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Sample records for jaime kigel gad

  1. 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:…

  2. 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.

  3. 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…

  4. 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…

  5. 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.

  6. 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.

  7. [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).

  8. 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....

  9. 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.

  10. 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

  11. 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

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

    MedlinePlus

    ... health, money, or family problems. But people with generalized anxiety disorder (GAD) feel extremely worried or feel nervous about ... I find more information? To learn more about generalized anxiety disorder, visit: MedlinePlus (National Library of Medicine) http: / / medlineplus. ...

  13. 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.

  14. 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.

  15. 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.

  16. 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

  17. 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

  18. 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.

  19. 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

  20. 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.

  1. 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

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 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.

  11. 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.

  12. 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

  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. 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.

  15. [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.

  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. 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.

  18. 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

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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

  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. 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.

  6. 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

  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. 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

  9. 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.

  10. 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

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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…

  16. 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.

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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

  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. 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.

  14. 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).

  15. 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

  16. 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.

  17. 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

  18. 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

  19. 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

  20. 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.

  1. 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.

  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. 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.

  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. 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

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 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.

  11. 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."

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. [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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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)

  7. 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:

  8. 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.

  9. Screening for Generalized Anxiety Disorder (GAD)

    MedlinePlus

    ... a Trainee/Postdoctoral Fellow/Resident Join as a Student Committees Committee Guidelines Scientific Council Special Interest Groups ... Blog Posts Podcasts & Videos Children and Teens College Students Women Older Adults Military & Military Families Support ADAA ...

  10. 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.

  11. 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.

  12. 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).

  13. VizieR Online Data Catalog: Variable stars in NGC 6715 (Figuera Jaimes+, 2016)

    NASA Astrophysics Data System (ADS)

    Figuera Jaimes, R.; Bramich, D. M.; Kains, N.; Skottfelt, J.; Jorgensen, U. G.; Horne, K.; Dominik, M.; Alsubai, K. A.; Bozza, V.; Burgdorf, M. J.; Calchi Novati, S.; Ciceri, S.; D'Ago, G.; Evans, D. F.; Galianni, P.; Gu, S. H.; Harpsoe, K. B. W.; Haugbolle, T.; Hinse, T. C.; Hundertmark, M.; Juncher, D.; Kerins, E.; Korhonen, H.; Kuffmeier, M.; Mancini, L.; Peixinho, N.; Popovas, A.; Rabus, M.; Rahvar, S.; Scarpetta, G.; Schmidt, R. W.; Snodgrass, C.; Southworth, J.; Starkey, D.; Street, R. A.; Surdej, J.; Tronsgaard, R.; Unda-Sanzana, E.; von Essen, C.; Wang, X. B.; Wertz, O.

    2016-06-01

    Observations were taken during 2013, 2014, and 2015 as part of an ongoing program at the 1.54m Danish telescope at the ESO observatory at La Silla in Chile that was implemented from April to September each year. table1.dat file contains the time-series I photometry for all the variables in NGC 6715 studied in this work. 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. (3 data files).

  14. 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.

  15. 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.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  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. 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.

  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. 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.

  1. 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

  2. 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.

  3. 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

  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, 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.

  6. Assessing Nonresponse Bias at Follow-up in a Large Prospective Cohort of Relatively Young and Mobile Military Service Members

    DTIC Science & Technology

    2010-10-21

    Jaime Horton (jaime.horton@med.navy.mil) Gary D Gackstetter (Gary.Gackstetter@anser.org) Besa Smith...Littman 1,2§, Edward J Boyko 1 , Isabel G Jacobson 3 , Jaime Horton 3 , Gary D Gackstetter 4 , Besa Smith 3 , Tomoko Hooper 5 , Timothy S Wells 3...0 7 (0 .9 7 , 4 .4 1 ) P ro b le m d ri n k in g N o 1 .0 0 1 .0 0 1 .0 0 1 .0 0 1 .0 0 1 .0 0 1 .0 0 1 .0

  7. 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

  8. 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

  9. 77 FR 74918 - Unblocking of Specially Designated Nationals and Blocked Persons Pursuant to Executive Order 12978

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-12-18

    ...) . 12. GONZALEZ QUINTERO, Melba Patricia, c/o DISTRIBUIDORA DE DROGAS CONDOR S.A., Bogota, Colombia; c/o...) (individual) . 13. IDARRAGA ORTIZ, Jaime, c/o DISTRIBUIDORA DE DROGAS CONDOR LTDA., Bogota, Colombia;...

  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. Shock Capturing with PDE-Based Artificial Viscosity for an Adaptive, Higher-Order Discontinuous Galerkin Finite Element Method

    DTIC Science & Technology

    2008-06-01

    Jaime Peraire Professor of Aeronautics and Astronautics Certified...faults are my own. In addition to my advisor, the other members of my thesis committee, Prof. Jaime Peraire and Prof. Mark Drela, also deserve considerable...er ro r p = 1 p = 2 p = 3 p = 4 (a) NS, Resolution switch × p = 40 80 160 320 10 −3 10 −2 10 −1 10 0 Elements L 1 er ro r p = 1 p = 2 p = 3

  12. 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.

  13. Generalized Anxiety Disorder: When Worry Gets Out of Control

    MedlinePlus

    ... GAD? Where can I find more information? Share Generalized Anxiety Disorder: When Worry Gets Out of Control Download PDF ... health, money, or family problems. But people with generalized anxiety disorder (GAD) feel extremely worried or feel nervous about ...

  14. 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.

  15. 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.

  16. Living With Anxiety Disorders, Worried Sick | NIH MedlinePlus the Magazine

    MedlinePlus

    ... his life with generalized anxiety disorder (GAD) and panic attacks, describes here how he sought help to turn ... was diagnosed with generalized anxiety disorder (GAD) including panic attacks. I discovered that my feelings were coming from ...

  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. 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…

  19. 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…

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. Authoritarian Decision-Making and Alternative Patterns of Power and Influence: The Mexican IBM Case

    DTIC Science & Technology

    1988-05-01

    Mercado de Valores 44, 37 (10 September 1984), pp. 926-929. 120. See Jaime Contreras, "Rechazo la CNIE la Solicitud de la IBM Para Instalar una...Interview with Alejandro del Toro, 5 March 1987. 65. Rodolfo Guerrero, "El Ingreso de IBM a Mexico generara divisas, empleos y desarollo: M. Kun...Jaime. "Rechazo la CNIE la SolIcitud de la IBM Para Instalar una Planta de Computadoras."Excelsior, 28 January 1985. El Financiero, "IBM Intends to

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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

  3. 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.

  4. [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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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...

  12. 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.

  13. 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…

  14. 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

  15. 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…

  16. 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…

  17. "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…

  18. 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.

  19. 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…

  20. 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…

  1. Efficient Training Methods for Conditional Random Fields

    DTIC Science & Technology

    2008-02-01

    Learning (ICML), 2007. [63] Bruce G. Lindsay. Composite likelihood methods. Contemporary Mathematics, pages 221–239, 1988. 189 [64] Yan Liu, Jaime ...Conference on Machine Learning (ICML), pages 737–744, 2005. [107] Erik F. Tjong Kim Sang and Sabine Buchholz. Introduction to the CoNLL-2000 shared task

  2. 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.

  3. 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;...

  4. 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…

  5. 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…

  6. 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…

  7. 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.

  8. 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

  9. 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

  10. 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

  11. 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…

  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. 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…

  15. 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…

  16. 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.

  17. 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.

  18. 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.

  19. Vector-mediated chromosomal integration of the glutamate decarboxylase gene in streptococcus thermophilus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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. ...

  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. 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.

  3. 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…

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  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. 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

  20. 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.

  1. Generalized anxiety disorder: connections with self-reported attachment.

    PubMed

    Cassidy, Jude; Lichtenstein-Phelps, June; Sibrava, Nicholas J; Thomas, Charles L; Borkovec, Thomas D

    2009-03-01

    Even though generalized anxiety disorder (GAD) is one of the most common of the anxiety disorders, relatively little is known about its precursors. Bowlby's attachment theory provides a framework within which these precursors can be considered. According to Bowlby, adult anxiety may be rooted in childhood experiences that leave a child uncertain of the availability of a protective figure in times of trouble.Furthermore, adult "current state of mind with respect to attachment" is thought to relate to adult anxiety. Both attachment-related components were assessed with 8 subscales of the Perceptions of Adult Attachment Questionnaire(PAAQ). Clinically severe GAD clients who were about to begin therapy reported experiencing less maternal love in childhood, greater maternal rejection/neglect, and more maternal role-reversal/enmeshment than did control participants.In keeping with a cumulative risk model, risk for GAD increased as indices of poor childhood attachment experience increased. GAD clients, in contrast to controls,also reported greater current vulnerability in relation to their mothers as well as more difficulty accessing childhood memories. Logistic regression analyses revealed that elevations on PAAQ subscales could significantly predict GAD vs.non-GAD status. Results and the implications for advancing the theory and treatment of GAD are discussed.

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. 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.

  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. 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

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. Latin America Report

    DTIC Science & Technology

    2007-11-02

    Investment Over More Debt (Jaime Contreras ; EXCELSIOR, 1 Oct 86) 81 Reform-Minded Attorney General Carrying Out Surprise Visits (LA JORNADA, 1 Oct 86...was its then president, Javier Bustamante Diaz. 25 Eduardo Mestre Sarmiento received a loan totaling 9,851,520 pesos from the Bank of the Workers...34Sincerely, "German Tabares Cardona, superintendent of banks" 26 JPRS-LAM-86-110 2 December 1986 Separately, Javier Bustamante Diaz, the president

  9. 78 FR 44943 - EcoEléctrica, L.P.; Notice of Application

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-25

    ... Energy Regulatory Commission EcoEl ctrica, L.P.; Notice of Application Take notice that on July 3, 2013, EcoEl ctrica, L.P. (EcoEl ctrica), Road 337, Km. 3.7, Bo. Tallaboa Poniente, Pe uelas, PR 00624, filed... directed to Jaime L. Sanabria, EcoEl ctrica, L.P., Road 337, Km. 3.7, Bo. Tallaboa Poniente, Pe uelas,...

  10. 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

  11. Symposium Proceedings on Intervention Programs Aimed at Increasing Minority Participation in Mathematics-Based Fields Held in Washington, DC on 27-28 May 1988

    DTIC Science & Technology

    1988-05-28

    whistling in the dark. Recently, I had a heartening experience, as I read of how a teacher of mathe- matics, Jaime Escalante . in a Los Angeles high school...taking this course. This story, revealed in the movie, Stand and Deliver, tells of the success of Mr. Escalante and his students. Their hard work paid off...offer some recommendations for corrective measures. There is no doubt, however, that we need more believers and doers like Mr. Escalante , and more hard

  12. 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

  13. Does a Longer Delay in Fixation of Talus Fractures Cause Osteonecrosis?

    DTIC Science & Technology

    2011-01-01

    Does a Longer Delay in Fixation of Talus Fractures Cause Osteonecrosis ? CPT Jaime L. Bellamy, DO,1 CDR John J. Keeling, MD,2 Joseph Wenke, PhD,3 LTC...and development of osteonecrosis and posttraumatic arthritis. The Joint Theater Trauma Registry was queried by ICD-9 codes for talus fractures...Soldiers, ages 18 to 40, with talus fracture between 2001 and 2008 were included. Radiographs identified the injury type, Hawkins sign, osteonecrosis , and

  14. Under the Shadow of the Big Stick: U.S. Intervention in Cuba, 1906-1909

    DTIC Science & Technology

    2009-05-21

    Cuba: From Columbus to Castro and Beyond, 4 th ed. (Washington D.C.: Pergamon- Brassey ‟ s International Defense Publishers, 1997), 155. 2 than the...Suchlicki, Jaime. Cuba: From Columbus to Castro and Beyond. 4 th ed. Washington, D.C.: Pergamon- Brassey ‟ s Internationl Defense Publishers, 1997...Intervention in Cuba, 1906- 1909 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR( S ) MAJ Bruce A. Vitor II 5d. PROJECT

  15. JPRS Report East Asia Southeast Asia

    DTIC Science & Technology

    2007-11-02

    Datuk Abdullah Badawi , who ran for the UMNO deputy presidency and ended runner-up. Mr T,im said that although the National Front won four-fifths of...also asked the Capcom chief, Brigadier General Alexander Aguirre, to provide the necessary training to barangay men who will be licensed to carry...Jaime Ferrer, saying that arming civilians was not a solution. On the other hand, Capcon [Captial Regional Command] Chief Brigadier General Alexander

  16. Design Optimization and Simulation of Wave Propagation in Metamaterials

    DTIC Science & Technology

    2014-09-24

    AFRL-OSR-VA-TR-2014-0232 Design Optimizations Simulation of Wave Propagation in Metamaterials Robert Freund MASSACHUSETTS INSTITUTE OF TECHNOLOGY...In Metamaterials FA9550-11-1-0141 FA9550-11-1-0141 Freund, Robert Peraire, Jaime Nguyen, Cuong Massachusetts Institute of Technology 77...cannot be achieved with conventional materials. For instance, metamaterials can be designed to bend electromagnetic waves around an object so that

  17. From Malicious Eyes: A Method for Concise Representation of Ad-Hoc Networks and Efficient Attack Survivability Analysis

    DTIC Science & Technology

    2012-07-01

    a modification of OSPF that is optimized for mobile ad-hoc networks . OSPFv3MDR uses IPv6 addressing. Topology. In attempts to achieve a suitable...From Malicious Eyes: A Method for Concise Representation of Ad-Hoc Networks and Efficient Attack Survivability Analysis by Jaime C. Acosta...White Sands Missile Range, NM 88002-5501 ARL-TR-6035 July 2012 From Malicious Eyes: A Method for Concise Representation of Ad-Hoc Networks

  18. University of California Conference on Statistical Mechanics (4th) Held March 26-28, 1990

    DTIC Science & Technology

    1990-03-28

    Martinez , Department of Physics, UC San Diego John McGrann, Department of Physics, UC Irvine David Mitchell, Joseph Henry Laboratory, Department of Physics...UC San Diego Bill Reynolds, INLS, UC San Diego Prof. Juan Carlos Reina, Department of Physics, Texas A & M University Joseph Rudnick, Department of...PHASE TRANSITION Jaime Ruiz Garcia, Doctor of Philosophy, 1989 Dissertation directed by: Sandra C. Greer Professor Department of Chemistry Recently

  19. 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.

  20. 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

  1. 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

  2. Cocaine. A Trans-National Issue

    DTIC Science & Technology

    1993-04-01

    economic challenges, and iresident Jaime Paz Zamora has continued a strict austerity program initiated by his predecessor Victor Paz Estenssoro...the Chapare region of Bolivia are the principal centers of cultivation. While there is a deep seated cultura : foundation for the cultivation and use...employed, then 50 percent or more of those employed in Bolivia benefit to some degree from coca cultivation. Jairae Paz Zamora has compared the impact on

  3. JPRS Report, West Europe.

    DTIC Science & Technology

    2007-11-02

    the chief of staff, Fernando Nardiz, and the chief of logistical backup, Jaime de Inclan y Giraldo, the most imporatant position will be that of the...needed. But at that time, Aeronautical Construction, Inc (CASA), the state aeronautics industry then headed by Fernando de Caralt, had not intended to...his predeces- sor , Carl Algernon, makes the job especially demanding. Important To Investigate Why "Somewhat naively I had hoped not to get bogged

  4. 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

  5. Escitalopram

    MedlinePlus

    Escitalopram is used to treat depression and generalized anxiety disorder (GAD; excessive worry and tension that disrupts daily life and lasts for 6 months or longer). Escitalopram is in a class of antidepressants ...

  6. Generalized anxiety disorder - children

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/007687.htm Generalized anxiety disorder - children To use the sharing features on this page, please enable JavaScript. Generalized anxiety disorder (GAD) is a mental disorder in which a ...

  7. Generalized anxiety disorder -- self-care

    MedlinePlus

    ... this page: //medlineplus.gov/ency/patientinstructions/000685.htm Generalized anxiety disorder - self-care To use the sharing features on this page, please enable JavaScript. Generalized anxiety disorder (GAD) is a mental condition in which you ...

  8. Generalized anxiety disorder

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/000917.htm Generalized anxiety disorder To use the sharing features on this page, please enable JavaScript. Generalized anxiety disorder (GAD) is a mental disorder in which a ...

  9. Heart rate and heart rate variability in panic, social anxiety, obsessive-compulsive, and generalized anxiety disorders at baseline and in response to relaxation and hyperventilation.

    PubMed

    Pittig, Andre; Arch, Joanna J; Lam, Chi W R; Craske, Michelle G

    2013-01-01

    It remains unclear if diminished high frequency heart rate variability (HF-HRV) can be found across anxiety disorders. HF-HRV and heart rate (HR) were examined in panic (PD), generalized anxiety (GAD), social anxiety (SAD), and obsessive-compulsive disorder (OCD) relative to healthy controls at baseline and during anxiety stressors. All disorders evidenced diminished baseline HF-HRV relative to controls. Baseline HRV differences were maintained throughout relaxation. For hyperventilation, PD and GAD demonstrated greater HR than controls. Psychotropic medication did not account for HF-HRV differences except in OCD. Age and sex evidenced multiple main effects. Findings suggest that low baseline HF-HRV represents a common index for inhibitory deficits across PD, GAD, and SAD, which is consistent with the notion of autonomic inflexibility in anxiety disorders. Elevated HR responses to hyperventilation, however, are specific to PD and GAD.

  10. 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

  11. Insomnia Symptoms Following Treatment for Comorbid Panic Disorder With Agoraphobia and Generalized Anxiety Disorder.

    PubMed

    Cousineau, Héloïse; Marchand, André; Bouchard, Stéphane; Bélanger, Claude; Gosselin, Patrick; Langlois, Frédéric; Labrecque, Joane; Dugas, Michel J; Belleville, Geneviève

    2016-04-01

    Patients with panic disorder with agoraphobia (PDA) or generalized anxiety disorder (GAD) frequently also suffer from insomnia. However, the impact of cognitive-behavioral therapy (CBT) for anxiety disorders on insomnia has been understudied. Furthermore, comorbidity between anxiety disorders is common. Our main objective was to assess the impact of CBT for PDA or GAD on insomnia. In a quasi-experimental design, 86 participants with PDA and GAD received conventional CBT for their primary disorder or combined CBT for both disorders. Overall, CBTs had a significant impact on reducing insomnia symptoms (η = 0.58). However, among people with insomnia at pretest (67%), 33% still had an insomnia diagnosis, and the majority (63%) had clinically significant residual insomnia following treatment. In conclusion, the CBTs had a positive effect on the reduction of insomnia, but a significant proportion of participants still had insomnia problems following treatment. Clinicians should address insomnia during CBT for PDA and GAD.

  12. The Social Interaction Phobia Scale: Continued support for the psychometric validity of the SIPS using clinical and non-clinical samples.

    PubMed

    Menatti, Alison R; Weeks, Justin W; Carleton, R Nicholas; Morrison, Amanda S; Heimberg, Richard G; Hope, Debra A; Blanco, Carlos; Schneier, Franklin R; Liebowitz, Michael R

    2015-05-01

    The present study sought to extend findings supporting the psychometric validity of a promising measure of social anxiety (SA) symptoms, the Social Interaction Phobia Scale (SIPS; Carleton et al., 2009). Analyses were conducted using three samples: social anxiety disorder (SAD) patients, generalized anxiety disorder (GAD) patients, and healthy controls. SIPS scores of SAD patients demonstrated internal consistency and construct validity, and the previously demonstrated three-factor structure of the SIPS was replicated. Further, the SIPS total score uniquely predicted SA symptoms, and SIPS scores were significantly higher for SAD patients than GAD patients or controls. Two cut-off scores that discriminated SAD patients from GAD patients and from healthy controls were identified. The current study is the first to replicate the SIPS three-factor model in a large, treatment-seeking sample of SAD patients and establish a cut-off score discriminating SAD from GAD patients. Findings support the SIPS as a valid, SAD-specific assessment instrument.

  13. Endogenous synthesis of taurine and GABA in rat ocular tissues.

    PubMed

    Heinämäki, A A

    1988-01-01

    The endogenous production of taurine and gamma-aminobutyric acid (GABA) in rat ocular tissues was investigated. The activities of taurine-producing enzyme, cysteine sulfinic acid decarboxylase (CSAD), and GABA-synthesizing enzyme, glutamic acid decarboxylase (GAD), were observed in the retina, lens, iris-ciliary body and cornea. The highest specific activity of CSAD was in the cornea and that of GAD in the retina. The discrepancy between CSAD activity and taurine content within the ocular tissues indicates that intra- or extraocular transport processes may regulate the concentration of taurine in the rat eye. The GAD activity and the content of GABA were distributed in parallel within the rat ocular tissues. The quantitative results suggest that the GAD/GABA system has functional significance only in the retina of the rat eye.

  14. Gabor-based anisotropic diffusion for speckle noise reduction in medical ultrasonography.

    PubMed

    Zhang, Qi; Han, Hong; Ji, Chunhong; Yu, Jinhua; Wang, Yuanyuan; Wang, Wenping

    2014-06-01

    In ultrasound (US), optical coherence tomography, synthetic aperture radar, and other coherent imaging systems, images are corrupted by multiplicative speckle noise that obscures image interpretation. An anisotropic diffusion (AD) method based on the Gabor transform, named Gabor-based anisotropic diffusion (GAD), is presented to suppress speckle in medical ultrasonography. First, an edge detector using the Gabor transform is proposed to capture directionality of tissue edges and discriminate edges from noise. Then the edge detector is embedded into the partial differential equation of AD to guide the diffusion process and iteratively denoise images. To enhance GAD's adaptability, parameters controlling diffusion are determined from a fully formed speckle region that is automatically detected. We evaluate the GAD on synthetic US images simulated with three models and clinical images acquired in vivo. Compared with seven existing speckle reduction methods, the GAD is superior to other methods in terms of noise reduction and detail preservation.

  15. Opsoclonus-myoclonus-ataxia syndrome with autoantibodies to glutamic acid decarboxylase.

    PubMed

    Markakis, Ioannis; Alexiou, Eleni; Xifaras, Michael; Gekas, Georgios; Rombos, Antonios

    2008-06-01

    Opsoclonus-myoclonus-ataxia syndrome (OMS) is a rare neurological disorder of probably autoimmune origin. Most cases are associated with a remote neoplasm or a viral infection; however in some instances no underlying aetiology can be demonstrated. We report the presence of anti-glutamic acid decarboxylase antibodies (anti-GAD Abs) in the serum and CSF of a patient with idiopathic OMS. Treatment with intravenous immunoglobulin led to a remarkable clinical improvement with parallel reduction of anti-GAD titers. Anti-GAD Abs have been associated with several neurological syndromes. They could also be responsible for the clinical triad of OMS, by impairing GABAergic transmission in specific brainstem and cerebellar circuits. We propose that testing for anti-GAD Abs should be performed in OMS, especially when no other aetiological association can be demonstrated.

  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. The Feasibility, Acceptability, and Efficacy of Delivering Internet-Based Self-Help and Guided Self-Help Interventions for Generalized Anxiety Disorder to Indian University Students: Design of a Randomized Controlled Trial

    PubMed Central

    Newman, Michelle G; Ruzek, Josef I; Kuhn, Eric; Manjula, M; Jones, Megan; Thomas, Neil; Abbott, Jo-Anne M; Sharma, Smita; Taylor, C. Barr

    2015-01-01

    Background Generalized anxiety disorder (GAD) is one of the most common mental disorders among university students; however, many students go untreated due to treatment costs, stigma concerns, and limited access to trained mental health professionals. These barriers are heightened in universities in India, where there are scant mental health care services and severe stigma surrounding help seeking. Objective To evaluate the feasibility, acceptability, and efficacy of Internet-based, or “online,” cognitive behavioral therapy (CBT)-based unguided and guided self-help interventions (using the programs GAD Online and Lantern, respectively) to reduce GAD symptoms in students with clinical and subthreshold GAD and, ultimately, reduce the prevalence and incidence of GAD among the student population. Methods Students will be recruited via 3 colleges in Hyderabad, India, and referred for a campus-wide online screening. Self-report data will be collected entirely online. A total of 300 qualifying students will be randomized in a 1:1:1 ratio to receive GAD Online, Lantern, or to be in a wait-list control condition, stratified by clinical and subthreshold GAD symptomatology. Students will complete a postintervention assessment after 3 months and a follow-up assessment 6 months later, at which point students in the wait-list control condition will receive one of the programs. The primary outcome is GAD symptom severity at 3 months postintervention. Secondary outcomes include GAD caseness at 9 months, other anxiety and depression symptoms, self-efficacy, and functional measures (eg, sleep, social functioning) at 3 and 9 months, respectively. Primary analyses will be differences between each of the intervention groups and the wait-list control group, analyzed on an intention-to-treat (ITT) basis using mixed-design ANOVA. Results The study commenced in February 2015. The sample was recruited over a 3-week period at each college. The trial is expected to end in December 2015

  18. A literature review of quetiapine for generalized anxiety disorder.

    PubMed

    Kreys, Tiffany-Jade M; Phan, Stephanie V

    2015-02-01

    To evaluate the efficacy and tolerability of quetiapine for the treatment of generalized anxiety disorder (GAD), a literature search of the Medline database was conducted from inception to May 2014. The search was not restricted by language. Keywords used in the search were quetiapine and generalized anxiety disorder or anxiety. All studies assessing the use of quetiapine as monotherapy or adjunct therapy for the primary management of GAD in adults 18-65 years of age were included in this review. The nine studies included in this review were three studies evaluating the use of quetiapine extended release (XR) as monotherapy for acute GAD treatment, one study evaluating quetiapine XR monotherapy for maintenance treatment of GAD, and five studies evaluating quetiapine (2 XR, 3 immediate release) as adjunct therapy for acute GAD treatment. Quetiapine displayed both efficacy and tolerability in all monotherapy trials evaluating its use for acute and long-term treatment of GAD. Despite some limitations to and heterogeneity among the five adjunct therapy studies, three studies showed that quetiapine resulted in statistically significant changes in the Hamilton Anxiety Rating Scale or Clinical Global Impressions-Severity of Illness Scale scores. Although future studies of longer duration with broader inclusion criteria are needed to further evaluate the benefits and risks of quetiapine for GAD, in patients failing to respond to conventional antidepressant therapy, quetiapine may be a potential treatment option. With appropriate monitoring and management of adverse effects, the potential benefits of quetiapine in patients with treatment-refractory GAD may outweigh the risks associated with its use.

  19. Study of Life Events and Personality Dimensions in Generalized Anxiety Disorder

    PubMed Central

    2016-01-01

    Introduction Life events, recognized as stressors, due to their unanticipated nature, can cause psychiatric illness. Also there is some line of continuity between neurotic illness and antecedent personality traits. Aim To study generalized anxiety disorder in relation to Life events and personality dimensions. Materials and Methods Certain hypotheses were tested in two groups, namely 30 Generalized Anxiety Disorder patients (GAD) and 30 matched controls, by utilizing assessment tools. These include: GAD patients experience more undesirable Life events than normal; GAD patients with high level of anxiety experience more undesirable Life events; Neuroticism is related to the severity of anxiety; Extroverts experience more anxiety; Level of anxiety in females is higher; GAD patients with higher education level experience more anxiety, while those with lower education level somatize more. The group differences were examined using Chi-Square test, Student t-test and ANOVA. Pearson’s Correlation Co-efficient was used to find the correlation between anxiety and the undesirable Life events. The level of statistical significance was set at p<0.05. Results GAD patients experienced significantly more undesirable Life events than the matched controls. Patients with high level of anxiety experienced more undesirable Life events, with the coefficient of correlation being quite high. A significant association between Neuroticism scale and GAD was observed. Conclusion The study suggests a possible causative link between the undesirable Life events and GAD; and a significant association between Neuroticism dimension and the anxiety disorder. Role of environmental stressors and personality traits in treatment outcome among GAD patients awaits further, prospective studies. PMID:27190927

  20. Reduction in memory in passive avoidance learning, exploratory behaviour and synaptic plasticity in mice with a spontaneous deletion in the ubiquitin C-terminal hydrolase L1 gene.

    PubMed

    Sakurai, Mikako; Sekiguchi, Masayuki; Zushida, Ko; Yamada, Kazuyuki; Nagamine, Satoshi; Kabuta, Tomohiro; Wada, Keiji

    2008-02-01

    Overexpression of ubiquitin C-terminal hydrolase L1 (UCH-L1) in mice rescues amyloid beta-protein-induced decreases in synaptic plasticity and memory. However, the physiological role of UCH-L1 in the brain is not fully understood. In the present study, we investigated the role of UCH-L1 in the brain by utilizing gracile axonal dystrophy (gad) mice with a spontaneous deletion in the gene Uch-l1 as a loss-of-function model. Although gad mice exhibit motor paresis beginning at approximately 12 weeks of age, it is possible to analyse their brain phenotypes at a younger age when no motor paresis is evident. Maintenance of memory in a passive avoidance test and exploratory behaviour in an open field test were reduced in 6-week-old gad mice. The maintenance of theta-burst stimulation-induced long-term potentiation (LTP) of field synaptic responses from Schaffer collaterals to CA1 pyramidal cells in hippocampal slices was also impaired in gad mice. The LTP in gad mice was insensitive to actinomycin D, suggesting that a transcription-dependent component of the LTP is impaired. Phosphorylation of cyclic AMP response element binding protein (CREB) in the CA1 region of hippocampal slices from gad mice occurred earlier than in the slices from wild-type mice and was transient, suggesting that CREB phosphorylation is altered in gad mice. These results suggest that memory in passive avoidance learning, exploratory behaviour and hippocampal CA1 LTP are reduced in gad mice. We propose that UCH-L1-mediated maintenance of the temporal integrity and persistence of CREB phosphorylation underlies these impairments.

  1. Autoreactive Human TCR Initiate Insulitis and Impaired Glucose Tolerance in HLA DR4 Transgenic Mice

    PubMed Central

    Gebe, John A.; Unrath, Kellee A.; Yue, Betty B.; Miyake, Tom; Falk, Ben A.; Nepom, Gerald T.

