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Sample records for jaime kigel gad

  1. Learning with Jaime.

    ERIC Educational Resources Information Center

    Yoshizawa, Dianne

    1997-01-01

    Illustrates the "hypothesis-test" teaching approach with one kindergarten student. Notes that it was the author's stepping back to watch for multiple interpretations of her observations of Jaime's behavior that gave Jaime space to think, to use his voice to make connections, and to grow. (SR)

  2. The Jaime Escalante Math Program.

    ERIC Educational Resources Information Center

    Escalante, Jaime

    This article describes the Jaime Escalante Math Program, a system that in 1989 helped an East Los Angeles high school set a record by administering over 450 Advanced Placement exams, having administered only 10 tests in 1978. The article is presented in three sections. The first section describes the program, discussing origins and backgrounds:…

  3. Jaime Urrutia Fucugauchi Receives 2013 International Award: Citation

    NASA Astrophysics Data System (ADS)

    Lomnitz, Cinna

    2014-01-01

    Jaime Urrutia Fucugauchi was born in Chihuahua, Mexico. His surname Urrutia means "distant" in Basque, and Fucugauchi means roughly "Good luck—come in!" in Japanese. And Jaime, of course, is "James" in Spanish. Thus, Jaime was international from birth. There could hardly have been a better candidate for the AGU International Award.

  4. Spatializing Sexuality in Jaime Hernandez's "Locas"

    ERIC Educational Resources Information Center

    Jones, Jessica E.

    2009-01-01

    Focusing on Jaime Hernandez's "Locas: The Maggie and Hopey Stories," part of the "Love and Rockets" comic series, I argue that the graphic landscape of this understudied comic offers an illustration of the theories of space in relation to race, gender, and sexuality that have been critical to understandings of Chicana…

  5. Spatializing Sexuality in Jaime Hernandez's "Locas"

    ERIC Educational Resources Information Center

    Jones, Jessica E.

    2009-01-01

    Focusing on Jaime Hernandez's "Locas: The Maggie and Hopey Stories," part of the "Love and Rockets" comic series, I argue that the graphic landscape of this understudied comic offers an illustration of the theories of space in relation to race, gender, and sexuality that have been critical to understandings of Chicana…

  6. Jaime Torres Bodet: Centenario de su Natalicio (Jaime Torres Bodet: 100th Anniversary of His Birth).

    ERIC Educational Resources Information Center

    Revista Interamericana de Educacion de Adultos, 2002

    2002-01-01

    Articles in this issue, written in Spanish, focus on the following: the philosophy of Jaime Torres Bodet (humanistic vision of adult education; objectives of public education in Mexico; Mexico and the issue of culture; The Mexican National Museum of History; Enrique Gonzalez Martinez, poet of all hours; Marti, Cuba's champion; educational…

  7. Adaptation of a GAD Treatment for Hypochondriasis

    ERIC Educational Resources Information Center

    Langlois, Frederic; Ladouceur, Robert

    2004-01-01

    Health preoccupations are present in both generalized anxiety disorder (GAD) and hypochondriasis. Contrary to GAD, in which excessive anxiety and worry encompass a number of events or activities, health is the central theme of worry in hypochondriasis. A recent study demonstrated that two processes involved in GAD are also involved in health…

  8. GAD65 autoimmunity-clinical studies.

    PubMed

    Uibo, Raivo; Lernmark, Ake

    2008-01-01

    Type 1 diabetes (T1D) in children and particularly in teenagers and adults is strongly associated with autoreactivity to the Mr 65,000 isoform of glutamic acid decarboxylase (GAD65). Autoantibodies to GAD65 are common at the time of clinical diagnosis and may be present for years prior to the onset of hyperglycemia. GAD65 autoantibodies predict conversion to insulin dependence when present in patients classified with type 2 diabetes nowadays more often referred to as patients with latent autoimmune diabetes in the adult (LADA) or type 1,5 diabetes. Analyses of T cells with HLA DRB1 0401-tetramers with GAD65-specific peptides as well as of anti-idiotypic GAD65 autoantibodies suggest that GAD65 autoreactivity is common. The immunological balance is disturbed and the appearance of GAD65 autoantibodies represents markers of autoreactive loss of pancreatic beta cells. Extensive experimental animal research, in particular of the Non-obese diabetic (NOD) mouse, showed that GAD65 therapies reduce insulitis and prevent spontaneous diabetes. Recombinant human GAD65 produced by current Good Manufacturing Practice (cGMP) and formulated with alum was found to be safe in Phase I and II placebo-controlled, double-blind, randomized clinical trials. The approach to modulate GAD65 autoreactivity with subcutaneous immunotherapy (SCIT) showed promise as alum-formulated GAD65 induced a dose-dependent reduction in the disappearance rate of endogenous residual C-peptide production. Additional controlled clinical trials are needed to uncover the mechanisms by which subcutaneous injections of recombinant human GAD65 may alter GAD65 autoreactivity.

  9. Mapping of glutamic acid decarboxylase (GAD) genes

    SciTech Connect

    Edelhoff, S.; Adler, D.A.; Disteche, C.M.; Grubin, C.E.; Karlsen, A.E.; Lernmark, A.; Foster, D. )

    1993-07-01

    Glutamic acid decarboxylase (GAD) catalyzes the synthesis of [gamma]-aminobutyric acid (GABA), which is known as a major inhibitory neurotransmitter in the central nervous system (CNS), but is also present outside the CNS. Recent studies showed that GAD is the major target of autoantibodies associated with the development of insulin-dependent diabetes mellitus and of the rare stiff man syndrome. Studies of GAD expression have demonstrated multiple transcripts, suggesting several isoforms of GAD. In this study, three different genes were mapped by in situ hybridization to both human and mouse chromosomes. The GAD1 gene was mapped to human chromosome 2q31 and to mouse chromosome 2D in a known region of conservation between human and mouse. GAD2, previously mapped to human chromosome 10p11.2-p12, was mapped to mouse chromosome 2A2-B, which identifies a new region of conservation between human and mouse chromosomes. A potential GAD3 transcript was mapped to human chromosome 22q13 and to mouse chromosome 15E in a known region of conservation between human and mouse. It is concluded that the GAD genes may form a family with as many as three related members. 30 refs., 5 figs.

  10. [Book review] Middle American Herpetology, by Jaime Villa, Larry David Wilson, and Jerry D. Johnson

    USGS Publications Warehouse

    Scott, N.J.

    1989-01-01

    Review of: Middle American Herpetology: a bibliographic checklist. By Jaime Villa, Larry David Wilson and Jerry D. Johnson. 1988. University of Missouri Press, Columbia, Missouri 65211. 132 p., 16 color plates, $35.00 (hardcover).

  11. [Generalized anxiety disorders (GAD)--a neglected illness? Background und aims of the GAD-P study].

    PubMed

    Wittchen, H U; Linden, M; Schwarzer, W; Riemann, D; Boerner, R J; Bandelow, B

    2001-01-01

    In the past Generalized anxiety disorder (GAD)--previously classified as anxiety neurosis--was regarded as not being a separate diagnostic entity. On the basis of new explicit criteria for GAD in the 90ies, GAD-specific pharmacological (i.e. SNRI) and psychological treatments with improved efficacy have become available. The Generalized Anxiety and Depression in Primary care study (GAD-P) investigates the prevalence of GAD in primary care settings and evaluates the patterns of care provided. Aims, methods and findings of the GAD-P study are described in this supplement.

  12. 77 FR 31045 - Order Prohibiting Involvement in NRC-Licensed Activities; In the Matter of Jaime Sánchez

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-24

    ... [Federal Register Volume 77, Number 101 (Thursday, May 24, 2012)] [Notices] [Pages 31045-31047] [FR Doc No: 2012-12621] NUCLEAR REGULATORY COMMISSION [NRC-2012-0115; IA-11-036] Order Prohibiting Involvement in NRC-Licensed Activities; In the Matter of Jaime S[aacute]nchez I Jaime S[aacute]nchez (Mr....

  13. Cultural-based biases of the GAD-7.

    PubMed

    Parkerson, Holly A; Thibodeau, Michel A; Brandt, Charles P; Zvolensky, Michael J; Asmundson, Gordon J G

    2015-04-01

    The GAD-7 is a popular measure of generalized anxiety disorder (GAD) symptoms that has been used across many cultural groups. Existing evidence demonstrates that the prevalence of GAD varies across self-identified ethnic/cultural groups, a phenomenon that some researchers attribute to cross-cultural measurement error rather than to actual differences in rates of GAD. Nonetheless, the effect of culture on factor structure and response patterns to the GAD-7 have not been examined and could result over- or under-estimated GAD-7 scores across different cultural groups. The current investigation assessed the factor structure of the GAD-7 in White/Caucasian, Hispanic, and Black/African American undergraduates and tested for cultural-based biases. A modified one-factor model exhibited good fit across subsamples. Results revealed that Black/African American participants with high GAD symptoms scored lower on the GAD-7 than other participants with similar GAD symptoms. Results highlight the need for culturally sensitive GAD screening tools. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. POSTPARTUM GAD IS A RISK FACTOR FOR POSTPARTUM MDD: THE COURSE AND LONGITUDINAL RELATIONSHIPS OF POSTPARTUM GAD AND MDD

    PubMed Central

    Prenoveau, Jason; Craske, Michelle; Counsell, Nicholas; West, Valerie; Davies, Beverley; Cooper, Peter; Rapa, Elizabeth; Stein, Alan

    2013-01-01

    Background The objective was to examine the course and longitudinal associations of generalized anxiety disorder (GAD) and major depressive disorder (MDD) in mothers over the postpartum 2 years. Method Using a prospective naturalistic design, 296 mothers recruited from a large community pool were assessed for GAD and MDD at 3, 6, 10, 14, and 24 months postpartum. Structured clinical interviews were used for diagnoses, and symptoms were assessed using self-report questionnaires. Logistic regression analyses were used to examine diagnostic stability and longitudinal relations, and latent variable modeling was employed to examine change in symptoms. Results MDD without co-occurring GAD, GAD without co-occurring MDD, and co-occurring GAD and MDD, displayed significant stability during the postpartum period. Whereas MDD did not predict subsequent GAD, GAD predicted subsequent MDD (in the form of GAD + MDD). Those with GAD + MDD at 3 months postpartum were significantly less likely to be diagnosis free during the follow-up period than those in other diagnostic categories. At the symptom level, symptoms of GAD were more trait-like than those of depression. Conclusions Postpartum GAD and MDD are relatively stable conditions, and GAD is a risk factor for MDD but not vice versa. Given the tendency of MDD and GAD to be persistent, especially when comorbid, and the increased risk for MDD in mothers with GAD, as well as the potential negative effects of cumulative exposure to maternal depression and anxiety on child development, the present findings clearly highlight the need for screening and treatment of GAD in addition to MDD during the postpartum period. PMID:23288653

  15. Interaction of NAP-22 with brain glutamic acid decarboxylase (GAD).

    PubMed

    Maekawa, Shohei; Kobayashi, Yuumi; Odagaki, Sin-Ichi; Makino, Midori; Kumanogoh, Haruko; Nakamura, Shun; Morita, Mitsuhiro; Hayashi, Fumio

    2013-03-14

    NAP-22 (also called BASP1 or CAP-23) is a neuron-enriched protein localized mainly in the synaptic vesicles and the synaptic plasma membrane. Biochemically, it is recovered in the lipid raft fraction. In order to understand the physiological function of the neuronal lipid raft, NAP-22 binding proteins were screened with a pull-down assay. Glutamic acid decarboxylase (GAD) was detected through LC-MS/MS, and Western blotting using a specific antibody confirmed the result. Two isoforms of GAD, GAD65 and GAD67, were expressed in bacteria as GST-fusion forms and the interaction with NAP-22 was confirmed in vitro. Partial co-localization of NAP-22 with GAD65 and GAD67 was also observed in cultured neurons. The binding showed no effect on the enzymatic activity of GAD65 and GAD67. These results hence suggest that NAP-22 could participate in the transport of GAD65 and GAD67 to the presynaptic termini and their retention on the synaptic vesicles as an anchoring protein.

  16. Testing the GAD throughout the Precambrian

    NASA Astrophysics Data System (ADS)

    Veikkolainen, T.; Pesonen, L. J.; Korhonen, K.

    2013-05-01

    A long tradition has emerged in using the inclination frequency analysis to study the functionality of the Geocentric Axial Dipole (GAD) hypothesis in paleomagnetism. Here a test is presented, based on 3016 records of the Earth's Precambrian geomagnetic field as acquired from a novel catalogue maintained by University of Helsinki, and Yale University. The technique is based on fitting zonal (axial) dipolar (GAD), quadrupolar (G2) and octupolar (G3) harmonics to find the best-fitting inclination distribution. The influence of various factors, such as the geologic age, rock type, magnetic polarity, quality of data and its spatial distribution has been tested. Finally, the most plausible estimates for the zonal non-dipolar contributions of the field have been determined as 0 % for G2 and 6 % for G3. Another way to analyze the zonal harmonics of the geomagnetic field and the validity of GAD is based on the asymmetry between the normal and reversed polarities. To get an insight to the morphology of the field in the late Paleoproterozoic, we have also run a reversal simulation using data mainly from the 1.88 Ga Stark Formation, Canada, revealing the both stable polarity directions (N, R) and also transitional directions between them. In the global Precambrian perspective, an overall moderate dependence of the inclination asymmetry on paleolatitude is visible with a distinct mid-latitude peak. However, the required values to account for the observed deviation from GAD are less than 5 % for G2 and less than 10 % for G3. Alternatively, paleosecular variation (PSV) can be used to shed light to processes in the geodynamo and to model the growth of the inner core. We have applied the CALS3K model of the field as a basis of a time simulation of declination-inclination pairs around a grid on the Earth and by this way in estimating PSV. Our approach is based on calculating S vs latitude curves at different time instances in the validity period of the model, and comparing them

  17. GAD1 Gene Expression in Blood of Patients with First-Episode Psychosis

    PubMed Central

    Yee, Jie Yin; Nurjono, Milawaty; Teo, Stephanie Ruth; Lee, Tih-Shih; Lee, Jimmy

    2017-01-01

    γ-Aminobutyric acid (GABA), the primary inhibitory neurotransmitter, has often been studied in relation to its role in the pathophysiology of schizophrenia. GABA is synthesized from glutamate by glutamic acid decarboxylase (GAD), derived from two genes, GAD1 and GAD2. GAD1 is expressed as both GAD67 and GAD25 mRNA transcripts with the former reported to have a lower expression level in schizophrenia compared to healthy controls and latter was reported to be predominantly expressed fetally, suggesting a role in developmental process. In this study, GAD67 and GAD25 mRNA levels were measured by quantitative PCR (qPCR) in peripheral blood of subjects with first-episode psychosis (FEP) and from healthy controls. We observed low GAD25 and GAD67 gene expression levels in human peripheral blood. There was no difference in GAD25 and GAD67 gene expression level, and GAD25/GAD67 ratio between patients with FEP and healthy controls. PANSS negative symptoms were associated with levels of GAD25 mRNA transcripts in patients with FEP. While the current study provides information on GAD25 and GAD67 mRNA transcript levels in whole blood of FEP patients, further correlation and validation work between brain regions, cerebrospinal fluid and peripheral blood expression profiling are required to provide a better understanding of GAD25 and GAD67. PMID:28122016

  18. Generalized Anxiety Disorder (GAD): When Worry Gets Out of Control

    MedlinePlus

    ... psychiatrist or psychologist. GAD is generally treated with psychotherapy, medication, or both. Talk with your doctor about the best treatment for you. Psychotherapy A type of psychotherapy called cognitive behavioral therapy ( ...

  19. Perceived attachment: relations to anxiety sensitivity, worry, and GAD symptoms.

    PubMed

    Viana, Andres G; Rabian, Brian

    2008-06-01

    This investigation examined the relation between perceived alienation from parents and peers, anxiety sensitivity (AS), and current worry and generalized anxiety disorder (GAD) symptoms with the goal of expanding the knowledge base on factors that may contribute to the development of AS and its role in worry. The mediating role of AS between perceptions of alienation and current worry and GAD symptoms was also examined. Ninety-four non-clinical worriers completed self-report questionnaires assessing their perceptions of attachment, AS levels, and worry and GAD symptoms. Even after controlling for worry and GAD symptoms, greater perceptions of alienation from mothers and peers were significantly associated with higher AS symptoms. AS as a unitary construct mediated the relation between perceptions of alienation from mothers and peers and worry and GAD symptoms. The facets fear of publicly observable symptoms and fear of cognitive dyscontrol also mediated this relation. The role of alienation in relation to AS, worry, and GAD symptoms is discussed along with directions for future research.

  20. Relationship between serum GAD-Ab and the genetic polymorphisms of GAD2 and type 2 diabetes mellitus.

    PubMed

    Li, Q; Qiao, Z R; Liu, D B; Zeng, J T; Zhang, J; Bo, Y; Zu, H Y; Hu, Q; Wu, X; Dong, S S

    2015-04-10

    In this study, we investigated the relationship between serum glutamic acid decarboxylase (GAD) autoantibody (Ab) levels and single nucleotide polymorphisms (SNPs) of the glutamic acid de-carboxylase 2 (GAD2) 5'-untranslated region and the susceptibility to type 2 diabetes in the Han population. The distributions of patients with SNPs in the GAD2 5'-untranslated region (rs2236418, rs185649317, and rs8190590) and type 2 diabetes and that of the healthy group were genotyped and analyzed using Sequenom MassArray SNP genotyp-ing. GAD-Ab levels were also detected. The frequency distributions of the AA, AG, and GG genotypes in the polymorphic site rs2236418 in the diabetes GAD-Ab-positive group were 45.9, 42.8, and 11.4%, respectively, whereas those in the control group were 36.6, 43.7, and 19.8%, respectively. The difference between the 2 groups was statis-tically significant (P < 0.05). Unlike the GG genotype, the AA and AA + AG genotypes increased the risk of GAD-Ab (odds ratios (95% confidence intervals) = 2.623 (1.351-4.937) and 2.152 (1.375-4.202), respectively). The associations of the 3 SNPs of the GAD2 gene 5'-un-translated region polymorphisms with susceptibility to type 2 diabe-tes in the Chongqing Han population were significant. The SNP of rs2236418 in the Chongqing Han population of diabetic patients with serum GAD-Ab levels was significantly correlated with the SNPs rs185649317 and rs8190590.

  1. Transcriptional Expression of Escherichia coli Glutamate-Dependent Acid Resistance Genes gadA and gadBC in an hns rpoS Mutant†

    PubMed Central

    Waterman, Scott R.; Small, P. L. C.

    2003-01-01

    Resistance to being killed by acidic environments with pH values lower than 3 is an important feature of both pathogenic and nonpathogenic Escherichia coli. The most potent E. coli acid resistance system utilizes two isoforms of glutamate decarboxylase encoded by gadA and gadB and a putative glutamate:γ-aminobutyric acid antiporter encoded by gadC. The gad system is controlled by two repressors (H-NS and CRP), one activator (GadX), one repressor-activator (GadW), and two sigma factors (σS and σ70). In contrast to results of previous reports, we demonstrate that gad transcription can be detected in an hns rpoS mutant strain of E. coli K-12, indicating that gad promoters can be initiated by σ70 in the absence of H-NS. PMID:12867478

  2. Transcriptional expression of Escherichia coli glutamate-dependent acid resistance genes gadA and gadBC in an hns rpoS mutant.

    PubMed

    Waterman, Scott R; Small, P L C

    2003-08-01

    Resistance to being killed by acidic environments with pH values lower than 3 is an important feature of both pathogenic and nonpathogenic Escherichia coli. The most potent E. coli acid resistance system utilizes two isoforms of glutamate decarboxylase encoded by gadA and gadB and a putative glutamate:gamma-aminobutyric acid antiporter encoded by gadC. The gad system is controlled by two repressors (H-NS and CRP), one activator (GadX), one repressor-activator (GadW), and two sigma factors (sigma(S) and sigma(70)). In contrast to results of previous reports, we demonstrate that gad transcription can be detected in an hns rpoS mutant strain of E. coli K-12, indicating that gad promoters can be initiated by sigma(70) in the absence of H-NS.

  3. Tomato Glutamate Decarboxylase Genes SlGAD2 and SlGAD3 Play Key Roles in Regulating γ-Aminobutyric Acid Levels in Tomato (Solanum lycopersicum).

    PubMed

    Takayama, Mariko; Koike, Satoshi; Kusano, Miyako; Matsukura, Chiaki; Saito, Kazuki; Ariizumi, Tohru; Ezura, Hiroshi

    2015-08-01

    Tomato (Solanum lycopersicum) can accumulate relatively high levels of γ-aminobutyric acid (GABA) during fruit development. However, the molecular mechanism underlying GABA accumulation and its physiological function in tomato fruits remain elusive. We previously identified three tomato genes (SlGAD1, SlGAD2 and SlGAD3) encoding glutamate decarboxylase (GAD), likely the key enzyme for GABA biosynthesis in tomato fruits. In this study, we generated transgenic tomato plants in which each SlGAD was suppressed and those in which all three SlGADs were simultaneously suppressed. A significant decrease in GABA levels, i.e. 50-81% compared with wild-type (WT) levels, was observed in mature green (MG) fruits of the SlGAD2-suppressed lines, while a more drastic reduction (up to <10% of WT levels) was observed in the SlGAD3- and triple SlGAD-suppressed lines. These findings suggest that both SlGAD2 and SlGAD3 expression are crucial for GABA biosynthesis in tomato fruits. The importance of SlGAD3 expression was also confirmed by generating transgenic tomato plants that over-expressed SlGAD3. The MG and red fruits of the over-expressing transgenic lines contained higher levels of GABA (2.7- to 5.2-fold) than those of the WT. We also determined that strong down-regulation of the SlGADs had little effect on overall plant growth, fruit development or primary fruit metabolism under normal growth conditions. © The Author 2015. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  4. Prevalence of anxiety disorders among Finnish primary care high utilizers and validation of Finnish translation of GAD-7 and GAD-2 screening tools

    PubMed Central

    Ylisaukko-Oja, Tero; Jokelainen, Jari; Hirsikangas, Sari; Kanste, Outi; Kyngäs, Helvi; Timonen, Markku

    2014-01-01

    Abstract Objective. To analyse the prevalence of GAD and other anxiety disorders, as well as sensitivity and specificity of GAD-7 among high utilizers of health care. Setting. Four municipal health centres in Northern Finland. Subjects. A psychiatric interview was conducted for 150 high utilizers of health care. Main outcome measures. Prevalence of GAD as well as sensitivity and specificity of GAD-7. Results. The prevalence of GAD was 4% in this study group of Finnish high utilizers of health care. The sensitivity of GAD-7 was 100.0% (95% CI 54.1–100.0) and the specificity of GAD-7 was 82.6% (95% CI 75.4–88.4) with a cut-off point of 7 or more. Conclusion. GAD is rather common among high utilizers of primary care, although the prevalence of 4% is lower than that previously reported. GAD-7 is a valid and useful tool for detecting GAD among primary health care patients. PMID:24920316

  5. Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis

    PubMed Central

    Kass, Itamar; Hoke, David E.; Costa, Mauricio G. S.; Reboul, Cyril F.; Porebski, Benjamin T.; Cowieson, Nathan P.; Leh, Hervé; Pennacchietti, Eugenia; McCoey, Julia; Kleifeld, Oded; Borri Voltattorni, Carla; Langley, David; Roome, Brendan; Mackay, Ian R.; Christ, Daniel; Perahia, David; Buckle, Malcolm; Paiardini, Alessandro; De Biase, Daniela; Buckle, Ashley M.

    2014-01-01

    The human neuroendocrine enzyme glutamate decarboxylase (GAD) catalyses the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) using pyridoxal 5′-phosphate as a cofactor. GAD exists as two isoforms named according to their respective molecular weights: GAD65 and GAD67. Although cytosolic GAD67 is typically saturated with the cofactor (holoGAD67) and constitutively active to produce basal levels of GABA, the membrane-associated GAD65 exists mainly as the inactive apo form. GAD65, but not GAD67, is a prevalent autoantigen, with autoantibodies to GAD65 being detected at high frequency in patients with autoimmune (type 1) diabetes and certain other autoimmune disorders. The significance of GAD65 autoinactivation into the apo form for regulation of neurotransmitter levels and autoantibody reactivity is not understood. We have used computational and experimental approaches to decipher the nature of the holo → apo conversion in GAD65 and thus, its mechanism of autoinactivation. Molecular dynamics simulations of GAD65 reveal coupling between the C-terminal domain, catalytic loop, and pyridoxal 5′-phosphate–binding domain that drives structural rearrangement, dimer opening, and autoinactivation, consistent with limited proteolysis fragmentation patterns. Together with small-angle X-ray scattering and fluorescence spectroscopy data, our findings are consistent with apoGAD65 existing as an ensemble of conformations. Antibody-binding kinetics suggest a mechanism of mutually induced conformational changes, implicating the flexibility of apoGAD65 in its autoantigenicity. Although conformational diversity may provide a mechanism for cofactor-controlled regulation of neurotransmitter biosynthesis, it may also come at a cost of insufficient development of immune self-tolerance that favors the production of GAD65 autoantibodies. PMID:24927554

  6. Cofactor-dependent conformational heterogeneity of GAD65 and its role in autoimmunity and neurotransmitter homeostasis.

    PubMed

    Kass, Itamar; Hoke, David E; Costa, Mauricio G S; Reboul, Cyril F; Porebski, Benjamin T; Cowieson, Nathan P; Leh, Hervé; Pennacchietti, Eugenia; McCoey, Julia; Kleifeld, Oded; Borri Voltattorni, Carla; Langley, David; Roome, Brendan; Mackay, Ian R; Christ, Daniel; Perahia, David; Buckle, Malcolm; Paiardini, Alessandro; De Biase, Daniela; Buckle, Ashley M

    2014-06-24

    The human neuroendocrine enzyme glutamate decarboxylase (GAD) catalyses the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) using pyridoxal 5'-phosphate as a cofactor. GAD exists as two isoforms named according to their respective molecular weights: GAD65 and GAD67. Although cytosolic GAD67 is typically saturated with the cofactor (holoGAD67) and constitutively active to produce basal levels of GABA, the membrane-associated GAD65 exists mainly as the inactive apo form. GAD65, but not GAD67, is a prevalent autoantigen, with autoantibodies to GAD65 being detected at high frequency in patients with autoimmune (type 1) diabetes and certain other autoimmune disorders. The significance of GAD65 autoinactivation into the apo form for regulation of neurotransmitter levels and autoantibody reactivity is not understood. We have used computational and experimental approaches to decipher the nature of the holo → apo conversion in GAD65 and thus, its mechanism of autoinactivation. Molecular dynamics simulations of GAD65 reveal coupling between the C-terminal domain, catalytic loop, and pyridoxal 5'-phosphate-binding domain that drives structural rearrangement, dimer opening, and autoinactivation, consistent with limited proteolysis fragmentation patterns. Together with small-angle X-ray scattering and fluorescence spectroscopy data, our findings are consistent with apoGAD65 existing as an ensemble of conformations. Antibody-binding kinetics suggest a mechanism of mutually induced conformational changes, implicating the flexibility of apoGAD65 in its autoantigenicity. Although conformational diversity may provide a mechanism for cofactor-controlled regulation of neurotransmitter biosynthesis, it may also come at a cost of insufficient development of immune self-tolerance that favors the production of GAD65 autoantibodies.

  7. Decline in Titers of Anti-Idiotypic Antibodies Specific to Autoantibodies to GAD65 (GAD65Ab) Precedes Development of GAD65Ab and Type 1 Diabetes

    PubMed Central

    Larsson, Helena Elding; Jönsson, Ida; Lernmark, Åke; Ivarsson, Sten; Radtke, Jared R.; Hampe, Christiane S.

    2013-01-01

    The humoral Idiotypic Network consisting of antibodies and their anti-idiotypic antibodies (anti-Id) can be temporarily upset by antigen exposure. In the healthy immune response the original equilibrium is eventually restored through counter-regulatory mechanisms. In certain autoimmune diseases however, autoantibody levels exceed those of their respective anti-Id, indicating a permanent disturbance in the respective humoral Idiotypic Network. We investigated anti-Id directed to a major Type 1 diabetes (T1D)-associated autoantibody (GAD65Ab) in two independent cohorts during progression to disease. Samples taken from participants of the Natural History Study showed significantly lower anti-Id levels in individuals that later progressed to T1D compared to non-progressors (anti-Id antibody index of 0.06 vs. 0.08, respectively, p = 0.02). We also observed a significant inverse correlation between anti-Id levels and age at sampling, but only in progressors (p = 0.014). Finally, anti-Id levels in progressors showed a significant decline during progression as compared to longitudinal anti-Id levels in non-progressors (median rate of change: −0.0004 vs. +0.0004, respectively, p = 0.003), suggesting a loss of anti-Id during progression. Our analysis of the Diabetes Prediction in Skåne cohort showed that early in life (age 2) individuals at risk have anti-Id levels indistinguishable from those in healthy controls, indicating that low anti-Id levels are not an innate characteristic of the immune response in individuals at risk. Notably, anti-Id levels declined significantly in individuals that later developed GAD65Ab suggesting that the decline in anti-Id levels precedes the emergence of GAD65Ab (median rate of change: −0.005) compared to matched controls (median rate of change: +0.001) (p = 0.0016). We conclude that while anti-Id are present early in life, their levels decrease prior to the appearance of GAD65Ab and to the development of T1D. PMID

  8. Regulation of GAD65 expression by SMAR1 and p53 upon Streptozotocin treatment

    PubMed Central

    2012-01-01

    Background GAD65 (Glutamic acid decarboxylase 65 KDa isoform) is one of the most important auto-antigens involved in Type 1 diabetes induction. Although it serves as one of the first injury markers of β-islets, the mechanisms governing GAD65 expression remain poorly understood. Since the regulation of GAD65 is crucial for the proper functioning of insulin secreting cells, we investigated the stress induced regulation of GAD65 transcription. Results The present study shows that SMAR1 regulates GAD65 expression at the transcription level. Using a novel protein-DNA pull-down assay, we show that SMAR1 binding is very specific to GAD65 promoter but not to the other isoform, GAD67. We show that Streptozotocin (STZ) mediated DNA damage leads to upregulation of SMAR1 and p53 expression, resulting in elevated levels of GAD65, in both cell lines as well as mouse β-islets. SMAR1 and p53 act synergistically to up-regulate GAD65 expression upon STZ treatment. Conclusion We propose a novel mechanism of GAD65 regulation by synergistic activities of SMAR1 and p53. PMID:22978699

  9. gadA gene locus in Lactobacillus brevis NCL912 and its expression during fed-batch fermentation.

    PubMed

    Li, Haixing; Li, Wenming; Liu, Xiaohua; Cao, Yusheng

    2013-12-01

    Normally, Lactobacillus brevis has two glutamate decarboxylase (GAD) genes; gadA and gadB. Using PCR, we cloned the gadA gene from L. brevis strain NCL912, a high yield strain for the production of gamma-aminobutyric acid (GABA). However, despite using 61 different primer pairs, including degenerate primers from conserved regions, we were unable to use PCR to clone gadB from the NCL912 strain. Furthermore, we could not clone it by genomic walking over 3000 bp downstream of the aldo-keto reductase gene, a single-copy gene that is located 1003 bp upstream of gadB in L. brevis ATCC367. Altogether, the data suggest that L. brevis NCL912 does not contain a gadB gene. By genomic walking, we cloned regions upstream and downstream of the gadA gene to obtain a 4615 bp DNA fragment that included the complete gadA locus. The locus contained the GAD gene (gadA) and the glutamate:GABA antiporter gene (gadC), which appear to be transcribed in an operon (gadCA), and a transcriptional regulator (gadR) of gadCA. During whole fed-batch fermentation, the expression of gadR, gadC and gadA was synchronized and correlated well with GABA production. The gadA locus we cloned from NCL912 has reduced homology compared with gadA loci of other L. brevis strains, and these differences might explain the ability of NCL912 to produce higher levels of GABA in culture.

  10. mir-500-Mediated GAD67 Downregulation Contributes to Neuropathic Pain.

    PubMed

    Huang, Zhen-Zhen; Wei, Jia-You; Ou-Yang, Han-Dong; Li, Dai; Xu, Ting; Wu, Shao-Ling; Zhang, Xiao-Long; Liu, Cui-Cui; Ma, Chao; Xin, Wen-Jun

    2016-06-08

    Neuropathic pain is a common neurobiological disease involving multifaceted maladaptations ranging from gene modulation to synaptic dysfunction, but the interactions between synaptic dysfunction and the genes that are involved in persistent pain remain elusive. In the present study, we found that neuropathic pain induced by the chemotherapeutic drug paclitaxel or L5 ventral root transection significantly impaired the function of GABAergic synapses of spinal dorsal horn neurons via the reduction of the GAD67 expression. We also found that mir-500 expression was significantly increased and involved in the modulation of GAD67 expression via targeting the specific site of Gad1 gene in the dorsal horn. In addition, knock-out of mir-500 or using mir-500 antagomir rescued the GABAergic synapses in the spinal dorsal horn neurons and attenuated the sensitized pain behavior in the rats with neuropathic pain. To our knowledge, this is the first study to investigate the function significance and the underlying molecular mechanisms of mir-500 in the process of neuropathic pain, which sheds light on the development of novel therapeutic options for neuropathic pain. Neuropathic pain is a common neurobiological disease involving multifaceted maladaptations ranging from gene modulation to synaptic dysfunction, but the underlying molecular mechanisms remain elusive. The present study illustrates for the first time a mir-500-mediated mechanism underlying spinal GABAergic dysfunction and sensitized pain behavior in neuropathic pain induced by the chemotherapeutic drug paclitaxel or L5 ventral root transection, which sheds light on the development of novel therapeutic options for neuropathic pain. Copyright © 2016 the authors 0270-6474/16/366321-11$15.00/0.

  11. Diagnostic Validity of the Generalized Anxiety Disorder - 7 (GAD-7) among Pregnant Women

    PubMed Central

    Zhong, Qiu-Yue; Gelaye, Bizu; Zaslavsky, Alan M.; Fann, Jesse R.; Rondon, Marta B.; Sánchez, Sixto E.; Williams, Michelle A.

    2015-01-01

    Objective Generalized anxiety disorder (GAD) during pregnancy is associated with several adverse maternal and perinatal outcomes. A reliable and valid screening tool for GAD should lead to earlier detection and treatment. Among pregnant Peruvian women, a brief screening tool, the GAD-7, has not been validated. This study aims to evaluate the reliability and validity of the GAD-7. Methods Of 2,978 women who attended their first perinatal care visit and had the GAD-7 screening, 946 had a Composite International Diagnostic Interview (CIDI). The Cronbach’s alpha was calculated to examine the reliability. We assessed the criterion validity by calculating operating characteristics. The construct validity was evaluated using factor analysis and association with health status on the CIDI. The cross-cultural validity was explored using the Rasch Rating Scale Model (RSM). Results The reliability of the GAD-7 was good (Cronbach’s alpha = 0.89). A cutoff score of 7 or higher, maximizing the Youden Index, yielded a sensitivity of 73.3% and a specificity of 67.3%. One-factor structure of the GAD-7 was confirmed by exploratory and confirmatory factor analysis. Concurrent validity was supported by the evidence that higher GAD-7 scores were associated with poor self-rated physical and mental health. The Rasch RSM further confirmed the cross-cultural validity of the GAD-7. Conclusion The results suggest that the Spanish-language version of the GAD-7 may be used as a screening tool for pregnant Peruvian women. The GAD-7 has good reliability, factorial validity, and concurrent validity. The optimal cutoff score obtained by maximizing the Youden Index should be considered cautiously; women who screened positive may require further investigation to confirm GAD diagnosis. PMID:25915929

  12. GAD2 Alternative Transcripts in the Human Prefrontal Cortex, and in Schizophrenia and Affective Disorders

    PubMed Central

    Li, Chao; Gao, Yuan; Gondré-Lewis, Marjorie C.; Lipska, Barbara K.; Shin, Joo Heon; Xie, Bin; Ye, Tianzhang; Weinberger, Daniel R.; Kleinman, Joel E.; Hyde, Thomas M.

    2016-01-01

    Genetic variation and early adverse environmental events work together to increase risk for schizophrenia. γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in adult mammalian brain, plays a major role in normal brain development, and has been strongly implicated in the pathobiology of schizophrenia. GABA synthesis is controlled by two glutamic acid decarboxylase (GAD) genes, GAD1 and GAD2, both of which produce a number of alternative transcripts. Genetic variants in the GAD1 gene are associated with increased risk for schizophrenia, and reduced expression of its major transcript in the human dorsolateral prefrontal cortex (DLPFC). No consistent changes in GAD2 expression have been found in brains from patients with schizophrenia. In this work, with the use of RNA sequencing and PCR technologies, we confirmed and tracked the expression of an alternative truncated transcript of GAD2 (ENST00000428517) in human control DLPFC homogenates across lifespan besides the well-known full length transcript of GAD2. In addition, using quantitative RT-PCR, expression of GAD2 full length and truncated transcripts were measured in the DLPFC of patients with schizophrenia, bipolar disorder and major depression. The expression of GAD2 full length transcript is decreased in the DLPFC of schizophrenia and bipolar disorder patients, while GAD2 truncated transcript is increased in bipolar disorder patients but decreased in schizophrenia patients. Moreover, the patients with schizophrenia with completed suicide or positive nicotine exposure showed significantly higher expression of GAD2 full length transcript. Alternative transcripts of GAD2 may be important in the growth and development of GABA-synthesizing neurons as well as abnormal GABA signaling in the DLPFC of patients with schizophrenia and affective disorders. PMID:26848839

  13. GABA production and structure of gadB/gadC genes in Lactobacillus and Bifidobacterium strains from human microbiota.

    PubMed

    Yunes, R A; Poluektova, E U; Dyachkova, M S; Klimina, K M; Kovtun, A S; Averina, O V; Orlova, V S; Danilenko, V N

    2016-12-01

    Gamma-amino butyric acid (GABA) is an active biogenic substance synthesized in plants, fungi, vertebrate animals and bacteria. Lactic acid bacteria are considered the main producers of GABA among bacteria. GABA-producing lactobacilli are isolated from food products such as cheese, yogurt, sourdough, etc. and are the source of bioactive properties assigned to those foods. The ability of human-derived lactobacilli and bifidobacteria to synthesize GABA remains poorly characterized. In this paper, we screened our collection of 135 human-derived Lactobacillus and Bifidobacterium strains for their ability to produce GABA from its precursor monosodium glutamate. Fifty eight strains were able to produce GABA. The most efficient GABA-producers were Bifidobacterium strains (up to 6 g/L). Time profiles of cell growth and GABA production as well as the influence of pyridoxal phosphate on GABA production were studied for L. plantarum 90sk, L. brevis 15f, B. adolescentis 150 and B. angulatum GT102. DNA of these strains was sequenced; the gadB and gadC genes were identified. The presence of these genes was analyzed in 14 metagenomes of healthy individuals. The genes were found in the following genera of bacteria: Bacteroidetes (Bacteroides, Parabacteroides, Alistipes, Odoribacter, Prevotella), Proteobacterium (Esherichia), Firmicutes (Enterococcus), Actinobacteria (Bifidobacterium). These data indicate that gad genes as well as the ability to produce GABA are widely distributed among lactobacilli and bifidobacteria (mainly in L. plantarum, L. brevis, B. adolescentis, B. angulatum, B. dentium) and other gut-derived bacterial species. Perhaps, GABA is involved in the interaction of gut microbiota with the macroorganism and the ability to synthesize GABA may be an important feature in the selection of bacterial strains - psychobiotics.

  14. Highly-sensitive and specific enzyme-linked immunosorbent assays for GAD65 autoantibodies using a thioredoxin-GAD65 fusion antigen.

    PubMed

    Papouchado, M L; Valdez, S N; Ermácora, M R; Gañan, S; Poskus, E

    1997-09-24

    Autoantibodies against glutamic acid decarboxylase (GAD65) are present in the sera of most patients with recently diagnosed insulin-dependent diabetes mellitus (IDDM). These antibodies appear years before the clinical symptoms, and they are considered to be early markers of the disease. To detect GAD65 autoantibodies (GADA), we developed new enzyme-linked immunosorbent assays (ELISA) with a fusion protein thioredoxin-GAD65 (Trx-GAD65) produced in E. coli as the antigen. These assays were compared with the reference radiobinding assay (RBA). Since most GADA are directed against native epitopes, and adsorption of GAD65 to plastic may cause disruption of its native conformation, the new assays rely on the following immobilization procedures: (a) capture ELISA (c-ELISA) with Trx-GAD65 (protocol A) or biotin-Trx-GAD (protocol B) indirectly immobilized by a non-adsorptive process; (b) ELISA with antigen-antibody preincubation in solution (p-ELISA) in which GADA were reacted first with Trx-GAD65 (protocol C) or biotin-Trx-GAD (protocol D) and the free antigen was determined by conventional ELISA. The results obtained with 42 newly diagnosed IDDM patients and 30 normal individuals were as follows: RBA had 79% sensitivity (percentage of IDDM patients detected) and 97% specificity (100% minus the percentage of false positives). c-ELISA showed low sensitivity (36 and 50%, respectively for protocols A and B), and high specificity (100 and 97%, respectively). p-ELISA were highly-sensitive (74 and 79%, respectively) and specific (97 and 93% for protocols C and D, respectively). Thus, protocols C and D had a performance similar to the reference method. The results reported here provide the basis for simple, highly-sensitive, specific, and widely-applicable tests for GADA that eliminate many of the drawbacks of the radioactive methods.

  15. Glutamic acid decarboxylase autoantibody assay using 125I-labelled recombinant GAD65 produced in yeast.

    PubMed

    Powell, M; Prentice, L; Asawa, T; Kato, R; Sawicka, J; Tanaka, H; Petersen, V; Munkley, A; Morgan, S; Rees Smith, B; Furmaniak, J

    1996-12-30

    We describe a new method for measuring autoantibodies (Ab) to the 65 kDa isoform of glutamic acid carboxylase (GAD65). In particular, GAD65 without the hydrophobic N-terminal region has been produced in yeast, purified, labelled with 125I and reacted with GAD65 Ab. Antibody bound 125I-GAD65 is then precipitated by the addition of solid phase protein A. With the assay, GAD65 Ab were detected in 59 of 71 (83%) islet cell antibody (ICA) positive IDDM patients and in 8 of 23 (35%) ICA negative IDDM patients (overall 67 of 94 (71%) of IDDM patients). Low concentrations of GAD65 Ab were also detected in 2/98 (2%) healthy blood donors and 1/27 (4%) Graves' disease patients had a high level of antibody. GAD65 Ab were not detected in any of 10 Hashimoto's thyroiditis, 20 Addison's disease or 19 myasthenia gravis sera. There was good agreement between the 125I assay and the current reference method based on 35S-labelled full-length GAD65 (produced by in vitro transcription/translation reaction) and solid phase protein A (r = 0.91, n = 108). Overall, our 125I assay showed sensitivity, precision and disease group specificity at least as good as any assay so far described. These features, combined with a simple assay protocol and the convenience of 125I counting and handling indicate that the method is suitable for routine GAD65 Ab measurements.

  16. Characterization of hydroxyl radical modified GAD65: a potential autoantigen in type 1 diabetes.

    PubMed

    Khan, Mohd Wajid A; Sherwani, Subuhi; Khan, Wahid A; Ali, Rashid

    2009-02-01

    Glutamic acid decarboxylase-65 (GAD(65)) is an immunological marker of type 1 autoimmune diabetes. High titre of autoantibodies against GAD(65) (GAD(65)Abs) have also been detected in some other autoimmune diseases. In search of a potential immunological marker of type 1 diabetes, in vitro GAD(65) was modified by hydroxyl radical followed by the study of structural and conformational perturbed protein by different spectroscopic techniques (UV, fluorescence and CD) and thermal denaturation profile. Binding studies of circulating autoantibodies from diabetic groups (type 1 and type 2) with native and reactive oxygen species (ROS) modified GAD(65), exhibited high recognition of type 1 diabetic serum autoantibodies with modified antigen (p < 0.001) over unmodified GAD(65). Binding specificity of isolated IgG of patients (n = 17) from each diabetic group and control group (n = 10) was checked by inhibition enzyme linked immunosorbent assay (ELISA) and quantitative precipitin titration assay. Relative affinity of ROS-GAD(65)Abs for modified and native GAD(65) was in the order of 1.56 x 10(- 6) and 2.72 x 10(- 7) M, as calculated by Langmuir plot. In coherence, ROS oxidation of GAD(65) causes conformational perturbation, generating highly immunogenic unique neoepitopes that may be one of the factors in antigen-driven induction of type 1 diabetes autoantibodies that can serve as a potential marker in early diagnosis/prognosis of the disease.

  17. A brief measure for assessing generalized anxiety disorder: the GAD-7.

    PubMed

    Spitzer, Robert L; Kroenke, Kurt; Williams, Janet B W; Löwe, Bernd

    2006-05-22

    Generalized anxiety disorder (GAD) is one of the most common mental disorders; however, there is no brief clinical measure for assessing GAD. The objective of this study was to develop a brief self-report scale to identify probable cases of GAD and evaluate its reliability and validity. A criterion-standard study was performed in 15 primary care clinics in the United States from November 2004 through June 2005. Of a total of 2740 adult patients completing a study questionnaire, 965 patients had a telephone interview with a mental health professional within 1 week. For criterion and construct validity, GAD self-report scale diagnoses were compared with independent diagnoses made by mental health professionals; functional status measures; disability days; and health care use. A 7-item anxiety scale (GAD-7) had good reliability, as well as criterion, construct, factorial, and procedural validity. A cut point was identified that optimized sensitivity (89%) and specificity (82%). Increasing scores on the scale were strongly associated with multiple domains of functional impairment (all 6 Medical Outcomes Study Short-Form General Health Survey scales and disability days). Although GAD and depression symptoms frequently co-occurred, factor analysis confirmed them as distinct dimensions. Moreover, GAD and depression symptoms had differing but independent effects on functional impairment and disability. There was good agreement between self-report and interviewer-administered versions of the scale. The GAD-7 is a valid and efficient tool for screening for GAD and assessing its severity in clinical practice and research.

  18. A paleointensity test of the geocentric axial dipole (GAD) hypothesis

    NASA Astrophysics Data System (ADS)

    Veikkolainen, Toni; Heimpel, Moritz; Evans, Michael E.; Pesonen, Lauri J.; Korhonen, Kimmo

    2017-04-01

    The geocentric axial dipole (GAD) model is central to many aspects of geophysics, including plate tectonics and paleoclimate. But its validity is by no means firmly established, particularly for the Precambrian. One test that has met with some success involves the distribution of paleomagnetic inclination angles. It works because any given field morphology has its own distinct probability distribution function (PDF) against which data compilations can be tested. Here, we investigate a second possible test using published paleointensity data. Once again, any given field morphology has a specific PDF of intensity. Likely field models consist of an underlying GAD on which is superimposed modest zonal quadrupole and octupole components. The corresponding paleointensity PDFs turn out to have more complicated shapes than their inclination counterparts, often having multiple maxima and minima. Given sufficient data, this complexity offers greater discrimination between models. In this paper, the potential of the paleointensity test is assessed using an extension of the PINT paleointensity database. We found it useful to analyse the Phanerozoic and Precambrian intervals separately. Despite the inherent limitations of this kind of analysis, a tripartite geodynamo with small zonal multipoles appears to be a good starting point on a way towards more fine-tuned models.

  19. Validation and standardization of the Generalized Anxiety Disorder Screener (GAD-7) in the general population.

    PubMed

    Löwe, Bernd; Decker, Oliver; Müller, Stefanie; Brähler, Elmar; Schellberg, Dieter; Herzog, Wolfgang; Herzberg, Philipp Yorck

    2008-03-01

    The 7-item Generalized Anxiety Disorder Scale (GAD-7) is a practical self-report anxiety questionnaire that proved valid in primary care. However, the GAD-7 was not yet validated in the general population and thus far, normative data are not available. To investigate reliability, construct validity, and factorial validity of the GAD-7 in the general population and to generate normative data. Nationally representative face-to-face household survey conducted in Germany between May 5 and June 8, 2006. Five thousand thirty subjects (53.6% female) with a mean age (SD) of 48.4 (18.0) years. The survey questionnaire included the GAD-7, the 2-item depression module from the Patient Health Questionnaire (PHQ-2), the Rosenberg Self-Esteem Scale, and demographic characteristics. Confirmatory factor analyses substantiated the 1-dimensional structure of the GAD-7 and its factorial invariance for gender and age. Internal consistency was identical across all subgroups (alpha = 0.89). Intercorrelations with the PHQ-2 and the Rosenberg Self-Esteem Scale were r = 0.64 (P < 0.001) and r = -0.43 (P < 0.001), respectively. As expected, women had significantly higher mean (SD) GAD-7 anxiety scores compared with men [3.2 (3.5) vs. 2.7 (3.2); P < 0.001]. Normative data for the GAD-7 were generated for both genders and different age levels. Approximately 5% of subjects had GAD-7 scores of 10 or greater, and 1% had GAD-7 scores of 15 or greater. Evidence supports reliability and validity of the GAD-7 as a measure of anxiety in the general population. The normative data provided in this study can be used to compare a subject's GAD-7 score with those determined from a general population reference group.

  20. Common Distribution of gad Operon in Lactobacillus brevis and its GadA Contributes to Efficient GABA Synthesis toward Cytosolic Near-Neutral pH

    PubMed Central

    Wu, Qinglong; Tun, Hein Min; Law, Yee-Song; Khafipour, Ehsan; Shah, Nagendra P.

    2017-01-01

    Many strains of lactic acid bacteria (LAB) and bifidobacteria have exhibited strain-specific capacity to produce γ-aminobutyric acid (GABA) via their glutamic acid decarboxylase (GAD) system, which is one of amino acid-dependent acid resistance (AR) systems in bacteria. However, the linkage between bacterial AR and GABA production capacity has not been well established. Meanwhile, limited evidence has been provided to the global diversity of GABA-producing LAB and bifidobacteria, and their mechanisms of efficient GABA synthesis. In this study, genomic survey identified common distribution of gad operon-encoded GAD system in Lactobacillus brevis for its GABA production among varying species of LAB and bifidobacteria. Importantly, among four commonly distributed amino acid-dependent AR systems in Lb. brevis, its GAD system was a major contributor to maintain cytosolic pH homeostasis by consuming protons via GABA synthesis. This highlights that Lb. brevis applies GAD system as the main strategy against extracellular and intracellular acidification demonstrating its high capacity of GABA production. In addition, the abundant GadA retained its activity toward near-neutral pH (pH 5.5–6.5) of cytosolic acidity thus contributing to efficient GABA synthesis in Lb. brevis. This is the first global report illustrating species-specific characteristic and mechanism of efficient GABA synthesis in Lb. brevis. PMID:28261168

  1. Common Distribution of gad Operon in Lactobacillus brevis and its GadA Contributes to Efficient GABA Synthesis toward Cytosolic Near-Neutral pH.

    PubMed

    Wu, Qinglong; Tun, Hein Min; Law, Yee-Song; Khafipour, Ehsan; Shah, Nagendra P

    2017-01-01

    Many strains of lactic acid bacteria (LAB) and bifidobacteria have exhibited strain-specific capacity to produce γ-aminobutyric acid (GABA) via their glutamic acid decarboxylase (GAD) system, which is one of amino acid-dependent acid resistance (AR) systems in bacteria. However, the linkage between bacterial AR and GABA production capacity has not been well established. Meanwhile, limited evidence has been provided to the global diversity of GABA-producing LAB and bifidobacteria, and their mechanisms of efficient GABA synthesis. In this study, genomic survey identified common distribution of gad operon-encoded GAD system in Lactobacillus brevis for its GABA production among varying species of LAB and bifidobacteria. Importantly, among four commonly distributed amino acid-dependent AR systems in Lb. brevis, its GAD system was a major contributor to maintain cytosolic pH homeostasis by consuming protons via GABA synthesis. This highlights that Lb. brevis applies GAD system as the main strategy against extracellular and intracellular acidification demonstrating its high capacity of GABA production. In addition, the abundant GadA retained its activity toward near-neutral pH (pH 5.5-6.5) of cytosolic acidity thus contributing to efficient GABA synthesis in Lb. brevis. This is the first global report illustrating species-specific characteristic and mechanism of efficient GABA synthesis in Lb. brevis.

  2. Adenovector GAD65 gene delivery into the rat trigeminal ganglion produces orofacial analgesia

    PubMed Central

    Vit, Jean-Philippe; Ohara, Peter T; Sundberg, Christopher; Rubi, Blanca; Maechler, Pierre; Liu, Chunyan; Puntel, Mariana; Lowenstein, Pedro; Castro, Maria; Jasmin, Luc

    2009-01-01

    Background Our goal is to use gene therapy to alleviate pain by targeting glial cells. In an animal model of facial pain we tested the effect of transfecting the glutamic acid decarboxylase (GAD) gene into satellite glial cells (SGCs) of the trigeminal ganglion by using a serotype 5 adenovector with high tropisms for glial cells. We postulated that GABA produced from the expression of GAD would reduce pain behavior by acting on GABA receptors on neurons within the ganglion. Results Injection of adenoviral vectors (AdGAD65) directly into the trigeminal ganglion leads to sustained expression of the GAD65 isoform over the 4 weeks observation period. Immunohistochemical analysis showed that adenovirus-mediated GAD65 expression and GABA synthesis were mainly in SGCs. GABAA and GABAB receptors were both seen in sensory neurons, yet only GABAA receptors decorated the neuronal surface. GABA receptors were not found on SGCs. Six days after injection of AdGAD65 into the trigeminal ganglion, there was a statistically significant decrease of pain behavior in the orofacial formalin test, a model of inflammatory pain. Rats injected with control virus (AdGFP or AdLacZ) had no reduction in their pain behavior. AdGAD65-dependent analgesia was blocked by bicuculline, a selective GABAA receptor antagonist, but not by CGP46381, a selective GABAB receptor antagonist. Conclusion Transfection of glial cells in the trigeminal ganglion with the GAD gene blocks pain behavior by acting on GABAA receptors on neuronal perikarya. PMID:19656360

  3. 5-S-GAD, a novel radical scavenging compound, prevents lens opacity development.

    PubMed

    Akiyama, Nobuko; Umeda, Izumi O; Sogo, Shunji; Nishigori, Hideo; Tsujimoto, Masafumi; Natori, Shunji

    2009-02-15

    The ability of N-beta-alanyl-5-S-glutathionyl-3,4-dihydroxyphenylalanine (5-S-GAD)-a novel catechol derivative isolated from an insect as an antibacterial substance-to scavenge free radicals and prevent cataract progression was examined. 5-S-GAD scavenged 1,1-diphenylpicrylhydrazyl (DPPH) and superoxide anions (O(2)(*)(-)), and inhibited lipid peroxidation. It also significantly inhibited the onset of glucocorticoid-induced lens opacification in chick embryos. These effects of 5-S-GAD were stronger than those of N-acetylcarnosine and TEMPOL, which are reported to be effective radical scavengers in the prevention of cataract progression. 5-S-GAD clearly delayed the maturation of cataracts induced by diamide in cultured lenses of rats. Daily instillation of 5-S-GAD retarded the development of lens opacity in galactose-fed rats. Biochemical analysis of the lenses revealed that 20-kDa proteins, presumably consisting of alpha-crystallin, were the most susceptible to oxidative stress, which leads to the carbonylation of the side chains of these proteins. alpha-Crystallin carbonylation induced by diamide or galactose was notably inhibited by 5-S-GAD in a dose-dependent manner. Our results show that 5-S-GAD prevents acute lens opacification in these short-term experimental models, possibly in part by virtue of its antioxidative property, and 5-S-GAD is expected to have long-term pharmaceutical effects.

  4. Modulation of TCR responsiveness by the Grb2-family adaptor, Gads.

    PubMed

    Lugassy, Jennie; Corso, Jasmin; Beach, Dvora; Petrik, Thomas; Oellerich, Thomas; Urlaub, Henning; Yablonski, Deborah

    2015-01-01

    T cell antigen receptor (TCR) signaling depends on three interacting adaptor proteins: SLP-76, Gads, and LAT. Their mechanisms of signaling have been extensively explored, with the aid of fortuitously isolated LAT- and SLP-76-deficient T cell lines, but no such tools were available for Gads, a Grb2-family adaptor that bridges the TCR-inducible interaction between SLP-76 and LAT. TALEN-directed genome editing was applied to disrupt the first coding exon of human Gads in the Jurkat T cell line. Gads was dispensable for TCR-induced phosphorylation of SLP-76, but was a dose-dependent amplifier of TCR-induced CD69 expression. Gads conferred responsiveness to weak TCR stimuli, leading to PLC-γ1 phosphorylation and calcium flux. TALEN-derived, Gads-deficient T cell lines provide a uniquely tractable genetic platform for exploring its regulatory features, such as Gads phosphorylation at T262, which we observed by mass spectrometry. Upon mutation of this site, TCR responsiveness and sensitivity to weak TCR stimuli were increased. This study demonstrates the feasibility of TALEN-based reverse genetics in Jurkat T cells, while enriching our understanding of Gads as a regulated modulator of TCR sensitivity.

  5. GAD67-mediated GABA synthesis and signaling regulate inhibitory synaptic innervation in the visual cortex.

    PubMed

    Chattopadhyaya, Bidisha; Di Cristo, Graziella; Wu, Cai Zhi; Knott, Graham; Kuhlman, Sandra; Fu, Yu; Palmiter, Richard D; Huang, Z Josh

    2007-06-21

    The development of GABAergic inhibitory circuits is shaped by neural activity, but the underlying mechanisms are unclear. Here, we demonstrate a novel function of GABA in regulating GABAergic innervation in the adolescent brain, when GABA is mainly known as an inhibitory transmitter. Conditional knockdown of the rate-limiting synthetic enzyme GAD67 in basket interneurons in adolescent visual cortex resulted in cell autonomous deficits in axon branching, perisomatic synapse formation around pyramidal neurons, and complexity of the innervation fields; the same manipulation had little influence on the subsequent maintenance of perisomatic synapses. These effects of GABA deficiency were rescued by suppressing GABA reuptake and by GABA receptor agonists. Germline knockdown of GAD67 but not GAD65 showed similar deficits, suggesting a specific role of GAD67 in the maturation of perisomatic innervation. Since intracellular GABA levels are modulated by neuronal activity, our results implicate GAD67-mediated GABA synthesis in activity-dependent regulation of inhibitory innervation patterns.

  6. Subsets of Spiny Striosomal Striatal Neurons Revealed in the Gad1-GFP BAC Transgenic Mouse.

    PubMed

    Cuzon Carlson, Verginia C; Mathur, Brian N; Davis, Margaret I; Lovinger, David M

    2011-11-01

    OBJECTIVE: To characterize GFP-expressing cells in the striatum of Cb6-Tg(Gad1-EGFP)G42Zjh/J mice, in which the Gad1 (also referred to as GAD67) promoter drives GFP expression (Gad1-GFP mouse). BACKGROUND: GFP-expressing cells of the GAD1-GFP mouse have been described to be a population of parvalbumin-positive basket interneurons residing in the cerebral cortex and the cerebellum. However, the cells in the dorsal striatum of these mice have not been characterized. METHODS: Using a combination of immunohistochemistry, electrophysiology, DiI labeling, and retrograde tracing, we investigated the phenotypes of GFP-expressing cells in the GAD1-GFP mice. RESULTS: A small number of striatal neurons express GFP in these mice. In the mature striatum, these cells are preferentially located in the lateral striatum with a strong expression in the lateral striatal streak. The GAD1-GFP positive neurons are distinct from the standard fast-spiking and low-threshold-spiking GAD-67 expressing striatal interneurons and appear to be a subset of medium spiny neurons. These neurons are generally colocalized with striosomal markers such as dynorphin, mu-opioid receptors, as well as CB1 and calretinin-immunopositive fibers. Striatal Gad1-GFP neurons can be separated into two groups based on the shape of the somata and patterns of action potential firing. Retrograde labeling indicated that a proportion of these cells are projection neurons. CONCLUSIONS: The examination of GAD1-GFP cells in these mice revealed 2 subpopulations of ventral striosomal striatal medium spiny neurons, based on morphology, patch-matrix segregation and membrane properties.

  7. [The medical and pharmaceutical profession and the mutual care system in the writings of Jaime Vera (1859-1918)].

    PubMed

    Léon Sanz, Pilar

    2006-01-01

    This article presents the perspectives of the physician and politician Jaime Vera y López (1859-1918), co-founder of the Spanish Socialist Workers' Party, on the medical profession, medical practice, and healthcare systems. It compares the Report (Informe) that he presented to the Comisión de Reformas Sociales (1884) with his later writings published in the socialist press ("Farmacia y cooperación obrera,, 1914 and "La locura en los niños. Camino del remedio", 1916). We observe the discrepancies between the political-programme documents and the articles centring on professional questions and highlight how his theoretical focus is modified when applied to matters of medical practice.

  8. Identification of a dominant epitope of glutamic acid decarboxylase (GAD-65) recognized by autoantibodies in stiff-man syndrome

    PubMed Central

    1993-01-01

    Glutamic acid decarboxylase (GAD) is the enzyme that synthesizes the neurotransmitter gamma-aminobutyric acid (GABA) in neurons and in pancreatic beta cells. It is a major target of autoimmunity in Stiff- Man syndrome (SMS), a rare neurological disease, and in insulin- dependent diabetes mellitus. The two GAD isoforms, GAD-65 and GAD-67, are the products of two different genes. GAD-67 and GAD-65 are very similar to each other in amino acid sequence and differ substantially only at their NH2-terminal region. We have investigated the reactivity of autoantibodies of 30 Stiff-Man syndrome patients to GAD. All patient sera contained antibodies that recognize strongly GAD-65, but also GAD- 67, when tested by immunoprecipitation on brain extracts and by immunoprecipitation or immunocytochemistry on cells transfected with either the GAD-65 or the GAD-67 gene. When tested by Western blotting, all patient sera selectively recognized GAD-65. Western blot analysis of deletion mutants of GAD-65 demonstrated that autoantibodies are directed predominantly against two regions of the GAD-65 molecule. All SMS sera strongly recognized a fragment contained between amino acid 475 and the COOH terminus (amino acid 585). Within this region, amino acids 475-484 and 571-585 were required for reactivity. The requirement of these two discontinuous segments implies that the epitope is influenced by conformation. This reactivity is similar to that displayed by the monoclonal antibody GAD 6, suggesting the presence of a single immunodominant epitope (SMS-E1) in this region of GAD-65. In addition, most SMS sera recognized at least one epitope (SMS-E2) in the NH2-terminal domain of GAD-65 (amino acids 1-95). The demonstration in SMS patients of a strikingly homogeneous humoral autoimmune response against GAD and the identification of dominant autoreactive target regions may help to elucidate the molecular mechanisms of GAD processing and presentation involved in GAD autoimmunity. Moreover, the

  9. Reliability and validity of the Portuguese version of the Generalized Anxiety Disorder (GAD-7) scale.

    PubMed

    Sousa, Tiago V; Viveiros, Vânia; Chai, Maria V; Vicente, Filipe L; Jesus, Gustavo; Carnot, Maria J; Gordo, Ana C; Ferreira, Pedro L

    2015-04-25

    Generalized anxiety disorder has a strong impact on health-related quality of life. For this reason, it seems relevant to develop strategies allowing early diagnoses in order to promote appropriate treatments. The objective of this study was to culturally adapt and validate the GAD-7 for the Portuguese patients with generalized anxiety disorder. For the cultural adaptation of the Portuguese version of the GAD-7 scale we started with a previous translation made by Mapi Institute and decided to perform a clinical review followed by a cognitive debriefing with patients. Once piloted, this version was then tested in a larger sample for feasibility and reliability (1-week test-retest). Construct validity was assessed by the relationship between GAD-7 and socio-demographic and clinical variables. Its unidimensionality was tested by principal component factor analysis. Criterion validity was assessed by comparing GAD-7 scores with those obtained by HADS, and EQ-5D. STAI was mainly used as a screening indicator for patient inclusion. GAD-7 was considered feasible with a mean completion time of 2.3 minutes and no major floor or ceiling effects. We found an excellent Cronbach's alpha internal consistency score (0.880) and the test-retest and interclass correlation coefficients were also very good. Regarding the construct validity, younger patients, those with higher education, employed and without anxiety symptoms revealed lower GAD-7 scores, meaning better health. The unidimensionality of GAD-7 index was also confirmed by principal component factor analysis. At last, GAD-7 was significantly correlated with other health outcome indices and the classification levels created by it and by HADS showed to be dependent. The excellent metric properties confirmed the cultural adaptation and validity of GAD-7 into Portuguese population, allowing the clinicians an early detection and treatment of these patients.

  10. Clinical characteristics of patients with cerebellar ataxia associated with anti-GAD antibodies.

    PubMed

    Aguiar, Tiago Silva; Fragoso, Andrea; Albuquerque, Carolina Rouanet de; Teixeira, Patrícia de Fátima; Souza, Marcus Vinícius Leitão de; Zajdenverg, Lenita; Alves-Leon, Soniza Vieira; Rodacki, Melanie; Lima, Marco Antônio Sales Dantas de

    2017-03-01

    This retrospective and descriptive study evaluated the clinical characteristics and outcomes of patients with CA-GAD-ab. Three patients with cerebellar ataxia, high GAD-ab titers and autoimmune endocrine disease were identified. Patients 1 and 2 had classic stiff person syndrome and insidious-onset cerebellar ataxia, while Patient 3 had pure cerebellar ataxia with subacute onset. Patients received intravenous immunoglobulin therapy with no response in Patients 1 and 3 and partial recovery in Patient 2. CA-GAD-ab is rare and its clinical presentation may hamper diagnosis. Clinicians should be able to recognize this potentially treatable autoimmune cerebellar ataxia.

  11. [Stiff-person syndrome and other neurological disorders associated with anti-GAD antibodies].

    PubMed

    Hijazi, J; Bedat-Millet, A-L; Hannequin, D

    2010-01-01

    Autoantibodies to glutamic acid decarboxylase (GAD), originally identified in the stiff-person syndrome, are also associated with rare cases of therapy-resistant epilepsy and sporadic cerebellar ataxia. The association of GAD antibodies with these three syndromes and other auto-immune diseases, particularly type 1 diabetes mellitus, argues for their auto-immune origin. Anti-GAD antibodies inhibit GABAergic circuits inducing a neuronal hyper-excitability that seems to be responsible for these three syndromes. However, an additional mechanism seems to be involved in the degenerative component of the cerebellar ataxia associated with anti-GAD antibodies. A more accurate diagnosis and the study of neuropathological cases are necessary to document the different mechanisms implicated in these neurological disorders.

  12. Stiff Person syndrome and other anti-GAD-associated neurologic disorders.

    PubMed

    Dayalu, Praveen; Teener, James W

    2012-11-01

    Antibodies directed against glutamic acid decarboxylase (GAD) are present in many patients with stiff person syndrome and increasingly found in patients with other symptoms indicative of central nervous system (CNS) dysfunction, such as ataxia. The classic clinical features of stiff person syndrome include muscular stiffness with superimposed painful muscular spasms. Gait is often impaired. Other CNS disorders associated with GAD antibodies include progressive encephalomyelitis with rigidity and myoclonus (PERM), limbic encephalitis, and even epilepsy. Glutamic acid decarboxylase is the rate-limiting enzyme in the production of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter. Presumably, antibodies directed against GAD impair GABA production, but the precise pathogenic mechanism of GAD-antibody-related neurologic disorders is uncertain. Many patients respond to treatment with immunomodulating therapy. Symptomatic treatment with agents that enhance GABA activity, such as benzodiazepines and baclofen, is also helpful for many patients.

  13. Regulatory Focus and Anxiety: A Self-Regulatory Model of GAD-Depression Comorbidity

    PubMed Central

    Klenk, Megan M.; Strauman, Timothy J.; Higgins, E. Tory

    2010-01-01

    The etiology of generalized anxiety disorder (GAD), including its high degree of comorbidity with major depressive disorder (MDD), remains a conceptual and clinical challenge. In this article, we discuss the relevance of regulatory focus theory, an influential theory of self-regulation, for understanding vulnerability to GAD as well as GAD/MDD comorbidity. The theory postulates two systems for pursuing desired end states: the promotion and prevention systems. Drawing upon studies documenting the affective and motivational consequences of failing to attain promotion versus prevention goals, as well as the literature linking promotion failure with depression, we propose how dysfunction within the prevention system could lead to GAD – with, as well as without, MDD. PMID:21516196

  14. Gad67 haploinsufficiency reduces amyloid pathology and rescues olfactory memory deficits in a mouse model of Alzheimer's disease.

    PubMed

    Wang, Yue; Wu, Zheng; Bai, Yu-Ting; Wu, Gang-Yi; Chen, Gong

    2017-10-10

    Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder, affecting millions of people worldwide. Although dysfunction of multiple neurotransmitter systems including cholinergic, glutamatergic and GABAergic systems has been associated with AD progression the underlying mechanisms remain elusive. We and others have recently found that GABA content is elevated in AD brains and linked to cognitive deficits in AD mouse models. The glutamic acid decarboxylase 67 (GAD67) is the major enzyme converting glutamate into GABA and has been implied in a number of neurological disorders such as epilepsy and schizophrenia. However, whether Gad67 is involved in AD pathology has not been well studied. Here, we investigate the functional role of GAD67 in an AD mouse model with Gad67 haploinsufficiency that is caused by replacing one allele of Gad67 with green fluorescent protein (GFP) gene during generation of GAD67-GFP mice. To genetically reduce GAD67 in AD mouse brains, we crossed the Gad67 haploinsufficient mice (GAD67-GFP(+/-)) with 5xFAD mice (harboring 5 human familial AD mutations in APP and PS1 genes) to generate a new line of bigenic mice. Immunostaining, ELISA, electrophysiology and behavior test were applied to compare the difference between groups. We found that reduction of GAD67 resulted in a significant decrease of amyloid β production in 5xFAD mice. Concurrently, the abnormal astrocytic GABA and tonic GABA currents, as well as the microglial reactivity were significantly reduced in the 5xFAD mice with Gad67 haploinsufficiency. Importantly, the olfactory memory deficit of 5xFAD mice was rescued by Gad67 haploinsufficiency. Our results demonstrate that GAD67 plays an important role in AD pathology, suggesting that GAD67 may be a potential drug target for modulating the progress of AD.

  15. Treatment of immune-mediated temporal lobe epilepsy with GAD antibodies.

    PubMed

    Malter, M P; Frisch, C; Zeitler, H; Surges, R; Urbach, H; Helmstaedter, C; Elger, C E; Bien, C G

    2015-08-01

    Temporal lobe epilepsy with antibodies (abs) against the glutamic acid decarboxylase 65 isoform (GAD-TLE) is known as an immune-mediated neurological syndrome. Here we evaluate the therapy response to various immunotherapies and epilepsy surgery in this syndrome. All patients with GAD-TLE and follow-up data and stored serum and CSF samples, identified and treated at the Bonn centre from 2002 to 2010, were studied retrospectively. Seizure freedom for ≥1 year and reduction of ≥50%, i.e. therapy response, were assessed. GAD-ab titres and neuropsychological performances were documented prior and after individual interventions. Thirteen patients with GAD-TLE were identified with the following seizure responses: corticosteroids (5 responders out of 11 treated patients); i.v. immunoglobulins (1/5), apheresis therapy (1/8); and natalizumab (1/1), selective amygdala-hippocampectomy (2/3). None of the patients achieved sustained seizure freedom apart from one patient. This patient was on antiepileptic drug treatment after discontinuation of immunotherapy. The seizure response to immunotherapies in patients with GAD-TLE was poor. Corticosteroids were the most effective regarding seizure response. Especially the poor effects of apheresis therapies support the idea that GAD-abs are not directly pathogenic. None of three patients was seizure-free after temporal lobe surgery suggesting that GAD-TLE patients respond worse than others to this type of intervention. Our results reflect the chronic course of the disease with low likelihood for patients with GAD-TLE to attain long-term seizure freedom. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  16. Treatment with GAD65 or BSA does not protect against diabetes in BB rats.

    PubMed

    Petersen, J S; Mackay, P; Plesner, A; Karlsen, A; Gotfredsen, C; Verland, S; Michelsen, B; Dyrberg, T

    1997-01-01

    The M(r) 65,000 isoform of glutamic acid decarboxylase (GAD65) has been implicated as the initiating islet cell antigen in the pathogenesis of diabetes, primarily based on studies in non-obese diabetic (NOD) mice. To test the role of this islet cell autoantigen in the pathogenesis of spontaneously occurring diabetes in another animal model, purified recombinant human islet GAD65 was injected i.v. at 200 micrograms/animal into 18-day-old diabetes-prone BB rats. For controls, bovine serum albumin (BSA), which has also been implicated in the pathogenesis of diabetes, or buffer alone was injected into age matched BB rats. At 210 days of age there were no differences in diabetes incidence in the 3 groups, i.e. 73% (11 of 15) in the GAD65-treated, 81% (13 of 16) in the BSA-treated and 65% (11 of 17) in the buffer-treated animals, or in the median age at onset of disease, i.e. 79 days (range 65-111), 87 days (range 60-107) and 86 days (range 74-109), respectively. The lack of protection against diabetes following GAD65 treatment could hypothetically be explained by no or by an aberrant expression of GAD in BB-rat islet cells. However, immunohistochemistry of pancreata and immunoblotting analysis of isolated islets showed that the expression of GAD65 and GAD67 was similar in BB and Lewis rats. In conclusion, these data indicate that neither GAD65 nor BSA autoimmunity is important for the development of diabetes in BB rats, in contrast to the situation in NOD mice, and further emphasizes that extrapolation from only one animal model to autoimmune diabetes in general may not be appropriate.

  17. Ascending midbrain dopaminergic axons require descending GAD65 axon fascicles for normal pathfinding

    PubMed Central

    García-Peña, Claudia M.; Kim, Minkyung; Frade-Pérez, Daniela; Ávila-González, Daniela; Téllez, Elisa; Mastick, Grant S.; Tamariz, Elisa; Varela-Echavarría, Alfredo

    2014-01-01

    The Nigrostriatal pathway (NSP) is formed by dopaminergic axons that project from the ventral midbrain to the dorsolateral striatum as part of the medial forebrain bundle. Previous studies have implicated chemotropic proteins in the formation of the NSP during development but little is known of the role of substrate-anchored signals in this process. We observed in mouse and rat embryos that midbrain dopaminergic axons ascend in close apposition to descending GAD65-positive axon bundles throughout their trajectory to the striatum. To test whether such interaction is important for dopaminergic axon pathfinding, we analyzed transgenic mouse embryos in which the GAD65 axon bundle was reduced by the conditional expression of the diphtheria toxin. In these embryos we observed dopaminergic misprojection into the hypothalamic region and abnormal projection in the striatum. In addition, analysis of Robo1/2 and Slit1/2 knockout embryos revealed that the previously described dopaminergic misprojection in these embryos is accompanied by severe alterations in the GAD65 axon scaffold. Additional studies with cultured dopaminergic neurons and whole embryos suggest that NCAM and Robo proteins are involved in the interaction of GAD65 and dopaminergic axons. These results indicate that the fasciculation between descending GAD65 axon bundles and ascending dopaminergic axons is required for the stereotypical NSP formation during brain development and that known guidance cues may determine this projection indirectly by instructing the pathfinding of the axons that are part of the GAD65 axon scaffold. PMID:24926237

  18. GAD1 Upregulation Programs Aggressive Features of Cancer Cell Metabolism in the Brain Metastatic Microenvironment.

    PubMed

    Schnepp, Patricia M; Lee, Dennis D; Guldner, Ian H; O'Tighearnaigh, Treasa K; Howe, Erin N; Palakurthi, Bhavana; Eckert, Kaitlyn E; Toni, Tiffany A; Ashfeld, Brandon L; Zhang, Siyuan

    2017-04-11

    The impact of altered amino acid metabolism on cancer progression is not fully understood. We hypothesized that a metabolic transcriptome shift during metastatic evolution is crucial for brain metastasis. Here we report a powerful impact in this setting caused by epigenetic upregulation of glutamate decarboxylase 1 (GAD1), a regulator of the GABA neurotransmitter metabolic pathway. In cell-based culture and brain metastasis models, we found that downegulation of the DNA methyltransferase DNMT1 induced by the brain microenvironment-derived clusterin resulted in decreased GAD1 promoter methylation and subsequent upregulation of GAD1 expression in brain metastatic tumor cells. In a system to dynamically visualize cellular metabolic responses mediated by GAD1, we monitored the cytosolic NADH:NAD+ equilibrium in tumor cells. Reducing GAD1 in metastatic cells by primary glia cell co-culture abolished the capacity of metastatic cells to utilize extracellular glutamine, leading to cytosolic accumulation of NADH and increased oxidative status. Similarly, genetic or pharmacological disruption of the GABA metabolic pathway decreased the incidence of brain metastasis in vivo. Taken together, our results show how epigenetic changes in GAD1 expression alter local glutamate metabolism in the brain metastatic microenvironment, contributing to a metabolic adaption that facilitates metastasis outgrowth in that setting.

  19. High diversity in the TCR repertoire of GAD65 autoantigen-specific human CD4+ T cells.

    PubMed

    Eugster, Anne; Lindner, Annett; Catani, Mara; Heninger, Anne-Kristin; Dahl, Andreas; Klemroth, Sylvia; Kühn, Denise; Dietz, Sevina; Bickle, Marc; Ziegler, Anette-Gabrielle; Bonifacio, Ezio

    2015-03-15

    Autoreactive CD4(+) T cells are an essential feature of type 1 diabetes mellitus. We applied single-cell TCR α- and β-chain sequencing to peripheral blood GAD65-specific CD4(+) T cells, and TCR α-chain next-generation sequencing to bulk memory CD4(+) T cells to provide insight into TCR diversity in autoimmune diabetes mellitus. TCRs obtained for 1650 GAD65-specific CD4(+) T cells isolated from GAD65 proliferation assays and/or GAD65 557I tetramer staining in 6 patients and 10 islet autoantibody-positive children showed large diversity with 1003 different TCRs identified. TRAV and TRBV gene usage was broad, and the TRBV5.1 gene was most prominent within the GAD65 557I tetramer(+) cells. Limited overlap (<5%) was observed between TCRs of GAD65-proliferating and GAD65 557I tetramer(+) CD4(+) T cells. Few TCRs were repeatedly found in GAD65-specific cells at different time points from individual patients, and none was seen in more than one subject. However, single chains were often shared between patients and used in combination with different second chains. Next-generation sequencing revealed a wide frequency range (<0.00001-1.62%) of TCR α-chains corresponding to GAD65-specific T cells. The findings support minor selection of genes and TCRs for GAD65-specific T cells, but fail to provide strong support for TCR-targeted therapies. Copyright © 2015 by The American Association of Immunologists, Inc.

  20. GAD67 deficiency in parvalbumin interneurons produces deficits in inhibitory transmission and network disinhibition in mouse prefrontal cortex.

