRP, a marker for glutamatergic neurons in the lPBN) neurons that project to the CeA, outlining a neuroanatomical circuit that is activated by cisplatin. CeA gene expressions of AMPA and NMDA glutamate receptor subunits were markedly increased after cisplatin treatment, suggesting that CeA glutamate receptor signaling plays a role in mediating cisplatin side effects. Consistent with gene expression results, behavioral/pharmacological data showed that CeA AMPA/kainate receptor blockade attenuates cisplatin-induced pica (a proxy for nausea/behavioral malaise in nonvomiting laboratory rodents) and that CeA NMDA receptor blockade attenuates cisplatin-induced anorexia and body weight loss in addition to pica, demonstrating that glutamate receptor signaling in the CeA is critical for the energy balance dysregulation caused by cisplatin treatment. Together, these data highlight a novel circuit and CGRP/glutamatergic mechanism through which cisplatin-induced malaise and energy balance dysregulation are mediated. To treat cancer effectively, patients must follow prescribed chemotherapy treatments without interruption, yet most cancer treatments produce side effects that devastate quality of life (e.g., nausea, vomiting, anorexia, weight loss). Although hundreds of

Glutamate Receptors in the Central Nucleus of the Amygdala Mediate Cisplatin-Induced Malaise and Energy Balance Dysregulation through Direct Hindbrain Projections

Science.gov (United States)

Alhadeff, Amber L.; Holland, Ruby A.; Nelson, Alexandra; Grill, Harvey J.

2015-01-01

Cisplatin chemotherapy is used commonly to treat a variety of cancers despite severe side effects such as nausea, vomiting, and anorexia that compromise quality of life and limit treatment adherence. The neural mechanisms mediating these side effects remain elusive despite decades of clinical use. Recent data highlight the dorsal vagal complex (DVC), lateral parabrachial nucleus (lPBN), and central nucleus of the amygdala (CeA) as potential sites of action in mediating the side effects of cisplatin. Here, results from immunohistochemical studies in rats identified a population of cisplatin-activated DVC neurons that project to the lPBN and a population of cisplatin-activated lPBN calcitonin gene-related peptide (CGRP, a marker for glutamatergic neurons in the lPBN) neurons that project to the CeA, outlining a neuroanatomical circuit that is activated by cisplatin. CeA gene expressions of AMPA and NMDA glutamate receptor subunits were markedly increased after cisplatin treatment, suggesting that CeA glutamate receptor signaling plays a role in mediating cisplatin side effects. Consistent with gene expression results, behavioral/pharmacological data showed that CeA AMPA/kainate receptor blockade attenuates cisplatin-induced pica (a proxy for nausea/behavioral malaise in nonvomiting laboratory rodents) and that CeA NMDA receptor blockade attenuates cisplatin-induced anorexia and body weight loss in addition to pica, demonstrating that glutamate receptor signaling in the CeA is critical for the energy balance dysregulation caused by cisplatin treatment. Together, these data highlight a novel circuit and CGRP/glutamatergic mechanism through which cisplatin-induced malaise and energy balance dysregulation are mediated. SIGNIFICANCE STATEMENT To treat cancer effectively, patients must follow prescribed chemotherapy treatments without interruption, yet most cancer treatments produce side effects that devastate quality of life (e.g., nausea, vomiting, anorexia, weight loss

Indoxyl Sulfate as a Mediator Involved in Dysregulation of Pulmonary Aquaporin-5 in Acute Lung Injury Caused by Acute Kidney Injury

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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.

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

Salivary cortisol in depressed patients versus control persons

DEFF Research Database (Denmark)

Knorr, Ulla; Vinberg, Maj; Kessing, Lars V

2010-01-01

The pathophysiology of depression has been associated to dysregulation of the hypothalamic-pituitary-adrenal axis and the use of salivary cortisol measures is increasingly being incorporated into research. The aim of the present study was to investigate whether salivary cortisol differs...... for patients with depression and control persons. We did a systematic review with sequential meta-analysis and meta-regression according to the PRISMA Statement based on comprehensive database searches for studies of depressed patients compared to control persons in whom salivary cortisol was measured. Twenty...... case-control studies, including 1354 patients with depression and 1052 control persons were identified. In a random-effects meta-analysis salivary cortisol was increased for depressed patients as compared to control persons on average 2.58 nmol/l (95% C.I.: 0.95-4.21) p=0.002 in the morning...

Dysregulated RNA-Induced Silencing Complex (RISC) Assembly within CNS Corresponds with Abnormal miRNA Expression during Autoimmune Demyelination.

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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.

Dysregulated LIF-STAT3 pathway is responsible for impaired embryo implantation in a Streptozotocin-induced diabetic mouse model

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Tong-Song Wang

2015-07-01

Full Text Available The prevalence of diabetes is increasing worldwide with the trend of patients being young and creating a significant burden on health systems, including reproductive problems, but the effects of diabetes on embryo implantation are still poorly understood. Our study was to examine effects of diabetes on mouse embryo implantation, providing experimental basis for treating diabetes and its complications. Streptozotocin (STZ was applied to induce type 1 diabetes from day 2 of pregnancy or pseudopregnancy in mice. Embryo transfer was used to analyze effects of uterine environment on embryo implantation. Our results revealed that the implantation rate is significantly reduced in diabetic mice compared to controls, and the change of uterine environment is the main reason leading to the decreased implantation rate. Compared to control, the levels of LIF and p-STAT3 are significantly decreased in diabetic mice on day 4 of pregnancy, and serum estrogen level is significantly higher. Estrogen stimulates LIF expression under physiological level, but the excessive estrogen inhibits LIF expression. LIF, progesterone or insulin supplement can rescue embryo implantation in diabetic mice. Our data indicated that the dysregulated LIF-STAT3 pathway caused by the high level of estrogen results in the impaired implantation in diabetic mice, which can be rescued by LIF, progesterone or insulin supplement.

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

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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

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

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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…

Dysregulated choline metabolism in T-cell lymphoma: role of choline kinase-α and therapeutic targeting

International Nuclear Information System (INIS)

Xiong, J; Bian, J; Wang, L; Zhou, J-Y; Wang, Y; Zhao, Y; Wu, L-L; Hu, J-J; Li, B; Chen, S-J; Yan, C; Zhao, W-L

2015-01-01

Cancer cells have distinct metabolomic profile. Metabolic enzymes regulate key oncogenic signaling pathways and have an essential role on tumor progression. Here, serum metabolomic analysis was performed in 45 patients with T-cell lymphoma (TCL) and 50 healthy volunteers. The results showed that dysregulation of choline metabolism occurred in TCL and was related to tumor cell overexpression of choline kinase-α (Chokα). In T-lymphoma cells, pharmacological and molecular silencing of Chokα significantly decreased Ras-GTP activity, AKT and ERK phosphorylation and MYC oncoprotein expression, leading to restoration of choline metabolites and induction of tumor cell apoptosis/necropotosis. In a T-lymphoma xenograft murine model, Chokα inhibitor CK37 remarkably retarded tumor growth, suppressed Ras-AKT/ERK signaling, increased lysophosphatidylcholine levels and induced in situ cell apoptosis/necropotosis. Collectively, as a regulatory gene of aberrant choline metabolism, Chokα possessed oncogenic activity and could be a potential therapeutic target in TCL, as well as other hematological malignancies with interrupted Ras signaling pathways

Steroid dysregulation and stomatodynia (burning mouth syndrome).

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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.

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

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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…

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

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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)

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

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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.

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

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.

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.

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

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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…

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.

An evaluation of anxiety sensitivity, emotional dysregulation, and negative affectivity among daily cigarette smokers: relation to smoking motives and barriers to quitting.

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Gonzalez, Adam; Zvolensky, Michael J; Vujanovic, Anka A; Leyro, Teresa M; Marshall, Erin C

2008-12-01

The present investigation evaluated the relations between anxiety sensitivity and motivational bases of cigarette smoking, as well as barriers to quitting smoking, above and beyond concurrent substance use, negative affectivity, and emotional dysregulation among a community sample of 189 daily cigarette smokers (46% women; M(age)=24.97 years, SD=9.78). Results indicated that anxiety sensitivity was significantly related to coping, addictive, and habitual smoking motives, as well as greater perceived barriers to quitting. These effects were evident above and beyond the variance accounted for by concurrent tobacco, alcohol, and marijuana use and discernable from shared variance with negative affectivity and emotional dysregulation. Emotional dysregulation was significantly related to stimulation, habitual, and sensorimotor smoking motives and greater perceived barriers to quitting, whereas negative affectivity was only significantly related to smoking for relaxation. These findings uniquely add to a growing literature suggesting anxiety sensitivity is an important and unique cognitive factor for better understanding clinically-relevant psychological processes related to cigarette smoking.

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...

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

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.

Life Goals Increase Self-regulation Among Male Patients with Alcohol Use Disorder.

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Won, Sung-Doo; Kim, Im-Yel

2018-01-24

Alcohol use disorder (AUD) has been conceptualized as a chronic self-regulation failure. The aim of this study was to examine the most probable pathways related to self-regulation among patients with AUD. In this study, a hypothetical model was proposed that focused on the relationship between risk factors (extrinsic life goals, emotion dysregulation) and protective factors (intrinsic life goals, self-control, and abstinence self-efficacy). Male patients with AUD (N = 188) were recruited from alcohol centers of four psychiatric hospitals between March 2015 and September 2015. All participants completed psychological assessments, including the Future Oriented Goals Scale (FOGS), the Alcohol Abstinence Self-Efficacy Scale (AASE), the Brief Self-Control Scale (BSCS), and the Difficulties in Emotion Regulation Scale (DERS) as well as sociodemographic characteristics. The final model was found to be a good fit to data. In testing indirect effects, it was shown that intrinsic life goals via emotion dysregulation, self-control, and alcohol abstinence self-efficacy decreased alcohol self-regulation failure. On the other hand, extrinsic life goals via these factors increased alcohol self-regulation failure. Conclusions/Importance: These results suggest that intrinsic goals might indirectly be the important and protective factors for AUD. Moreover, the findings implicate that self-regulation through goal setting may be necessary to alleviate symptoms and improve function among patients with AUD.

Renal filtration function in patients with gout

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N. N. Kushnarenko

2016-01-01

Full Text Available Aim. To study circadian blood pressure (BP profile in patients with gout depending on the presence of arterial hypertension (HT and their relationship to the renal filtration function.Material and methods. Patients with gout (n=87 were included into the study. All the patients underwent ambulatory BP monitoring (ABPM with the assessment of circadian BP profile, determination of uric acid serum levels, glomerular filtration rate (GFR was evaluated by CKD-EPI method. Depending on GFR level, all the patients were divided into 2 groups - with renal dysfunction or without one.Results. ABPM revealed circadian BP dysregulation in 55% of gout patients both with HT and without HT. Chronic kidney disease (CKD was revealed in 72.4% of male patients, with the prevalence in patients with HT (76.6 vs 61%; p<0.001. Correlations between uric acid levels and some ABPM indicators and GFR were determined.Conclusion. Obtained data suggest the contribution of hyperuricemia in disorders of systemic and renal hemodynamics, leading to the early development of CKD.

Dysregulation of the Bmi-1/p16Ink4a pathway provokes an aging-associated decline of submandibular gland function

Science.gov (United States)

Yamakoshi, Kimi; Katano, Satoshi; Iida, Mayu; Kimura, Hiromi; Okuma, Atsushi; Ikemoto-Uezumi, Madoka; Ohtani, Naoko; Hara, Eiji; Maruyama, Mitsuo

2015-01-01

Bmi-1 prevents stem cell aging, at least partly, by blocking expression of the cyclin-dependent kinase inhibitor p16Ink4a. Therefore, dysregulation of the Bmi-1/p16Ink4a pathway is considered key to the loss of tissue homeostasis and development of associated degenerative diseases during aging. However, because Bmi-1 knockout (KO) mice die within 20 weeks after birth, it is difficult to determine exactly where and when dysregulation of the Bmi-1/p16Ink4a pathway occurs during aging in vivo. Using real-time in vivo imaging of p16Ink4a expression in Bmi-1-KO mice, we uncovered a novel function of the Bmi-1/p16Ink4a pathway in controlling homeostasis of the submandibular glands (SMGs), which secrete saliva into the oral cavity. This pathway is dysregulated during aging in vivo, leading to induction of p16Ink4a expression and subsequent declined SMG function. These findings will advance our understanding of the molecular mechanisms underlying the aging-related decline of SMG function and associated salivary gland hypofunction, which is particularly problematic among the elderly. PMID:25832744

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.

Including patients’ perspectives in patient information leaflets: A polyocular approach

DEFF Research Database (Denmark)

Fage-Butler, Antoinette Mary

2013-01-01

Existing research reveals that patients’ perspectives are missing from mandatory patient information leaflets (PILs). At the same time, there is overwhelming consensus that they should be included in this genre, and a corresponding need for potential approaches to tackle this problem. This paper ...

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

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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…

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....

Different proliferative capacity of lung fibroblasts obtained from control subjects and patients with emphysema

NARCIS (Netherlands)

Noordhoek, JA; Postma, DS; Chong, LL; Vos, JTWM; Kauffman, HF; Timens, W; van Straaten, JFM

2003-01-01

To characterize the possible role of a dysregulated proliferative capacity of pulmonary fibroblasts in insufficient tissue repair in lungs from patients with pulmonary emphysema, the authors undertook in vitro proliferative studies with pulmonary fibroblasts obtained from lung tissue of patients

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.

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

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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…

Effects of Food Additives on Immune Cells As Contributors to Body Weight Gain and Immune-Mediated Metabolic Dysregulation.

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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.

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.

Eyeball pressure stimulation induces subtle sympathetic activation in patients with a history of moderate or severe traumatic brain injury.

Science.gov (United States)

Wang, Ruihao; Hösl, Katharina M; Ammon, Fabian; Markus, Jörg; Koehn, Julia; Roy, Sankanika; Liu, Mao; de Rojas Leal, Carmen; Muresanu, Dafin; Flanagan, Steven R; Hilz, Max J

2018-06-01

After traumatic brain injury (TBI), there may be persistent central-autonomic-network (CAN) dysfunction causing cardiovascular-autonomic dysregulation. Eyeball-pressure-stimulation (EPS) normally induces cardiovagal activation. In patients with a history of moderate or severe TBI (post-moderate-severe-TBI), we determined whether EPS unveils cardiovascular-autonomic dysregulation. In 51 post-moderate-severe-TBI patients (32.7 ± 10.5 years old, 43.1 ± 33.4 months post-injury), and 30 controls (29.1 ± 9.8 years), we recorded respiration, RR-intervals (RRI), systolic and diastolic blood-pressure (BPsys, BPdia), before and during EPS (120 sec; 30 mmHg), using an ocular-pressure-device (Okulopressor®). We calculated spectral-powers of mainly sympathetic low (LF: 0.04-0.15 Hz) and parasympathetic high (HF: 0.15-0.5 Hz) frequency RRI-fluctuations, sympathetically mediated LF-powers of BPsys, and calculated normalized (nu) LF- and HF-powers of RRI. We compared parameters between groups before and during EPS by repeated-measurement-analysis-of-variance with post-hoc analysis (significance: p < 0.05). At rest, sympathetically mediated LF-BPsys-powers were significantly lower in the patients than the controls. During EPS, only controls significantly increased RRIs and parasympathetically mediated HFnu-RRI-powers, but decreased LF-RRI-powers, LFnu-RRI-powers, and LF-BPsys-powers; in contrast, the patients slightly though significantly increased BPsys upon EPS, without changing any other parameter. In post-moderate-severe-TBI patients, autonomic BP-modulation was already compromised at rest. During EPS, our patients failed to activate cardiovagal modulation but slightly increased BPsys, indicating persistent CAN dysregulation. Our findings unveil persistence of subtle cardiovascular-autonomic dysregulation even years after TBI. Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

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.

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

Emotional Dysregulation in Adults With Attention-Deficit/Hyperactivity Disorder-Validity, Predictability, Severity, and Comorbidity.

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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.

DSM-5 intermittent explosive disorder: Relationship with Disruptive Mood Dysregulation Disorder.

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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.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): Response to ventilatory challenges.

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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.

Cytokine-Mediated Loss of Blood Dendritic Cells During Epstein-Barr Virus-Associated Acute Infectious Mononucleosis: Implication for Immune Dysregulation.

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Panikkar, Archana; Smith, Corey; Hislop, Andrew; Tellam, Nick; Dasari, Vijayendra; Hogquist, Kristin A; Wykes, Michelle; Moss, Denis J; Rickinson, Alan; Balfour, Henry H; Khanna, Rajiv

2015-12-15

Acute infectious mononucleosis (IM) is associated with altered expression of inflammatory cytokines and disturbed T-cell homeostasis, however, the precise mechanism of this immune dysregulation remains unresolved. In the current study we demonstrated a significant loss of circulating myeloid and plasmacytoid dendritic cells (DCs) during acute IM, a loss correlated with the severity of clinical symptoms. In vitro exposure of blood DCs to acute IM plasma resulted in loss of plasmacytoid DCs, and further studies with individual cytokines showed that exposure to interleukin 10 could replicate this effect. Our data provide important mechanistic insight into dysregulated immune homeostasis during acute IM. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome may have a hypothalamus-periaqueductal gray localization.

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Chow, Cristelle; Fortier, Marielle Valerie; Das, Lena; Menon, Anuradha P; Vasanwala, Rashida; Lam, Joyce C M; Ng, Zhi Min; Ling, Simon Robert; Chan, Derrick W S; Choong, Chew Thye; Liew, Wendy K M; Thomas, Terrence

2015-05-01

Anatomical localization of the rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome has proved elusive. Most patients had neuroimaging after cardiorespiratory collapse, revealing a range of ischemic lesions. A 15-year-old obese boy with an acute febrile encephalopathy had hypoventilation, autonomic dysfunction, visual hallucinations, hyperekplexia, and disordered body temperature, and saltwater regulation. These features describe the ROHHAD syndrome. Cerebrospinal fluid analysis showed pleocytosis, elevated neopterins, and oligoclonal bands, and serology for systemic and antineuronal antibodies was negative. He improved after receiving intravenous steroids, immunoglobulins, and long-term mycophenolate. Screening for neural crest tumors was negative. Magnetic resonance imaging of the brain early in his illness showed focal inflammation in the periaqueductal gray matter and hypothalamus. This unique localization explains almost all symptoms of this rare autoimmune encephalitis. Copyright © 2015 Elsevier Inc. All rights reserved.

Reactivation of adiponectin expression in obese patients after bariatric surgery.

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Hindle, A Katharine; Edwards, Claire; McCaffrey, Tim; Fu, Sidney W; Brody, Fred

2010-06-01

Bariatric surgery can resolve type 2 diabetes in morbidly obese patients. However, the underlying mechanism is unknown. This study aimed to identify potential biomarkers or molecular pathways that are altered after bariatric surgery in diabetic and nondiabetic patients. The study enrolled 17 morbidly obese patients undergoing bariatric surgery. Eight of the patients were diabetic, and nine were nondiabetic. In addition, a control group of four nonobese, nondiabetic volunteers was included. Patient blood samples were drawn before and after the operation. All blood samples were stabilized in Paxgene tubes (PreAnalytix). Total RNA was extracted and purified using the Paxgene Blood RNA Kit. For each sample, 100 ng of total RNA was amplified and labeled using the Ovation RNA Amplification System V2 with the Ovation Whole Blood reagent before hybridization to an Affymetrix Focus array containing more than 8,500 verified genes. Microarray results were analyzed with the GeneSpring GX 10.0 program, which uses an analysis of variance (ANOVA), and verified with real-time quantitative polymerase chain reaction (QPCR) using SYBR green (ABI). Microarray analysis showed that 167 genes were upregulated and 39 were downregulated in the obese diabetic patients. Preoperatively, adiponectin was downregulated 1.5-fold in diabetic versus nondiabetic patients. This was confirmed with quantitative PCR analysis. Preoperatively, morbidly obese patients showed a 3.12-fold downregulation of adiponectin expression versus the control group (p = 0.05). Interestingly, postoperative adiponectin levels were upregulated 2.79-fold (p = 0.02), which is close to the level of the normal control group. Adiponectin is dysregulated in obese patients and significantly dysregulated in obese diabetic patients. These findings correlate with the association between low levels of adiponectin and a predisposition to insulin resistance or diabetes. The data suggest that reactivation of adiponectin expression may

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.

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...

Emotional self-control and dysregulation: A dual-process analysis of pathways to externalizing/internalizing symptomatology and positive well-being in younger adolescents.

