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Dysregulation
Kinds of Dysregulation Selected AbstractsCB1 receptors: emerging evidence for central and peripheral mechanisms that regulate energy balance, metabolism, and cardiovascular healthDIABETES/METABOLISM: RESEARCH AND REVIEWS, Issue 7 2007Daniela Cota Abstract Insulin resistance, dyslipidaemia and obesity are the major cardiometabolic risk factors contributing to the development of type 2 diabetes and cardiovascular disease (CVD). Owing to the increasing prevalence of obesity, type 2 diabetes, and CVD, new and effective pharmacologic therapies are urgently needed. In this regard, the endogenous cannabinoid system (ECS), a neuromodulatory system involved in the regulation of various aspects of energy balance and eating behaviour through central and peripheral mechanisms, may present the potential to meet this need. In the central nervous system (CNS), cannabinoid type 1 (CB1) receptors and their respective ligands, the endocannabinoids, have a significant role in the modulation of food intake and motivation to consume palatable food. CB1 receptors have also been found in organs involved in the regulation of metabolic homeostasis, such as liver, white adipose tissue, muscle and pancreas. Dysregulation of the ECS has been associated with the development of dyslipidaemia, glucose intolerance, and obesity, and CB1 receptor blockade may have a role in ameliorating these metabolic abnormalities. Thus, pharmacologic options targeting the ECS may provide a novel, effective approach to the prevention and management of CVD, type 2 diabetes and obesity. Copyright © 2007 John Wiley & Sons, Ltd. [source] Evaluation of apoptosis in cytologic specimensDIAGNOSTIC CYTOPATHOLOGY, Issue 9 2010Viktor Shtilbans Ph.D. Abstract A hallmark of neoplasia is dysregulated apoptosis, programmed cell death. Apoptosis is crucial for normal tissue homeostasis. Dysregulation of apoptotic pathways leads to reduced cytocidal responses to chemotherapeutic drugs or radiation and is a frequent contributor to therapeutic resistance in cancer. The literature pertaining to detection of apoptotic pathway constituents in cytologic specimens is reviewed herein. Virtually all methods for detecting apoptosis, including classic cytomorphologic evaluation, TUNEL assay, immunocytochemistry, and gene sequence analysis, may be applied to cytologic samples as well as tissue. Components of both intrinsic and extrinsic apoptotic pathways have been studied, including many reports examining p53 and bcl-2, as well as studies of caspase inhibitory proteins XIAP and survivin, death receptors and ligands such as Fas, Fas-ligand, and TRAIL. p53 undergoes oncogenic alteration more than any other protein; its immunocytochemical detection almost always connotes loss of its physiologic role as an inducer of apoptosis in response to a damaged genome. Several reports establish cytologic sampling as being as useful as tissue sampling. In one respect cytologic sampling is superior to tissue sampling in particular, by allowing clinicians to repeat sampling of the same tumor before and after administration of therapy; a number of reports use this approach to attempt to predict tumor response by assaying the effect of chemotherapy on the induction of apoptosis. Diagn. Cytopathol. 2010;38:685,697. © 2010 Wiley-Liss, Inc. [source] Gene expression analysis in absence epilepsy using a monozygotic twin designEPILEPSIA, Issue 9 2008Ingo Helbig Summary Purpose: To identify genes involved in idiopathic absence epilepsies by analyzing gene expression using a monozygotic (MZ) twin design. Methods: Genome-wide gene expression in lymphoblastoid cell lines (LCLs) was determined using microarrays derived from five discordant and four concordant MZ twin pairs with idiopathic absence epilepsies and five unaffected MZ twin pairs. Gene expression was analyzed using three strategies: discordant MZ twins were compared as matched pairs, MZ twins concordant for epilepsy were compared to control MZ twins, and a singleton design of affected versus unaffected MZ twin individuals was used irrespective of twin pairing. An overlapping gene list was generated from these analyses. Dysregulation of genes recognized from the microarray experiment was validated using quantitative real time PCR (qRT-PCR) in the twin sample and in an independent sample of 18 sporadic absence cases and 24 healthy controls. Results: Sixty-five probe sets were identified from the three combined microarray analysis strategies. Sixteen genes were chosen for validation and nine of these genes confirmed by qRT-PCR in the twin sample. Differential expression for EGR1 (an immediate early gene) and RCN2 (coding for the calcium-binding protein Reticulocalbin 2) were reconfirmed by qRT-PCR in the independent sample. Discussion: Using a unique sample of discordant MZ twins, our study identified genes with altered expression, which suggests novel mechanisms in idiopathic absence epilepsy. Dysregulation of EGR1 and RCN2 is implicated in idiopathic absence epilepsy. [source] Dysregulation of monocyte oxidative burst in streptococcal endocarditisEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 10 2001E. Presterl Background Streptococcal subacute endocarditis is characterized by low-grade systemic inflammation. Although structural cardiac defects are pivotal, phagocytic cells, i.e. monocytes and neutrophils, are involved in the induction and the course of bacterial endocarditis. Decreased production of reactive oxygen metabolites was described in long-lasting infections. We hypothesized that the oxidative burst of phagocytes induced by the infecting organism is defective in patients with streptococcal endocarditis. Patients and methods The monocytes and neutrophils of 11 patients with streptococcal native valve endocarditis were challenged with the respective pathogens and two control streptococcal strains, and the oxidative burst was determined by fluorescence-activated cell sorter analysis. These experiments were done before any antibiotic therapy was administered, and repeated at least 12 months after recovery. Eight volunteers served as healthy controls. Results The monocyte response to the respective pathogens was decreased in the patient groups compared to the response to the control streptococci. After cure the monocyte response to the pathogens was not