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  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 sexuality. Set in a barrio…

  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. Adaptation of a GAD Treatment for Hypochondriasis

    ERIC Educational Resources Information Center

    Langlois, Frederic; Ladouceur, Robert

    2004-01-01

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

  6. Genes of the GadX-GadW regulon in Escherichia coli.

    PubMed

    Tucker, Don L; Tucker, Nancy; Ma, Zhuo; Foster, John W; Miranda, Regina L; Cohen, Paul S; Conway, Tyrrell

    2003-05-01

    Acid in the stomach is thought to be a barrier to bacterial colonization of the intestine. Escherichia coli, however, has three systems for acid resistance, which overcome this barrier. The most effective of these systems is dependent on transport and decarboxylation of glutamate. GadX regulates two genes that encode isoforms of glutamate decarboxylase critical to this system, but additional genes associated with the glutamate-dependent acid resistance system remained to be identified. The gadX gene and a second downstream araC-like transcription factor gene, gadW, were mutated separately and in combination, and the gene expression profiles of the mutants were compared to those of the wild-type strain grown in neutral and acidified media under conditions favoring induction of glutamate-dependent acid resistance. Cluster and principal-component analyses identified 15 GadX-regulated, acid-inducible genes. Reverse transcriptase mapping demonstrated that these genes are organized in 10 operons. Analysis of the strain lacking GadX but possessing GadW confirmed that GadX is a transcriptional activator under acidic growth conditions. Analysis of the strain lacking GadW but possessing GadX indicated that GadW exerts negative control over three GadX target genes. The strain lacking both GadX and GadW was defective in acid induction of most but not all GadX target genes, consistent with the roles of GadW as an inhibitor of GadX-dependent activation of some genes and an activator of other genes. Resistance to acid was decreased under certain conditions in a gadX mutant and even more so by combined mutation of gadX and gadW. However, there was no defect in colonization of the streptomycin-treated mouse model by the gadX mutant in competition with the wild type, and the gadX gadW mutant was a better colonizer than the wild type. Thus, E. coli colonization of the mouse does not appear to require glutamate-dependent acid resistance. PMID:12730179

  7. The exon-intron organization of the genes (GAD1 and GAD2) encoding two human glutamate decarboxylases (GAD[sub 67] and GAD[sub 65]) suggests that they derive from a common ancestral GAD

    SciTech Connect

    Bu, D.F.; Tobin, A.J. )

    1994-05-01

    The authors have cloned and characterized human genes (GAD1 and GAD2) encoding the two human glutamate decarboxylases, GAD[sub 67] and GAD[sub 65]. The coding region of the GAD[sub 65] gene consists of 16 exons, spanning more than 79 kb of genomic DNA. Exon 1 contains the 5[prime] untranslated region of GAD[sub 65] mRNA, and exon 16 specifies the protein's carboxy terminal and at least part of the mRNA's 3[prime] untranslated sequence. Similarly, the coding region of the GAD[sub 67] gene consists of 16 exons, spread over more than 45 kb of genomic DNA. The GAD[sub 67] gene contains an additional exon (exon 0) that, together with part of exon 1, specifies the 5[prime] untranslated region of GAD[sub 67] mRNA. Exon 16 specifies the entire 3[prime] untranslated region of GAD[sub 67] mRNA. Exons 1-3 encode the most divergent region of GAD[sub 65] and GAD[sub 67]. The remaining exon-intron boundaries occur at identical positions in the two cDNAs, suggesting that they derive from a common ancestral GAD gene. 26 refs., 4 figs., 2 tabs.

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

    MedlinePlus

    ... to have GAD? For More Information Share Generalized Anxiety Disorder (GAD): When Worry Gets Out of Control ... go badly? If so, you may have an anxiety disorder called generalized anxiety disorder (GAD). What is ...

  9. GAD65 epitope mapping and search for novel autoantibodies in GAD-associated neurological disorders.

    PubMed

    Fouka, P; Alexopoulos, H; Akrivou, S; Trohatou, O; Politis, P K; Dalakas, M C

    2015-04-15

    Antibodies against Glutamic-acid-decarboxylase (GAD65) are seen in various CNS excitability disorders including stiff-person syndrome, cerebellar ataxia, encephalitis and epilepsy. To explore pathogenicity, we examined whether distinct epitope specificities or other co-existing antibodies may account for each disorder. The epitope recognized by all 27 tested patients, irrespective of clinical phenotype, corresponded to the catalytic core of GAD. No autoantibodies against known GABAergic antigens were found. In a screen for novel specificities using live hippocampal neurons, three epilepsy patients, but no other, were positive. We conclude that no GAD-specific epitope defines any neurological syndrome but other antibody specificities may account for certain phenotypes. PMID:25867471

  10. 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

    ... under 10 CFR 2.315(c), must be filed in accordance with NRC E-Filing rule (72 FR 49139, August 28, 2007... From the Federal Register Online via the Government Publishing Office NUCLEAR REGULATORY COMMISSION Order Prohibiting Involvement in NRC-Licensed Activities; In the Matter of Jaime S nchez I Jaime...

  11. FUTURES with Jaime Escalante: Development of a Successful, Research-Based Instructional Video Series.

    ERIC Educational Resources Information Center

    Beckmann, Shelley L.

    "FUTURES with Jaime Escalante" is an educational video series aimed at increasing interest in mathematics. The series of 12 videotapes is aimed at junior high and early high school students and demonstrates that mathematics is a prerequisite for many careers. The series seeks to change students' attitudes toward mathematics and defuse the ideas…

  12. Expression of GADS enhances FLT3-induced mitogenic signaling.

    PubMed

    Chougule, Rohit A; Cordero, Eugenia; Moharram, Sausan A; Pietras, Kristian; Rönnstrand, Lars; Kazi, Julhash U

    2016-03-22

    GADS is a member of a family of SH2 and SH3 domain-containing adaptors that functions in tyrosine kinase-mediated signaling cascades. Its expression is largely restricted to hematopoietic tissues and cell lines. Therefore, GADS is mainly involved in leukocyte-specific protein tyrosine kinase signaling. GADS is known to interact with tyrosine-phosphorylated SHC, BCR-ABL and KIT. The SH2 domain of GADS has a similar binding specificity to that of GRB2 but its SH3 domain displays a different binding specificity, and thus it is involved in other downstream signaling pathways than GRB2. In the present study, we examined the role of GADS in FLT3 signaling. FLT3 is a type III receptor tyrosine kinase, which is mutated in more than 30% of acute myeloid leukemia (AML) and the most common mutations is the internal tandem duplication (ITD) mutations. We observed that expression of GADS enhanced oncogenic FLT3-ITD-induced cell proliferation and colony formation in vitro. In a mouse xenograft model, GADS accelerated FLT3-ITD-dependent tumor formation. Furthermore, expression of GADS induced a transcriptional program leading to upregulation of MYC and mTORC1 target genes. GADS localizes to the cell membrane and strongly binds to ligand-stimulated wild-type FLT3 or is constitutively associated with the oncogenic mutant FLT3-ITD. We mapped the binding sites in FLT3 to pY955 and pY969 which overlaps with the GRB2 binding sites. Expression of GADS enhanced FLT3-mediated phosphorylation of AKT, ERK1/2, p38 and STAT5. Taken together, our data suggests that GADS is an important downstream component of FLT3 signaling and expression of GADS potentiates FLT3-mediated mitogenic signaling. PMID:26895103

  13. Expression of GADS enhances FLT3-induced mitogenic signaling

    PubMed Central

    Chougule, Rohit A.; Cordero, Eugenia; Moharram, Sausan A.; Pietras, Kristian; Rönnstrand, Lars; Kazi, Julhash U.

    2016-01-01

    GADS is a member of a family of SH2 and SH3 domain-containing adaptors that functions in tyrosine kinase-mediated signaling cascades. Its expression is largely restricted to hematopoietic tissues and cell lines. Therefore, GADS is mainly involved in leukocyte-specific protein tyrosine kinase signaling. GADS is known to interact with tyrosine-phosphorylated SHC, BCR-ABL and KIT. The SH2 domain of GADS has a similar binding specificity to that of GRB2 but its SH3 domain displays a different binding specificity, and thus it is involved in other downstream signaling pathways than GRB2. In the present study, we examined the role of GADS in FLT3 signaling. FLT3 is a type III receptor tyrosine kinase, which is mutated in more than 30% of acute myeloid leukemia (AML) and the most common mutations is the internal tandem duplication (ITD) mutations. We observed that expression of GADS enhanced oncogenic FLT3-ITD-induced cell proliferation and colony formation in vitro. In a mouse xenograft model, GADS accelerated FLT3-ITD-dependent tumor formation. Furthermore, expression of GADS induced a transcriptional program leading to upregulation of MYC and mTORC1 target genes. GADS localizes to the cell membrane and strongly binds to ligand-stimulated wild-type FLT3 or is constitutively associated with the oncogenic mutant FLT3-ITD. We mapped the binding sites in FLT3 to pY955 and pY969 which overlaps with the GRB2 binding sites. Expression of GADS enhanced FLT3-mediated phosphorylation of AKT, ERK1/2, p38 and STAT5. Taken together, our data suggests that GADS is an important downstream component of FLT3 signaling and expression of GADS potentiates FLT3-mediated mitogenic signaling. PMID:26895103

  14. Recent gene conversions between duplicated glutamate decarboxylase genes (gadA and gadB) in pathogenic Escherichia coli.

    PubMed

    Bergholz, Teresa M; Tarr, Cheryl L; Christensen, Lisa M; Betting, David J; Whittam, Thomas S

    2007-10-01

    Escherichia coli have evolved adaptive systems to resist strongly acidic habitats in part through the production of 2 biochemically identical isoforms of glutamate decarboxylase (GAD), encoded by the gadA and gadB genes. These genes occur in E. coli and other members of the genospecies (e.g., Shigella spp.) and originated as part of a genomic fitness island acquired early in Escherichia evolution. The present duplicated gad loci are widely spaced on the E. coli chromosome, and the 2 genes are 97% similar in sequence. Comparison of the nucleotide sequences of the gadA and gadB in 16 strains of pathogenic E. coli revealed 3.8% and 5.0% polymorphism in the 2 genes, respectively. Alignment of the homologous genes identified a total of 120 variable sites, including 21 fixed nucleotide differences between the loci within the first 82 codons of the genes. Twenty-three phylogenetically informative sites were polymorphic for the same nucleotides in both genes suggesting recent gene conversions or intergenic recombination. Phylogenetic analysis based on the synonymous substitutions per synonymous site indicated 2 cases in which specific gadA and gadB alleles were more closely related to one another than to other alleles at the corresponding locus. The results indicate that at least 3 gene conversion events have occurred after the gad gene duplication in the evolution of E. coli. Despite multiple gene conversion events, the upstream regulatory regions and the 5' end of each gene remains distinct, suggesting that maintaining functionally different gad genes is important in this acid-resistance mechanism in pathogenic E. coli. PMID:17675652

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

    MedlinePlus

    Generalized Anxiety Disorder: When Worry Gets Out of Control Are you extremely worried about everything in your life, even ... go badly? If so, you may have an anxiety disorder called generalized anxiety disorder (GAD). national institute ...

  16. Gluconic acid production by gad mutant of Klebsiella pneumoniae.

    PubMed

    Wang, Dexin; Wang, Chenhong; Wei, Dong; Shi, Jiping; Kim, Chul Ho; Jiang, Biao; Han, Zengsheng; Hao, Jian

    2016-08-01

    Klebsiella pneumoniae produces many economically important chemicals. Using glucose as a carbon source, the main metabolic product in K. pneumoniae is 2,3-butanediol. Gluconic acid is an intermediate of the glucose oxidation pathway. In the current study, a metabolic engineering strategy was used to develop a gluconic acid-producing K. pneumoniae strain. Deletion of gad, resulting in loss of gluconate dehydrogenase activity, led to the accumulation of gluconic acid in the culture broth. Gluconic acid accumulation by K. pneumoniae Δgad was an acid-dependent aerobic process, with accumulation observed at pH 5.5 or lower, and at higher levels of oxygen supplementation. Under all other conditions tested, 2,3-butanediol was the main metabolic product of the process. In fed batch fermentation, a final concentration of 422 g/L gluconic acid was produced by K. pneumoniae Δgad, and the conversion ratio of glucose to gluconic acid reached 1 g/g. The K. pneumoniae Δgad described in this study is the first genetically modified strain used for gluconic acid production, and this optimized method for gluconic acid production may have important industrial applications. Gluconic acid is an intermediate of this glucose oxidation pathway. Deletion of gad, resulting in loss of gluconate dehydrogenase activity, led to the accumulation of gluconic acid in the culture broth. In fed batch fermentation, a final concentration of 422 g/L gluconic acid was produced by the K. pneumoniae Δgad strain, and the conversion ratio of glucose to gluconic acid reached 1 g/g. PMID:27339313

  17. 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

  18. 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. PMID:24164637

  19. 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

  20. 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

  1. A glutamic acid decarboxylase (CgGAD) highly expressed in hemocytes of Pacific oyster Crassostrea gigas.

    PubMed

    Li, Meijia; Wang, Lingling; Qiu, Limei; Wang, Weilin; Xin, Lusheng; Xu, Jiachao; Wang, Hao; Song, Linsheng

    2016-10-01

    Glutamic acid decarboxylase (GAD), a rate-limiting enzyme to catalyze the reaction converting the excitatory neurotransmitter glutamate to inhibitory neurotransmitter γ-aminobutyric acid (GABA), not only functions in nervous system, but also plays important roles in immunomodulation in vertebrates. However, GAD has rarely been reported in invertebrates, and never in molluscs. In the present study, one GAD homologue (designed as CgGAD) was identified from Pacific oyster Crassostrea gigas. The full length cDNA of CgGAD was 1689 bp encoding a polypeptide of 562 amino acids containing a conserved pyridoxal-dependent decarboxylase domain. CgGAD mRNA and protein could be detected in ganglion and hemocytes of oysters, and their abundance in hemocytes was unexpectedly much higher than those in ganglion. More importantly, CgGAD was mostly located in those granulocytes without phagocytic capacity in oysters, and could dynamically respond to LPS stimulation. Further, after being transfected into HEK293 cells, CgGAD could promote the production of GABA. Collectively, these findings suggested that CgGAD, as a GABA synthase and molecular marker of GABAergic system, was mainly distributed in hemocytes and ganglion and involved in neuroendocrine-immune regulation network in oysters, which also provided a novel insight to the co-evolution between nervous system and immune system. PMID:27208883

  2. Structural model of human GAD65: prediction and interpretation of biochemical and immunogenic features.

    PubMed

    Capitani, Guido; De Biase, Daniela; Gut, Heinz; Ahmed, Shaheen; Grütter, Markus G

    2005-04-01

    The 65 kDa human isoform of glutamate decarboxylase, GAD65, plays a central role in neurotransmission in higher vertebrates and is a typical autoantigen in several human autoimmune diseases, such as insulin-dependent diabetes mellitus (IDDM), Stiff-man syndrome and autoimmune polyendocrine syndrome type I. In autoimmune diabetes, an attack of inflammatory cells to endocrine pancreatic beta-cells leads to their complete destruction, eventually resulting in the inability to produce sufficient insulin for the body's requirements. Even though the etiology of beta-cell destruction is still a matter of debate, the role and antigenic potency of GAD65 are widely recognized. Herein a model of GAD65 is presented, which is based on the recently solved crystal structures of mammalian DOPA decarboxylase and of bacterial glutamate decarboxylase. The model provides for the first time a detailed and accurate structure of the GAD65 subunit (all three domains) and of its dimeric quaternary assembly. It reveals the structural basis for specific antibody recognition to GAD65 as opposed to GAD67, the other human isoform, which shares 81% sequence similarity with GAD65 and is much less antigenic. Literature data on monoclonal antibody binding are perfectly consistent with the detailed features of the model, which allows explanation of several findings on GAD65 immunogenicity. Importantly, by analyzing the active site, we identified the residues most likely involved in catalysis and substrate recognition, paving the way for rational mutagenesis studies of the GAD65 reaction mechanism, specificity and inhibition. PMID:15690345

  3. Epigenetic Suppression of GADs Expression is Involved in Temporal Lobe Epilepsy and Pilocarpine-Induced Mice Epilepsy.

    PubMed

    Wang, Jin-Gang; Cai, Qing; Zheng, Jun; Dong, Yu-Shu; Li, Jin-Jiang; Li, Jing-Chen; Hao, Guang-Zhi; Wang, Chao; Wang, Ju-Lei

    2016-07-01

    Recent studies have shown that histone acetylation is involved with the regulation of enzyme glutamate decarboxylases (GADs), including GAD67 and GAD65. Here, we investigated the histone acetylation modifications of GADs in the pathogenesis of epilepsy and explored the therapeutic effect of a novel second-generation histone deacetylase inhibitor (HDACi) JNJ-26481585 in epilepsy animals. We revealed the suppression of GADs protein and mRNA level, and histone hypoacetylation in patients with temporal lobe epilepsy and pilocarpine-induced epilepsy mice model. Double-immunofluorescence also indicated that the hypoacetyl-H3 was located in hippocampal GAD67/GAD65 positive neurons in epilepsy mice. JNJ-26481585 significantly reversed the decrease of the GAD67/GAD65 both protein and mRNA levels, and the histone hypoacetylation of GABAergic neurons in epilepsy mice. Meanwhile, single-cell real-time PCR performed in GFP-GAD67/GAD65 transgenic mice demonstrated that JNJ-26481585 induced increase of GAD67/GAD65 mRNA level in GABAergic neurons. Furthermore, JNJ-26481585 significantly alleviated the epileptic seizures in mice model. Together, our findings demonstrate inhibition of GADs gene via histone acetylation plays an important role in the pathgenesis of epilepsy, and suggest JNJ-26481585 as a promising therapeutic strategy for epilepsy. PMID:27220336

  4. Function coupling of otoferlin with GAD65 acts to modulate GABAergic activity.

    PubMed

    Wu, Wu; Rahman, Mona N; Guo, Jun; Roy, Natalie; Xue, Lihua; Cahill, Catherine M; Zhang, Shetuan; Jia, Zongchao

    2015-04-01

    Otoferlin, an integral membrane protein implicated in a late stage of exocytosis, has been reported to play a critical role in hearing although the underlying mechanisms remain elusive. However, its widespread tissue distribution infers a more ubiquitous role in synaptic vesicle trafficking. Glutamate, an excitatory neurotransmitter, is converted to its inhibitory counterpart, γ-aminobutyric acid (GABA), by L-glutamic acid decarboxylase (GAD), which exists in soluble (GAD67) and membrane-bound (GAD65) forms. For the first time, we have revealed a close association between otoferlin and GAD65 in both HEK293 and neuronal cells, including SH-SY5Y neuroblastoma and primary rat hippocampus cells, showing a direct interaction between GAD65 and otoferlin's C2 domains. In primary rat hippocampus cells, otoferlin and GAD65 co-localized in a punctate pattern within the cell body, as well as in the axon along the path of vesicular traffic. Significantly, GABA is virtually abolished in otoferlin-knockdown neuronal cells whereas otoferlin overexpression markedly increases endogenous GABA. GABA attenuation in otoferlin-knockdown primary cells is correlated with diminished L-type calcium current. This previously unknown and close correlation demonstrates that otoferlin, through GAD65, modulates GABAergic activity. The discovery of otoferlin-GAD65 functional coupling provides a new avenue for understanding the molecular mechanism by which otoferlin functions in neurological pathways. PMID:25701657

  5. Predictors of CBT outcome in older adults with GAD.

    PubMed

    Hundt, Natalie E; Amspoker, Amber B; Kraus-Schuman, Cynthia; Cully, Jeffrey A; Rhoades, Howard; Kunik, Mark E; Stanley, Melinda A

    2014-12-01

    The current study is a secondary analysis of data from a randomized controlled trial of CBT for late-life GAD (Stanley et al., 2014) which provided an opportunity to examine predictors of outcome among those who received CBT. Participants were 150 older adults who were randomized to receive 10 sessions of CBT. Completer analyses found that homework completion, number of sessions attended, lower worry severity, lower depression severity, and recruitment site predicted 6-month worry outcome on the PSWQ-A, whereas homework completion, credibility of the therapy, lower anxiety severity, and site predicted 6-month anxiety outcome on the STAI-T. In intent-to-treat multivariate analyses, however, only initial worry and anxiety severity, site, and number of sessions completed predicted treatment outcome. These results are largely consistent with predictors of outcome in younger adults and suggest that lower initial symptom severity and variables consistent with greater engagement in treatment predict outcome. PMID:25445074

  6. Predictors of CBT Outcome in Older Adults with GAD

    PubMed Central

    Hundt, Natalie E.; Amspoker, Amber B.; Kraus-Schuman, Cynthia; Cully, Jeffrey A.; Rhoades, Howard; Kunik, Mark E.; Stanley, Melinda A.

    2014-01-01

    The current study is a secondary analysis of data from a randomized controlled trial of CBT for late-life GAD (Stanley et al., 2014) which provided an opportunity to examine predictors of outcome among those who received CBT. Participants were 150 older adults who were randomized to receive 10 sessions of CBT. Completer analyses found that homework completion, number of sessions attended, lower worry severity, lower depression severity, and recruitment site predicted 6-month worry outcome on the PSWQ-A, whereas homework completion, credibility of the therapy, lower anxiety severity, and site predicted better 6-month anxiety outcome on the STAI-T. In intent-to-treat multivariate analyses, however, only initial worry and anxiety severity, site, and number of sessions completed predicted treatment outcome. These results are largely consistent with predictors of outcome in younger adults and suggest that lower initial symptom severity and variables consistent with greater engagement in treatment predict outcome. PMID:25445074

  7. Phosphorylation of the amino-terminus of the AGC kinase Gad8 prevents its interaction with TORC2.

    PubMed

    Du, Wei; Forte, Gabriella M; Smith, Duncan; Petersen, Janni

    2016-03-01

    Cell proliferation, metabolism, migration and survival are coordinated through the tight control of two target of rapamycin (TOR) kinase complexes: TORC1 and TORC2. Here, we show that a novel phosphorylation of fission yeast Gad8 (AGC kinase) on the evolutionarily conserved threonine 6 (Thr6) prevents the physical association between Gad8 and TORC2. Accordingly, this block to protein interactions by Gad8 Thr6 phosphorylation decreases TORC2-controlled activation of Gad8. Likewise, phosphorylation of Gad8 Thr6, possibly by PKC, prevents the association of Gad8 with TORC2 thereby increasing TORC2 activity, because it reduces Gad8-mediated feedback inhibition of TORC2. Consistently, the introduction of a Gad8 T6D mutant, that mimics phosphorylation, increased TORC2 activity. Increased PKC(Pck2) expression prevented Gad8-TORC2 binding and so reduced the TORC2-mediated phosphorylation of Gad8 serine 546 that activates Gad8. Interestingly, independent of the Ser546 phosphorylation status, Gad8 Thr6 phosphorylation is important for remodelling the actin cytoskeleton and survival upon potassium ion and heat stresses. In contrast, Ser546 phosphorylation is required for the control of G1 arrest, mating, cell length at division and vascular size. Finally, these findings reveal a novel mode of TORC2 activation that is essential for cell survival following stress. PMID:26935949

  8. Phosphorylation of the amino-terminus of the AGC kinase Gad8 prevents its interaction with TORC2

    PubMed Central

    Du, Wei; Forte, Gabriella M.; Smith, Duncan; Petersen, Janni

    2016-01-01

    Cell proliferation, metabolism, migration and survival are coordinated through the tight control of two target of rapamycin (TOR) kinase complexes: TORC1 and TORC2. Here, we show that a novel phosphorylation of fission yeast Gad8 (AGC kinase) on the evolutionarily conserved threonine 6 (Thr6) prevents the physical association between Gad8 and TORC2. Accordingly, this block to protein interactions by Gad8 Thr6 phosphorylation decreases TORC2-controlled activation of Gad8. Likewise, phosphorylation of Gad8 Thr6, possibly by PKC, prevents the association of Gad8 with TORC2 thereby increasing TORC2 activity, because it reduces Gad8-mediated feedback inhibition of TORC2. Consistently, the introduction of a Gad8 T6D mutant, that mimics phosphorylation, increased TORC2 activity. Increased PKCPck2 expression prevented Gad8–TORC2 binding and so reduced the TORC2-mediated phosphorylation of Gad8 serine 546 that activates Gad8. Interestingly, independent of the Ser546 phosphorylation status, Gad8 Thr6 phosphorylation is important for remodelling the actin cytoskeleton and survival upon potassium ion and heat stresses. In contrast, Ser546 phosphorylation is required for the control of G1 arrest, mating, cell length at division and vascular size. Finally, these findings reveal a novel mode of TORC2 activation that is essential for cell survival following stress. PMID:26935949

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

    PubMed

    Léon Sanz, Pilar

    2006-01-01

    This article presents the perspectives of the physician and politician Jaime Vera y López (1859-1918), co-founder of the Spanish Socialist Workers' Party, on the medical profession, medical practice, and healthcare systems. It compares the Report (Informe) that he presented to the Comisión de Reformas Sociales (1884) with his later writings published in the socialist press ("Farmacia y cooperación obrera,, 1914 and "La locura en los niños. Camino del remedio", 1916). We observe the discrepancies between the political-programme documents and the articles centring on professional questions and highlight how his theoretical focus is modified when applied to matters of medical practice. PMID:17214138

  10. Testing the Proterozoic GAD Hypothesis with Reconstructed Tomography Dynamo Models

    NASA Astrophysics Data System (ADS)

    Panzik, J. E.; Driscoll, P. E.; Rudolph, M. L.

    2014-12-01

    Pre-Mesozoic continental reconstructions and paleoclimatic inferences from paleomagnetism rely critically upon the assumption of a time-averaged geocentric axial dipole (GAD) magnetic field. Though the geomagnetic field of the past 5 myr has been extensively studied and small geometric variations are being refined (e.g., Johnson et al., 2008, GGG 9), the pre-Mesozoic geomagnetic field geometry remains unresolved and is suggested to have large, non-dipolar contributions (e.g. Kent and Smethurst, 1998, EPSL 160, 391-402). We address the paleo-morphology by looking at inclination versus paleolatitude histograms derived from numerical geodynamo simulations with spatially variable CMB heat flux, similar to the method used by Bloxham (2000, Nature 405, 63-65). We will be using homogeneous heat flux simulations as a standard and compare the results to those of a present day tomography and a reconstracted 200 Ma tomography CMB heat flux. By comparing the relative contribution of non-dipolar components to the dipole field, we find that strong CMB heat flux heterogeneity is necessary to create the large non-dipolar contributions inferred for the paleomagnetic field.