    2008-01-01

    A human TcR derived from an autoreactive T cell specific for GAD65, from a subject at high risk for autoimmune diabetes, was introduced into HLA-DR4 transgenic mice. The source of TCR was a CD4+ TH1+T cell clone which responded to an immunodominant epitope of the human islet protein GAD65, an epitope shared with both GAD65 and GAD67 in the mouse. The resulting HLA-DR4/GAD-TcR transgenic mice on a Rag2o/o/I-Abo/o/B6 background exhibited a CD4+ infiltrate into pancreatic islets that correlated with a loss of insulin in infiltrated islets. These mice also exhibited a subclinical impaired tolerance to exogenously fed glucose as assayed by an intraperitoneal glucose tolerance test. T cells containing the GAD65/67 (555–567) responsive TcR undergo strong negative selection as evidenced by a 10-fold lower thymocyte cellularity compared to non-TcR transgenic mice, and clonotype peripheral T cells represented approximately 1 percent of CD4+ T cells in Rag2 sufficient mice. Upon in vitro stimulation, GAD65/67 555–567 responsive T cells secrete IFN-γ, minimal IL2 and TNFα and no IL4, IL5, IL10, or IL17, consistent with a TH1 profile. These data demonstrate that CD4+ T cells specific for a naturally processed epitope within GAD can specifically home to pancreatic islets and lead to impaired islet beta cell function in diabetes-associated HLA-DR4 transgenic mice on the relatively non-autoimmune C57BL/6 background. The relatively slow progression and patchy insulitis are reminiscent of the chronic pre-clinical phase similar to a majority of human at-risk subjects, and models these indolent features of human T1D. PMID:17949947

  2. Overexpression and optimization of glutamate decarboxylase in Lactobacillus plantarum Taj-Apis362 for high gamma-aminobutyric acid production

    PubMed Central

    Tajabadi, Naser; Baradaran, Ali; Ebrahimpour, Afshin; Rahim, Raha A; Bakar, Fatimah A; Manap, Mohd Yazid A; Mohammed, Abdulkarim S; Saari, Nazamid

    2015-01-01

    Gamma-aminobutyric acid (GABA) is an important bioactive compound biosynthesized by microorganisms through decarboxylation of glutamate by glutamate decarboxylase (GAD). In this study, a full-length GAD gene was obtained by cloning the template deoxyribonucleic acid to pTZ57R/T vector. The open reading frame of the GAD gene showed the cloned gene was composed of 1410 nucleotides and encoded a 469 amino acids protein. To improve the GABA-production, the GAD gene was cloned into pMG36e-LbGAD, and then expressed in Lactobacillus plantarum Taj-Apis362 cells. The overexpression was confirmed by SDS-PAGE and GAD activity, showing a 53 KDa protein with the enzyme activity increased by sevenfold compared with the original GAD activity. The optimal fermentation conditions for GABA production established using response surface methodology were at glutamic acid concentration of 497.973 mM, temperature 36°C, pH 5.31 and time 60 h. Under the conditions, maximum GABA concentration obtained (11.09 mM) was comparable with the predicted value by the model at 11.23 mM. To our knowledge, this is the first report of successful cloning (clone-back) and overexpression of the LbGAD gene from L. plantarum to L. plantarum cells. The recombinant Lactobacillus could be used as a starter culture for direct incorporation into a food system during fermentation for production of GABA-rich products. PMID:25757029

  3. Aging in the rat hippocampus is associated with widespread reductions in the number of glutamate decarboxylase-67 positive interneurons but not interneuron degeneration.

    PubMed

    Stanley, Dirk P; Shetty, Ashok K

    2004-04-01

    Increased excitability of principal excitatory neurons is one of the hallmarks of aging in the hippocampus, signifying a diminution in the number and/or function of inhibitory interneurons with aging. To elucidate this, we performed comprehensive GABA-ergic interneuron cell counts in all layers of the dentate gyrus and the CA1 and CA3 subfields, using serial sections from adult, middle-aged and aged Fischer 344 rats. Sections were immunostained for glutamate decarboxylase-67 (GAD-67, a synthesizing enzyme of GABA) and GAD-67 immunopositive interneurons were counted using an unbiased cell counting method, the optical fractionator. Substantial declines in the absolute number of GAD-67 immunopositive interneurons were found in all hippocampal layers/subfields of middle-aged and aged animals, in comparison with the adult animals. However, the counts were comparable between the middle-aged and aged groups for all regions. Interestingly, determination of the absolute number of interneurons using neuron-specific nuclear antigen (NeuN) expression in the strata oriens and radiatum of CA1 and CA3 subfields revealed an analogous number of interneurons across the three age groups. Furthermore, the ratio of GAD-67 immunopositive and NeuN positive interneurons decreased from adult age to middle age but remained relatively static between middle age and old age. Collectively, the results underscore that aging in the hippocampus is associated with wide-ranging decreases in the number of GAD-67 immunopositive interneurons and most of the age-related changes in GAD-67 immunopositive interneuron numbers transpire by middle age. Additionally, this study provides novel evidence that age-related reductions in hippocampal GAD-67 immunopositive interneuron numbers are due to loss of GAD-67 expression in interneurons rather than interneuron degeneration.

  4. Posttraumatic stress disorder's dysphoria dimension and relations with generalized anxiety disorder symptoms.

    PubMed

    Durham, Tory A; Elhai, Jon D; Fine, Thomas H; Tamburrino, Marijo; Cohen, Gregory; Shirley, Edwin; Chan, Philip K; Liberzon, Israel; Galea, Sandro; Calabrese, Joseph R

    2015-07-30

    The present study investigated symptom relations between two highly comorbid disorders--posttraumatic stress disorder (PTSD) and generalized anxiety disorder (GAD)--by exploring their underlying dimensions. Based on theory and prior empirical research it was expected that the dysphoria factor of PTSD would be more highly related to GAD. As part of a longitudinal project of mental health among Ohio National Guard Soldiers, 1266 subjects were administered the Posttraumatic Stress Disorder Checklist (PCL) and Generalized Anxiety Disorder-7 scale (GAD-7). Confirmatory factor analyses (CFAs) were conducted to examine two models of PTSD and to determine which PTSD factors were more related to the GAD factor. The results indicate that the GAD factor was significantly more highly correlated with PTSD's dysphoria factor than with all other PTSD factors, including PTSD's reexperiencing factor, avoidance factor, and hyperarousal factor. Results indicate GAD was not significantly more highly correlated with numbing than most other factors of PTSD. The results are consistent with prior research. Implications of the results are discussed in regards to PTSD in DSM-5, comorbidity and diagnostic specificity.

  5. Reliability and validity of DSM-IV generalized anxiety disorder features.

    PubMed

    Gordon, Dina; Heimberg, Richard G

    2011-08-01

    The reliability of generalized anxiety disorder (GAD) features has been shown to be moderate, based on research utilizing the Anxiety Disorders Interview Schedule for DSM-IV (ADIS-IV), a semi-structured diagnostic interview. This may be a function of the criteria for the diagnosis of GAD, which have undergone much revision since its first inclusion in the Diagnostic and Statistical Manual of Mental Disorders. The reliability and validity of disorder feature ratings were examined in a diverse sample of patients who presented for assessment and treatment of excessive worry, generalized anxiety, or tension at an anxiety specialty clinic and who met criteria for a principal diagnosis of GAD (N=129). Internal consistency of the ratings of excessiveness of worry, uncontrollability of worry, and the associated symptom cluster was moderate to low and varied by disorder feature. Inter-rater reliability for all features of GAD and severity of the disorder varied between good and poor. Additional findings showed that the GAD features, as measured using the ADIS-IV module, have modest to strong convergent validity, varying by feature, and poor discriminant validity when tested against measures of social anxiety. Potential reasons for rater disagreement are discussed. Results are also considered in terms of how they may inform the evolving criteria for GAD in DSM-V.

  6. Primary Versus Secondary Diagnosis of Generalized Anxiety Disorder in Youth: Is the Distinction an Important One?

    PubMed

    Ollendick, Thomas H; Jarrett, Matthew A; White, Bradley A; White, Susan W; Grills, Amie E

    2016-08-01

    Examine whether children with a primary diagnosis of generalized anxiety disorder (GAD) differ from children with a secondary diagnosis of GAD on clinician, parent, teacher, and youth-report measures. Based on consensus diagnoses, 64 youth referred to a general outpatient assessment clinic were categorized as having either a primary or secondary diagnosis of GAD. A semi-structured diagnostic interview was used to guide diagnostic decisions and assign primary versus secondary diagnostic status. We predicted that youth with a primary GAD diagnosis would present with greater anxiety symptomatology and symptom impairment on a variety of anxiety-related measures than youth with a secondary GAD diagnosis. Contrary to our hypotheses, no differences were found between those with primary versus secondary GAD diagnoses on measures of symptom severity and clinical impairment, comorbid diagnoses, or youth and teacher-report measures. Our findings have potential implications for the current practice of requiring primary anxiety diagnostic status as an inclusion criterion in clinical research and treatment outcome studies. Assuming our findings are confirmed in larger samples and with other anxiety disorders, future clinical trials and basic psychopathology research might not exclude youth based on absence of a particular anxiety disorder as the primary disorder but rather include individuals for whom that anxiety disorder is secondary as well.

  7. Inhibition of parvalbumin-expressing interneurons results in complex behavioral changes.

    PubMed

    Brown, J A; Ramikie, T S; Schmidt, M J; Báldi, R; Garbett, K; Everheart, M G; Warren, L E; Gellért, L; Horváth, S; Patel, S; Mirnics, Károly

    2015-12-01

    Reduced expression of the Gad1 gene-encoded 67-kDa protein isoform of glutamic acid decarboxylase (GAD67) is a hallmark of schizophrenia. GAD67 downregulation occurs in multiple interneuronal sub-populations, including the parvalbumin-positive (PVALB+) cells. To investigate the role of the PV-positive GABAergic interneurons in behavioral and molecular processes, we knocked down the Gad1 transcript using a microRNA engineered to target specifically Gad1 mRNA under the control of Pvalb bacterial artificial chromosome. Verification of construct expression was performed by immunohistochemistry. Follow-up electrophysiological studies revealed a significant reduction in γ-aminobutyric acid (GABA) release probability without alterations in postsynaptic membrane properties or changes in glutamatergic release probability in the prefrontal cortex pyramidal neurons. Behavioral characterization of our transgenic (Tg) mice uncovered that the Pvalb/Gad1 Tg mice have pronounced sensorimotor gating deficits, increased novelty-seeking and reduced fear extinction. Furthermore, NMDA (N-methyl-d-aspartate) receptor antagonism by ketamine had an opposing dose-dependent effect, suggesting that the differential dosage of ketamine might have divergent effects on behavioral processes. All behavioral studies were validated using a second cohort of animals. Our results suggest that reduction of GABAergic transmission from PVALB+ interneurons primarily impacts behavioral domains related to fear and novelty seeking and that these alterations might be related to the behavioral phenotype observed in schizophrenia.

  8. Gamma-aminobutric acid and glutamate decarboxylas (l-glutamate 1-carboxy-lyase e.c. 4.1.1.15) in the nervous system of the cockroach, periplaneta americana.i.regional distribution and properties of the enzyme.

    PubMed

    Baxter, C F; Torralba, G F

    1975-02-14

    Both the central and peripheral nervous system of the cockroach Periplaneta americana contain gamma-aminobutyric acid (GABA) and glutamate decarboxylase (GAD). In the central ganglia of the cockroach, an average of more that 60 mumoles of GABA are formed from glutamate (Glu) per gram wet weight of tissue per hour. This activity level of the GAD apoenzyme is considerably higher than that found in the central nervous system of crustaceans, amphibians, avians and mammals but is similar to that reported for nervous system tissues from other insect species. A comparison of properties of the crude cockroach enzyme with GAD from crustacean and mammalian origin revealed both similarities and differences: whereas crude cockroach GAD has cofactor requirements and an affinity for Glu substrate (Km 2.8 X 10-2) which are similar to GAD from lobster and mouse, it is uniquely inhibited by both Cl-and by GABA. The GAD from cockroach nervous tissues has two apparent pH optima of which the lower one is preferentially inhibited by a compound which is found in the nerve sheath and the fat body tissue adjacent to ganglia and axons.

  9. Longitudinal associations between perceived parent-adolescent attachment relationship quality and generalized anxiety disorder symptoms in adolescence.

    PubMed

    van Eijck, Fenna E A M; Branje, Susan J T; Hale, William W; Meeus, Wim H J

    2012-08-01

    This longitudinal study examined the direction of effects between adolescents' generalized anxiety disorder (GAD) symptoms and perceived parent-adolescent attachment relationship quality, as well as the moderating role of gender and age. 1,313 Dutch adolescents (48.5% boys) from two age cohorts of early (n = 923, M(age) = 12 at W1) and middle (n = 390, M(age) = 16 at W1) adolescents completed questionnaires regarding their attachment relationship to parents and GAD symptoms in four waves. Cross-lagged path analyses demonstrated that adolescents' GAD symptoms and perceived father-adolescent attachment relationship quality bidirectionally negatively affected each other over time. For mothers, adolescents' GAD symptoms negatively predicted perceived mother-adolescent attachment relationship quality over time. The within-wave correlated residuals between perceived attachment relationship quality with fathers and GAD symptoms were stronger for boys than for girls and stronger for the cohort of middle adolescents than for the cohort of early adolescents. This study demonstrates that both the parents' and the adolescents' gender as well as the adolescents' age affects the relation between adolescents' GAD symptoms and perceived parent-adolescent attachment relationship quality.

  10. Cognitive load and emotional processing in generalized anxiety disorder: electrocortical evidence for increased distractibility.

    PubMed

    MacNamara, Annmarie; Proudfit, Greg Hajcak

    2014-08-01

    Generalized anxiety disorder (GAD) may be characterized by emotion regulation deficits attributable to an imbalance between top-down (i.e., goal-driven) and bottom-up (i.e., stimulus-driven) attention. In prior work, these attentional processes were examined by presenting unpleasant and neutral pictures within a working memory paradigm. The late positive potential (LPP) measured attention toward task-irrelevant pictures. Results from this prior work showed that working memory load reduced the LPP across participants; however, this effect was attenuated for individuals with greater self-reported state anxiety, suggesting reduced top-down control. In the current study, the same paradigm was used with 106 medication-free female participants-71 with GAD and 35 without GAD. Unpleasant pictures elicited larger LPPs, and working memory load reduced the picture-elicited LPP. Compared with healthy controls, participants with GAD showed large LPPs to unpleasant pictures presented under high working memory load. Self-reported symptoms of anhedonic depression were related to a reduced effect of working memory load on the LPP elicited by neutral pictures. These results indicate that individuals with GAD show less flexible modulation of attention when confronted with unpleasant stimuli. Furthermore, among those with GAD, anhedonic depression may broaden attentional deficits to neutral distracters.

  11. Preliminary evidence for a role of the adrenergic nervous system in generalized anxiety disorder.

    PubMed

    Zhang, Xiaobin; Norton, Joanna; Carrière, Isabelle; Ritchie, Karen; Chaudieu, Isabelle; Ryan, Joanne; Ancelin, Marie-Laure

    2017-02-15

    Generalized anxiety disorder (GAD) is a common chronic condition that is understudied compared to other psychiatric disorders. An altered adrenergic function has been reported in GAD, however direct evidence for genetic susceptibility is missing. This study evaluated the associations of gene variants in adrenergic receptors (ADRs) with GAD, with the involvement of stressful events. Data were obtained from 844 French community-dwelling elderly aged 65 or over. Anxiety disorders were assessed using the Mini-International Neuropsychiatry Interview, according to DSM-IV criteria. Eight single-nucleotide polymorphisms (SNPs) involved with adrenergic function were genotyped; adrenergic receptors alpha(1A) (ADRA1A), alpha(2A) (ADRA2A), and beta2 (ADRB2) and transcription factor TCF7L2. Questionnaires evaluated recent stressful life events as well as early environment during childhood and adolescence. Using multivariate logistic regression analyses four SNPs were significantly associated with GAD. A 4-fold modified risk was found with ADRA1A rs17426222 and rs573514, and ADRB2 rs1042713 which remained significant after Bonferroni correction. Certain variants may moderate the effect of adverse life events on the risk of GAD. Replication in larger samples is needed due to the small case number. This is the first study showing that ADR variants are susceptibility factors for GAD, further highlighting the critical role of the adrenergic nervous system in this disorder.

  12. Activators of the Glutamate-Dependent Acid Resistance System Alleviate Deleterious Effects of YidC Depletion in Escherichia coli▿

    PubMed Central

    Yu, Zhong; Bekker, Martijn; Tramonti, Angela; Cook, Gregory M.; van Ulsen, Peter; Scheffers, Dirk-Jan; de Mattos, Joost Teixeira; De Biase, Daniela; Luirink, Joen

    2011-01-01

    The function of the essential inner membrane protein (IMP) YidC in Escherichia coli has been studied for a limited number of model IMPs and primarily using targeted approaches. These studies suggested that YidC acts at the level of insertion, folding, and quality control of IMPs, both in the context of the Sec translocon and as a separate entity. To further our understanding of YidC's role in IMP biogenesis, we screened a random overexpression library for factors that rescued the growth of cells upon YidC depletion. We found that the overexpression of the GadX and GadY regulators of the glutamate-dependent acid resistance system complemented the growth defect of YidC-depleted cells. Evidence is presented that GadXY overexpression counteracts the deleterious effects of YidC depletion on at least two fronts. First, GadXY prepares the cells for the decrease in respiratory capacity upon the depletion of YidC. Most likely, GadXY-regulated processes reduce the drop in proton-motive force that impairs the fitness of YidC-depleted cells. Second, in GadXY-overproducing cells increased levels of the general chaperone GroEL cofractionate with the inner membranes, which may help to keep newly synthesized inner membrane proteins in an insertion-competent state when YidC levels are limiting. PMID:21216990

  13. Impairment and Functioning in a Sample of Primary Care Patients With Generalized Anxiety Disorder: Results From the Primary Care Anxiety Project

    PubMed Central

    Beard, Courtney; Pagano, Maria E.; Maki, Kristin M.; Culpepper, Larry; Keller, Martin B.

    2010-01-01

    Objective: To examine the extent of functional impairment associated with generalized anxiety disorder (GAD) in a sample of primary care patients. Method: Participants (N = 128) were part of the Primary Care Anxiety Project (PCAP), a study conducted in 15 primary care practices in the northeastern United States. Patients were recruited in primary care practice waiting rooms from July 1997 to May 2001. Participants screening positive for anxiety symptoms received a diagnostic interview and an assessment of health-related functioning (Medical Outcomes Study 36-item Short-Form Health Survey [SF-36]). Effect sizes are reported for comparisons of SF-36 scores between patients with a DSM-IV diagnosis of GAD and general population and medical sample norms. Results: Relative to general population normative SF-36 scores, primary care patients with GAD evidenced impaired functioning on both the physical and mental component summary scales. Patients with GAD also evidenced greater impairment in psychosocial functioning than that previously reported for samples of patients with major medical illnesses, including type II diabetes, hypertension, recent myocardial infarction, and congestive heart failure. This finding held true even when GAD patients with comorbid medical illnesses and comorbid Axis I mental disorders were excluded from the comparison. Conclusions: Primary care patients with GAD experience substantial impairment that cannot be accounted for by concurrent medical illnesses or comorbid Axis I mental disorders. PMID:21274362

  14. Characterization of glutamate decarboxylase from Lactobacillus plantarum and its C-terminal function for the pH dependence of activity.

    PubMed

    Shin, Sun-Mi; Kim, Hana; Joo, Yunhye; Lee, Sang-Jae; Lee, Yong-Jik; Lee, Sang Jun; Lee, Dong-Woo

    2014-12-17

    The gadB gene encoding glutamate decarboxylase (GAD) from Lactobacillus plantarum was cloned and expressed in Escherichia coli. The recombinant enzyme exhibited maximal activity at 40 °C and pH 5.0. The 3D model structure of L. plantarum GAD proposed that its C-terminal region (Ile454-Thr468) may play an important role in the pH dependence of catalysis. Accordingly, C-terminally truncated (Δ3 and Δ11 residues) mutants were generated and their enzyme activities compared with that of the wild-type enzyme at different pH values. Unlike the wild-type GAD, the mutants showed pronounced catalytic activity in a broad pH range of 4.0-8.0, suggesting that the C-terminal region is involved in the pH dependence of GAD activity. Therefore, this study may provide effective target regions for engineering pH dependence of GAD activity, thereby meeting industrial demands for the production of γ-aminobutyrate in a broad range of pH values.

  15. The language of worry: examining linguistic elements of worry models.

    PubMed

    Geronimi, Elena M C; Woodruff-Borden, Janet

    2015-01-01

    Despite strong evidence that worry is a verbal process, studies examining linguistic features in individuals with generalised anxiety disorder (GAD) are lacking. The aim of the present study is to investigate language use in individuals with GAD and controls based on GAD and worry theoretical models. More specifically, the degree to which linguistic elements of the avoidance and intolerance of uncertainty worry models can predict diagnostic status was analysed. Participants were 19 women diagnosed with GAD and 22 control women and their children. After participating in a diagnostic semi-structured interview, dyads engaged in a free-play interaction where mothers' language sample was collected. Overall, the findings provided evidence for distinctive linguistic features of individuals with GAD. That is, after controlling for the effect of demographic variables, present tense, future tense, prepositions and number of questions correctly classified those with GAD and controls such that a considerable amount of the variance in diagnostic status was explained uniquely by language use. Linguistic confirmation of worry models is discussed.

  16. Globular adiponectin elicits neuroprotection by inhibiting NADPH oxidase-mediated oxidative damage in ischemic stroke.

    PubMed

    Song, W; Huo, T; Guo, F; Wang, H; Wei, H; Yang, Q; Dong, H; Wang, Q; Xiong, L

    2013-09-17

    Recent studies indicate that adiponectin can attenuate cerebral ischemic lesions via its functional area located in the C-terminal globular domain, which is called globular adiponectin (gAD). However, the mechanisms underlying this action remain unclear. In this study, we investigated the antioxidant properties of gAD during cerebral ischemia. Adult male C57BL/6 mice received an intracerebral injection of gAD with or without tetrabromocinnamic acid (TBCA, a NADPH oxidase activator). Mice were subjected to middle cerebral artery occlusion (MCAO) after gAD injection. Infarct volume, neurological function, the activity of antioxidant enzymes (superoxide dismutase [SOD], catalase), the content of malondialdehyde (MDA), and the expression of Bax, Bcl-2, cleaved caspase-3 and NADPH oxidase 2 (NOX2) were examined at 24h after MCAO. Infarct volume was attenuated in gAD-transduced mice when compared with mice in the MCAO group, with significant improvement in neurological function. In addition, neuronal apoptosis was attenuated, along with the expression of Bax/Bcl-2 and cleaved caspase 3. Furthermore, the activities of SOD and catalase increased, and the content of MDA reduced. However, TBCA blocked the effect of gAD on cerebral protection and its antioxidant abilities. Taken together, these results demonstrate that the neuroprotective action of gAD may result from the promotion of antioxidant capacity by inhibiting the NOX2 signaling system.

  17. Expanding the active pH range of Escherichia coli glutamate decarboxylase by breaking the cooperativeness.

    PubMed

    Thu Ho, Ngoc Anh; Hou, Chen Yuan; Kim, Woo Hyun; Kang, Taek Jin

    2013-02-01

    Bacterial glutamate decarboxylase (GAD) transforms glutamate into γ-aminobutyric acid (GABA) with the consumption of a proton. The enzyme is active under acidic environments only and sharply loses its activity as pH approaches neutrality with concomitant structural deformation. In an attempt to understand better the role of this cooperative loss of activity upon pH shifts, we prepared and studied a series of GAD site-specific mutants. In this report, we show that the cooperativeness was kept intact by at least two residues, Glu89 and His465, of which Glu89 is newly identified to be involved in the cooperativity system of GAD. Double mutation on these residues not only broke the cooperativity in the activity change but also yielded a mutant GAD that retained the activity at neutral pH. The resulting mutant GAD that was active at neutral pH inhibited the cell growth in a glycerol medium by converting intracellular Glu into GABA in an uncontrolled manner, which explains in part why the cooperativeness of GAD has to be kept by several layers of safety keepers. This unexpected result might be utilized to convert a low-valued by-product of biodiesel production, glycerol, into value-added product, GABA.

  18. Preliminary evidence for a role of the adrenergic nervous system in generalized anxiety disorder

    PubMed Central

    Zhang, Xiaobin; Norton, Joanna; Carrière, Isabelle; Ritchie, Karen; Chaudieu, Isabelle; Ryan, Joanne; Ancelin, Marie-Laure

    2017-01-01

    Generalized anxiety disorder (GAD) is a common chronic condition that is understudied compared to other psychiatric disorders. An altered adrenergic function has been reported in GAD, however direct evidence for genetic susceptibility is missing. This study evaluated the associations of gene variants in adrenergic receptors (ADRs) with GAD, with the involvement of stressful events. Data were obtained from 844 French community-dwelling elderly aged 65 or over. Anxiety disorders were assessed using the Mini-International Neuropsychiatry Interview, according to DSM-IV criteria. Eight single-nucleotide polymorphisms (SNPs) involved with adrenergic function were genotyped; adrenergic receptors alpha(1A) (ADRA1A), alpha(2A) (ADRA2A), and beta2 (ADRB2) and transcription factor TCF7L2. Questionnaires evaluated recent stressful life events as well as early environment during childhood and adolescence. Using multivariate logistic regression analyses four SNPs were significantly associated with GAD. A 4-fold modified risk was found with ADRA1A rs17426222 and rs573514, and ADRB2 rs1042713 which remained significant after Bonferroni correction. Certain variants may moderate the effect of adverse life events on the risk of GAD. Replication in larger samples is needed due to the small case number. This is the first study showing that ADR variants are susceptibility factors for GAD, further highlighting the critical role of the adrenergic nervous system in this disorder. PMID:28198454

  19. Disturbed sleep/wake rhythms and neuronal cell loss in lateral hypothalamus and retina of mice with a spontaneous deletion in the ubiquitin carboxyl-terminal hydrolase L1 gene.

    PubMed

    Pfeffer, Martina; Plenzig, Stefanie; Gispert, Suzana; Wada, Keiji; Korf, Horst-Werner; Von Gall, Charlotte

    2012-02-01

    Many neurodegenerative disorders including Parkinson's disease (PD) and Alzheimer's disease (AD) are associated with sleep disturbances with presumably multifactorial etiology. Ubiquitin C-terminal hydrolase L1 (UCH-L1) is involved in the pathophysiology of PD and AD. In the present study, we analyzed locomotor rhythms, orexin A-immunoreaction (Ir) in the lateral hypothalamus (LH) and melanopsin-Ir in the retina of gracile axonal dystrophy (gad) mice with a spontaneous deletion in the Uch-l1 gene. In constant darkness, gad mice showed circadian rhythms in locomotor activity, indicating the integrity of the endogenous circadian rhythm generator. However, gad mice showed an increased activity during subjective day and a decreased number of orexin A-immunoreactive neurons in the LH compared with the wild type (WT). In addition, gad mice showed increased locomotor activity in the light period when kept in a standard photoperiod and entrainment to phase shifts was significantly slower than in WT. Moreover, melanopsin-Ir was significantly reduced in the retina of gad mice, suggesting an impairment of circadian light perception in gad mice.

  20. Impact of inhibitory constraint of interneurons on neuronal excitability.

    PubMed

    Lee, Vallent; Maguire, Jamie

    2013-12-01

    Tonic inhibition is thought to dampen the excitability of principal neurons; however, little is known about the role of tonic GABAergic inhibition in interneurons and the impact on principal neuron excitability. In many brain regions, tonic GABAergic inhibition is mediated by extrasynaptic, δ-subunit-containing GABAA receptors (GABAARs). In the present study we demonstrate the importance of GABAAR δ-subunit-mediated tonic inhibition in interneurons. Selective elimination of the GABAAR δ-subunit from interneurons was achieved by crossing a novel floxed Gabrd mouse model with GAD65-Cre mice (Gabrd/Gad mice). Deficits in GABAAR δ-subunit expression in GAD65-positive neurons result in a decrease in tonic GABAergic inhibition and increased excitability of both molecular layer (ML) and stratum radiatum (SR) interneurons. Disinhibition of interneurons results in robust alterations in the neuronal excitability of principal neurons and decreased seizure susceptibility. Gabrd/Gad mice have enhanced tonic and phasic GABAergic inhibition in both CA1 pyramidal neurons and dentate gyrus granule cells (DGGCs). Consistent with alterations in hippocampal excitability, CA1 pyramidal neurons and DGGCs from Gabrd/Gad mice exhibit a shift in the input-output relationship toward decreased excitability compared with those from Cre(-/-) littermates. Furthermore, seizure susceptibility, in response to 20 mg/kg kainic acid, is significantly decreased in Gabrd/Gad mice compared with Cre(-/-) controls. These data demonstrate a critical role for GABAAR δ-subunit-mediated tonic GABAergic inhibition of interneurons on principal neuronal excitability and seizure susceptibility.

  1. Emotional intensity reduces later generalized anxiety disorder symptoms when fear of anxiety and negative problem-solving appraisal are low.

    PubMed

    Sugiura, Yoshinori; Sugiura, Tomoko

    2015-08-01

    While research based on the emotion dysregulation model indicates a positive relationship between intense emotions and generalized anxiety disorder (GAD) symptoms, emotion-focused intervention involves the use of techniques to enhance emotional experiences, based on the notion that GAD patients are engaging in avoidance strategies. To reveal the conditions under which intense emotions lead to reduced GAD symptoms, we designed a longitudinal study to monitor changes in GAD symptoms among students (N = 129) over 3 months. Our focus was on possible moderators of the effect of emotional intensity. Results indicated that when fear of emotions and negative appraisals about problem solving were low, negative emotional intensity reduced later GAD symptoms. Moreover, under the condition of high responsibility to continue thinking, emotional intensity tended to reduce later GAD symptoms. Results suggest that reduced fear of emotions and reduced negative appraisals about problem solving may enhance the use of emotional processing techniques (e.g., emotional exposure). The interaction between responsibility to continue thinking and emotional intensity requires further examination.

  2. Subthreshold and threshold DSM-IV generalized anxiety disorder in Singapore: Results from a nationally representative sample.

    PubMed

    Lee, Siau Pheng; Sagayadevan, Vathsala; Vaingankar, Janhavi Ajit; Chong, Siow Ann; Subramaniam, Mythily

    2015-05-01

    Previous nationally representative studies have reported prevalence of DSM-IV generalized anxiety disorder (GAD). However, subthreshold and threshold GAD expressions remain poorly understood. The current study examined the prevalence, correlates and co-morbidity of a broader diagnosis of GAD in Singapore. The Singapore Mental Health Study (SMHS) was an epidemiological survey conducted in the population (N=6616) aged 18 years and older. The Composite International Diagnostic Interview version 3.0 (CIDI 3.0) was used to establish mental disorder diagnoses. The lifetime prevalence for subthreshold GAD (2.1%) and threshold GAD (1.5%) in the current sample was found to be lower than in Western populations. Younger age group, Indian ethnicity, previously married, chronic physical conditions, and being unemployed were associated with higher odds of having more severe expression of generalized anxiety. The relatively lower prevalence rate of subthreshold GAD expression suggests possible cultural interferences in the reporting and manifestation of anxiety symptomatology. Despite the low prevalence, significant impacts on functioning and comorbidity among subthreshold generalized anxiety cases indicate the importance of early treatment to ensure a better prognosis.

  3. Community Violence Exposure and Generalized Anxiety Symptoms: Does Executive Functioning Serve a Moderating Role Among Low Income, Urban Youth?

