Persistent Dysregulation Research Articles

Childhood trauma and cortisol response to the Trier Social Stress Test in symptomatic patients with eating disorders

IntroductionChildhood trauma exposure is associated with the risk of eating disorders (EDs) in adulthood. The biological basis of this link may involve a persistent dysregulation of the endogenous stress response system, in particular the hypothalamic-pituitary-adrenal (HPA) axis, as a consequence of early life maltreatment.ObjectiveAdult patients with EDs and history of childhood trauma may have a dysregulation of the HPA axis that could be different from EDs patients without childhood trauma exposure.AimsIn order to assess the effects of childhood trauma experiences on HPA-axis activity in EDs, we compared the salivary cortisol response to the Trier Social Stress Test (TSST) of adult patients with EDs according to their history of childhood trauma.MethodTwenty-seven EDs patients and 13 healthy women participated in the study. Salivary cortisol responses during exposure to the TSST was measured. Participants also completed the childhood trauma questionnaire (CTQ) and eating-related psychopathological rating scales.ResultsAccording to CTQ, 15 individuals with EDs reported childhood maltreatment whereas 12 EDs patients and all the healthy women did not experience childhood maltreatment. Compared with the control group, non-maltreated EDs patient group exhibited a slightly enhanced cortisol response to TSST, whereas the group of non-maltreated EDs patients showed a normal cortisol response. Moreover, EDs patients with childhood maltreatment exhibited statistically significant blunting of cortisol compared to non-maltreated ones.ConclusionsThe present findings support the evidence that, in patients with EDs, there is a dysregulation of HPA-axis activity and that childhood trauma exposure may contribute to this dysregulation.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Post-cocaine changes in regulator of G-protein signaling (RGS) proteins in the dorsal striatum: Relevance for cocaine-seeking and protein kinase C-mediated phosphorylation.

Persistent cocaine-induced neuroadaptations within the cortico-striatal circuitry might be related to elevated risk of relapse observed in human addicts even after months or years of drug-free abstinence. Identification of these neuroadaptations may lead development of novel, neurobiologically-based treatments of relapse. In the current study, 12 adult male Sprague-Dawley rats self-administered cocaine (or received yoked-saline) for two weeks followed by three weeks of home-cage abstinence. At this point, we analyzed expression of proteins involved in regulation of Gαi- and Gαq-protein signaling in the dorsal striatum (dSTR). Animals abstinent from chronic cocaine showed decreased expression of regulator of G-protein signaling 2 (RGS2) and RGS4, as well as upregulation of RGS9. These data, together with the increased ratio of Gαq-to-Gαi proteins indicated, "sensitized" Gαq signaling in the dSTR of abstinent cocaine animals. To evaluate activation of Gαq signaling during relapse, another group of abstinent cocaine animals (and yoked saline controls, 22 rats together) was reintroduced to the cocaine context and PKC-mediated phosphorylation in the dSTR was analyzed. Re-exposure to the cocaine context triggered cocaine seeking and increase in phosphorylation of cellular PKC substrates, including phospho-ERK and phospho-CREB. In conclusion, this study demonstrates persistent dysregulation of RGS proteins in the dSTR of abstinent cocaine animals that may produce an imbalance in local Gαq-to-Gαi signaling. This imbalance might be related to augmented PKC-mediated phosphorylation during relapse to cocaine-seeking. Future studies will address whether selective targeting of RGS proteins in the dSTR can be utilized to suppress PKC-mediated phosphorylation and relapse to cocaine-seeking.