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Wills, Thomas A; Simons, Jeffrey S; Sussman, Steve; Knight, Rebecca

2016-06-01

There is little knowledge about how emotional regulation contributes to vulnerability versus resilience to substance use disorder. With younger adolescents, we studied the pathways through which emotion regulation attributes are related to predisposing factors for disorder. A sample of 3561 adolescents (M age 12.5 years) was surveyed. Measures for emotional self-control (regulation of sadness and anger), emotional dysregulation (angerability, affective lability, and rumination about sadness or anger), and behavioral self-control (planfulness and problem solving) were obtained. A structural model was analyzed with regulation attributes related to six intermediate variables that are established risk or protective factors for adolescent substance use (e.g., academic involvement, stressful life events). Criterion variables were externalizing and internalizing symptomatology and positive well-being. Indirect pathways were found from emotional regulation to symptomatology through academic competence, stressful events, and deviance-prone attitudes and cognitions. Direct effects were also found: from emotional dysregulation to externalizing and internalizing symptomatology; emotional self-control to well-being; and behavioral self-control (inverse) to externalizing symptomatology. Emotional self-control and emotional dysregulation had independent effects and different types of pathways. Adolescents scoring high on emotional dysregulation are at risk for substance dependence because of more externalizing and internalizing symptomatology. Independently, youth with better behavioral and emotional self-control are at lower risk. This occurs partly through relations of regulation constructs to environmental variables that affect levels of symptomatology (e.g., stressful events, poor academic performance). Effects of emotion regulation were found at an early age, before the typical onset of substance disorder. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd

Effects of Food Additives on Immune Cells As Contributors to Body Weight Gain and Immune-Mediated Metabolic Dysregulation

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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.

Serum oxidative-anti-oxidative stress balance is dysregulated in patients with hepatitis C virus-related hepatocellular carcinoma.

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Nishimura, Mamoru; Takaki, Akinobu; Tamaki, Naofumi; Maruyama, Takayuki; Onishi, Hideki; Kobayashi, Sayo; Nouso, Kazuhiro; Yasunaka, Tetsuya; Koike, Kazuko; Hagihara, Hiroaki; Kuwaki, Kenji; Nakamura, Shinichiro; Ikeda, Fusao; Iwasaki, Yoshiaki; Tomofuji, Takaaki; Morita, Manabu; Yamamoto, Kazuhide

2013-10-01

Oxidative stress is associated with progression of chronic liver disease (CLD). This association is best established in chronic hepatitis C. However, the anti-oxidative state is not well characterized. The objective of the present study was to investigate the balance of oxidative and anti-oxidative stress in CLD patients. We recruited a study population of 208 patients, including healthy volunteers (HV; n = 15), patients with hepatitis B virus (HBV)-related CLD without or with hepatocellular carcinoma (HBV-non-HCC, n = 25, and HBV-HCC, n = 50, respectively), and patients with hepatitis C virus (HCV)-related CLD without or with HCC (HCV-non-HCC, n = 49, and HCV-HCC, n = 69, respectively). Serum levels of reactive oxygen metabolites (ROM) and anti-oxidative markers (OXY-adsorbent test; OXY) were determined, and the balance of these values was used as the oxidative index. Correlations among ROM, OXY, oxidative index and clinical characteristics were investigated. Patients with CLD exhibited elevated ROM and oxidative index compared to HV. Among patients with CLD, HCV positive status correlated with increased ROM. In CLD, HCV-HCC patients exhibited the highest ROM levels. Among HCV-related CLD patients, lower OXY correlated with HCC positive status, but was recovered by eradication of HCC. In HCV-HCC, lower OXY correlated with high PT-INR. HCV positive CLD patients displayed higher oxidative stress and HCV-HCC patients displayed lower anti-oxidative state. Anti-oxidative state depression was associated with liver reservoir-related data in HCV-HCC and could be reversed with HCC eradication. © 2012 The Japan Society of Hepatology.

Orthostatic Dysregulation during Postural Change on the Dental Chair and Intraoperative Monitoring by Heart Rate Variability Analysis

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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.

Influence of the hypothalamic-pituitary-adrenal axis dysregulation on the metabolic profile of patients affected by diabetes mellitus-associated late onset hypogonadism.

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Tirabassi, G; Chelli, F M; Ciommi, M; Lenzi, A; Balercia, G

2016-01-01

Functional hypercortisolism (FH) is generated by clinical states able to chronically activate the hypothalamic-pituitary-adrenal (HPA) axis [e.g. diabetes mellitus (DM)]. No study has evaluated FH influence in worsening the metabolic profile of male patients affected by DM-associated hypogonadism. In this retrospective work, we assess the possible association between HPA axis-dysregulation and cardiovascular risk factors in men simultaneously affected by DM and late-onset hypogonadism (LOH). Fourteen DM and LOH subjects affected by FH (Hypercort-DM-LOH) and fourteen DM and LOH subjects who were not suffering from FH (Normocort-DM-LOH) were retrospectively considered. Clinical, hormonal and metabolic parameters were retrieved. All metabolic parameters, except for systolic blood pressure, were significantly worse in Hypercort-DM-LOH than in Normocort-DM-LOH. After adjustment for body mass index, waist and total testosterone, Hypercort-DM-LOH subjects showed significantly worse metabolic parameters than Normocort-DM-LOH ones. In Normocort-DM-LOH, no significant correlation between general/hormonal parameters and metabolic variables was present. In Hypercort-DM-LOH, positive and significant correlations of cortisol area under the curve (AUC) after corticotropin releasing hormone with glycemia, triglycerides and blood pressure were evident; on the other hand, negative and significant correlation was present between cortisol AUC and high density lipoprotein (HDL) cholesterol. The associations of AUC cortisol with glycemia, HDL cholesterol and diastolic blood pressure (DBP) were further confirmed at quantile regression after adjustment for therapy. FH may determine a worsening of the metabolic profile in DM-associated hypogonadism. Copyright © 2015 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by

International collaboration including patients is essential to develop new therapies for patients with myositis.

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Lundberg, Ingrid E; Vencovsky, Jiri

2017-05-01

To discuss the needs for international collaborations between investigators in different disciplines working with myositis and with patients with myositis. Recent advances in detection of several myositis-specific autoantibodies that are associated with distinct clinical phenotypes, will enable studies in new well defined clinically homogenous subgroups of myositis This is likely to lead to development of new information on molecular pathogenesis that might be different in different myositis subgroups. Subgrouping patients according to autoantibody profile may also be important to assess outcome, to identify prognostic biomarkers and in clinical trials. As these are rare disorders international collaboration is essential to enrol large enough cohorts of the subgroups. To facilitate such collaboration we have developed a web-based international myositis register, www.euromyositis.eu, which includes validated outcome measures and patient reported outcome measures. This register is to support research but also to support decision-making in the clinic. We welcome investigators to join the Euromyositis register. Myositis is a heterogeneous disorder with varying treatment response and outcome. There is a high unmet need for new therapies which can only be achieved by increased knowledge on molecular disease mechanisms. Subgrouping patients according to autoantibody profile may be a new way forward to get a better understanding on disease mechanisms and to develop novel therapies.

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

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.

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.

Cerebrospinal fluid hypocretin 1 deficiency, overweight, and metabolic dysregulation in patients with narcolepsy.

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Heier, Mona S; Jansson, Tine S; Gautvik, Kaare M

2011-12-15

The possible relationship between cerebrospinal fluid (CSF) hypocretin and leptin levels, overweight, and association to risk factors for diabetes 2 in narcolepsy with cataplexy were compared to patients with idiopathic hypersomnia and controls. 26 patients with narcolepsy, cataplexy, and hypocretin deficiency; 23 patients with narcolepsy, cataplexy, and normal hypocretin values; 11 patients with idiopathic hypersomnia; and 43 controls. Body mass index (BMI), serum leptin, and HbA1C were measured in patients and controls; and CSF hypocretin 1 and leptin measured in all patients. Female and male patients with narcolepsy and hypocretin deficiency had the highest mean BMI (27.8 and 26.2, respectively), not statistically different from patients with narcolepsy and normal hypocretin or controls, but statistically higher than the patients with idiopathic hypersomnia (p 30) was increased in both narcolepsy groups. Serum and CSF leptin levels correlated positively to BMI in patients and controls, but not to CSF hypocretin concentrations. HbA1C was within normal levels and similar in all groups. The study confirms a moderate tendency to obesity (BMI > 30) and overweight in patients with narcolepsy and cataplexy. Obesity was not correlated to hypocretin deficiency or reduced serum or CSF leptin concentrations. We suggest that overweight and possible metabolic changes previously reported in narcolepsy, may be caused by other mechanisms.

Whole body MRI, including diffusion-weighted imaging in follow-up of patients with testicular cancer.

Science.gov (United States)

Mosavi, Firas; Laurell, Anna; Ahlström, Håkan

2015-11-01

Whole body (WB) magnetic resonance imaging (MRI), including diffusion-weighted imaging (DWI) has become increasingly utilized in cancer imaging, yet the clinical utility of these techniques in follow-up of testicular cancer patients has not been evaluated. The purpose of this study was to evaluate the feasibility of WB MRI with continuous table movement (CTM) technique, including multistep DWI in follow-up of patients with testicular cancer. WB MRI including DWI was performed in follow-up of 71 consecutive patients (median age, 37 years; range 19-84) with histologically confirmed testicular cancer. WB MRI protocol included axial T1-Dixon and T2-BLADE sequences using CTM technique. Furthermore, multi-step DWI was performed using b-value 50 and 1000 s/mm(2). One criterion for feasibility was patient tolerance and satisfactory image quality. Another criterion was the accuracy in detection of any pathological mass, compared to standard of reference. Signal intensity in DWI was used for evaluation of residual mass activity. Clinical, laboratory and imaging follow-up were applied as standard of reference for the evaluation of WB MRI. WB MRI was tolerated in nearly all patients (69/71 patients, 97%) and the image quality was satisfactory. Metal artifacts deteriorated the image quality in six patients, but it did not influence the overall results. No case of clinical relapse was observed during the follow-up time. There was a good agreement between conventional WB MRI and standard of reference in all patients. Three patients showed residual masses and DWI signal was not restricted in these patients. Furthermore, DWI showed abnormally high signal intensity in a normal-sized retroperitoneal lymph node indicating metastasis. The subsequent (18)F-FDG PET/CT could verify the finding. WB MRI with CTM technique including multi-step DWI is feasible in follow-up of patients with testicular cancer. DWI may contribute to important added-value data to conventional MRI sequences

Epigenetic mechanism of maternal post-traumatic stress disorder in delayed rat offspring development: dysregulation of methylation and gene expression.

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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.

Bringing Value-Based Perspectives to Care: Including Patient and Family Members in Decision-Making Processes

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Graeme Kohler

2017-11-01

Full Text Available n a gap in consistent application of system-level strategies that can effectively translate organizational policies around patient and family engagement into practice. Methods The broad objective of this initiative was to develop a system-level implementation strategy to include patient and family advisors (PFAs at decision-making points in primary healthcare (PHC based on wellestablished evidence and literature. In this opportunity sponsored by the Canadian Foundation for Healthcare Improvement (CFHI a co-design methodology, also well-established was applied in identifying and developing a suitable implementation strategy to engage PFAs as members of quality teams in PHC. Diabetes management centres (DMCs was selected as the pilot site to develop the strategy. Key steps in the process included review of evidence, review of the current state in PHC through engagement of key stakeholders and a co-design approach. Results The project team included a diverse representation of members from the PHC system including patient advisors, DMC team members, system leads, providers, Public Engagement team members and CFHI improvement coaches. Key outcomes of this 18-month long initiative included development of a working definition of patient and family engagement, development of a Patient and Family Engagement Resource Guide and evaluation of the resource guide. Conclusion This novel initiative provided us an opportunity to develop a supportive system-wide implementation plan and a strategy to include PFAs in decision-making processes in PHC. The well-established co-design methodology further allowed us to include value-based (customer driven quality and experience of care perspectives of several important stakeholders including patient advisors. The next step will be to implement the strategy within DMCs, spread the strategy PHC, both locally and provincially with a focus on sustainability.

Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX syndrome: a paradigm of immunodeficiency with autoimmunity

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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.

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

HPA axis dysregulation, NR3C1 polymorphisms and glucocorticoid receptor isoforms imbalance in metabolic syndrome.

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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.

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

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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.

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

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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.

Effect of family structure and TPH2 G-703T on the stability of dysregulation profile throughout adolescence.

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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.

A first-in-human phase I study of SAR125844, a selective MET tyrosine kinase inhibitor, in patients with advanced solid tumours with MET amplification.

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Angevin, Eric; Spitaleri, Gianluca; Rodon, Jordi; Dotti, Katia; Isambert, Nicolas; Salvagni, Stefania; Moreno, Victor; Assadourian, Sylvie; Gomez, Corinne; Harnois, Marzia; Hollebecque, Antoine; Azaro, Analia; Hervieu, Alice; Rihawi, Karim; De Marinis, Filippo

2017-12-01

Dysregulated MET signalling is implicated in oncogenesis. The safety and preliminary efficacy of a highly selective MET kinase inhibitor (SAR125844) was investigated in patients with advanced solid tumours and MET dysregulation. This was a phase I dose-escalation (3 + 3 design [50-740 mg/m 2 ]) and dose-expansion study. In the dose escalation, patients had high total MET (t-MET) expression by immunohistochemistry (IHC) or MET amplification by fluorescence in situ hybridisation. In the dose expansion, patients had MET amplification (including a subset of patients with non-small cell lung cancer [NSCLC]) or phosphorylated-MET (p-MET) expression (IHC). Objectives were determination of maximum tolerated dose (MTD) of once-weekly intravenous SAR125844 based on dose-limiting toxicities; safety and pharmacokinetic profile; preliminary efficacy of SAR125844 MTD in the expansion cohort. In total, 72 patients were enrolled: dose escalation, N = 33; dose expansion, N = 39; 570 mg/m 2 was established as the MTD. Most frequent treatment-emergent adverse events (AEs) were asthenia/fatigue (58.3%), nausea (31.9%), and abdominal pain, constipation, and dyspnea (27.8% for each); 58.3% of patients reported grade 3 AEs (19.4% were treatment related). Of the 29 evaluable patients with MET amplification treated at 570 mg/m 2 , five achieved a partial response, including four of 22 with NSCLC; 17 patients had stable disease. No response was observed in patients with high p-MET solid tumours. There was no correlation between tumour response and t-MET status or MET gene copy number. The MTD of once-weekly SAR125844 was 570 mg/m 2 ; SAR125844 was well tolerated, with significant antitumour activity in patients with MET-amplified NSCLC. NCT01391533. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Neural Correlates of Irritability in Disruptive Mood Dysregulation and Bipolar Disorders.

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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.

Transcriptome-wide mega-analyses reveal joint dysregulation of immunologic genes and transcription regulators in brain and blood in schizophrenia.

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Hess, Jonathan L; Tylee, Daniel S; Barve, Rahul; de Jong, Simone; Ophoff, Roel A; Kumarasinghe, Nishantha; Tooney, Paul; Schall, Ulrich; Gardiner, Erin; Beveridge, Natalie Jane; Scott, Rodney J; Yasawardene, Surangi; Perera, Antionette; Mendis, Jayan; Carr, Vaughan; Kelly, Brian; Cairns, Murray; Tsuang, Ming T; Glatt, Stephen J

2016-10-01

The application of microarray technology in schizophrenia research was heralded as paradigm-shifting, as it allowed for high-throughput assessment of cell and tissue function. This technology was widely adopted, initially in studies of postmortem brain tissue, and later in studies of peripheral blood. The collective body of schizophrenia microarray literature contains apparent inconsistencies between studies, with failures to replicate top hits, in part due to small sample sizes, cohort-specific effects, differences in array types, and other confounders. In an attempt to summarize existing studies of schizophrenia cases and non-related comparison subjects, we performed two mega-analyses of a combined set of microarray data from postmortem prefrontal cortices (n=315) and from ex-vivo blood tissues (n=578). We adjusted regression models per gene to remove non-significant covariates, providing best-estimates of transcripts dysregulated in schizophrenia. We also examined dysregulation of functionally related gene sets and gene co-expression modules, and assessed enrichment of cell types and genetic risk factors. The identities of the most significantly dysregulated genes were largely distinct for each tissue, but the findings indicated common emergent biological functions (e.g. immunity) and regulatory factors (e.g., predicted targets of transcription factors and miRNA species across tissues). Our network-based analyses converged upon similar patterns of heightened innate immune gene expression in both brain and blood in schizophrenia. We also constructed generalizable machine-learning classifiers using the blood-based microarray data. Our study provides an informative atlas for future pathophysiologic and biomarker studies of schizophrenia. Published by Elsevier B.V.

Dysregulation of Nutrient Sensing and CLEARance in Presenilin Deficiency

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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.

Dysregulated autophagy in restrictive cardiomyopathy due to Pro209Leu mutation in BAG3.

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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.

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

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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

Confabulation: Developing the 'emotion dysregulation' hypothesis.

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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.

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

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

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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…

Haploinsufficiency of BAZ1B contributes to Williams syndrome through transcriptional dysregulation of neurodevelopmental pathways.

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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.

Fever in trauma patients: evaluation of risk factors, including traumatic brain injury.

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Bengualid, Victoria; Talari, Goutham; Rubin, David; Albaeni, Aiham; Ciubotaru, Ronald L; Berger, Judith

2015-03-01

The role of fever in trauma patients remains unclear. Fever occurs as a response to release of cytokines and prostaglandins by white blood cells. Many factors, including trauma, can trigger release of these factors. To determine whether (1) fever in the first 48 hours is related to a favorable outcome in trauma patients and (2) fever is more common in patients with head trauma. Retrospective study of trauma patients admitted to the intensive care unit for at least 2 days. Data were analyzed by using multivariate analysis. Of 162 patients studied, 40% had fever during the first 48 hours. Febrile patients had higher mortality rates than did afebrile patients. When adjusted for severity of injuries, fever did not correlate with mortality. Neither the incidence of fever in the first 48 hours after admission to the intensive care unit nor the number of days febrile in the unit differed between patients with and patients without head trauma (traumatic brain injury). About 70% of febrile patients did not have a source found for their fever. Febrile patients without an identified source of infection had lower peak white blood cell counts, lower maximum body temperature, and higher minimum platelet counts than did febrile patients who had an infectious source identified. The most common infection was pneumonia. No relationship was found between the presence of fever during the first 48 hours and mortality. Patients with traumatic brain injury did not have a higher incidence of fever than did patients without traumatic brain injury. About 30% of febrile patients had an identifiable source of infection. Further studies are needed to understand the origin and role of fever in trauma patients. ©2015 American Association of Critical-Care Nurses.

Interacting effects of maternal responsiveness, infant regulatory problems and dopamine D4 receptor gene in the development of dysregulation during childhood: A longitudinal analysis.

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Poustka, Luise; Zohsel, Katrin; Blomeyer, Dorothea; Jennen-Steinmetz, Christine; Schmid, Brigitte; Trautmann-Villalba, Patricia; Hohmann, Sarah; Becker, Katja; Esser, Günter; Schmidt, Martin H; Brandeis, Daniel; Banaschewski, Tobias; Laucht, Manfred

2015-11-01

Recent longitudinal studies have indicated that affective and behavioral dysregulation in childhood is associated with an increased risk for various negative outcomes in later life. However, few studies to date have examined early mechanisms preceding dysregulation during early childhood. Aim of this study was to elucidate early mechanisms relating to dysregulation in later life using data from an epidemiological cohort study on the long-term outcome of early risk factors from birth to adulthood. At age 3 months, mothers and infants were videotaped during a nursing and playing situation. Maternal responsiveness was evaluated by trained raters. Infant regulatory problems were assessed on the basis of a parent interview and direct observation by trained raters. At age 8 and 11 years, 290 children (139 males) were rated on the Child Behavior Checklist (CBCL). Additionally, participants were genotyped for the dopamine D4 receptor (DRD4) exon 3 VNTR polymorphism. A significant three-way interaction between maternal responsiveness, DRD4 genotype and infant regulatory problems was detected predicting the CBCL-dysregulation profile (CBCL-DP). Carriers of the DRD4 7r allele with regulatory problems at age 3 months showed significantly more behavior problems associated with the CBCL-DP during childhood when exposed to less maternal responsiveness. In contrast, no effect of maternal responsiveness was observed in DRD4 7r carriers without infant regulatory problems and in non-carriers of the DRD4 7r allele. This prospective longitudinal study extends earlier findings regarding the association of the CBCL-DP with early parenting and later psychopathology, introducing both DRD4 genotype and infant regulatory problems as important moderators. Copyright © 2015 Elsevier Ltd. All rights reserved.

Bringing Value-Based Perspectives to Care: Including Patient and Family Members in Decision-Making Processes.