    PubMed

    Lazarus, Matthew S; Krishnan, Keerthi; Huang, Z Josh

    2015-05-01

    In mammalian neocortex, the delicate balance of neural circuits is regulated by a rich repertoire of inhibitory control mechanisms mediated by diverse classes of GABAergic interneurons. A key step common to all GABAergic neurons is the synthesis of GABA, catalyzed by 2 isoforms of glutamic acid decarboxylases (GAD). Among these, GAD67 is the rate-limiting enzyme. GAD67 level is regulated by neural activity and is altered in multiple neuropsychiatric disorders. The significance of altered GAD67 levels on inhibitory transmission, however, remains unclear. The presence of GAD65, postsynaptic GABA receptor regulation, and the diversity of cortical interneurons make the link from GAD67 levels to GABA transmission less than straightforward. Here, we selectively removed one allele of the GAD67 gene, Gad1, in PV interneurons in juvenile mice. We found substantial deficits in transmission from PV to pyramidal neurons in prefrontal cortex, along with increases of pyramidal cell excitability and excitation/inhibition balance in PV cells. Synaptic deficits recovered in adult mice, suggesting engagement of homeostatic and compensatory mechanisms. These results demonstrate that GAD67 levels directly influence synaptic inhibition. Thus, GAD67 deficiency in PV cells likely contributes to cortical dysfunction in disease states; the reversibility of synaptic deficits suggests nonpermanent damage to inhibitory circuitry.

  1. The GAD65 knock out mouse - a model for GABAergic processes in fear- and stress-induced psychopathology.

    PubMed

    Müller, Iris; Çalışkan, Gürsel; Stork, Oliver

    2015-01-01

    The γ-amino butyric acid (GABA) synthetic enzyme glutamic acid decarboxylase (GAD)65 is critically involved in the activity-dependent regulation of GABAergic inhibition in the central nervous system. It is also required for the maturation of the GABAergic system during adolescence, a phase that is critical for the development of several neuropsychiatric diseases. Mice bearing a null mutation of the GAD65 gene develop hyperexcitability of the amygdala and hippocampus, and a phenotype of increased anxiety and pathological fear memory reminiscent of posttraumatic stress disorder. Although genetic association of GAD65 in human has not yet been reported, these findings are in line with observations of reduced GABAergic function in these brain regions of anxiety disorder patients. The particular value of GAD65(-/-) mice thus lies in modeling the effects of reduced GABAergic function in the mature nervous system. The expression of GAD65 and a second GAD isozyme, GAD67, are differentially regulated in response to stress in limbic brain areas suggesting that by controlling GABAergic inhibition these enzymes determine the vulnerability for the development of pathological anxiety and other stress-induced phenotypes. In fact, we could recently show that GAD65 haplodeficiency, which results in delayed postnatal increase of GABA levels, provides resilience to juvenile-stress-induced anxiety to GAD65(+/-) mice thus foiling the increased fear and anxiety in homozygous GAD65(-/-) mice.

  2. Combinational Spinal GAD65 Gene Delivery and Systemic GABA-Mimetic Treatment for Modulation of Spasticity

    PubMed Central

    Kakinohana, Osamu; Hefferan, Michael P.; Miyanohara, Atsushi; Nejime, Tetsuya; Marsala, Silvia; Juhas, Stefan; Juhasova, Jana; Motlik, Jan; Kucharova, Karolina; Strnadel, Jan; Platoshyn, Oleksandr; Lazar, Peter; Galik, Jan; Vinay, Laurent; Marsala, Martin

    2012-01-01

    Background Loss of GABA-mediated pre-synaptic inhibition after spinal injury plays a key role in the progressive increase in spinal reflexes and the appearance of spasticity. Clinical studies show that the use of baclofen (GABAB receptor agonist), while effective in modulating spasticity is associated with major side effects such as general sedation and progressive tolerance development. The goal of the present study was to assess if a combined therapy composed of spinal segment-specific upregulation of GAD65 (glutamate decarboxylase) gene once combined with systemic treatment with tiagabine (GABA uptake inhibitor) will lead to an antispasticity effect and whether such an effect will only be present in GAD65 gene over-expressing spinal segments. Methods/Principal Findings Adult Sprague-Dawley (SD) rats were exposed to transient spinal ischemia (10 min) to induce muscle spasticity. Animals then received lumbar injection of HIV1-CMV-GAD65 lentivirus (LVs) targeting ventral α-motoneuronal pools. At 2–3 weeks after lentivirus delivery animals were treated systemically with tiagabine (4, 10, 20 or 40 mg/kg or vehicle) and the degree of spasticity response measured. In a separate experiment the expression of GAD65 gene after spinal parenchymal delivery of GAD65-lentivirus in naive minipigs was studied. Spastic SD rats receiving spinal injections of the GAD65 gene and treated with systemic tiagabine showed potent and tiagabine-dose-dependent alleviation of spasticity. Neither treatment alone (i.e., GAD65-LVs injection only or tiagabine treatment only) had any significant antispasticity effect nor had any detectable side effect. Measured antispasticity effect correlated with increase in spinal parenchymal GABA synthesis and was restricted to spinal segments overexpressing GAD65 gene. Conclusions/Significance These data show that treatment with orally bioavailable GABA-mimetic drugs if combined with spinal-segment-specific GAD65 gene overexpression can represent a novel

  3. Immunocytochemical localization of glutamic acid decarboxylase (GAD) and substance P in neural areas mediating motion-induced emesis: Effects of vagal stimulation on GAD immunoreactivity

    NASA Technical Reports Server (NTRS)

    Damelio, F.; Gibbs, M. A.; Mehler, W. R.; Daunton, Nancy G.; Fox, Robert A.

    1991-01-01

    Immunocytochemical methods were employed to localize the neurotransmitter amino acid gamma-aminobutyric acid (GABA) by means of its biosynthetic enzyme glutamic acid decarboxylase (GAD) and the neuropeptide substance P in the area postrema (AP), area subpostrema (ASP), nucleus of the tractus solitarius (NTS), and gelatinous nucleus (GEL). In addition, electrical stimulation was applied to the night vagus nerve at the cervical level to assess the effects on GAD-immunoreactivity (GAR-IR). GAD-IR terminals and fibers were observed in the AP, ASP, NTS, and GEL. They showed pronounced density at the level of the ASP and gradual decrease towards the solitary complex. Nerve cells were not labelled in our preparations. Ultrastructural studies showed symmetric or asymmetric synaptic contracts between labelled terminals and non-immunoreactive dendrites, axons, or neurons. Some of the labelled terminals contained both clear- and dense-core vesicles. Our preliminary findings, after electrical stimulation of the vagus nerve, revealed a bilateral decrease of GAD-IR that was particularly evident at the level of the ASP. SP-immunoreactive (SP-IR) terminals and fibers showed varying densities in the AP, ASP, NTS, and GEL. In our preparations, the lateral sub-division of the NTS showed the greatest accumulation. The ASP showed medium density of immunoreactive varicosities and terminals and the AP and GEL displayed scattered varicose axon terminals. The electron microscopy revealed that all immunoreactive terminals contained clear-core vesicles which make symmetric or asymmetric synaptic contact with unlabelled dendrites. It is suggested that the GABAergic terminals might correspond to vagal afferent projections and that GAD/GABA and substance P might be co-localized in the same terminal allowing the possibility of a regulated release of the transmitters in relation to demands.

  4. Insomnia and generalized anxiety disorder: effects of cognitive behavior therapy for gad on insomnia symptoms.

    PubMed

    Bélanger, Lynda; Morin, Charles M; Langlois, Frédéric; Ladouceur, Robert

    2004-01-01

    Although clinical practice suggests that sleep complaints are frequent among patients with generalized anxiety disorder (GAD), frequency, severity, types of insomnia complaints, and relationship to GAD diagnosis severity in patients diagnosed using Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria are not well documented. Clinical data about the impact on insomnia symptoms of treating GAD worries are also lacking. The present study examined these aspects in 44 GAD patients who participated in a treatment study specifically addressing excessive worries through CBT interventions. All patients were assessed using a structured clinical interview and the Anxiety Disorder Interview Schedule-IV (ADIS-IV). They also completed anxiety and insomnia inventories, including the Insomnia Severity Index (ISI), a self-report measure which assesses insomnia type, severity and interference with daily life. Among this sample, 47.7% reported difficulties initiating sleep, 63.6% reported difficulties maintaining sleep, and 56.8% complained of waking too early in the morning. The majority of these patients (86.5%) reported never having experienced insomnia without having excessive worries. However, insomnia severity and GAD severity were not correlated. In this sample, patients with severe GAD did not necessarily report more severe insomnia symptoms. Regarding treatment impact on insomnia complaints, ISI post-treatment scores were significantly lower after treatment. Mean post-treatment scores almost reached ISI's "absence of clinical insomnia" category. Results indicate that this CBT package for GAD does have a significant impact on sleep quality even if sleep disturbances were not specifically addressed during treatment.

  5. Glutamate alteration of glutamic acid decarboxylase (GAD) in GABAergic neurons: the role of cysteine proteases.

    PubMed

    Monnerie, Hubert; Le Roux, Peter D

    2008-09-01

    Brain cell vulnerability to neurologic insults varies greatly, depending on their neuronal subpopulation. Among cells that survive a pathological insult such as ischemia or brain trauma, some may undergo morphological and/or biochemical changes that could compromise brain function. We previously reported that surviving cortical GABAergic neurons exposed to glutamate in vitro displayed an NMDA receptor (NMDAR)-mediated alteration in the levels of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD65/67) [Monnerie, H., Le Roux, P., 2007. Reduced dendrite growth and altered glutamic acid decarboxylase (GAD) 65- and 67-kDa isoform protein expression from mouse cortical GABAergic neurons following excitotoxic injury in vitro. Exp. Neurol. 205, 367-382]. In this study, we examined the mechanisms by which glutamate excitotoxicity caused a change in cortical GABAergic neurons' GAD protein levels. Removing extracellular calcium prevented the NMDAR-mediated decrease in GAD protein levels, measured using Western blot techniques, whereas inhibiting calcium entry through voltage-gated calcium channels had no effect. Glutamate's effect on GAD protein isoforms was significantly attenuated by preincubation with the cysteine protease inhibitor N-Acetyl-L-Leucyl-L-Leucyl-L-norleucinal (ALLN). Using class-specific protease inhibitors, we observed that ALLN's effect resulted from the blockade of calpain and cathepsin protease activities. Cell-free proteolysis assay confirmed that both proteases were involved in glutamate-induced alteration in GAD protein levels. Together these results suggest that glutamate-induced excitotoxic stimulation of NMDAR in cultured cortical neurons leads to altered GAD protein levels from GABAergic neurons through intracellular calcium increase and protease activation including calpain and cathepsin. Biochemical alterations in surviving cortical GABAergic neurons in various disease states may contribute to the altered balance between excitation

  6. Immuno-chemistry of hydroxyl radical modified GAD-65: A possible role in experimental and human diabetes mellitus.

    PubMed

    Moinuddin; Ansari, Nadeem A; Shahab, Uzma; Habeeb, Safia; Ahmad, Saheem

    2015-10-01

    The repertoire of known auto-antigens is limited to a very small proportion of all human proteins, and the reason why only some proteins become auto-antigens is unclear. The 65 kDa isoform of the enzyme glutamic acid decarboxylase (GAD-65) is a major auto-antigen in type I diabetes, and in various neurological diseases. Most patients with type I diabetes (70-80%) have auto-antibodies against GAD-65, which often appear years before clinical onset of the autoimmune diabetes. Thus, the aim of the study is to focus on the immunogenicity of GAD65 and its reactive oxygen species (ROS) conformer in STZ-induced diabetic rats and on human diabetic patients. In the present study, GAD-65 was modified by hydroxyl radical following Fenton's reaction. The modifications in the structure of the GAD-65 are supported by UV-vis and fluorescence spectral studies. Immunogenicity of both native and hydroxyl radical modified GAD-65 (ROS-GAD-65) was studied in experimental rabbits and was confirmed by inducing type I diabetes in experimental male albino rats using streptozotocin (45 mg/kg). We found that ROS-GAD-65 was a better immunogen as compared to the native GAD-65. A considerable high binding to ROS-GAD-65 was observed as compared to native GAD-65 in both the serum antibodies from diabetes animal models and as well as in the serum samples of type I diabetes. Hydrogen peroxide under the exposure of UV light produces hydroxyl radical (·OH) which is most potent oxidant, and could cause protein damage (GAD-65) to the extent of generating neo-epitopes on the molecule, thus making it immunogenic.

  7. CREB-Dependent Regulation of GAD65 Transcription by BDNF/TrkB in Cortical Interneurons.

    PubMed

    Sánchez-Huertas, Carlos; Rico, Beatriz

    2011-04-01

    In the cerebral cortex, the functional output of projection neurons is fine-tuned by inhibitory neurons present in the network, which use γ-aminobutyric acid (GABA) as their main neurotransmitter. Previous studies have suggested that the expression levels of the rate-limiting GABA synthetic enzyme, GAD65, depend on brain derived neurotrophic factor (BDNF)/TrkB activation. However, the molecular mechanisms by which this neurotrophic factor and its receptor controls GABA synthesis are still unknown. Here, we show a direct regulation of the GAD65 gene by BDNF-TrkB signaling via CREB in cortical interneurons. Conditional ablation of TrkB in cortical interneurons causes a cell-autonomous decrease in the synaptically enriched GAD65 protein and its transcripts levels, suggesting that transcriptional regulation of the GAD65 gene is altered. Dissection of the intracellular pathway that underlies this process revealed that BDNF/TrkB signaling controls the transcription of GAD65 in a Ras-ERK-CREB-dependent manner. Our study reveals a novel molecular mechanism through which BDNF/TrkB signaling may modulate the maturation and function of cortical inhibitory circuits.

  8. GAD67-mediated GABA Synthesis and Signaling Regulate Inhibitory Synaptic Innervation in the Visual Cortex

    PubMed Central

    Chattopadhyaya, Bidisha; Di Cristo, Graziella; Wu, Cai Zhi; Knott, Graham; Kuhlman, Sandra; Fu, Yu; Palmiter, Richard D.; Huang, Z. Josh

    2007-01-01

    The development of GABAergic inhibitory circuits is shaped by neural activity, but the underlying mechanisms are unclear. we demonstrate a novel function of GABA in regulating GABAergic innervation in the adolescent brain, when GABA is mainly known as an inhibitory transmitter. Conditional knockdown of the rate-limiting synthetic enzyme GAD67 in basket interneurons in adolescent visual cortex resulted in cell autonomous deficits in axon branching, perisomatic synapse formation around pyramidal neurons, and complexity of the innervation fields; the same manipulation had little influence on the subsequent maintenance of perisomatic synapses. These effects of GABA deficiency were rescued by suppressing GABA re-uptake and by GABA receptor agonists. Germ-line knockdown of GAD67 but not GAD65 showed similar deficits, suggesting a specific role of GAD67 in the maturation of perisomatic innervation. Since intracellular GABA levels are modulated by neuronal activity, our results implicate GAD67-mediated GABA synthesis in activity-dependent regulation of inhibitory innervation patterns. PMID:17582330

  9. Global Regulator of Virulence A (GrvA) Coordinates Expression of Discrete Pathogenic Mechanisms in Enterohemorrhagic Escherichia coli through Interactions with GadW-GadE

    PubMed Central

    Morgan, Jason K.; Harro, Carly M.; Vendura, Khoury W.; Shaw, Lindsey N.

    2015-01-01

    ABSTRACT Global regulator of virulence A (GrvA) is a ToxR-family transcriptional regulator that activates locus of enterocyte effacement (LEE)-dependent adherence in enterohemorrhagic Escherichia coli (EHEC). LEE activation by GrvA requires the Rcs phosphorelay response regulator RcsB and is sensitive to physiologically relevant concentrations of bicarbonate, a known stimulant of virulence systems in intestinal pathogens. This study determines the genomic scale of GrvA-dependent regulation and uncovers details of the molecular mechanism underlying GrvA-dependent regulation of pathogenic mechanisms in EHEC. In a grvA-null background of EHEC strain TW14359, RNA sequencing analysis revealed the altered expression of over 700 genes, including the downregulation of LEE- and non-LEE-encoded effectors and the upregulation of genes for glutamate-dependent acid resistance (GDAR). Upregulation of GDAR genes corresponded with a marked increase in acid resistance. GrvA-dependent regulation of GDAR and the LEE required gadE, the central activator of GDAR genes and a direct repressor of the LEE. Control of gadE by GrvA was further determined to occur through downregulation of the gadE activator GadW. This interaction of GrvA with GadW-GadE represses the acid resistance phenotype, while it concomitantly activates the LEE-dependent adherence and secretion of immune subversion effectors. The results of this study significantly broaden the scope of GrvA-dependent regulation and its role in EHEC pathogenesis. IMPORTANCE Enterohemorrhagic Escherichia coli (EHEC) is an intestinal human pathogen causing acute hemorrhagic colitis and life-threatening hemolytic-uremic syndrome. For successful transmission and gut colonization, EHEC relies on the glutamate-dependent acid resistance (GDAR) system and a type III secretion apparatus, encoded on the LEE pathogenicity island. This study investigates the mechanism whereby the DNA-binding regulator GrvA coordinates activation of the LEE with

  10. [Glutamate decarboxylase (GAD)--an autoantigen in insulin-dependent diabetes mellitus (IDDM)].

    PubMed

    Tursky, T; Bandzuchova, E

    1999-02-01

    The number of antibodies to pancreatic beta-cell antigens in IDDM increased in the last years, involving antibodies to glutamic acid decarboxylase (GADab). A short review is given about the diagnostic and prognostic value of GADab determination in IDDM. The GAD plays an important, possibly a key role in the initial immunological events leading to the destruction of beta cells. The question is open whether the immunological reaction against GAD is a primary one, or if it is a result of mimicry of a part of an infectious protein antigen (Coxackie virus). The immunological reaction to GAD is associated with both humoral and cellular responses. The cellular response seems to be more important than the humoral one. The cellular response may be mediated through the HLA complex class I cells (cytotoxic lymphocytes) and the HLA complex class II cells (helper lymphocytes). There are arguments for both possibilities. The principles of GADab determination are shortly described. (Ref. 34.)

  11. Cysteamine treatment ameliorates alterations in GAD67 expression and spatial memory in heterozygous reeler mice.

    PubMed

    Kutiyanawalla, Ammar; Promsote, Wanwisa; Terry, Alvin; Pillai, Anilkumar

    2012-09-01

    Brain-derived neurotrophic factor (BDNF) signalling through its receptor, TrkB is known to regulate GABAergic function and glutamic acid decarboxylase (GAD) 67 expression in neurons. Alterations in BDNF signalling have been implicated in the pathophysiology of schizophrenia and as a result, they are a potential therapeutic target. Interestingly, heterozygous reeler mice (HRM) have decreased GAD67 expression in the frontal cortex and hippocampus and they exhibit many behavioural and neurochemical abnormalities similar to schizophrenia. In this study, we evaluated the potential of cysteamine, a neuroprotective compound to improve the deficits in GAD67 expression and cognitive function in HRM. We found that cysteamine administration (150 mg/kg.d, through drinking water) for 30 d significantly ameliorated the decreases in GAD67, mature BDNF and full-length TrkB protein levels found in frontal cortex and hippocampus of HRM. A significant attenuation of the increased levels of truncated BDNF in frontal cortex and hippocampus, as well as truncated TrkB in frontal cortex of HRM was also observed following cysteamine treatment. In behavioural studies, HRM were impaired in a Y-maze spatial recognition memory task, but not in a spontaneous alternation task or a sensorimotor, prepulse inhibition (PPI) procedure. Cysteamine improved Y-maze spatial recognition in HRM to the level of wide-type controls and it improved PPI in both wild-type and HRM. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in GAD67 expression suggesting that TrkB signalling plays an important role in GAD67 regulation by cysteamine.

  12. Cysteamine treatment ameliorates alterations in GAD67 expression and spatial memory in heterozygous reeler mice

    PubMed Central

    Kutiyanawalla, Ammar; Promsote, Wanwisa; Terry, Alvin; Pillai, Anilkumar

    2011-01-01

    Brain derived neurotrophic factor (BDNF) signaling through its receptor, TrkB is known to regulate GABAergic function and glutamic acid decarboxylase (GAD) 67 expression in neurons. Alterations in BDNF signaling have been implicated in the pathophysiology of schizophrenia and as a result, they are a potential therapeutic target. Interestingly, heterozygous reeler mice (HRM) have decreased GAD67 expression in the frontal cortex and hippocampus and they exhibit many behavioral and neurochemical abnormalities similar to schizophrenia. In the present study, we evaluated the potential of cysteamine, a neuroprotective compound to improve the deficits in GAD67 expression and cognitive function in HRM. We found that cysteamine administration (150 mg/kg/day, through drinking water) for 30 days significantly ameliorated the decreases in GAD67, mature BDNF and full-length TrkB protein levels found in frontal cortex and hippocampus of HRM. A significant attenuation of the increased levels of truncated BDNF in frontal cortex and hippocampus, as well as truncated TrkB in frontal cortex of HRM was also observed following cysteamine treatment. In behavioral studies, HRM were impaired in a Y-maze spatial recognition memory task, but not in a spontaneous alternation task or a sensorimotor, prepulse inhibition (PPI) procedure. Cysteamine improved Y-maze spatial recognition in HRM to the level of wide-type controls and it improved PPI in both wild-type and HRM. Finally, mice deficient in TrkB, showed a reduced response to cysteamine in GAD67 expression suggesting that TrkB signaling plays an important role in GAD67 regulation by cysteamine. PMID:21777509

  13. GADS is Required for TCR-Mediated Calcium Influx and Cytokine Release, but not Cellular Adhesion, in Human T Cells

    PubMed Central

    Bilal, Mahmood Y.; Zhang, Elizabeth Y.; Dinkel, Brittney; Hardy, Daimon; Yankee, Thomas M.; Houtman, Jon C.D.

    2015-01-01

    GRB2 related adaptor protein downstream of Shc (GADS) is a member of the GRB2 family of adaptors and is critical for TCR-induced signaling. The current model is that GADS recruits SLP-76 to the LAT complex, which facilitates the phosphorylation of SLP-76, the activation of PLC-γ1, T cell adhesion and cytokine production. However, this model is largely based on studies of disruption of the GADS/SLP-76 interaction and murine T cell differentiation in GADS deficient mice. The role of GADS in mediating TCR-induced signals in human CD4+ T cells has not been thoroughly investigated. In this study, we have suppressed the expression of GADS in human CD4+ HuT78 T cells. GADS deficient HuT78 T cells displayed similar levels of TCR-induced SLP-76 and PLC-γ1 phosphorylation but exhibited substantial decrease in TCR-induced IL-2 and IFN-γ release. The defect in cytokine production occurred because of impaired calcium mobilization due to reduced recruitment of SLP-76 and PLC-γ1 to the LAT complex. Surprisingly, both GADS deficient HuT78 and GADS deficient primary murine CD8+ T cells had similar TCR-induced adhesion when compared to control T cells. Overall, our results show that GADS is required for calcium influx and cytokine production, but not cellular adhesion, in human CD4+ T cells, suggesting that the current model for T cell regulation by GADS is incomplete. PMID:25636200

  14. Guinea Pig Horizontal Cells Express GABA, the GABA-Synthesizing Enzyme GAD65, and the GABA Vesicular Transporter

    PubMed Central

    Guo, Chenying; Hirano, Arlene A.; Stella, Salvatore L.; Bitzer, Michaela; Brecha, Nicholas C.

    2013-01-01

    γ-Aminobutyric acid (GABA) is likely expressed in horizontal cells of all species, although conflicting physiological findings have led to considerable controversy regarding its role as a transmitter in the outer retina. This study has evaluated key components of the GABA system in the outer retina of guinea pig, an emerging retinal model system. The presence of GABA, its rate-limiting synthetic enzyme glutamic acid decarboxylase (GAD65 and GAD67 isoforms), the plasma membrane GABA transporters (GAT-1 and GAT-3), and the vesicular GABA transporter (VGAT) was evaluated by using immunohistochemistry with well-characterized antibodies. The presence of GAD65 mRNA was also evaluated by using laser capture microdissection and reverse transcriptase-polymerase chain reaction. Specific GABA, GAD65, and VGAT immunostaining was localized to horizontal cell bodies, as well as to their processes and tips in the outer plexiform layer. Furthermore, immunostaining of retinal whole mounts and acutely dissociated retinas showed GAD65 and VGAT immunoreactivity in both A-type and B-type horizontal cells. However, these cells did not contain GAD67, GAT-1, or GAT-3 immunoreactivity. GAD65 mRNA was detected in horizontal cells, and sequencing of the amplified GAD65 fragment showed approximately 85% identity with other mammalian GAD65 mRNAs. These studies demonstrate the presence of GABA, GAD65, and VGAT in horizontal cells of the guinea pig retina, and support the idea that GABA is synthesized from GAD65, taken up into synaptic vesicles by VGAT, and likely released by a vesicular mechanism from horizontal cells. PMID:20235161

  15. Cognitive content-specificity in future expectancies: role of hopelessness and intolerance of uncertainty in depression and GAD symptoms.

    PubMed

    Miranda, Regina; Fontes, Monique; Marroquín, Brett

    2008-10-01

    The present study examined cognitive content-specificity in future-event predictions associated with symptoms of depression and generalized anxiety disorder (GAD). College undergraduates (N=284) completed measures of depression, GAD, and rated their certainty that a given set of positive and negative outcomes were or were not likely to happen in their future. Participants also completed measures of hopelessness and intolerance of uncertainty (IU). Individuals (N=263) completed the same measures again 6 weeks later. Certainty in an absence of positive future outcomes was associated with symptoms of depression but not GAD, and hopelessness mediated this relationship - concurrently and when examining change scores over 6 weeks. Certainty in negative outcomes was concurrently associated with both symptoms of depression and GAD, and hopelessness partially mediated these relationships. IU predicted concurrent increases in depression and GAD symptoms, and negative-outcome certainty partially mediated the IU-depression but not the IU-GAD symptom relationship. Change in certainty did not mediate the relationship between changes in IU and GAD symptoms but partially mediated the relationship between change in IU and depression symptoms over time. Hopelessness appears to play a unique role in the relationship between reduced anticipation of positive future outcomes and depression. Although less clearly suggested by the data, IU may contribute to both depression and GAD symptoms but may do so through different pathways.

  16. Stiff-person syndrome (SPS) and anti-GAD-related CNS degenerations: protean additions to the autoimmune central neuropathies.

    PubMed

    Ali, Fatima; Rowley, Merrill; Jayakrishnan, Bindu; Teuber, Suzanne; Gershwin, M Eric; Mackay, Ian R

    2011-09-01

    Stiff Person Syndrome (SPS) is a rare autoimmune neurological disease attributable to autoantibodies to glutamic acid decarboxylase (anti-GAD) more usually associated with the islet beta cell destruction of autoimmune type 1 diabetes (T1D). SPS is characterized by interference in neurons with the synthesis/activity of the inhibitory neurotransmitter gamma amino butyric acid (GABA) resulting in the prototypic progressive spasmodic muscular rigidity of SPS, or diverse neurological syndromes, cerebellar ataxia, intractable epilepsy, myoclonus and several others. Remarkably, a single autoantibody, anti-GAD, can be common to widely different disease expressions, i.e. T1D and SPS. One explanation for these data is the differences in epitope engagement between the anti-GAD reactivity in SPS and T1D: in both diseases, anti-GAD antibody reactivity is predominantly to a conformational epitope region in the PLP- and C-terminal domains of the 65 kDa isoform but, additionally in SPS, there is reactivity to conformational epitope(s) on GAD67, and short linear epitopes in the C-terminal region and at the N-terminus of GAD65. Another explanation for disease expressions in SPS includes ready access of anti-GAD to antigen sites due to immune responsiveness within the CNS itself according to intrathecal anti-GAD-specific B cells and autoantibody. Closer study of the mysterious stiff-person syndrome should enhance the understanding of this disease itself, and autoimmunity in general.

  17. Spontaneous downbeat nystagmus as a clue for the diagnosis of ataxia associated with anti-GAD antibodies.

    PubMed

    Vale, Thiago Cardoso; Pedroso, José Luiz; Alquéres, Rafaela Almeida; Dutra, Lívia Almeida; Barsottini, Orlando Graziani Povoas

    2015-12-15

    Glutamic acid decarboxylase (GAD) is the enzyme that catalyzes the conversion of glutamic acid to the neurotransmitter gamma-amino butyric acid. Antibodies against GAD (anti-GAD-Ab) are associated with an array of autoimmune-related neurological conditions, such as stiff-person syndrome, cerebellar ataxia, epilepsy and limbic encephalitis. The clinical spectrum of ataxia associated with anti-GAD-Ab comprises slowly progressive cerebellar ataxia syndrome evolving in months or years, associated with cerebellar atrophy on brain MRI. There are few reports of patients with ataxia associated with anti-GAD-Ab presenting with abnormal ocular movements, such as downbeat nystagmus (DBN).We present two patients with ataxia associated with anti-GAD-Ab from a large series of ataxic subjects who presented with cerebellar ataxia combined with spontaneous DBN. All patients underwent a thorough neurological evaluation with the use of ataxia scales, brain MRI scans, cerebrospinal fluid examination, 18FDG-PET/CT scans, laboratory work-up with on coneural and immune encephalitis antibodies, serum and cerebrospinal fluid levels of anti-GAD-Ab, and the antibody specificity index to measure the intrathecal synthesis of anti-GAD-Ab. All patients were treated with cycles of intravenous immunoglobulin and had mild/partial ataxia improvement and no improvement of DBN. The finding of DBN may work as a diagnostic clue in the context of adult-onset non-hereditary ataxias.

  18. Refractory status epilepticus and autoimmune encephalitis with GABAAR and GAD65 antibodies: A case report.

    PubMed

    Gagnon, Maude-Marie; Savard, Martin; Mourabit Amari, Karim

    2016-04-01

    Autoimmune encephalitis is an inflammatory disorder of the brain that may be associated with different neuronal antibodies. Recently, an increasing number of valuable autoantibodies have been identified, including GABAAR antibodies, which appear to be associated with a severe form of encephalitis with refractory status epilepticus. We report here on a patient with encephalitis associated with GAD65 and GABAAR antibodies, an entity that remains an understudied topic, with an unanticipated clinical presentation and we describe the longitudinal follow-up. We report a case of encephalitis associated with GAD65 and GABAAR antibodies; we describe clinical and paraclinical features and the longitudinal follow-up. Our case presented with dysgueusia, dysosmia and episodes of hyperventilation that evolved into a refractory status epilepticus. Multiple anticonvulsant drugs were required. An aggressive immunotherapy was associated with a relative favorable outcome, in regard of epilepsy and cognitive functions. However, a relapse occurred and a full recovery was not observed at the last follow-up visit. There was no correlation between GAD65 antibodies titers and disease activity. Autoimmune encephalitis associated with GABAAR and GAD65 antibodies might be a severe and refractory disease. The appropriate treatment is currently unknown for those patients. Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  19. Genetic variation in GAD1 is associated with cortical thickness in the parahippocampal gyrus

    PubMed Central

    Brauns, Stefan; Gollub, Randy L.; Walton, Esther; Hass, Johanna; Smolka, Michael N.; White, Tonya; Wassink, Thomas H.; Calhoun, Vince D.; Ehrlich, Stefan

    2014-01-01

    Patients with schizophrenia show widespread cortical thickness reductions throughout the brain. Likewise, reduced expression of the γ-Aminobutyric acid (GABA) synthesizing enzyme glutamic acid decarboxylase (GAD1) and a single nucleotide polymorphism (SNP) rs3749034 in the corresponding gene have been associated with schizophrenia. We tested whether this SNP is associated with reduced cortical thickness, an intermediate phenotype for schizophrenia. Because of the well known interactions between the GABAergic and dopaminergic systems, we examined whether associations between GAD1 rs3749034 and cortical thickness are modulated by the catechol-O-methyltransferase (COMT) Val158Met genotype. Structural MRI and genotype data was obtained from 94 healthy subjects enrolled in the Mind Clinical Imaging Consortium study to examine the relations between GAD1 genotype and cortical thickness. Our data show a robust reduction of cortical thickness in the left parahippocampal gyrus (PHG) in G allele homozygotes of GAD1 rs3749034. When we stratified our analyses according to the COMT Val158Met genotype, cortical thickness reductions of G allele homozygotes were only found in the presence of the Val allele. Genetic risk variants of schizophrenia in the GABAergic system might interact with the dopaminergic system and impact brain structure and functioning. Our findings point to the importance of the GABAergic system in the pathogenesis of schizophrenia. PMID:23566421

  20. Benzodiazepine Discontinuation among Adults with GAD: A Randomized Trial of Cognitive-Behavioral Therapy

    ERIC Educational Resources Information Center

    Gosselin, Patrick; Ladouceur, Robert; Morin, Charles M.; Dugas, Michel J.; Baillargeon, Lucie

    2006-01-01

    This study evaluated the specific effectiveness of cognitive-behavior therapy (CBT) combined with medication tapering for benzodiazepine discontinuation among generalized anxiety disorder (GAD) patients by using a nonspecific therapy control group. Sixty-one patients who had used benzodiazepines for more than 12 months were randomly assigned to…

  1. Benzodiazepine Discontinuation among Adults with GAD: A Randomized Trial of Cognitive-Behavioral Therapy

    ERIC Educational Resources Information Center

    Gosselin, Patrick; Ladouceur, Robert; Morin, Charles M.; Dugas, Michel J.; Baillargeon, Lucie

    2006-01-01

    This study evaluated the specific effectiveness of cognitive-behavior therapy (CBT) combined with medication tapering for benzodiazepine discontinuation among generalized anxiety disorder (GAD) patients by using a nonspecific therapy control group. Sixty-one patients who had used benzodiazepines for more than 12 months were randomly assigned to…

  2. Biodistribution and safety assessment of AAV2-GAD following intrasubthalamic injection in the rat

    PubMed Central

    Fitzsimons, Helen L.; Riban, Veronique; Bland, Ross J.; Wendelken, Jennifer L.; Sapan, Christine V.; During, Matthew J.

    2010-01-01

    Background The steps necessary to translate promising new biological therapies to the clinic are poorly documented. For gene therapy there are unique aspects that need to be addressed in biodistribution studies. Notably, spread of the vector beyond the intended target cells or tissue may result in persistent unwanted biological activity or unpredictable biological events, thus it is critical to evaluate risks associated with viral vector-mediated gene transfer prior to embarking on human clinical trials. Methods Here we present a rodent study comprising of a comprehensive assessment of vector biodistribution through the brain, blood and major organs of rats injected into the subthalamic nucleus with recombinant adeno-associated virus (AAV) expressing glutamic acid decarboxylase (GAD). In addition, behavioral and histological analyses were also performed. Results AAV genomes were not detected in blood or CSF, and did not disseminate to organs outside of the brain in the majority of animals. In the brain, an average 97.3% of AAV2-GAD genomes were restricted to the area of the ipsilateral STN. There were no discernable effects of AAV2-GAD on general health and behavioral assessment of the animals did not reveal any alteration in general behavior, exploration, locomotion or motor symmetry. Conclusions This study met FDA requirements, in addition to efficacy and toxicity studies in rodents and non-human primates, to support and supplement a Phase II clinical trial for gene transfer of AAV2-GAD to the human STN for the potential therapy of Parkinson’s disease. PMID:20352617

  3. Low agreement between radio binding assays in analyzing glutamic acid decarboxylase (GAD65Ab) autoantibodies in patients classified with type 2 diabetes.

    PubMed

    Daka, Bledar; Svensson, Maria K; Lernmark, Ke; Mincheva-Nilsson, Lucia; Hallmans, Goran; Rolandsson, Olov

    2009-09-01

    Autoantibodies against glutamic acid decarboxylase (GAD65Ab) are used in the classification of diabetes in adults. We assessed the concordance in GAD65 autoantibody levels within subjects between three different GAD65Ab radio binding assays (RBA). Plasma samples from 112 diabetes patients (median age 50 years) initially classified with type 2 diabetes was randomly selected from a local diabetes registry. Coded samples were analyzed with two RBA employing (35)S-labeled GAD65. The first used the pEx9 plasmid (pEx9 RBA), the second employed the pThGAD65 plasmid (pThGAD65 RBA) to label GAD65 by in vitro transcription translation. We also used a commercial kit employing plasmid pGAD17 labelled with (125)I (pGAD17 RBA). Subsequent analyses followed standard procedures. Two different cut-offs for GAD65Ab positivity were used in all three assays. We calculated the correlation, concordance, and agreement between the assays. The proportion of GAD65Ab positivity differed between assays when low cut-offs were used (pEx9 RBA 25%, pThGAD65 RBA 17.9%, and pGAD17 RBA 12.5%, respectively). When high cut-offs were applied, the concordance between the pEx9 RBA and the pThGAD65 RBA was 97.3 while their concordance to the pGAD17 RBA was lower (88.4 and 87.4, respectively). There was a low agreement between both pEx9 RBA and pGAD17 RBA (0.45, 95% CI 0.20-0.70) and between pThGAD65 RBA and pGAD17 RBA (0.43, 95% CI 0.18-0.68). We found discrepancies in determining the GAD65Ab positivity, which constitutes a problem when GAD65Ab are used clinically. Further methodological GAD65Ab assays studies are warranted.

  4. Modulation of antigen presentation by autoreactive B cell clones specific for GAD65 from a type I diabetic patient

    PubMed Central

    BANGA, J P; MOORE, J K; DUHINDAN, N; MADEC, A M; VAN ENDERT, P M; ORGIAZZI, J; ENDL, J

    2004-01-01

    We used a GAD65-specific human B–T cell line cognate system in vitro to investigate the modulation of GAD65 presentation by autoantibody, assessed in a proliferation assay. Generally, if the T cell determinant overlaps or resides within the antibody epitope, effects of presentation are blunted while if they are distant can lead to potent presentation. For three different autoreactive B–T cell line cognate pairs, the modulation of GAD65 presentation followed the mode of overlapping or distant epitopes with resultant potent or undetectable presentation. However, other cognate pairs elicited variability in this pattern of presentation. Notably, one B cell line, DPC, whose antibody epitope did not overlap with the T cell determinants, was consistently poor in presenting GAD65. Using the fluorescent dye Alexa Fluor 647 conjugated to GAD65 to study receptor-mediated antigen endocytosis showed that all the antigen-specific B cell clones were efficient in intracellular accumulation of the antigen. Additionally, multicolour immunofluorescence microscopy showed that the internalized GAD65/surface IgG complexes were rapidly targeted to a perinuclear compartment in all GAD-specific B cell clones. This analysis also demonstrated that HLA-DM expression was reduced strongly in DPC compared to the stimulatory B cell clones. Thus the capability of antigen-specific B cells to capture and present antigen to human T cell lines is dependent on the spatial relationship of B and T cell epitopes as well other factors which contribute to the efficiency of presentation. PMID:14678267

  5. Oral Administration of Silkworm-Produced GAD65 and Insulin Bi-Autoantigens against Type 1 Diabetes

    PubMed Central

    Liu, Baoping; Yue, Yuan; Yang, Yun; Jin, Yongfeng

    2016-01-01

    Induction of mucosal tolerance by oral administration of protein antigens is a potential therapeutic strategy for preventing and treating type 1 diabetes (T1D); however, the requirement for a large dosage of protein limits clinical applications because of the low efficacy. In this study, we generated a fusion protein CTB-Ins-GAD composed of CTB (cholera toxin B subunit), insulin, and three copies of GAD65 peptide 531–545, which were efficiently produced in silkworm pupae, to evaluate its protective effect against T1D. We demonstrate that oral administration of CTB-Ins-GAD suppressed T1D by up to 78%, which is much more effective than GAD65 single-antigen treatment. Strikingly, CTB-Ins-GAD enhance insulin- and GAD65-specific Th2-like immune responses, which repairs the Th1/Th2 imbalance and increases the number of CD4+CD25+Foxp3+ T cell and suppresses insulin- and GAD65-reactive spleen T lymphocyte proliferation and migration. Our results strongly suggest that the combined dual antigens promote the induction of oral tolerance, thus providing an effective and economic immunotherapy against T1D in combination with a silkworm bioreactor. PMID:26783749

  6. FUTURES with Jaime Escalante

    SciTech Connect

    1996-08-01

    The United States Department of Energy awarded the Foundation for Advancements in Science and Education (FASE) $826,000 as support to produce the second set of FUTURES segments consisting of 12, 15-minute programs. The programs provide motivation for students to study math by connecting math to the work place and real-life problem scenarios. The programs are broadcast in 50 states through PBS Elementary and Secondary Service (E/SS). The grant term ended on December 16, 1993 and this final report documents program and financial activity results. The 12 episodes are titled: Animal Care, Meteorology, Mass Communication, Advanced Energy, Oceanography, Graphic Design, Future Habitats, Environmental Science & Technology, Fitness & Physical Performance, Interpersonal Communications, Advanced Transportation and Product Design. Each program addresses as many as ten careers or job types within the broader field named. Minority and gender-balanced role models appear throughout the programs.

  7. Psychometric evaluation of the Generalized Anxiety Disorder Screener GAD-7, based on a large German general population sample.

    PubMed

    Hinz, Andreas; Klein, Annette M; Brähler, Elmar; Glaesmer, Heide; Luck, Tobias; Riedel-Heller, Steffi G; Wirkner, Kerstin; Hilbert, Anja

    2017-03-01

    The Generalized Anxiety Disorder Scales GAD-7 and GAD-2 are instruments for the assessment of anxiety. The aims of this study are to test psychometric properties of these questionnaires, to provide normative values, and to investigate associations with sociodemographic factors, quality of life, psychological variables, and behavioral factors. A German community sample (n=9721) with an age range of 18-80 years was surveyed using the GAD-7 and several other questionnaires. Confirmatory factor analyses confirmed the unidimensionality and measurement invariance of the GAD-7 across age and gender. Females were more anxious than males (mean scores: M=4.07 vs. M=3.01; effect size: d=0.33). There was no linear age trend. A total of 5.9% fulfilled the cut-off criterion of 10 and above. Anxiety was correlated with low quality of life, fatigue, low habitual optimism, physical complaints, sleep problems, low life satisfaction, low social support, low education, unemployment, and low income. Cigarette smoking and alcohol consumption were also associated with heightened anxiety, especially in women. When comparing the GAD-7 (7 items) with the ultra-short GAD-2 (2 items), the GAD-7 instrument was superior to the GAD-2 regarding several psychometric criteria. The response rate (33%) was low. Because of the cross-sectional character of the study, causal conclusions cannot be drawn. A further limitation is the lack of a gold standard for diagnosing anxiety. The GAD-7 can be recommended for use in clinical research and routine. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Selective loss of parvalbumin-positive GABAergic interneurons in the cerebral cortex of maternally stressed Gad1-heterozygous mouse offspring.

    PubMed

    Uchida, T; Furukawa, T; Iwata, S; Yanagawa, Y; Fukuda, A

    2014-03-11

    Exposure to maternal stress (MS) and mutations in GAD1, which encodes the γ-aminobutyric acid (GABA) synthesizing enzyme glutamate decarboxylase (GAD) 67, are both risk factors for psychiatric disorders. However, the relationship between these risk factors remains unclear. Interestingly, the critical period of MS for psychiatric disorders in offspring corresponds to the period of GABAergic neuron neurogenesis and migration in the fetal brain, that is, in the late stage of gestation. Indeed, decrement of parvalbumin (PV)-positive GABAergic interneurons in the medial prefrontal cortex (mPFC) and hippocampus (HIP) has often been observed in schizophrenia patients. In the present study, we used GAD67-green fluorescent protein (GFP) knock-in mice (that is, mice in which the Gad1 gene is heterozygously deleted; GAD67(+/GFP)) that underwent prenatal stress from embryonic day 15.0 to 17.5 and monitored PV-positive GABAergic neurons to address the interaction between Gad1 disruption and stress. Administration of 5-bromo-2-deoxyuridine revealed that neurogenesis of GFP-positive GABAergic neurons, but not cortical plate cells, was significantly diminished in fetal brains during MS. Differential expression of glucocorticoid receptors by different progenitor cell types may underlie this differential outcome. Postnatally, the density of PV-positive, but not PV-negative, GABAergic neurons was significantly decreased in the mPFC, HIP and somatosensory cortex but not in the motor cortex of GAD67(+/GFP) mice. By contrast, these findings were not observed in wild-type (GAD67(+/+)) offspring. These results suggest that prenatal stress, in addition to heterozygous deletion of Gad1, could specifically disturb the proliferation of neurons destined to be PV-positive GABAergic interneurons.

  9. A comparative study of extraction techniques for maximum recovery of glutamate decarboxylase (GAD) from Aspergillus oryzae NSK

    PubMed Central

    2013-01-01

    Background γ-Amino butyric acid (GABA) is a major inhibitory neurotransmitter of the mammalian central nervous system that plays a vital role in regulating vital neurological functions. The enzyme responsible for producing GABA is glutamate decarboxylase (GAD), an intracellular enzyme that both food and pharmaceutical industries are currently using as the major catalyst in trial biotransformation process of GABA. We have successfully isolated a novel strain of Aspergillus oryzae NSK that possesses a relatively high GABA biosynthesizing capability compared to other reported GABA-producing fungal strains, indicating the presence of an active GAD. This finding has prompted us to explore an effective method to recover maximum amount of GAD for further studies on the GAD’s biochemical and kinetic properties. The extraction techniques examined were enzymatic lysis, chemical permeabilization, and mechanical disruption. Under the GAD activity assay used, one unit of GAD activity is expressed as 1 μmol of GABA produced per min per ml enzyme extract (U/ml) while the specific activity was expressed as U/mg protein. Results Mechanical disruption by sonication, which yielded 1.99 U/mg of GAD, was by far the most effective cell disintegration method compared with the other extraction procedures examined. In contrast, the second most effective method, freeze grinding followed by 10% v/v toluene permeabilization at 25°C for 120 min, yielded only 1.17 U/mg of GAD, which is 170% lower than the sonication method. Optimized enzymatic lysis with 3 mg/ml Yatalase® at 60°C for 30 min was the least effective. It yielded only 0.70 U/mg of GAD. Extraction using sonication was further optimized using a one-variable-at-a-time approach (OVAT). Results obtained show that the yield of GAD increased 176% from 1.99 U/mg to 3.50 U/mg. Conclusion Of the techniques used to extract GAD from A. oryzae NSK, sonication was found to be the best. Under optimized conditions, about 176% of GAD

  10. Defense of GAD during the 1950s and early 1960s

    NASA Astrophysics Data System (ADS)

    Frankel, H. R.

    2012-12-01

    Paleomagnetists favoring continental offered empirical and theoretical support for the GAD hypothesis. Initial support came from the discovery that the mean directions of rock units, regardless of polarity, laid down back through the Upper Tertiary centered on the rotational pole. Armed with Fisher's statistics, Hospers (1951, 1953) found that the mean direction of the NRM of Icelandic lava flows back through the Miocene better agreed with the GAD field than with the present field. Similarly, Campbell and Runcorn (1956), Creer (1956), and Irving and Green (1957) respectively found that the natural remanent magnetization of Late Tertiary Columbia River basalts, Quaternary basalts of Argentina, and Late Cenozoic New Volcanics of Victoria supported the hypothesis. If significant continental drift or "true" polar wander has occurred, paleomagnetic data alone cannot determine if the axial element of the GAD hypothesis holds earlier than Late Tertiary. Extending the GAD hypothesis back in time requires an approach involving a means independent of paleomagnetism for determining past latitudes. Irving was the first to realize that the paleoclimatology would work. If the GAD hypothesis holds, then paleolatitudes based on paleomagnetism and paleoclimatology should agree. Irving (1956) found that, except for the Squantum Tillite, the paleomagnetically and paleoclimatically determined paleolatitudes for Europe, North America, India, and Tasmania were in agreement. He concluded that the magnetic and rotational axes have coincided since the Paleozoic. Blackett (1961) also compared paleoclimatic and paleomagnetic data-sets. Irving and Briden (1962, 1964) further appealed to paleoclimatology to defend the hypothesis. Determining the paleolatitude spectra for several paleoclimatic indicators, they found the present latitude of fossil instances inconsistent with the latitude of modern instances while their paleomagnetically determined paleolatitudes, which assumed the GAD hypothesis

  11. Gender Differences in Associations of Glutamate Decarboxylase 1 Gene (GAD1) Variants with Panic Disorder

    PubMed Central

    Weber, Heike; Scholz, Claus Jürgen; Domschke, Katharina; Baumann, Christian; Klauke, Benedikt; Jacob, Christian P.; Maier, Wolfgang; Fritze, Jürgen; Bandelow, Borwin; Zwanzger, Peter Michael; Lang, Thomas; Fehm, Lydia; Ströhle, Andreas; Hamm, Alfons; Gerlach, Alexander L.; Alpers, Georg W.; Kircher, Tilo; Wittchen, Hans-Ulrich; Arolt, Volker; Pauli, Paul; Deckert, Jürgen; Reif, Andreas

    2012-01-01

    Background Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females. Methodology/Principal Findings Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype×gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype×gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score. Conclusions/Significance The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder. PMID:22662185

  12. GAD65 haplodeficiency conveys resilience in animal models of stress-induced psychopathology.

    PubMed

    Müller, Iris; Obata, Kunihiko; Richter-Levin, Gal; Stork, Oliver

    2014-01-01

    GABAergic mechanisms are critically involved in the control of fear and anxiety, but their role in the development of stress-induced psychopathologies, including post-traumatic stress disorder (PTSD) and mood disorders is not sufficiently understood. We studied these functions in two established mouse models of risk factors for stress-induced psychopathologies employing variable juvenile stress and/or social isolation. A battery of emotional tests in adulthood revealed the induction of contextually generalized fear, anxiety, hyperarousal and depression-like symptoms in these paradigms. These reflect the multitude and complexity of stress effects in human PTSD patients. With factor analysis we were able to identify parameters that reflect these different behavioral domains in stressed animals and thus provide a basis for an integrated scoring of affectedness more closely resembling the clinical situation than isolated parameters. To test the applicability of these models to genetic approaches we further tested the role of GABA using heterozygous mice with targeted mutation of the GABA synthesizing enzyme GAD65 [GAD65(+/-) mice], which show a delayed postnatal increase in tissue GABA content in limbic and cortical brain areas. Unexpectedly, GAD65(+/-) mice did not show changes in exploratory activity regardless of the stressor type and were after the variable juvenile stress procedure protected from the development of contextual generalization in an auditory fear conditioning experiment. Our data demonstrate the complex nature of behavioral alterations in rodent models of stress-related psychopathologies and suggest that GAD65 haplodeficiency, likely through its effect on the postnatal maturation of GABAergic transmission, conveys resilience to some of these stress-induced effects.

  13. GAD1 gene polymorphisms are associated with hyperactivity in Attention-Deficit/Hyperactivity Disorder.

    PubMed

    Bruxel, Estela M; Akutagava-Martins, Glaucia C; Salatino-Oliveira, Angélica; Genro, Julia P; Zeni, Cristian P; Polanczyk, Guilherme V; Chazan, Rodrigo; Schmitz, Marcelo; Rohde, Luis A; Hutz, Mara H

    2016-12-01

    Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood. Recent studies suggest a role for γ-aminobutyric acid (GABA) on ADHD hyperactive/impulsive symptoms due to behavioral disinhibition resulting from inappropriate modulation of both glutamatergic and GABAergic signaling. The glutamic acid decarboxylase (GAD1) gene encodes a key enzyme of GABA biosynthesis. The aim of the present study was to investigate the possible influence of GAD1 SNPs rs3749034 and rs11542313 on ADHD susceptibility. The clinical sample consisted of 547 families with ADHD probands recruited at the ADHD Outpatient Clinics from Hospital de Clínicas de Porto Alegre. Hyperactive/impulsive symptoms were evaluated based on parent reports from the Swanson, Nolan, and Pelham Scale-version IV (SNAP-IV). The C allele of rs11542313 was significantly overtransmitted from parents to ADHD probands (P = 0.02). Hyperactive/impulsive score was higher in rs3749034G allele (P = 0.005, Cohen's D = 0.19) and rs11542313C allele (P = 0.03; Cohen's D = 0.16) carriers. GAD1 haplotypes were also associated with higher hyperactive/impulsive scores in ADHD youths (global P-value = 0.01). In the specific haplotype test, the GC haplotype was the one with the highest hyperactive/impulsive scores (P = 0.03). Our results suggest that the GAD1 gene is associated with ADHD susceptibility, contributing particularly to the hyperactive/impulsive symptom domain. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  14. The GABA-synthetic enzyme GAD65 controls circadian activation of conditioned fear pathways.

    PubMed

    Bergado-Acosta, Jorge R; Müller, Iris; Richter-Levin, Gal; Stork, Oliver

    2014-03-01

    Circadian fluctuations of fear and anxiety symptoms are observable in persons with post-traumatic stress disorder, generalized anxiety, and panic disorder; however, the underlying neurobiological mechanisms are not sufficiently understood. In the present study, we investigated the putative role of inhibitory neurotransmission in the circadian fluctuation of fear symptoms, using mice with genetic ablation of the γ-amino butyric acid (GABA) synthesizing isoenzyme, glutamic acid decarboxylase GAD65. We observed in these mutant mice an altered expression of conditioned fear with a profound reduction of freezing, and an increase of hyperactivity bouts occurring only when both fear conditioning training and retrieval testing were done at the beginning of their active phase. Mutants further showed an increased arousal response at this time of the day, although, circadian rhythm of home cage activity was unaltered. Hyperactivity and reduced freezing during fear memory retrieval were accompanied by an increased induction of the immediate early gene cFos suggesting hyperactivation of the hippocampus, amygdala, and medial hypothalamus. Our data suggest a role of GAD65-mediated GABA synthesis in the encoding of circadian information to fear memory. GAD65 deficits in a state-dependent manner result in increased neural activation in fear circuits and elicit panic-like flight responses during fear memory retrieval.

  15. Gad1 mRNA as a reliable indicator of altered GABA release from orexigenic neurons in the hypothalamus

    PubMed Central

    Dicken, Matthew S.; Hughes, Alexander R.; Hentges, Shane T.

    2016-01-01

    The strength of γ-aminobutyric acid (GABA)-mediated inhibitory synaptic input is a principle determinant of neuronal activity. However, because of differences in the number of GABA afferent inputs and the sites of synapses, it is difficult to directly assay for altered GABA transmission between specific cells. The present study tested the hypothesis that the level of mRNA for the GABA synthetic enzyme glutamate decarboxylase (GAD) can provide a reliable proxy for GABA release. This was tested in a mouse hypothalamic circuit important in the regulation of energy balance. Fluorescent in situ hybridization results show that the expression of Gad1 mRNA (encoding the GAD67 enzyme) was increased in hypothalamic neuropeptide Y/agouti-related peptide (NPY/AgRP) neurons after an overnight fast, consistent with the ability of GABA from these neurons to stimulate food intake. Optogenetic studies confirmed that the observed increase in Gad1 mRNA correlated with an increase in the probability of GABA release from NPY/AgRP neurons onto downstream proopiomelanocortin neurons. Likewise, there was an increase in the readily releasable pool of GABA in NPY/AgRP neurons. Selective inhibition of GAD activity in NPY/AgRP neurons decreased GABA release, indicating that GAD67 activity, which is largely dictated by expression level, is a key determinant of GABA release. Altogether, it appears that Gad expression may be a reliable proxy of altered GABAergic transmission. Examining changes in Gad mRNA as a proxy for GABA release may be particularly helpful when the downstream targets are not known or when limited tools exist for detecting GABA release at a particular synapse. PMID:26370162

  16. Aberrant Accumulation of the Diabetes Autoantigen GAD65 in Golgi Membranes in Conditions of ER Stress and Autoimmunity.

    PubMed

    Phelps, Edward A; Cianciaruso, Chiara; Michael, Iacovos P; Pasquier, Miriella; Kanaani, Jamil; Nano, Rita; Lavallard, Vanessa; Billestrup, Nils; Hubbell, Jeffrey A; Baekkeskov, Steinunn

    2016-09-01

    Pancreatic islet β-cells are particularly susceptible to endoplasmic reticulum (ER) stress, which is implicated in β-cell dysfunction and loss during the pathogenesis of type 1 diabetes (T1D). The peripheral membrane protein GAD65 is an autoantigen in human T1D. GAD65 synthesizes γ-aminobutyric acid, an important autocrine and paracrine signaling molecule and a survival factor in islets. We show that ER stress in primary β-cells perturbs the palmitoylation cycle controlling GAD65 endomembrane distribution, resulting in aberrant accumulation of the palmitoylated form in trans-Golgi membranes. The palmitoylated form has heightened immunogenicity, exhibiting increased uptake by antigen-presenting cells and T-cell stimulation compared with the nonpalmitoylated form. Similar accumulation of GAD65 in Golgi membranes is observed in human β-cells in pancreatic sections from GAD65 autoantibody-positive individuals who have not yet progressed to clinical onset of T1D and from patients with T1D with residual β-cell mass and ongoing T-cell infiltration of islets. We propose that aberrant accumulation of immunogenic GAD65 in Golgi membranes facilitates inappropriate presentation to the immune system after release from stressed and/or damaged β-cells, triggering autoimmunity.

  17. Efficient Production of γ-GABA Using Recombinant E. coli Expressing Glutamate Decarboxylase (GAD) Derived from Eukaryote Saccharomyces cerevisiae.

    PubMed

    Xiong, Qiang; Xu, Zheng; Xu, Lu; Yao, Zhong; Li, Sha; Xu, Hong

    2017-06-27

    γ-Aminobutyric acid (γ-GABA) is a non-proteinogenic amino acid, which acts as a major regulator in the central nervous system. Glutamate decarboxylase (namely GAD, EC 4.1.1.15) is known to be an ideal enzyme for γ-GABA production using L-glutamic acid as substrate. In this study, we cloned and expressed GAD gene from eukaryote Saccharomyces cerevisiae (ScGAD) in E. coli BL21(DE3). This enzyme was further purified and its optimal reaction temperature and pH were 37 °C and pH 4.2, respectively. The cofactor of ScGAD was verified to be either pyridoxal 5'-phosphate (PLP) or pyridoxal hydrochloride. The optimal concentration of either cofactor was 50 mg/L. The optimal medium for E. coli-ScGAD cultivation and expression were 10 g/L lactose, 5 g/L glycerol, 20 g/L yeast extract, and 10 g/L sodium chloride, resulting in an activity of 55 U/mL medium, three times higher than that of using Luria-Bertani (LB) medium. The maximal concentration of γ-GABA was 245 g/L whereas L-glutamic acid was near completely converted. These findings provided us a good example for bio-production of γ-GABA using recombinant E. coli expressing a GAD enzyme derived from eukaryote.

  18. CD4+ T cells recognize diverse epitopes within GAD65: implications for repertoire development and diabetes monitoring

    PubMed Central

    Yang, Junbao; James, Eddie A.; Sanda, Srinath; Greenbaum, Carla; Kwok, William W.

    2013-01-01

    Summary Type 1 diabetes is associated with T‐cell responses to β‐cell antigens such as GAD65. Single T‐cell epitopes have been investigated for immune monitoring with some success, but multiple epitopes may be required to fully characterize responses in all subjects. We used a systematic approach to examine the diversity of the GAD65‐specific T‐cell repertoire in subjects with DRB1*04:01 haplotypes. Using class II tetramers, we observed responses to 15 GAD65 epitopes, including five novel epitopes. The majority were confirmed to be processed and presented. Upon stimulation with peptides, GAD‐specific responses were equally broad in subjects with diabetes and healthy controls in the presence or absence of CD25+ T cells, suggesting that a susceptible HLA is sufficient to generate a potentially autoreactive repertoire. Without depleting CD25+ cells, GAD113–132 and GAD265–284 responses were significantly stronger in subjects with diabetes. Although nearly every individual responded to at least one GAD65 epitope, most were seen in less than half of the subjects tested, suggesting that multiple epitopes are recommended for immune monitoring. PMID:23228173

  19. COOH-Terminal Clustering of Autoantibody and T-Cell Determinants on the Structure of GAD65 Provide Insights Into the Molecular Basis of Autoreactivity

    SciTech Connect

    Fenalti, Gustavo; Hampe, Christiane S.; Arafat, Yasir; Law, Ruby H.P.; Banga, J. Paul; Mackay, Ian R.; Whisstock, James C.; Buckle, Ashley M.; Rowley, Merrill J.

    2008-11-19

    To gain structural insights into the autoantigenic properties of GAD65 in type 1 diabetes, we analyzed experimental epitope mapping data in the context of the recently determined crystal structures of GAD65 and GAD67, to allow 'molecular positioning' of epitope sites for B- and T-cell reactivity. Data were assembled from analysis of reported effects of mutagenesis of GAD65 on its reactivity with a panel of 11 human monoclonal antibodies (mAbs), supplemented by use of recombinant Fab to cross-inhibit reactivity with GAD65 by radioimmunoprecipitation of the same mAbs. COOH-terminal region on GAD65 was the major autoantigenic site. B-cell epitopes were distributed within two separate clusters around different faces of the COOH-terminal domain. Inclusion of epitope sites in the pyridoxal phosphate- and NH{sub 2}-terminal domains was attributed to the juxtaposition of all three domains in the crystal structure. Epitope preferences of different mAbs to GAD65 aligned with different clinical expressions of type 1 diabetes. Epitopes for four of five known reactive T-cell sequences restricted by HLA DRB1*0401 were aligned to solvent-exposed regions of the GAD65 structure and colocalized within the two B-cell epitope clusters. The continuous COOH-terminal epitope region of GAD65 was structurally highly flexible and therefore differed markedly from the equivalent region of GAD67. Structural features could explain the differing antigenicity, and perhaps immunogenicity, of GAD65 versus GAD67. The proximity of B- and T-cell epitopes within the GAD65 structure suggests that antigen-antibody complexes may influence antigen processing by accessory cells and thereby T-cell reactivity.

  20. Current theoretical models of generalized anxiety disorder (GAD): conceptual review and treatment implications.

    PubMed

    Behar, Evelyn; DiMarco, Ilyse Dobrow; Hekler, Eric B; Mohlman, Jan; Staples, Alison M

    2009-12-01

    Theoretical conceptualizations of generalized anxiety disorder (GAD) continue to undergo scrutiny and refinement. The current paper critiques five contemporary models of GAD: the Avoidance Model of Worry and GAD [Borkovec, T. D. (1994). The nature, functions, and origins of worry. In: G. Davey & F. Tallis (Eds.), Worrying: perspectives on theory assessment and treatment (pp. 5-33). Sussex, England: Wiley & Sons; Borkovec, T. D., Alcaine, O. M., & Behar, E. (2004). Avoidance theory of worry and generalized anxiety disorder. In: R. Heimberg, C. Turk, & D. Mennin (Eds.), Generalized anxiety disorder: advances in research and practice (pp. 77-108). New York, NY, US: Guilford Press]; the Intolerance of Uncertainty Model [Dugas, M. J., Letarte, H., Rheaume, J., Freeston, M. H., & Ladouceur, R. (1995). Worry and problem solving: evidence of a specific relationship. Cognitive Therapy and Research, 19, 109-120; Freeston, M. H., Rheaume, J., Letarte, H., Dugas, M. J., & Ladouceur, R. (1994). Why do people worry? Personality and Individual Differences, 17, 791-802]; the Metacognitive Model [Wells, A. (1995). Meta-cognition and worry: a cognitive model of generalized anxiety disorder. Behavioural and Cognitive Psychotherapy, 23, 301-320]; the Emotion Dysregulation Model [Mennin, D. S., Heimberg, R. G., Turk, C. L., & Fresco, D. M. (2002). Applying an emotion regulation framework to integrative approaches to generalized anxiety disorder. Clinical Psychology: Science and Practice, 9, 85-90]; and the Acceptance-based Model of GAD [Roemer, L., & Orsillo, S. M. (2002). Expanding our conceptualization of and treatment for generalized anxiety disorder: integrating mindfulness/acceptance-based approaches with existing cognitive behavioral models. Clinical Psychology: Science and Practice, 9, 54-68]. Evidence in support of each model is critically reviewed, and each model's corresponding evidence-based therapeutic interventions are discussed. Generally speaking, the models share an

  1. Comparative Autonomic Responses to Diagnostic Interviewing between Individuals with GAD, MDD, SAD and Healthy Controls

    PubMed Central

    Diamond, Allison E.; Fisher, Aaron J.

    2017-01-01

    Dysregulation of the autonomic nervous system (ANS) has been well documented in individuals diagnosed with a range of psychological disorders, including generalized anxiety disorder (GAD) and major depressive disorder (MDD). Moreover, these disorders both confer an increased risk of cardiovascular disease—which may relate to increased sympathetic and decreased parasympathetic tone. Extant research has indicated a reduction in autonomic flexibility in GAD, and while reduced flexibility has also been seen in MDD, the specific physiological alterations have been more difficult to categorize due to methodological limitations, including high co-morbidity rates with anxiety disorders. Prior studies have largely assessed autonomic functioning in stress paradigms or at the trait level, yet to date, no research has investigated the ANS during a diagnostic interview, a ubiquitous task employed in both research and clinical settings. In this study we sought to identify physiological differences in both branches of the ANS across diagnostic categories in the context of a diagnostic interview. Participants (n = 82) were administered a structured clinical interview, during which heart rate (HR), respiratory sinus arrhythmia (RSA) and pre-ejection period (PEP) were recorded in participants carrying a diagnosis of GAD (n = 34), MDD (n = 22), Social Anxiety Disorder (SAD; n = 15) and healthy controls (n = 27). Person-specific linear regression models were employed to assess the level and slope for HR, RSA and PEP throughout the course of the interview. A multivariate analysis of variance (MANOVA) model was conducted to baseline differences in HR, RSA and PEP between diagnostic groups. Multiple regression models were then conducted to differences in slope of HR, RSA and PEP throughout the course of the interview amongst diagnostic groups, including both suppression and worry as moderators. Results indicated significant increases in RSA throughout the interview in MDD (p = 0

  2. Epigenetic regulation of RELN and GAD1 in the frontal cortex (FC) of autism spectrum disorder (ASD) subjects.

    PubMed

    Zhubi, Adrian; Chen, Ying; Guidotti, Alessandro; Grayson, Dennis R

    2017-02-14

    Both Reelin (RELN) and glutamate decarboxylase 67 (GAD1) have been implicated in the pathophysiology of Autism Spectrum Disorders (ASD). We have previously shown that both mRNAs are reduced in the cerebella (CB) of ASD subjects through a mechanism that involves increases in the amounts of MECP2 binding to the corresponding promoters. In the current study, we examined the expression of RELN, GAD1, GAD2, and several other mRNAs implicated in this disorder in the frontal cortices (FC) of ASD and CON subjects. We also focused on the role that epigenetic processes play in the regulation of these genes in ASD brain. Our goal is to better understand the molecular basis for the down-regulation of genes expressed in GABAergic neurons in ASD brains. We measured mRNA levels corresponding to selected GABAergic genes using qRT-PCR in RNA isolated from both ASD and CON groups. We determined the extent of binding of MECP2 and DNMT1 repressor proteins by chromatin immunoprecipitation (ChIP) assays. The amount of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) present in the promoters of the target genes was quantified by methyl DNA immunoprecipitation (MeDIP) and hydroxyl MeDIP (hMeDIP). We detected significant reductions in the mRNAs associated with RELN and GAD1 and significant increases in mRNAs encoding the Ten-eleven Translocation (TET) enzymes 1, 2, and 3. We also detected increased MECP2 and DNMT1 binding to the corresponding promoter regions of GAD1, RELN, and GAD2. Interestingly, there were decreased amounts of 5mC at both promoters and little change in 5hmC content in these same DNA fragments. Our data demonstrate that RELN, GAD1, and several other genes selectively expressed in GABAergic neurons, are down-regulated in post-mortem ASD FC. In addition, we observed increased DNMT1 and MECP2 binding at the corresponding promoters of these genes. The finding of increased MECP2 binding to the RELN, GAD1 and GAD2 promoters, with reduced amounts of 5mC and unchanged

  3. Loss of glutamic acid decarboxylase (Gad67) in Gpr88-expressing neurons induces learning and social behavior deficits in mice.

    PubMed

    Zhang, K; Hill, K; Labak, S; Blatt, G J; Soghomonian, J-J

    2014-09-05

    GABA is the neurotransmitter of striatal projection neurons, however the contribution of the striatal GABAergic output to behavior is not well understood. We assessed motor function, spatial learning, social behavior, olfactory and object recognition preferences in mice lacking the GABA-synthesizing enzyme glutamic acid decarboxylase, Gad67, in neurons expressing the protein Gpr88, an orphan G-protein-coupled receptor primarily expressed in the striatum. Gad67-deficient mice show no impairments in motor coordination and balance, but exhibit enhanced locomotor activity and stereotypic grooming behavior. Furthermore, Gad67-deficient mice show impairments in spatial learning, social behavior, olfactory preferences, and they prefer a familiar compared to a novel object in the object recognition test. These findings provide original evidence that striatal Gad67 expression is involved in the modulation of learning and social behavior. Some of the behavioral abnormalities observed in Gad67-deficient mice are reminiscent of Autism-spectrum-disorder (ASD) deficits, suggesting that abnormal striatal GABAergic output may contribute to behavioral deficits in ASD. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Co-expression of GAD67 and choline acetyltransferase reveals a novel neuronal phenotype in the mouse medulla oblongata

    PubMed Central

    Gotts, Jittima; Atkinson, Lucy; Edwards, Ian J.; Yanagawa, Yuchio; Deuchars, Susan A.; Deuchars, Jim

    2015-01-01

    GABAergic and cholinergic systems play an important part in autonomic pathways. To determine the distribution of the enzymes responsible for the production of GABA and acetylcholine in areas involved in autonomic control in the mouse brainstem, we used a transgenic mouse expressing green fluorescent protein (GFP) in glutamate decarboxylase 67 (GAD67) neurones, combined with choline acetyl transferase (ChAT) immunohistochemistry. ChAT-immunoreactive (IR) and GAD67-GFP containing neurones were observed throughout the brainstem. A small number of cells contained both ChAT-IR and GAD67-GFP. Such double labelled cells were observed in the NTS (predominantly in the intermediate and central subnuclei), the area postrema, reticular formation and lateral paragigantocellular nucleus. All ChAT-IR neurones in the area postrema contained GAD67-GFP. Double labelled neurones were not observed in the dorsal vagal motor nucleus, nucleus ambiguus or hypoglossal nucleus. Double labelled ChAT-IR/GAD67-GFP cells in the NTS did not contain neuronal nitric oxide synthase (nNOS) immunoreactivity, whereas those in the reticular formation and lateral paragigantocellular nucleus did. The function of these small populations of double labelled cells is currently unknown, however their location suggests a potential role in integrating signals involved in oromotor behaviours. PMID:26015156

  5. Schizosaccharomyces pombe AGC family kinase Gad8p forms a conserved signaling module with TOR and PDK1-like kinases

    PubMed Central

    Matsuo, Tomohiko; Kubo, Yoshiya; Watanabe, Yoshinori; Yamamoto, Masayuki

    2003-01-01

    The TOR protein is a phosphoinositide kinase-related kinase widely conserved among eukaryotes. Fission yeast tor1 encodes an ortholog of TOR, which is required for sexual development and growth under stressed conditions. We isolated gad8, which encodes a Ser/Thr kinase of the AGC family, as a high-copy suppressor of the sterility of a tor1 mutant. Disruption of gad8 caused phenotypes similar to those of tor1 disruption. Gad8p was less phosphorylated and its kinase activity was undetectable in tor1Δ cells. Three amino acid residues corresponding to conserved phosphorylation sites in the AGC family kinases, namely Thr387 in the activation loop, Ser527 in the turn motif and Ser546 in the hydrophobic motif, were important for the kinase activity of Gad8p. Tor1p was responsible for the phosphorylation of Ser527 and Ser546, whereas Ksg1p, a PDK1-like kinase, appeared to phosphorylate Thr387 directly. Altogether, Tor1p, Ksg1p and Gad8p appear to constitute a signaling module for sexual development and growth under stressed conditions in fission yeast, which resembles the mTOR–PDK1–S6K1 system in mammals and may represent a basic signaling module ubiquitous in eukaryotes. PMID:12805221

  6. Co-expression of GAD67 and choline acetyltransferase reveals a novel neuronal phenotype in the mouse medulla oblongata.

    PubMed

    Gotts, Jittima; Atkinson, Lucy; Edwards, Ian J; Yanagawa, Yuchio; Deuchars, Susan A; Deuchars, Jim

    2015-12-01

    GABAergic and cholinergic systems play an important part in autonomic pathways. To determine the distribution of the enzymes responsible for the production of GABA and acetylcholine in areas involved in autonomic control in the mouse brainstem, we used a transgenic mouse expressing green fluorescent protein (GFP) in glutamate decarboxylase 67 (GAD67) neurones, combined with choline acetyl transferase (ChAT) immunohistochemistry. ChAT-immunoreactive (IR) and GAD67-GFP containing neurones were observed throughout the brainstem. A small number of cells contained both ChAT-IR and GAD67-GFP. Such double labelled cells were observed in the NTS (predominantly in the intermediate and central subnuclei), the area postrema, reticular formation and lateral paragigantocellular nucleus. All ChAT-IR neurones in the area postrema contained GAD67-GFP. Double labelled neurones were not observed in the dorsal vagal motor nucleus, nucleus ambiguus or hypoglossal nucleus. Double labelled ChAT-IR/GAD67-GFP cells in the NTS did not contain neuronal nitric oxide synthase (nNOS) immunoreactivity, whereas those in the reticular formation and lateral paragigantocellular nucleus did. The function of these small populations of double labelled cells is currently unknown, however their location suggests a potential role in integrating signals involved in oromotor behaviours.

  7. Effect of NaCl on aerobic denitrification by strain Achromobacter sp. GAD-3.

    PubMed

    Gui, Mengyao; Chen, Qian; Ni, Jinren

    2017-03-01

    This paper presents the effect of NaCl on aerobic denitrification by a novel aerobic denitrifier strain Achromobacter sp. GAD-3. Results indicated that the aerobic denitrification process was inhibited by NaCl concentrations ≥20 g L(-1), leading to lower nitrate removal rates (1.67∼4.0 mg L(-1) h(-1)), higher nitrite accumulation (50.2∼87.4 mg L(-1)), and increasing N2O emission ratios (13∼72 mg L(-1)/mg L(-1)). Poor performance of aerobic denitrification at high salinity was attributed to the suppression of active microbial biomass and electron donating capacity of strain GAD-3. Further studies on the corresponding inhibition of the denitrifying gene expression by higher salinities revealed the significant sensitivity order of nosZ (for N2O reductase) > cnorB (for NO reductase) ≈ nirS (for cytochrome cd(1) nitrite reductase) > napA (for periplasmic nitrate reductase), accompanied with a time-lapse expression between nosZ and cnorB based on reverse transcription and real-time quantitative polymerase chain reaction (RT-qPCR) analysis. The insights into the effect of NaCl on aerobic denitrification are of great significance to upgrade wastewater treatment plants (WWTPs) containing varying levels of salinity.

  8. The amyloid fold of Gad m 1 epitopes governs IgE binding.

    PubMed

    Sánchez, Rosa; Martínez, Javier; Castro, Ana; Pedrosa, María; Quirce, Santiago; Rodríguez-Pérez, Rosa; Gasset, María

    2016-09-06

    Amyloids are polymeric structural states formed from locally or totally unfolded protein chains that permit surface reorganizations, stability enhancements and interaction properties that are absent in the precursor monomers. β-Parvalbumin, the major allergen in fish allergy, forms amyloids that are recognized by IgE in the patient sera, suggesting a yet unknown pathological role for these assemblies. We used Gad m 1 as the fish β-parvalbumin model and a combination of approaches, including peptide arrays, recombinant wt and mutant chains, biophysical characterizations, protease digestions, mass spectrometry, dot-blot and ELISA assays to gain insights into the role of amyloids in the IgE interaction. We found that Gad m 1 immunoreactive regions behave as sequence-dependent conformational epitopes that provide a 1000-fold increase in affinity and the structural repetitiveness required for optimal IgE binding and cross-linking upon folding into amyloids. These findings support the amyloid state as a key entity in type I food allergy.

  9. Alterations in hypoglossal motor neurons due to GAD67 and VGAT deficiency in mice.

    PubMed

    Fogarty, Matthew J; Kanjhan, Refik; Yanagawa, Yuchio; Noakes, Peter G; Bellingham, Mark C

    2017-03-01

    There is an emerging body of evidence that glycinergic and GABAergic synaptic inputs onto motor neurons (MNs) help regulate the final number of MNs and axonal muscle innervation patterns. Using mutant glutamate decarboxylase 67 (GAD67) and vesicular inhibitory amino acid transporter (VGAT) deficient mice, we describe the effect that deficiencies of presynaptic GABAergic and/or glycinergic release have on the post-synaptic somato-dendritic structure of motor neurons, and the development of excitatory and inhibitory synaptic inputs to MNs. We use whole-cell patch clamp recording of synaptic currents in E18.5 hypoglossal MNs from brainstem slices, combined with dye-filling of these recorded cells with Neurobiotin™, high-resolution confocal imaging and 3-dimensional reconstructions. Hypoglossal MNs from GAD67- and VGAT-deficient mice display decreased inhibitory neurotransmission and increased excitatory synaptic inputs. These changes are associated with increased dendritic arbor length, increased complexity of dendritic branching, and increased density of spiny processes. Our results show that presynaptic release of inhibitory amino acid neurotransmitters are potent regulators of hypoglossal MN morphology and key regulators of synaptic inputs during this critical developmental time point. Copyright © 2016 Elsevier Inc. All rights reserved.

  10. Lesson of the month 2: Autoimmune sequelae of anti-GAD antibodies - thinking outside the box.

    PubMed

    Ward, Rebecca J; Varughese, George I; Jose, Biju; Abraham, Roby J

    2017-10-01

    A 52 year-old female with no significant medical problems presented with left-sided weakness, unsteady gait and speech disturbance. It was thought that she had neuro-inflammation and she remained clinically stable. Several years later, she was diagnosed with latent autoimmune diabetes of adulthood. Her neurological symptoms deteriorated and she was admitted into hospital. The cerebrospinal fluid was normal, as were an array of blood tests. Imaging tests, including magnetic resonance imaging, computerised tomography and positron emission tomography scans were normal. However, her anti-glutamic acid decarboxylase antibody serum level, which had been taken in the diabetes outpatient clinic, returned at 2,000,000 IU/mL (normal range 0-10). This led to the diagnosis of glutamic acid decarboxylase (GAD) positive cerebellar ataxia. She was treated with plasma exchange and intravenous immunoglobulins and over next 12 weeks her symptoms improved. Our case highlights the need for appropriate treatment of patients with GAD positive cerebellar ataxia to achieve good outcomes. © Royal College of Physicians 2017. All rights reserved.

  11. Treating late-life GAD in primary care: An effectiveness pilot study

    PubMed Central

    Calleo, Jessica S.; Bush, Amber L.; Cully, Jeffrey A.; Wilson, Nancy L.; Kraus-Schuman, Cynthia; Rhoades, Howard M.; Novy, Diane M.; Masozera, Nicholas; Williams, Susan; Horsfield, Matthew; Kunik, Mark E.; Stanley, Melinda A.