different to the response to the control strains. The monocyte response of the healthy volunteers did not show any differences between the patients' pathogens and the control strains. The neutrophil oxidative burst to the pathogens was similar to that to the control streptococci in both patient and the volunteer group. Conclusion The decreased response of patient monocytes to the pathogens may contribute to the low-grade inflammatory response and to the course of streptococcal endocarditis. [source] IL-6: Regulator of Treg/Th17 balanceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2010Akihiro Kimura Abstract IL-6 is a pleiotropic cytokine involved in the physiology of virtually every organ system. Recent studies have demonstrated that IL-6 has a very important role in regulating the balance between IL-17-producing Th17 cells and regulatory T cells (Treg). The two T-cell subsets play prominent roles in immune functions: Th17 cell is a key player in the pathogenesis of autoimmune diseases and protection against bacterial infections, while Treg functions to restrain excessive effector T-cell responses. IL-6 induces the development of Th17 cells from naïve T cells together with TGF-,; in contrast, IL-6 inhibits TGF-,-induced Treg differentiation. Dysregulation or overproduction of IL-6 leads to autoimmune diseases such as multiple sclerosis (MS) and rheumatoid arthritis (RA), in which Th17 cells are considered to be the primary cause of pathology. Given the critical role of IL-6 in altering the balance between Treg and Th17 cells, controlling IL-6 activities is potentially an effective approach in the treatment of various autoimmune and inflammatory diseases. Here, we review the role of IL-6 in regulating Th17/Treg balance and describe the critical functions of IL-6 and Th17 in immunity and immune-pathology. [source] PRECLINICAL STUDY: Corticotropin-releasing factor-1 receptor antagonists decrease heroin self-administration in long- but not short-access ratsADDICTION BIOLOGY, Issue 2 2009Thomas N. Greenwell ABSTRACT Dysregulation of the stress-related corticotropin-releasing factor (CRF) system has been implicated in the development of drug dependence. The present study examined the effects of administering CRF type 1 (CRF1) receptor antagonists on heroin self-administration in animals allowed short (1 hour) or long (8,12 hours) access to intravenous heroin self-administration sessions. The nonpeptide CRF1 antagonists MJL-1-109-2 (1 hour versus 8 hours access) or R121919 (1 hour versus 12 hours access) were systemically injected in both short- and long-access rats. MJL-1-109-2 (10 mg/kg) and R121919 (10 and 20 mg/kg) reduced heroin self-administration in long-access animals without altering heroin intake in short-access animals. Both MJL-1-109-2 and R121919 decreased first-hour intravenous heroin self-administration selectively in long-access rats, with R121919 decreasing cumulative heroin intake across the 12-hour session. The results demonstrate that blockade of the CRF,CRF1 receptor system attenuates the increased heroin intake of rats with extended access to the drug. [source] Forced swim stress activates rat hippocampal serotonergic neurotransmission involving a corticotropin-releasing hormone receptor-dependent mechanismEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 12 2002Astrid C. E. Linthorst Summary Serotonin is important for adequate coping with stress. Aberrant serotonin function is implicated in the aetiology of major depression and anxiety disorders. Dysregulation of the hypothalamic,pituitary,adrenocortical axis, involving elevated corticotropin-releasing hormone (CRH) activity, also plays a role in these stress-related illnesses. Here we studied the effects of stress on hippocampal serotonin and the role of the CRH system using in vivo microdialysis. First, rats were subjected to a forced swim stress, resulting in a dramatic increase in hippocampal serotonin (1500% of baseline), which was associated with the occurrence of diving behaviour. The diving-associated increase in serotonin depended on activation of CRH receptors, as it was antagonized by intracerebroventricular pretreatment with D -Phe-CRH12,41. Secondly, the effects of intracerebroventricular administration of CRH and urocortin (0.03,1.0 µg) were studied. Both CRH and urocortin caused a dose-dependent rise in hippocampal serotonin (maximally 350% of baseline) and 5-hydroxyindoleacetic acid levels, suggesting the involvement of CRH receptor type 1. Because the effects of urocortin were prolonged, CRH receptor type 2 could play a role in a later phase of the neurotransmitter response. Experiments using adrenalectomized rats showed that CRH-induced serotonin changes were adrenally independent. These data suggest that the raphe-hippocampal serotonin system is able to mount, CRH receptor-dependent, responses to specific stressful situations that surpass the usually observed maximal increases of about 300% of baseline during stress and enhanced vigilance. [source] The CRHR1 gene: a marker for suicidality in depressed males exposed to low stressGENES, BRAIN AND BEHAVIOR, Issue 1 2008D. Wasserman The risk of suicide, which causes about 1 million deaths each year, is considered to augment as the levels of stress increases. Dysregulation in the stress response of the hypothalamic-pituitary-adrenocortical (HPA) axis, involving the corticotrophin-releasing hormone (CRH) and its main receptor (CRHR1), is associated with depression, frequent among suicidal males. Here we have analyzed single nucleotide polymorphisms (SNPs) in these genes, in family trios with suicide attempter offspring (n = 542), by using the transmission disequilibrium test both in a two-staged screening/replication sample design and in detailed reanalysis in the entire sample. Stratification based on the levels of lifetime stress showed reproducible association and linkage of an SNP in the CRHR1 gene (rs4792887) to suicide attempters exposed to low levels of stress (P = 0.002), among whom most males were depressed (P = 0.001). The identified allele may represent a part of the genetic susceptibility for suicidality by increasing HPA axis activity upon exposure to low levels of stress. [source] Association of serotonin transporter gene-linked polymorphic region and variable number of tandem repeat polymorphism of the serotonin transporter gene