  11. Anti-GAD65 Containing Cerebrospinal Fluid Does not Alter GABAergic Transmission

    PubMed Central

    Hackert, Jana K.; Müller, Lorenz; Rohde, Marco; Bien, Christian G.; Köhling, Rüdiger; Kirschstein, Timo

    2016-01-01

    Glutamic acid decarboxylase of 65 kDa (GAD65) antibodies have been reported in a variety of neurological disorders such as stiff-person syndrome (SPS), sporadic ataxia and some cases of epilepsy. Since the target is believed to be the cytoplasmic enzyme GAD65, the key enzyme of γ-aminobutyric acid (GABA) synthesis, the pathophysiological role of these antibodies is poorly understood. Here, we stereotactically injected human cerebrospinal fluid (CSF) containing GAD65-antibodies into the hippocampus of rats in vivo and then prepared hippocampal slices 1–2 days after post-operative recovery. We characterized both evoked and spontaneous GABAergic transmission in vitro using sharp microelectrode and patch-clamp recordings in CA1 neurons. Intracellular recordings with sharp microelectrodes from CA1 neurons showed that evoked GABAAR- or GABABR-mediated inhibitory postsynaptic potentials (IPSP) remained unaltered in anti-GAD65 tissue. These results were confirmed with patch-clamp recordings showing no difference in evoked gabazine-sensitive inhibitory postsynaptic currents (IPSCs). In addition, spontaneous IPSCs also showed no difference between anti-GAD65 tissue and controls with respect to the mean frequency, the mean amplitude and the sIPSC distribution. In conclusion, stereotactic injection of GAD65-antibodies into the hippocampus leaves evoked and spontaneous GABAergic synaptic transmission intact. Hence, dysfunction of the inhibitory GABAergic system does not appear to be the major mechanism of epileptogenicity in this disease. PMID:27242441

  12. Expression of GABA Signaling Molecules KCC2, NKCC1, and GAD1 in Cortical Development and Schizophrenia

    PubMed Central

    Lipska, Barbara K.; Ali, Towhid; Mathew, Shiny V.; Law, Amanda J.; Metitiri, Ochuko E.; Straub, Richard E.; Ye, Tianzhang; Colantuoni, Carlo; Herman, Mary M.; Bigelow, Llewellyn B.; Weinberger, Daniel R.; Kleinman, Joel E.

    2011-01-01

    GABA signaling molecules are critical for both human brain development and the pathophysiology of schizophrenia. We examined the expression of transcripts derived from three genes related to GABA signaling [GAD1 (GAD67 and GAD25), SLC12A2 (NKCC1), and SLC12A5 (KCC2)] in the prefrontal cortex (PFC) and hippocampal formation of a large cohort of nonpsychiatric control human brains (n = 240) across the lifespan (from fetal week 14 to 80 years) and in patients with schizophrenia (n = 30–31), using quantitative RT-PCR. We also examined whether a schizophrenia risk-associated promoter SNP in GAD1 (rs3749034) is related to expression of these transcripts. Our studies revealed that development and maturation of both the PFC and hippocampal formation are characterized by progressive switches in expression from GAD25 to GAD67 and from NKCC1 to KCC2. Previous studies have demonstrated that the former leads to GABA synthesis, and the latter leads to switching from excitatory to inhibitory neurotransmission. In the hippocampal formation, GAD25/GAD67 and NKCC1/KCC2 ratios are increased in patients with schizophrenia, reflecting a potentially immature GABA physiology. Remarkably, GAD25/GAD67 and NKCC1/KCC2 expression ratios are associated with rs3749034 genotype, with risk alleles again predicting a relatively less mature pattern. These findings suggest that abnormalities in GABA signaling critical to brain development contribute to genetic risk for schizophrenia. PMID:21795557

  13. Decoding genome-wide GadEWX-transcriptional regulatory networks reveals multifaceted cellular responses to acid stress in Escherichia coli.

    PubMed

    Seo, Sang Woo; Kim, Donghyuk; O'Brien, Edward J; Szubin, Richard; Palsson, Bernhard O

    2015-01-01

    The regulators GadE, GadW and GadX (which we refer to as GadEWX) play a critical role in the transcriptional regulation of the glutamate-dependent acid resistance (GDAR) system in Escherichia coli K-12 MG1655. However, the genome-wide regulatory role of GadEWX is still unknown. Here we comprehensively reconstruct the genome-wide GadEWX transcriptional regulatory network and RpoS involvement in E. coli K-12 MG1655 under acidic stress. Integrative data analysis reveals that GadEWX regulons consist of 45 genes in 31 transcription units and 28 of these genes were associated with RpoS-binding sites. We demonstrate that GadEWX directly and coherently regulate several proton-generating/consuming enzymes with pairs of negative-feedback loops for pH homeostasis. In addition, GadEWX regulate genes with assorted functions, including molecular chaperones, acid resistance, stress response and other regulatory activities. These results show how GadEWX simultaneously coordinate many cellular processes to produce the overall response of E. coli to acid stress. PMID:26258987

  14. Decoding genome-wide GadEWX-transcriptional regulatory networks reveals multifaceted cellular responses to acid stress in Escherichia coli

    PubMed Central

    Seo, Sang Woo; Kim, Donghyuk; O'Brien, Edward J.; Szubin, Richard; Palsson, Bernhard O.

    2015-01-01

    The regulators GadE, GadW and GadX (which we refer to as GadEWX) play a critical role in the transcriptional regulation of the glutamate-dependent acid resistance (GDAR) system in Escherichia coli K-12 MG1655. However, the genome-wide regulatory role of GadEWX is still unknown. Here we comprehensively reconstruct the genome-wide GadEWX transcriptional regulatory network and RpoS involvement in E. coli K-12 MG1655 under acidic stress. Integrative data analysis reveals that GadEWX regulons consist of 45 genes in 31 transcription units and 28 of these genes were associated with RpoS-binding sites. We demonstrate that GadEWX directly and coherently regulate several proton-generating/consuming enzymes with pairs of negative-feedback loops for pH homeostasis. In addition, GadEWX regulate genes with assorted functions, including molecular chaperones, acid resistance, stress response and other regulatory activities. These results show how GadEWX simultaneously coordinate many cellular processes to produce the overall response of E. coli to acid stress. PMID:26258987

  15. 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. PMID:25470336

  16. Detection of GAD65 antibodies in diabetes and other autoimmune diseases using a simple radioligand assay.

    PubMed

    Petersen, J S; Hejnaes, K R; Moody, A; Karlsen, A E; Marshall, M O; Høier-Madsen, M; Boel, E; Michelsen, B K; Dyrberg, T

    1994-03-01

    Autoantibodies to glutamic acid decarboxylase (GAD) are frequent at or before the onset of insulin-dependent diabetes mellitus (IDDM). We have developed a simple, reproducible, and quantitative immunoprecipitation radioligand assay using as antigen in vitro transcribed and translated [35S]methionine-labeled human islet GAD65. By using this assay, 77% (77 of 100) of serum samples from recent-onset IDDM patients were positive for GAD65 antibodies compared with 4% (4 of 100) of serum samples from healthy control subjects. In competition analysis with unlabeled purified recombinant human islet GAD65, binding to tracer was inhibited in 74% (74 of 100) of the GAD65-positive IDDM serum samples compared with 2% of the control samples. The levels of GAD antibodies expressed as an index value relative to a standard serum, analyzed with or without competition, were almost identical (r = 0.991). The intra- and interassay variations of a positive control serum sample were 2.9 and 7.6%, respectively (n = 4). The frequency of GAD antibodies was significantly higher with IDDM onset before the age of 30 (80%, 59 of 74) than after the age of 30 (48%, 10 of 21) (P < 0.01). The prevalence of islet cell antibodies showed a similar pattern relative to age at onset. Because simultaneous occurrences of multiple autoimmune phenomena are common, we analyzed sera from patients with other autoimmune diseases. The frequency of GAD antibodies in sera positive for DNA autoantibodies (8% [2 of 25] and 4% [1 of 25] in competition analysis) or rheuma factor autoantibodies [12% (4 of 35) and 3% (1 of 35) in competition analysis] was not different from that in control samples. In contrast, in sera positive for ribonucleoprotein antibodies the frequency of GAD antibodies was significantly increased (73% [51 of 70] and 10% [7 of 70] in competition analysis [P < 0.025]). In conclusion, even large numbers of serum samples can now be tested for GAD65 antibodies in a relatively short time, allowing

  17. 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.

  18. Postnatal exposure to MK801 induces selective changes in GAD67 or parvalbumin.

    PubMed

    Turner, Christopher Paul; DeBenedetto, Danielle; Ware, Emily; Stowe, Robert; Lee, Andrew; Swanson, John; Walburg, Caroline; Lambert, Alexandra; Lyle, Melissa; Desai, Priyanka; Liu, Chun

    2010-03-01

    Brain injury during the last trimester to the first 1-4 years in humans is now thought to trigger an array of intellectual and emotional problems later in life, including disorders such as schizophrenia. In adult schizophrenic brains, there is a specific loss of neurons that co-express glutamic acid decarboxylase-parvalbumin (GAD67-PV). Loss of this phenotype is thought to occur in mature animals previously exposed to N-methyl-D: -aspartate receptor (NMDAR) antagonists during late gestation or at postnatal day 7 (P7). However, in similarly treated animals, we have previously shown that GAD67 and PV are unaltered in the first 24 h. To more precisely define when changes in these markers first occur, we exposed rat pups (P7 or P6-P10) to the NMDAR antagonist MK801 and at P11 co-stained brain sections for GAD67 or PV. In the cingulate cortex, we found evidence for a reduction in PV (GAD67 levels were very low to undetectable). In contrast, in the somatosensory cortex, we found that expression of GAD67 was reduced, but PV remained stable. Further, repeated but not single doses of MK801 were necessary to see such changes. Thus, depending on the region, NMDAR antagonism appears to influence expression of PV or GAD67, but not both. These observations could not have been predicted by previous studies and raise important questions as to how the GAD67-PV phenotype is lost once animals reach maturity. More importantly, such differential effects may be of great clinical importance, given that cognitive deficits are seen in children exposed to anesthetics that act by blocking the NMDAR. PMID:19885653

  19. 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

  20. 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

  1. Miller-Fisher Syndrome: Are Anti-GAD Antibodies Implicated in Its Pathophysiology?

    PubMed Central

    Papagiannopoulos, Sotirios; Theodoridou, Varvara; Argyropoulou, Ourania; Bostantjopoulou, Sevasti

    2016-01-01

    Miller-Fisher syndrome (MFS) is considered as a variant of the Guillain-Barre syndrome (GBS) and its characteristic clinical features are ophthalmoplegia, ataxia, and areflexia. Typically, it is associated with anti-GQ1b antibodies; however, a significant percentage (>10%) of these patients are seronegative. Here, we report a 67-year-old female patient who presented with the typical clinical features of MFS. Workup revealed antibodies against glutamic acid decarboxylase (GAD) in relatively high titers while GQ1b antibodies were negative. Neurological improvement was observed after intravenous gamma globulin and follow-up examinations showed a continuous clinical amelioration with simultaneous decline of anti-GAD levels which finally returned to normal values. This case indicates that anti-GAD antibodies may be associated with a broader clinical spectrum and future studies in GQ1b-seronegative patients could determine ultimately their clinical and pathogenetic significance in this syndrome. PMID:27239355

  2. 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

  3. Antigen presentation of detergent free glutamate decarboxylase (GAD65) is affected by human serum albumin as carrier protein

    PubMed Central

    Steed, Jordan; Gilliam, Lisa K.; Harris, Robert A.; Lernmark, Åke; Hampe, Christiane S.

    2008-01-01

    1. Summary The smaller isoform of glutamate decarboxylase (GAD65) is a major autoantigen in type 1 diabetes (TID). Its hydrophobic character requires detergent to keep the protein in solution, which complicates studies of antigen processing and presentation. In this study an attempt was made to replace detergent with human serum albumin (HSA) for in vitro antigen presentation. Different preparations of recombinant human GAD65 complexed with HSA were incubated with Priess B cells (HLA DRB1*0401) and antigen presentation was tested with HLA DRB1*0401-restricted and epitope-specific T33.1 (GAD65 epitope 274-286) and T35 (GAD65 epitope 115-127) T cell hybridomas. Specific epitope recognition by T33.1 (274-286) and T35 (115-127) cells varied between the different GAD65/HSA preparations, and a reverse pattern of antigen presentation were detected by the two hybridoma. The HSA-specific T-cell hybridoma 17.9 response to the different GAD65/HSA preparations followed the same pattern as that observed for the T33.1 cells. The content of immunoreactive GAD65 measured with four GAD65 antibodies indicated that the lowest GAD65 concentration resulted in the highest 274-286, but the lowest 115-127 presentation. This suggests that HSA-GAD65 complexes qualitatively affect the epitope specificity of GAD65 presentation. HSA may enhance the 274-286 epitope presentation, while suppressing the 115-127 epitope. PMID:18353353

  4. A 750 bp sensory integration region directs global control of the Escherichia coli GadE acid resistance regulator.

    PubMed

    Sayed, Atef K; Foster, John W

    2009-03-01

    Escherichia coli survives pH 2 environments through an acid resistance (AR) system regulated by the transcriptional activator GadE. Numerous proteins control gadE at an upstream, conserved, 798 bp intergenic region. We show this region produces three transcripts starting at -124 (T1), -324/-317 (T2) and -566 (T3) bp from the gadE start codon. Transcriptional lacZ fusions to gadE promoter regions revealed P1 and P3 were active while P2 alone was not. However, pairing P3 with P2 activated P2 and increased expression 20-fold above P3 alone. The fusions were transferred to Salmonella, which lacks this AR system, and plasmid-borne E. coli-specific regulators EvgA, YdeO, GadE and GadX were introduced. Data revealed that YdeO and GadX activate P3, P2 and P3P2, while GadE autoactivates P1 and represses P3 and P3P2. The developing model indicates that different signals activate YdeO, GadX, or an MnmE-dependent regulator, which stimulate gadE transcription from the P3 and P2 promoters. Once made, GadE activates P1 and represses P3 and P2. The P1 region also enables efficient downstream transcription and translation of the P3 or P2 transcripts. Evidence indicates the entire 750 bp sensory integration locus is necessary for a versatile response. PMID:19220752

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

    PubMed Central

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

    2011-01-01

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

  6. Prefrontal White Matter Structure Mediates the Influence of GAD1 on Working Memory.

    PubMed

    Lett, Tristram A; Kennedy, James L; Radhu, Natasha; Dominguez, Luis G; Chakravarty, M Mallar; Nazeri, Arash; Farzan, Faranak; Walter, Henrik; Heinz, Andreas; Mulsant, Benoit H; Daskalakis, Zafiris J; Voineskos, Aristotle N

    2016-08-01

    The glutamic acid decarboxylase 1 (GAD1) gene is a major determinant of γ-aminobutyric acid (GABA), the most abundant inhibitory neurotransmitter modulating local neuronal circuitry. GABAergic dysfunction and expression of GAD1 have been implicated in the pathophysiology of schizophrenia, and in working memory impairment. We examined the influence of the functional GAD1 rs3749034 variant on white matter fractional anisotropy (FA), cortical thickness, and working memory performance in schizophrenia patients and healthy controls (N=197). Using transcranial magnetic stimulation with electroencephalography (TMS-EEG), we subsequently examined the effect of rs3749034 on long-interval cortical inhibition (LICI) in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia patients and healthy controls (N=66). We found that the rs3749034 T-allele carrier risk group had lower voxel-wise FA in the prefrontal cortex region (PFWE-corrected<0.05) but not cortical thickness. Mixed-model regression revealed a significant effect on attentional processing and working memory across four performance measures (F1,182=11.5, P=8 × 10(-4)). FA in the prefrontal cortex was associated with digit-span performance. Voxel-wise mediation analysis revealed that the effect GAD1 on poorer digit-span performance statistically predicted the lower white matter FA (PFWE-corrected<0.05). In exploratory analysis, we found a prominent GAD1 genotype-by-diagnosis interaction on DLPFC LICI (F1,56=14.3, P=4.1 × 10(-4)). Our findings converge on variation in GAD1 gene predicting a susceptibility mechanism that affects white matter FA, GABAergic inhibitory neurotransmission in the DLPFC, and working memory performance. Furthermore, via voxel mediation of FA and TMS-EEG intervention, we provide evidence for a potentially causal mechanism through which aberrant DLPFC GABA signaling may contribute to working memory dysfunction. PMID:26822489

  7. Limbic Encephalitis Associated With GAD65 Antibodies: Brief Review of the Relevant literature.

    PubMed

    Gagnon, Maude-Marie; Savard, Martin

    2016-07-01

    Recently, many cases of autoimmune limbic encephalitis with positive GAD65 (glutamic acid decarboxylase) antibodies have been described in the scientific literature. However, it remains an understudied topic of great relevance to practicing neurologists. Thus, we report here a review of published cases, in English, of autoimmune limbic encephalitis with this type of antibodies, focusing on presenting symptoms and signs, associated conditions, and findings upon investigation. We also report treatment responses. We aim to offer a better description of the clinical spectrum of autoimmune limbic encephalitis associated with GAD65 antibodies as well as to expose its paraclinical features and outcome. PMID:27030381

  8. 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. PMID:21680149

  9. Assessment of CD4+ T Cell Responses to Glutamic Acid Decarboxylase 65 Using DQ8 Tetramers Reveals a Pathogenic Role of GAD65 121–140 and GAD65 250–266 in T1D Development

    PubMed Central

    Chow, I-Ting; Yang, Junbao; Gates, Theresa J.; James, Eddie A.; Mai, Duy T.; Greenbaum, Carla; Kwok, William W.

    2014-01-01

    Susceptibility to type 1 diabetes (T1D) is strongly associated with MHC class II molecules, particularly HLA-DQ8 (DQ8: DQA1*03:01/DQB1*03:02). Monitoring T1D-specific T cell responses to DQ8-restricted epitopes may be key to understanding the immunopathology of the disease. In this study, we examined DQ8-restricted T cell responses to glutamic acid decarboxylase 65 (GAD65) using DQ8 tetramers. We demonstrated that GAD65121–140 and GAD65250–266 elicited responses from DQ8+ subjects. Circulating CD4+ T cells specific for these epitopes were detected significantly more often in T1D patients than in healthy individuals after in vitro expansion. T cell clones specific for GAD65121–140 and GAD65250–266 carried a Th1-dominant phenotype, with some of the GAD65121–140-specific T cell clones producing IL-17. GAD65250–266-specific CD4+ T cells could also be detected by direct ex vivo staining. Analysis of unmanipulated peripheral blood mononuclear cells (PBMCs) revealed that GAD65250–266-specific T cells could be found in both healthy and diabetic individuals but the frequencies of specific T cells were higher in subjects with type 1 diabetes. Taken together, our results suggest a proinflammatory role for T cells specific for DQ8-restricted GAD65121–140 and GAD65250–266 epitopes and implicate their possible contribution to the progression of T1D. PMID:25405480

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

    PubMed Central

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

    2013-01-01

    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 family functioning. ODD and GAD symptom groups were defined using various combinations of mother and teacher reports. ODD symptom groups were associated with conduct disorder symptoms, and GAD symptom groups with major depressive disorder symptoms, regardless of rater. Attention deficit/hyperactivity disorder (ADHD) symptoms were associated with ODD and GAD symptom groups; however, covarying ADHD symptoms altered few findings. The ODD+GAD symptom groups were associated with higher rates of co-occurring symptoms and risk factors within (source-specific syndromes) and across (cross-informant comorbidity) informants. PMID:18470769

  11. 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…

  12. Three ways to test the validity of the Geocentric Axial Dipole (GAD) hypothesis in the Precambrian

    NASA Astrophysics Data System (ADS)

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

    2012-12-01

    One of the most fundamental aspects of paleomagnetism is the assumption that the temporal mean of the geomagnetic field is indistinguishable from a field generated by a geocentric axial dipole (GAD hypothesis). When the theory became mainstream, various ways to test its functionality were presented, based on e.g. deep-sea sediment cores, paleoclimatic indicators and paleointensity. Most suspicion of the dipolar nature of the geomagnetic field has dealt with the Precambrian. To analyze this bias, we have used the data from the novel paleomagnetic database, collected by University of Helsinki, and Yale University for over a decade's time. Altogether 3016 observations from all major Precambrian continents were gathered, and a thorough compilation of reversals of the Archean and Proterozoic geomagnetic field was done. Observations were filtered using different criteria, e.g. geologic age, rock type (igneous vs. metamorphic vs. sedimentary) and reliability according to the modified Voo-grading. Testing the GAD has rested on a) inclination frequency analysis, b) asymmetries in reversal data, and c) paleosecular variation (PSV) using CALS7K, CALS3K, GUFM and IGRF models as references. The results suggest that the geomagnetic field of the Precambrian is not far from the field predicted by the GAD model. The inclination frequency analysis supports the existence of a small octupolar (ca. 6 % of GAD) component and a quadrupole of 0-8 % of GAD as evaluated using chi-square testing. Conclusions drawn from the asymmetry analysis and PSV are statistically indifferent from this. The deviation from the GAD is smallest for the highest-quality observations, especially so called key poles. They have well-defined isotopic ages, small error parameters in their Fisher data and their primary remanent magnetization has been properly isolated. This also means that the observed functionality of GAD cannot be a misconception caused by secondary magnetizations acquired in the Phanerozoic

  13. 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

  14. 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

  15. Bacteria of food and human intestine are the most possible sources of the gad-trigger of type 1 diabetes.

    PubMed

    Mulder, Sieger Jeen

    2005-01-01

    Type 1 diabetes incidence increases at about 3% per year in the Western world. From genetically predisposed people only 20-50% develop the disease. To unravel these mysteries, literature was searched to determine the disease background and to find suggestions for research and prevention. A promising hypothesis was found: the enzyme glutamic acid decarboxylase (GAD) in bacteria may be the source of type 1 diabetes. Epidemiological data can be accounted for this possibility. GAD-containing bacteria can originate from raw foods, especially salted or dried or smoked raw meat and fish products or from proliferation in the ileum of the human small intestine. Proliferation of GAD-containing bacteria in the ileum is probably the most frequent causation of type 1 diabetes. This proliferation is stimulated by the consumption of nitrate-containing ingredients such as vegetables, fruits or nitrate-polluted water and by sugars dissolved in liquids, for example lactose in milk or sugars in juicy fruits and fruit-juices. In the ileum GAD is released from bacteria by endocrine enzymes of the small intestine. Released GAD enters Peyer's patches (PP) in the ileum wall, where it is bound or enclosed by immune cells. These cells move GAD by the lymph- and bloodstream to the immune system for priming and elimination. In case of type 1 diabetes, however, malfunction of PP causes GAD freely move in the lymph stream where it settles on vascular endothelial cells and pancreatic beta-cells. GAD-settlement on beta-cells gives an inflammatory immune response, leading to destruction of the beta-cells and to type 1 diabetes. A perspective for prevention of the disease in predisposed individuals is discussed. It is concluded that GAD-containing bacteria and malfunction of PP should be taken into account in future type 1 diabetes research. PMID:15922105

  16. Inflammation-Induced Acid Tolerance Genes gadAB in Luminal Commensal Escherichia coli Attenuate Experimental Colitis

    PubMed Central

    Tchaptchet, Sandrine; Fan, Ting-Jia; Goeser, Laura; Schoenborn, Alexi; Gulati, Ajay S.; Sartor, R. Balfour

    2013-01-01

    Dysregulated immune responses to commensal intestinal bacteria, including Escherichia coli, contribute to the development of inflammatory bowel diseases (IBDs) and experimental colitis. Reciprocally, E. coli responds to chronic intestinal inflammation by upregulating expression of stress response genes, including gadA and gadB. GadAB encode glutamate decarboxylase and protect E. coli from the toxic effects of low pH and fermentation acids, factors present in the intestinal lumen in patients with active IBDs. We hypothesized that E. coli upregulates gadAB during inflammation to enhance its survival and virulence. Using real-time PCR, we determined gadAB expression in luminal E. coli from ex-germfree wild-type (WT) and interleukin-10 (IL-10) knockout (KO) (IL-10−/−) mice selectively colonized with a commensal E. coli isolate (NC101) that causes colitis in KO mice in isolation or in combination with 7 other commensal intestinal bacterial strains. E. coli survival and host inflammatory responses were measured in WT and KO mice colonized with NC101 or a mutant lacking the gadAB genes (NC101ΔgadAB). The susceptibility of NC101 and NC101ΔgadAB to killing by host antimicrobial peptides and their translocation across intestinal epithelial cells were evaluated using bacterial killing assays and transwell experiments, respectively. We show that expression of gadAB in luminal E. coli increases proportionately with intestinal inflammation in KO mice and enhances the susceptibility of NC101 to killing by the host antimicrobial peptide cryptdin-4 but decreases bacterial transmigration across intestinal epithelial cells, colonic inflammation, and mucosal immune responses. Chronic intestinal inflammation upregulates acid tolerance pathways in commensal E. coli isolates, which, contrary to our original hypothesis, limits their survival and colitogenic potential. Further investigation of microbial adaptation to immune-mediated inflammation may provide novel insights into the