    2011-01-01

    Objective To increase sustainability of Cognitive Behavior Therapy (CBT) in primary care for late-life anxiety, we incorporated non-expert counselors, options for telephone meetings, and integration with primary care clinicians. Method This open trial examines the feasibility, satisfaction and clinical outcomes of CBT delivered by experienced and non-experienced counselors for older adults with generalized anxiety disorder (GAD). Clinical outcomes assessed worry (Penn State Worry Questionnaire), GAD (Generalized Anxiety Disorder Severity Scale), and anxiety (Beck Anxiety Inventory and Structured Interview Guide for Hamilton Anxiety Scale). Results Following 3 months of treatment, Cohen’s d effect sizes for worry and anxiety ranged from .48 to .78. Patients treated by experienced and non-experienced counselors had similar reductions in worry and anxiety, although treatment outcomes were more improved on the Beck Anxiety Inventory for experienced therapists. Conclusion Preliminary results suggest adapted CBT can effectively reduce worry. The piloted modifications can provide acceptable and feasible evidence-based care. PMID:23588228

  12. The amyloid fold of Gad m 1 epitopes governs IgE binding

    PubMed Central

    Sánchez, Rosa; Martínez, Javier; Castro, Ana; Pedrosa, María; Quirce, Santiago; Rodríguez-Pérez, Rosa; Gasset, María

    2016-01-01

    Amyloids are polymeric structural states formed from locally or totally unfolded protein chains that permit surface reorganizations, stability enhancements and interaction properties that are absent in the precursor monomers. β-Parvalbumin, the major allergen in fish allergy, forms amyloids that are recognized by IgE in the patient sera, suggesting a yet unknown pathological role for these assemblies. We used Gad m 1 as the fish β-parvalbumin model and a combination of approaches, including peptide arrays, recombinant wt and mutant chains, biophysical characterizations, protease digestions, mass spectrometry, dot-blot and ELISA assays to gain insights into the role of amyloids in the IgE interaction. We found that Gad m 1 immunoreactive regions behave as sequence-dependent conformational epitopes that provide a 1000-fold increase in affinity and the structural repetitiveness required for optimal IgE binding and cross-linking upon folding into amyloids. These findings support the amyloid state as a key entity in type I food allergy. PMID:27597317

  13. Using the GAD-Q-IV to identify generalized anxiety disorder in psychiatric treatment seeking and primary care medical samples.

    PubMed

    Moore, Michael T; Anderson, Nicholas L; Barnes, Jill M; Haigh, Emily A P; Fresco, David M

    2014-01-01

    The fourth edition of the Generalized Anxiety Disorder Questionnaire (GAD-Q-IV) is a self-report measure that is commonly used to screen for the presence of generalized anxiety disorder (GAD). The current investigation attempted to identify an optimal cut score using samples obtained from an outpatient psychiatric (n=163) and primary care clinic (n=99). Results indicated that a cut score of 7.67 provided an optimal balance of sensitivity (.85) and specificity (.74) comparable to a previously identified cut score (5.7) across both samples (sensitivity=.90, specificity=.66). However, both cut scores were consistently outperformed by a score representing the criteria for GAD described in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (sensitivity=.89, specificity=.82).

  14. Cultural adaptation into Spanish of the generalized anxiety disorder-7 (GAD-7) scale as a screening tool

    PubMed Central

    2010-01-01

    Background Generalized anxiety disorder (GAD) is a prevalent mental health condition which is underestimated worldwide. This study carried out the cultural adaptation into Spanish of the 7-item self-administered GAD-7 scale, which is used to identify probable patients with GAD. Methods The adaptation was performed by an expert panel using a conceptual equivalence process, including forward and backward translations in duplicate. Content validity was assessed by interrater agreement. Criteria validity was explored using ROC curve analysis, and sensitivity, specificity, predictive positive value and negative value for different cut-off values were determined. Concurrent validity was also explored using the HAM-A, HADS, and WHO-DAS-II scales. Results The study sample consisted of 212 subjects (106 patients with GAD) with a mean age of 50.38 years (SD = 16.76). Average completion time was 2'30''. No items of the scale were left blank. Floor and ceiling effects were negligible. No patients with GAD had to be assisted to fill in the questionnaire. The scale was shown to be one-dimensional through factor analysis (explained variance = 72%). A cut-off point of 10 showed adequate values of sensitivity (86.8%) and specificity (93.4%), with AUC being statistically significant [AUC = 0.957-0.985); p < 0.001]. The scale significantly correlated with HAM-A (0.852, p < 0.001), HADS (anxiety domain, 0.903, p < 0.001), and WHO-DAS II (0.696, p > 0.001). Limitations Elderly people, particularly those very old, may need some help to complete the scale. Conclusion After the cultural adaptation process, a Spanish version of the GAD-7 scale was obtained. The validity of its content and the relevance and adequacy of items in the Spanish cultural context were confirmed. PMID:20089179

  15. Long-term follow-up of a randomized AAV2-GAD gene therapy trial for Parkinson’s disease

    PubMed Central

    Niethammer, Martin; Tang, Chris C.; LeWitt, Peter A.; Rezai, Ali R.; Leehey, Maureen A.; Ojemann, Steven G.; Eskandar, Emad N.; Kostyk, Sandra K.; Sarkar, Atom; Siddiqui, Mustafa S.; Schwalb, Jason M.; Poston, Kathleen L.; Kurlan, Roger M.; Richard, Irene H.; Sapan, Christine V.; Eidelberg, David; During, Matthew J.; Kaplitt, Michael G.

    2017-01-01

    BACKGROUND. We report the 12-month clinical and imaging data on the effects of bilateral delivery of the glutamic acid decarboxylase gene into the subthalamic nuclei (STN) of advanced Parkinson’s disease (PD) patients. METHODS. 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2-GAD delivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and 18F-fluorodeoxyglucose (FDG) PET imaging. RESULTS. Improvements under the blind in Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores in the AAV2-GAD group compared with the sham group continued at 12 months [time effect: F(4,138) = 11.55, P < 0.001; group effect: F(1,35) = 5.45, P < 0.03; repeated-measures ANOVA (RMANOVA)]. Daily duration of levodopa-induced dyskinesias significantly declined at 12 months in the AAV2-GAD group (P = 0.03; post-hoc Bonferroni test), while the sham group was unchanged. Analysis of all FDG PET images over 12 months revealed significant metabolic declines (P < 0.001; statistical parametric mapping RMANOVA) in the thalamus, striatum, and prefrontal, anterior cingulate, and orbitofrontal cortices in the AAV2-GAD group compared with the sham group. Across all time points, changes in regional metabolism differed for the two groups in all areas, with significant declines only in the AAV2-GAD group (P < 0.005; post-hoc Bonferroni tests). Furthermore, baseline metabolism in the prefrontal cortex (PFC) correlated with changes in motor UPDRS scores; the higher the baseline PFC metabolism, the better the clinical outcome. CONCLUSION. These findings show that clinical benefits after gene therapy with STN AAV2-GAD in PD patients persist at 12 months. TRIAL REGISTRATION. ClinicalTrials.gov NCT00643890. FUNDING. Neurologix Inc. PMID:28405611

  16. Lack of Support for the Association Between GAD2 Polymorphisms andSevere Human Obesity

    SciTech Connect

    Swarbrick, Michael M.; Waldenmaier, Bjorn; Pennacchio, Len A.; Lind,Denise L.; Cavazos, Martha M.; Geller, Frank; Merriman, Raphael; Ustaszewska, Anna; Malloy, Mary; Scherag, Andre; Hsueh, Wen-Chi; Rief,Winfried; Mauvais-Jarvis, Franck; Pullinger, Clive R.; Kane, John P.; Dent, Robert; McPherson, Ruth; Kwok, Pui-Yan; Hinney, Anke; Hebebrand,Johannes; Vaisse, Christian

    2004-11-17

    Demonstration of association between common genetic variants and chronic human diseases such as obesity could have profound implications for the prediction, prevention and treatment of these conditions. Unequivocal proof of such an association, however, requires adherence to established methodological guidelines, which include independent replication of initial positive findings. Recently, single nucleotide polymorphisms (SNPs) within GAD2 were found to be associated with class III obesity (BMI > 40 kg/m2) in 188 families (612 individuals) segregating the condition and a case-control study of 575 cases and 646 lean controls. Functional data supporting a pathophysiological role for one of the SNPs (-243A>G) were also presented. In the present study, we attempted to replicate this association in larger groups of subjects, and to extend the functional studies of the -243A>G SNP. In 2,327 subjects comprising 692 German nuclear families with severe, early-onset obesity, we found no evidence for a relationship between the three GAD2 SNPs and obesity, whether SNPs were studied individually or as haplotypes. In two independent case-control studies (a total of 680 class III obesity cases and 1,186 lean controls), there was no significant relationship between the -243A>G SNP and obesity (odds ratio (OR) = 0.99, 95% CI 0.83 - 1.18,in the pooled sample). These negative findings were reinforced by a meta-analysis for the association between the 243G allele and class III obesity, which yielded an OR of 1.11 (95% CI 0.90 - 1.36) in a total sample of 1,252 class III obese cases and 1,800 lean controls. Finally,we were unable to confirm or extend the functional data pertaining to the -243A>G variant. Potential confounding variables in association studies involving common variants and complex diseases (low power to detect modest genetic effects, over-interpretation of marginal data, population stratification and biological plausibility) are also discussed in the context of GAD2 and

  17. GABA metabolism pathway genes, UGA1 and GAD1, regulate replicative lifespan in Saccharomycescerevisiae

    SciTech Connect

    Kamei, Yuka; Tamura, Takayuki; Yoshida, Ryo; Ohta, Shinji; Fukusaki, Eiichiro; Mukai, Yukio

    2011-04-01

    Highlights: {yields}We demonstrate that two genes in the yeast GABA metabolism pathway affect aging. {yields} Deletion of the UGA1 or GAD1 genes extends replicative lifespan. {yields} Addition of GABA to wild-type cultures has no effect on lifespan. {yields} Intracellular GABA levels do not differ in longevity mutants and wild-type cells. {yields} Levels of tricarboxylic acid cycle intermediates positively correlate with lifespan. -- Abstract: Many of the genes involved in aging have been identified in organisms ranging from yeast to human. Our previous study showed that deletion of the UGA3 gene-which encodes a zinc-finger transcription factor necessary for {gamma}-aminobutyric acid (GABA)-dependent induction of the UGA1 (GABA aminotransferase), UGA2 (succinate semialdehyde dehydrogenase), and UGA4 (GABA permease) genes-extends replicative lifespan in the budding yeast Saccharomycescerevisiae. Here, we found that deletion of UGA1 lengthened the lifespan, as did deletion of UGA3; in contrast, strains with UGA2 or UGA4 deletions exhibited no lifespan extension. The {Delta}uga1 strain cannot deaminate GABA to succinate semialdehyde. Deletion of GAD1, which encodes the glutamate decarboxylase that converts glutamate into GABA, also increased lifespan. Therefore, two genes in the GABA metabolism pathway, UGA1 and GAD1, were identified as aging genes. Unexpectedly, intracellular GABA levels in mutant cells (except for {Delta}uga2 cells) did not differ from those in wild-type cells. Addition of GABA to culture media, which induces transcription of the UGA structural genes, had no effect on replicative lifespan of wild-type cells. Multivariate analysis of {sup 1}H nuclear magnetic resonance spectra for the whole-cell metabolite levels demonstrated a separation between long-lived and normal-lived strains. Gas chromatography-mass spectrometry analysis of identified metabolites showed that levels of tricarboxylic acid cycle intermediates positively correlated with lifespan

  18. HSV vector-mediated GAD67 suppresses neuropathic pain induced by perineural HIV gp120 in rats through inhibition of ROS and Wnt5a

    PubMed Central

    Kanda, Hirotsugu; Kanao, Megumi; Liu, Shue; Yi, Hyun; Iida, Takafumi; Levitt, Roy C; Candiotti, Keith A; Lubarsky, David A; Hao, Shuanglin

    2016-01-01

    Human immunodeficiency virus (HIV)-related neuropathic pain is a debilitating chronic condition that is severe and unrelenting. Despite the extensive research, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments. Loss of GABAergic tone may play an important role in the neuropathic pain state. Glutamic acid decarboxylase 67 (GAD67) is one of isoforms that catalyze GABA synthesis. Here, we used recombinant herpes simplex virus (HSV-1) vectors that encode gad1 gene to evaluate the therapeutic potential of GAD67 in peripheral HIV gp120-induced neuropathic pain in rats. We found that 1) subcutaneous inoculation of the HSV vectors expressing GAD67 attenuated mechanical allodynia in the model of HIV gp120-induced neuropathic pain, 2) the anti-allodynic effect of GAD67 was reduced by GABA-A and-B receptors antagonists, 3) HSV vectors expressing GAD67 reversed the lowered GABA-IR expression, and 4) the HSV vectors expressing GAD67 suppressed the upregulated mitochondrial superoxide and Wnt5a in the spinal dorsal horn. Taken together, our studies support the concept that recovering GABAergic tone by the HSV vectors may reverse HIV-associated neuropathic pain through suppressing mitochondrial superoxide and Wnt5a. Our studies provide validation of HSV-mediated GAD67 gene therapy in the treatment of HIV-related neuropathic pain. PMID:26752351

  19. HSV vector-mediated GAD67 suppresses neuropathic pain induced by perineural HIV gp120 in rats through inhibition of ROS and Wnt5a.

    PubMed

    Kanda, H; Kanao, M; Liu, S; Yi, H; Iida, T; Levitt, R C; Candiotti, K A; Lubarsky, D A; Hao, S

    2016-04-01

    Human immunodeficiency virus (HIV)-related neuropathic pain is a debilitating chronic condition that is severe and unrelenting. Despite the extensive research, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments. Loss of GABAergic tone may have an important role in the neuropathic pain state. Glutamic acid decarboxylase 67 (GAD67) is one of the isoforms that catalyze GABA synthesis. Here, we used recombinant herpes simplex virus (HSV-1) vectors that encode gad1 gene to evaluate the therapeutic potential of GAD67 in peripheral HIV gp120-induced neuropathic pain in rats. We found that (1) subcutaneous inoculation of the HSV vectors expressing GAD67 attenuated mechanical allodynia in the model of HIV gp120-induced neuropathic pain, (2) the anti-allodynic effect of GAD67 was reduced by GABA-A and-B receptors antagonists, (3) HSV vectors expressing GAD67 reversed the lowered GABA-IR expression and (4) the HSV vectors expressing GAD67 suppressed the upregulated mitochondrial superoxide and Wnt5a in the spinal dorsal horn. Taken together, our studies support the concept that recovering GABAergic tone by the HSV vectors may reverse HIV-associated neuropathic pain through suppressing mitochondrial superoxide and Wnt5a. Our studies provide validation of HSV-mediated GAD67 gene therapy in the treatment of HIV-related neuropathic pain.

  20. Mapping of the gracile axonal dystrophy (gad) gene to a region between D5Mit197 and D5Mit113 on proximal mouse chromosome 5

    SciTech Connect

    Suh, J.G.; Yamanishi, T.; Matsui, K.

    1995-06-10

    The gracile axonal dystrophy (gad) mouse, which shows hereditary sensory ataxia and motor paresis, has been morphologically characterized by the dying back type of axonal degeneration in the nerve terminals of dorsal root ganglion cells and motor neurons. In the present study, using an intraspecific backcross between gad and C57BL/6J mice, the gracile axonal dystrophy (gad) gene was mapped to a region between D5Mit197 and D5Mit113. Estimated distances between gad and D5Mit197 and between gad and D5Mit113 are 0.4 {plus_minus} 0.3 and 5.0 {plus_minus} 1.0 cM, respectively. The gene order was defined: centromere-D5Mit81-D5Mit233-D5Mit184/D5Mit254-D5Mit256-D5Mit197-gad-D5Mit113-D5Mit7. The mouse map location of the gad locus appears to be in a region homologous to human 4p15-p16. Our present data suggest that the nearest flanking marker D5Mit197 provides a useful anchor for the isolation of the gad gene in a yeast artificial chromosome contig. 19 refs., 2 figs.

  1. A unique combination of autoimmune limbic encephalitis, type 1 diabetes, and Stiff person syndrome associated with GAD-65 antibody.

    PubMed

    Sharma, Chandra Mohan; Pandey, Rajendra Kumar; Kumawat, Banshi Lal; Khandelwal, Dinesh; Gandhi, Pankaj

    2016-01-01

    Antibodies to GAD-65 have been implicated in the pathogenesis of type 1 diabetes, limbic encephalitis and Stiff person syndrome, however these diseases rarely occur concurrently. We intend to present a rare case of 35 year old female who was recently diagnosed as having type 1 diabetes presented with 1½ month history of recurrent seizures, subacute onset gait ataxia, dysathria, psychiatric disturbance and cognitive decline. No tumor was found on imaging and the classic paraneoplastic panel was negative. Cerebrospinal fluid and blood was positive for GAD-65 antibodies. Patient showed significant improvement with immunomodulatory therapy. Association of GAD-65 antibodies has been found with various disorders including type 1 diabetes, limbic encephalitis, Stiff person syndrome, cerebellar ataxia and palatal myoclonus. This case presents with unique combination of type 1 diabetes, Stiff person syndrome and limbic encephalitis associated with GAD-65 antibodies that is responsive to immunotherapy. It also highlights the emerging concept of autoimmunity in the causation of various disorders and there associations.

  2. Co-Occurring ODD and GAD Symptom Groups: Source-Specific Syndromes and Cross-Informant Comorbidity

    ERIC Educational Resources Information Center

    Drabick, Deborah A. G.; Gadow, Kenneth D.; Loney, Jan

    2008-01-01

    Despite important clinical and nosological implications, the comorbidity of oppositional defiant disorder (ODD) and generalized anxiety disorder (GAD) has received little attention. A clinic-based sample of 243 boys (ages 6-10 years), their parents, and teachers participated in an evaluation that involved assessments of behavioral, academic, and…

  3. Co-Occurring ODD and GAD Symptom Groups: Source-Specific Syndromes and Cross-Informant Comorbidity

    ERIC Educational Resources Information Center

    Drabick, Deborah A. G.; Gadow, Kenneth D.; Loney, Jan

    2008-01-01

    Despite important clinical and nosological implications, the comorbidity of oppositional defiant disorder (ODD) and generalized anxiety disorder (GAD) has received little attention. A clinic-based sample of 243 boys (ages 6-10 years), their parents, and teachers participated in an evaluation that involved assessments of behavioral, academic, and…

  4. Chronic social subordination stress modulates glutamic acid decarboxylase (GAD) 67 mRNA expression in central stress circuits

    PubMed Central

    Makinson, Ryan; Lundgren, Kerstin H.; Seroogy, Kim B.; Herman, James P.

    2015-01-01

    Chronic social subordination is a well-known precipitant of numerous psychiatric and physiological health concerns. In this study, we examine the effects of chronic social stress in the visible burrow system (VBS) on the expression of glutamic acid decarboxylase (GAD) 67 and brain-derived neurotropic factor (BDNF) mRNA in forebrain stress circuitry. Male rats in the VBS system form a dominance hierarchy, whereby subordinate males exhibit neuroendocrine and physiological profiles characteristic of chronic exposure to stress. We found that social subordination decreases GAD67 mRNA in the peri-paraventricular nucleus region of the hypothalamus and the interfascicular nucleus of the bed nucleus of the stria terminalis (BNST), and increases in GAD67 mRNA in the hippocampus, medial prefrontal cortex, and dorsal medial hypothalamus. Expression of BDNF mRNA increased in the dorsal region of the BNST, but remained unchanged in all other regions examined. Results from this study indicate that social subordination is associated with several region-specific alterations in GAD67 mRNA expression in central stress circuits, whereas changes in the expression of BDNF mRNA are limited to the BNST. PMID:26066725

  5. Validity of the GAD-7 scale as an outcome measure of disability in patients with generalized anxiety disorders in primary care.

    PubMed

    Ruiz, Miguel A; Zamorano, Enric; García-Campayo, Javier; Pardo, Antonio; Freire, Olga; Rejas, Javier

    2011-02-01

    To explore the validity of the GAD-7 scale as an outcome measure of disability in primary care. A random sample of 212 subjects was recruited in primary care clinics; 50% diagnosed with generalized anxiety disorder (GAD) by DSM-IV criteria and 50% concurrent matched controls. The GAD-7, the Hamilton Anxiety Scale (HAM-A), and the abridged 12-item version of World Health Organization Disability Scale (WHO-DAS-II) were administered. The number of visits to primary care and specialty clinics was also recorded. Strong and significant (p<0.001) correlations were found between GAD-7 and HAM-A (r=0.852) and WHO-DAS-II (r=0.704) scores, particularly for Participation in Society (r=0.741), Understanding and Communication (r=0.679), and Life Activities (0.638) dimensions. Moderate but significant correlations were also found between GAD-7 score and the number of visits to Primary Care (r=0.393) and Specialty clinics (r=0.373). In all cases, an overall relation was observed between GAD-7 severity levels and disability scores [F (3,208)=25.4, p<0.001] as assessed by the WHO-DAS II, with higher mean disability values related to higher severity levels. The GAD-7 scale has been shown to highly correlate not only with specific anxiety but also with disability measures. It has been shown that more severe GAD levels correlate with higher disability states and tend to demand more health care attention. As the GAD-7 is self-administered and is not time consuming, this instrument could be a good choice to explore the level of patient disability in subjects with GAD in primary care settings. © 2010 Elsevier B.V. All rights reserved.

  6. Effects of Increase in Amplitude of Occipital Alpha & Theta Brain Waves on Global Functioning Level of Patients with GAD.

    PubMed

    Dadashi, Mohsen; Birashk, Behrooz; Taremian, Farhad; Asgarnejad, Ali Asghar; Momtazi, Saeed

    2015-01-01

    The basic objective of this study is to investigate the effects of alpha and theta brain waves amplitude increase in occipital area on reducing the severity of symptoms of generalized anxiety disorder and to increase the global functioning level in patients with GAD. This study is a quasi-experimental study with pre-test and post-test with two groups. For this purpose, 28 patients who had been referred to Sohrawardi psychiatric and clinical psychology center in Zanjan were studied based on the interview with the psychiatrist, clinical psychologist and using clinical diagnostic criteria for the Diagnostic and Statistical Manual of Mental Disorders text revision - the DSM-IV-TR Fourth Edition diagnosis of GAD, 14 subjects were studied in neurofeedback treatment group and 14 subjects in the waiting list group. Patients in both groups were evaluated at pre-test and post-test with General Anxiety Disorder Scale (GAD-7) and Global Assessment Functioning Scale (GAFs). The treatment group received fifteen 30-minute alpha training sessions and fifteen 30-minute theta brain training sessions in occipital area by neurofeedback training (treatment group). This evaluation was performed according to the treatment protocol to increase the alpha and theta waves. And no intervention was done in the waiting list group. But due to ethical issues after the completion of the study all the subjects in the waiting list group were treated. The results showed that increase of alpha and theta brain waves amplitude in occipital area in people with GAD can increase the global functioning level and can reduce symptoms of generalized anxiety disorder in a treatment group, but no such change was observed in the waiting list group. Increase of alpha and theta brain waves amplitude in occipital area can be useful in the treatment of people with GAD.

  7. Effects of Increase in Amplitude of Occipital Alpha & Theta Brain Waves on Global Functioning Level of Patients with GAD

    PubMed Central

    Dadashi, Mohsen; Birashk, Behrooz; Taremian, Farhad; Asgarnejad, Ali Asghar; Momtazi, Saeed

    2015-01-01

    Introduction: The basic objective of this study is to investigate the effects of alpha and theta brain waves amplitude increase in occipital area on reducing the severity of symptoms of generalized anxiety disorder and to increase the global functioning level in patients with GAD. Methods: This study is a quasi-experimental study with pre-test and post-test with two groups. For this purpose, 28 patients who had been referred to Sohrawardi psychiatric and clinical psychology center in Zanjan were studied based on the interview with the psychiatrist, clinical psychologist and using clinical diagnostic criteria for the Diagnostic and Statistical Manual of Mental Disorders text revision - the DSM-IV-TR Fourth Edition diagnosis of GAD, 14 subjects were studied in neurofeedback treatment group and 14 subjects in the waiting list group. Patients in both groups were evaluated at pre-test and post-test with General Anxiety Disorder Scale (GAD-7) and Global Assessment Functioning Scale (GAFs). The treatment group received fifteen 30-minute alpha training sessions and fifteen 30-minute theta brain training sessions in occipital area by neurofeedback training (treatment group). This evaluation was performed according to the treatment protocol to increase the alpha and theta waves. And no intervention was done in the waiting list group. But due to ethical issues after the completion of the study all the subjects in the waiting list group were treated. Results: The results showed that increase of alpha and theta brain waves amplitude in occipital area in people with GAD can increase the global functioning level and can reduce symptoms of generalized anxiety disorder in a treatment group, but no such change was observed in the waiting list group. Discussion: Increase of alpha and theta brain waves amplitude in occipital area can be useful in the treatment of people with GAD. PMID:27504152

  8. N(6)-(3-methoxyl-4-hydroxybenzyl) adenine riboside induces sedative and hypnotic effects via GAD enzyme activation in mice.

    PubMed

    Shi, Y; Dong, J W; Tang, L N; Kang, R X; Shi, J G; Zhang, J J

    2014-11-01

    N(6)-(3-methoxyl-4-hydroxybenzyl) adenine riboside (B2) is an analog of N(6)-(4-hydroxybenzyl) adenine riboside (NHBA), which was originally isolated from Gastrodia elata Blume. Our laboratory has previously demonstrated that B2 can produce strong sedative and hypnotic effects, but the mechanism remains to be determined. There is evidence that gamma-aminobutyric acid (GABA) acts as an inhibitory neurotransmitter in the brain, plays a major role in sleep regulation, and participates in the sedative and hypnotic effects of B2. Therefore, we studied the interactions between B2 and several GABAergic neurochemical parameters based on the sedative and hypnotic effects of B2. The GABA and glutamic acid (Glu) in the mouse brain were derivatized with o-phthalaldehyde (OPA) and measured by high performance liquid chromatography-electrochemical detection (HPLC-ECD). The GAD and GABA-T enzyme activities were determined by measuring GABA and NADH production, respectively. The sleep structure analyses were performed by EEG studies in mice. B2 increased the GABA levels and GAD enzyme activity in the mouse hypothalamus and cortex. The EEG results confirmed that B2 significantly shortened the sleep latency and increased the amount of NREM sleep. The GAD enzyme inhibitor semicarbazide (SCZ) blocked the sedative and hypnotic effects of B2. These findings suggest that the GAD enzyme plays a significant role in the sedative and hypnotic effects of B2. Therefore B2 may be a promising candidate for further clinical studies and the appropriate use of GAD agonist may be a promising approach for sleep disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. MDMA decreases glutamic acid decarboxylase (GAD) 67-immunoreactive neurons in the hippocampus and increases seizure susceptibility: Role for glutamate.

    PubMed

    Huff, Courtney L; Morano, Rachel L; Herman, James P; Yamamoto, Bryan K; Gudelsky, Gary A

    2016-12-01

    3,4-Methylenedioxy-methamphetamine (MDMA) is a unique psychostimulant that continues to be a popular drug of abuse. It has been well documented that MDMA reduces markers of 5-HT axon terminals in rodents, as well as humans. A loss of parvalbumin-immunoreactive (IR) interneurons in the hippocampus following MDMA treatment has only been documented recently. In the present study, we tested the hypothesis that MDMA reduces glutamic acid decarboxylase (GAD) 67-IR, another biochemical marker of GABA neurons, in the hippocampus and that this reduction in GAD67-IR neurons and an accompanying increase in seizure susceptibility involve glutamate receptor activation. Repeated exposure to MDMA (3×10mg/kg, ip) resulted in a reduction of 37-58% of GAD67-IR cells in the dentate gyrus (DG), CA1, and CA3 regions, as well as an increased susceptibility to kainic acid-induced seizures, both of which persisted for at least 30days following MDMA treatment. Administration of the NMDA antagonist MK-801 or the glutamate transporter type 1 (GLT-1) inducer ceftriaxone prevented both the MDMA-induced loss of GAD67-IR neurons and the increased vulnerability to kainic acid-induced seizures. The MDMA-induced increase in the extracellular concentration of glutamate in the hippocampus was significantly diminished in rats treated with ceftriaxone, thereby implicating a glutamatergic mechanism in the neuroprotective effects of ceftriaxone. In summary, the present findings support a role for increased extracellular glutamate and NMDA receptor activation in the MDMA-induced loss of hippocampal GAD67-IR neurons and the subsequent increased susceptibility to evoked seizures.

  10. Ultra-short screening instruments for major depressive episode and generalized anxiety disorder in epilepsy: The NDDIE-2 and the GAD-SI.

    PubMed

    Micoulaud-Franchi, Jean-Arthur; Bartolomei, Fabrice; McGonigal, Aileen

    2017-03-01

    Systematic screening is recommended for major depressive episode (MDE) with the Neurological Disorders Depression Inventory for Epilepsy NDDI-E, 6 items and generalized anxiety disorder (GAD) with the GAD 7 items in patients with epilepsy (PWE). Shorter versions of the NDDI-E and the GAD-7 could facilitate increased screening by busy clinicians and be more accessible to patients with mild cognitive and/or language impairments. The effectiveness of ultra-short versions of the NDDI-E (2 items) and the GAD-7 (the GAD-2, 2 items, and the GAD-SI with a single item) in comparison with the original versions were statistically tested using ROC analysis. ROC analysis of the NDDIE-2 showed an AUC of 0.926 (p<0.001), a sensitivity of 81.82% and a specificity of 89.16%, without significant difference with the NDDI-E (z=1.582, p=0.11). ROC analysis of the GAD-SI showed an AUC of 0.872 (p<0.001), a sensitivity of 83.67% and a specificity of 82.29%, without significant difference with the GAD-7 (z=1.281, p=0.2). The GAD-2 showed poorer psychometric properties. The limitation is the use of data from previously reported subjects in a single language version, the NDDIE-2 that lacks detection of dysphoric symptoms in comparison with the NDDIE-6 and the GAD-SI that exhibited a more than 10% lower sensitivity than the GAD-7. This study highlights the potential utility of the NDDIE-2 and the GAD-SI as ultra-short screening tools for MDE and GAD respectively in PWE. Further studies in a larger population, including multi-lingual versions, could be a valuable next step. However, the brevity and simplicity of this tool could be an advantage in PWE who present cognitive difficulties, especially attentional or language deficits. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Activity-Dependent Bidirectional Regulation of GAD Expression in a Homeostatic Fashion Is Mediated by BDNF-Dependent and Independent Pathways.

    PubMed

    Hanno-Iijima, Yoko; Tanaka, Masami; Iijima, Takatoshi

    2015-01-01

    Homeostatic synaptic plasticity, or synaptic scaling, is a mechanism that tunes neuronal transmission to compensate for prolonged, excessive changes in neuronal activity. Both excitatory and inhibitory neurons undergo homeostatic changes based on synaptic transmission strength, which could effectively contribute to a fine-tuning of circuit activity. However, gene regulation that underlies homeostatic synaptic plasticity in GABAergic (GABA, gamma aminobutyric) neurons is still poorly understood. The present study demonstrated activity-dependent dynamic scaling in which NMDA-R (N-methyl-D-aspartic acid receptor) activity regulated the expression of GABA synthetic enzymes: glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67). Results revealed that activity-regulated BDNF (brain-derived neurotrophic factor) release is necessary, but not sufficient, for activity-dependent up-scaling of these GAD isoforms. Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF-independent pathways, both triggered by NMDA-R activity. Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF. In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion. Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses.

  12. Activity-Dependent Bidirectional Regulation of GAD Expression in a Homeostatic Fashion Is Mediated by BDNF-Dependent and Independent Pathways

    PubMed Central

    Hanno-Iijima, Yoko; Tanaka, Masami; Iijima, Takatoshi

    2015-01-01

    Homeostatic synaptic plasticity, or synaptic scaling, is a mechanism that tunes neuronal transmission to compensate for prolonged, excessive changes in neuronal activity. Both excitatory and inhibitory neurons undergo homeostatic changes based on synaptic transmission strength, which could effectively contribute to a fine-tuning of circuit activity. However, gene regulation that underlies homeostatic synaptic plasticity in GABAergic (GABA, gamma aminobutyric) neurons is still poorly understood. The present study demonstrated activity-dependent dynamic scaling in which NMDA-R (N-methyl-D-aspartic acid receptor) activity regulated the expression of GABA synthetic enzymes: glutamic acid decarboxylase 65 and 67 (GAD65 and GAD67). Results revealed that activity-regulated BDNF (brain-derived neurotrophic factor) release is necessary, but not sufficient, for activity-dependent up-scaling of these GAD isoforms. Bidirectional forms of activity-dependent GAD expression require both BDNF-dependent and BDNF-independent pathways, both triggered by NMDA-R activity. Additional results indicated that these two GAD genes differ in their responsiveness to chronic changes in neuronal activity, which could be partially caused by differential dependence on BDNF. In parallel to activity-dependent bidirectional scaling in GAD expression, the present study further observed that a chronic change in neuronal activity leads to an alteration in neurotransmitter release from GABAergic neurons in a homeostatic, bidirectional fashion. Therefore, the differential expression of GAD65 and 67 during prolonged changes in neuronal activity may be implicated in some aspects of bidirectional homeostatic plasticity within mature GABAergic presynapses. PMID:26241953

  13. Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain

    PubMed Central

    1992-01-01

    Pancreatic beta-cells and gamma-aminobutyric acid (GABA)-secreting neurons both express the enzyme glutamic acid decarboxylase (GAD) which is a major target of autoantibodies associated with beta-cell destruction and impairment of GABA-ergic neurotransmitter pathways. The predominant form of GAD in pancreatic beta-cells, GAD65, is synthesized as a soluble hydrophilic molecule, which is modified to become firmly membrane anchored. Here we show by immunogold electron microscopy that GAD65 is localized to the membrane of small vesicles which are identical in size to small synaptic-like microvesicles in pancreatic beta-cells. The NH2-terminal domain of GAD65 is the site of a two-step modification, the last of which results in a firm membrane anchoring that involves posttranslational hydroxylamine sensitive palmitoylation. GAD65 can be released from the membrane by an apparent enzyme activity in islets, suggesting that the membrane anchoring step is reversible and potentially regulated. The hydrophobic modifications and consequent membrane anchoring of GAD65 to microvesicles that store its product GABA may be of functional importance and, moreover, significant for its selective role as an autoantigen. PMID:1321158

  14. The assessment of generalized anxiety disorder: psychometric validation of the Spanish version of the self-administered GAD-2 scale in daily medical practice

    PubMed Central

    2012-01-01

    Aim To psychometrically validate the Spanish version of the self-administered 2-item GAD-2 scale for screening probable patients with generalised anxiety disorder (GAD). Methods The GAD-2 was self-administered by patients diagnosed with GAD according to DSM-IV criteria and by age- and sex-matched controls who were recruited at random in mental health and primary care centres. Criteria validity was explored using ROC curve analysis, and sensitivity, specificity and positive and negative predictive values were determined for different cut-off values. Concurrent validity was also established using the HAM-A, HADS, and WHODAS II scales. Results The study sample consisted of 212 subjects (106 patients with GAD) with a mean age of 50.38 years (SD = 16.76). No items of the scale were left blank. Floor and ceiling effects were negligible. No patients with GAD had to be assisted to complete the questionnaire. Reliability (internal consistency) was high; Cronbach’s α = 0.875. A cut-off point of 3 showed adequate sensitivity (91.5%) and specificity (85.8%), with a statistically significant area under the curve (AUC = 0.937, p < 0.001), to distinguish GAD patients from controls. Concurrent validity was also high and significant with HAM-A (0.806, p < 0.001), HADS (anxiety domain, 0.825, p < 0.001) and WHO-DAS II (0.642, p < 0.001) scales. Conclusion The Spanish version of the GAD-2 scale has been shown to have appropriate psychometric properties to rapidly detect probable cases of GAD in the Spanish cultural context under routine clinical practice conditions. PMID:22992432

  15. The assessment of generalized anxiety disorder: psychometric validation of the Spanish version of the self-administered GAD-2 scale in daily medical practice.

    PubMed

    García-Campayo, Javier; Zamorano, Enric; Ruiz, Miguel A; Pérez-Páramo, María; López-Gómez, Vanessa; Rejas, Javier

    2012-09-19

    To psychometrically validate the Spanish version of the self-administered 2-item GAD-2 scale for screening probable patients with generalised anxiety disorder (GAD). The GAD-2 was self-administered by patients diagnosed with GAD according to DSM-IV criteria and by age- and sex-matched controls who were recruited at random in mental health and primary care centres. Criteria validity was explored using ROC curve analysis, and sensitivity, specificity and positive and negative predictive values were determined for different cut-off values. Concurrent validity was also established using the HAM-A, HADS, and WHODAS II scales. The study sample consisted of 212 subjects (106 patients with GAD) with a mean age of 50.38 years (SD = 16.76). No items of the scale were left blank. Floor and ceiling effects were negligible. No patients with GAD had to be assisted to complete the questionnaire. Reliability (internal consistency) was high; Cronbach's α = 0.875. A cut-off point of 3 showed adequate sensitivity (91.5%) and specificity (85.8%), with a statistically significant area under the curve (AUC = 0.937, p < 0.001), to distinguish GAD patients from controls. Concurrent validity was also high and significant with HAM-A (0.806, p < 0.001), HADS (anxiety domain, 0.825, p < 0.001) and WHO-DAS II (0.642, p < 0.001) scales. The Spanish version of the GAD-2 scale has been shown to have appropriate psychometric properties to rapidly detect probable cases of GAD in the Spanish cultural context under routine clinical practice conditions.

  16. Glutamic acid decarboxylase (anti-GAD) & tissue transglutaminase (anti-TTG) antibodies in patients with thyroid autoimmunity

    PubMed Central

    Marwaha, R.K.; Garg, M.K.; Tandon, N.; Kanwar, Ratnesh; Narang, A.; Sastry, A.; Saberwal, A.; Bhadra, Kuntal

    2013-01-01

    Background & objectives: Several autoimmune disorders have been reported to be associated with autoimmune thyroiditis and may coexist with other organ-specific autoantibodies. The aim of the present study was to evaluate the presence of tissue transglutaminase (anti-TTG) and glutamic acid decarboxylase (anti-GAD) antibodies in patients suffering from autoimmune thyroiditis as diagnosed by anti-thyroid peroxidase (anti-TPO) antibodies, which may indicate high risk for developing celiac disease or type 1 diabetes mellitus. Methods: Five thousand children and 2800 adults were screening as part of a general health examination done on a voluntary basis in four different parts of Delhi. A total of 577 subjects positive for anti-TPO antibody constituted the cases. Equal number of age and sex matched anti-TPO antibody negative controls were randomly selected from the same cohort to form paired case control study. The cases and controls were further divided into two groups as follows: group-1 (children and adolescent <18 yr), group-2 (adults >18 yr). Serum samples of cases and controls were analysed for thyroid function test (FT3, FT4, and TSH), anti-TTG and anti-GAD antibodies. Results: A total of 1154 subjects (577 cases and 577 controls) were included in this study. Hypothyroidism was present in 40.2 per cent (232) cases compared to only 4.7 per cent (27) in controls (P<0.001). Anti-TTG and anti-GAD antibodies were present in 6.9 and 12.5 per cent subjects among cases compared to 3.5 per cent (P=0.015) and 4.3 per cent (P=0.001) in controls, respectively. Only anti-GAD antibody were significantly positive in cases among children and adolescents (P =0.0044) and adult (P=0.001) compared to controls. Levels of anti-TTG and anti-GAD antibodies increased with increasing titre of anti-TPO antibody. Interpretation & conclusions: Our findings showed high positivity of anti-GAD and anti-TTG antibodies among subjects with thyroid autoimmunity. It is, therefore, important to have

  17. Evaluation of the interaction between genetic variants of GAD1 and miRNA in bipolar disorders.

    PubMed

    Chung, Yu-Chu Ella; Chen, Shao-Chien; Chuang, Li-Chung; Shih, Wei-Liang; Chiu, Yi-Hang; Lu, Mong-Liang; Chen, Hsi-Chung; Kuo, Po-Hsiu

    2017-12-01

    Glutamic acid dehydrogenase 1 (GAD1) serves as the rate-limiting enzyme for synthesizing GABA, and is reported to be associated with several psychiatric disorders. The present study examined the effects of GAD1 genetic variants on bipolar disorder (BD) and its subtypes. Moreover, we investigated functional interactions between genetic variants and miRNAs via algorithm prediction and experimental validation. A case-control study was conducted with 280 BD patients and 200 healthy controls. Eight tag SNPs in GAD1 were genotyped. For associated markers, we performed in silico prediction for their potential functions through SNP-miRNA interactions by establishing a scoring system to combine information from several miRNA predictive algorithms. We then tested allelic expression differences using Dual-Glo luciferase reporter assays for the selected SNP-miRNA pair. Lastly, we examined the associations of the GAD1 gene and BD in two additional independent datasets with a few thousand samples for replication. Marker rs3749034 was associated with BD, in particular the BD-II subtype. According to our scoring system, several candidate miRNAs were predicted to interact with rs3749034, and hsa-miR-504 had the highest score. Findings from an in vitro experiment revealed a non-statistically significant trend for lower gene expression level with the A allele of rs3749034 compared with the G allele. The association between rs3749034 and BD was not replicated in either of the independent datasets. Instead, other rarer genetic variants in GAD1 showed suggestive signals (e.g. rs575441409, p-value = 3.8*10(-4), D' = 1 with rs3749034) with BD in the Taiwanese dataset. The present study considered common genetic variants only. In addition, we only used a 293T cell-line in conducting luciferase reporter assays, as no primary cell-lines from patient samples were available to differentiate the effects between BD subtypes. Our results demonstrate a weak effect of the GAD1 gene on the risk of

  18. Status spasticus and psoas muscle edema due to anti-GAD antibody associated stiff-man syndrome.

    PubMed

    Maramattom, Boby Varkey

    2015-08-01

    Severe muscle rigidity and spasms are uncommon causes of Intensive Care Unit (ICU) admissions. Stiff-man syndrome (SMS) is a rare disorder characterized by continuous muscle spasms, axial muscle rigidity, "tin soldier gait," and continuous motor unit activity on electromyography. There are three clinical variants of SMS; stiff-limb syndrome, classical SMS, and paraneoplastic encephalomyelitis with rigidity and myoclonus. Three types of antibodies have been associated with SMS; however, anti-glutamic acid decarboxylase (GAD) antibodies are the most frequent and are seen in the idiopathic type of SMS. The spasms of SMS can be very disabling and severe enough to cause muscle ruptures and skeletal fractures. We present a case of anti-GAD positive SMS with "status spasticus" causing bilateral psoas myoedema and rhabdomyolysis due to repeated axial muscle jerking in a 64-year-old man and discuss the differential diagnosis of a "jerking patient in the ICU."

  19. Fear of recurrence: a case report of a woman breast cancer survivor with GAD treated successfully by CBT.

    PubMed

    Montel, Sébastien

    2010-01-01

    General anxiety disorder (GAD) characterized by persistent, excessive and unrealistic worry about everyday things can affect everybody, including cancer patient survivor.In this paper, we present a case report of a breast cancer survivor with GAD treated by cognitive-behavioural therapy (CBT), who was excessively worried about recurrence of the disease 2 years after the end of any treatment. Cognitive reframing, associated to behavioural exposure and relaxation, were used in order to treat this woman. We describe precisely how the therapy was conducted. Results showed a substantial improvement of the fear of recurrence which 'naturally' extended to other stressful situations not worked during the therapy. Actually, these results are encouraging since it showed that CBT can be efficient in complicated situation involving survivor of a serious disease like cancer who additionally suffers from an anxiety disorder. It also underlines how it is important to be concerned by the distress of cancer survivors.

  20. Parvalbumin and GAD65 interneuron inhibition in the ventral hippocampus induces distinct behavioral deficits relevant to schizophrenia.

    PubMed

    Nguyen, Robin; Morrissey, Mark D; Mahadevan, Vivek; Cajanding, Janine D; Woodin, Melanie A; Yeomans, John S; Takehara-Nishiuchi, Kaori; Kim, Jun Chul

    2014-11-05

    Hyperactivity within the ventral hippocampus (vHPC) has been linked to both psychosis in humans and behavioral deficits in animal models of schizophrenia. A local decrease in GABA-mediated inhibition, particularly involving parvalbumin (PV)-expressing GABA neurons, has been proposed as a key mechanism underlying this hyperactive state. However, direct evidence is lacking for a causal role of vHPC GABA neurons in behaviors associated with schizophrenia. Here, we probed the behavioral function of two different but overlapping populations of vHPC GABA neurons that express either PV or GAD65 by selectively inhibiting these neurons with the pharmacogenetic neuromodulator hM4D. We show that acute inhibition of vHPC GABA neurons in adult mice results in behavioral changes relevant to schizophrenia. Inhibiting either PV or GAD65 neurons produced distinct behavioral deficits. Inhibition of PV neurons, affecting ∼80% of the PV neuron population, robustly impaired prepulse inhibition of the acoustic startle reflex (PPI), startle reactivity, and spontaneous alternation, but did not affect locomotor activity. In contrast, inhibiting a heterogeneous population of GAD65 neurons, affecting ∼40% of PV neurons and 65% of cholecystokinin neurons, increased spontaneous and amphetamine-induced locomotor activity and reduced spontaneous alternation, but did not alter PPI. Inhibition of PV or GAD65 neurons also produced distinct changes in network oscillatory activity in the vHPC in vivo. Together, these findings establish a causal role for vHPC GABA neurons in controlling behaviors relevant to schizophrenia and suggest a functional dissociation between the GABAergic mechanisms involved in hippocampal modulation of sensorimotor processes.

  1. Increased GAD67 mRNA expression in cerebellar interneurons in autism: implications for Purkinje cell dysfunction.

    PubMed

    Yip, Jane; Soghomonian, Jean-Jacques; Blatt, Gene J

    2008-02-15

    It has been widely reported that in autism, the number of Purkinje cells (PCs) is decreased, and recently, decreased expression of glutamic acid decarboxylase 67 (GAD67) mRNA in Purkinje cells also has been observed. However, the autism literature has not addressed key GABAergic inputs into Purkinje cells. Inhibitory basket and stellate cell interneurons in the molecular layer of the cerebellar cortex provide direct key GABAergic input into Purkinje cells and could potently influence the output of Purkinje cells to deep cerebellar nuclei. We investigated the capacity for interneuronal synthesis of gamma-amino butyric acid (GABA) in both types of interneurons that innervate the remaining PCs in the posterolateral cerebellar hemisphere in autism. The level of GAD67 mRNA, one of the isoforms of the key synthesizing enzymes for GABA, was quantified at the single-cell level using in situ hybridization in brains of autistic and aged-matched controls. The National Institutes of Health imaging system showed that expression of GAD67 mRNA in basket cells was significantly up-regulated, by 28%, in eight autistic brains compared with that in eight control brains (mean +/- SEM pixels per cell, 1.03 +/- 0.05 versus 0.69 +/- 0.05, respectively; P < 0.0001 by independent t test). Stellate cells showed a trend toward a small increase in GAD67 mRNA levels, but this did not reach significance. The results suggest that basket cells likely provide increased GABAergic feed-forward inhibition to PCs in autism, directly affecting PC output to target neurons in the dentate nucleus and potentially disrupting its modulatory role in key motor and/or cognitive behaviors in autistic individuals.

  2. GAD1 Encodes a Secreted Peptide That Regulates Grain Number, Grain Length, and Awn Development in Rice Domestication[OPEN

    PubMed Central

    Hua, Lei; Zhao, Xinhui; Zhang, Weifeng; Liu, Fengxia; Fu, Yongcai; Cai, Hongwei; Sun, Xianyou; Gu, Ping; Xie, Daoxin

    2016-01-01

    Cultivated rice (Oryza sativa) was domesticated from wild rice (Oryza rufipogon), which typically displays fewer grains per panicle and longer grains than cultivated rice. In addition, wild rice has long awns, whereas cultivated rice has short awns or lacks them altogether. These changes represent critical events in rice domestication. Here, we identified a major gene, GRAIN NUMBER, GRAIN LENGTH AND AWN DEVELOPMENT1 (GAD1), that regulates those critical changes during rice domestication. GAD1 is located on chromosome 8 and is predicted to encode a small secretary signal peptide belonging to the EPIDERMAL PATTERNING FACTOR-LIKE family. A frame-shift insertion in gad1 destroyed the conserved cysteine residues of the peptide, resulting in a loss of function, and causing the increased number of grains per panicle, shorter grains, and awnless phenotype characteristic of cultivated rice. Our findings provide a useful paradigm for revealing functions of peptide signal molecules in plant development and helps elucidate the molecular basis of rice domestication. PMID:27634315

  3. The impact of pretrauma analogue GAD and posttraumatic emotional reactivity following exposure to the September 11 terrorist attacks: a longitudinal study.

    PubMed

    Farach, Frank J; Mennin, Douglas S; Smith, Rita L; Mandelbaum, Matthew

    2008-09-01

    The relation between analogue generalized anxiety disorder (GAD) assessed the day before the events of September 11, 2001 (9/11) and long-term outcome was examined in 44 young adults who were directly exposed the following day to the terrorist attacks in New York City. After controlling for high exposure to the attacks, preattack analogue GAD was associated with greater social and work disability, loss of psychosocial resources, anxiety and mood symptoms, and worry, but not symptoms of posttraumatic stress, assessed 12 months after 9/11. Fear and avoidance of emotions assessed 4 months after 9/11 statistically mediated the relation between preattack analogue GAD and social and work disability, loss of psychosocial support, mood and anxiety symptoms, and worry at 12-month follow-up. Avoidance of emotions 4 months after 9/11 also mediated the relation between preattack analogue GAD and posttraumatic stress symptoms 12 months after 9/11.

  4. High T cell responses to the glutamic acid decarboxylase (GAD) isoform 67 reflect a hyperimmune state that precedes the onset of insulin-dependent diabetes.

    PubMed

    Honeyman, M C; Stone, N; de Aizpurua, H; Rowley, M J; Harrison, L C

    1997-04-01

    Pancreatic islet beta-cell destruction leading to insulin-dependent diabetes mellitus (IDDM) is an autoimmune T cell-mediated process. Peripheral blood T cells, which proliferate to islet antigens such as glutamic acid decarboxylase (GAD), (pro)insulin or tyrosine phosphatase IA-2, can be detected in at-risk, first degree relatives of people with IDDM. However, cross-sectional studies cannot define the relationship between T cell responses and progression to IDDM. Longitudinal studies were therefore undertaken on 50 at-risk, first degree relatives tested at least yearly for up to 4 years, during which time five developed IDDM. Peripheral blood T cell responses to a GAD67(aa208-404)-glutathione-S-transferase (GST) fusion protein, GST, insulin and tetanus toxoid were measured, together with antibodies to islet cells, GAD, insulin and IA-2. High levels of antibodies to GAD or insulin were generally associated with low T cell responses to these antigens. Relatives who developed IDDM were characterized by high levels of antibodies to insulin and/or islet cells, and high T cell responses to GAD67-GST and tetanus, but not insulin, in the 24 months before clinical diagnosis. Cross-sectionally, T cell responses to GAD67(aa208-404)-GST and to full-length GAD65-GST were highly correlated (r=0.75, P<0.002). In conclusion, increased cellular immunity to the mid region of GAD67 was a marker of late pre-clinical IDDM, but appears to reflect a more general, transient state of cellular immune hyperresponsiveness.

  5. Prenatal exposure to bacterial endotoxin reduces the number of GAD67- and reelin-immunoreactive neurons in the hippocampus of rat offspring.

    PubMed

    Nouel, Dominique; Burt, Melissa; Zhang, Ying; Harvey, Louise; Boksa, Patricia

    2012-04-01

    Epidemiological studies implicate prenatal infection as a risk factor for the development of schizophrenia and autism. Subjects with schizophrenia and autism are reported to exhibit reduced levels of glutamic acid decarboxylase 67 (GAD67), a marker for GABA neurons, in various brain regions. Reduced levels of reelin, a secretory glycoprotein present in a subpopulation of GABA neurons, have also been found in these disorders. To test if prenatal infection can cause abnormalities in GAD67 and reelin in the brains of offspring, this study used a rat model of prenatal exposure to the bacterial endotoxin, lipopolysaccharide (LPS), and assessed numbers of GAD67-immunoreactive (GAD67+) and reelin-immunoreactive (reelin+) neurons in the hippocampus of offspring. In offspring at postnatal day 14 (PD14), GAD67+ cell counts were reduced in the dentate gyrus of the prenatal LPS group compared to prenatal saline controls, while at PD28, GAD67+ cells counts were reduced in the prenatal LPS group in both the dentate gyrus and the CA1. There was a decrease in the number of reelin+ cells in the prenatal LPS offspring compared to controls in the dentate gyrus at PD14. However using Western blotting, no significant effects of prenatal LPS on levels of GAD67 or reelin protein were observed in various brain regions at PD14. These findings support the idea that prenatal infection can cause reductions in postnatal expression of GAD67 and reelin, and in this way, possibly contribute to the pathophysiology of schizophrenia or autism. Copyright © 2011 Elsevier B.V. and ECNP. All rights reserved.

  6. Structural basis for differential recognition of tyrosine-phosphorylated sites in the linker for activation of T cells (LAT) by the adaptor Gads

    PubMed Central

    Cho, Sangwoo; Velikovsky, C Alejandro; Swaminathan, Chittoor P; Houtman, Jon C D; Samelson, Lawrence E; Mariuzza, Roy A

    2004-01-01

    The transmembrane protein, linker for activation of T cells (LAT), is essential for T-cell activation and development. Phosphorylation of LAT at multiple tyrosines creates binding sites for the adaptors Gads and Grb2, leading to nucleation of multiprotein signaling complexes. Human LAT contains five potential binding sites for Gads, of which only those at Tyr171 and Tyr191 appear necessary for T-cell function. We asked whether Gads binds preferentially to these sites, as differential recognition could assist in assembling defined LAT-based complexes. Measured calorimetrically, Gads-SH2 binds LAT tyrosine phosphorylation sites 171 and 191 with higher affinities than the other sites, with the differences ranging from only several fold weaker binding to no detectable interaction. Crystal structures of Gads-SH2 complexed with phosphopeptides representing sites 171, 191 and 226 were determined to 1.8−1.9 Å resolutions. The structures reveal the basis for preferential recognition of specific LAT sites by Gads, as well as for the relatively greater promiscuity of the related adaptor Grb2, whose binding also requires asparagine at position +2 C-terminal to the phosphorylated tyrosine. PMID:15029250

  7. GAD67-GFP+ Neurons in the Nucleus of Roller. II. Subthreshold and Firing Resonance Properties

    PubMed Central

    Berger, A. J.

    2011-01-01

    In the companion paper we show that GAD67-GFP+ (GFP+) inhibitory neurons located in the Nucleus of Roller of the mouse brain stem can be classified into two main groups (tonic and phasic) based on their firing patterns in responses to injected depolarizing current steps. In this study we examined the responses of GFP+ cells to fluctuating sinusoidal (“chirp”) current stimuli. Membrane impedance profiles in response to chirp stimulation showed that nearly all phasic cells exhibited subthreshold resonance, whereas the majority of tonic GFP+ cells were nonresonant. In general, subthreshold resonance was associated with a relatively fast passive membrane time constant and low input resistance. In response to suprathreshold chirp current stimulation at a holding potential just below spike threshold the majority of tonic GFP+ cells fired multiple action potentials per cycle at low input frequencies (<5 Hz) and either stopped firing or were not entrained by the chirp at higher input frequencies (= tonic low-pass cells). A smaller group of phasic GFP+ cells did not fire at low input frequency but were able to phase-lock 1:1 at intermediate chirp frequencies (= band-pass cells). Spike timing reliability was tested with repeated chirp stimuli and our results show that phasic cells were able to reliably fire when they phase-locked 1:1 over a relatively broad range of input frequencies. Most tonic low-pass cells showed low reliability and poor phase-locking ability. Computer modeling suggested that these different firing resonance properties among GFP+ cells are due to differences in passive and active membrane properties and spiking mechanisms. This heterogeneity of resonance properties might serve to selectively activate subgroups of interneurons. PMID:21047931

  8. Evaluation of GAD67 immunoreactivity in the region of substantia nigra pars reticulata in resistance to development of convulsive seizure in genetic absence epilepsy rats

    PubMed Central

    Gulcebi, Medine; Akman, Ozlem; Carcak, Nihan; Karamahmutoglu, Tugba; Onat, Filiz

    2016-01-01

    OBJECTIVE: Nonconvulsive absence epilepsy and convulsive epilepsy seizures are rarely seen in the same patient. It has been demonstrated that there is a resistance to development of convulsive seizures in genetic absence epilepsy models. The present study investigated glutamic acid decarboxylase (GAD) immunoreactivity in the brain region related to the interaction of these two seizure types, namely substantia nigra pars reticulata (SNR) subregions, SNRanterior and SNRposterior. METHODS: Nonepileptic adult male Wistar rats and Genetic Absence Epilepsy Rats from Strasbourg (GAERS) were used. Experimental groups of Wistar and GAERS were electrically stimulated for kindling model to induce convulsive epileptic seizures. An electrical stimulation cannula was stereotaxically implanted to the basolateral amygdala and recording electrodes were placed on the cortex. Sagittal sections of SNR were used to evaluate immunohistochemical reaction. Sections were incubated with anti-GAD67 antibody. Densitometric analysis of GAD67 immunoreactive neurons was performed using photographs of stained sections. One-way analysis of variance and post hoc Bonferroni test were used for statistical analysis of the data. RESULTS: There was no difference in GAD67 immunoreactivity of SNR subregions of control Wistar and control GAERS. An increase in GAD67 immunoreactivity was detected in SNRposterior subregion of stimulated Wistar rats, whereas there was a decrease in GAD67 immunoreactivity in SNRposterior of stimulated GAERS. The difference in GAD67 immunoreactivity between these two groups was statistically significant. CONCLUSION: Level of synthetized gamma-aminobutyric acid in SNRposterior subregion plays an important role in the interaction of nonconvulsive absence epilepsy seizures and convulsive epilepsy seizures. PMID:28275746

  9. Number and regional distribution of GAD65 mRNA-expressing interneurons in the rat hippocampal formation.

    PubMed

    Czéh, B; Abrahám, Hajnalka; Tahtakran, Siroun; Houser, Carolyn R; Seress, L

    2013-12-01

    In rodent models for neuropsychiatric disorders reduced number of hippocampal interneurons have been reported, but the total number of GABAergic neurons in the normal rat hippocampus is yet unknown. We used in situ hybridization method to label the 65 isoform of glutamic acid decarboxylase (GAD65) and counted the number of GAD65 mRNA-expressing neurons along the entire septo-temporal axis of the hippocampus. We found that 2/3 of the interneurons were in Ammon's horn (61,590) and 1/3 in the dentate gyrus (28,000). We observed the following numbers in Ammon's horn: CA3 area 33,400, CA2 area 4,190, CA1 area 24,000 and in the dentate gyrus: 6,000 in the molecular and 9,000 in the granule cell layers and 13,000 in the hilus. GAD65 mRNA-expressing neurons were significantly more numerous in dorsal than in ventral hippocampus. The ratio between interneurons and principal cells was lowest in the granule cell layer (0.9%) and highest in hilus (21%). In Ammon's horn this ratio was constant being 13% in CA3 and 8% in CA1-2 areas. In the entire hippocampal formation, the interneuron/principal cell ratio was 6%, with a significant difference between Ammon's horn (9.5%) and the dentate gyrus (2.8%) including the hilus. Such low ratios could suggest that even a limited loss of GABAergic neurons in the hippocampus may have a considerable functional impact.

  10. Radioimmunoassay for glutamic acid decarboxylase (GAD65) autoantibodies as a diagnostic aid for stiff-man syndrome and a correlate of susceptibility to type 1 diabetes mellitus.

    PubMed

    Walikonis, J E; Lennon, V A

    1998-12-01

    To establish and validate a double-antibody radioimmunoassay (RIA) for detecting serum auto-antibodies against glutamic acid decarboxylase (GAD65). This enzyme catalyzes synthesis of the neurotransmitter gamma-aminobutyric acid in neurons and pancreatic islet cells. We compared the frequency of GAD65 and other "thyrogastric" autoantibodies in adult patients with stiff-man (Moersch-Woltman) syndrome, type 1 diabetes, or polyendocrine disorders and in healthy subjects. The frequency of pancreatic islet cell antibody (ICA) detection was also assessed. The GAD65 RIA was validated by testing blinded samples, by confirming the specificity of low-titered positive results by "cold" antigen inhibition, and by comparing the RIA results with results of a kit assay incorporating staphylococcal protein A as immunoprecipitant. Recombinant GAD65 protein labeled with 125I was used as antigen, and a combination of anti-human IgG and IgM was used as immunoprecipitant. Seropositivity was determined for ICA and gastric parietal cell antibodies by indirect immunofluorescence assays and for thyroid peroxidase (microsome) and thyroglobulin antibodies by agglutination assays. We detected GAD65-specific antibodies in all but 1 of 46 local patients with stiff-man syndrome (98%); 16 had evidence of diabetes. Positive values exceeded 20 nmol/L in 96%, and 89% were ICA-positive; 76% had additional thyrogastric antibodies. Of 41 patients with type 1 diabetes (17 local and 24 workshop serum specimens), 33 were GAD65 antibody-positive (80%); 85% of these positive values were 20 nmol/L or lower. Only 18% of sera from patients with type 1 diabetes were ICA-positive, but 59% had other thyrogastric autoantibodies. Of 20 patients with autoimmune endocrinopathies without diabetes or stiff-man syndrome, 35% were GAD65 antibody-positive, 5% were ICA-positive, and 90% were thyrogastric antibody-positive. Of 117 healthy control subjects, 8% were GAD65 antibody-positive, and a third of those had other

  11. Combination therapy with an anti-IL-1β antibody and GAD65 DNA vaccine can reverse recent-onset diabetes in the RIP-GP mouse model.

    PubMed

    Pagni, Philippe P; Bresson, Damien; Rodriguez-Calvo, Teresa; Bel Hani, Amira; Manenkova, Yulia; Amirian, Natalie; Blaszczak, Alecia; Faton, Sina; Sachithanantham, Sowbarnika; von Herrath, Matthias G

    2014-06-01

    Type 1 diabetes is thought to be an autoimmune condition in which self-reactive T cells attack insulin-secreting pancreatic β-cells. As a proinflammatory cytokine produced by β-cells or macrophages, interleukin-1β (IL-1β) represents a potential therapeutic target in diabetes. We reasoned IL-1β blockade could be combined with islet antigen-specific approaches involving GAD of 65 kDa (GAD65)-expressing plasmids, as previously shown in combination therapies (CTs) with anti-CD3. Thus, we investigated whether anti-IL-1β antibody alone or combined with GAD65 vaccine could reverse diabetes development in a virus-induced mouse model. Given alone, anti-IL-1β had no effect on diabetes, while GAD65 plasmid resulted in 33% disease reversal after a 5-week observation. However, CTs cured 53% of animals and prevented worsening of glycemic control in nonprotected individuals for up to 12 weeks. While the GAD65 vaccine arm of the CT was associated with increased forkhead box p3(+) regulatory T-cell frequency in pancreatic lymph nodes, islet infiltration by CD11b(+/high) cells was less frequent upon CT, and its extent correlated with treatment success or failure. Altogether, our CTs provided prolonged improvement of clinical and immunological features. Despite unsuccessful clinical trials using anti-IL-1β monotherapy, these data hold promise for treatment of type 1 diabetic patients with IL-1β blockade combined with antigen-specific vaccines.

  12. Jet Stream Analysis and Forecast Errors Using GADS Aircraft Observations in the DAO, ECMWF, and NCEP Models

    NASA Technical Reports Server (NTRS)

    Cardinali, Carla; Rukhovets, Leonid; Tenenbaum, Joel

    2003-01-01

    We have utilized an extensive set of independent British Airways flight data recording wind vector and temperature observations (the Global Aircraft Data Set [GADS] archive) in three ways: (a) as an independent check of operational analyses; (b) as an analysis observing system experiment (OSE) as if the GADS observations were available in real time; and (c) as the corresponding forecast simulation experiment applicable to future operational forecasts. Using a 31 day sample (0000 UTC 20 December 2000 through 0000 UTC 20 January 2000) from Winter 2000, we conclude that over the data-dense continental U. S. analyzed jet streaks are too weak by -2% to -5%. Over nearby data-sparse regions of Canada, analyzed jet streaks are too weak by -5% to -9%. The second range provides a limit on the accuracy of current jet streak analyses over the portions of the -85% of the earth's surface that are poorly covered by non-satellite observations. The -5% to -9% range is relevant for the pre-third generation satellite (AIRS, IASI, GIFTS) era.

  13. GAD Antibodies as Key Link Between Chronic Intestinal Pseudoobstruction, Autonomic Neuropathy, and Limb Stiffness in a Nondiabetic Patient

    PubMed Central

    Maier, Andrea; Mannartz, Vera; Wasmuth, Hermann; Trautwein, Christian; Neumann, Ulf-Peter; Weis, Joachim; Grosse, Joachim; Fuest, Matthias; Hilz, Max-J.; Schulz, Joerg B.; Haubrich, Christina

    2015-01-01

    Abstract Chronic intestinal pseudoobstruction (CIP) can be a severe burden and even a life-threatening disorder. Typically, several years of uncertainty are passing before diagnosis. We are reporting the case of a young woman with a decade of severe, progressive gastrointestinal dysmotility. Unusually, she had also developed an autonomic neuropathy, and a stiff limb syndrome. In addition to achalasia and CIP the young woman also developed neuropathic symptoms: orthostatic intolerance, urinary retention, a Horner syndrome, and lower limb stiffness. Careful interdisciplinary diagnostics excluded underlying infectious, rheumatoid, metabolic or tumorous diseases. The detection of GAD (glutamic acid decarboxylase) antibodies, however, seemed to link CIP, autonomic neuropathy, and limb stiffness and pointed at an autoimmune origin of our patient's complaints. This was supported by the positive effects of intravenous immunoglobulin. In response to this therapy the body weight had stabilized, orthostatic tolerance had improved, and limb stiffness was reversed. The case suggested that GAD antibodies should be considered in CIP also in nondiabetic patients. This may support earlier diagnosis and immunotherapy. PMID:26252289

  14. Immunocytochemical localization of glutamic acid decarboxylase (GAD) and glutamine synthetase (GS) in the area postrema of the cat. Light and electron microscopy

    NASA Technical Reports Server (NTRS)

    D'Amelio, Fernando E.; Mehler, William R.; Gibbs, Michael A.; Eng, Lawrence F.; Wu, Jang-Yen

    1987-01-01

    Morphological evidence is presented of the existence of the putative neurotransmitter gamma-aminobutyric acid (GABA) in axon terminals and of glutamine synthetase (GS) in ependymoglial cells and astroglial components of the area postrema (AP) of the cat. Purified antiserum directed against the GABA biosynthetic enzyme glutamic acid decarboxylase (GAD) and GS antiserum were used. The results showed that punctate structures of variable size corresponding to axon terminals exhibited GAD-immunoreactivity and were distributed in varying densities. The greatest accumulation occurred in the caudal and middle segment of the AP and particularly in the area subpostrema, where the aggregation of terminals was extremely dense. The presence of both GAD-immunoreactive profiles and GS-immunostained ependymoglial cells and astrocytes in the AP provide further evidence of the functional correlation between the two enzymes.

  15. Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial.

    PubMed

    Wherrett, Diane K; Bundy, Brian; Becker, Dorothy J; DiMeglio, Linda A; Gitelman, Stephen E; Goland, Robin; Gottlieb, Peter A; Greenbaum, Carla J; Herold, Kevan C; Marks, Jennifer B; Monzavi, Roshanak; Moran, Antoinette; Orban, Tihamer; Palmer, Jerry P; Raskin, Philip; Rodriguez, Henry; Schatz, Desmond; Wilson, Darrell M; Krischer, Jeffrey P; Skyler, Jay S

    2011-07-23

    Glutamic acid decarboxylase (GAD) is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. In animal models of autoimmunity, treatment with a target antigen can modulate aggressive autoimmunity. We aimed to assess whether immunisation with GAD formulated with aluminum hydroxide (GAD-alum) would preserve insulin production in recent-onset type 1 diabetes. Patients aged 3-45 years who had been diagnosed with type 1 diabetes for less than 100 days were enrolled from 15 sites in the USA and Canada, and randomly assigned to receive one of three treatments: three injections of 20 μg GAD-alum, two injections of 20 μg GAD-alum and one of alum, or 3 injections of alum. Injections were given subcutaneously at baseline, 4 weeks later, and 8 weeks after the second injection. The randomisation sequence was computer generated at the TrialNet coordinating centre. Patients and study personnel were masked to treatment assignment. The primary outcome was the baseline-adjusted geometric mean area under the curve (AUC) of serum C-peptide during the first 2 h of a 4-h mixed meal tolerance test at 1 year. Secondary outcomes included changes in glycated haemoglobin A(1c) (HbA(1c)) and insulin dose, and safety. Analysis included all randomised patients with known measurements. This trial is registered with ClinicalTrials.gov, number NCT00529399. 145 patients were enrolled and treated with GAD-alum (n=48), GAD-alum plus alum (n=49), or alum (n=48). At 1 year, the 2-h AUC of C-peptide, adjusted for age, sex, and baseline C-peptide value, was 0·412 nmol/L (95% CI 0·349-0·478) in the GAD-alum group, 0·382 nmol/L (0·322-0·446) in the GAD-alum plus alum group, and 0·413 nmol/L (0·351-0·477) in the alum group. The ratio of the population mean of the adjusted geometric mean 2-h AUC of C-peptide was 0·998 (95% CI 0·779-1·22; p=0·98) for GAD-alum versus alum, and 0·926 (0·720-1·13; p=0·50) for GAD-alum plus alum versus alum. HbA(1c), insulin use, and

  16. Immunocytochemical localization of glutamic acid decarboxylase (GAD) and glutamine synthetase (GS) in the area postrema of the cat. Light and electron microscopy

    NASA Technical Reports Server (NTRS)

    D'Amelio, Fernando E.; Mehler, William R.; Gibbs, Michael A.; Eng, Lawrence F.; Wu, Jang-Yen

    1987-01-01

    Morphological evidence is presented of the existence of the putative neurotransmitter gamma-aminobutyric acid (GABA) in axon terminals and of glutamine synthetase (GS) in ependymoglial cells and astroglial components of the area postrema (AP) of the cat. Purified antiserum directed against the GABA biosynthetic enzyme glutamic acid decarboxylase (GAD) and GS antiserum were used. The results showed that punctate structures of variable size corresponding to axon terminals exhibited GAD-immunoreactivity and were distributed in varying densities. The greatest accumulation occurred in the caudal and middle segment of the AP and particularly in the area subpostrema, where the aggregation of terminals was extremely dense. The presence of both GAD-immunoreactive profiles and GS-immunostained ependymoglial cells and astrocytes in the AP provide further evidence of the functional correlation between the two enzymes.

  17. A stereological comparison of GAD67 and reelin expression in the hippocampal stratum oriens of offspring from two mouse models of maternal inflammation during pregnancy.

    PubMed

    Harvey, Louise; Boksa, Patricia

    2012-03-01

    Epidemiological evidence suggests that maternal infection during pregnancy may be a risk factor for schizophrenia and autism. Altered expression of glutamic acid decarboxylase (GAD67) and reelin in the hippocampus has been reported in post-mortem studies of people with schizophrenia or autism. We used two mouse models of maternal inflammation, featuring either the viral RNA mimic, poly (I:C), or the bacterial endotoxin, lipopolysaccharide (LPS), to compare effects of maternal inflammation on GAD67 and reelin expression in the hippocampal stratum oriens of juvenile mice. Pregnant Swiss-Webster mice were treated with poly (I:C) or LPS on gestational day 9. At postnatal days (PD) 14 and 28, brains from male and female offspring were processed immunohistochemically, and NeuN-, GAD67- and reelin-positive cells estimated using unbiased stereological cell counting methods. In offspring at PD14, GAD67 and reelin expression were unaffected by prenatal poly (I:C) or prenatal LPS treatment, although prenatal LPS mice showed increased neuronal (NeuN) density at this age. However, at PD28, mice prenatally treated with poly (I:C) displayed a decreased number of reelin-positive cells in dorsal stratum oriens. Interestingly, at PD28, we also found increased GAD67 expression in the ventral stratum oriens in male mice prenatally treated with LPS, and in female mice prenatally treated with poly (I:C). Our findings describe sex-, age-, and immunogen-specific alterations in regional hippocampal GAD67 and reelin expression as a result of early maternal inflammation. These neurodevelopmental changes could have significant effects on GABAergic neurotransmission and synaptic plasticity. Copyright © 2011 Elsevier Ltd. All rights reserved.

  18. Garcinol Upregulates GABAA and GAD65 Expression, Modulates BDNF-TrkB Pathway to Reduce Seizures in Pentylenetetrazole (PTZ)-Induced Epilepsy

    PubMed Central

    Hao, Fang; Jia, Li-Hua; Li, Xiao-Wan; Zhang, Ying-Rui; Liu, Xue-Wu

    2016-01-01

    Background Epilepsy is the most predominant neurological disorder characterized by recurrent seizures. Despite treatment with antiepileptic drugs, epilepsy still is a challenge to treat, due to the associated adverse effects of the drugs. Previous investigations have shown critical roles of BDNF-TrkB signalling and expression of glutamic acid decarboxylase 65 (GAD65) and GABAA in the brain during epilepsy. Thus, drugs that could modulate BDNF-TrkB signal and expression of GAD65 and GABAA could aid in therapy. Recent experimental data have focussed on plant-derived compounds in treatments. Garcinol (camboginol), is a polyisoprenylated benzophenone derived from the fruit of Garcinia indica. We investigated the effects of garcinol in pentylenetetrazole (PTZ)-induced epileptic models. Material/Methods Seizure scores were measured in epilepsy kindled mice. Neuronal degeneration and apoptosis were assessed by Nissl staining, TUNEL assay, and Fluoro-Jade B staining. Immunohistochemistry was performed to evaluate cleaved caspase-3 expressions. Expression of BDNF, TrkB, GABAA, GAD65, Bad, Bcl-2, Bcl-xL, and Bax were determined by western blots. Results Significantly reduced seizure scores and mortality rates were observed with pretreatment with garcinol. Elevated expression of apoptotic proteins and caspase-3 in kindled mice were effectively downregulated by garcinol. Epileptogenic mice presented increased BDNF and TrkB with considerably decreased GABAA and GAD65 expression. Garcinol significantly enhanced GABAA and GAD65 while it suppressed BDNF and TrkB. Garcinol enhanced the performance of mice in Morris water maze tests. Conclusions Garcinol exerts neuroprotective effects via supressing apoptosis and modulating BDNF-TrkB signalling and GAD65/GABAA expressions and also enhanced cognition and memory of the mice. PMID:27855137

  19. Trimming of two major type 1 diabetes driving antigens, GAD65 and IA-2, allows for successful expression in Lactococcus lactis.

    PubMed

    Robert, S; Van Huynegem, K; Gysemans, C; Mathieu, C; Rottiers, P; Steidler, L

    2015-01-01

    Type 1 diabetes (T1D) is a chronic autoimmune disease characterised by excessive immune reactions against auto-antigens of pancreatic β-cells. Restoring auto-antigen tolerance remains the superior therapeutic strategy. Oral auto-antigen administration uses the tolerogenic nature of the gut-associated immune system to induce antigen-specific tolerance. However, due to gastric degradation, proper mucosal product delivery often imposes a challenge. Recombinant Lactococcus lactis have proven to be effective and safe carriers for gastrointestinal delivery of therapeutic products: L. lactis secreting diabetes-associated auto-antigens in combination with interleukin (IL)-10 have demonstrated therapeutic efficacy in a well-defined mouse model for T1D. Here, we describe the construction of recombinant L. lactis secreting the 65 kDa isoform of glutamic acid decarboxylase (GAD65) and tyrosine phosphatase-like protein ICA512 (IA-2), two major T1D-related auto-antigens. Attempts to secrete full size human GAD65 and IA-2 protein by L. lactis were unsuccessful. Trimming of GAD65 and IA-2 was investigated to optimise antigen secretion while maintaining sufficient bacterial growth. GAD65370-575 and IA-2635-979 showed to be efficiently secreted by recombinant L. lactis. Antigen secretion was verified by immunoblotting. Plasmid-derived GAD65 and IA-2 expression was combined in single strains with human IL-10 expression, a desired combination to allow tolerance induction. This study reports the generation of recombinant L. lactis secreting two major diabetes-related auto-antigens: human GAD65 and IA-2, by themselves or combined with the anti-inflammatory cytokine human IL-10. Prohibitive sequence obstacles hampering antigen secretion were resolved by trimming the full size proteins.

  20. The effect of sevoflurane inhalation on gabaergic neurons activation: observation on the GAD67-GFP knock-in mouse.

    PubMed

    Han, Li-Chun; Zhang, Hui; Wang, Wei; Wei, Yan-Yan; Sun, Xing-Xing; Yanagawa, Youchio; Li, Yun-Qing; Xu, Li-Xian; Wu, Sheng-Xi

    2010-12-01

    The mechanisms underlying volatile anesthesia agents are not well elucidated. Emerging researches have focused on the participation of γ-aminobutyric acid (GABA) neurons but there still lacks morphological evidence. To elucidate the possible activation of GABAergic neurons by sevoflurane inhalation in morphology, Fos (as neuronal activity marker) and GABA neurons double labeling were observed on the brain of glutamic acid decarboxylase (GAD) 67-GFP knock-in mice after sevoflurane inhalation. Twenty GAD67-GFP knock-in mice were divided into three groups: S1 group: incomplete anesthesia state induced by sevoflurane; S2 group: complete anesthesia state induced by sevoflurane; control(C) group. Sevoflurane induced a significant increase of Fos expression in the dorsomedial hypothalamic nucleus (DM), periaqueductal grey (PAG), hippocampus (CA1, DG), paraventricular thalamic nucleus (PV), lateral septal nucleus (LS), and cingulate cortex (Cg1 and Cg2) in S1 group compared to C group, and increase of Fos expression in S2 group compared to S1 group. In S2 group, Fos was only expressed in the medial amygdaloid nucleus (MeA), Edinger-Westphal (E-W) nucleus, arcuate hypothalamic nucleus (Arc) and the ventral part of paraventricular hypothalamic nucleus (PaV). Double immunofluroscent staining indicated that in LS, almost all Fos were present in GABAergic neurons. In CA1, DG, DM, cg1, cg2, and PAG, Fos was expressed as well, but only few were present in GABAergic neurons. Fos expression was very high in thalamus, but no coexistence were found as no GABAergic neuron was detected in this area. Our results provided morphological evidence that GABAergic transmission in specific brain areas may participate in the sevoflurane-induced anesthesia.

  1. Rapid detection of generalized anxiety disorder and major depression in epilepsy: Validation of the GAD-7 as a complementary tool to the NDDI-E in a French sample.

    PubMed

    Micoulaud-Franchi, Jean-Arthur; Lagarde, Stanislas; Barkate, Gérald; Dufournet, Boris; Besancon, Cyril; Trébuchon-Da Fonseca, Agnès; Gavaret, Martine; Bartolomei, Fabrice; Bonini, Francesca; McGonigal, Aileen

    2016-04-01

    Generalized anxiety disorder (GAD) in people with epilepsy (PWE) is underdiagnosed and undertreated. The GAD-7 is a screening questionnaire to detect GAD. However, the usefulness of the GAD-7 as a screening tool in PWE remains to be validated. Thus, we aimed to: (1) validate the GAD-7 in French PWE and (2) assess its complementarity with regard to the previously validated screening tool for depression, the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). This study was performed under the auspices of the ILAE Commission on Neuropsychiatry. People with epilepsy >18 years of age were recruited from the specialist epilepsy unit in Marseille, France. The Mini-International Neuropsychiatric Interview (MINI) was performed as gold standard, and the Penn State Worry Questionnaire (PSWQ) and the NDDI-E were performed for external validity. Data were compared between PWE with/without GAD using Chi(2) test and Student's t-test. Internal structural validity, external validity, and receiver operator characteristics were analyzed. A principal component factor analysis with Varimax rotation was performed on the 13 items of the GAD-7 (7 items) plus the NDDI-E (6 items). Testing was performed on 145 PWE: mean age = 39.38 years old (SD=14.01, range: 18-75); 63.4% (92) women; 75.9% with focal epilepsy. Using the MINI, 49 (33.8%) patients had current GAD. Cronbach's alpha coefficient was 0.898, indicating satisfactory internal consistency. Correlation between GAD-7 and the PSQW scores was high (r (145)=.549, P<.0001), indicating good external validity. Factor analysis shows that the anxiety investigated with the GAD-7 and depression investigated with the NDDI-E reflect distinct factors. Receiver operator characteristic analysis showed area under the curve of 0.899 (95% CI 0.838-0.943, P < 0.0001) indicating good capacity of the GAD-7 to detect GAD (defined by MINI). Cutoff for maximal sensitivity and specificity was 7. Mean GAD-7 score in PWE with GAD was 13.22 (SD

  2. Inhibition of altered peptide ligand-mediated antagonism of human GAD65-responsive CD4+ T cells by non-antagonizable T cells.