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Kohler, Graeme; Sampalli, Tara; Ryer, Ashley; Porter, Judy; Wood, Les; Bedford, Lisa; Higgins-Bowser, Irene; Edwards, Lynn; Christian, Erin; Dunn, Susan; Gibson, Rick; Ryan Carson, Shannon; Vallis, Michael; Zed, Joanna; Tugwell, Barna; Van Zoost, Colin; Canfield, Carolyn; Rivoire, Eleanor

2017-03-06

Recent evidence shows that patient engagement is an important strategy in achieving a high performing healthcare system. While there is considerable evidence of implementation initiatives in direct care context, there is limited investigation of implementation initiatives in decision-making context as it relates to program planning, service delivery and developing policies. Research has also shown a gap in consistent application of system-level strategies that can effectively translate organizational policies around patient and family engagement into practice. The broad objective of this initiative was to develop a system-level implementation strategy to include patient and family advisors (PFAs) at decision-making points in primary healthcare (PHC) based on wellestablished evidence and literature. In this opportunity sponsored by the Canadian Foundation for Healthcare Improvement (CFHI) a co-design methodology, also well-established was applied in identifying and developing a suitable implementation strategy to engage PFAs as members of quality teams in PHC. Diabetes management centres (DMCs) was selected as the pilot site to develop the strategy. Key steps in the process included review of evidence, review of the current state in PHC through engagement of key stakeholders and a co-design approach. The project team included a diverse representation of members from the PHC system including patient advisors, DMC team members, system leads, providers, Public Engagement team members and CFHI improvement coaches. Key outcomes of this 18-month long initiative included development of a working definition of patient and family engagement, development of a Patient and Family Engagement Resource Guide and evaluation of the resource guide. This novel initiative provided us an opportunity to develop a supportive system-wide implementation plan and a strategy to include PFAs in decision-making processes in PHC. The well-established co-design methodology further allowed us to

Dysregulation in microRNA expression is associated with alterations in immune functions in combat veterans with post-traumatic stress disorder.

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Juhua Zhou

Full Text Available While the immunological dysfunction in combat Veterans with post-traumatic stress disorder (PTSD has been well documented, the precise mechanisms remain unclear. The current study evaluated the role of microRNA (miR in immunological dysfunction associated with PTSD. The presence of peripheral blood mononuclear cells (PBMC and various lymphocyte subsets in blood collected from PTSD patients were analyzed. Our studies demonstrated that the numbers of both PBMC and various lymphocyte subsets increased significantly in PTSD patients. When T cells were further analyzed, the percentage of Th1 cells and Th17 cells increased, regulatory T cells(Tregs decreased, while Th2 cells remained unaltered in PTSD patients. These data correlated with increased plasma levels of IFN-γ and IL-17 while IL-4 showed no significant change. The increase in PBMC counts, Th1 and Th17 cells seen in PTSD patients correlated with the clinical scores. High-throughput analysis of PBMCs for 1163 miRs showed that the expression of a significant number of miRs was altered in PTSD patients. Pathway analysis of dysregulated miRs seen in PTSD patients revealed relationship between selected miRNAs and genes that showed direct/indirect role in immunological signaling pathways consistent with the immunological changes seen in these patients. Of interest was the down-regulation of miR-125a in PTSD, which specifically targeted IFN-γ production. Together, the current study demonstrates for the first time that PTSD was associated with significant alterations in miRNAs, which may promote pro-inflammatory cytokine profile. Such epigenetic events may provide useful tools to identify potential biomarkers for diagnosis, and facilitate therapy of PTSD.

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.

Dysregulated Homeostasis of Acetylcholine Levels in Immune Cells of RR-Multiple Sclerosis Patients

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Maria Di Bari

2016-11-01

Full Text Available Multiple sclerosis (MS is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS patients. We demonstrated that lower ACh levels in serum of RR-MS patients were inversely correlated with the increased activity of the hydrolyzing enzymes acetylcholinesterase (AChE and butyrylcholinesterase (BuChE. Interestingly, the expression of the ACh biosynthetic enzyme and the protein carriers involved in non-vesicular ACh release were found overexpressed in peripheral blood mononuclear cells of MS patients. The inflammatory state of the MS patients was confirmed by increased levels of TNFα, IL-12/IL-23p40, IL-18. The lower circulating ACh levels in sera of MS patients are dependent on the higher activity of cholinergic hydrolyzing enzymes. The smaller ratio of ACh to TNFα, IL-12/IL-23p40 and IL-18 in MS patients, with respect to healthy donors (HD, is indicative of an inflammatory environment probably related to the alteration of cholinergic system homeostasis.

Calcium dysregulation, functional calpainopathy, and endoplasmic reticulum stress in sporadic inclusion body myositis.

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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.

FAS/FASL are dysregulated in chordoma and their loss-of-function impairs zebrafish notochord formation.

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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.

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

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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.

Dysregulation of Autophagy Contributes to Anal Carcinogenesis.

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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.

Prevalence and correlates of psychopathology in children and adolescents evaluated with the strengths and difficulties questionnaire dysregulation profile in a clinical setting.

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Carballo, Juan José; Serrano-Drozdowskyj, Elena; García Nieto, Rebeca; Díaz de Neira-Hernando, Mónica; Pérez-Fominaya, Margarita; Molina-Pizarro, Cristian Antonio; De León-Martínez, Victoria; Baca-García, Enrique

2014-01-01

The clinical presentation of children and adolescents referred to mental health services is frequently complicated by comorbid and severe affective and behavioral dysregulation. This dysregulation phenotype seems to be an indicator of overall psychopathology, symptom severity and functional impairment. Currently, this phenotype is assessed by the Child Behavior Checklist. However, the widely used Strengths and Difficulties Questionnaire (SDQ) has been recently validated to screen the Dysregulation Profile (SDQ-DP) in clinical settings. The objective of this study was to determine the prevalence and demographic, psychosocial and clinical correlates of the SDQ-DP phenotype in a Spanish clinical sample. In a clinical sample of 623 consecutively referred children and adolescents (4-17 years old), we compared clinical and sociodemographic correlates between subjects who met the SDQ-DP criteria (DP) and those who did not (NO_DP). Sociodemographic data, parent-rated SDQ, Children's Global Assessment Scale, Clinical Global Impression, family Apgar scale and clinical diagnoses were collected by experienced child and adolescent psychiatrists. Overall in our sample, 175 subjects (28.1%) met the SDQ-DP criteria (DP group). Compared with the NO_DP group, the DP subjects had significantly higher scores on internalizing and externalizing psychopathology, problems with peers and overall problems as well as significantly lower scores on prosocial behavior. Clinical diagnoses assigned revealed that DP subjects showed significantly greater psychiatric comorbidity. DP subjects also showed significantly worse family functioning and increased symptom severity and significantly lower scores on psychosocial functioning. A high prevalence of children and adolescents with the dysregulated profile, assessed by the SDQ-DP, was found in our clinical setting. The SDQ-DP may serve as an index of overall psychological severity and functional impairment. In addition, it may indicate family

Placental adaptations to micronutrient dysregulation in the programming of chronic disease.

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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.

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.

Comparison of personality characteristics in Parkinson disease patients with and without impulse control disorders and in healthy volunteers.

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Farnikova, Katerina; Obereigneru, Radko; Kanovsky, Petr; Prasko, Jan

2012-03-01

We aimed to assess personality characteristics in patients with Parkinson disease (PD) with and without impulse control disorders (ICD). We tested patients and controls with the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) scales that have expected high sensitivity to apparent addictive behavior. We recorded mean disease duration and mean levodopa dose in the PD groups. Of the 46 PD patients, 13 had ICD: hypersexuality, binge eating, or dopamine dysregulation. The PD patients with ICD had a longer duration of disease (11 vs. 5 y) and were taking higher doses of levodopa (900 vs. 500 mg/d). They scored above the pathologic threshold in 4 domains of the MMPI-2 Clinical Scales and in 8 Clinical Subscales and Content Scales. The most significant abnormality was Alienation-Self and Others. ICDs in the general population have similarities to disorders of substance addiction. In PD patients, some personality profiles could play a role in development of ICDs or dopamine dysregulation syndrome. The MMPI-2 may be a useful test for PD patients in general, and for detecting ICD in particular.

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

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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.

Regulation and dysregulation of esophageal peristalsis by the integrated function of circular and longitudinal muscle layers in health and disease.

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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.

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.

Friction-Induced Mitochondrial Dysregulation Contributes to Joint Deterioration in Prg4 Knockout Mice

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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.

Identification of a Sj?gren's syndrome susceptibility locus at OAS1 that influences isoform switching, protein expression, and responsiveness to type I interferons

OpenAIRE

Li, He; Reksten, Tove Ragna; Ice, John A.; Kelly, Jennifer A.; Adrianto, Indra; Rasmussen, Astrid; Wang, Shaofeng; He, Bo; Grundahl, Kiely M.; Glenn, Stuart B.; Miceli-Richard, Corinne; Bowman, Simon; Lester, Sue; Eriksson, Per; Eloranta, Maija-Leena

2017-01-01

Sjogrens syndrome (SS) is a common, autoimmune exocrinopathy distinguished by keratoconjunctivitis sicca and xerostomia. Patients frequently develop serious complications including lymphoma, pulmonary dysfunction, neuropathy, vasculitis, and debilitating fatigue. Dysregulation of type I interferon (IFN) pathway is a prominent feature of SS and is correlated with increased autoantibody titers and disease severity. To identify genetic determinants of IFN pathway dysregulation in SS, we performe...

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.

Pancreatic Islet Protein Complexes and Their Dysregulation in Type 2 Diabetes

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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...

Transcriptional dysregulation causes altered modulation of inhibition by haloperidol.

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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

miRNA-21 is dysregulated in response to vein grafting in multiple models and genetic ablation in mice attenuates neointima formation

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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

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.

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.

Impulse control disorders in patients with Parkinson's disease.

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Gescheidt, Tomás; Bares, Martin

2011-03-01

In patients with Parkinson's disease with higher prevalence than in current population there appear pathological behaviours characterized by compulsion, repetitiveness and impulsivity, which are connected with material profit or pleasurable experience. They are, in particular, pathological gambling, hypersexuality, compulsive shopping and compulsive eating (in the literature they are collectively referred to as impulse control disorders). Pathological preoccupation with repeated mechanical activities (so-called punding) and excessive compulsive intake of dopaminergic medication (so-called dopamine dysregulation syndrome or also syndrome of hedonistic homeostatic dysregulation) are of similar nature. The paper treats briefly the risk factors and prevalence of these pathological behaviours. In current clinical practice, these psychiatric complications frequently escape doctors' attention, they are underdiagnosed. Although no generally valid recommendations for their therapy are currently available, they can be influenced medically. Of advantage can be modified dopaminergic medication (usually dose reduction ofdopaminergic agonists); multidisciplinary approach to the problem is appropriate. The pathological behaviours given above can frequently lead to considerable material losses and markedly aggravate patients' handicap in the social sphere; it can be expected that in the future they can become a problem also from the ethical and legal points of view.

Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD): exome sequencing of trios, monozygotic twins and tumours.

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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

2015-08-25

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. We sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin of one (discovery cohort), to identify constitutional and somatic de novo sequence variants. We further analyzed this exome data to search for candidate genes under autosomal dominant and recessive models, and to identify structural variations. Candidate genes were tested by exome or Sanger sequencing in a replication cohort of 28 ROHHAD singletons. The analysis of the trio-based exomes found 13 de novo variants. However, no two patients had de novo variants in the same gene, and additional patient exomes and mutation analysis in the replication cohort did not provide strong genetic evidence to implicate any of these sequence variants in ROHHAD. Somatic comparisons revealed no coding differences between any blood and tumour samples, or between the two discordant MZ twins. Neither autosomal dominant nor recessive analysis yielded candidate genes for ROHHAD, and we did not identify any potentially causative structural variations. Clinical exome sequencing is highly unlikely to be a useful diagnostic test in patients with true ROHHAD. As ROHHAD has a high risk for fatality if not properly managed, it remains imperative to expand the search for non-exomic genetic risk factors, as well as to investigate other possible mechanisms of disease. In so doing, we will be able to confirm objectively the ROHHAD diagnosis and to contribute to our understanding of obesity, respiratory control, hypothalamic function, and autonomic regulation.

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

[Individual parameters of general low-frequency magnetic therapy as a possibility for improving the clinical efficacy of the combined treatment of patients with essential arterial hypertension].

Science.gov (United States)

Fedotov, V D; Maslov, A G; Lobkaeva, E P; Krylov, V N; Obukhova, E O

2012-01-01

A new approach is proposed for the choice of low-frequency magnetic therapy on an individual basis using the results of analysis of heart rhythm variability. The clinical efficiency of low-frequency magnetic therapy incorporated in the combined treatment of 65 patients aged between 25 and 45 years with essential arterial hypertension was estimated. The statistically significant positive effects of the treatment included normalization of blood pressure and characteristics of heart rhythm variability as well as resolution of clinical symptoms of vegetative dysregulation.

Advances in our understanding of immunization and vaccines for patients with systemic lupus erythematosus.

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Bragazzi, Nicola Luigi; Watad, Abdulla; Sharif, Kassem; Adawi, Mohammad; Aljadeff, Gali; Amital, Howard; Shoenfeld, Yehuda

2017-10-01

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease. In SLE, immune system dysfunction is postulated to result by virtue of the disease itself as well as by the impact of treatment modalities employed. A myriad of immune dysregulations occur including complement system dysfunction among others. Infectious agents are known to complicate the disease course in close to 25-45% of SLE patients. Areas covered: In this review a discussion of the immunogenicity and safety of viral and bacterial vaccinations in SLE was performed. The search included ISI Web of Science (WoS), Scopus, MEDLINE/PubMed, Google-Scholar, DOAJ, EbscoHOST, Scirus, Science Direct, Cochrane Library and ProQuest. Proper string made up of a key-words including 'SLE', 'vaccination', 'safety' and 'efficacy' was used. Expert commentary: Vaccination of SLE patients is proven to be immunogenic. Concerns regarding vaccine safety are postulated, yet no direct relationship between vaccination and disease exacerbation were established. While live virus vaccines are generally contraindicated in immunosuppressive states, generally live attenuated vaccinations are recommended in SLE patients on a case-to-case basis. In SLE patients, clinical parameters such as vaccination during disease exacerbations have not been intensively studied and therefore while apparently safe, vaccination is generally recommended while disease is quiescent.

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.

Acquired partial lipodystrophy and C3 glomerulopathy: Dysregulation of the complement system as a common mechanism

Directory of Open Access Journals (Sweden)

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

Normative development of the Child Behavior Checklist Dysregulation Profile from early childhood to adolescence: Associations with personality pathology.

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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.

Transcriptional differences between normal and glioma-derived glial progenitor cells identify a core set of dysregulated genes.

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Auvergne, Romane M; Sim, Fraser J; Wang, Su; Chandler-Militello, Devin; Burch, Jaclyn; Al Fanek, Yazan; Davis, Danielle; Benraiss, Abdellatif; Walter, Kevin; Achanta, Pragathi; Johnson, Mahlon; Quinones-Hinojosa, Alfredo; Natesan, Sridaran; Ford, Heide L; Goldman, Steven A

2013-06-27

Glial progenitor cells (GPCs) are a potential source of malignant gliomas. We used A2B5-based sorting to extract tumorigenic GPCs from human gliomas spanning World Health Organization grades II-IV. Messenger RNA profiling identified a cohort of genes that distinguished A2B5+ glioma tumor progenitor cells (TPCs) from A2B5+ GPCs isolated from normal white matter. A core set of genes and pathways was substantially dysregulated in A2B5+ TPCs, which included the transcription factor SIX1 and its principal cofactors, EYA1 and DACH2. Small hairpin RNAi silencing of SIX1 inhibited the expansion of glioma TPCs in vitro and in vivo, suggesting a critical and unrecognized role of the SIX1-EYA1-DACH2 system in glioma genesis or progression. By comparing the expression patterns of glioma TPCs with those of normal GPCs, we have identified a discrete set of pathways by which glial tumorigenesis may be better understood and more specifically targeted. Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

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

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.

Improvement in Detection of Wrong-Patient Errors When Radiologists Include Patient Photographs in Their Interpretation of Portable Chest Radiographs.

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Tridandapani, Srini; Olsen, Kevin; Bhatti, Pamela

2015-12-01

This study was conducted to determine whether facial photographs obtained simultaneously with radiographs improve radiologists' detection rate of wrong-patient errors, when they are explicitly asked to include the photographs in their evaluation. Radiograph-photograph combinations were obtained from 28 patients at the time of portable chest radiography imaging. From these, pairs of radiographs were generated. Each unique pair consisted of one new and one old (comparison) radiograph. Twelve pairs of mismatched radiographs (i.e., pairs containing radiographs of different patients) were also generated. In phase 1 of the study, 5 blinded radiologist observers were asked to interpret 20 pairs of radiographs without the photographs. In phase 2, each radiologist interpreted another 20 pairs of radiographs with the photographs. Radiologist observers were not instructed about the purpose of the photographs but were asked to include the photographs in their review. The detection rate of mismatched errors was recorded along with the interpretation time for each session for each observer. The two-tailed Fisher exact test was used to evaluate differences in mismatch detection rates between the two phases. A p value of error detection rates without (0/20 = 0%) and with (17/18 = 94.4%) photographs were different (p = 0.0001). The average interpretation times for the set of 20 radiographs were 26.45 (SD 8.69) and 20.55 (SD 3.40) min, for phase 1 and phase 2, respectively (two-tailed Student t test, p = 0.1911). When radiologists include simultaneously obtained photographs in their review of portable chest radiographs, there is a significant improvement in the detection of labeling errors. No statistically significant difference in interpretation time was observed. This may lead to improved patient safety without affecting radiologists' throughput.

Investigation of patients with atypical or severe hyperandrogenaemia including androgen-secreting ovarian teratoma.

LENUS (Irish Health Repository)

Dennedy, Michael Conall

2012-02-01

Approximately 7% of women of reproductive age manifest polycystic ovary syndrome (PCOS) and <0.5% have other causes of hyperandrogenism including congenital adrenal hyperplasia (CAH), androgen-secreting tumour of an ovary or an adrenal gland, Cushing\\'s syndrome or hyperthecosis. The presence of features atypical of PCOS should prompt more extensive evaluation than that usually undertaken. Features atypical of PCOS include the onset of symptoms outside the decade of 15-25 years, rapid progression of symptoms, the development of virilization and a serum testosterone concentration in excess of twice the upper limit of the reference range. Ethnic background, family history and specific clinical findings, e.g. Cushingoid appearance, may inform a focused investigation. Otherwise, patients should have measurement of 17-hydroxyprogesterone (17-OHP) under basal conditions ideally in the early morning, and if abnormal, they should have measurement of 17-OHP one hour after the administration of synthetic ACTH, 250 microg i.v., to screen for CAH, which is present in approximately 2% of hyperandrogenic patients. The overnight cortisol suppression test employing 1 mg dexamethasone at midnight is a sensitive test for Cushing\\'s syndrome. Coronal tomographic (CT) scanning of the adrenals and transvaginal ultrasonography of the ovaries are the investigations of choice when screening for tumours in these organs. Less frequently required is catheterization and sampling from both adrenal and ovarian veins, which is a technically demanding procedure with potential complications which may provide definitive diagnostic information not available from other investigations. Illustrative case reports highlight some complexities in the investigation of hyperandrogenic patients presenting with features atypical of PCOS and include only the ninth case report of an androgen-secreting ovarian teratoma.

Students’ Learning Experiences from Didactic Teaching Sessions Including Patient Case Examples as Either Text or Video: A Qualitative Study

DEFF Research Database (Denmark)

Pedersen, Kamilla; Holdgaard, Martin Møller; Paltved, Charlotte

2017-01-01

' perceptions of psychiatric patients and students' reflections on meeting and communicating with psychiatric patients. METHODS: The authors conducted group interviews with 30 medical students who volunteered to participate in interviews and applied inductive thematic content analysis to the transcribed....... Students taught with video-based patient cases, in contrast, often referred to the patient cases when highlighting new insights, including the importance of patient perspectives when communicating with patients. CONCLUSION: The format of patient cases included in teaching may have a substantial impact...... unintended stigma and influence an authoritative approach in medical students towards managing patients in clinical psychiatry....

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.

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

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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.

Karotinaemi hos patient med excessivt betakarotinfødeindtag og dysreguleret diabetes mellitus

DEFF Research Database (Denmark)

Mikkelsen, Carsten Sauer; Mikkelsen, Dorthe Bisgaard; Lindegaard, Hanne Merete

2009-01-01

-carotene, but normal vitamine A value and liver enzymes. The patient reported an excessive intake of carrots (approximately 1 kg per day). The status of physiological amenorrhoea and dysregulated diabetes mellitus may have deteriorated the yellow discolouration of the skin. Udgivelsesdato: 2009-Jan-26......A case of carotinaemia in a patient with excessive beta-carotene food-intake, diabetes mellitus and physiological amenorrhea is reported. The patient developed yellow discolouration in the palms and the soles of her feet. Blood samples showed a significantly increased lever of serum beta...