in lichen simplex chronicus patients with psychiatric statusINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 10 2008Necmettin Kirtak MD Background, The serotonin (5-hydroxytryptamine; 5-HT) is a key neurotransmitter in the central nervous system and a responsible mediator for the itch. Dysregulation of serotonergic pathways has been implicated in the pathogenesis of many complex neuropsychiatric diseases. Objectives, The purpose of this study was to evaluate the relationship between lichen simplex chronicus and dysfunction and serotonin transporter (5-HTT) gene polymorphism. Methods, Thirty-nine patients with lichen simplex chronicus and 61 healthy control subjects were examined. Results, The results for the patients and control subjects were not significantly different (P > 0.05) in long/long (L/L) and long/short (L/S) genotypes of 5-HTT gene-linked polymorphic region (HTTLPR) polymorphism, but short/short S/S genotype was lower in lichen simplex chronicus patients (17.9%) than in controls (42.6%). This difference was statistically significant (P = 0.028). The results for the patients and control subjects were not significantly different in 12/12, 10/12 and 10/10 genotypes of variable number of tandem repeat (VNTR) polymorphism (P > 0.05). Beck depression inventory (BDI) scores and symptom checklist-90-revised (SCL-90) psychotic subscale were overrepresented significantly in the 12/12 genotypes than 10/12 genotypes. State and Trait Anxiety Inventory tests (STAI-I and -II) point averages were not statistically significant (P > 0.05) Conclusion, S/S genotypes of HTTLPR polymorphism in the 5-HTT gene may be related to lichen simplex chronicus and that patients who have 12/12 genotypes of VNTR polymorphism may be affected psychiatrically. [source] Apoptosis in prostate cancer: Bax correlation with stageINTERNATIONAL JOURNAL OF UROLOGY, Issue 4 2005ZAHRA AMIRGHOFRAN Abstract Background:, Dysregulation of apoptosis may contribute to the process of prostate tumorigenesis by reducing the rate of cell death. Bcl-2 and bax are important molecules involved in the regulation of apoptosis. The aim of the present study is to examine apoptosis and related regulatory molecular markers in a group of Iranian patients with prostate cancer. Methods:, Paraffin-embedded tissues from 50 patients of prostate carcinoma were examined for the expression of bcl-2 antiapoptotic and bax proapoptotic markers and also proliferation marker, Ki-67, by immunohistochemistry. Detection of apoptotic cells was performed using TUNEL method. Correlation between apoptotic index, proliferation index and bcl-2 and bax expression with stage, pathological grade and Gleason score was determined. Results:, Apoptosis was detected in 12% of prostate cancers. No correlation was observed between apoptosis and differentiation status of carcinoma. Bcl-2 expression was detected in 21 of samples. A significant correlation between bcl-2 expression and Ki-67 staining index (r = 0.349, P = 0.012) was observed. High bax protein expression was shown in our study. We found a significant correlation between bax expression and stage of carcinoma (r = 0.388, P = 0.031), but not with the apoptosis index, suggesting the presence of a non-functional bax protein or the role of other proapoptotic molecules. Conclusion:, The patients in the present study showed a different pattern of apoptosis positivity compared to other reports. Bax expression may be a useful marker for prognosis of prostate cancer. [source] Calcium ions in neuronal degenerationIUBMB LIFE, Issue 9 2008Urszula Wojda Abstract Neuronal Ca2+ homeostasis and Ca2+ signaling regulate multiple neuronal functions, including synaptic transmission, plasticity, and cell survival. Therefore disturbances in Ca2+ homeostasis can affect the well-being of the neuron in different ways and to various degrees. Ca2+ homeostasis undergoes subtle dysregulation in the physiological ageing. Products of energy metabolism accumulating with age together with oxidative stress gradually impair Ca2+ homeostasis, making neurons more vulnerable to additional stress which, in turn, can lead to neuronal degeneration. Neurodegenerative diseases related to aging, such as Alzheimer's disease, Parkinson's disease, or Huntington's disease, develop slowly and are characterized by the positive feedback between Ca2+ dyshomeostasis and the aggregation of disease-related proteins such as amyloid beta, alfa-synuclein, or huntingtin. Ca2+ dyshomeostasis escalates with time eventually leading to neuronal loss. Ca2+ dyshomeostasis in these chronic pathologies comprises mitochondrial and endoplasmic reticulum dysfunction, Ca2+ buffering impairment, glutamate excitotoxicity and alterations in Ca2+ entry routes into neurons. Similar changes have been described in a group of multifactorial diseases not related to ageing, such as epilepsy, schizophrenia, amyotrophic lateral sclerosis, or glaucoma. Dysregulation of Ca2+ homeostasis caused by HIV infection or by sudden accidents, such as brain stroke or traumatic brain injury, leads to rapid neuronal death. The differences between the distinct types of Ca2+ dyshomeostasis underlying neuronal degeneration in various types of pathologies are not clear. Questions that should be addressed concern the sequence of pathogenic events in an affected neuron and the pattern of progressive degeneration in the brain itself. Moreover, elucidation of the selective vulnerability of various types of neurons affected in the diseases described here will require identification of differences in the types of Ca2+ homeostasis and signaling among these neurons. This information will be required for improved targeting of Ca2+ homeostasis and signaling components in future therapeutic strategies, since no effective treatment is currently available to prevent neuronal degeneration in any of the pathologies described here. © 2008 IUBMB IUBMB Life, 60(9): 575,590, 2008 [source] Hypothalamic,Pituitary,Adrenocortical Axis Dysregulation in Acute Temporomandibular Disorder and Low Back Pain: A Marker for Chronicity?,JOURNAL OF APPLIED BIOBEHAVIORAL RESEARCH, Issue 3-4 2006John P. Garofalo Dysregulation of the hypothalamic,pituitary,adrenocortical (HPA) axis is believed to be a valid biological marker of stress. This study evaluating changes in patients with temporomandibular disorders (TMD) and low back pain (LBP) to