Rhinovirus Infection Results in Increased and More Persistent Dysregulation of Gene Expression

Rhinovirus Infection Results in Increased and More Persistent Dysregulation of Gene Expression

Rad51 recombinase prevents Mre11 nuclease-dependent degradation and excessive PrimPol-mediated elongation of nascent DNA after UV irradiation

After UV irradiation, DNA polymerases specialized in translesion DNA synthesis (TLS) aid DNA replication. However, it is unclear whether other mechanisms also facilitate the elongation of UV-damaged DNA. We wondered if Rad51 recombinase (Rad51), a factor that escorts replication forks, aids replication across UV lesions. We found that depletion of Rad51 impairs S-phase progression and increases cell death after UV irradiation. Interestingly, Rad51 and the TLS polymerase polη modulate the elongation of nascent DNA in different ways, suggesting that DNA elongation after UV irradiation does not exclusively rely on TLS events. In particular, Rad51 protects the DNA synthesized immediately before UV irradiation from degradation and avoids excessive elongation of nascent DNA after UV irradiation. In Rad51-depleted samples, the degradation of DNA was limited to the first minutes after UV irradiation and required the exonuclease activity of the double strand break repair nuclease (Mre11). The persistent dysregulation of nascent DNA elongation after Rad51 knockdown required Mre11, but not its exonuclease activity, and PrimPol, a DNA polymerase with primase activity. By showing a crucial contribution of Rad51 to the synthesis of nascent DNA, our results reveal an unanticipated complexity in the regulation of DNA elongation across UV-damaged templates.

Maternal Iron Status in Pregnancy and Long-Term Health Outcomes in the Offspring.

Iron is an essential micronutrient and is important not only in carrying oxygen but also to the catalytic activity of a variety of enzymes. In the fetus, it is vital to the synthesis of hemoglobin and in brain development. Iron deficiency (ID) anemia in pregnancy is a common problem, even in high-income country settings. Around 50% of pregnant women worldwide are anemic, with at least half of this burden due to ID. Iron supplements are widely recommended and used during pregnancy globally. However, the evidence on the extent of benefit they contribute to the offspring's health is not well established, and their routine use has its side effects and drawbacks. Dietary iron intake is difficult to assess accurately and it is unlikely to be sufficient to meet the demands of pregnancy if women start with inadequate body iron stores at conception. Evidence from experimental animal models suggests that maternal ID during pregnancy is associated with fetal growth restriction, as well as offspring obesity and high blood pressure later in life. The possible biological mechanisms for this observed association may be due to ID-induced changes in placental structure and function, enzyme expression, nutrient absorption, and fetal organ development. However, such evidence is limited in human studies. Prenatal ID in experimental animal models also adversely affected the developing brain structures, neurotransmitter systems, and myelination resulting in acute brain dysfunction during the period of deficiency and persistence of various postnatal neurobehavioral abnormalities as well as persistent dysregulation of some genes into adult life after iron repletion pointing to the possibility of gene expression changes. The evidence from human population studies is limited and heterogeneous and more research is needed in the future, investigating the effects of ID in pregnancy on future offspring health outcomes.

Mo1744 Ulcerative Colitis Patients With Endoscopic Healing After Infliximab or Vedolizumab Therapy Have Persistent Dysregulation in Colonic Mucosal Gene Expression

Mo1744 Ulcerative Colitis Patients With Endoscopic Healing After Infliximab or Vedolizumab Therapy Have Persistent Dysregulation in Colonic Mucosal Gene Expression

Cough hypersensitivity as a neuro-immune interaction.

Cough is an intrinsic protective reflex. However, chronic cough affects a considerable proportion of general population and has a major impact on quality of life. A recent paradigm shift to ‘cough hypersensitivity syndrome’ suggests that chronic cough arises from hypersensitivity of the airway sensory nerves. As cough reflex is determined by interaction of the nervous system with immune system, persistent dysregulation of one or both of these systems may lead to chronic cough hypersensitivity. Here we review the current evidence for the neuro-immune interactions that underlie cough hypersensitivity and discuss future therapeutic strategies.