Dysregulation in cortical reactivity to emotional faces in PTSD patients with high dissociation symptoms

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Aleksandra Klimova

2013-09-01

Full Text Available Background: Predominant dissociation in posttraumatic stress disorder (PTSD is characterized by restricted affective responses to positive stimuli. To date, no studies have examined neural responses to a range of emotional expressions in PTSD with high dissociative symptoms. Objective: This study tested the hypothesis that PTSD patients with high dissociative symptoms will display increased event-related potential (ERP amplitudes in early components (N1, P1 to threatening faces (angry, fearful, and reduced later ERP amplitudes (Vertex Positive Potential (VPP, P3 to happy faces compared to PTSD patients with low dissociative symptoms. Methods: Thirty-nine civilians with PTSD were classified as high dissociative (n=16 or low dissociative (n=23 according to their responses on the Clinician Administered Dissociative States Scale. ERPs were recorded, whilst participants viewed emotional (happy, angry, fear and neutral facial expressions in a passive viewing task. Results: High dissociative PTSD patients displayed significantly increased N120 amplitude to the majority of facial expressions (neutral, happy, and angry compared to low dissociative PTSD patients under conscious and preconscious conditions. The high dissociative PTSD group had significantly reduced VPP amplitude to happy faces in the conscious condition. Conclusion: High dissociative PTSD patients displayed increased early (preconscious cortical responses to emotional stimuli, and specific reductions to happy facial expressions in later (conscious, face-specific components compared to low dissociative PTSD patients. Dissociation in PTSD may act to increase initial pre-attentive processing of affective stimuli, and specifically reduce cortical reactivity to happy faces when consciously processing these stimuli.

A Phase-1b study of tivantinib (ARQ 197) in adult patients with hepatocellular carcinoma and cirrhosis

Science.gov (United States)

Santoro, A; Simonelli, M; Rodriguez-Lope, C; Zucali, P; Camacho, L H; Granito, A; Senzer, N; Rimassa, L; Abbadessa, G; Schwartz, B; Lamar, M; Savage, R E; Bruix, J

2013-01-01

Background: The mesenchymal-epithelial transition factor (MET) receptor is dysregulated in hepatocellular carcinoma (HCC), and tivantinib (ARQ 197) is an oral, selective, MET inhibitor. Methods: This Phase-1b study assessed tivantinib safety as primary objective in patients with previously treated HCC and Child-Pugh A or B liver cirrhosis. Patients received oral tivantinib 360 mg twice daily until disease progression or unacceptable toxicity. Results: Among 21 HCC patients, common drug-related adverse events (AEs) were neutropaenia, anaemia, asthenia, leucopaenia, anorexia, diarrhoea, and fatigue. No drug-related worsening of liver function or performance status occurred, but one Child-Pugh B patient experienced drug-related bilirubin increase. Four patients had drug-related serious AEs, including one neutropaenia-related death. Haematologic toxicities were more frequent than in previous tivantinib studies but were manageable with prompt therapy. Best response was stable disease (median, 5.3 months) in 9 of 16 evaluable patients (56%). Median time to progression was 3.3 months. Conclusion: Tivantinib demonstrated a manageable safety profile and preliminary antitumour activity in patients with HCC and Child-Pugh A or B cirrhosis. PMID:23287988

Wechsler profiles in referred children with intellectual giftedness: Associations with trait-anxiety, emotional dysregulation, and heterogeneity of Piaget-like reasoning processes.

Science.gov (United States)

Guénolé, Fabian; Speranza, Mario; Louis, Jacqueline; Fourneret, Pierre; Revol, Olivier; Baleyte, Jean-Marc

2015-07-01

It is common that intellectually gifted children (IQ ≥ 130) are referred to paediatric or child neuropsychiatry clinics for socio-emotional problems and/or school underachievement or maladjustment. Among them, those displaying developmental asynchrony - a heterogeneous developmental pattern reflected in a significant verbal-performance discrepancy (SVPD) on Wechsler's intelligence profile - are thought to be more emotionally and behaviourally impaired than others. Our purpose was to investigate this clinical dichotomy using a cognitive psychopathological approach. Trait-anxiety and emotional dysregulation were investigated in two groups of referred gifted children (n = 107 and 136, respectively), a pilot-study of reasoning processes on extensive Piaget-like tasks was also performed in an additional small group (n = 12). Compared to those with a homogenous Wechsler profile, children with a SVPD exhibited: 1) a decreased prevalence of social preoccupation-anxiety (11.1% versus 27.4%; p emotional dysregulation (58.7% versus 41.3%; p emotional and behavioural problems in gifted children and call for further investigation of this profile. Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

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

Directory of Open Access Journals (Sweden)

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.

Analyses of SLC13A5-epilepsy patients reveal perturbations of TCA cycle.

Science.gov (United States)

Bainbridge, Matthew N; Cooney, Erin; Miller, Marcus; Kennedy, Adam D; Wulff, Jacob E; Donti, Taraka; Jhangiani, Shalini N; Gibbs, Richard A; Elsea, Sarah H; Porter, Brenda E; Graham, Brett H

2017-08-01

To interrogate the metabolic profile of five subjects from three families with rare, nonsense and missense mutations in SLC13A5 and Early Infantile Epileptic Encephalopathies (EIEE) characterized by severe, neonatal onset seizures, psychomotor retardation and global developmental delay. Mass spectrometry of plasma, CSF and urine was used to identify consistently dysregulated analytes in our subjects. Distinctive elevations of citrate and dysregulation of citric acid cycle intermediates, supporting the hypothesis that loss of SLC13A5 function alters tricarboxylic acid cycle (TCA) metabolism and may disrupt metabolic compartmentation in the brain. Our results indicate that analysis of plasma citrate and other TCA analytes in SLC13A5 deficient patients define a diagnostic metabolic signature that can aid in diagnosing children with this disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Mentalization in adults with attention deficit hyperactivity disorder: Comparison with controls and patients with borderline personality disorder.

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Perroud, Nader; Badoud, Deborah; Weibel, Sébastien; Nicastro, Rosetta; Hasler, Roland; Küng, Anne-Lise; Luyten, Patrick; Fonagy, Peter; Dayer, Alexandre; Aubry, Jean-Michel; Prada, Paco; Debbané, Martin

2017-10-01

Emotion dysregulation and interpersonal hardships constitute core features of borderline personality disorder (BPD). Research has established the link between these core dysregulations and fluctuations in the capacity to appreciate the mental states that underlie behavior (mentalizing, operationalized as reflective functioning (RF)). As emotion dysregulation and interpersonal hardships also characterize adults with attention deficit hyperactivity disorder (ADHD), this study sought to examine the potential RF impairments affecting this population. 101 adults with ADHD, 108 with BPD and 236 controls were assessed using the RF questionnaire (RFQ), evaluating how individuals employ information about mental states to better understand their own and others' behaviors. The RFQ comprises two dimensions, certainty (RF_c) and uncertainty (RF_u) about mental states. RF scores helped distinguish ADHD from controls, but also from BPD (F = 48.1 (2/441) ; p attentional and hyperactive/impulsive symptoms) was correlated with RF impairments. In conclusion, RF may constitute an important process underlying attentional, hyperactive/impulsive as well as emotional symptoms in ADHD; it should therefore be considered in the assessment of these patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Rhinovirus infection results in stronger and more persistent genomic dysregulation: Evidence for altered innate immune response in asthmatics at baseline, early in infection, and during convalescence.

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Peter W Heymann

Full Text Available Rhinovirus (HRV is associated with the large majority of virus-induced asthma exacerbations in children and young adults, but the mechanisms remain poorly defined.Asthmatics and non-asthmatic controls were inoculated with HRV-A16, and nasal epithelial samples were obtained 7 days before, 36 hours after, and 7 days after viral inoculation. RNA was extracted and subjected to RNA-seq analysis.At baseline, 57 genes were differentially expressed between asthmatics and controls, and the asthmatics had decreased expression of viral replication inhibitors and increased expression of genes involved in inflammation. At 36 hours (before the emergence of peak symptoms, 1329 genes were significantly altered from baseline in the asthmatics compared to 62 genes in the controls. At this time point, asthmatics lacked an increase in IL-10 signaling observed in the controls. At 7 days following HRV inoculation, 222 genes were significantly dysregulated in the asthmatics, whereas only 4 genes were dysregulated among controls. At this time point, the controls but not asthmatics demonstrated upregulation of SPINK5.As judged by the magnitude and persistence of dysregulated genes, asthmatics have a substantially different host response to HRV-A16 infection compared with non-asthmatic controls. Gene expression differences illuminate biologically plausible mechanisms that contribute to a better understanding of the pathogenesis of HRV-induced asthma exacerbations.

Dysregulation of the ADAM17/Notch signalling pathways in endometriosis: from oxidative stress to fibrosis.

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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

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

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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.

Dopamine dysregulation syndrome, addiction and behavioral changes in Parkinson's disease.

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Merims, Doron; Giladi, Nir

2008-01-01

Degeneration of the dopaminergic system in Parkinson's disease and longstanding exposure to dopaminergic drugs may cause reward system malfunction. This may manifest as addiction to l-dopa and behavioral disturbances associated with the impulse control system. These disturbances include: gambling, excessive spending (shopping), hypersexuality and binge eating. We included one such patient's personal story to emphasize the devastating consequences of these potentially reversible phenomena: the patient describes in his own words how gambling induced by an exposure dopamine agonist therapy significantly worsened his disease-related difficulties.

Quantitative proteomics reveals the mechanism and consequence of gliotoxin-mediated dysregulation of the methionine cycle in Aspergillus niger.

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Manzanares-Miralles, Lara; Sarikaya-Bayram, Özlem; Smith, Elizabeth B; Dolan, Stephen K; Bayram, Özgür; Jones, Gary W; Doyle, Sean

2016-01-10

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) required for homocysteine generation from S-adenosylhomocysteine (SAH), and spermidine synthase (p=0.0068), involved in the recycling of Met, was observed. Analysis of Met-related metabolites revealed significant increases in the levels of Met and adenosine, in correlation with proteomic data. Methyltransferase MT-II is responsible for bisthiobis(methylthio)gliotoxin (BmGT) formation, deletion of MT-II abolished BmGT formation and led to increased GT sensitivity in A. niger. Proteomic analysis also revealed that GT exposure also significantly (pniger. Thus, it provides new opportunities to exploit the response of GT-naïve fungi to GT. Copyright © 2015 Elsevier B.V. All rights reserved.

Dysregulation of the descending pain system in temporomandibular disorders revealed by low-frequency sensory transcutaneous electrical nerve stimulation: a pupillometric study.

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Annalisa Monaco

Full Text Available Using computerized pupillometry, our previous research established that the autonomic nervous system (ANS is dysregulated in patients suffering from temporomandibular disorders (TMDs, suggesting a potential role for ANS dysfunction in pain modulation and the etiology of TMD. However, pain modulation hypotheses for TMD are still lacking. The periaqueductal gray (PAG is involved in the descending modulation of defensive behavior and pain through μ, κ, and δ opioid receptors. Transcutaneous electrical nerve stimulation (TENS has been extensively used for pain relief, as low-frequency stimulation can activate µ receptors. Our aim was to use pupillometry to evaluate the effect of low-frequency TENS stimulation of μ receptors on opioid descending pathways in TMD patients. In accordance with the Research Diagnostic Criteria for TMD, 18 females with myogenous TMD and 18 matched-controls were enrolled. All subjects underwent subsequent pupillometric evaluations under dark and light conditions before, soon after (end of stimulation and long after (recovery period sensorial TENS. The overall statistics derived from the darkness condition revealed no significant differences in pupil size between cases and controls; indeed, TENS stimulation significantly reduced pupil size in both groups. Controls, but not TMD patients, displayed significant differences in pupil size before compared with after TENS. Under light conditions, TMD patients presented a smaller pupil size compared with controls; the pupil size was reduced only in the controls. Pupil size differences were found before and during TENS and before and after TENS in the controls only. Pupillometry revealed that stimulating the descending opioid pathway with low-frequency sensory TENS of the fifth and seventh pairs of cranial nerves affects the peripheral target. The TMD patients exhibited a different pattern of response to TENS stimulation compared with the controls, suggesting that impaired

Child behavior checklist dysregulation profile in children with disruptive behavior disorders: A longitudinal study.

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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.

Role of Melanin in Melanocyte Dysregulation of Reactive Oxygen Species

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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.

The Increasing Prevalence in Intersex Variation from Toxicological Dysregulation in Fetal Reproductive Tissue Differentiation and Development by Endocrine-Disrupting Chemicals

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Alisa L. Rich

2016-01-01

Full Text Available An increasing number of children are born with intersex variation (IV; ambiguous genitalia/hermaphrodite, pseudohermaphroditism, etc.. Evidence shows that endocrine-disrupting chemicals (EDCs in the environment can cause reproductive variation through dysregulation of normal reproductive tissue differentiation, growth, and maturation if the fetus is exposed to EDCs during critical developmental times in utero. Animal studies support fish and reptile embryos exhibited IV and sex reversal when exposed to EDCs. Occupational studies verified higher prevalence of offspring with IV in chemically exposed workers (male and female. Chemicals associated with endocrine-disrupting ability in humans include organochlorine pesticides, polychlorinated biphenyls, bisphenol A, phthalates, dioxins, and furans. Intersex individuals may have concurrent physical disorders requiring lifelong medical intervention and experience gender dysphoria. An urgent need exists to determine which chemicals possess the greatest risk for IV and the mechanisms by which these chemicals are capable of interfering with normal physiological development in children.

Questioned validity of Gene Expression Dysregulated Domains in Down's Syndrome [v1; ref status: indexed, http://f1000r.es/5ky

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Long H. Do

2015-07-01

Full Text Available Recently, in studies examining fibroblasts obtained from the tissues of one set of monozygotic twins (i.e. fetuses derived from the same egg discordant for trisomy 21 (Down syndrome; DS, Letourneau et al., reported the presence of a defined pattern of dysregulation within specific genomic domains they referred to as Gene Expression Dysregulated Domains (GEDDs. GEDDs were described as alternating segments of increased or decreased gene expression affecting all chromosomes. Strikingly, GEDDs in fibroblasts were largely conserved in induced pluripotent cells (iPSCs generated from the twin’s fibroblasts as well as in fibroblasts from the Ts65Dn mouse model of DS. Our recent analysis failed to find GEDDs. We reexamined the human iPSCs RNAseq data from Letourneau et al., and data from this same research group published earlier examining iPSCs from the same monozygotic twins. An independent analysis of RNAseq data from Ts65Dn fibroblasts also failed to confirm presence of GEDDs. Our analysis questions the validity of GEDDs in DS.

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

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...

Mood induction in depressive patients: a comparative multidimensional approach.

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Irina Falkenberg

Full Text Available Anhedonia, reduced positive affect and enhanced negative affect are integral characteristics of major depressive disorder (MDD. Emotion dysregulation, e.g. in terms of different emotion processing deficits, has consistently been reported. The aim of the present study was to investigate mood changes in depressive patients using a multidimensional approach for the measurement of emotional reactivity to mood induction procedures. Experimentally, mood states can be altered using various mood induction procedures. The present study aimed at validating two different positive mood induction procedures in patients with MDD and investigating which procedure is more effective and applicable in detecting dysfunctions in MDD. The first procedure relied on the presentation of happy vs. neutral faces, while the second used funny vs. neutral cartoons. Emotional reactivity was assessed in 16 depressed and 16 healthy subjects using self-report measures, measurements of electrodermal activity and standardized analyses of facial responses. Positive mood induction was successful in both procedures according to subjective ratings in patients and controls. In the cartoon condition, however, a discrepancy between reduced facial activity and concurrently enhanced autonomous reactivity was found in patients. Relying on a multidimensional assessment technique, a more comprehensive estimate of dysfunctions in emotional reactivity in MDD was available than by self-report measures alone and this was unsheathed especially by the mood induction procedure relying on cartoons. The divergent facial and autonomic responses in the presence of unaffected subjective reactivity suggest an underlying deficit in the patients' ability to express the felt arousal to funny cartoons. Our results encourage the application of both procedures in functional imaging studies for investigating the neural substrates of emotion dysregulation in MDD patients. Mood induction via cartoons appears to

Convergent dysregulation of frontal cortical cognitive and reward systems in eating disorders.

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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.

Expression of vasoactive proteins in gastric antral mucosa reflects vascular dysfunction in patients with cirrhosis and portal hypertension.

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Trebicka, Jonel; Wix, Cyrus; von Heydebrand, Matthias; Hittatiya, Kanishka; Reiberger, Thomas; Klein, Sabine; Schierwagen, Robert; Kristiansen, Glen; Peck-Radosavljevic, Markus; Fischer, Hans-Peter; Møller, Søren; Bendtsen, Flemming; Krag, Aleksander; Sauerbruch, Tilman

2015-04-01

Patients with cirrhosis display hypocontractility of splanchnic vessels because of dysregulation of vasoactive proteins, such as decreased effect of RhoA/ROCK and increased activity of β-Arrestin-2 and eNOS. However, it is unknown whether the dysregulation of vasoactive proteins is displayed in other vessels. We investigated whether expression of vasoactive proteins can be evaluated in gastric mucosa vessels. Biopsies from the gastric mucosa of 111 patients with cirrhosis were collected at three different centres and from 13 controls. Forty-nine patients had received TIPS. Portal pressure gradient was measured in 49 patients with TIPS and in 16 patients without TIPS. Biopsies from the antrum were conserved in formaldehyde for immunohistochemistry or shock-frozen for PCR and Western blot. The mucosal transcription of vascular markers (αSMA, CD31) was higher in cirrhotic patients than controls, which was confirmed by immunohistochemistry. On average, relative mucosal levels of RhoA and ROCK were lower, while β-Arrestin-2 levels were higher in cirrhotic patients compared to controls. Transcriptional levels of eNOS increased with presence of ascites and grade of oesophageal varices. Patients with TIPS showed less pronounced markers of vascular dysfunction in gastric mucosa. This is the first evidence that the expression of vasoactive proteins in mucosa from the gastric antrum of patients with cirrhosis reflects their vascular dysfunction and possibly changes after therapeutic interventions. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism.

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Hasan, Maroof; Gonugunta, Vijay K; Dobbs, Nicole; Ali, Aktar; Palchik, Guillermo; Calvaruso, Maria A; DeBerardinis, Ralph J; Yan, Nan

2017-01-24

Three-prime repair exonuclease 1 knockout (Trex1 -/- ) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1 -/- mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism. We also genetically separated the inflammatory and metabolic phenotypes by showing that Sting deficiency rescued both inflammatory and metabolic phenotypes, whereas Irf3 deficiency only rescued inflammation on the Trex1 -/- background, and many metabolic defects persist in Trex1 -/- Irf3 -/- cells and mice. We also showed that Leptin deficiency (ob/ob) increased lipogenesis and prolonged survival of Trex1 -/- mice without dampening inflammation. Mechanistically, we identified TBK1 as a key regulator of mTORC1 activity in Trex1 -/- cells. Together, our data demonstrate that chronic innate immune activation of TBK1 suppresses mTORC1 activity, leading to dysregulated cellular metabolism.

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

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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.

The Host Response in Patients with Sepsis Developing Intensive Care Unit-acquired Secondary Infections.

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van Vught, Lonneke A; Wiewel, Maryse A; Hoogendijk, Arie J; Frencken, Jos F; Scicluna, Brendon P; Klein Klouwenberg, Peter M C; Zwinderman, Aeilko H; Lutter, Rene; Horn, Janneke; Schultz, Marcus J; Bonten, Marc M J; Cremer, Olaf L; van der Poll, Tom

2017-08-15

Sepsis can be complicated by secondary infections. We explored the possibility that patients with sepsis developing a secondary infection while in the intensive care unit (ICU) display sustained inflammatory, vascular, and procoagulant responses. To compare systemic proinflammatory host responses in patients with sepsis who acquire a new infection with those who do not. Consecutive patients with sepsis with a length of ICU stay greater than 48 hours were prospectively analyzed for the development of ICU-acquired infections. Twenty host response biomarkers reflective of key pathways implicated in sepsis pathogenesis were measured during the first 4 days after ICU admission and at the day of an ICU-acquired infection or noninfectious complication. Of 1,237 admissions for sepsis (1,089 patients), 178 (14.4%) admissions were complicated by ICU-acquired infections (at Day 10 [6-13], median with interquartile range). Patients who developed a secondary infection showed higher disease severity scores and higher mortality up to 1 year than those who did not. Analyses of biomarkers in patients who later went on to develop secondary infections revealed a more dysregulated host response during the first 4 days after admission, as reflected by enhanced inflammation, stronger endothelial cell activation, a more disturbed vascular integrity, and evidence for enhanced coagulation activation. Host response reactions were similar at the time of ICU-acquired infectious or noninfectious complications. Patients with sepsis who developed an ICU-acquired infection showed a more dysregulated proinflammatory and vascular host response during the first 4 days of ICU admission than those who did not develop a secondary infection.