determine whether dysregulation of this system represents a marker for chronicity. Salivary cortisol samples were collected from 78 patients (TMD = 41, LBP = 37) upon waking up and 20 minutes later daily for 2 weeks. High-risk patients for chronic pain had different overall cortisol levels versus low-risk patients. High-risk patients exhibited greater variability in terms of cortisol secretion compared with low-risk patients, F(1, 1,243) = 17.73, p < .000. These results provide evidence of a neuroendocrine mechanism underlying a constellation of psychosocial risk factors for chronic pain. [source] Dysregulation of the BMP-p38 MAPK Signaling Pathway in Cells From Patients With Fibrodysplasia Ossificans Progressiva (FOP),,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2006Jennifer L Fiori Abstract FOP is a disabling disorder in which skeletal muscle is progressively replaced with bone. Lymphocytes, our model system for examining BMP signaling, cannot signal through the canonical Smad pathway unless exogenous Smad1 is supplied, providing a unique cell type in which the BMP,p38 MAPK pathway can be examined. FOP lymphocytes exhibit defects in the BMP,p38 MAPK pathway, suggesting that altered BMP signaling underlies ectopic bone formation in this disease. Introduction: Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by progressive heterotopic ossification of connective tissues. Whereas the primary genetic defect in this condition is unknown, BMP4 mRNA and protein and BMP receptor type IA (BMPRIA) protein are overexpressed in cultured lymphocytes from FOP patients, supporting that altered BMP signaling is involved in this disease. In this study, we examined downstream signaling targets to study the BMP,Smad and BMP,p38 mitogen-activated protein kinase (MAPK) pathways in FOP. Materials and Methods: Protein phosphorylation was assayed by immunoblots, and p38 MAPK activity was measured by kinase assays. To examine BMP target genes, the mRNA expression of ID1, ID3, and MSX2 was determined by quantitative real-time PCR. Statistical analysis was performed using Student's t -test or ANOVA. Results: FOP lymphocytes exhibited increased levels of p38 phosphorylation and p38 MAPK activity in response to BMP4 stimulation. Furthermore, in response to BMP4, FOP cells overexpressed the downstream signaling targets ID1 by 5-fold and ID3 by 3-fold compared with controls. ID1 and ID3 mRNA induction was specifically blocked with a p38 MAPK inhibitor, but not extracellular signal-related kinase (ERK) or c-Jun N-terminal kinase (JNK) inhibitors. MSX2, a known Smad pathway target gene, is not upregulated in control or FOP cells in response to BMP, suggesting that lymphocytes do not use this limb of the BMP pathway. However, introduction of Smad1 into lymphocytes made the cells competent to regulate MSX2 mRNA after BMP4 treatment. Conclusions: Lymphocytes are a cell system that signals primarily through the BMP,p38 MAPK pathway rather than the BMP,Smad pathway in response to BMP4. The p38 MAPK pathway is dysregulated in FOP lymphocytes, which may play a role in the pathogenesis of FOP. [source] Emerging functions of p21-activated kinases in human cancer cellsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2002Rakesh Kumar The p21 activated kinases (Paks), an evolutionarily conserved family of serine/threonine kinases, are important for a variety of cellular functions including cell morphogenesis, motility, survival, mitosis, and angiogenesis. Paks are widely expressed in numerous tissues and are activated by growth factors and extracellular signals through GTPase-dependent and -independent mechanisms. Overexpression of Paks in epithelial cancer cells has been shown to increase migration potential, increase anchorage independent growth, and cause abnormalities in mitosis. Dysregulation of Paks has been reported in several human tumors and neurodegenerative diseases. A growing list of novel Pak interacting proteins has opened up exciting avenues of investigation by which to understand the functions of Paks in tumorigenesis. In this review, we will summarize the current knowledge of the Paks family with respect to emerging cellular functions and possible contributions to cancer. © 2002 Wiley-Liss, Inc. [source] QT Interval Dispersion and Cardiac Sympathovagal Balance Shift in Rats With Acute Ethanol WithdrawalALCOHOLISM, Issue 2 2010Seiko Shirafuji Background:, Dysregulation of autonomic nervous system function and impaired homogeneity of myocardial repolarization are 2 important mechanisms for the genesis of ventricular arrhythmias in nonalcoholic subjects. Our previous study suggested that acute ethanol withdrawal promoted the shift of cardiac sympathovagal balance toward sympathetic predominance and reduced the vagal tone, which were related to a higher incidence of ventricular arrhythmia and related death. However, the homogeneity of myocardial repolarization and its relation with the cardiac sympathovagal balance are unknown, especially in alcoholic subjects. The aim of the present study was to clarify these points. Methods:, Male Wistar rats were treated with a continuous ethanol liquid diet for 49 days, and then subjected to 1-day withdrawal and 1-day withdrawal with 7-day carvedilol (can block the sympathetic nervous system completely via ,1, ,2, and , adrenergic receptors) pretreatment. The cardiac sympathovagal balance and homogeneity of myocardial repolarization were evaluated based on the heart rate variability (HRV) and QT interval dispersion (QTd: dynamic changes in QT interval duration). Results:, The increase in QTd was observed only in rats at 1-day withdrawal, but not in nonalcoholic, continuous ethanol intake, and 1-day withdrawal with 7-day carvedilol pretreatment rats. At 1-day withdrawal, the low-frequency power/high-frequency power (LF/HF) ratio in HRV was elevated and correlated with the QTd. The increased QTd and elevated LF/HF ratio were normalized by the 7-day carvedilol pretreatment in rats at 1-day ethanol withdrawal. Conclusions:, In rats with an abrupt termination of the chronic continuous ethanol intake, the homogeneity of myocardial repolarization impaired and correlated with the cardiac sympathovagal balance. Carvedilol pretreatment is associated with a reduction in both the QTd and LF/HF ratio, raising the possibility that the cardiac sympathovagal balance shift may