    PubMed

    Burgers, Darcy E; Drabick, Deborah A G

    2016-11-01

    Although community violence exposure (CVE) confers risk for generalized anxiety symptoms, not all youth who are exposed to violence exhibit such symptoms, suggesting that other factors moderate this relation. One candidate for moderation is executive functioning (EF), which is linked to both CVE and generalized anxiety symptoms. Nevertheless, little research has examined whether EF moderates the CVE-anxiety relation. To address this gap, we examined associations among CVE (i.e., direct victimization and witnessed violence), EF abilities (i.e., emotional control and shifting), and parent- and child-reported generalized anxiety disorder (GAD) symptoms among low income, urban youth (N = 104, 50 % male, M = 9.93 ± 1.22 years). In terms of main effects, lower levels of emotional control were associated with increased parent-reported GAD symptoms, whereas lower levels of shifting abilities were associated with increased parent- and child-reported GAD symptoms across both subtypes of CVE. EF abilities moderated the relation between direct victimization and both parent- and child-reported GAD symptoms, but did not moderate the relation between witnessed violence and GAD symptoms. Post-hoc probing indicated that when youth were exposed to higher levels of direct victimization, those with lower EF abilities exhibited elevated GAD symptoms. However, the level of direct victimization did not impact the level of GAD symptoms among youth with higher EF abilities. Findings have implications for prevention and intervention programs among at-risk youth who are exposed to community violence.

  4. Progressive loss of glutamic acid decarboxylase, parvalbumin, and calbindin D28K immunoreactive neurons in the cerebral cortex and hippocampus of adult rat with experimental hydrocephalus.

    PubMed

    Tashiro, Y; Chakrabortty, S; Drake, J M; Hattori, T

    1997-02-01

    The authors investigated functional neuronal changes in experimental hydrocephalus using immunohistochemical techniques for glutamic acid decarboxylase (GAD) and two neuronal calcium-binding proteins: parvalbumin (PV) and calbindin D28K (CaBP). Hydrocephalus was induced in 16 adult Wistar rats by intracisternal injection of a kaolin solution, which was confirmed microscopically via atlantooccipital dural puncture. Four control rats received the same volume of sterile saline. Immunohistochemical staining for GAD, PV, and CaBP, and Nissl staining were performed at 1, 2, 3, and 4 weeks after the injection. Hydrocephalus occurred in 90% of kaolin-injected animals with various degrees of ventricular dilation. In the cerebral cortex, GAD-, PV-, and CaBP-immunoreactive (IR) interneurons initially lost their stained processes together with a concomitant loss of homogeneous neuropil staining, followed by the reduction of their total number. With progressive ventricular dilation, GAD- and PV-IR axon terminals on the cortical pyramidal cells disappeared, whereas the number of CaBP-IR pyramidal cells decreased, and ultimately in the most severe cases of hydrocephalus, GAD, PV, and CaBP immunoreactivity were almost entirely diminished. In the hippocampus, GAD-, PV-, and CaBP-IR interneurons demonstrated a reduction of their processes and terminals surrounding the pyramidal cells, with secondary reduction of CaBP-IR pyramidal and granular cells. On the other hand, Nissl staining revealed almost no morphological changes induced by ischemia or neuronal degeneration even in the most severe cases of hydrocephalus. Hydrocephalus results in the progressive functional impairment of GAD-, PV-, and CaBP-IR neuronal systems in the cerebral cortex and hippocampus, often before there is evidence of morphological injury. The initial injury of cortical and hippocampal interneurons suggests that the functional deafferentation from intrinsic projection fibers may be the initial neuronal event

  5. Neural mechanisms of symptom improvements in generalized anxiety disorder following mindfulness training☆☆☆

    PubMed Central

    Hölzel, Britta K.; Hoge, Elizabeth A.; Greve, Douglas N.; Gard, Tim; Creswell, J. David; Brown, Kirk Warren; Barrett, Lisa Feldman; Schwartz, Carl; Vaitl, Dieter; Lazar, Sara W.

    2013-01-01

    Mindfulness training aims to impact emotion regulation. Generalized anxiety disorder (GAD) symptoms can be successfully addressed through mindfulness-based interventions. This preliminary study is the first to investigate neural mechanisms of symptom improvements in GAD following mindfulness training. Furthermore, we compared brain activation between GAD patients and healthy participants at baseline. 26 patients with a current DSM-IV GAD diagnosis were randomized to an 8-week Mindfulness Based Stress Reduction (MBSR, N = 15) or a stress management education (SME, N = 11) active control program. 26 healthy participants were included for baseline comparisons. BOLD response was assessed with fMRI during affect labeling of angry and neutral facial expressions. At baseline, GAD patients showed higher amygdala activation than healthy participants in response to neutral, but not angry faces, suggesting that ambiguous stimuli reveal stronger reactivity in GAD patients. In patients, amygdala activation in response to neutral faces decreased following both interventions. BOLD response in ventrolateral prefrontal regions (VLPFC) showed greater increase in MBSR than SME participants. Functional connectivity between amygdala and PFC regions increased significantly pre- to post-intervention within the MBSR, but not SME group. Both, change in VLPFC activation and amygdala–prefrontal connectivity were correlated with change in Beck Anxiety Inventory (BAI) scores, suggesting clinical relevance of these changes. Amygdala–prefrontal connectivity turned from negative coupling (typically seen in down-regulation of emotions), to positive coupling; potentially suggesting a unique mechanism of mindfulness. Findings suggest that in GAD, mindfulness training leads to changes in fronto-limbic areas crucial for the regulation of emotion; these changes correspond with reported symptom improvements. PMID:24179799

  6. Role of the NR2A/2B subunits of the N-methyl-D-aspartate receptor in glutamate-induced glutamic acid decarboxylase alteration in cortical GABAergic neurons in vitro.

    PubMed

    Monnerie, H; Hsu, F-C; Coulter, D A; Le Roux, P D

    2010-12-29

    The vulnerability of brain neuronal cell subpopulations to neurologic insults varies greatly. Among cells that survive a pathological insult, for example ischemia or brain trauma, some may undergo morphological and/or biochemical changes that may compromise brain function. The present study is a follow-up of our previous studies that investigated the effect of glutamate-induced excitotoxicity on the GABA synthesizing enzyme glutamic acid decarboxylase (GAD65/67)'s expression in surviving DIV 11 cortical GABAergic neurons in vitro [Monnerie and Le Roux, (2007) Exp Neurol 205:367-382, (2008) Exp Neurol 213:145-153]. An N-methyl-D-aspartate receptor (NMDAR)-mediated decrease in GAD expression was found following glutamate exposure. Here we examined which NMDAR subtype(s) mediated the glutamate-induced change in GAD protein levels. Western blotting techniques on cortical neuron cultures showed that glutamate's effect on GAD proteins was not altered by NR2B-containing diheteromeric (NR1/NR2B) receptor blockade. By contrast, blockade of triheteromeric (NR1/NR2A/NR2B) receptors fully protected against a decrease in GAD protein levels following glutamate exposure. When receptor location on the postsynaptic membrane was examined, extrasynaptic NMDAR stimulation was observed to be sufficient to decrease GAD protein levels similar to that observed after glutamate bath application. Blocking diheteromeric receptors prevented glutamate's effect on GAD proteins after extrasynaptic NMDAR stimulation. Finally, NR2B subunit examination with site-specific antibodies demonstrated a glutamate-induced, calpain-mediated alteration in NR2B expression. These results suggest that glutamate-induced excitotoxic NMDAR stimulation in cultured GABAergic cortical neurons depends upon subunit composition and receptor location (synaptic vs. extrasynaptic) on the neuronal membrane. Biochemical alterations in surviving cortical GABAergic neurons in various disease states may contribute to the altered

  7. Diminished autonomic neurocardiac function in patients with generalized anxiety disorder

    PubMed Central

    Kim, Kyungwook; Lee, Seul; Kim, Jong-Hoon

    2016-01-01

    Background Generalized anxiety disorder (GAD) is a chronic and highly prevalent disorder that is characterized by a number of autonomic nervous system symptoms. The purpose of this study was to investigate the linear and nonlinear complexity measures of heart rate variability (HRV), measuring autonomic regulation, and to evaluate the relationship between HRV parameters and the severity of anxiety, in medication-free patients with GAD. Methods Assessments of linear and nonlinear complexity measures of HRV were performed in 42 medication-free patients with GAD and 50 healthy control subjects. In addition, the severity of anxiety symptoms was assessed using the State-Trait Anxiety Inventory and Beck Anxiety Inventory. The values of the HRV measures of the groups were compared, and the correlations between the HRV measures and the severity of anxiety symptoms were assessed. Results The GAD group showed significantly lower standard deviation of RR intervals and the square root of the mean squared differences of successive normal sinus intervals values compared to the control group (P<0.01). The approximate entropy value, which is a nonlinear complexity indicator, was also significantly lower in the patient group than in the control group (P<0.01). In correlation analysis, there were no significant correlations between HRV parameters and the severity of anxiety symptoms. Conclusion The present study indicates that GAD is significantly associated with reduced HRV, suggesting that autonomic neurocardiac integrity is substantially impaired in patients with GAD. Future prospective studies are required to investigate the effects of pharmacological or non-pharmacological treatment on neuroautonomic modulation in patients with GAD. PMID:27994467

  8. The psychometric properties of the generalized anxiety disorder-7 scale in Hispanic Americans with English or Spanish language preference.

    PubMed

    Mills, Sarah D; Fox, Rina S; Malcarne, Vanessa L; Roesch, Scott C; Champagne, Brian R; Sadler, Georgia Robins

    2014-07-01

    The Generalized Anxiety Disorder-7 scale (GAD-7) is a self-report questionnaire that is widely used to screen for anxiety. The GAD-7 has been translated into numerous languages, including Spanish. Previous studies evaluating the structural validity of the English and Spanish versions indicate a unidimensional factor structure in both languages. However, the psychometric properties of the Spanish language version have yet to be evaluated in samples outside of Spain, and the measure has not been tested for use among Hispanic Americans. This study evaluated the reliability, structural validity, and convergent validity of the English and Spanish language versions of the GAD-7 for Hispanic Americans in the United States. A community sample of 436 Hispanic Americans with an English (n = 210) or Spanish (n = 226) language preference completed the GAD-7. Multiple-group confirmatory factor analysis (CFA) was used to examine the goodness-of-fit of the unidimensional factor structure of the GAD-7 across language-preference groups. Results from the multiple-group CFA indicated a similar unidimensional factor structure with equivalent response patterns and item intercepts, but different variances, across language-preference groups. Internal consistency was good for both English and Spanish language-preference groups. The GAD-7 also evidenced good convergent validity as demonstrated by significant correlations in expected directions with the Perceived Stress Scale, the Patient Health Questionnaire-9, and the Physical Health domain of the World Health Organization Quality of Life-BREF assessment. The unidimensional GAD-7 is suitable for use among Hispanic Americans with an English or Spanish language preference.

  9. In vitro Gd-DTPA relaxometry studies in oxygenated venous human blood and aqueous solution at 3 and 7 T.

    PubMed

    Kalavagunta, Chaitanya; Michaeli, Shalom; Metzger, Gregory J

    2014-01-01

    In vitro T(1) and T(2) (*) relaxivities (r(1) and r(2) (*) ) of Gd-DTPA (GaD) in oxygenated human venous blood (OVB) and aqueous solution (AS) at 3 and 7 T were calculated. GaD concentrations ([GaD]) in OVB and AS were prepared in the range 0-5 mM. All measurements were acquired at 37 ± 2 °C. At both 3 and 7 T, a linear relationship was observed between [GaD] and R(1) in both AS and OVB. At 7 T, r(1) in AS decreased by 7.5% (p = 0.045) while there was a negligible change in OVB. With respect to R(2) (*) , a linear relationship with [GaD] was only observed in AS, while a more complex relationship was observed in OVB; quadratic below and linear above 2 mM at both field strengths. There was a significant increase of over 4-fold in r(2) (*) with GaD in OVB at 7 T (for [GaD] above 2 mM, p <0.01) as compared with 3 T. Furthermore, in comparison to r1 , r2 (*) in AS was less than 2-fold higher at both field strengths while in OVB it was ~20-fold and ~90-fold higher at 3 and 7 T, respectively. This observation emphasizes the importance of r(2) (*) knowledge at high magnetic fields, ≥3 T. The comparison between r(1) and r(2) (*) presented in this work is crucial in the design and optimization of high-field MRI studies making use of paramagnetic contrast agents. This is especially true in multiple compartment systems such as blood, where r(2) (*) dramatically increases while r1 remains relatively constant with increasing magnetic field strength.

  10. A Very Large Number of GABAergic Neurons Are Activated in the Tuberal Hypothalamus during Paradoxical (REM) Sleep Hypersomnia

    PubMed Central

    Sapin, Emilie; Bérod, Anne; Léger, Lucienne; Herman, Paul A.; Luppi, Pierre-Hervé; Peyron, Christelle

    2010-01-01

    We recently discovered, using Fos immunostaining, that the tuberal and mammillary hypothalamus contain a massive population of neurons specifically activated during paradoxical sleep (PS) hypersomnia. We further showed that some of the activated neurons of the tuberal hypothalamus express the melanin concentrating hormone (MCH) neuropeptide and that icv injection of MCH induces a strong increase in PS quantity. However, the chemical nature of the majority of the neurons activated during PS had not been characterized. To determine whether these neurons are GABAergic, we combined in situ hybridization of GAD67 mRNA with immunohistochemical detection of Fos in control, PS deprived and PS hypersomniac rats. We found that 74% of the very large population of Fos-labeled neurons located in the tuberal hypothalamus after PS hypersomnia were GAD-positive. We further demonstrated combining MCH immunohistochemistry and GAD67 in situ hybridization that 85% of the MCH neurons were also GAD-positive. Finally, based on the number of Fos-ir/GAD+, Fos-ir/MCH+, and GAD+/MCH+ double-labeled neurons counted from three sets of double-staining, we uncovered that around 80% of the large number of the Fos-ir/GAD+ neurons located in the tuberal hypothalamus after PS hypersomnia do not contain MCH. Based on these and previous results, we propose that the non-MCH Fos/GABAergic neuronal population could be involved in PS induction and maintenance while the Fos/MCH/GABAergic neurons could be involved in the homeostatic regulation of PS. Further investigations will be needed to corroborate this original hypothesis. PMID:20668680

  11. Increased glutamate decarboxylase mRNA levels in the striatum and pallidum of MPTP-treated primates.

    PubMed

    Soghomonian, J J; Pedneault, S; Audet, G; Parent, A

    1994-10-01

    The mRNA levels encoding for the enzyme glutamate decarboxylase (GAD67) were measured by computerized image analysis after in situ hybridization histochemistry and radioautography in the striatum and pallidum of normal squirrel monkeys (Saimiri sciureus), or after treatment with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). All MPTP-injected monkeys exhibited profound motor deficits including akinesia. The dopaminergic innervation, as visualized and quantified on x-ray films after 3H-mazindol binding on tissue sections, was uniformly lost throughout the striatum of MPTP-treated monkeys. Brain sections processed with a probe synthesized from a feline or human GAD67 cDNA exhibited intense radioautographic labeling throughout the striatum. When measured on x-ray films, the intensity of GAD67 mRNA labeling was increased in the striatum of MPTP-treated versus control monkeys. Increased labeling reached statistical significance in the dorsolateral sector of the rostral putamen and throughout the putamen and the caudate at the caudal, postcommissural, level. Analysis of emulsion radioautographs demonstrated that the increase in GAD67 mRNA labeling in MPTP-treated monkeys occurred in individual neurons of the striatum. In the external and internal segments of the pallidum, numerous neurons labeled with the GAD67 cRNA probe were visualized on emulsion radioautographs. The intensity of GAD67 mRNA labeling in single neurons of both pallidal segments was increased in MPTP-treated versus control monkeys. Construction of the histograms of frequency distribution of labeling indicated that this increase occurred in a majority of labeled neurons. The present study demonstrates that GAD67 mRNA levels are significantly altered in the striatum and pallidum of parkinsonian monkeys. The preferential increase of GAD67 mRNA labeling in the dorsolateral putamen, which receives afferents from the sensorimotor cortex, provides further evidence of the involvement of

  12. Worry and Rumination in Generalized Anxiety Disorder and Obsessive Compulsive Disorder.

    PubMed

    Dar, Kaiser A; Iqbal, Naved

    2015-01-01

    Ample work has already been conducted on worry and rumination as negative thought processes involved in the etiology of most of the anxiety and mood related disorders. However, minimal effort has been exerted to investigate whether one type of negative thought process can make way for another type of negative thought process, and if so, how it subsequently results in experiencing a host of symptoms reflective of one or the other type of psychological distress. Therefore, the present study was taken up to investigate whether rumination mediates the relationship between worry and generalized anxiety disorder (GAD), and between worry and obsessive compulsive disorder (OCD) in two clinical groups. Self-report questionnaires tapping worry, rumination, generalized anxiety disorder (GAD), and obsessive compulsive disorder (OCD) were administered to a clinical sample of 60 patients aged 30-40. Worry, rumination, generalized anxiety disorder (GAD), and obsessive compulsive disorder (OCD) correlated substantially with each other, however, rumination did not mediate the relationship between worry and generalized anxiety disorder (GAD) and between worry and obsessive compulsive disorder (OCD). We also analyzed differences of outcome variables within two clinical groups. These results showed that worry and rumination were significantly different between GAD and OCD groups.

  13. A community-based epidemiological study of health anxiety and generalized anxiety disorder.

    PubMed

    Lee, Sing; Lam, Ivy M H; Kwok, Kathleen P S; Leung, Candi M C

    2014-03-01

    This community-based study examined the frequency of worry about personal health in respondents with and without generalized anxiety disorder (GAD), and the impact of health anxiety on the disorder. A random community-based telephone survey of 5118 Chinese respondents aged 18-64 was conducted. A fully structured questionnaire covered the DSM-IV-TR criteria of GAD, major depressive episode (MDE), eight domains of worry, the seven-item Whiteley Index (WI-7), health service use, and socio-demographic information. Worry about personal health ranked fifth (75.6%) among eight domains of worries examined. GAD respondents with high level of health anxiety were significantly older, less educated, and had lower family income. High health anxiety significantly increased the occurrence of one-year MDE, previous persistent worry, previous persistent low mood, number of domains of worries, number of non-core DSM-IV-TR GAD symptoms, health service use, and mistrust of doctors. Health anxiety is common in GAD and may signify greater severity of the disorder.

  14. Diagnosis and management of generalized anxiety disorder and panic disorder in adults.

    PubMed

    Locke, Amy B; Kirst, Nell; Shultz, Cameron G

    2015-05-01

    Generalized anxiety disorder (GAD) and panic disorder (PD) are among the most common mental disorders in the United States, and they can negatively impact a patient's quality of life and disrupt important activities of daily living. Evidence suggests that the rates of missed diagnoses and misdiagnosis of GAD and PD are high, with symptoms often ascribed to physical causes. Diagnosing GAD and PD requires a broad differential and caution to identify confounding variables and comorbid conditions. Screening and monitoring tools can be used to help make the diagnosis and monitor response to therapy. The GAD-7 and the Severity Measure for Panic Disorder are free diagnostic tools. Successful outcomes may require a combination of treatment modalities tailored to the individual patient. Treatment often includes medications such as selective serotonin reuptake inhibitors and/or psychotherapy, both of which are highly effective. Among psychotherapeutic treatments, cognitive behavior therapy has been studied widely and has an extensive evidence base. Benzodiazepines are effective in reducing anxiety symptoms, but their use is limited by risk of abuse and adverse effect profiles. Physical activity can reduce symptoms of GAD and PD. A number of complementary and alternative treatments are often used; however, evidence is limited for most. Several common botanicals and supplements can potentiate serotonin syndrome when used in combination with antidepressants. Medication should be continued for 12 months before tapering to prevent relapse.

  15. A Case Series on the Effects of Kripalu Yoga for Generalized Anxiety Disorder.

    PubMed

    Morgan, Jessica R; Sullivan, Marlysa; Masuda, Akihiko; Tully, Erin; Cohen, Lindsey L; Anderson, Page L

    2016-07-14

    Generalized anxiety disorder (GAD) is a prevalent psychiatric disorder associated with substantial impairment and poor treatment response. Yoga influences processes that are linked to the maintenance of GAD including mindfulness, anxiety, and heart rate variability, but has yet to be evaluated among people with the disorder. The present study is a first step toward documenting the efficacy of yoga for reducing worry among people with GAD using a single-subject AB design case series and daily ratings of worry. Standardized self-report measures of worry, trait anxiety, experiential avoidance, mindfulness, and heart rate variability were assessed pre- and post-intervention. Three participants with primary GAD received eight twice-weekly Kripalu yoga sessions following a baseline data collection period. All participants showed systematic improvement in daily worry ratings on at least one index and all scores on self-reported measures of worry, anxiety, experiential avoidance, and mindfulness changed in the expected direction following yoga (with one or two exceptions). Participants also showed improved heart rate variability during a worry period from pre- to post-intervention. Yoga has the potential to improve the processes linked to GAD and should stimulate further research in this area.

  16. Conditioned Fear Acquisition and Generalization in Generalized Anxiety Disorder.

    PubMed

    Tinoco-González, Daniella; Fullana, Miquel Angel; Torrents-Rodas, David; Bonillo, Albert; Vervliet, Bram; Blasco, María Jesús; Farré, Magí; Torrubia, Rafael

    2015-09-01

    Abnormal fear conditioning processes (including fear acquisition and conditioned fear-generalization) have been implicated in the pathogenesis of anxiety disorders. Previous research has shown that individuals with panic disorder present enhanced conditioned fear-generalization in comparison to healthy controls. Enhanced conditioned fear-generalization could also characterize generalized anxiety disorder (GAD), but research so far is inconclusive. An important confounding factor in previous research is comorbidity. The present study examined conditioned fear-acquisition and fear-generalization in 28 patients with GAD and 30 healthy controls using a recently developed fear acquisition and generalization paradigm assessing fear-potentiated startle and online expectancies of the unconditioned stimulus. Analyses focused on GAD patients without comorbidity but included also patients with comorbid anxiety disorders. Patients and controls did not differ as regards fear acquisition. However, contrary to our hypothesis, both groups did not differ either in most indexes of conditioned fear-generalization. Moreover, dimensional measures of GAD symptoms were not correlated with conditioned fear-generalization indexes. Comorbidity did not have a significant impact on the results. Our data suggest that conditioned fear-generalization is not enhanced in GAD. Results are discussed with special attention to the possible effects of comorbidity on fear learning abnormalities.

  17. Qualitative changes in symptomatology as an effect of treatment with escitalopram in generalized anxiety disorder and major depressive disorder.

    PubMed

    Lecrubier, Yves; Dolberg, Ornah T; Andersen, Henning F; Weiller, Emmauelle

    2008-04-01

    The purpose of this article is to examine the similarities and differences between patients with Major Depressive Disorder (MDD) versus Generalized Anxiety Disorder (GAD) versus MDD with anxiety symptoms. Data were analysed from all randomized double-blind clinical studies with escitalopram that measured symptoms using either Hamilton Anxiety Scale (HAMA) or Montgomery-Asberg Depression Rating Scale (MADRS). The contribution of each item of a scale to the total score was calculated before and after treatment, in remitters. Most single items of the HAMA contribute nearly equally in patients with GAD. In patients with MDD, four symptoms (i.e. anxious mood, tension, insomnia and concentration) contribute to most to the HAMA total score. In patients with GAD, three symptoms (tension, sleep and concentration) contribute two-thirds of the MADRS total score. In contrast, most MADRS items contribute equally to the total score in patients with MDD. After treatment to remission, the profile of residual symptoms MDD or GAD was similar to the symptom profile before treatment. Anxiety symptoms are very common in patients with MDD or GAD, and the symptomatic pattern is similar. In both disorders, the symptomatic pattern of residual symptoms is similar to the pattern of symptoms before treatment.

  18. Intolerance of uncertainty, social anxiety, and generalized anxiety: Differences by diagnosis and symptoms.

    PubMed

    Counsell, Alyssa; Furtado, Melissa; Iorio, Christina; Anand, Leena; Canzonieri, Alexandra; Fine, Alexa; Fotinos, Kathryn; Epstein, Irvin; Katzman, Martin A

    2017-02-20

    Research suggests that Intolerance of Uncertainty (IU) is related to the severity of suffering in Generalized Anxiety Disorder (GAD). However, its role in Social Anxiety Disorder (SAD) has not been extensively studied. This study examines IU in a clinical sample of 248 individuals referred to a tertiary care clinic. Few individuals had a diagnosis of pure SAD or pure GAD, but we examined differences of IU scores by diagnostic category. We further examined the relationships between IU scores, social anxiety scores, and worry through a structural equation model. We found that diagnostic category (SAD versus GAD) accounted for little variability in IU scores, but IU scores were strongly related to symptoms of both GAD and SAD. Results highlight that IU is related to both social anxiety and worry; however aspects of IU associated with being unable to act or avoiding uncertainty are more strongly associated with SAD symptoms, whereas aspects of IU more associated with general stress and perceiving uncertainty as unfair are more strongly associated with GAD symptoms. Our results suggest that IU is an important concept for both social anxiety and generalized anxiety, however the relationship between IU and symptoms of these disorders manifests differently.

  19. Anti-glutamic acid decarboxylase antibody positive neurological syndromes

    PubMed Central

    Tohid, Hassaan

    2016-01-01

    A rare kind of antibody, known as anti-glutamic acid decarboxylase (GAD) autoantibody, is found in some patients. The antibody works against the GAD enzyme, which is essential in the formation of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter found in the brain. Patients found with this antibody present with motor and cognitive problems due to low levels or lack of GABA, because in the absence or low levels of GABA patients exhibit motor and cognitive symptoms. The anti-GAD antibody is found in some neurological syndromes, including stiff-person syndrome, paraneoplastic stiff-person syndrome, Miller Fisher syndrome (MFS), limbic encephalopathy, cerebellar ataxia, eye movement disorders, and epilepsy. Previously, excluding MFS, these conditions were called ‘hyperexcitability disorders’. However, collectively, these syndromes should be known as “anti-GAD positive neurological syndromes.” An important limitation of this study is that the literature is lacking on the subject, and why patients with the above mentioned neurological problems present with different symptoms has not been studied in detail. Therefore, it is recommended that more research is conducted on this subject to obtain a better and deeper understanding of these anti-GAD antibody induced neurological syndromes. PMID:27356651

  20. The treatment of generalized anxiety disorder with pregabalin, an atypical anxiolytic.

    PubMed

    Strawn, Jeffrey R; Geracioti, Thomas D

    2007-04-01

    A constellation of pharmacologic treatments for generalized anxiety disorder (GAD) have been developed over the past five decades, although each has a number of potential drawbacks in clinical practice. This review addresses one potentially new pharmacologic treatment for generalized anxiety disorder, the gamma-aminobutyric acid analogue pregabalin. We review the mechanism of action, and pharmacokinetic and pharmacodynamic properties of pregabalin as well as the results of 5 double-blind, placebo-controlled trials of pregabalin in the treatment of generalized anxiety disorder (GAD). Based entirely on data from these industry-sponsored (Pfizer), multi-site clinical trials in patients with GAD, pregabalin appears to be generally well tolerated and has rapid onset of action (approximately 1 week), comparable efficacy to benzodiazepines and lower discontinuation rates compared with other pharmacologic treatments. Thus in GAD, a disorder that is often suboptimally responsive to traditional psychotherapeutic and psychopharmacologic interventions - secondary to poor efficacy, tolerability, and/or side-effects - pregabalin may have a primary role in GAD patients, especially in those with certain psychiatric comorbidities or individuals who are on multi-drug regimens for medical comorbidities.

  1. Latent profile analyses of posttraumatic stress disorder, depression and generalized anxiety disorder symptoms in trauma-exposed soldiers.

    PubMed

    Contractor, Ateka A; Elhai, Jon D; Fine, Thomas H; Tamburrino, Marijo B; Cohen, Gregory; Shirley, Edwin; Chan, Philip K; Liberzon, Israel; Galea, Sandro; Calabrese, Joseph R

    2015-09-01

    Posttraumatic stress disorder (PTSD) is comorbid with major depressive disorder (MDD; Kessler et al., 1995) and generalized anxiety disorder (GAD; Brown et al., 2001). We aimed to (1) assess discrete patterns of post-trauma PTSD-depression-GAD symptoms using latent profile analyses (LPAs), and (2) assess covariates (gender, income, education, age) in defining the best fitting class solution. The PTSD Checklist (assessing PTSD symptoms), GAD-7 scale (assessing GAD symptoms), and Patient Health Questionnaire-9 (assessing depression) were administered to 1266 trauma-exposed Ohio National Guard soldiers. Results indicated three discrete subgroups based on symptom patterns with mild (class 1), moderate (class 2) and severe (class 3) levels of symptomatology. Classes differed in symptom severity rather than symptom type. Income and education significantly predicted class 1 versus class 3 membership, and class 2 versus class 3. In conclusion, there is heterogeneity regarding severity of PTSD-depression-GAD symptomatology among trauma-exposed soldiers, with income and education predictive of class membership.

  2. Diabetes autoantibodies do not predict progression to diabetes in adults: the Diabetes Prevention Program

    PubMed Central

    Dabelea, D.; Ma, Y.; Knowler, W. C.; Marcovina, S.; Saudek, C. D.; Arakaki, R.; White, N. H.; Kahn, S. E.; Orchard, T. J.; Goldberg, R.; Palmer, J.; Hamman, R. F.

    2014-01-01

    Aims To determine if the presence of diabetes autoantibodies predicts the development of diabetes among participants in the Diabetes Prevention Program. Methods A total of 3050 participants were randomized into three treatment groups: intensive lifestyle intervention, metformin and placebo. Glutamic acid decarboxylase (GAD) 65 autoantibodies and insulinoma-associated-2 autoantibodies were measured at baseline and participants were followed for 3.2 years for the development of diabetes. Results The overall prevalence of GAD autoantibodies was 4.0%, and it varied across racial/ethnic groups from 2.4% among Asian-Pacific Islanders to 7.0% among non-Hispanic black people. There were no significant differences in BMI or metabolic variables (glucose, insulin, HbA1c, estimated insulin resistance, corrected insulin response) stratified by baseline GAD antibody status. GAD autoantibody positivity did not predict diabetes overall (adjusted hazard ratio 0.98; 95% CI 0.56–1.73) or in any of the three treatment groups. Insulinoma-associated-2 autoantibodies were positive in only one participant (0.033%). Conclusions These data suggest that ‘diabetes autoimmunity’, as reflected by GAD antibodies and insulinoma-associated-2 autoantibodies, in middle-aged individuals at risk for diabetes is not a clinically relevant risk factor for progression to diabetes. PMID:24646311

  3. Atypical antipsychotics in primary generalized anxiety disorder or comorbid with mood disorders.

    PubMed

    Gao, Keming; Sheehan, David V; Calabrese, Joseph R

    2009-08-01

    Generalized anxiety disorder (GAD) is a chronic, highly prevalent and debilitating disorder that commonly co-occurrs with mood disorders. Current available agents for GAD are limited either by their slow onsets of actions, unsatisfactory anxiolytic effects or potential for abuse/dependence. Atypical antipsychotics have been studied as alternatives. Olanzapine, risperidone and quetiapine immediate release have been explored in the treatment of refractory GAD and risperidone in bipolar anxiety with randomized, double-blind, placebo-controlled trials, but the results were not consistent. By contrast, quetiapine extended release (quetiapine-XR) 150 mg/day monotherapy yielded consistent anxiolytic effects across three studies that were superior to placebo and as effective as paroxetine 20 mg/day and escitalopram 10 mg/day but with an earlier onset of action. In a 52-week treatment of GAD, quetiapine-XR was superior to placebo in the prevention of anxiety relapses. Overall, atypical antipsychotics were relatively well tolerated, with common side effects of somnolence and sedation. However, in contrast to antidepressants and benzodiazepines, the long-term risk and benefit of atypical antipsychotics in the treatment of GAD is yet to be determined.