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

    PubMed Central

    2013-01-01

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

  18. Lack of Support for the Association between GAD2 Polymorphisms and Severe Human Obesity

    PubMed Central

    2005-01-01

    The 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 independent replication of initial positive findings. Recently, three (−243 A>G, +61450 C>A, and +83897 T>A) single nucleotide polymorphisms (SNPs) within glutamate decarboxylase 2 (GAD2) were found to be associated with class III obesity (body mass index > 40 kg/m2). The association was observed among 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 (−243 A>G) were also presented. The gene GAD2 encodes the 65-kDa subunit of glutamic acid decarboxylase—GAD65. In the present study, we attempted to replicate this association in larger groups of individuals, and to extend the functional studies of the −243 A>G SNP. Among 2,359 individuals comprising 693 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 −243 A>G SNP and obesity (OR = 0.99, 95% CI 0.83–1.18, p = 0.89) in the pooled sample. These negative findings were recapitulated in a meta-analysis, incorporating all published data for the association between the −243G allele and class III obesity, which yielded an OR of 1.11 (95% CI 0.90–1.36, p = 0.28) in a total sample of 1,252 class III obese cases and 1,800 lean controls. Moreover, analysis of common haplotypes encompassing the GAD2 locus revealed no association with severe obesity in families with the condition. We also obtained functional data

  19. 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

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

    PubMed Central

    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. PMID:25147515

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

    PubMed Central

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

    2012-01-01

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

  2. GADS software for parametric linkage analysis of quantitative traits distributed as a point-mass mixture.

    PubMed

    Axenovich, Tatiana I; Zorkoltseva, Irina V

    2012-02-01

    Often the quantitative data coming from proteomics and metabolomics studies have irregular distribution with a spike. None of the wide used methods for human QTL mapping are applicable to such traits. Researchers have to reduce the sample, excluding the spike, and analyze only continuous measurements. In this study, we propose a method for the parametric linkage analysis of traits with a spike in the distribution, and a software GADS, which implements this method. Our software includes not only the programs for parametric linkage analysis, but also the program for complex segregation analysis, which allows the estimation of the model parameters used in linkage. We tested our method on the real data about vertical cup-to-disc ratio, the important characteristic of the optic disc associated with glaucoma, in a large pedigree from a Dutch isolated population. Significant linkage signal was identified on chromosome 6 with the help of GADS, whereas the analysis of the normal distributed part of the sample demonstrated only a suggestive linkage peak on this chromosome. The software GADS is freely available at http://mga.bionet.nsc.ru/soft/index.html. PMID:22340440

  3. Loss of topoisomerase I function affects the RpoS-dependent and GAD systems of acid resistance in Escherichia coli

    PubMed Central

    Stewart, Natalee; Feng, Jingyang; Liu, Xiaoping; Chaudhuri, Devyani; Foster, John W.; Drolet, Marc; Tse-Dinh, Yuk-Ching

    2006-01-01

    SUMMARY Acid resistance (AR) for Escherichia coli is important for its survival in the human gastrointestinal tract and involves three systems. The first AR system is dependent on the sigma factor RpoS. The second system (GAD system) requires glutamate decarboxylase isoforms encoded by the gadA and gadB genes. The third system (ARG system) requires arginine decarboxylase encoded by adiA. Loss of topoisomerase I function from topA deletion or Tn10 insertion mutations lowered the resistance to killing by pH 2 or 2.5 treatment by 10 to >100 fold. The RpoS and GAD systems were both affected by the topA mutation but the ARG system of acid resistance was not affected. Northern blot analysis showed that induction of gadA and gadB transcription in stationary phase and at pH 5.5 was decreased in the topA mutant. Western blot analysis showed that the topA mutation did not affect accumulation of RpoS, GadX or GadW proteins. Topoisomerase I could have a direct influence on transcription of acid resistance genes. This influence did not involve R-loop formation as the overexpression of RNase H did not alleviate the decrease of acid resistance from the topA mutation. The effect of the topA mutation could be suppressed by the hns mutation so topoisomerase I might be required to counteract the effect of H-NS protein on gene expression in addition to its influence on RpoS-dependent transcription. PMID:16079354

  4. A novel expression platform for the production of diabetes-associated autoantigen human glutamic acid decarboxylase (hGAD65)

    PubMed Central

    Wang, Xiaofeng; Brandsma, Martin; Tremblay, Reynald; Maxwell, Denis; Jevnikar, Anthony M; Huner, Norm; Ma, Shengwu

    2008-01-01

    Background Human glutamic acid decarboxylase 65 (hGAD65) is a key autoantigen in type 1 diabetes, having much potential as an important marker for the prediction and diagnosis of type 1 diabetes, and for the development of novel antigen-specific therapies for the treatment of type 1 diabetes. However, recombinant production of hGAD65 using conventional bacterial or mammalian cell culture-based expression systems or nuclear transformed plants is limited by low yield and low efficiency. Chloroplast transformation of the unicellular eukaryotic alga Chlamydomonas reinhardtii may offer a potential solution. Results A DNA cassette encoding full-length hGAD65, under the control of the C. reinhardtii chloroplast rbcL promoter and 5'- and 3'-UTRs, was constructed and introduced into the chloroplast genome of C. reinhardtii by particle bombardment. Integration of hGAD65 DNA into the algal chloroplast genome was confirmed by PCR. Transcriptional expression of hGAD65 was demonstrated by RT-PCR. Immunoblotting verified the expression and accumulation of the recombinant protein. The antigenicity of algal-derived hGAD65 was demonstrated with its immunoreactivity to diabetic sera by ELISA and by its ability to induce proliferation of spleen cells from NOD mice. Recombinant hGAD65 accumulated in transgenic algae, accounts for approximately 0.25–0.3% of its total soluble protein. Conclusion Our results demonstrate the potential value of C. reinhardtii chloroplasts as a novel platform for rapid mass production of immunologically active hGAD65. This demonstration opens the future possibility for using algal chloroplasts as novel bioreactors for the production of many other biologically active mammalian therapeutic proteins. PMID:19014643

  5. 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. PMID:27284108

  6. 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.

  7. 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.

  8. Distinct neurochemical and functional properties of GAD67-containing 5-HT neurons in the rat dorsal raphe nucleus.

    PubMed

    Shikanai, Hiroki; Yoshida, Takayuki; Konno, Kohtarou; Yamasaki, Miwako; Izumi, Takeshi; Ohmura, Yu; Watanabe, Masahiko; Yoshioka, Mitsuhiro

    2012-10-10

    The serotonergic (5-HTergic) system arising from the dorsal raphe nucleus (DRN) is implicated in various physiological and behavioral processes, including stress responses. The DRN is comprised of several subnuclei, serving specific functions with distinct afferent and efferent connections. Furthermore, subsets of 5-HTergic neurons are known to coexpress other transmitters, including GABA, glutamate, or neuropeptides, thereby generating further heterogeneity. However, despite the growing evidence for functional variations among DRN subnuclei, relatively little is known about how they map onto neurochemical diversity of 5-HTergic neurons. In the present study, we characterized functional properties of GAD67-expressing 5-HTergic neurons (5-HT/GAD67 neurons) in the rat DRN, and compared with those of neurons expressing 5-HTergic molecules (5-HT neurons) or GAD67 alone. While 5-HT/GAD67 neurons were absent in the dorsomedial (DRD) or ventromedial (DRV) parts of the DRN, they were selectively distributed in the lateral wing of the DRN (DRL), constituting 12% of the total DRL neurons. They expressed plasmalemmal GABA transporter 1, but lacked vesicular inhibitory amino acid transporter. By using whole-cell patch-clamp recording, we found that 5-HT/GAD67 neurons had lower input resistance and firing frequency than 5-HT neurons. As revealed by c-Fos immunohistochemistry, neurons in the DRL, particularly 5-HT/GAD67 neurons, showed higher responsiveness to exposure to an open field arena than those in the DRD and DRV. By contrast, exposure to contextual fear conditioning stress showed no such regional differences. These findings indicate that 5-HT/GAD67 neurons constitute a unique neuronal population with distinctive neurochemical and electrophysiological properties and high responsiveness to innocuous stressor. PMID:23055511

  9. ELISA Test for Analyzing of Incidence of Type 1 Diabetes Autoantibodies (GAD and IA2) in Children and Adolescents

    PubMed Central

    Delic-Sarac, Marina; Mutevelic, Selma; Karamehic, Jasenko; Subasic, Djemo; Jukic, Tomislav; Coric, Jozo; Ridjic, Ognjen; Panjeta, Mirsad; Zunic, Lejla

    2016-01-01

    Introduction: Anti GAD (antibodies on glutamic acid decarboxylase) and anti-IA2 antibodies (against tyrosine phosphatase), today, have their place and importance in diagnosis and prognosis of Type 1 diabetes. Huge number of patients with diabetes mellitus type 1 have these antibodies. Insulin antibodies are of critical importance in diagnosis of diabetes mellitus type 1 for pediatric population. Materials and methods: During 2014, the samples of 80 patients from Clinical Center University Sarajevo (CCUS) Pediatrics clinic’s, Endocrinology department were analyzed on anti-GAD and IA2 antibodies. The samples of serums of all patients were analyzed with ELISA tests using Anti GAD ELISA (IgG) kites from EUROIMMUN company. These are quantitative in vitro tests for human antibodies against decarboxylase of glutamine acid (GAD) and IA2, in serum or EDTA plasm. Results: During the period of one year, in CCUS’s Organizational unit, Institute for Clinical Immunology, 80 samples of patients with anti GAD and IA2 antibodies were analyzed. Out of total number of samples, 41 were male patients, or 51% and 39 female, or 49%. The youngest patient was born in 2012, and the oldest in 1993. Age average was represented by the patients born in 2001. Share of positive results for IA2 antibodies and GAD antibodies was 37% for IA2 antibodies, and 63% for GAD antibodies. Discussion: During an autoimmune – mediated Diabetes mellitus type 1 leads to T-cell mediated destruction of beta cells of pancreatic islets, reduced production of insulin and glucose metabolism. Studies have shown that these bodies are the most intense single marker for identifying persons with increased risk for diabetes development. PMID:27041813

  10. Gads (Grb2-related adaptor downstream of Shc) is required for BCR-ABL-mediated lymphoid leukemia

    PubMed Central

    Gillis, LC; Berry, DM; Minden, MD; McGlade, CJ; Barber, DL

    2016-01-01

    Philadelphia chromosome-positive leukemias, including chronic myeloid leukemia and B-cell acute lymphoblastic leukemia (B-ALL), are driven by the oncogenic BCR-ABL fusion protein. Animal modeling experiments utilizing retroviral transduction and subsequent bone marrow transplantation have demonstrated that BCR-ABL generates both myeloid and lymphoid disease in mice receiving whole bone marrow transduced with BCR-ABL. Y177 of BCR-ABL is critical to the development of myeloid disease, and phosphorylation of Y177 has been shown to induce GRB2 binding to BCR-ABL, followed by activation of the Ras and phosphoinositide 3 kinase signaling pathways. We show that the GRB2-related adapter protein, GADS, also associates with BCR-ABL, specifically through Y177 and demonstrate that BCR-ABL-driven lymphoid disease requires Gads. BCR-ABL transduction of Gads(−/−) bone marrow results in short latency myeloid disease within 3–4 weeks of transplant, while wild-type mice succumb to both a longer latency lymphoid and myeloid diseases. We report that GADS mediates a unique BCR-ABL complex with SLP-76 in BCR-ABL-positive cell lines and B-ALL patient samples. These data suggest that GADS mediates lymphoid disease downstream of BCR-ABL through the recruitment of specific signaling intermediates. PMID:23399893

  11. 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. PMID:26015156

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

    PubMed

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

    2016-01-01

    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. 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

  14. GAD65 Autoantibodies Detected by Electrochemiluminescence Assay Identify High Risk for Type 1 Diabetes

    PubMed Central

    Miao, Dongmei; Guyer, K. Michelle; Dong, Fran; Jiang, Ling; Steck, Andrea K.; Rewers, Marian; Eisenbarth, George S.; Yu, Liping

    2013-01-01

    The identification of diabetes-relevant islet autoantibodies is essential for predicting and preventing type 1 diabetes (T1D). The aim of the current study was to evaluate a newly developed electrochemiluminescence (ECL)-GAD antibody (GADA) assay and compare its sensitivity and disease relevance with standard radioassay. The assay was validated with serum samples from 227 newly diagnosed diabetic children; 68 prediabetic children who were prospectively followed to T1D; 130 nondiabetic children with confirmed islet autoantibodies to insulin, GAD65, IA-2, and/or ZnT8 longitudinally followed for 12 ± 3.7 years; and 181 age-matched, healthy, antibody-negative children. The ECL-GADA assay had a sensitivity similar to that of the standard GADA radioassay in children newly diagnosed with T1D, prediabetic children, and high-risk children with multiple positive islet autoantibodies. On the other hand, only 9 of 39 nondiabetic children with only a single islet autoantibody (GADA only) by radioassay were positive for ECL-GADA. GADA not detectable by ECL assay is shown to be of low affinity and likely not predictive of future diabetes. In conclusion, the new ECL assay identifies disease-relevant GADA by radioassay. It may help to improve the prediction and correct diagnosis of T1D among subjects positive only for GADA and no other islet autoantibodies. PMID:23974918

  15. 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). PMID:24334213

  16. 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

  17. 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

  18. Models of the geodynamo over geologic time and the inclination test of the GAD hypothesis

    NASA Astrophysics Data System (ADS)

    Heimpel, M. H.

    2012-12-01

    The assumption that Earth's mean magnetic field has been a geocentric axial dipole (GAD) over geologic time is fundamental to paleomagnetism and plate-tectonics. Previous models have linked inclination distributions to latitudinal heat flow variations (Bloxham, 2000). While verifying and extending those previous results, I show here that radial heat flow structure controls geomagnetic field morphology as well. The inclination test of the GAD hypothesis (Evans,1976) is used to interpret numerical dynamo models, some with latitudinally variable buoyancy flux boundary conditions and others with uniform flux boundary conditions. All of the models are chosen to be Earth-like, and at or near the polarity reversing dynamical regime. As was found in previous work, the global inclination distribution is a function of the buoyancy flux at the core-mantle boundary (CMB). However, I find here that the sign of a latitudinally quadrupolar variable flux condition is critical for dynamo stability. Enhanced polar cooling causes inclination shallowing and tends to stabilize the dynamos to reversals, while enhanced equatorial cooling destabilizes the dynamo, resulting in complex field morphology and high reversal frequency. The uniform flux models represent three convective states of the mantle and core. 1. Present era Earth - likely a typical state of the geodynamo. 2. Global convective overturn, associated with flood basalt volcanism, anomalous magnetic reversal frequency, climate change and mass extinctions. 3. Ancient Earth prior to solid inner core formation. For these uniform flux models the inclination distribution anomaly scales with the relative buoyancy flux at the CMB versus the inner core boundary. Consistent with the CALS10k model of Earth's magnetic field over the past ten millennia (Korte et al., 2011), the present era Earth-like dynamos are GAD-like, with very small time-averaged inclination anomalies. In contrast, the global overturn and ancient Earth dynamos show

  19. 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

  20. 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

  1. In vivo knockdown of GAD67 in the amygdala disrupts fear extinction and the anxiolytic-like effect of diazepam in mice.

    PubMed

    Heldt, S A; Mou, L; Ressler, K J

    2012-01-01

    In mammals, γ-aminobutyric acid (GABA) transmission in the amygdala is particularly important for controlling levels of fear and anxiety. Most GABA synthesis in the brain is catalyzed in inhibitory neurons from L-glutamic acid by the enzyme glutamic acid decarboxylase 67 (GAD67). In the current study, we sought to examine the acquisition and extinction of conditioned fear in mice with knocked down expression of the GABA synthesizing enzyme GAD67 in the amygdala using a lentiviral-based (LV) RNA interference strategy to locally induce loss-of-function. In vitro experiments revealed that our LV-siRNA-GAD67 construct diminished the expression of GAD67 as determined with western blot and fluorescent immunocytochemical analyses. In vivo experiments, in which male C57BL/6J mice received bilateral amygdala microinjections, revealed that LV-siRNA-GAD67 injections produce significant inhibition of endogenous GAD67 when compared with control injections. In contrast, no significant changes in GAD65 expression were detected in the amygdala, validating the specificity of LV knockdown. Behavioral experiments showed that LV knockdown of GAD67 results in a deficit in the extinction, but not the acquisition or retention, of fear as measured by conditioned freezing. GAD67 knockdown did not affect baseline locomotion or basal measures of anxiety as measured in open field apparatus. However, diminished GAD67 in the amygdala blunted the anxiolytic-like effect of diazepam (1.5 mg kg(-1)) as measured in the elevated plus maze. Together, these studies suggest that of GABAergic transmission in amygdala mediates the inhibition of conditioned fear and the anxiolytic-like effect of diazepam in adult mice. PMID:23149445

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

    PubMed Central

    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. PMID:27011652

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

    ERIC Educational Resources Information Center

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

    2008-01-01

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

  4. Type 1 diabetes and GAD65 limbic encephalitis: a case report of a 10-year-old girl.

    PubMed

    Grilo, Ema; Pinto, Joana; Caetano, Joana Serra; Pereira, Helena; Cardoso, Patrícia; Cardoso, Rita; Dinis, Isabel; Pereira, Cristina; Fineza, Isabel; Mirante, Alice

    2016-08-01

    Limbic encephalitis is a rare neurological disorder that may be difficult to recognize. Clinical features include memory impairment, temporal lobe seizures and affective disturbance. We report the case of a 10-year-old girl with type 1 diabetes mellitus that presented with seizures, depressed mood and memory changes. The diagnosis of glutamic acid decarboxylase 65 (GAD65) mediated limbic encephalitis relied on cerebral magnetic resonance imaging lesions and high serological and cerebrospinal fluid GAD65-antibodies titers. High-dose steroidal therapy was started with clinical improvement. Relapse led to a second high-dose steroid treatment followed by rituximab with remission. A correlation between serum GAD65-antibodies levels and symptoms was found, demonstrating GAD65-antibodies titers may be useful for clinical follow-up and immunotherapy guidance. This report raises awareness of this serious neurological condition that may be associated with type 1 diabetes, underlining the importance of an early diagnosis and prompt treatment for a better prognosis. PMID:27115322

  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.

  6. 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. PMID:26241953

  7. 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

  8. Common genetic variation in the GAD1 gene and the entire family of DLX homeobox genes and autism spectrum disorders

    PubMed Central

    Chang, Shun-Chiao; Pauls, David L.; Lange, Christoph; Sasanfar, Roksana; Santangelo, Susan L.

    2010-01-01

    Biological and positional evidence supports the involvement of the GAD1 and distal-less homeobox genes (DLXs) in the etiology of autism. We investigated 42 SNPs in these genes as risk factors for autism spectrum disorders (ASD) in a large family-based association study of 715 nuclear families. No single marker showed significant association after correction for multiple testing. A rare haplotype in the DLX1 promoter was associated with ASD (p-value = 0.001). Given the importance of rare variants to the etiology of autism revealed in recent studies, the observed rare haplotype may be relevant to future investigations. Our observations, when taken together with previous findings, suggest that common genetic variation in the GAD1 and DLX genes is unlikely to play a critical role in ASD susceptibility. PMID:21302352

  9. Parvalbumin and GAD65 Interneuron Inhibition in the Ventral Hippocampus Induces Distinct Behavioral Deficits Relevant to Schizophrenia

    PubMed Central

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

    2014-01-01

    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. PMID:25378161

  10. Superior perception of phasic physiological arousal and the detrimental consequences of the conviction to be aroused on worrying and metacognitions in GAD.

    PubMed

    Andor, Tanja; Gerlach, Alexander L; Rist, Fred

    2008-02-01

    Although people suffering from generalized anxiety disorder (GAD) often report arousal symptoms, psychophysiological studies show no evidence of autonomic hyperarousal. Hypersensitivity toward and catastrophic interpretation of phasic arousal cues may explain this discrepancy. The authors tested (a) whether GAD sufferers perceive nonspecific skin conductance fluctuations (NSCFs), an indicator of phasic autonomic arousal, better than controls do and (b) whether the conviction to be aroused contributes to the maintenance of worrying and metacognitive beliefs about worrying. Thirty-three GAD sufferers and 34 healthy controls participated in 2 experiments. In Experiment 1, participants were asked to detect their own NSCFs during a signal detection task. GAD sufferers accurately detected more of their NSCFs than did controls, who tended to miss NSCFs. In Experiment 2, participants were instructed to relax following worry induction. While relaxing, they received nonveridical feedback indicating either arousal or relaxation. Arousal feedback conserved negative metacognitive beliefs regarding worrying and also maintained negative mood and worry exclusively in GAD participants. These findings suggest that superior perception of phasic arousal cues and their catastrophic misinterpretation increases worrying, negative metacognitive beliefs about worrying, and anxious mood in GAD. PMID:18266497

  11. The spatiotemporal segregation of GAD forms defines distinct GABA signaling functions in the developing mouse olfactory system and provides novel insights into the origin and migration of GnRH neurons.

    PubMed

    Vastagh, Csaba; Schwirtlich, Marija; Kwakowsky, Andrea; Erdélyi, Ferenc; Margolis, Frank L; Yanagawa, Yuchio; Katarova, Zoya; Szabó, Gábor

    2015-03-01

    Gamma-aminobutyric acid (GABA) has a dual role as an inhibitory neurotransmitter in the adult central nervous system (CNS) and as a signaling molecule exerting largely excitatory actions during development. The rate-limiting step of GABA synthesis is catalyzed by two glutamic acid decarboxylase isoforms GAD65 and GAD67 coexpressed in the GABAergic neurons of the CNS. Here we report that the two GADs show virtually nonoverlapping expression patterns consistent with distinct roles in the developing peripheral olfactory system. GAD65 is expressed exclusively in undifferentiated neuronal progenitors confined to the proliferative zones of the sensory vomeronasal and olfactory epithelia In contrast GAD67 is expressed in a subregion of the nonsensory epithelium/vomeronasal organ epithelium containing the putative Gonadotropin-releasing hormone (GnRH) progenitors and GnRH neurons migrating from this region through the frontonasal mesenchyme into the basal forebrain. Only GAD67+, but not GAD65+ cells accumulate detectable GABA. We further demonstrate that GAD67 and its embryonic splice variant embryonic GAD (EGAD) concomitant with GnRH are dynamically regulated during GnRH neuronal migration in vivo and in two immortalized cell lines representing migratory (GN11) and postmigratory (GT1-7) stage GnRH neurons, respectively. Analysis of GAD65/67 single and double knock-out embryos revealed that the two GADs play complementary (inhibitory) roles in GnRH migration ultimately modulating the speed and/or direction of GnRH migration. Our results also suggest that GAD65 and GAD67/EGAD characterized by distinct subcellular localization and kinetics have disparate functions during olfactory system development mediating proliferative and migratory responses putatively through specific subcellular GABA pools. PMID:25125027

  12. 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

  13. Polymorphisms in the GAD2 gene-region are associated with susceptibility for unipolar depression and with a risk factor for anxiety disorders.

    PubMed

    Unschuld, Paul G; Ising, Marcus; Specht, Michael; Erhardt, Angelika; Ripke, Stephan; Heck, Angela; Kloiber, Stefan; Straub, Verica; Brueckl, Tanja; Müller-Myhsok, Bertram; Holsboer, Florian; Binder, Elisabeth B

    2009-12-01

    Glutamate decarboxylase (GAD) is the rate limiting enzyme for conversion of glutamic acid to gamma-aminobutyric acid (GABA). The GAD 65 kDa isoform is encoded by the gene GAD2 and is mainly expressed in synaptic terminals. It serves as an apoenzyme, which shows enhanced availability in situations of stress, responding to short-term demands for GABA. We analyzed 18 single nucleotide polymorphisms (SNPs) in the GAD2-gene region for associations with psychiatric diagnosis and behavioral inhibition (BI) derived from the personality traits neuroticism and extraversion as defined by the Eysenck Personality Questionaire (EPQ). A total of 268 patients with anxiety disorder (AD), 541 with unipolar depression (MD), and 541 healthy controls were included. We observe associations for five tag-SNPs with BI in the AD- and control samples as well as two additional case-control associations in the MD-sample. The associated SNPs lie within a 16KB linkage disequilibrium-block, including putative 5' GAD2-promoter-elements as well as the 3' end of the gene MYO3A. Using open access mRNA-expression data, we could show that BI-associated SNPs appear to be associated with differences in MYO3A- but not GAD2 lymphoblastoid-mRNA expression levels. These results support earlier studies that suggest associations of polymorphisms within the GAD2 locus with anxiety and affective disorders. However, data from expression studies imply that these polymorphisms could tag functional effects on the neighboring gene MYO3A, which is also expressed in the brain, including the cingulate cortex and the amygdala. PMID:19229853

  14. The Frequency of Langerhans Islets β-Cells Autoantibodies (Anti-GAD) in Georgian Children and Adolescents with Chronic Autoimmune Thyroiditis.