Program and AbstractsThirty-fourth Annual Meeting of the Surgical Infection SocietyBaltimore, MarylandMay 1–3, 2014

Program and AbstractsThirty-fourth Annual Meeting of the Surgical Infection SocietyBaltimore, MarylandMay 1–3, 2014

Neonatal Peripheral Immune Challenge Activates Microglia and Inhibits Neurogenesis in the Developing Murine Hippocampus

The early postnatal period represents an important window in rodent hippocampal development with peak hilar neurogenesis and widespread microgliogenesis occurring in the first week of life. Inflammation occurring during this period may negatively influence development, potentially facilitating or increasing susceptibility to later-life pathology. We administered the Gram-negative bacterial coat protein lipopolysaccharide (LPS) systemically at postnatal day 5 (1 mg/kg i.p.) and assessed potential effects on microgliogenesis, inflammation and neurogenesis in the developing hippocampus. LPS administration led to an acute but transient increase in absolute number and density of ionized calcium-binding adaptor molecule 1-immunoreactive microglia, a change attributable to increased proliferation of central nervous system-resident microglia/microglial precursor cells but not infiltration of peripheral monocyte-derived macrophages. qRT-PCR analysis of hippocampal gene expression showed these LPS-mediated changes to be associated with persistent dysregulation of genes associated with both M1 and M2 microglial phenotypes, indicating prolonged alteration in hippocampal inflammatory status. Further, analysis of progenitor cell regulation in the hippocampal subgranular zone revealed a transient inhibition of the neuronal differentiation pathway up to 2 weeks after LPS administration, a change occurring specifically through effects on type 3 neural progenitor cells and independently of altered cell proliferation or survival of newly born cells. Together, our results show that systemic inflammation occurring during the early neonatal period is sufficient to alter inflammatory status and dysregulate the ongoing process of neurogenesis in the developing hippocampal germinal niche.

Nicotine administration in adolescence reprograms the subsequent response to nicotine treatment and withdrawal in adulthood: Sex-selective effects on cerebrocortical serotonergic function

Nicotine exposure in adolescence produces lasting changes in subsequent behavioral responses to addictive agents. We gave nicotine to adolescent rats (postnatal days PN30-47), simulating plasma levels in smokers, and then examined the subsequent effects of nicotine given again in adulthood (PN90-107), focusing on cerebrocortical serotonin levels and utilization (turnover) as an index of presynaptic activity of circuits involved in emotional state. Our evaluations encompassed responses during the period of adult nicotine treatment (PN105) and withdrawal (PN110, PN120, PN130), as well as long-term changes (PN180). In males, prior exposure to nicotine in adolescence greatly augmented the increase in serotonin turnover evoked by nicotine given in adulthood, an interaction that was further exacerbated during withdrawal. The effect was sufficiently large that it led to significant depletion of serotonin stores, an effect that was not seen with nicotine given alone in either adolescence or adulthood. In females, adolescent nicotine exposure blunted or delayed the spike in serotonin turnover evoked by withdrawal from adult nicotine treatment, a totally different effect from the interaction seen in males. Combined with earlier work showing persistent dysregulation of serotonin receptor expression and receptor coupling, the present results indicate that adolescent nicotine exposure reprograms future responses of 5HT systems to nicotine, changes that may contribute to life-long vulnerability to relapse and re-addiction.

Prenatal Alcohol Exposure Is Associated with Altered Subcellular Distribution of Glucocorticoid and Mineralocorticoid Receptors in the Adolescent Mouse Hippocampal Formation