  4. Characterization and immobilization on nickel-chelated Sepharose of a glutamate decarboxylase A from Lactobacillus brevis BH2 and its application for production of GABA.

    PubMed

    Lee, Ji-Yeon; Jeon, Sung-Jong

    2014-01-01

    A gene encoding glutamate decarboxylase A (GadA) from Lactobacillus brevis BH2 was expressed in a His-tagged form in Escherichia coli cells, and recombinant protein exists as a homodimer consisting of identical subunits of 53 kDa. GadA was absolutely dependent on the ammonium sulfate concentration for catalytic activity and secondary structure formation. GadA was immobilized on the metal affinity resin with an immobilization yield of 95.8%. The pH optima of the immobilized enzyme were identical with those of the free enzyme. However, the optimum temperature for immobilized enzyme was 5 °C higher than that for the free enzyme. The immobilized GadA retained its relative activity of 41% after 30 reuses of reaction within 30 days and exhibited a half-life of 19 cycles within 19 days. A packed-bed bioreactor with immobilized GadA showed a maximum yield of 97.8% GABA from 50 mM l-glutamate in a flow-through system under conditions of pH 4.0 and 55 °C.

  5. Distribution of messenger RNAs encoding the enzymes glutaminase, aspartate aminotransferase and glutamic acid decarboxylase in rat brain.

    PubMed

    Najlerahim, A; Harrison, P J; Barton, A J; Heffernan, J; Pearson, R C

    1990-05-01

    In situ hybridization histochemistry (ISHH) using synthetic oligonucleotide probes has been used to identify cells containing the mRNAs coding for glutaminase (GluT), aspartate aminotransferase (AspT) and glutamic acid decarboxylase (GAD). The distribution of GAD mRNA confirms previous descriptions and matches the distribution of GAD detected using specific antibodies. AspT mRNA is widely distributed in the brain, but is present at high levels in GABAergic neuronal populations, some that may be glutamatergic, and in a subset of neurons which do not contain significant levels of either GAD or GluT mRNA. Particularly prominent are the neurons of the magnocellular division of the red nucleus, the large cells in the deep cerebellar nuclei and the vestibular nuclei and neurons of the lateral superior olivary nucleus. GluT mRNA does not appear to be present at high levels in all GAD-containing neurons, but is seen prominently in many neuronal populations that may use glutamate as a neurotransmitter, such as neocortical and hippocampal pyramidal cells, the granule cells of the cerebellum and neurons of the dentate gyrus of the hippocampus. The heaviest labelling of GluT mRNA is seen in the lateral reticular nucleus of the medulla. ISHH using probes directed against the mRNAs encoding these enzymes may be an important technique for identifying glutamate and aspartate using neuronal populations and for examining their regulation in a variety of experimental and pathological circumstances.

  6. Pharmacotherapy for Pediatric Generalized Anxiety Disorder: A Systematic Evaluation of Efficacy, Safety and Tolerability

    PubMed Central

    Dobson, Eric T.; Strawn, Jeffrey R.

    2016-01-01

    Background Randomized controlled trials consistently support the efficacy of antidepressants in treating youth with generalized anxiety disorder (GAD), although integrated examinations of efficacy, safety, and tolerability of psychotropic medications in GAD specifically are rare. With this in mind, we sought to describe the efficacy, safety and tolerability of psychopharmacologic interventions in youth with GAD. Methods Randomized, double-blind, placebo-controlled, prospective trials of psychopharmacologic interventions in youth with GAD were identified through a PubMed/Medline (1966–2015) search. Both authors manually reviewed trials and, to evaluate comparative efficacy and tolerability across medications, numbers needed to treat (NNT) (based on Pediatric Anxiety Rating Scale (PARS) remission criteria (PARS ≤8 [1]), and number needed to harm (NNH) for selected treatment-emergent adverse events (TEAEs) were calculated. Finally, treatment-emergent suicidality and taper-emergent/post-study adverse events are reported descriptively. Results Five trials that involved 1,186 patients and evaluated four medications were reviewed and efficacy data were extracted with regard to dimensional measures of anxiety. SSRI/SNRIs demonstrated efficacy in the reduction of anxiety symptoms with NNTs ranging from 2.8 to 9.3. TEAEs varied considerably between studies but tended to be mild and generally did not lead to discontinuation. Conclusions Data from five trials of SSRI/SNRI in youth with GAD, many of whom had co-occurring separation and social anxiety disorders, suggest superiority to placebo and favorable tolerability profiles. PMID:26660158

  7. Noradrenergic function in generalized anxiety disorder, major depressive disorder, and healthy subjects.

    PubMed

    Sevy, S; Papadimitriou, G N; Surmont, D W; Goldman, S; Mendlewicz, J

    1989-01-15

    Plasma norepinephrine (NE), free 3-methoxy-4-hydroxyphenethylene glycol (MHPG), and binding of tritiated yohimbine to platelet membranes were measured in 14 patients with generalized anxiety disorder (GAD), who were matched for age and sex with 14 patients with unipolar major depressive disorder (MDD) and 14 normal subjects. Plasma NE and MHPG levels were increased and the number of alpha2-adrenoreceptors (Bmax) was decreased in GAD patients compared with MDD and normal subjects. No differences were found between MDD patients and normal subjects for plasma NE, MHPG, and alpha2-adrenoreceptor binding. Plasma NE and MHPG were significantly correlated in MDD patients and tended toward a significant positive correlation in GAD patients. Plasma MHPG and affinity of binding platelet alpha2-adrenoreceptors (Kd) were significantly correlated in normal subjects. Thus, noradrenergic activity seems to be increased in patients with GAD, but not in patients with MDD. In GAD patients, higher levels of catecholamines may lead to a down-regulation of presynaptic alpha2-adrenoreceptors.

  8. Examination of the interrelations between the factors of PTSD, major depression, and generalized anxiety disorder in a heterogeneous trauma-exposed sample using DSM 5 criteria.

    PubMed

    Price, Matthew; van Stolk-Cooke, Katherine

    2015-11-01

    Exposure to traumatic events places individuals at high risk for multiple psychiatric disorders, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and generalized anxiety disorder (GAD). The high rates of comorbidity among these conditions merit evaluation in order to improve diagnosis and treatment approaches. The current study evaluated the association between PTSD, MDD, and GAD factors as presented in the DSM 5. 602 trauma-exposed individuals who experienced an event that met Criterion A for the DSM 5 PTSD diagnosis were recruited through Amazon.com, Inc.'s Mechanical Turk (MTurk) to complete an assessment of the impact of stressful events on their lives. High interrelations were detected among the 4 PTSD factors, 2 MDD factors that corresponded to somatic and affective symptoms, and the single GAD factor. The affective factor of MDD was most strongly related to the emotional numbing factor of PTSD, whereas the somatic factor of MDD was most strongly related to the hyperarousal factor of PTSD. The GAD factor was most strongly related to the hyperarousal factor of PTSD, relative to the other PTSD factors. The strength of the interrelations between factors of the three disorders is largely a function of the overlap in symptoms and calls into question the uniqueness of negative affective symptoms of PTSD, MDD and GAD. Results suggest that improved understanding of the trauma reaction requires a focus on the unique presentation of each individual and assessment of multiple disorders.

  9. Simulating effects of a wind-turbine array using LES and RANS

    NASA Astrophysics Data System (ADS)

    Vanderwende, Brian J.; Kosović, Branko; Lundquist, Julie K.; Mirocha, Jeffrey D.

    2016-09-01

    Growth in wind power production has motivated investigation of wind-farm impacts on in situ flow fields and downstream interactions with agriculture and other wind farms. These impacts can be simulated with both large-eddy simulations (LES) and mesoscale wind-farm parameterizations (WFP). The Weather Research and Forecasting (WRF) model offers both approaches. We used the validated generalized actuator disk (GAD) parameterization in WRF-LES to assess WFP performance. A 12-turbine array was simulated using the GAD model and the WFP in WRF. We examined the performance of each scheme in both convective and stable conditions. The GAD model and WFP produced qualitatively similar wind speed deficits and turbulent kinetic energy (TKE) production across the array in both stability regimes, though the magnitudes of velocity deficits and TKE production levels were underestimated and overestimated, respectively. While wake growth slowed in the latter half of the WFP array as expected, wakes did not approach steady state by the end of the array as simulated by the GAD model. A sensitivity test involving the deactivation of explicit TKE production by the WFP resulted in turbulence levels within the array well that were below those produced by the GAD in both stable and unstable conditions. Finally, the WFP overestimated downwind power production deficits in stable conditions because of the lack of wake stabilization in the latter half of the array.

  10. Pregabalin for the treatment of generalized anxiety disorder: an update

    PubMed Central

    Baldwin, David S; Ajel, Khalil; Masdrakis, Vasilios G; Nowak, Magda; Rafiq, Rizwan

    2013-01-01

    A previous review summarized what was then known about the potential role of pregabalin in the treatment of patients with generalized anxiety disorder (GAD): this review provides an update on its pharmacological properties and presumed mechanism of action, the liability for abuse, and efficacy and tolerability in patients with GAD. Pregabalin has a similar molecular structure to the inhibitory neurotransmitter gamma amino butyric acid (GABA) but its mechanism of action does not appear to be mediated through effects on GABA. Instead, its anxiolytic effects may arise through high-affinity binding to the alpha-2-delta sub-unit of the P/Q type voltage-gated calcium channel in “over-excited” presynaptic neurons, thereby reducing the release of excitatory neurotransmitters such as glutamate. The findings of randomized controlled trials and meta-analyses together indicate that pregabalin is efficacious in both acute treatment and relapse prevention in GAD, with some evidence of an early onset of effect, and broad efficacy in reducing the severity of psychological and physical symptoms of anxiety. It also has efficacy as an augmenting agent after non-response to antidepressant treatment in GAD. Continuing vigilance is needed in assessing its potential abuse liability but the tolerability profile of pregabalin may confer some advantages over other pharmacological treatments in the short term for treatment in patients with GAD. PMID:23836974

  11. Effects of ABA and CaCl₂ on GABA accumulation in fava bean germinating under hypoxia-NaCl stress.

    PubMed

    Yang, Runqiang; Hui, Qianru; Gu, Zhenxin

    2016-01-01

    Effects of exogenous abscisic acid (ABA) and CaCl2 on γ-aminobutyric acid (GABA) accumulation of germinated fava bean under hypoxia-NaCl stress were investigated. Exogenous ABA resulted in the enhancement of glutamate decarboxylase (GAD) and diamine oxidase (DAO) activity as well as GABA content in cotyledon and shoot. CaCl2 increased both enzyme activities in shoot and GABA content in cotyledon and shoot. ABA downregulated GAD expression in cotyledon and radicle, while upregulated that in shoot; it also upregulated DAO expression in each organ. CaCl2 upregulated GAD expression in cotyledon, while downregulated that in radicle. However, it upregulated DAO expression in shoot, downregulated that in radicle. ABA inhibitor fluridon and ethylenediaminetetraacetic acid inhibited GAD and DAO activities significantly so that inhibited GABA accumulation through reducing ABA biosynthesis and chelating Ca(2+), respectively. However, they upregulated GAD and DAO expression in varying degrees. These results indicate that ABA and Ca(2+) participate in GABA biosynthesis in fava bean during germination under hypoxia-NaCl stress.

  12. Aberrant Functional Connectivity between the Amygdala and the Temporal Pole in Drug-Free Generalized Anxiety Disorder

    PubMed Central

    Li, Wei; Cui, Huiru; Zhu, Zhipei; Kong, Li; Guo, Qian; Zhu, Yikang; Hu, Qiang; Zhang, Lanlan; Li, Hui; Li, Qingwei; Jiang, Jiangling; Meyers, Jordan; Li, Jianqi; Wang, Jijun; Yang, Zhi; Li, Chunbo

    2016-01-01

    The amygdala and the dorsolateral prefrontal cortex (DLPFC) play important roles in “emotion dysregulation,” which has a profound impact on etiologic research of generalized anxiety disorder (GAD). The present study analyzed both eyes-open and eyes-closed resting state functional MRI (rs-fMRI) of 43 subjects (21 GAD patients with medicine free and 22 matched healthy controls). The amygdala and the DLPFC were defined as regions of interest (ROI) to analyze functional connectivity (FC) in GAD patients compared with healthy controls. The main findings revealed GAD patients had increased FC between the amygdala and the temporal pole compared to healthy controls, which was found in both eyes-open and eyes-closed rs-fMRI. And altered FC between the ROIs and brain regions that mainly belonged to the default mode network (DMN) were found. These findings suggest that the abnormal FC between the amygdala and the temporal pole may contribute to the pathophysiology of GAD, and provide insights into the current understanding of the emotion dysregulation of anxiety disorders. PMID:27867352

  13. Native and structurally modified gum arabic: exploring the effect of the gum's microstructure in obtaining electroactive nanoparticles.

    PubMed

    Cornelsen, Patricia A; Quintanilha, Ronaldo C; Vidotti, Marcio; Gorin, Philip A J; Simas-Tosin, Fernanda F; Riegel-Vidotti, Izabel C

    2015-03-30

    Electroactive nanoparticles combining gum arabic (GA) and polyaniline (PANI) were prepared by chemical synthesis. The gum consists of highly branched anionic polysaccharides with some protein content. GA was structurally modified by Smith controlled degradation, in order to reduce its degree of branching (GAD), aiming the elucidation of the relationship between the structure and the properties of complex polysaccharides. The modification was studied by SEC, GC-MS, (13)C NMR and colorimetric methods. GAD has lower molecular mass, lower degree of branching and lower uronic acid content. Besides it is enriched in galactose and protein when compared with GA. The obtained composites (GA-PANI and GAD-PANI) were thoroughly characterized. Although the use of both polysaccharides (GA and GAD) produced highly stable electroactive nanoparticles, the best combination of properties was achieved for GA-PANI. The sample GAD was not able to prevent the occurrence of crosslinking between PANI chains, possibly due to its lower microstructural complexity which diminishes the occurrence of hydrogen bonds between the polymers.

  14. Mapping of an autoreactive epitope within glutamate decarboxylase using a diabetes-associated human monoclonal autoantibody and an epitope cDNA library.

    PubMed

    Richter, W; Northemann, W; Müller, M; Böhm, B O

    1996-04-01

    Glutamate decarboxylase (GAD65) is a major autoantigen in insulin-dependent diabetes (IDDM) and the neurological disorder Stiff-Man-Syndrome (SMS). We derived a human monoclonal autoantibody (MICA 2) from peripheral blood of a patient newly diagnosed with IDDM, which reacted with GAD65 in Western blots. This indicated that a linear epitope is recognized by MICA 2. Using an epitope cDNA library we mapped the MICA 2 epitope to a contiguous stretch of 26 amino acids (506-531) in the C-terminus of GAD65. Neither blocking experiments with synthetic peptides nor analysis of overlapping decapeptides expressed as fusion proteins allowed us to further narrow down the epitope to the typical size of linear epitopes of 6-8 amino acids. We suggest that a miniconformational epitope provided by amino acids 506-531 is recognized by MICA 2, which withstands SDS gel electrophoresis without destruction or partially refolds during the Western blot procedure. A sequence homology with human heat shock protein 60 (HSP60) maps to this region of GAD65 but no cross-reactivity of MICA 2 with HSP60 occurred. Our data demonstrate that reactivity of an antibody in Western blots does not necessarily define a classic linear epitope of 6-8 amino acids and describe a new autoreactive epitope in GAD65 different from those reported for sera from patients with SMS.

  15. Internet-delivered acceptance-based behaviour therapy for generalized anxiety disorder: A randomized controlled trial.

    PubMed

    Dahlin, Mats; Andersson, Gerhard; Magnusson, Kristoffer; Johansson, Tomas; Sjögren, Johan; Håkansson, Andreas; Pettersson, Magnus; Kadowaki, Åsa; Cuijpers, Pim; Carlbring, Per

    2016-02-01

    Generalized anxiety disorder (GAD) is a disabling condition which can be treated with cognitive behaviour therapy (CBT). The present study tested the effects of therapist-guided internet-delivered acceptance-based behaviour therapy on symptoms of GAD and quality of life. An audio CD with acceptance and mindfulness exercises and a separate workbook were also included in the treatment. Participants diagnosed with GAD (N = 103) were randomly allocated to immediate therapist-guided internet-delivered acceptance-based behaviour therapy or to a waiting-list control condition. A six month follow-up was also included. Results using hierarchical linear modelling showed moderate to large effects on symptoms of GAD (Cohen's d = 0.70 to 0.98), moderate effects on depressive symptoms (Cohen's d = 0.51 to 0.56), and no effect on quality of life. Follow-up data showed maintained effects. While there was a 20% dropout rate, sensitivity analyses showed that dropouts did not differ in their degree of change during treatment. To conclude, our study suggests that internet-delivered acceptance-based behaviour therapy can be effective in reducing the symptoms of GAD.

  16. Enzymatic production of γ-aminobutyric acid in soybeans using high hydrostatic pressure and precursor feeding.

    PubMed

    Ueno, Shigeaki; Katayama, Takumi; Watanabe, Takae; Nakajima, Kanako; Hayashi, Mayumi; Shigematsu, Toru; Fujii, Tomoyuki

    2013-01-01

    The effects were investigated of the glutamic acid (Glu) substrate concentration on the generation and kinetics of γ-aminobutyric acid (GABA) in soybeans treated under high hydrostatic pressure (HHP; 200 MPa for 10 min at 25 °C). The conversion of Glu to GABA decreased with increasing initial Glu concentration in the soybeans. The crude glutamate decarboxylase (GAD) obtained from the HHP-treated soybeans showed substrate inhibition. The GABA production rate in the HHP-treated soybeans fitted the following substrate inhibition kinetic equation: v0=(VmaxS0)/(Km+S0+(S0)2/Ki). The Km value for the HHP-treated soybeans was significantly higher than that of the untreated soybeans. The Km values in this study show the affinity between Glu and GAD, and indicate that the HHP-treated soybeans had lower affinity between Glu and GAD than the untreated soybeans. GAD extracted from the HHP-treated soybeans showed a similar value to that in the HHP-treated soybeans. The intact biochemical system was so damaged in the HHP-treated soybeans that it showed substrate inhibition kinetics similar to that of the extracted GAD. The combination of HHP and precursor feeding proved to be a novel tool that can be used to increase the concentration of a target component.

  17. Amygdala functional connectivity as a longitudinal biomarker of symptom changes in generalized anxiety

    PubMed Central

    Makovac, Elena; Watson, David R.; Meeten, Frances; Garfinkel, Sarah N.; Cercignani, Mara; Critchley, Hugo D.

    2016-01-01

    Generalized anxiety disorder (GAD) is characterized by excessive worry, autonomic dysregulation and functional amygdala dysconnectivity, yet these illness markers have rarely been considered together, nor their interrelationship tested longitudinally. We hypothesized that an individual’s capacity for emotion regulation predicts longer-term changes in amygdala functional connectivity, supporting the modification of GAD core symptoms. Sixteen patients with GAD (14 women) and individually matched controls were studied at two time points separated by 1 year. Resting-state fMRI data and concurrent measurement of vagally mediated heart rate variability were obtained before and after the induction of perseverative cognition. A greater rise in levels of worry following the induction predicted a stronger reduction in connectivity between right amygdala and ventromedial prefrontal cortex, and enhanced coupling between left amygdala and ventral tegmental area at follow-up. Similarly, amplified physiological responses to the induction predicted increased connectivity between right amygdala and thalamus. Longitudinal shifts in a distinct set of functional connectivity scores were associated with concomitant changes in GAD symptomatology over the course of the year. Results highlight the prognostic value of indices of emotional dysregulation and emphasize the integral role of the amygdala as a critical hub in functional neural circuitry underlying the progression of GAD symptomatology. PMID:27369066

  18. Associations Between Compulsive Buying and Substance Dependence/Abuse, Major Depressive Episode, and Generalized Anxiety Disorder Among Men and Women

    PubMed Central

    Zhang, Chenshu; Brook, Judith S.; Leukefeld, Carl G.; Brook, David W.

    2016-01-01

    Aims The objective of this study was to examine the associations between compulsive buying (CB) and substance dependence/abuse, major depressive episode (MDE), and generalized anxiety disorder (GAD) at mean age 43. Methods Participants came from a community-based random sample of residents in two New York counties (N=548). The participants were followed from adolescence to early midlife. The mean age of participants at the most recent interview was 43.0 (SD=2.8). Fifty five percent of the participants were females. Over 90% of the participants were white. The prevalence of substance dependence/abuse, MDE, and GAD (during the past 5 years before the interviews) was 6.6%, 13.7, and 11.5%, respectively. Results Logistic regression analyses showed that CB was significantly associated with substance dependence/abuse [Adjusted Odds Ratio (A.O.R.) = 1.60], MDE (A.O.R. = 1.70), and GAD (A.O.R. = 1.63), despite controlling for substance dependence/abuse, MDE, and GAD, respectively, at mean age 37, and demographic factors. Discussion Since the study sample is limited to predominantly white participants (over 90%) with a close association to a small geographic area, the findings may not be generalizable to racial/ethnic minority groups or individuals living in other parts of the country. Nevertheless, it is important that clinicians treating substance dependence/abuse, MDE, and GAD consider the role of CB. PMID:27215919

  19. The extent and nature of imagery during worry and positive thinking in generalized anxiety disorder.

    PubMed

    Hirsch, Colette R; Hayes, Sarra; Mathews, Andrew; Perman, Gemma; Borkovec, Tom

    2012-02-01

    Clients in treatment for Generalized Anxiety Disorder (GAD) were compared to a control group to assess the extent and nature of imagery during worry or while thinking about a personally relevant positive future event. Two methods were used to assess mentation and were completed in counter balanced order within the worry and positive conditions. One method assessed the occurrence of imagery by requiring participants to categorize their mentation as verbal thoughts or images every 10 s. The other method involved participants estimating the duration of any imagery that occurred in the previous 10 s. Imagery during worry occurred less often than while thinking about a positive event for both groups, but GAD clients had a more pronounced deficit of imagery during worry than the control group. Images that occurred were briefer during worry than while thinking about a positive future event and were briefer in the GAD than the control group for both worry and positive conditions. The results thus confirmed that imagery is less common during worry in clients with GAD but also demonstrated that the imagery that does occur in GAD is briefer.

  20. Aberrant Functional Connectivity between the Amygdala and the Temporal Pole in Drug-Free Generalized Anxiety Disorder.

    PubMed

    Li, Wei; Cui, Huiru; Zhu, Zhipei; Kong, Li; Guo, Qian; Zhu, Yikang; Hu, Qiang; Zhang, Lanlan; Li, Hui; Li, Qingwei; Jiang, Jiangling; Meyers, Jordan; Li, Jianqi; Wang, Jijun; Yang, Zhi; Li, Chunbo

    2016-01-01

    The amygdala and the dorsolateral prefrontal cortex (DLPFC) play important roles in "emotion dysregulation," which has a profound impact on etiologic research of generalized anxiety disorder (GAD). The present study analyzed both eyes-open and eyes-closed resting state functional MRI (rs-fMRI) of 43 subjects (21 GAD patients with medicine free and 22 matched healthy controls). The amygdala and the DLPFC were defined as regions of interest (ROI) to analyze functional connectivity (FC) in GAD patients compared with healthy controls. The main findings revealed GAD patients had increased FC between the amygdala and the temporal pole compared to healthy controls, which was found in both eyes-open and eyes-closed rs-fMRI. And altered FC between the ROIs and brain regions that mainly belonged to the default mode network (DMN) were found. These findings suggest that the abnormal FC between the amygdala and the temporal pole may contribute to the pathophysiology of GAD, and provide insights into the current understanding of the emotion dysregulation of anxiety disorders.

  1. A Case Series on the Effects of Kripalu Yoga for Generalized Anxiety Disorder.

    PubMed

    Morgan, Jessica R; Sullivan, Marlysa; Masuda, Akihiko; Tully, Erin; Cohen, Lindsey L; Anderson, Page L

    2016-01-01

    Generalized anxiety disorder (GAD) is a prevalent psychiatric disorder associated with substantial impairment and poor treatment response. Yoga influences processes that are linked to the maintenance of GAD including mindfulness, anxiety, and heart rate variability, but has yet to be evaluated among people with the disorder. The present study is a first step toward documenting the efficacy of yoga for reducing worry among people with GAD using a single-subject AB design case series and daily ratings of worry. Standardized self-report measures of worry, trait anxiety, experiential avoidance, mindfulness, and heart rate variability were assessed pre- and post-intervention. Three participants with primary GAD received eight twice-weekly Kripalu yoga sessions following a baseline data collection period. All participants showed systematic improvement in daily worry ratings on at least one index and all scores on self-reported measures of worry, anxiety, experiential avoidance, and mindfulness changed in the expected direction following yoga (with one or two exceptions). Participants also showed improved heart rate variability during a worry period from pre- to post-intervention. Yoga has the potential to improve the processes linked to GAD and should stimulate further research in this area.

  2. Working memory dysfunction associated with brain functional deficits and cellular metabolic changes in patients with generalized anxiety disorder.

    PubMed

    Moon, Chung-Man; Sundaram, Thirunavukkarasu; Choi, Nam-Gil; Jeong, Gwang-Woo

    2016-08-30

    Generalized anxiety disorder (GAD) is associated with brain functional and morphological changes in connected with emotional dysregulation and cognitive deficit. This study dealt with the neural functional deficits and metabolic abnormalities in working memory (WM) task with emotion-inducing distractors in patients with GAD. Fourteen patients with GAD and 14 healthy controls underwent functional magnetic resonance imaging (fMRI) and proton magnetic resonance spectroscopy ((1)H-MRS) at 3T. In response to the emotional distractors in WM tasks, the patients concurrently showed higher activity in the hippocampus and lower activities in the superior occipital gyrus, superior parietal gyrus, dorsolateral prefrontal cortex (DLPFC) and precentral gyrus compared to the controls. MRS revealed significantly lower choline/creatine (Cho/Cr) and choline/N-acetylaspartate (Cho/NAA) ratios in the DLPFC. In particular, the Cho ratios were positively correlated with the brain activities based on blood oxygenation level-dependent signal change in the DLPFC. This study provides the first evidence for the association between the metabolic alterations and functional deficit in WM processing with emotion-inducing distractors in GAD. These findings will be helpful to understand the neural dysfunction in connection with WM impairment in GAD.

  3. Models of comorbidity for multifactorial disorders.

    PubMed Central

    Neale, M C; Kendler, K S

    1995-01-01

    We develop several formal models for comorbidity between multifactorial disorders. Based on the work of D. N. Klein and L. P. Riso, the models include (i) alternate forms, where the two disorders have the same underlying continuum of liability; (ii) random multiformity, in which affection status on one disorder abruptly increases risk for the second; (iii) extreme multiformity, where only extreme cases have an abruptly increased risk for the second disorder; (iv) three independent disorders, in which excess comorbid cases are due to a separate, third disorder; (v) correlated liabilities, where the risk factors for the two disorders correlate; and (vi) direct causal models, where the liability for one disorder is a cause of the other disorder. These models are used to make quantitative predictions about the relative proportions of pairs of relatives who are classified according to whether each relative has neither disorder, disorder A but not B, disorder B but not A, or both A and B. For illustration, we analyze data on major depression (MD) and generalized anxiety disorder (GAD) assessed in adult female MZ and DZ twins, which enable estimation of the relative impact of genetic and environmental factors. Several models are rejected--that comorbid cases are due to chance; multiformity of GAD; a third independent disorder; and GAD being a cause of MD. Of the models that fit the data, correlated liabilities, MD causes GAD, and reciprocal causation seem best. MD appears to be a source of liability for GAD. Possible extensions to the models are discussed. PMID:7573055

  4. Area Handbook Series: Chile: A Country Study

    DTIC Science & Technology

    1982-05-01

    in the government’s Mini- mum Employment Program (Programa del Empleo Minimo- PEM), and these workers represented about 5 percent of the labor force...unemployment was serious. In 1975 the government instituted a Minimum Employ- ment Program (Programa del Empleo Minimo-PEM). The pro- gram was geared to...Jos6, Sj., and Jaime Ruiz-Tagle P. "El Empleo Min- imo: 8Ayuda social o verguenza nacional?" Mensaje [San- tiago], 29, No. 289, June 1980, 257-63

  5. Cathodoluminescence Study of the Properties of Stacking Faults in 4H-SiC Homoepitaxial Layers

    DTIC Science & Technology

    2009-01-01

    Cathodoluminescence study of the properties of stacking faults in 4H- SiC homoepitaxial layers Serguei I. Maximenko,1,a Jaime A. Freitas, Jr.,1 Paul...2009 In-grown stacking faults in n-type 4H- SiC epitaxial layers have been investigated by real-color cathodoluminescence imaging and spectroscopy...carried out at room and liquid helium temperatures. Stacking faults with 8H stacking order were observed, as well as double layer and multilayer 3C- SiC

  6. U.S. Military Engagement with Mexico: Uneasy Past and Challenging Future

    DTIC Science & Technology

    2010-01-01

    2009, available at www.defense.gov/news/news- article.aspx?id=53381; accessed December 2009. 82. Ibid. 83. Jaime Hernandez , “Mexico To Go to Naval...no longer on Newsmax server (www.newsmax.com); and Alicia A. Caldwell, “Military chief: No plan to ramp up border presence,” News- vine, 17 April 2009...available at www.newsvine.com/_news/2009/04/17/2697918- military-chief-no-plan-to-ramp-up-border-presence; accessed January 2010. 88. Alicia A

  7. Increasing Rates of Obesity Among HIV-Infected Persons During the HIV Epidemic

    DTIC Science & Technology

    2010-04-01

    Sabin CA, Youle M, Madge S, Tyrer M, et al. (1999) Changes in AIDS-defining illnesses in a London clinic, 1987–1998. J Acquir Immune Defic Syndr 21...from the DAD study. AIDS 17: 1179–93. 31. Friis-Møller N, Sabin CA, Weber R, Reiss P, El-Sadr WM, et al. (2003) Data Collection on Adverse Events of Anti...weight. N Engl J Med 341: 427–34. 37. Duran AC, Almeida LB, Segurado AA, Jaime PC (2008) Diet quality of persons living with HIV/AIDS on highly active

  8. Two-Dimensional Flow Modeling: Proceedings of the National U.S. Army Corps of Engineers-Sponsored Seminar on the Two-Dimensional Flow Modeling (1st), 7-9 July 1981,

    DTIC Science & Technology

    1982-03-01

    Niederauer (Enerly, Inc.), Lee Butler (WES), Danny Fread (NOAA). Theodor Strelkoff (Hydraulic Enuineering), Robert MacArthur (HEC), Warren Mellema (4RD), Jaime ...Mississippi, Sabine , and Neches Rivers as shown in Figures 1 and 2. Work is on-going to gradually extend this service to other Gulf Coast rivers in Texas...MEXICO FIG. 2-HURRICANE STORM SURGE FORECASTING OF SABINE AND NECHES RIVERS 16 DAM -Z - PLAN VIEW- SEC. VIEW f-f FIG. 3- DAM-BREAK FLOOD ONTO A VERY WIDE

  9. Health Impact of US Military Service in a Large Population-Based Military Cohort: Findings of the Millennium Cohort Study, 2001-2008

    DTIC Science & Technology

    2011-01-01

    Jaime Horton; Sydney Lee, MS; Travis Leleu; Gordon Lynch; Jamie McGrew; Hope McMaster, MA, PhD; Amanda...n o t su m t o 1 0 0 . b D ep lo y ed i n s u p p o rt o f th e G lo b al W ar o n T er ro ri sm b et w ee n S ep te m b er 1 , 2 0 0...in g % P ro b le m D ri n k in g % D is o rd er ed E a ti n g d % D ep re ss io n e %

  10. Acquisition of a High-Resolution High-Intensity X-ray Diffractometer for Research and Education

    DTIC Science & Technology

    2015-07-20

    Strontium  Titanate (STO) thin films   on two different substrates  Authors: Sudeshna Chattopadhyay, Nuwanjula S. Samarasingha Arachchige, and Jaime Moya...Texas at Austin.    Figure E.1: Specular x‐ray reflectivity data  for  strontium  titanate, SrTiO3 (STO), on  different substrates (Si and Ge

  11. Students grapple with life and death issues.

    PubMed

    Bishop, Jaime

    2010-10-01

    The 2010 Architects for Health (AfH) Student Health Design Awards, presented recently at the RIBA's London headquarters, saw the highest number of entries--at nearly 100--in the event's four-year history, with architecture and interior design students from all over the world demonstrating their talent, imagination, and creative skills, in the quest for the top prize. Jaime Bishop, a director of Fleet Architects, AfH Executive board member, and the competition's organiser, outlines the Awards' key aims, describes the shortlisted and winning entries, discusses how candidates addressed the brief, and explains how the judges selected this year's winner and two runners-up.