be responsible for the impaired homogeneity of myocardial repolarization, and that ,-blocker pretreatment may decrease the mortality risk during alcoholic withdrawal. [source] Alcohol, Psychological Dysregulation, and Adolescent Brain DevelopmentALCOHOLISM, Issue 3 2008Duncan B. Clark While adolescent alcohol consumption has been asserted to adversely alter brain development, research in human adolescents has not yet provided us with sufficient evidence to support or refute this position. Brain constituents actively developing during adolescence include the prefrontal cortex, limbic system areas, and white matter myelin. These areas serving cognitive, behavioral, and emotional regulation may be particularly vulnerable to adverse alcohol effects. Alternatively, deficits or developmental delays in these structures and their functions may underlie liability to accelerated alcohol use trajectories in adolescence. This review will describe a conceptual framework for considering these relationships and summarize the available studies on the relationships among risk characteristics, alcohol involvement and brain development during this period. The cross-sectional designs and small samples characterizing available studies hamper definitive conclusions. This article will describe some of the opportunities contemporary neuroimaging techniques offer for advancing understanding of adolescent neurodevelopment and alcohol involvement. [source] Stress Hormone Dysregulation at Rest and After Serotonergic Stimulation Among Alcohol-Dependent Men With Extended Abstinence and ControlsALCOHOLISM, Issue 5 2001Robert M. Anthenelli Background: Alcohol dependence has been associated with long-lasting alterations in limbic-hypothalamic-pituitary-adrenal (LHPA) axis and serotonin (5-hydroxytryptamine [5-HT]) function. Other conditions that are associated with alcoholism (cigarette smoking and antisocial personality disorder [ASPD]) have been linked with disturbances in these interrelated systems. We evaluated the stress hormone response to 5-HTergic stimulation in alcohol-dependent men with extended abstinence (average abstinence duration, 4.3 months) and controls to determine the relative contributions of alcoholism, cigarette smoking, and ASPD on baseline and provoked plasma cortisol and adrenocorticotropin hormone (ACTH) concentrations. Methods: One hundred nine alcohol-abstinent men with alcohol dependence (62%), habitual smoking (70%), and ASPD (43%) received d,l-fenfluramine (100 mg po) in a randomized, double-blind, placebo-controlled, crossover trial. The group of recovering alcohol-dependent individuals included abstinent primary alcohol-dependent men and alcohol-dependent men with ASPD, whereas the group of non-alcohol-dependent men comprised healthy controls and non-alcohol-dependent men with ASPD. Plasma cortisol and ACTH levels were obtained at AM baseline and at half-hour intervals after drug administration. Subjective ratings of drug response and physiological measures were also obtained at baseline and every 30 min. Results: Abstinent alcohol-dependent men had significantly lower (approximately 20%) AM baseline plasma cortisol concentrations than non-alcohol-dependent men on both challenge days; however, no differences between the groups were observed with regard to resting AM plasma ACTH levels. After adjusting for these baseline differences, recovering alcohol-dependent men (area under curve = 35.6 ± 37.4 [,g/dl] × min) had a twofold greater cortisol response to fenfluramine than non-alcohol-dependent men (area under curve = 17.5 ± 32.5 [,g/dl] × min) (F= 5.1;df= 1,105;p < 0.03). The elevated cortisol response, which occurred primarily along the descending limb of the response curve, was paralleled by a nonsignificant statistical trend for alcohol-dependent men to also exhibit a greater ACTH response to fenfluramine at the 210-min (p < 0.07) and 240-min (p < 0.09) time points as compared with non-alcohol-dependent men. Cigarette smoking and ASPD did not affect hormonal responses, nor could the groups' subjective ratings and physiological measures be distinguished. Conclusions: Alcohol-dependent men with extended abstinence differed from age- and race-matched non-alcohol-dependent men in resting AM and fenfluramine-induced plasma cortisol levels. This dysfunction in glucocorticoid homeostatic mechanisms was associated with alcoholism and not with smoking or ASPD. We also observed a nonsignificant statistical trend for plasma ACTH levels to be elevated among alcohol-dependent men along the descending limb of the response curve. Alcohol-dependent men seemed to have inherited or acquired damage to 5-HT-regulated LHPA axis function, the precise mechanisms and sites of which remain to be determined. [source] Serotonin, Impulsivity, and Alcohol Use Disorders in the Older Adolescent: A Psychobiological StudyALCOHOLISM, Issue 11 2000Paul H. Soloff Background: Alcohol use disorders (AUDs) among adolescents are associated with a high prevalence of conduct disorder (CD), much as type II alcoholism in adults is associated with impulsive-aggressive behavior and antisocial personality traits. Adults with impulsive personality disorders and AUD demonstrate diminished central serotonergic responsiveness to serotonergic agonists. Dysregulation of central serotonergic function may contribute to a vulnerability to impulsive-aggressive behavior, CD, and AUD. We studied older adolescents, both male and female, to examine the relationships between sex, dispositional impulsivity, aggressivity, CD, and responsiveness to serotonergic challenge with d,l fenfluramine (FEN) early in the development of AUD. Methods: Thirty-six adolescents between the ages of 16 and 21 years were assessed for DSM-IV AUD and other Axis I disorders by using the Psychoactive Substance Use Disorders section of the Structured Clinical Interview for DSM III-R, the Schedule for Affective Disorders and Schizophrenia for School-Age Children,Present and Lifetime Version, and CD interviews. Impulsivity and aggressivity were assessed by the Barratt Impulsiveness Scale, Lifetime History of Aggression, Buss-Durkee Hostility Inventory, Eysenck Impulsiveness Questionnaire, Youth Self Report, and Multidimensional Personality Questionnaires. FEN was administered as 0.8 mg/kg to a maximum of 60 mg, and blood was sampled at fixed intervals for