    PubMed

    Balakhadze, Mariam; Giorgadze, Elene; Lomidze, Marina

    2016-01-01

    Aim. Chronic autoimmune thyroiditis and type 1 diabetes mellitus are organ-specific autoimmune diseases. There is large evidence that autoimmunity against the thyroid gland in patients with type 1 diabetes mellitus is increased, but little is known about anti-islet cell autoimmune status in patients with chronic autoimmune thyroiditis. We evaluated the concentration of antibodies against glutamic acid decarboxylase (GAD) which are widely used as a diagnostic and predictive tool for type 1 diabetes mellitus, in school-aged Georgian children with chronic autoimmune thyroiditis. Methods. The frequency of anti-GAD antibodies was measured in Georgian school-aged children with chronic autoimmune thyroiditis and compared to healthy age and sex matched controls. Results. Of the 41 patients with chronic autoimmune thyroiditis 4 (9.8%) were positive for GAD antibodies. The frequency of GAD positivity in the chronic autoimmune thyroiditis group was significantly higher than in the control subjects (P = 0.036). Conclusion. In the study we found that the frequency of GAD antibody positivity in autoimmune thyroiditis patients was significantly higher (9.8%, P = 0.036) than in the control group. Our findings support the concept that patients with autoimmune thyroid disease may develop type 1 diabetes mellitus in future life. PMID:27429616

  15. The Frequency of Langerhans Islets β-Cells Autoantibodies (Anti-GAD) in Georgian Children and Adolescents with Chronic Autoimmune Thyroiditis

    PubMed Central

    Giorgadze, Elene

    2016-01-01

    Aim. Chronic autoimmune thyroiditis and type 1 diabetes mellitus are organ-specific autoimmune diseases. There is large evidence that autoimmunity against the thyroid gland in patients with type 1 diabetes mellitus is increased, but little is known about anti-islet cell autoimmune status in patients with chronic autoimmune thyroiditis. We evaluated the concentration of antibodies against glutamic acid decarboxylase (GAD) which are widely used as a diagnostic and predictive tool for type 1 diabetes mellitus, in school-aged Georgian children with chronic autoimmune thyroiditis. Methods. The frequency of anti-GAD antibodies was measured in Georgian school-aged children with chronic autoimmune thyroiditis and compared to healthy age and sex matched controls. Results. Of the 41 patients with chronic autoimmune thyroiditis 4 (9.8%) were positive for GAD antibodies. The frequency of GAD positivity in the chronic autoimmune thyroiditis group was significantly higher than in the control subjects (P = 0.036). Conclusion. In the study we found that the frequency of GAD antibody positivity in autoimmune thyroiditis patients was significantly higher (9.8%, P = 0.036) than in the control group. Our findings support the concept that patients with autoimmune thyroid disease may develop type 1 diabetes mellitus in future life. PMID:27429616

  16. The neural substrates of response inhibition to negative information across explicit and implicit tasks in GAD patients: electrophysiological evidence from an ERP study

    PubMed Central

    Yu, Fengqiong; Zhu, Chunyan; Zhang, Lei; Chen, Xingui; Li, Dan; Zhang, Long; Ye, Rong; Dong, Yi; Luo, Yuejia; Hu, Xinlong; Wang, Kai

    2015-01-01

    Background: It has been established that the inability to inhibit a response to negative stimuli is the genesis of anxiety. However, the neural substrates of response inhibition to sad faces across explicit and implicit tasks in general anxiety disorder (GAD) patients remain unclear. Methods: Electrophysiological data were recorded when subjects performed two modified emotional go/no-go tasks in which neutral and sad faces were presented: one task was explicit (emotion categorization), and the other task was implicit (gender categorization). Results: In the explicit task, electrophysiological evidence showed decreased amplitudes of no-go/go difference waves at the N2 interval in the GAD group compared to the control group. However, in the implicit task, the amplitudes of no-go/go difference waves at the N2 interval showed a reversed trend. Source localization analysis on no-go/N2 components revealed a decreased current source density (CSD) in the right dorsal lateral prefrontal cortex in GAD individuals relative to controls. In the implicit task, the left superior temporal gyrus and the left inferior parietal lobe showed enhanced activation in GAD individuals and may compensate for the dysfunction of the right dorsal lateral prefrontal cortex. Conclusion: These findings indicated that the processing of response inhibition to socially sad faces in GAD individuals was interrupted in the explicit task. However, this processing was preserved in the implicit task. The neural substrates of response inhibition to sad faces were dissociated between implicit and explicit tasks. PMID:25852597

  17. Enhanced GAD65 production in plants using the MagnICON transient expression system: Optimization of upstream production and downstream processing.

    PubMed

    Merlin, Matilde; Gecchele, Elisa; Arcalis, Elsa; Remelli, Sabrina; Brozzetti, Annalisa; Pezzotti, Mario; Avesani, Linda

    2016-03-01

    Plants have emerged as competitive production platforms for pharmaceutical proteins that are required in large quantities. One example is the 65-kDa isoform of human glutamic acid decarboxylase (GAD65), a major autoimmune diabetes autoantigen that has been developed as a vaccine candidate for the primary prevention of diabetes. The expression of GAD65 in plants has been optimized but large-scale purification is hampered by its tendency to associate with membranes. We investigated the potential for large-scale downstream processing by evaluating different combinations of plant-based expression systems and engineered forms of GAD65 in terms of yield, subcellular localization and solubility in detergent-free buffer. We found that a modified version of GAD65 lacking the first 87 amino acids accumulates to high levels in the cytosol and can be extracted in detergent-free buffer. The highest yields of this variant protein were achieved using the MagnICON transient expression system. This combination of truncated GAD65 and the MagnICON system dramatically boosts the production of the recombinant protein and helps to optimize downstream processing for the establishment of a sustainable plant-based production platform for an autoimmune diabetes vaccine candidate. PMID:26710327

  18. The Jaime Escalante Math Program.

    ERIC Educational Resources Information Center

    Escalante, Jaime; Dirmann, Jack

    1990-01-01

    Describes the success of the Escalante Math Program in East Los Angeles in teaching mathematics to poor minority students. Fundamental principles of the program include the following: (1) accountability; (2) hard work; (3) demand; (4) love; (5) parental involvement; (6) respect and values; (7) nutrition; and (8) drug use prevention. Discusses…

  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. Spatial and temporal pattern of changes in the number of GAD65-immunoreactive inhibitory terminals in the rat superficial dorsal horn following peripheral nerve injury.

    PubMed

    Lorenzo, Louis-Etienne; Magnussen, Claire; Bailey, Andrea L; St Louis, Manon; De Koninck, Yves; Ribeiro-da-Silva, Alfredo

    2014-01-01

    Inhibitory interneurons are an important component of dorsal horn circuitry where they serve to modulate spinal nociception. There is now considerable evidence indicating that reduced inhibition in the spinal dorsal horn contributes to neuropathic pain. A loss of these inhibitory neurons after nerve injury is one of the mechanisms being proposed to account for reduced inhibition; however, this remains controversial. This is in part because previous studies have focused on global measurements of inhibitory neurons without assessing the number of inhibitory synapses. To address this, we conducted a quantitative analysis of the spatial and temporal changes in the number of inhibitory terminals, as detected by glutamic acid decarboxylase 65 (GAD65) immunoreactivity, in the superficial dorsal horn of the spinal cord following a chronic constriction injury (CCI) to the sciatic nerve in rats. Isolectin B4 (IB4) labelling was used to define the location within the dorsal horn directly affected by the injury to the peripheral nerve. The density of GAD65 inhibitory terminals was reduced in lamina I (LI) and lamina II (LII) of the spinal cord after injury. The loss of GAD65 terminals was greatest in LII with the highest drop occurring around 3-4 weeks and a partial recovery by 56 days. The time course of changes in the number of GAD65 terminals correlated well with both the loss of IB4 labeling and with the altered thresholds to mechanical and thermal stimuli. Our detailed analysis of GAD65+ inhibitory terminals clearly revealed that nerve injury induced a transient loss of GAD65 immunoreactive terminals and suggests a potential involvement for these alterations in the development and amelioration of pain behaviour. PMID:25189404

  3. 2-ketogluconic acid secretion by incorporation of Pseudomonas putida KT 2440 gluconate dehydrogenase (gad) operon in Enterobacter asburiae PSI3 improves mineral phosphate solubilization.

    PubMed

    Kumar, Chanchal; Yadav, Kavita; Archana, G; Naresh Kumar, G

    2013-09-01

    Enterobacter asburiae PSI3 is known to efficiently solubilize rock phosphate by secretion of approximately 50 mM gluconic acid in Tris-buffered medium in the presence of 75 mM glucose and in a mixture of seven aldosugars each at 15 mM concentration, mimicking alkaline vertisol soils. Efficacy of this bacterium in the rhizosphere requires P release in the presence of low amount of sugars. To achieve this, E. asburiae PSI3 has been manipulated to express gluconate dehydrogenase (gad) operon of Pseudomonas putida KT 2440 to produce 2-ketogluconic acid. E. asburiae PSI3 harboring gad operon had 438 U of GAD activity, secreted 11.63 mM 2-ketogluconic and 21.65 mM gluconic acids in Tris-rock phosphate-buffered medium containing 45 mM glucose. E. asburiae PSI3 gad transformant solubilized 0.84 mM P from rock phosphate in TRP-buffered liquid medium. In the presence of a mixture of seven sugars each at 12 mM, the transformant brought about a drop in pH to 4.1 and released 0.53 mM P. PMID:23666029

  4. PeerGAD: a peer-review-based and community-centric web application for viewing and annotating prokaryotic genome sequences

    PubMed Central

    D’Ascenzo, Mark D.; Collmer, Alan; Martin, Gregory B.

    2004-01-01

    PeerGAD is a web-based database-driven application that allows community-wide peer-reviewed annotation of prokaryotic genome sequences. The application was developed to support the annotation of the Pseudomonas syringae pv. tomato strain DC3000 genome sequence and is easily portable to other genome sequence annotation projects. PeerGAD incorporates several innovative design and operation features and accepts annotations pertaining to gene naming, role classification, gene translation and annotation derivation. The annotator tool in PeerGAD is built around a genome browser that offers users the ability to search and navigate the genome sequence. Because the application encourages annotation of the genome sequence directly by researchers and relies on peer review, it circumvents the need for an annotation curator while providing added value to the annotation data. Support for the Gene Ontology™ vocabulary, a structured and controlled vocabulary used in classification of gene roles, is emphasized throughout the system. Here we present the underlying concepts integral to the functionality of PeerGAD. PMID:15184545

  5. A Requirement of TolC and MDR Efflux Pumps for Acid Adaptation and GadAB Induction in Escherichia coli

    PubMed Central

    Tatsumi, Ryoko; Rosner, Judah L.; Wachi, Masaaki; Slonczewski, Joan L.

    2011-01-01

    Background The TolC outer membrane channel is a key component of several multidrug resistance (MDR) efflux pumps driven by H+ transport in Escherichia coli. While tolC expression is under the regulation of the EvgA-Gad acid resistance regulon, the role of TolC in growth at low pH and extreme-acid survival is unknown. Methods and Principal Findings TolC was required for extreme-acid survival (pH 2) of strain W3110 grown aerobically to stationary phase. A tolC deletion decreased extreme-acid survival (acid resistance) of aerated pH 7.0-grown cells by 105-fold and of pH 5.5-grown cells by 10-fold. The requirement was specific for acid resistance since a tolC defect had no effect on aerobic survival in extreme base (pH 10). TolC was required for expression of glutamate decarboxylase (GadA, GadB), a key component of glutamate-dependent acid resistance (Gad). TolC was also required for maximal exponential growth of E. coli K-12 W3110, in LBK medium buffered at pH 4.5–6.0, but not at pH 6.5–8.5. The TolC growth requirement in moderate acid was independent of Gad. TolC-associated pump components EmrB and MdtB contributed to survival in extreme acid (pH 2), but were not required for growth at pH 5. A mutant lacking the known TolC-associated efflux pumps (acrB, acrD, emrB, emrY, macB, mdtC, mdtF, acrEF) showed no growth defect at acidic pH and a relatively small decrease in extreme-acid survival when pre-grown at pH 5.5. Conclusions TolC and proton-driven MDR efflux pump components EmrB and MdtB contribute to E. coli survival in extreme acid and TolC is required for maximal growth rates below pH 6.5. The TolC enhancement of extreme-acid survival includes Gad induction, but TolC-dependent growth rates below pH 6.5 do not involve Gad. That MDR resistance can enhance growth and survival in acid is an important consideration for enteric organisms passing through the acidic stomach. PMID:21541325

  6. Co-expression of GAD67 and choline acetyltransferase in neurons in the mouse spinal cord: A focus on lamina X.

    PubMed

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

    2016-09-01

    Lamina X of the spinal cord is a functionally diverse area with roles in locomotion, autonomic control and processing of mechano and nociceptive information. It is also a neurochemically diverse region. However, the different populations of cells in lamina X remain to be fully characterised. To determine the co-localisation of the enzymes responsible for the production of GABA and acetylcholine (which play major roles in the spinal cord) in lamina X of the adult and juvenile mouse, we used a transgenic mouse expressing green fluorescent protein (GFP) in glutamate decarboxylase 67 (GAD67) neurons, combined with choline acetyltransferase (ChAT) immunohistochemistry. ChAT-immunoreactive (IR) and GAD67-GFP containing neurons were observed in lamina X of both adult and juvenile mice and in both age groups a population of cells containing both ChAT-IR and GAD67-GFP were observed in lumbar, thoracic and cervical spinal cord. Such dual labelled cells were predominantly located ventral to the central canal. Immunohistochemistry for vesicular acetylcholine transporter (VAChT) and GAD67 revealed a small number of double labelled terminals located lateral, dorsolateral and ventrolateral to the central canal. This study therefore describes in detail a population of ChAT-IR/GAD67-GFP neurons predominantly ventral to the central canal of the cervical, thoracic and lumbar spinal cord of adult and juvenile mice. These cells potentially correspond to a sub-population of the cholinergic central canal cluster cells which may play a unique role in controlling spinal cord circuitry. PMID:27378584

  7. Glucose Activates TORC2-Gad8 Protein via Positive Regulation of the cAMP/cAMP-dependent Protein Kinase A (PKA) Pathway and Negative Regulation of the Pmk1 Protein-Mitogen-activated Protein Kinase Pathway*

    PubMed Central

    Cohen, Adiel; Kupiec, Martin; Weisman, Ronit

    2014-01-01

    The target of rapamycin (TOR) kinase belongs to the highly conserved eukaryotic family of phosphatidylinositol 3-kinase-related kinases. TOR proteins are found at the core of two evolutionary conserved complexes, known as TORC1 and TORC2. In fission yeast, TORC2 is dispensable for proliferation under optimal growth conditions but is required for starvation and stress responses. TORC2 has been implicated in a wide variety of functions; however, the signals that regulate TORC2 activity have so far remained obscure. TORC2 has one known direct substrate, the AGC kinase Gad8, which is related to AKT in human cells. Gad8 is phosphorylated by TORC2 at Ser-546 (equivalent to AKT Ser-473), leading to its activation. Here, we show that glucose is necessary and sufficient to induce Gad8 Ser-546 phosphorylation in vivo and Gad8 kinase activity in vitro. The glucose signal that activates TORC2-Gad8 is mediated via the cAMP/PKA pathway, a major glucose-sensing pathway. By contrast, Pmk1, similar to human extracellular signal-regulated kinases and a major stress-induced mitogen activated protein kinase (MAPK) in fission yeast, inhibits TORC2-dependent Gad8 phosphorylation and activation. Inhibition of TORC2-Gad8 also occurs in response to ionic or osmotic stress, in a manner dependent on the cAMP/PKA and Pmk1-MAPK signaling pathways. Our findings highlight the significance of glucose availability in regulation of TORC2-Gad8 and indicate a novel link between the cAMP/PKA, Pmk1/MAPK, and TORC2-Gad8 signaling. PMID:24928510

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

    PubMed Central

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

    2015-01-01

    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 two days and given one retention trial on the third day, with brains removed 30 minutes 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. PMID:25591480

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

    PubMed

    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

  10. Improvements in impaired GABA and GAD65/67 production in the spinal dorsal horn contribute to exercise-induced hypoalgesia in a mouse model of neuropathic pain

    PubMed Central

    Taguchi, MS, Satoru; Tajima, Fumihiro; Senba, Emiko

    2016-01-01

    Background Physical exercise effectively attenuates neuropathic pain, and multiple events including the inhibition of activated glial cells in the spinal dorsal horn, activation of the descending pain inhibitory system, and reductions in pro-inflammatory cytokines in injured peripheral nerves may contribute to exercise-induced hypoalgesia. Since fewer GABAergic hypoalgesic interneurons exist in the dorsal horn in neuropathic pain model animals, the recovery of impaired GABAergic inhibition in the dorsal horn may improve pain behavior. We herein determined whether the production of gamma-aminobutyric acid (GABA) and glutamic acid decarboxylase (GAD) in the dorsal horn is restored by treadmill running and contributes to exercise-induced hypoalgesia in neuropathic pain model mice. C57BL/6 J mice underwent partial sciatic nerve ligation (PSL). PSL-Runner mice ran on a treadmill at 7 m/min for 60 min/day, 5 days/week, from two days after PSL. Results Mechanical allodynia and heat hyperalgesia developed in PSL-Sedentary mice but were significantly attenuated in PSL-Runner mice. PSL markedly decreased GABA and GAD65/67 levels in neuropils in the ipsilateral dorsal horn, while treadmill running inhibited these reductions. GABA+ neuronal nuclei+ interneuron numbers in the ipsilateral dorsal horn were significantly decreased in PSL-Sedentary mice but not in PSL-Runner mice. Pain behavior thresholds positively correlated with GABA and GAD65/67 levels and GABAergic interneuron numbers in the ipsilateral dorsal horns of PSL-Sedentary and -Runner mice. Conclusions Treadmill running prevented PSL-induced reductions in GAD65/67 production, and, thus, GABA levels may be retained in interneurons and neuropils in the superficial dorsal horn. Therefore, improvements in impaired GABAergic inhibition may be involved in exercise-induced hypoalgesia. PMID:27030712

  11. Association of aberrant neural synchrony and altered GAD67 expression following exposure to maternal immune activation, a risk factor for schizophrenia

    PubMed Central

    Dickerson, D D; Overeem, K A; Wolff, A R; Williams, J M; Abraham, W C; Bilkey, D K

    2014-01-01

    A failure of integrative processes within the brain, mediated via altered GABAergic inhibition, may underlie several features of schizophrenia. The present study examined, therefore, whether maternal immune activation (MIA), a risk factor for schizophrenia, altered inhibitory markers in the hippocampus and medial prefrontal cortex (mPFC), while also altering electroencephalogram (EEG) coherence between these regions. Pregnant rats were treated with saline or polyinosinic:polycytidylic acid mid-gestation. EEG depth recordings were made from the dorsal and ventral hippocampus and mPFC of male adult offspring. Glutamic decarboxylase (GAD67) levels were separately assayed in these regions using western blot. GAD67 expression was also assessed within parvalbumin-positive cells in the dorsal and ventral hippocampus using immunofluorescence alongside stereological analysis of parvalbumin-positive cell numbers. EEG coherence was reduced between the dorsal hippocampus and mPFC, but not the ventral hippocampus and mPFC, in MIA animals. Western blot and immunofluorescence analyses revealed that GAD67 expression within parvalbumin-positive cells was also reduced in the dorsal hippocampus relative to ventral hippocampus in MIA animals when compared with controls. This reduction was observed in the absence of parvalbumin-positive neuronal loss. Overall, MIA produced a selective reduction in EEG coherence between the dorsal hippocampus and mPFC that was paralleled by a similarly specific reduction in GAD67 within parvalbumin-positive cells of the dorsal hippocampus. These results suggest a link between altered inhibitory mechanisms and synchrony and, therefore point to potential mechanisms via which a disruption in neurodevelopmental processes might lead to pathophysiology associated with schizophrenia. PMID:25072323

  12. Association of the −243A>G, +61450C>A Polymorphisms of the Glutamate Decarboxylase 2 (GAD2) Gene with Obesity and Insulin Level in North Indian Population

    PubMed Central

    PRAKASH, Jai; MITTAL, Balraj; AWASTHI, Shally; SRIVASTAVA, Neena

    2016-01-01

    Background: Obesity associated with type 2 diabetes, and hypertension increased mortality and morbidity. Glutamate decarboxylase 2 (GAD2) gene is associated with obesity and it regulate food intake and insulin level. We investigated the association of GAD-2gene −243A>G (rs2236418) and +61450C>A (rs992990) polymorphisms with obesity and related phenotypes. Methods: Insulin, glucose and lipid levels were estimated using standard protocols. All subjects were genotyped (PCR-RFLP) method. Results: The −243A>G polymorphism of the GAD-2 gene was significantly associated with higher risk of obesity (P<0.05). Conclusion: GAD-2 gene polymorphisms influence obesity and related phenotype in complex manner, probably by regulating the food intake, insulin and body weight. PMID:27252915

  13. Correlations of Clusters of Non-Convulsive Seizure and Magnetic Resonance Imaging in a Case With GAD65-Positive Autoimmune Limbic Encephalitis

    PubMed Central

    Gardner, Rachael; Rangaswamy, Rajesh; Peng, Yen-Yi

    2016-01-01

    With the increased availability of laboratory tests, glutamic acid decarboxylase (GAD) antibody-positive limbic encephalitis has become an emerging diagnosis. The myriad symptoms of limbic encephalitis make the diagnosis challenging. Symptoms range from seizures, memory loss, dementia, confusion, to psychosis. We present a case of a 21-year-old female with GAD65 antibody-positive limbic encephalitis. The case is unique because the clinical course suggests that non-convulsive seizures are the major cause of this patient’s clinical manifestations. The following is the thesis: systemic autoimmune disease, associated with the GAD65 antibody, gives rise to seizures, in particular, non-convulsive seizures. Temporal lobes happen to be the most susceptible sites to develop seizures. The greater part of these seizures can be non-convulsive and hard to recognize without electroencephalogram (EEG) monitoring. The variable symptoms mirror the severity and locations of these seizures. The magnetic resonance imaging (MRI) signal abnormities in the bilateral hippocampus, fornix, and mammillary body correlate with the density of these seizures in the similar manner, which suggests it is secondary to post-ictal edema. PMID:27429684

  14. Correlations of Clusters of Non-Convulsive Seizure and Magnetic Resonance Imaging in a Case With GAD65-Positive Autoimmune Limbic Encephalitis.

    PubMed

    Gardner, Rachael; Rangaswamy, Rajesh; Peng, Yen-Yi

    2016-08-01

    With the increased availability of laboratory tests, glutamic acid decarboxylase (GAD) antibody-positive limbic encephalitis has become an emerging diagnosis. The myriad symptoms of limbic encephalitis make the diagnosis challenging. Symptoms range from seizures, memory loss, dementia, confusion, to psychosis. We present a case of a 21-year-old female with GAD65 antibody-positive limbic encephalitis. The case is unique because the clinical course suggests that non-convulsive seizures are the major cause of this patient's clinical manifestations. The following is the thesis: systemic autoimmune disease, associated with the GAD65 antibody, gives rise to seizures, in particular, non-convulsive seizures. Temporal lobes happen to be the most susceptible sites to develop seizures. The greater part of these seizures can be non-convulsive and hard to recognize without electroencephalogram (EEG) monitoring. The variable symptoms mirror the severity and locations of these seizures. The magnetic resonance imaging (MRI) signal abnormities in the bilateral hippocampus, fornix, and mammillary body correlate with the density of these seizures in the similar manner, which suggests it is secondary to post-ictal edema. PMID:27429684

  15. 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. PMID:25956759

  16. Pressure-temperature stability, Ca2+ binding, and pressure-temperature phase diagram of cod parvalbumin: Gad m 1.

    PubMed

    Somkuti, Judit; Bublin, Merima; Breiteneder, Heimo; Smeller, László

    2012-07-31

    Fish allergy is associated with IgE-mediated hypersensitivity reactions to parvalbumins, which are small calcium-binding muscle proteins and represent the major and sole allergens for 95% of fish-allergic patients. We performed Fourier transform infrared and tryptophan fluorescence spectroscopy to explore the pressure-temperature (p-T) phase diagram of cod parvalbumin (Gad m 1) and to elucidate possible new ways of pressure-temperature inactivation of this food allergen. Besides the secondary structure of the protein, the Ca(2+) binding to aspartic and glutamic acid residues was detected. The phase diagram was found to be quite complex, containing partially unfolded and molten globule states. The Ca(2+) ions were essential for the formation of the native structure. A molten globule conformation appears at 50 °C and atmospheric pressure, which converts into an unordered aggregated state at 75 °C. At >200 MPa, only heat unfolding, but no aggregation, was observed. A pressure of 500 MPa leads to a partially unfolded state at 27 °C. The complete pressure unfolding could only be reached at an elevated temperature (40 °C) and pressure (1.14 GPa). A strong correlation was found between Ca(2+) binding and the protein conformation. The partially unfolded state was reversibly refolded. The completely unfolded molecule, however, from which Ca(2+) was released, could not refold. The heat-unfolded protein was trapped either in the aggregated state or in the molten globule state without aggregation at elevated pressures. The heat-treated and the combined heat- and pressure-treated protein samples were tested with sera of allergic patients, but no change in allergenicity was found. PMID:22765301

  17. A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons.

    PubMed

    Kinney, Jefferson W; Davis, Christopher N; Tabarean, Iustin; Conti, Bruno; Bartfai, Tamas; Behrens, M Margarita

    2006-02-01

    Several lines of evidence suggest that a hypoglutamatergic condition may induce a phenotypic loss of cortical parvalbumin (PV)-positive GABAergic interneurons, such as that observed in brain tissue of schizophrenic subjects. However, it is not known whether the loss of PV interneurons is a consequence of the hypoglutamatergic condition or a secondary aspect of the disease. We characterized the signaling and subunit expression of NMDA receptors in cultured cortical PV interneurons and determined whether a hypoglutamatergic condition, created by direct application of sublethal concentrations of ketamine or subunit-selective NMDA receptor antagonists, can affect the expression of the GABAergic markers as observed in vivo. Real-time PCR performed on mRNA isolated from single neurons showed that PV interneurons present a fivefold higher NR2A/NR2B ratio than pyramidal neurons. Brief, nontoxic, exposure to NMDA led to an increase in ERK1/2 (extracellular signal-regulated kinase 1/2) and cAMP response element-binding protein phosphorylation in PV interneurons, and this increase was blocked by the NR2A-selective antagonist NVP-AAM077. Application of the nonselective NMDA receptor antagonist ketamine, at sublethal concentrations, induced a time and dose-dependent decrease in parvalbumin and GAD67 immunoreactivity specifically in PV interneurons. These effects were reversible and were also observed with the NR2A-selective antagonist, whereas the NR2B-selective antagonist Ro-25-6981 only partially reduced GAD67 immunoreactivity. Coexposure to the calcium channel opener BayK, or the group I metabotropic glutamate receptor agonist DHPG [(RS)-3,5-dihydroxyphenylglycine] attenuated the decrease in GAD67 and parvalbumin induced by the NMDA receptor antagonists. These results suggest that the activity of NR2A-containing NMDA receptors play a pivotal role in the maintenance of the GABAergic function of PV interneurons. PMID:16452684

  18. Decreased GAD65 mRNA levels in select subpopulations in the cerebellar dentate nuclei in autism: an in situ hybridization study

    PubMed Central

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

    2009-01-01

    The laterally positioned dentate nuclei lie in a key position in the cerebellum to receive input from Purkinje cells in the lateral cerebellar hemisphere participating in both motor and cognitive functions. Although neuropathology of the four cerebellar nuclei using Nissl staining has been qualitatively reported in children and adults with autism, surprisingly the dentate nuclei appeared less affected despite reported reductions in Purkinje cells in the posterolateral cerebellar hemisphere. To determine any underlying abnormalities in the critically important GABAergic system, the rate-limiting GABAsynthesizing enzyme, glutamic acid decarboxylase (GAD) type 65 was measured via in situ hybridization histochemistry in dentate somata. GAD65 mRNA labeling revealed two distinct subpopulations of neurons in adult control and autism post-mortem brains: small-sized cells (about 10–12 µm in diameter, presumed interneurons) and larger-sized neurons (about 18–20 µm in diameter, likely feedback to IO neurons). A mean 51% reduction in GAD65 mRNA levels was found in the larger labeled cells in the autistic group compared to the control group (p=0.009; independent t-test) but not in the smaller cell subpopulation. This suggests a disturbance in the intrinsic cerebellar circuitry in the autism group potentially interfering with the synchronous firing of inferior olivary neurons, and the timing of Purkinje cell firing and inputs to the dentate nuclei. Disturbances in critical neural substrates within these key circuits could disrupt afferents to motor and/or cognitive cerebral association areas in the autistic brain likely contributing to the marked behavioral consequences characteristic of autism. PMID:19358307

  19. 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.