  12. Identification and Treatment of Generalized Anxiety Disorder in Children in Primary Care.

    PubMed

    Dillon-Naftolin, Erin

    2016-10-01

    Youth with anxiety often present to their pediatricians with a chief complaint of physical symptoms without any mention of anxiety or worry. Even in the absence of reported symptoms of anxiety in such presentations, screening for an anxiety disorder as the potential source of the somatic complaints should be pursued. Generalized anxiety disorder (GAD) is a common disorder characterized by excessive anxiety and worry about a number of events coupled with at least one physical symptom. GAD is commonly underdiagnosed and treated. Consequently, many youth undergo extensive medical testing in search of a cause for their somatic symptoms before anxiety is considered. It is important to screen for anxiety early in the process of evaluating somatic complaints. This review highlights the evidence base for identifying and treating GAD in children and provides an update on its epidemiology and etiology. [Pediatr Ann. 2016;45(10):e349-e355.].

  13. Maternal immune activation alters glutamic acid decarboxylase-67 expression in the brains of adult rat offspring

    PubMed Central

    Cassella, Sarah N.; Hemmerle, Ann M.; Lundgren, Kerstin H.; Kyser, Tara L.; Ahlbrand, Rebecca; Bronson, Stefanie L.; Richtand, Neil M.; Seroogy, Kim B.

    2016-01-01

    Activation of the maternal innate immune system, termed “maternal immune activation” (MIA), represents a common environmental risk factor for schizophrenia. Whereas evidence suggests dysregulation of GABA systems may underlie the pathophysiology of schizophrenia, a role for MIA in alteration of GABAergic systems is less clear. Here, pregnant rats received either the viral mimetic polyriboinosinic-polyribocytidilic acid or vehicle injection on gestational day 14. Glutamic acid decarboxylase-67 (GAD67) mRNA expression was examined in male offspring at postnatal day (P)14, P30 and P60. At P60, GAD67 mRNA was elevated in hippocampus and thalamus and decreased in prefrontal cortex of MIA offspring. MIA-induced alterations in GAD expression could contribute to the pathophysiology of schizophrenia. PMID:26830319

  14. Use of Gilliam Asperger's disorder scale in differentiating high and low functioning autism and ADHD.

    PubMed

    Mayes, Susan Dickerson; Calhoun, Susan L; Murray, Michael J; Morrow, Jill D; Yurich, Kirsten K L; Cothren, Shiyoko; Purichia, Heather; Bouder, James N

    2011-02-01

    Little is known about the validity of Gilliam Asperger's Disorder Scale (GADS), although it is widely used. This study of 199 children with high functioning autism or Asperger's disorder, 195 with low functioning autism, and 83 with attention deficit hyperactivity disorder (ADHD) showed high classification accuracy (autism vs. ADHD) for clinicians' GADS Quotients (92%), and somewhat lower accuracy (77%) for parents' Quotients. Both children with high and low functioning autism had clinicians' Quotients (M=99 and 101, respectively) similar to the Asperger's Disorder mean of 100 for the GADS normative sample. Children with high functioning autism scored significantly higher on the cognitive patterns subscale than children with low functioning autism, and the latter had higher scores on the remaining subscales: social interaction, restricted patterns of behavior, and pragmatic skills. Using the clinicians' Quotient and Cognitive Patterns score, 70% of children were correctly identified as having high or low functioning autism or ADHD.

  15. New developments in the management of major depressive disorder and generalized anxiety disorder: role of quetiapine.

    PubMed

    Baune, Bernhard T

    2008-12-01

    Quetiapine has demonstrated efficacy in schizophrenia, bipolar disorder and in the treatment of specific symptom clusters such as agitation and sleep problems in mood disorders. In this review, randomized controlled studies demonstrating efficacy, safety and tolerability of quetiapine in major depressive disorder (MDD) and general anxiety disorder (GAD) are evaluated. The results show that quetiapine monotherapy and quetiapine augmentation of antidepressant treatment in MDD and GAD are efficacious for short-term and maintenance treatment at a dose range between 50 and 300 mg/day. Quetiapine appears to have a specific but overall mild side-effect profile, though, some adverse effects such as sedation and somnolence may lead to withdrawal from treatment in some patients. Overall, the available evidence suggests that there is a significant role for quetiapine in the treatment of MDD and GAD.

  16. Contextual conditioning in rats as an animal model for generalized anxiety disorder.

    PubMed

    Luyten, Laura; Vansteenwegen, Debora; van Kuyck, Kris; Gabriëls, Loes; Nuttin, Bart

    2011-06-01

    Animal models of psychiatric disorders are important translational tools for exploring new treatment options and gaining more insight into the disease. Thus far, there is no systematically validated animal model for generalized anxiety disorder (GAD), a severely impairing and difficult-to-treat disease. In this review, we propose contextual conditioning (CC) as an animal model for GAD. We argue that this model has sufficient face validity (there are several symptom similarities), predictive validity (it responds to clinically effective treatments), and construct validity (the underlying mechanisms are comparable). Although the refinement and validation of an animal model is a never-ending process, we want to give a concise overview of the currently available evidence. We suggest that the CC model might be a valuable preclinical tool to enhance the development of new treatment strategies and our understanding of GAD.

  17. [Efficacy and possible mechanisms of action of a new peptide anxiolytic selank in the therapy of generalized anxiety disorders and neurasthenia].

    PubMed

    Zozulia, A A; Neznamov, G G; Siuniakov, T S; Kost, N V; Gabaeva, M V; Sokolov, O Iu; Serebriakova, E V; Siranchieva, O A; Andriushenko, A V; Telesheva, E S; Siuniakov, S A; Smulevich, A B; Miasoedov, N F; Seredenin, S B

    2008-01-01

    Sixty-two patients with generalized anxiety disorder (GAD) and neurasthenia were studied. The effect of selank (30 patients) was compared to that of medazepam (32 patients). Patient's state was assessed with psychometric scales (Hamilton, Zung, CGI). Enkephalin activity in the blood serum was measured as well. The anxiolytic effects of both drugs were similar but selank had also antiasthenic and psychostimulant effects. The clinical-biological study revealed that patients with GAD and neurasthenia had the decreased level of tau(1/2) leu-enkephalin which was correlated with disease duration, severity of symptoms related to anxiety and asthenia and autonomic disorders. The increase of this parameter and stronger positive correlations with anxiety level were observed during the treatment with selank mostly in patients with GAD.

  18. Glutamic acid decarboxylase autoimmunity in Batten disease and other disorders.

    PubMed

    Pearce, David A; Atkinson, Mark; Tagle, Danilo A

    2004-12-14

    Degenerative diseases of the CNS, such as stiff-person syndrome (SPS), progressive cerebellar ataxia, and Rasmussen encephalitis, have been characterized by the presence of autoantibodies. Recent findings in individuals with Batten disease and in animal models for the disorder indicate that this condition may be associated with autoantibodies against glutamic acid decarboxylase (GAD), an enzyme that converts the excitatory neurotransmitter glutamate to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Anti-GAD autoantibodies could result in excess excitatory neurotransmitters, leading to the seizures and other symptoms observed in patients with Batten disease. The pathogenic potential of GAD autoantibodies is examined in light of what is known for other autoimmune disorders, such as multiple sclerosis, SPS, Rasmussen encephalitis, and type 1 diabetes, and may have radical implications for diagnosis and management of Batten disease.

  19. Group cognitive-behavioral therapy for generalized anxiety disorder: treatment outcome and long-term follow-up.

    PubMed

    Dugas, Michel J; Ladouceur, Robert; Léger, Eliane; Freeston, Mark H; Langlois, Frédéric; Provencher, Martin D; Boisvert, Jean-Marie

    2003-08-01

    A recently developed cognitive-behavioral treatment for generalized anxiety disorder (GAD) targets intolerance of uncertainty by the reevaluation of positive beliefs about worry, problem-solving training, and cognitive exposure. As previous studies have established the treatment's efficacy when delivered individually, the present study tests the treatment in a group format as a way to enhance its cost-benefit ratio. A total of 52 GAD patients received 14 sessions of cognitive-behavioral therapy in small groups of 4 to 6 participants. A wait-list control design was used, and standardized clinician ratings and self-report questionnaires assessed GAD symptoms, intolerance of uncertainty, anxiety, depression, and social adjustment. Results show that the treatment group, relative to the wait-list group, had greater posttest improvement on all dependent variables and that treated participants made further gains over the 2-year follow-up phase of the study.

  20. Combined medication and cognitive therapy for generalized anxiety disorder.

    PubMed

    Crits-Christoph, Paul; Newman, Michelle G; Rickels, Karl; Gallop, Robert; Gibbons, Mary Beth Connolly; Hamilton, Jessica L; Ring-Kurtz, Sarah; Pastva, Amy M

    2011-12-01

    The current study assessed efficacy of combined cognitive behavioral therapy (CBT) and venlafaxine XR compared to venlafaxine XR alone in the treatment of generalized anxiety disorder (GAD) within settings where medication is typically offered as the treatment for this disorder. Patients with DSM-IV-diagnosed GAD who were recently enrolled in a long-term venlafaxine XR study were randomly offered (n=77), or not offered (n=40), the option of adding 12 sessions of CBT. Of those offered CBT, 33% (n=26) accepted and attended at least one treatment session. There were no differences between the combined treatment group and the medication only group on primary or secondary efficacy measures in any of the sample comparisons. Many patients who present in medical/psychopharmacology settings seeking treatment for GAD decline the opportunity to receive adjunctive treatment. Of those that receive CBT, there appears to be no additional benefit of combined treatment compared to venlafaxine XR alone.

  1. Parental Involvement in Infant Sleep Routines Predicts Differential Sleep Patterns in Children With and Without Anxiety Disorders.

    PubMed

    Cowie, Jennifer; Palmer, Cara A; Hussain, Hira; Alfano, Candice A

    2016-08-01

    This study compared parents' retrospective reports of their involvement in infant settling strategies and their relation to current sleep patterns among children (N = 84, ages 7-11) with generalized anxiety disorder (GAD) and healthy controls. Parents of children with GAD were significantly more likely to report rocking their infants to sleep and putting infants down when they were already asleep than parents of healthy controls, even when accounting for infant health-related factors and parental anxiety. Greater involvement in infant sleep routines also predicted sleep patterns (measured via actigraphy) during childhood, though opposite relationships were observed in the two groups. Early involvement was related to poorer sleep in control children but better sleep for children with GAD even after controlling for current parenting practices. Findings suggest differential effects of early sleep-related parenting for children with and without later anxiety disorders with possible implications for early intervention.

  2. Identification and molecular cloning of glutamate decarboxylase gene from Lactobacillus casei

    PubMed Central

    Tavakoli, Yasaman; Esmaeili, Abolghasem; Rabbani, Mohammad

    2015-01-01

    Gamma-amino butyric acid (GABA) possesses several physiological functions such as neurotransmission, induction of hypotension, diuretic and tranquilizer effects. Production of GABA-enriched products by lactic acid bacteria has been a focus of different researches in recent years because of their safety and health-promoting specifities. In this study, glutamate decarboxylase (gad) gene of a local strains Lactobacillus casei was identified and cloned. In order to clone the gad gene from this strain, the PCR was carried out using primers designed based on conserved regions. The PCR product was purified and ligated into PGEM-T vector. Comparison of obtained sequences shows that this fragment codes the pyridoxal 5′-phosphate binding region. This strain could possibly be used for the industrial GABA production and also for development of functional fermented foods. Gad gene manipulation can also either decrease or increase the activity of enzyme in bacteria. PMID:27844008

  3. Health functioning impairments associated with posttraumatic stress disorder, anxiety disorders, and depression.

    PubMed

    Zayfert, Claudia; Dums, Aricca R; Ferguson, Robert J; Hegel, Mark T

    2002-04-01

    Although anxiety disorders have been associated with impairments in self-reported health functioning, the relative effect of various anxiety disorders has not been studied. We compared health functioning of patients with a principal diagnosis of posttraumatic stress disorder (PTSD), panic disorder (PD), generalized anxiety disorder (GAD), and major depressive disorder (MDD). Patients with PTSD and MDD were equally impaired on overall mental health functioning, and both were significantly worse than patients with PD and GAD. PTSD was associated with significantly worse physical health functioning relative to PD, GAD, and MDD. Hierarchical regression showed that the association of PTSD with physical health functioning was unique and was not caused by the effects of age, depression, or comorbid anxiety disorders. Both PTSD and comorbid anxiety accounted for unique variance in mental functioning. These results highlight the association of PTSD with impaired physical and mental functioning and suggest that effective treatment of PTSD may affect overall health.

  4. Ubiquitin C-terminal hydrolase L1 deficiency decreases bone mineralization.

    PubMed

    Shim, Sehwan; Kwon, Young-Bae; Yoshikawa, Yasuhiro; Kwon, Jungkee

    2008-06-01

    Ubiquitin C-terminal hydrolase L1 is a component of the ubiquitin proteasome system, which evidences unique biological activities. In this study, we report the pattern of UCH-L1 expression, and show that it regulates bone mineralization in osteogenesis. UCH-L1 was expressed in osteoblasts, osteoclasts, and hematopoietic precursor cells of bone marrow in the metaphysis and diaphysis of the femora. To further assess the involvement of UCH-L1 in the regulation of bone mineralization, we evaluated the bone mineral density (BMD) rate of gad mice, using the Latheta computed tomography system. Male gad mice evidenced a significantly decreased BMD rate in the metaphysis and diaphysis of the femora. These findings of decreased BMD rate in the bones of gad mice may suggest that UCH-L1 function regulates bone mineralization during osteogenesis.

  5. Bad Dream Frequency in Older Adults with Generalized Anxiety Disorder: Prevalence, Correlates, and Effect of Cognitive Behavioral Treatment for Anxiety

    PubMed Central

    Nadorff, Michael R.; Porter, Ben; Rhoades, Howard M.; Greisinger, Anthony J.; Kunik, Mark E.; Stanley, Melinda A.

    2012-01-01

    This study investigated the relation between generalized anxiety disorder (GAD) and frequency of bad dreams in older adults. A secondary analysis from a randomized clinical trial comparing cognitive behavioral therapy for anxiety (CBT) to enhanced usual care (EUC), it assessed bad dream frequency at baseline, post-treatment (3 months), and 6, 9, 12 and 15 months. Of 227 participants (mean age = 67.4), 134 met GAD diagnostic criteria (CBT = 70, EUC = 64), with the remaining 93 serving as a comparison group. Patients with GAD had significantly more bad dreams than those without, and bad dream frequency was significantly associated with depression, anxiety, worry, and poor quality of life. CBT for anxiety significantly reduced bad dream frequency at post-treatment and throughout follow-up compared to EUC. PMID:23470116

  6. GABA shunt and polyamine degradation pathway on γ-aminobutyric acid accumulation in germinating fava bean (Vicia faba L.) under hypoxia.

    PubMed

    Yang, Runqiang; Guo, Qianghui; Gu, Zhenxin

    2013-01-01

    GABA shunt and polyamine degradation pathway on γ-aminobutyric acid (GABA) accumulation in germinating fava bean under hypoxia was investigated. GABA content, GAD and DAO activity were significantly increased under hypoxia treatment. Glu and polyamine contents enhanced largely and thus supplied as sufficient substrates for GABA formation. In contrast, GABA content decreased, mainly in the embryo, after removing the hypoxia stress. DAO activity, Glu and polyamines contents decreased, while an increment of GAD activity was observed. This indicated that GAD activity can be not only regulated by hypoxia, but by the rapid growth of embryo after the recovery from hypoxia stress. When treated with AG, DAO activity was almost inhibited completely, and the GABA content decreased by 32.96% and 32.07% after treated for 3 and 5 days, respectively. Hence, it can be inferred that about 30% of GABA formed in germinating fava bean under hypoxia was supplied by polyamine degradation pathway.

  7. Sexual violence therapy group in a women's correctional facility: a preliminary evaluation.

    PubMed

    Karlsson, Marie E; Bridges, Ana J; Bell, Jessica; Petretic, Patricia

    2014-06-01

    This pilot study was an evaluation of an 8-week exposure-based therapy group targeting sexual trauma in incarcerated women, an underserved population with high rates of trauma exposure. Preliminary findings from 14 female prisoners showed significant decreases in depressive and anxiety symptoms from pre- to posttreatment. Of the women who were above the screening cutoff for possible posttraumatic stress disorder (PTSD; n = 13), depression (n = 12), and generalized anxiety disorder (GAD; n = 12) at pretreatment, approximately 60% had recovered, meaning they had symptom reductions that placed them below the cutoff at posttreatment (n = 8 for PTSD; n = 8 for depression, and n = 9 for GAD). In addition, 85% of participants reported a clinically significant reduction in depressive symptoms and 50% in GAD symptoms. The findings show promise for successful group treatment of sexual violence sequelae in incarcerated women.

  8. Bad dream frequency in older adults with generalized anxiety disorder: prevalence, correlates, and effect of cognitive behavioral treatment for anxiety.

    PubMed

    Nadorff, Michael R; Porter, Ben; Rhoades, Howard M; Greisinger, Anthony J; Kunik, Mark E; Stanley, Melinda A

    2014-01-01

    This study investigated the relation between generalized anxiety disorder (GAD) and frequency of bad dreams in older adults. A secondary analysis from a randomized clinical trial comparing cognitive behavioral therapy (CBT) for anxiety to enhanced usual care (EUC) assessed bad dream frequency at baseline, post treatment (3 months), and at 6, 9, 12, and 15 months. Of 227 participants (mean age = 67.4), 134 met GAD diagnostic criteria (CBT = 70, EUC = 64), with the remaining 93 serving as a comparison group. Patients with GAD had significantly more bad dreams than those without, and bad dream frequency was significantly associated with depression, anxiety, worry, and poor quality of life. CBT for anxiety significantly reduced bad dream frequency at post treatment and throughout follow up compared to EUC.

  9. Heat source reconstruction from noisy temperature fields using a gradient anisotropic diffusion filter

    NASA Astrophysics Data System (ADS)

    Beitone, C.; Balandraud, X.; Delpueyo, D.; Grédiac, M.

    2017-01-01

    This paper presents a post-processing technique for noisy temperature maps based on a gradient anisotropic diffusion (GAD) filter in the context of heat source reconstruction. The aim is to reconstruct heat source maps from temperature maps measured using infrared (IR) thermography. Synthetic temperature fields corrupted by added noise are first considered. The GAD filter, which relies on a diffusion process, is optimized to retrieve as well as possible a heat source concentration in a two-dimensional plate. The influence of the dimensions and the intensity of the heat source concentration are discussed. The results obtained are also compared with two other types of filters: averaging filter and Gaussian derivative filter. The second part of this study presents an application for experimental temperature maps measured with an IR camera. The results demonstrate the relevancy of the GAD filter in extracting heat sources from noisy temperature fields.

  10. The effect of mindfulness meditation training on biological acute stress responses in generalized anxiety disorder.

    PubMed

    Hoge, Elizabeth A; Bui, Eric; Palitz, Sophie A; Schwarz, Noah R; Owens, Maryann E; Johnston, Jennifer M; Pollack, Mark H; Simon, Naomi M

    2017-01-25

    Mindfulness-Based interventions have increased in popularity in psychiatry, but the impact of these treatments on disorder-relevant biomarkers would greatly enhance efficacy and mechanistic evidence. If Generalized Anxiety Disorder (GAD) is successfully treated, relevant biomarkers should change, supporting the impact of treatment and suggesting improved resilience to stress. Seventy adults with GAD were randomized to receive either Mindfulness-Based Stress Reduction (MBSR) or an attention control class; before and after, they underwent the Trier Social Stress Test (TSST). Area-Under-the-Curve (AUC) concentrations were calculated for adrenocorticotropic hormone (ACTH) and pro-inflammatory cytokines. MBSR participants had a significantly greater reduction in ACTH AUC compared to control participants. Similarly, the MBSR group had a greater reduction in inflammatory cytokines' AUC concentrations. We found larger reductions in stress markers for patients with GAD in the MBSR class compared to control; this provides the first combined hormonal and immunological evidence that MBSR may enhance resilience to stress.

  11. Neurobiological substrates of cognitive rigidity and autonomic inflexibility in generalized anxiety disorder.

    PubMed

    Ottaviani, Cristina; Watson, David R; Meeten, Frances; Makovac, Elena; Garfinkel, Sarah N; Critchley, Hugo D

    2016-09-01

    Generalized anxiety disorder (GAD) is characterized by difficulties in inhibiting both perseverative thoughts (worry and rumination) and autonomic arousal. We investigated the neurobiological substrates of such abnormal inhibitory processes, hypothesizing aberrant functional coupling within 'default mode' (DMN) and autonomic brain networks. Functional imaging and heart rate variability (HRV) data were acquired from GAD patients and controls during performance of three tracking tasks interspersed with a perseverative cognition (PC) induction. After detection of infrequent target stimuli, activity within putative DMN hubs was suppressed, consistent with a redirection of attentional resources from internal to external focus. This magnitude of activity change was attenuated in patients and individuals with higher trait PC, but was predicted by individual differences in HRV. Following the induction of PC in controls, this pattern of neural reactivity became closer to that of GAD patients. Results support, at a neural level, the association between cognitive inflexibility and autonomic rigidity.

  12. DSM-III personality disorders in generalized anxiety, panic/agoraphobia, and obsessive-compulsive disorders.

    PubMed

    Mavissakalian, M R; Hamann, M S; Abou Haidar, S; de Groot, C M

    1993-01-01

    In an earlier report, we stated that personality profiles of patients with panic disorder/agoraphobia (n = 187) and obsessive-compulsive disorder ([ODC] n = 51) were similar, albeit more pronounced in OCD, suggesting that the link between panic disorder/agoraphobia and DSM-III personality disorders (PDs) or traits may be nonspecific. The present report extends the comparative study of DSM-III PDs/traits, as assessed by the Personality Diagnostic Questionnaire (PDQ), by adding a third diagnostic group of 39 patients with generalized anxiety disorder (GAD). The personality assessment of panic disorder/agoraphobia and GAD patients yielded virtually identical results on the PDQ and Eysenck Personality Inventory (EPI). Because GAD lacks the prominent panic, phobic, and obsessive-compulsive symptoms of other anxiety disorders, the present findings provide strong support for a nonspecific link between panic disorder/agoraphobia and DSM-III PDs/traits and for the presence of common personality characteristics in anxiety disorders.

  13. Comparison of scores on the Checklist for Autism Spectrum Disorder, Childhood Autism Rating Scale, and Gilliam Asperger's Disorder Scale for children with low functioning autism, high functioning autism, Asperger's disorder, ADHD, and typical development.

    PubMed

    Mayes, Susan Dickerson; Calhoun, Susan L; Murray, Michael J; Morrow, Jill D; Yurich, Kirsten K L; Mahr, Fauzia; Cothren, Shiyoko; Purichia, Heather; Bouder, James N; Petersen, Christopher

    2009-12-01

    Reliability and validity for three autism instruments were compared for 190 children with low functioning autism (LFA), 190 children with high functioning autism or Asperger's disorder (HFA), 76 children with attention deficit hyperactivity disorder (ADHD), and 64 typical children. The instruments were the Checklist for Autism Spectrum Disorder (designed for children with LFA and HFA), Childhood Autism Rating Scale (CARS) for children with LFA, and Gilliam Asperger's Disorder Scale (GADS). For children with LFA or ADHD, classification accuracy was 100% for the Checklist and 98% for the CARS clinician scores. For children with HFA or ADHD, classification accuracy was 99% for the Checklist and 93% for the GADS clinician scores. Clinician-parent diagnostic agreement was high (90% Checklist, 90% CARS, and 84% GADS).

  14. Abnormalities in gray and white matter volumes associated with explicit memory dysfunction in patients with generalized anxiety disorder.

    PubMed

    Moon, Chung-Man; Jeong, Gwang-Woo

    2017-03-01

    Background The neuroanatomical abnormalities associated with behavioral dysfunction on explicit memory in patients generalized anxiety disorder (GAD) have not yet been clearly identified. Purpose To investigate the regional gray matter (GM) and white matter (WM) volume alterations over the whole brain in patients with GAD, as well as the correlation between the brain structural abnormality and explicit memory dysfunction. Material and Methods Twenty patients with GAD and 20 healthy controls matched for age, sex, and education level underwent high-resolution T1-weighted magnetic resonance imaging (MRI). The participants performed the explicit memory tasks with the neutral and anxiety-inducing words. Results Patients with GAD showed significantly reduced GM volumes in the midbrain (MB), thalamus, hippocampus (Hip), insula, and superior temporal gyrus (STG); and reduced WM volumes in the MB, anterior limb of the internal capsule (ALIC), dorsolateral prefrontal cortex (DLPFC), and precentral gyrus (PrG). It is important to note that the GM volume of the Hip and the WM volume of the DLPFC were positively correlated with the recognition accuracy (%) in the explicit memory tasks with neutral and anxiety-inducing words, respectively. On the other hand, the WM volume of the PrG was negatively correlated with the reaction time in the same memory tasks. Conclusion This study demonstrated the regional volume changes on whole-brain GM and WM and the correlation between the brain structural alteration and explicit memory dysfunction in GAD patients. These findings would be helpful to understand the association between the brain structure abnormality and the functional deficit in the explicit memory in GAD.

  15. Perinatal Generalized Anxiety Disorder: Assessment and Treatment.

    PubMed

    Misri, Shaila; Abizadeh, Jasmin; Sanders, Shawn; Swift, Elena

    2015-09-01

    Perinatal generalized anxiety disorder (GAD) has a high prevalence of 8.5%-10.5% during pregnancy and 4.4%-10.8% postpartum. Despite its attendant dysfunction in the patient, this potentially debilitating mental health condition is often underdiagnosed. This overview will provide guidance for clinicians in making timely diagnosis and managing symptoms appropriately. A significant barrier to the diagnosis of GAD in the perinatal population is difficulty in distinguishing normal versus pathological worry. Because a perinatal-specific screening tool for GAD is nonexistent, early identification, diagnosis and treatment is often compromised. The resultant maternal dysfunction can potentially impact mother-infant bonding and influence neurodevelopmental outcomes in the children. Comorbid occurrence of GAD and major depressive disorder changes the illness course and its treatment outcome. Psychoeducation is a key component in overcoming denial/stigma and facilitating successful intervention. Treatment strategies are contingent upon illness severity. Cognitive behavior therapy (CBT), relaxation, and mindfulness therapy are indicated for mild GAD. Moderate/severe illness requires pharmacotherapy and CBT, individually or in combination. No psychotropic medications are approved by the FDA or Health Canada in pregnancy or the postpartum; off-label pharmacological treatment is instituted only if the benefit of therapy outweighs its risk. SSRIs/SNRIs are the first-line treatment for anxiety disorders due to data supporting their efficacy and overall favorable side effect profile. Benzodiazepines are an option for short-term treatment. While research on atypical antipsychotics is evolving, some can be considered for severe manifestations where the response to antidepressants or benzodiazepines has been insufficient. A case example will illustrate the onset, clinical course, and treatment strategies of GAD through pregnancy and the postpartum.

  16. Mesomere-derived glutamate decarboxylase-expressing blastocoelar mesenchyme cells of sea urchin larvae

    PubMed Central

    Katow, Hideki; Katow, Tomoko; Abe, Kouki; Ooka, Shioh; Kiyomoto, Masato; Hamanaka, Gen

    2014-01-01

    Summary The ontogenetic origin of blastocoelar glutamate decarboxylase (GAD)-expressing cells (GADCs) in larvae of the sea urchin Hemicentrotus pulcherrimus was elucidated. Whole-mount in situ hybridisation (WISH) detected transcription of the gene that encodes GAD in H. pulcherrimus (Hp-gad) in unfertilised eggs and all blastomeres in morulae. However, at and after the swimming blastula stage, the transcript accumulation was particularly prominent in clumps of ectodermal cells throughout the embryonic surface. During the gastrula stage, the transcripts also accumulated in the endomesoderm and certain blastocoelar cells. Consistent with the increasing number of Hp-gad transcribing cells, immunoblot analysis indicated that the relative abundance of Hp-Gad increased considerably from the early gastrula stage until the prism stage. The expression pattern of GADCs determined by immunohistochemistry was identical to the pattern of Hp-gad transcript accumulation determined using WISH. In early gastrulae, GADCs formed blastocoelar cell aggregates around the blastopore with primary mesenchyme cells. The increase in the number of blastocoelar GADCs was inversely proportional to the number of ectodermal GADCs ranging from a few percent of total GADCs in early gastrulae to 80% in late prism larvae; this depended on ingression of ectodermal GADCs into the blastocoel. Some of the blastocoelar GADCs were fluorescein-positive in the larvae that developed from the 16-cell stage chimeric embryos; these comprised fluorescein-labeled mesomeres and unlabelled macromeres and micromeres. Our finding indicates that some of the blastocoelar GADCs are derived from the mesomeres and thus they are the new group of mesenchyme cells, the tertiary mesenchyme cells. PMID:24357228

  17. Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder

    PubMed Central

    Wang, Zuowei; Kemp, David E.; Chan, Philip K.; Fang, Yiru; Ganocy, Stephen J.; Calabrese, Joseph R.; Gao, Keming

    2012-01-01

    Quetiapine extended-release (quetiapine-XR) has been studied in patients with schizophrenia, bipolar mania, bipolar depression, major depressive disorder (MDD), and generalized anxiety disorder (GAD). The purpose of this study was to compare the tolerability and sensitivity of quetiapine-XR among these psychiatric conditions. The discontinuation due to adverse events (DAEs) and reported somnolence in randomized, double-blind, placebo-controlled studies of quetiapine-XR in these psychiatric conditions were examined. The absolute risk reduction or increase and the number needed to treat to benefit (NNTB) or harm (NNTH) for DAEs and reported somnolence of quetiapine-XR ≥300 mg/d relative to placebo were estimated. Data from one study in schizophrenia (n=465), one in mania (n=316), one in bipolar depression (n=280), two in refractory MDD (n=624), two in MDD (n=669) and three in GAD (n=1109) were available. The risk for DAEs of quetiapine-XR relative to placebo was significantly increased in bipolar depression (NNTH=9), refractory MDD (NNTH=8), MDD (NNTH=9), and GAD (NNTH=5), but not in schizophrenia and mania. The risk for reported somnolence of quetiapine-XR relative to placebo was significantly increased in schizophrenia (600 mg/d NNTH=15 and 800 mg/d NNTH=11), mania (NNTH=8), bipolar depression (NNTH=4), refractory MDD (NNTH=5), MDD (NNTH=5) and GAD (NNTH=5). These results suggest that patients with GAD had the poorest tolerability during treatment with quetiapine-XR, but they had a similar sensitivity as those with bipolar depression and MDD. Patients with schizophrenia or mania had a higher tolerability and a lower sensitivity than those with bipolar depression, MDD, or GAD. PMID:20875219

  18. Electrophysiological characteristics of inhibitory neurons of the prepositus hypoglossi nucleus as analyzed in Venus-expressing transgenic rats.