prolactin, cortisol, fenfluramine, and norfenfluramine levels. Results: Eighteen adolescents (12 male, 6 female) with AUD scored significantly higher on all measures of impulsivity and aggressivity compared with 18 healthy controls (12 male, 6 female). There were no significant differences between groups in peak prolactin or cortisol responses (minus baseline), or area-under-the-curve determinations (AUC); however, 9 subjects with AUD and comorbid CD had significantly elevated cortisol AUC levels compared with subjects with AUD and no CD or with normal controls. In the total sample, cortisol AUC was associated positively with measures of aggression. Conclusions: Adolescents with early-onset AUD are characterized by impulsivity and aggressivity compared with healthy peers but do not demonstrate the diminished prolactin or cortisol responses to FEN characteristic of adult alcoholics with impulsive-aggression. [source] Survival and apoptosis: a dysregulated balance in liver cancerLIVER INTERNATIONAL, Issue 2 2007Isabel Fabregat Abstract Background/Aims: Dysregulation of the balance between proliferation and cell death represents a protumorigenic principle in human hepatocarcinogenesis. This article aims to provide a review of the current findings about how physiological hepatocyte apoptosis is regulated and whether or not its dysregulation might contribute to the progression towards a hepatocellular carcinoma (HCC) process. Results: Although some physiological proapoptotic molecules are downregulated or inactivated in HCC, such as Fas, p53, Bax or Bid, dysregulation of the balance between death and survival is mainly due to overactivation of antiapoptotic signals. Thus, some growth factors that mediate cell survival are upregulated in HCC, as well as the molecules involved in the machinery responsible for cleavage of their proforms to an active peptide. The expression of the pten gene is reduced or absent in almost half the HCCs and the Spred family of Ras/ERK inhibitors is also dysregulated in HCC, which consequently lead to the overactivation of relevant survival kinases: AKT and ERKs. Alterations in the expression and/or activity of molecules involved in counteracting apoptosis, such as NF-,B, Bcl-XL, Mcl-1 or c-IAP1, have also been observed in HCC. Conclusions: Therefore, therapeutic strategies to inhibit selectively antiapoptotic signals in tumour cells have the potential to provide powerful tools to treat liver cancer. [source] Apoptosis and proliferation in Helicobacter pylori -associated gastric intestinal metaplasiaALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 9 2001W. K. Leung Background: Imbalance between apoptosis and proliferation may be one of the mechanisms underlying H. pylori associated gastric carcinogenesis. Aim: To examine the cell kinetics of gastric intestinal metaplasia and the effect of H. pylori eradication. Methods: Endoscopic gastric biopsies were obtained from 100 H. pylori -infected patients. Apoptosis was determined by triphosphate nick-end labelling (TUNEL) and apoptotic nuclei counting, whereas proliferation was assessed by Ki67 immunostaining. Gastric biopsies were repeated in a sub-group of intestinal metaplasia patients after H. pylori eradication. Results: Antral apoptotic index was significantly lower in intestinal metaplasia than in non-intestinal metaplasia (0.19% vs. 0.51%; P < 0.0001) whereas the level of proliferation was comparable (28% vs. 22%, P=0.15). Serial antral biopsies taken from 14 intestinal metaplasia patients before and 1 year after H. pylori eradication showed a significant drop in proliferation in both intestinal metaplasia (50% vs. 12%, P < 0.001) and non-intestinal metaplasia area (47% vs. 9%, P < 0.001). A similar fall in apoptosis was detected in non-metaplastic region (0.58% vs. 0.38%, P < 0.001) but not in intestinal metaplasia (0.24% vs. 0.27%, P=0.56), resulting in a significant increase in the apoptosis/proliferation ratio (0.005,0.021; P=0.03). Conclusions: Dysregulation in apoptosis control of gastric intestinal metaplasia may contribute to gastric carcinogenesis, which may be retarded by clearance of H. pylori. [source] Dysregulation of the stress response in asthmatic childrenALLERGY, Issue 1 2009K. N. Priftis The stress system co-ordinates the adaptive responses of the organism to stressors of any kind. Inappropriate responsiveness may account for increased susceptibility to a variety of disorders, including asthma. Accumulated evidence from animal models suggests that exogenously applied stress enhances airway reactivity and increases allergen-induced airway inflammation. This is in agreement with the clinical observation that stressful life events increase the risk of a new asthma attack. Activation of the hypothalamic,pituitary,adrenal (HPA) axis by specific cytokines increases the release of cortisol, which in turn feeds back and suppresses the immune reaction. Data from animal models suggest that inability to increase glucocorticoid production in response to stress is associated with increased airway inflammation with mechanical dysfunction of the lungs. Recently, a growing body of evidence shows that asthmatic subjects who are not treated with inhaled corticosteroids (ICS) are likely to have an attenuated activity and/or responsiveness of their HPA axis. In line with this concept, most asthmatic children demonstrate improved HPA axis responsiveness on conventional doses of ICS, as their airway inflammation subsides. Few patients may experience further deterioration of adrenal function, a phenomenon which may be genetically determined. [source] Tumor suppressor gene Co-operativity in compound Patched1 and suppressor of fused heterozygous mutant miceMOLECULAR CARCINOGENESIS, Issue 5 2009Jessica Svärd Abstract Dysregulation of the Hedgehog signaling pathway is central to the development of certain tumor types, including medulloblastoma and basal cell carcinoma (BCC). Patched1 (Ptch1) and Suppressor of fused (Sufu) are two essential negative regulators of the pathway with tumor suppressor activity. Ptch1+/, mice are predisposed to developing medulloblastoma and rhabdomyosarcoma, while Sufu+/, mice develop a skin phenotype characterized by basaloid epidermal proliferations. Here, we have studied tumor development in Sufu+/,Ptch1+/, mice to determine the effect of compound heterozygosity on the onset, incidence, and spectrum of