  20. LACK OF FUNCTIONAL GABAB RECEPTORS ALTERS Kiss1, Gnrh1 AND Gad1 mRNA EXPRESSION IN THE MEDIAL BASAL HYPOTHALAMUS AT POSTNATAL DAY 4

    PubMed Central

    Di Giorgio, Noelia P.; Catalano, Paolo N.; López, Paula V.; González, Betina; Semaan, Sheila J.; López, Gabriela C.; Kauffman, Alexander S.; Rulli, Susana B.; Somoza, Gustavo M.; Bettler, Bernhard; Libertun, Carlos; Lux-Lantos, Victoria A.

    2013-01-01

    Background/Aims Adult mice lacking functional GABAB receptors (GABAB1KO) show altered Gnrh1 and Gad1 expressions in the preoptic area-anterior hypothalamus (POA-AH) and females display disruption of cyclicity and fertility. Here we addressed whether sexual differentiation of the brain and the proper wiring of the GnRH and kisspeptin systems were already disturbed in postnatal day 4 (PND4) GABAB1KO mice. Methods PND4 wild type (WT) and GABAB1KO mice of both sexes were sacrificed; tissues were collected to determine mRNA expression (qPCR), amino acids (HPLC), and hormones (RIA and/or IHC). Results GnRH neuron number (IHC) did not differ among groups in olfactory bulbs or OVLT-POA. Gnrh1 mRNA (qPCR) in POA-AH was similar among groups. Gnrh1 mRNA in medial basal hypothalamus (MBH) was similar in WTs but was increased in GABAB1KO females compared to GABAB1KO males. Hypothalamic GnRH (RIA) was sexually different in WTs (males > females) but this sex difference was lost in GABAB1KOs; the same pattern was observed when analyzing only the MBH, but not in the POA-AH. Arcuate nucleus Kiss1 mRNA (micropunch-qPCR) was higher in WT females than in WT males and GABAB1KO females. Gad1 mRNA in MBH was increased in GABAB1KO females compared to GABAB1KO males. Serum LH and gonadal estradiol content were also increased in GABAB1KOs. Conclusion We demonstrate that GABABRs participate in the sexual differentiation of the ARC/MBH, because sex differences in several reproductive genes, such as Gad1, Kiss1 and Gnrh1, are critically disturbed in GABAB1KO mice at PND4, probably altering the organization and development of neural circuits governing the reproductive axis. PMID:24080944

  1. Gad8 Protein Is Found in the Nucleus Where It Interacts with the MluI Cell Cycle Box-binding Factor (MBF) Transcriptional Complex to Regulate the Response to DNA Replication Stress.

    PubMed

    Cohen, Adiel; Kupiec, Martin; Weisman, Ronit

    2016-04-22

    The target of rapamycin (TOR) kinase is found at the core of two evolutionarily conserved complexes known as TOR complexes 1 and 2 (TORC1 and TORC2). In fission yeast, TORC2 is dispensable for proliferation under optimal growth conditions but is required for starvation and stress responses. We have previously reported that loss of function of TORC2 renders cells highly sensitive to DNA replication stress; however, the mechanism underlying this sensitivity is unknown. TORC2 has one known direct substrate, the kinase Gad8, which is related to AKT in human cells. Here we show that both TORC2 and its substrate Gad8 are found in the nucleus and are bound to the chromatin. We also demonstrate that Gad8 physically interacts with the MluI cell cycle box-binding factor (MBF) transcription complex that regulates the G1/S progression and the response to DNA stress. In mutant cells lacking TORC2 or Gad8, the binding of the MBF complex to its cognate promoters is compromised, and the induction of MBF target genes in response to DNA replication stress is reduced. Consistently, the protein levels of Cdt2 and Cig2, two MBF target genes, are reduced in the absence of TORC2-Gad8 signaling. Taken together, our findings highlight critical functions of TORC2 in the nucleus and suggest a role in surviving DNA replication stress via transcriptional regulation of MBF target genes. PMID:26912660

  2. 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. PMID:21626307

  3. Olfactory Enrichment Influences Adult Neurogenesis Modulating GAD67 and Plasticity-Related Molecules Expression in Newborn Cells of the Olfactory Bulb

    PubMed Central

    Peretto, Paolo; Fasolo, Aldo; De Marchis, Silvia

    2009-01-01

    The olfactory bulb (OB) is a highly plastic region of the adult mammalian brain characterized by continuous integration of inhibitory interneurons of the granule (GC) and periglomerular cell (PGC) types. Adult-generated OB interneurons are selected to survive in an experience-dependent way but the mechanisms that mediate the effects of experience on OB neurogenesis are unknown. Here we focus on the new-generated PGC population which is composed by multiple subtypes. Using paradigms of olfactory enrichment and/or deprivation combined to BrdU injections and quantitative confocal immunohistochemical analyses, we studied the effects of olfactory experience on adult-generated PGCs at different survival time and compared PGC to GC modulation. We show that olfactory enrichment similarly influences PGCs and GCs, increasing survival of newborn cells and transiently modulating GAD67 and plasticity-related molecules expression. However, PGC maturation appears to be delayed compared to GCs, reflecting a different temporal dynamic of adult generated olfactory interneuron integration. Moreover, olfactory enrichment or deprivation do not selectively modulate the survival of specific PGC phenotypes, supporting the idea that the integration rate of distinct PGC subtypes is independent from olfactory experience. PMID:19626121

  4. 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. PMID:26868988

  5. Oral delivery of glutamic acid decarboxylase (GAD)-65 and IL10 by Lactococcus lactis reverses diabetes in recent-onset NOD mice.

    PubMed

    Robert, Sofie; Gysemans, Conny; Takiishi, Tatiana; Korf, Hannelie; Spagnuolo, Isabella; Sebastiani, Guido; Van Huynegem, Karolien; Steidler, Lothar; Caluwaerts, Silvia; Demetter, Pieter; Wasserfall, Clive H; Atkinson, Mark A; Dotta, Francesco; Rottiers, Pieter; Van Belle, Tom L; Mathieu, Chantal

    2014-08-01

    Growing insight into the pathogenesis of type 1 diabetes (T1D) and numerous studies in preclinical models highlight the potential of antigen-specific approaches to restore tolerance efficiently and safely. Oral administration of protein antigens is a preferred method for tolerance induction, but degradation during gastrointestinal passage can impede such protein-based therapies, reducing their efficacy and making them cost-ineffective. To overcome these limitations, we generated a tolerogenic bacterial delivery technology based on live Lactococcus lactis (LL) bacteria for controlled secretion of the T1D autoantigen GAD65370-575 and the anti-inflammatory cytokine interleukin-10 in the gut. In combination with short-course low-dose anti-CD3, this treatment stabilized insulitis, preserved functional β-cell mass, and restored normoglycemia in recent-onset NOD mice, even when hyperglycemia was severe at diagnosis. Combination therapy did not eliminate pathogenic effector T cells, but increased the presence of functional CD4(+)Foxp3(+)CD25(+) regulatory T cells. These preclinical data indicate a great therapeutic potential of orally administered autoantigen-secreting LL for tolerance induction in T1D. PMID:24677716

  6. 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. PMID:27031595

  7. GAD67-GFP+ neurons in the Nucleus of Roller: a possible source of inhibitory input to hypoglossal motoneurons. I. Morphology and firing properties.

    PubMed

    van Brederode, J F M; Yanagawa, Y; Berger, A J

    2011-01-01

    In this study we examined the electrophysiological and morphological properties of inhibitory neurons located just ventrolateral to the hypoglossal motor (XII) nucleus in the Nucleus of Roller (NR). In vitro experiments were performed on medullary slices derived from postnatal day 5 (P5) to P15 GAD67-GFP knock-in mouse pups. on cell recordings from GFP+ cells in NR in rhythmic slices revealed that these neurons are spontaneously active, although their spiking activity does not exhibit inspiratory phase modulation. Morphologically, GFP+ cells were bi- or multipolar cells with small- to medium-sized cell bodies and small dendritic trees that were often oriented parallel to the border of the XII nucleus. GFP+ cells were classified as either tonic or phasic based on their firing responses to depolarizing step current stimulation in whole cell current clamp. Tonic GFP+ cells fired a regular train of action potentials (APs) throughout the duration of the pulse and often showed rebound spikes after a hyperpolarizing step. In contrast, phasic GFP+ neurons did not fire throughout the depolarizing current step but instead fired fewer than four APs at the onset of the pulse or fired multiple APs, but only after a marked delay. Phasic cells had a significantly smaller input resistance and shorter membrane time constant than tonic GFP+ cells. In addition, phasic GFP+ cells differed from tonic cells in the shape and time course of their spike afterpotentials, the minimum firing frequency at threshold current amplitude, and the slope of their current-frequency relationship. These results suggest that GABAergic neurons in the NR are morphologically and electrophysiologically heterogeneous cells that could provide tonic inhibitory synaptic input to HMs. PMID:21047932

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

    PubMed Central

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

    2014-01-01

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

  9. CD226 rs763361 is associated with the susceptibility to type 1 diabetes and greater frequency of GAD65 autoantibody in a Brazilian cohort.

    PubMed

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

    2014-01-01

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

  10. 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. PMID:26148972

  11. GAD Antibodies as Key Link Between Chronic Intestinal Pseudoobstruction, Autonomic Neuropathy, and Limb Stiffness in a Nondiabetic Patient: A CARE-Compliant Case Report and Review of the Literature.

    PubMed

    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

    2015-08-01

    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

  12. STEREOLOGICAL ESTIMATES OF THE BASAL FOREBRAIN CELL POPULATION IN THE RAT, INCLUDING NEURONS CONTAINING CHOLINE ACETYLTRANSFERASE (ChAT), GLUTAMIC ACID DECARBOXYLASE (GAD) OR PHOSPHATE-ACTIVATED GLUTAMINASE (PAG) AND COLOCALIZING VESICULAR GLUTAMATE TRANSPORTERS (VGluTs)

    PubMed Central

    GRITTI, I.; HENNY, P.; GALLONI, F.; MAINVILLE, L.; MARIOTTI, M.; JONES, B. E.

    2006-01-01

    The basal forebrain (BF) plays an important role in modulating cortical activity and influencing attention, learning and memory. These activities are fulfilled importantly yet not entirely by cholinergic neurons. Noncholinergic neurons also contribute and are comprised by GABAergic neurons and other possibly glutamatergic neurons. The aim of the present study was to estimate the total number of cells in the BF of the rat and the proportions of that total represented by cholinergic, GABAergic and glutamatergic neurons. For this purpose, cells were counted using unbiased stereological methods within the medial septum, diagonal band, magnocellular preoptic nucleus, substantia innominata and globus pallidus in sections stained for Nissl substance and/or the neurotransmitter enzymes, choline acetyltransferase (ChAT), glutamic acid decarboxylase (GAD) or phosphate-activated glutaminase (PAG). In Nissl-stained sections, the total number of neurons in the BF was estimated as ~355,000 and the numbers of ChAT-immuno-positive (+) as ~22,000, GAD+ ~119,000 and PAG+ ~316,000, corresponding to ~5%, ~35% and ~90% of the total. Thus, of the large population of BF neurons, only a small proportion has the capacity to synthesize acetylcholine (ACh), one third to synthesize GABA and the vast majority to synthesize glutamate (Glu). Moreover, through the presence of PAG, a proportion of ACh- and GABA-synthesizing neurons also have the capacity to synthesize Glu. In sections dual fluorescent immunostained for vesicular transporters, VGluT3 and not VGluT2 was present in the cell bodies of most PAG+ and ChAT+ and half the GAD+ cells. Given previous results showing that VGluT2 and not VGluT3 was present in BF axon terminals and not colocalized with VAChT or VGAT, we conclude that the BF cell population influences cortical and subcortical regions through neurons which release ACh, GABA or Glu from their terminals but which in part can also synthesize and release Glu from their soma or

  13. Mudsill Theory, the Lancaster Amish and Jaime Escalante.

    ERIC Educational Resources Information Center

    Gatto, John Taylor

    1996-01-01

    Traces current educational philosophy and practices to 19th-century philosophers who proposed the "mudsill theory," the notion that ordinary children could not be intellectually successful and must be coerced and prepared for work by compulsory schooling. Points to the success of relatively underschooled self-sufficient Lancaster Amish and street…

  14. Jaime Urrutia Fucugauchi Receives 2013 International Award: Response

    NASA Astrophysics Data System (ADS)

    Fucugauchi, Jaime Urrutia

    2014-01-01

    Thank you, Cinna, for your kind and generous citation and for your friendship. It is a great recognition having been selected for the 2013 International Award. I feel honored, especially considering the international breadth of AGU, fostering scientific excellence and promoting research in Earth and space sciences worldwide. AGU has evolved over the years, becoming increasingly international and multidisciplinary, providing the intellectual framework and networking for research collaboration. I have been privileged to serve as International Secretary of the Union, which together with work in the committees permitted me to better appreciate the range of activities and the programs AGU does to serve its membership and the geophysics community.

  15. Screening for Generalized Anxiety Disorder (GAD)

    MedlinePlus

    ... Screening for Posttraumatic Stress Disorder (PTSD) Screening for Social Anxiety Disorder Screening for Specific Phobias Screening for an Anxiety Disorder: Children Screening for an Anxiety Disorder: Family Member Self-Help Strategies: Webinars to Calm Anxious Minds "Triumph" E-News ...

  16. Screening for Generalized Anxiety Disorder (GAD)

    MedlinePlus

    ... Anxiety Disorder Treating Anxiety Disorders: Educational Videos Clinical Practice Review for Major Depressive Disorder Meetings & Events Mental Health Apps Announcements Awards Alies Muskin Career Development ...

  17. 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. PMID:25979087

  18. VizieR Online Data Catalog: Variable stars in globular clusters (Figuera Jaimes+, 2016)

    NASA Astrophysics Data System (ADS)

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

    2016-02-01

    Observations were taken during 2013 and 2014 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 the globular clusters 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. (2 data files).

  19. Health assessment for Mathis Brothers Landfill, Kensington, Georgia, Region 4. CERCLIS No. GAD980838619. Preliminary report

    SciTech Connect

    Not Available

    1988-09-29

    The Mathis Brothers Landfill (MBL) is on the National Priorities List. MBL is a 20-acre site and is located on the east side of Marble Top Road, one-half mile south of State Highway 136 near Kensington (Walker), Georgia. MBL was licensed by the State to accept nonhazardous waste. The landfill is uncapped and rusted, leaking drums presently exist on-site. No removal operations have occurred. On-site contaminants of concern include lead, various residues from herbicide manufacturing and latex waste from carpet manufacturing. Based on the available information, the site is considered to be of potential public health concern because of the risk to human health caused by the possibility of exposure to hazardous substances.

  20. "Our Ultimate Competition," a Speech by John Neufeld, and Readers' Responses to Neufeld's "Boys Lie" by Matthew Ellis, Jaime Miller and Liz Ackert.

    ERIC Educational Resources Information Center

    Moore, John Noell, Ed.

    2000-01-01

    Suggests the ultimate competition for writers of contemporary adolescent fiction is life--the world that children inhabit is getting stranger and stranger. Discusses parents' and adolescents' different reactions to the novel "Boys Lie," which addresses the issues of rape and sexual harassment. Presents reactions to the speech and the responses of…

  1. 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. PMID:16533865

  2. Endostatin Polymorphism 4349G/A(D104N) is not Associated with Aggressiveness of Disease in Postate Cancer

    PubMed Central

    Li, He Cheng; Cai, Qiu Yin; Shinohara, Eric T.; Cai, Hui; Cao, Carolyn; Fei Wang, Zuo; Teng, Ming; Zheng, Wei; Lu, Bo

    2005-01-01

    Endostatin is an important inhibitory molecule which mediates the sequential steps involved in angiogenesis. Lower level or impaired function of endostatin is associated with a higher risk of developing malignant solid tumors and with a worse prognosis of the disease. The endostatin N104 polymorphism might be associated with an impaired ability to inhibit angiogenesis. We analyzed the tissues from 98 Caucasian prostate cancer patients for the presence of D104N polymorphism. The frequencies of homozygous 4349G/G(104D/D), and heterozygous 4349G/A(104D/N) were 83.67%(82/98) and 16.33%(16/98), respectively; no individuals were homozygous 4349A/A(104N/N). With the Fisher’s exact test we found the genotype of D104N was not significantly related to age, tumor grade, PSA and clinical stage (P > 0.05). There was no difference in relapse free survival(RFS) or overall survival(OS) between patients with 104D/N and those with 104D/D (P = 0.8283, 0.3713 respectively). We concluded that endostatin polymorphism was not associated with the aggressiveness of prostate cancer in Caucasian patients. PMID:15735323

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

    PubMed Central

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

    2016-01-01

    Aims Glutamic acid decarboxylase autoantibodies (GADAb) differentiate slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) from phenotypic type 2 diabetes, but many GADAb-positive patients with diabetes do not progress to insulin-requiring diabetes. To characterize GADAb-positive patients with adult-onset diabetes who do not require insulin therapy for >5 years (NIR-SPIDDM), we conducted a nationwide cross-sectional survey in Japan. Methods We collected 82 GADAb-positive patients who did not require insulin therapy for >5 years (NIR-SPIDDM) and compared them with 63 patients with insulin-requiring SPIDDM (IR-SPIDDM). Clinical and biochemical characteristics, HLA-DRB1-DQB1 haplotypes, and predictive markers for progression to insulin therapy were investigated. Results Compared with the IR-SPIDDM group, the NIR-SPIDDM patients showed later diabetes onset, higher body mass index, longer duration before diagnosis, and less frequent hyperglycemic symptoms at onset. In addition, C-peptide, LDL-cholesterol, and TG were significantly higher in the NIR-SPIDDM compared to IR-SPIDDM patients. The NIR-SPIDDM group had lower frequency of susceptible HLA-DRB1*04:05-DQB1*04:01 and a higher frequency of resistant HLA-DRB1*15:01-DQB1*06:02 haplotype compared to IR-SPIDDM. A multivariable analysis showed that age at diabetes onset (OR = 0.82), duration before diagnosis of GADAb-positive diabetes (OR = 0.82), higher GADAb level (≥10.0 U/ml) (OR = 20.41), and fasting C-peptide at diagnosis (OR = 0.07) were independent predictive markers for progression to insulin-requiring diabetes. An ROC curve analysis showed that the optimal cut-off points for discriminating two groups was the GADAb level of 13.6 U/ml, age of diabetes onset of 47 years, duration before diagnosis of 5 years, and fasting C-peptide of 0.65 ng/ml. Conclusions Clinical, biochemical and genetic characteristics of patients with NIR-SPIDDM are different from those of IR-SPIDDM patients. Age of diabetes onset, duration before GADAb-positivity, GADAb level, and fasting C-peptide at diagnosis must be carefully considered in planning prevention trials for SPIDDM. PMID:27177031

  4. 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.

  5. Exact distinction of excitatory and inhibitory neurons in neural networks: a study with GFP-GAD67 neurons optically and electrophysiologically recognized on multielectrode arrays.

    PubMed

    Becchetti, Andrea; Gullo, Francesca; Bruno, Giuseppe; Dossi, Elena; Lecchi, Marzia; Wanke, Enzo

    2012-01-01

    Distinguishing excitatory from inhibitory neurons with multielectrode array (MEA) recordings is a serious experimental challenge. The current methods, developed in vitro, mostly rely on spike waveform analysis. These however often display poor resolution and may produce errors caused by the variability of spike amplitudes and neuron shapes. Recent recordings in human brain suggest that the spike waveform features correlate with time-domain statistics such as spiking rate, autocorrelation, and coefficient of variation. However, no precise criteria are available to exactly assign identified units to specific neuronal types, either in vivo or in vitro. To solve this problem, we combined MEA recording with fluorescence imaging of neocortical cultures from mice expressing green fluorescent protein (GFP) in GABAergic cells. In this way, we could sort out "authentic excitatory neurons" (AENs) and "authentic inhibitory neurons" (AINs). We thus characterized 1275 units (from 405 electrodes, n = 10 experiments), based on autocorrelation, burst length, spike number (SN), spiking rate, squared coefficient of variation, and Fano factor (FF) (the ratio between spike-count variance and mean). These metrics differed by about one order of magnitude between AINs and AENs. In particular, the FF turned out to provide a firing code which exactly (no overlap) recognizes excitatory and inhibitory units. The difference in FF between all of the identified AEN and AIN groups was highly significant (p < 10(-8), ANOVA post-hoc Tukey test). Our results indicate a statistical metric-based approach to distinguish excitatory from inhibitory neurons independently from the spike width. PMID:22973197

  6. 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

  7. Generalized anxiety disorder in a nonclinical sample of children: Symptom presentation and predictors of impairment

    PubMed Central

    Layne, Ann E.; Bernat, Debra H.; Victor, Andrea M.; Bernstein, Gail A.

    2012-01-01

    Presentation of generalized anxiety disorder (GAD) in a nonclinical sample of children (7–11 years old) and factors that predict overall impairment were examined. Symptom presentation was compared in children with GAD (n = 49) and anxious children without GAD (n = 42). Children with GAD endorsed significantly more worries, greater intensity of worries, and more DSM-IV associated symptoms than anxious children without GAD. Eighty-six percent of children with GAD had a comorbid diagnosis with 4% having a depressive disorder. Number of associated symptoms was most predictive of GAD impairment based on child perspective and intensity of worry was most predictive based on clinician perspective. Overall, findings from the current study are consistent with reports based on clinical samples. The DSM-IV-TR criteria for GAD were supported, with the exception that children with GAD typically present with several associated symptoms, rather than only one. PMID:18815006

  8. 76 FR 81482 - Information Collection; Submission for OMB Review, Comment Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-28

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

  9. Two-Thirds of Americans Report Daily Discrimination in Poll

    MedlinePlus

    ... to race, ethnicity, age, disability, gender or sexual orientation," Jaime Diaz-Granados, executive director for education at the American Psychological Association (APA), said in a news release from ...

  10. 76 FR 65184 - Proposed Information Collection; Comment Request

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-10-20

    ... AND COMMUNITY SERVICE Proposed Information Collection; Comment Request AGENCY: Corporation for National and Community Service. ACTION: Notice. SUMMARY: The Corporation for National and Community Service... National and Community Service, Minnesota State Office; Attention Jaime Renner, State Program...

  11. 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)

  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. 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 ...

  14. 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…

  15. 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…

  16. Neuronal circuit-dependent alterations in expression of two isoforms of glutamic acid decarboxylase in the hippocampus following electroconvulsive shock: A stereology-based study.