BackgroundAccumulating evidence indicates that several of the long-term consequences of prenatal alcohol exposure (PAE) are the result of changes in the development and function of cortico-limbic structures, including the hippocampal formation. The glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) are key regulators of hippocampal formation development, structure, and functioning and, thus, are potential mediators of PAE’s effects on this brain region. In the present studies, we assessed the impact of PAE on components of corticosteroid signaling pathways in the mouse hippocampal formation.MethodsThroughout pregnancy, mouse dams were offered either 10% (w/v) ethanol sweetened with 0.066% (w/v) saccharin (SAC) or 0.066% (w/v) SAC alone using a limited (4-hour) access, drinking-in-the-dark paradigm. The hippocampal formation was isolated from naïve postnatal day 40 to 50 offspring, and subcellular fractions were prepared. Using immunoblotting techniques, we measured the levels of GR, MR, 11-β-hydroxysteroid dehydrogenase 1 (11β-HSD1), and the FK506-binding proteins 51 (FKBP51, FKBP5) and 52 (FKBP52, FKBP4). Finally, we determined the effect of PAE on context discrimination, a hippocampal-dependent learning/memory task.ResultsPAE was associated with reduced MR and elevated GR nuclear localization in the hippocampal formation, whereas cytosolic levels of both receptors were not significantly altered. FKBP51 levels were reduced, while FKBP52 levels were unaltered, and 11β-HSD1 levels were increased in postnuclear fractions isolated from PAE mouse hippocampal formation. These neurochemical alterations were associated with reduced context discrimination.ConclusionsThe data support a model in which PAE leads to increased nuclear localization of GRs secondary to reductions in FKBP51 and increases in 11β-HSD1 levels in the adolescent mouse hippocampal formation. Persistent dysregulation of GR subcellular distribution is predicted to damage the hippocampal formation and may underlie many of the effects of PAE on hippocampal-dependent functioning.

Eculizumab and recurrent C3 glomerulonephritis

Hyperactivity of the alternative complement pathway is the principle defect in C3 glomerulopathies (C3G). Eculizumab, a monoclonal antibody that binds C5 to prevent formation of the membrane attack complex, has been shown to be beneficial in some patients with this disease. In this open-label, proof-of-concept efficacy-and-safety study, a patient with the initial diagnosis of dense deposit disease (DDD) and allograft recurrence of C3 glomerulonephritis (C3GN) was treated with eculizumab every other week for 1 year. The patient had pathological evidence of C3GN and proteinuria >1 g/day at enrollment. He underwent graft biopsy before enrollment and repeat biopsy at 6 and 12 months. Although no mutations were identified in complement genes, functional studies were positive for C3 nephritic factors and elevated levels of soluble membrane attack complex (sMAC). On therapy, sMAC levels normalized and although proteinuria initially decreased, it increased reaching pre-treatment levels at 12 months. Although serum creatinine remained stable, repeat allograft biopsies showed progression of disease. Clinical and histopathologic data suggest a partial response to eculizumab in this patient. While eculizumab blocked activation of the terminal complement cascade, persistent dysregulation of the alternative pathway remained, indicating eculizumab alone cannot control disease in this patient. Additional research is required to identify effective anticomplement therapy for this group of C3G patients.

Blunted HPA axis response to stress is related to a persistent Dysregulation Profile in youth

The Child Behavior Checklist Dysregulation Profile (DP) in youth has been shown to be a predictor of psychopathology later in life. We examined the activity of the hypothalamic pituitary adrenal (HPA) axis in youth with remitted, new, persistent, and no DP. Data from 489 youth (47% boys) participating in a Dutch longitudinal general population study were included (Wave 1 mean age=11.5, Wave 2=14.2). Wave 2 diurnal cortisol patterns and levels in response to a laboratory stress paradigm were compared in youth with DP at Wave 1 only, Wave 2 only, both Waves, and neither Wave. Youth with the DP at Wave 2 only or at both time points showed blunted cortisol responses to stress relative to the other two groups. There were no group or sex differences in diurnal cortisol activity. More research is needed to determine how the association between DP symptoms and HPA axis functioning changes over time.

Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice

It is becoming increasingly apparent that the causes of autism spectrum disorders (ASD) are due to both genetic and environmental factors. Animal studies provide important translational models for elucidating specific genetic or environmental factors that contribute to ASD-related behavioral deficits. For example, mouse research has demonstrated a link between maternal immune activation and the expression of ASD-like behaviors. Although these studies have provided insights into the potential causes of ASD, they are limited in their ability to model the important interactions between genetic variability and environmental insults. This is of particular concern given the broad spectrum of severity observed in the human population, suggesting that subpopulations may be more susceptible to the adverse effects of particular environmental insults. It is hypothesized that the severity of effects of maternal immune activation on ASD-like phenotypes is influenced by the genetic background in mice. To test this, pregnant dams of two inbred strains (that is, C57BL/6J and BTBR T+tf/J) were exposed to the viral mimic polyinosinic-polycytidylic acid (polyI:C), and their offspring were tested for the presence and severity of ASD-like behaviors. To identify differences in immune system regulation, spleens were processed and measured for alterations in induced cytokine responses. Strain-treatment interactions were observed in social approach, ultrasonic vocalization, repetitive grooming and marble burying behaviors. Interestingly, persistent dysregulation of adaptive immune system function was only observed in BTBR mice. Data suggest that behavioral and immunological effects of maternal immune activation are strain-dependent in mice.

Psoriasis, a new challenge for laboratory medicine

Psoriasis is an immune-mediated, chronic, inflammatory disease that affects the skin and joints. Because of its high incidence and of its clinical symptoms it has a very strong social impact. In a genetically predisposed individual, the maintenance of the skin barrier integrity is strongly compromised in response to either environmental or self-antigenic insults. A persistent dysregulation of the skin immune system causes the typical evolutive skin lesions of psoriasis and recurrence of the disease. The most efficient laboratory approach consists of a well-defined evaluation of immune response in order to help diagnosis, to monitor evolution, and to evaluate the effects of individualized therapeutic treatments.

Intrauterine growth restriction leads to a dysregulation of Wilms’ tumour supressor gene 1 (WT1) and to early podocyte alterations

Intrauterine growth restriction (IUGR) leads to low nephron number and higher incidence of renal disease. We hypothesized that IUGR induces early podocyte alterations based on a dysregulation of Wilms' tumour suppressor gene 1 (WT1), a key player of nephrogenesis and mediator of podocyte integrity. IUGR was induced in rats by maternal protein restriction during pregnancy. Kidneys were harvested from male offspring at Days 1 and 70 of life. qRT-PCR, immunohistochemistry and electron microscopy were performed in renal tissue. Albuminuria was assessed by enzyme-linked immunosorbent assay. At Day 70 of life, higher albuminuria and overt alterations of podocyte ultrastructure were detected in IUGR animals in spite of normal blood pressure. Moreover, we found increased glomerular immunoreactivity and expression of desmin, while synaptopodin and nephrin were decreased. Glomerular immunoreactivity and expression of WT1 were increased in IUGR animals at this time point with an altered expressional ratio of WT1 +KTS and -KTS isoforms. These changes of WT1 expression were already present at the time of birth. IUGR results in early podocyte damage possibly due to a dysregulation of WT1. We suggest that an imbalance of WT1 isoforms to the disadvantage of -KTS affects nephrogenesis in IUGR rats and that persistent dysregulation of WT1 results in a reduced ability to maintain podocyte integrity, rendering IUGR rats more susceptible for renal disease.

Calcium-mediated repression of β-catenin and its transcriptional signaling mediates neural crest cell death in an avian model of fetal alcohol syndrome