    PubMed

    Gebe, John A; Masewicz, Susan A; Kochik, Sharon A; Reijonen, Helena; Nepom, Gerald T

    2004-12-01

    Altered peptide ligands derived from T cell-reactive self antigens have been shown to be protective therapeutic agents in animal models of autoimmunity. In this study we identified several altered peptide ligands derived from the type 1 diabetes-associated autoantigen human glutamic acid decarboxylase 65 (hGAD65) epitope that were capable of antagonizing a subset of a panel of human CD4(+) GAD65 (555-567)-responsive T cell clones derived from a diabetic individual. While no altered peptide ligand was able to antagonize all six clones in the T cell panel, a single-substituted peptide of isoleucine to methionine at position 561, which resides at the TCR contact p5 position, was able to antagonize five out of the six hGAD65-responsive clones. In a mixed T cell culture system we observed that altered peptide ligand-mediated antagonism is inhibited in a dose-dependent manner by the presence of non-antagonizable hGAD65 (555-567)-responsive T cells. From an analysis of the cytokines present in the mixed T cell cultures, interleukin-2 was sufficient to inhibit altered peptide ligand-induced antagonism. The inhibition of altered peptide ligand-mediated antagonism of self-antigen-responsive T cells by non-antagonizable T cells has implications in altered peptide ligand therapy where T cell antagonism is the goal.

  3. Autoantibodies to glutamic acid decarboxylase (GAD), 64,000-Mr islet cell protein (64K) antibodies and islet cell antibodies (ICA) in insulin-dependent diabetes mellitus with and without autoimmune diseases in Japan.

    PubMed

    Akawaza, S; Kawasaki, E; Yano, M; Abiru, N; Yamaguchi, Y; Nagataki, S

    1994-10-01

    IDDM is known to be a heterogeneous disease which is frequently complicated with other autoimmune diseases (AID). We previously reported that IDDM patients with AID were characterized by late onset of diabetes, persistent ICA-positivity and increased association with DR9, while those without AID were characterized by rapid decline of ICA with duration of diabetes and increased association with DR4. The present study was performed to investigate the prevalence of autoantibodies to glutamic acid decarboxylase (GAD), autoantibodies to 64KDa islet cell protein (64K antibodies) and islet cell antibodies (ICA) in Japanese IDDM patients with and without AID. In short-duration diabetes (< 1 year), the prevalence of GAD antibodies, 64K antibodies and ICA were 100%, 100%, and 100%, respectively, in IDDM patients with AID, and 82%, 64% and 82%, respectively, in patients without AID. In long-standing diabetes (3-28 years), the prevalence of GAD antibodies were 76%, 48% and 33%, respectively, in IDDM patients with AID, and 48%, 28% and 16%, respectively, in patients without AID. The mean levels of GAD antibodies, 64K antibodies and ICA in IDDM patients with AID was significantly higher than in those without AID. Furthermore, the prevalence of GAD antibodies were detected more frequently than ICA and 64K antibodies in long standing IDDM patients. Our results demonstrate that the prevalence of GAD antibodies in IDDM patients were as high as those reported in Caucasians, and high levels of GAD antibodies were observed in IDDM patients with AID.

  4. Toward dissecting the etiology of schizophrenia: HDAC1 and DAXX regulate GAD67 expression in an in vitro hippocampal GABA neuron model

    PubMed Central

    Subburaju, S; Coleman, A J; Ruzicka, W B; Benes, F M

    2016-01-01

    Schizophrenia (SZ) is associated with GABA neuron dysfunction in the hippocampus, particularly the stratum oriens of sector CA3/2. A gene expression profile analysis of human postmortem hippocampal tissue followed by a network association analysis had shown a number of genes differentially regulated in SZ, including the epigenetic factors HDAC1 and DAXX. To characterize the contribution of these factors to the developmental perturbation hypothesized to underlie SZ, lentiviral vectors carrying short hairpin RNA interference (shRNAi) for HDAC1 and DAXX were used. In the hippocampal GABA neuron culture model, HiB5, transduction with HDAC1 shRNAi showed a 40% inhibition of HDAC1 mRNA and a 60% inhibition of HDAC1 protein. GAD67, a enzyme associated with GABA synthesis, was increased twofold (mRNA); the protein showed a 35% increase. The expression of DAXX, a co-repressor of HDAC1, was not influenced by HDAC1 inhibition. Transduction of HiB5 cells with DAXX shRNAi resulted in a 30% inhibition of DAXX mRNA that translated into a 90% inhibition of DAXX protein. GAD1 mRNA was upregulated fourfold, while its protein increased by ~30%. HDAC1 expression was not altered by inhibition of DAXX. However, a physical interaction between HDAC1 and DAXX was demonstrated by co-immunoprecipitation. Inhibition of HDAC1 or DAXX increased expression of egr-1, transcription factor that had previously been shown to regulate the GAD67 promoter. Our in vitro results point to a key role of both HDAC1 and DAXX in the regulation of GAD67 in GABAergic HiB5 cells, strongly suggesting that these epigenetic/transcription factors contribute to mechanisms underlying GABA cell dysfunction in SZ. PMID:26812044

  5. Sex-specific impairment and recovery of spatial learning following the end of chronic unpredictable restraint stress: potential relevance of limbic GAD.

    PubMed

    Ortiz, J Bryce; Taylor, Sara B; Hoffman, Ann N; Campbell, Alyssa N; Lucas, Louis R; Conrad, Cheryl D

    2015-04-01

    Chronic restraint stress alters hippocampal-dependent spatial learning and memory in a sex-dependent manner, impairing spatial performance in male rats and leaving intact or facilitating performance in female rats. Moreover, these stress-induced spatial memory deficits improve following post-stress recovery in males. The current study examined whether restraint administered in an unpredictable manner would eliminate these sex differences and impact a post-stress period on spatial ability and limbic glutamic acid decarboxylase (GAD65) expression. Male (n=30) and female (n=30) adult Sprague-Dawley rats were assigned to non-stressed control (Con), chronic stress (Str-Imm), or chronic stress given a post-stress recovery period (Str-Rec). Stressed rats were unpredictably restrained for 21 days using daily non-repeated combinations of physical context, duration, and time of day. Then, all rats were tested on the radial arm water maze (RAWM) for 2 days and given one retention trial on the third day, with brains removed 30min later to assess GAD65 mRNA. In Str-Imm males, deficits occurred on day 1 of RAWM acquisition, an impairment that was not evident in the Str-Rec group. In contrast, females did not show significant outcomes following chronic stress or post-stress recovery. In males, amygdalar GAD65 expression negatively correlated with RAWM performance on day 1. In females, hippocampal CA1 GAD65 positively correlated with RAWM performance on day 1. These results demonstrate that GABAergic function may contribute to the sex differences observed following chronic stress. Furthermore, unpredictable restraint and a recovery period failed to eliminate the sex differences on spatial learning and memory.

  6. Fission yeast TOR complex 2 activates the AGC-family Gad8 kinase essential for stress resistance and cell cycle control.

    PubMed

    Ikeda, Kyoko; Morigasaki, Susumu; Tatebe, Hisashi; Tamanoi, Fuyuhiko; Shiozaki, Kazuhiro

    2008-02-01

    Members of the mitogen-activated protein kinase (MAPK) subfamily responsive to environmental stress stimuli are known as SAPKs (stress-activated protein kinases), which are conserved from yeast to humans. In the fission yeast Schizosaccharomyces pombe, Spc1/Sty1 SAPK is activated by diverse forms of stress, such as osmostress, oxidative stress and heat shock, and induces gene expression through the Atf1 transcription factor. Sin1 (SAPK interacting protein 1) was originally isolated as a protein that interacts with Spc1, and its orthologs were also found in diverse eukaryotes. Here we report that Sin1 is not required for the stress gene expression regulated by Spc1 and Atf1, and that Sin1 is an essential component of TOR (target of rapamycin) complex 2 (TORC2). TORC2 is not essential for cell viability in S. pombe but plays important roles in cellular survival of stress conditions through phosphorylation and activation of an AGC-family protein kinase, Gad8. In addition, inactivation of Gad8 results in a synthetic growth defect with cdc25-22, a temperature-sensitive mutation of the Cdc25 phosphatase that activates Cdc2 kinase at G(2)/M. Gad8 also positively regulates expression of the CDK inhibitor gene rum1+, which is essential for cell cycle arrest in G(1) after nitrogen starvation. These results strongly suggest that the TORC2-Gad8 pathway has multiple physiological functions in cellular stress resistance and cell cycle progression at both G(1)/S and G(2)/M transitions.

  7. Measuring anxiety after spinal cord injury: Development and psychometric characteristics of the SCI-QOL Anxiety item bank and linkage with GAD-7

    PubMed Central

    Kisala, Pamela A.; Tulsky, David S.; Kalpakjian, Claire Z.; Heinemann, Allen W.; Pohlig, Ryan T.; Carle, Adam; Choi, Seung W.

    2015-01-01

    Objective To develop a calibrated item bank and computer adaptive test to assess anxiety symptoms in individuals with spinal cord injury (SCI), transform scores to the Patient Reported Outcomes Measurement Information System (PROMIS) metric, and create a statistical linkage with the Generalized Anxiety Disorder (GAD)-7, a widely used anxiety measure. Design Grounded-theory based qualitative item development methods; large-scale item calibration field testing; confirmatory factor analysis; graded response model item response theory analyses; statistical linking techniques to transform scores to a PROMIS metric; and linkage with the GAD-7. Setting Five SCI Model System centers and one Department of Veterans Affairs medical center in the United States. Participants Adults with traumatic SCI. Main Outcome Measures Spinal Cord Injury-Quality of Life (SCI-QOL) Anxiety Item Bank Results Seven hundred sixteen individuals with traumatic SCI completed 38 items assessing anxiety, 17 of which were PROMIS items. After 13 items (including 2 PROMIS items) were removed, factor analyses confirmed unidimensionality. Item response theory analyses were used to estimate slopes and thresholds for the final 25 items (15 from PROMIS). The observed Pearson correlation between the SCI-QOL Anxiety and GAD-7 scores was 0.67. Conclusions The SCI-QOL Anxiety item bank demonstrates excellent psychometric properties and is available as a computer adaptive test or short form for research and clinical applications. SCI-QOL Anxiety scores have been transformed to the PROMIS metric and we provide a method to link SCI-QOL Anxiety scores with those of the GAD-7. PMID:26010966

  8. vglut2 and gad expression reveal distinct patterns of dual GABAergic versus glutamatergic cotransmitter phenotypes of dopaminergic and noradrenergic neurons in the zebrafish brain

    PubMed Central

    Filippi, Alida; Mueller, Thomas; Driever, Wolfgang

    2014-01-01

    Throughout the vertebrate lineage, dopaminergic neurons form important neuromodulatory systems that influence motor behavior, mood, cognition, and physiology. Studies in mammals have established that dopaminergic neurons often use γ-aminobutyric acid (GABA) or glutamatergic cotransmission during development and physiological function. Here, we analyze vglut2, gad1b and gad2 expression in combination with tyrosine hydroxylase immunoreactivity in 4-day-old larval and 30-day-old juvenile zebrafish brains to determine which dopaminergic and noradrenergic groups may use GABA or glutamate as a second transmitter. Our results show that most dopaminergic neurons also express GABAergic markers, including the dopaminergic groups of the olfactory bulb (homologous to mammalian A16) and the subpallium, the hypothalamic groups (A12, A14), the prethalamic zona incerta group (A13), the preoptic groups (A15), and the pretectal group. Thus, the majority of catecholaminergic neurons are gad1b/2-positive and coexpress GABA. A very few gad1/2-negative dopaminergic groups, however, express vglut2 instead and use glutamate as a second transmitter. These glutamatergic dual transmitter phenotypes are the Orthopedia transcription factor–dependent, A11-type dopaminergic neurons of the posterior tuberculum. All together, our results demonstrate that all catecholaminergic groups in zebrafish are either GABAergic or glutamatergic. Thus, cotransmission of dopamine and noradrenaline with either GABA or glutamate appears to be a regular feature of zebrafish catecholaminergic systems. We compare our results with those that have been described for mammalian systems, discuss the phenomenon of transmitter dualism in the context of developmental specification of GABAergic and glutamatergic regions in the brain, and put this phenomenon in an evolutionary perspective. J. Comp. Neurol. 522:2019–2037, 2014. PMID:24374659

  9. Screening instruments for a population of older adults: The 10-item Kessler Psychological Distress Scale (K10) and the 7-item Generalized Anxiety Disorder Scale (GAD-7).

    PubMed

    Vasiliadis, Helen-Maria; Chudzinski, Veronica; Gontijo-Guerra, Samantha; Préville, Michel

    2015-07-30

    Screening tools that appropriately detect older adults' mental disorders are of great public health importance. The present study aimed to establish cutoff scores for the 10-item Kessler Psychological Distress (K10) and the 7-item Generalized Anxiety Disorder (GAD-7) scales when screening for depression and anxiety. We used data from participants (n = 1811) in the Enquête sur la Santé des Aînés-Service study. Depression and anxiety were measured using DSM-V and DSM-IV criteria. Receiver operating characteristic (ROC) curve analysis provided an area under the curve (AUC) of 0.767 and 0.833 for minor and for major depression when using K10. A cutoff of 19 was found to balance sensitivity (0.794) and specificity (0.664) for minor depression, whereas a cutoff of 23 was found to balance sensitivity (0.692) and specificity (0.811) for major depression. When screening for an anxiety with GAD-7, ROC analysis yielded an AUC of 0.695; a cutoff of 5 was found to balance sensitivity (0.709) and specificity (0.568). No significant differences were found between subgroups of age and gender. Both K10 and GAD-7 were able to discriminate between cases and non-cases when screening for depression and anxiety in an older adult population of primary care service users. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. ¹H, ¹³C and ¹⁵N resonance assignments and second structure information of Gad m 1: a β-parvalbumin allergen from Atlantic cod (Gadus morhua).

    PubMed

    Moraes, A H; Ackerbauer, D; Kostadinova, M; Bublin, M; Ferreira, F; Almeida, F C L; Breiteneder, H; Valente, A P

    2013-10-01

    Gad m 1 is the major allergen from Atlantic cod. It belongs to β-parvalbumin protein family and is characterized by the presence of two calcium-binding sites so called EF-hand motifs. β-Parvalbumins such as Gad m 1 are the most important fish allergens and their high cross-reactivity is the cause of the observed polysensitization to various fish species in allergic patients. Despite extensive efforts, the complete elucidation of β-parvalbumin-IgE complexes has not been achieved yet. Allergen structural studies are essential for the development of novel immunotherapy strategies, including vaccination with hypoallergenic derivatives and chimeric molecules. Here, we report for the first time the NMR study of a β-parvalbumin: Gad m 1. This report includes: (1)H, (13)C and (15)N resonance assignments of Gad m 1 as well as the second structure information based on the (13)C chemical shifts.

  11. The theoretical and practical determination of clinical cut-offs for the British Sign Language versions of PHQ-9 and GAD-7.

    PubMed

    Belk, Rachel A; Pilling, Mark; Rogers, Katherine D; Lovell, Karina; Young, Alys

    2016-11-03

    The PHQ-9 and the GAD-7 assess depression and anxiety respectively. There are standardised, reliability-tested versions in BSL (British Sign Language) that are used with Deaf users of the IAPT service. The aim of this study is to determine their appropriate clinical cut-offs when used with Deaf people who sign and to examine the operating characteristics for PHQ-9 BSL and GAD-7 BSL with a clinical Deaf population. Two datasets were compared: (i) dataset (n = 502) from a specialist IAPT service for Deaf people; and (ii) dataset (n = 85) from our existing study of Deaf people who self-reported having no mental health difficulties. Parameter estimates, with the precision of AUC value, sensitivity, specificity, positive predicted value (ppv) and negative predicted value (npv), were carried out to provide the details of the clinical cut-offs. Three statistical choices were included: Maximising (Youden: maximising sensitivity + specificity), Equalising (Sensitivity = Specificity) and Prioritising treatment (False Negative twice as bad as False Positive). Standard measures (as defined by IAPT) were applied to examine caseness, recovery, reliable change and reliable recovery for the first dataset. The clinical cut-offs for PHQ-9 BSL and GAD-7 BSL are 8 and 6 respectively. This compares with the original English version cut-offs in the hearing population of 10 and 8 respectively. The three different statistical choices for calculating clinical cut-offs all showed a lower clinical cut-off for the Deaf population with respect to the PHQ-9 BSL and GAD-7 BSL with the exception of the Maximising criteria when used with the PHQ-9 BSL. Applying the new clinical cut-offs, the percentage of Deaf BSL IAPT service users showing reliable recovery is 54.0 % compared to 63.7 % using the cut-off scores used for English speaking hearing people. These compare favourably with national IAPT data for the general population. The correct clinical cut-offs for the PHQ-9 BSL and

  12. Severe anaphylactic reactions to glutamic acid decarboxylase (GAD) self peptides in NOD mice that spontaneously develop autoimmune type 1 diabetes mellitus

    PubMed Central

    Pedotti, Rosetta; Sanna, Maija; Tsai, Mindy; DeVoss, Jason; Steinman, Lawrence; McDevitt, Hugh; Galli, Stephen J

    2003-01-01

    Background Insulin dependent (i.e., "type 1") diabetes mellitus (T1DM) is considered to be a T cell mediated disease in which TH1 and Tc autoreactive cells attack the pancreatic islets. Among the beta-cell antigens implicated in T1DM, glutamic acid decarboxylase (GAD) 65 appears to play a key role in the development of T1DM in humans as well as in non-obese diabetic (NOD) mice, the experimental model for this disease. It has been shown that shifting the immune response to this antigen from TH1 towards TH2, via the administration of GAD65 peptides to young NOD mice, can suppress the progression to overt T1DM. Accordingly, various protocols of "peptide immunotherapy" of T1DM are under investigation. However, in mice with experimental autoimmune encephalomyelitis (EAE), another autoimmune TH1 mediated disease that mimics human multiple sclerosis, anaphylactic shock can occur when the mice are challenged with certain myelin self peptides that initially were administered with adjuvant to induce the disease. Results Here we show that NOD mice, that spontaneously develop T1DM, can develop fatal anaphylactic reactions upon challenge with preparations of immunodominant GAD65 self peptides after immunization with these peptides to modify the development of T1DM. Conclusions These findings document severe anaphylaxis to self peptide preparations used in an attempt to devise immunotherapy for a spontaneous autoimmune disease. Taken together with the findings in EAE, these results suggest that peptide therapies designed to induce a TH1 to TH2 shift carry a risk for the development of anaphylactic reactivity to the therapeutic peptides. PMID:12597780

  13. The gad2 promoter is a transcriptional target of estrogen receptor α (ERα) and ERβ: A unifying hypothesis to explain diverse effects of estradiol

    PubMed Central

    Hudgens, Edward D.; Ji, Lan; Carpenter, Clifford D.; Petersen, Sandra L.

    2009-01-01

    Estradiol (E2) regulates a wide range of neural functions, many of which require activation of estrogen receptor α (ERα) and/or ERβ, ligand-gated transcriptional regulators. Surprisingly, very few neural gene targets of ERs have been identified and these cannot easily explain the myriad effects of E2. GABA regulates most of the same neural functions as E2 and GABAergic neurons throughout the brain contain ER. Therefore, we examined whether E2 directly regulates expression of glutamic acid decarboxylase 2, the enzyme primarily responsible for GABA synthesis for synaptic release. Using dual-luciferase assays we found that E2, but not other gonadal steroids, stimulated the activity of a 2691-bp rat gad2 promoter reporter construct. Activation required either ERα or ERβ and ERβ did not repress ERα-mediated transactivation. Site-directed mutagenesis studies identified three EREs with cell-specific functions. An ERE at -711 upstream of the gad2 translational start site was essential for transactivation in both MCF-7 breast cancer cells and SN56.B5.G4 neural cells, but an ERE at -546 enhanced transcription only in neural cells. A third ERE at -1958 was inactive in neural cells, but exerted potent transcriptional repression in E2-treated MCF-7 cells. Chromatin immunoprecipitation (ChIP) assays in mouse GABAergic N42 cells confirmed that E2 induced ERα binding to a DNA fragment containing sequences corresponding to the -546 and -711 EREs of the rat promoter. Based on these data, we propose that direct transcriptional regulation of gad2 may explain, at least in part, the ability of E2 to impact such a diverse array of neural functions. PMID:19587286

  14. Role of GAD2 and HTR1B genes in early-onset obsessive-compulsive disorder: results from transmission disequilibrium study.

    PubMed

    Mas, S; Pagerols, M; Gassó, P; Ortiz, A; Rodriguez, N; Morer, A; Plana, M T; Lafuente, A; Lazaro, L

    2014-04-01

    One of the leading biological models of obsessive-compulsive disorder (OCD) is the frontal-striatal-thalamic model. This study undertakes an extensive exploration of the variability in genes related to the regulation of the frontal-striatal-thalamic system in a sample of early-onset OCD trios. To this end, we genotyped 266 single nucleotide polymorphisms (SNPs) in 35 genes in 84 OCD probands and their parents. Finally, 75 complete trios were included in the analysis. Twenty SNPs were overtransmitted from parents to early-onset OCD probands and presented nominal pointwise P < 0.05 values. Three of these polymorphisms achieved P < 2 × 10(-4), the significant P-value after Bonferroni corrections: rs8190748 and rs992990 localized in GAD2 and rs2000292 in HTR1B. When we stratified our sample according to gender, different trends were observed between males and females. In males, SNP rs2000292 (HTR1B) showed the lowest P-value (P = 0.0006), whereas the SNPs in GAD2 were only marginally significant (P = 0.01). In contrast, in females HTR1B polymorphisms were not significant, whereas rs8190748 (GAD2) showed the lowest P-value (P = 0.0006). These results are in agreement with several lines of evidence that indicate a role for the serotonin and γ-Aminobutyric acid (GABA) pathways in the risk of early-onset OCD and with the gender differences in OCD pathophysiology reported elsewhere. However, our results need to be replicated in studies with larger cohorts in order to confirm these associations.

  15. Color threshold and ratio of S100 beta, MAP5, NF68/200, GABA & GAD. I. Distribution in inner ear afferents

    NASA Technical Reports Server (NTRS)

    Fermin, C. D.; Martin, D. S.; Hara, H.

    1997-01-01

    Afferents of chick embryos (Gallus domesticus) VIIIth nerve were examined at E3, E6, E9, E13, El7, and hatching (NH) for anti-S100 beta, anti-MAP5, anti-GABA, anti-GAD and anti-NF68/200 stain. Different ages were processed together to determine if the distribution of these antibodies changed during synaptogenesis and myelination. Color thresholding showed that saturation of pixels changed for S100 beta only 5%, for NF68/200 10%, and for MAP5, 10%, between E9-NH. Color ratio of NF68/200 over MAP5 was 1.00 at E13 and 0.25 at E16 and NH. S100 beta, GABA and GAD were co-expressed on nerve endings at the edge of the maculae and center of the cristae, whereas hair cells in the center of the maculae expressed either S100 beta or GABA, but not both. S100 beta/NF68/200 shared antigenic sites on the chalices, but NF68/200 expression was higher than S100 beta in the chalices at hatching. MAP5 was expressed in more neurons than NF68/200 at E11, whereas NF68/200 was more abundant than MAP5 at hatching. The results suggest that: 1) the immunoexpression of these neuronal proteins is modulated concomitantly with the establishment of afferent synapses and myelination; 2) S100 beta may serve a neurotrophic function in the chalices where it is co-expressed with the neurotransmitter GABA and its synthesizing enzyme GAD.

  16. Escherichia coli K-12 survives anaerobic exposure at pH 2 without RpoS, Gad, or hydrogenases, but shows sensitivity to autoclaved broth products.

    PubMed

    Riggins, Daniel P; Narvaez, Maria J; Martinez, Keith A; Harden, Mark M; Slonczewski, Joan L

    2013-01-01

    Escherichia coli and other enteric bacteria survive exposure to extreme acid (pH 2 or lower) in gastric fluid. Aerated cultures survive via regulons expressing glutamate decarboxylase (Gad, activated by RpoS), cyclopropane fatty acid synthase (Cfa) and others. But extreme-acid survival is rarely tested under low oxygen, a condition found in the stomach and the intestinal tract. We observed survival of E. coli K-12 W3110 at pH 1.2-pH 2.0, conducting all manipulations (overnight culture at pH 5.5, extreme-acid exposure, dilution and plating) in a glove box excluding oxygen (10% H2, 5% CO2, balance N2). With dissolved O2 concentrations maintained below 6 µM, survival at pH 2 required Cfa but did not require GadC, RpoS, or hydrogenases. Extreme-acid survival in broth (containing tryptone and yeast extract) was diminished in media that had been autoclaved compared to media that had been filtered. The effect of autoclaved media on extreme-acid survival was most pronounced when oxygen was excluded. Exposure to H2O2 during extreme-acid treatment increased the death rate slightly for W3110 and to a greater extent for the rpoS deletion strain. Survival at pH 2 was increased in strains lacking the anaerobic regulator fnr. During anaerobic growth at pH 5.5, strains deleted for fnr showed enhanced transcription of acid-survival genes gadB, cfa, and hdeA, as well as catalase (katE). We show that E. coli cultured under oxygen exclusion (<6 µM O2) requires mechanisms different from those of aerated cultures. Extreme acid survival is more sensitive to autoclave products under oxygen exclusion.

  17. [Problems and deficiencies in family physician's management of generalized anxiety disorders. Results of the GAD-P study and priorities for an improved care].

    PubMed

    Wittchen, H U; Hoyer, J; Beesdo, K; Krause, P

    2001-01-01

    The core findings of the GAD-P study (Generalized anxiety and depression in primary care) are summarized and measures to improve the quality of care of patients with generalized anxiety disorders are discussed. In addition to the identification of core research deficits the paper emphasizes the standard use of time-efficient diagnostic screening instruments, because urgently needed improved recognition and diagnosis is the prerequisite for appropriate treatment. Further the role of the media to combat stigma processes, as well as patient education materials to improve compliance and to enhance treatment outcome effects for this neglected disorder that frequently runs a chronic course are highlighted.

  18. GABA and GAD expression in the X-organ sinus gland system of the Procambarus clarkii crayfish: inhibition mediated by GABA between X-organ neurons.

    PubMed

    Pérez-Polanco, Paola; Garduño, Julieta; Cebada, Jorge; Zarco, Natanael; Segovia, José; Lamas, Mónica; García, Ubaldo

    2011-09-01

    In crustaceans, the X-organ-sinus gland (XO-SG) neurosecretory system is formed of distinct populations of neurons that produce two families of neuropeptides: crustacean hyperglycemic hormone and adipokinetic hormone/red pigment-concentrating hormone. On the basis of electrophysiological evidence, it has been proposed that γ-aminobutyric acid (GABA) regulates both electrical and secretory activity of the XO-SG system. In this work we observed that depolarizing current pulses to neurons located in the external rim of the X-organ induced repetitive firing that suppressed the spontaneous firing of previously active X-organ neurons. Picrotoxin reversibly blocked this inhibitory effect suggesting that the GABA released from the stimulated neuron inhibited neighboring cells. Immunoperoxidase in X-organ serial sections showed co-localization of GABA and glutamic acid decarboxylase (GAD) including the aforementioned neurons. Immunofluorescence in whole mount preparations showed that two subpopulations of crustacean hyperglycemic hormone-containing neurons colocalized with GABA. The expression of GAD mRNA was determined in crayfish tissue and X-organ single cells by RT-PCR. Bioinformatics analysis shows, within the amplified region, 90.4% consensus and 41.9% identity at the amino acid level compared with Drosophila melanogaster and Caenorhabditis elegans. We suggest that crustacean hyperglycemic hormone-GABA-containing neurons can regulate the excitability of other X-organ neurons that produce different neurohormones.

  19. Fluorescent Labeling of Newborn Dentate Granule Cells in GAD67-GFP Transgenic Mice: A Genetic Tool for the Study of Adult Neurogenesis

    PubMed Central

    Zhao, Shengli; Zhou, Yang; Gross, Jimmy; Miao, Pei; Qiu, Li; Wang, Dongqing; Chen, Qian; Feng, Guoping

    2010-01-01

    Neurogenesis in the adult hippocampus is an important form of structural plasticity in the brain. Here we report a line of BAC transgenic mice (GAD67-GFP mice) that selectively and transitorily express GFP in newborn dentate granule cells of the adult hippocampus. These GFP+ cells show a high degree of colocalization with BrdU-labeled nuclei one week after BrdU injection and express the newborn neuron marker doublecortin and PSA-NCAM. Compared to mature dentate granule cells, these newborn neurons show immature morphological features: dendritic beading, fewer dendritic branches and spines. These GFP+ newborn neurons also show immature electrophysiological properties: higher input resistance, more depolarized resting membrane potentials, small and non-typical action potentials. The bright labeling of newborn neurons with GFP makes it possible to visualize the details of dendrites, which reach the outer edge of the molecular layer, and their axon (mossy fiber) terminals, which project to the CA3 region where they form synaptic boutons. GFP expression covers the whole developmental stage of newborn neurons, beginning within the first week of cell division and disappearing as newborn neurons mature, about 4 weeks postmitotic. Thus, the GAD67-GFP transgenic mice provide a useful genetic tool for studying the development and regulation of newborn dentate granule cells. PMID:20824075

  20. Lack of functional GABA(B) receptors alters GnRH physiology and sexual dimorphic expression of GnRH and GAD-67 in the brain.

    PubMed

    Catalano, Paolo N; Di Giorgio, Noelia; Bonaventura, María M; Bettler, Bernhard; Libertun, Carlos; Lux-Lantos, Victoria A

    2010-03-01

    GABA, the main inhibitory neurotransmitter, acts through GABA(A/C) and GABA(B) receptors (GABA(B)Rs); it is critical for gonadotropin regulation. We studied whether the lack of functional GABA(B)Rs in GABA(B1) knockout (GABA(B1)KO) mice affected the gonadotropin axis physiology. Adult male and female GABA(B1)KO and wild-type (WT) mice were killed to collect blood and tissue samples. Gonadotropin-releasing hormone (GnRH) content in whole hypothalami (HT), olfactory bulbs (OB), and frontoparietal cortexes (CT) were determined (RIA). GnRH expression by quantitative real-time PCR (qRT-PCR) was evaluated in preoptic area-anterior hypothalamus (POA-AH), medial basal-posterior hypothalamus (MBH-PH), OB, and CT. Pulsatile GnRH secretion from hypothalamic explants was measured by RIA. GABA, glutamate, and taurine contents in HT and CT were determined by HPLC. Glutamic acid decarboxylase-67 (GAD-67) mRNA was measured by qRT-PCR in POA-AH, MBH-PH, and CT. Gonadotropin content, serum levels, and secretion from adenohypophyseal cell cultures (ACC) were measured by RIA. GnRH mRNA expression was increased in POA-AH of WT males compared with females; this pattern of expression was inversed in GABA(B1)KO mice. MBH-PH, OB, and CT did not follow this pattern. In GABA(B1)KO females, GnRH pulse frequency was increased and GABA and glutamate contents were augmented. POA-AH GAD-67 mRNA showed the same expression pattern as GnRH mRNA in this area. Gonadotropin pituitary contents and serum levels showed no differences between genotypes. Increased basal LH secretion and decreased GnRH-stimulated gonadotropin response were observed in GABA(B1)KO female ACCs. These results support the hypothesis that the absence of functional GABA(B)Rs alters GnRH physiology and critically affects sexual dimorphic expression of GnRH and GAD-67 in POA-AH.

  1. Comparative analysis of acid resistance in Listeria monocytogenes and Salmonella enterica strains before and after exposure to poultry decontaminants. Role of the glutamate decarboxylase (GAD) system.

    PubMed

    Alonso-Hernando, Alicia; Alonso-Calleja, Carlos; Capita, Rosa

    2009-12-01

    Data on the ability of chemical poultry decontaminants to induce an acid stress response in pathogenic bacteria are lacking. This study was undertaken in order to compare the survival rates in acid broths of Listeria monocytogenes and Salmonella enterica strains, both exposed to and not exposed to decontaminants. The contribution of the glutamate decarboxylase (GAD) acid resistance system to the survival of bacteria in acid media was also examined. Four strains (L. monocytogenes serovar 1/2, L. monocytogenes serovar 4b, S. enterica serotype Typhymurium and S. enterica serotype Enteritidis) were tested before (control) and after exposure to trisodium phosphate, acidified sodium chlorite, citric acid, chlorine dioxide and peroxyacids (strains were repeatedly passed through media containing increasing concentrations of a compound). Stationary-phase cells (10(8) cfu/ml) were inoculated into tryptic soy broth (TSB) acidified with citric acid (pH 2.7 and 5.0) with or without glutamate (10 mM) added, and incubated at 37 degrees C for 15 min. Survival percentages (calculated from viable colonies) varied from 2.47 +/- 0.67% to 91.93 +/- 5.83%. L. monocytogenes cells previously exposed to acid decontaminants (citric acid and peroxyacids) showed, when placed in acid TSB, a higher (P < 0.05) percentage of survival (average 38.80 +/- 30.52%) than control and pre-exposed to non-acidic decontaminants strains (22.82 +/- 23.80%). Similar (P > 0.05) survival percentages were observed in previously exposed to different decontaminants and control Salmonella strains. The GAD acid resistance system did not apparently play any role in the survival of L. monocytogenes or S. enterica at a low pH. This study demonstrates for the first time that prior exposure to acidic poultry decontaminants increases the percentage of survival of L. monocytogenes exposed to severe acid stress. These results have important implications for the meat industry when considering which decontaminant treatment to

  2. Characterization of GABAergic neurons in rapid-eye-movement sleep controlling regions of the brainstem reticular formation in GAD67-green fluorescent protein knock-in mice.

    PubMed

    Brown, Ritchie E; McKenna, James T; Winston, Stuart; Basheer, Radhika; Yanagawa, Yuchio; Thakkar, Mahesh M; McCarley, Robert W

    2008-01-01

    Recent experiments suggest that brainstem GABAergic neurons may control rapid-eye-movement (REM) sleep. However, understanding their pharmacology/physiology has been hindered by difficulty in identification. Here we report that mice expressing green fluorescent protein (GFP) under the control of the GAD67 promoter (GAD67-GFP knock-in mice) exhibit numerous GFP-positive neurons in the central gray and reticular formation, allowing on-line identification in vitro. Small (10-15 microm) or medium-sized (15-25 microm) GFP-positive perikarya surrounded larger serotonergic, noradrenergic, cholinergic and reticular neurons, and > 96% of neurons were double-labeled for GFP and GABA, confirming that GFP-positive neurons are GABAergic. Whole-cell recordings in brainstem regions important for promoting REM sleep [subcoeruleus (SubC) or pontine nucleus oralis (PnO) regions] revealed that GFP-positive neurons were spontaneously active at 3-12 Hz, fired tonically, and possessed a medium-sized depolarizing sag during hyperpolarizing steps. Many neurons also exhibited a small, low-threshold calcium spike. GFP-positive neurons were tested with pharmacological agents known to promote (carbachol) or inhibit (orexin A) REM sleep. SubC GFP-positive neurons were excited by the cholinergic agonist carbachol, whereas those in the PnO were either inhibited or excited. GFP-positive neurons in both areas were excited by orexins/hypocretins. These data are congruent with the hypothesis that carbachol-inhibited GABAergic PnO neurons project to, and inhibit, REM-on SubC reticular neurons during waking, whereas carbachol-excited SubC and PnO GABAergic neurons are involved in silencing locus coeruleus and dorsal raphe aminergic neurons during REM sleep. Orexinergic suppression of REM during waking is probably mediated in part via excitation of acetylcholine-inhibited GABAergic neurons.

  3. Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum.

    PubMed

    Zhubi, A; Chen, Y; Dong, E; Cook, E H; Guidotti, A; Grayson, D R

    2014-01-21

    Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by symptoms related to altered social interactions/communication and restricted and repetitive behaviors. In addition to genetic risk, epigenetic mechanisms (which include DNA methylation/demethylation) are thought to be important in the etiopathogenesis of ASD. We studied epigenetic mechanisms underlying the transcriptional regulation of candidate genes in cerebella of ASD patients, including the binding of MeCP2 (methyl CpG binding protein-2) to the glutamic acid decarboxylase 67 (GAD1), glutamic acid decarboxylase 65 (GAD2), and Reelin (RELN) promoters and gene bodies. Moreover, we performed methyl DNA immunoprecipitation (MeDIP) and hydroxymethyl DNA immunoprecipitation (hMeDIP) to measure total 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in the same regions of these genes. The enrichment of 5-hmC and decrease in 5-mC at the GAD1 or RELN promoters detected by 5-hmC and 5-mC antibodies was confirmed by Tet-assisted bisulfite (TAB) pyrosequencing. The results showed a marked and significant increase in MeCP2 binding to the promoter regions of GAD1 and RELN, but not to the corresponding gene body regions in cerebellar cortex of ASD patients. Moreover, we detected a significant increase in TET1 expression and an enrichment in the level of 5-hmC, but not 5-mC, at the promoters of GAD1 and RELN in ASD when compared with CON. Moreover, there was increased TET1 binding to these promoter regions. These data are consistent with the hypothesis that an increase of 5-hmC (relative to 5-mC) at specific gene domains enhances the binding of MeCP2 to 5-hmC and reduces expression of the corresponding target genes in ASD cerebella.

  4. Adenosine A2A Receptor Gene Knockout Prevents l-3,4-Dihydroxyphenylalanine-Induced Dyskinesia by Downregulation of Striatal GAD67 in 6-OHDA-Lesioned Parkinson’s Mice

    PubMed Central

    Yin, Su-bing; Zhang, Xiao-guang; Chen, Shuang; Yang, Wen-ting; Zheng, Xia-wei; Zheng, Guo-qing

    2017-01-01

    l-3,4-Dihydroxyphenylalanine (l-DOPA) remains the primary pharmacological agent for the symptomatic treatment of Parkinson’s disease (PD). However, the development of l-DOPA-induced dyskinesia (LID) limits the long-term use of l-DOPA for PD patients. Some data have reported that adenosine A2A receptor (A2AR) antagonists prevented LID in animal model of PD. However, the mechanism in which adenosine A2AR blockade alleviates the symptoms of LID has not been fully clarified. Here, we determined to knock out (KO) the gene of A2AR and explored the possible underlying mechanisms implicated in development of LID in a mouse model of PD. A2AR gene KO mice were unilaterally injected into the striatum with 6-hydroxydopamine (6-OHDA) in order to damage dopamine neurons on one side of the brain. 6-OHDA-lesioned mice were then injected once daily for 21 days with l-DOPA. Abnormal involuntary movements (AIMs) were evaluated on days 3, 8, 13, and 18 after l-DOPA administration, and real-time polymerase chain reaction and immunohistochemistry for glutamic acid decarboxylase (GAD) 65 and GAD67 were performed. We found that A2AR gene KO was effective in reducing AIM scores and accompanied with decrease of striatal GAD67, rather than GAD65. These results demonstrated that the possible mechanism involved in alleviation of AIM symptoms by A2AR gene KO might be through reducing the expression of striatal GAD67. PMID:28377741

  5. Ketamine alters cortical integration of GABAergic interneurons and induces long-term sex-dependent impairments in transgenic Gad67-GFP mice

    PubMed Central

    Aligny, C; Roux, C; Dourmap, N; Ramdani, Y; Do-Rego, J-C; Jégou, S; Leroux, P; Leroux-Nicollet, I; Marret, S; Gonzalez, B J

    2014-01-01

    Ketamine, a non-competitive N-methyl-D-aspartate (NMDA) antagonist, widely used as an anesthetic in neonatal pediatrics, is also an illicit drug named Super K or KitKat consumed by teens and young adults. In the immature brain, despite several studies indicating that NMDA antagonists are neuroprotective against excitotoxic injuries, there is more and more evidence indicating that these molecules exert a deleterious effect by suppressing a trophic function of glutamate. In the present study, we show using Gad67-GFP mice that prenatal exposure to ketamine during a time-window in which GABAergic precursors are migrating results in (i) strong apoptotic death in the ganglionic eminences and along the migratory routes of GABAergic interneurons; (ii) long-term deficits in interneuron density, dendrite numbers and spine morphology; (iii) a sex-dependent deregulation of γ-aminobutyric acid (GABA) levels and GABA transporter expression; (iv) sex-dependent changes in the response to glutamate-induced calcium mobilization; and (v) the long-term sex-dependent behavioral impairment of locomotor activity. In conclusion, using a preclinical approach, the present study shows that ketamine exposure during cortical maturation durably affects the integration of GABAergic interneurons by reducing their survival and differentiation. The resulting molecular, morphological and functional modifications are associated with sex-specific behavioral deficits in adults. In light of the present data, it appears that in humans, ketamine could be deleterious for the development of the brain of preterm neonates and fetuses of addicted pregnant women. PMID:24991763

  6. The extended-release formulation of quetiapine fumarate (quetiapine XR) adjunctive treatment in partially responsive generalized anxiety disorder (GAD): An open label naturalistic study.

    PubMed

    Gabriel, A

    2011-01-01

    To assess the effect of adjunctive treatment with extended-release formulation of quetiapine fumarate (quetiapine XR) to other antidepressants in the treatment of partially responsive, poorly functioning patients with generalized anxiety disorder was assessed. Twenty four consenting adult outpatients with confirmed DSM-IV diagnosis of generalized disorder were identified. All patients failed at least one 8-week treatment trial with SSRI or SNRI antidepressant. All were treated with quetiapine XR as an add on treatment to citalopram or vanlafaxine antidepressant for at least 12 weeks. The primary efficacy measure was the Clinical Global Impression Scale (CGI-S). Other scales included; the Hamilton Anxiety Scale (HAM-A) scale, Sheehan Disability Scale, and the Abnormal Involuntary Movement Scale (AIMS). Baseline measures prior to adding quetiapine XR were compared to those at 4, 8 and 12 weeks with the adjunctive treatment. Twenty three patients completed the trial. There was significant rapid resolution of the anxiety symptoms in all effectiveness measures, including the symptoms of anxiety as shown by changes from baseline in HAM-A, and CGI at four weeks. Improvement was maintained to week twelve. Impairments in work, social, and home responsibilities were also reduced significantly, and there were no significant changes in weight at 12 weeks. Patients tolerated the adjunctive treatment well. Quetiapine XR may have anxiolytic properties and could be used effectively as adjunctive treatment with SSRIs in GAD patients with partial response to SSRs or SNRISs. However double blind randomized trials are needed to support these results.

  7. Gadè deceptions and lies told by the ill: The Caribbean sociocultural construction of truth in patient-healer encounters.

    PubMed

    Massé, Raymond

    2002-08-01

    A constructivist approach in medical anthropology suggests that the boundary between lies and truth in sickness narratives is thin. Based on fieldwork in the French (Martinique) and English (Saint-Lucia) Carribbean with gadé and quimboiseurs (local folk healers), this paper addresses the gap between naïve romanticism and radical cynicism in the anthropological analysis of patient-healer encounters. Is the sick person lying when she accuses evil spirits for her behaviour or sickness? Is the quimboiseur who is building a meaningful explanation or diagnosis simply a liar taking advantage of his client's credulity? The challenge for anthropology is not to determine whether or not a person is lying when attributing their ill fortune to witchcraft. Instead, in this paper, the author approaches lying as a language-game played by both patients and folk healers. Concepts of lying as games, tactical lies, pragmatic creativity, and constructive lies are introduced here as a perspective for a reconsideration of lying as a pertinent research object.

  8. Adaptation and initial validation of the Patient Health Questionnaire - 9 (PHQ-9) and the Generalized Anxiety Disorder - 7 Questionnaire (GAD-7) in an Arabic speaking Lebanese psychiatric outpatient sample.

    PubMed

    Sawaya, Helen; Atoui, Mia; Hamadeh, Aya; Zeinoun, Pia; Nahas, Ziad

    2016-05-30

    The Patient Health Questionnaire - 9 (PHQ-9) and Generalized Anxiety Disorder - 7 (GAD-7) are short screening measures used in medical and community settings to assess depression and anxiety severity. The aim of this study is to translate the screening tools into Arabic and evaluate their psychometric properties in an Arabic-speaking Lebanese psychiatric outpatient sample. The patients completed the questionnaires, among others, prior to being evaluated by a clinical psychiatrist or psychologist. The scales' internal consistency and factor structure were measured and convergent and discriminant validity were established by comparing the scores with clinical diagnoses and the Psychiatric Diagnostic Screening Questionnaire - MDD subset (PDSQ - MDD). Results showed that the PHQ-9 and GAD-7 are reliable screening tools for depression and anxiety and their factor structures replicated those reported in the literature. Sensitivity and specificity analyses showed that the PHQ-9 is sensitive but not specific at capturing depressive symptoms when compared to clinician diagnoses whereas the GAD-7 was neither sensitive nor specific at capturing anxiety symptoms. The implications of these findings are discussed in reference to the scales themselves and the cultural specificity of the Lebanese population.

  9. 3 Screen islet cell autoantibody ELISA: A sensitive and specific ELISA for the combined measurement of autoantibodies to GAD65, to IA-2 and to ZnT8.

    PubMed

    Amoroso, Marie; Achenbach, Peter; Powell, Michael; Coles, Rebecca; Chlebowska, Monika; Carr, Lorraine; Furmaniak, Jadwiga; Scholz, Marlon; Bonifacio, Ezio; Ziegler, Anette-G; Rees Smith, Bernard

    2016-11-01

    3 Screen, a new ELISA for the combined measurement of autoantibodies to GAD65, to IA-2 and to ZnT8, has been developed and evaluated. In the assay serum samples were incubated (overnight; 2-8°C) in ELISA plate wells coated with GAD65, IA-2 and ZnT8 followed by a wash step and incubation with biotinylated GAD65, IA-2 and ZnT8 (1h; 2-8°C,). The assay was completed by addition of streptavidin-peroxidase and tetramethylbenzidine. Samples tested in the 3 Screen were also analysed in ELISAs and radiobinding assays for the three individual autoantibodies. 129/132 (98%) samples from newly diagnosed T1DM children and 1/100 non-diabetic children controls were positive in 3 Screen. There was good agreement between 3 Screen and the individual autoantibody assays. Dilution of positive samples showed good linearity characteristics. In the 2015 Islet Autoantibody Standardization Program 3 Screen achieved 94% sensitivity, 95.6% specificity and 0.948 area under curve by ROC analysis. 3 Screen provides a simple and sensitive method for combined measurement of three major diabetes associated autoantibodies in a single sample. The assay should be a useful tool for large scale population screening for individuals at risk of developing T1DM.

  10. CD226 rs763361 Is Associated with the Susceptibility to Type 1 Diabetes and Greater Frequency of GAD65 Autoantibody in a Brazilian Cohort

    PubMed Central

    Mattana, Teresa Cristina Colvara; Santos, Aritania Sousa; Fukui, Rosa Tsuneshiro; Mainardi-Novo, Debora Teixeira Oliveira; Costa, Vinícius Silva; Santos, Rosa Ferreira; Matioli, Sergio Russo; Rossi da Silva, Maria Elizabeth

    2014-01-01

    CD226 rs763361 variant increases susceptibility to type 1 diabetes (T1D) in Caucasians. There is no data about CD226 variants in the very heterogeneous Brazilian population bearing a wide degree of admixture. We investigated its association with T1D susceptibility, clinical phenotypes, and autoimmune manifestations (islet and extrapancreatic autoantibodies). Casuistry. 532 T1D patients and 594 controls in a case-control study. Initially, CD226 coding regions and boundaries were sequenced in a subset of 106 T1D patients and 102 controls. In a second step, two CD226 variants, rs763361 (exon 7) and rs727088 (3′ UTR region), involved with CD226 regulation, were genotyped in the entire cohort. C-peptide and autoantibody levels were determined. No new polymorphic variant was found. The variants rs763361 and rs727088 were in strong linkage disequilibrium. The TT genotype of rs763361 was associated with TID risk (OR = 1.503;  95%  CI = 1.135–1.991; P = 0.0044), mainly in females (P = 0.0012), greater frequency of anti-GAD autoantibody (31.9% × 24.5%; OR = 1.57; CI = 1.136–2.194; P = 0.0081), and lower C-peptide levels when compared to those with TC + CC genotypes (0.41 ± 0.30 ng/dL versus 0.70 ± 0.53 ng/dL P = 0.0218). Conclusions. The rs763361 variant of CD226 gene (TT genotype) was associated with susceptibility to T1D and with the degree of aggressiveness of the disease in T1D patients from Brazil. Ancestry had no effect. PMID:24891767

  11. The association between the PTPN22 1858C>T variant and type 1 diabetes depends on HLA risk and GAD65 autoantibodies

    PubMed Central

    Maziarz, Marlena; Janer, Marta; Roach, Jared; Hagopian, William; Palmer, Jerry P; Deutsch, Kerry; Sanjeevi, Carani B; Kockum, Ingrid; Breslow, Norman; Lernmark, Åke

    2011-01-01

    The single nucleotide polymorphism 1858C>T in the PTPN22 gene is associated with type 1 diabetes (T1D) in several populations. Previous reports have suggested the association may be modified by HLA, as well as by islet autoantibodies. In a large case-control study of Swedish incident T1D patients and controls, 0–34 years of age, we tested whether the odds ratio (OR) measure of association was dependent on HLA or autoantibodies against the islet autoantigens GAD65 (GADA), insulin, IA-2 or islet cell. The association between the carrier status of 1858C>T allele in PTPN22 (PTPN22(CT+TT)) and T1D was modified by HLA. In addition, in GADA-positive T1D, the OR was 2.83 (2.00, 3.99), whereas in GADA-negative T1D, the OR was 1.41 (0.98, 2.04) (p for comparison=0.007). The OR of association between PTPN22(CT+TT) and GADA-positive T1D declined with increasing HLA risk category from 6.12 to 1.54 (p=0.003); no such change was detected in GADA-negative T1D (p=0.722) (p for comparison=0.001). However, the absolute difference in risk between PTPN22(CC) and PTPN22(CT+TT) subjects with high risk HLA was 5 times higher than that for subjects with low risk HLA. We hypothesize that the altered T-cell function due to the PTPN22(1858C>T) polymorphism is exclusively associated with GADA-positive T1D at diagnosis. PMID:20445565

  12. Disease progression and search for monogenic diabetes among children with new onset type 1 diabetes negative for ICA, GAD- and IA-2 Antibodies

    PubMed Central

    2010-01-01

    Background To investigate disease progression the first 12 months after diagnosis in children with type 1 diabetes negative (AAB negative) for pancreatic autoantibodies [islet cell autoantibodies(ICA), glutamic acid decarboxylase antibodies (GADA) and insulinoma-associated antigen-2 antibodies (IA-2A)]. Furthermore the study aimed at determining whether mutations in KCNJ11, ABCC8, HNF1A, HNF4A or INS are common in AAB negative diabetes. Materials and methods In 261 newly diagnosed children with type 1 diabetes, we measured residual β-cell function, ICA, GADA, and IA-2A at 1, 6 and 12 months after diagnosis. The genes KCNJ11, ABCC8, HNF1A, HNF4A and INS were sequenced in subjects AAB negative at diagnosis. We expressed recombinant K-ATP channels in Xenopus oocytes to analyse the functional effects of an ABCC8 mutation. Results Twenty-four patients (9.1%) tested AAB negative after one month. Patients, who were AAB-negative throughout the 12-month period, had higher residual β-cell function (P = 0.002), lower blood glucose (P = 0.004), received less insulin (P = 0.05) and had lower HbA1c (P = 0.02) 12 months after diagnosis. One patient had a heterozygous mutation leading to the substitution of arginine at residue 1530 of SUR1 (ABCC8) by cysteine. Functional analyses of recombinant K-ATP channels showed that R1530C markedly reduced the sensitivity of the K-ATP channel to inhibition by MgATP. Morover, the channel was highly sensitive to sulphonylureas. However, there was no effect of sulfonylurea treatment after four weeks on 1.0-1.2 mg/kg/24 h glibenclamide. Conclusion GAD, IA-2A, and ICA negative children with new onset type 1 diabetes have slower disease progression as assessed by residual beta-cell function and improved glycemic control 12 months after diagnosis. One out of 24 had a mutation in ABCC8, suggesting that screening of ABCC8 should be considered in patients with AAB negative type 1 diabetes. PMID:20863361

  13. Phenotypic characterization of orofacial movement topography in mutants with disruption of amino acid mechanisms: glutamate N2A/B/D [GluRε1/2/4] subtypes and the GABA synthesizing enzyme GAD65.

    PubMed

    Tomiyama, K; Kato, R; Hara, Y; Kobayashi, M; Mishina, M; Yanagawa, Y; Kinsella, A; Koshikawa, N; Waddington, J L

    2013-10-10

    To investigate the role of glutamate receptor subtypes and GABA in orofacial function, six individual topographies of orofacial movement, both spontaneous and induced by the dopamine D1-like receptor agonist [R/S]-3-methyl-6-chloro-7,8-dihydroxy-1-[3-methyl-phenyl]-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF 83959), were quantified in mutant mice with deletion of (a) GluN2A, B or D receptors, and (b) the GABA synthesizing enzyme, 65-kD isoform of glutamate decarboxylase (GAD65). In GluN2A mutants, habituation of head movements was disrupted and vibrissae movements were reduced, with an overall increase in locomotion; responsivity to SKF 83959 was unaltered. In GluN2B mutants, vertical and horizontal jaw movements and incisor chattering were increased, with an overall decrease in locomotion; under challenge with SKF 83959, head and vibrissae movements were reduced. In GluN2D mutants, horizontal jaw movements, incisor chattering and vibrissae movements were increased, with reduced tongue protrusions and no overall change in locomotion; under challenge with SKF 83959, horizontal jaw movements were increased. In GAD65 mutants, vertical jaw movements were increased, with disruption to habituation of locomotion; under challenge with SKF 83959, vertical and horizontal jaw movements and incisor chattering were decreased. Effects on orofacial movements differed from their effects on regulation of overall locomotor behavior. These findings (a) indicate novel, differential roles for GluN2A, B and D receptors and for GAD65-mediated GABA in the regulation of individual topographies of orofacial movement and (b) reveal how these roles differ from and/or interact with the established role of D1-like receptors in pattern generators and effectors for such movements. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  14. Multiple microRNAs within the 14q32 cluster target the mRNAs of major type 1 diabetes autoantigens IA-2, IA-2β, and GAD65.

    PubMed

    Abuhatzira, Liron; Xu, Huanyu; Tahhan, Georges; Boulougoura, Afroditi; Schäffer, Alejandro A; Notkins, Abner L

    2015-10-01

    Islet antigen (IA)-2, IA-2β, and glutamate decarboxylase (GAD65) are major autoantigens in type 1 diabetes (T1D). Autoantibodies to these autoantigens appear years before disease onset and are widely used as predictive markers. Little is known, however, about what regulates the expression of these autoantigens. The present experiments were initiated to test the hypothesis that microRNAs (miRNAs) can target and affect the levels of these autoantigens. Bioinformatics was used to identify miRNAs predicted to target the mRNAs coding IA-2, IA-2β, and GAD65. RNA interference for the miRNA processing enzyme Dicer1 and individual miRNA mimics and inhibitors were used to confirm the effect in mouse islets and MIN6 cells. We show that the imprinted 14q32 miRNA cluster contains 56 miRNAs, 32 of which are predicted to target the mRNAs of T1D autoantigens and 12 of which are glucose-sensitive. Using miRNA mimics and inhibitors, we confirmed that at least 7 of these miRNAs modulate the mRNA levels of the T1D autoantigens. Dicer1 knockdown significantly reduced the mRNA levels of all 3 autoantigens, further confirming the importance of miRNAs in this regulation. We conclude that miRNAs are involved in regulating the expression of the major T1D autoantigens.

  15. Les phonemes, j'aime (I Love Phonemes).

    ERIC Educational Resources Information Center

    Kaneman-Pougatch, Massia

    1986-01-01

    Outlines interesting approaches and exercises for pronunciation instruction in the French class. The focus is on auditory discrimination, integration, phoneme-grapheme correspondence, and creativity with sounds. (MSE)

  16. Honoring the life and accomplishments of Jaime A. Escalante.

    THOMAS, 111th Congress

    Rep. Napolitano, Grace F. [D-CA-38

    2010-04-15

    04/30/2010 Referred to the Subcommittee on Early Childhood, Elementary, and Secondary Education. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

  17. Honoring the life and accomplishments of Jaime A. Escalante.

    THOMAS, 111th Congress

    Rep. Napolitano, Grace F. [D-CA-38

    2010-04-15

    House - 04/30/2010 Referred to the Subcommittee on Early Childhood, Elementary, and Secondary Education. (All Actions) Tracker: This bill has the status IntroducedHere are the steps for Status of Legislation:

  18. Long-term effect of rituximab in a case with late-onset Rasmussen´s encephalitis with anti-ganglioside IgGQ1b and anti-GAD antibodies positivity. Case Report.

    PubMed

    Timarova, Gabriela; Lisa, Iveta; Kukumberg, Peter

    2016-07-01

    Rasmussen's encephalitis is a rare autoimmune encephalitis usually involving one brain hemisphere, presenting with refractory epileptic seizures, and neurological and cognitive decline. Only 10% of cases start later in adolescence/adulthood. The only effective treatment for refractory seizures in childhood is hemispherectomy. For late-onset cases with mild neurological deficit the hemispherectomy is usually postponed because of its severe consequences. Immunotherapy shows some temporal effect for seizure control and slowing the brain atrophy, mainly in late onset Rasmussen's encephalitis. We report a patient with late onset Rasmussen´s encephalitis with anti-ganglioside IgGQ1b and anti-GAD antibodies positivity, who failed immunotherapy with cytostatics, immunoglobulins and steroids. Anti-ganglioside IgGQ1b antibodies are typically associated with a Miller-Fisher variant of Guillain-Barre syndrome and Bickerstaff's brainstem encephalitis. The association with Rasmussen´s encephalitis was not described before. Patient´s neurological deficit was mild and hemispherectomy was refused. The treatment with rituximab, an anti-CD20+ monoclonal antibody, led to 36-month control of seizures without any signs of progression of neurological deficit and MRI brain atrophy. Although the treatment is associated with long term B-cells depletion, patient doesn´t suffer from any clinically relevant infection. The biological treatment with monoclonal antibodies might be the way to stabilize patients with Rasmussen´s encephalitis, mainly late-onset, to prevent them from harmful and devastating hemispherectomy.

  19. Higher FoxP3 mRNA expression in peripheral blood mononuclear cells of GAD65 or IA-2 autoantibody-positive compared with autoantibody-negative persons.

    PubMed

    Link, Maire; Salur, Liina; Kisand, Kai; Rajasalu, Tarvo; Tillmann, Vallo; Uibo, Raivo

    2008-10-01

    The role of regulatory T cells (Tregs) in type 1 diabetes has been studied extensively. The most prevalent way to define Tregs has been by their surface expression of CD4 and CD25. As currently the transcription factor FoxP3 and the low expression of CD127 are regarded to be the most specific markers of Tregs, we analysed the number of Tregs defined by these molecules in peripheral blood mononuclear cells of diabetic patients and healthy controls. The gene expression of transforming growth factor beta and two isoforms of FoxP3 was measured as well. There were no significant differences between diabetic patients and healthy controls regarding the number of Tregs, or the expression of FoxP3 isoforms and TGFbeta in peripheral blood mononuclear cells. However, we found significantly higher expression of both full-length and Delta2FoxP3 in study subjects, positive for either GAD65 or IA-2 autoantibodies. The ratio of the expression of different isoforms was not changed. This study shows the possible role of FoxP3 in the development of tissue characteristic humoral immunity in type 1 diabetes.

  20. Genetic manipulation of the γ-aminobutyric acid (GABA) shunt in rice: overexpression of truncated glutamate decarboxylase (GAD2) and knockdown of γ-aminobutyric acid transaminase (GABA-T) lead to sustained and high levels of GABA accumulation in rice kernels.

    PubMed

    Shimajiri, Yasuka; Oonishi, Takayuki; Ozaki, Kae; Kainou, Kumiko; Akama, Kazuhito

    2013-06-01

    Gamma-aminobutyric acid (GABA) is a non-protein amino acid commonly present in all organisms. Because cellular levels of GABA in plants are mainly regulated by synthesis (glutamate decarboxylase, GAD) and catabolism (GABA-transaminase, GABA-T), we attempted seed-specific manipulation of the GABA shunt to achieve stable GABA accumulation in rice. A truncated GAD2 sequence, one of five GAD genes, controlled by the glutelin (GluB-1) or rice embryo globulin promoters (REG) and GABA-T-based trigger sequences in RNA interference (RNAi) cassettes controlled by one of these promoters as well, was introduced into rice (cv. Koshihikari) to establish stable transgenic lines under herbicide selection using pyriminobac. T₁ and T₂ generations of rice lines displayed high GABA concentrations (2-100 mg/100 g grain). In analyses of two selected lines from the T₃ generation, there was a strong correlation between GABA level and the expression of truncated GAD2, whereas the inhibitory effect of GABA-T expression was relatively weak. In these two lines both with two T-DNA copies, their starch, amylose, and protein levels were slightly lower than non-transformed cv. Koshihikari. Free amino acid analysis of mature kernels of these lines demonstrated elevated levels of GABA (75-350 mg/100 g polished rice) and also high levels of several amino acids, such as Ala, Ser, and Val. Because these lines of seeds could sustain their GABA content after harvest (up to 6 months), the strategy in this study could lead to the accumulation GABA and for these to be sustained in the edible parts. © 2013 Society for Experimental Biology, Association of Applied Biologists and John Wiley & Sons Ltd.

  1. Screening for Generalized Anxiety Disorder (GAD)

    MedlinePlus

    ... and Past Conferences 2017 Conference 2017 Continuing Education Credits Mobile App Program Professional Education Continuing Education Credits Webinars for Mental Health Treatment Providers Continuing Education ...

  2. Screening for Generalized Anxiety Disorder (GAD)

    MedlinePlus

    ... Day Workshop With Reid Wilson Conference Continuing Education Credits Sponsors & Exhibitors 2018 Conference Sponsors 2018 Conference Exhibitors ... Webinars for Mental Health Treatment Providers Continuing Education Credits Webinar Sponsorship Opportunities ADAA Publications/Special Offerings Podcasts ...

  3. Ctip2-, Satb2-, Prox1-, and GAD65-Expressing Neurons in Rat Cultures: Preponderance of Single- and Double-Positive Cells, and Cell Type-Specific Expression of Neuron-Specific Gene Family Members, Nsg-1 (NEEP21) and Nsg-2 (P19).

    PubMed

    Digilio, Laura; Yap, Chan Choo; Winckler, Bettina

    2015-01-01

    The brain consists of many distinct neuronal cell types, but which cell types are present in widely used primary cultures of embryonic rodent brain is often not known. We characterized how abundantly four cell type markers (Ctip2, Satb2, Prox1, GAD65) were represented in cultured rat neurons, how easily neurons expressing different markers can be transfected with commonly used plasmids, and whether neuronal-enriched endosomal proteins Nsg-1 (NEEP21) and Nsg-2 (P19) are ubiquitously expressed in all types of cultured neurons. We found that cultured neurons stably maintain cell type identities that are reflective of cell types in vivo. This includes neurons maintaining simultaneous expression of two transcription factors, such as Ctip2+/Satb2+ or Prox1+/Ctip2+ double-positive cells, which have also been described in vivo. Secondly, we established the superior efficiency of CAG promoters for both Lipofectamine-mediated transfection as well as for electroporation. Thirdly, we discovered that Nsg-1 and Nsg-2 were not expressed equally in all neurons: whereas high levels of both Nsg-1 and Nsg-2 were found in Satb2-, Ctip2-, and GAD65-positive neurons, Prox1-positive neurons in hippocampal cultures expressed low levels of both. Our findings thus highlight the importance of identifying neuronal cell types for doing cell biology in cultured neurons: Keeping track of neuronal cell type might uncover effects in assays that might otherwise be masked by the mixture of responsive and non-responsive neurons in the dish.

  4. Enlargement of Axo-Somatic Contacts Formed by GAD-Immunoreactive Axon Terminals onto Layer V Pyramidal Neurons in the Medial Prefrontal Cortex of Adolescent Female Mice Is Associated with Suppression of Food Restriction-Evoked Hyperactivity and Resilience to Activity-Based Anorexia.

    PubMed

    Chen, Yi-Wen; Wable, Gauri Satish; Chowdhury, Tara Gunkali; Aoki, Chiye

    2016-06-01

    Many, but not all, adolescent female mice that are exposed to a running wheel while food restricted (FR) become excessive wheel runners, choosing to run even during the hours of food availability, to the point of death. This phenomenon is called activity-based anorexia (ABA). We used electron microscopic immunocytochemistry to ask whether individual differences in ABA resilience may correlate with the lengths of axo-somatic contacts made by GABAergic axon terminals onto layer 5 pyramidal neurons (L5P) in the prefrontal cortex. Contact lengths were, on average, 40% greater for the ABA-induced mice, relative to controls. Correspondingly, the proportion of L5P perikaryal plasma membrane contacted by GABAergic terminals was 45% greater for the ABA mice. Contact lengths in the anterior cingulate cortex correlated negatively and strongly with the overall wheel activity after FR (R = -0.87, P < 0.01), whereas those in the prelimbic cortex correlated negatively with wheel running specifically during the hours of food availability of the FR days (R = -0.84, P < 0.05). These negative correlations support the idea that increases in the glutamic acid decarboxylase (GAD) terminal contact lengths onto L5P contribute toward ABA resilience through suppression of wheel running, a behavior that is intrinsically rewarding and helpful for foraging but maladaptive within a cage.

  5. VizieR Online Data Catalog: Variable stars in globular NGC7492 (Figuera Jaimes+, 2013)

    NASA Astrophysics Data System (ADS)

    Figuera Jaimes, R.; Arellano Ferro, A.; Bramich, D. M.; Giridhar, S.; Kuppuswamy, K.

    2013-07-01

    table3.dat file contains the time-series V, R and I photometry for all the RR Lyrae, long-period, SX Phe variables and candidates in NGC 7492. We list standard and instrumental magnitudes and their uncertainties corresponding to the variable star identification, filter, and epoch of mid-exposure. For completeness, we also list the reference flux, difference flux, and photometric scale factor, along with the uncertainties on the reference and difference fluxes. Observations were made from 2004/10/04 to 2012/06/29 with the 2.0m telescope of the Indian Astronomical Observatory (IAO) at Hanle, India, using the Johnson-Kron-Cousins V, R, and I filters. (2 data files).

  6. Health assessment for Monsanto Corporation, Augusta, Georgia, Region 4. CERCLIS No. GAD001700699. Preliminary report

    SciTech Connect

    Not Available

    1989-01-19

    The Monsanto Corporation 75-acre site is located in Augusta (Richmond County), Georgia. Preliminary on-site groundwater sampling results (the most recent occurring in 1986) identified arsenic, the only contaminant reported. Based on available information, the site is considered to be of potential public health concern because of the risk to human health caused by the possibility of human exposure to hazardous substances.

  7. The GAD-given Right of Dentate Gyrus Granule Cells to Become GABAergic.

    PubMed

    Mody, Istvan

    2002-09-01

    JANUS, THE ANCIENT ROMAN GOD OF GATES AND DOORS HAD TWO FACES: one looked into the past, and the other, into the future. Do neurons possess a Janus face when it comes to neurotransmitters, or a given neuron is to be forever solely gamma-aminobutyric acid (GABA) ergic, glutamatergic, dopaminergic, peptidergic, or YOURPREFERREDTRANSMITTERergic? The answer is that the terminals of many neurons are homes to even more than two neurotransmitters. All this in spite of the "one neuron-one transmitter" usual misinterpretation of Sir Henry Hallett Dale's postulate, originally meant to indicate that a metabolic process taking place in the cell body can influence all processes of the same neuron. A large variety of neurons in the CNS, many of them GABAergic, produce and release chemicals that satisfy some of the criteria used to define neurotransmitters. The usual scenario for a dual-transmitter terminal is that the fast-acting transmitter such as GABA or glutamate is stored in regular synaptic vesicles, whereas a neuropeptide is stored in dense core vesicles (1). The vesicular zinc found in many glutamatergic terminals also may be considered to be a second neurotransmitter, based on its vesicular packaging with the aid of a specific vesicular transporter, and its postsynaptic actions through high-affinity binding sites and permeation through certain channels (2). Whenever a "fast" and a "slow" neurotransmitter are present in the same presynaptic terminal, it is customary to assume that their release can be differentially regulated (1). There is little convincing experimental support for this phenomenon in the mammalian CNS. The coexistence of two "fast" neurotransmitters in the same terminal is less frequent, but not unheard of. In neonatal sympathetic neurons cocultured with cardiac myocytes, norepinephrine and acetylcholine coexist and have opposite actions on the cardiac muscle cells (3). Very recently we learned that brain-derived neurotrophic factor acting at the low-affinity neurotrophin receptor p75(NTR), perhaps as part of a programmed developmental switch, can convert the phenotype of the sympathetic neuron from noradrenergic to cholinergic (4). Other examples of two fast neurotransmitters released from the same neuron include GABA and glycine in interneurons of the spinal cord (5) and glutamate and dopamine in ventral midbrain dopamine neurons (6). Of all CNS neurons, the granule cells of the dentate gyrus appear to be the champions of neurotransmitter colocalization: glutamate, enkephalin, dynorphin, zinc, and finally GABA (2)(7)(8)(9). With this many transmitters in a single neuron, there are probably different ways in which they can be released. Dynorphin and other opioid peptides can be released directly from the dendrites to inhibit excitatory transmission (8). A similar mechanism may take place for GABA, as described in cortical GABAergic neurons (10).

  8. DPD epitope-specific glutamic acid decarboxylase GAD)65 autoantibodies in children with Type 1 diabetes

    USDA-ARS?s Scientific Manuscript database

    To study whether DPD epitope-specific glutamate decarboxylase autoantibodies are found more frequently in children with milder forms of Type 1 diabetes. We prospectively evaluated 75 children with new-onset autoimmune Type 1 diabetes, in whom we collected demographic, anthropometric and clinical dat...

  9. Aging somatosensory cortex displays increased density of WFA-binding perineuronal nets associated with GAD-negative neurons.

    PubMed

    Karetko-Sysa, M; Skangiel-Kramska, J; Nowicka, D

    2014-09-26

    The mechanisms of aging in the brain and the subsequent decrease in cognitive abilities remain elusive. While most studies refer to research conducted in old and senile animals, little is known about the early symptoms of normal, healthy aging. In this study, we examined whether perineuronal nets (PNNs), a special form of extracellular matrix (ECM) tightly associated with neurons that is thought to be involved in limiting neuronal plasticity, undergo changes in density during early aging. Using histochemistry and immunohistochemistry, we found that in middle-aged mice (1-year-old), the density of WFA-binding PNNs in the somatosensory cortex as well as in the visual cortex was increased in comparison to that in young adults (3-month-old). Moreover, in the somatosensory cortex, this increase was not associated with any of the GABAergic neuron types that were examined. We propose that early age-related changes in neuronal plasticity may be associated with this increase and can be conceptualized as the spreading of structural brakes for synaptic rearrangements.

  10. Transpositional inactivation of gadW enhances curli production and biofilm formation in Enterohemorrhagic Escherichia coli O157:H7

    USDA-ARS?s Scientific Manuscript database

    Enterohemorrhagic Escherichia coli (EHEC) O157:H7 has been shown to produce variants that either express or are repressed in the expression of curli fimbriae promoting bacterial attachment, aggregation, and biofilm formation. The variant expression of curli fimbriae in some instances could result fr...

  11. A validation of the 7.5% CO2 model of GAD using paroxetine and lorazepam in healthy volunteers.

    PubMed

    Bailey, Jayne E; Kendrick, Adrian; Diaper, Alison; Potokar, John P; Nutt, David J

    2007-01-01

    The inhalation of 7.5% carbon dioxide (CO2) in healthy subjects produces an increase in blood pressure and heart rate, and increased feelings of anxiety, fear and tension (Bailey et al. 2005). As this state is similar to that of general anxiety rather than panic, we further validated this by examining the effects of anxiolytic medication. Two separate studies in healthy volunteers are described; study one is a double-blind, placebo-controlled study of a single dose of 2 mg lorazepam and study two describes the effects of 21 days of treatment with paroxetine. Gas challenges were air and 7.5% CO2 inhaled for 20 minutes, delivered on day 0 (before treatment) and day 21 (after treatment) in the paroxetine study. Subjective effects were measured using visual analogue scales and questionnaires. When compared with placebo, lorazepam 2 mg significantly reduced peak CO2-induced subjective fear, feelings of wanting to leave, tension and worry. In the paroxetine study, when compared with day 0, day 21 showed a significantly attenuated peak CO2-induced nervousness and a trend for reduced ratings of anxiety, fear, feel like leaving, tense and worried. In these studies we have shown that this CO2 model of anxiety is sensitive to lorazepam and to a lesser extent paroxetine. This gives support to its utility as an experimental model of general anxiety disorder in healthy volunteers.

  12. Prevalence of symptoms of depression and anxiety in adults with cystic fibrosis based on the PHQ-9 and GAD-7 screening questionnaires.

    PubMed

    Quon, Bradley S; Bentham, Wayne D; Unutzer, Jurgen; Chan, Ya-Fen; Goss, Christopher H; Aitken, Moira L

    2015-01-01

    To examine the prevalence of symptoms of depression and anxiety among patients with cystic fibrosis (CF) who were followed up at the University of Washington Adult CF clinic and to identify sociodemographic and clinical factors associated with symptoms. A total of 178 adults with CF were asked to complete the Patient Health Questionnaire-9 for depression and General Anxiety Disorder-7 for anxiety when clinically stable. Clinically significant symptoms of depression and anxiety were defined in the following 2 ways: (1) symptom definition-presence of moderate-to-severe symptoms based on the questionnaires and (2) composite definition-symptom definition or the use of psychiatric medications to manage symptoms. Associations between Patient Health Questionnaire-9 and General Anxiety Disorder-7 scores with sociodemographic (gender, age, age of CF diagnosis, vocation, and spousal status) and clinical factors (forced expiratory volume in 1 second, body mass index, and CF-related diabetes on insulin) were examined. Of 178 patients, 153 (85%) completed the screening questionnaires. Based on the symptom definition, 7% of patients had symptoms of depression and 5% had symptoms of anxiety. Using the composite definition, 22% of patients had symptoms of depression and 10% had symptoms of anxiety. Based on the Patient Health Questionnaire-9, 5% of patients reported suicidal thoughts. In multiple linear regression analysis, only forced expiratory volume in 1 second % predicted was independently associated with Patient Health Questionnaire-9 depression scores, and no sociodemographic or clinical factors were associated with General Anxiety Disorder-7 anxiety scores. We conclude that all adults with CF should be screened for symptoms of depression and anxiety given the difficulty in identifying strong clinical risk factors and the unexpected high rates of suicidal ideation. Copyright © 2015 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.

  13. Distribution and ultrastructure of neurons in opossum piriform cortex displaying immunoreactivity to GABA and GAD and high-affinity tritiated GABA uptake

    SciTech Connect

    Haberly, L.B.; Hansen, D.J.; Feig, S.L.; Presto, S.

    1987-12-08

    GABAergic neurons have been identified in the piriform cortex of the opossum at light and electron microscopic levels by immunocytochemical localization of GABA and the GABA-synthesizing enzyme glutamic acid decarboxylase and by autoradiographic visualization of high-affinity /sup 3/H-GABA uptake. Four major neuron populations have been distinguished on the basis of soma size, shape, and segregation at specific depths and locations: large horizontal cells in layer Ia of the anterior piriform cortex, small globular cells with thin dendrites concentrated in layers Ib and II of the posterior piriform cortex, and multipolar and fusiform cells concentrated in the deep part of layer III in anterior and posterior parts of the piriform cortex and the subjacent endopiriform nucleus. All four populations were well visualized with both antisera, but the large layer Ia horizontal cells displayed only very light /sup 3/H-GABA uptake, thus suggesting a lack of local axon collaterals or lack of high-affinity GABA uptake sites. The large, ultrastructurally distinctive somata of layer Ia horizontal cells receive a very small number of symmetrical synapses; the thin, axonlike dendrites of small globular cells are exclusively postsynaptic and receive large numbers of both symmetrical and asymmetrical synapses, in contrast to somata which receive a small number of both types; and the deep multipolar and fusiform cells receive a highly variable number of symmetrical and asymmetrical synapses on somata and proximal dendrites. Labeled puncta of axon terminal dimensions were found in large numbers in the neuropil surrounding pyramidal cell somata in layer II and in the endopiriform nucleus. Moderately large numbers of labeled puncta were found in layer I at the depth of pyramidal cell apical dendrites with greater numbers in layer Ia at the depth of distal apical segments than in layer Ib.

  14. Evidence That HLA Class I and II Associations With Type 1 Diabetes, Autoantibodies to GAD and Autoantibodies to IA-2, Are Distinct

    PubMed Central

    Howson, Joanna M.M.; Stevens, Helen; Smyth, Deborah J.; Walker, Neil M.; Chandler, Kyla A.; Bingley, Polly J.; Todd, John A.

    2011-01-01

    OBJECTIVE A major feature of type 1 diabetes is the appearance of islet autoantibodies before diagnosis. However, although the genetics of type 1 diabetes is advanced, the genetics of islet autoantibodies needs further investigation. The primary susceptibility loci in type 1 diabetes, the HLA class I and II genes, are believed to determine the specificity and magnitude of the autoimmune response to islet antigens. We investigated the association of glutamic acid decarboxylase autoantibodies (GADA) and insulinoma-associated antigen-2 autoantibodies (IA-2A) with the HLA region. RESEARCH DESIGN AND METHODS Associations of GADA and IA-2A with HLA-DRB1, HLA-DQB1, HLA-B, HLA-C, HLA-A, MICA, and 3,779 single nucleotide polymorphisms (SNPs) were analyzed in 2,531 childhood-onset case subjects (median time since diagnosis 5 years). All analyses were adjusted for age-at-diagnosis and duration of diabetes. RESULTS GADA and IA-2A were associated with an older age-at-diagnosis (P < 10−19). For GADA, the primary association was with HLA-DQB1 (P = 9.00 × 10−18), with evidence of a second independent effect in the HLA class I region with SNP, rs9266722 (P = 2.84 × 10−6). HLA-DRB1 had the strongest association with IA-2A (P = 1.94 × 10−41), with HLA-A*24 adding to the association, albeit negatively (P = 1.21 × 10−10). There was no evidence of association of either IA-2A or GADA with the highly type 1 diabetes predisposing genotype, HLA-DRB1*03/04. CONCLUSIONS Despite genetic association of type 1 diabetes and the islet autoantibodies localizing to the same HLA class II genes, HLA-DRB1 and HLA-DQB1, the effects of the class II alleles and genotypes involved are quite different. Therefore, the presence of autoantibodies is unlikely to be causal, and their role in pathogenesis remains to be established. PMID:21831970

  15. More Power to the Executive? A Preliminary Test of CBT plus Executive Skills Training for Treatment of Late-Life GAD

    ERIC Educational Resources Information Center

    Mohlman, Jan

    2008-01-01

    One hypothesized reason for the lower rates of cognitive behavior therapy (CBT) response among older as compared to younger anxiety patients is that they are more likely to show age-related deficits in executive skills, which are complex cognitive skills involved in the regulation of negative affect. Following an 8-week baseline period, this pilot…

  16. Clinical and Genetic Characteristics of Non-Insulin-Requiring Glutamic Acid Decarboxylase (GAD) Autoantibody-Positive Diabetes: A Nationwide Survey in Japan.