    PubMed

    Shino, M; Kaneko, R; Yanagawa, Y; Kawaguchi, Y; Saito, Y

    2011-12-01

    The identification and characterization of excitatory and inhibitory neurons are significant steps in understanding neural network functions. In this study, we investigated the intrinsic electrophysiological properties of neurons in the prepositus hypoglossi nucleus (PHN), a brainstem structure that is involved in gaze holding, using whole-cell recordings in brainstem slices from vesicular GABA transporter (VGAT)-Venus transgenic rats, in which inhibitory neurons express the fluorescent protein Venus. To characterize the intrinsic properties of these neurons, we recorded afterhyperpolarization (AHP) profiles and firing patterns from Venus-expressing [Venus⁺] and Venus-non-expressing [Venus⁻] PHN neurons. Although both types of neurons showed a wide variety of AHP profiles and firing patterns, oscillatory firing was specific to Venus⁺ neurons, while a firing pattern showing only a few spikes was specific to Venus⁻ neurons. In addition, AHPs without a slow component and delayed spike generation were preferentially displayed by Venus⁺ neurons, whereas a firing pattern with constant interspike intervals was preferentially displayed by Venus⁻ neurons. We evaluated the mRNAs expression of glutamate decarboxylase (GAD65, GAD67) and glycine transporter 2 (GlyT2) to determine whether the recorded Venus⁺ neurons were GABAergic or glycinergic. Of the 67 Venus⁺ neurons tested, GlyT2 expression alone was detected in only one neuron. Approximately 40% (28/67) expressed GAD65 and/or GAD67 (GABAergic neuron), and the remainder (38/67) expressed both GAD(s) and GlyT2 (GABA&GLY neuron). These results suggest that most inhibitory PHN neurons use either GABA or both GABA and glycine as neurotransmitters. Although the overall distribution of firing patterns in GABAergic neurons was similar to that of GABA&GLY neurons, only GABA&GLY neurons exhibited a firing pattern with a long first interspike interval. These differential electrophysiological properties will be useful

  19. Glutamic acid decarboxylase 65: a link between GABAergic synaptic plasticity in the lateral amygdala and conditioned fear generalization.

    PubMed

    Lange, Maren D; Jüngling, Kay; Paulukat, Linda; Vieler, Marc; Gaburro, Stefano; Sosulina, Ludmila; Blaesse, Peter; Sreepathi, Hari K; Ferraguti, Francesco; Pape, Hans-Christian

    2014-08-01

    An imbalance of the gamma-aminobutyric acid (GABA) system is considered a major neurobiological pathomechanism of anxiety, and the amygdala is a key brain region involved. Reduced GABA levels have been found in anxiety patients, and genetic variations of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, have been associated with anxiety phenotypes in both humans and mice. These findings prompted us to hypothesize that a deficiency of GAD65, the GAD isoform controlling the availability of GABA as a transmitter, affects synaptic transmission and plasticity in the lateral amygdala (LA), and thereby interferes with fear responsiveness. Results indicate that genetically determined GAD65 deficiency in mice is associated with (1) increased synaptic length and release at GABAergic connections, (2) impaired efficacy of GABAergic synaptic transmission and plasticity, and (3) reduced spillover of GABA to presynaptic GABAB receptors, resulting in a loss of the associative nature of long-term synaptic plasticity at cortical inputs to LA principal neurons. (4) In addition, training with high shock intensities in wild-type mice mimicked the phenotype of GAD65 deficiency at both the behavioral and synaptic level, indicated by generalization of conditioned fear and a loss of the associative nature of synaptic plasticity in the LA. In conclusion, GAD65 is required for efficient GABAergic synaptic transmission and plasticity, and for maintaining extracellular GABA at a level needed for associative plasticity at cortical inputs in the LA, which, if disturbed, results in an impairment of the cue specificity of conditioned fear responses typifying anxiety disorders.

  20. Pregabalin: a review of its use in adults with generalized anxiety disorder.

    PubMed

    Frampton, James E

    2014-09-01

    Pregabalin (Lyrica(®)), a well established anxiolytic agent, has been approved in the EU for the treatment of generalized anxiety disorder (GAD) in adults. It has a distinct mechanism of action relative to other anti-anxiety agents (α2δ binding at presynaptic voltage dependent calcium channels leading to inhibition of excitatory neurotransmission), a rapid onset of effect (typically ≤1 week) and broad spectrum activity against both the psychic and somatic symptoms of GAD. In long-term studies, pregabalin maintained improvements in anxiety symptoms that occurred in response to short-term treatment and delayed the time to relapse of GAD compared with placebo. Common comorbidities of GAD, such as insomnia, gastrointestinal symptoms and subsyndromal depression, have no effect on the anxiolytic efficacy of, and moreover are specifically improved by, pregabalin. Treatment with pregabalin is generally well tolerated; the drug has an adverse event profile that includes dizziness, somnolence and weight gain. The potential for abuse of pregabalin is low; the risk of withdrawal symptoms is generally low when the drug is discontinued gradually (over 1 week). Alongside selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs), pregabalin is considered a first-line agent for the long-term treatment of GAD by the World Federation of Societies of Biological Psychiatry. It should be stressed, however, that definitive head-to-head studies comparing pregabalin with SSRI/SNRIs, including in patients with GAD and co-morbid major depressive disorder, are currently lacking. Recently, a study of SSRI/SNRI augmentation with pregabalin yielded positive results, while another study of switching from long-term benzodiazepine therapy to pregabalin was inconclusive; further investigations on these topics are warranted.

  1. Role of the multidrug resistance regulator MarA in global regulation of the hdeAB acid resistance operon in Escherichia coli.

    PubMed

    Ruiz, Cristian; McMurry, Laura M; Levy, Stuart B

    2008-02-01

    MarA, a transcriptional regulator in Escherichia coli, affects functions such as multiple-antibiotic resistance (Mar) and virulence. Usually an activator, MarA is a repressor of hdeAB and other acid resistance genes. We found that, in wild-type cells grown in LB medium at pH 7.0 or pH 5.5, repression of hdeAB by MarA occurred only in stationary phase and was reduced in the absence of H-NS and GadE, the main regulators of hdeAB. Moreover, repression of hdeAB by MarA was greater in the absence of GadX or Lrp in exponential phase at pH 7.0 and in the absence of GadW or RpoS in stationary phase at pH 5.5. In turn, MarA enhanced repression of hdeAB by H-NS and hindered activation by GadE in stationary phase and also reduced the activity of GadX, GadW, RpoS, and Lrp on hdeAB under some conditions. As a result of its direct and indirect effects, overexpression of MarA prevented most of the induction of hdeAB expression as cells entered stationary phase and made the cells sevenfold more sensitive to acid challenge at pH 2.5. These findings show that repression of hdeAB by MarA depends on pH, growth phase, and other regulators of hdeAB and is associated with reduced resistance to acid conditions.

  2. Effects of Exercise on Sleep Among Young Women With Generalized Anxiety Disorder

    PubMed Central

    Herring, Matthew P.; Kline, Christopher E.; O’Connor, Patrick J.

    2015-01-01

    Statement of the Problem Generalized Anxiety Disorder (GAD) and disturbed sleep are prevalent, debilitating, and frequently comorbid problems for which successful treatment remains limited. Exercise can promote sleep but whether it does among GAD patients is unknown. Methods Thirty sedentary women (18–37y) with a primary DSM-IV diagnosis of GAD were randomized to six weeks of resistance (RET) or aerobic exercise training (AET), or waitlist (WL). RET and AET involved twice-weekly sessions of either lower-body weightlifting or leg cycling matched on multiple features of exercise. Outcomes included total sleep time (TST), lights out time, awakening out of bed time, time in bed (TIB), sleep onset latency (SOL), wakefulness after sleep onset, and sleep efficiency. Hedges’ d effect sizes and 95% confidence intervals were calculated for each exercise condition compared to WL. Regression examined baseline associations between anxiety and sleep and associated change. Results Twenty-two of 26 participants reported poor baseline sleep (Pittsburgh Sleep Quality Index >5). RET significantly decreased weekend TIB (d=−1.79; [−2.89, −0.70]) and SOL (d=−1.30; [−2.32, −0.28]), and significantly increased weekend sleep efficiency (d=1.30; [0.29,2.32]). AET significantly reduced weekend TIB (d=−1.13; [−2.16, −0.11]) and SOL (d=−1.08; [−2.09, −0.06]). Reduced GAD clinical severity rating was significantly associated with improved weekend sleep efficiency among RET (t6=−3.48, p≤0.013). Conclusions Short-term exercise training improves sleep outcomes among GAD patients, especially for RET and weekend sleep. Findings suggest improved sleep may be associated with reduced clinical severity among GAD patients. PMID:26566400

  3. Effectiveness of Therapeutic Massage for Generalized Anxiety Disorder: A Randomized Controlled Trial

    PubMed Central

    Sherman, Karen J.; Ludman, Evette J.; Cook, Andrea J.; Hawkes, Rene J.; Roy-Byrne, Peter P.; Bentley, Susan; Brooks, Marissa Z.; Cherkin, Daniel C.

    2010-01-01

    Background Although massage is one of the most popular complementary and alternative medical (CAM) treatments for anxiety, its effectiveness has never been rigorously evaluated for a diagnosed anxiety disorder. This study evaluates the effectiveness of therapeutic massage for persons with generalized anxiety disorder (GAD). Methods Sixty-eight persons with GAD were randomized to therapeutic massage (n=23), thermotherapy (n=22) or relaxing room therapy (n=23) for a total of 10 sessions over 12 weeks. Mean reduction in anxiety was measured by the Hamilton Anxiety Rating Scale (HARS). Secondary outcomes included 50% reduction in HARS and symptom resolution of GAD, changes in depressive symptoms (PHQ-8), worry and GAD-related disability. We compared changes in these outcomes in the massage and control groups post- treatment and at 6 months using generalized estimating equation (GEE) regression. Results All groups had improved by the end of treatment (adjusted mean change scores for the HARS ranged from −10.0 to −13.0; p< 0.001) and maintained their gains at the 26 week follow-up. No differences were seen between groups (p=0.39). Symptom reduction and resolution of GAD, depressive symptoms, worry and disability showed similar patterns. Conclusions Massage was not superior to the control treatments, and all showed some clinically important improvements, likely due to some beneficial but generalized relaxation response. Because the relaxing room treatment is substantially less expensive than the other treatments, a similar treatment packaged in a clinically credible manner might be the most cost effective option for persons with GAD who want to try relaxation-oriented CAM therapies. PMID:20186971

  4. Comorbid generalized anxiety disorder and its association with quality of life in patients with major depressive disorder

    PubMed Central

    Zhou, Yongjie; Cao, Zhongqiang; Yang, Mei; Xi, Xiaoyan; Guo, Yiyang; Fang, Maosheng; Cheng, Lijuan; Du, Yukai

    2017-01-01

    The comorbidity of major depressive disorder (MDD) and generalized anxiety disorder (GAD) is common and often predicts poorer outcomes than either disorder alone. This study aimed to examine the prevalence of comorbid GAD and its association with quality of life (QOL) among MDD patients. A total of 1225 psychiatric outpatients were screened using the Hospital Anxiety and Depression Scale (HADS). Those who scored ≥8 on the HADS were interviewed using DSM-IV criteria by two senior psychiatrists. Patients diagnosed with MDD were further assessed using the 9-item Patient Health Questionnaire, Social Support Rating Scale, Pittsburgh Sleep Quality Index, and World Health Organization QOL Scale, brief version (WHOQOL-BREF). Ultimately, 667 patients were diagnosed with MDD, of 71.7% of whom had GAD. Compared to those with MDD alone, comorbid patients had lower scores on the physical (38.64 ± 10.35 vs.36.54 ± 12.32, P = 0.026) and psychological (35.54 ± 12.98 vs. 30.61 ± 14.66, P < 0.001) domains of the WHOQOL-BREF. The association between comorbid GAD and poor QOL on the two domains remained statistically significant in the multiple linear regression (unstandardized coefficients: −1.97 and −4.65, P < 0.001). In conclusion, the prevalence of comorbid GAD in MDD patients is high, and co-occurring GAD may exacerbate impaired physical and psychological QOL in Chinese MDD patients. PMID:28098176

  5. Verification of γ-Amino-Butyric Acid (GABA) Signaling System Components in Periodontal Ligament Cells In Vivo and In Vitro.

    PubMed

    Konermann, Anna; Kantarci, Alpdogan; Wilbert, Steven; Van Dyke, Thomas; Jäger, Andreas

    2016-11-01

    CNS key neurotransmitter γ-amino-butyric acid (GABA) and its signaling components are likewise detectable in non-neuronal tissues displaying inter alia immunomodulatory functions. This study aimed at identifying potential glutamate decarboxylase (GAD)65 and GABA receptor expression in periodontal ligament (PDL) cells in vivo and in vitro, with particular regard to inflammation and mechanical loading. Gene expression was analyzed in human PDL cells at rest or in response to IL-1ß (5 ng/ml) or TNFα (5 ng/ml) challenge via qRT-PCR. Western blot determined constitutive receptor expression, and confocal laser scanning fluorescence microscopy visualized expression changes induced by inflammation. ELISA quantified GAD65 release. Immunocytochemistry was performed for GABA component detection in vitro on mechanically loaded PDL cells, and in vivo on rat upper jaw biopsies with mechanically induced root resorptions. Statistical significance was set at p < 0.05. GABAB1, GABAB2, GABAA1, and GABAA3 were ubiquitously expressed both on gene and protein level. GABAA2 and GAD65 were undetectable in resting cells, but induced by inflammation. GABAB1 exhibited the highest basal gene expression (6.97 % ± 0.16). IL-1ß markedly increased GABAB2 on a transcriptional (57.28-fold ± 12.40) and protein level seen via fluorescence microscopy. TNFα-stimulated PDL cells released GAD65 (3.68 pg/ml ± 0.17 after 24 h, 5.77 pg/ml ± 0.65 after 48 h). Immunocytochemistry revealed GAD65 expression in mechanically loaded PDL cells. In vivo, GABA components were varyingly expressed in an inflammatory periodontal environment. PDL cells differentially express GABA signaling components and secrete GAD65. Inflammation and mechanical loading regulate these neurotransmitter molecules, which are also detectable in vivo and are potentially involved in periodontal pathophysiology.

  6. Fetal growth and the lifetime risk of generalized anxiety disorder

    PubMed Central

    Vasiliadis, Helen-Maria; Buka, Stephen L.; Martin, Laurie T.; Gilman, Stephen E.

    2010-01-01

    Background Anxiety disorders are thought to have their origins in early childhood, though they have not yet been studied as a potential outcome of impaired fetal growth, which has been implicated in the developmental etiologies of many psychopathologies. This study investigated the association between indicators of fetal growth and the development of generalized anxiety disorder (GAD). Methods Indicators of fetal growth, including birth weight (BW) and ponderal index (PI), were assessed among 682 offspring of participants in the Providence, RI, site of the Collaborative Perinatal Project. Participants were interviewed as adults, and their lifetime histories of GAD were assessed using the Diagnostic Interview Schedule. We used Cox regression to estimate the association between fetal growth indicators and the development of GAD. Results The lifetime risk of GAD differed between infants in the highest category of BW and PI and all others. Newborns with birth weights below 3.5 kg (hazard ratio, HR: 2.38; CI=1.25, 4.55), in the lowest four BW z-score quintiles (HR=2.49; CI=1.14, 5.45) or a PI in the lowest four quintiles (HR=2.33; CI=1.04, 5.00) had higher lifetime risks of GAD. Conclusion In contrast to prior studies on psychiatric outcomes in relation to fetal growth, there was not a linear relationship between birth weight and GAD. While these results generally support the hypothesis that a healthy nutritional fetal uptake, as indicated by BW and PI, is associated with better lifetime mental health, further work is needed to characterize the nature of the association between fetal growth and subsequent psychopathology. PMID:20734359

  7. The Relationship between Intelligence and Anxiety: An Association with Subcortical White Matter Metabolism

    PubMed Central

    Coplan, Jeremy D.; Hodulik, Sarah; Mathew, Sanjay J.; Mao, Xiangling; Hof, Patrick R.; Gorman, Jack M.; Shungu, Dikoma C.

    2012-01-01

    We have demonstrated in a previous study that a high degree of worry in patients with generalized anxiety disorder (GAD) correlates positively with intelligence and that a low degree of worry in healthy subjects correlates positively with intelligence. We have also shown that both worry and intelligence exhibit an inverse correlation with certain metabolites in the subcortical white matter. Here we re-examine the relationships among generalized anxiety, worry, intelligence, and subcortical white matter metabolism in an extended sample. Results from the original study were combined with results from a second study to create a sample comprised of 26 patients with GAD and 18 healthy volunteers. Subjects were evaluated using the Penn State Worry Questionnaire, the Wechsler Brief intelligence quotient (IQ) assessment, and proton magnetic resonance spectroscopic imaging (1H-MRSI) to measure subcortical white matter metabolism of choline and related compounds (CHO). Patients with GAD exhibited higher IQ’s and lower metabolite concentrations of CHO in the subcortical white matter in comparison to healthy volunteers. When data from GAD patients and healthy controls were combined, relatively low CHO predicted both relatively higher IQ and worry scores. Relatively high anxiety in patients with GAD predicted high IQ whereas relatively low anxiety in controls also predicted high IQ. That is, the relationship between anxiety and intelligence was positive in GAD patients but inverse in healthy volunteers. The collective data suggest that both worry and intelligence are characterized by depletion of metabolic substrate in the subcortical white matter and that intelligence may have co-evolved with worry in humans. PMID:22347183

  8. Broadening of Generalized Anxiety Disorders Definition Does not Affect the Response to Psychiatric Care: Findings from the Observational ADAN Study

    PubMed Central

    Álvarez, Enrique; Carrasco, Jose L; Olivares, José M; López-Gómez, Vanessa; Vilardaga, Inma; Perez, María

    2012-01-01

    Objective: To elucidate the consequences of broadening DSM-IV criteria for generalized anxiety disorder (GAD), we examined prospectively the evolution of GAD symptoms in two groups of patients; one group diagnosed according to DSM-IV criteria and the other, according to broader criteria. Method: Multicentre, prospective and observational study conducted on outpatient psychiatric clinics. Patients were selected from October 2007 to January 2009 and diagnosed with GAD according to DSM-IV criteria (DSM-IV group) or broader criteria. Broader criteria were considered 1-month of excessive or non-excessive worry and only 2 of the associated symptoms listed on DSM-IV for GAD diagnosis. Socio-demographic data, medical history and functional outcome measures were collected three times during a 6-month period. Results: 3,549 patients were systematically recruited; 1,815 patients in DSM-IV group (DG) and 1,264 in broad group (BG); 453 patients did not fulfil inclusion criteria and were excluded. Most patients (87.9% in DG, 82.0% in BG) were currently following pharmacological therapies (mainly benzodiazepines) to manage their anxiety symptoms. The changes observed during the study were: 49.0% and 58.0%, respectively of patients without anxiety symptoms as per HAM-A scale at the 6 month visit (p=0.261) and 59.7% and 67.7%, respectively (p=0.103) of responder rates (> 50% reduction of baseline scoring). Conclusion: Broadening of GAD criteria does not seem to affect psychiatric care results in subjects with GAD, is able to identify the core symptoms of the disease according to the DSM-IV criteria and could lead to an earlier diagnosis. PMID:23173012

  9. Perinatal Generalized Anxiety Disorder: Assessment and Treatment

    PubMed Central

    Abizadeh, Jasmin; Sanders, Shawn; Swift, Elena

    2015-01-01

    Abstract Perinatal generalized anxiety disorder (GAD) has a high prevalence of 8.5%–10.5% during pregnancy and 4.4%–10.8% postpartum. Despite its attendant dysfunction in the patient, this potentially debilitating mental health condition is often underdiagnosed. This overview will provide guidance for clinicians in making timely diagnosis and managing symptoms appropriately. A significant barrier to the diagnosis of GAD in the perinatal population is difficulty in distinguishing normal versus pathological worry. Because a perinatal-specific screening tool for GAD is nonexistent, early identification, diagnosis and treatment is often compromised. The resultant maternal dysfunction can potentially impact mother–infant bonding and influence neurodevelopmental outcomes in the children. Comorbid occurrence of GAD and major depressive disorder changes the illness course and its treatment outcome. Psychoeducation is a key component in overcoming denial/stigma and facilitating successful intervention. Treatment strategies are contingent upon illness severity. Cognitive behavior therapy (CBT), relaxation, and mindfulness therapy are indicated for mild GAD. Moderate/severe illness requires pharmacotherapy and CBT, individually or in combination. No psychotropic medications are approved by the FDA or Health Canada in pregnancy or the postpartum; off-label pharmacological treatment is instituted only if the benefit of therapy outweighs its risk. SSRIs/SNRIs are the first-line treatment for anxiety disorders due to data supporting their efficacy and overall favorable side effect profile. Benzodiazepines are an option for short-term treatment. While research on atypical antipsychotics is evolving, some can be considered for severe manifestations where the response to antidepressants or benzodiazepines has been insufficient. A case example will illustrate the onset, clinical course, and treatment strategies of GAD through pregnancy and the postpartum. PMID:26125602

  10. A downstream process allowing the efficient isolation of a recombinant amphiphilic protein from tobacco leaves.

    PubMed

    Gecchele, Elisa; Schillberg, Stefan; Merlin, Matilde; Pezzotti, Mario; Avesani, Linda

    2014-06-01

    The 65-kDa isoform of human glutamic acid decarboxylase (hGAD65) is a major autoantigen in autoimmune diabetes. The heterologous production of hGAD65 for diagnostic and therapeutic applications is hampered by low upstream productivity and the absence of a robust and efficient downstream process for product isolation. A tobacco-based platform has been developed for the production of an enzymatically-inactive form of the protein (hGAD65mut), but standard downstream processing strategies for plant-derived recombinant proteins cannot be used in this case because the product is amphiphilic. We therefore evaluated different extraction buffers and an aqueous micellar two-phase system (AMTPS) to optimize the isolation and purification of hGAD65mut from plants. We identified the extraction conditions offering the greatest selectivity for hGAD65mut over native tobacco proteins using a complex experimental design approach. Under our optimized conditions, the most efficient initial extraction and partial purification strategy achieved an overall hGAD65mut yield of 92.5% with a purification factor of 12.3 and a concentration factor of 23.8. The process also removed a significant quantity of phenols, which are major contaminants present in tobacco tissue. This is the first report describing the use of AMTPS for the partial purification of an amphiphilic recombinant protein from plant tissues and our findings could also provide a working model for the initial recovery and partial purification of hydrophobic recombinant proteins from transgenic tobacco plants.

  11. Downbeat down south.

    PubMed

    Chen, Ying; Morgan, Michael L; Palau, Angelina Espino Barros; Mudd, Janice A; Lee, Andrew G; Barton, Jason J S

    2015-01-01

    A 59-year-old woman with late-onset diabetes mellitus presented with a 4-week history of oscillopsia and vertigo. Physical examination revealed downbeating nystagmus in the primary position that worsened on right gaze and left gaze. Magnetic resonance imaging of the brain and orbits showed enhancement and signal abnormality in the right temporal lobe without evidence of a cervicomedullary junction lesion. Serum anti-glutamic acid decarboxylase 65 (GAD65) antibody titer was markedly elevated. Given these findings, her vertigo and downbeat nystagmus were likely secondary to elevated anti-GAD antibodies.

  12. Telephone-Delivered Cognitive Behavioral Therapy and Telephone-Delivered Nondirective Supportive Therapy for Rural Older Adults With Generalized Anxiety Disorder

    PubMed Central

    Brenes, Gretchen A.; Danhauer, Suzanne C.; Lyles, Mary F.; Hogan, Patricia E.; Miller, Michael E.

    2016-01-01

    IMPORTANCE Generalized anxiety disorder (GAD) is common in older adults; however, access to treatment may be limited, particularly in rural areas. OBJECTIVE To examine the effects of telephone-delivered cognitive behavioral therapy (CBT) compared with telephone-delivered nondirective supportive therapy (NST) in rural older adults with GAD. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial in the participants’ homes of 141 adults aged 60 years and older with a principal or coprincipal diagnosis of GAD who were recruited between January 27, 2011, and October 22, 2013. INTERVENTIONS Telephone-delivered CBT consisted of as many as 11 sessions (9 were required) focused on recognition of anxiety symptoms, relaxation, cognitive restructuring, the use of coping statements, problem solving, worry control, behavioral activation, exposure therapy, and relapse prevention, with optional chapters on sleep and pain. Telephone-delivered NST consisted of 10 sessions focused on providing a supportive atmosphere in which participants could share and discuss their feelings and did not provide any direct suggestions for coping. MAIN OUTCOMES AND MEASURES Primary outcomes included interviewer-rated anxiety severity (Hamilton Anxiety Rating Scale) and self-reported worry severity (Penn State Worry Questionnaire–Abbreviated) measured at baseline, 2 months’ follow-up, and 4 months’ follow-up. Mood-specific secondary outcomes included self-reported GAD symptoms (GAD Scale 7 Item) measured at baseline and 4 months’ follow-up and depressive symptoms (Beck Depression Inventory) measured at baseline, 2 months’ follow-up, and 4 months’ follow-up. Among the 141 participants, 70 were randomized to receive CBT and 71 to receive NST. RESULTS At 4 months’ follow-up, there was a significantly greater decline in worry severity among participants in the telephone-delivered CBT group (difference in improvement, −4.07; 95%CI, −6.26 to −1.87; P = .004) but no significant

  13. [Successful treatment with rituximab in a refractory Stiff-person syndrome].

    PubMed

    Sevy, A; Franques, J; Chiche, L; Pouget, J; Attarian, S

    2012-04-01

    Stiff person syndrome is a rare autoimmune disorder characterized by axial and limb progressive stiffness with surimposed spasms and production of autoantibodies to glutamic acid decarboxylase (GAD). We report a case of a 50-year-old woman who developed a stiff person syndrome resistant to conventional immunosuppressive treatments. Eight months after treatment, indexes of stiffness and spasm frequency improved, while however, the blood and CSF rates of anti-GAD increased. This observation illustrates the complexity of stiff person syndrome immunopathogenesis as well as the relevance of rituximab in this indication.

  14. Locating transition states on potential energy surfaces by the gentlest ascent dynamics

    NASA Astrophysics Data System (ADS)

    Bofill, Josep Maria; Quapp, Wolfgang; Caballero, Marc

    2013-09-01

    The system of ordinary differential equations for the method of the gentlest ascent dynamics (GAD) has been derived which was previously proposed [W. E and X. Zhou, Nonlinearity 24, 1831 (2011)]. For this purpose we use diverse projection operators to a given initial direction. Using simple examples we explain the two possibilities of a GAD curve: it can directly find the transition state by a gentlest ascent, or it can go the roundabout way over a turning point and then find the transition state going downhill along its ridge. An outlook to generalised formulas for higher order saddle-points is added.

  15. Key Enzymes of the Semiphosphorylative Entner-Doudoroff Pathway in the Haloarchaeon Haloferax volcanii: Characterization of Glucose Dehydrogenase, Gluconate Dehydratase, and 2-Keto-3-Deoxy-6-Phosphogluconate Aldolase

    PubMed Central

    Sutter, Jan-Moritz; Tästensen, Julia-Beate; Johnsen, Ulrike; Soppa, Jörg

    2016-01-01

    ABSTRACT The halophilic archaeon Haloferax volcanii has been proposed to degrade glucose via the semiphosphorylative Entner-Doudoroff (spED) pathway. So far, the key enzymes of this pathway, glucose dehydrogenase (GDH), gluconate dehydratase (GAD), and 2-keto-3-deoxy-6-phosphogluconate (KDPG) aldolase (KDPGA), have not been characterized, and their functional involvement in glucose degradation has not been demonstrated. Here we report that the genes HVO_1083 and HVO_0950 encode GDH and KDPGA, respectively. The recombinant enzymes show high specificity for glucose and KDPG and did not convert the corresponding C4 epimers galactose and 2-keto-3-deoxy-6-phosphogalactonate at significant rates. Growth studies of knockout mutants indicate the functional involvement of both GDH and KDPGA in glucose degradation. GAD was purified from H. volcanii, and the encoding gene, gad, was identified as HVO_1488. GAD catalyzed the specific dehydration of gluconate and did not utilize galactonate at significant rates. A knockout mutant of GAD lost the ability to grow on glucose, indicating the essential involvement of GAD in glucose degradation. However, following a prolonged incubation period, growth of the Δgad mutant on glucose was recovered. Evidence is presented that under these conditions, GAD was functionally replaced by xylonate dehydratase (XAD), which uses both xylonate and gluconate as substrates. Together, the characterization of key enzymes and analyses of the respective knockout mutants present conclusive evidence for the in vivo operation of the spED pathway for glucose degradation in H. volcanii. IMPORTANCE The work presented here describes the identification and characterization of the key enzymes glucose dehydrogenase, gluconate dehydratase, and 2-keto-3-deoxy-6-phosphogluconate aldolase and their encoding genes of the proposed semiphosphorylative Entner-Doudoroff pathway in the haloarchaeon Haloferax volcanii. The functional involvement of the three enzymes was

  16. Profound Amnesia after Temporal Lobectomy: An Autoimmune Process Resembling Patient H.M.?

    PubMed Central

    Bonello, Michael; Larner, Andrew J.; Marson, Anthony G.