Fetal alcohol syndrome (FAS) is a common birth defect in many societies. Affected individuals have neurodevelopmental disabilities and a distinctive craniofacial dysmorphology. These latter deficits originate during early development from the ethanol-mediated apoptotic depletion of cranial facial progenitors, a population known as the neural crest. We showed previously that this apoptosis is caused because acute ethanol exposure activates G-protein-dependent intracellular calcium within cranial neural crest progenitors, and this calcium transient initiates the cell death. The dysregulated signals that reside downstream of ethanol's calcium transient and effect neural crest death are unknown. Here we show that ethanol's repression of the transcriptional effector β-catenin causes the neural crest losses. Clinically relevant ethanol concentrations (22-78 mM) rapidly deplete nuclear β-catenin from neural crest progenitors, with accompanying losses of β-catenin transcriptional activity and downstream genes that govern neural crest induction, expansion, and survival. Using forced expression studies, we show that β-catenin loss of function (via dominant-negative T cell transcription factor [TCF]) recapitulates ethanol's effects on neural crest apoptosis, whereas β-catenin gain-of-function in ethanol's presence preserves neural crest survival. Blockade of ethanol's calcium transient using Bapta-AM normalizes β-catenin activity and prevents the neural crest losses, whereas ionomycin treatment is sufficient to destabilize β-catenin. We propose that ethanol's repression of β-catenin causes the neural crest losses in this model of FAS. β-Catenin is a novel target for ethanol's teratogenicity. β-Catenin/Wnt signals participate in many developmental events and its rapid and persistent dysregulation by ethanol may explain why the latter is such a potent teratogen.

Sigmoid Th17 populations, the HIV latent reservoir, and microbial translocation in men on long-term antiretroviral therapy

Th17 cells play an important role in mucosal defence and repair and are highly susceptible to infection by HIV. Antiretroviral therapy (ART) suppresses HIV viremia and can restore CD4(+) numbers in the blood and gastrointestinal mucosa, but the resolution of systemic inflammation and gut microbial translocation is often incomplete. We hypothesized that this might relate to persistent dysregulation of gut CD4(+) Th17 subsets. Blood and sigmoid biopsies were collected from HIV-uninfected men, chronically HIV-infected, ART-naive men, and men on effective ART for more than 4 years. Sigmoid provirus levels were assayed blind to participant status, as were CD4(+) Th17 subsets, systemic markers of microbial translocation, and cellular immune activation. There was minimal CD4(+) Th17 dysregulation in the blood until later stage HIV infection, but gastrointestinal Th17 depletion was apparent much earlier, along with increased plasma markers of microbial translocation. Plasma lipopolysaccharide (LPS) remained elevated despite overall normalization of sigmoid Th17 populations on long-term ART, although there was considerable interindividual variability in Th17 reconstitution. An inverse correlation was observed between plasma LPS levels and gut Th17 frequencies, and higher plasma LPS levels correlated with an increased gut HIV proviral reservoir. Sigmoid Th17 populations were preferentially depleted during HIV infection. Despite overall CD4(+) T-cell reconstitution, sigmoid Th17 frequencies after long-term ART were heterogeneous and higher frequencies were correlated with reduced microbial translocation.

Allostatic Load and Child Maltreatment in Infancy

Allostatic load refers to the persistent dysregulation in physiologic systems that occurs in response to severe, frequent or chronic stressors. Childhood maltreatment has been associated with physical health problems, neurobiological changes and long-term emotional and behavioral difficulties. This article utilizes the framework of allostatic load to examine the impact of maltreatment in infancy through the case of an infant who experienced severe abuse and neglect by her biological mother and a traumatic separation from her foster mother. Children involved in the child welfare system are especially vulnerable to allostatic load because of disruptions in caretaking, frequent abuse or neglect and inadequate medical and mental health care. Allostatic load provides a way of conceptualizing the impact of severe maltreatment and disrupted attachment on neuroendocrine, cardiovascular and immune function and how these experiences may contribute to impaired physical health and premature death in very young children.

Behavioral Outcomes of Infants with Persistent Dysregulation of Crying, Sleeping, and Feeding

Most infants experience transient problems with some combination of crying, sleeping, or feeding. However, as many as 20% of infants experience one or more persistent conditions: crying (beyond the 3-month colic period); nightly challenges with settling to sleep or awakenings; and ongoing feeding issues (usually resistance to nursing, formula, or solid foods). Are regulatory symptoms in early infancy associated with …