Identification of distinct miRNA target regulation between breast cancer molecular subtypes using AGO2-PAR-CLIP and patient datasets

NARCIS (Netherlands)

Farazi, Thalia A.; ten Hoeve, Jelle J.; Brown, Miguel; Mihailovic, Aleksandra; Horlings, Hugo M.; van de Vijver, Marc J.; Tuschl, Thomas; Wessels, Lodewyk F. A.

2014-01-01

Various microRNAs (miRNAs) are up- or downregulated in tumors. However, the repression of cognate miRNA targets responsible for the phenotypic effects of this dysregulation in patients remains largely unexplored. To define miRNA targets and associated pathways, together with their relationship to

Deranged endocannabinoid responses to hedonic eating in underweight and recently weight-restored patients with anorexia nervosa.

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Monteleone, Alessio Maria; Di Marzo, Vincenzo; Aveta, Teresa; Piscitelli, Fabiana; Dalle Grave, Riccardo; Scognamiglio, Pasquale; El Ghoch, Marwan; Calugi, Simona; Monteleone, Palmiero; Maj, Mario

2015-02-01

A dysregulation of reward mechanisms was suggested in the pathophysiology of anorexia nervosa (AN), but the role of the endogenous mediators of reward has been poorly investigated. Endocannabinoids, including anandamide and 2-arachidonoylglycerol, and the endocannabinoid-related compounds oleoylethanolamide and palmitoylethanolamide modulate food-related and unrelated reward. Hedonic eating, which is the consumption of food just for pleasure and not homeostatic need, is a suitable paradigm to explore food-related reward. We investigated responses of endocannabinoids and endocannabinoid-related compounds to hedonic eating in AN. Peripheral concentrations of anandamide, 2-arachidonoylglycerol, oleoylethanolamide, and palmitoylethanolamide were measured in 7 underweight and 7 weight-restored AN patients after eating favorite and nonfavorite foods in the condition of no homeostatic needs, and these measurements were compared with those of previously studied healthy control subjects. 1) In healthy controls, plasma 2-arachidonoylglycerol concentrations decreased after both types of meals but were significantly higher in hedonic eating; in underweight AN patients, 2-arachidonoylglycerol concentrations did not show specific time patterns after eating either favorite or nonfavorite foods, whereas in weight-restored patients, 2-arachidonoylglycerol concentrations showed similar increases with both types of meals. 2) Anandamide plasma concentrations exhibited no differences in their response patterns to hedonic eating in the groups. 3) Compared with 2-arachidonoylglycerol, palmitoylethanolamide concentrations exhibited an opposite response pattern to hedonic eating in healthy controls; this pattern was partially preserved in underweight AN patients but not in weight-restored ones. 4) Like palmitoylethanolamide, oleoylethanolamide plasma concentrations tended to be higher in nonhedonic eating than in hedonic eating in healthy controls; moreover, no difference between healthy

Upregulated GABA inhibitory function in AD/HD children with Child Behavior Checklist–Dysregulation Profile: 123I-iomazenil SPECT study

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Shinichiro eNagamitsu

2015-06-01

Full Text Available 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 (AD/HD and dysregulation assessed with a dimensional measure. Brain single photon emission computed tomography (SPECT was performed in 35 children with AD/HD 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 AD/HD 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.

Aging-induced dysregulation of dicer1-dependent microRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells.

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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.

Upregulated GABA Inhibitory Function in ADHD Children with Child Behavior Checklist–Dysregulation Profile: 123I-Iomazenil SPECT Study

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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

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

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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.

Increased Blood Levels of Growth Factors, Proinflammatory Cytokines, and Th17 Cytokines in Patients with Newly Diagnosed Type 1 Diabetes.

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Alnek, Kristi; Kisand, Kalle; Heilman, Kaire; Peet, Aleksandr; Varik, Karin; Uibo, Raivo

2015-01-01

The production of several cytokines could be dysregulated in type 1 diabetes (T1D). In particular, the activation of T helper (Th) type 1 (Th1) cells has been proposed to underlie the autoimmune pathogenesis of the disease, although roles for inflammatory processes and the Th17 pathway have also been shown. Nevertheless, despite evidence for the role of cytokines before and at the onset of T1D, the corresponding findings are inconsistent across studies. Moreover, conflicting data exist regarding the blood cytokine levels in T1D patients. The current study was performed to investigate genetic and autoantibody markers in association with the peripheral blood cytokine profiles by xMap multiplex technology in newly diagnosed young T1D patients and age-matched healthy controls. The onset of young-age T1D was characterized by the upregulation of growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-7, the proinflammatory cytokine IL-1β (but not IL-6 or tumor necrosis factor [TNF]-α), Th17 cytokines, and the regulatory cytokines IL-10 and IL-27. Ketoacidosis and autoantibodies (anti-IA-2 and -ZnT8), but not human leukocyte antigen (HLA) genotype, influenced the blood cytokine levels. These findings broaden the current understanding of the dysregulation of systemic levels of several key cytokines at the young-age onset of T1D and provide a further basis for the development of novel immunoregulatory treatments in this disease.

Parametric modulation of neural activity by emotion in youth with bipolar disorder, youth with severe mood dysregulation, and healthy volunteers.

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Thomas, Laura A; Brotman, Melissa A; Muhrer, Eli J; Rosen, Brooke H; Bones, Brian L; Reynolds, Richard C; Deveney, Christen M; Pine, Daniel S; Leibenluft, Ellen

2012-12-01

CONTEXT Youth with bipolar disorder (BD) and those with severe, nonepisodic irritability (severe mood dysregulation [SMD]) exhibit amygdala dysfunction during facial emotion processing. However, studies have not compared such patients with each other and with comparison individuals in neural responsiveness to subtle changes in facial emotion; the ability to process such changes is important for social cognition. To evaluate this, we used a novel, parametrically designed faces paradigm. OBJECTIVE To compare activation in the amygdala and across the brain in BD patients, SMD patients, and healthy volunteers (HVs). DESIGN Case-control study. SETTING Government research institute. PARTICIPANTS Fifty-seven youths (19 BD, 15 SMD, and 23 HVs). MAIN OUTCOME MEASURE Blood oxygenation level-dependent data. Neutral faces were morphed with angry and happy faces in 25% intervals; static facial stimuli appeared for 3000 milliseconds. Participants performed hostility or nonemotional facial feature (ie, nose width) ratings. The slope of blood oxygenation level-dependent activity was calculated across neutral-to-angry and neutral-to-happy facial stimuli. RESULTS In HVs, but not BD or SMD participants, there was a positive association between left amygdala activity and anger on the face. In the neutral-to-happy whole-brain analysis, BD and SMD participants modulated parietal, temporal, and medial-frontal areas differently from each other and from that in HVs; with increasing facial happiness, SMD patients demonstrated increased, and BD patients decreased, activity in the parietal, temporal, and frontal regions. CONCLUSIONS Youth with BD or SMD differ from HVs in modulation of amygdala activity in response to small changes in facial anger displays. In contrast, individuals with BD or SMD show distinct perturbations in regions mediating attention and face processing in association with changes in the emotional intensity of facial happiness displays. These findings demonstrate

SPECIFIC FEATURES OF ANTI-TUBERCULOSIS CHEMOTHERAPY TOLERANCE IN THE LIGHT OF PSYCHOLOGICAL STATUS OF PATIENTS

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N. V. Zolotova

2017-01-01

Full Text Available Specific features of psychological state were studied in 295 pulmonary tuberculosis patients with satisfactory tolerance to anti-tuberculosis medications and 75 patients poorly tolerating the treatment.Before the treatment start the patients who later demonstrated adverse reactions to treatment were diagnosed with more intense neurotic and hypochondriac personal features, destructive reactions and higher level of emotional tension and frustration – all the above promote dysregulation of the host adaptation. The research demonstrated the need to consider psychological aspects when studying the tolerance to anti-tuberculosis chemotherapy. 

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.

Students' Learning Experiences from Didactic Teaching Sessions Including Patient Case Examples as Either Text or Video: A Qualitative Study.

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Pedersen, Kamilla; Moeller, Martin Holdgaard; Paltved, Charlotte; Mors, Ole; Ringsted, Charlotte; Morcke, Anne Mette

2017-10-06

The aim of this study was to explore medical students' learning experiences from the didactic teaching formats using either text-based patient cases or video-based patient cases with similar content. The authors explored how the two different patient case formats influenced students' perceptions of psychiatric patients and students' reflections on meeting and communicating with psychiatric patients. The authors conducted group interviews with 30 medical students who volunteered to participate in interviews and applied inductive thematic content analysis to the transcribed interviews. Students taught with text-based patient cases emphasized excitement and drama towards the personal clinical narratives presented by the teachers during the course, but never referred to the patient cases. Authority and boundary setting were regarded as important in managing patients. Students taught with video-based patient cases, in contrast, often referred to the patient cases when highlighting new insights, including the importance of patient perspectives when communicating with patients. The format of patient cases included in teaching may have a substantial impact on students' patient-centeredness. Video-based patient cases are probably more effective than text-based patient cases in fostering patient-centered perspectives in medical students. Teachers sharing stories from their own clinical experiences stimulates both engagement and excitement, but may also provoke unintended stigma and influence an authoritative approach in medical students towards managing patients in clinical psychiatry.

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

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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.

Specific balance training included in an endurance-resistance exercise program improves postural balance in elderly patients undergoing haemodialysis.

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Frih, Bechir; Mkacher, Wajdi; Jaafar, Hamdi; Frih, Ameur; Ben Salah, Zohra; El May, Mezry; Hammami, Mohamed

2018-04-01

The purpose of this study was to evaluate the effects of 6 months of specific balance training included in endurance-resistance program on postural balance in haemodialysis (HD) patients. Forty-nine male patients undergoing HD were randomly assigned to an intervention group (balance training included in an endurance-resistance training, n = 26) or a control group (resistance-endurance training only, n = 23). Postural control was assessed using six clinical tests; Timed Up and Go test, Tinetti Mobility Test, Berg Balance Scale, Unipodal Stance test, Mini-Balance Evaluation Systems Test and Activities Balance Confidence scale. All balance measures increased significantly after the period of rehabilitation training in the intervention group. Only the Timed Up and Go, Berg Balance Scale, Mini-Balance Evaluation Systems Test and Activities Balance Confidence scores were improved in the control group. The ranges of change in these tests were greater in the balance training group. In HD patients, specific balance training included in a usual endurance-resistance training program improves static and dynamic balance better than endurance-resistance training only. Implications for rehabilitation Rehabilitation using exercise in haemodialysis patients improved global mobility and functional abilities. Specific balance training included in usual endurance resistance training program could lead to improved static and dynamic balance.

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

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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.

Antibody isotypes, including IgG subclasses, in Ecuadorian patients with pulmonary Paragonimiasis

Directory of Open Access Journals (Sweden)

Angel Guevara E.

1995-08-01

Full Text Available An ELISA test was developed to detect Paragonimus-specific antibodies, including IgG subclasses, using P. mexicanus crude water-soluble antigens. The test was standardized to detect antibodies in sera of Ecuadorian patients with pulmonary paragonimiasis and negative controls from the endemic area. The detected mean levels of IgG (0.753, SEM: 0.074 and IgM (0.303, SEM: 0.033 were significantly elevated (P<0.05. Within the IgG subclasses, IgG4 showed the highest detected mean level (0.365, SEM: 0.116 and the other three subclasses showed considerably lower mean levels (IgG1, 0.186 SEM: 0.06; IgG2, 0.046 SEM: 0.01; IgG3, 0.123 SEM: 0.047. The number of P. mexicanus eggs found in sputum of infected individuals showed a positive correlation with the level of antibodies detected for IgM, IgG and its subclasses (P<0.001. The relevance of these findings in Ecuadorian patients suffering from pulmonary paragonimiasis is discussed.

Survey indicated that core outcome set development is increasingly including patients, being conducted internationally and using Delphi surveys.

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Biggane, Alice M; Brading, Lucy; Ravaud, Philippe; Young, Bridget; Williamson, Paula R

2018-02-17

There are numerous challenges in including patients in a core outcome set (COS) study, these can vary depending on the patient group. This study describes current efforts to include patients in the development of COS, with the aim of identifying areas for further improvement and study. Using the COMET database, corresponding authors of COS projects registered or published from 1 January 2013 to 2 February 2017 were invited via a personalised email to participate in a short online survey. The survey and emails were constructed to maximise the response rate by following the academic literature on enhancing survey responses. Personalised reminder emails were sent to non-responders. This survey explored the frequency of patient input in COS studies, who was involved, what methods were used and whether or not the COS development was international. One hundred and ninety-two COS developers were sent the survey. Responses were collected from 21 February 2017 until 7 May 2017. One hundred and forty-six unique developers responded, yielding a 76% response rate and data in relation to 195 unique COSs (as some developers had worked on multiple COSs). Of focus here are their responses regarding 162 COSs at the published, completed or ongoing stages of development. Inclusion of patient participants was indicated in 87% (141/162) of COSs in the published completed or ongoing stages and over 94% (65/69) of ongoing COS projects. Nearly half (65/135) of COSs included patient participants from two or more countries and 22% (30/135) included patient participants from five or more countries. The Delphi survey was reported as being used singularly or in combination with other methods in 85% (119/140) of projects. Almost a quarter (16/65) of ongoing studies reported using a combination of qualitative interviews, Delphi survey and consensus meeting. These findings indicated that the Delphi survey is the most popular method of facilitating patient participation, while the combination of

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

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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.

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

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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

Clinical and immunologic outcome of patients with cartilage hair hypoplasia after hematopoietic stem cell transplantation.

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Bordon, Victoria; Gennery, Andrew R; Slatter, Mary A; Vandecruys, Els; Laureys, Genevieve; Veys, Paul; Qasim, Waseem; Waseem, Qasim; Friedrich, Wilhelm; Wulfraat, Nico M; Scherer, Franziska; Cant, Andrew J; Fischer, Alain; Cavazzana-Calvo, Marina; Cavazanna-Calvo, Marina; Bredius, Robbert G M; Notarangelo, Luigi D; Mazzolari, Evelina; Neven, Benedicte; Güngör, Tayfun; Tayfun, Güngör

2010-07-08

Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disease caused by mutations in the RMRP gene. Beside dwarfism, CHH has a wide spectrum of clinical manifestations including variable grades of combined immunodeficiency, autoimmune complications, and malignancies. Previous reports in single CHH patients with significant immunodeficiencies have demonstrated that allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for the severe immunodeficiency, while growth failure remains unaffected. Because long-term experience in larger cohorts of CHH patients after HSCT is currently unreported, we performed a European collaborative survey reporting on 16 patients with CHH and immunodeficiency who underwent HSCT. Immune dysregulation, lymphoid malignancy, and autoimmunity were important features in this cohort. Thirteen patients were transplanted in early childhood ( approximately 2.5 years). The other 3 patients were transplanted at adolescent age. Of 16 patients, 10 (62.5%) were long-term survivors, with a median follow-up of 7 years. T-lymphocyte numbers and function have normalized, and autoimmunity has resolved in all survivors. HSCT should be considered in CHH patients with severe immunodeficiency/autoimmunity, before the development of severe infections, major organ damage, or malignancy might jeopardize the outcome of HSCT and the quality of life in these patients.

Intensive Care Management of Thoracic Aortic Surgical Patients, Including Thoracic and Infradiaphragmatic Endovascular Repair (EVAR/TEVAR).

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Cole, Sheela Pai

2015-12-01

The patient with thoracic aortic disease can present for open or endovascular repair. Thoracic endovascular aortic repair (TEVAR) has emerged as a minimally invasive option for a multitude of aortic pathology, including dissections, aneurysms, traumatic injuries, and ulcers. Postoperative management of these patients depends on the extent of procedure, whether it was open or endovascular, and, finally, on the preoperative comorbidities present. While procedural success has catapulted TEVAR to popularity, midterm results have been mixed. Additionally, periprocedural complications such as paraplegia and renal failure remain a significant morbidity in these patients. © The Author(s) 2015.

Self-harm in patients with schizophrenia spectrum disorders.

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Mork, Erlend; Mehlum, Lars; Barrett, Elizabeth A; Agartz, Ingrid; Harkavy-Friedman, Jill M; Lorentzen, Steinar; Melle, Ingrid; Andreassen, Ole A; Walby, Fredrik A

2012-01-01

This study describes the prevalence, clinical characteristics, and gender profile of self-harm in a cross-sectional sample of 388 patients with schizophrenia spectrum disorders. All patients were interviewed and assessed with respect to lifetime self-harm and relevant clinical variables. An overall of 49% of the patients reported self-harm which was associated with female gender, having had a depressive episode, younger age at psychosis onset, alcohol abuse or dependence, current suicidality, awareness of illness, and low adherence to prescribed medication. Higher awareness of having a mental disorder was associated with self-harm in men only, while emotional dysregulation was associated with self-harm in women only. We conclude that while self-harm in patients with schizophrenia spectrum disorders is highly prevalent in both genders, risk factors in men and women differ in several important ways.

Influenza virus induces apoptosis via BAD-mediated mitochondrial dysregulation.

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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.

Dysregulated physiological stress systems and accelerated cellular aging.

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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.

Failure to Deliver and Translate-New Insights into RNA Dysregulation in ALS.

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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.

A role for repressive complexes and H3K9 di-methylation in PRDM5-associated brittle cornea syndrome

DEFF Research Database (Denmark)

Porter, Louise F; Galli, Giorgio G; Williamson, Sally

2015-01-01

skin fibroblasts and retinal tissue from BCS2 patients, to elucidate the epigenetic role of PRDM5 and mechanisms of its dysregulation in disease.First we report abnormal retinal vascular morphology in the eyes of two cousins with BCS2 (PRDM5 Δ exons 9-14) using immunohistochemistry, and mine data from......, and dysregulated H3K9 di-methylation in skin fibroblasts of three patients (p.Arg590*, p.Glu134* and Δ exons 9-14) by western blotting. These findings suggest that defective interaction of PRDM5 with repressive complexes, and dysregulation of H3K9 di-methylation, play a role in PRDM5-associated disease.......Type 2 brittle cornea syndrome (BCS2) is an inherited connective tissue disease with a devastating ocular phenotype caused by mutations in the transcription factor PRDM5 hypothesised to exert epigenetic effects through histone and DNA methylation. Here we investigate clinical samples, including...

Immune dysregulation and cognitive vulnerability in the aging brain: Interactions of microglia, IL-1β, BDNF and synaptic plasticity.

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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.

Baseline characteristics of patients with heart failure and preserved ejection fraction included in the Karolinska Rennes (KaRen) study.

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Donal, Erwan; Lund, Lars H; Oger, Emmanuel; Hage, Camilla; Persson, Hans; Reynaud, Amélie; Ennezat, Pierre-Vladimir; Bauer, Fabrice; Sportouch-Dukhan, Catherine; Drouet, Elodie; Daubert, Jean-Claude; Linde, Cecilia

2014-02-01

Karolinska Rennes (KaRen) is a prospective observational study to characterize heart failure patients with preserved ejection fraction (HFpEF) and to identify prognostic factors for long-term mortality and morbidity. To report characteristics and echocardiography at entry and after 4-8 weeks of follow-up. Patients were included following an acute heart failure presentation with B-type natriuretic peptide (BNP)>100 ng/L or N-terminal pro-BNP (NT-proBNP)>300 ng/L and left ventricular ejection fraction (LVEF)>45%. The mean ± SD age of 539 included patients was 77 ± 9 years and 56% were women. Patient history included hypertension (78%), atrial tachyarrhythmia (44%), prior heart failure (40%) and anemia (37%), but left bundle branch block was rare (3.8%). Median NT-proBNP was 2448 ng/L (n=438), and median BNP 429 ng/L (n=101). Overall, 101 patients did not return for the follow-up visit, including 13 patients who died (2.4%). Apart from older age (80 ± 9 vs. 76 ± 9 years; P=0.006), there were no significant differences in baseline characteristics between patients who did and did not return for follow-up. Mean LVEF was lower at entry than follow-up (56% vs. 62%; P<0.001). At follow-up, mean E/e' was 12.9 ± 6.1, left atrial volume index 49.4±17.8mL/m(2). Mean global left ventricular longitudinal strain was -14.6 ± 3.9%; LV mass index was 126.6 ± 36.2g/m(2). Patients in KaRen were old with slight female dominance and hypertension as the most prevalent etiological factor. LVEF was preserved, but with increased LV mass and depressed LV diastolic and longitudinal systolic functions. Few patients had signs of electrical dyssynchrony (ClinicalTrials.gov.- NCT00774709). Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Enhancing the efficacy of treatment for temporomandibular patients with muscular diagnosis through cognitive-behavioral intervention, including hypnosis: a randomized study.