    PubMed

    Yasui, Junichi; Kawasaki, Eiji; Tanaka, Shoichiro; Awata, Takuya; Ikegami, Hiroshi; Imagawa, Akihisa; Uchigata, Yasuko; Osawa, Haruhiko; Kajio, Hiroshi; Kawabata, Yumiko; Shimada, Akira; Takahashi, Kazuma; Yasuda, Kazuki; Yasuda, Hisafumi; Hanafusa, Toshiaki; Kobayashi, Tetsuro

    2016-01-01

    Glutamic acid decarboxylase autoantibodies (GADAb) differentiate slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) from phenotypic type 2 diabetes, but many GADAb-positive patients with diabetes do not progress to insulin-requiring diabetes. To characterize GADAb-positive patients with adult-onset diabetes who do not require insulin therapy for >5 years (NIR-SPIDDM), we conducted a nationwide cross-sectional survey in Japan. We collected 82 GADAb-positive patients who did not require insulin therapy for >5 years (NIR-SPIDDM) and compared them with 63 patients with insulin-requiring SPIDDM (IR-SPIDDM). Clinical and biochemical characteristics, HLA-DRB1-DQB1 haplotypes, and predictive markers for progression to insulin therapy were investigated. Compared with the IR-SPIDDM group, the NIR-SPIDDM patients showed later diabetes onset, higher body mass index, longer duration before diagnosis, and less frequent hyperglycemic symptoms at onset. In addition, C-peptide, LDL-cholesterol, and TG were significantly higher in the NIR-SPIDDM compared to IR-SPIDDM patients. The NIR-SPIDDM group had lower frequency of susceptible HLA-DRB1*04:05-DQB1*04:01 and a higher frequency of resistant HLA-DRB1*15:01-DQB1*06:02 haplotype compared to IR-SPIDDM. A multivariable analysis showed that age at diabetes onset (OR = 0.82), duration before diagnosis of GADAb-positive diabetes (OR = 0.82), higher GADAb level (≥10.0 U/ml) (OR = 20.41), and fasting C-peptide at diagnosis (OR = 0.07) were independent predictive markers for progression to insulin-requiring diabetes. An ROC curve analysis showed that the optimal cut-off points for discriminating two groups was the GADAb level of 13.6 U/ml, age of diabetes onset of 47 years, duration before diagnosis of 5 years, and fasting C-peptide of 0.65 ng/ml. Clinical, biochemical and genetic characteristics of patients with NIR-SPIDDM are different from those of IR-SPIDDM patients. Age of diabetes onset, duration before GADAb-positivity, GADAb level, and fasting C-peptide at diagnosis must be carefully considered in planning prevention trials for SPIDDM.

  17. Slowly progressive insulin-dependent (type 1) diabetes positive for anti-GAD antibody ELISA test may be strongly associated with a future insulin-dependent state.

    PubMed

    Oikawa, Yoichi; Tanaka, Hajime; Uchida, Junko; Atsumi, Yoshihiro; Osawa, Masaya; Katsuki, Takeshi; Kawai, Toshihide; Shimada, Akira

    2017-02-27

    Slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM), believed to be caused by β-cell destruction through islet-cell autoimmunity, gradually progresses to an insulin-dependent state over time. Although the presence of anti-glutamic acid decarboxylase antibody (GADA) is required for the diagnosis of SPIDDM, a recent change in the GADA assay kit from radioimmunoassay (RIA) to enzyme-linked immunosorbent assay (ELISA) yields mismatched GADA test results between the two kits, leading to confusion in understanding the pathological conditions of SPIDDM in Japan. Thus, this study aimed to clarify the difference in the clinical characteristics of GADA-ELISA-positive and GADA-ELISA-negative patients originally diagnosed as SPIDDM by GADA-RIA test. As a result, 42 of 63 original GADA-RIA-positive SPIDDM patients (66.7%) were found to be GADA-ELISA-positive, whereas the remaining 21 patients (33.3%) were found to be GADA-ELISA-negative. In patients with shorter disease duration, GADA-ELISA-positive patients showed significantly lower serum C-peptide levels than GADA-ELISA-negative patients. Meanwhile, in patients with longer disease duration, serum C-peptide levels were comparably decreased in GADA-ELISA-positive and GADA-ELISA-negative patients. A significant inverse correlation between serum C-peptide level and disease duration was observed in GADA-ELISA-negative patients, but not in GADA-ELISA-positive patients, suggesting that insulin secretory capacity may be gradually impaired over time also in GADA-ELISA-negative SPIDDM patients. In conclusion, physicians should be aware that GADA-ELISA-positive SPIDDM may be strongly associated with a future insulin-dependent state. Meanwhile, physicians should be careful in treating GADA-ELISA-negative SPIDDM patients diagnosed as type 2 DM, and cautiously follow the clinical course, in accordance with SPIDDM.

  18. Early continuous white noise exposure alters auditory spatial sensitivity and expression of GAD65 and GABAA receptor subunits in rat auditory cortex.

    PubMed

    Xu, Jinghong; Yu, Liping; Cai, Rui; Zhang, Jiping; Sun, Xinde

    2010-04-01

    Sensory experiences have important roles in the functional development of the mammalian auditory cortex. Here, we show how early continuous noise rearing influences spatial sensitivity in the rat primary auditory cortex (A1) and its underlying mechanisms. By rearing infant rat pups under conditions of continuous, moderate level white noise, we found that noise rearing markedly attenuated the spatial sensitivity of A1 neurons. Compared with rats reared under normal conditions, spike counts of A1 neurons were more poorly modulated by changes in stimulus location, and their preferred locations were distributed over a larger area. We further show that early continuous noise rearing induced significant decreases in glutamic acid decarboxylase 65 and gamma-aminobutyric acid (GABA)(A) receptor alpha1 subunit expression, and an increase in GABA(A) receptor alpha3 expression, which indicates a returned to the juvenile form of GABA(A) receptor, with no effect on the expression of N-methyl-D-aspartate receptors. These observations indicate that noise rearing has powerful adverse effects on the maturation of cortical GABAergic inhibition, which might be responsible for the reduced spatial sensitivity.

  19. No Contribution of GAD-65 and IA-2 Autoantibodies around Time of Diagnosis to the Increasing Incidence of Juvenile Type 1 Diabetes: A 9-Year Nationwide Danish Study.

    PubMed

    Thorsen, Steffen U; Pipper, Christian B; Mortensen, Henrik B; Pociot, Flemming; Johannesen, Jesper; Svensson, Jannet

    2016-01-01

    Aims. A new perspective on autoantibodies as pivotal players in the pathogenesis of type 1 diabetes (T1D) has recently emerged. Our key objective was to examine whether increased levels of autoantibodies against the β-cell autoantigens glutamic acid decarboxylase (isoform 65) (GADA) and insulinoma associated antigen-2A (IA-2A) mirrored the 3.4% annual increase in incidence of T1D. Methods. From the Danish Childhood Diabetes Register, we randomly selected 500 patients and 500 siblings for GADA and IA-2A analysis (1997 through 2005). Blood samples were taken within three months after onset. A robust log-normal regression model was used. Nine hundred children and adolescents had complete records and were included in the analysis. Cochran-Armitage test for trend was used to evaluate changes in prevalence of autoantibody positivity by period. Results. No significant changes in levels of GADA and IA-2A were found over our 9-year study period. No trends in autoantibody positivity-in either patients or siblings-were found. Levels of GADA and IA-2A were significantly associated with HLA risk groups and GADA with age. Conclusion. The prevalence of positivity and the levels of GADA and IA-2A have not changed between 1997 and 2005 in newly diagnosed patients with T1D and their siblings without T1D.

  20. Three Distinct Glutamate Decarboxylase Genes in Vertebrates

    PubMed Central

    Grone, Brian P.; Maruska, Karen P.

    2016-01-01

    Gamma-aminobutyric acid (GABA) is a widely conserved signaling molecule that in animals has been adapted as a neurotransmitter. GABA is synthesized from the amino acid glutamate by the action of glutamate decarboxylases (GADs). Two vertebrate genes, GAD1 and GAD2, encode distinct GAD proteins: GAD67 and GAD65, respectively. We have identified a third vertebrate GAD gene, GAD3. This gene is conserved in fishes as well as tetrapods. We analyzed protein sequence, gene structure, synteny, and phylogenetics to identify GAD3 as a homolog of GAD1 and GAD2. Interestingly, we found that GAD3 was lost in the hominid lineage. Because of the importance of GABA as a neurotransmitter, GAD3 may play important roles in vertebrate nervous systems. PMID:27461130

  1. A heterozygous deletion in the glutamate decarboxylase 67 gene enhances maternal and fetal stress vulnerability.

    PubMed

    Uchida, Taku; Oki, Yutaka; Yanagawa, Yuchio; Fukuda, Atsuo

    2011-04-01

    Both down-regulation of glutamate decarboxylase 67 (GAD67) and maternal exposure to severe stress during pregnancy can increase the risk of schizophrenia and related psychotic disorders in the offspring. To investigate a gene-environment interaction, we performed the restraint-and-light stress to pregnant GAD67-GFP knock-in (GAD67(+/GFP)) and wild-type (GAD67(+/+)) mice three times a day for 45 min per session during gestational day (G) 15.0-17.5. The stress hormone (corticosterone) level of pregnant GAD67(+/GFP) mice (the overall GABA content is reduced because of the destruction of one allele of the endogenous GAD67 gene) was higher than that of GAD67(+/+), even without stress. The fetal body weights (GAD67(+/+)) in the GAD67(+/GFP) mothers were lower than those in the GAD67(+/+) mothers. GAD67(+/GFP) fetuses exhibited higher corticosterone (CORT) levels than GAD67(+/+) fetuses, even in non-stressed GAD67(+/+) mothers. Fetal body weight-decreases and CORT-increases by maternal stress (GAD67(+/+) mother) were significantly more in the GAD67(+/GFP) fetuses than the GAD67(+/+) fetuses. These results indicate that a GAD67 heterozygous deletion itself enhances vulnerability by many aspects, e.g., maternal stress, maternity, and being in utero. Thus, an abnormality in GAD67 could interact with environmental risk factors of psychiatric disorders, including schizophrenia.

  2. Comorbidity of Generalized Anxiety Disorder and Substance Use Disorders: Results from the National Epidemiologic Survey on Alcohol and Related Conditions

    PubMed Central

    Alegría, Analucía A.; Hasin, Deborah S.; Nunes, Edward V.; Liu, Shang-Min; Davies, Carrie; Grant, Bridget F.; Blanco, Carlos

    2009-01-01

    Objective Prior research has consistently documented a strong association between generalized anxiety disorder (GAD) and substance use disorder (SUD). GAD and SUD comorbidity (GAD-SUD) represents clinical challenges as the patients’ symptoms are often more severe and are frequently prolonged making their management more complex when compared with individuals with GAD only. The purpose of this study was to examine whether individuals with GAD-SUD differ meaningfully from individuals with GAD and no SUD comorbidity (GAD-NSUD) in terms of demographic characteristics, risk factors, psychiatric comorbidity and clinical correlates. Methods Data were derived from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) (N=43,093). Diagnoses were made using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV version. Results We found that the lifetime prevalence rate of GAD-SUD is about 2.04% while that of GAD-NSUD is of 2.10%. Individuals with GAD-SUD showed higher psychiatric comorbidity rates than those with GAD-NSUD. Treatment seeking rates for GAD are equally low in GAD-SUD and GAD-NSUD. Both groups were as likely to receive pharmacological treatment for anxiety. Conclusion The findings of our study indicate that individuals of GAD-SUD constitutes half of the lifetime prevalence of GAD and that GAD-SUD is associated with high overall vulnerability for additional psychopathology, particularly in the externalizing spectrum, higher disability and higher use of alcohol and drugs to relieve anxiety symptoms. PMID:20923623

  3. Fiches pratiques: La Phonetique, moi j'aime!; Dites-le avec des fleurs; Votre argent m'interresse!; Son nom d'Emily L.... (Practical Ideas: Phonetics, I Love It!; Say It with Flowers; Your Money Interests Me!; Her Name, Emily L....).

    ERIC Educational Resources Information Center

    Francais dans le Monde, 1990

    1990-01-01

    Four ideas for French classroom activities are described: a phonetics exercise focusing on two vowels; an activity developing self-expressive skills using advertisements for flowers; an exercise for developing vocabulary relating to money and investment; and a literary study of a 1987 novel. (MSE)

  4. Fiches pratiques: La Phonetique, moi j'aime!; Dites-le avec des fleurs; Votre argent m'interresse!; Son nom d'Emily L.... (Practical Ideas: Phonetics, I Love It!; Say It with Flowers; Your Money Interests Me!; Her Name, Emily L....).

    ERIC Educational Resources Information Center

    Francais dans le Monde, 1990

    1990-01-01

    Four ideas for French classroom activities are described: a phonetics exercise focusing on two vowels; an activity developing self-expressive skills using advertisements for flowers; an exercise for developing vocabulary relating to money and investment; and a literary study of a 1987 novel. (MSE)

  5. Public health assessment for petitioned public health assessment, Old Douglas County Landfill (a/k/a Douglas County/Cedar Mountain Landfill), Douglasville, Douglas County, Georgia, Region 4: CERCLIS Number GAD984279232. Final report

    SciTech Connect

    1998-12-11

    The Old Douglas County Landfill in Douglasville, Georgia, operated from 1973 until 1987 as a municipal waste landfill. Existing landfill records specify that household wastes were received, however, industrial wastes are suspected to have been disposed at this landfill. The Agency for Toxic Substances and Disease Registry (ATSDR) concludes that private well water near the landfill is safe to drink. The surface water from Gothard`s Creek and the settling ponds on the landfill do not have chemicals present at levels of public health concern. The settling ponds on the landfill and parts of Gothard`s Creek contain elevated levels of lead, manganese, and iron in the sediment that are not harmfull to humans under typical exposure conditions. The soil located on- and off-site also had elevated levels of lead, manganese, and iron, however, these metals do not pose a threat to human health under typical exposure conditions. Currently, human contact with contaminants in soil, sediment, and surface water associated with Old Douglas County Landfill is not expected to result in adverse health effects. ATSDR determined that the methane monitoring locations and frequency at the landfill are inadequate to fully evaluate conditions at the perimeter of the landfill or near adjacent houses.

  6. Public health assessment for petitioned public health assessment, Escambia Brunswick Wood (a/k/a Brunswick Wood Preserving), Brunswick, Glynn County, Georgia, Region 4. CERCLIS Number GAD981024466; Final report

    SciTech Connect

    1999-02-09

    Brunswick Wood Preserving (BWP) is in Brunswick, Glynn County, in eastern Georgia. Both owners of the site manufactured wooden poles and pilings, which were treated with creosote and solutions of pentachlorophenate. This activity, as well as improper storage and disposal practices, lead to the contamination of several environmental media with chromated copper arsenate (CCA), pentachlorophenol (PCP), polycyclic aromatic hydrocarbons (PAH`s), and dioxin. The site is categorized as an indeterminant public health hazard based upon data reviewed and observations made by ATSDR. This conclusion category was selected because the extent and magnitude of groundwater contamination and the extent of contamination in Burnett Creek have not been fully characterized. Data reviewed for this public health assessment does not indicate that exposure to chemicals at levels of concern is occurring.

  7. Gene controlling L-glutamic acid decarboxylase synthesis in Escherichia coli K-12.

    PubMed

    Lupo, M; Halpern, Y S

    1970-08-01

    Genetically related Escherichia coli K-12 strains were found to differ widely in their l-glutamic acid decarboxylase (GAD) activity. This variation is due to differences in the amount of GAD produced by the different cultures, rather than to the appearance of altered enzymes differing in catalytic activity. A regulatory gene, gadR, which controls the amount of GAD was mapped on the E. coli K-12 chromosome. A strain with a lesion in the structural gene for GAD is described.

  8. The Author and His Works

    ERIC Educational Resources Information Center

    Spain Today, 1971

    1971-01-01

    Works of Emilio Garcia Gomez, Dario Fernandez Florez, Armando Lopez Salinas, Jaime de Arminan, Luis Lopez Anglada, and Carmen Bravo Villasante are analyzed in this continuing series on Spanish authors. (DS)

  9. 76 FR 81482 - Information Collection; Submission for OMB Review, Comment Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-28

    ..., Jaime Renner, at (612) 334-4085 or email to jrenner@cns.gov . Individuals who use a telecommunications...) Electronically by email to: smar@omb.eop.gov . SUPPLEMENTARY INFORMATION: The OMB is particularly interested in...

  10. The Author and His Works

    ERIC Educational Resources Information Center

    Spain Today, 1971

    1971-01-01

    Works of Emilio Garcia Gomez, Dario Fernandez Florez, Armando Lopez Salinas, Jaime de Arminan, Luis Lopez Anglada, and Carmen Bravo Villasante are analyzed in this continuing series on Spanish authors. (DS)

  11. Latin America Report.

    DTIC Science & Technology

    1985-08-09

    Ruiz Perdomo the tenth. The 13th will be headed by Col Jaime Sadonic Sanchez , replacing Col Jaime Ruiz , and the 14th by Col Sigifredo Delgado Caldas...for mayor of Manaus will be Lt Gov Manuel Ribeiro of the PMDB, with the PFL’s Aristides Queiros as candidate for deputy mayor. There is also...Force], an officer who has held several important posts. The director of police, Maj Gen Victor Alberto Delgado Mallarino, will be the first general

  12. Characteristics of Generalized Anxiety Disorder in Patients With Dementia

    PubMed Central

    Calleo, Jessica; Kunik, Mark E.; Reid, Dana; Kraus-Schuman, Cynthia; Paukert, Amber; Regev, Tziona; Wilson, Nancy; Petersen, Nancy J.; Snow, A. Lynn; Stanley, Melinda

    2011-01-01

    Background Overlap of cognitive and anxiety symptoms (i.e., difficulty concentrating, fatigue, restlessness) contributes to inconsistent, complicated assessment of generalized anxiety disorder (GAD)in persons with dementia. Methods Anxious dementia patients completed a psychiatric interview, the Penn State Worry Questionnaire-Abbreviated, and the Rating for Anxiety in Dementia scale. Analyses to describe the 43 patients with and without GAD included the Wilcoxon Mann-Whitney two-sample test, Fisher’s exact test. Predictors of GAD diagnosis were identified using logistic regression. Results Those with GAD were more likely to be male, have less severe dementia and endorsed more worry, and anxiety compared to patients without GAD. Gender, muscle tension and fatigue differentiated those with GAD from those without GAD. Conclusions Although this study is limited by a small sample, it describes clinical characteristics of GAD in dementia, highlighting the importance of muscle tension and fatigue in recognizing GAD in persons with dementia. PMID:22062223

  13. Pathogenic Roles of Glutamic Acid Decarboxylase 65 Autoantibodies in Cerebellar Ataxias.

    PubMed

    Mitoma, Hiroshi; Manto, Mario; Hampe, Christiane S

    2017-01-01

    Reports suggesting a pathogenic role of autoantibodies directed against glutamic acid decarboxylase 65 (GAD65Abs) in cerebellar ataxias (CAs) are reviewed, and debatable issues such as internalization of antibodies by neurons and roles of epitopes are discussed. GAD65 is one of two enzymes that catalyze the conversion of glutamate to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). A pathogenic role of GAD65Ab in CAs is suggested by in vivo and in vitro studies. (1) Intracerebellar administration of cerebrospinal fluid (CSF) immunoglobulins (IgGs) obtained from GAD65Ab-positive CA patients impairs cerebellar modulation of motor control in rats. (2) CSF IgGs act on terminals of GABAergic neurons and decrease the release of GABA in cerebellar slices from rats and mice. (3) Absorption of GAD65Ab by recombinant GAD65 diminishes the above effects, and monoclonal human GAD65Ab (b78) mimic the effects of CSF IgGs in vivo and in vitro. Studies using GAD65-KO mice confirm that the target molecule is GAD65. (4) Notably, the effects of GAD65Ab depend on the epitope specificity of the monoclonal GAD65Ab. Taken together, these results indicate that epitope-specific GAD65Ab-induced impairment of GABA release is involved in the pathogenesis of GAD65Ab-positive CA and support the early detection of GAD65Ab-associated CA to initiate immunotherapy before irreversible neuronal death in the cerebellum.

  14. Pathogenic Roles of Glutamic Acid Decarboxylase 65 Autoantibodies in Cerebellar Ataxias

    PubMed Central

    Hampe, Christiane S.

    2017-01-01

    Reports suggesting a pathogenic role of autoantibodies directed against glutamic acid decarboxylase 65 (GAD65Abs) in cerebellar ataxias (CAs) are reviewed, and debatable issues such as internalization of antibodies by neurons and roles of epitopes are discussed. GAD65 is one of two enzymes that catalyze the conversion of glutamate to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). A pathogenic role of GAD65Ab in CAs is suggested by in vivo and in vitro studies. (1) Intracerebellar administration of cerebrospinal fluid (CSF) immunoglobulins (IgGs) obtained from GAD65Ab-positive CA patients impairs cerebellar modulation of motor control in rats. (2) CSF IgGs act on terminals of GABAergic neurons and decrease the release of GABA in cerebellar slices from rats and mice. (3) Absorption of GAD65Ab by recombinant GAD65 diminishes the above effects, and monoclonal human GAD65Ab (b78) mimic the effects of CSF IgGs in vivo and in vitro. Studies using GAD65-KO mice confirm that the target molecule is GAD65. (4) Notably, the effects of GAD65Ab depend on the epitope specificity of the monoclonal GAD65Ab. Taken together, these results indicate that epitope-specific GAD65Ab-induced impairment of GABA release is involved in the pathogenesis of GAD65Ab-positive CA and support the early detection of GAD65Ab-associated CA to initiate immunotherapy before irreversible neuronal death in the cerebellum. PMID:28386570

  15. Functional impairment related to painful physical symptoms in patients with generalized anxiety disorder with or without comorbid major depressive disorder: post hoc analysis of a cross-sectional study

    PubMed Central

    2011-01-01

    Background Generalized anxiety disorder (GAD) is the most frequent anxiety disorder in primary care patients. It is known that painful physical symptoms (PPS) are associated with GAD, regardless the presence of comorbid major depressive disorder (MDD). However the specific role of such symptoms in patients' functional impairment is not well understood. The objective of the present study is to assess functional impairment related to the presence of PPS in patients with GAD. Methods This is a post hoc analysis of a cross-sectional study. Functioning, in the presence (overall pain score >30; Visual Analog Scale) or absence of PPS, was assessed using the Sheehan Disability Scale (SDS) in three groups of patients; 1) GAD and comorbid MDD (GAD+MDD+), 2) GAD without comorbid MDD (GAD+MDD-), 3) controls (GAD-MDD-). ANCOVA models were used. Results Of those patients with GAD+MDD+ (n = 559), 436 (78.0%) had PPS, compared with GAD+MDD- (249 of 422, 59%) and controls (95 of 336, 28.3%). Functioning worsened in both GAD groups in presence of PPS (SDS least squares mean total score: 16.1 vs. 9.8, p < 0.0001, GAD+MDD+; 14.3 vs. 8.2, p < 0.0001, GAD+MDD-). The presence of PPS was significantly associated with less productivity. Conclusions Functional impairment related to the presence of PPS was relevant. Clinical implications should be considered. PMID:21510887

  16. Cloning and primary structure of a human islet isoform of glutamic acid decarboxylase from chromosome 10

    SciTech Connect

    Karlsen, A.E.; Hagopian, W.A.; Grubin, C.E.; Dube, S.; Disteche, C.M.; Adler, D.A.; Baermeier, H.; Lernmark, A. ); Mathewes, S.; Grant, F.J.; Foster, D. )

    1991-10-01

    Glutamic acid decarboxylase which catalyzes formation of {gamma}-aminobutyric acid from L-glutamic acid, is detectable in different isoforms with distinct electrophoretic and kinetic characteristics. GAD has also been implicated as an autoantigen in the vastly differing autoimmune disease stiff-man syndrome and insulin-dependent diabetes mellitus. Despite the differing GAD isoforms, only one type of GAD cDNA (GAD-1), localized to a syntenic region of chromosome 2, has been isolated from rat, mouse, and cat. Using sequence information from GAD-1 to screen a human pancreatic islet cDNA library, the authors describe the isolation of an additional GAD cDNA (GAD-2), which was mapped to the short arm of human chromosome 10. Genomic Southern blotting with GAD-2 demonstrated a hybridization pattern different form that detected by GAD-1. GAD-2 recognizes a 5.6-kilobase transcript in both islets and brain, in contrast to GAD-1, which detects a 3.7-kilobase transcript in brain only. The deduced 585-amino acid sequence coded for by GAD-2 shows < 65% identify to previously published, highly conserved GAD-1 brain sequences, which show > 96% deduced amino acid sequence homology among the three species.

  17. Impact of Comorbid Depressive Disorders on Subjective and Physiological Responses to Emotion in Generalized Anxiety Disorder

    PubMed Central

    Seeley, Saren H.; Mennin, Douglas S.; Aldao, Amelia; McLaughlin, Katie A.; Rottenberg, Jonathan; Fresco, David M.

    2016-01-01

    Generalized anxiety disorder (GAD) and unipolar depressive disorders (UDD) have been shown to differ from each other in dimensions of affective functioning despite their high rates of comorbidity. We showed emotional film clips to a community sample (n = 170) with GAD, GAD with secondary UDD, or no diagnosis. Groups had comparable subjective responses to the clips, but the GAD group had significantly lower heart rate variability (HRV) during fear and after sadness, compared to controls. While HRV in the GAD and control groups rose in response to the sadness and happiness clips, it returned to baseline levels afterwards in the GAD group, potentially indicating lesser ability to sustain attention on emotional stimuli. HRV in the GAD + UDD group changed only in response to sadness, but was otherwise unvarying between timepoints. Though preliminary, these findings suggest comorbid UDD as a potential moderator of emotional responding in GAD. PMID:27660375

  18. Structural characterization of the mechanism through which human glutamic acid decarboxylase auto-activates

    PubMed Central

    Langendorf, Christopher G.; Tuck, Kellie L.; Key, Trevor L. G.; Fenalti, Gustavo; Pike, Robert N.; Rosado, Carlos J.; Wong, Anders S. M.; Buckle, Ashley M.; Law, Ruby H. P.; Whisstock, James C.

    2012-01-01

    Imbalances in GABA (γ-aminobutyric acid) homoeostasis underlie psychiatric and movement disorders. The ability of the 65 kDa isoform of GAD (glutamic acid decarboxylase), GAD65, to control synaptic GABA levels is influenced through its capacity to auto-inactivate. In contrast, the GAD67 isoform is constitutively active. Previous structural insights suggest that flexibility in the GAD65 catalytic loop drives enzyme inactivation. To test this idea, we constructed a panel of GAD65/67 chimaeras and compared the ability of these molecules to auto-inactivate. Together, our data reveal the important finding that the C-terminal domain of GAD plays a key role in controlling GAD65 auto-inactivation. In support of these findings, we determined the X-ray crystal structure of a GAD65/67 chimaera that reveals that the conformation of the catalytic loop is intimately linked to the C-terminal domain. PMID:23126365

  19. Impact of Comorbid Depressive Disorders on Subjective and Physiological Responses to Emotion in Generalized Anxiety Disorder.

    PubMed

    Seeley, Saren H; Mennin, Douglas S; Aldao, Amelia; McLaughlin, Katie A; Rottenberg, Jonathan; Fresco, David M

    2016-06-01

    Generalized anxiety disorder (GAD) and unipolar depressive disorders (UDD) have been shown to differ from each other in dimensions of affective functioning despite their high rates of comorbidity. We showed emotional film clips to a community sample (n = 170) with GAD, GAD with secondary UDD, or no diagnosis. Groups had comparable subjective responses to the clips, but the GAD group had significantly lower heart rate variability (HRV) during fear and after sadness, compared to controls. While HRV in the GAD and control groups rose in response to the sadness and happiness clips, it returned to baseline levels afterwards in the GAD group, potentially indicating lesser ability to sustain attention on emotional stimuli. HRV in the GAD + UDD group changed only in response to sadness, but was otherwise unvarying between timepoints. Though preliminary, these findings suggest comorbid UDD as a potential moderator of emotional responding in GAD.

  20. What's the Worry with Social Anxiety? Comparing Cognitive Processes in Children with Generalized Anxiety Disorder and Social Anxiety Disorder.

    PubMed

    Hearn, Cate S; Donovan, Caroline L; Spence, Susan H; March, Sonja; Holmes, Monique C

    2016-12-05

    Social anxiety disorder (SAD) in children is often comorbid with generalized anxiety disorder (GAD). We investigated whether worry, intolerance of uncertainty, beliefs about worry, negative problem orientation and cognitive avoidance, that are typically associated with GAD, are present in children with SAD. Participants included 60 children (8-12 years), matched on age and gender. Groups included children: with primary GAD and without SAD (GAD); with primary SAD and without GAD (SAD); and without an anxiety disorder (NAD). GAD and SAD groups scored significantly higher than the NAD group on worry, intolerance of uncertainty, negative beliefs about worry and negative problem orientation, however, they did not score differently from each other. Only the GAD group scored significantly higher than the NAD group on cognitive avoidance. These findings further understanding of the structure of SAD and suggest that the high comorbidity between SAD and GAD may be due to similar underlying processes within the disorders.

  1. Living with Anxiety Disorders, Worried Sick

    MedlinePlus

    ... who suffered for most of his life with generalized anxiety disorder (GAD) and panic attacks, describes here how he ... help through a counselor. I was diagnosed with generalized anxiety disorder (GAD) including panic attacks. I discovered that my ...

  2. Anxiety Disorders

    MedlinePlus

    ... here. generalized anxiety disorder social phobia panic disorder Generalized Anxiety Disorder (GAD) Click for more information All of us ... health, money, or family problems. But people with generalized anxiety disorder (GAD) are extremely worried about these and many ...

  3. Presumed case of "stiff-horse syndrome" caused by decreased gamma-aminobutyric acid (GABA) production in an American Paint mare.

    PubMed

    Purcell, Tawna Backman; Sellers, Ann Davidson; Goehring, Lutz S

    2012-01-01

    Glutamic acid decarboxylase (GAD) converts glutamic acid into the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Increased serum GAD (auto) antibody concentrations were found in a mare with increased postural musculature tone resulting in stiffness and recumbence. The mare was treated with dexamethasone which resulted in resolution of clinical signs and decreased GAD antibody concentrations.

  4. Generalized Anxiety Disorder: A Comparison of Symptom Change in Adults Receiving Cognitive-Behavioral Therapy or Applied Relaxation

    ERIC Educational Resources Information Center

    Donegan, Eleanor; Dugas, Michel J.

    2012-01-01

    Objective: Generalized anxiety disorder (GAD) is characterized by excessive worry and somatic symptoms of anxiety (e.g., restlessness, muscle tension). Several psychological treatments lead to significant reductions in GAD symptoms by posttreatment. However, little is known about how GAD symptoms change over time. Our main goal was to examine how…

  5. Integrating Religion and Spirituality into Treatment for Late-Life Anxiety: Three Case Studies

    ERIC Educational Resources Information Center

    Barrera, Terri L.; Zeno, Darrell; Bush, Amber L.; Barber, Catherine R.; Stanley, Melinda A.

    2012-01-01

    Generalized anxiety disorder (GAD) is common in older adults and, although cognitive behavioral therapy (CBT) is an efficacious treatment for late-life GAD, effect sizes are only moderate and attrition rates are high. One way to increase treatment acceptability and enhance current cognitive behavioral treatments for GAD in older adults might be to…

  6. The latent structure of generalized anxiety disorder in midlife adults.

    PubMed

    Marcus, David K; Sawaqdeh, Abere; Kwon, Paul

    2014-02-28

    Generalized anxiety disorder (GAD) is identified as a discrete disorder in the DSM-5, but evidence suggests that GAD and the related construct of pathological worry possesses a dimensional latent structure. The objective of this study was to ascertain the latent structure of GAD using taxometric methods. A subsample of adults (N=2061) from the Midlife in the United States Study, a national sample of Americans, provided the data. Additional data from individuals who were re-interviewed 10 year later (n=1228) were also analyzed. Items corresponding to the DSM-IV-TR diagnostic criteria for GAD were used to generate indicators for the taxometric analyses. Multiple taxometric procedures provided no evidence that GAD has a categorical or taxonic latent structure. Instead, the results were more consistent with the proposition that GAD exists on a continuum. Evidence that GAD is dimensional suggests that dichotomizing individuals into GAD versus non-GAD groups will typically result in decreased statistical power. They also suggest that any diagnostic thresholds for identifying GAD are likely to be arbitrary. The findings are consistent with models that locate GAD within the framework of extant dimensional models of personality and with research that emphasizes a multifactorial etiology for GAD. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  7. Generalized Anxiety Disorder: A Comparison of Symptom Change in Adults Receiving Cognitive-Behavioral Therapy or Applied Relaxation

    ERIC Educational Resources Information Center

    Donegan, Eleanor; Dugas, Michel J.

    2012-01-01

    Objective: Generalized anxiety disorder (GAD) is characterized by excessive worry and somatic symptoms of anxiety (e.g., restlessness, muscle tension). Several psychological treatments lead to significant reductions in GAD symptoms by posttreatment. However, little is known about how GAD symptoms change over time. Our main goal was to examine how…

  8. Integrating Religion and Spirituality into Treatment for Late-Life Anxiety: Three Case Studies

    ERIC Educational Resources Information Center

    Barrera, Terri L.; Zeno, Darrell; Bush, Amber L.; Barber, Catherine R.; Stanley, Melinda A.

    2012-01-01

    Generalized anxiety disorder (GAD) is common in older adults and, although cognitive behavioral therapy (CBT) is an efficacious treatment for late-life GAD, effect sizes are only moderate and attrition rates are high. One way to increase treatment acceptability and enhance current cognitive behavioral treatments for GAD in older adults might be to…

  9. Comparative efficacy of the generalized anxiety disorder 7-item scale and the Edinburgh Postnatal Depression Scale as screening tools for generalized anxiety disorder in pregnancy and the postpartum period.

    PubMed

    Simpson, William; Glazer, Melanie; Michalski, Natalie; Steiner, Meir; Frey, Benicio N

    2014-08-01

    About 24.1% of pregnant women suffer from at least 1 anxiety disorder, 8.5% of whom suffer specifically from generalized anxiety disorder (GAD). GAD is often associated with major depressive disorder (MDD). During the perinatal period, the presence of physical and somatic symptoms often makes differentiation between depression and anxiety more challenging. To date, no screening tools have been developed to detect GAD in the perinatal population. We investigated the psychometric properties of the GAD 7-item Scale (GAD-7) as a screening tool for GAD in pregnant and postpartum women. Two hundred and forty perinatal women (n = 155 pregnant and n = 85 postpartum) referred for psychiatric consultation were enrolled. On the day of initial assessment, all women completed the GAD-7 and the Edinburgh Postnatal Depression Scale (EPDS). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-based diagnoses were made by experienced psychiatrists. Scores from the GAD-7 and EPDS were compared with the clinical diagnoses to evaluate the psychometric properties of the GAD-7 and EPDS when used as a screening tool for GAD. The GAD-7 yielded a sensitivity of 61.3% and specificity of 72.7% at an optimal cut-off score of 13. Compared with the EPDS and the EPDS-3A subscale, the GAD-7 displayed greater accuracy and specificity over a greater range of cut-off scores and more accurately identified GAD in patients with comorbid MDD. Our findings suggest that the GAD-7 represents a clinically useful scale for the detection of GAD in perinatal women.

  10. Characterization of the intracellular glutamate decarboxylase system: analysis of its function, transcription, and role in the acid resistance of various strains of Listeria monocytogenes.

    PubMed

    Karatzas, Kimon-Andreas G; Suur, Laura; O'Byrne, Conor P

    2012-05-01

    The glutamate decarboxylase (GAD) system is important for the acid resistance of Listeria monocytogenes. We previously showed that under acidic conditions, glutamate (Glt)/γ-aminobutyrate (GABA) antiport is impaired in minimal media but not in rich ones, like brain heart infusion. Here we demonstrate that this behavior is more complex and it is subject to strain and medium variation. Despite the impaired Glt/GABA antiport, cells accumulate intracellular GABA (GABA(i)) as a standard response against acid in any medium, and this occurs in all strains tested. Since these systems can occur independently of one another, we refer to them as the extracellular (GAD(e)) and intracellular (GAD(i)) systems. We show here that GAD(i) contributes to acid resistance since in a ΔgadD1D2 mutant, reduced GABA(i) accumulation coincided with a 3.2-log-unit reduction in survival at pH 3.0 compared to that of wild-type strain LO28. Among 20 different strains, the GAD(i) system was found to remove 23.11% ± 18.87% of the protons removed by the overall GAD system. Furthermore, the GAD(i) system is activated at milder pH values (4.5 to 5.0) than the GAD(e) system (pH 4.0 to 4.5), suggesting that GAD(i) is the more responsive of the two and the first line of defense against acid. Through functional genomics, we found a major role for GadD2 in the function of GAD(i), while that of GadD1 was minor. Furthermore, the transcription of the gad genes in three common reference strains (10403S, LO28, and EGD-e) during an acid challenge correlated well with their relative acid sensitivity. No transcriptional upregulation of the gadT2D2 operon, which is the most important component of the GAD system, was observed, while gadD3 transcription was the highest among all gad genes in all strains. In this study, we present a revised model for the function of the GAD system and highlight the important role of GAD(i) in the acid resistance of L. monocytogenes.

  11. Disorder-specific cognitive profiles in major depressive disorder and generalized anxiety disorder

    PubMed Central

    2014-01-01

    Background This investigation examines differences in cognitive profiles in subjects with major depressive disorder (MDD) and generalized anxiety disorder (GAD). Methods Data were used from subjects with current MDD (n = 655), GAD (n = 107) and comorbid MDD/GAD (n = 266) diagnosis from the Netherlands Study of Depression and Anxiety (NESDA). The Composite Interview Diagnostic Instrument was used to diagnose MDD and GAD. Cognitive profiles were measured using the Leiden Index of Depression Sensitivity, the Anxiety Sensitivity Index, and the Penn State Worry Questionnaire. Results Results showed that differences in cognitive profiles between single MDD and single GAD subjects were present: scores on hopelessness/suicidality and rumination were significantly higher in MDD than GAD, whereas anxiety sensitivity for physical concerns and pathological worry were higher in GAD than MDD. The cognitive profile of comorbid MDD/GAD showed more extreme depression cognitions compared to single disorders, and a similar anxiety profile compared to single GAD subjects. Conclusions Despite the commonalities in cognitive profiles in MDD and GAD, there are differences suggesting that MDD and GAD have disorder-specific cognitive profiles. Findings of this investigation give support for models like the cognitive content-specificity model and the tripartite model and could provide useful handles for treatment focus. PMID:24690413

  12. Pyridoxine Supplementation Improves the Activity of Recombinant Glutamate Decarboxylase and the Enzymatic Production of Gama-Aminobutyric Acid

    PubMed Central

    Huang, Yan; Su, Lingqia; Wu, Jing

    2016-01-01

    Glutamate decarboxylase (GAD) catalyzes the irreversible decarboxylation of L-glutamate to the valuable food supplement γ-aminobutyric acid (GABA). In this study, GAD from Escherichia coli K12, a pyridoxal phosphate (PLP)-dependent enzyme, was overexpressed in E. coli. The GAD produced in media supplemented with 0.05 mM soluble vitamin B6 analog pyridoxine hydrochloride (GAD-V) activity was 154.8 U mL-1, 1.8-fold higher than that of GAD obtained without supplementation (GAD-C). Purified GAD-V exhibited increased activity (193.4 U mg-1, 1.5-fold higher than that of GAD-C), superior thermostability (2.8-fold greater than that of GAD-C), and higher kcat/Km (1.6-fold higher than that of GAD-C). Under optimal conditions in reactions mixtures lacking added PLP, crude GAD-V converted 500 g L-1 monosodium glutamate (MSG) to GABA with a yield of 100%, and 750 g L-1 MSG with a yield of 88.7%. These results establish the utility of pyridoxine supplementation and lay the foundation for large-scale enzymatic production of GABA. PMID:27438707

  13. Disorder-specific cognitive profiles in major depressive disorder and generalized anxiety disorder.

    PubMed

    Hendriks, Sanne M; Licht, Carmilla M M; Spijker, Jan; Beekman, Aartjan T F; Hardeveld, Florian; de Graaf, Ron; Penninx, Brenda W J H

    2014-04-01

    This investigation examines differences in cognitive profiles in subjects with major depressive disorder (MDD) and generalized anxiety disorder (GAD). Data were used from subjects with current MDD (n = 655), GAD (n = 107) and comorbid MDD/GAD (n = 266) diagnosis from the Netherlands Study of Depression and Anxiety (NESDA). The Composite Interview Diagnostic Instrument was used to diagnose MDD and GAD. Cognitive profiles were measured using the Leiden Index of Depression Sensitivity, the Anxiety Sensitivity Index, and the Penn State Worry Questionnaire. Results showed that differences in cognitive profiles between single MDD and single GAD subjects were present: scores on hopelessness/suicidality and rumination were significantly higher in MDD than GAD, whereas anxiety sensitivity for physical concerns and pathological worry were higher in GAD than MDD. The cognitive profile of comorbid MDD/GAD showed more extreme depression cognitions compared to single disorders, and a similar anxiety profile compared to single GAD subjects. Despite the commonalities in cognitive profiles in MDD and GAD, there are differences suggesting that MDD and GAD have disorder-specific cognitive profiles. Findings of this investigation give support for models like the cognitive content-specificity model and the tripartite model and could provide useful handles for treatment focus.

  14. Gender differences in Generalized Anxiety Disorder: Results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC)

    PubMed Central

    Vesga-López, Oriana; Schneier, Franklin; Wang, Samuel; Heimberg, Richard; Liu, Shang-Min; Hasin, Deborah S.; Blanco, Carlos

    2016-01-01

    Objective To assess gender differences in the epidemiology, comorbidity and treatment-seeking patterns of DSM-IV Generalized Anxiety Disorder (GAD) in the United States. Method Data were derived from the 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), a large cross-sectional survey of a representative sample (N=43,093) of the U.S. population. Results The lifetime and twelve-month male:female prevalence ratios of DSM-IV GAD were 1:1.9 and 1:2.2, respectively. Men with GAD had significantly higher rates of comorbid alcohol and drug use disorders, nicotine dependence, and antisocial personality disorder. Women with GAD had significantly higher rates of comorbid mood disorders (except bipolar disorder) and anxiety disorders (except social anxiety disorder). Men with GAD reported greater use of alcohol and non-prescription medications to help relieve GAD symptoms. GAD in women was associated with higher family history of depression. Disability associated with GAD was greater in women than in men. Rates of treatment-seeking for DSM-IV GAD were low for both genders, but particularly low among men. Conclusion There are significant gender differences in the prevalence, comorbidity pattern, sociodemographic and clinical correlates, course, and treatment-seeking rates of persons with DSM-IV GAD. Increased recognition and treatment of GAD, particularly among men, could lead to a substantial reductions in the societal and personal burden and improve the quality of life of those afflicted with this disorder. PMID:19192444

  15. Gender differences in generalized anxiety disorder: results from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

    PubMed

    Vesga-López, Oriana; Schneier, Franklin R; Wang, Samuel; Heimberg, Richard G; Liu, Shang-Min; Hasin, Deborah S; Blanco, Carlos

    2008-10-01

    To assess gender differences in the epidemiology, comorbidity, and treatment-seeking patterns of DSM-IV generalized anxiety disorder (GAD) in the United States. Data were derived from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions, a large cross-sectional survey of a representative sample (N = 43,093) of the U.S. population. The lifetime and 12-month male:female prevalence ratios of DSM-IV GAD were 1:1.9 and 1:2.2, respectively. Men with GAD had significantly higher rates of comorbid alcohol and drug use disorders, nicotine dependence, and antisocial personality disorder. Women with GAD had significantly higher rates of comorbid mood disorders (except bipolar disorder) and anxiety disorders (except social anxiety disorder). Men with GAD reported greater use of alcohol and drugs to help relieve GAD symptoms. GAD in women was associated with higher rates of family history of depression. Disability associated with GAD was greater in women than in men. Rates of treatment seeking for DSM-IV GAD were low for both genders, but particularly low among men. There are significant gender differences in the prevalence, comorbidity pattern, sociodemographic and clinical correlates, course, and treatment-seeking rates of persons with DSM-IV GAD. Increased recognition and treatment of GAD, particularly among men, could lead to substantial reductions in the societal and personal burden and improve the quality of life of those afflicted with this disorder. Copyright 2008 Physicians Postgraduate Press, Inc.

  16. Broadening the Definition of Generalized Anxiety Disorder: Effects on Prevalence and Associations with Other Disorders in the National Comorbidity Survey Replication

    PubMed Central

    Ruscio, Ayelet Meron; Chiu, Wai Tat; Roy-Byrne, Peter; Stang, Paul E.; Stein, Dan J.; Wittchen, Hans-Ulrich; Kessler, Ronald C.

    2008-01-01

    Concerns have been raised that the DSM-IV requirements of six-month duration, excessive worry, and three associated symptoms exclude a substantial number of people with clinically significant anxiety from a diagnosis of generalized anxiety disorder (GAD). We examined the implications of relaxing these three criteria for the estimated prevalence and predictive validity of GAD using nationally representative data from the US National Comorbidity Survey Replication. Relaxing all three criteria more than doubles the estimated prevalence of GAD. Broadly-defined GAD significantly predicts the subsequent first onset of a wide range of temporally secondary disorders. The odds of secondary disorders are somewhat smaller for broadly-defined than DSM-IV GAD, though few of these differences are statistically significant. Results suggest that subthreshold manifestations of GAD are significantly related to elevated risk of subsequent psychopathology. Further research is needed to determine whether broadening the current diagnostic criteria results in a more valid characterization of GAD. PMID:17118626

  17. Panic attacks in generalized anxiety disorder.

    PubMed

    Van Ameringen, Michael; Simpson, William; Patterson, Beth; Mancini, Catherine

    2013-01-01

    Panic attacks have been reported by patients with generalized anxiety disorder (GAD) in response to catastrophic worry. This has not been characterized in the literature. We examined the prevalence of GAD panic attacks in an anxiety disorders clinic sample. Charts of 254 patients with DSM-IV GAD were retrospectively evaluated. The presence and type of panic attacks were examined as well as correlates including comorbidity, baseline symptom severity, demographic variables, and family history. Twenty-one percent had GAD panic attacks, 21.7% had situationally predisposed attacks, 15.6% had situationally bound attacks, and 39.4% had unexpected panic attacks. The individuals who had GAD panic attacks had higher scores on the Anxiety Sensitivity Index compared with those who also had other types of panic attacks. One in five patients with GAD reported GAD panic attacks; however, these individuals did not differ significantly on the correlates that were evaluated. These findings require replication and further evaluation.

  18. An examination of recent non-clinical panic attacks, panic disorder, anxiety sensitivity, and emotion regulation difficulties in the prediction of generalized anxiety disorder in an analogue sample.

    PubMed

    Tull, Matthew T; Stipelman, Brooke A; Salters-Pedneault, Kristalyn; Gratz, Kim L

    2009-03-01

    Both non-clinical panic attacks and panic disorder (PD) have been found to be associated with generalized anxiety disorder (GAD). This study examined a proxy risk factor model of the relationship between non-clinical panic attacks, PD, and GAD. Specifically, it was proposed that non-clinical panic attacks and PD predict GAD only due to their shared association with anxiety sensitivity (AS) and difficulties in emotion regulation. Results demonstrated that emotion regulation difficulties reliably predicted GAD above and beyond the experience of non-clinical panic attacks and PD. However, although PD lost strength as a predictor, it remained significantly associated with GAD in the full model, providing only partial support for the proposed proxy risk factor model. Findings speak to the underlying role of emotion regulation difficulties in GAD, and suggest that it may be the shared relationship of these difficulties with both PD and GAD that partially explain the association of these disorders.

  19. Perceived Emotion Control Moderates the Relationship between Neuroticism and Generalized Anxiety Disorder.

    PubMed

    Bourgeois, Michelle L; Brown, Timothy A

    2015-08-01

    The relationships between neuroticism, perceived emotion control, and generalized anxiety disorder (GAD) severity were examined in 293 individuals diagnosed with GAD at a specialty anxiety disorders clinic. Hierarchical regression analyses performed within a structural equation modeling framework revealed that (1) neuroticism and perceived emotion control both predicted a latent variable of GAD in the expected direction, and (2) perceived emotion control moderated the relationship between neuroticism and GAD severity, such that lower levels of perceived emotion control were associated with a stronger relationship between neuroticism and GAD severity. The other dimensions of perceived control (i.e., stress and threat control) did not moderate the effect of neuroticism on GAD severity. The findings are discussed with regard to their implications to conceptual models of the psychopathology of GAD, and theory-based differential relationships between dimensions of vulnerability, perceived control, and anxiety disorders.

  20. Escitalopram for persistent symptoms of generalized anxiety disorder after CBT: a pilot study.

    PubMed

    Schneier, Franklin R; Belzer, Kenneth D; Kishon, Ronit; Amsel, Lawrence; Simpson, Helen Blair

    2010-06-01

    Cognitive behavioral therapy (CBT) and pharmacotherapy are each efficacious for generalized anxiety disorder (GAD). It is not known, however, whether GAD partial and nonresponders to one treatment modality benefit from the other. This study explored acceptability and efficacy of escitalopram for persons with persistent GAD symptoms after a course of CBT. Twenty-four patients with GAD were treated with CBT and 15 completed at least 12 sessions. Eight completers continued to have clinically significant symptoms and were offered 12 weeks of treatment with escitalopram, and 7 started escitalopram treatment. During CBT, patients evidenced significant improvement in GAD, depression, and quality of life. During escitalopram treatment, patients evidenced trends toward further improvement in GAD, depression, and quality of life. Escitalopram phase completers had initially reported low-to-moderate preferences for medication treatment. Escitalopram may benefit GAD patients with clinically significant symptoms after CBT and merits further study under controlled conditions in a larger sample.

  1. Validity of the Associated Symptom Criteria for Generalized Anxiety Disorder: Observations From the Singapore Mental Health Study.

    PubMed

    Lee, Siau Pheng; Ong, Clarissa; Vaingankar, Janhavi Ajit; Chong, Siow Ann; Subramaniam, Mythily

    2017-05-01

    Previous findings on the diagnostic validity and reliability of generalized anxiety disorder (GAD)-associated symptom criteria suggest need for further evaluation. The current study examined convergent validity and specificity of GAD-associated symptoms in a representative Singapore community sample. The Singapore of Mental Health Study a cross-sectional epidemiological survey conducted among 6166 Singapore residents aged 18 and older. The Composite International Diagnostic Interview version 3.0 was used to diagnose mental disorders. Associated symptoms in the GAD criteria and autonomic hyperactivity symptoms showed convergent validity with a GAD diagnosis. However, associated symptoms of GAD were also linked to major depressive disorder (MDD), bipolar disorder, and obsessive-compulsive disorder, suggesting lack of adequate specificity. The inability of the diagnostic criteria to differentiate GAD from symptoms of other conditions highlights the need to better define its associated symptoms criteria. The relationship of overlapping symptoms between GAD and MDD is also discussed.

  2. Sequential Treatment of Comorbid Insomnia and Generalized Anxiety Disorder.

    PubMed

    Belleville, Geneviève; Ivers, Hans; Bélanger, Lynda; Blais, France C; Morin, Charles M

    2016-09-01

    To explore the efficacy of cognitive-behavior therapy (CBT) for patients with comorbid generalized anxiety disorder (GAD) and insomnia using 2 sequential treatments. Using a single-case methodology, 10 women (mean age = 45) with chronic insomnia and GAD were randomly assigned to CBT for GAD followed by CBT for insomnia, or to CBT for insomnia followed by CBT for GAD. Sleep and anxiety were measured via diagnostic interviews, daily diaries, and self-report questionnaires. Time series analyses, group effect sizes, and indications of clinically significant change revealed improvements on anxiety, worry, and sleep after CBT for GAD. Following CBT for insomnia, positive changes were observed on sleep and, to a lesser extent, anxiety and worry. In the presence of comorbid GAD and insomnia, initiating treatment for GAD first produced superior clinical benefits in anxiety and sleep. The addition of insomnia-specific treatment led to additional improvements in worry and sleep quality. © 2016 Wiley Periodicals, Inc.

  3. Perceived Emotion Control Moderates the Relationship between Neuroticism and Generalized Anxiety Disorder

    PubMed Central

    Bourgeois, Michelle L.; Brown, Timothy A.

    2015-01-01

    The relationships between neuroticism, perceived emotion control, and generalized anxiety disorder (GAD) severity were examined in 293 individuals diagnosed with GAD at a specialty anxiety disorders clinic. Hierarchical regression analyses performed within a structural equation modeling framework revealed that (1) neuroticism and perceived emotion control both predicted a latent variable of GAD in the expected direction, and (2) perceived emotion control moderated the relationship between neuroticism and GAD severity, such that lower levels of perceived emotion control were associated with a stronger relationship between neuroticism and GAD severity. The other dimensions of perceived control (i.e., stress and threat control) did not moderate the effect of neuroticism on GAD severity. The findings are discussed with regard to their implications to conceptual models of the psychopathology of GAD, and theory-based differential relationships between dimensions of vulnerability, perceived control, and anxiety disorders. PMID:26236059

  4. Molecular analysis of the glutamate decarboxylase locus in Streptococcus thermophilus ST110.

    PubMed

    Somkuti, G A; Renye, J A; Steinberg, D H

    2012-07-01

    γ-aminobutyric acid (GABA) is generated from glutamate by the action of glutamic acid decarboxylase (GAD) and characterized by hypotensive, diuretic, and tranquilizing effects in humans and animals. The production of GABA by lactic acid starter bacteria would enhance the functionality of fermented dairy foods including cheeses and yogurt. The survey of 42 strains of the yogurt starter culture Streptococcus thermophilus by PCR techniques indicated the presence of a glutamate decarboxylase gene (gadB) in 16 strains. DNA sequencing data indicated that the GAD/GABA antiporter locus (gadB/gadC) in GAD(+) S. thermophilus strains is flanked by transposase elements (5' and 3') and positioned between the luxS (5') and the HD-superfamily hydrolase genes (3'). The PCR amplification product of a ca. 2-kb genomic fragment that included the gadB and its putative promoter region was inserted into a shuttle vector, which was used to transform Escherichia coli DH5α. Subsequently, the recombinant plasmid pMEU5a-1/gadB (7.24 kb) was electrotransformed into the GAD-negative strain S. thermophilus ST128. The ST128 transformants carrying the plasmid-encoded gadB produced functional GAD enzyme as evidenced by the conversion of glutamate to GABA at a rate similar to strains with the gadB/gadC operon located on the chromosome. The results demonstrated the potential to impart to non-GABA-producing strains of S. thermophilus and other lactic acid bacteria the GAD(+) phenotype that improves their appeal in possible applications in the development of health-promoting functional foods.

  5. Associations between diabetes, major depressive disorder and generalized anxiety disorder comorbidity, and disability: findings from the 2012 Canadian Community Health Survey--Mental Health (CCHS-MH).

    PubMed

    Deschênes, Sonya S; Burns, Rachel J; Schmitz, Norbert

    2015-02-01

    To examine the associations between diabetes, disability, and the likelihood of comorbid major depressive disorder (MDD) and generalized anxiety disorder (GAD). Data were obtained from the 2012 Canadian Community Health Survey - Mental Health (N=17 623). Diabetes assessment consisted of a self-reported diagnosis of diabetes made by a health care professional. Disability was assessed via self-report. 12-Month and lifetime MDD and GAD were assessed with the Composite International Diagnostic Interview 3.0. In multinomial logistic regression models adjusted for sociodemographic and health-related factors, having diabetes was associated with a greater likelihood of 12-month comorbid MDD and GAD (OR=1.99, 95% CI [1.22, 3.25], p=.006), compared with those with neither MDD nor GAD. No significant associations were found for MDD without GAD or GAD without MDD. This pattern of effects held when lifetime diagnoses of MDD and GAD were considered. For individuals with diabetes (n=1730), adjusted binary logistic regression models demonstrated that with 12-month diagnoses, MDD without GAD (OR=2.79, 95% CI [1.39-5.62], p=.004), GAD without MDD (OR=3.69, 95% CI [1.34-10.11], p=.01), and comorbid MDD and GAD (OR=4.17, 95% CI [1.66-10.51], p=.002) were associated with greater disability than the control group. Only comorbid MDD and GAD were associated with disability when lifetime diagnoses of MDD and GAD were considered. Individuals with diabetes may be particularly vulnerable to comorbid MDD and GAD, and MDD-GAD comorbidity may exacerbate disability in persons with diabetes. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Biochemical and spectroscopic properties of Brucella microti glutamate decarboxylase, a key component of the glutamate-dependent acid resistance system

    PubMed Central

    Grassini, Gaia; Pennacchietti, Eugenia; Cappadocio, Francesca; Occhialini, Alessandra; De Biase, Daniela

    2015-01-01

    In orally acquired bacteria, the ability to counteract extreme acid stress (pH ⩽ 2.5) ensures survival during transit through the animal host stomach. In several neutralophilic bacteria, the glutamate-dependent acid resistance system (GDAR) is the most efficient molecular system in conferring protection from acid stress. In Escherichia coli its structural components are either of the two glutamate decarboxylase isoforms (GadA, GadB) and the antiporter, GadC, which imports glutamate and exports γ-aminobutyrate, the decarboxylation product. The system works by consuming protons intracellularly, as part of the decarboxylation reaction, and exporting positive charges via the antiporter. Herein, biochemical and spectroscopic properties of GadB from Brucella microti (BmGadB), a Brucella species which possesses GDAR, are described. B. microti belongs to a group of lately described and atypical brucellae that possess functional gadB and gadC genes, unlike the most well-known “classical” Brucella species, which include important human pathogens. BmGadB is hexameric at acidic pH. The pH-dependent spectroscopic properties and activity profile, combined with in silico sequence comparison with E. coli GadB (EcGadB), suggest that BmGadB has the necessary structural requirements for the binding of activating chloride ions at acidic pH and for the closure of its active site at neutral pH. On the contrary, cellular localization analysis, corroborated by sequence inspection, suggests that BmGadB does not undergo membrane recruitment at acidic pH, which was observed in EcGadB. The comparison of GadB from evolutionary distant microorganisms suggests that for this enzyme to be functional in GDAR some structural features must be preserved. PMID:25853037

  7. Ballistic Flash Characterization of Entry-Side Flash

    DTIC Science & Technology

    2012-02-01

    5 Sep 2012_ Darryl K. Ahner, LTC, USA (Member) date ________//SIGNED//_______________________ 5 Sep 2012_ Mr. Jaime J...I would like to thank Mr. Jaime Bestard who was instrumental in making sure we were always heading in the right direction...Position vs. Time for AL 2024 Model -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 0 10 20 30 40 50 60Di st an ce F ro m O rig in (m ) Scaled Time (sec/.000121

  8. Childhood Maltreatment Is Associated with Larger Left Thalamic Gray Matter Volume in Adolescents with Generalized Anxiety Disorder

    PubMed Central

    Liao, Mei; Yang, Fan; Zhang, Yan; He, Zhong; Song, Ming; Jiang, Tianzi; Li, Zexuan; Lu, Shaojia; Wu, Weiwei; Su, Linyan; Li, Lingjiang

    2013-01-01

    Background Generalized anxiety disorder (GAD) is a common anxiety disorder that usually begins in adolescence. Childhood maltreatment is highly prevalent and increases the possibility for developing a variety of mental disorders including anxiety disorders. An earlier age at onset of GAD is significantly related to maltreatment in childhood. Exploring the underpinnings of the relationship between childhood maltreatment and adolescent onset GAD would be helpful in identifying the potential risk markers of this condition. Methods Twenty-six adolescents with GAD and 25 healthy controls participated in this study. A childhood trauma questionnaire (CTQ) was introduced to assess childhood maltreatment. All subjects underwent high-resolution structural magnetic resonance scans. Voxel-based morphometry (VBM) was used to investigate gray matter alterations. Results Significantly larger gray matter volumes of the right putamen were observed in GAD patients compared to healthy controls. In addition, a significant diagnosis-by-maltreatment interaction effect for the left thalamic gray matter volume was revealed, as shown by larger volumes of the left thalamic gray matter in GAD patients with childhood maltreatment compared with GAD patients without childhood maltreatment as well as with healthy controls with/without childhood maltreatment. A significant positive association between childhood maltreatment and left thalamic gray matter volume was only seen in GAD patients. Conclusions These findings revealed an increased volume in the subcortical regions in adolescent GAD, and the alterations in the left thalamus might be involved in the association between childhood maltreatment and the occurrence of GAD. PMID:23951265

  9. [Validation of the PRIME-MD for the detection of generalized anxiety disorder].

    PubMed

    Mata, Salvador; González, Alfonso; Lavie, Reneé; Resler, Gustavo

    2008-03-01

    The objectives of this study were first, to validate the Primary Care Evaluation of Mental Disorders (PRIME-MD) as an instrument that identifies the generalized anxiety disorder (GAD) in psychiatric consultations and second, to determine the frequency of GAD in two types of psychiatric consultation settings. To begin with, 1000 medical records of outpatients from the Psychiatry Department of the Hospital Vargas de Caracas were checked to determine the frequency of GAD diagnosis. Then, the PRIME-MD was validated with 100 outpatients from the Hospital Vargas de Caracas and 200 outpatients from private hospitals. The frequency of GAD diagnosis was 2.8% in the medical records checked. The prevalence of GAD in the 300 patients evaluated was 3.7%. The PRIME-MD showed 90.9% of sensitivity and 88.9% of specificity for the diagnosis of GAD. The global comorbidity of GAD was 36.6%. GAD was more frequent in patients between 40 and 49 years old, with a female/male rate of 2:1. Overall, the GAD frequency was lower than in other studies. The PRIME-MD proved to be a valid instrument to diagnose GAD in psychiatric outpatients.

  10. Childhood maltreatment is associated with larger left thalamic gray matter volume in adolescents with generalized anxiety disorder.

    PubMed

    Liao, Mei; Yang, Fan; Zhang, Yan; He, Zhong; Song, Ming; Jiang, Tianzi; Li, Zexuan; Lu, Shaojia; Wu, Weiwei; Su, Linyan; Li, Lingjiang

    2013-01-01

    Generalized anxiety disorder (GAD) is a common anxiety disorder that usually begins in adolescence. Childhood maltreatment is highly prevalent and increases the possibility for developing a variety of mental disorders including anxiety disorders. An earlier age at onset of GAD is significantly related to maltreatment in childhood. Exploring the underpinnings of the relationship between childhood maltreatment and adolescent onset GAD would be helpful in identifying the potential risk markers of this condition. Twenty-six adolescents with GAD and 25 healthy controls participated in this study. A childhood trauma questionnaire (CTQ) was introduced to assess childhood maltreatment. All subjects underwent high-resolution structural magnetic resonance scans. Voxel-based morphometry (VBM) was used to investigate gray matter alterations. Significantly larger gray matter volumes of the right putamen were observed in GAD patients compared to healthy controls. In addition, a significant diagnosis-by-maltreatment interaction effect for the left thalamic gray matter volume was revealed, as shown by larger volumes of the left thalamic gray matter in GAD patients with childhood maltreatment compared with GAD patients without childhood maltreatment as well as with healthy controls with/without childhood maltreatment. A significant positive association between childhood maltreatment and left thalamic gray matter volume was only seen in GAD patients. These findings revealed an increased volume in the subcortical regions in adolescent GAD, and the alterations in the left thalamus might be involved in the association between childhood maltreatment and the occurrence of GAD.

  11. An examination of distress intolerance in undergraduate students high in symptoms of generalized anxiety disorder.

    PubMed

    MacDonald, Emma M; Pawluk, Elizabeth J; Koerner, Naomi; Goodwill, Alasdair M

    2015-01-01

    People with generalized anxiety disorder (GAD) engage in maladaptive coping strategies to reduce or avoid distress. Evidence suggests that uncertainty and negative emotions are triggers for distress in people with GAD; however, there may also be other triggers. Recent conceptualizations have highlighted six types of experiences that people report having difficulty withstanding: uncertainty, negative emotions, ambiguity, frustration, physical discomfort, and the perceived consequences of anxious arousal. The present study examined the extent to which individuals high in symptoms of GAD are intolerant of these distress triggers, compared to individuals high in depressive symptoms, and individuals who are low in GAD and depressive symptoms. Undergraduate students (N = 217) completed self-report measures of GAD symptoms, depressive symptoms, and distress intolerance. Individuals high in GAD symptoms reported greater intolerance of all of the distress triggers compared to people low in symptoms of GAD and depression. Individuals high in GAD symptoms reported greater intolerance of physical discomfort compared to those high in depressive symptoms. Furthermore, intolerance of physical discomfort was the best unique correlate of GAD status, suggesting that it may be specific to GAD (versus depression). These findings support continued investigation of the transdiagnosticity and specificity of distress intolerance.

  12. Generalised anxiety disorder symptoms and utilisation of health care services. A cross-sectional study from the "Northern Finland 1966 Birth Cohort".

    PubMed

    Kujanpää, Tero; Jokelainen, Jari; Auvinen, Juha; Timonen, Markku

    2016-06-01

    To analyse the utilization of health care services of people who tested positive for GAD compared to those who tested negative. A cross-sectional study from the Northern Finland 1966 Birth Cohort. A total of 10,282 members followed from birth in a longitudinal study were asked to participate in a follow-up survey at the age of 46. As part of this survey they filled in questionnaries concerning health care utilization and their illness history as well as the GAD-7 screening tool. Althogether 5,480 cohort members responded to the questionnaries. Number of visits in different health care services among people who tested positive for GAD with the GAD-7 screening tool compared to those who tested negative. People who tested positive for GAD had 112% more total health care visits, 74% more total physician visits, 115% more visits to health centres, 133% more health centre physician visits, 160% more visits to secondary care, and 775% more mental health care visits than those who tested negative. People with GAD symptoms utilize health care services more than other people. Key Points Generalised anxiety disorder (GAD) is a common but poorly identified mental health problem in primary care. People who tested positive for GAD utilise more health care services than those who tested negative. About 58% of people who tested positive for GAD had visited their primary care physician during the past year. Only 29% of people who tested positive for GAD had used mental health services during the past year.

  13. Effects of anti-glutamic acid decarboxylase antibodies associated with neurological diseases.

    PubMed

    Manto, Mario-Ubaldo; Laute, Marie-Aline; Aguera, Michèle; Rogemond, Véronique; Pandolfo, Massimo; Honnorat, Jérome

    2007-06-01

    Glutamic acid decarboxylase (GAD) catalyzes the conversion of glutamic acid into GABA. GAD autoantibodies (GAD-Ab) have been described in diabetes mellitus and in diseases involving the central nervous system such as stiff-person syndrome and cerebellar ataxia. However, the pathogenic role of GAD-Ab in neurological diseases remains a matter of debate. Using neurophysiological and neurochemical methods, we analyzed the effects of intracerebellar and paraspinal administration of GAD-Ab in rats. Intracerebellar administration of IgG from patients with GAD-Ab and neurological involvement (IgG-GAD) blocked the potentiation of the corticomotor response normally associated with trains of repetitive peripheral nerve stimulation. When injected in the lumbar paraspinal region, IgG-GAD induced continuous motor activity with repetitive discharges, abnormal exteroceptive reflexes, and increased excitability of anterior horn neurons, as assessed by F/M ratios. Furthermore, IgG-GAD significantly reduced the N-methyl-D-aspartate-mediated production of nitric oxide in cerebellar nuclei and impaired the synaptic regulation of glutamate after N-methyl-D-aspartate administration. These effects were not observed after administration of IgG from the following groups: (1) patients with GAD-Ab, diabetes mellitus, and without neurological complications; and (2) control patients. These results indicate that stiff-person syndrome and cerebellar ataxia are the direct consequence of antibody-mediated neuronal dysfunction.

  14. Should Excessive Worry Be Required for a Diagnosis of Generalized Anxiety Disorder? Results from the US National Comorbidity Survey Replication

    PubMed Central

    Ruscio, Ayelet Meron; Lane, Michael; Roy-Byrne, Peter; Stang, Paul E.; Stein, Dan J.; Wittchen, Hans-Ulrich; Kessler, Ronald C.

    2007-01-01

    Background Excessive worry is required by DSM-IV, but not ICD-10, for a diagnosis of generalized anxiety disorder (GAD). No large-scale epidemiological study has ever examined the implications of this requirement for estimates of prevalence, severity, or correlates of GAD. Methods Data were analyzed from the US National Comorbidity Survey Replication, a nationally representative, face-to-face survey of adults in the US household population that was fielded in 2001–2003. DSM-IV GAD was assessed with Version 3.0 of the WHO Composite International Diagnostic Interview. Non-excessive worriers meeting all other DSM-IV criteria for GAD were compared with respondents who met full GAD criteria as well as with other survey respondents to consider the implications of removing the excessiveness requirement. Results The estimated lifetime prevalence of GAD increases by approximately 40% when the excessiveness requirement is removed. Excessive GAD begins earlier in life, has a more chronic course, and is associated with greater symptom severity and psychiatric comorbidity than non-excessive GAD. However, non-excessive cases nonetheless evidence substantial persistence and impairment of GAD as well as significantly elevated comorbidity compared to respondents without GAD. Non-excessive cases also have socio-demographic characteristics and familial aggregation of GAD comparable to excessive cases. Conclusions Although individuals who meet all criteria for GAD other than excessiveness have a somewhat milder presentation than those with excessive worry, their syndromes are sufficiently similar to those with excessive worry to warrant a GAD diagnosis. PMID:16300690

  15. Hair cortisol concentrations and cortisol stress reactivity in generalized anxiety disorder, major depression and their comorbidity.

    PubMed

    Steudte-Schmiedgen, Susann; Wichmann, Susann; Stalder, Tobias; Hilbert, Kevin; Muehlhan, Markus; Lueken, Ulrike; Beesdo-Baum, Katja

    2017-01-01

    Studies investigating cortisol secretion in patients with generalized anxiety disorder (GAD) have reported heterogeneous findings. Further, current knowledge on the specificity of endocrine changes for GAD and/or comorbid major depression (MD) is limited. Hence, the current study investigated long-term integrated cortisol secretion, as indexed by hair cortisol concentrations (HCC), and experimentally-induced cortisol stress reactivity in relation to GAD, MD and their comorbidity. Carefully characterized groups of 17 GAD patients including 8 with comorbid MD (GAD-MD), 12 MD patients and 21 healthy controls were recruited. Alongside psychometric data, HCC (N = 43) and salivary cortisol stress reactivity in response to the Trier Social Stress Test (N = 45) were determined. Findings revealed that MD patients exhibited lower HCC compared to controls and GAD patients, with no differences between the latter two groups. Interestingly, when the GAD group was separated into two groups based on MD comorbidity, lower HCC in MD patients were found compared to controls and GAD-noMD patients, but did not show differences when compared to GAD-MD patients. No HCC differences were seen between GAD-MD or GAD-noMD patients and healthy controls. No TSST group differences emerged. Our findings suggest MD to be related to long-term attenuation in cortisol secretion. While no group differences emerged between patients with GAD, neither with nor without MD, and controls, the current results provide tentative evidence that MD determines long-term endocrine changes, with pure GAD showing a distinct pattern. Future studies are needed to confirm our findings in larger samples of pure and comorbid groups.

  16. Lower glutamic acid decarboxylase 65kD mRNA and protein levels in the prefrontal cortex in schizoaffective disorder but not schizophrenia

    PubMed Central

    Glausier, JR; Kimoto, S; Fish, KN; Lewis, DA

    2014-01-01

    Background Altered GABA signaling in the prefrontal cortex (PFC) has been associated with cognitive dysfunction in schizophrenia and schizoaffective disorder. PFC levels of the GABA-synthesizing enzyme glutamic acid decarboxylase 67kD (GAD67) has been consistently reported to be lower in these disorders, but the status of the second GABA-synthesizing enzyme, GAD65, remains unclear. Methods GAD65 mRNA levels were quantified in PFC area 9 by quantitative polymerase chain reaction from 62 subjects with schizophrenia or schizoaffective disorder and 62 matched healthy comparison subjects. GAD65 relative protein levels were quantified in a subset of subject pairs by confocal immunofluorescence microscopy. Results Mean GAD65 mRNA levels were 13.6% lower in schizoaffective disorder subjects, but did not differ in schizophrenia subjects, relative to their matched healthy comparison subjects. In the subjects with schizoaffective disorder, mean GAD65 protein levels were 19.4% lower and were correlated with GAD65 mRNA levels. Lower GAD65 mRNA and protein measures within schizoaffective disorder subjects was not attributable to factors commonly comorbid with the diagnosis. Conclusions In concert with previous studies, these findings suggest that schizoaffective disorder is associated with lower levels of both GAD65 and GAD67 mRNA and protein in the PFC, whereas subjects with schizophrenia have lower mean levels of only GAD67 mRNA and protein. Because cognitive function is generally better preserved in subjects with schizoaffective disorder relative to subjects with schizophrenia, these findings may support an interpretation that GAD65 down-regulation provides a homeostatic response complementary to GAD67 down-regulation expression that serves to reduce inhibition in the face of lower PFC network activity. PMID:24993056

  17. Validity of the Generalized Anxiety Disorder-7 scale in an acute psychiatric sample.

    PubMed

    Kertz, Sarah; Bigda-Peyton, Joe; Bjorgvinsson, Throstur

    2013-01-01

    Generalized anxiety disorder (GAD) is one of the most prevalent psychiatric presentations; however, GAD has the lowest diagnostic reliability of the anxiety disorders and is poorly recognized in clinical practice. A more reliable assessment of GAD could lead to earlier detection and treatment of the disorder, which has an otherwise debilitating course and significant associated impairment. The 7-item GAD Scale (GAD-7) has shown promise as a measure with good clinical utility and strong psychometric properties in primary care and community settings but has yet to be assessed in acute psychiatric populations. This study examined the validity of the GAD-7 in a sample of 232 patients enrolled in a partial hospital programme. Patients completed a diagnostic interview and a battery of self-report measures before and after treatment. Findings suggest that the GAD-7 has good internal consistency and good convergent validity with worry, anxiety, depression and stress, and the measure was sensitive to change over the course of a short intensive cognitive-behavioural therapy partial hospital programme. However, the confirmatory analysis failed to support the hypothesized unidimensional factor structure; and although the GAD-7 demonstrated good sensitivity (.83), specificity was poor (.46) in identifying patients with GAD. Overall, the GAD-7 appears to be a valid measure of generalized anxiety symptoms in this sample, on the basis of good internal consistency, convergent validity and sensitivity to change, but does not perform well as a screener for GAD. The GAD-7 Scale is an easy-to-score, self-report measure of core generalized anxiety disorder symptoms. The GAD-7 Scale has good internal consistency and convergent validity with depression, anxiety, stress and worry, and is sensitive to change. The GAD-7 Scale appears to be a good measure of generalized anxiety symptoms in an acute psychiatric sample. The GAD-7 Scale does not perform well as a screener for GAD and should not

  18. The relationships between perfectionism, pathological worry and generalised anxiety disorder.

    PubMed

    Handley, Alicia K; Egan, Sarah J; Kane, Robert T; Rees, Clare S

    2014-04-02

    The relationships between perfectionism, pathological worry and generalised anxiety disorder (GAD) were investigated in a clinical sample presenting for treatment of perfectionism. This study explored the utility of perfectionism in predicting pathological worry in a sample of individuals with elevated perfectionism and GAD (n = 36). Following this, the study examined whether perfectionism could predict a principal GAD diagnosis in the full sample (n = 42). Scores on the perfectionism dimensions Concern over Mistakes, Personal Standards, and Clinical Perfectionism significantly predicted pathological worry among participants with GAD after controlling for gender and depression. The perfectionism dimension Doubts about Actions significantly predicted whether individuals from the full sample received a principal diagnosis of GAD. These findings support certain dimensions of perfectionism having significant associations with pathological worry and GAD.

  19. Preliminary evidence for an emotion dysregulation model of generalized anxiety disorder.

    PubMed

    Mennin, Douglas S; Heimberg, Richard G; Turk, Cynthia L; Fresco, David M

    2005-10-01

    Three studies provide preliminary support for an emotion dysregulation model of generalized anxiety disorder (GAD). In study 1, students with GAD reported heightened intensity of emotions, poorer understanding of emotions, greater negative reactivity to emotional experience, and less ability to self-soothe after negative emotions than controls. A composite emotion regulation score significantly predicted the presence of GAD, after controlling for worry, anxiety, and depressive symptoms. In study 2, these findings were largely replicated with a clinical sample. In study 3, students with GAD, but not controls, displayed greater increases in self-reported physiological symptoms after listening to emotion-inducing music than after neutral mood induction. Further, GAD participants had more difficulty managing their emotional reactions. Implications for GAD and psychopathology in general are discussed.

  20. An examination of generalized anxiety disorder and dysthymia utilizing the Rorschach inkblot method.

    PubMed

    Slavin-Mulford, Jenelle; Clements, Alyssa; Hilsenroth, Mark; Charnas, Jocelyn; Zodan, Jennifer

    2016-06-30

    This study examined transdiagnostic features of generalized anxiety disorder (GAD) and dysthymia in an outpatient clinical sample. Fifteen patients who met DSM-IV criteria for GAD and twenty-one patients who met DSM-IV criteria for dysthymia but who did not have comorbid anxiety disorder were evaluated utilizing the Rorschach. Salient clinical variables were then compared. Results showed that patients with GAD scored significantly higher on variables related to cognitive agitation and a desire/need for external soothing. In addition, there was a trend for patients with GAD to produce higher scores on a measure of ruminative focus on negative aspects of the self. Thus, not surprisingly, GAD patients' experienced more distress than the dysthymic patients. The implications of these findings are discussed with regards to better understanding the shared and distinct features of GAD and dysthymia.

  1. Examining the latent structure of worry and generalized anxiety in a clinical sample.

    PubMed

    Kertz, Sarah J; McHugh, R Kathryn; Lee, Josephine; Björgvinsson, Thröstur

    2014-01-01

    Generalized anxiety disorder (GAD) is characterized by "pathological" worry, suggesting that GAD worriers differ qualitatively from non-GAD worriers. However, results from taxometric studies of worry in undergraduate and community samples have been mixed and to date, no studies have utilized clinical samples. The current study examined the latent structure of worry and GAD symptoms in a diagnostically heterogeneous clinical sample. Indicators were selected from the Penn State Worry Questionnaire-Abbreviated (n=1175) and the GAD-7 (n=638) and submitted to three taxometric procedures: MAXCOV, MAMBAC, and L-Mode. Results from all three procedures suggested that both worry and generalized anxiety are best conceptualized as dimensional constructs. Findings also indicated that ongoing conceptualization, assessment, and treatment of worry and GAD may be hampered by the application of a categorical framework.