    PubMed

    Jinno, Shozo; Kosaka, Toshio

    2009-11-01

    There is an increasing body of evidence suggesting that GABAergic dysfunction is involved in various psychiatric disorders. The goal of our study was to investigate the influences of electroconvulsive therapy (ECT), one of the most effective treatments for depression, on the GABAergic system in the hippocampus. In this stereology-based study, we identified GABAergic neurons by immunostaining for two isoforms of glutamic acid decarboxylase (GAD), GAD65, and GAD67 and estimated the expression changes induced by single or repeated electroconvulsive shock (ECS; an animal model of ECT). The numerical density (ND) of entire population of GABAergic neurons (expressing GAD65 and/or GAD67) was seldom altered by the administration of ECS. GAD67-positive (GAD67(+)) neurons were also rarely affected by ECS. On the other hand, the ND of GAD65(+) neurons was changed in a layer-specific manner. In the CA1 region, the ND of GAD65(+) neurons was increased in the strata radiatum/lacunosum-moleculare (SR/SLM) by repeated ECS. In the CA3 region, the ND of GAD65(+) neurons was decreased in the stratum oriens and SR/SLM after single ECS. The expression ratio of GAD65 in GABAergic neurons was increased specifically in layers receiving afferents from the entorhinal cortex (EC), i.e., SR/SLM of the CA1 region and molecular layer of the dentate gyrus (DG), after repeated ECS administration, whereas the expression ratio of GAD67 in GABAergic neurons was decreased in several layers by the same treatment. These results indicate that the ECS-induced changes in ND of GAD65(+) or GAD67(+) neurons were most likely due to alterations in GAD expression rather than actual increases or decreases in cell numbers. Altogether, the neuronal circuit-dependent alterations in GABA-mediated signaling may play a contributory role in the depression treatment process introduced by ECT. PMID:19283776

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

    PubMed Central

    2014-01-01

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

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

    PubMed

    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

  19. 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

  20. Generalized Anxiety and C-Reactive Protein Levels: A Prospective, Longitudinal Analysis

    PubMed Central

    Copeland, William E.; Shanahan, Lilly; Worthman, Carol; Angold, Adrian; Costello, E. Jane

    2012-01-01

    Background Generalized Anxiety Disorder (GAD) is highly comorbid with depression. Depression is associated with elevated levels of the inflammation marker C-reactive protein (CRP), cross-sectionally and over time. To date, no studies have looked at the association of CRP with GAD. Methods Ten waves of data from the prospective population-based Great Smoky Mountains Study (N = 1,420) were used, covering children in the community aged 9-16, 19, and 21 years old. Structured interviews were used at each assessment to assess GAD symptoms, diagnosis, and cumulative episodes. Bloodspots were collected and assayed for CRP levels. Results GAD was associated with increased levels of CRP in bivariate cross-sectional analyses. These bivariate associations, however, were attenuated after accounting for demographic, substance use, and health-related covariates. In longitudinal models, there was little evidence that CRP predicted later GAD. Associations from GAD to later CRP were attenuated in models adjusted for health-related coavariates and there was evidence that the GAD-CRP association was mediated by BMI and medication use. Conclusions Similar to depression, GAD was associated with elevated levels of CRP, but the effect of GAD on CRP levels was explained by the effect of GAD on health-related behaviors such as BMI and medication use. This study suggests differences in the association between inflammation and depression and GAD. PMID:22716910

  1. Generalized anxiety disorder: between neglect and an epidemic.

    PubMed

    Starcevic, Vladan; Portman, Michael E; Beck, Aaron T

    2012-08-01

    This article reviews the main issues associated with the concept and the diagnosis of generalized anxiety disorder (GAD) and examines the proposed DSM-5 diagnostic criteria for GAD. The lack of specific features, which is the primary issue for GAD, will not be addressed in DSM-5. The hallmark of the condition will remain pathological worry, although it also characterizes other disorders. Likewise, the proposed behavioral diagnostic criteria lack specificity for GAD, and it is not clear how these will be assessed. The proposed changes will lower the diagnostic threshold for GAD in DSM-5. Although this will not necessarily lead to a better recognition of GAD and an improvement in the perception of its relevance and clinical utility, many currently subthreshold cases will qualify for this diagnosis. The likely inclusion of many such "false-positives" will result in an artificial increase in the prevalence of GAD and will have further negative consequences. PMID:22850300

  2. 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

  3. 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

  4. Expression of the neurotransmitter-synthesizing enzyme glutamic acid decarboxylase in male germ cells.

    PubMed Central

    Persson, H; Pelto-Huikko, M; Metsis, M; Söder, O; Brene, S; Skog, S; Hökfelt, T; Ritzén, E M

    1990-01-01

    The gene encoding glutamic acid decarboxylase (GAD), the key enzyme in the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid, is shown to be expressed in the testis of several different species. Nucleotide sequence analysis of a cDNA clone isolated from the human testis confirmed the presence of GAD mRNA in the testis. The major GAD mRNA in the testis was 2.5 kilobases. Smaller amounts of a 3.7-kilobase mRNA with the same size as GAD mRNA in the brain was also detected in the testis. In situ hybridization using a GAD-specific probe revealed GAD mRNA expressing spermatocytes and spermatids located in the middle part of rat seminiferous tubules. Studies on the ontogeny of GAD mRNA expression showed low levels of GAD mRNA in testes of prepubertal rats, with increasing levels as sexual maturation is reached, compatible with GAD mRNA expression in germ cells. In agreement with this, fractionation of cells from the rat seminiferous epithelium followed by Northern (RNA) blot analysis showed the highest levels of GAD mRNA associated with spermatocytes and spermatids. Evidence for the presence of GAD protein in the rat testis was obtained from the demonstration of GAD-like immunoreactivity in seminiferous tubules, predominantly at a position where spermatids and spermatozoa are found. Furthermore, GAD-like immunoreactivity was seen in the midpiece of ejaculated human spermatozoa, the part that is responsible for generating energy for spermatozoan motility. Images PMID:1697032

  5. Cytokine regulation of glutamate decarboxylase biosynthesis in isolated rat islets of Langerhans.

    PubMed Central

    Schmidli, R S; Faulkner-Jones, B E; Harrison, L C; James, R F; DeAizpurua, H J

    1996-01-01

    Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease in which cytokines are thought to play an important role in beta-cell destruction and immune regulation. A major target of beta-cell autoimmunity in IDDM is the enzyme glutamate decarboxylase (GAD). We hypothesized that cytokines in the insulitis lesion modulate the synthesis of GAD. This may, in turn, modify the rate of beta-cell destruction. Accordingly we cultured rat islets in the presence and absence of cytokines, and measured synthesis of both isoforms of GAD, GAD65 and GAD67, by [35S]methionine incorporation and immunoprecipitation with a rabbit antiserum that recognizes both GAD65 and GAD67. Incubation of islets with interleukin (IL)-1 beta (1 ng/ml, 24 h), tumour necrosis factor alpha (TNF-alpha; 200 units/ml, 24 h) or interferon gamma (IFN-gamma; 500 units/ml, 72 h) significantly decreased the synthesis of both GAD65 and GAD67, but reduced neither total protein synthesis nor insulin accumulation in the medium or content. Incubation of islets for 24 h in IFN-alpha (1000 units/ml), TNF-beta (50 ng/ml), IL 2 (1000 units/ml), IL-4 (100 ng/ml), IL-6 (10 ng/ml), IL-10 (20 ng/ml), IL-12 (10 ng/ml) or transforming growth factor beta 2 (TGF-beta 2; 5 ng/ml) did not significantly alter GAD65 or GAD67 synthesis. Inhibition of GAD65 and GAD67 protein synthesis by IL-1 beta, TNF-alpha or IFN-gamma was reversed by co-incubation with the nitric oxide synthase inhibitor, NG-monomethyl arginine (NMMA). Expression of both GAD65 and GAD67 mRNA, measured by RNase protection assay, was also decreased by IL-1 beta and completely restored to baseline levels by NMMA. Thus the synthesis of both isoforms of islet GAD is selectively decreased in the presence of IL-1 beta, TNF-alpha or IFN-gamma by a NO-mediated mechanism, probably at the level of cytokine gene transcription. As GAD autoimmunity has been previously shown to have a pathogenic role in an animal model of IDDM, its inhibition by cytokines might limit

  6. 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. PMID:27107389

  7. Generalized anxiety disorder: A comorbid disease.

    PubMed

    Nutt, David; Argyropoulos, Spilos; Hood, Sean; Potokar, John

    2006-07-01

    Generalized anxiety disorder (GAD) frequently occurs comorbidly with other conditions, including depression and somatic complaints. Comorbid GAD sufferers have increased psychologic and social impairment, request additional treatment, and have an extended course and poorer outcome than those with GAD alone; therapy should alleviate both the psychic and somatic symptoms of GAD without negatively affecting the comorbid condition. The ideal treatment would provide relief from both GAD and the comorbid condition, reducing the need for polypharmacy. Physicians need suitable tools to assist them in the detection and monitoring of GAD patients-the GADI, a new, self-rating scale, may meet this requirement. Clinical data have shown that various neurobiologic irregularities (e.g., in the GABA and serotonin systems) are associated with the development of anxiety. Prescribing physicians must take into account these abnormalities when choosing a drug. Effective diagnosis and treatment should improve patients' quality of life and their prognosis for recovery. PMID:16737802

  8. Age and racial differences in the presentation and treatment of Generalized Anxiety Disorder in primary care.

    PubMed

    Brenes, Gretchen A; Knudson, Mark; McCall, W Vaughn; Williamson, Jeff D; Miller, Michael E; Stanley, Melinda A

    2008-10-01

    Despite the prevalence and impact of Generalized Anxiety Disorder (GAD) in the primary care setting, little is known about its presentation in this setting. The purpose of this study is to examine age and racial differences in the presentation and treatment of GAD in medical patients. Participants were recruited from one family medicine clinic and one internal medicine clinic. The prevalence of GAD was lowest for older adults. Age differences were found in the presentation of GAD, with young adults reporting greater cognitive symptoms of anxiety, negative affect, and depressive symptoms. African-Americans with GAD reported more positive affect and lower rates of treatment. The lower levels of negative affect and depressive symptoms reported among older adults may affect the recognition of GAD by primary care physicians. Further research is needed to better understand the causes of racial differences in treatment. PMID:18182275

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

    PubMed Central

    2014-01-01

    Background The relationships between perfectionism, pathological worry and generalised anxiety disorder (GAD) were investigated in a clinical sample presenting for treatment of perfectionism. Method This study explored the utility of perfectionism in predicting pathological worry in a sample of individuals with elevated perfectionism and GAD (n = 36). Following this, the study examined whether perfectionism could predict a principal GAD diagnosis in the full sample (n = 42). Results Scores on the perfectionism dimensions Concern over Mistakes, Personal Standards, and Clinical Perfectionism significantly predicted pathological worry among participants with GAD after controlling for gender and depression. The perfectionism dimension Doubts about Actions significantly predicted whether individuals from the full sample received a principal diagnosis of GAD. Conclusions These findings support certain dimensions of perfectionism having significant associations with pathological worry and GAD. PMID:24693946

  10. Protecting quantum entanglement and nonlocality for tripartite states under decoherence

    NASA Astrophysics Data System (ADS)

    Zhang, Rui; Yin, Yu Hao; Ma, Wen Chao; Ye, Liu

    2016-06-01

    Quantum entanglement and nonlocality will suffer inevitable harm from decoherence environment. Based on GHZ state, we study the harm of the generalized amplitude damping (GAD) operation and the protection by the single local filtering (SLF) operation in this paper. We verify that the SLF functions to depress the loss of entanglement and nonlocality from GAD. This conclusion will guide us to select the best method to protect the GHZ state from GAD decoherence.

  11. Characterization of continuous B-cell epitopes in the N-terminus of glutamate decarboxylase67 using monoclonal antibodies.

    PubMed

    Agca, Selin; Houen, Gunnar; Trier, Nicole Hartwig

    2014-12-01

    Glutamate decarboxylase (GAD) is an autoantigen associated with the autoimmune disorders Type-1 diabetes (T1D) and stiff-person syndrome (SPS). The protein, being an essential enzyme involved in the production of the inhibitory neurotransmitter γ-aminobutyric acid, exists in two isoforms, GAD67 and GAD65. Both isoforms may be targeted by autoantibodies in SPS and T1D patients, although SPS primarily is associated with the presence of GAD67 autoantibodies, whereas T1D mainly is associated with the presence of GAD65 autoantibodies. In this study, we describe antibody reactivity to overlapping GAD67 peptides covering the complete protein sequence by modified peptide enzyme-linked immunosorbent assay in order to identify potential GAD67 epitopes using two monoclonal antibodies (mAbs). Both GAD67 mAbs showed reactivity to linear epitopes located at the N-terminal end of GAD67. The epitopes of GAD mAb 1 and 2 were identified as the amino acid sequences NAGADPNTTN and TETDFSNLF, respectively, corresponding to amino acids 14-23 and 91-99. Fine mapping of the epitopes revealed that antibody reactivity was related to amino acid side-chain functionality, rather than amino acid side-chain specificity. Additionally, results suggested that non-contact amino acids in the epitope structure were essential for antibody reactivity. The exact role of these amino acids remains to be determined, but they are thought to be involved in backbone hydrogen bonds or stabilization of the epitope structure. As only limited knowledge is available in relation to antigenic regions of GAD67, this study contributes to characterization of GAD67 epitopes and may be a first step in the development of peptide-based therapeutics against SPS. PMID:25358241

  12. 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. PMID:26515497

  13. [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. PMID:27443004

  14. 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. PMID:26490569

  15. Venlafaxine

    MedlinePlus

    ... acting) capsules are also used to treat generalized anxiety disorder (GAD; excessive worrying that is difficult to control), social anxiety disorder (extreme fear of interacting with others or ...

  16. Extracellular expression of glutamate decarboxylase B in Escherichia coli to improve gamma-aminobutyric acid production.

    PubMed

    Zhao, Anqi; Hu, Xiaoqing; Li, Ye; Chen, Cheng; Wang, Xiaoyuan

    2016-12-01

    Escherichia coli overexpressing glutamate decarboxylase GadB can produce gamma-aminobutyric acid with addition of monosodium glutamate. The yield and productivity of gamma-aminobutyric acid might be significantly improved if the overexpressed GadB in E. coli cells can be excreted outside, where it can directly transforms monosodium glutamate to gamma-aminobutyric acid. In this study, GadB was fused to signal peptides TorA or PelB, respectively, and overexpressed in E. coli BL21(DE3). It was found that TorA could facilitate GadB secretion much better than PelB. Conditions for GadB secretion and gamma-aminobutyric acid production were optimized in E. coli BL21(DE3)/pET20b-torA-gadB, leading the secretion of more than half of the overexpressed GadB. Fed-batch fermentation for GadB expression and gamma-aminobutyric acid production of BL21(DE3)/pET20b-torA-gadB was sequentially performed in one fermenter; 264.4 and 313.1 g/L gamma-aminobutyric acid were obtained with addition of monosodium glutamate after 36 and 72 h, respectively. PMID:27549808

  17. 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

  18. Alleviation of high-fat diet-induced atherosclerosis and glucose intolerance by a novel GLP-1 fusion protein in ApoE(-/-) mice.

    PubMed

    Kong, Yuelin; Tong, Yue; Chen, Chen; Gao, Mingming; Gao, Xiangdong; Yao, Wenbing

    2016-07-01

    We have previously constructed an engineered anti-diabetic fusion protein using glucagon-like peptide-1 and the globular domain of adiponectin. Herein, we evaluated the therapeutic effects of this fusion protein (GAD) on high-fat diet (HFD)-fed ApoE(-/-) mice. The lipid-lowering effect of GAD was determined in C57BL/6 mice using a lipid tolerance test. The effects of GAD on HFD-induced glucose intolerance, atherosclerosis, and hepatic steatosis were evaluated in HFD-fed ApoE(-/-) mice using glucose tolerance test, histological examinations and real-time quantitative PCR. The anti-inflammation activity of GAD was assessed in vitro on macrophages. GAD improved lipid metabolism in C57BL/6 mice. GAD treatment alleviated glucose intolerance, reduced blood lipid level, and attenuated atherosclerotic lesion in HFD-fed ApoE(-/-) mice, which was associated with a repressed macrophage infiltration in the vessel wall. GAD treatment also blocked hepatic macrophage infiltration and prevented hepatic inflammation. GAD suppressed lipopolysaccharide-triggered inflammation responses on macrophages, which can be abolished by H89, an inhibitor of protein kinase A. These findings demonstrate that GAD is able to generate a variety of metabolic benefits in HFD-fed ApoE(-/-) mice and indicate that this engineered fusion protein is a promising lead structure for anti-atherosclerosis drug discovery. PMID:26832342

  19. 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...

  20. 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…

  1. "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…

  2. 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

    ...) (``IEEPA''), issued Executive Order 12978 (60 FR 54579, October 24, 1995) (the ``Order''). In the Order...) (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...

  3. 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…

  4. 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 indigenous…

  5. My Many Years of Working with the Gifted: An Academic Approach. The Fourth Lecture in the Series.

    ERIC Educational Resources Information Center

    Stanley, Julian C.

    This lecture examines the failure of the United States to produce literate, mathematically competent high school graduates and criticizes "cyclic faddism" as a ploy of desperate educators who keep going back to methods that have been tried and found wanting. Bright spots in education are cited, including the achievement of Jaime Escalante's…

  6. 76 FR 34197 - Anchorage; Change to Cottonwood Island Anchorage, Columbia River, Oregon and Washington

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-13

    ...: You may submit comments identified by docket number USCG- 2011-0348 using any one of the following... on submitting comments. FOR FURTHER INFORMATION CONTACT: If you have questions on this proposed rule...; telephone ] 503-240-9319, e-mail Jaime.A.Sayers@uscg.mil . If you have questions on viewing or...

  7. Pre-Service Geometry Education in South Africa: A Typical Case?

    ERIC Educational Resources Information Center

    van der Sandt, Suriza

    2007-01-01

    A two year study investigating the state of pre-service teachers' (PTs') (n=224), teachers' (n=18) and students' knowledge (n=123) of Grade 7 geometry (using the van Hiele theory (1986) and acquisition scales of Gutierrez, Jaime & Fortuny (1991)) is reported. Results indicate that both teachers and PTs fail to reach the expected level of geometric…

  8. 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 educational…

  9. 75 FR 69160 - Quarterly Publication of Individuals, Who Have Chosen To Expatriate, as Required by Section 6039G

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-10

    ... Richie James Drake Richman Eliot Marshall Richter Andrea Virginia Rigazzi Alain R. Ritter John D. Roden... Beattie Daniel Becker Kaja K. Bednarz Andrew James Beirnes Denise Bell William Anthony Bergandi Marco Lee... Machlin Rachel Shirley Maduro Jaime Eduardo Maggard James Douglas Magnoni Olivia Malik Akhtar...

  10. 77 FR 27078 - Cancellation of May 8, 2012, Meeting of the Wekiva River System Advisory Management Committee

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-08

    ..., 2012, 77 FR 23277, is cancelled. Instead, members of the Committee will meet on May 8, 2012, solely to share information and discuss preparations for the Wekiva Wild and Scenic River Plan Dedication Ceremony... INFORMATION CONTACT: Jaime Doubek-Racine, DFO, Wekiva Wild and Scenic River, RTCA Program, Florida...

  11. Protocol for a randomised controlled trial investigating the effectiveness of an online e health application for the prevention of Generalised Anxiety Disorder

    PubMed Central

    2010-01-01

    Background Generalised Anxiety Disorder (GAD) is a highly prevalent psychiatric disorder. Effective prevention in young adulthood has the potential to reduce the prevalence of the disorder, to reduce disability and lower the costs of the disorder to the community. The present trial (the WebGAD trial) aims to evaluate the effectiveness of an evidence-based online prevention website for GAD. Methods/Design The principal clinical question under investigation is the effectiveness of an online GAD intervention (E-couch) using a community-based sample. We examine whether the effect of the intervention can be maximised by either human support, in the form of telephone calls, or by automated support through emails. The primary outcome will be a reduction in symptoms on the GAD-7 in the active arms relative to the non active intervention arms. Discussion The WebGAD trial will be the first to evaluate the use of an internet-based cognitive behavioural therapy (CBT) program contrasted with a credible control condition for the prevention of GAD and the first formal RCT evaluation of a web-based program for GAD using community recruitment. In general, internet-based CBT programs have been shown to be effective for the treatment of other anxiety disorders such as Post Traumatic Stress Disorder, Social Phobia, Panic Disorder and stress in clinical trials; however there is no evidence for the use of internet CBT in the prevention of GAD. Given the severe shortage of therapists identified in Australia and overseas, and the low rates of treatment seeking in those with a mental illness, the successful implementation of this protocol has important practical outcomes. If found to be effective, WebGAD will provide those experiencing GAD with an easily accessible, free, evidence-based prevention tool which can be promoted and disseminated immediately. Trial Registration Controlled-trials.com: ISRCTN76298775 PMID:20302678

  12. 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…

  13. Treating co-occurring chronic low back pain & generalized anxiety disorder.

    PubMed

    Janzen, Kristina; Peters-Watral, Brenda

    2016-01-16

    The complex, bidirectional correlation between chronic low back pain (CLBP) and generalized anxiety disorder (GAD), common ailments in primary care, can increase the risk of inadequate treatment. This article will review the relationship between CLBP and GAD and provide optimal management strategies for NPs caring for individuals with this dyad. PMID:26642348

  14. Characterization of the YdeO Regulon in Escherichia coli

    PubMed Central

    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. PMID:25375160

  15. 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…

  16. 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…

  17. Testing a cognitive model of generalized anxiety disorder in the eating disorders.

    PubMed

    Konstantellou, Anna; Campbell, Mari; Eisler, Ivan; Simic, Mima; Treasure, Janet

    2011-10-01

    Generalized anxiety disorder (GAD) is one of the most common comorbid disorders found in individuals with eating disorders. Despite this, little is known of shared vulnerability factors between the two disorders. The aim of the present study was to examine the four main components of a cognitive model for GAD in the eating disorders. One hundred and sixty-two females took part. Three groups were formed comprising of 19 participants with an eating disorder and GAD, 70 with an eating disorder without GAD and 73 healthy controls. All completed self-report questionnaires that measured eating attitudes, levels of GAD, intolerance of uncertainty, positive beliefs about worry, negative problem orientation, and cognitive avoidance. Participants with an eating disorder and GAD scored the highest on all four components when compared to healthy individuals and on most components when compared to those with an eating disorder. Participants with an eating disorder without GAD scored higher on all components compared to healthy controls. Findings extend our understanding of shared vulnerability factors between the eating disorders and GAD. PMID:21632204

  18. 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. PMID:27113431

  19. 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. PMID:23796524

  20. 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…

  1. 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. ...

  2. Therapeutic alteration of insulin-dependent diabetes mellitus progression by T cell tolerance to glutamic acid decarboxylase 65 peptides in vitro and in vivo.

    PubMed

    Wilson, S S; White, T C; DeLuca, D

    2001-07-01

    We have reported previously that nonobese diabetic (NOD) fetal pancreas organ cultures lose the ability to produce insulin when maintained in contact with NOD fetal thymus organ cultures (FTOC). Initial studies indicated that exposure to glutamic acid decarboxylase (GAD65) peptides in utero resulted in delay or transient protection from insulin-dependent diabetes mellitus (IDDM) in NOD mice. We also found that exposure of young adult NOD mice to the same peptides could result in acceleration of the disease. To more closely examine the effects of early and late exposure to diabetogenic Ags on T cells, we applied peptides derived from GAD65 (GAD AA 246-266, 509-528, and 524-543), to our "in vitro IDDM" (ivIDDM) model. T cells derived from NOD FTOC primed during the latter stages of organ culture, when mature T cell phenotypes are present, had the ability to proliferate to GAD peptides. ivIDDM was exacerbated under these conditions, suggesting that GAD responsiveness correlates with the ivIDDM phenotype, and parallels the acceleration of IDDM we had seen in young adult NOD mice. When GAD peptides were present during the initiation of FTOC, GAD proliferative responses were inhibited, and ivIDDM was reduced. This result suggests that tolerance to GAD peptides may reduce the production of diabetogenic T cells or their capacity to respond, as suggested by the in utero therapies studied in NOD mice. PMID:11418696

  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…

  4. Gamma-aminobutyric acid production using immobilized glutamate decarboxylase followed by downstream processing with cation exchange chromatography.

    PubMed

    Lee, Seungwoon; Ahn, Jungoh; Kim, Yeon-Gu; Jung, Joon-Ki; Lee, Hongweon; Lee, Eun Gyo

    2013-01-01

    We have developed a gamma-aminobutyric acid (GABA) production technique using his-tag mediated immobilization of Escherichia coli-derived glutamate decarboxylase (GAD), an enzyme that catalyzes the conversion of glutamate to GABA. The GAD was obtained at 1.43 g/L from GAD-overexpressed E. coli fermentation and consisted of 59.7% monomer, 29.2% dimer and 2.3% tetramer with a 97.6% soluble form of the total GAD. The harvested GAD was immobilized to metal affinity gel with an immobilization yield of 92%. Based on an investigation of specific enzyme activity and reaction characteristics, glutamic acid (GA) was chosen over monosodium glutamate (MSG) as a substrate for immobilized GAD, resulting in conversion of 2.17 M GABA in a 1 L reactor within 100 min. The immobilized enzymes retained 58.1% of their initial activities after ten consecutive uses. By using cation exchange chromatography followed by enzymatic conversion, GABA was separated from the residual substrate and leached GAD. As a consequence, the glutamic acid was mostly removed with no detectable GAD, while 91.2% of GABA was yielded in the purification step. PMID:23322022

  5. 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. PMID:26940489

  6. The Impact of Written Exposure on Worry: A Preliminary Investigation

    ERIC Educational Resources Information Center

    Goldman, Natalie; Dugas, Michel J.; Sexton, Kathryn A.; Gervais, Nicole J.

    2007-01-01

    The main goal of this study was to examine the effect of written exposure on generalized anxiety disorder (GAD)-related symptoms in high worriers. Thirty nonclinical high worriers were randomly assigned to either a written exposure condition or a control writing condition. Self-report measures were used to assess worry, GAD somatic symptoms,…

  7. 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. PMID:20060098

  8. 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. PMID:26398003

  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. PMID:26934635

  10. Generalized anxiety disorder: What are we missing?

    PubMed

    Allgulander, Christer

    2006-07-01

    One of the most prevalent anxiety conditions seen in primary care is generalized anxiety disorder (GAD). Numerous physical ailments frequently accompany the psychic symptoms of anxiety, which often drive patients to ask for help. In spite of the high incidence of GAD, only 30% of sufferers are diagnosed. Furthermore, very few patients are prescribed medication or referred to a psychiatrist. The key aim is to ensure the early detection and management of these patients. Developing physician education programs may improve the identification of GAD. The use of simple diagnostic tools would also aid the early detection of sufferers. Physicians require more long-term data, including that on the influence of ethnicity and genetics, to assist them to better understand and more effectively manage GAD. By achieving early diagnosis and treatment of GAD, physicians can ensure that a lesser burden is inflicted upon sufferers, thus improving their quality of life. PMID:16730165

  11. Brain Activation Patterns Associated with the Effects of Emotional Distracters during Working Memory Maintenance in Patients with Generalized Anxiety Disorder

    PubMed Central

    Park, Jong-Il; Kim, Gwang-Won; Jeong, Gwang-Woo; Chung, Gyung Ho

    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. PMID:26766958

  12. 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. PMID:26766958

  13. Inattention symptoms and the diagnosis of comorbid attention-deficit/hyperactivity disorder among youth with generalized anxiety disorder

    PubMed Central

    Elkins, R. Meredith; Carpenter, Aubrey L.; Pincus, Donna B.; Comer, Jonathan S.

    2014-01-01

    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 = 0.84, 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. PMID:25260213

  14. 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

  15. 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. PMID:26564548

  16. Understanding the Association Between Chronic Obstructive Pulmonary Disease and Current Anxiety: A Population-Based Study.