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Ferrando, Maite; Galdón, María José; Durá, Estrella; Andreu, Yolanda; Jiménez, Yolanda; Poveda, Rafael

2012-01-01

This study evaluated the efficacy of a cognitive-behavioral therapy (CBT), including hypnosis, in patients with temporomandibular disorders (TMDs) with muscular diagnosis. Seventy-two patients (65 women and 7 men with an average age of 39 years) were selected according to the Research Diagnostic Criteria for TMD, and assigned to the experimental group (n = 41), receiving the 6-session CBT program, and the control group (n = 31). All patients received conservative standard treatment for TMD. The assessment included pain variables and psychologic distress. There were significant differences between the groups, the experimental group showing a higher improvement in the variables evaluated. Specifically, 90% of the patients under CBT reported a significant reduction in frequency of pain and 70% in emotional distress. The improvement was stable over time, with no significant differences between posttreatment and 9-month follow-up. CBT, including hypnosis, significantly improved conservative standard treatment outcome in TMD patients. Copyright © 2012 Elsevier Inc. All rights reserved.

The utility of including pathology reports in improving the computational identification of patients

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Wei Chen

2016-01-01

Full Text Available Background: Celiac disease (CD is a common autoimmune disorder. Efficient identification of patients may improve chronic management of the disease. Prior studies have shown searching International Classification of Diseases-9 (ICD-9 codes alone is inaccurate for identifying patients with CD. In this study, we developed automated classification algorithms leveraging pathology reports and other clinical data in Electronic Health Records (EHRs to refine the subset population preselected using ICD-9 code (579.0. Materials and Methods: EHRs were searched for established ICD-9 code (579.0 suggesting CD, based on which an initial identification of cases was obtained. In addition, laboratory results for tissue transglutaminse were extracted. Using natural language processing we analyzed pathology reports from upper endoscopy. Twelve machine learning classifiers using different combinations of variables related to ICD-9 CD status, laboratory result status, and pathology reports were experimented to find the best possible CD classifier. Ten-fold cross-validation was used to assess the results. Results: A total of 1498 patient records were used including 363 confirmed cases and 1135 false positive cases that served as controls. Logistic model based on both clinical and pathology report features produced the best results: Kappa of 0.78, F1 of 0.92, and area under the curve (AUC of 0.94, whereas in contrast using ICD-9 only generated poor results: Kappa of 0.28, F1 of 0.75, and AUC of 0.63. Conclusion: Our automated classification system presented an efficient and reliable way to improve the performance of CD patient identification.

An Evaluation of Anxiety Sensitivity, Emotional Dysregulation, and Negative Affectivity among Daily Cigarette Smokers: Relation to Smoking Motives and Barriers to Quitting

OpenAIRE

Gonzalez, Adam; Zvolensky, Michael J.; Vujanovic, Anka A.; Leyro, Teresa M.; Marshall, Erin C.

2008-01-01

The present investigation evaluated the relations between anxiety sensitivity and motivational bases of cigarette smoking, as well as barriers to quitting smoking, above and beyond concurrent substance use, negative affectivity, and emotional dysregulation among a community sample of 189 daily cigarette smokers (46% women; Mage = 24.97 years, SD = 9.78). Results indicated that anxiety sensitivity was significantly related to coping, addictive, and habitual smoking motives, as well as greater ...

CRISPR/Cas9-mediated targeted gene correction in amyotrophic lateral sclerosis patient iPSCs.

Science.gov (United States)

Wang, Lixia; Yi, Fei; Fu, Lina; Yang, Jiping; Wang, Si; Wang, Zhaoxia; Suzuki, Keiichiro; Sun, Liang; Xu, Xiuling; Yu, Yang; Qiao, Jie; Belmonte, Juan Carlos Izpisua; Yang, Ze; Yuan, Yun; Qu, Jing; Liu, Guang-Hui

2017-05-01

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with cellular and molecular mechanisms yet to be fully described. Mutations in a number of genes including SOD1 and FUS are associated with familial ALS. Here we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts of familial ALS patients bearing SOD1 +/A272C and FUS +/G1566A mutations, respectively. We further generated gene corrected ALS iPSCs using CRISPR/Cas9 system. Genome-wide RNA sequencing (RNA-seq) analysis of motor neurons derived from SOD1 +/A272C and corrected iPSCs revealed 899 aberrant transcripts. Our work may shed light on discovery of early biomarkers and pathways dysregulated in ALS, as well as provide a basis for novel therapeutic strategies to treat ALS.

Virus-Specific T Cells for the Immunocompromised Patient

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Amy Houghtelin

2017-10-01

Full Text Available While progress has been made in the treatment of both hematologic cancers and solid tumors, chemorefractory or relapsed disease often portends a dismal prognosis, and salvage chemotherapy or radiation expose patients to intolerable toxicities and may not be effective. Hematopoietic stem cell transplant offers the promise of cure for many patients, and while mismatched, unrelated or haploidentical donors are increasingly available, the recipients are at higher risk of severe immunosuppression and immune dysregulation due to graft versus host disease. Viral infections remain a primary cause of severe morbidity and mortality in this patient population. Again, many therapeutic options for viral disease are toxic, may be ineffective or generate resistance, or fail to convey long-term protection. Adoptive cell therapy with virus-specific T cells (VSTs is a targeted therapy that is efficacious and has minimal toxicity in immunocompromised patients with CMV and EBV infections in particular. Products have since been generated specific for multiple viral antigens (multi-VST, which are not only effective but also confer protection in 70–90% of recipients when used as prophylaxis. Notably, these products can be generated from either virus-naive or virus-experienced autologous or allogeneic sources, including partially matched HLA-matched third-party donors. Obstacles to effective VST treatment are donor availability and product generation time. Banking of third-party VST is an attractive way to overcome these constraints and provide products on an as-needed basis. Other developments include epitope discovery to broaden the number of viral antigens targets in a single product, the optimization of VST generation from naive donor sources, and the modification of VSTs to enhance persistence and efficacy in vivo.

Virus-Specific T Cells for the Immunocompromised Patient.

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Houghtelin, Amy; Bollard, Catherine M

2017-01-01

While progress has been made in the treatment of both hematologic cancers and solid tumors, chemorefractory or relapsed disease often portends a dismal prognosis, and salvage chemotherapy or radiation expose patients to intolerable toxicities and may not be effective. Hematopoietic stem cell transplant offers the promise of cure for many patients, and while mismatched, unrelated or haploidentical donors are increasingly available, the recipients are at higher risk of severe immunosuppression and immune dysregulation due to graft versus host disease. Viral infections remain a primary cause of severe morbidity and mortality in this patient population. Again, many therapeutic options for viral disease are toxic, may be ineffective or generate resistance, or fail to convey long-term protection. Adoptive cell therapy with virus-specific T cells (VSTs) is a targeted therapy that is efficacious and has minimal toxicity in immunocompromised patients with CMV and EBV infections in particular. Products have since been generated specific for multiple viral antigens (multi-VST), which are not only effective but also confer protection in 70-90% of recipients when used as prophylaxis. Notably, these products can be generated from either virus-naive or virus-experienced autologous or allogeneic sources, including partially matched HLA-matched third-party donors. Obstacles to effective VST treatment are donor availability and product generation time. Banking of third-party VST is an attractive way to overcome these constraints and provide products on an as-needed basis. Other developments include epitope discovery to broaden the number of viral antigens targets in a single product, the optimization of VST generation from naive donor sources, and the modification of VSTs to enhance persistence and efficacy in vivo .

Dysregulation of the HPA axis as a core pathophysiology mediating co-morbid depression in neurodegenerative diseases

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Xin eDu

2015-03-01

Full Text Available There is increasing evidence of prodromal manifestation of neuropsychiatric symptoms in a variety of neurodegenerative diseases such as Parkinson’s disease and Huntington’s disease. These affective symptoms may be observed many years before the core diagnostic symptoms of the neurological condition. It is becoming more apparent that depression is a significant modifying factor of the trajectory of disease progression, and even treatment outcomes. It is therefore crucial that we understand the potential pathophysiologies related to the primary condition, which could contribute to the development of depression. The hypothalamic-pituitary-adrenal (HPA axis is a key neuroendocrine signaling system involved in physiological homeostasis and stress response. Disturbances of this system lead to severe hormonal imbalances, and the majority of such patients also present with behavioural deficits and/or mood disorders. Dysregulation of the HPA axis is also strongly implicated in the pathology of major depressive disorder. Consistent with this, anti-depressant drugs such as the selective serotonin reuptake inhibitors (SSRI have been shown to alter HPA axis activity. In this review, we will summarize the current state of knowledge regarding HPA axis pathology in Alzheimer’s, Parkinson’s and Huntington’s diseases, differentiating between prodromal and later stages of disease progression where possible. Both clinical and preclinical evidence will be examined, but we highlight animal model studies as being particularly useful for uncovering novel mechanisms of pathology related to co-morbid mood disorders. Finally, we purpose utilizing the pre-clinical evidence to better inform prospective, intervention studies.

Possible evidence for re-regulation of HPA axis and brain reward systems over time in treatment in prescription opioid-dependent patients.

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Bunce, Scott C; Harris, Jonathan D; Bixler, Edward O; Taylor, Megan; Muelly, Emilie; Deneke, Erin; Thompson, Kenneth W; Meyer, Roger E

2015-01-01

There is growing evidence for a neuroadaptive model underlying vulnerability to relapse in opioid dependence. The purpose of this study was to evaluate clinical measures hypothesized to mirror elements of allostatic dysregulation in patients dependent on prescription opioids at 2 time points after withdrawal, compared with healthy control participants. Recently withdrawn (n = 7) prescription opioid-dependent patients were compared with the patients in supervised residential care for 2 to 3 months (extended care; n = 7) and healthy controls (n = 7) using drug cue reactivity, affect-modulated startle response tasks, salivary cortisol, and 8 days of sleep actigraphy. Prefrontal cortex was monitored with functional near-infrared spectroscopy during the cue reactivity task. Startle response results indicated reduced hedonic response to natural rewards among patients recently withdrawn from opioids relative to extended care patients. The recently withdrawn patients showed increased activation to pill stimuli in right dorsolateral prefrontal cortex relative to extended care patients. Cortisol levels were elevated among recently withdrawn patients and intermediate for extended care relative to healthy controls. Actigraphy indicated disturbed sleep between recently withdrawn patients and extended care patients; extended care patients were similar to controls. Dorsolateral prefrontal cortex activation to drug and natural reward cues, startle responses to natural reward cues, day-time cortisol levels, time in bed, and total time spent sleeping were all correlated with the number of days since last drug use (ie, time in supervised residential treatment). These results suggest possible re-regulation of dysregulated hypothalamic-pituitary-adrenal axis and brain reward systems in prescription opioid-dependent patients over the drug-free period in residential treatment.

Cell cloning-based transcriptome analysis in Rett patients: relevance to the pathogenesis of Rett syndrome of new human MeCP2 target genes.

Science.gov (United States)

Nectoux, J; Fichou, Y; Rosas-Vargas, H; Cagnard, N; Bahi-Buisson, N; Nusbaum, P; Letourneur, F; Chelly, J; Bienvenu, T

2010-07-01

More than 90% of Rett syndrome (RTT) patients have heterozygous mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene that encodes the methyl-CpG-binding protein 2, a transcriptional modulator. Because MECP2 is subjected to X chromosome inactivation (XCI), girls with RTT either express the wild-type or mutant allele in each individual cell. To test the consequences of MECP2 mutations resulting from a genome-wide transcriptional dysregulation and to identify its target genes in a system that circumvents the functional mosaicism resulting from XCI, we carried out gene expression profiling of clonal populations derived from fibroblast primary cultures expressing exclusively either the wild-type or the mutant MECP2 allele. Clonal cultures were obtained from skin biopsy of three RTT patients carrying either a non-sense or a frameshift MECP2 mutation. For each patient, gene expression profiles of wild-type and mutant clones were compared by oligonucleotide expression microarray analysis. Firstly, clustering analysis classified the RTT patients according to their genetic background and MECP2 mutation. Secondly, expression profiling by microarray analysis and quantitative RT-PCR indicated four up-regulated genes and five down-regulated genes significantly dysregulated in all our statistical analysis, including excellent potential candidate genes for the understanding of the pathophysiology of this neurodevelopmental disease. Thirdly, chromatin immunoprecipitation analysis confirmed MeCP2 binding to respective CpG islands in three out of four up-regulated candidate genes and sequencing of bisulphite-converted DNA indicated that MeCP2 preferentially binds to methylated-DNA sequences. Most importantly, the finding that at least two of these genes (BMCC1 and RNF182) were shown to be involved in cell survival and/or apoptosis may suggest that impaired MeCP2 function could alter the survival of neurons thus compromising brain function without inducing cell death.

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

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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.

Increased Blood Levels of Growth Factors, Proinflammatory Cytokines, and Th17 Cytokines in Patients with Newly Diagnosed Type 1 Diabetes.

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Kristi Alnek

Full Text Available The production of several cytokines could be dysregulated in type 1 diabetes (T1D. In particular, the activation of T helper (Th type 1 (Th1 cells has been proposed to underlie the autoimmune pathogenesis of the disease, although roles for inflammatory processes and the Th17 pathway have also been shown. Nevertheless, despite evidence for the role of cytokines before and at the onset of T1D, the corresponding findings are inconsistent across studies. Moreover, conflicting data exist regarding the blood cytokine levels in T1D patients. The current study was performed to investigate genetic and autoantibody markers in association with the peripheral blood cytokine profiles by xMap multiplex technology in newly diagnosed young T1D patients and age-matched healthy controls. The onset of young-age T1D was characterized by the upregulation of growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF and interleukin (IL-7, the proinflammatory cytokine IL-1β (but not IL-6 or tumor necrosis factor [TNF]-α, Th17 cytokines, and the regulatory cytokines IL-10 and IL-27. Ketoacidosis and autoantibodies (anti-IA-2 and -ZnT8, but not human leukocyte antigen (HLA genotype, influenced the blood cytokine levels. These findings broaden the current understanding of the dysregulation of systemic levels of several key cytokines at the young-age onset of T1D and provide a further basis for the development of novel immunoregulatory treatments in this disease.

Dysregulation of Macrophage Activation Profiles by Engineered Nanoparticles

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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

Addictive behaviors and Parkinson's disease.

Science.gov (United States)

Witjas, T; Eusebio, A; Fluchère, F; Azulay, J-P

2012-01-01

In Parkinson's disease, the degeneration of the dopaminergic system and the longstanding exposure to dopamine replacement therapy (DRT) may cause, in a group of vulnerable patients, dysregulation of the brain reward system. These patients develop DRT-related compulsions, which include addiction to levodopa or dopamine dysregulation syndrome (DDS), punding, and impulse control disorders (ICDs). ICDs or behavioral addiction reported in Parkinson's disease include pathological gambling, hypersexuality, compulsive buying and binge eating. Although the underlying pathophysiology is still poorly understood, these behaviors are linked by their reward-based and repetitive nature. Such behaviors may result in devastating psychosocial impairment for the patients and are often hidden. The recognition of these behaviors is important and allows a better clinical management. Although the limited data do not permit particular therapeutic strategies, some approaches are worth considering: DRT reduction, trials of non-dopaminergic medications and subthalamic chronic stimulation. Copyright © 2012. Published by Elsevier Masson SAS.

Iron dysregulation combined with aging prevents sepsis-induced apoptosis.

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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.

Identification of novel target genes involved in Indian Fanconi anemia patients using microarray.

Science.gov (United States)

Shyamsunder, Pavithra; Ganesh, Kripa S; Vidyasekar, Prasanna; Mohan, Sheila; Verma, Rama Shanker

2013-12-01

Fanconi anemia (FA) is a genetic disorder characterized by progressive bone marrow failure and a predisposition to cancers. Mutations have been documented in 15 FA genes that participate in the FA-BRCA DNA repair pathway, a fundamental pathway in the development of the disease and the presentation of its characteristic symptoms. Certain symptoms such as oxygen sensitivity, hematological abnormalities and impaired immunity suggest that FA proteins could participate in or independently control other pathways as well. In this study, we identified 9 DNA repair genes that were down regulated in a genome wide analysis of 6 Indian Fanconi anemia patients. Functional clustering of a total of 233 dysregulated genes identified key biological processes that included regulation of transcription, DNA repair, cell cycle and chromosomal organization. Microarray data revealed the down regulation of ATXN3, ARID4A and ETS-1, which were validated by RTPCR in a subsequent sample set of 9 Indian FA patients. Here we report for the first time a gene expression profile of Fanconi anemia patients from the Indian population and a pool of genes that might aid in the acquisition and progression of the FA phenotype. © 2013 Elsevier B.V. All rights reserved.

Types of adult attention-deficit hyperactivity disorder (ADHD): baseline characteristics, initial response, and long-term response to treatment with methylphenidate.

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Reimherr, Fred W; Marchant, Barrie K; Gift, Thomas E; Steans, Tammy A; Wender, Paul H

2015-06-01

Much recent research describes the importance of emotional symptoms in ADHD. While there is no accepted system for including emotionality in diagnosing ADHD, the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) provides a tool to facilitate this. It assesses a range of adult ADHD symptoms which load on two factors: inattentive and emotional dysregulation. The consistently high inattentive factor was used to define significant elevation on the more variable emotional dysregulation factor (which contains four WRAADDS domains: hyperactivity/restlessness, temper, affective lability, and emotional over-reactivity) allowing the definition of two ADHD diagnostic types. We compared these two types on a broad range of adult subject characteristics, including response to methylphenidate (MPH) treatment assessed during two clinical trials. Marked impairment in three of the four emotional domains reflected a symptom severity level equivalent to that of the inattentive factor. 59 % met this threshold, defining them as ADHD emotion dysregulation presentation, as opposed to 41 % with ADHD inattentive presentation. Cluster analysis validated these groups by generating similar clusters with 85 % agreement regarding membership. ADHD emotional dysregulation presentation subjects showed more childhood ADHD symptoms, adult symptoms of oppositional defiant disorder, and evidence of personality disorder. Both types showed similar improvement during the double-blind MPH arm of the trials and during a 6-month open-label phase. Based on the presence of symptoms of emotional dysregulation, ADHD in adults can be conceptualized as two types. Impairment and comorbidity in adults with ADHD are largely concentrated in ADHD emotional dysregulation presentation patients.

Dysregulated corticostriatal activity in open-field behavior and the head-twitch response induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine.

Science.gov (United States)

Rangel-Barajas, Claudia; Estrada-Sánchez, Ana María; Barton, Scott J; Luedtke, Robert R; Rebec, George V

2017-02-01

The substituted amphetamine, 2,5-dimethoxy-4-iodoamphetamine (DOI), is a hallucinogen that has been used to model a variety of psychiatric conditions. Here, we studied the effect of DOI on neural activity recorded simultaneously in the primary motor cortex (M1) and dorsal striatum of freely behaving FvB/N mice. DOI significantly decreased the firing rate of individually isolated neurons in M1 and dorsal striatum relative to pre-drug baseline. It also induced a bursting pattern of activity by increasing both the number of spikes within a burst and burst duration. In addition, DOI increased coincident firing between simultaneously recorded neuron pairs within the striatum and between M1 and dorsal striatum. Local field potential (LFP) activity also increased in coherence between M1 and dorsal striatum after DOI in the low frequency gamma band (30-50 Hz), while corticostriatal coherence in delta, theta, alpha, and beta activity decreased. We also assessed corticostriatal LFP activity in relation to the DOI-induced head-twitch response (HTR), a readily identifiable behavior used to assess potential treatments for the conditions it models. The HTR was associated with increased delta and decreased theta power in both M1 and dorsal striatum. Together, our results suggest that DOI dysregulates corticostriatal communication and that the HTR is associated with this dysregulation. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

Loss of function mutations in the progranulin gene are related to pro-inflammatory cytokine dysregulation in frontotemporal lobar degeneration patients

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Spalletta Gianfranco

2011-06-01

Full Text Available Abstract The progranulin gene (PGRN encodes a pleiotropic molecule with anti-inflammatory actions and neuronal protective effects. Accordingly, PGRN-deficient mice have been demonstrated to develop enhanced inflammation and progressive neurodegeneration. Loss of function mutations of the PGRN gene have been also reported to cause frontotemporal lobar degeneration (FTLD, a neurodegenerative disease leading to dementia generally in the presenium. Since neurodegeneration might be negatively impacted by chronic inflammation, the possible influence of PGRN defects on inflammatory pathways appears to be of great relevance for the understanding of neurodegeneration pathogenic processes in those patients. However, no data about the inflammatory profile of PGRN-defective subjects have been so far provided. In this study, we analyzed serum levels of the pro-inflammatory mediators IL-6, TNF-α and IL-18 in FTLD patients with or without PGRN mutations, at both pre-symptomatic and symptomatic stages. We provide evidence that circulating IL-6 is increased in PGRN-mutated FTLD patients, as compared to both PGRN non-mutated FTLD patients and controls. In contrast, levels of IL-6 were not altered in asymptomatic subjects carrying the PGRN mutations. Finally, TNF-α and IL-18 serum levels did not differ among all groups of included subjects. We conclude that the profile of circulating pro-inflammatory cytokines is altered in PGRN-related symptomatic FTLD. Thus, our findings point to IL-6 as a possible specific mediator and a potential therapeutic target in this monogenic disease, suggesting that an enhanced inflammatory response might be indeed involved in its progression.