  2. Emotion dysregulation and sleep difficulties in generalized anxiety disorder.

    PubMed

    Tsypes, Aliona; Aldao, Amelia; Mennin, Douglas S

    2013-03-01

    Diagnostic criteria for generalized anxiety disorder (GAD) include sleep problems, which often persist even after successful treatment of the disorder. The purpose of this study was to examine emotion dysregulation as a potential contributor to sleep problems in GAD patients. Participants comprised two groups: 59 individuals diagnosed with GAD and 66 healthy controls. They were assessed for the presence of mood and anxiety disorders and then completed self-report questionnaires assessing problems with sleep and emotion regulation. Participants in the GAD group scored significantly higher on a number of sleep outcomes than did the control group. Importantly, difficulties with emotion regulation statistically mediated the relationship between GAD and a wide range of outcomes of sleep dysfunction independently of the effects of depression and secondary anxiety diagnoses. Emotion regulation difficulties that characterize GAD mediate the relationship between symptoms of this disorder and a wide range of sleep problems. Implications for treatment and future research directions are discussed.

  3. Cognitive conflict adaptation in generalized anxiety disorder.

    PubMed

    Larson, Michael J; Clawson, Ann; Clayson, Peter E; Baldwin, Scott A

    2013-10-01

    Individuals with generalized anxiety disorder (GAD) display poor emotional conflict adaptation, a cognitive control process requiring the adjustment of performance based on previous-trial conflict. It is unclear whether GAD-related conflict adaptation difficulties are present during tasks without emotionally-salient stimuli. We examined conflict adaptation using the N2 component of the event-related potential (ERP) and behavioral responses on a Flanker task from 35 individuals with GAD and 35 controls. Groups did not differ on conflict adaptation accuracy; individuals with GAD also displayed intact RT conflict adaptation. In contrast, individuals with GAD showed decreased amplitude N2 principal component for conflict adaptation. Correlations showed increased anxiety and depressive symptoms were associated with longer RT conflict adaptation effects and lower ERP amplitudes, but not when separated by group. We conclude that individuals with GAD show reduced conflict-related component processes that may be influenced by compensatory activity, even in the absence of emotionally-salient stimuli.

  4. The relationship between perceived discrimination and Generalized Anxiety Disorder among African Americans, Afro Caribbeans, and non-Hispanic Whites.

    PubMed

    Soto, José A; Dawson-Andoh, Nana A; BeLue, Rhonda

    2011-03-01

    The present study examined the relationship between frequency of race based and non-race based discrimination experiences and Generalized Anxiety Disorder (GAD) in a sample of 3570 African Americans, 1438 Afro Caribbeans, and 891 non-Hispanic Whites from the National Survey of American Life (NSAL). Because GAD and the experience of racial discrimination are both associated with symptoms of worry and tension, we expected race based discrimination to predict GAD prevalence for African Americans, but not other groups. We did not expect non-race based discrimination to predict GAD. Results showed that while more frequent experiences of non-race based discrimination predicted GAD for all groups, experiencing race based discrimination was associated with significantly higher odds of endorsing lifetime GAD for African Americans only. Results are interpreted in light of the different contexts that these three ethnic groups represent relative to their history within the United States as well as their present day circumstances.

  5. Developing Native Social Intuition in Preparation for an Internship in Japan.

    ERIC Educational Resources Information Center

    Yamashita, Margaret Y.

    The program of the Japan-American Institute of Management Sciences (JAIMS) in Hawaii, a nonprofit graduate-level institution intended to support training for cross-cultural business leadership, is described and discussed. Two curricula, the Japan-focused Master of Business Administration program and the Japan-focused Management Program are offered…

  6. International Priorities for Teacher Education. World Assembly 1969.

    ERIC Educational Resources Information Center

    International Council on Education for Teaching, Washington, DC.

    Four papers are included in this pamphlet, the proceedings of the World Assembly at Abidjan, Ivory Coast. The keynote address, "A Turning Point in History" by Jaime Benitez, President of the University of Puerto Rico, discusses the Apollo 11 moon landing as an object lesson on values with international implications for shifting…

  7. "You Are a Flaw in the Pattern": Difference, Autonomy and Bullying in YA Fiction

    ERIC Educational Resources Information Center

    Lopez-Ropero, Lourdes

    2012-01-01

    Though portrayals of bullying in children's books stretch back to Victorian public school stories, this article sees a new subgenre about bullying in young adult novels emerging in the post-Columbine years. Selected works by Jerry Spinelli, Walter Dean Myers, Jaime Adoff, Carol Plum-Ucci and Rita Williams-Garcia are examined, although the article…

  8. Student and Teacher Negotiations of Racial Identity in an Afro-Ecuadorian Region

    ERIC Educational Resources Information Center

    Johnson, Ethan Allen

    2009-01-01

    In this article, using data collected primarily through interviews and observations the researcher explores how students and teachers of African descent at the Jaime Hurtado Academy understand and interpret race and racism in the city and province of Esmeraldas, which is the only region of the country where Afro-Ecuadorians comprise the largest…

  9. Negotiating Peace with the Moro Islamic Liberation Front in the Southern Philippines

    DTIC Science & Technology

    2005-12-01

    presidency of Corazon Aquino, Ramos’ predecessor) was to be re-engineered into a wider autonomous regional government subject to referendum in the...President, Franklin Drilon, the influential Makati Business Club, and former President Corazon Aquino. Four months after, the political situation... Corazon Aquino and Jaime Cardinal Sin, two influential people at the time, spearheaded large demonstrations against charter change

  10. Critical Issues in Native North America. IWGIA Document No. 62.

    ERIC Educational Resources Information Center

    Churchill, Ward, Ed.

    This collection of articles compares the problems and issues facing indigenous nations within the United States and Canada and examines forms of native resistance. Glenn T. Morris and M. Annette Jaimes summarize the evolution of the "legal status" of indigenous nations under U.S. law and examine how U.S. legal definitions undermine…

  11. "You Are a Flaw in the Pattern": Difference, Autonomy and Bullying in YA Fiction

    ERIC Educational Resources Information Center

    Lopez-Ropero, Lourdes

    2012-01-01

    Though portrayals of bullying in children's books stretch back to Victorian public school stories, this article sees a new subgenre about bullying in young adult novels emerging in the post-Columbine years. Selected works by Jerry Spinelli, Walter Dean Myers, Jaime Adoff, Carol Plum-Ucci and Rita Williams-Garcia are examined, although the article…

  12. Schooling as a Regime of Equality and Reproducing Difference in an Afro-Ecuadorian Region

    ERIC Educational Resources Information Center

    Johnson, Ethan

    2009-01-01

    In this article I compare and contrast curricular, ceremonial and pedagogical practices with how students and teachers make sense of racial identity and discrimination at the Jaime Hurtado Academy in the city and province of Esmeraldas, Ecuador, which is the only region of the nation where Afro-Ecuadorian people comprise a majority of the…

  13. Toward Social Justice: The Characteristics of an Effective Mathematics Intervention Program for Urban Middle School Students

    ERIC Educational Resources Information Center

    Bowens, Bryan D.; Warren, Susan R.

    2016-01-01

    This two-part investigation (a) assessed the impact of the Jaime Escalante Math Program (JEMP), a structured summer mathematics intervention program, on the math achievement of urban middle school students, (b) identified the characteristics of the program that the administrators and teachers perceived to contribute to student achievement, and (c)…

  14. 76 FR 7907 - Quarterly Publication of Individuals, Who Have Chosen To Expatriate, as Required by Section 6039G

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-11

    ... AIMEE GOBLET DARWIN ANGELA MARY BRUCE DAVID CARY RICHARD DAVID-PELLERIN STEPHANIE DE CANDIA FABRIZIO DE MELO JAIME A P DELETAILLE SEBASTIEN JAMES SPENCER DELLOYE BRUCE CHRISTIAN DEROLD CHRISTIAN DESCHLER... ALEXANDER S HOWELL JR WARREN RAYMOND HUANG DAVID HUANG JEFFREY HUM DANIEL SHI-AN HYLTON NOEL HYONG JAMES...

  15. Strong Medicine: A Talk with Former Principal Henry Gradillas.

    ERIC Educational Resources Information Center

    Barry, Paul

    1989-01-01

    With motivational insight, educational understanding, and independence, a maverick educator transformed an East Los Angeles high school previously on a disaster course. In the process, one of his most gifted and imaginative teachers, Jaime Escalante, became a media celebrity. (Author/MSE)

  16. 76 FR 11566 - Unblocking of Specially Designated Nationals and Blocked Persons Pursuant to Executive Order 12978

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-02

    ...) (individual) MORALES ESPINAR, Carmen Rosa, c/o COLFARMA PERU S.A., Lima, Peru; DOB 9 Aug 1976; D.N.I. 10006822 (Peru) (individual) MORALES LUYO, Luis Jaime, c/o COLFARMA PERU S.A., Lima, Peru; LE Number 08195408 (Peru) (individual) OTALORA RESTREPO, Edgar Marino, c/o DISDROGAS LTDA., Yumbo, Valle, Colombia;...

  17. Immigrant Charter Schools: A Better Choice?

    ERIC Educational Resources Information Center

    Jackson, Camille

    2010-01-01

    Third-grader Jaime of Denver, Colorado, was having a hard time concentrating in school. The son of Mexican immigrants, he had learned to speak English perfectly in his dual-language public school, but reading and writing was another story. When her mother, Xochitl Rico, knew about Cesar Chavez Academy, a new tuition-free charter school where the…

  18. Immigrant Charter Schools: A Better Choice?

    ERIC Educational Resources Information Center

    Jackson, Camille

    2010-01-01

    Third-grader Jaime of Denver, Colorado, was having a hard time concentrating in school. The son of Mexican immigrants, he had learned to speak English perfectly in his dual-language public school, but reading and writing was another story. When her mother knew about Cesar Chavez Academy, a new tuition-free charter school where the majority of…

  19. Changing the Face of Study Abroad

    ERIC Educational Resources Information Center

    Norton, Ingrid

    2008-01-01

    Poor youths from tradition-minded Hispanic families like Jaime Alvarez never thought study abroad was for them. Such perceptions can be difficult to change. The perception of study abroad as reserved for rich white students is difficult to challenge. In this article, the author describes how study abroad has become a possibility for minority…

  20. Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology

    EPA Science Inventory

    ATS 2013 Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology Urmila P Kodavanti, Debora Andrews, Mette C Schaldweiler, Jaime M Cyphert, Darol E Dodd, and Stephen H Gavett NHEERL, U.S. EPA, Research Triangle Park, NC; NIEH...

  1. To accelerate or not to accelerate? That is the question

    NASA Astrophysics Data System (ADS)

    Riendeau, Diane

    2010-10-01

    Thanks to Jim Hicks, Barrington High School, and Jaime Stasiorowski and Kristen Piggott, Deerfield High School, for their help with this month's column. If you have a YouTube video you use in class, please send the link and a brief description to: driendeau@dist113.org.

  2. Cross-Sectional Comparison of Sleep-Disordered Breathing in Native Peruvian Highlanders and Lowlanders.

    PubMed

    Pham, Luu V; Meinzen, Christopher; Arias, Rafael S; Schwartz, Noah G; Rattner, Adi; Miele, Catherine H; Smith, Philip L; Schneider, Hartmut; Miranda, J Jaime; Gilman, Robert H; Polotsky, Vsevolod Y; Checkley, William; Schwartz, Alan R

    2017-03-01

    Pham, Luu V., Christopher Meinzen, Rafael S. Arias, Noah G. Schwartz, Adi Rattner, Catherine H. Miele, Philip L. Smith, Hartmut Schneider, J. Jaime Miranda, Robert H. Gilman, Vsevolod Y. Polotsky, William Checkley, and Alan R. Schwartz. Cross-sectional comparison of sleep-disordered breathing in native Peruvian highlanders and lowlanders. High Alt Med Biol. 18:11-19, 2017.

  3. Critical Issues in Native North America. IWGIA Document No. 62.

    ERIC Educational Resources Information Center

    Churchill, Ward, Ed.

    This collection of articles compares the problems and issues facing indigenous nations within the United States and Canada and examines forms of native resistance. Glenn T. Morris and M. Annette Jaimes summarize the evolution of the "legal status" of indigenous nations under U.S. law and examine how U.S. legal definitions undermine…

  4. Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology

    EPA Science Inventory

    ATS 2013 Biomarkers of asbestos-induced lung injury: the influence of fiber characteristics and exposure methodology Urmila P Kodavanti, Debora Andrews, Mette C Schaldweiler, Jaime M Cyphert, Darol E Dodd, and Stephen H Gavett NHEERL, U.S. EPA, Research Triangle Park, NC; NIEH...

  5. Pairwise Document Classification for Relevance Feedback

    DTIC Science & Technology

    2009-11-01

    Pairwise Document Classification for Relevance Feedback Jonathan L. Elsas, Pinar Donmez, Jamie Callan, Jaime G. Carbonell Language Technologies...Collins-Thompson and J. Callan. Query expansion using random walk models. In CIKM ’05, page 711. ACM, 2005. [5] P. Donmez and J. Carbonell . Paired

  6. Student and Teacher Negotiations of Racial Identity in an Afro-Ecuadorian Region

    ERIC Educational Resources Information Center

    Johnson, Ethan Allen

    2009-01-01

    In this article, using data collected primarily through interviews and observations the researcher explores how students and teachers of African descent at the Jaime Hurtado Academy understand and interpret race and racism in the city and province of Esmeraldas, which is the only region of the country where Afro-Ecuadorians comprise the largest…

  7. Introduction to Literary Analysis: Its Place in the High School Curriculum.

    ERIC Educational Resources Information Center

    Cardenas, Daniel N.

    1968-01-01

    To demonstrate how well-selected literature of the second language can play an important role in the curriculum of the fourth-and fifth-year high school School Spanish course and reinforce language learning, an outline for an analysis of the poem "Dedalo" by Jaime Torres Bodet is presented. Steps in this analysis include explanations of the…

  8. Virtual Borders Between Chile and Its Neighbors: Argentina, Peru and Bolivia

    DTIC Science & Technology

    2007-03-30

    of public services. In addition, they produce pressure on the labor market, not only to occupy jobs, but also the loss of wages, deepening with it...new values and technologies. 29 Jaime García Covarrubias, “ Identidad Nacional,” Memorial del Ejército de Chile, N0 459, (Santiago: April 1998), 60

  9. Schooling as a Regime of Equality and Reproducing Difference in an Afro-Ecuadorian Region

    ERIC Educational Resources Information Center

    Johnson, Ethan

    2009-01-01

    In this article I compare and contrast curricular, ceremonial and pedagogical practices with how students and teachers make sense of racial identity and discrimination at the Jaime Hurtado Academy in the city and province of Esmeraldas, Ecuador, which is the only region of the nation where Afro-Ecuadorian people comprise a majority of the…

  10. How Brazil joined the quest for a yellow fever vaccine. Interview by Claudia Jurberg and Julia D'Aloisio..

    PubMed

    Benchimol, Jaime

    2013-03-01

    Brazil recently announced an agreement between its Bio-Manguinhos vaccine unit and two US companies to research and develop a new yellow fever vaccine. Claudia Jurberg and Julia D'Aloisio talk to Jaime Benchimol about the controversial history of the development of the vaccine that benefits millions of people today.

  11. Glutamic acid decarboxylase 65 and 67 expression in the lateral septum is up-regulated in association with the postpartum period in mice.

    PubMed

    Zhao, Changjiu; Driessen, Terri; Gammie, Stephen C

    2012-08-27

    The postpartum period in mammals undergoes a variety of physiological adaptations, including metabolic, behavioral and neuroendocrine alterations. GABA signaling has been strongly linked to various emotional states, stress responses and offspring protection. However, whether GABA signaling may change in the lateral septum (LS), a core brain region for regulating behavioral, emotional and stress responses in postpartum mice has not previously been examined. In this study, we tested whether the expression of two isoforms of glutamic acid decarboxylase (GAD), GAD65 (GAD2) and GAD67 (GAD1), the rate-limiting enzyme for GABA synthesis, exhibits altered expression in postpartum mice relative to nonmaternal, virgin mice. Using microdissected septal tissue from virgin and age-matched postpartum females, quantitative real-time PCR and Western blotting were carried out to assess GAD mRNA and protein expression, respectively. We found both protein and mRNA expression of GAD67 in the whole septum was up-regulated in postpartum mice. By contrast, no significant difference in the whole septum was observed in GAD65 expression. We then conducted a finer level of analysis using smaller microdissections and found GAD67 to be significantly increased in rostral LS, but not in caudal LS or medial septum (MS). Further, GAD65 mRNA expression in rostral LS, but not in caudal LS or MS was also significantly elevated in postpartum mice. These findings suggest that an increased GABA production in rostral LS of the postpartum mice via elevated GAD65 and GAD67 expression may contribute to multiple alterations in behavioral and emotional states, and responses to stress that occur during the postpartum period. Given that rostral LS contains GABA neurons that are projection neurons or local interneurons, it still needs to be determined whether the function of elevated GABA is for local or distant action or both.

  12. Autocrine/paracrine function of globular adiponectin: inhibition of lipid metabolism and inflammatory response in 3T3-L1 adipocytes.

    PubMed

    Lazra, Yulia; Falach, Alona; Frenkel, Lital; Rozenberg, Konstantin; Sampson, Sanford; Rosenzweig, Tovit

    2015-05-01

    Adiponectin is an adipose-derived hormone, with beneficial effects on insulin sensitivity and inflammation. The aim of this study was to clarify the autocrine/paracrine effects of globular adiponectin (gAd) administrated during differentiation on the function of the mature adipocytes. Experiments were performed on 3T3-L1 preadipocytes treated with gAd (10 nM), starting at an early stage of differentiation. gAd treatment during differentiation was without effect on mRNA expression of adiponectin and AdipoR2, but increased AdipoR1 expression. PPARgamma, perillipin and FABP4 mRNA expressions were lower in gAd-treated adipocytes, accompanied by a reduction in lipid accumulation. While mRNA expression of HSL was not affected by gAd compared to untreated adipocytes, both ATGL and FAS were reduced, indicating that gAd regulates both lipolysis and lipogenesis. PPARα, ACOX2 and UCPs mRNA expressions were not affected by gAd, indicating that the reduction in lipid content is not attributed to an increase in fatty-acid oxidation. In accord with the lower PPARγ expression, there was reduced Glut4 mRNA expression; however, insulin-induced PKB phosphorylation was enhanced by gAd, and glucose uptake was not altered. To investigate the effect of gAd on LPS-induced inflammatory response, cells were treated with gAd either during differentiation or 24 h before induction of inflammation in differentiated adipocytes. LPS-induced inflammatory response, as indicated by increase in IL6 and MCP-1 mRNA expression. gAd given through differentiation was much more effective in abrogating LPS-dependent cytokines production than gAd given to the mature adipocyte. In conclusion, elevated gAd at differentiation of 3T3-L1 cells leads to reduced lipid content, reduced lipid metabolism and high resistance to inflammation.

  13. Abnormal DNA methylation in the lumbar spinal cord following chronic constriction injury in rats.

    PubMed

    Wang, Ying; Lin, Zhi-Ping; Zheng, Hui-Zhe; Zhang, Shuang; Zhang, Zong-Luan; Chen, Yan; You, Yi-Sheng; Yang, Ming-Hua

    2016-01-01

    Pathogenesis of neuropathic pain is complex and not clearly understood. Glutamate decarboxylase 67 (GAD 67) is a key synthetic enzyme for the main inhibitory transmitter gamma-aminobutyric acid (GABA), and diminishes in the spinal dorsal horn in rats following chronic constriction injury (CCI). GAD 67 is coded by gene GAD 1. DNA methylation can regulate the expression of GAD 67 by regulating the methylation of GAD 1 promoter in the psychotic brain. DNA methylation is primarily mediated by DNA methyltransferases (DNMTs) and methyl-DNA binding domain proteins (MBDs). In this study, in order to discover whether DNA methylation regulates GAD 67 expression in the spinal cord in CCI rats and is involved in neuropathic pain, we examined mRNA levels of DNMTs, MBDs and GAD 67 with real-time reverse transcriptase-polymerase chain reaction (qRT-PCR), and methylation of GAD 1 promoter with Pyromark CpG Assays in the lumbar spinal cord in CCI rats on day 14 after surgery. Our results showed that DNMT3a, DNMT3b and methyl-CpG binding protein 2 (MeCP2) expression increased, MBD2 expression decreased, and DNMT1, MBD1 and MBD3 expression hardly changed in the lumbar spinal cord in CCI rats on day 14 after surgery. GAD 67 expression decreased, and methylation of GAD 1 promoter increased in the lumbar spinal cord in CCI rats on day 14 after surgery. These results indicate that decreased GAD 67 may be associated with increased GAD 1 promoter methylation, which may be mediated by DNMT3a, DNMT3b, MeCP2 and MBD2 in CCI rats. These indicate that abnormal DNA methylation may be highly involved in CCI-induced neuropathic pain.

  14. Late postnatal shifts of parvalbumin and nitric oxide synthase expression within the GABAergic and glutamatergic phenotypes of inferior colliculus neurons.

    PubMed

    Fujimoto, Hisataka; Konno, Kotaro; Watanabe, Masahiko; Jinno, Shozo

    2017-03-01

    The inferior colliculus (IC) is partitioned into three subdivisions: the dorsal and lateral cortices (DC and LC) and the central nucleus (ICC), and serves as an integration center of auditory information. Recent studies indicate that a certain population of IC neurons may represent the non-GABAergic phenotype, while they express well-established cortical/hippocampal GABAergic neuron markers. In this study we used the optical disector to investigate the phenotype of IC neurons expressing parvalbumin (PV) and/or nitric oxide synthase (NOS) in C57BL/6J mice during the late postnatal period. Four major types of IC neurons were defined by the presence (+) or absence (-) of PV, NOS, and glutamic acid decarboxylase 67 (GAD67): PV(+) /NOS(-) /GAD67(+) , PV(+) /NOS(+) /GAD67(+) , PV(+) /NOS(-) /GAD67(-) , and PV(-) /NOS(+) /GAD67(-) . Fluorescent in situ hybridization for vesicular glutamate transporter 2 mRNA indicated that almost all GAD67(-) IC neurons represented the glutamatergic phenotype. The numerical densities (NDs) of total GAD67(+) IC neurons remained unchanged in all subdivisions. The NDs of PV(+) /NOS(-) /GAD67(+) neurons and PV(-) /NOS(+) /GAD67(-) neurons were reduced with age in the ICC, while they remained unchanged in the DC and LC. By contrast, the NDs of PV(+) /NOS(+) /GAD67(+) neurons and PV(+) /NOS(-) /GAD67(-) neurons were increased with age in the ICC, although there were no changes in the DC and LC. The cell body size of GAD67(+) IC neurons did not vary according to the expression of PV with or without NOS. The present findings indicate that the expression of PV and NOS may shift with age within the GABAergic and glutamatergic phenotypes of IC neurons during the late postnatal period. J. Comp. Neurol. 525:868-884, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  15. Castration decreases single cell levels of mRNA encoding glutamic acid decarboxylase in the diagonal band of broca and the sexually dimorphic nucleus of the preoptic area.

    PubMed

    Sagrillo, C A; Selmanoff, M

    1997-09-01

    Using quantitative in situ hybridization histochemistry (ISHH), we determined the effect of castration on single cell levels of glutamic acid decarboxylase (GAD) mRNA in discrete hypothalamic regions of the male rat brain associated with the control of gonadotropin secretion. A 48-base oligodeoxynucleotide probe was used to detect with equal affinity the two isoforms of GAD message, GAD65 and GAD67. GAD message also was quantitated in a number of selected areas of the brain to contrast GAD gene expression amongst several populations of GABAergic neurons. Comparison of 11 brain regions demonstrated a 9.3-fold range in the quantity of single cell GAD mRNA with levels being highest in the amygdala and the diagonal band of Broca, moderate in the piriform cortex, caudate nucleus, substantia innominata, globus pallidus, cingulate cortex and medial septal nucleus, and lowest in the lateral septal nucleus and the medial preoptic nucleus (MPN). Castration markedly reduced single cell GAD mRNA levels in the DBB and the MPN, two discrete hypothalamic structures known to contain dendritic fields, cell bodies, and axons of GnRH neurons projecting to the median eminence. A striking finding was a dense core of steroid-sensitive GABAergic neurons within the MPN comprising the sexually dimorphic nucleus of the preoptic area (SDN-POA). Similar to the MPN as a whole, the amount of GAD mRNA expressed by cells in the SDN-POA of sham operated control rats was greater than in castrated animals. GAD mRNA levels were inversely related to serum LH titers, suggesting a role for these neurons in the mechanism controlling gonadal steroid negative feedback on LH secretion. This report provides the basis for future work to determine if GAD65, GAD67 or whether both isoforms are affected by gonadal steroid input.

  16. Monoclonal antibodies to 65kDa glutamate decarboxylase induce epitope specific effects on motor and cognitive functions in rats.

    PubMed

    Hampe, Christiane S; Petrosini, Laura; De Bartolo, Paola; Caporali, Paola; Cutuli, Debora; Laricchiuta, Daniela; Foti, Francesca; Radtke, Jared R; Vidova, Veronika; Honnorat, Jérôme; Manto, Mario

    2013-06-05

    Stiff Person Syndrome (SPS) is a rare autoimmune movement disorder characterized by the presence of autoantibodies specific to the smaller isoform of glutamate decarboxylase (GAD65). A pathological role of these antibodies has been suggested by their capacity to inhibit GAD65 enzyme activity and by the observation that rats receiving cerebellar injections of GAD65Ab showed cerebellar motor hyperexcitability. To assess the effect of epitope-specific GAD65Ab on cognitive and motor functions, we conducted behavioral experiments in rats that received cerebellar injections with two distinct monoclonal GAD65Ab (b96.11 and b78). Rats received three injections of GAD65Ab b96.11 (5 or 7 μg), GAD65Ab b78 (5 or 7 μg), or saline at the level of three cerebellar nuclei. Animals were submitted to neurological evaluation and Morris Water Maze (MWM) test. Cellular internalization of GAD65Ab was analyzed by Flow Cytometry, Fluorescence and Bright Field microscopy. Monoclonal GAD65Ab induced dose-dependent and epitope-specific effects on motor and cognitive functions. Injections of the higher dose altered motor and spatial procedural behaviors, while the lower dose induced only modest cerebellar motor symptoms and did not affect MWM performances. While b96.11 provoked immediate severe effects, which rapidly decreased, b78 induced moderate but prolonged effects. Both GAD65Ab were taken up by live cells in a dose-dependent manner. Our findings support the hypothesis that epitope-specific GAD65Ab induce cerebellar dysfunction impairing motor and procedural abilities. This is the first demonstration of a critical role of cerebellar nuclei GAD65 enzyme in procedural spatial functions.

  17. Monoclonal antibodies to 65kDa glutamate decarboxylase induce epitope specific effects on motor and cognitive functions in rats

    PubMed Central

    2013-01-01

    Background Stiff Person Syndrome (SPS) is a rare autoimmune movement disorder characterized by the presence of autoantibodies specific to the smaller isoform of glutamate decarboxylase (GAD65). A pathological role of these antibodies has been suggested by their capacity to inhibit GAD65 enzyme activity and by the observation that rats receiving cerebellar injections of GAD65Ab showed cerebellar motor hyperexcitability. To assess the effect of epitope-specific GAD65Ab on cognitive and motor functions, we conducted behavioral experiments in rats that received cerebellar injections with two distinct monoclonal GAD65Ab (b96.11 and b78). Methods Rats received three injections of GAD65Ab b96.11 (5 or 7 μg), GAD65Ab b78 (5 or 7 μg), or saline at the level of three cerebellar nuclei. Animals were submitted to neurological evaluation and Morris Water Maze (MWM) test. Cellular internalization of GAD65Ab was analyzed by Flow Cytometry, Fluorescence and Bright Field microscopy. Results Monoclonal GAD65Ab induced dose-dependent and epitope-specific effects on motor and cognitive functions. Injections of the higher dose altered motor and spatial procedural behaviors, while the lower dose induced only modest cerebellar motor symptoms and did not affect MWM performances. While b96.11 provoked immediate severe effects, which rapidly decreased, b78 induced moderate but prolonged effects. Both GAD65Ab were taken up by live cells in a dose-dependent manner. Conclusions Our findings support the hypothesis that epitope-specific GAD65Ab induce cerebellar dysfunction impairing motor and procedural abilities. This is the first demonstration of a critical role of cerebellar nuclei GAD65 enzyme in procedural spatial functions. PMID:23738610

  18. Interpersonal Problems, Mindfulness, and Therapy Outcome in an Acceptance-Based Behavior Therapy for Generalized Anxiety Disorder

    PubMed Central

    Millstein, Daniel J.; Orsillo, Susan M.; Hayes-Skelton, Sarah A.; Roemer, Lizabeth

    2015-01-01

    Objective To better understand the role interpersonal problems play in response to two treatments for generalized anxiety disorder (GAD); an acceptance based behavior therapy (ABBT) and applied relaxation (AR), and to examine how the development of mindfulness may be related to change in interpersonal problems over treatment and at follow-up. Method Eighty-one individuals diagnosed with GAD (65.4% female, 80.2% identified as White, average age 32.92) were randomized to receive 16 sessions of either ABBT or AR. GAD severity, interpersonal problems, and mindfulness were measured at pre-treatment, post-treatment, 6-month follow-up, and 12-month follow-up. Results Mixed effect regression models did not reveal any significant effects of pre-treatment interpersonal problems on GAD severity over treatment. After controlling for post-treatment GAD severity, remaining post-treatment interpersonal problems predicted 6- but not 12- month GAD severity. Participants in both conditions experienced a large decrease in interpersonal problems over treatment. Increases in mindfulness over treatment and through follow-up were associated with decreases in interpersonal problems, even when accounting for reductions in overall GAD severity. Conclusions Interpersonal problems may be an important target of treatment in GAD, even if pre-treatment interpersonal problems are not predictive of outcome. Developing mindfulness in individuals with GAD may help ameliorate interpersonal difficulties among this population. PMID:26228536

  19. Developmental Risk Factors in Generalized Anxiety Disorder and Panic Disorder

    PubMed Central

    Newman, Michelle G.; Shin, Ki Eun; Zuellig, Andrea R.

    2016-01-01

    Background There is a lack of clarity regarding specific risk factors discriminating generalized anxiety disorder (GAD) from panic disorder (PD). Goal This study investigated whether GAD and PD could be discriminated through differences in developmental etiological factors including childhood parental loss/separation, psychological disorders, and maternal and paternal attachment. Method Twenty people with adult generalized anxiety disorder (GAD), 20 with adult panic disorder (PD), 11 with adult comorbid GAD and PD, and 21 adult non-anxious controls completed diagnostic interviews to assess symptoms of mental disorders in adulthood and childhood. Participants also reported on parental attachment, loss, and separation. Results Childhood diagnoses of GAD and PD differentiated clinical groups from controls as well as from each other, suggesting greater likelihood for homotypic over heterotypic continuity. Compared to controls, specific phobia was associated with all three clinical groups, and childhood depression, social phobia, and PTSD were uniquely associated with adult GAD. Both maternal and paternal attachment also differentiated clinical groups from controls. However, higher levels of subscales reflecting maternal insecure avoidant attachment (e.g., no memory of early childhood experiences and balancing/forgiving current state of mind) emerged as more predictive of GAD relative to PD. There were no group differences in parental loss or separation. Conclusions These results support differentiation of GAD and PD based on developmental risk factors. Recommendations for future research and implications of the findings for understanding the etiology and symptomatology of GAD and PD are discussed. PMID:27466747

  20. [Enhancing glutamate decarboxylase activity by site-directed mutagenesis: an insight from Ramachandran plot].

    PubMed

    Ke, Piyu; Huang, Jun; Hu, Sheng; Zhao, Weirui; Lü, Changjiang; Yu, Kai; Lei, Yinlin; Wang, Jinbo; Mei, Lehe

    2016-01-01

    Glutamate decarboxylase (GAD) can catalyze the decarboxylation of glutamate into γ-aminobutyrate (GABA) and is the only enzyme of GABA biosynthesis. Improving GAD activity and thermostability will be helpful for the highly efficient biosynthesis of GABA. According to the Ramachandran plot information of GAD 1407 three-dimensional structure from Lactobacillus brevis CGMCC No. 1306, we identified the unstable site K413 as the mutation target, constructed the mutant GAD by site-directed mutagenesis and measured the thermostability and activity of the wide type and mutant GAD. Mutant K413A led to a remarkably slower inactivation rate, and its half-life at 50 °C reached 105 min which was 2.1-fold higher than the wild type GAD1407. Moreover, mutant K413I exhibited 1.6-fold higher activity in comparison with the wide type GAD1407, although it had little improvement in thermostability of GAD. Ramachandran plot can be considered as a potential approach to increase GAD thermostability and activity.

  1. Role of the Proteasome in Excitotoxicity-Induced Cleavage of Glutamic Acid Decarboxylase in Cultured Hippocampal Neurons

    PubMed Central

    Armelão, Mário; Herrmann, Dennis; Pimentel, Diogo O.; Leal, Graciano; Caldeira, Margarida V.; Bahr, Ben A.; Bengtson, Mário; Almeida, Ramiro D.; Duarte, Carlos B.

    2010-01-01

    Glutamic acid decarboxylase is responsible for synthesizing GABA, the major inhibitory neurotransmitter, and exists in two isoforms—GAD65 and GAD67. The enzyme is cleaved under excitotoxic conditions, but the mechanisms involved and the functional consequences are not fully elucidated. We found that excitotoxic stimulation of cultured hippocampal neurons with glutamate leads to a time-dependent cleavage of GAD65 and GAD67 in the N-terminal region of the proteins, and decrease the corresponding mRNAs. The cleavage of GAD67 was sensitive to the proteasome inhibitors MG132, YU102 and lactacystin, and was also abrogated by the E1 ubiquitin ligase inhibitor UBEI-41. In contrast, MG132 and UBEI-41 were the only inhibitors tested that showed an effect on GAD65 cleavage. Excitotoxic stimulation with glutamate also increased the amount of GAD captured in experiments where ubiquitinated proteins and their binding partners were isolated. However, no evidences were found for direct GADs ubiquitination in cultured hippocampal neurons, and recombinant GAD65 was not cleaved by purified 20S or 26S proteasome preparations. Since calpains, a group of calcium activated proteases, play a key role in GAD65/67 cleavage under excitotoxic conditions the results suggest that GADs are cleaved after ubiquitination and degradation of an unknown binding partner by the proteasome. The characteristic punctate distribution of GAD65 along neurites of differentiated cultured hippocampal neurons was significantly reduced after excitotoxic injury, and the total GAD activity measured in extracts from the cerebellum or cerebral cortex at 24h postmortem (when there is a partial cleavage of GADs) was also decreased. The results show a role of the UPS in the cleavage of GAD65/67 and point out the deregulation of GADs under excitotoxic conditions, which is likely to affect GABAergic neurotransmission. This is the first time that the UPS has been implicated in the events triggered during excitotoxicity

  2. Personality disorders, but not cancer severity or treatment type, are risk factors for later generalised anxiety disorder and major depressive disorder in non metastatic breast cancer patients.

    PubMed

    Champagne, Anne-Laure; Brunault, Paul; Huguet, Grégoire; Suzanne, Isabelle; Senon, Jean-Louis; Body, Gilles; Rusch, Emmanuel; Magnin, Guillaume; Voyer, Mélanie; Réveillère, Christian; Camus, Vincent

    2016-02-28

    This study aimed to determine whether personality disorders were associated with later Major Depressive Disorder (MDD) or Generalised Anxiety Disorder (GAD) in breast cancer patients. This longitudinal and multicentric study included 120 French non-metastatic breast cancer patients. After cancer diagnosis (T1) and 7 months after diagnosis (T3), we assessed MDD and GAD (Mini International Neuropsychiatric Interview 5.0). We assessed personality disorders 3 months after diagnosis (VKP). We used multiple logistic regression analysis to determine what were the factors associated with GAD and MDD at T3. At T3, prevalence rate was 10.8% for MDD and 19.2% for GAD. GAD at T3 was significantly and independently associated with GAD at T1 and with existence of a personality disorder, no matter the cluster type. MDD at T3 was significantly and independently associated with MDD at T1 and with the existence of a cluster C personality disorder. Initial cancer severity and the type of treatment used were not associated with GAD or MDD at T3. Breast cancer patients with personality disorders are at higher risk for GAD and MDD at the end of treatment. Patients with GAD should be screened for personality disorders. Specific interventions for patients with personality disorders could prevent psychiatric disorders.

  3. Autoreactive T cells in a partially humanized murine model of T1D.

    PubMed

    Gebe, John A; Falk, Ben; Unrath, Kellee; Nepom, Gerald T

    2007-04-01

    Glutamic acid decarboxylase (GAD65) and insulin are implicated as target antigens in the pathogenesis of human diabetes through correlative measurements of humoral and cellular reactivity to them in diabetics and at-risk diabetic individuals. Recently, an age-dependent loss of tolerance to one of several naturally processed epitopes of GAD65 (555-567) has been observed to precede diabetes in diabetes-prone mice transgenic for diabetes-correlated human class II genes. Extended studies in these mice (RIP-B7/DR0404) now show that tolerance is maintained to another DR4-restricted naturally processed region within GAD65. While tolerance is lost to GAD65 (555-567) in B7/DR0404 mice prior to diabetes, these mice remain T cell-tolerant to GAD65 (273-286). Prediabetes loss of tolerance to GAD65 (555-567) has now been shown to correlate with an impaired response to exogenous glucose in an intraperitoneal (i.p.) glucose tolerance test. In addition, these mice exhibit a T cell response to insulin A(6-21) at the hyperglycemic state. Investigating a possible cause-and-effect relationship between T cell reactivity to GAD65 and diabetes pathogenesis, GAD65 (555-567) T cell receptor (TcR) transgenic mice have been generated and future work is aimed at understanding the importance of T cell GAD65 reactivity and its role in diabetes progression.

  4. Extracellular expression of glutamate decarboxylase B in Escherichia coli to improve gamma-aminobutyric acid production.

    PubMed

    Zhao, Anqi; Hu, Xiaoqing; Li, Ye; Chen, Cheng; Wang, Xiaoyuan

    2016-12-01

    Escherichia coli overexpressing glutamate decarboxylase GadB can produce gamma-aminobutyric acid with addition of monosodium glutamate. The yield and productivity of gamma-aminobutyric acid might be significantly improved if the overexpressed GadB in E. coli cells can be excreted outside, where it can directly transforms monosodium glutamate to gamma-aminobutyric acid. In this study, GadB was fused to signal peptides TorA or PelB, respectively, and overexpressed in E. coli BL21(DE3). It was found that TorA could facilitate GadB secretion much better than PelB. Conditions for GadB secretion and gamma-aminobutyric acid production were optimized in E. coli BL21(DE3)/pET20b-torA-gadB, leading the secretion of more than half of the overexpressed GadB. Fed-batch fermentation for GadB expression and gamma-aminobutyric acid production of BL21(DE3)/pET20b-torA-gadB was sequentially performed in one fermenter; 264.4 and 313.1 g/L gamma-aminobutyric acid were obtained with addition of monosodium glutamate after 36 and 72 h, respectively.

  5. Comparative effectiveness of antinociceptive gene therapies in animal models of diabetic neuropathic pain.

    PubMed

    Wang, Y; Nowicki, M O; Wang, X; Arnold, W D; Fernandez, S A; Mo, X; Wechuk, J; Krisky, D; Goss, J; Wolfe, D; Popovich, P G; Lawler, S; Chiocca, E A

    2013-07-01

    Peripheral neuropathic pain is one of the most common and debilitating complications of diabetes. Several genes have been shown to be effective in reducing neuropathic pain in animal models of diabetes after transfer to the dorsal root ganglion using replication-defective herpes simplex virus (HSV)1-based vectors, yet there has never been a comparative analysis of their efficacy. We compared four different HSV1-based vectors engineered to produce one of two opioid receptor agonists (enkephalin or endomorphin), or one of two isoforms of glutamic acid decarboxylase (GAD65 or GAD67), alone and in combination, in the streptozotocin-induced diabetic rat and mouse models. Our results indicate that a single subcutaneous hindpaw inoculation of vectors expressing GAD65 or GAD67 reduced diabetes-induced mechanical allodynia to a degree that was greater than daily injections of gabapentin in rats. Diabetic mice that developed thermal hyperalgesia also responded to GAD65 or endomorphin gene delivery. The results suggest that either GAD65 or GAD67 vectors are the most effective in the treatment of diabetic pain. The vector combinations, GAD67+endomorphin, GAD67+enkephalin or endomorphin+enkephalin also produced a significant antinociceptive effect but the combination did not appear to be superior to single gene treatment. These findings provide further justification for the clinical development of antinociceptive gene therapies for the treatment of diabetic peripheral neuropathies.

  6. Family History of Psychological Problems in Generalized Anxiety Disorder

    PubMed Central

    McLaughlin, Katie A.; Behar, Evelyn; Borkovec, TD

    2014-01-01

    The current investigation examined self-reported family history of psychological problems in a large sample of individuals diagnosed with generalized anxiety disorder (GAD) and nonanxious controls. The GAD participants were all individuals receiving cognitive–behavioral therapy as part of two large randomized clinical trials. Family history information was obtained from the Anxiety Disorders Interview Schedule-Revised (ADIS-R; DiNardo & Barlow, 1988). The results indicate that, compared to control participants, individuals with GAD were more likely to have family members with anxiety problems, but not other psychological problems. Possible mechanisms for the familial transmission of GAD are discussed. PMID:18509873

  7. Update on managing generalized anxiety disorder in older adults.

    PubMed

    Clifford, Kalin M; Duncan, Nakia A; Heinrich, Krista; Shaw, Jennifer

    2015-04-01

    With the recent updates to the Diagnostic and Statistical Manual of Mental Disorders (5th edition; DSM-5), there are many questions on how to care for older adults with generalized anxiety disorder (GAD) and other psychiatric conditions. The current article reviews the new changes to the DSM-5 for diagnosis of GAD, discusses new anxiety assessment scales that are validated in older adults, evaluates pharmacological agents that have been studied in older adults for GAD treatment, and provides monitoring recommendations to help those who provide care to older adults experiencing GAD.

  8. Dynamic expression of a glutamate decarboxylase gene in multiple non-neural tissues during mouse development

    PubMed Central

    Maddox, Dennis M; Condie, Brian G

    2001-01-01

    Background Glutamate decarboxylase (GAD) is the biosynthetic enzyme for the neurotransmitter γ-aminobutyric acid (GABA). Mouse embryos lacking the 67-kDa isoform of GAD (encoded by the Gad1 gene) develop a complete cleft of the secondary palate. This phenotype suggests that this gene may be involved in the normal development of tissues outside of the CNS. Although Gad1 expression in adult non-CNS tissues has been noted previously, no systematic analysis of its embryonic expression outside of the nervous system has been performed. The objective of this study was to define additional structures outside of the central nervous system that express Gad1, indicating those structures that may require its function for normal development. Results Our analysis detected the localized expression of Gad1 transcripts in several developing tissues in the mouse embryo from E9.0-E14.5. Tissues expressing Gad1 included the tail bud mesenchyme, the pharyngeal pouches and arches, the ectodermal placodes of the developing vibrissae, and the apical ectodermal ridge (AER), mesenchyme and ectoderm of the limb buds. Conclusions Some of the sites of Gad1 expression are tissues that emit signals required for patterning and differentiation (AER, vibrissal placodes). Other sites correspond to proliferating stem cell populations that give rise to multiple differentiated tissues (tail bud mesenchyme, pharyngeal endoderm and mesenchyme). The dynamic expression of Gad1 in such tissues suggests a wider role for GABA signaling in development than was previously appreciated. PMID:11178105

  9. Developmental risk factors in generalized anxiety disorder and panic disorder.

    PubMed

    Newman, Michelle G; Shin, Ki Eun; Zuellig, Andrea R

    2016-12-01

    There is a lack of clarity regarding specific risk factors discriminating generalized anxiety disorder (GAD) from panic disorder (PD). This study investigated whether GAD and PD could be discriminated through differences in developmental etiological factors including childhood parental loss/separation, psychological disorders, and maternal and paternal attachment. Twenty people with adult generalized anxiety disorder (GAD), 20 with adult panic disorder (PD), 11 with adult comorbid GAD and PD, and 21 adult non-anxious controls completed diagnostic interviews to assess symptoms of mental disorders in adulthood and childhood. Participants also reported on parental attachment, loss and separation. Childhood diagnoses of GAD and PD differentiated clinical groups from controls as well as from each other, suggesting greater likelihood for homotypic over heterotypic continuity. Compared to controls, specific phobia was associated with all three clinical groups, and childhood depression, social phobia, and PTSD were uniquely associated with adult GAD. Both maternal and paternal attachment also differentiated clinical groups from controls. However, higher levels of subscales reflecting maternal insecure avoidant attachment (e.g., no memory of early childhood experiences and balancing/forgiving current state of mind) emerged as more predictive of GAD relative to PD. There were no group differences in parental loss or separation. These results support differentiation of GAD and PD based on developmental risk factors. Recommendations for future research and implications of the findings for understanding the etiology and symptomatology of GAD and PD are discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Gray and white matter volume abnormalities in generalized anxiety disorder by categorical and dimensional characterization

    PubMed Central

    Hilbert, Kevin; Pine, Daniel S.; Muehlhan, Markus; Lueken, Ulrike; Steudte-Schmiedgen, Susann; Beesdo-Baum, Katja

    2016-01-01

    Increasing efforts have been made to investigate the underlying pathophysiology of generalized anxiety disorder (GAD), but only limited consistent information is available on gray (GM) and white matter (WM) volume changes in affected adults. Additionally, few studies employed dimensional approaches to GAD pathology. This study compares structural brain imaging data from n = 19 GAD subjects and n = 24 healthy comparison (HC) subjects, all medication-free and matched on age, sex and education. Separate categorical and dimensional models were employed using voxel-based morphometry for GM and WM. Significantly higher GM volumes were found in GAD subjects mainly in basal ganglia structures and less consistently in the superior temporal pole. For WM, GAD subjects showed Significantly lower volumes in the dlPFC. Largely consistent findings in dimensional and categorical models point toward these structural alterations being reliable and of importance for GAD. While lower volume in the dlPFC could reflect impaired emotional processing and control over worry in GAD, basal ganglia alterations may be linked to disturbed gain and loss anticipation as implicated in previous functional GAD studies. As perturbations in anticipation processes are central to GAD, these areas may warrant greater attention in future studies. PMID:26490569

  11. The prevalence and burden of subthreshold generalized anxiety disorder: a systematic review

    PubMed Central

    2014-01-01

    Background To review the prevalence and impact of generalized anxiety disorder (GAD) below the diagnostic threshold and explore its treatment needs in times of scarce healthcare resources. Methods A systematic literature search was conducted until January 2013 using PUBMED/MEDLINE, PSYCINFO, EMBASE and reference lists to identify epidemiological studies of subthreshold GAD, i.e. GAD symptoms that do not reach the current thresholds of DSM-III-R, DSM-IV or ICD-10. Quality of all included studies was assessed and median prevalences of subthreshold GAD were calculated for different subpopulations. Results Inclusion criteria led to 15 high-quality and 3 low-quality epidemiological studies with a total of 48,214 participants being reviewed. Whilst GAD proved to be a common mental health disorder, the prevalence for subthreshold GAD was twice that for the full syndrome. Subthreshold GAD is typically persistent, causing considerably more suffering and impairment in psychosocial and work functioning, benzodiazepine and primary health care use, than in non-anxious individuals. Subthreshold GAD can also increase the risk of onset and worsen the course of a range of comorbid mental health, pain and somatic disorders; further increasing costs. Results are robust against bias due to low study quality. Conclusions Subthreshold GAD is a common, recurrent and impairing disease with verifiable morbidity that claims significant healthcare resources. As such, it should receive additional research and clinical attention. PMID:24886240

  12. Gray and white matter volume abnormalities in generalized anxiety disorder by categorical and dimensional characterization.

    PubMed

    Hilbert, Kevin; Pine, Daniel S; Muehlhan, Markus; Lueken, Ulrike; Steudte-Schmiedgen, Susann; Beesdo-Baum, Katja

    2015-12-30

    Increasing efforts have been made to investigate the underlying pathophysiology of generalized anxiety disorder (GAD), but only limited consistent information is available on gray (GM) and white matter (WM) volume changes in affected adults. Additionally, few studies employed dimensional approaches to GAD pathology. This study compares structural brain imaging data from n=19 GAD subjects and n=24 healthy comparison (HC) subjects, all medication-free and matched on age, sex and education. Separate categorical and dimensional models were employed using voxel-based morphometry for GM and WM. Significantly higher GM volumes were found in GAD subjects mainly in basal ganglia structures and less consistently in the superior temporal pole. For WM, GAD subjects showed significantly lower volumes in the dlPFC. Largely consistent findings in dimensional and categorical models point toward these structural alterations being reliable and of importance for GAD. While lower volume in the dlPFC could reflect impaired emotional processing and control over worry in GAD, basal ganglia alterations may be linked to disturbed gain and loss anticipation as implicated in previous functional GAD studies. As perturbations in anticipation processes are central to GAD, these areas may warrant greater attention in future studies.

  13. On the effect of alkaline pH and cofactor availability in the conformational and oligomeric state of Escherichia coli glutamate decarboxylase.

    PubMed

    Giovannercole, F; Mérigoux, C; Zamparelli, C; Verzili, D; Grassini, G; Buckle, M; Vachette, P; De Biase, D

    2017-01-05

    Escherichia coli glutamate decarboxylase (EcGad) is a homohexameric pyridoxal 5'-phosphate (PLP)-dependent enzyme. It is the structural component of the major acid resistance system that protects E. coli from strong acid stress (pH < 3), typically encountered in the mammalian gastrointestinal tract. In fact EcGad consumes one proton/catalytic cycle while yielding γ-aminobutyrate and carbon dioxide from the decarboxylation of l-glutamate. Two isoforms of Gad occur in E. coli (GadA and GadB) that are 99% identical in sequence. GadB is the most intensively investigated. Prompted by the observation that some transcriptomic and proteomic studies show EcGad to be expressed in conditions far from acidic, we investigated the structural organization of EcGadB in solution in the pH range 7.5-8.6. Small angle X-ray scattering, combined with size exclusion chromatography, and analytical ultracentrifugation analysis show that the compact and entangled EcGadB hexameric structure undergoes dissociation into dimers as pH alkalinizes. When PLP is not present, the dimeric species is the most abundant in solution, though evidence for the occurrence of a likely tetrameric species was also obtained. Trp fluorescence emission spectra as well as limited proteolysis studies suggest that PLP plays a key role in the acquisition of a folding necessary for the canonical catalytic activity.

  14. The 1-month prevalence of generalized anxiety disorder according to DSM-IV, DSM-V, and ICD-10 among nondemented 75-year-olds in Gothenburg, Sweden.

    PubMed

    Nilsson, Johan; Östling, Svante; Waern, Margda; Karlsson, Björn; Sigström, Robert; Guo, Xinxin; Skoog, Ingmar

    2012-11-01

    To examine the 1-month prevalence of generalized anxiety disorder (GAD) according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), Diagnostic and Statistical Manual of Mental, Fifth Edition (DSM-V), and International Classification of Diseases, Tenth Revision (ICD-10), and the overlap between these criteria, in a population sample of 75-year-olds. We also aimed to examine comorbidity between GAD and other psychiatric diagnoses, such as depression. During 2005-2006, a comprehensive semistructured psychiatric interview was conducted by trained nurses in a representative population sample of 75-year-olds without dementia in Gothenburg, Sweden (N = 777; 299 men and 478 women). All psychiatric diagnoses were made according to DSM-IV. GAD was also diagnosed according to ICD-10 and DSM-V. The 1-month prevalence of GAD was 4.1% (N = 32) according to DSM-IV, 4.5% (N = 35) according to DSM-V, and 3.7% (N = 29) according to ICD-10. Only 46.9% of those with DSM-IV GAD fulfilled ICD-10 criteria, and only 51.7% and 44.8% of those with ICD-10 GAD fulfilled DSM-IV/V criteria. Instead, 84.4% and 74.3% of those with DSM-IV/V GAD and 89.7% of those with ICD-10 GAD had depression. Also other psychiatric diagnoses were common in those with ICD-10 and DSM-IV GAD. Only a small minority with GAD, irrespective of criteria, had no other comorbid psychiatric disorder. ICD-10 GAD was related to an increased mortality rate. While GAD was common in 75-year-olds, DSM-IV/V and ICD-10 captured different individuals. Current definitions of GAD may comprise two different expressions of the disease. There was greater congruence between GAD in either classification system and depression than between DSM-IV/V GAD and ICD-10 GAD, emphasizing the close link between these entities. 2012 American Association for Geriatric Psychiatry

  15. Subcellular localization of the voltage-gated potassium channels Kv3.1b and Kv3.3 in the cerebellar dentate nucleus of glutamic acid decarboxylase 67-green fluorescent protein transgenic mice.

    PubMed

    Alonso-Espinaco, V; Elezgarai, I; Díez-García, J; Puente, N; Knöpfel, T; Grandes, P

    2008-09-09

    Deep cerebellar dentate nuclei are in a key position to control motor planning as a result of an integration of cerebropontine inputs and hemispheric Purkinje neurons signals, and their influence through synaptic outputs onto extracerebellar hubs. GABAergic dentate neurons exhibit broader action potentials and slower afterhyperpolarization than non-GABAergic (presumably glutamatergic) neurons. Specific potassium channels may be involved in these distinct firing profiles, particularly, Kv3.1 and Kv3.3 subunits which rapidly activate at relatively positive potentials to support the generation of fast action potentials. To investigate the subcellular localization of Kv3.1b and Kv3.3 in GAD- and GAD+ dentate neurons of glutamic acid decarboxylase 67-green fluorescent protein (GAD67-GFP) knock-in mice a preembedding immunocytochemical method for electron microscopy was used. Kv3.1b and Kv3.3 were in membranes of cell somata, dendrites, axons and synaptic terminals of both GAD- and GAD+ dentate neurons. The vast majority of GAD- somatodendritic membrane segments domains labeled for Kv3.1b and Kv3.3 (96.1% and 84.7%, respectively) whereas 56.2% and 69.8% of GAD- axonal membrane segments were immunopositive for these subunits. Furthermore, density of Kv3.1b immunoparticles was much higher in GAD- somatodendritic than axonal domains. As to GAD+ neurons, only 70.6% and 50% of somatodendritic membrane segments, and 53.3% and 59.5% of axonal membranes exhibited Kv3.1b and Kv3.3 labeling, respectively. In contrast to GAD- cells, GAD+ cells exhibited a higher density labeling for both Kv3 subunits at their axonal than at their somatodendritic membranes. Taken together, Kv3.1b and Kv3.3 potassium subunits are expressed in both GAD- and GAD+ cells, albeit at different densities and distribution. They likely contribute to the distinct biophysical properties of both GAD- and GAD+ neurons in the dentate nucleus.

  16. Glutamic acid decarboxylase autoantibody-positivity post-partum is associated with impaired β-cell function in women with gestational diabetes mellitus.

    PubMed

    Lundberg, T P; Højlund, K; Snogdal, L S; Jensen, D M

    2015-02-01

    To investigate whether the presence of glutamic acid decarboxylase (GAD) autoantibodies post-partum in women with prior gestational diabetes mellitus was associated with changes in metabolic characteristics, including β-cell function and insulin sensitivity. During 1997-2010, 407 women with gestational diabetes mellitus were offered a 3-month post-partum follow-up including anthropometrics, serum lipid profile, HbA1c and GAD autoantibodies, as well as a 2-h oral glucose tolerance test (OGTT) with blood glucose, serum insulin and C-peptide at 0, 30 and 120 min. Indices of insulin sensitivity and insulin secretion were estimated to assess insulin secretion adjusted for insulin sensitivity, disposition index (DI). Twenty-two (5.4%) women were positive for GAD autoantibodies (GAD+ve) and the remainder (94.6%) were negative for GAD autoantibodies (GAD-ve). The two groups had similar age and prevalence of diabetes mellitus. Women who were GAD+ve had significantly higher 2-h OGTT glucose concentrations during their index-pregnancy (10.5 vs. 9.8 mmol/l, P = 0.001), higher fasting glucose (5.2 vs. 5.0 mmol/l, P = 0.02) and higher 2-h glucose (7.8 vs. 7.1 mmol/l, P = 0.05) post-partum. Fasting levels of C-peptide and insulin were lower in GAD+ve women compared with GAD-ve women (520 vs. 761 pmol/l, P = 0.02 and 33 vs. 53 pmol/l, P = 0.05) Indices of insulin sensitivity were similar in GAD+ve and GAD-ve women, whereas all estimates of DI were significantly reduced in GAD+ve women. GAD+ve women had higher glucose levels and impaired insulin secretion adjusted for insulin sensitivity (DI) compared with GAD-ve women. The combination of OGTT and GAD autoantibodies post-partum identify women with impaired β-cell function. These women should be followed with special focus on development of Type 1 diabetes. © 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.

  17. WCA recommendations for the long-term treatment of generalized anxiety disorder.

    PubMed

    Allgulander, Christer; Bandelow, Borwin; Hollander, Eric; Montgomery, Stuart A; Nutt, David J; Okasha, Ahmed; Pollack, Mark H; Stein, Dan J; Swinson, Richard P

    2003-08-01

    What are the current recommendations for the long-term treatment of generalized anxiety disorder (GAD)? GAD is a common disorder with a lifetime prevalence of 4% to 7% in the general population. GAD is characterized by excessive, uncontrollable worry or anxiety about a number of events or activities that the individual experiences on more days than not over a 6-month period. Onset of GAD symptoms usually occurs during an individual's early twenties; however, high rates of GAD have also been seen in children and adolescents. The clinical course of GAD is often chronic, with 40% of patients reporting illness lasting >5 years. GAD is associated with pronounced functional impairment, resulting in decreased vocational function and reduced quality of life. Patients with GAD tend to be high users of outpatient medical care, which contributes significantly to healthcare costs. Currently, benzodiazepines and buspirone are prescribed frequently to treat GAD. Although both show efficacy in acute treatment trials, few long-term studies have been performed. Benzodiazepines are not recommended for long-term treatment of GAD, due to associated development of tolerance, psychomotor impairment, cognitive and memory changes, physical dependence, and a withdrawal reaction on discontinuation. The antidepressant venlafaxine extended-release (XR) has received approval for the treatment of GAD in the United States and many other countries. Venlafaxine XR has demonstrated efficacy over placebo in two randomized treatment trials of 6 months' duration as well as in other acute trials. Paroxetine is the first of the selective serotonin reuptake inhibitors (SSRIs) to receive US approval for the treatment of GAD. Paroxetine demonstrated superiority to placebo in short-term trials, and investigations into the use of other SSRIs are ongoing. This suggests that other SSRIs, and serotonin and noradrenaline reuptake inhibitors, are likely to be effective in the treatment of GAD. Of the

  18. Vulnerability of hippocampal GABA-ergic interneurons to kainate-induced excitotoxic injury during old age.

    PubMed

    Shetty, Ashok K; Hattiangady, Bharathi; Rao, Muddanna S

    2009-08-01

    Hippocampal inhibitory interneurons expressing glutamate decarboxylase-67 (GAD-67) considerably decline in number during old age. Studies in young adult animals further suggest that hippocampal GAD-67+ interneuron population is highly vulnerable to excitotoxic injury. However, the relative susceptibility of residual GAD-67+ interneurons in the aged hippocampus to excitotoxic injury is unknown. To elucidate this, using both adult and aged F344 rats, we performed stereological counting of GAD-67+ interneurons in different layers of the dentate gyrus and CA1 & CA3 sub-fields, at 3 months post-excitotoxic hippocampal injury inflicted through an intracerebroventricular administration of kainic acid (KA). Substantial reductions of GAD-67+ interneurons were found in all hippocampal layers and sub-fields after KA-induced injury in adult animals. Contrastingly, there was no significant change in GAD-67+ interneuron population in any of the hippocampal layers and sub-fields following similar injury in aged animals. Furthermore, the stability of GAD-67+ interneurons in aged rats after KA was not attributable to milder injury, as the overall extent of KA-induced hippocampal principal neuron loss was comparable between adult and aged rats. Interestingly, because of the age-related disparity in vulnerability of interneurons to injury, the surviving GAD-67+ interneuron population in the injured aged hippocampus remained comparable to that observed in the injured adult hippocampus despite enduring significant reductions in interneuron number with aging. Thus, unlike in the adult hippocampus, an excitotoxic injury to the aged hippocampus does not result in significantly decreased numbers of GAD-67+ interneurons. Persistence of GAD-67+ interneuron population in the injured aged hippocampus likely reflects an age-related change in the response of GAD-67+ interneurons to excitotoxic hippocampal injury. These results have implications towards understanding mechanisms underlying the

  19. Characteristics of subjects with comorbidity of symptoms of generalized anxiety and major depressive disorders and the corresponding threshold and subthreshold conditions in an Arab general population sample

    PubMed Central

    Ohaeri, Jude U.; Awadalla, Abdel W.

    2012-01-01

    Summary Background There is controversy about differential meaningfulness between comorbid generalized anxiety disorder (GAD)/ major depressive disorder (MDD), the corresponding “pure” disorders and subthreshold conditions. We compared subjects who met DSM-IVTR criteria of symptoms and functional impairment for comorbid GAD/MDD, versus those with GAD, MDD, subthreshold conditions, and without significant symptoms. The comparison measures were socio-demographics, clinical severity, and quality of life (QOL). Material/Methods Participants (N=3155: 55.1% female, aged 16–87 yrs) were a general population sample of Kuwaitis who self-completed DSM-IVTR criteria-based questionnaires and the WHOQOL-BREF in 2006/7. We scrutinized the questionnaires and classified them into categories. Results Of the 273 GAD and 210 MDD cases, the prevalence of comorbidity among cases with GAD was 30.8%, and 40% among MDD. Of the 398 subthreshold GAD and 194 subthreshold MDD cases, 58 had subthreshold anxiety/depression comorbidity. Comorbid threshold GAD/MDD cases were significantly older, and more likely to be women, divorced and unemployed, compared with GAD and MDD. In all measures, the threshold GAD/MDD comorbidity was the severest condition. There was a monotonic decrease in QOL with increasing anxiety-depression symptoms. For the predictors of subjective QOL, the GAD/MDD comorbidity group differed markedly from the others. Conclusions The high prevalence of comorbidity and subthreshold conditions supports the recommendation to assess them routinely, regardless of the primary reason for consultation. Our findings support a dimensional model with comorbid GAD/MDD at the higher end of a continuum, and differing from the “pure” conditions by a later onset and predictors of subjective wellbeing. PMID:22367127

  20. Characterization of epileptic seizure dynamics using Gabor atom density.

    PubMed

    Jouny, Christophe C; Franaszczuk, Piotr J; Bergey, Gregory K

    2003-03-01

    The study of epileptic electroencephalograph (EEG) dynamics can potentially provide insights into seizure onset, evolution and termination. We propose a new synthetic measure based on time-frequency decomposition to provide detailed characterization of these dynamic changes. The matching pursuit (MP) method allows for continuous time-frequency decomposition. We have developed a derivative of the MP method, the Gabor atom density method (GAD) that facilitates interpretation during the dynamic ictal period. The GAD analysis was applied to intracranial recordings of complex partial seizures (n = 43) of mesial temporal origin in 7 patients. Complex partial seizure occurrence is systematically associated with a GAD increase of 400 +/- 150%. The GAD increase coincides with the electrographical evidence of seizure onset. The similarity between seizures in a given patient is very high with uniform onset slope, maximum level and termination pattern. Global GAD responses over all channels can reveal detailed seizure propagation patterns including secondary independent foci and secondary generalization. The GAD measure based on the MP decomposition is a reliable tool to detect seizure occurrence in long-term recordings, to differentiate seizures from artifacts on a multi-channel basis and to examine patterns of seizure propagation. The reproducible GAD pattern suggests consistent changes in signal inner structure and may provide new clues about seizure dynamics and evolution. The GAD method can provide information about seizure dynamics that can contribute to methods of seizure detection. These analyses may lead to better understanding of seizure termination and help facilitate application of responsive seizure control devices in humans.

  1. Gamma-Aminobutyric Acid Production Using Immobilized Glutamate Decarboxylase Followed by Downstream Processing with Cation Exchange Chromatography

    PubMed Central

    Lee, Seungwoon; Ahn, Jungoh; Kim, Yeon-Gu; Jung, Joon-Ki; Lee, Hongweon; Lee, Eun Gyo

    2013-01-01

    We have developed a gamma-aminobutyric acid (GABA) production technique using his-tag mediated immobilization of Escherichia coli-derived glutamate decarboxylase (GAD), an enzyme that catalyzes the conversion of glutamate to GABA. The GAD was obtained at 1.43 g/L from GAD-overexpressed E. coli fermentation and consisted of 59.7% monomer, 29.2% dimer and 2.3% tetramer with a 97.6% soluble form of the total GAD. The harvested GAD was immobilized to metal affinity gel with an immobilization yield of 92%. Based on an investigation of specific enzyme activity and reaction characteristics, glutamic acid (GA) was chosen over monosodium glutamate (MSG) as a substrate for immobilized GAD, resulting in conversion of 2.17 M GABA in a 1 L reactor within 100 min. The immobilized enzymes retained 58.1% of their initial activities after ten consecutive uses. By using cation exchange chromatography followed by enzymatic conversion, GABA was separated from the residual substrate and leached GAD. As a consequence, the glutamic acid was mostly removed with no detectable GAD, while 91.2% of GABA was yielded in the purification step. PMID:23322022

  2. Comparison of Younger and Older Adults' Acceptability of Treatment for Generalized Anxiety Disorder Co-Occurring with Parkinson's Disease

    ERIC Educational Resources Information Center

    Lundervold, Duane A.; Ament, Patrick A.; Holt, Peter S.; Hunt, Lauren S.

    2013-01-01

    Acceptability ratings of medication or Behavioral Relaxation Training (BRT), for general anxiety disorder (GAD) co-occurring with Parkinson's Disease (PD) were obtained from younger ("n" = 79) and older ("n" = 54) adults. Participants read a case description of an older adult with PD and comorbid GAD followed by a description…

  3. Cognitive-Behavioral Therapy for Comorbid Generalized Anxiety Disorder and Panic Disorder with Agoraphobia

    ERIC Educational Resources Information Center

    Labrecque, Joane; Dugas, Michel J.; Marchand, Andre; Letarte, Andree

    2006-01-01

    The goal of this study was to evaluate the efficacy of a cognitive-behavioral treatment package for comorbid generalized anxiety disorder (GAD) and panic disorder with agoraphobia (PDA). A single-case, multiple-baseline, across-subjects design was used with 3 primary GAD patients with secondary PDA. The efficacy of the treatment was evaluated with…

  4. Metacognitive, Cognitive and Developmental Predictors of Generalised Anxiety Disorder Symptoms

    ERIC Educational Resources Information Center

    Tan, Shary; Moulding, Richard; Nedeljkovic, Maja; Kyrios, Michael

    2010-01-01

    Generalised anxiety disorder (GAD) is the most significant and common of the anxiety disorders. Intolerance of uncertainty (IU) and negative metacognitive beliefs are two prominent cognitive factors in models of GAD, however only one study to date has examined the relative contribution of these factors. Therefore, this study aimed to investigate…

  5. Comparative cost analysis of generalized anxiety disorder and major depressive disorder patients in secondary care from a national hospital registry in Finland.

    PubMed

    Kujanpää, Tero; Ylisaukko-Oja, Tero; Jokelainen, Jari; Linna, Miika; Timonen, Markku

    2014-07-01

    Major depressive disorder (MDD) has shown to cause high costs to society. Earlier research indicates that generalized anxiety disorder (GAD) also causes high costs, but only limited data is available in varying settings. To analyse the secondary care costs of GAD compared with those of MDD. Retrospective database analysis from Finnish Hospital Discharge Registers (FHDR). All GAD and MDD patients diagnosed between 1 January 2007 and 31 December 2007 in FHDR were recorded and individual-level secondary care costs during a 48-month follow-up period were measured. The total mean cost of GAD with history of MDD or some other anxiety disorder was significantly higher than that of MDD with history of GAD or some other anxiety disorder during the 48-month follow-up period. The costs of pure GAD were comparable with those of pure MDD, but after adjusting for age and sex, the costs of pure MDD were higher than those of pure GAD. The economic burden of individual GAD patients is comparable with that of MDD patients in secondary care.

  6. The Influence of Gender, Age, Psychological Resilience and Family Interaction Factors upon Anxiety and Depression in Non-Autism Spectrum Disorder Siblings of Children with an Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Bitsika, Vicki; Sharpley, Christopher F.; Mailli, Rebecca

    2015-01-01

    The influence of gender, age, Psychological resilience and family interaction factors upon generalised anxiety disorder (GAD) and major depressive disorder (MDD) was investigated in 75 non-autism spectrum disorder (NASD) siblings who had a brother or sister with an autism spectrum disorder (ASD). GAD and MDD were much more prevalent than in…

  7. Alterations in white matter volume and its correlation with clinical characteristics in patients with generalized anxiety disorder.

    PubMed

    Moon, Chung-Man; Jeong, Gwang-Woo

    2015-11-01

    Only a few morphological studies have focused on changes in white matter (WM) volume in patients with generalized anxiety disorder (GAD). We evaluated alterations in WM volume and its correlation with symptom severity and duration of illness in adults with GAD. The 44 subjects were comprised of 22 patients with GAD (13 males and nine females) diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) and 22 age-matched healthy controls (13 males and nine females). High-resolution magnetic resonance imaging (MRI) data were processed by voxel-based morphometry (VBM) analysis based on diffeomorphic anatomical registration using the exponentiated Lie algebra (DARTEL) algorithm in SPM8. Patients with GAD showed significantly reduced WM volume, particularly in the dorsolateral prefrontal cortex (DLPFC), anterior limb of the internal capsule (ALIC), and midbrain. In addition, DLPFC volume was negatively correlated with GAD-7 score and illness duration. ALIC volume was negatively correlated with GAD-7 score. Female patients had significantly less orbitofrontal cortex volume compared to that in male patients. The findings demonstrate localized changes in WM volume associated with cognitive and emotional dysfunction in patients with GAD. The finding will be helpful for understanding the neuropathology in patients with GAD.

  8. The Influence of Gender, Age, Psychological Resilience and Family Interaction Factors upon Anxiety and Depression in Non-Autism Spectrum Disorder Siblings of Children with an Autism Spectrum Disorder

    ERIC Educational Resources Information Center

    Bitsika, Vicki; Sharpley, Christopher F.; Mailli, Rebecca

    2015-01-01

    The influence of gender, age, Psychological resilience and family interaction factors upon generalised anxiety disorder (GAD) and major depressive disorder (MDD) was investigated in 75 non-autism spectrum disorder (NASD) siblings who had a brother or sister with an autism spectrum disorder (ASD). GAD and MDD were much more prevalent than in…

  9. Characterization of the YdeO regulon in Escherichia coli.

    PubMed

    Yamanaka, Yuki; Oshima, Taku; Ishihama, Akira; Yamamoto, Kaneyoshi

    2014-01-01

    Enterobacteria are able to survive under stressful conditions within animals, such as acidic conditions in the stomach, bile salts during transfer to the intestine and anaerobic conditions within the intestine. The glutamate-dependent (GAD) system plays a major role in acid resistance in Escherichia coli, and expression of the GAD system is controlled by the regulatory cascade consisting of EvgAS > YdeO > GadE. To understand the YdeO regulon in vivo, we used ChIP-chip to interrogate the E. coli genome for candidate YdeO binding sites. All of the seven operons identified by ChIP-chip as being potentially regulated by YdeO were confirmed as being under the direct control of YdeO using RT-qPCR, EMSA, DNaseI-footprinting and reporter assays. Within this YdeO regulon, we identified four stress-response transcription factors, DctR, NhaR, GadE, and GadW and enzymes for anaerobic respiration. Both GadE and GadW are involved in regulation of the GAD system and NhaR is an activator for the sodium/proton antiporter gene. In conjunction with co-transcribed Slp, DctR is involved in protection against metabolic endoproducts under acidic conditions. Taken all together, we suggest that YdeO is a key regulator of E. coli survival in both acidic and anaerobic conditions.

  10. The Clinical Application of Emotion Research in Generalized Anxiety Disorder: Some Proposed Procedures

    ERIC Educational Resources Information Center

    Huppert, Jonathan D.; Alley, Amie C.

    2004-01-01

    Major psychological theories of generalized anxiety disorder (GAD) have begun to suggest that worry may function as avoidance of emotions. On the basis of these findings, a number of researchers have begun to develop techniques to address emotional deficits in GAD. However, most techniques suggested to date have been from outside a…

  11. A Bowen Family Systems Model of Generalized Anxiety Disorder and Romantic Relationship Distress.

    PubMed

    Priest, Jacob B

    2015-07-01

    Many individuals with generalized anxiety disorder (GAD) do not respond well to currently available treatments. Moreover, treatments are less effective when GAD is accompanied by romantic relationship distress. In order to develop effective treatments for GAD and relationship distress, it is necessary to conduct theory-based research to identify links common to both GAD and romantic relationship distress. Drawing on Bowen's family systems theory, the roles of family abuse/violence and differentiation in GAD and romantic relationship distress were examined using existing data from the National Comorbidity Survey Replication (n = 2,312; 2005). As predicted, family abuse/violence was directly linked to both GAD and romantic relationship distress. Differentiation mediated the relationship between family abuse/violence and GAD, and partially mediated the relationship between family abuse/violence and romantic relationship distress. Findings suggest that current and past relationship processes may help maintain chronic anxiety and that Bowen's theory may be a useful framework for developing couple therapy treatment of GAD and romantic relationship distress. © 2013 American Association for Marriage and Family Therapy.

  12. A Case of Premature Termination in a Treatment for Generalized Anxiety Disorder

    ERIC Educational Resources Information Center

    Boswell, James F.; Llera, Sandra J.; Newman, Michelle G.; Castonguay, Louis G.

    2011-01-01

    In this paper we present a case of failure in an integrative treatment for generalized anxiety disorder (GAD) combining cognitive-behavioral therapy, an empirically supported treatment for GAD, and interpersonal-emotional processing therapy. The client of focus dropped out of treatment after the 8th session. Based on our analysis of this case, we…

  13. Efficacy of an Acceptance-Based Behavior Therapy for Generalized Anxiety Disorder: Evaluation in a Randomized Controlled Trial

    ERIC Educational Resources Information Center

    Roemer, Lizabeth; Orsillo, Susan M.; Salters-Pedneault, Kristalyn

    2008-01-01

    Generalized anxiety disorder (GAD) is a chronic anxiety disorder, associated with comorbidity and impairment in quality of life, for which improved psychosocial treatments are needed. GAD is also associated with reactivity to and avoidance of internal experiences. The current study examined the efficacy of an acceptance-based behavioral therapy…

  14. Cognitive-Behavioral Therapy for Comorbid Generalized Anxiety Disorder and Panic Disorder with Agoraphobia

    ERIC Educational Resources Information Center

    Labrecque, Joane; Dugas, Michel J.; Marchand, Andre; Letarte, Andree

    2006-01-01

    The goal of this study was to evaluate the efficacy of a cognitive-behavioral treatment package for comorbid generalized anxiety disorder (GAD) and panic disorder with agoraphobia (PDA). A single-case, multiple-baseline, across-subjects design was used with 3 primary GAD patients with secondary PDA. The efficacy of the treatment was evaluated with…

  15. Presentation of opsoclonus myoclonus ataxia syndrome with glutamic acid decarboxylase antibodies.

    PubMed

    Bhandari, Hanul Srinivas

    2012-08-08

    In this rare case, the patient presented with opsoclonus, myoclonus and ataxia. Serological and imaging studies revealed high glutamic acid decarboxylase antibody (GAD-Ab) levels. High-dose corticosteroids were of no benefit and subsequent intravenous immunoglobulin (IVIg) administration proved resolution of the condition. Levetiracetam proved useful in symptomatically controlling the myoclonus. Follow-up GAD-Ab levels were within normal limits.

  16. Specific γ-aminobutyric acid decomposition by gabP and gabT under neutral pH in recombinant Corynebacterium glutamicum.

    PubMed

    Ni, Yalan; Shi, Feng; Wang, Nannan

    2015-11-01

    Corynebacterium glutamicum that expresses the exogenous L-glutamate decarboxylase (GAD) gene can synthesize γ-aminobutyric acid (GABA). To prevent GABA decomposition in the recombinant C. glutamicum GAD strain, GABA uptake and the GABA shunt pathway were blocked. GABA uptake is catalyzed by GABA permease encoded by gabP. The first reaction of the GABA shunt pathway is catalyzed by the GABA transaminase encoded by gabT. Initially, the effects of pH on GABA decomposition in recombinant C. glutamicum co-expressing two GAD genes (gadB1 and gadB2) were analyzed, demonstrating that GABA could be decomposed under neutral pH. Next, the gabP and gabT were individually deleted, and the GABA production of the related GAD strains was investigated by controlling the pH of the final fermentation stage at a neutral state. During this stage, the GABA concentration of the gabT-deleted GAD strain decreased from 23.9 ± 1.8 to 17.7 ± 0.7 g/l. However, the GABA concentration of the gabP-deleted GAD strain remained at 18.6-19.4 g/l. This study demonstrated that GABA was decomposed under neutral pH and that the deletion of gabP could effectively alleviate GABA decomposition in C. glutamicum.

  17. New Strategies for Combining Mindfulness with Integrative Cognitive Behavioral Therapy for the Treatment of Generalized Anxiety Disorder.

    PubMed

    Rapgay, Lobsang; Bystritsky, Alexander; Dafter, Roger E; Spearman, Michelle

    2011-06-01

    Generalized anxiety disorder (GAD) severely impacts social functioning, distress levels, and utilization of medical care compared with that of other major psychiatric disorders. Neither pharmacological nor psychotherapy interventions have adequately controlled cardinal symptoms of GAD: pervasive excessive anxiety and uncontrollable worry. Research has established cognitive behavioral therapy (CBT) as the most effective psychotherapy for controlling GAD; however, outcomes remain at only 50% reduction, with high relapse rates. Mindfulness has been integrated with CBT to treat people suffering from numerous psychiatric disorders, with mindfulness based stress reduction (MBSR) being the most researched. Preliminary evidence supports MBSR's potential for controlling GAD symptoms and key researchers suggest mindfulness practices possess key elements for treating GAD. Classical mindfulness (CM) differs significantly from MBSR and possesses unique potentials for directly targeting process and state GAD symptoms inadequately treated by CBT. This article introduces the theory and practice of CM, its differences from MBSR, and a critical review of MBSR and CBT treatments for GAD. CM strategies designed to complement CBT targeting cardinal GAD symptoms are outlined with a case study illustrating its use.

  18. Psychometric comparison of the generalized anxiety disorder scale-7 and the Penn State Worry Questionnaire for measuring response during treatment of generalised anxiety disorder.