    PubMed

    Fuller-Thomson, Esme; Lacombe-Duncan, Ashley

    2016-10-01

    This study's objectives were to investigate the independent relationship between COPD and past-year Generalized Anxiety Disorder (GAD) in a population-based sample of adult Canadians and to identify significant correlates of GAD among COPD patients. A series of logistic regression analyses were conducted with a sample of 11,163 respondents aged 50+ from the 2012 Canadian Community Health Survey-Mental Health to determine the degree to which the direct association between COPD and GAD was attenuated by socio-demographic factors, social support, health behaviors, sleep problems, pain, functional limitations, and early childhood adversities. Additional analyses were completed using the sub-sample of those diagnosed with COPD (n = 746) to determine predictors of GAD. One in 17 (5.8%) of older individuals with COPD had past-year GAD, in comparison to 1.7% of those without (p < .001). The age-sex-race adjusted odds of GAD were four times higher for those with COPD compared to those without COPD (OR = 3.90, 95%CI: 2.64, 5.77). After full adjustment for 18 characteristics, these odds declined to 1.72 (95%CI: 1.10, 2.71). Factors associated with GAD among those with COPD include not having a confidant (OR = 7.85, 95%CI: 3.47, 17.75), exposure to parental domestic violence (OR = 5.63, 95% CI: 2.07, 15.34) and lifetime depressive disorders (OR = 3.59, 95% CI:1.61,7.98). Those with COPD have substantially higher odds of GAD even after most known risk factors for GAD are accounted for. These findings have implications for targeted outreach and screening, particularly for patients with pain and functional limitations. The importance of a multidisciplinary healthcare team is underscored by the multiple issues that may impact GAD among COPD patients. PMID:26830204

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

    PubMed Central

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

    2016-01-01

    Objective To analyse the utilization of health care services of people who tested positive for GAD compared to those who tested negative. Setting A cross-sectional study from the Northern Finland 1966 Birth Cohort. Subjects A total of 10,282 members followed from birth in a longitudinal study were asked to participate in a follow-up survey at the age of 46. As part of this survey they filled in questionnaries concerning health care utilization and their illness history as well as the GAD-7 screening tool. Althogether 5,480 cohort members responded to the questionnaries. Main outcome measures Number of visits in different health care services among people who tested positive for GAD with the GAD-7 screening tool compared to those who tested negative. Results People who tested positive for GAD had 112% more total health care visits, 74% more total physician visits, 115% more visits to health centres, 133% more health centre physician visits, 160% more visits to secondary care, and 775% more mental health care visits than those who tested negative. Conclusion People with GAD symptoms utilize health care services more than other people. Key PointsGeneralised anxiety disorder (GAD) is a common but poorly identified mental health problem in primary care.People who tested positive for GAD utilise more health care services than those who tested negative.About 58% of people who tested positive for GAD had visited their primary care physician during the past year.Only 29% of people who tested positive for GAD had used mental health services during the past year. PMID:27054674

  18. Enhanced expression of glutamate decarboxylase 65 improves symptoms of rat parkinsonian models.

    PubMed

    Lee, B; Lee, H; Nam, Y R; Oh, J H; Cho, Y H; Chang, J W

    2005-08-01

    In this study, we report the amelioration of parkinsonian symptoms in rat Parkinson's disease (PD) models, as a result of the expression of glutamate decarboxylase (GAD) 65 with a modified cytomegalovirus (CMV) promoter. The transfer of the gene for gamma-amino butryic acid (GAD), the rate-limiting enzyme in gama-amino butrylic acid (GABA) production, has been investigated as a means to increase inhibitory synaptic activity. Electrophysiological evidence suggests that the transfer of the GAD65 gene to the subthalamic nucleus (STN) can change the excitatory output of this nucleus to inhibitory output. Our in vitro results also demonstrated higher GAD65 expression in cells transfected with the JDK promoter, as compared to cells transfected with the CMV promoter. Also, a rat PD model in which recombinant adeno-associated virus-2 (rAAV2)-JDK-GAD65 was delivered into the STN exhibited significant behavioral improvements, as compared to the saline-injected group. Interestingly, we observed that these behavioral improvements were more obvious in rat PD models in which rAAV2-JDK-GAD65 was injected into the STN than in rat PD models in which rAAV2-CMV-GAD65 was injected into the STN. Moreover, according to electrophysiological data, the rAAV2-JDK-GAD65-injected group exhibited more constant improvements in firing rates than did the rAAV2-CMV-GAD65-injected group. These data indicate that the JDK promoter, when coupled with GAD65 expression, is more effective with regard to parkinsonian symptoms than is the CMV promoter. PMID:15829994

  19. 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

  20. POSTTRANSLATIONAL MODIFICATION OF GLUTAMIC ACID DECARBOXYLASE 67 BY INTERMITTENT HYPOXIA: Evidence for the involvement of dopamine D1 receptor signaling$

    PubMed Central

    Raghuraman, Gayatri; Prabhakar, Nanduri R.; Kumar, Ganesh K.

    2010-01-01

    Intermittent hypoxia (IH) associated with sleep apnea leads to cardio-respiratory morbidities. Previous studies have shown that IH alters the synthesis of neurotransmitters including catecholamines and neuropeptides in brainstem regions associated with regulation of cardio-respiratory functions. GABA, a major inhibitory neurotransmitter in the central nervous system, has been implicated in cardio-respiratory control. GABA synthesis is primarily catalyzed by glutamic acid decarboxylase (GAD). Here, we tested the hypothesis that IH like its effect on other transmitters also alters GABA synthesis. The impact of IH on GABA synthesis was investigated in pheochromocytoma 12 (PC12) cells, a neuronal cell line which is known to express active form of GAD67 in the cytosolic fraction and also assessed the underlying mechanisms contributing to IH-evoked response. Exposure of cell cultures to IH decreased GAD67 activity and GABA level. IH-evoked decrease in GAD67 activity was due to increased cAMP - protein kinase A (PKA) - dependent phosphorylation of GAD67, but not as a result of changes in either GAD67 mRNA or protein expression. PKA inhibitor restored GAD67 activity and GABA levels in IH treated cells. PC12 cells express dopamine 1 receptor (D1R), a G-protein coupled receptor whose activation increased adenylyl cyclase (AC) activity. Treatment with either D1R antagonist or AC inhibitor reversed IH-evoked GAD67 inhibition. Silencing D1R expression with siRNA reversed cAMP elevation and GAD67 inhibition by IH. These results provide evidence for the role of D1R-cAMP-PKA signaling in IH mediated inhibition of GAD67 via protein phosphorylation resulting in down regulation of GABA synthesis. PMID:20969567

  1. Possible role for glutamic acid decarboxylase in fibromyalgia symptoms: a conceptual model for chronic pain.

    PubMed

    Fitzgerald, Caris T; Carter, Lawrence P

    2011-09-01

    Fibromyalgia (FM) is a condition of chronic generalized musculoskeletal pain that is thought to be a disorder of central pain sensitization. A number of neurotransmitters in the ascending and descending pain pathways have been implicated in FM including glutamate and GABA. Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in the conversion of glutamate to GABA and decreased expression or activity of this enzyme could result in an imbalance of excitatory and inhibitory neurotransmission in the ascending and descending pain pathways. Specifically, the expression and activity of the predominant isoform of GAD (GAD65) is influenced by several factors that are associated with FM such as female sex, poor diet, obesity, sedentary lifestyle, and stress. We hypothesize that decreased GAD expression and/or activity plays a role in the development and exacerbation of FM leading to impairments in the three common domains of FM symptomatology: increased pain (hyperalgesia and allodynia), disrupted sleep, and disturbances in mood (anxiety and depression). There are several lines of evidence that appear to support a role of GAD in FM. First, the defining symptom of FM is pain and GAD65 knockout mice have been shown to exhibit supraspinal hyperalgesia. Second, GAD has been implicated in disorders of muscle stiffness and rigidity and morning stiffness is a common symptom of FM. Third, stress, depression, and anxiety, which are often comorbid with FM, decrease GAD activity. Fourth, FM is associated with poor sleep, specifically disrupted non-rapid eye movement (NREM) sleep, and the pharmacological induction of NREM sleep is associated with the activation of GAD-containing neurons in the preoptic hypothalamus. Fifth, FM is more commonly diagnosed in women than men and the activity of GAD is reduced by low levels of its cofactor pyroxidine, which is less well-absorbed by women and can be further lowered by diet, tobacco, and alcohol intake. Sixth, FM patients tend to be

  2. 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. PMID:24965288

  3. 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

  4. Experience and appraisal of worry among high worriers with and without generalized anxiety disorder.

    PubMed

    Ruscio, Ayelet Meron; Borkovec, T D

    2004-12-01

    Recent research has revealed that a large number of highly worried individuals do not qualify for a diagnosis of generalized anxiety disorder (GAD). This raises the intriguing question of why some high worriers are more impaired and distressed by their worrying than others, particularly when the severity of their worry is the same. The present investigation sought to address this question by examining whether GAD and non-GAD high worriers differ in their actual worry experiences, their subjective appraisals of worry experiences, or both experiences and appraisals of worry. GAD and non-GAD worriers, selected for matching levels of trait worry severity, completed an attention-focus task with thought sampling before and after a brief worry induction. They also completed questionnaires assessing their experiences during and after the worry induction, as well as their general beliefs about worry. GAD worriers experienced less control over negative intrusive thoughts immediately after worrying, reported greater somatic hyperarousal following worry, and endorsed several negative beliefs about worry more strongly than their worry-matched controls. Results suggest that GAD is associated with unique experiences and appraisals that distinguish it from other forms of severe worry. PMID:15500816

  5. Polysomnographic Sleep Characteristics of Generally-Anxious and Healthy Children Assessed in the Home Environment

    PubMed Central

    Patriquin, Michelle A.; Mellman, Thomas A.; Glaze, Daniel G.; Alfano, Candice A.

    2014-01-01

    Background Using laboratory-based polysomnography (PSG) we recently provided evidence of significantly prolonged sleep onset latency (SOL) and reduced latency to rapid eye movement (REM) sleep among non-depressed children with generalized anxiety disorder (GAD) compared to healthy age-matched controls. In the current study we conducted unattended ambulatory PSG in a new sample of children with GAD and controls in order to examine sleeping characteristics in the home environment. Method Thirty-two children (ages of 7–11 years) including 16 children with primary GAD and 16 controls receiving no psychotropic medications were studied. The anxious group had a primary diagnosis of GAD without secondary mood disorders and controls were free of any medical or psychiatric diagnoses. All participants underwent structured diagnostic assessments and completed one night of home-based polysomnography (PSG). Results Children with GAD exhibited significantly higher sleep efficiency (SE) and fewer rapid eye movement (REM) sleep periods compared to controls. Self-reported somatic arousal during the pre-sleep period was negatively correlated with the percentage of total REM sleep among controls, but positively correlated with REM sleep percentage in the GAD group. Limitations A small sample size and one night of PSG only. Conclusions Home-based PSG recording do not provide evidence of disrupted sleep patterns in children with GAD. Contextual factors that better elucidate differences between laboratory and home-based sleep findings are suggested as important directions for future research. PMID:24751311

  6. Influence of light on the free amino acid content and γ-aminobutyric acid synthesis in Brassica juncea seedlings.

    PubMed

    Li, Xiaohua; Kim, Yeon Bok; Uddin, Md Romij; Lee, Sanghyun; Kim, Sun-Ju; Park, Sang Un

    2013-09-11

    Glutamate decarboxylase (GAD; EC 4.1.1.15) is an important enzyme in γ-aminobutyric acid (GABA) biosynthesis. Here we report the influence of light on amino acid accumulation and investigate the molecular mechanism by which light influences GABA biosynthesis at the seedling stage of two mustard (Brassica juncea) cultivars (green-leaf and purple-leaf). Gene expression profiles of four GAD-encoding genes (GAD1, GAD2, GAD4a, and GAD4b) and their impact on GABA biosynthesis were analyzed. Light exerted an obvious influence on amino acid accumulation in mustard seedlings. GAD gene expression was also significantly regulated by light/dark or dark treatment, which differentially regulated GABA biosynthesis in B. juncea seedlings. High-performance liquid chromatography (HPLC) revealed that the seeds of purple cultivars contain a higher amount of free amino acids and GABA than do the seeds of green cultivars. After seed germination, however, the accumulation of free amino acids peaked in dark-treated seedlings on day 9 in both cultivars, whereas GABA synthesis peaked at 9 days under light conditions. This study may provide a foundation for understanding the effect of light on amino acids, particularly GABA biosynthesis in Brassica plants. PMID:23909820

  7. 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

  8. Glutamic acid decarboxylase activity is stimulated in quail retina neuronal cells transformed by Rous sarcoma virus and is regulated by pp60v-src.

    PubMed Central

    Crisanti, P; Lorinet, A M; Calothy, G; Pessac, B

    1985-01-01

    Rous sarcoma virus (RSV) stimulates in quail embryo neuro-retina (NR) cultures the specific activity of glutamic acid decarboxylase (GAD), the enzyme responsible for the synthesis of gamma-aminobutyric acid, a major inhibitory neurotransmitter in NR and in central nervous system. In quail embryo NR cultures transformed by ts NY-68, a thermodependent transformation-defective mutant of RSV, stimulation of GAD activity is regulated by pp60v-src, the product of the src gene of RSV. Fibroblasts and myoblasts have a very low GAD activity that is not stimulated after transformation by RSV. Neuronal clones, previously derived from ts NY-68-transformed established NR cell lines, have a high GAD activity which is regulated by pp60v-src, while other clones have a low GAD activity apparently not regulated by pp60v-src. These data indicate that pp60v-src selectively activates the expression of GAD in distinct neuronal cells of quail embryo NR cultures transformed by RSV. GAD activity is also stimulated in NR cells infected with viruses containing v-mil. PMID:2992933

  9. 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. PMID:26279129

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

    PubMed

    Marganska, Anna; Gallagher, Michelle; Miranda, Regina

    2013-01-01

    Differences in attachment style have been linked to both emotion regulation and psychological functioning, but the emotion regulatory mechanism through which attachment style might impact symptoms of depression and anxiety is unclear. The present study examined the explanatory role of emotion dysregulation in the relation between adult attachment style and symptoms of depression and generalized anxiety disorder (GAD) in a sample of 284 adults. Secure attachment was associated with lower depression and GAD symptoms and lower emotion dysregulation, whereas insecure attachment styles were generally associated with higher depression and GAD scores and higher emotion dysregulation. Perceived inability to generate effective emotion regulation strategies mediated the relation between insecure attachment and both depression and GAD symptoms. Nonacceptance of negative emotions and inability to control impulsive behaviors emerged as additional mediators of the relation between insecure attachment styles and GAD symptoms. The differential contribution of attachment style and emotion regulation to the prediction of depression and GAD symptoms may reflect differences in vulnerability to depression and GAD. PMID:23330631

  11. Comparison of spiritual well-being and coping strategies of patients with generalized anxiety disorder and with minor general medical conditions.

    PubMed

    Amjad, Faiza; Bokharey, Iram Zehra

    2015-04-01

    The purpose of the present study was to compare the spiritual well-being and coping strategies of patients with generalized anxiety disorder (GAD) and those with general medical conditions (GMC). The sample was comprised of 40 participants with GAD fulfilling the diagnostic criteria of DSM IV-TR and 50 participants with GMC. The descriptive statistics, correlation analysis and independent sample t test were used for data analysis. The results revealed the significant negative correlation of spiritual wellness with GAD symptoms and positive correlation between spiritual wellness, active practical and religious-focused coping strategies. The independent sample t test showed that spiritual wellness of participants with GMC was higher than participants with GAD. Moreover, out of 13 dimensions of spiritual wellness inventory, the scores of participants with minor general medical conditions in the dimensions of conception of divinity, present centeredness, hope, forgiveness, conscientiousness and spiritual freedom remained significantly higher than those with GAD. The participants with GMC used more active practical coping strategies and religious-focused coping strategies than participants with GAD. There was no difference between two groups of participants in using active distracting coping strategies, while avoidance-focused coping strategies were used by participants with GAD more than those with GMC. PMID:24535043

  12. 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. PMID:23397694

  13. 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. PMID:26708039

  14. Dopamine up-regulates Th17 phenotype from individuals with generalized anxiety disorder.

    PubMed

    Ferreira, Thais B; Kasahara, Taissa M; Barros, Priscila O; Vieira, Morgana M M; Bittencourt, Vera Carolina B; Hygino, Joana; Andrade, Regis M; Linhares, Ulisses C; Andrade, Arnaldo F; Bento, Cleonice A

    2011-09-15

    Our objective was to evaluate the effect of stress-related dose of dopamine (DA) on the in vitro proliferation and cytokine production in polyclonally-activated T cells from healthy individuals or individuals with generalized anxiety disorder (GAD). Our results demonstrated that cell cultures from GAD group proliferated less following T cell activation, as compared with control group. The addition of DA reduced the proliferative response in cell cultures from healthy but not from GAD individuals. The cytokine profile in GAD individuals revealed Th1 and Th2 deficiencies associated with a dominant Th17 phenotype, which was enhanced by DA. A similar DA-induced immunomodulation was also observed in PPD-activated cell cultures from GAD individuals. Unlike the control, DA-enhanced Th17 cytokine production in GAD individuals was not affected by glucocorticoid. In conclusion, our results show that the T cell functional dysregulation in GAD individuals is significantly amplified by DA. These immune abnormalities can have impact in increasing the susceptibility of individuals with anxiety disorders to infectious diseases and inflammatory/autoimmune disorders. PMID:21872345

  15. Structure-function relationships in histidine-rich antimicrobial peptides from Atlantic cod.

    PubMed

    McDonald, Mark; Mannion, Michael; Pike, Damien; Lewis, Krystina; Flynn, Andrew; Brannan, Alex M; Browne, Mitchell J; Jackman, Donna; Madera, Laurence; Power Coombs, Melanie R; Hoskin, David W; Rise, Matthew L; Booth, Valerie

    2015-07-01

    Gad-1 and Gad-2 are antimicrobial peptide (AMP) sequences encoded by paralogous genes. They are rich in histidine, which suggests that their activity might be pH-dependent. We examined their structure-function relationships with a view to learning how to improve AMP therapeutic ratios. Activity assays with Gram-negative bacteria and cancer cell lines demonstrate that Gad-2 is substantially more active at slightly acidic pH than it is at neutral pH. By contrast, the activity of Gad-1 at lower pH is similar to its activity at pH7. Circular dichroism spectra indicate that the greater functional plasticity of Gad-2 correlates with a greater structural plasticity; Gad-2's percent helicity varies dramatically with altered pH and lipid environment. Interestingly, Gad-2's highest levels of helicity do not correspond to the conditions where it is most active. High resolution solution NMR structures were determined in SDS micelles at pH5, conditions that induce an intermediate level of helicity in the peptides. Gad-1 is more helical than Gad-2, with both peptides exhibiting the greatest helical tendencies in their central region and lowest helicity in their N-termini. The high resolution structures suggest that maximum activity relies on the appropriate balance between an N-terminal region with mixed hydrophobic/hydrophilic structure features and an amphipathic central and C-terminal region. Taken together with previous studies, our results suggest that to improve the therapeutic ratio of AMPs, consideration should be given to including sequential histidine-pairs, keeping the overall charge of the peptide modest, and retaining a degree of structural plasticity and imperfect amphipathicity. PMID:25839356

  16. Symptoms of Generalised Anxiety disorder but not Panic Disorder at age 15 increase the risk of depression at 18 in the ALSPAC cohort study

    PubMed Central

    Davies, Simon J C; Pearson, Rebecca; Stapinski, Lexine; Bould, Helen; Christmas, David M; Button, Katherine S; Skapinakis, Petros; Lewis, Glyn; Evans, Jonathan

    2016-01-01

    Background Generalised Anxiety Disorder (GAD) and Panic Disorder (PD) differ in their biology and co-morbidities. We hypothesised that GAD but not PD symptoms at 15 are associated with depression diagnosis at 18. Methods Using longitudinal data from the ALSPAC birth cohort we examined relations of GAD and PD symptoms (measured by DAWBA) at 15 to depression at 18 (by CIS-R) using logistic regression. We excluded adolescents already depressed at 15 and adjusted for social class, maternal education, birth order, gender, alcohol intake and smoking. We repeated these analyses following multiple imputation for missing data. Results In the sample with complete data (n=2835), high and moderate GAD symptoms in adolescents not depressed at 15, were associated with increased risk of depression at 18 both in unadjusted analyses and adjusting for PD symptoms at 15 and the above potential confounders. The adjusted OR for depression at 18 in adolescents with high relative to low GAD scores was 5.2 [95% C.I. 3.0 - 9.1; overall p<0.0001]. There were no associations between PD symptoms and depression at 18 in any model (high relative to low PD scores, adjusted OR= 1.3 [95% C.I. 0.3 - 4.8], overall p=0.737). Missing data imputation strengthened the relations of GAD symptoms with depression (high relative to low GAD scores, OR= 6.2, [95% C.I. 3.9 - 9.9]) but those for PD became weaker. Conclusion Symptoms of GAD but not PD at 15 are associated with depression at 18. Clinicians should be aware that adolescents with GAD symptoms may develop depression. PMID:26315278

  17. Cortical Gene Expression After a Conditional Knockout of 67 kDa Glutamic Acid Decarboxylase in Parvalbumin Neurons.

    PubMed

    Georgiev, Danko; Yoshihara, Toru; Kawabata, Rika; Matsubara, Takurou; Tsubomoto, Makoto; Minabe, Yoshio; Lewis, David A; Hashimoto, Takanori

    2016-07-01

    In the cortex of subjects with schizophrenia, expression of glutamic acid decarboxylase 67 (GAD67), the enzyme primarily responsible for cortical GABA synthesis, is reduced in the subset of GABA neurons that express parvalbumin (PV). This GAD67 deficit is accompanied by lower cortical levels of other GABA-associated transcripts, including GABA transporter-1, PV, brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B, somatostatin, GABAA receptor α1 subunit, and KCNS3 potassium channel subunit mRNAs. In contrast, messenger RNA (mRNA) levels for glutamic acid decarboxylase 65 (GAD65), another enzyme for GABA synthesis, are not altered. We tested the hypothesis that this pattern of GABA-associated transcript levels is secondary to the GAD67 deficit in PV neurons by analyzing cortical levels of these GABA-associated mRNAs in mice with a PV neuron-specific GAD67 knockout. Using in situ hybridization, we found that none of the examined GABA-associated transcripts had lower cortical expression in the knockout mice. In contrast, PV, BDNF, KCNS3, and GAD65 mRNA levels were higher in the homozygous mice. In addition, our behavioral test battery failed to detect a change in sensorimotor gating or working memory, although the homozygous mice exhibited increased spontaneous activities. These findings suggest that reduced GAD67 expression in PV neurons is not an upstream cause of the lower levels of GABA-associated transcripts, or of the characteristic behaviors, in schizophrenia. In PV neuron-specific GAD67 knockout mice, increased levels of PV, BDNF, and KCNS3 mRNAs might be the consequence of increased neuronal activity secondary to lower GABA synthesis, whereas increased GAD65 mRNA might represent a compensatory response to increase GABA synthesis. PMID:26980143

  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

    2015-01-01

    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. PMID:25826111

  19. Glutamate Decarboxylase-Dependent Acid Resistance in Brucella spp.: Distribution and Contribution to Fitness under Extremely Acidic Conditions

    PubMed Central

    Damiano, Maria Alessandra; Bastianelli, Daniela; Al Dahouk, Sascha; Köhler, Stephan; Cloeckaert, Axel

    2014-01-01

    Brucella is an expanding genus of major zoonotic pathogens, including at least 10 genetically very close species occupying a wide range of niches from soil to wildlife, livestock, and humans. Recently, we have shown that in the new species Brucella microti, the glutamate decarboxylase (Gad)-dependent system (GAD system) contributes to survival at a pH of 2.5 and also to infection in mice by the oral route. In order to study the functionality of the GAD system in the genus Brucella, 47 isolates, representative of all known species and strains of this genus, and 16 strains of the closest neighbor genus, Ochrobactrum, were studied using microbiological, biochemical, and genetic approaches. In agreement with the genome sequences, the GAD system of classical species was not functional, unlike that of most strains of Brucella ceti, Brucella pinnipedialis, and newly described species (B. microti, Brucella inopinata BO1, B. inopinata-like BO2, and Brucella sp. isolated from bullfrogs). In the presence of glutamate, these species were more acid resistant in vitro than classical terrestrial brucellae. Expression in trans of the gad locus from representative Brucella species in the Escherichia coli MG1655 mutant strain lacking the GAD system restored the acid-resistant phenotype. The highly conserved GAD system of the newly described or atypical Brucella species may play an important role in their adaptation to acidic external and host environments. Furthermore, the GAD phenotype was shown to be a useful diagnostic tool to distinguish these latter Brucella strains from Ochrobactrum and from classical terrestrial pathogenic Brucella species, which are GAD negative. PMID:25381237

  20. Refractory status epilepticus and glutamic acid decarboxylase antibodies in adults: presentation, treatment and outcomes.

    PubMed

    Khawaja, Ayaz M; Vines, Brannon L; Miller, David W; Szaflarski, Jerzy P; Amara, Amy W

    2016-03-01

    Glutamic acid decarboxylase antibodies (GAD-Abs) have been implicated in refractory epilepsy. The association with refractory status epilepticus in adults has been rarely described. We discuss our experience in managing three adult patients who presented with refractory status epilepticus associated with GAD-Abs. Case series with retrospective chart and literature review. Three patients without pre-existing epilepsy who presented to our institution with generalized seizures between 2013 and 2014 were identified. Seizures proved refractory to first and second-line therapies and persisted beyond 24 hours. Patient 1 was a 22-year-old female who had elevated serum GAD-Ab titres at 0.49 mmol/l (normal: <0.02) and was treated with multiple immuno- and chemotherapies, with eventual partial seizure control. Patient 2 was a 61-year-old black female whose serum GAD-Ab titre was 0.08 mmol/l. EEG showed persistent generalized periodic discharges despite maximized therapy with anticonvulsants but no immunotherapy, resulting in withdrawal of care and discharge to nursing home. Patient 3 was a 50-year-old black female whose serum GAD-Ab titre was 0.08 mmol/l, and was discovered to have pulmonary sarcoidosis. Treatment with steroids and intravenous immunoglobulin resulted in seizure resolution. Due to the responsiveness to immunotherapy, there may be an association between GAD-Abs and refractory seizures, including refractory status epilepticus. Causation cannot be established since GAD-Abs may be elevated secondary to concurrent autoimmune diseases or formed de novo in response to GAD antigen exposure by neuronal injury. Based on this report and available literature, there may be a role for immuno- and chemotherapy in the management of refractory status epilepticus associated with GAD-Abs. PMID:26878120

  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. Threshold and subthreshold generalized anxiety disorder among US adolescents: prevalence, sociodemographic, and clinical characteristics

    PubMed Central

    Burstein, M.; Beesdo-Baum, K.; He, J.-P.; Merikangas, K. R.