    2014-01-01

    We describe a patient who developed significant cognitive decline with profound amnesia following non-dominant temporal lobectomy for refractory seizures, in whom the original suspicion of structural pathology was revised following the discovery of clinical and neuropathological markers of inflammation, neuropsychological evidence of bilateral involvement, and high titres of antibodies directed against glutamic acid decarboxylase (GAD). This case adds to the evidence that the diagnosis of non-paraneoplastic anti-GAD limbic encephalitis merits consideration in any patient with a refractory seizure disorder and cognitive decline. PMID:25473398

  17. Autoreactive human T-cell receptor initiates insulitis and impaired glucose tolerance in HLA DR4 transgenic mice.

    PubMed

    Gebe, John A; Unrath, Kellee A; Yue, Betty B; Miyake, Tom; Falk, Ben A; Nepom, Gerald T

    2008-06-01

    A human T-cell receptor (TcR) derived from an autoreactive T-cell specific for GAD65, from a subject at high risk for autoimmune diabetes, was introduced into HLA-DR4 transgenic mice. The source of TcR was a CD4(+) T(H)1(+) T-cell clone which responded to an immunodominant epitope of the human islet protein GAD65, an epitope shared with both GAD65 and GAD67 in the mouse. The resulting HLA-DR4/GAD-TcR transgenic mice on a Rag2(o/o)/I-Ab(o/o)/B6 background exhibited a CD4(+) infiltrate into pancreatic islets that correlated with a loss of insulin in infiltrated islets. These mice also exhibited a subclinical impaired tolerance to exogenously fed glucose as assayed by an intraperitoneal glucose tolerance test. T cells containing the GAD65/67 (555-567) responsive TcR undergo strong negative selection as evidenced by a 10-fold lower thymocyte cellularity compared to non-TcR transgenic mice, and clonotype peripheral T cells represented approximately 1% of CD4(+) T cells in Rag2 sufficient mice. Upon in vitro stimulation, GAD65/67 555-567 responsive T cells secrete interferon-gamma, minimal interleukin (IL)-2 and tumor necrosis factor-alpha, and no IL-4, IL-5, IL-10, or IL-17, consistent with a T(H)1 profile. These data demonstrate that CD4(+) T cells specific for a naturally processed epitope within GAD can specifically home to pancreatic islets and lead to impaired islet beta-cell function in diabetes-associated HLA-DR4 transgenic mice on the relatively non-autoimmune C57BL/6 background. The relatively slow progression and patchy insulitis are reminiscent of the chronic pre-clinical phase similar to a majority of human at-risk subjects, and models these indolent features of human T1D.

  18. Brainstem brain-derived neurotrophic factor signaling is required for histone deacetylase inhibitor-induced pain relief.

    PubMed

    Tao, Wenjuan; Chen, Quan; Wang, Lu; Zhou, Wenjie; Wang, Yunping; Zhang, Zhi

    2015-06-01

    Our previous study demonstrated that persistent pain can epigenetically suppress the transcription of Gad2 [encoding glutamic acid decarboxylase 65 (GAD65)] and consequently impair the inhibitory function of GABAergic synapses in central pain-modulating neurons. This contributes to the development of persistent pain sensitization. Histone deacetylase (HDAC) inhibitors increased GAD65 activity considerably, restored GABA synaptic function, and rendered sensitized pain behavior less pronounced. However, the molecular mechanisms by which HDAC regulates GABAergic transmission through GAD65 under pain conditions are unknown. This work showed that HDAC inhibitor-induced increases in colocalization of GAD65 and synaptic protein synapsin I on the presynaptic axon terminals of the nucleus raphe magnus (NRM) were blocked by a TrkB receptor antagonist K252a [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester], indicating that BDNF-TrkB signaling may be required in GAD65 modulation of GABA synaptic function. At the brain-derived neurotrophic factor (BDNF) promoter, HDAC inhibitors induced significant increases in H3 hyperacetylation, consistent with the increase in BDNF mRNA and total proteins. Although exogenous BDNF facilitated GABA miniature inhibitory postsynaptic currents and GAD65 accumulation in NRM neuronal synapses in normal rats, it failed to do so in animals subjected to persistent inflammation. In addition, blockade of the TrkB receptor with K252a has no effect on miniature inhibitory postsynaptic currents and synaptic GAD65 accumulation under normal conditions. In addition, the analgesic effects of HDAC inhibitors on behavior were blocked by NRM infusion of K252a. These findings suggest that BDNF-TrkB signaling is required for drugs that reverse the epigenetic effects of chronic pain at the gene level, such as HDAC inhibitors.

  19. A case of childhood stiff-person syndrome with striatal lesions: a possible entity distinct from the classical adult form.

    PubMed

    Sanefuji, Masafumi; Torisu, Hiroyuki; Kira, Ryutaro; Yamashita, Hiroshi; Ejima, Kazuna; Shigeto, Hiroshi; Takada, Yui; Yoshida, Keiko; Hara, Toshiro

    2013-06-01

    Parainfectious or autoimmune striatal lesions have been repeatedly described in children. We report a 7-year-old girl with painful muscle spasms, leading to the diagnosis of childhood stiff-person syndrome (SPS). Striatal lesions were demonstrated by diffusion-weighted magnetic resonance imaging (MRI) and single-photon emission computed tomography but not by conventional MRI. Autoantibodies against glutamic acid decarboxylase (GAD) were absent. Steroid pulse therapy and high-dose intravenous immunoglobulin resolved all the symptoms with slight sequelae. Childhood SPS may be characterized by absent anti-GAD antibodies and a transient benign clinical course, and it may have a pathomechanism distinct from that in adult SPS.

  20. Six-year follow-up of pancreatic β cell function in adults with latent autoimmune diabetes

    PubMed Central

    Yang, Lin; Zhou, Zhi-Guang; Huang, Gan; Ouyang, Ling-Li; Li, Xia; Yan, Xiang

    2005-01-01

    AIM: To investigate the characteristics of the progression of islet β cell function in Chinese latent autoimmune diabetes in adult (LADA) patients with glutamic acid decarboxylase antibody (GAD-Ab) positivity, and to explore the prognostic factors for β cell function. METHODS: Forty-five LADA patients with GAD-Ab positivity screened from phenotypic type 2 diabetic (T2DM) patients and 45 T2DM patients without GAD-Ab matched as controls were followed-up every 6 mo. Sixteen patients in LADA1 and T2DM1 groups respectively have been followed-up for 6 years, while 29 patients in LADA2 and T2DM2 groups respectively for only 1.5 years. GAD-Ab was determined by radioligand assay, and C-peptides (CP) by radioimmune assay. RESULTS: The percentage of patients whose fasting CP (FCP) decreased more than 50% compared with the baseline reached to 25.0% at 1.5th year in LADA1 group, and FCP level decreased (395.8±71.5 vs 572.8±72.3 pmol/L, P<0.05) at 2.5th year and continuously went down to the end of follow-up. No significant changes of the above parameters were found in T2DM1 group. The average decreased percentages of FCP per year in LADA and T2DM patients were 15.8% (4.0-91.0%) and 5.2% (-3.5 to 35.5%, P = 0.000) respectively. The index of GAD-Ab was negatively correlated with the FCP in LADA patients (rs = -0.483, P = 0.000). The decreased percentage of FCP per year in LADA patients were correlated with GAD-Ab index, body mass index (BMI) and age at onset (rs = 0.408, -0.301 and -0.523 respectively, P<0.05). Moreover, GAD-Ab was the only risk factor for predicting β cell failure in LADA patients (B = 1.455, EXP (B) = 4.283, P = 0.023). CONCLUSION: The decreasing rate of islet β cell function in LADA, being highly heterogeneous, is three times that of T2DM patients. The titer of GAD-Ab is an important predictor for the progression of islet β cell function, and age at onset and BMI could also act as the predictors. PMID:15902725

  1. Expression of neuronal nicotinic acetylcholine receptor subunit mRNAs in rat hippocampal GABAergic interneurons.

    PubMed

    Son, Jong-Hyun; Winzer-Serhan, Ursula H

    2008-11-10

    Hippocampal inhibitory interneurons are a diverse population of cells widely scattered in the hippocampus, where they regulate hippocampal circuit activity. The hippocampus receives cholinergic projections from the basal forebrain, and functional studies have suggested the presence of different subtypes of nicotinic acetylcholine receptors (AChRs) on gamma-aminobutyric acid (GABA)ergic interneurons. Single-cell polymerase chain reaction analysis had confirmed that several nAChR subunit mRNAs are co-expressed with glutamate decarboxylase 67 (GAD67), the marker for GABAergic interneurons. In this anatomical study, we systematically investigated the co-expression of GAD67 with different nAChR subunits by using double in situ hybridization with a digoxigenin-labeled GAD67 probe and (35)S-labeled probes for nAChR subunits (alpha2, alpha3, alpha4, alpha5, alpha6, alpha7, beta2, beta3, and beta4). The results revealed that most GAD67-positive interneurons expressed beta2, and 67 % also expressed alpha7 mRNA. In contrast, mRNA expression of other subunits was limited; only 13 % of GAD67-positive neurons co-expressed alpha4, and less than 10% expressed transcripts for alpha2, alpha3, alpha5, or beta4. Most GAD67/alpha2 co-expression was located in CA1/CA3 stratum oriens, and GAD67/alpha5 co-expression was predominantly detected in CA1/CA3 stratum radiatum/lacunosum moleculare and the dentate gyrus. Expression of alpha6 and beta3 mRNAs was rarely detected in the hippocampus, and mRNAs were not co-expressed with GAD67. These findings suggest that the majority of nicotinic responses in GABAergic interneurons should be mediated by a homomeric alpha7 or heteromeric alpha7*-containing nAChRs. Other possible combinations such as alpha2beta2*, alpha4beta2*, or alpha5beta2* heteromeric nAChRs could contribute to functional nicotinic response in subsets of GABAergic interneurons but overall would have a minor role.

  2. Sound in ecclesiastical spaces in Cordoba. Architectural projects incorporating acoustic methodology (El sonido del espacio eclesial en Cordoba. El proyecto arquitectonico como procedimiento acustico)

    NASA Astrophysics Data System (ADS)

    Suarez, Rafael

    2003-11-01

    This thesis is concerned with the acoustic analysis of ecclesiastical spaces, and the subsequent implementation of acoustic design methodology in architectural renovations. One begins with an adequate architectural design of specific elements (shape, materials, and textures), with the intention of elimination of acoustic deficiencies that are common in such spaces. These are those deficiencies that impair good speech intelligibility and good musical audibility. The investigation is limited to churches in the province of Cordoba and to churches built after the reconquest of Spain (1236) and up until the 18th century. Selected churches are those that have undergone architectural renovations to adapt them to new uses or to make them more suitable for liturgical use. The thesis attempts to summarize the acoustic analyses and the acoustical solutions that have been implemented. The results are presented in a manner that should be useful for the adoption of a model for the functional renovation of ecclesiastical spaces. Such would allow those involved in architectural projects to specify the nature of the sound, even though somewhat intangible, within the ecclesiastical space. Thesis advisors: Jaime Navarro and Juan J. Sendra Copies of this thesis written in Spanish may be obtained by contacting the advisor, Jaime Navarro, E.T.S. de Arquitectura de Sevilla, Dpto. de Construcciones Arquitectonicas I, Av. Reina Mercedes, 2, 41012 Sevilla, Spain. E-mail address: jnavarro@us.es

  3. Acoustics of native-American ceremonial sites in prehispanic America (Acustica en los espacios escenios rituales prehispanicos)

    NASA Astrophysics Data System (ADS)

    Martinez, Maria Isabel

    2003-11-01

    This thesis establishes a methodology that incorporates the latest procedures used in architectural acoustics for the study of open spaces of this general type, and definitions are given for the acoustic variables of interest. The ``Juego de Pelota'' (ball game) sites are the only ceremonial sites built specifically for the performance of a fertility ritual, and are ideal for the study of prehispanic architectural topographies. Analysis of the acoustic properties of such sites revealed that the topographical characteristics of the elevation profiles of these architectural structures determine the acoustic behavior of these spaces. Such profiles are classified into three basic types: (i) inclined profile, (ii) terraced profile, and (iii) mixed profile. The terraced profiles are the most efficient, and the mixed profiles are the least efficient, in regard to acoustics. The consideration of the acoustic behavior of architectural structures intended for the ``Ball Game,'' as the designs evolved over time, leads to the conclusion that acoustical sensations that contributed effectively to the characteristic mystical atmosphere of the ceremonial rituals were characteristic only of those sites constructed in the ``classical'' period. Thesis advisors: Jaime Navarro and Juan J. Sendra Copies of this thesis written in Spanish may be obtained by contacting the advisor, Jaime Navarro, E.T.S. de Arquitectura de Sevilla, Dpto. de Construcciones Arquitectonicas I, Av. Reina Mercedes, 2, 41012 Sevilla, Spain. E-mail address: jnavarro@us.es

  4. An Open Trial of an Acceptance-Based Behavior Therapy for Generalized Anxiety Disorder

    ERIC Educational Resources Information Center

    Roemer, Lizabeth; Orsillo, Susan M.

    2007-01-01

    Research suggests that experiential avoidance may play an important role in generalized anxiety disorder (GAD; see 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…

  5. Assessment of Generalized Anxiety Disorder Diagnostic Criteria in the National Comorbidity Survey and Virginia Adult Twin Study of Psychiatric and Substance Use Disorders

    ERIC Educational Resources Information Center

    Kubarych, Thomas S.; Aggen, Steven H.; Hettema, John M.; Kendler, Kenneth S.; Neale, Michael C.

    2008-01-01

    The authors investigated measurement properties of the "Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition," generalized anxiety disorder (GAD) criteria in the National Comorbidity Survey and the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD). The two studies used different widely used…

  6. Children with Generalized Anxiety Disorder Do Not Have Peer Problems, Just Fewer Friends

    ERIC Educational Resources Information Center

    Scharfstein, Lindsay; 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).…

  7. Are Children with "Pure" Generalized Anxiety Disorder Impaired? A Comparison with Comorbid and Healthy Children

    ERIC Educational Resources Information Center

    Alfano, Candice A.

    2012-01-01

    Despite the approach of the "Diagnostic and Statistical Manual of Mental Disorders" (5th ed.), generalized anxiety disorder (GAD) of childhood continues to face questions as to whether it should be considered a distinct clinical disorder. A potentially critical issue embedded in this debate involves the role of functional impairment which has yet…

  8. Anxiety Symptoms in Boys with Autism Spectrum Disorder, Attention-Deficit Hyperactivity Disorder, or Chronic Multiple Tic Disorder and Community Controls

    ERIC Educational Resources Information Center

    Guttmann-Steinmetz, Sarit; Gadow, Kenneth D.; DeVincent, Carla J.; Crowell, Judy

    2010-01-01

    We compared symptoms of generalized anxiety disorder (GAD) and separation anxiety disorder (SAD) in 5 groups of boys with neurobehavioral syndromes: attention-deficit/hyperactivity disorder (ADHD) plus autism spectrum disorder (ASD), ADHD plus chronic multiple tic disorder (CMTD), ASD only, ADHD only, and community Controls. Anxiety symptoms were…

  9. A Randomized Controlled Trial of Cognitive-Behavioral Therapy for Generalized Anxiety Disorder with Integrated Techniques from Emotion-Focused and Interpersonal Therapies

    ERIC Educational Resources Information Center

    Newman, Michelle G.; Castonguay, Louis G.; Borkovec, Thomas D.; Fisher, Aaron J.; Boswell, James F.; Szkodny, Lauren E.; Nordberg, Samuel S.

    2011-01-01

    Objective: Recent models suggest that generalized anxiety disorder (GAD) symptoms may be maintained by emotional processing avoidance and interpersonal problems. Method: This is the first randomized controlled trial to test directly whether cognitive-behavioral therapy (CBT) could be augmented with the addition of a module targeting interpersonal…

  10. A Multitrait-Multimethod Analysis of the Construct Validity of Child Anxiety Disorders in a Clinical Sample

    ERIC Educational Resources Information Center

    Langer, David A.; Wood, Jeffrey J.; Bergman, R. Lindsey; Piacentini, John C.

    2010-01-01

    The present study examines the construct validity of separation anxiety disorder (SAD), social phobia (SoP), panic disorder (PD), and generalized anxiety disorder (GAD) in a clinical sample of children. Participants were 174 children, 6 to 17 years old (94 boys) who had undergone a diagnostic evaluation at a university hospital based clinic.…

  11. The Factor Structure and Dimensional Scoring of the Generalized Anxiety Disorder Questionnaire for "DSM-IV"

    ERIC Educational Resources Information Center

    Rodebaugh, Thomas L.; Holaway, Robert M.; Heimberg, Richard G.

    2008-01-01

    Despite favorable psychometric properties, the Generalized Anxiety Disorder Questionnaire for the "Diagnostic and Statistical Manual of Mental Disorders" (4th ed.) (GAD-Q-IV) does not have a known factor structure, which calls into question use of its original weighted scoring system (usually referred to as the dimensional score).…

  12. Intrinsic Functional Connectivity of Amygdala-Based Networks in Adolescent Generalized Anxiety Disorder

    ERIC Educational Resources Information Center

    Roy, Amy K.; Fudge, Julie L.; Kelly, Clare; Perry, Justin S. A.; Daniele, Teresa; Carlisi, Christina; Benson, Brenda; Castellanos, F. Xavier; Milham, Michael P.; Pine, Daniel S.; Ernst, Monique

    2013-01-01

    Objective: Generalized anxiety disorder (GAD) typically begins during adolescence and can persist into adulthood. The pathophysiological mechanisms underlying this disorder remain unclear. Recent evidence from resting state functional magnetic resonance imaging (R-fMRI) studies in adults suggests disruptions in amygdala-based circuitry; the…

  13. The Developmental Course of Anxiety Symptoms during Adolescence: The TRAILS Study

    ERIC Educational Resources Information Center

    Van Oort, F. V. A.; Greaves-Lord, K.; Verhulst, F. C.; Ormel, J.; Huizink, A. C.

    2009-01-01

    Background: Little is known about the development of anxiety symptoms from late childhood to late adolescence. The present study determined developmental trajectories of symptoms of separation anxiety disorder (SAD), social phobia (SoPh), generalized anxiety disorder (GAD), panic disorder (PD), and obsessive-compulsive disorder (OCD) in a large…

  14. The NEO Five-Factor Inventory: Latent Structure and Relationships with Dimensions of Anxiety and Depressive Disorders in a Large Clinical Sample

    ERIC Educational Resources Information Center

    Rosellini, Anthony J.; Brown, Timothy A.

    2011-01-01

    The present study evaluated the latent structure of the NEO Five-Factor Inventory (NEO FFI) and relations between the five-factor model (FFM) of personality and dimensions of "DSM-IV" anxiety and depressive disorders (panic disorder, generalized anxiety disorder [GAD], obsessive-compulsive disorder, social phobia [SOC], major depressive disorder…

  15. A Fresh Look at Potential Mechanisms of Change in Applied Relaxation for Generalized Anxiety Disorder: A Case Series

    ERIC Educational Resources Information Center

    Hayes-Skelton, Sarah A.; Usmani, Aisha; Lee, Jonathan K.; Roemer, Lizabeth; Orsillo, Susan M.

    2012-01-01

    Applied relaxation (AR), which involves noticing early signs of anxiety and responding with a relaxation response, is an empirically supported treatment for generalized anxiety disorder (GAD). However, research on hypothesized mechanisms of AR (e.g., reduced muscle tension) has been mixed, making it likely that additional mechanisms are…

  16. Generalized Anxiety Disorder: Connections with Self-Reported Attachment

    ERIC Educational Resources Information Center

    Cassidy, Jude; Lichtenstein-Phelps, June; Sibrava, Nicholas J.; Thomas, Charles L., Jr.; Borkovec, Thomas D.

    2009-01-01

    Even though generalized anxiety disorder (GAD) is one of the most common of the anxiety disorders, relatively little is known about its precursors. Bowlby's attachment theory provides a framework within which these precursors can be considered. According to Bowlby, adult anxiety may be rooted in childhood experiences that leave a child uncertain…

  17. Relations among Perceived Control over Anxiety-Related Events, Worry, and Generalized Anxiety Disorder in a Sample of Adolescents

    ERIC Educational Resources Information Center

    Frala, Jamie L.; Leen-Feldner, Ellen W.; Blumenthal, Heidemarie; Barreto, Carolina C.

    2010-01-01

    This study examined the associations among perceived control over anxiety-related events, worry, and both symptoms and diagnoses of generalized anxiety disorder (GAD). The sample was comprised of 140 adolescents (60 girls) between the ages of 10 and 17 years (M[subscript age] = 14.6 years; SD = 2.25) recruited from the general community. Findings…

  18. A Psychometric Analysis of the Revised Child Anxiety and Depression Scale-Parent Version in a Clinical Sample

    ERIC Educational Resources Information Center

    Ebesutani, Chad; Bernstein, Adam; Nakamura, Brad J.; Chorpita, Bruce F.; Weisz, John R.

    2010-01-01

    The Revised Child Anxiety and Depression Scale-Parent Version (RCADS-P) is a 47-item parent-report questionnaire of youth anxiety and depression, with scales corresponding to the DSM-IV categories of Separation Anxiety Disorder, Social Phobia, Generalized Anxiety Disorder (GAD), Panic Disorder, Obsessive-Compulsive Disorder, and Major Depressive…

  19. Homotypic versus Heterotypic Continuity of Anxiety Symptoms in Young Adolescents: Evidence for Distinctions between DSM-IV Subtypes

    ERIC Educational Resources Information Center

    Ferdinand, Robert F.; Dieleman, Gwen; Ormel, Johan; Verhulst, Frank C.

    2007-01-01

    Objective: To investigate homotypic and heterotypic longitudinal patterns of symptoms of separation anxiety disorder (SAD), generalized anxiety disorder (GAD), social phobia (SoPh), panic disorder (PD), and obsessive compulsive disorder (OCD) in young adolescents from the Dutch general population. Method: 2,067 individuals (51.4% girls) from a…

  20. Cognition about Cognition: Metacognitive Therapy and Change in Generalized Anxiety Disorder and Social Phobia

    ERIC Educational Resources Information Center

    Wells, Adrian

    2007-01-01

    Metacognitive theory and therapy views the persistence of negative beliefs and thoughts as a result of metacognitions controlling cognition. This paper describes, with reference to the treatment of generalized anxiety disorder (GAD) and social phobia, how metacognition contributes to cognitive stability and to change. Metacognitive therapy offers…

  1. New advances in the treatment of generalized anxiety disorder: the multimodal antidepressant vortioxetine.

    PubMed

    Orsolini, Laura; Tomasetti, Carmine; Valchera, Alessandro; Iasevoli, Felice; Buonaguro, Elisabetta Filomena; Vellante, Federica; Fornaro, Michele; Fiengo, Annastasia; Mazza, Monica; Vecchiotti, Roberta; Perna, Giampaolo; de Bartolomeis, Andrea; Martinotti, Giovanni; Di Giannantonio, Massimo; De Berardis, Domenico

    2016-05-01

    Generalized Anxiety Disorder (GAD) is a persistent condition characterized by chronic anxiety, exaggerated worry and tension, mainly comorbid with Major Depressive Disorder (MDD). Currently, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are recommended as first-line treatment of GAD. However, some patients may not respond to the treatment or discontinue due to adverse effects. Vortioxetine (VRX) is a multimodal antidepressant with a unique mechanism of action, by acting as 5-HT3A, 5-HT1D and 5-HT7 receptor antagonist, partial agonist at the 5-HT1A and 5-HT1B receptors and inhibitor at the 5-HT transporter. Preliminary clinical trials showed contrasting findings in terms of improvement of the anxiety symptomatology and/or cognitive impairment. Here, we aim to systematically review the evidence currently available on the efficacy, safety and tolerability of VRX in the treatment of GAD. The generalizability of results on the efficacy of VRX in patients with anxiety symptomatology and GAD is limited due to few and contrasting RCTs so far available. Only two studies, of which one prevention relapse trial, reported a significant improvement in anxiety symptomatology compared to three with negative findings.

  2. Adolescents' Perceptions of Parenting Behaviours and Its Relationship to Adolescent Generalized Anxiety Disorder Symptoms

    ERIC Educational Resources Information Center

    Hale, William W., III; Engels, Rutger; Meeus, Wim

    2006-01-01

    This study examined the relationship between how adolescents perceived parenting behaviours and adolescent Generalized Anxiety Disorder (GAD) symptom scores. The 1,106 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…

  3. Transdiagnostic versus disorder-specific and clinician-guided versus self-guided internet-delivered treatment for generalized anxiety disorder and comorbid disorders: A randomized controlled trial.

    PubMed

    Dear, B F; Staples, L G; Terides, M D; Karin, E; Zou, J; Johnston, L; Gandy, M; Fogliati, V J; Wootton, B M; McEvoy, P M; Titov, N

    2015-12-01

    Generalized anxiety disorder (GAD) can be treated effectively with either disorder-specific cognitive behavior therapy (DS-CBT) or transdiagnostic CBT (TD-CBT). The relative benefits of DS-CBT and TD-CBT for GAD and the relative benefits of delivering treatment in clinician guided (CG-CBT) and self-guided (SG-CBT) formats have not been examined. Participants with GAD (n=338) were randomly allocated to receive an internet-delivered TD-CBT or DS-CBT intervention delivered in either CG-CBT or SG-CBT formats. Large reductions in symptoms of GAD (Cohen's d ≥ 1.48; avg. reduction ≥ 50%) and comorbid major depressive disorder (Cohen's d ≥ 1.64; avg. reduction ≥ 45%), social anxiety disorder (Cohen's d ≥ 0.80; avg. reduction ≥ 29%) and panic disorder (Cohen's d ≥ 0.55; avg. reduction ≥ 33%) were found across the conditions. No substantive differences were observed between DS-CBT and TD-CBT or CG-CBT and SG-CBT, highlighting the public health potential of carefully developed TD-CBT and SG-CBT.

  4. Interpersonal and Emotional Processes in Generalized Anxiety Disorder Analogues during Social Interaction Tasks

    ERIC Educational Resources Information Center

    Erickson, Thane M.; Newman, Michelle G.

    2007-01-01

    Persons with chronic worry and generalized anxiety disorder (GAD) report maladaptive social cognitions, interpersonal behaviors, and emotional regulation. Because research has neither investigated these processes in actual social situations nor explored whether they take heterogeneous forms, the present study provides the first attempt to do so in…

  5. Targeted Behavioral Therapy for childhood generalized anxiety disorder: a time-series analysis of changes in anxiety and sleep.

    PubMed

    Clementi, Michelle A; Alfano, Candice A

    2014-03-01

    This study examined the efficacy of Targeted Behavioral Therapy (TBT), a newly developed intervention targeting features of childhood generalized anxiety disorder (GAD). Using a time-series design, 4 children (7-12 years) with primary GAD were treated with TBT, which includes sleep improvement strategies, systematic desensitization for reducing intolerance of uncertainty, and in vivo exposures for anxiety. Diagnostic interviews and questionnaires were administered at baseline, post-treatment and 3 months follow-up. Anxiety symptoms and sleep characteristics/problems were rated weekly during a 4-week baseline and 14-weeks of treatment. Two children remitted at post-treatment and no child had a GAD diagnosis at follow-up. Child but not parent report revealed improvements in both worry and sleep. Despite improvements from pre- to post-assessment, considerable symptom fluctuation observed during the baseline period preclude conclusion that symptom changes are specifically attributable to the course of treatment. Overall, preliminary support is provided for the efficacy of TBT for childhood GAD.

  6. The Developmental Psychopathology of Worry

    ERIC Educational Resources Information Center

    Kertz, Sarah J.; Woodruff-Borden, Janet

    2011-01-01

    Although childhood generalized anxiety disorder is generally understudied, worry, the cardinal feature of GAD, appears to be relatively common in youth. Despite its prevalence, there are few conceptual models of the development of clinical worry in children. The current review provides a framework for integrating the developmental psychopathology…

  7. The British Sign Language Versions of the Patient Health Questionnaire, the Generalized Anxiety Disorder 7-Item Scale, and the Work and Social Adjustment Scale

    ERIC Educational Resources Information Center

    Rogers, Katherine D.; Young, Alys; Lovell, Karina; Campbell, Malcolm; Scott, Paul R.; Kendal, Sarah

    2013-01-01

    The present study is aimed to translate 3 widely used clinical assessment measures into British Sign Language (BSL), to pilot the BSL versions, and to establish their validity and reliability. These were the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder 7-item (GAD-7) scale, and the Work and Social Adjustment Scale (WSAS).…

  8. A Taxometric Investigation of the Latent Structure of Worry: Dimensionality and Associations with Depression, Anxiety, and Stress

    ERIC Educational Resources Information Center

    Olatunji, Bunmi O.; Broman-Fulks, Joshua J.; Bergman, Shawn M.; Green, Bradley A.; Zlomke, Kimberly R.

    2010-01-01

    Worry has been described as a core feature of several disorders, particularly generalized anxiety disorder (GAD). The present study examined the latent structure of worry by applying 3 taxometric procedures (MAXEIG, MAMBAC, and L-Mode) to data collected from 2 large samples. Worry in the first sample (Study 1) of community participants (n = 1,355)…

  9. Specificity of Treatment Effects: Cognitive Therapy and Relaxation for Generalized Anxiety and Panic Disorders

    ERIC Educational Resources Information Center

    Siev, Jedidiah; Chambless, Dianne L.

    2007-01-01

    The aim of this study was to address claims that among bona fide treatments no one is more efficacious than another by comparing the relative efficacy of cognitive therapy (CT) and relaxation therapy (RT) in the treatment of generalized anxiety disorder (GAD) and panic disorder without agoraphobia (PD). Two fixed-effects meta-analyses were…

  10. Efficacy of Cognitive-Behavioral Therapy for Comorbid Panic Disorder with Agoraphobia and Generalized Anxiety Disorder

    ERIC Educational Resources Information Center

    Labrecque, Joane; Marchand, Andre; Dugas, Michel J.; Letarte, Andree

    2007-01-01

    The goal of this study was to evaluate the efficacy of cognitive-behavioral therapy for comorbid panic disorder with agoraphobia (PDA) and generalized anxiety disorder (GAD) by combining treatment strategies for both disorders. A single-case, multiple-baseline design across participants was used. Three participants with primary PDA and secondary…

  11. Can the Components of a Cognitive Model Predict the Severity of Generalized Anxiety Disorder?

    ERIC Educational Resources Information Center

    Dugas, Michel J.; Savard, Pierre; Gaudet, Adrienne; Turcotte, Julie; Laugesen, Nina; Robichaud, Melisa; Francis, Kylie; Koerner, Naomi

    2007-01-01

    Over the past decade, a number of well-controlled studies have supported the validity of a cognitive model of generalized anxiety disorder (GAD) that has four main components: intolerance of uncertainty, positive beliefs about worry, negative problem orientation, and cognitive avoidance. Although these studies have shown that the model components…

  12. Longitudinal Associations between Perceived Parent-Adolescent Attachment Relationship Quality and Generalized Anxiety Disorder Symptoms in Adolescence

    ERIC Educational Resources Information Center

    van Eijck, Fenna E. A. M.; Branje, Susan J. T.; Hale, William W., III; Meeus, Wim H. J.