    PubMed

    Dear, Blake F; Titov, Nickolai; Sunderland, Matthew; McMillan, Dean; Anderson, Tracy; Lorian, Carolyn; Robinson, Emma

    2011-01-01

    The Penn State Worry Questionnaire (PSWQ) is a widely used measure of the worry characteristic of generalised anxiety disorder (GAD). The 7-item Generalized Anxiety Disorder Scale (GAD-7) is a new brief screening tool for GAD, which is being increasingly used in research and clinical practice. The present study sought to provide comparison data on the relative psychometric properties of these two scales. The data of 195 adults who met Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for GAD and who participated in two randomised treatment controlled trials were used. Factor analyses, internal consistency, correlational analyses, responsiveness to change, and agreement between the scales based on indentified clinical cutoffs were conducted. Factor analyses confirmed a one-factor structure for the GAD-7 and a three-factor structure involving two method factors for the PSWQ. Both the GAD-7 and the PSWQ demonstrated adequate internal consistency (Cronbach's alpha: .79-.91 and .86-.91, respectively), and moderate correlations (r = .51-.71) were observed between the scales across the treatment time points. The scales exhibited small correlations with the Sheehan Disability Scale at pretreatment (GAD-7 r = .38; PSWQ r = .26), but moderate correlations at posttreatment and follow-up (r = .59-.79). Agreement between the scales was limited using various clinical cutoffs identified within the literature. Both measures were sensitive to change, although the GAD-7 appeared to be more sensitive and may, therefore, confer some advantages in clinical work.

  19. Efficacy of pregabalin in depressive symptoms associated with generalized anxiety disorder: a pooled analysis of 6 studies.

    PubMed

    Stein, Dan J; Baldwin, David S; Baldinetti, Francesca; Mandel, Francine

    2008-06-01

    Epidemiological evidence supports comorbidity of generalized anxiety disorder (GAD) and major depressive disorder (MDD) or dysthymia, and its association with significant disability. As pregabalin, a new alpha(2)-delta anxiolytic treatment for GAD, unlike most other licensed treatments for GAD has not undergone investigation in patients with MDD, we examined its efficacy in depressive symptoms associated with GAD, through a post-hoc analysis of the existing clinical trial database. The results provide consistent evidence that in patients with GAD pregabalin reduced associated symptoms of depression. This was seen in the 150 mg/day, 300-450 mg/day and 600 mg/day dosing groups. Even in subjects with more prominent depressive symptoms, pregabalin remained effective for both sub-syndromal depression and GAD symptoms, with pregabalin 300-450 mg/day demonstrating the most beneficial response. In conclusion, pregabalin, an alternative treatment option for GAD with a novel mechanism of action, also demonstrated efficacy in treating depressive symptoms typically encountered in GAD patients.

  20. The long-term clinical course of generalized anxiety disorder.

    PubMed

    Keller, Martin B

    2002-01-01

    Although generalized anxiety disorder (GAD) is a common disorder associated with significant levels of morbidity, little is known of its long-term course and outcomes. During the first 5 years, GAD follows a chronic course with low rates of remission and moderate rates of relapse/recurrence following remission. Retrospective studies suggest that this chronic pattern may last up to 20 years. It is hoped that, as with depression, long-term prospective studies in GAD will provide insight into the course, nature, and outcomes of the disorder over time. The studies will also identify any changes in the duration and severity of episodes of GAD over time, enabling treatments to effectively reflect the course of the disorder. Studies of other anxiety disorders and depression suggest that the course and outcome of the disorder may be influenced by certain factors such as stressful life events, anxiety sensitivity/negative affect, gender, subsyndromal symptoms, and comorbid disorders. Currently, studies are underway to determine the effects of these factors on the risk of relapse/recurrence, maintenance of full symptoms, and development of subsyndromal symptoms in GAD. GAD is currently underrecognized and undertreated, but it is hoped that this will change with the ever-increasing awareness of anxiety disorders. As treatment for GAD becomes more common, future prospective studies will identify the effect of therapy on the course and nature of the disorder, leading to increased understanding of GAD and the development of effective treatment strategies tailored for individual patients.

  1. Glutamate decarboxylase from Lactobacillus brevis: activation by ammonium sulfate.

    PubMed

    Hiraga, Kazumi; Ueno, Yoshie; Oda, Kohei

    2008-05-01

    In this study, the glutamate decarboxylase (GAD) gene from Lactobacillus brevis IFO12005 (Biosci. Biotechnol. Biochem., 61, 1168-1171 (1997)), was cloned and expressed. The deduced amino acid sequence showed 99.6% and 53.1% identity with GAD of L. brevis ATCC367 and L. lactis respectively. The His-tagged recombinant GAD showed an optimum pH of 4.5-5.0, and 54 kDa on SDS-PAGE. The GAD activity and stability was significantly dependent on the ammonium sulfate concentration, as observed in authentic GAD. Gel filtration showed that the inactive form of the GAD was a dimer. In contrast, the ammonium sulfate-activated form was a tetramer. CD spectral analyses at pH 5.5 revealed that the structures of the tetramer and the dimer were similar. Treatment of the GAD with high concentrations of ammonium sulfate and subsequent dilution with sodium glutamate was essential for tetramer formation and its activation. Thus the biochemical properties of the GAD from L. brevis IFO12005 were significantly different from those from other sources.

  2. Investigation of the cognitive variables associated with worry in children with Generalised Anxiety Disorder and their parents.

    PubMed

    Donovan, Caroline L; Holmes, Monique C; Farrell, Lara J

    2016-03-01

    Intolerance of uncertainty (IU), negative beliefs about worry (NBW), positive beliefs about worry (PBW), negative problem orientation (NPO) and cognitive avoidance (CA) have been found to be integral in the conceptualisation of Generalised Anxiety Disorder (GAD) in adults, yet they have rarely been investigated in children with GAD. This study sought to determine (a) whether IU, NBW, PBW, NPO and CA differ between children diagnosed with GAD and non-anxious children and (b) to examine whether IU, NBW, PBW, NPO and CA differ between parents of children diagnosed with GAD and parents of children without an anxiety disorder. Participants were 50 children (aged 7-12 years), plus one of their parents. The 25 GAD children and 25 non-anxious children were matched on age and gender. Parents and children completed clinical diagnostic interviews, as well as a battery of questionnaires measuring worry, IU, NBW, PBW, NPO and CA. Children with GAD endorsed significantly higher levels of worry, IU, NBW, NPO and CA, but not PBW compared to non-anxious children. Parents of children with GAD did not differ from parents of non-anxious children on any of the variables. The study was limited by it's use of modified adult measures for some variables and a lack of heterogeneity in the sample. The cognitive variables of IU, NBW, NPO and CA may also be important in the conceptualisation and treatment of GAD in children as they are in adults. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Efficacy of Problem-Solving Training and Cognitive Exposure in the Treatment of Generalized Anxiety Disorder: A Case Replication Series

    ERIC Educational Resources Information Center

    Provencher, Martin D.; Dugas, Michel J.; Ladouceur, Robert

    2004-01-01

    Recent advances in our understanding of worry and generalized anxiety disorder (GAD) have led to the development of efficacious treatments for GAD. Although multidimensional treatment packages have shown efficacy, we know little about the efficacy and clinical utility of individual treatment components. This study evaluates the efficacy of…

  4. Efficacy of an Acceptance-Based Behavior Therapy for Generalized Anxiety Disorder: Evaluation in a Randomized Controlled Trial

    ERIC Educational Resources Information Center

    Roemer, Lizabeth; Orsillo, Susan M.; Salters-Pedneault, Kristalyn

    2008-01-01

    Generalized anxiety disorder (GAD) is a chronic anxiety disorder, associated with comorbidity and impairment in quality of life, for which improved psychosocial treatments are needed. GAD is also associated with reactivity to and avoidance of internal experiences. The current study examined the efficacy of an acceptance-based behavioral therapy…

  5. A Case of Premature Termination in a Treatment for Generalized Anxiety Disorder

    ERIC Educational Resources Information Center

    Boswell, James F.; Llera, Sandra J.; Newman, Michelle G.; Castonguay, Louis G.

    2011-01-01

    In this paper we present a case of failure in an integrative treatment for generalized anxiety disorder (GAD) combining cognitive-behavioral therapy, an empirically supported treatment for GAD, and interpersonal-emotional processing therapy. The client of focus dropped out of treatment after the 8th session. Based on our analysis of this case, we…

  6. Vector-mediated chromosomal integration of the glutamate decarboxylase gene in streptococcus thermophilus

    USDA-ARS?s Scientific Manuscript database

    The integrative vector pINTRS was used to transfer glutamate decarboxylase (GAD) activity to Streptococcus thermophilus ST128, thus allowing for the production of '-aminobutyric acid (GABA). In pINTRS, the gene encoding glutamate decarboxylase, gadB, was flanked by DNA fragments homologous to a S. ...

  7. Failure in Cognitive Suppression of Negative Affect in Adolescents with Generalized Anxiety Disorder.

    PubMed

    Yin, Dazhi; Liu, Wenjing; Zeljic, Kristina; Lv, Qian; Wang, Zhiwei; You, Meina; Men, Weiwei; Fan, Mingxia; Cheng, Wenhong; Wang, Zheng

    2017-07-26

    Hyperactivity of limbic (e.g., amygdalar) responses to negative stimuli has been implicated in the pathophysiology of generalized anxiety disorder (GAD). Evidence has also suggested that even a simple cognitive task involving emotionally salient stimuli can modulate limbic and prefrontal neural activation. However, whether neural modulation of emotional stimulus processing in a cognitive task is defective in adolescents with GAD has not yet been investigated. In this study, 20 adolescents with GAD and 14 comparable healthy controls underwent event-related functional magnetic resonance imaging (fMRI) coupled with an emotional valence evaluation task. During the evaluation of negative versus neutral stimuli, we found significant activation of the right inferior frontal gyrus (IFG) in healthy controls, while the bilateral amygdala was activated in GAD patients. Between-group analyses showed dramatically reduced task-activation of the right IFG in GAD patients, and the magnitude of IFG activity negatively correlated with symptom severity. Psychophysiological interaction analysis further revealed significantly decreased functional interaction between right IFG and anterior cingulate cortex and ventromedial prefrontal cortex in GAD patients compared with healthy controls. Taken together, our findings show failure to suppress negative affect by recruiting a cognitive distraction in adolescents with GAD, providing new insights into the pathophysiology of GAD.

  8. Physiology-Oriented Engineering Strategy to Improve Gamma-Aminobutyrate Production in Lactobacillus brevis.

    PubMed

    Lyu, Chang-Jiang; Zhao, Wei-Rui; Hu, Sheng; Huang, Jun; Lu, Tao; Jin, Zhi-Hua; Mei, Le-He; Yao, Shan-Jing

    2017-02-01

    Gamma-aminobutyrate (GABA) is an important chemical in the pharmaceutical field. GABA-producing lactic acid bacteria (LAB) offer the opportunity of developing this health-oriented product. In this study, the gadA, gadB, gadC, gadCB, and gadCA gene segments of Lactobacillus brevis were cloned into pMG36e, and strain Lb. brevis/pMG36e-gadA was selected for thorough characterization in terms of GABA production after analysis of GAD activities. Subsequently, a physiology-oriented engineering strategy was adopted to construct an FoF1-ATPase deficient strain NRA6 with higher GAD activity. As expected, strain NRA6 could produce GABA at a concentration of 43.65 g/L with a 98.42% GABA conversion rate in GYP fermentation medium, which is 1.22-fold higher than that obtained by the wild-type strain in the same condition. This work demonstrates how the acid stress response mechanisms of LAB can be employed to develop cell factories with improved production efficiency and contributes to research into the development of the physiology-oriented engineering.

  9. Efficient increase of ɣ-aminobutyric acid (GABA) content in tomato fruits by targeted mutagenesis.

    PubMed

    Nonaka, Satoko; Arai, Chikako; Takayama, Mariko; Matsukura, Chiaki; Ezura, Hiroshi

    2017-08-01

    γ-Aminobutyric acid (GABA) is a non-proteinogenic amino acid that has hypotensive effects. Tomato (Solanum lycopersicum L.) is among the most widely cultivated and consumed vegetables in the world and contains higher levels of GABA than other major crops. Increasing these levels can further enhance the blood pressure-lowering function of tomato fruit. Glutamate decarboxylase (GAD) is a key enzyme in GABA biosynthesis; it has a C-terminal autoinhibitory domain that regulates enzymatic function, and deleting this domain increases GAD activity. The tomato genome has five GAD genes (SlGAD1-5), of which two (SlGAD2 and SlGAD3) are expressed during tomato fruit development. To increase GABA content in tomato, we deleted the autoinhibitory domain of SlGAD2 and SlGAD3 using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas)9 technology. Introducing a stop codon immediately before the autoinhibitory domain increased GABA accumulation by 7 to 15 fold while having variable effects on plant and fruit size and yield. This is the first study describing the application of the CRISPR/Cas9 system to increase GABA content in tomato fruits. Our findings provide a basis for the improvement of other types of crop by CRISPR/Cas9-based genetic modification.

  10. Roles of serotonin 5-HT3 receptor in the formation of dendrites and axons in the rat cerebral cortex: an in vitro study.

    PubMed

    Hayashi, Takahiro; Ohtani, Akiko; Onuki, Fumiaki; Natsume, Masaki; Li, Fei; Satou, Tomomi; Yoshikawa, Masaaki; Senzaki, Kouji; Shiga, Takashi

    2010-01-01

    The serotonin type 3 (5-HT(3)) receptor is an only ligand-gated ion channel among 14 serotonin receptors. Here, we examined the roles of the 5-HT(3) receptor in the formation of dendrites and axons, using a dissociation culture of embryonic rat cerebral cortex. Cortical neurons at embryonic day 16 were cultured for 4 days in the presence of a selective 5-HT(3) receptor agonist with or without an antagonist. Neurons were then immunostained by antibodies against microtubule-associated protein 2 (MAP2) and glutamic acid decarboxylase (GAD) 65. All cells expressed MAP2, whereas only limited number of cells expressed GAD65. From the immunoreactivity and the cell shape, we tentatively divided neurons into 3 types; GAD-positive multipolar, GAD-positive bipolar/tripolar and GAD-negative neurons. The total length of axons and dendrites, the number of primary dendrites and the dendritic branching of GAD-negative neurons were decreased by the agonist (10 or 100nM), most of which were reversed by the concomitant treatment of the antagonist. In contrast, no or little effect was observed on the formation of dendrites and axons of GAD-positive multipolar neurons, and the neurite formation of GAD-positive bipolar/tripolar neurons. The present study revealed differential roles of the 5-HT(3) receptor in the formation of dendrites and axons of subtypes of cortical neurons.

  11. Neuropsychological functioning in young subjects with generalized anxiety disorder with and without pharmacotherapy.

    PubMed

    Tempesta, D; Mazza, M; Serroni, N; Moschetta, F S; Di Giannantonio, M; Ferrara, M; De Berardis, D

    2013-08-01

    The purpose of this study was to investigate the neuropsychological functioning and the effect of antidepressant drug intake on cognitive performance in a group of relatively young generalized anxiety disorder (GAD) patients. Forty patients with a DSM-IV diagnosis of GAD and 31 healthy subjects participated in the study (Control group, CON). None of the selected subjects had comorbid depression. GAD subjects were divided into two different subgroups: 18 were taking antidepressants [GAD-pharmacotherapy (GAD-p group)] and 22 were treatment-naïve (GAD group). Each group was administered with a comprehensive neuropsychological battery to assess attention, memory and executive functions. Performance on executive and non-verbal memory tasks of both GAD groups was largely worse than the CON group. However, these deficits seem to be more marked in patients taking antidepressants, especially in the domains of attention, non-verbal memory and executive functions. The present study indicates that GAD is associated with cognitive impairments among young adults. However, the observed association of neuropsychological deficits and the use of pharmacotherapy suggest a possible effect of antidepressant treatment on attention, executive functioning and non-verbal memory.

  12. What's in a name? Intolerance of uncertainty, other uncertainty-relevant constructs, and their differential relations to worry and generalized anxiety disorder.

    PubMed

    Koerner, Naomi; Mejia, Teresa; Kusec, Andrea

    2017-03-01

    A number of studies have examined the association of intolerance of uncertainty (IU) to trait worry and generalized anxiety disorder (GAD). However, few studies have examined the extent of overlap between IU and other psychological constructs that bear conceptual resemblance to IU, despite the fact that IU-type constructs have been discussed and examined extensively within psychology and other disciplines. The present study investigated (1) the associations of IU, trait worry, and GAD status to a negative risk orientation, trait curiosity, indecisiveness, perceived constraints, self-oriented and socially prescribed perfectionism, intolerance of ambiguity, the need for predictability, and the need for order and structure and (2) whether IU is a unique correlate of trait worry and of the presence versus absence of Probable GAD, when overlap with other uncertainty-relevant constructs is accounted for. N = 255 adults completed self-report measures of the aforementioned constructs. Each of the constructs was significantly associated with IU. Only IU, and a subset of the other uncertainty-relevant constructs were correlated with trait worry or distinguished the Probable GAD group from the Non-GAD group. IU was the strongest unique correlate of trait worry and of the presence versus absence of Probable GAD. Indecisiveness, self-oriented perfectionism and the need for predictability were also unique correlates of trait worry or GAD status. Implications of the findings are discussed, in particular as they pertain to the definition, conceptualization, and cognitive-behavioral treatment of IU in GAD.

  13. Intolerance of uncertainty, causal uncertainty, causal importance, self-concept clarity and their relations to generalized anxiety disorder.

    PubMed

    Kusec, Andrea; Tallon, Kathleen; Koerner, Naomi

    2016-06-01

    Although numerous studies have provided support for the notion that intolerance of uncertainty plays a key role in pathological worry (the hallmark feature of generalized anxiety disorder (GAD)), other uncertainty-related constructs may also have relevance for the understanding of individuals who engage in pathological worry. Three constructs from the social cognition literature, causal uncertainty, causal importance, and self-concept clarity, were examined in the present study to assess the degree to which these explain unique variance in GAD, over and above intolerance of uncertainty. N = 235 participants completed self-report measures of trait worry, GAD symptoms, and uncertainty-relevant constructs. A subgroup was subsequently classified as low in GAD symptoms (n = 69) or high in GAD symptoms (n = 54) based on validated cut scores on measures of trait worry and GAD symptoms. In logistic regressions, only elevated intolerance of uncertainty and lower self-concept clarity emerged as unique correlates of high (vs. low) GAD symptoms. The possible role of self-concept uncertainty in GAD and the utility of integrating social cognition theories and constructs into clinical research on intolerance of uncertainty are discussed.

  14. Substance Abuse Counselor and Client Reports of Mental Health Screening and Enhanced Practices

    DTIC Science & Technology

    2012-09-01

    Health Questionnaire (PHQ-9) for depression,29 Generalized Anxiety Disorder screen (GAD-7),30 and the Brief Traumatic Brain Injury Screen (BTBIS).31...brief measure for assessing generalized anxiety disorder : the GAD-7. Arch Intern Med 2006; 166: 1092–7. 31. Schwab K, Baker G, Ivins B, Sluss-Tiller M

  15. Gamma-aminobutyric acid depletion affects stomata closure and drought tolerance of Arabidopsis thaliana.

    PubMed

    Mekonnen, Dereje Worku; Flügge, Ulf-Ingo; Ludewig, Frank

    2016-04-01

    A rapid accumulation of γ-aminobutyric acid (GABA) during biotic and abiotic stresses is well documented. However, the specificity of the response and the primary role of GABA under such stress conditions are hardly understood. To address these questions, we investigated the response of the GABA-depleted gad1/2 mutant to drought stress. GABA is primarily synthesized from the decarboxylation of glutamate by glutamate decarboxylase (GAD) which exists in five copies in the genome of Arabidopsis thaliana. However, only GAD1 and GAD2 are abundantly expressed, and knockout of these two copies dramatically reduced the GABA content. Phenotypic analysis revealed a reduced shoot growth of the gad1/2 mutant. Furthermore, the gad1/2 mutant was wilted earlier than the wild type following a prolonged drought stress treatment. The early-wilting phenotype was due to an increase in stomata aperture and a defect in stomata closure. The increase in stomata aperture contributed to higher stomatal conductance. The drought oversensitive phenotype of the gad1/2 mutant was reversed by functional complementation that increases GABA level in leaves. The functionally complemented gad1/2 x pop2 triple mutant contained more GABA than the wild type. Our findings suggest that GABA accumulation during drought is a stress-specific response and its accumulation induces the regulation of stomatal opening thereby prevents loss of water.

  16. Activating glutamate decarboxylase activity by removing the autoinhibitory domain leads to hyper γ-aminobutyric acid (GABA) accumulation in tomato fruit.

    PubMed

    Takayama, Mariko; Matsukura, Chiaki; Ariizumi, Tohru; Ezura, Hiroshi

    2017-01-01

    The C-terminal extension region of SlGAD3 is likely involved in autoinhibition, and removing this domain increases GABA levels in tomato fruits. γ-Aminobutyric acid (GABA) is a ubiquitous non-protein amino acid with several health-promoting benefits. In many plants including tomato, GABA is synthesized via decarboxylation of glutamate in a reaction catalyzed by glutamate decarboxylase (GAD), which generally contains a C-terminal autoinhibitory domain. We previously generated transgenic tomato plants in which tomato GAD3 (SlGAD3) was expressed using the 35S promoter/NOS terminator expression cassette (35S-SlGAD3-NOS), yielding a four- to fivefold increase in GABA levels in red-ripe fruits compared to the control. In this study, to further increase GABA accumulation in tomato fruits, we expressed SlGAD3 with (SlGAD3 (OX) ) or without (SlGAD3ΔC (OX) ) a putative autoinhibitory domain in tomato using the fruit ripening-specific E8 promoter and the Arabidopsis heat shock protein 18.2 (HSP) terminator. Although the GABA levels in SlGAD3 (OX) fruits were equivalent to those in 35S-SlGAD3-NOS fruits, GABA levels in SlGAD3ΔC (OX) fruits increased by 11- to 18-fold compared to control plants, indicating that removing the autoinhibitory domain increases GABA biosynthesis activity. Furthermore, the increased GABA levels were accompanied by a drastic reduction in glutamate and aspartate levels, indicating that enhanced GABA biosynthesis affects amino acid metabolism in ripe-fruits. Moreover, SlGAD3ΔC (OX) fruits exhibited an orange-ripe phenotype, which was associated with reduced levels of both carotenoid and mRNA transcripts of ethylene-responsive carotenogenic genes, suggesting that over activation of GAD influences ethylene sensitivity. Our strategy utilizing the E8 promoter and HSP terminator expression cassette, together with SlGAD3 C-terminal deletion, would facilitate the production of tomato fruits with increased GABA levels.

  17. Time-course of SKF-81297-induced increase in glutamic acid decarboxylase 65 and 67 mRNA levels in striatonigral neurons and decrease in GABA(A) receptor alpha1 subunit mRNA levels in the substantia nigra, pars reticulata, in adult rats with a unilateral 6-hydroxydopamine lesion.

    PubMed

    Yamamoto, N; Soghomonian, J-J

    2008-06-26

    Striatal projection neurons use GABA as their neurotransmitter and express the rate-limiting synthesizing enzyme glutamic acid decarboxylase (GAD) and the vesicular GABA transporter vGAT. The chronic systemic administration of an agonist of dopamine D1/D5-preferring receptors is known to alter GAD mRNA levels in striatonigral neurons in intact and dopamine-depleted rats. In the present study, the effects of a single or subchronic systemic administration of the dopamine D1/D5-preferring receptor agonist SKF-81297 on GAD65, GAD67, PPD and vGAT mRNA levels in the striatum and GABA(A) receptor alpha1 subunit mRNA levels in the substantia nigra, pars reticulata, were measured in rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion. After a single injection of SKF-81297, striatal GAD65 mRNA levels were significantly increased at 3 but not 72 h. In contrast, striatal GAD67 mRNA levels were increased and nigral alpha1 mRNA levels were decreased at 72 but not 3 h. Single cell analysis on double-labeled sections indicated that increased GAD or vGAT mRNA levels after acute SKF-81297 occurred in striatonigral neurons identified by their lack of preproenkephalin expression. Subchronic SKF-81297 induced significant increases in striatal GAD67, GAD65, preprodynorphin and vGAT mRNA levels and decreases in nigral alpha1 mRNA levels. In the striatum contralateral to the 6-OHDA lesion, subchronic but not acute SKF-81297 induced a significant increase in GAD65 mRNA levels. The other mRNA levels were not significantly altered. Finally, striatal GAD67 mRNA levels were negatively correlated with nigral alpha1 mRNA levels in the dopamine-depleted but not dopamine-intact side. The results suggest that different signaling pathways are involved in the modulation by dopamine D1/D5 receptors of GAD65 and GAD67 mRNA levels in striatonigral neurons. They also suggest that the down-regulation of nigral GABA(A) receptors is linked to the increase in striatal GAD67 mRNA levels in the dopamine

  18. Generalized anxiety disorder: What are we missing?

    PubMed

    Allgulander, Christer

    2006-07-01

    One of the most prevalent anxiety conditions seen in primary care is generalized anxiety disorder (GAD). Numerous physical ailments frequently accompany the psychic symptoms of anxiety, which often drive patients to ask for help. In spite of the high incidence of GAD, only 30% of sufferers are diagnosed. Furthermore, very few patients are prescribed medication or referred to a psychiatrist. The key aim is to ensure the early detection and management of these patients. Developing physician education programs may improve the identification of GAD. The use of simple diagnostic tools would also aid the early detection of sufferers. Physicians require more long-term data, including that on the influence of ethnicity and genetics, to assist them to better understand and more effectively manage GAD. By achieving early diagnosis and treatment of GAD, physicians can ensure that a lesser burden is inflicted upon sufferers, thus improving their quality of life.

  19. New insights into the diagnosis and pharmacologic management of generalized anxiety disorder.

    PubMed

    Ninan, Philip T

    2002-01-01

    The omnipresent worry and anxiety that are characteristic of generalized anxiety disorder (GAD) significantly reduce social and occupational functioning. Yet many clinical investigations of GAD fail to evaluate treatment-related changes in function. As a consequence, many patients who respond to pharmacologic treatment (defined as having a > or = 50% reduction in symptoms) still exhibit subsyndromal symptoms that predispose to relapse. This is particularly true for patients with GAD who have comorbid psychiatric or medical conditions. In recent years, the goal of treatment for anxiety disorders has been set toward the achievement of full remission--that is, a virtually asymptomatic state. Remission indicates an improvement not only of symptoms but also of functionality. Benzodiazepines, azapirones, and antidepressants are the three main classes of agents currently used in the treatment of GAD. Some antidepressants have been shown to better facilitate remission. This article will summarize evidence for the clinical utility of pharmacotherapeutic agents commonly used in the treatment of GAD.

  20. A novel theory of experiential avoidance in generalized anxiety disorder: A review and synthesis of research supporting a contrast avoidance model of worry☆,☆☆

    PubMed Central

    Newman, Michelle G.; Llera, Sandra J.

    2011-01-01

    An important emphasis of the literature on generalized anxiety disorder (GAD) has been to achieve a greater understanding of the function of emotion (e.g., avoidance, dysregulation) in the etiology and maintenance of this disorder. The purpose of the following paper is to propose a new way of conceptualizing emotional sequelae in GAD by detailing the Contrast Avoidance Model of Worry. In presenting this model, we review theory and data that led to our current position, which is that individuals with GAD are more sensitive to feeling emotionally vulnerable to unexpected negative events, and that worry (the key pathological feature of GAD) is employed to prolong and maintain a negative emotional state thereby avoiding an unexpected negative emotional shift, or contrast experience. We also discuss implications for treatment given the presence of a new target for emotional exposure techniques. Finally, we establish the Contrast Avoidance Model within the framework of extant theories and models of pathogenic processes of GAD. PMID:21334285

  1. Generalized anxiety disorder publications: where do we stand a decade later?

    PubMed

    Dugas, Michel J; Anderson, Kristin G; Deschenes, Sonya S; Donegan, Eleanor

    2010-10-01

    The purpose of this study was to extend previous work examining publication rates for the anxiety disorders and publication topics for generalized anxiety disorder (GAD). Specifically, we examined anxiety disorder publication rates in MEDLINE and PsycINFO from 1998 to 2008. The results show: (1) that with the exception of panic disorder, there was a significant increase in the annual rate of publications for every anxiety disorder; (2) that GAD had the second lowest annual rate of publications in every year - with no more than 8% of anxiety disorder publications devoted to GAD in any given year; and (3) that GAD publications focused more often on treatment (44%) than on descriptive issues (26%), process issues (22%), and general reviews (8%). Given that citation analysis appears to be a valid indicator of research progress, the current findings suggest that research on GAD continues to lag behind research on most other anxiety disorders.

  2. Inattention symptoms and the diagnosis of comorbid attention-deficit/hyperactivity disorder among youth with generalized anxiety disorder.

    PubMed

    Elkins, R Meredith; Carpenter, Aubrey L; Pincus, Donna B; Comer, Jonathan S

    2014-12-01

    Generalized anxiety disorder (GAD) and attention-deficit/hyperactivity disorder (ADHD) commonly co-occur in childhood. Inattention symptoms can be hallmarks of both conditions, however assessment tools of inattention may not effectively distinguish between the two conditions. The present study used receiver operating characteristic (ROC) analyses to examine the high-end specificity of the Attention Problems Scale of the Child Behavior Checklist (CBCL) for detecting comorbid ADHD among youth with GAD (N=46). Results support the utility of the Attention Problems Scale for accurately distinguishing between the two groups (AUC=.84, SE=.06). Specifically, a cut score of 63 achieved the most favorable values across diagnostic utility indices; 74% of GAD youth with ADHD scored above this cutoff and 91% of GAD youth without ADHD scored below this cutoff. Findings provide support for the use of the CBCL Attention Problems Scale to supplement diagnostic interviews and identify inattention associated with ADHD among GAD youth.

  3. Mechanisms of Selective Attention in Generalized Anxiety Disorder

    PubMed Central

    Yiend, Jenny; Mathews, Andrew; Burns, Tom; Dutton, Kevin; Fernández-Martín, Andrés; Georgiou, George A.; Luckie, Michael; Rose, Alexandra; Russo, Riccardo; Fox, Elaine

    2015-01-01

    A well-established literature has identified different selective attentional orienting mechanisms underlying anxiety-related attentional bias, such as engagement and disengagement of attention. These mechanisms are thought to contribute to the onset and maintenance of anxiety disorders. However, conclusions to date have relied heavily on experimental work from subclinical samples. We therefore investigated individuals with diagnosed generalized anxiety disorder (GAD), healthy volunteers, and individuals with high trait anxiety (but not meeting GAD diagnostic criteria). Across two experiments we found faster disengagement from negative (angry and fearful) faces in GAD groups, an effect opposite to that expected on the basis of the subclinical literature. Together these data challenge current assumptions that we can generalize, to those with GAD, the pattern of selective attentional orienting to threat found in subclinical groups. We suggest a decisive two-stage experiment identifying stimuli of primary salience in GAD, then using these to reexamine orienting mechanisms across groups. PMID:26504675

  4. Interpersonal Pathoplasticity in Individuals with Generalized Anxiety Disorder

    PubMed Central

    Przeworski, Amy; Newman, Michelle G.; Pincus, Aaron L.; Kasoff, Michele B.; Yamasaki, Alissa S.; Castonguay, Louis G.; Berlin, Kristoffer S.

    2011-01-01

    Recent theories of Generalized Anxiety Disorder (GAD) have emphasized interpersonal and personality functioning as important aspects of the disorder. The current paper examines heterogeneity in interpersonal problems in two studies of individuals with GAD (n = 47 and n = 83). Interpersonal subtypes were assessed using the Inventory of Interpersonal Problems (IIP-C; Alden, Wiggins, & Pincus, 1990). Across both studies, individuals with GAD exhibited heterogeneous interpersonal problems, and cluster analyses of these patients' interpersonal characteristics yielded four replicable clusters identified as intrusive, exploitable, cold, and nonassertive subtypes. Consistent with our pathoplasticity hypotheses, clusters did not differ in GAD severity, anxiety severity, depression severity. Clusters in study two differed on rates of personality disorders, including avoidant personality disorder, further providing support for the validity of interpersonal subtypes. The presence of interpersonal subtypes in GAD may have important implications for treatment planning and efficacy. PMID:21553942

  5. Metacognitions in generalized anxiety disorder: theoretical and practical perspectives.

    PubMed

    Heiden, Colin van der

    2013-02-01

    Cognitive behavioral therapy has been found to be efficacious in the treatment of generalized anxiety disorder (GAD). However, reviews of the clinical significance has indicated that approximately 50% of patients with GAD return to a 'well' status following treatment. So how might the field advance? One way is to base new treatments on GAD maintenance mechanisms. A treatment that does this is metacognitive therapy (MCT), which targets the beliefs about worrying, instead of worrying itself. So far, MCT has been evaluated in two open trials, and two randomized controlled trials, all of which achieved quite favorable results. That is, MCT achieved statistically significant decreases in GAD symptoms, with large effect sizes and high recovery rates, and was found to be superior to two forms of cognitive behavioral therapy. In this article, an overview of MCT and results of the studies on the effectiveness of MCT for GAD is given.

  6. The DSM-IV-based Generalized Anxiety Disorder Severity Scale: preliminary validation using data from a trial of agomelatine versus placebo.

    PubMed

    Stein, Dan J; Fincham, Dylan; Seedat, Soraya; de Bodinat, Christian; Ahokas, Antti

    2009-06-01

    Currently available symptom severity measures for Generalized Anxiety Disorder (GAD) are not optimal. This study investigates the reliability and validity of a new measure for GAD. The Generalized Anxiety Disorder Severity Scale (DGSS), comprising 8 DSM-IV GAD symptoms assessed in terms of frequency and intensity, was used in a trial of agomelatine versus placebo for the treatment of GAD. Internal reliability, concurrent validity, responsiveness to change, most robust items, and factor structure were computed. The DGSS demonstrated good internal reliability, correlated significantly with the Hamilton Anxiety Scale and Clinical Global Impression severity scale, and demonstrated a clear change in response to agomelatine. The most robust DGSS items were derived, and an exploratory factor analysis yielded a 2-factor structure of the DGSS. The DGSS is potentially a useful scale for the assessment of GAD in clinical trials of this disorder.

  7. Evaluation of oxidative and antioxidative parameters in generalized anxiety disorder.

    PubMed

    Emhan, Ali; Selek, Salih; Bayazıt, Hüseyin; Fatih Karababa, İbrahim; Katı, Mahmut; Aksoy, Nurten

    2015-12-30

    Generalized anxiety disorder (GAD) is a prevalent psychiatric disorder. The exact causes of GAD still unknown, in addition to neurochemical and neuroanatomic disorders, genetic and environmental factors are discussed in etiology. In our study we aimed to evaluate the oxidative metabolism's status and investigate the role of oxidative metabolites in GAD. Blood samples were taken from enrolled subjects in appropriate way and total antioxidant status (TAS), total oxidant status (TOS), and oxidative stress index (OSI) were studied in Harran University Biochemistry Labs. Results were compared between groups. The patients' TOS and OSI levels were significantly higher than control group. The patients' TAS levels were significantly lower than controls'. According to our findings, oxidative stress mechanism might have a role in GAD pathophysiology. In the future, total antioxidants may be used as a biologic marker in GAD etiology but more research is needed.

  8. Brain Activation Patterns Associated with the Effects of Emotional Distracters during Working Memory Maintenance in Patients with Generalized Anxiety Disorder.

    PubMed

    Park, Jong-Il; Kim, Gwang-Won; Jeong, Gwang-Woo; Chung, Gyung Ho; Yang, Jong-Chul

    2016-01-01

    Few studies have assessed the neural mechanisms of the effects of emotion on cognition in generalized anxiety disorder (GAD) patients. In this functional MRI (fMRI), we investigated the effects of emotional interference on working memory (WM) maintenance in GAD patients. Fifteen patients with GAD participated in this study. Event-related fMRI data were obtained while the participants performed a WM task (face recognition) with neutral and anxiety-provoking distracters. The GAD patients showed impaired performance in WM task during emotional distracters and showed greater activation on brain regions such as DLPFC, VLPFC, amygdala, hippocampus which are responsible for the active maintenance of goal relevant information in WM and emotional processing. Although our results are not conclusive, our finding cautiously suggests the cognitive-affective interaction in GAD patients which shown interfering effect of emotional distracters on WM maintenance.

  9. Heightened reward learning under stress in generalized anxiety disorder: a predictor of depression resistance?

    PubMed

    Morris, Bethany H; Rottenberg, Jonathan

    2015-02-01

    Stress-induced anhedonia is associated with depression vulnerability (Bogdan & Pizzagalli, 2006). We investigated stress-induced deficits in reward learning in a depression-vulnerable group with analogue generalized anxiety disorder (GAD, n = 34), and never-depressed healthy controls (n = 41). Utilizing a computerized signal detection task, reward learning was assessed under stressor and neutral conditions. Controls displayed intact reward learning in the neutral condition, and the expected stress-induced blunting. The GAD group as a whole also showed intact reward learning in the neutral condition. When GAD subjects were analyzed as a function of prior depression history, never-depressed GAD subjects showed heightened reward learning in the stressor condition. Better reward learning under stress among GAD subjects predicted lower depression symptoms 1 month later. Robust reward learning under stress may indicate depression resistance among anxious individuals.

  10. Generalized anxiety disorder and medical illness.

    PubMed

    Culpepper, Larry

    2009-01-01

    Patients with generalized anxiety disorder (GAD) often have multiple medical comorbidities. The adrenal system and genetic and environmental factors are intermediaries between anxiety and medical illnesses such as chronic pain conditions and gastrointestinal, cardiovascular, endocrine, and respiratory disorders. Medical disorders associated with anxiety include migraine, rheumatoid arthritis, peptic ulcer disease, irritable bowel syndrome, coronary heart disease, hyperthyroidism, diabetes, asthma, and chronic obstructive pulmonary disorder. Compared to people with pain conditions without GAD, individuals with pain conditions and GAD experience and register pain differently; they also have increased awareness of symptoms. Comorbid medical illnesses may influence treatment choice for GAD. Treatment of anxiety in young patients with GAD needs to be long-term to decrease vulnerability to medical conditions.

  11. Future-oriented decision-making in Generalized Anxiety Disorder is evident across different versions of the Iowa Gambling Task.

    PubMed

    Mueller, Erik M; Nguyen, Jennifer; Ray, William J; Borkovec, Thomas D

    2010-06-01

    Generalized Anxiety Disorder (GAD) and excessive worrying are characterized by a preoccupation with the future. Thus, enhanced identification of potential future punishments or omissions of reward may be related to the disorder. To test this hypothesis, n=47 students meeting GAD criteria according to the GADQ-IV (GAD analogues) or not (control participants) performed the Iowa Gambling Task, which has been related to sensitivity to future consequences. In order to disentangle sensitivity to future loss and sensitivity to high short-term loss magnitudes, which could also lead to enhanced Iowa Gambling Task performance, participants also performed a modified version of the task with reversed contingencies. In both versions, GAD analogues learned to avoid decisions with high probability of long-term loss significantly faster than control participants. Results, therefore, indicate that GAD is characterized by enhanced processing of potential future losses rather than sensitivity to large short-term loss.

  12. Adolescent's perceptions of parenting behaviours and its relationship to adolescent Generalized Anxiety Disorder symptoms.

    PubMed

    Hale, William W; Engels, Rutger; Meeus, Wim

    2006-06-01

    This study examined the relationship between how adolescents perceived parenting behaviours and adolescent Generalized Anxiety Disorder (GAD) symptom scores. The 1106 junior high and high school students (12-19 years old; 49.6% males and 50.4% females) completed questionnaires regarding their perception of parenting behaviours and self-rated symptoms of GAD. The findings of this study demonstrate that adolescent perceptions of parental alienation and rejection are strongly associated with adolescent GAD symptom scores. Additionally, mid-adolescence females perceive more parental alienation in relation to their GAD symptom scores than both early and mid-adolescent males. And early adolescent males perceive more parental rejection in relation to their GAD symptom scores than mid-adolescent males.

  13. A novel theory of experiential avoidance in generalized anxiety disorder: a review and synthesis of research supporting a contrast avoidance model of worry.

    PubMed

    Newman, Michelle G; Llera, Sandra J

    2011-04-01

    An important emphasis of the literature on generalized anxiety disorder (GAD) has been to achieve a greater understanding of the function of emotion (e.g., avoidance, dysregulation) in the etiology and maintenance of this disorder. The purpose of the following paper is to propose a new way of conceptualizing emotional sequelae in GAD by detailing the Contrast Avoidance Model of Worry. In presenting this model, we review theory and data that led to our current position, which is that individuals with GAD are more sensitive to feeling emotionally vulnerable to unexpected negative events, and that worry (the key pathological feature of GAD) is employed to prolong and maintain a negative emotional state thereby avoiding an unexpected negative emotional shift, or contrast experience. We also discuss implications for treatment given the presence of a new target for emotional exposure techniques. Finally, we establish the Contrast Avoidance Model within the framework of extant theories and models of pathogenic processes of GAD.

  14. Episodic future thinking in generalized anxiety disorder.

    PubMed

    Wu, Jade Q; Szpunar, Karl K; Godovich, Sheina A; Schacter, Daniel L; Hofmann, Stefan G

    2015-12-01

    Research on future-oriented cognition in generalized anxiety disorder (GAD) has primarily focused on worry, while less is known about the role of episodic future thinking (EFT), an imagery-based cognitive process. To characterize EFT in this disorder, we used the experimental recombination procedure, in which 21 GAD and 19 healthy participants simulated positive, neutral and negative novel future events either once or repeatedly, and rated their phenomenological experience of EFT. Results showed that healthy controls spontaneously generated more detailed EFT over repeated simulations. Both groups found EFT easier to generate after repeated simulations, except when GAD participants simulated positive events. They also perceived higher plausibility of negative-not positive or neutral-future events than did controls. These results demonstrate a negativity bias in GAD individuals' episodic future cognition, and suggest their relative deficit in generating vivid EFT. We discuss implications for the theory and treatment of GAD.

  15. Patients with generalized anxiety disorder and a history of trauma: somatic symptom endorsement.

    PubMed

    Brawman-Mintzer, Olga; Monnier, Jeannine; Wolitzky, Kate B; Falsetti, Sherry A

    2005-05-01

    The authors investigated the types and rates of trauma exposure and differences in symptom endorsement in a clinical sample of patients diagnosed with generalized anxiety disorder (GAD). Fifty-eight patients with GAD were assessed using the Structured Clinical Interview (SCID) and Trauma Assessment for Adults. In order to explore the relationship between specific traumatic event(s) and clinical presentation, the presence of somatic symptoms associated with GAD, including muscle tension, autonomic hyperactivity, and vigilance/scanning clusters (using DSM-III-R criteria), were examined. Patients with a history of sexual assault before 18 years (25.9%) endorsed fewer somatic symptoms, specifically fewer motor tension and autonomic GAD symptoms, than patients with other types of trauma. These findings indicate that early exposure to serious trauma, specifically childhood sexual assault, may lead to a different clinical presentation in GAD patients.

  16. Effects of glutamate decarboxylase and gamma-aminobutyric acid (GABA) transporter on the bioconversion of GABA in engineered Escherichia coli.

    PubMed

    Le Vo, Tam Dinh; Kim, Tae Wan; Hong, Soon Ho

    2012-05-01

    Gamma-aminobutyric acid (GABA) is a non-essential amino acid and a precursor of pyrrolidone, a monomer of nylon 4. GABA can be biosynthesized through the decarboxylation of L: -glutamate by glutamate decarboxylase. In this study, the effects of glutamate decarboxylase (gadA, gadB), glutamate/GABA antiporter (gadC) and GABA aminotransferase (gabT) on GABA production were investigated in Escherichia coli. Glutamate decarboxylase was overexpressed alone or with the glutamate/GABA antiporter to enhance GABA synthesis. GABA aminotransferase, which redirects GABA into the TCA cycle, was knock-out mutated. When gadB and gadC were co-overexpressed in the gabT mutant strain, a final GABA concentration of 5.46 g/l was obtained from 10 g/l of monosodium glutamate (MSG), which corresponded to a GABA yield of 89.5%.

  17. Episodic Future Thinking in Generalized Anxiety Disorder

    PubMed Central

    Wu, Jade Q.; Szpunar, Karl K.; Godovich, Sheina A.; Schacter, Daniel L.; Hofmann, Stefan G.

    2015-01-01

    Research on future-oriented cognition in generalized anxiety disorder (GAD) has primarily focused on worry, while less is known about the role of episodic future thinking (EFT), an imagery-based cognitive process. To characterize EFT in this disorder, we used the experimental recombination procedure, in which 21 GAD and 19 healthy participants simulated positive, neutral and negative novel future events either once or repeatedly, and rated their phenomenological experience of EFT. Results showed that healthy controls spontaneously generated more detailed EFT over repeated simulations. Both groups found EFT easier to generate after repeated simulations, except when GAD participants simulated positive events. They also perceived higher plausibility of negative—not positive or neutral—future events than did controls. These results demonstrate a negativity bias in GAD individuals’ episodic future cognition, and suggest their relative deficit in generating vivid EFT. We discuss implications for the theory and treatment of GAD. PMID:26398003

  18. Prevention of post-stroke generalized anxiety disorder, using escitalopram or problem-solving therapy.

    PubMed

    Mikami, Katsunaka; Jorge, Ricardo E; Moser, David J; Arndt, Stephan; Jang, Mijin; Solodkin, Ana; Small, Steven L; Fonzetti, Pasquale; Hegel, Mark T; Robinson, Robert G

    2014-01-01

    This study examined the efficacy of antidepressant treatment for preventing the onset of generalized anxiety disorder (GAD) among patients with recent stroke. Of 799 patients assessed, 176 were randomized, and 149 patients without evidence of GAD at the initial visit were included in this double-blind treatment with escitalopram (N=47) or placebo (N=49) or non-blinded problem-solving therapy (PST; 12 total sessions; N=53). Participants given placebo over 12 months were 4.95 times more likely to develop GAD than patients given escitalopram and 4.00 times more likely to develop GAD than patients given PST. Although these results should be considered preliminary, the authors found that both escitalopram and PST were effective in preventing new onset of post-stroke GAD.

  19. Impaired Retrieval Inhibition of Threat Material in Generalized Anxiety Disorder.

    PubMed

    Kircanski, Katharina; Johnson, Douglas C; Mateen, Maria; Bjork, Robert A; Gotlib, Ian H

    2016-03-01

    Generalized Anxiety Disorder (GAD) is characterized by cognitive biases toward threat-relevant information, but the underlying mechanisms are unclear. We translated a retrieval-practice paradigm from cognitive science to investigate impaired inhibition of threat information as one such mechanism. Participants diagnosed with GAD and never-disordered control participants learned a series of cue-target pairs; whereas some cues were associated only with neutral targets, others were associated with both neutral and threat targets. Next, participants practiced retrieving neutral targets, which typically suppresses the subsequent recall of unpracticed associated targets (retrieval-induced forgetting; RIF). Finally, participants were tested on their recall of all targets. Despite showing intact RIF of neutral targets, the GAD group failed to exhibit RIF of threat targets. Furthermore, within the GAD group, less RIF of threat targets correlated with greater pervasiveness of worry. Deficits in inhibitory control over threat-relevant information may underlie the cognitive pathology of GAD, which has important treatment implications.

  20. Sympathetic and hypothalamic-pituitary-adrenal asymmetry in generalized anxiety disorder.

    PubMed

    Reeves, Jonathan W; Fisher, Aaron J; Newman, Michelle G; Granger, Douglas A

    2016-06-01

    Physiologic investigations of generalized anxiety disorder (GAD) have skewed toward assessment of the autonomic nervous system, largely neglecting hypothalamic-pituitary-adrenal (HPA) axis variables. Although these systems coordinate-suggesting a degree of symmetry-to promote adaptive functioning, most studies opt to monitor either one system or the other. Using a ratio of salivary alpha-amylase (sAA) over salivary cortisol, the present study examined symmetry between the sympathetic nervous system (SNS) and HPA axis in individuals with GAD (n = 71) and healthy controls (n = 37). Compared to healthy controls, individuals with GAD exhibited greater baseline ratios of sAA/cortisol and smaller ratios of sAA/cortisol following a mental arithmetic challenge. We propose that the present study provides evidence for SNS-HPA asymmetry in GAD. Further, these results suggest that increased SNS suppression in GAD may be partially mediated by cortisol activity.

  1. PSYCHIATRIC COMORBIDITY DOES NOT ONLY DEPEND ON DIAGNOSTIC THRESHOLDS: AN ILLUSTRATION WITH MAJOR DEPRESSIVE DISORDER AND GENERALIZED ANXIETY DISORDER.

    PubMed

    van Loo, Hanna M; Schoevers, Robert A; Kendler, Kenneth S; de Jonge, Peter; Romeijn, Jan-Willem

    2016-02-01

    High rates of psychiatric comorbidity are subject of debate: To what extent do they depend on classification choices such as diagnostic thresholds? This paper investigates the influence of different thresholds on rates of comorbidity between major depressive disorder (MDD) and generalized anxiety disorder (GAD). Point prevalence of comorbidity between MDD and GAD was measured in 74,092 subjects from the general population (LifeLines) according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria. Comorbidity rates were compared for different thresholds by varying the number of necessary criteria from ≥ 1 to all nine symptoms for MDD, and from ≥ 1 to all seven symptoms for GAD. According to DSM thresholds, 0.86% had MDD only, 2.96% GAD only, and 1.14% both MDD and GAD (odds ratio (OR) 42.6). Lower thresholds for MDD led to higher rates of comorbidity (1.44% for ≥ 4 of nine MDD symptoms, OR 34.4), whereas lower thresholds for GAD hardly influenced comorbidity (1.16% for ≥ 3 of seven GAD symptoms, OR 38.8). Specific patterns in the distribution of symptoms within the population explained this finding: 37.3% of subjects with core criteria of MDD and GAD reported subthreshold MDD symptoms, whereas only 7.6% reported subthreshold GAD symptoms. Lower thresholds for MDD increased comorbidity with GAD, but not vice versa, owing to specific symptom patterns in the population. Generally, comorbidity rates result from both empirical symptom distributions and classification choices and cannot be reduced to either of these exclusively. This insight invites further research into the formation of disease concepts that allow for reliable predictions and targeted therapeutic interventions. © 2015 Wiley Periodicals, Inc.

  2. The association between parents' ratings of ASD symptoms and anxiety in a sample of high-functioning boys and adolescents with Autism Spectrum Disorder.

    PubMed

    Bitsika, Vicki; Sharpley, Christopher F

    2017-04-01

    The relationship between symptoms of Autism Spectrum Disorder (ASD) and Generalised Anxiety Disorder (GAD) is complex and sometimes confounding. However, exploration of that relationship has significant potential to assist in treatment or avoidance of GAD by identifying ASD-related behaviours as 'targets' for intervention with anxious children as well as for preventative treatments that could be implemented into daily routines before children become anxious. To further understanding of this relationship, the association between parent-ratings of their sons' ASD symptoms and GAD symptoms was investigated in two samples of boys with high-functioning ASD. Parents of a sample of 90 pre-adolescent (M age=8.8yr) and 60 adolescent males (M age=14.6yr) completed the Social Responsiveness Scale (SRS) and the GAD subscale of the Child and Adolescent Symptom Inventory (CASI-4 GAD) about their sons. Pre-adolescents had significantly higher SRS scale scores than adolescents. For pre-adolescents, high levels of tension in social situations were associated with 3.5-times greater likelihood of having GAD; for adolescents, experiencing difficulty in changes in routine was associated with a 10-fold increase in risk of GAD. In addition to focussing upon GAD itself, preventative and treatment options aimed at reducing GAD or its risk might profitably recognise and focus upon these two aspects of ASD that are different across the two age groups but each of which was significantly associated with GAD severity and prevalence in this study. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Whole-brain gray matter volume abnormalities in patients with generalized anxiety disorder: voxel-based morphometry.

    PubMed

    Moon, Chung-Man; Kim, Gwang-Won; Jeong, Gwang-Woo

    2014-02-12

    Patients with generalized anxiety disorder (GAD) experience psychological distress because of excessive and uncontrollable anxiety in everyday life. Only a few morphological studies have so far focused on specific brain regions of interest as well as the gray matter volume changes in GAD patients. This study evaluated gray matter volume alterations in whole-brain areas between GAD patients and healthy controls, and sex differences between the specific brain areas with significant volume changes in GAD patients using voxel-based morphometry. Twenty-two patients with GAD (13 men and nine women), who were diagnosed using the DSM-IV-TR, and 22 age-matched healthy controls (13 men and nine women) participated in this study. The high-resolution MRI data were processed using voxel-based morphometry analysis on the basis of diffeomorphic anatomical registration through an exponentiated Lie algebra algorithm in Statistical Parametric Mapping 8. There was no significant difference in the total intracranial volume between GAD patients and controls, but a significant difference was observed between sexes (P<0.05). Patients with GAD showed significant volume reductions in the hippocampus, midbrain, thalamus, insula, and superior temporal gyrus compared with the controls. As for the sex comparison, female patients showed a significant increase in the volume of the dorsolateral prefrontal cortex relative to male patients. Also, the volume of the dorsolateral prefrontal cortex in female patients was correlated positively with the Hamilton Anxiety Rating Scale score (γ=0.68, P=0.04). The specific morphological variations in patient with GAD will be helpful to understand the neural mechanism associated with a symptom of GAD. Furthermore, the findings would be valuable for the diagnostic accuracy of GAD using morphometric MRI analysis.

  4. Comparison of the course of substance use disorders among individuals with and without generalized anxiety disorder in a nationally representative sample.

    PubMed

    Magidson, Jessica F; Liu, Shang-Min; Lejuez, C W; Blanco, Carlos

    2012-05-01

    Generalized anxiety disorder (GAD) and substance use disorders (SUDs) are highly comorbid, and GAD-SUD comorbidity is associated with a host of poor psychosocial outcomes, including higher rates of hospitalization, disability, functional impairment, and inferior GAD and SUD treatment outcomes. Despite the noted severity of this group and clinical implications, current research is limited in a few distinct ways; studies have rarely utilized a longitudinal design and non-treatment seeking individuals to examine how GAD comorbidity impacts SUD outcomes over time. The current study utilized a nationally representative sample of individuals in the U.S. assessed in the National Epidemiological Survey on Alcohol and Related Conditions (NESARC) at Wave 1 (2001-2002) and Wave 2 (2004-2005), comparing individuals who met criteria for both DSM-IV past year GAD and SUD (n = 286) and those who met criteria for past year SUD only without GAD (n = 5730) at Wave 1. Results indicated that GAD-SUD individuals were significantly more severe than the SUD only group across almost all outcomes assessed (with the exception of alcohol frequency); individuals with GAD-SUD had a more severe psychiatric history, worse health-related quality of life at both waves, greater incidence of new Axis I disorders, higher rates of treatment seeking, and greater self-reported drug use at the follow up. The current study is the first to compare individuals with SUD with and without comorbid GAD over time using a nationally representative sample. Findings further support the clinical severity of this group and suggest the need for GAD-SUD treatment options.

  5. Generalized anxiety disorder and the proposed associated symptoms criterion change for DSM-5 in a treatment-seeking sample of anxious youth

    PubMed Central

    Comer, Jonathan S.; Pincus, Donna B.; Hofmann, Stefan G.

    2012-01-01

    Background A current proposal for the DSM-5 generalized anxiety disorder (GAD) definition is to remove fatigue, difficulty concentrating, irritability, and sleep disturbance from the list of associated symptoms, and to require the presence of one of two retained symptoms (restlessness or muscle tension) for diagnosis. Relevant evaluations in youth to support such a change are sparse. Methods The present study evaluated patterns and correlates of the DSM-IV GAD associated symptoms in a large outpatient sample of anxious youth (N=650) to empirically consider how the proposed diagnostic change might impact the prevalence and sample composition of GAD in children. Results Logistic regression found irritability to be the most associated, and restlessness to be the least associated, with GAD diagnosis. Fatigue, difficulty concentrating, and sleep disturbances—which have each been suggested to be nonspecific to GAD due to their prevalence in depression—showed sizable associations with GAD even after accounting for depression and attention problems. Among GAD youth, 10.9% would not meet the proposed DSM-5 associated symptoms criterion. These children were comparable to GAD youth who would meet the proposed criteria with regard to clinical severity, symptomatology, and functioning. Conclusions A substantial proportion of youth with excessive, clinically impairing worry may be left unclassified by the DSM-5 if the proposed GAD associated symptoms criterion is adopted. Despite support for the proposed criterion change in adult samples, the present findings suggest that in children it may increase the false negative rate. This calls into question whether the proposed associated symptoms criterion is optimal for defining childhood GAD. PMID:22952043

  6. Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia.

    PubMed

    Manto, Mario U; Hampe, Christiane S; Rogemond, Véronique; Honnorat, Jérome

    2011-02-04

    To investigate whether Stiff-person syndrome (SPS) and cerebellar ataxia (CA) are associated with distinct GAD65-Ab epitope specificities and neuronal effects. Purified GAD65-Ab from neurological patients and monoclonal GAD65-Ab with distinct epitope specificities (b78 and b96.11) were administered in vivo to rat cerebellum. Effects of intra-cerebellar administration of GAD65-Ab were determined using neurophysiological and neurochemical methods. Intra-cerebellar administration of GAD65-Ab from a SPS patient (Ab SPS) impaired the NMDA-mediated turnover of glutamate, but had no effect on NMDA-mediated turnover of glycerol. By contrast, GAD65-Ab from a patient with cerebellar ataxia (Ab CA) markedly decreased the NMDA-mediated turnover of glycerol. Both GAD65-Ab increased the excitability of the spinal cord, as assessed by the F wave/M wave ratios. The administration of BFA, an inhibitor of the recycling of vesicles, followed by high-frequency stimulation of the cerebellum, severely impaired the cerebello-cortical inhibition only when Ab CA was used. Moreover, administration of transcranial direct current stimulation (tDCS) of the motor cortex revealed a strong disinhibition of the motor cortex with Ab CA. Monoclonal antibodies b78 and b96.11 showed distinct effects, with greater effects of b78 in terms of increase of glutamate concentrations, impairment of the adaptation of the motor cortex to repetitive peripheral stimulation, disinhibition of the motor cortex following tDCS, and increase of the F/M ratios. Ab SPS shared antibody characteristics with b78, both in epitope recognition and ability to inhibit enzyme activity, while Ab CA had no effect on GAD65 enzyme activity. These results suggest that, in vivo, neurological impairments caused by GAD65-Ab could vary according to epitope specificities. These results could explain the different neurological syndromes observed in patients with GAD65-Ab.

  7. Respective implications of glutamate decarboxylase antibodies in stiff person syndrome and cerebellar ataxia

    PubMed Central

    2011-01-01

    Background To investigate whether Stiff-person syndrome (SPS) and cerebellar ataxia (CA) are associated with distinct GAD65-Ab epitope specificities and neuronal effects. Methods Purified GAD65-Ab from neurological patients and monoclonal GAD65-Ab with distinct epitope specificities (b78 and b96.11) were administered in vivo to rat cerebellum. Effects of intra-cerebellar administration of GAD65-Ab were determined using neurophysiological and neurochemical methods. Results Intra-cerebellar administration of GAD65-Ab from a SPS patient (Ab SPS) impaired the NMDA-mediated turnover of glutamate, but had no effect on NMDA-mediated turnover of glycerol. By contrast, GAD65-Ab from a patient with cerebellar ataxia (Ab CA) markedly decreased the NMDA-mediated turnover of glycerol. Both GAD65-Ab increased the excitability of the spinal cord, as assessed by the F wave/M wave ratios. The administration of BFA, an inhibitor of the recycling of vesicles, followed by high-frequency stimulation of the cerebellum, severely impaired the cerebello-cortical inhibition only when Ab CA was used. Moreover, administration of transcranial direct current stimulation (tDCS) of the motor cortex revealed a strong disinhibition of the motor cortex with Ab CA. Monoclonal antibodies b78 and b96.11 showed distinct effects, with greater effects of b78 in terms of increase of glutamate concentrations, impairment of the adaptation of the motor cortex to repetitive peripheral stimulation, disinhibition of the motor cortex following tDCS, and increase of the F/M ratios. Ab SPS shared antibody characteristics with b78, both in epitope recognition and ability to inhibit enzyme activity, while Ab CA had no effect on GAD65 enzyme activity. Conclusions These results suggest that, in vivo, neurological impairments caused by GAD65-Ab could vary according to epitope specificities. These results could explain the different neurological syndromes observed in patients with GAD65-Ab. PMID:21294897

  8. Herpes simplex virus vector-mediated gene delivery of glutamic acid decarboxylase reduces detrusor overactivity in spinal cord injured rats

    PubMed Central

    Miyazato, Minoru; Sugaya, Kimio; Goins, William F.; Goss, James R.; Chancellor, Michael B.; de Groat, William C.; Glorioso, Joseph C.; Yoshimura, Naoki

    2010-01-01

    We examined whether replication-defective herpes simplex virus (HSV) vectors encoding the 67 Kd form of the glutamic acid decarboxylase (GAD67) gene product, the gamma-aminobutyric acid (GABA) synthesis enzyme, can suppress detrusor overactivity (DO) in spinal cord injury (SCI) rats. One week after spinalization, HSV vectors expressing GAD and green fluorescent protein (GFP) (HSV-GAD) were injected into the bladder wall. SCI rats without HSV injection (HSV-untreated) and those injected with lacZ-encoding reporter gene HSV vectors (HSV-LacZ) were used as controls. Three weeks after viral injection, continuous cystometry was performed under awake conditions in all three groups. In the HSV-GAD group, the number and amplitude of non-voiding contractions (NVCs) were significantly decreased (40–45% and 38–40%, respectively) along with an increase in voiding efficiency, compared with HSV-untreated and HSV-LacZ groups, but micturition pressure was not different among the three groups. Intrathecal application of bicuculline partly reversed the decreased number and amplitude of NVCs, and decreased voiding efficiency in the HSV-GAD group. In the HSV-GAD group, GAD67 mRNA and protein levels were significantly increased in L6-S1 dorsal root ganglia (DRG) compared with the HSV-LacZ group while 57% of DRG cells were GFP-positive, and these neurons showed increased GAD67-like immunoreactivity compared with the HSV-LacZ group. These results indicate that GAD gene therapy effectively suppresses DO following SCI predominantly via activation of spinal GABAA receptors. Thus, HSV-based GAD gene transfer to bladder afferent pathways may represent a novel approach for the treatment of neurogenic DO. PMID:19225548

  9. Thermostabilization of glutamate decarboxylase B from Escherichia coli by structure-guided design of its pH-responsive N-terminal interdomain.

    PubMed

    Jun, Chanha; Joo, Jeong Chan; Lee, Jung Heon; Kim, Yong Hwan

    2014-03-20

    Glutamate decarboxylase B (GadB) from Escherichia coli is a highly active biocatalyst that can convert l-glutamate to γ-aminobutyrate (GABA), a precursor of 2-pyrrolidone (a monomer of Nylon 4). In contrast to vigorous studies of pH shifting of GadB, mesophilic GadB has not been stabilized by protein engineering. In this study, we improved the thermostability of GadB through structural optimization of its N-terminal interdomain. According to structural analysis, the N-terminal fourteen residues (1-14) of homo-hexameric GadB formed a triple-helix bundle interdomain at acidic pH and contributed to the thermostability of GadB in preliminary tests as the pH shifted from 7.6 to 4.6. GadB thermostabilization was achieved by optimization of hydrophobic and electrostatic interactions at the N-terminal interdomain. A triple mutant (GadB-TM: Gln5Asp/Val6Ile/Thr7Glu) showed higher thermostability than the wild-type (GadB-WT), i.e., 7.9 and 7.7°C increases in the melting temperature (Tm) and the temperature at which 50% of the initial activity remained after 10min incubation (T50(10)), respectively. The triple mutant showed no reduction of catalytic activity in enzyme kinetics. Molecular dynamics (MD) simulation at high temperature showed that reinforced interactions of the triple mutant rigidified the N-terminal interdomain compared to the wild-type, leading to GadB thermostabilization.

  10. Distribution and development of glutamic acid decarboxylase immunoreactivity in the spinal cord of the dogfish Scyliorhinus canicula (elasmobranchs).

    PubMed

    Sueiro, Catalina; Carrera, Iván; Molist, Pilar; Rodríguez-Moldes, Isabel; Anadón, Ramón

    2004-10-11

    The adult distribution and development of gamma-aminobutyric acid (GABA)-synthesizing cells and fibers in the spinal cord of the lesser spotted dogfish (Scyliorhinus canicula L.) was studied by means of immunohistochemistry using antibodies against glutamic acid decarboxylase (GAD). Complementary immunostaining with antibodies against GABA, tyrosine hydroxylase (TH), and HuC/HuD (members of the Hu/Elav family of RNA-associated proteins) and staining with a reduced silver procedure ("en bloc" Bielschowski method), Nissl, and hematoxylin were also used. In adults, GAD-immunoreactive (GAD-ir) cells were observed in the ventral horns, in the spinal nucleus of the dorsal horn, at the base of the dorsal horns, and around the central canal, where some GAD-ir cells were cerebrospinal fluid-contacting (CSF-c). In addition, a few GAD-ir cells were observed in the lateral funiculus between the ventral horn and the marginal nucleus. The adult spinal cord was richly innervated by GAD-ir fibers. Large numbers of GAD-ir fibers and boutons were observed in the dorsal and ventral horns and also interstitially in the dorsal, lateral, and ventral funiculi. In addition, a rich GAD-ir innervation was observed in the marginal nucleus of the spinal cord. In the embryonic spinal cord, GAD-ir cells develop very early: The earliest cells were observed in the very thin mantle/marginal layer of stage 22 embryos in a short length of the spinal cord. At stages 25 and 26, several types of GAD-ir cells (commissural and noncommissural) were distinguished, and two of these cells were of CSF-c type. At stages 28, 30, and 31, the GAD-ir populations exhibited a marked longitudinal columnar organization. Double-immunolabeling experiments in embryos showed the presence of two different GAD-ir CSF-c cell populations, one ventral that is simultaneously TH-ir and other more dorsal that is TH-negative. By stage 33 (prehatching), GAD-expressing cells are present in virtually all loci, as in adults

  11. Directed evolution and mutagenesis of glutamate decarboxylase from Lactobacillus brevis Lb85 to broaden the range of its activity toward a near-neutral pH.

    PubMed

    Shi, Feng; Xie, Yilong; Jiang, Junjun; Wang, Nannan; Li, Yongfu; Wang, Xiaoyuan

    2014-01-01

    Glutamate decarboxylase (GAD) transforms l-glutamate into γ-aminobutyric acid (GABA) with the consumption of a proton. GAD derived from lactic acid bacteria exhibits optimum activity at pH 4.0-5.0 and significantly loses activity at near-neutral pH. To broaden the active range of the GAD GadB1 from Lactobacillus brevis Lb85 toward a near-neutral pH, irrational design using directed evolution and rational design using site-specific mutagenesis were performed. For directed evolution of GadB1, a sensitive high-throughput screening strategy based on a pH indicator was established. One improved mutant, GadB1(T17I/D294G/Q346H), was selected from 800 variants after one round of EP-PCR. It exhibited 3.9- and 25.0-fold increase in activity and catalytic efficiency, respectively at pH 6.0. Through site-specific mutagenesis, several improved mutants were obtained, with GadB1(E312S) being the best one. The combined mutant GadB1(T17I/D294G/E312S/Q346H) showed even higher catalytic efficiency, 13.1- and 43.2-fold that of wild-type GadB1 at pH 4.6 and 6.0, respectively. The amount of GABA produced in gadB1(T17I/D294G/Q346H)-, gadB1(E312S)- and gadB1(T17I/D294G/E312S/Q346H)-expressing Corynebacterium glutamicum ATCC 13032 from endogenous l-glutamate increased by 9.6%, 20.3% and 63.9%, respectively. These results indicate that these mutations have beneficial effects on expanding the active pH range and on GABA biosynthesis, suggesting these GadB1 variants as potent candidates for GABA production.

  12. BDNF Val66Met polymorphism and plasma levels in Chinese Han population with obsessive-compulsive disorder and generalized anxiety disorder.

    PubMed

    Wang, Yuan; Zhang, Haiyin; Li, Ying; Wang, Zhen; Fan, Qing; Yu, Shunying; Lin, Zhiguang; Xiao, Zeping

    2015-11-01

    Anxiety disorders are a category of mental disorders characterized by feelings of anxiety and fear, which include generalized anxiety disorder (GAD). Obsessive-Compulsive Disorder (OCD) used to be categorized as anxiety disorder in DSM-IV. However OCD was no longer included in anxiety disorders and came into its own category titled as Obsessive-Compulsive and Related Disorders (OCRD) in DSM-5. It will be interesting to explore is there any different biological characteristics between OCD and anxiety disorders. Brain-derived neurotrophic factor (BDNF) was a potential candidate gene in both OCD and GAD. The results of genetic association studies between BDNF and OCD have been inconsistent. BDNF plasma/serum levels in OCD have been found lower than those in healthy controls. However the heritable reason of the lowered BDNF levels was not well elucidated. The amount of studies about BDNF and GAD were relatively small. The aims of this study were to determine whether single nucleotide polymorphism Val66Met of BDNF was associated with OCD and GAD, to examine BDNF plasma levels in OCD and GAD, and to explore whether Val66Met variation influences BDNF plasma levels. We genotyped Val66Met variation in 148 OCD patients, 108 GAD patients and 99 healthy controls. Within the same sample, BDNF plasma levels were determined in 113 OCD patients, 102 GAD patients and 63 healthy controls. Val66Met variation was not associated with OCD or GAD. BDNF plasma levels in OCD and GAD patients were significant lower than those in healthy controls. Val66Met variation had no influence on BDNF plasma levels. No difference was found between OCD and GAD. Results do not change no matter taking OCD and GAD as one group or separated two. First, the sample size for genotyping was relatively small, which leaded to a low statistical power of the genetic part in this study. Second, we genotyped just one SNP in BDNF gene. Third, parts of the participants did not be assayed for BDNF plasma levels. Our

  13. Contribution of parvalbumin and somatostatin-expressing GABAergic neurons to slow oscillations and the balance in beta-gamma oscillations across cortical layers.

    PubMed

    Kuki, Toshinobu; Fujihara, Kazuyuki; Miwa, Hideki; Tamamaki, Nobuaki; Yanagawa, Yuchio; Mushiake, Hajime

    2015-01-01

    Cortical interneurons are classified into several subtypes that contribute to cortical oscillatory activity. Parvalbumin (PV)-expressing cells, a type of inhibitory interneuron, are involved in the gamma oscillations of local field potentials (LFPs). Under ketamine-xylazine anesthesia or sleep, mammalian cortical circuits exhibit slow oscillations in which the active-up state and silent-down state alternate at ~1 Hz. The up state is composed of various high-frequency oscillations, including gamma oscillations. However, it is unclear how PV cells and somatostatin (SOM) cells contribute to the slow oscillations and the high-frequency oscillations nested in the up state. To address these questions, we used mice lacking glutamate decarboxylase 67, primarily in PV cells (PV-GAD67 mice) or in SOM cells (SOM-GAD67 mice). We then compared LFPs between PV-GAD67 mice and SOM-GAD67 mice. PV cells target the proximal regions of pyramidal cells, whereas SOM cells are dendrite-preferring interneurons. We found that the up state was shortened in duration in the PV-GAD67 mice, but tended to be longer in SOM-GAD67 mice. Firing rate tended to increase in PV-GAD67 mice, but tended to decrease in SOM-GAD67 mice. We also found that delta oscillations tended to increase in SOM-GAD67 mice, but tended to decrease in PV-GAD67 mice. Current source density and wavelet analyses were performed to determine the depth profiles of various high-frequency oscillations. High gamma and ripple (60-200 Hz) power decreased in the neocortical upper layers specifically in PV-GAD67 mice, but not in SOM-GAD67. In addition, beta power (15-30 Hz) increased in the deep layers, specifically in PV-GAD67 mice. These results suggest that PV cells play important roles in persistence of the up state and in the balance between gamma and beta bands across cortical layers, whereas SOM and PV cells may make an asymmetric contribution to regulate up-state and delta oscillations.

  14. Incorporating Temporal Information in Microblog Retrieval

    DTIC Science & Technology

    2012-11-01

    Urbana-Champaign Urbana-Champaign, IL, USA willis8@illinois.edu Richard Medlin School of Information & Library Science University of North Carolina at...Chapel Hill Chapel Hill, NC, USA rich_medlin@med.unc.edu Jaime Arguello † School of Information & Library Science University of North Carolina at...published prior to time tQ. The School of Information and Library Science at the Uni- versity of Carolina at Chapel Hill submitted four runs to the Microblog

  15. University of California Conference on Statistical Mechanics (4th) Held March 26-28, 1990

    DTIC Science & Technology

    1990-03-28

    Friskin, Physics Department, UC Santa Barbara Alejandro Garcia , Physics Department, San Jose State Jaime Garcia , Department of Chemistry, UCLA Claude...Waterloo, Ontario Enrique Peacock- Lopez , Department of Chemistry, Williams College Zhang Qing, Department of Chemistry, UC Berkeley Wouter-Jan Rappel, INLS...San Francisco Duane Siemens, Physics Department, UC Davis Ralph A. Smith, Physics Department, U C San Diego Erik Sorensenm, Physics Department, UC Santa

  16. Bigger Is Bigger

    NASA Astrophysics Data System (ADS)

    Riendeau, Diane

    2009-09-01

    When you really want to get a point across to your students, you set up explorations or experiments, and do demonstrations. Sometimes I find myself thinking, ``If I only had....'' This month's videos add ``wow'' factor to the experiences you provide for your students in the classroom! Thanks to Jaime Stasiorowski (Deerfield High School), Tony Zito (Dutchess Community College), and Bob Beichner (NC State) and Chris Chiaverina for their contributions to this month's column.

  17. Trajectory Optimization With Detection Avoidance for Visually Identifying an Aircraft

    DTIC Science & Technology

    2005-06-01

    Thesis Supervisor Certified by Brent Appleby Lecturer in Aeronautics and CSDL Technical Supervisor Thesis Advisor Accepted by Jaime Peraire Professor of...Leena Singh Title: Senior Member of the Technical Staff Thesis Advisor: Dr. Brent Appleby Title: Division Leader - Control, Information, and Decision...Systems 3 [This page intentionally left blank.] Acknowledgments I would like to thank my advisors Leena Singh and Brent Appleby for their help with this

  18. Ambition and vision at student awards.

    PubMed

    Bishop, Jaime

    2010-01-01

    Eighty entries from students from schools of architecture and interior design all over the world were whittled down to just eight in the 2009 Architects for Health (AfH) Student Health Awards. Jaime Bishop, a director of Fleet Architects, AfH executive board member, and the competition's organiser, describes the shortlisted and winning entries, discusses how candidates addressed the brief, and explains how the winner and two "runners-up" were chosen.

  19. An Evaluation of B-ISDN for the Communication Architecture Requirements of Distributed Interactive Simulation (DIS)

    DTIC Science & Technology

    1994-03-01

    Amy, Robert M., Standards by Consensus, IEEE Communications Magazine , January 1994. [Bae91] Bae, Jaime Jungok, Tatsuya Suda, Survey of Traffic Control...Networks, IEEE Communications Magazine , April 1992. [Kor92] Korzenioski, Paul, ATM: The Next Wave?, RS Magazine, December 1992. 58 Aj [Maced94] Macedonia...Newman, Peter, ATM Technology for Corporate Networks, IEEE Communications Magazine , April 1992. [NRL94] Naval Research Laboratory, NRL’s ATM Testbed

  20. Regenerative Liquid Propellant Gun Igniter Concepts

    DTIC Science & Technology

    1987-10-01

    AL 35898-5500 Ft Enox , KY 40121 Commander 1 Commiander US Army Belvoir R&D Ctr US Army Development and ATTNt STRBE-WC Eployment Agency Tech Library...REGENERATIVE LIQUID PROPELLANT GUN IGNITER CONCEPTS JOHN D. KNAPTON AVI BIRK JAIMES DESPIRITO CRIS WATSON DTIC E-1FCTE OCTOBER- 1987 SMAR 1 41988D...5 I. INTRODUCTION 1 . BACKGROUND, ........ . . . . . . . . . . . . . . . . . . . 2 . P R O PELL AN T * 6

  1. SIMS: Single Interface to Multiple Sources

    DTIC Science & Technology

    1996-07-01

    IOS Press, Amsterdam, 1993. [7] Anthony Barrett, Keith Golden, Scott Penberthy, and Daniel Weld. UCPOP user’s manual (version 2.0). Technical Report...Fox, Wen-Te K. Lin, Anil Nori, and Daniel Ries. Storage and access sturctures to support a semantic data model. In Proceedings of the 8th...Jaime G. Carbonell, Craig A. Knoblock, Daniel R. Kuokka, Oren Etzioni, and Yolanda Gil. Explanation-based learning: A problem solving perspective

  2. Automatically Generating Abstractions for Planning

    DTIC Science & Technology

    1993-06-01

    Etzioni, Manuela Veloso, Yolanda Gil, Qiang Yang, Josh Tenenberg, and Claire Bono all provided a great deal of inspiration and support, as well as a lot...statistical significance test. Finally, Oren, Yolanda , and the anonymous reviewers all provided very helpful comments on earlier drafts of this...2-3), 1990, 363-392. [46] Steven Minton, Jaime G. Carbonell, Craig A. Knoblock, Daniel R. Kuokka, Oren Et- zioni, and Yolanda Gil. Explanation-based

  3. Bigger Is Bigger

    NASA Astrophysics Data System (ADS)

    Riendeau, Diane

    2009-09-01

    When you really want to get a point across to your students, you set up explorations or experiments, and do demonstrations. Sometimes I find myself thinking, ``If I only had....'' This month's videos add ``wow'' factor to the experiences you provide for your students in the classroom! Thanks to Jaime Stasiorowski (Deerfield High School), Tony Zito (Dutchess Community College), and Bob Beichner (NC State) and Chris Chiaverina for their contributions to this month's column.

  4. An Analysis Platform for Mobile Ad Hoc Network (MANET) Scenario Execution Log Data

    DTIC Science & Technology

    2016-01-01

    ARL-TR-7574 ● JAN 2016 US Army Research Laboratory An Analysis Platform for Mobile Ad Hoc Network (MANET) Scenario Execution Log...Analysis Platform for Mobile Ad Hoc Network (MANET) Scenario Execution Log Data by Jaime C Acosta and Yadira Jacquez Survivability/Lethality Analysis...August 2015 4. TITLE AND SUBTITLE An Analysis Platform for Mobile Ad Hoc Network (MANET) Scenario Execution Log Data 5a. CONTRACT NUMBER 5b. GRANT

  5. Latin America Report

    DTIC Science & Technology

    1985-10-22

    to a religion that consoled the afflicted but that did not speak out against injustice, lies and deception. That is why those who feel adversely...individual matter. "They understand a faith that consoles the afflicted but not that speaks out against injustice, lies and deception. This is why...Reynal, Juan Ochoa, Ruben Barrio, Jaime Galvan, Luis Roberto Licon, Eugenio Baeza, Jesus Yanez, Miguel Anchondo, Dereck Dumn, Ronald Taylor

  6. Bodybuilding, Energy, and Weight-Loss Supplements are Associated with Deployment and Physical Activity in U.S. Military Personnel

    DTIC Science & Technology

    2012-05-01

    the herbal weight-loss supplement hydroxycut. Ann Intern Med. 2005;142:477–478. 22. Baum M, Weiss M. The influence of a taurine containing drink on...Naval Health Research Center Bodybuilding, Energy, and Weight-Loss Supplements Are Associated With Deployment and Physical Activity in U.S...Weight-Loss Supplements Are Associated With Deployment and Physical Activity in U.S. Military Personnel ISABEL G. JACOBSON, MPH, JAIME L. HORTON, BS

  7. Polynomials with Restricted Coefficients and Their Applications

    DTIC Science & Technology

    1987-01-01

    JAMES S . BYRNES, PRINCIPAL INVESTIGATOR DONALD. J. NEWMAN, PRINCIPAL SCIENTIST MARTIN GOLDSTEIN, SENIOR SCIENTIST AIR FORCE OFFICE OF SCIENTIFIC...lacludd SecuntrY ClaaIflcationJ Polynomials with Restricted Coefficienks a@,d Thei• Applic tions 12. PERSONAL AUTHOR( S ) JAI.MES S . Byrnes 13a, TYPE OF...COEFFICIENTS AND THEIR APPLICATIONS PREPARED BY: JAMES S . BYRNES, PRINCIPAL INVESTIGATOR DONALD J. NEWMAN, PRINCIPAL SCIENTIST S " MARTIN GOLDSTEIN

  8. [A comparative study of N400 in generalized anxiety disorder versus obsessive compulsive disorder patients].