tumors. We found significantly more (2.3-fold) basaloid proliferations in Sufu+/,Ptch1+/, compared to Sufu+/, female, but not male, mice. For medulloblastoma, the cumulative 1-yr incidence was 1.5-fold higher in Sufu+/,Ptch1+/, compared to Ptch1+/, female mice but this strong trend was not statistically significant. Together this suggests a weak genetic interaction of the two tumor suppressor genes. We noted a few rhabdomyosarcomas and pancreatic cysts in the Sufu+/,Ptch1+/, mice, but the numbers were not significantly different from the single heterozygous mice. Hydrocephalus developed in ,20% of the Ptch1+/, and Sufu+/,Ptch1+/, but not in Sufu+/, mice. Interestingly, most of the medulloblastomas from the Sufu+/,Ptch1+/, mice had lost expression of the remaining Ptch1 wild-type allele but not the Sufu wild-type allele. On the contrary, Sufu as well as Gli1 and Gli2 expression was upregulated in the medulloblastomas compared to adult cerebellum in Ptch1+/, and Sufu+/,Ptch1+/, mice. This suggests that Sufu expression may be regulated by Hedgehog pathway activity and could constitute another negative feedback loop in the pathway. © 2008 Wiley-Liss, Inc. [source] Dietary Fructose: Implications for Dysregulation of Energy Homeostasis and Lipid/Carbohydrate MetabolismNUTRITION REVIEWS, Issue 5 2005Peter J. Havel DVM Fructose intake and the prevalence of obesity have both increased over the past two to three decades. Compared with glucose, the hepatic metabolism of fructose favors lipogenesis, which may contribute to hyperlipidemia and obesity. Fructose does not increase insulin and leptin or suppress ghrelin, which suggests an endocrine mechanism by which it induces a positive energy balance. This review examines the available data on the effects of dietary fructose on energy homeostasis and lipid/carbohydrate metabolism. Recent publications, studies in human subjects, and areas in which additional research is needed are emphasized. [source] Cancer stem cell hypothesis in thyroid cancerPATHOLOGY INTERNATIONAL, Issue 9 2006Ping Zhang There is increasing evidence that many types of cancer contain their own stem cells: cancer stem cells, which are characterized by their self-renewing capacity and differentiation ability. Cancer could be regarded as an abnormal organ initiated by cancer stem cells, and cancer stem cells might play a decisive role in tumor initiation and progression. Dysregulation of stem cell self-renewal is a likely requirement for the development of cancer, and stem cells seem more likely to be the transformed target cells in carcinogenesis. This cancer stem cell model has great implications for understanding of oncogenesis and treatment for cancer. Abundant evidence suggests that, parallel to other solid tumors, cancer stem cells also exist in thyroid cancer, although their characteristics are largely unknown to date. The present review will discuss the potential traits of cancer stem cells in thyroid cancer and their transformation targets: stem cells in the thyroid gland. [source] Transgenic neuronal nitric oxide synthase expression induces axotomy-like changes in adult motoneuronsTHE JOURNAL OF PHYSIOLOGY, Issue 18 2010Fernando Montero Dysregulation of protein expression, function and/or aggregation is a hallmark of a number of neuropathological conditions. Among them, upregulation and/or de novo expression of the neuronal isoform of nitric oxide (NO) synthase (nNOS) commonly occurs in diverse neurodegenerative diseases and in axotomized motoneurons. We used adenoviral (AVV) and lentiviral (LVV) vectors to study the effects of de novo nNOS expression on the functional properties and synaptic array of motoneurons. AVV-nNOS injection into the genioglossus muscle retrogradely transduced neonatal hypoglossal motoneurons (HMNs). Ratiometric real-time NO imaging confirmed that transduced HMNs generated NO gradients in brain parenchyma (space constant: ,12.3 ,m) in response to a glutamatergic stimulus. Unilateral AVV-nNOS microinjection in the hypoglossal nucleus of adult rats induced axotomy-like changes in HMNs. Specifically, we found alterations in axonal conduction properties and the recruitment order of motor units and reductions in responsiveness to synaptic drive and in the linear density of synaptophysin-positive puncta opposed to HMN somata. Functional alterations were fully prevented by chronic treatment with nNOS or soluble guanylyl cyclase inhibitors. Synaptic and functional changes were also completely avoided by prior intranuclear injection of a neuron-specific LVV system for miRNA-mediated nNOS knock-down (LVV-miR-shRNA/nNOS). Furthermore, synaptic and several functional changes evoked by XIIth nerve injury were to a large extent prevented by intranuclear administration of LVV-miR-shRNA/nNOS. We suggest that nNOS up-regulation creates a repulsive NO gradient for synaptic boutons underlying most of the functional impairment undergone by injured motoneurons. This further strengthens the case for nNOS targeting as a plausible strategy for treatment of peripheral neuropaties and neurodegenerative disorders. [source] Dysregulation of human bestrophin-1 by ceramide-induced dephosphorylationTHE JOURNAL OF PHYSIOLOGY, Issue 18 2009Qinghuan Xiao Best vitelliform macular dystrophy is an inherited autosomal dominant, juvenile onset form of macular degeneration caused by mutations in a chloride ion channel, human bestrophin-1 (hBest1). Mutations in Best1 have also been linked to several other forms of retinopathy. In addition to mutations, hBest1 dysfunction might come about by disruption of other processes that regulate Best1 function. Here we show that hBest1 chloride channel activity is regulated by ceramide and phosphorylation. We have identified a protein kinase C (PKC) phosphorylation site (serine 358) in hBest1 that is important for sustained channel function. Channel activity is maintained by PKC activators, protein phosphatase inhibitors, or pseudo-phosphorylation by substitution of glutamic acid for serine 358. When ceramide levels are elevated by exogenous addition of ceramide to the bath, by addition of bacterial sphingomyelinase, or by hypertonic stress, S358 is rapidly dephosphorylated. The dephosphorylation is mediated by protein phosphatase 2A. Hypertonic stress-induced dephosphorylation is blocked by a dihydroceramide, an inactive form of ceramide, and