Microvascular decompression for trigeminal neuralgia: comments on a series of 250 cases, including 10 patients with multiple sclerosis.

Science.gov (United States)

Broggi, G; Ferroli, P; Franzini, A; Servello, D; Dones, I

2000-01-01

To examine surgical findings and results of microvascular decompression (MVD) for trigeminal neuralgia (TN), including patients with multiple sclerosis, to bring new insight about the role of microvascular compression in the pathogenesis of the disorder and the role of MVD in its treatment. Between 1990 and 1998, 250 patients affected by trigeminal neuralgia underwent MVD in the Department of Neurosurgery of the "Istituto Nazionale Neurologico C Besta" in Milan. Limiting the review to the period 1991-6, to exclude the "learning period" (the first 50 cases) and patients with less than 1 year follow up, surgical findings and results were critically analysed in 148 consecutive cases, including 10 patients with multiple sclerosis. Vascular compression of the trigeminal nerve was found in all cases. The recurrence rate was 15.3% (follow up 1-7 years, mean 38 months). In five of 10 patients with multiple sclerosis an excellent result was achieved (follow up 12-39 months, mean 24 months). Patients with TN for more than 84 months did significantly worse than those with a shorter history (p<0.05). There was no mortality and most complications occurred in the learning period. Surgical complications were not related to age of the patients. Aetiopathogenesis of trigeminal neuralgia remains a mystery. These findings suggest a common neuromodulatory role of microvascular compression in both patients with or without multiple sclerosis rather than a direct causal role. MVD was found to be a safe and effective procedure to relieve typical TN in patients of all ages. It should be proposed as first choice surgery to all patients affected by TN, even in selected cases with multiple sclerosis, to give them the opportunity of pain relief without sensory deficits.

Appraisal Of Quality Of Life Of Diabetic Patients, Including Life ...

African Journals Online (AJOL)

The review showed that patients with diabetes mellitus had signi cantly low ... of life (physical health, psychological health, social relations, and environment). ... of quality of life regarding gender, age, or the level of education of the patients. ... neuropathy, impaired vision, elevated blood lipids and amputation of toes or feet.

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.

The Kynurenine Pathway: a Proposed Mechanism Linking Diabetes and Periodontal Disease in Diabetic Patients

OpenAIRE

Rishabh Kapila; KS Nagesh; Asha R. Iyengar; Subash BV. Adiga

2011-01-01

Introduction: Diabetes mellitus is a metabolic disease characte-rized by dysregulation of carbohydrate, protein and lipid metabolism. Diabetes could result, in part, in activation of tryptophan metabolism. Diabetic patients are more susceptible to gingivitis and periodontitis than healthy subjects. The salivary kynurenine derivatives are also implicated in the onset and development of periodontal dis-ease in humans.The hypothesis: We propose that the tryptophan metabolites via kynurenine path...

Patient experienced continuity of care in the psychiatric healthcare system-a study including immigrants, refugees and ethnic danes.

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Jensen, Natasja Koitzsch; Johansen, Katrine Schepelern; Kastrup, Marianne; Krasnik, Allan; Norredam, Marie

2014-09-17

The purpose of this study was to investigate continuity of care in the psychiatric healthcare system from the perspective of patients, including vulnerable groups such as immigrants and refugees. The study is based on 19 narrative interviews conducted with 15 patients with diverse migration backgrounds (immigrants, descendents, refugees, and ethnic Danes). Patients were recruited from a community psychiatric centre situated in an area with a high proportion of immigrants and refugees. Data were analysed through the lens of a theoretical framework of continuity of care in psychiatry, developed in 2004 by Joyce et al., which encompasses four domains: accessibility, individualised care, relationship base and service delivery. Investigating continuity of care, we found issues of specific concern to immigrants and refugees, but also commonalities across the groups. For accessibility, areas pertinent to immigrants and refugees include lack of knowledge concerning mental illness and obligations towards children. In terms of individualised care, trauma, additional vulnerability, and taboo concerning mental illness were of specific concern. In the domain of service delivery, social services included assistance with immigration papers for immigrants and refugees. In the relationship base domain, no differences were identified. Implications for priority area: The treatment courses of patients in the psychiatric field are complex and diverse and the patient perspective of continuity of care provides important insight into the delivery of care. The study highlights the importance of person-centred care irrespective of migration background though it may be beneficial to have an awareness of areas that may be of more specific concern to immigrants and refugees. The study sheds light on concerns specific to immigrants and refugees in a framework of continuity of care, but also commonalities across the patient groups.

Intraerythrocyte and serum electrolytes in diabetic patients hypertension

International Nuclear Information System (INIS)

Yasmin, F.; Haleem, D.J.; Haleem, M. A.

2006-01-01

To determine the serum and intraerythrocyte concentrations of vasoactive ions in patients of diabetes mellitus of either gender with hypertension. The study was conducted on 48 volunteers. Out of 48, 24(12 men and 12 women) were hypertensive patients with diabetes mellitus. Remaining (12 men and 12 women) were normal healthy subjects. Biochemical estimations were done by flame photometry and spectrophotometry. Data were analyzed by Two-way ANOVA followed by Newman-Keuls test. A decrease in serum concentrations of sodium, calcium, magnesium, phosphorus, chloride and intraerythrocyte potassium and an increase in the levels of glucose, haematocrit and intraerythrocyte sodium was observed in both male and female patients with diabetes mellitus and hypertension. No significant changes were observed in serum potassium levels. The results suggest that dysregulations of electrolyte balance caused by hyperinsulinemia or altered glucose metabolism may lead to hypertension. (author)

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.

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.

Should metformin be included in fertility treatment of PCOS patients?

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Haas, Jigal; Bentov, Yaakov

2017-03-01

Metformin, a drug developed for the treatment of patients with type II diabetes, has become commonly prescribed medication for PCOS patients. Initially, metformin was prescribed for patients with impaired glucose tolerance at the pre conception period, however more recently its use was expanded to many of the PCOS patients and for the whole duration of pregnancy. Several studies examining the effects of Metformin during pregnancy reported a lower pregnancy loss, reduced gestational diabetes and no increased risk for birth defects, however, several more recent studies also raised concerns about its safe use. The therapeutic effect of metformin stems from its ability to inhibit the action of the first complex of the electron transport resulting in reduced ATP production. At the initial stages of embryo development, the only source of ATP is the mitochondrial electron transport chain. Lowering ATP production at the critical stage of early embryo development may impair oocyte maturation and embryo development as well as reprogram the metabolic characteristics of the offspring. Copyright © 2017 Elsevier Ltd. All rights reserved.

Anesthetic Management of Narcolepsy Patients During Surgery: A Systematic Review.

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Hu, Sally; Singh, Mandeep; Wong, Jean; Auckley, Dennis; Hershner, Shelley; Kakkar, Rahul; Thorpy, Michael J; Chung, Frances

2018-01-01

Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness, sleep paralysis, and/or hypnagogic/hypnopompic hallucinations, and in some cases cataplexy. The response to anesthetic medications and possible interactions in narcolepsy patients is unclear in the perioperative period. In this systematic review, we aim to evaluate the current evidence on the perioperative outcomes and anesthetic considerations in narcolepsy patients. Electronic literature search of Medline, Medline in-process, Embase, Cochrane Database of Systematic Reviews databases, international conference proceedings, and abstracts was conducted in November 2015 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guideline. A total of 3757 articles were screened using a 2-stage strategy (title-abstract followed by full text). We included case studies/series, cohort studies, and randomized controlled trials of narcolepsy patients undergoing surgical procedures under anesthesia or sedation. Preoperative narcolepsy symptoms and sleep study data, anesthetic technique, and perioperative complications were extracted. Screening of articles, data extraction, and compilation were conducted by 2 independent reviewers and any conflict was resolved by the senior author. A total of 19 studies including 16 case reports and 3 case series were included and evaluated. The majority of these patients received general anesthesia, whereas a small percentage of patients received regional anesthesia. Reported complications of narcolepsy patients undergoing surgeries were mainly related to autonomic dysregulation, or worsening of narcolepsy symptoms intra/postoperatively. Narcolepsy symptoms worsened only in those patient populations where the preoperative medications were either discontinued or reduced (mainly in obstetric patients). In narcolepsy patients, use of depth of anesthesia monitoring and total intravenous technique may have some advantage in terms

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

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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

Neural correlates of emotional distractibility in bipolar disorder patients, unaffected relatives, and individuals with hypomanic personality.

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Kanske, Philipp; Heissler, Janine; Schönfelder, Sandra; Forneck, Johanna; Wessa, Michèle

2013-12-01

Neuropsychological deficits and emotion dysregulation are present in symptomatic and euthymic patients with bipolar disorder. However, there is little evidence on how cognitive functioning is influenced by emotion, what the neural correlates of emotional distraction effects are, and whether such deficits are a consequence or a precursor of the disorder. The authors used functional MRI (fMRI) to investigate these questions. fMRI was used first to localize the neural network specific to a certain cognitive task (mental arithmetic) and then to test the effect of emotional distractors on this network. Euthymic patients with bipolar I disorder (N=22), two populations at high risk for developing the disorder (unaffected first-degree relatives of individuals with bipolar disorder [N=17]), and healthy participants with hypomanic personality traits [N=22]) were tested, along with three age-, gender-, and education-matched healthy comparison groups (N=22, N=17, N=24, respectively). There were no differences in performance or activation in the task network for mental arithmetic. However, while all participants exhibited slower responses when emotional distractors were present, this response slowing was greatly enlarged in bipolar patients. Similarly, task-related activation was generally increased under emotional distraction; however, bipolar patients exhibited a further increase in right parietal activation that correlated positively with the response slowing effect. The results suggest that emotional dysregulation leads to exacerbated neuropsychological deficits in bipolar patients, as evidenced by behavioral slowing and task-related hyperactivation. The lack of such a deficit in high-risk populations suggests that it occurs only after disease onset, rather than representing a vulnerability marker.

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.

Increased level of miRNA 30b-3p in patients with prostatic hyperplasia and testosterone with high-level of prostate-specific antigen

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Wasnaa Jumaa Mohammad

2018-01-01

Full Text Available Background: Prostate cancer (PCa is the most common causing cancer-related in death in men and lack of reliable diagnostic tool. MicroRNAs are small molecules single-stranded RNA that affecting protein expression at the level of translation and dysregulation can dramatically affect cell metabolism. However, the using of circulating miRNAs as diagnostic biomarkers for diagnosis of PCa is still unknown. Methods: Ten patients with prostatic hyperplasia with high-level of PSA and 10 healthy controls were conducted in this study. The reverse transcription of miRNA based on quantitative polymerase chain reaction (qPCR were used for evaluating the dysregulation of miRNA 30b-3p and using of ELISA to evaluate the level of prostate-specific antigen (PSA and testosterone hormone. Results: Circulating miRNA 30b-3p level was increased in patients with prostatic hyperplasia with higher level of PSA as compared with healthy controls. Also, the testosterone hormone was increased in those patients as compared with normal level of testosterone in healthy individuals. Conclusion: The serum miRNA 30b-3p level increased in patients with hyperplasia in prostate and may be one of potential biomarker for diagnosis of PCa.

CRISPR/Cas9-mediated targeted gene correction in amyotrophic lateral sclerosis patient iPSCs

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Lixia Wang

2017-04-01

Full Text Available Abstract Amyotrophic lateral sclerosis (ALS is a complex neurodegenerative disease with cellular and molecular mechanisms yet to be fully described. Mutations in a number of genes including SOD1 and FUS are associated with familial ALS. Here we report the generation of induced pluripotent stem cells (iPSCs from fibroblasts of familial ALS patients bearing SOD1 +/A272C and FUS +/G1566A mutations, respectively. We further generated gene corrected ALS iPSCs using CRISPR/Cas9 system. Genome-wide RNA sequencing (RNA-seq analysis of motor neurons derived from SOD1 +/A272C and corrected iPSCs revealed 899 aberrant transcripts. Our work may shed light on discovery of early biomarkers and pathways dysregulated in ALS, as well as provide a basis for novel therapeutic strategies to treat ALS.

CHARACTERISTICS OF PATIENTS WITH CEREBRAL STROKE OR TRANSIENT ISCHEMIC ATTACK, INCLUDED INTO THE LIS-2 REGISTER (LYUBERTSY STUDY OF MORTALITY IN PATIENTS AFTER STROKE

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S. Yu. Martsevich

2015-01-01

Full Text Available Aim. To provide final data on the three-year period of the inclusion of patients; to give most accurate "portrait" of patients hospitalized with a brain stroke within the framework of the LIS-2 register (Lyubertsy study of mortality in patients after stroke.Material and methods. All patients (n=960 admitted to the Lyubertsy district hospital №2 with stroke for the period from 01.2009 to 12.2011 were included into the study.Results. Men accounted for 37.5%, women - 62.5%, mean age was 71.1±9.8 years. The history of hypertension was present in 833 patients (86.8%, atrial fibrillation in 252 (26.8% patients, 199 (20.7% patients had previously undergone stroke. In-hospital mortality was 21.6% (207 patients had died; mean age 72.9±9.8 years. Low frequency of the antihypertensive therapy (34.5%, lipid-lowering therapy (0.7%, antiplatelet agents (5.7%, anticoagulation therapy prescription in patients with atrial fibrillation was detected.Conclusion. Insufficient assignment of drugs with a proven effect on the prognosis in patients with risk factors prior to the development of the reference stroke draws attention. High incidence of recurrent strokes indicates an underactive secondary prevention.

Contributors to Frequent Telehealth Alerts Including False Alerts for Patients with Heart Failure: A Mixed Methods Exploration

Science.gov (United States)

Radhakrishna, K.; Bowles, K.; Zettek-Sumner, A.

2013-01-01

Summary Background Telehealth data overload through high alert generation is a significant barrier to sustained adoption of telehealth for managing HF patients. Objective To explore the factors contributing to frequent telehealth alerts including false alerts for Medicare heart failure (HF) patients admitted to a home health agency. Materials and Methods A mixed methods design that combined quantitative correlation analysis of patient characteristic data with number of telehealth alerts and qualitative analysis of telehealth and visiting nurses’ notes on follow-up actions to patients’ telehealth alerts was employed. All the quantitative and qualitative data was collected through retrospective review of electronic records of the home heath agency. Results Subjects in the study had a mean age of 83 (SD = 7.6); 56% were female. Patient co-morbidities (ppatient characteristics along with establishing patient-centered telehealth outcome goals may allow meaningful generation of telehealth alerts. Reducing avoidable telehealth alerts could vastly improve the efficiency and sustainability of telehealth programs for HF management. PMID:24454576

African-American esophageal squamous cell carcinoma expression profile reveals dysregulation of stress response and detox networks.

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Erkizan, Hayriye Verda; Johnson, Kory; Ghimbovschi, Svetlana; Karkera, Deepa; Trachiotis, Gregory; Adib, Houtan; Hoffman, Eric P; Wadleigh, Robert G

2017-06-19

Esophageal carcinoma is the third most common gastrointestinal malignancy worldwide and is largely unresponsive to therapy. African-Americans have an increased risk for esophageal squamous cell carcinoma (ESCC), the subtype that shows marked variation in geographic frequency. The molecular architecture of African-American ESCC is still poorly understood. It is unclear why African-American ESCC is more aggressive and the survival rate in these patients is worse than those of other ethnic groups. To begin to define genetic alterations that occur in African-American ESCC we conducted microarray expression profiling in pairs of esophageal squamous cell tumors and matched control tissues. We found significant dysregulation of genes encoding drug-metabolizing enzymes and stress response components of the NRF2- mediated oxidative damage pathway, potentially representing key genes in African-American esophageal squamous carcinogenesis. Loss of activity of drug metabolizing enzymes would confer increased sensitivity of esophageal cells to xenobiotics, such as alcohol and tobacco smoke, and may account for the high incidence and aggressiveness of ESCC in this ethnic group. To determine whether certain genes are uniquely altered in African-American ESCC we performed a meta-analysis of ESCC expression profiles in our African-American samples and those of several Asian samples. Down-regulation of TP53 pathway components represented the most common feature in ESCC of all ethnic groups. Importantly, this analysis revealed a potential distinctive molecular underpinning of African-American ESCC, that is, a widespread and prominent involvement of the NRF2 pathway. Taken together, these findings highlight the remarkable interplay of genetic and environmental factors in the pathogenesis of African-American ESCC.

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

Identification of the miRNA-mRNA regulatory network of small cell osteosarcoma based on RNA-seq.

Science.gov (United States)

Xie, Lin; Liao, Yedan; Shen, Lida; Hu, Fengdi; Yu, Sunlin; Zhou, Yonghong; Zhang, Ya; Yang, Yihao; Li, Dongqi; Ren, Minyan; Yuan, Zhongqin; Yang, Zuozhang

2017-06-27

Small cell osteosarcoma (SCO) is a rare subtype of osteosarcoma characterized by highly aggressive progression and a poor prognosis. The miRNA and mRNA expression profiles of peripheral blood mononuclear cells (PBMCs) were obtained in 3 patients with SCO and 10 healthy individuals using high-throughput RNA-sequencing. We identified 37 dysregulated miRNAs and 1636 dysregulated mRNAs in patients with SCO compared to the healthy controls. Specifically, the 37 dysregulated miRNAs consisted of 27 up-regulated miRNAs and 10 down-regulated miRNAs; the 1636 dysregulated mRNAs consisted of 555 up-regulated mRNAs and 1081 down-regulated mRNAs. The target-genes of miRNAs were predicted, and 1334 negative correlations between miRNAs and mRNAs were used to construct an miRNA-mRNA regulatory network. Dysregulated genes were significantly enriched in pathways related to cancer, mTOR signaling and cell cycle signaling. Specifically, hsa-miR-26b-5p, hsa-miR-221-3p and hsa-miR-125b-2-3p were significantly dysregulated miRNAs and exhibited a high degree of connectivity with target genes. Overall, the expression of dysregulated genes in tumor tissues and peripheral blood samples of patients with SCO measured by quantitative real-time polymerase chain reaction corroborated with our bioinformatics analyses based on the expression profiles of PBMCs from patients with SCO. Thus, hsa-miR-26b-5p, hsa-miR-221-3p and hsa-miR-125b-2-3p may be involved in SCO tumorigenesis.

Comparison of global gene expression of gastric cardia and noncardia cancers from a high-risk population in china.

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Gangshi Wang

Full Text Available To profile RNA expression in gastric cancer by anatomic subsites as an initial step in identifying molecular subtypes and providing targets for early detection and therapy.We performed transcriptome analysis using the Affymetrix GeneChip U133A in gastric cardia adenocarcinomas (n = 62 and gastric noncardia adenocarcinomas (n = 72 and their matched normal tissues from patients in Shanxi Province, and validated selected dysregulated genes with additional RNA studies. Expression of dysregulated genes was also related to survival of cases.Principal Component Analysis showed that samples clustered by tumor vs. normal, anatomic location, and histopathologic features. Paired t-tests of tumor/normal tissues identified 511 genes whose expression was dysregulated (P<4.7E-07 and at least two-fold difference in magnitude in cardia or noncardia gastric cancers, including nearly one-half (n = 239, 47% dysregulated in both cardia and noncardia, one-fourth dysregulated in cardia only (n = 128, 25%, and about one-fourth in noncardia only (n = 144, 28%. Additional RNA studies confirmed profiling results. Expression was associated with case survival for 20 genes in cardia and 36 genes in noncardia gastric cancers.The dysregulated genes identified here represent a comprehensive starting point for future efforts to understand etiologic heterogeneity, develop diagnostic biomarkers for early detection, and test molecularly-targeted therapies for gastric cancer.

Using machine learning and surface reconstruction to accurately differentiate different trajectories of mood and energy dysregulation in youth.

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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

Using machine learning and surface reconstruction to accurately differentiate different trajectories of mood and energy dysregulation in youth.

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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

Long-term pain relief with optimized medical treatment including antioxidants and step-up interventional therapy in patients with chronic pancreatitis.