    PubMed

    Zhang, Chen; Chen, Xing-shi; Ren, Qing-sheng; Yi, Zheng-hui; Chen, Chong; Fang, Yi-ru

    2012-09-18

    To explore the features of events-related potentials (ERP) component N400 in generalized anxiety disorder (GAD) versus obsessive compulsive disorder (OCD) patients and understand the cognitive pattern and processing characteristic for Chinese characters. ERP component N400 was recorded by Guangzhou Runjie WJ-1 ERP apparatus. And 41 GAD patients, 69 OCD patients and 58 normal controls (NC) were tested by the Chinese idioms ending with matching (congruent) or mismatching (incongruent) words. (1) Latencies: Significant differences were found of N400 latencies in ending words with the same pronunciation but different forms and meanings (NC: (377 ± 40) ms, OCD: (395 ± 43) ms, GAD: (396 ± 43) ms, congruent; NC: (415 ± 32) ms, OCD: (429 ± 35) ms, GAD: (430 ± 36) ms, incongruent), ending words with the same meaning but different pronunciations and forms (NC: (411 ± 32) ms, OCD: (424 ± 40) ms, GAD: (433 ± 39) ms, incongruent), ending words with different pronunciations, forms and meanings (NC: (399 ± 47) ms, OCD: (427 ± 53) ms, GAD: (434 ± 42) ms, congruent; NC: (442 ± 36) ms, OCD: (465 ± 35) ms, GAD: (474 ± 35) ms, incongruent) (P < 0.05 - 0.01). Compared with NC, the N400 latencies were prolonged in GAD and OCD patients. Compared with OCD patients, the GAD patients also showed prolonged N400 latencies in ending words with different pronunciations, forms and meanings (incongruent situation). (2) Significant differences were found of N400 amplitudes in ending words with the same pronunciation but different forms and meanings (NC: (9 ± 5) µV, OCD: (6 ± 5) µV, GAD: (6 ± 5) µV, congruent; NC: (11 ± 6) µV, OCD: (5 ± 4) µV, GAD: (6 ± 4) µV, incongruent), ending words with similar forms but different pronunciations and meanings (NC: (9 ± 5) µV, OCD: (5 ± 4) µV, GAD: (7 ± 5) µV, congruent; NC: (14 ± 6) µV, OCD: (6 ± 5) µV, GAD: (9 ± 7) µV, incongruent), ending words with different pronunciations, forms and meanings (NC: (9 ± 5) µV, OCD: (5

  9. Plasmacatalytic removal of lead acetate assisted by precipitation.

    PubMed

    Haddou, Nabila; Ghezzar, Mouffok Redouane; Abdelmalek, Fatiha; Ognier, Stéphanie; Martel, Marc; Addou, Ahmed

    2014-07-01

    The Gliding Arc Discharge (GAD) is an efficient non-thermal plasma technique able to degrade organic compounds dispersed in water at atmospheric pressure. The degradation of the organometallic lead acetate (PbAc) in aqueous solution was performed by two distinct plasmageneous processes: GAD and GAD/TiO2. The global oxidation of the organic matter was followed by Chemical Oxygen Demand (COD) and the mineralization was determined by the Total Organic Carbon (TOC). The Pb(2+) ions released during the degradation process were measured by Atomic Absorption Spectroscopy (AAS). For 2h of GAD treatment, the degradation rate of PbAc (10mM) reached 83% and for the same duration of GAD/TiO2 process ([TiO2]=1gL(-1)), it reached 93%. The release of Pb(2+) ions in the solution was respectively of 95% and 57% for GAD and GAD/TiO2 processes. The released Pb(2+) ions were removed by precipitation process in a basic medium at pH=11.1. A reaction mechanism was proposed to explain the PbAc molecule degradation and the Pb(2+) elimination. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Psychometric Properties of the Generalized Anxiety Disorder Questionnaire for DSM-IV Among Four Racial Groups

    PubMed Central

    Robinson, Christina M.; Klenck, Suzanne C.; Norton, Peter J.

    2010-01-01

    The Generalized Anxiety Disorder Questionnaire-IV (GAD-Q-IV) is a self-report diagnostic measure of generalized anxiety disorder. Previous studies have established the psychometric properties of the GAD-Q-IV revealing excellent diagnostic specificity and sensitivity as well as good test-retest reliability and convergent and discriminant validity (Newman et al., 2002). Recent analyses with other measures of anxiety symptoms have revealed differences across racial or national groups. Given that the GAD-Q-IV was tested primarily on Caucasian (78%) participants, the purpose of this study was to demonstrate the psychometric properties of the GAD-Q-IV across four racial groups: African American, Caucasian, Hispanic/Latino, and Asian. A student sample of 585 undergraduate psychology students completed the GAD-Q-IV as well as other measures of anxiety symptoms. A clinical replication sample was obtained from 188 clinical participants who completed the GAD-Q-IV as part of a larger psychotherapy study. Results indicated excellent and very similar factor structures in the student sample, and similar psychometric properties across both samples across the racial groups. Implications for the use of the GAD-Q-IV across racial groups are discussed. PMID:20830629

  11. Comparison of automatical thoughts among generalized anxiety disorder, major depressive disorder and generalized social phobia patients.

    PubMed

    Gül, A I; Simsek, G; Karaaslan, Ö; Inanir, S

    2015-08-01

    Automatic thoughts are measurable cognitive markers of the psychopathology and coping styles of individuals. This study measured and compared the automatic thoughts of patients with generalized anxiety disorder (GAD), major depressive disorder (MDD), and generalized social phobia (GSP). Fifty-two patients with GAD, 53 with MDD, and 50 with GSP and 52 healthy controls completed the validated Automatic Thoughts Questionnaire (ATQ) and a structured psychiatric interview. Patients with GAD, MDD, and GSP also completed the validated Generalized Anxiety Disorder-7 questionnaire, the Beck Depression Inventory (BDI), and the Liebowitz Social Anxiety Scale (LSAS) to determine the severity of their illnesses. All scales were completed before treatment and after diagnosis. The ATQ scores of all pairs of groups were compared. The ATQ scores of the GAD, MDD, and GSP groups were significantly higher than were those of the control group. We also found significant correlations among scores on the GAD-7, BDI, and LSAS. The mean age of patients with GSP was lower than was that of the other groups (30.90 ± 8.35). The significantly higher ATQ scores of the MDD, GAD, and GSP groups, compared with the control group, underscore the common cognitive psychopathology characterizing these three disorders. This finding confirms that similar cognitive therapy approaches should be effective for these patients. This study is the first to compare GAD, MDD, and GSP from a cognitive perspective.

  12. Diagnostic utility of worry and rumination: a comparison between generalized anxiety disorder and major depressive disorder.

    PubMed

    Yang, Min-Jeong; Kim, Bin-Na; Lee, Eun-Ho; Lee, Dongsoo; Yu, Bum-Hee; Jeon, Hong Jin; Kim, Ji-Hae

    2014-09-01

    Although previous reports have addressed worry and rumination as prominent cognitive processes in generalized anxiety disorder (GAD) and major depressive disorder (MDD) and their distinct correlation with anxious and depressive symptoms, the differential association of worry and rumination with the diagnosis of GAD and MDD remains unclear. The purpose of this study was to investigate the distinct features of worry and rumination in factor structure and their predictive validity for the diagnosis of GAD and MDD. Four hundred and sixty-eight patients with GAD (n = 148) and MDD (n = 320) were enrolled and the diagnoses were confirmed with the Structured Clinical Interview for DSM-IV. Participants completed the Penn State Worry Questionnaire and Ruminative Response Scale and the severity of anxiety and depressive symptoms was assessed via clinician ratings. In joint factor analysis using the Penn State Worry Questionnaire and Ruminative Response Scale items, worry and rumination emerged as distinct factors. In logistic regression analyses, worry contributed to a higher probability of the diagnosis of GAD than rumination, as rumination did in MDD than worry. This is the first comprehensive study investigating the diagnostic utility of worry and rumination in a well-defined clinical sample of both GAD and MDD. Our results suggest that worry and rumination are distinct cognitive processes and play a differential role in the diagnosis of GAD and MDD, distinguishing them at the cognitive level. © 2014 The Authors. Psychiatry and Clinical Neurosciences © 2014 Japanese Society of Psychiatry and Neurology.

  13. Asking patients about their general level of functioning: Is IT worth IT for common mental disorders?

    PubMed

    Olariu, Elena; Forero, Carlos G; Álvarez, Pilar; Castro-Rodriguez, José-Ignacio; Blasco, M J; Alonso, Jordi

    2015-10-30

    Functional disability (FD) is a diagnostic criterion for the psychiatric diagnosis of many mental disorders (e.g. generalized anxiety disorder (GAD); major depressive episode (MDE)). We aimed to assess the contribution of measuring FD to diagnosing GAD and MDE using clinical (Global Assessment of Functioning, GAF) and self-reported methods (Analog scale of functioning, ASF and World Health Organization Disability Assessment Schedule WHODAS 2.0). Patients seeking professional help for mood/anxiety symptoms (N=244) were evaluated. The MINI interview was used to determine the presence of common mental disorders. Symptoms were assessed with two short checklists. Logistic and hierarchical logistic models were used to determine the diagnostic accuracy and the added diagnostic value of FD assessment in detecting GAD and MDE. For GAD, FD alone had a diagnostic accuracy of 0.79 (GAF), 0.79 (ASF) and 0.78 (WHODAS) and for MDE of 0.83, 0.84 and 0.81, respectively. Self-reported measures of FD improved the diagnostic performance of the number of symptoms (4% AUC increase) for GAD, but not for MDE. If assessed before symptom evaluation, FD can discriminate well between patients with and without GAD/MDE. When assessed together with symptoms, self-reported methods improve GAD detection rates. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  14. Anxiety, social support, and physical health in a sample of spouses of OEF/OIF service members.

    PubMed

    Fields, Jordan A; Nichols, Linda O; Martindale-Adams, Jennifer; Zuber, Jeffrey; Graney, Marshall

    2012-12-01

    The goal of this study was to examine the relationships between heightened anxiety, social support, and physical health in a sample of spouses of returning Iraq and Afghanistan service members. 86 spouses were recruited nationally as part of a pilot trial of a military spouse telephone support group. Participants completed measures of physical and mental health via telephone including a screening tool for generalized anxiety disorder (GAD). Scores for social support and health outcomes were compared across two groups (positive vs. negative screens for GAD) using one-way analysis of variance analysis procedures. Path analytic techniques were used to evaluate the relative effects of anxiety and perceived social support on overall health and physical health comorbidities. A total of 38 participants screened positive for GAD. Participants with probable GAD reported having less social support than those screening negative for GAD. GAD participants also reported poorer overall health and more physical health comorbidities than their GAD-negative counterparts. Path analysis indicated that heightened anxiety is associated with worse overall health and social support does not buffer this interaction. The results suggest that anxiety-related health is a critical factor to be addressed in spouses of service members.

  15. Can lncRNAs be indicators for the diagnosis of early onset or acute schizophrenia and distinguish major depressive disorder and generalized anxiety disorder?-A cross validation analysis.

    PubMed

    Cui, Xuelian; Niu, Wei; Kong, Lingming; He, Mingjun; Jiang, Kunhong; Chen, Shengdong; Zhong, Aifang; Li, Wanshuai; Lu, Jim; Zhang, Liyi

    2017-03-28

    Depression and anxiety are apparent symptoms in the early onset or acute phase of schizophrenia (SZ), which complicate timely diagnosis and treatment. It is imperative to seek an indicator to distinguish schizophrenia from depressive and anxiety disorders. Using lncRNA microarray profiling and RT-PCR, three up-regulated lncRNAs in SZ, six down-regulated lncRNAs in major depressive disorder (MDD), and three up-regulated lncRNAs in generalized anxiety disorder (GAD) had been identified as potential biomarkers. All the lncRNAs were, then, cross-validated in 40 SZ patients, 40 MDD patients, 40 GAD patients, and 40 normal controls. Compared with controls, three up-regulated SZ lncRNAs had a significantly down-regulated expression in GAD, and no remarkable differences existed between MDD and the controls. Additionally, the six down-regulated MDD lncRNAs were expressed in an opposite fashion in SZ, and the expression of the three up-regulated GAD lncRNAs were significantly different between SZ and GAD. These results indicate that the expression patterns of the three up-regulated SZ lncRNAs could not be completely replicated in MDD and GAD, and vice versa. Thus, these three SZ lncRNAs seem to be established as potential indicators for diagnosis of schizophrenia and distinguishing it from MDD and GAD.© 2017 Wiley Periodicals, Inc.

  16. Removal kinetics of antibodies against glutamic acid decarboxylase by various plasmapheresis modalities in the treatment of neurological disorders.

    PubMed

    Ohkubo, Atsushi; Okado, Tomokazu; Kurashima, Naoki; Maeda, Takuma; Miyamoto, Satoko; Nakamura, Ayako; Seshima, Hiroshi; Iimori, Soichiro; Sohara, Eisei; Uchida, Shinichi; Rai, Tatemitsu

    2014-06-01

    Plasmapheresis is one of the acute treatment modalities for neurological disorders associated with antibodies against glutamic acid decarboxylase (anti-GAD). However, there is little information about the removal kinetics of anti-GAD by various plasmapheresis modalities. Here, we investigated the removal rate of anti-GAD and fibrinogen (Fib) by immunoadsorption (IA), plasma exchange using a conventional plasma separator (OP-PE), and plasma exchange using a high cut-off selective membrane plasma separator (EC-PE) in two cases of anti-GAD-associated neurological diseases. In case 1, IA and OP-PE were used, and the percent reductions were as follows: anti-GAD: 38.2% and 69.1% and Fib: 67.7% and 68.2%, respectively. In case 2, OP-PE and EC-PE were used, and the percent reductions were as follows: anti-GAD: 65.8% and 48.5% and Fib: 68.5% and 19.8%, respectively. OP-PE could remove anti-GAD more efficiently than IA. Further, EC-PE could maintain coagulation factors such as Fib better than IA and OP-PE. It is important to select the appropriate plasmapheresis modality on the basis of the removal kinetics.

  17. Influence of light on the free amino acid content and γ-aminobutyric acid synthesis in Brassica juncea seedlings.

    PubMed

    Li, Xiaohua; Kim, Yeon Bok; Uddin, Md Romij; Lee, Sanghyun; Kim, Sun-Ju; Park, Sang Un

    2013-09-11

    Glutamate decarboxylase (GAD; EC 4.1.1.15) is an important enzyme in γ-aminobutyric acid (GABA) biosynthesis. Here we report the influence of light on amino acid accumulation and investigate the molecular mechanism by which light influences GABA biosynthesis at the seedling stage of two mustard (Brassica juncea) cultivars (green-leaf and purple-leaf). Gene expression profiles of four GAD-encoding genes (GAD1, GAD2, GAD4a, and GAD4b) and their impact on GABA biosynthesis were analyzed. Light exerted an obvious influence on amino acid accumulation in mustard seedlings. GAD gene expression was also significantly regulated by light/dark or dark treatment, which differentially regulated GABA biosynthesis in B. juncea seedlings. High-performance liquid chromatography (HPLC) revealed that the seeds of purple cultivars contain a higher amount of free amino acids and GABA than do the seeds of green cultivars. After seed germination, however, the accumulation of free amino acids peaked in dark-treated seedlings on day 9 in both cultivars, whereas GABA synthesis peaked at 9 days under light conditions. This study may provide a foundation for understanding the effect of light on amino acids, particularly GABA biosynthesis in Brassica plants.

  18. Generalized anxiety disorder is under-recognized in clinical practice in patients with alcohol dependence in France.

    PubMed

    Charriau, Violaine; Elyakoubi, M'hammed; Millet, Bruno; Drapier, Dominique; Robin, Didier; Moirand, Romain

    2013-02-01

    Generalized Anxiety Disorder (GAD) is a frequent disabling disorder that often occurs with alcohol dependence. However comorbidity between substance use disorders and psychiatric disorders is often under-diagnosed. This study tried to evaluate an under-recognition of GAD by clinicians in alcoholic inpatients. Two groups of alcohol-dependent inpatients, hospitalized in the same non-academic psychiatric hospital in France, were included. The first group (Group 1) (n = 205) was included retrospectively within all patients hospitalized for alcohol dependence from may to November 2007. A record review was performed to determine the number of GAD (and other psychiatric disorders) diagnosis which was reported on these files by the clinicians. The second group (Group 2) (n = 199) was included prospectively from May to November 2008. GAD diagnosis was screened with the Worry and Anxiety Questionnaire and then confirmed with the Mini International Neurodiagnostic Interview. The two groups were similar in terms of social and demographic variables. GAD prevalence rate was significantly higher in Group 2 (30.7% with Confidence Interval [0.242; 0.371]) than in Group 1 (2.4% with Confidence Interval [0.003; 0.045]). This study confirms our hypothesis of an under-recognition of GAD by clinicians in alcohol dependant inpatients. It also confirms the high prevalence rate of comorbidity between alcohol dependence and GAD.

  19. Non-Antidepressant Treatment of Generalized Anxiety Disorder.

    PubMed

    Zahreddine, Nada; Richa, Sami

    2013-02-04

    Introduction: Generalized anxiety disorder (GAD) is a prevalent and very disabling anxiety disorder. First-line medications are antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and noradrenalin reuptake inhibitors (SNRIs). However, a substantial number of patients do not reach remission while on antidepressants and they may develop troublesome side effects, which highlights the necessity of new therapeutic options for GAD.  Methods: The purpose of this review is to discuss all non-antidepressant treatments studied in GAD. We searched MedLine for English articles published between 1980 and 2012, containing the following keywords: "generalized (or generalised) anxiety disorder" OR "anxiety disorder", AND "drug therapy" OR "herbal medicine". 76 articles were finally selected. Results: Pregabalin is the anticonvulsant with the most robust level of evidence in GAD. It rapidly reduces anxiety, have a safe side effect profile and presents a low potential for abuse. Among antipsychotics, quetiapine is the one of choice in GAD, with similar efficacy to SSRIs in low dosages, yet with lower overall tolerability. Benzodiazepines, buspirone and hydroxyzine are Food and Drugs administration (FDA) approved for GAD and have relatively good evidence of efficacy. Other drugs (betablockers, zolpidem, riluzole, etc…) and natural remedies (e.g. Piper methysticum) could be potential treatment options, yet additional research is warranted. Conclusion:  Pregabalin and quetiapine are the two most promising non-antidepressant treatments for GAD.

  20. Photon manipulation in silicon nanophotonic circuits

    NASA Astrophysics Data System (ADS)

    Elshaari, Ali Wanis

    2011-12-01

    CD8+ T cells are the branch of the adaptive immune system responsible for recognizing and killing tumor cells or cells infected with intracellular pathogens, such as Listeria monocytogenes (LM). However, when CD8+ T cells target our own tissues, they can cause autoimmune diseases, such as type I diabetes, rheumatoid arthritis. For CD8+ T cells to fulfill these functions, the T cell receptors (TCRs) on CD8+ T cells must recognize pathogens or antigens presented on the surface of target cells. TCR ligation triggers multiple signaling pathways that lead to the activation and proliferation of CD8+ T cells. The goal of our research is to define the TCR-proximal signaling events that regulate CD8+ T cell-mediated immunity. To accomplish this goal, we are focusing on an adaptor protein Gads, which is critical for optimal TCR-mediated calcium mobilization. We reported the first analysis of the function of Gads in peripheral naive CD8+ T cells. To examine the function of Gads in CD8+ T cell mediated immune responses, we crossed Gads-/- mice with mice expressing an MHC class I-restricted transgenic TCR recognizing ovalbumin (OVA). The transgenic mice are called ovalbumin-specific T cell receptor-major histocompatibility complex class I restricted (OT-I) mice. We investigated the effect of Gads on the proliferation of CD8+ T cells following stimulation with peptide antigen in vivo and in vitro. We stimulated splenocytes from Gads+/+ OT-I and Gads -/- OT-I mice with the peptide agonist. The experiments revealed that Gads is required for optimal proliferation of CD8+ T cells. The regulation of Gads is most evident at the early time points of proliferation. Then we demonstrated that Gads-/- CD8+ T cells have impaired TCR-mediated exit from G0 phase of the cell cycle. In addition, Gads-/- CD8+ T cells have delayed expression of c-myc and the activation markers CD69 and CD25, upon stimulation with peptide antigen. Next, we investigated how Gads affects CD8+ T cell

  1. Association between latent toxoplasmosis and major depression, generalised anxiety disorder and panic disorder in human adults.

    PubMed

    Gale, Shawn D; Brown, Bruce L; Berrett, Andrew; Erickson, Lance D; Hedges, Dawson W

    2014-08-01

    Latent infection with the apicomplexan Toxoplasma gondii (Nicolle et Manceaux, 1908) has been associated with schizophrenia, bipolar disorder and self-harm behaviour. However, the potential relationship between T. gondii immunoglobulin G antibody (IgG) seropositivity and generalised-anxiety disorder (GAD) and panic disorder (PD) has not been investigated. The associations between serum reactivity to T. gondii and major depressive disorder (MDD), GAD and PD were evaluated in a total sample of 1 846 adult participants between the ages of 20 and 39 years from the United States Center for Disease Control's National Health and Nutrition Examination Survey (NHANES). Approximately 16% of the overall sample was seropositive for T. gondii and 7% of the sample met criteria for MDD, 2% for GAD and 2% for PD. There were no significant associations between T. gondii IgG seroprevalence and MDD (OR = 0.484, 95% CI = 0.186-1.258), GAD (OR = 0.737, 95% CI = 0.218-2.490) or PD (OR = 0.683, 95% CI = 0.206-2.270) controlling for sex, ethnicity, poverty-to-income ratio and educational attainment. However, limited evidence suggested a possible association between absolute antibody titres for T. gondii and GAD and PD but not MDD. Toxoplasma gondii seroprevalence was not associated with MDD, GAD or PD within the context of the limitations of this study, although there may be an association of T. gondii serointensity with and GAD and PD, which requires further study.

  2. Generalized anxiety disorder: how to treat, and for how long?

    PubMed

    Lam, Raymond W

    2006-01-01

    Generalized anxiety disorder (GAD) is a common, chronic and disabling anxiety disorder with considerable comorbidity with depression as well as with other anxiety disorders. Although tricyclic antidepressants and benzodiazepines have been found to be efficacious in patients with GAD, tolerability problems and other risks limit their use in clinical practice. In placebo-controlled, acute (<8 weeks) trials, several medications, including the selective serotonin reuptake inhibitors ([SSRIs] escitalopram, paroxetine, and sertraline) and others (venlafaxine, buspirone, pregabalin), have demonstrated efficacy in patients with GAD. Indeed, current guidelines for the treatment of GAD recommend SSRIs as first-line pharmacological therapy because of their efficacy and tolerability profiles. Although GAD is a chronic condition that is usually present for years, with symptoms typically fluctuating in intensity over time, there have been few randomized, controlled trials of pharmacotherapy beyond the acute phase of treatment. However, data from recent relapse-prevention studies and longer-term maintenance studies with paroxetine, venlafaxine and escitalopram strongly support the value of continued treatment for at least a further 6 months. This article focuses on pharmacological treatment, and reviews recently available data from acute, long-term and relapse-prevention trials in patients with GAD. In addition, issues relating to the natural course of GAD are highlighted as important considerations to guide selection of pharmacotherapy.

  3. Prefrontal-limbic connectivity during worry in older adults with generalized anxiety disorder.

    PubMed

    Mohlman, Jan; Eldreth, Dana A; Price, Rebecca B; Staples, Alison M; Hanson, Catherine

    2017-04-01

    Although generalized anxiety disorder (GAD) is one of the most prevalent anxiety disorders in older adults, very little is known about the neurobiology of worry, the hallmark symptom of GAD in adults over the age of 60. This study investigated the neurobiology and neural circuitry of worry in older GAD patients and controls. Twenty older GAD patients and 16 age-matched controls (mean age = 67.88) were compared on clinical measures and neural activity during worry using functional magnetic resonance imaging. As expected, worry elicited activation in frontal regions, amygdala, and insula within the GAD group, with a similar but less prominent frontal pattern was observed in controls. Effective connectivity analyses revealed a positive directional circuit in the GAD group extending from ventromedial through dorsolateral prefrontal cortices, converging on the amygdala. A less complex circuit was observed in controls with only dorsolateral prefrontal regions converging on the amygdala; however, a separate circuit passing through the orbitofrontal cortex converged on the insula. Results elucidate a different neurobiology of pathological versus normal worry in later life. A limited resource model is implicated wherein worry in GAD competes for the same neural resources (e.g. prefrontal cortical areas) that are involved in the adaptive regulation of emotion through cognitive and behavioral strategies.

  4. Brain morphological alterations and cellular metabolic changes in patients with generalized anxiety disorder: A combined DARTEL-based VBM and (1)H-MRS study.

    PubMed

    Moon, Chung-Man; Jeong, Gwang-Woo

    2016-05-01

    Generalized anxiety disorder (GAD) is characterized by emotional dysregulation and cognitive deficit in conjunction with brain morphometric and metabolic alterations. This study assessed the combined neural morphological deficits and metabolic abnormality in patients with GAD. Thirteen patients with GAD and 13 healthy controls matched for age, sex, and education level underwent high-resolution T1-weighted MRI and proton magnetic resonance spectroscopy ((1)H-MRS) at 3Tesla. In this study, the combination of voxel-based morphometry (VBM) and (1)H-MRS was used to assess the brain morphometric and metabolic alterations in GAD. The patients showed significantly reduced white matter (WM) volumes in the midbrain (MB), precentral gyrus (PrG), dorsolateral prefrontal cortex (DLPFC) and anterior limb of the internal capsule (ALIC) compared to the controls. In MRS study, the choline/creatine (Cho/Cr) and choline/N-acetylaspartate (Cho/NAA) ratios in the DLPFC were significantly lower in the patients. Particularly, the WM volume variation of the DLPFC was positively correlated with both of the Cho/Cr and Cho/NAA ratios in patients with GAD. This study provides an evidence for the association between the morphometric deficit and metabolic changes in GAD. This finding would be helpful to understand the neural dysfunction and pathogenesis in connection with cognitive impairments in GAD. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. The Association between Generalized Anxiety Disorder, Subthreshold Anxiety Symptoms and Fear of Falling among Older Adults: Preliminary Results from a Pilot Study.

    PubMed

    Payette, Marie-Christine; Bélanger, Claude; Benyebdri, Fethia; Filiatrault, Johanne; Bherer, Louis; Bertrand, Josie-Anne; Nadeau, Alexandra; Bruneau, Marie-Andrée; Clerc, Doris; Saint-Martin, Monique; Cruz-Santiago, Diana; Ménard, Caroline; Nguyen, Philippe; Vu, T T Minh; Comte, Francis; Bobeuf, Florian; Grenier, Sébastien

    2017-01-01

    A relationship between generalized anxiety disorder (GAD) and fear of falling (FOF) has long been proposed but never specifically studied. This study aimed at analyzing the relationship between FOF and GAD or anxiety symptoms, while controlling for major depressive episodes (MDE), depressive symptoms, fall risk, and sociodemographic variables. Twenty-five older adults participated in this pilot study. Assessments included the following: Anxiety Disorder Interview Schedule, Geriatric Anxiety Inventory, Geriatric Depression Scale, Falls-Efficacy Scale-International. A multidisciplinary team evaluated fall risk. FOF was significantly correlated with GAD, MDE, anxiety and depressive symptoms, and fall risk, but not with sociodemographic variables. Multiple regression analyses indicated that GAD and anxiety symptoms were significantly and independently associated with FOF. Although the results of this pilot study should be replicated with larger samples, they suggest that FOF is associated with GAD and anxiety symptoms even when considering physical factors that increase the risk of falling. Treatment of FOF in patients with GAD may present a particular challenge because of the central role of intolerance of uncertainty, which may prevent patients from regaining confidence despite the reduction of fall risk. Clinicians should screen for GAD and anxiety symptoms in patients with FOF to improve detection and treatment.

  6. Long noncoding RNAs: New evidence for overlapped pathogenesis between major depressive disorder and generalized anxiety disorder.

    PubMed

    Cui, Xuelian; Niu, Wei; Kong, Lingming; He, Mingjun; Jiang, Kunhong; Chen, Shengdong; Zhong, Aifang; Li, Wanshuai; Lu, Jim; Zhang, Liyi

    2017-01-01

    About half of patients with major depressive disorder (MDD) have clinically meaningful levels of anxiety. Greater severity of depressive illness and functional impairment has been reported in patients with high levels of anxiety accompanying depression. The pathogenesis for the comorbidity was still unsure. This study aimed to determine whether there would be molecular link for overlapped pathogenesis between MDD and anxiety disorder. Using long noncoding RNA (lncRNA) microarray profiling and reverse transcription polymerase chain reaction, six downregulated lncRNAs and three upregulated lncRNAs had been identified to be the potential biomarkers for MDD and generalized anxiety disorder (GAD), respectively. Then, the lncRNAs were cross-checked in forty MDD patients, forty GAD patients, and forty normal controls. Compared with normal controls, six downregulated MDD lncRNAs also had a significantly lower expression in GAD (P < 0.01), and there was no significant difference between GAD and MDD (P > 0.05). In addition, three upregulated GAD lncRNAs had no different expression in MDD (P > 0.05), but there was remarkable difference between MDD and GAD (P < 0.01). These results indicated that lncRNAs in peripheral blood mononuclear cells could be potential molecular link between MDD and GAD, which added new evidence to the overlapped pathogenesis and suggested that anxious depression could be a valid diagnostic subtype of MDD.

  7. Differential attentional bias in generalized anxiety disorder and panic disorder

    PubMed Central

    Chen, Jing; Wang, Zhiyan; Wu, Yan; Cai, Yiyun; Shen, Yifeng; Wang, Liwei; Shi, Shenxun

    2013-01-01

    Background Cognitive theorists relate anxiety disorders to the way in which emotional information is processed. The existing research suggests that patients with anxiety disorders tend to allocate their attention toward threat-related information selectively, and this may differ among different types of anxious subjects. The aim of this study was to explore attentional bias in patients with generalized anxiety disorder (GAD) and panic disorder (PD) using the emotional Stroop task and compare the differences between them. Methods Forty-two patients with GAD, 34 patients with PD, and 46 healthy controls performed the emotional Stroop task with four word types, ie, GAD-related words, PD-related words, neutral words, and positive words. Results Patients with GAD and those with PD were slower than healthy controls to respond to all stimuli. Patients with GAD had longer response latencies in color-naming both PD-relevant words and GAD relevant words. Patients with PD had longer response latencies only in color-naming PD-related words, similar to healthy controls. Conclusion Patients with GAD and those with PD had a different pattern of attentional bias, and there was insufficient evidence to support the existence of specific attentional bias in patients with PD. PMID:23326197

  8. Suppression of detrusor-sphincter dyssynergia by herpes simplex virus vector-mediated gene delivery of glutamic acid decarboxylase in spinal cord injures rats

    PubMed Central

    Miyazato, Minoru; Sugaya, Kimio; Saito, Seiichi; Chancellor, Michael B.; Goins, William F.; Goss, James R.; de Groat, William C.; Glorioso, Joseph C.; Yoshimura, Naoki

    2010-01-01

    Purpose We investigated whether replication-defective herpes simplex virus (HSV) vectors encoding genes of glutamic acid decarboxylase (GAD), the gamma-aminobutyric acid synthesis enzyme, can suppress detrusor-sphincter dyssynergia (DSD) in rats with spinal cord injury (SCI). Materials and Methods One week after spinalization, HSV vectors expressing GAD and green fluorescent protein (HSV-GAD) were injected to the bladder wall. SCI rats without HSV injection (sham) and those injected with LacZ-encoding HSV vectors (HSV-LacZ) were used as controls. Three weeks after viral injection, simultaneous recordings of urethral pressure and intravesical pressure were performed under an awake condition in three groups. Results In the HSV-GAD group, the urethral pressure rise during bladder contractions was significantly reduced by 77–79% compared with sham or HSV-LacZ groups, but bladder activity and urethral baseline pressure were not different among three groups. Intrathecal application of bicuculline, a GABAA antagonist, almost completely reversed the decrease in urethral pressure rise during bladder contractions whereas intrathecal saclofen, a GABAB antagonist, partially reversed it. In the HSV-GAD group, GAD67 mRNA was significantly increased in L6-S1 dorsal root ganglia, where bladder afferents originate, compared with the HSV-LacZ group. Conclusions HSV-based GAD gene transfer to bladder afferent pathway may represent a novel approach for the treatment of DSD in SCI. PMID:20663524

  9. Field characterization of external grease abatement devices.

    PubMed

    Aziz, Tarek N; Holt, Leon M; Keener, Kevin M; Groninger, John W; Ducoste, Joel J

    2012-03-01

    This study characterized some of the physical and chemical features of large outside field grease abatement devices (GADs). 24-hour measurements of several food service establishments' (FSEs') influent GAD flowrates indicated highly intermittent conditions with hydraulic retention times (HRTs) that exceeded the common recommendation (30 minutes) by two to five times. Investigation into the chemical characteristics of GADs indicated highly variable influent and effluent fat, oil, and grease (FOG) concentrations. Low pH and dissolved oxygen values were measured throughout the GAD, indicating the likely occurrence of anaerobic microbial processes. Detailed spatial and temporal observations of the accumulation of FOG and food solids were also discussed. Though the FOG layer remained relatively constant for all GAD configurations investigated, results indicated that commonly-used GAD configurations with a straight submerged inlet tee or no-inlet tee configuration may result in the transport of food solids into the second compartment. The present research showed increased accumulation of food solids in the first compartment with a retro-fit flow distributive inlet. This retro-fit displays promise for potentially improving the separation characteristics of existing GADs.

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

    PubMed

    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.

  11. Impairment and quality of life in individuals with generalized anxiety disorder.

    PubMed

    Henning, Eric R; Turk, Cynthia L; Mennin, Douglas S; Fresco, David M; Heimberg, Richard G

    2007-01-01

    Once considered to be a disorder associated with minimal impairment, the link between generalized anxiety disorder (GAD) and impairment across a broad constellation of domains is now well established. However, less is known about how comorbidity affects these relationships or how GAD impacts one's perceived life satisfaction or quality of life. To investigate these questions, data from 52 treatment-seeking individuals with GAD (33 with comorbid Axis I diagnoses) were compared to data from 55 nonanxious controls. Individuals with GAD reported more impairment at work and in their social functioning than they did with home and family responsibilities. They also reported lower quality of life than nonanxious controls, particularly in regard to self-esteem, goals and values, money, work, play, learning, creativity, friends, and relatives. Trait worry was positively correlated with impairment and inversely related to life satisfaction within the clinical sample. Individuals with GAD, with and without comorbid Axis I diagnoses, showed few differences on measures of impairment (differing only on impairment in social functioning). However, individuals with GAD and comorbid disorders perceived their lives as less satisfying than did individuals with GAD without comorbid diagnoses.

  12. Refractory status epilepticus and glutamic acid decarboxylase antibodies in adults: presentation, treatment and outcomes.

    PubMed

    Khawaja, Ayaz M; Vines, Brannon L; Miller, David W; Szaflarski, Jerzy P; Amara, Amy W

    2016-03-01

    Glutamic acid decarboxylase antibodies (GAD-Abs) have been implicated in refractory epilepsy. The association with refractory status epilepticus in adults has been rarely described. We discuss our experience in managing three adult patients who presented with refractory status epilepticus associated with GAD-Abs. Case series with retrospective chart and literature review. Three patients without pre-existing epilepsy who presented to our institution with generalized seizures between 2013 and 2014 were identified. Seizures proved refractory to first and second-line therapies and persisted beyond 24 hours. Patient 1 was a 22-year-old female who had elevated serum GAD-Ab titres at 0.49 mmol/l (normal: <0.02) and was treated with multiple immuno- and chemotherapies, with eventual partial seizure control. Patient 2 was a 61-year-old black female whose serum GAD-Ab titre was 0.08 mmol/l. EEG showed persistent generalized periodic discharges despite maximized therapy with anticonvulsants but no immunotherapy, resulting in withdrawal of care and discharge to nursing home. Patient 3 was a 50-year-old black female whose serum GAD-Ab titre was 0.08 mmol/l, and was discovered to have pulmonary sarcoidosis. Treatment with steroids and intravenous immunoglobulin resulted in seizure resolution. Due to the responsiveness to immunotherapy, there may be an association between GAD-Abs and refractory seizures, including refractory status epilepticus. Causation cannot be established since GAD-Abs may be elevated secondary to concurrent autoimmune diseases or formed de novo in response to GAD antigen exposure by neuronal injury. Based on this report and available literature, there may be a role for immuno- and chemotherapy in the management of refractory status epilepticus associated with GAD-Abs.

  13. Genome-wide association study of generalized anxiety symptoms in the Hispanic Community Health Study/Study of Latinos.

    PubMed

    Dunn, Erin C; Sofer, Tamar; Gallo, Linda C; Gogarten, Stephanie M; Kerr, Kathleen F; Chen, Chia-Yen; Stein, Murray B; Ursano, Robert J; Guo, Xiuqing; Jia, Yucheng; Qi, Qibin; Rotter, Jerome I; Argos, Maria; Cai, Jianwen; Penedo, Frank J; Perreira, Krista; Wassertheil-Smoller, Sylvia; Smoller, Jordan W

    2017-03-01

    Although generalized anxiety disorder (GAD) is heritable and aggregates in families, no genomic loci associated with GAD have been reported. We aimed to discover potential loci by conducting a genome-wide analysis of GAD symptoms in a large, population-based sample of Hispanic/Latino adults. Data came from 12,282 participants (aged 18-74) in the Hispanic Community Health Study/Study of Latinos. Using a shortened Spielberger Trait Anxiety measure, we analyzed the following: (i) a GAD symptoms score restricted to the three items tapping diagnostic features of GAD as defined by DSM-V; and (ii) a total trait anxiety score based on summing responses to all ten items. We first calculated the heritability due to common variants (h(2)SNP ) and then conducted a genome-wide association study (GWAS) of GAD symptoms. Replication was attempted in three independent Hispanic cohorts (Multi-Ethnic Study of Atherosclerosis, Women's Health Initiative, Army STARRS). The GAD symptoms score showed evidence of modest heritability (7.2%; P = 0.03), while the total trait anxiety score did not (4.97%; P = 0.20). One genotyped SNP (rs78602344) intronic to thrombospondin 2 (THBS2) was nominally associated (P = 5.28 × 10(-8) ) in the primary analysis adjusting for psychiatric medication use and significantly associated with the GAD symptoms score in the analysis excluding medication users (P = 4.18 × 10(-8) ). However, meta-analysis of the replication samples did not support this association. Although we identified a genome-wide significant locus in this sample, we were unable to replicate this finding. Evidence for heritability was also only detected for GAD symptoms, and not the trait anxiety measure, suggesting differential genetic influences within the domain of trait anxiety. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  14. Enhancement of γ-aminobutyric acid production in recombinant Corynebacterium glutamicum by co-expressing two glutamate decarboxylase genes from Lactobacillus brevis.

    PubMed

    Shi, Feng; Jiang, Junjun; Li, Yongfu; Li, Youxin; Xie, Yilong

    2013-11-01

    γ-Aminobutyric acid (GABA), a non-protein amino acid, is a bioactive component in the food, feed and pharmaceutical fields. To establish an effective single-step production system for GABA, a recombinant Corynebacterium glutamicum strain co-expressing two glutamate decarboxylase (GAD) genes (gadB1 and gadB2) derived from Lactobacillus brevis Lb85 was constructed. Compared with the GABA production of the gadB1 or gadB2 single-expressing strains, GABA production by the gadB1-gadB2 co-expressing strain increased more than twofold. By optimising urea supplementation, the total production of L-glutamate and GABA increased from 22.57 ± 1.24 to 30.18 ± 1.33 g L⁻¹, and GABA production increased from 4.02 ± 0.95 to 18.66 ± 2.11 g L⁻¹ after 84-h cultivation. Under optimal urea supplementation, L-glutamate continued to be consumed, GABA continued to accumulate after 36 h of fermentation, and the pH level fluctuated. GABA production increased to a maximum level of 27.13 ± 0.54 g L⁻¹ after 120-h flask cultivation and 26.32 g L⁻¹ after 60-h fed-batch fermentation. The conversion ratio of L-glutamate to GABA reached 0.60-0.74 mol mol⁻¹. By co-expressing gadB1 and gadB2 and optimising the urea addition method, C. glutamicum was genetically improved for de novo biosynthesis of GABA from its own accumulated L-glutamate.

  15. Overexpression of Glutamate Decarboxylase in Mesenchymal Stem Cells Enhances Their Immunosuppressive Properties and Increases GABA and Nitric Oxide Levels

    PubMed Central

    González, Marisol; Vilches, Rodrigo; Rojas, Pablo; Vásquez, Manuel; Kurte, Mónica; Vega-Letter, Ana María; Carrión, Flavio; Figueroa, Fernando; Rojas, Patricio; Irarrázabal, Carlos

    2016-01-01

    The neurotransmitter GABA has been recently identified as a potent immunosuppressive agent that targets both innate and adaptive immune systems and prevents disease progression of several autoimmunity models. Mesenchymal stem cells (MSCs) are self-renewing progenitor cells that differentiate into various cell types under specific conditions, including neurons. In addition, MSC possess strong immunosuppressive capabilities. Upon cytokine priming, undifferentiated MSC suppress T-cell proliferation via cell-to-cell contact mechanisms and the secretion of soluble factors like nitric oxide, prostaglandin E2 and IDO. Although MSC and MSC-derived neuron-like cells express some GABAergic markers in vitro, the role for GABAergic signaling in MSC-mediated immunosuppression remains completely unexplored. Here, we demonstrate that pro-inflammatory cytokines selectively regulate GAD-67 expression in murine bone marrow-MSC. However, expression of GAD-65 is required for maximal GABA release by MSC. Gain of function experiments using GAD-67 and GAD-65 co-expression demonstrates that GAD increases immunosuppressive function in the absence of pro-inflammatory licensing. Moreover, GAD expression in MSC evokes an increase in both GABA and NO levels in the supernatants of co-cultured MSC with activated splenocytes. Notably, the increase in NO levels by GAD expression was not observed in cultures of isolated MSC expressing GAD, suggesting crosstalk between these two pathways in the setting of immunosuppression. These results indicate that GAD expression increases MSC-mediated immunosuppression via secretion of immunosuppressive agents. Our findings may help reconsider GABAergic activation in MSC for immunological disorders. PMID:27662193

  16. Implications of modifying the duration requirement of generalized anxiety disorder in developed and developing countries

    PubMed Central

    Lee, Sing; Tsang, Adley; Ruscio, Ayelet Meron; Haro, Josep Maria; Stein, Dan; Alonso, Jordi; Angermeyer, Matthias; Bromet, Evelyn; Demyttenaere, Koen; de Girolamo, Giovanni; de Graaf, Ron; Gureje, Oye; Iwata, Noboru; Karam, Elie G.; Lepine, Jean-Pierre; Levinson, Daphna; Medina-Mora, Maria Elena; Browne, Mark Oakley; Posada-Villa, José; Kessler, Ronald C.

    2009-01-01

    Background A number of western studies have suggested that the 6-month duration requirement of generalized anxiety disorder (GAD) does not represent a critical threshold in terms of onset, course, or risk factors of the disorder. No study has examined the consequences of modifying the duration requirement across a wide range of correlates in both developed and developing countries. Methods Population surveys were carried out in 7 developing and 10 developed countries using the WHO Composite International Diagnostic Interview (total sample size = 85,052). Prevalence of GAD was estimated using different minimum duration criteria. Age of onset, symptom persistence, subsequent mental disorders, impairment, and recovery were compared across GAD subgroups defined by different duration criteria. Results Lifetime prevalence estimates for GAD lasting 1 month, 3 months, 6 months, and 12 months were 7.5%, 5.24%, 4.11%, and 2.95% for developed countries and 2.65%, 1.78%, 1.47%, and 1.17% for developing countries, respectively. There was little difference between GAD of 6 months duration and GAD of shorter durations (1–2 months, 3–5 months) in symptom severity, age of onset, persistence, impairment, or comorbidity. Those with GAD lasting 12 months or more were the most severe, chronic, and impaired of the four duration subgroups. Conclusion In both developed and developing countries, the clinical profile of GAD is similar regardless of duration. The DSM-IV 6-month duration criterion is not an optimal marker of severity, impairment, or need for early treatment. Future iterations of the DSM and ICD should consider shortening the duration requirement of GAD. PMID:19091158

  17. GABAB receptor antibodies in limbic encephalitis and anti-GAD–associated neurologic disorders

    PubMed Central

    Boronat, A.; Sabater, L.; Saiz, A.; Dalmau, J.

    2011-01-01

    Background: γ-Aminobutyric acid-B receptor antibodies (GABABR-ab) were recently described in 15 patients with limbic encephalitis (LE), associated with small-cell lung cancer (SCLC) or with concurrent glutamic acid decarboxylase (GAD) antibodies. We analyzed the frequency of GABABR-ab in 147 patients with LE or neurologic syndromes associated with GAD-ab. Methods: We examined the presence of GABABR-ab in 70 patients with LE (33 paraneoplastic with onconeural antibodies, 18 paraneoplastic without onconeural antibodies [5 with Gad-ab], and 19 idiopathic with either GAD-ab [5 patients] or seronegative) and 77 patients with GAD-ab-associated neurologic syndromes other than LE (29 stiff-person syndrome, 28 cerebellar ataxia, 14 epilepsy, and 6 with diverse paraneoplastic neurologic syndromes). GABABR-ab were analyzed in serum or CSF by indirect immunofluorescence on HEK293 cells transfected with GABAB1 and GABAB2 receptor subunits. Results: GABABR-ab were detected in 10 of the 70 patients with LE (14%). Eight had SCLC and 2 were idiopathic. One of the 8 patients with LE with SCLC had an additional onconeural antibody (Hu) and 2 GAD-ab. GABABR-ab were identified in 7 (70%) of the 10 patients with LE and SCLC without onconeural antibodies. GABABR-ab antibodies were not found in patients with GAD-ab and stiff-person syndrome, idiopathic cerebellar ataxia, or epilepsy. However, one patient with GAD-ab, paraneoplastic cerebellar ataxia, and anaplastic carcinoid of the thymus also presented GABABR-ab. Conclusions: GABABR-ab are the most common antibodies found in LE associated with SCLC previously considered “seronegative.” In patients with GAD-ab, the frequency of GABABR-ab is low and only observed in the context of cancer. PMID:21357831

  18. Clinical characteristics and treatment outcomes of patients with major depressive disorder and comorbid anxiety disorders - results from a European multicenter study.

    PubMed

    Dold, Markus; Bartova, Lucie; Souery, Daniel; Mendlewicz, Julien; Serretti, Alessandro; Porcelli, Stefano; Zohar, Joseph; Montgomery, Stuart; Kasper, Siegfried

    2017-08-01

    This naturalistic European multicenter study aimed to elucidate the association between major depressive disorder (MDD) and comorbid anxiety disorders. Demographic and clinical information of 1346 MDD patients were compared between those with and without concurrent anxiety disorders. The association between explanatory variables and the presence of comorbid anxiety disorders was examined using binary logistic regression analyses. 286 (21.2%) of the participants exhibited comorbid anxiety disorders, 10.8% generalized anxiety disorder (GAD), 8.3% panic disorder, 8.1% agoraphobia, and 3.3% social phobia. MDD patients with comorbid anxiety disorders were characterized by younger age (social phobia), outpatient status (agoraphobia), suicide risk (any anxiety disorder, panic disorder, agoraphobia, social phobia), higher depressive symptom severity (GAD), polypsychopharmacy (panic disorder, agoraphobia), and a higher proportion receiving augmentation treatment with benzodiazepines (any anxiety disorder, GAD, panic disorder, agoraphobia, social phobia) and pregabalin (any anxiety disorder, GAD, panic disorder). The results in terms of treatment response were conflicting (better response for panic disorder and poorer for GAD). The logistic regression analyses revealed younger age (any anxiety disorder, social phobia), outpatient status (agoraphobia), suicide risk (agoraphobia), severe depressive symptoms (any anxiety disorder, GAD, social phobia), poorer treatment response (GAD), and increased administration of benzodiazepines (any anxiety disorder, agoraphobia, social phobia) and pregabalin (any anxiety disorder, GAD, panic disorder) to be associated with comorbid anxiety disorders. Our findings suggest that the various anxiety disorders subtypes display divergent clinical characteristics and are associated with different variables. Especially comorbid GAD appears to be characterized by high symptom severity and poor treatment response. Copyright © 2017 Elsevier Ltd. All

  19. Symptoms of generalized anxiety disorder but not panic disorder at age 15 years increase the risk of depression at 18 years in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort study.

    PubMed

    Davies, S J C; Pearson, R M; Stapinski, L; Bould, H; Christmas, D M; Button, K S; Skapinakis, P; Lewis, G; Evans, J

    2016-01-01

    Generalized anxiety disorder (GAD) and panic disorder (PD) differ in their biology and co-morbidities. We hypothesized that GAD but not PD symptoms at the age of 15 years are associated with depression diagnosis at 18 years. Using longitudinal data from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort we examined relationships of GAD and PD symptoms (measured by the Development and Well-Being Assessment) at 15 years with depression at 18 years (by the Clinical Interview Schedule - Revised) using logistic regression. We excluded adolescents already depressed at 15 years and adjusted for social class, maternal education, birth order, gender, alcohol intake and smoking. We repeated these analyses following multiple imputation for missing data. In the sample with complete data (n = 2835), high and moderate GAD symptoms in adolescents not depressed at 15 years were associated with increased risk of depression at 18 years both in unadjusted analyses and adjusting for PD symptoms at 15 years and the above potential confounders. The adjusted odds ratio (OR) for depression at 18 years in adolescents with high relative to low GAD scores was 5.2 [95% confidence interval (CI) 3.0-9.1, overall p < 0.0001]. There were no associations between PD symptoms and depression at 18 years in any model (high relative to low PD scores, adjusted OR = 1.3, 95% CI 0.3-4.8, overall p = 0.737). Missing data imputation strengthened the relationship of GAD symptoms with depression (high relative to low GAD scores, OR = 6.2, 95% CI 3.9-9.9) but those for PD became weaker. Symptoms of GAD but not PD at 15 years are associated with depression at 18 years. Clinicians should be aware that adolescents with GAD symptoms may develop depression.

  20. Firing properties of anatomically identified neurons in the medial septum of anesthetized and unanesthetized restrained rats.

    PubMed

    Simon, Axelle Pascale; Poindessous-Jazat, Frédérique; Dutar, Patrick; Epelbaum, Jacques; Bassant, Marie-Hélène

    2006-08-30

    Cholinergic and GABAergic neurons in the medial septum-diagonal band of Broca (MS-DB) project to the hippocampus where they are involved in generating theta rhythmicity. So far, the functional properties of neurochemically identified MS-DB neurons are not fully characterized. In this study, MS-DB neurons recorded in urethane anesthetized rats and in unanesthetized restrained rats were labeled with neurobiotin and processed for immunohistochemistry against glutamic acid decarboxylase (GAD), parvalbumin (PV), and choline acetyltransferase (ChAT). The majority of the 90 labeled neurons (75.5%) were GAD+. Among them, 34.0% were also PV+, but none were ChAT+. Only 8.8% of the labeled neurons were found ChAT+. Remaining neurons (15.5%) were not identified. In anesthetized rats, all of the PV/GAD+ and 65% of GAD+ neurons exhibited burst-firing activity at the theta frequency. PV/GAD+ neurons displayed higher discharge rate and longer burst duration compared with GAD+ neurons. At variance, all of the ChAT+ neurons were slow-firing. Cluster-firing and tonic-firing were observed in GAD+ and unidentified neurons. In unanesthetized rats, during wakefulness or rapid eye movement sleep with hippocampal theta, the bursting neurons were PV/GAD+ or GAD+, whereas all of the ChAT+ neurons were slow-firing. Across the sleep-wake cycle, the GABAergic component of the septohippocampal pathway was always more active than the cholinergic one. The fact that cholinergic MS-DB neurons do not display theta-related bursting or tonic activity but have a very low firing rate questions how acetylcholine exerts its activating role in the septohippocampal system.

  1. Structure-function relationships in histidine-rich antimicrobial peptides from Atlantic cod.

    PubMed

    McDonald, Mark; Mannion, Michael; Pike, Damien; Lewis, Krystina; Flynn, Andrew; Brannan, Alex M; Browne, Mitchell J; Jackman, Donna; Madera, Laurence; Power Coombs, Melanie R; Hoskin, David W; Rise, Matthew L; Booth, Valerie

    2015-07-01

    Gad-1 and Gad-2 are antimicrobial peptide (AMP) sequences encoded by paralogous genes. They are rich in histidine, which suggests that their activity might be pH-dependent. We examined their structure-function relationships with a view to learning how to improve AMP therapeutic ratios. Activity assays with Gram-negative bacteria and cancer cell lines demonstrate that Gad-2 is substantially more active at slightly acidic pH than it is at neutral pH. By contrast, the activity of Gad-1 at lower pH is similar to its activity at pH7. Circular dichroism spectra indicate that the greater functional plasticity of Gad-2 correlates with a greater structural plasticity; Gad-2's percent helicity varies dramatically with altered pH and lipid environment. Interestingly, Gad-2's highest levels of helicity do not correspond to the conditions where it is most active. High resolution solution NMR structures were determined in SDS micelles at pH5, conditions that induce an intermediate level of helicity in the peptides. Gad-1 is more helical than Gad-2, with both peptides exhibiting the greatest helical tendencies in their central region and lowest helicity in their N-termini. The high resolution structures suggest that maximum activity relies on the appropriate balance between an N-terminal region with mixed hydrophobic/hydrophilic structure features and an amphipathic central and C-terminal region. Taken together with previous studies, our results suggest that to improve the therapeutic ratio of AMPs, consideration should be given to including sequential histidine-pairs, keeping the overall charge of the peptide modest, and retaining a degree of structural plasticity and imperfect amphipathicity. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Current considerations in the treatment of generalized anxiety disorder.

    PubMed

    Katzman, Martin A

    2009-01-01

    Generalized anxiety disorder (GAD) is a chronic disorder that frequently co-occurs with a variety of co-morbidities in patients with somatic conditions and other mental disorders. GAD is highly prevalent and is one of the most common anxiety disorders seen by primary care physicians. The individual and societal cost associated with GAD is high and the marked level of impairment experienced by patients with this disorder is equivalent in magnitude to that reported in patients with major depressive disorder. Furthermore, patients with GAD are at risk of suicide or suicide attempts, and are frequent users of healthcare services. Thus, GAD is a serious and chronic condition that requires appropriate long-term treatment. The focus of acute treatment for patients with GAD is the improvement of symptoms, while the primary goal of long-term clinical management is remission, i.e. the complete resolution of both symptoms and functional impairment. The consensus across current treatment guidelines is that first-line treatment for patients with GAD should consist of an antidepressant, either a selective serotonin reuptake inhibitor (SSRI) such as sertraline, paroxetine or escitalopram, or a selective serotonin noradrenaline (norepinephrine) reuptake inhibitor (SNRI) such as venlafaxine or duloxetine. However, the SSRIs and SNRIs have efficacy limitations, such as lack of response in many patients, a 2- to 4-week delay before the onset of symptom relief, lack of full remission, and risk of relapse. In addition, there are troublesome adverse effects associated with both the SSRIs and SNRIs. Evidence from early clinical studies of the atypical antipsychotics in the treatment of anxiety and GAD indicate that they may have a potential role in the treatment of GAD, either as monotherapy or as augmentation to standard treatment.

  3. Functional neuroanatomy on the working memory under emotional distraction in patients with generalized anxiety disorder.

    PubMed

    Moon, Chung-Man; Jeong, Gwang-Woo

    2015-10-01

    Patients with generalized anxiety disorder (GAD) suffer the symptoms of psychological distress, including excessive and uncontrollable anxiety. Until now, the functional neuroanatomy for working memory (WM) in conjunction with the major anxiety symptoms in GAD patients has not yet been clearly identified. This study investigated the neural activation patterns associated with the effect of neutral and anxiety-inducing distractors during the delayed-response WM task in GAD patients. Eighteen patients with GAD and 18 age-matched healthy controls participated in this study. The functional magnetic resonance images were obtained while the subjects performed a delayed-response WM task with neutral and anxiety-inducing distractors. During the neutral distractor, GAD patients compared to controls showed significantly lower activities in the fusiform gyrus, superior parietal gyrus, precuneus, superior occipital gyrus, lingual gyrus, cuneus, calcarine gyrus, parahippocampal gyrus and cerebellar cortex. During the anxiety-inducing distractor, GAD patients showed significantly higher activity in the hippocampus, whereas they showed lower activities in the dorsolateral prefrontal cortex, fusiform gyrus, superior parietal gyrus, precuneus, superior occipital gyrus and cerebellar cortex. The blood-oxygen-level dependent signal changes in the dorsolateral prefrontal cortex in GAD patients during the anxiety-inducing distractor were negatively correlated with Anxiety Sensitivity Index-Revised scores. This study identified the specific brain areas associated with the interaction between emotional regulation and cognitive function associated with neutral and anxiety-inducing distractors during WM maintenance in GAD patients. These findings will be helpful for understanding the neural mechanism on the WM-related cognitive deficits and emotional dysfunction with typical anxiety symptoms in GAD. © 2015 The Authors. Psychiatry and Clinical Neurosciences © 2015 Japanese Society of

  4. Self-conscious emotions in worry and generalized anxiety disorder.

    PubMed

    Schoenleber, Michelle; Chow, Philip I; Berenbaum, Howard

    2014-09-01

    Current theories regarding worry and generalized anxiety disorder (GAD) highlight the potential avoidance functions of worry, and it has been suggested that worry functions to avoid self-conscious emotions in particular. Therefore, the present study examined the roles of proneness and aversion to self-conscious emotions in worry and GAD. Cross-sectional data from two samples were collected: (1) a sample of 726 undergraduates, and (2) a selected sample of 51 community members, 37.3% of whom met DSM-IV criteria for GAD. Zero-order correlations and hierarchical multiple regression analyses were used to examine associations of self-conscious emotion constructs to worry and GAD. Proneness to guilt and shame (propensities for experiencing guilt and shame, respectively) were assessed via the Test of Self-Conscious Affect-3. Aversion to guilt and shame (perceptions of guilt and shame, respectively, as especially painful, undesirable emotions) were assessed using the Guilt Aversion Assessment and Shame-Aversive Reactions Questionnaire, respectively. Worry was assessed using the Penn State Worry Questionnaire, and GAD was assessed via the Structured Clinical Interview for DSM-IV-TR Axis I Disorders. Correlations indicated positive associations between self-conscious emotion constructs and worry/GAD. However, in the selected community sample, regression analyses indicated that only shame aversion was positively associated with worry/GAD, over and above all other self-conscious emotion constructs and depression. Results suggest a prominent role for an intolerance for shame in worry and GAD, which is broadly consistent with psychological models of worry. Future directions for research and clinical implications are discussed. Positive clinical implications: Evidence supporting the theorized importance of self-conscious emotions in worry and GAD. Specifically highlights the need to address intolerance for shame in treatment. Limitations: Small sample size in Study 2. Use of cross

  5. Disease-specific monoclonal antibodies targeting glutamate decarboxylase impair GABAergic neurotransmission and affect motor learning and behavioral functions.

    PubMed

    Manto, Mario; Honnorat, Jérôme; Hampe, Christiane S; Guerra-Narbona, Rafael; López-Ramos, Juan Carlos; Delgado-García, José María; Saitow, Fumihito; Suzuki, Hidenori; Yanagawa, Yuchio; Mizusawa, Hidehiro; Mitoma, Hiroshi

    2015-01-01

    Autoantibodies to the smaller isoform of glutamate decarboxylase (GAD) can be found in patients with type 1 diabetes and a number of neurological disorders, including stiff-person syndrome, cerebellar ataxia and limbic encephalitis. The detection of disease-specific autoantibody epitopes led to the hypothesis that distinct GAD autoantibodies may elicit specific neurological phenotypes. We explored the in vitro/in vivo effects of well-characterized monoclonal GAD antibodies. We found that GAD autoantibodies present in patients with stiff person syndrome (n = 7) and cerebellar ataxia (n = 15) recognized an epitope distinct from that recognized by GAD autoantibodies present in patients with type 1 diabetes mellitus (n = 10) or limbic encephalitis (n = 4). We demonstrated that the administration of a monoclonal GAD antibody representing this epitope specificity; (1) disrupted in vitro the association of GAD with γ-Aminobutyric acid containing synaptic vesicles; (2) depressed the inhibitory synaptic transmission in cerebellar slices with a gradual time course and a lasting suppressive effect; (3) significantly decreased conditioned eyelid responses evoked in mice, with no modification of learning curves in the classical eyeblink-conditioning task; (4) markedly impaired the facilitatory effect exerted by the premotor cortex over the motor cortex in a paired-pulse stimulation paradigm; and (5) induced decreased exploratory behavior and impaired locomotor function in rats. These findings support the specific targeting of GAD by its autoantibodies in the pathogenesis of stiff-person syndrome and cerebellar ataxia. Therapies of these disorders based on selective removal of such GAD antibodies could be envisioned.

  6. Glutamate Decarboxylase 1 Overexpression as a Poor Prognostic Factor in Patients with Nasopharyngeal Carcinoma

    PubMed Central

    Lee, Yi-Ying; Chao, Tung-Bo; Sheu, Ming-Jen; Tian, Yu-Feng; Chen, Tzu-Ju; Lee, Sung-Wei; He, Hong-Lin; Chang, I-Wei; Hsing, Chung-Hsi; Lin, Ching-Yih; Li, Chien-Feng

    2016-01-01

    Background: Glutamate decarboxylase 1 (GAD1) which serves as a rate-limiting enzyme involving in the production of γ-aminobutyric acid (GABA), exists in the GABAergic neurons in the central nervous system (CNS). Little is known about the relevance of GAD1 to nasopharyngeal carcinoma (NPC). Through data mining on a data set derived from a published transcriptome database, this study first identified GAD1 as a differentially upregulated gene in NPC. We aimed to evaluate GAD1 expression and its prognostic effect on patients with early and locoregionally advanced NPC. Methods: We evaluated GAD1 immunohistochemistry and performed an H-score analysis on biopsy specimens from 124 patients with nonmetastasized NPC receiving treatment. GAD1 overexpression was defined as an H score higher than the median value. The findings of such an analysis are correlated with clinicopathological behaviors and survival rates, namely disease-specific survival (DSS), distant-metastasis-free survival (DMeFS), and local recurrence-free survival (LRFS) rates. Results: GAD1 overexpression was significantly associated with an increase in the primary tumor status (p < 0.001) and American Joint Committee on Cancer (AJCC) stages III-IV (p = 0.002) and was a univariate predictor of adverse outcomes of DSS (p = 0.002), DMeFS (p < 0.0001), and LRFS (p = 0.001). In the multivariate comparison, in addition to advanced AJCC stages III-IV, GAD1 overexpression remained an independent prognosticator of short DSS (p = 0.004, hazard ratio = 2.234), DMeFS (p < 0.001, hazard ratio = 4.218), and LRFS (p = 0.013, hazard ratio = 2.441) rates. Conclusions: Our data reveal that GAD1 overexpression was correlated with advanced disease status and may thus be a critical prognostic indicator of poor outcomes in NPC and a potential therapeutic target to facilitate the development of effective treatment modalities. PMID:27698909

  7. Disease-specific monoclonal antibodies targeting glutamate decarboxylase impair GABAergic neurotransmission and affect motor learning and behavioral functions

    PubMed Central

    Manto, Mario; Honnorat, Jérôme; Hampe, Christiane S.; Guerra-Narbona, Rafael; López-Ramos, Juan Carlos; Delgado-García, José María; Saitow, Fumihito; Suzuki, Hidenori; Yanagawa, Yuchio; Mizusawa, Hidehiro; Mitoma, Hiroshi

    2015-01-01

    Autoantibodies to the smaller isoform of glutamate decarboxylase (GAD) can be found in patients with type 1 diabetes and a number of neurological disorders, including stiff-person syndrome, cerebellar ataxia and limbic encephalitis. The detection of disease-specific autoantibody epitopes led to the hypothesis that distinct GAD autoantibodies may elicit specific neurological phenotypes. We explored the in vitro/in vivo effects of well-characterized monoclonal GAD antibodies. We found that GAD autoantibodies present in patients with stiff person syndrome (n = 7) and cerebellar ataxia (n = 15) recognized an epitope distinct from that recognized by GAD autoantibodies present in patients with type 1 diabetes mellitus (n = 10) or limbic encephalitis (n = 4). We demonstrated that the administration of a monoclonal GAD antibody representing this epitope specificity; (1) disrupted in vitro the association of GAD with γ-Aminobutyric acid containing synaptic vesicles; (2) depressed the inhibitory synaptic transmission in cerebellar slices with a gradual time course and a lasting suppressive effect; (3) significantly decreased conditioned eyelid responses evoked in mice, with no modification of learning curves in the classical eyeblink-conditioning task; (4) markedly impaired the facilitatory effect exerted by the premotor cortex over the motor cortex in a paired-pulse stimulation paradigm; and (5) induced decreased exploratory behavior and impaired locomotor function in rats. These findings support the specific targeting of GAD by its autoantibodies in the pathogenesis of stiff-person syndrome and cerebellar ataxia. Therapies of these disorders based on selective removal of such GAD antibodies could be envisioned. PMID:25870548

  8. Glutamic acid decarboxylase-67-positive hippocampal interneurons undergo a permanent reduction in number following kainic acid-induced degeneration of ca3 pyramidal neurons.

    PubMed

    Shetty, A K; Turner, D A

    2001-06-01

    Kainic acid (KA)-induced degeneration of CA3 pyramidal neurons leads to synaptic reorganization and hyperexcitability in both dentate gyrus and CA1 region of the hippocampus. We hypothesize that the substrate for hippocampal inhibitory circuitry incurs significant and permanent alterations following degeneration of CA3 pyramidal neurons. We quantified changes in interneuron density (N(v)) in all strata of the dentate gyrus and the CA1 and CA3 subfields of adult rats at 1, 4, and 6 months following intracerebroventricular (icv) KA administration, using glutamic acid decarboxylase-67 (GAD-67) immunocytochemistry. At 1 month postlesion, GAD-67-positive interneuron density was significantly reduced in all strata of every hippocampal region except stratum pyramidale of CA1. The reduction in GAD-67-positive interneuron density either persisted or exacerbated at 4 and 6 months postlesion in every stratum of all hippocampal regions. Further, the soma of remaining GAD-67-positive interneurons in dentate gyrus and CA3 subfield showed significant hypertrophy. Thus, both permanent reductions in the density of GAD-67-positive interneurons in all hippocampal regions and somatic hypertrophy of remaining GAD-67-positive interneurons in dentate gyrus and CA3 subfield occur following icv KA. In contrast, the density of interneurons visualized with Nissl in CA1 and CA3 regions was nearly equivalent to that in the intact hippocampus at all postlesion time points. Collectively, these results suggest that persistent reductions in GAD-67-positive interneuron density observed throughout the hippocampus following CA3 lesion are largely due to a permanent loss of GAD-67 expression in a significant fraction of interneurons, rather than widespread degeneration of interneurons. Nevertheless, a persistent decrease in interneuron activity, as evidenced by permanent down-regulation of GAD-67 in a major fraction of interneurons, would likely enhance the degree of hyperexcitability in the CA3

  9. Glutamate Decarboxylase-Dependent Acid Resistance in Brucella spp.: Distribution and Contribution to Fitness under Extremely Acidic Conditions

    PubMed Central

    Damiano, Maria Alessandra; Bastianelli, Daniela; Al Dahouk, Sascha; Köhler, Stephan; Cloeckaert, Axel

    2014-01-01

    Brucella is an expanding genus of major zoonotic pathogens, including at least 10 genetically very close species occupying a wide range of niches from soil to wildlife, livestock, and humans. Recently, we have shown that in the new species Brucella microti, the glutamate decarboxylase (Gad)-dependent system (GAD system) contributes to survival at a pH of 2.5 and also to infection in mice by the oral route. In order to study the functionality of the GAD system in the genus Brucella, 47 isolates, representative of all known species and strains of this genus, and 16 strains of the closest neighbor genus, Ochrobactrum, were studied using microbiological, biochemical, and genetic approaches. In agreement with the genome sequences, the GAD system of classical species was not functional, unlike that of most strains of Brucella ceti, Brucella pinnipedialis, and newly described species (B. microti, Brucella inopinata BO1, B. inopinata-like BO2, and Brucella sp. isolated from bullfrogs). In the presence of glutamate, these species were more acid resistant in vitro than classical terrestrial brucellae. Expression in trans of the gad locus from representative Brucella species in the Escherichia coli MG1655 mutant strain lacking the GAD system restored the acid-resistant phenotype. The highly conserved GAD system of the newly described or atypical Brucella species may play an important role in their adaptation to acidic external and host environments. Furthermore, the GAD phenotype was shown to be a useful diagnostic tool to distinguish these latter Brucella strains from Ochrobactrum and from classical terrestrial pathogenic Brucella species, which are GAD negative. PMID:25381237

  10. Glutamate decarboxylase-dependent acid resistance in Brucella spp.: distribution and contribution to fitness under extremely acidic conditions.

    PubMed

    Damiano, Maria Alessandra; Bastianelli, Daniela; Al Dahouk, Sascha; Köhler, Stephan; Cloeckaert, Axel; De Biase, Daniela; Occhialini, Alessandra

    2015-01-01

    Brucella is an expanding genus of major zoonotic pathogens, including at least 10 genetically very close species occupying a wide range of niches from soil to wildlife, livestock, and humans. Recently, we have shown that in the new species Brucella microti, the glutamate decarboxylase (Gad)-dependent system (GAD system) contributes to survival at a pH of 2.5 and also to infection in mice by the oral route. In order to study the functionality of the GAD system in the genus Brucella, 47 isolates, representative of all known species and strains of this genus, and 16 strains of the closest neighbor genus, Ochrobactrum, were studied using microbiological, biochemical, and genetic approaches. In agreement with the genome sequences, the GAD system of classical species was not functional, unlike that of most strains of Brucella ceti, Brucella pinnipedialis, and newly described species (B. microti, Brucella inopinata BO1, B. inopinata-like BO2, and Brucella sp. isolated from bullfrogs). In the presence of glutamate, these species were more acid resistant in vitro than classical terrestrial brucellae. Expression in trans of the gad locus from representative Brucella species in the Escherichia coli MG1655 mutant strain lacking the GAD system restored the acid-resistant phenotype. The highly conserved GAD system of the newly described or atypical Brucella species may play an important role in their adaptation to acidic external and host environments. Furthermore, the GAD phenotype was shown to be a useful diagnostic tool to distinguish these latter Brucella strains from Ochrobactrum and from classical terrestrial pathogenic Brucella species, which are GAD negative.

  11. Risk factors for late-onset generalized anxiety disorder: results from a 12-year prospective cohort (the ESPRIT study).

    PubMed

    Zhang, X; Norton, J; Carrière, I; Ritchie, K; Chaudieu, I; Ancelin, M-L

    2015-03-31

    Generalized anxiety disorder (GAD) is a chronic and highly prevalent disorder associated with increased disability and mortality in the elderly. Treatment is difficult with low rate of full remission, thus highlighting the need to identify early predictors for prevention in elderly people. The aim of this study is to identify and characterize incident GAD predictors in elderly people. A total of 1711 individuals aged 65 years and above and free of GAD at baseline were randomly recruited from electoral rolls between 1999 and 2001 (the prospective ESPRIT study). The participants were examined at baseline and five times over 12 years. GAD and psychiatric comorbidity were diagnosed with a standardized psychiatric examination, the Mini-International Neuropsychiatry Interview on the basis of DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, fourth edition) criteria and validated by a clinical panel. During the follow-up, 8.4% (95% confidence interval=7.1-9.7%) of the participants experienced incident GAD, 80% being first episodes; the incident rate being 10 per 1000 person-years. The principal predictors of late-onset incident GAD over 12 years derived from a multivariate Cox model were being female, recent adverse life events, having chronic physical (respiratory disorders, arrhythmia and heart failure, dyslipidemia, cognitive impairment) and mental (depression, phobia and past GAD) health disorders. Poverty, parental loss or separation and low affective support during childhood, as well as history of mental problems in parents were also significantly and independently associated with incident GAD. GAD appears as a multifactorial stress-related affective disorder resulting from both proximal and distal risk factors, some of them being potentially modifiable by health care intervention.

  12. Kv3.1b and Kv3.3 channel subunit expression in murine spinal dorsal horn GABAergic interneurones.

    PubMed

    Nowak, A; Mathieson, H R; Chapman, R J; Janzsó, G; Yanagawa, Y; Obata, K; Szabo, G; King, A E

    2011-09-01

    GABAergic interneurones, including those within spinal dorsal horn, contain one of the two isoforms of the synthesizing enzyme glutamate decarboxylase (GAD), either GAD65 or GAD67. The physiological significance of these two GABAergic phenotypes is unknown but a more detailed anatomical and functional characterization may help resolve this issue. In this study, two transgenic Green Fluorescent Protein (GFP) knock-in murine lines, namely GAD65-GFP and GAD67-GFP (Δneo) mice, were used to profile expression of Shaw-related Kv3.1b and Kv3.3 K(+)-channel subunits in dorsal horn interneurones. Neuronal expression of these subunits confers specific biophysical characteristic referred to as 'fast-spiking'. Immuno-labelling for Kv3.1b or Kv3.3 revealed the presence of both of these subunits across the dorsal horn, most abundantly in laminae I-III. Co-localization studies in transgenic mice indicated that Kv3.1b but not Kv3.3 was associated with GAD65-GFP and GAD67-GFP immunopositive neurones. For comparison the distributions of Kv4.2 and Kv4.3 K(+)-channel subunits which are linked to an excitatory neuronal phenotype were characterized. No co-localization was found between GAD-GFP +ve neurones and Kv4.2 or Kv4.3. In functional studies to evaluate whether either GABAergic population is activated by noxious stimulation, hindpaw intradermal injection of capsaicin followed by c-fos quantification in dorsal horn revealed co-expression c-fos and GAD65-GFP (quantified as 20-30% of GFP +ve population). Co-expression was also detected for GAD67-GFP +ve neurones and capsaicin-induced c-fos but at a much reduced level of 4-5%. These data suggest that whilst both GAD65-GFP and GAD67-GFP +ve neurones express Kv3.1b and therefore may share certain biophysical traits, their responses to peripheral noxious stimulation are distinct.

  13. Apraxia in anti-glutamic acid decarboxylase-associated stiff person syndrome: link to corticobasal degeneration?

    PubMed

    Bowen, Lauren N; Subramony, S H; Heilman, Kenneth M

    2015-01-01

    Corticobasal syndrome (CBS) is associated with asymmetrical rigidity as well as asymmetrical limb-kinetic and ideomotor apraxia. Stiff person syndrome (SPS) is characterized by muscle stiffness and gait difficulties. Whereas patients with CBS have several forms of pathology, many patients with SPS have glutamic acid decarboxylase antibodies (GAD-ab), but these 2 disorders have not been reported to coexist. We report 2 patients with GAD-ab-positive SPS who also had signs suggestive of CBS, including asymmetrical limb rigidity associated with both asymmetrical limb-kinetic and ideomotor apraxia. Future studies should evaluate patients with CBS for GAD-ab and people with SPS for signs of CBS.

  14. Anti glutamate-decarboxylase antibodies: a liaison between localisation related epilepsy, stiff-person syndrome and type-1 diabetes mellitus.

    PubMed

    Szűcs, Anna; Barcs, Gábor; Winkler, Gábor; Soós, Zsuzsanna; Folyovich, András; Kelemen, Anna; Várallyay, Péter; Kamondi, Anita

    2014-07-30

    We present two patients with partial epilepsy, type-1 diabetes and stiff person syndrome associated with high serum auto-antibody levels to glutamate-decarboxylase (anti-GAD). Both patients were or have suffered from additional autoimmune conditions. The presence of stiff person syndrome and elevated anti-GAD levels have to make clinicians look for additional autoimmune conditions including type-1 diabetes. On the other hand, the co-morbidity of partial epilepsy with autoimmune conditions in patients with elevated serum anti-GAD suggests an autoimmune mechanism of partial epilepsy in these cases.

  15. Therapist empathy and client anxiety reduction in motivational interviewing: "She carries with me, the experience".

    PubMed

    Angus, Lynne E; Kagan, Fern

    2009-11-01

    In this article, we examine the use of motivational interviewing (MI) to treat generalized anxiety disorder (GAD) by means of case illustration that focuses on four categories drawn from the client's experience of the key ingredients in MI therapy. The case illustration, drawn from the York study on combining MI and cognitive behavior therapy in the treatment of GAD (uses the client's pre- and post-therapy narrative interviews) to arrive at categories representative of the client's experience of MI therapy. The results of the qualitative analysis highlight the key contributions to positive client outcomes and readiness for change in brief MI therapy for GAD.

  16. Children with Generalized Anxiety Disorder Do Not Have Peer Problems, Just Fewer Friends

    PubMed Central

    Alfano, Candice; Beidel, Deborah; Wong, Nina

    2011-01-01

    A common assumption is that all youth with anxiety disorders (AD) experience impaired peer relationships relative to healthy control children. Social impairments have been identified among youth with certain AD (e.g., social anxiety disorder; SAD), but less is known about the peer relationships of children with generalized anxiety disorder (GAD). We therefore compared the interpersonal functioning of youth with GAD, SAD, and controls (6 to 13 years). Despite having relatively fewer friends overall, children with GAD did not differ from controls in terms of the likelihood of having a best friend, participation in groups/clubs, and parent ratings of social competence. In comparison, youth with SAD were less socially competent, had fewer friends and difficulty making new friends compared to controls. Findings suggest that peer difficulties are not a universal feature of all childhood AD and highlight a need to better understand the social experiences and functioning of children with GAD. PMID:21739298

  17. Looking Northwest Along South End of Rod Loading Building Including ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    Looking Northwest Along South End of Rod Loading Building Including Mezzanine and Gad Loading Area - Hematite Fuel Fabrication Facility, Rod Loading Building, 3300 State Road P, Festus, Jefferson County, MO

  18. Therapeutic options: Addressing the current dilemma.