manumycin, an inhibitor of neutral sphingomyelinase. Our results support a model in which ceramide accumulation during early stages of retinopathy inhibits hBest1 function, leading to abnormal fluid transport across the retina, and enhanced inflammation. [source] ORIGINAL ARTICLE: Placental Fas/Fas Ligand Expression in Early Pregnancy LossesAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 1 2008Emine Seda Guvendag Guven Problem, The aim of this study was to compare the expression levels of Fas and Fas ligand (FasL) in first-trimester placentas obtained from spontaneous abortions in patients with antiphospholipid antibody syndrome (APS) or factor V (FV) Leiden mutation, compared with values in placentas from induced abortions in patients negative for these conditions. Method of study, We studied explants from 6- to 10-week-old placentas that had been prepared by collagenase digestion from 10 spontaneous abortions from APS-positive patients, nine spontaneous abortions in patients positive for FV Leiden mutation, and 10 induced abortions. All tissues were analyzed by flow cytometry for expression of Fas and FasL. Results, Flow cytometric analysis showed that placental FasL expression was significantly lower in abnormal pregnancies than in normal ones. However, no such difference was observed for Fas expression. Conclusion, FasL on placental cells may be involved in the maintenance of immune privilege, thereby ensuring the safety and growth of placental tissues. Dysregulation of apoptotic mechanisms may play a critical role in spontaneous abortions. [source] A Possible Role of CD4+CD25+ T Cells as Well as Transcription Factor Foxp3 in the Dysregulation of Allergic RhinitisTHE LARYNGOSCOPE, Issue 5 2007Geng Xu MD Abstract Background: Allergic rhinitis (AR) is a Th2 predominant disease, and its pathogenic mechanism is still poorly understood. CD4+CD25+ T cells account for approximately 5% to 10% peripheral CD4+ T cells and has been shown to regulate the activation of effector T cells in the periphery. The activity of CD4+CD25+ T cells is associated with the transcription factor Foxp3. The present study aimed to evaluate the possible role of CD4+CD25+ T cells as well as Foxp3 in the pathogenesis of AR. Methods: Nasal tissues and peripheral blood mononuclear cells (PBMCs) were obtained from 17 patients with AR and 11 control subjects. Foxp3 was detected in nasal tissues by immunohistochemistry and real-time reverse transcription-polymerase chain reaction (RT-PCR). CD4+CD25+ T cells and Foxp3 were evaluated in PBMCs by using flow cytometry. Concentrations of interleukin-2 (IL-2) and interferon-, (IFN-,) were measured by enzyme-linked immunosorbent assay (ELISA) in cultured PBMCs in the presence or absence of stimulation with phorbol ester (PMA) and Ionomycin. Results: The numbers of Foxp3+ cells was 129.5 ± 35.6 and 44.2 ± 20.5 cells/mm2 in nasal mucosa of two groups (P < .05). There were less Foxp3+ lymphocytes and decreased Foxp3 mRNA in AR compared with the control (P < .05). The frequencies of the CD4+CD25+ population in PBMCs of two groups were 1.99 ± 0.95% and 3.55 ± 1.27% (P < .05). There was significant difference in the frequencies of the Foxp3+CD4+ CD25+ population (1.81 ± 0.77 vs 3.37 ± 1.04, P < .05) and mean fluorescence intensity (MFI) of Foxp3 (5.93 ± 2.64 vs 11.72 ± 4.29, P < .05) in PBMCs of two groups. After stimulation, the concentrations of IL-2 and IFN-, were 182.72 ± 85.11 pg/mL and 348.94 ± 151.88 pg/mL in PBMCs with AR, while those were 90.6 ± 61.5 pg/mL and 155.64 ± 68.33 pg/mL in controls (P < .05). Conclusion: Our results indicate that CD4+ CD25+ regulatory T cells as well as Foxp3 may play a crucial role in immunological imbalance of AR. These findings suggest that increasing Foxp3 and CD4+CD25+ T cells have the potential to be new therapeutic targets for the treatment of AR. [source] Dysregulation of the Cytokine Network in the Uterus of the Diabetic RatAMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY, Issue 6 2001SERGE PAMPFER Insulin-dependent (type 1) diabetes is an auto-immune disorder that produces secondary complications in numerous non-immunological systems. Changes in the synthesis and action pattern of several cytokines have been associated with the development of these alterations. Based on the clinical facts that the pregnant and non-pregnant functions of the reproductive system are also disrupted by diabetes, our laboratory has decided to concentrate its research activities on the hypothesis that cytokines may be implicated in the uteropathy and embryopathy associated with the metabolic disorder. This review article summarizes our major findings concerning the synthesis of TNF-, and IL-1, in the uterus of diabetic rats, and in cultures of rodent uterine cells upon their exposure to high concentrations of glucose. The paper also reviews evidence that both the peri-implanting embryo and the epithelial cell layer lining the uterine lumen are targets for the deleterious influence of excess TNF-,. If confirmed in the uterus of diabetic patients, these observations may explain how cytokines contribute to the dysregulation of crucial reproductive events like menstruation and embryo implantation in humans. [source] Apoptosis: mechanisms and clinical implicationsANAESTHESIA, Issue 11 2000P. C. A. Kam The balance between cell survival and death is under tight genetic control. A multiplicity of extracellular signals and intracellular mediators is involved in maintaining this balance. When the cell is exposed to physical, biochemical or biological injury, or deprived of necessary substances, it activates a series of stress-response genes. With minimal insults, the cell may recover. With greater insults, single cell death, or apoptosis, results; the cell dies and is recycled to its neighbours. If the insult overwhelms a large number of cells then necrosis ensues, with an accompanying inflammatory response. Dysregulation of the controlling mechanisms of this system results in disease. Deficient apoptosis is associated with cancer, auto-immunity and viral infections. Excessive apoptosis is associated with ischaemic heart disease, stroke, neurodegenerative disease, sepsis and multiple organ dysfunction syndrome. There are myriad therapeutic options unfolding as understanding is gained of apoptosis and its control. [source] | |||||||||||||||||||||||||||||||||||||