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Shalimar; Midha, Shallu; Hasan, Ajmal; Dhingra, Rajan; Garg, Pramod Kumar

2017-01-01

Abdominal pain is difficult to treat in patients with chronic pancreatitis (CP). Medical therapy including antioxidants has been shown to relieve pain of CP in the short-term. Our aim was to study the long-term results of optimized medical and interventional therapy for pain relief in patients with CP with a step-up approach. All consecutive patients with CP were included prospectively in the study. They were treated medically with a well-balanced diet, pancreatic enzymes, and antioxidants (9000 IU beta-carotene, 0.54 g vitamin C, 270 IU vitamin E, 600 µg organic selenium, and 2 g methionine). Endoscopic therapy and/or surgery were offered if medical therapy failed. Pain relief was the primary outcome measure. A total of 313 patients (mean age 26.16 ± 12.17; 244 males) with CP were included; 288 (92%) patients had abdominal pain. The etiology of CP was idiopathic in 224 (71.6%) and alcohol in 82 (26.2%). At 1-year follow-up, significant pain relief was achieved in 84.7% of patients: 52.1% with medical therapy, 16.7% with endoscopic therapy, 7.6% with surgery, and 8.3% spontaneously. The mean pain score decreased from 6.36 ± 1.92 to 1.62 ± 2.10 (P pain free at those follow-up periods. Significant pain relief is achieved in the majority of patients with optimized medical and interventional treatment. © 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

The clinical correlation of regulatory T cells and cyclic adenosine monophosphate in enterovirus 71 infection.

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Shih-Min Wang

Full Text Available Brainstem encephalitis (BE and pulmonary edema (PE are notable complications of enterovirus 71 (EV71 infection.This study investigated the immunoregulatory characterizations of EV71 neurological complications by disease severity and milrinone treatment.Patients <18 years with virologically confirmed EV71 infections were enrolled and divided into 2 groups: the hand, foot, and mouth disease (HFMD or BE group, and the autonomic nervous system (ANS dysregulation or PE group. Cytokine and cyclic adenosine monophosphate (cAMP levels, and the regulatory T cell (Tregs profiles of the patients were determined.Patients with ANS dysregulation or PE exhibited significantly low frequency of CD4(+CD25(+Foxp3+ and CD4(+Foxp3(+ T cells compared with patients with HFMD or BE. The expression frequency of CD4-CD8- was also significantly decreased in patients with ANS dysregulation or PE. Among patients with ANS dysregulation or PE, the expression frequency of CD4+Foxp3+ increased markedly after milrinone treatment, and was associated with reduction of plasma levels IL-6, IL-8 and IL-10. Plasma concentrations of cAMP were significantly decreased in patients with ANS dysregulation or PE compared with patients with HFMD or BE; however, cAMP levels increased after milrinone treatment.These findings suggested decreased different regulatory T populations and cAMP expression correlate with increased EV71 disease severity. Improved outcome after milrinone treatment may associate with increased regulatory T populations, cAMP expression and modulation of cytokines levels.

The Bioinformatic Analysis of the Dysregulated Genes and MicroRNAs in Entorhinal Cortex, Hippocampus, and Blood for Alzheimer’s Disease

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Xiaocong Pang

2017-01-01

Full Text Available Aim. The incidence of Alzheimer’s disease (AD has been increasing in recent years, but there exists no cure and the pathological mechanisms are not fully understood. This study aimed to find out the pathogenesis of learning and memory impairment, new biomarkers, potential therapeutic targets, and drugs for AD. Methods. We downloaded the microarray data of entorhinal cortex (EC and hippocampus (HIP of AD and controls from Gene Expression Omnibus (GEO database, and then the differentially expressed genes (DEGs in EC and HIP regions were analyzed for functional and pathway enrichment. Furthermore, we utilized the DEGs to construct coexpression networks to identify hub genes and discover the small molecules which were capable of reversing the gene expression profile of AD. Finally, we also analyzed microarray and RNA-seq dataset of blood samples to find the biomarkers related to gene expression in brain. Results. We found some functional hub genes, such as ErbB2, ErbB4, OCT3, MIF, CDK13, and GPI. According to GO and KEGG pathway enrichment, several pathways were significantly dysregulated in EC and HIP. CTSD and VCAM1 were dysregulated significantly in blood, EC, and HIP, which were potential biomarkers for AD. Target genes of four microRNAs had similar GO_terms distribution with DEGs in EC and HIP. In addtion, small molecules were screened out for AD treatment. Conclusion. These biological pathways and DEGs or hub genes will be useful to elucidate AD pathogenesis and identify novel biomarkers or drug targets for developing improved diagnostics and therapeutics against AD.

Differential expression of NK receptors CD94 and NKG2A by T cells in rheumatoid arthritis patients in remission compared to active disease.

LENUS (Irish Health Repository)

Walsh, Ceara E

2011-01-01

TNF inhibitors (TNFi) have revolutionised the treatment of rheumatoid arthritis (RA). Natural killer (NK) cells and Natural Killer Cell Receptor+ T (NKT) cells comprise important effector lymphocytes whose activity is tightly regulated through surface NK receptors (NKRs). Dysregulation of NKRs in patients with autoimmune diseases has been shown, however little is known regarding NKRs expression in patients with TNFi-induced remission and in those who maintain remission vs disease flare following TNFi withdrawal.

Expression patterns of signaling lymphocytic activation molecule family members in peripheral blood mononuclear cell subsets in patients with systemic lupus erythematosus.

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Karampetsou, Maria P; Comte, Denis; Kis-Toth, Katalin; Kyttaris, Vasileios C; Tsokos, George C

2017-01-01

Genome-wide linkage analysis studies (GWAS) studies in systemic lupus erythematosus (SLE) identified the 1q23 region on human chromosome 1, containing the Signaling Lymphocytic Activation Molecule Family (SLAMF) cluster of genes, as a lupus susceptibility locus. The SLAMF molecules (SLAMF1-7) are immunoregulatory receptors expressed predominantly on hematopoietic cells. Activation of cells of the adaptive immune system is aberrant in SLE and dysregulated expression of certain SLAMF molecules has been reported. We examined the expression of SLAMF1-7 on peripheral blood T cells, B cells, monocytes, and their respective differentiated subsets, in patients with SLE and healthy controls in a systematic manner. SLAMF1 levels were increased on both T cell and B cells and their differentiated subpopulations in patients with SLE. SLAMF2 was increased on SLE CD4+ and CD8+ T cells. The frequency of SLAMF4+ and SLAMF7+ central memory and effector memory CD8+ T cells was reduced in SLE patients. Naïve CD4+ and CD8+ SLE T cells showed a slight increase in SLAMF3 levels. No differences were seen in the expression of SLAMF5 and SLAMF6 among SLE patients and healthy controls. Overall, the expression of various SLAMF receptors is dysregulated in SLE and may contribute to the immunopathogenesis of the disease.

Prevalence of pain medication prescriptions in France, Germany, and the UK - a cross-sectional study including 4,270,142 patients.

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Jacob, Louis; Kostev, Karel

2018-01-01

The goal of the present study was to analyze the prevalence of pain medication prescriptions in general practices in France, Germany, and the UK. This study included all patients aged ≥18 years followed in 2016 in general practitioner practices in France, Germany and the UK. The primary outcome was the prevalence of patients receiving prescriptions for pain medications in France, Germany, and the UK in 2016. The following drugs were included in the analysis: anti-inflammatory and antirheumatic products, non-steroids and analgesics including opioids, antimigraine preparations, and other analgesics and antipyretics. Demographic variables included age and gender. This study included 4,270,142 patients. The prevalences of pain medication prescriptions were 57.3% in France, 29.6% in Germany, and 21.7% in the UK. Although this prevalence generally remained consistent between age groups in France (54.3%-60.3%), it increased with age in Germany (18-30 years: 23.8%; >70 years: 35.8%) and in the UK (18-30 years: 9.3%; >70 years: 43.8%). Finally, the prevalence of pain medication prescriptions was higher in women than in men in all three countries. Paracetamol was prescribed to 82.3% and 60.1% of patients receiving pain medication in France and the UK, respectively, whereas ibuprofen was prescribed to 46.5% of individuals in Germany. The prevalence of pain medication prescriptions was higher in France than in Germany and the UK. Further research is needed to gain a better understanding of the differences in the prescription patterns between these three European countries.

Preferences for Depression Treatment Including Internet-Based Interventions: Results From a Large Sample of Primary Care Patients

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Marie Dorow

2018-05-01

Full Text Available Background: To date, little is known about treatment preferences for depression concerning new media. This study aims to (1 investigate treatment preferences for depression including internet-based interventions and (2 examine subgroup differences concerning age, gender and severity of depression as well as patient-related factors associated with treatment preferences.Methods: Data were derived from the baseline assessment of the @ktiv-trial. Depression treatment preferences were assessed from n = 641 primary care patients with mild to moderate depression regarding the following treatments: medication, psychotherapy, combined treatment, alternative treatment, talking to friends and family, exercise, self-help literature, and internet-based interventions. Depression severity was specified by GPs according to ICD-10 criteria. Ordinal logistic regression models were conducted to identify associated factors of treatment preferences.Results: Patients had a mean age of 43.9 years (SD = 13.8 and more than two thirds (68.6% were female. About 43% of patients had mild depression while 57% were diagnosed with moderate depression. The majority of patients reported strong preferences for psychotherapy, talking to friends and family, and exercise. About one in five patients was very likely to consider internet-based interventions in case of depression. Younger patients expressed significantly stronger treatment preferences for psychotherapy and internet-based interventions than older patients. The most salient factors associated with treatment preferences were the patients' education and perceived self-efficacy.Conclusions: Patients with depression report individually different treatment preferences.Our results underline the importance of shared decision-making within primary care. Future studies should investigate treatment preferences for different types of internet-based interventions.

Non-invasive coronary angiography for patients with acute atypical chest pain discharged after negative screening including maximal negative treadmill stress test. A prospective study.

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Bonello, L; Armero, S; Jacquier, A; Com, O; Sarran, A; Sbragia, P; Panuel, M; Arques, S; Paganelli, F

2009-05-01

Among patients admitted in the emergency department for acute atypical chest pain those with an acute coronary syndrome (ACS) who are mistakenly discharged home have high mortality. A recent retrospective study has demonstrated that multislice computed tomography (MSCT) coronary angiography could improve triage of these patients. We aimed to prospectively confirm these data on patients with a negative screening including maximal treadmill stress. 30 patients discharged from the emergency department after negative screening for an ACS were included. All patients underwent MSCT angiography of the coronary artery. Patients with coronary atheroma on MSCT had an invasive coronary angiography to confirm these findings. Seven patients (23%) had obstructive coronary artery disease on MSCT. Invasive coronary angiography (ICA) confirmed the diagnosis in all patients. In patients with no previously known coronary artery disease admitted to the emergency department with atypical acute chest pain and discharged after negative screening, including maximal treadmill stress test, MSCT coronary angiography is useful for the diagnosis of obstructive coronary artery disease.

N-of-1-pathways MixEnrich: advancing precision medicine via single-subject analysis in discovering dynamic changes of transcriptomes.

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Li, Qike; Schissler, A Grant; Gardeux, Vincent; Achour, Ikbel; Kenost, Colleen; Berghout, Joanne; Li, Haiquan; Zhang, Hao Helen; Lussier, Yves A

2017-05-24

Transcriptome analytic tools are commonly used across patient cohorts to develop drugs and predict clinical outcomes. However, as precision medicine pursues more accurate and individualized treatment decisions, these methods are not designed to address single-patient transcriptome analyses. We previously developed and validated the N-of-1-pathways framework using two methods, Wilcoxon and Mahalanobis Distance (MD), for personal transcriptome analysis derived from a pair of samples of a single patient. Although, both methods uncover concordantly dysregulated pathways, they are not designed to detect dysregulated pathways with up- and down-regulated genes (bidirectional dysregulation) that are ubiquitous in biological systems. We developed N-of-1-pathways MixEnrich, a mixture model followed by a gene set enrichment test, to uncover bidirectional and concordantly dysregulated pathways one patient at a time. We assess its accuracy in a comprehensive simulation study and in a RNA-Seq data analysis of head and neck squamous cell carcinomas (HNSCCs). In presence of bidirectionally dysregulated genes in the pathway or in presence of high background noise, MixEnrich substantially outperforms previous single-subject transcriptome analysis methods, both in the simulation study and the HNSCCs data analysis (ROC Curves; higher true positive rates; lower false positive rates). Bidirectional and concordant dysregulated pathways uncovered by MixEnrich in each patient largely overlapped with the quasi-gold standard compared to other single-subject and cohort-based transcriptome analyses. The greater performance of MixEnrich presents an advantage over previous methods to meet the promise of providing accurate personal transcriptome analysis to support precision medicine at point of care.

Serum proteomics reveals systemic dysregulation of innate immunity in type 1 diabetes

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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.

Interleukin-6-deficient mice refractory to IgA dysregulation but not anorexia induction by vomitoxin (deoxynivalenol) ingestion.

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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.

Dynamic ligand modulation of EPO receptor pools, and dysregulation by polycythemia-associated EPOR alleles.

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Seema Singh

Full Text Available Erythropoietin (EPO and its cell surface receptor (EPOR are essential for erythropoiesis; can modulate non-erythroid target tissues; and have been reported to affect the progression of certain cancers. Basic studies of EPOR expression and trafficking, however, have been hindered by low-level EPOR occurrence, and the limited specificity of anti-EPOR antibodies. Consequently, these aspects of EPOR biology are not well defined, nor are actions of polycythemia- associated mutated EPOR alleles. Using novel rabbit monoclonal antibodies to intracellular, PY- activated and extracellular EPOR domains, the following properties of the endogenous hEPOR in erythroid progenitors first are unambiguously defined. 1 High- Mr EPOR forms become obviously expressed only when EPO is limited. 2 EPOR-68K plus -70K species sequentially accumulate, and EPOR-70K comprises an apparent cell surface EPOR population. 3 Brefeldin A, N-glycanase and associated analyses point to EPOR-68K as a core-glycosylated intracellular EPOR pool (of modest size. 4 In contrast to recent reports, EPOR inward trafficking is shown (in UT7epo cells, and primary proerythroblasts to be sharply ligand-dependent. Beyond this, when C-terminal truncated hEPOR-T mutant alleles as harbored by polycythemia patients are co-expressed with the wild-type EPOR in EPO-dependent erythroid progenitors, several specific events become altered. First, EPOR-T alleles are persistently activated upon EPO- challenge, yet are also subject to apparent turn-over (to low-Mr EPOR products. Furthermore, during exponential cell growth EPOR-T species become both over-represented, and hyper-activated. Interestingly, EPOR-T expression also results in an EPO dose-dependent loss of endogenous wild-type EPOR's (and, therefore, a squelching of EPOR C-terminal- mediated negative feedback effects. New knowledge concerning regulated EPOR expression and trafficking therefore is provided, together with new insight into mechanisms via

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

Erythropoietin (EPO) and its cell surface receptor (EPOR) are essential for erythropoiesis; can modulate non-erythroid target tissues; and have been reported to affect the progression of certain cancers. Basic studies of EPOR expression and trafficking, however, have been hindered by low-level EPOR occurrence, and the limited specificity of anti-EPOR antibodies. Consequently, these aspects of EPOR biology are not well defined, nor are actions of polycythemia- associated mutated EPOR alleles. Using novel rabbit monoclonal antibodies to intracellular, PY- activated and extracellular EPOR domains, the following properties of the endogenous hEPOR in erythroid progenitors first are unambiguously defined. 1) High- Mr EPOR forms become obviously expressed only when EPO is limited. 2) EPOR-68K plus -70K species sequentially accumulate, and EPOR-70K comprises an apparent cell surface EPOR population. 3) Brefeldin A, N-glycanase and associated analyses point to EPOR-68K as a core-glycosylated intracellular EPOR pool (of modest size). 4) In contrast to recent reports, EPOR inward trafficking is shown (in UT7epo cells, and primary proerythroblasts) to be sharply ligand-dependent. Beyond this, when C-terminal truncated hEPOR-T mutant alleles as harbored by polycythemia patients are co-expressed with the wild-type EPOR in EPO-dependent erythroid progenitors, several specific events become altered. First, EPOR-T alleles are persistently activated upon EPO- challenge, yet are also subject to apparent turn-over (to low-Mr EPOR products). Furthermore, during exponential cell growth EPOR-T species become both over-represented, and hyper-activated. Interestingly, EPOR-T expression also results in an EPO dose-dependent loss of endogenous wild-type EPOR's (and, therefore, a squelching of EPOR C-terminal- mediated negative feedback effects). New knowledge concerning regulated EPOR expression and trafficking therefore is provided, together with new insight into mechanisms via which

Neural circuitry of masked emotional face processing in youth with bipolar disorder, severe mood dysregulation, and healthy volunteers.

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Thomas, Laura A; Brotman, Melissa A; Bones, Brian L; Chen, Gang; Rosen, Brooke H; Pine, Daniel S; Leibenluft, Ellen

2014-04-01

Youth with bipolar disorder (BD) and those with severe, non-episodic irritability (severe mood dysregulation, SMD) show face-emotion labeling deficits. These groups differ from healthy volunteers (HV) in neural responses to emotional faces. It is unknown whether awareness is required to elicit these differences. We compared activation in BD (N=20), SMD (N=18), and HV (N=22) during "Aware" and "Non-aware" priming of shapes by emotional faces. Subjects rated how much they liked the shape. In aware, a face (angry, fearful, happy, neutral, blank oval) appeared (187 ms) before the shape. In non-aware, a face appeared (17 ms), followed by a mask (170 ms), and shape. A Diagnosis-by-Awareness-by-Emotion ANOVA was not significant. There were significant Diagnosis-by-Awareness interactions in occipital regions. BD and SMD showed increased activity for non-aware vs. aware; HV showed the reverse pattern. When subjects viewed angry or neutral faces, there were Emotion-by-Diagnosis interactions in face-emotion processing regions, including the L precentral gyrus, R posterior cingulate, R superior temporal gyrus, R middle occipital gyrus, and L medial frontal gyrus. Regardless of awareness, BD and SMD differ in activation patterns from HV and each other in multiple brain regions, suggesting that BD and SMD are distinct developmental mood disorders. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Neural circuitry of masked emotional face processing in youth with bipolar disorder, severe mood dysregulation, and healthy volunteers

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Laura A. Thomas

2014-04-01

Full Text Available Youth with bipolar disorder (BD and those with severe, non-episodic irritability (severe mood dysregulation, SMD show face-emotion labeling deficits. These groups differ from healthy volunteers (HV in neural responses to emotional faces. It is unknown whether awareness is required to elicit these differences. We compared activation in BD (N = 20, SMD (N = 18, and HV (N = 22 during “Aware” and “Non-aware” priming of shapes by emotional faces. Subjects rated how much they liked the shape. In aware, a face (angry, fearful, happy, neutral, blank oval appeared (187 ms before the shape. In non-aware, a face appeared (17 ms, followed by a mask (170 ms, and shape. A Diagnosis-by-Awareness-by-Emotion ANOVA was not significant. There were significant Diagnosis-by-Awareness interactions in occipital regions. BD and SMD showed increased activity for non-aware vs. aware; HV showed the reverse pattern. When subjects viewed angry or neutral faces, there were Emotion-by-Diagnosis interactions in face-emotion processing regions, including the L precentral gyrus, R posterior cingulate, R superior temporal gyrus, R middle occipital gyrus, and L medial frontal gyrus. Regardless of awareness, BD and SMD differ in activation patterns from HV and each other in multiple brain regions, suggesting that BD and SMD are distinct developmental mood disorders.

Combined pharmacotherapy-multimodal psychotherapy in children with Disruptive Behavior Disorders.

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Masi, Gabriele; Milone, Annarita; Manfredi, Azzurra; Brovedani, Paola; Pisano, Simone; Muratori, Pietro

2016-04-30

Although multi-component psychotherapeutic interventions are first-line treatments for Disruptive Behavior Disorders (DBD), pharmacotherapy is often associated for more severe patients. Our aim was to explore effectiveness of an associated pharmacotherapy in referred children with DBD receiving a one-year psychotherapeutic intervention. Aggression, callous unemotional (CU) traits and emotional dysregulation were outcome measures. The sample included 144 children, aged 8-12 years, 41 (29%) with an ADHD comorbidity. Fifty-five (38%) patients received an additional pharmacotherapy with one medication, methylphenidate, a second generation antipsychotic, or a mood stabilizer. Data were collected before and after the one-year treatment. According to the Child Behavior Checklist (CBCL), aggressive behaviors, rule-breaking behaviors and emotional dysregulation improved in the whole group, as well as parent- and child-reported CU traits. The hierarchical regression model showed that additional pharmacotherapy significantly predicted lower scores at the CBCL aggressive behaviors and emotional dysregulation, but not CU traits at the end of the treatment. The interaction between methylphenidate and ADHD comorbidity predicted lower aggressive behaviors after the treatment. In summary, this naturalistic investigation suggest that an additional pharmacotherapy significantly improved aggression and emotional dysregulation, but not CU traits. When ADHD was comorbid, methylphenidate was more effective than antipsychotics or mood stabilizers in reducing aggression. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Do We Really Know How to Treat a Child with Bipolar Disorder or One with Severe Mood Dysregulation? Is There a Magic Bullet?

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Rajeev Jairam

2012-01-01