    2012-01-01

    This longitudinal study examined the direction of effects between adolescents' generalized anxiety disorder (GAD) symptoms and perceived parent-adolescent attachment relationship quality, as well as the moderating role of gender and age. 1,313 Dutch adolescents (48.5% boys) from two age cohorts of early (n = 923, M[subscript age] = 12 at W1) and…

  13. Mediated Moderation in Combined Cognitive Behavioral Therapy versus Component Treatments for Generalized Anxiety Disorder

    ERIC Educational Resources Information Center

    Newman, Michelle G.; Fisher, Aaron J.

    2013-01-01

    Objective: This study examined (a) duration of generalized anxiety disorder (GAD) as a moderator of cognitive behavioral therapy (CBT) versus its components (cognitive therapy and self-control desensitization) and (b) increases in dynamic flexibility of anxious symptoms during the course of psychotherapy as a mediator of this moderation. Degree of…

  14. Gender Mainstreaming in Education at the Level of Field Operations: The Case of CARE USA's Indicator Framework

    ERIC Educational Resources Information Center

    Miske, Shirley; Meagher, Margaret; DeJaeghere, Joan

    2010-01-01

    Following the adoption of gender mainstreaming at the Beijing Conference for Women in 1995 as a major strategy to promote gender equality and the recognition of gender analysis as central to this process, Gender and Development (GAD) frameworks have provided tools for gender analysis in various sectors. Gender mainstreaming in basic education has…

  15. Expression of NMDA glutamate receptor subunit mRNAs in neurochemically identified projection and interneurons in the striatum of the rat.

    PubMed

    Standaert, D G; Friberg, I K; Landwehrmeyer, G B; Young, A B; Penney, J B

    1999-01-22

    NMDA receptors are composed of proteins from two families: NMDAR1 and NMDAR2. We used quantitative double-label in situ hybridization to examine in rat brain the expression of NMDAR1, NMDAR2A, NMDAR2B, and NMDAR2C mRNA in six neurochemically defined populations of striatal neurons: preproenkephalin (ENK) and preprotachykinin (SP) expressing projection neurons, and somatostatin (SOM), glutamic acid decarboxylase 67 (GAD67), parvalbumin (PARV), and choline acetyltransferase (ChAT) expressing interneurons. NMDAR1 was expressed by all striatal neurons: strongly in ENK, SP, PARV and ChAT neurons, and less intensely in SOM and GAD67 positive cells. NMDAR2A mRNA was present at moderate levels in all striatal neurons except those containing ChAT. Labeling for NMDAR2B was strong in projection neurons and ChAT interneurons, and only moderate in SOM, GAD67 and PARV interneurons. NMDAR2C was scarce in striatal neurons, but a low level signal was detected in GAD67 positive cells. NMDAR2C expression was also observed in small cells not labeled by any of the markers, most likely glia. These data suggest that all striatal neurons have NMDA receptors, but different populations have different subunit compositions which may affect function as well as selective vulnerability.

  16. Leukemia inhibitory factor impairs structural and neurochemical development of rat visual cortex in vivo.

    PubMed

    Engelhardt, Maren; di Cristo, Graziella; Grabert, Jochen; Patz, Silke; Maffei, Lamberto; Berardi, Nicoletta; Wahle, Petra

    2017-03-01

    Minipump infusions into visual cortex in vivo at the onset of the critical period have revealed that the proinflammatory cytokine leukemia inhibitory factor (LIF) delays the maturation of thalamocortical projection neurons of the lateral geniculate nucleus, and tecto-thalamic projection neurons of the superior colliculus, and cortical layer IV spiny stellates and layer VI pyramidal neurons. Here, we report that P12-20 LIF infusion inhibits somatic maturation of pyramidal neurons and of all interneuron types in vivo. Likewise, DIV 12-20 LIF treatment in organotypic cultures prevents somatic growth GABA-ergic neurons. Further, while NPY expression is increased in the LIF-infused hemispheres, the expression of parvalbumin mRNA and protein, Kv3.1 mRNA, calbindin D-28k protein, and GAD-65 mRNA, but not of GAD-67 mRNA or calretinin protein is substantially reduced. Also, LIF treatment decreases parvalbumin, Kv3.1, Kv3.2 and GAD-65, but not GAD-67 mRNA expression in OTC. Developing cortical neurons are known to depend on neurotrophins. Indeed, LIF alters neurotrophin mRNA expression, and prevents the growth promoting action of neurotophin-4 in GABA-ergic neurons. The results imply that LIF, by altering neurotrophin expression and/or signaling, could counteract neurotrophin-dependent growth and neurochemical differentiation of cortical neurons.

  17. The Relationship Between Early Maladaptive Schemas, Depression, and Generalized Anxiety among Adults Seeking Residential Treatment for Substance Use Disorders.

    PubMed

    Shorey, Ryan C; Elmquist, Joanna; Anderson, Scott; Stuart, Gregory L

    2015-01-01

    Previous research has shown that early maladaptive schemas (EMS) play an important role in substance use, depression, and anxiety. However, few studies have examined the role of EMS within the context of all three concurrently. The goal of this study was to determine the role of EMS in predicting symptoms of Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD) among adults in residential treatment for substance dependence. We used pre-existing patient records of adults diagnosed with a substance use disorder from a residential substance use treatment facility (N=122). The EMS domains of disconnection and rejection and impaired limits were associated with symptoms of MDD and the domain of impaired autonomy and performance was associated with symptoms of GAD, even after controlling for age, gender, years of education, alcohol use, drug use, and symptoms of MDD (when predicting GAD) and GAD (when predicting MDD). Findings suggest that EMS may play an important role in comorbid mental health problems among men and women in residential substance use treatment. Continued treatment outcome research is needed to examine whether modification of EMS results in improved mental health and substance use outcomes.

  18. Antenatal anxiety disorder as a predictor of postnatal depression: a longitudinal study.

    PubMed

    Coelho, Helen F; Murray, Lynne; Royal-Lawson, Melanie; Cooper, Peter J

    2011-03-01

    Previous research has implicated high levels of antenatal anxiety as a predictor of postnatal depression, but there is a paucity of evidence on the relationship between the various forms of anxiety and postnatal depression. A longitudinal study of 246 mothers (56 with antenatal generalised anxiety disorder (GAD), 68 with antenatal generalised social phobia, 28 with both disorders in the antenatal period, and 94 with no antenatal GAD or social phobia) allowed us to explore whether antenatal social phobia and GAD predict high Edinburgh Postnatal Depression Scale (EPDS) scores (probable depression >12) at 10-14 days, 10-12 weeks, 10 months, 14 months, and 24 months postnatally. We found that, after accounting for the presence of other antenatal anxiety disorders, antenatal depression, maternal age at child's birth, socio-economic status and ethnicity in the models, antenatal GAD independently predicted depression at all time points after delivery. A less robust relationship was found for antenatal social phobia, which predicted postnatal depression at only 10 months after birth. One possibility consistent with our findings is that there may be differences in the timing of postnatal depression with different forms of antenatal anxiety disorders.

  19. Flooding of the root system in soybean: biochemical and molecular aspects of N metabolism in the nodule during stress and recovery.

    PubMed

    Souza, Sarah C R; Mazzafera, Paulo; Sodek, Ladaslav

    2016-05-01

    Nitrogen fixation of the nodule of soybean is highly sensitive to oxygen deficiency such as provoked by waterlogging of the root system. This study aimed to evaluate the effects of flooding on N metabolism in nodules of soybean. Flooding resulted in a marked decrease of asparagine (the most abundant amino acid) and a concomitant accumulation of γ-aminobutyric acid (GABA). Flooding also resulted in a strong reduction of the incorporation of (15)N2 in amino acids. Nodule amino acids labelled before flooding rapidly lost (15)N during flooding, except for GABA, which initially increased and declined slowly thereafter. Both nitrogenase activity and the expression of nifH and nifD genes were strongly decreased on flooding. Expression of the asparagine synthetase genes SAS1 and SAS2 was reduced, especially the former. Expression of genes encoding the enzyme glutamic acid decarboxylase (GAD1, GAD4, GAD5) was also strongly suppressed except for GAD2 which increased. Almost all changes observed during flooding were reversible after draining. Possible changes in asparagine and GABA metabolism that may explain the marked fluctuations of these amino acids during flooding are discussed. It is suggested that the accumulation of GABA has a storage role during flooding stress.

  20. Incomplete immune response to coxsackie B viruses associates with early autoimmunity against insulin

    PubMed Central

    Ashton, Michelle P.; Eugster, Anne; Walther, Denise; Daehling, Natalie; Riethausen, Stephanie; Kuehn, Denise; Klingel, Karin; Beyerlein, Andreas; Zillmer, Stephanie; Ziegler, Anette-Gabriele; Bonifacio, Ezio

    2016-01-01

    Viral infections are associated with autoimmunity in type 1 diabetes. Here, we asked whether this association could be explained by variations in host immune response to a putative type 1 etiological factor, namely coxsackie B viruses (CVB). Heterogeneous antibody responses were observed against CVB capsid proteins. Heterogeneity was largely defined by different binding to VP1 or VP2. Antibody responses that were anti-VP2 competent but anti-VP1 deficient were unable to neutralize CVB, and were characteristic of children who developed early insulin-targeting autoimmunity, suggesting an impaired ability to clear CVB in early childhood. In contrast, children who developed a GAD-targeting autoimmunity had robust VP1 and VP2 antibody responses to CVB. We further found that 20% of memory CD4+ T cells responding to the GAD65247-266 peptide share identical T cell receptors to T cells responding to the CVB4 p2C30-51 peptide, thereby providing direct evidence for the potential of molecular mimicry as a mechanism for GAD autoimmunity. Here, we highlight functional immune response differences between children who develop insulin-targeting and GAD-targeting autoimmunity, and suggest that children who lose B cell tolerance to insulin within the first years of life have a paradoxical impaired ability to mount humoral immune responses to coxsackie viruses. PMID:27604323

  1. Sensitivity enhancement of nanostructured SnO2 gas sensors fabricated using the glancing angle deposition method.

    PubMed

    Gwon, Hyo Jin; Moon, Hi Gyu; Jang, Ho Won; Yoon, Seok-Jin; Yoo, Kwang Soo

    2013-04-01

    0.5 wt.% Pd-catalyzed SnO2 thin-film gas sensors with microstructures controlled on a nanometer scale were fabricated by an e-beam evaporator using the glancing angle deposition (GAD) method. After annealing at 500 degrees C for 1 h, the sensors produced were polycrystalline with a nanoporous, tilted columnar microstructure. The gas-sensing properties of these SnO2 sensors were measured in the concentration range of 1 to 5 ppm NO2 at 250 degrees C and of 10 to 50 ppm C2H5OH at 400 degrees C, respectively. The sensors fabricated by e-beam evaporation in combination with the GAD method showed much higher sensitivities than normally prepared sensors and exhibited rapid response times. The gas sensitivity (S = R(gas)/R(air)) of the SnO2 sensor using the GAD method was 43.4 for 5 ppm NO2 and 0.08 for 10 ppm C2H5OH, respectively. These sensors showed excellent sensitivities compared to the normal thin film sensors (S = 2 for 5 ppm NO2 and 0.92 for 10 ppm C2H5OH). We consider that the nanostructured sensors produced using the GAD process could be used to detect various gases emitted by automobiles and industrial installations.

  2. Improvements in emotion regulation following repetitive transcranial magnetic stimulation for generalized anxiety disorder.

    PubMed

    Diefenbach, Gretchen J; Assaf, Michal; Goethe, John W; Gueorguieva, Ralitza; Tolin, David F

    2016-10-01

    Generalized anxiety disorder (GAD) is characterized by emotion regulation difficulties, which are associated with abnormalities in neural circuits encompassing fronto-limbic regions including the dorsolateral prefrontal cortex (DLPFC). The aim of this study was to determine whether DLPFC neuromodulation improves emotion regulation in patients with GAD. This is a secondary analysis from a randomized-controlled trial comparing 30 sessions of low-frequency right-sided active (n=13) versus sham (n=12, sham coil) repetitive transcranial magnetic stimulation (rTMS) at the right DLPFC in patients with GAD. Results indicated statistically significant improvements in self-reported emotion regulation difficulties at posttreatment and 3-month follow-up in the active group only. Improvements were found primarily in the domains of goal-directed behaviors and impulse control and were significantly associated with a global clinician rating of improvement. These preliminary results support rTMS as a treatment for GAD and suggest improved emotion regulation as a possible mechanism of change.

  3. A cytological and experimental study of the neuropil and primary olfactory afferences to the piriform cortex.

    PubMed

    Vargas-Barroso, Víctor; Larriva-Sahd, Jorge

    2013-09-01

    The microscopic organization of the piriform cortex (PC) was studied in normal and experimental material from adult albino rats. In rapid-Golgi specimens a set of collaterals from the lateral olfactory tract (i.e., sublayer Ia) to the neuropil of the Layer II (LII) was identified. Specimens from experimental animals that received electrolytic lesion of the main olfactory bulb three days before sacrificing, were further processed for pre-embedding immunocytochemistry to the enzyme glutamic acid decarboxylase 67 (GAD 67). This novel approach permitted a simultaneous visualization at electron microscopy of both synaptic degeneration and GAD67-immunoreactive (GAD-I) sites. Degenerating and GAD-I synapses were separately found in the neuropil of Layers I and II of the PC. Previously overlooked patches of neuropil were featured in sublayer Ia. These areas consisted of dendritic and axonal processes including four synaptic types. Tridimensional reconstructions from serial thin sections from LI revealed the external appearance of the varicose and tubular dendrites as well as the synaptic terminals therein. The putative source(s) of processes to the neuropil of sublayer Ia is discussed in the context of the internal circuitry of the PC and an alternative model is introduced.

  4. Considering ERP difference scores as individual difference measures: Issues with subtraction and alternative approaches.

    PubMed

    Meyer, Alexandria; Lerner, Matthew D; De Los Reyes, Andres; Laird, Robert D; Hajcak, Greg

    2017-01-01

    There is growing interest in psychophysiological and neural correlates of psychopathology, personality, and other individual differences. Many studies correlate a criterion individual difference variable (e.g., anxiety) with a psychophysiological measurement derived by subtracting scores taken from two within-subject conditions. These subtraction-based difference scores are intended to increase specificity by isolating variability of interest. Using data on the error-related negativity (ERN) and correct response negativity (CRN) in relation to generalized anxiety disorder (GAD), we highlight several conceptual and practical issues with subtraction-based difference scores and propose alternative approaches based on regression. We show that ERN and CRN are highly correlated, and that the ΔERN (i.e., ERN - CRN) is correlated in opposite directions both with ERN and CRN. Bivariate analyses indicate that GAD is related to ΔERN and ERN, but not CRN. We first show that, by using residualized scores, GAD relates both to a larger ERN and smaller CRN. Moreover, by probing the interaction of ERN and CRN, we show that the relationship between GAD and ERN varies by CRN. These latter findings are not evident when using traditional subtraction-based difference scores. We then completed follow-up analyses that suggested that an increased P300 in anxious individuals gave rise to the apparent anxiety/CRN relationship observed. These findings have important conceptual implications for facilitating the interpretability of results from individual difference studies of psychophysiology.

  5. Buffer-free production of gamma-aminobutyric acid using an engineered glutamate decarboxylase from Escherichia coli.

    PubMed

    Kang, Taek Jin; Ho, Ngoc Anh Thu; Pack, Seung Pil

    2013-08-15

    Escherichia coli glutamate decarboxylase (GAD) converts glutamate into γ-aminobutyric acid (GABA) through decarboxylation using proton as a co-substrate. Since GAD is active only at acidic conditions even though pH increases as the reaction proceeds, the conventional practice of using this enzyme involved the use of relatively high concentration of buffers, which might complicate the downstream purification steps. Here we show by simulation and experiments that the free acid substrate, glutamic acid, rather than its monosodium salt can act as a substrate and buffer at the same time. This yielded the buffer- and salt-free synthesis of GABA conveniently in a batch mode. Furthermore, we engineered GAD to hyper active ones by extending or reducing the length of the enzyme by just one residue at its C-terminus. Through the buffer-free reaction with engineered GAD, we could synthesize 1M GABA in 3h, which can be translated into a space-time yield of 34.3g/L/h.

  6. Differential Regulation of Glutamic Acid Decarboxylase Gene Expression after Extinction of a Recent Memory vs. Intermediate Memory

    ERIC Educational Resources Information Center

    Sangha, Susan; Ilenseer, Jasmin; Sosulina, Ludmila; Lesting, Jorg; Pape, Hans-Christian

    2012-01-01

    Extinction reduces fear to stimuli that were once associated with an aversive event by no longer coupling the stimulus with the aversive event. Extinction learning is supported by a network comprising the amygdala, hippocampus, and prefrontal cortex. Previous studies implicate a critical role of GABA in extinction learning, specifically the GAD65…

  7. Detection and transfer of the glutamate decarboxylase gene in Streptococcus thermophilus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    GABA (gamma-aminobutyric acid) 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 fermen...

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    GABA ('-aminobutyric acid) 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 da...

  9. Cognitive behaviour therapy for generalized anxiety disorder: Is CBT equally efficacious in adults of working age and older adults?

    PubMed

    Kishita, Naoko; Laidlaw, Ken

    2017-03-01

    The current meta-analysis compared the efficacy of CBT for GAD between adults of working age and older people. In addition, we conducted a qualitative content analysis of treatment protocols used in studies with older clients to explore potential factors that may enhance treatment outcomes with this particular client group. Applying the inclusion criteria resulted in the identification of 15 studies with 22 comparisons between CBT and control groups (770 patients). When examining overall effect sizes for CBT for GAD between older people and adults of working age there were no statistically significant differences in outcome. However, overall effect size of CBT for GAD was moderate for older people (g=0.55, 95% CI 0.22-0.88) and large for adults of working age (g=0.94, 95% CI 0.52-1.36), suggesting that there is still room for improvement in CBT with older people. The main difference in outcome between CBT for GAD between the two age groups was related to methodological quality in that no older people studies used an intention-to-treat design. The content analysis demonstrated that studies with older clients were conducted according to robust CBT protocols but did not take account of gerontological evidence to make them more age-appropriate.

  10. Systematic analysis of γ-aminobutyric acid (GABA) metabolism and function in the social amoeba Dictyostelium discoideum.

    PubMed

    Wu, Yuantai; Janetopoulos, Chris

    2013-05-24

    While GABA has been suggested to regulate spore encapsulation in the social amoeba Dictyostelium discoideum, the metabolic profile and other potential functions of GABA during development remain unclear. In this study, we investigated the homeostasis of GABA metabolism by disrupting genes related to GABA metabolism and signaling. Extracellular levels of GABA are tightly regulated during early development, and GABA is generated by the glutamate decarboxylase, GadB, during growth and in early development. However, overexpression of the prespore-specific homologue, GadA, in the presence of GadB reduces production of extracellular GABA. Perturbation of extracellular GABA levels delays the process of aggregation. Cytosolic GABA is degraded by the GABA transaminase, GabT, in the mitochondria. Disruption of a putative vesicular GABA transporter (vGAT) homologue DdvGAT reduces secreted GABA. We identified the GABAB receptor-like family member GrlB as the major GABA receptor during early development, and either disruption or overexpression of GrlB delays aggregation. This delay is likely the result of an abolished pre-starvation response and late expression of several "early" developmental genes. Distinct genes are employed for GABA generation during sporulation. During sporulation, GadA alone is required for generating GABA and DdvGAT is likely responsible for GABA secretion. GrlE but not GrlB is the GABA receptor during late development.

  11. Long term therapy of generalized anxiety disorder.

    PubMed

    Rouillon, Frédéric

    2004-04-01

    Generalized anxiety disorder (GAD) is a common (lifetime prevalence: 5.1%), recurrent condition, which often heralds other psychiatric disorders, notably depression. As by definition it is a disorder progressing over months, treatment should be designed on a long term basis. And yet, few studies have been conducted beyond the classical 6-8 weeks characterizing the acute treatment phase. This is especially true of anxiolytics, but also of antidepressants, with the exception of paroxetine and venlafaxine, which are the only drugs approved in this indication in Western countries. The efficacy of psychotherapy, notably relaxation and cognitive-behavioral therapy, is established in the treatment of GAD, but its preferred indications and possible combination with antidepressants are still to be specified. Long term, not to say very long term studies of GAD, as well as depression, will still be required in the future to improve its management and specify therapeutic modalities (combination treatment, optimal duration, continuous or intermittent therapy, choice of psychotherapeutic techniques or agents, em leader ). Early and adequately prolonged treatment should not only result in more numerous remission periods, but also in decreased frequency of co-morbidities whether depressive, addictive, or of another nature, and should also reduce the social impact of GAD.

  12. Fission yeast Ryh1 GTPase activates TOR Complex 2 in response to glucose.

    PubMed

    Hatano, Tomoyuki; Morigasaki, Susumu; Tatebe, Hisashi; Ikeda, Kyoko; Shiozaki, Kazuhiro

    2015-01-01

    The Target Of Rapamycin (TOR) is an evolutionarily conserved protein kinase that forms 2 distinct protein complexes referred to as TOR complex 1 (TORC1) and 2 (TORC2). Recent extensive studies have demonstrated that TORC1 is under the control of the small GTPases Rheb and Rag that funnel multiple input signals including those derived from nutritional sources; however, information is scarce as to the regulation of TORC2. A previous study using the model system provided by the fission yeast Schizosaccharomyces pombe identified Ryh1, a Rab-family GTPase, as an activator of TORC2. Here, we show that the nucleotide-binding state of Ryh1 is regulated in response to glucose, mediating this major nutrient signal to TORC2. In glucose-rich growth media, the GTP-bound form of Ryh1 induces TORC2-dependent phosphorylation of Gad8, a downstream target of TORC2 in fission yeast. Upon glucose deprivation, Ryh1 becomes inactive, which turns off the TORC2-Gad8 pathway. During glucose starvation, however, Gad8 phosphorylation by TORC2 gradually recovers independently of Ryh1, implying an additional TORC2 activator that is regulated negatively by glucose. The paired positive and negative regulatory mechanisms may allow fine-tuning of the TORC2-Gad8 pathway, which is essential for growth under glucose-limited environment.

  13. A Multifaith Spiritually Based Intervention Versus Supportive Therapy for Generalized Anxiety Disorder: A Pilot Randomized Controlled Trial

    PubMed Central

    Koszycki, Diana; Bilodeau, Cynthia; Raab-Mayo, Kelley; Bradwejn, Jacques

    2014-01-01

    Objectives We have previously reported that a multifaith spiritually based intervention (SBI) may have efficacy in the treatment of generalized anxiety disorder (GAD). This randomized pilot trial tested whether the SBI had greater efficacy than a nonspecific control condition in GAD. Method Twenty-three participants with GAD of at least moderate severity were randomized to 12 individual sessions of the SBI (n = 11) or supportive psychotherapy (SP)—our control condition (n = 12). Results Intent-to-treat analysis revealed the SBI fared better than SP in decreasing blind clinician ratings of anxiety and illness severity and self-report worry and intolerance of uncertainty, with large between-group effect sizes. The SBI also produced greater changes in spiritual well-being. Results remained the same when supplementary analyses were performed on the completer sample. Treatment gains were maintained at 3-months follow-up. Conclusions This small pilot trial demonstrates that a nondenominational SBI has greater efficacy than a rigorous control in improving symptoms of GAD and enhancing spiritual well-being. These results are encouraging and further research on the efficacy of the SBI and its underlying mechanisms is warranted. PMID:24114846

  14. High γ-aminobutyric acid production from lactic acid bacteria: emphasis on Lactobacillus brevis as a functional dairy starter.

    PubMed

    Wu, Qinglong; Shah, Nagendra P

    2016-03-15

    γ-Aminobutyric acid (GABA) and GABA-rich foods have shown anti-hypertensive and anti-depressant activities as the major functions in humans and animals. Hence, high GABA-producing lactic acid bacteria (LAB) could be used as functional starters for manufacturing novel fermented dairy foods. Glutamic acid decarboxylases (GADs) from LAB are highly conserved at the species level based on the phylogenetic tree of GADs from LAB. Moreover, two functionally distinct GADs and one intact gad operon were observed in all the completely sequenced Lactobacillus brevis strains suggesting its common capability to synthesize GABA. Difficulties and strategies for the manufacture of GABA-rich fermented dairy foods have been discussed and proposed, respectively. In addition, a genetic survey on the sequenced LAB strains demonstrated the absence of cell envelope proteinases in the majority of LAB including Lb. brevis, which diminishes their cell viabilities in milk environments due to their non-proteolytic nature. Thus, several strategies have been proposed to overcome the non-proteolytic nature of Lb. brevis in order to produce GABA-rich dairy foods.

  15. Dairy Streptococcus thermophilus improves cell viability of Lactobacillus brevis NPS-QW-145 and its γ-aminobutyric acid biosynthesis ability in milk.

    PubMed

    Wu, Qinglong; Law, Yee-Song; Shah, Nagendra P

    2015-08-06

    Most high γ-aminobutyric acid (GABA) producers are Lactobacillus brevis of plant origin, which may be not able to ferment milk well due to its poor proteolytic nature as evidenced by the absence of genes encoding extracellular proteinases in its genome. In the present study, two glutamic acid decarboxylase (GAD) genes, gadA and gadB, were found in high GABA-producing L. brevis NPS-QW-145. Co-culturing of this organism with conventional dairy starters was carried out to manufacture GABA-rich fermented milk. It was observed that all the selected strains of Streptococcus thermophilus, but not Lactobacillus delbrueckii subsp. bulgaricus, improved the viability of L. brevis NPS-QW-145 in milk. Only certain strains of S. thermophilus improved the gadA mRNA level in L. brevis NPS-QW-145, thus enhanced GABA biosynthesis by the latter. These results suggest that certain S. thermophilus strains are highly recommended to co-culture with high GABA producer for manufacturing GABA-rich fermented milk.

  16. Toddler Anxiety Disorders: A Pilot Study

    ERIC Educational Resources Information Center

    Warren, Susan L.; Umylny, Polina; Aron, Emily; Simmens, Samuel J.

    2006-01-01

    Objective: This research examined the validity of criteria for diagnosing social phobia (SOC) and generalized anxiety disorder (GAD), where the "DSM-IV" criteria were modified to better identify toddlers who could have these disorders. Method: Diagnoses were made with a semistructured clinical interview that included child observations.…

  17. Abnormal decision-making in generalized anxiety disorder: Aversion of risk or stimulus-reinforcement impairment?

    PubMed

    Teng, Cindy; Otero, Marcela; Geraci, Marilla; Blair, R J R; Pine, Daniel S; Grillon, Christian; Blair, Karina S

    2016-03-30

    There is preliminary data indicating that patients with generalized anxiety disorder (GAD) show impairment on decision-making tasks requiring the appropriate representation of reinforcement value. The current study aimed to extend this literature using the passive avoidance (PA) learning task, where the participant has to learn to respond to stimuli that engender reward and avoid responding to stimuli that engender punishment. Six stimuli engendering reward and six engendering punishment are presented once per block for 10 blocks of trials. Thirty-nine medication-free patients with GAD and 29 age-, IQ and gender matched healthy comparison individuals performed the task. In addition, indexes of social functioning as assessed by the Global Assessment of Functioning (GAF) scale were obtained to allow for correlational analyzes of potential relations between cognitive and social impairments. The results revealed a Group-by-Error Type-by-Block interaction; patients with GAD committed significantly more commission (passive avoidance) errors than comparison individuals in the later blocks (blocks 7,8, and 9). In addition, the extent of impairment on these blocks was associated with their functional impairment as measured by the GAF scale. These results link GAD with anomalous decision-making and indicate that a potential problem in reinforcement representation may contribute to the severity of expression of their disorder.

  18. Cytochemical Studies on Acetylcholine Synthesis and Metabolism in the Vestibular Cerebellum.

    DTIC Science & Technology

    1987-05-31

    proportion of their spinal input from the more distal parts of the lower limbs release taurine in their synaptic projection field, probably together with GABA ...Purkinje cells have GAD, motilin, and CSAD immunoreactivity. Existence and coexistence of GABA , motilin and taurine . in: Coexistence of Neuroactive...primate neuromuscular junctions of enzymes synthesizing four neuroactive substances: Acetylcholine, catecholamine, GABA , and taurine . In: Coexistence

  19. The British Sign Language versions of the Patient Health Questionnaire, the Generalized Anxiety Disorder 7-item Scale, and the Work and Social Adjustment Scale.

    PubMed

    Rogers, Katherine D; Young, Alys; Lovell, Karina; Campbell, Malcolm; Scott, Paul R; Kendal, Sarah

    2013-01-01

    The present study is aimed to translate 3 widely used clinical assessment measures into British Sign Language (BSL), to pilot the BSL versions, and to establish their validity and reliability. These were the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder 7-item (GAD-7) scale, and the Work and Social Adjustment Scale (WSAS). The 3 assessment measures were translated into BSL and piloted with the Deaf signing population in the United Kingdom (n = 113). Participants completed the PHQ-9, GAD-7, WSAS, and Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM) online. The reliability and validity of the BSL versions of PHQ-9, GAD-7, and WSAS have been examined and were found to be good. The construct validity for the PHQ-9 BSL version did not find the single-factor solution as found in the hearing population. The BSL versions of PHQ-9, GAD-7, and WSAS have been produced in BSL and can be used with the signing Deaf population in the United Kingdom. This means that now there are accessible mental health assessments available for Deaf people who are BSL users, which could assist in the early identification of mental health difficulties.

  20. GABAergic pathway in a rat model of chronic neuropathic pain: modulation after intrathecal transplantation of a human neuronal cell line.

    PubMed

    Vaysse, L; Sol, J C; Lazorthes, Y; Courtade-Saidi, M; Eaton, M J; Jozan, S

    2011-02-01

    Current understanding of chronic pain points a decrease in level of the inhibitory neurotransmitter GABA, in the spinal dorsal horn, leading to an imbalance between excitatory and inhibitory pathways. A subcloned derivative of the human NT2 cell line (hNT2.17) which, after neuronal differentiation, secretes different inhibitory neurotransmitters such as GABA and glycine has been recently isolated. In this study, we have investigated the effect of this new cell line on peripheral nerve injury induced by chronic constriction (CCI) and notably the effect on the cellular GABAergic pathway. Our data show that the decrease in GABA expression in the spinal dorsal horn of injured animals is concomitant with a decline of its synthetic enzyme GAD67-Ir and mRNA but not GAD65. Interestingly, in transplanted animals we observed a strong induction of GAD67 mRNA with one week after graft, which is followed by a recovery of GAD67 and GABA Ir. This effect paralleled a reduction of hindpaw hypersensitivity and thermal hyperalgesia induced by CCI. These results suggest that hNT2.17 GABA cells can modulate neuropathic pain after CCI certainly by minimizing the imbalance and restoring the cellular GABAergic pathway.