    2014-01-01

    Background Threshold and subthreshold forms of generalized anxiety disorder (GAD) are highly prevalent and impairing conditions among adults. However, there are few general population studies that have examined these conditions during the early life course. The primary objectives of this study were to: (1) examine the prevalence, and sociodemographic and clinical characteristics of threshold and subthreshold forms of GAD in a nationally representative sample of US youth; and (2) test differences in sociodemographic and clinical characteristics between threshold and subthreshold forms of the disorder. Method The National Comorbidity Survey-Adolescent Supplement is a nationally representative face-to-face survey of 10123 adolescents 13 to 18 years of age in the continental USA. Results Approximately 3% of adolescents met criteria for threshold GAD. Reducing the required duration from 6 months to 3 months resulted in a 65.7% increase in prevalence (5.0%); further relaxing the uncontrollability criterion led to an additional 20.7% increase in prevalence (6.1%). Adolescents with all forms of GAD displayed a recurrent clinical course marked by substantial impairment and co-morbidity with other psychiatric disorders. There were few significant differences in sociodemographic and clinical characteristics between threshold and subthreshold cases of GAD. Results also revealed age-related differences in the associated symptoms and clinical course of GAD. Conclusions Findings demonstrate the clinical significance of subthreshold forms of GAD among adolescent youth, highlighting the continuous nature of the GAD construct. Age-related differences in the associated symptoms and clinical course of GAD provide further support for criteria that capture variation in clinical features across development. PMID:24384401

  3. Distinguished Visitors to Paranal

    NASA Astrophysics Data System (ADS)

    Boffin, Henri; Madsen, Claus

    2007-12-01

    As part of his first official trip to Brazil and Chile, the European Science and Research Commissioner, Janez Potocnik, visited the ESO Paranal Observatory on 27 November. The Commissioner was accompanied by, among others, Jaime Pérez Vidal, Head of the Delegation of the European Commission (EC) to Chile, Mary Minch and Cornelia Nauen, respectively Director and Principal Administrator of International Scientific Cooperation for the EC, and Hervé Peró, Head of EC Unit Research Infrastructures.

  4. 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,...

  5. 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. PMID:25100431

  6. Appraisal of activating thoughts in generalized anxiety disorder.

    PubMed

    Upatel, Tanja; Gerlach, Alexander L

    2008-09-01

    Worrying may be an avoidance behaviour preventing the discomfort of imagining future threats. To study the link between phasic physiological activation and thought contents, we recruited 32 generalized anxiety disorder (GAD) patients and 31 controls and asked them to report whatever was in their mind just prior to whenever they were prompted. Half of 20 prompts were triggered by non-specific skin conductance fluctuations (activating thoughts). Controls judged activating thoughts as being less pleasant. GAD participants judged activating thoughts as more anxiety provoking, less relaxing and less controllable. Not the level of activation but the appraisal of activating thoughts in a catastrophic fashion differentiates GAD patients from controls. PMID:17900526

  7. [Neurons with Different Neurotransmitters in Embryonic Neocortical Allografts in the Rat Sciatic Nerve].

    PubMed

    Petrova, E S

    2016-01-01

    Different subsets of interneurons in the Wistar rat neocortex and in neocortical transplants developing in a damaged nerve were identified by the following immunohistochemical markers: glutamate decarboxylase (GAD 67) for GABAergic nerve cells, NO-synthase (NOS) for NO-ergic neurons, choline acetyltransferase (ChAT) for cholinergic cells, and tyrosine hydroxylase for catecholaminergic structures. Twenty-eight days after surgery, individual GAD 67-ir, NO-ir, ChAT-ir, and very rarely TH-ir cells were detected in the graft. It was shown that the number of GAD 67-ir neurons per unit area in the grafts was less than in the rat neocortex P20. PMID:27396173

  8. 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

  9. Expression, immobilization and enzymatic properties of glutamate decarboxylase fused to a cellulose-binding domain.

    PubMed

    Park, Hyemin; Ahn, Jungoh; Lee, Juwhan; Lee, Hyeokwon; Kim, Chunsuk; Jung, Joon-Ki; Lee, Hongweon; Lee, Eun Gyo

    2012-01-01

    Escherichia coli-derived glutamate decarboxylase (GAD), an enzyme that catalyzes the conversion of glutamic acid to gamma-aminobutyric acid (GABA), was fused to the cellulose-binding domain (CBD) and a linker of Trichoderma harzianum endoglucanase II. To prevent proteolysis of the fusion protein, the native linker was replaced with a S(3)N(10) peptide known to be completely resistant to E. coli endopeptidase. The CBD-GAD expressed in E. coli was successfully immobilized on Avicel, a crystalline cellulose, with binding capacity of 33 ± 2 nmol(CBD-GAD)/g(Avicel) and the immobilized enzymes retained 60% of their initial activities after 10 uses. The results of this report provide a feasible alternative to produce GABA using immobilized GAD through fusion to CBD. PMID:22312257

  10. A New Health Perk for Coffee Drinkers?

    MedlinePlus

    ... the coffee that are released in the roasting process," said senior researcher Dr. Gad Rennert. He is director of the Clalit National Israeli Cancer Control Center in Haifa, Israel. These findings can't ...

  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. PMID:27019339

  12. Studying Anxiety Disorders | NIH MedlinePlus the Magazine

    MedlinePlus

    ... page please turn Javascript on. Feature: Phobias and Anxiety Disorders Studying Anxiety Disorders Past Issues / Fall 2010 Table of Contents ... physical and psychological stress, and diet. 5 Major Anxiety Disorders Generalized Anxiety Disorder (GAD) : chronic anxiety, exaggerated ...

  13. 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. PMID:24977366

  14. Intrathecal-specific glutamic acid decarboxylase antibodies at low titers in autoimmune neurological disorders.

    PubMed

    Sunwoo, Jun-Sang; Chu, Kon; Byun, Jung-Ick; Moon, Jangsup; Lim, Jung-Ah; Kim, Tae-Joon; Lee, Soon-Tae; Jung, Keun-Hwa; Park, Kyung-Il; Jeon, Daejong; Jung, Ki-Young; Kim, Manho; Lee, Sang Kun

    2016-01-15

    Autoantibodies to glutamic acid decarboxylase (Gad-Abs) are implicated in various neurological syndromes. The present study aims to identify intrathecal-specific GAD-Abs and to determine clinical manifestations and treatment outcomes. Nineteen patients had GAD-Abs in cerebrospinal fluid but not in paired serum samples. Neurological syndromes included limbic encephalitis, temporal lobe epilepsy, cerebellar ataxia, autonomic dysfunction, and stiff-person syndrome. Immunotherapy had beneficial effects in 57.1% of patients, and the patients with limbic encephalitis responded especially well to immunotherapy. Intrathecal-specific antibodies to GAD at low titers may appear as nonspecific markers of immune activation within the central nervous system rather than pathogenic antibodies causing neuronal dysfunction. PMID:26711563

  15. Generalized anxiety disorder - self-care

    MedlinePlus

    ... medium- to long-term treatment for GAD. A benzodiazepine, which acts faster than an antidepressant to control ... effective over time. Your provider may prescribe a benzodiazepine to help your anxiety while you wait for ...

  16. Generalized anxiety disorder

    MedlinePlus

    GAD; Anxiety disorder ... you can help yourself get better by: Reducing caffeine Not using street drugs or large amounts of ... a helpful addition. Resources for more information include: Anxiety and Depression Association of America: www.adaa.org ...

  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. 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

  19. 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. PMID:25689246

  20. 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

  1. Vitamin D receptor initiation codon polymorphism influences genetic susceptibility to type 1 diabetes mellitus in the Japanese population

    PubMed Central

    Ban, Yoshiyuki; Taniyama, Matsuo; Yanagawa, Tatsuo; Yamada, Satoru; Maruyama, Taro; Kasuga, Akira; Ban, Yoshio

    2001-01-01

    Background Vitamin D has been shown to exert manifold immunomodulatory effects. Type 1 diabetes mellitus (T1DM) is regarded to be immune-mediated and vitamin D prevents the development of diabetes in the NOD mouse. We studied the association between T1DM and the initiation codon polymorphism in exon 2 of the vitamin D receptor gene in a Japanese population. We also investigated associations between the vitamin D receptor polymorphism and GAD65-antibody (Ab) positivity. We carried out polymerase chain reaction-restriction fragment length polymorphism analysis in 110 Japanese T1DM patients and 250 control subjects. GAD65 antibodies were assessed in 78 patients with T1DM. Results We found a significantly higher prevalence of the F allele / the FF genotype in the patients compared to the controls (P = 0.0069 and P = 0.014, respectively). Genotype and allele frequencies differed significantly between GAD65-Ab-positive patients and controls (P = 0.017 and P = 0.012, respectively), but neither between GAD65-Ab-negative patients and controls (P = 0.68 and P = 0.66, respectively) nor between GAD65-Ab-positive and -negative patients (P = 0.19 and P = 0.16, respectively). Conclusions Our findings suggest that the vitamin D receptor initiation codon polymorphism influences genetic susceptibility to T1DM among the Japanese. This polymorphism is also associated with GAD65-Ab-positive T1DM, although the absence of a significant difference between GAD65-Ab-negative patients and controls might be simply due to the small sample size of patients tested for GAD65 antibodies. PMID:11445000

  2. Lower Expression of Glutamic Acid Decarboxylase 67 in the Prefrontal Cortex in Schizophrenia: Contribution of Altered Regulation by Zif268

    PubMed Central

    Kimoto, Sohei; Bazmi, H. Holly; Lewis, David A.

    2015-01-01

    Objective Cognitive deficits of schizophrenia may be due at least in part to lower expression of the 67-kDa isoform of glutamic acid decarboxylase (GAD67), a key enzyme for GABA synthesis, in the dorsolateral prefrontal cortex of individuals with schizophrenia. However, little is known about the molecular regulation of lower cortical GAD67 levels in schizophrenia. The GAD67 promoter region contains a conserved Zif268 binding site, and Zif268 activation is accompanied by increased GAD67 expression. Thus, altered expression of the immediate early gene Zif268 may contribute to lower levels of GAD67 mRNA in the dorsolateral prefrontal cortex in schizophrenia. Method The authors used polymerase chain reaction to quantify GAD67 and Zif268 mRNA levels in dorsolateral pre-frontal cortex area 9 from 62 matched pairs of schizophrenia and healthy comparison subjects, and in situ hybridization to assess Zif268 expression at laminar and cellular levels of resolution. The effects of potentially confounding variables were assessed in human subjects, and the effects of antipsychotic treatments were tested in antipsychotic-exposed monkeys. The specificity of the Zif268 findings was assessed by quantifying mRNA levels for other immediate early genes. Results GAD67 and Zif268 mRNA levels were significantly lower and were positively correlated in the schizophrenia subjects. Both Zif268 mRNA-positive neuron density and Zif268 mRNA levels per neuron were significantly lower in the schizophrenia subjects. These findings were robust to the effects of the confounding variables examined and differed from other immediate early genes. Conclusions Deficient Zif268 mRNA expression may contribute to lower cortical GAD67 levels in schizophrenia, suggesting a potential mechanistic basis for altered cortical GABA synthesis and impaired cognition in schizophrenia. PMID:24874453

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

    PubMed

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

    2015-07-01

    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

  4. Brain structural abnormalities in patients with major depression with or without generalized anxiety disorder comorbidity.

    PubMed

    Canu, Elisa; Kostić, Milutin; Agosta, Federica; Munjiza, Ana; Ferraro, Pilar M; Pesic, Danilo; Copetti, Massimiliano; Peljto, Amir; Lecic Tosevski, Dusica; Filippi, Massimo

    2015-05-01

    An overlap frequently occurs between major depression disorder (MDD) and generalized anxiety disorder (GAD). Aim of this study was to assess cortical and white matter (WM) alterations in MDD patients with or without GAD comorbidity. Seventy-one MDD patients and 71 controls were recruited. All subjects underwent T1-weighted and diffusion tensor (DT)/MRI. MRI metrics of cortical thickness and WM integrity were obtained from atlas-based cortical regions and the interhemispheric and major long association WM tracts. Between-group MRI comparisons and multiple regressions with clinical scale scores were performed. Compared to controls, both MDD and MDD-GAD patients showed a cortical thinning of the middle frontal cortex bilaterally, left medial frontal gyrus and frontal pole. Compared to controls and MDD patients, MDD-GAD cases also showed a thinning of the right medial orbitofrontal and fusiform gyri, and left temporal pole and lateral occipital cortices. Compared to controls, MDD patients showed DT MRI abnormalities of the right parahippocampal tract and superior longitudinal fasciculus bilaterally, while no WM alterations were found in MDD-GAD. In all patients, brain abnormalities were related with symptom severity. MDD and MDD-GAD share a common pattern of cortical alterations located in the frontal regions. However, while both the cortex and WM integrity are affected in MDD, only the former is affected in MDD-GAD. These findings support the notion of MDD-GAD as a distinct clinical entity, providing insights into patient vulnerability for specific networks as well as into patient resilience factors reflected by the integrity of other cerebral circuits. PMID:25794861

  5. Factorial invariance of the Patient Health Questionnaire and Generalized Anxiety Disorder Questionnaire

    PubMed Central

    Ryan, Travis A; Bailey, Alastair; Fearon, Pasco; King, John

    2013-01-01

    Objectives The UK's Improving Access to Psychological Therapies (IAPT) programme uses the Patient Health Questionnaire Depression Scale (PHQ-9; Kroenke, Spitzer, & Williams, 2001, J. Gen. Intern. Med., 16, 606) and Generalized Anxiety Disorder Scale (GAD-7; Spitzer et al., 2006, Arch. Intern. Med., 166, 1092) to assess patients' symptoms of depression and anxiety respectively. Data are typically collected via telephone or face-to-face; however, no study has statistically investigated whether the questionnaires' items operate equivalently across these modes of data collection. This study aimed to address this omission. Methods & Results Questionnaire data from patients registered with an IAPT service in London (N = 23,672) were examined. Confirmatory factor analyses suggested that unidimensional factor structures adequately matched observed face-to-face and telephone data for the PHQ-9 and GAD-7. Invariance analyses revealed that while the PHQ-9 had equivalent factor loadings and latent means across data collection methods, the GAD-7 had equivalent factor loadings but unequal latent means. In support of the scales' convergent validity, positive associations between scores on the PHQ-9 and GAD-7 emerged. Conclusions With the exception of the GAD-7's latent means, the questionnaires' factor loadings and latent means were equivalent. This suggests that clinicians may meaningfully compare PHQ-9 data collected face-to-face and by telephone; however, such comparisons with the GAD-7 should be done with caution. Practitioner points The PHQ-9 and GAD-7's factor loadings were equivalent across data collection methods. Only the PHQ-9's latent means were equivalent across data collection methods. Clinicians may be confident collecting PHQ-9 data by telephone and face-to-face and, then, comparing such data. Caution is recommended when determining clinical effectiveness using telephone and face-to-face GAD-7 data. More psychometric research is warranted. PMID:24117915

  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. PMID:26386700

  7. The Impact of British Airways Wind Observations on the Goddard Earth Observing System Analyses and Forecasts

    NASA Technical Reports Server (NTRS)

    Rukhovets, Leonid; Sienkiewicz, M.; Tenenbaum, J.; Kondratyeva, Y.; Owens, T.; Oztunali, M.; Atlas, Robert (Technical Monitor)

    2001-01-01

    British Airways flight data recorders can provide valuable meteorological information, but they are not available in real-time on the Global Telecommunication System. Information from the flight recorders was used in the Global Aircraft Data Set (GADS) experiment as independent observations to estimate errors in wind analyses produced by major operational centers. The GADS impact on the Goddard Earth Observing System Data Assimilation System (GEOS DAS) analyses was investigated using GEOS-1 DAS version. Recently, a new Data Assimilation System (fvDAS) has been developed at the Data Assimilation Office, NASA Goddard. Using fvDAS , the, GADS impact on analyses and forecasts was investigated. It was shown the GADS data intensify wind speed analyses of jet streams for some cases. Five-day forecast anomaly correlations and root mean squares were calculated for 300, 500 hPa and SLP for six different areas: Northern and Southern Hemispheres, North America, Europe, Asia, USA These scores were obtained as averages over 21 forecasts from January 1998. Comparisons with scores for control experiments without GADS showed a positive impact of the GADS data on forecasts beyond 2-3 days for all levels at the most areas.

  8. Cognitive load and emotional processing in Generalized Anxiety Disorder: Electrocortical evidence for increased distractibility

    PubMed Central

    MacNamara, Annmarie; Proudfit, Greg Hajcak

    2014-01-01

    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 to 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. PMID:24933276

  9. Non-convulsive status epilepticus associated with glutamic acid decarboxylase antibody.

    PubMed

    Cikrikçili, Ugur; Ulusoy, Canan; Turan, Selin; Yildiz, Senay; Bilgiç, Basar; Hanagasi, Hasmet; Baykan, Betül; Tüzün, Erdem; Gürvit, Hakan

    2013-07-01

    Autoimmune encephalitis associated with glutamic acid decarboxylase antibodies (GAD-Ab) often presents with treatment-resistant partial seizures, as well as other central nervous system symptoms. In contrast to several other well-characterized autoantibodies, GAD-Ab has very rarely been associated with status epilepticus. We report a 63-year-old woman initially admitted with somnolence and psychiatric findings. The EEG findings, of generalized and rhythmical slow spike-wave activity over the posterior regions of both hemispheres, together with the clinical deterioration in responsiveness, led to the diagnosis of non-convulsive status epilepticus. Investigation of a broad panel of autoantibodies, revealed only increased serum GAD-Ab levels. Following methylprednisolone and intravenous immunoglobulin treatments, the patient's neurological symptoms improved, EEG findings disappeared and GAD-Ab levels significantly decreased. GAD-Ab should be added to the list of anti-neuronal antibodies associated with non-convulsive status epilepticus. Disappearance of clinical findings and seroreversion after immunotherapy suggest that GAD-Ab might be involved in seizure pathogenesis.  PMID:23820312

  10. Are attentional control resources reduced by worry in generalized anxiety disorder?

    PubMed

    Stefanopoulou, Evgenia; Hirsch, Colette R; Hayes, Sarra; Adlam, Anna; Coker, Sian

    2014-05-01

    This is the first study to examine attentional control capacities in generalized anxiety disorder (GAD). GAD is characterized by uncontrollable worry. Individuals diagnosed with GAD and healthy participants (HPs) performed a random key-pressing task while thinking about a worrisome or a positive future event, to assess the extent to which attentional control resources are used by worry. Attentional control was also assessed when participants were not instructed to think about a specific topic using the N-back task, which varies in task difficulty, and therefore is sensitive to subtle differences in ability to handle increasing demands on attentional control within the same paradigm. GAD participants (but not HPs) were less random while worrying than thinking about a positive event during the key-pressing task, suggesting that worry consumed more attentional control resources in this population. During the N-Back task, GAD participants performed worse than HPs during the high load conditions only, indicating greater difficulty in sustaining focus on conditions requiring a higher degree of attentional control, even without concurrent task activity. Poor attentional control might underpin the difficulty of GAD individuals to stop worrying and switch to thinking more benign information. Further research could investigate whether worry consumes attentional control resources in other psychological disorders with high rates of worry (e.g., panic disorder, psychosis), as well as the extent to which attentional control is used by other forms of repetitive thinking, such as depressive rumination. PMID:24886007

  11. 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

  12. Disruption of pknG enhances production of gamma-aminobutyric acid by Corynebacterium glutamicum expressing glutamate decarboxylase

    PubMed Central

    2014-01-01

    Gamma-aminobutyric acid (GABA), a building block of the biodegradable plastic polyamide 4, is synthesized from glucose by Corynebacterium glutamicum that expresses Escherichia coli glutamate decarboxylase (GAD) B encoded by gadB. This strain was engineered to produce GABA more efficiently from biomass-derived sugars. To enhance GABA production further by increasing the intracellular concentration of its precursor glutamate, we focused on engineering pknG (encoding serine/threonine protein kinase G), which controls the activity of 2-oxoglutarate dehydrogenase (Odh) in the tricarboxylic acid cycle branch point leading to glutamate synthesis. We succeeded in expressing GadB in a C. glutamicum strain harboring a deletion of pknG. C. glutamicum strains GAD and GAD ∆pknG were cultured in GP2 medium containing 100 g L−1 glucose and 0.1 mM pyridoxal 5′-phosphate. Strain GAD∆pknG produced 31.1 ± 0.41 g L−1 (0.259 g L−1 h−1) of GABA in 120 hours, representing a 2.29-fold higher level compared with GAD. The production yield of GABA from glucose by GAD∆pknG reached 0.893 mol mol−1. PMID:24949255

  13. A Randomized Controlled Trial of Ecological Momentary Intervention Plus Brief Group Therapy for Generalized Anxiety Disorder

    PubMed Central

    Newman, Michelle G.; Przeworski, Amy; Consoli, Andrés J.; Taylor, C. Barr

    2015-01-01

    Momentary intervention has been proposed as a cost-effective, generalizable, and ecologically valid method to increase the efficiency of face-to-face cognitive– behavioral therapy (CBT). The purpose of the current pilot study was to evaluate the efficacy of a six-session palmtop computer-assisted Group CBT for generalized anxiety disorder (GAD) (CAGT6) in comparison with a six-session Group CBT for GAD without the computer (CBGT6) and typical (12 session) Group CBT for GAD (CBGT12) in a randomized controlled trial. Thirty-four individuals with a primary diagnosis of GAD were randomized to one of the three conditions and completed measures of GAD and anxiety before therapy, after therapy, and at 6-, and 12-month follow-ups. Results indicated that CAGT6 was superior to CBGT6 at posttreatment, but not significantly different from CBGT12. At 6- and 12-month follow-ups, CAGT6 was neither significantly different from CBGT6, nor from CBGT12. Percentages of individuals achieving reliable change on two of the three GAD measures favored CAGT6 over CBGT6 at posttreatment, suggesting promise for the added value of the mobile technology. PMID:24059730

  14. Mediated Moderation in Combined Cognitive Behavioral Therapy Versus Component Treatments for Generalized Anxiety Disorder

    PubMed Central

    Newman, Michelle G.; Fisher, Aaron J.

    2015-01-01

    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 dynamic flexibility in daily symptoms was quantified as the inverse of spectral power due to daily to intradaily oscillations in four-times-daily diary data (Fisher, Newman, & Molenaar, 2011). Method This was a secondary analysis of the data of Borkovec, Newman, Pincus, and Lytle (2002). Seventy-six participants with a principle diagnosis of GAD were assigned randomly to combined CBT (n = 24), cognitive therapy (n = 25), or self-control desensitization (n = 27). Results Duration of GAD moderated outcome such that those with longer duration showed greater reliable change from component treatments than they showed from CBT, whereas those with shorter duration fared better in response to CBT. Decreasing predictability in daily and intradaily oscillations of anxiety symptoms during therapy reflected less rigidity and more flexible responding. Increases in flexibility over the course of therapy fully mediated the moderating effect of GAD duration on condition, indicating a mediated moderation process. Conclusions Individuals with longer duration of GAD may respond better to more focused treatments, whereas those with shorter duration of GAD may respond better to a treatment that offers more coping strategies. Importantly, the mechanism by which this moderation occurs appears to be the establishment of flexible responding during treatment. PMID:23398493

  15. 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. PMID:25623945

  16. Are Attentional Control Resources Reduced by Worry in Generalized Anxiety Disorder?

    PubMed Central

    2014-01-01

    This is the first study to examine attentional control capacities in generalized anxiety disorder (GAD). GAD is characterized by uncontrollable worry. Individuals diagnosed with GAD and healthy participants (HPs) performed a random key-pressing task while thinking about a worrisome or a positive future event, to assess the extent to which attentional control resources are used by worry. Attentional control was also assessed when participants were not instructed to think about a specific topic using the N-back task, which varies in task difficulty, and therefore is sensitive to subtle differences in ability to handle increasing demands on attentional control within the same paradigm. GAD participants (but not HPs) were less random while worrying than thinking about a positive event during the key-pressing task, suggesting that worry consumed more attentional control resources in this population. During the N-Back task, GAD participants performed worse than HPs during the high load conditions only, indicating greater difficulty in sustaining focus on conditions requiring a higher degree of attentional control, even without concurrent task activity. Poor attentional control might underpin the difficulty of GAD individuals to stop worrying and switch to thinking more benign information. Further research could investigate whether worry consumes attentional control resources in other psychological disorders with high rates of worry (e.g., panic disorder, psychosis), as well as the extent to which attentional control is used by other forms of repetitive thinking, such as depressive rumination. PMID:24886007

  17. Increased Error-Related Brain Activity Distinguishes Generalized Anxiety Disorder With and Without Comorbid Major Depressive Disorder

    PubMed Central

    Weinberg, Anna; Klein, Daniel N.; Hajcak, Greg

    2013-01-01

    Generalized anxiety disorder (GAD) and major depressive disorder (MDD) are so frequently comorbid that some have suggested that the 2 should be collapsed into a single overarching “distress” disorder. Yet there is also increasing evidence that the 2 categories are not redundant. Neurobehavioral markers that differentiate GAD and MDD would be helpful in ongoing efforts to refine classification schemes based on neurobiological measures. The error-related negativity (ERN) may be one such marker. The ERN is an event-related potential component presenting as a negative deflection approximately 50 ms following an erroneous response and reflects activity of the anterior cingulate cortex. There is evidence for an enhanced ERN in individuals with GAD, but the literature in MDD is mixed. The present study measured the ERN in 26 GAD, 23 comorbid GAD and MDD, and 36 control participants, all of whom were female and medication-free. Consistent with previous research, the GAD group was characterized by a larger ERN and an increased difference between error and correct trials than controls. No such enhancement was evident in the comorbid group, suggesting comorbid depression may moderate the relationship between the ERN and anxiety. The present study further suggests that the ERN is a potentially useful neurobiological marker for future studies that consider the pathophysiology of multiple disorders in order to construct or refine neurobiologically based diagnostic phenotypes. PMID:22564180

  18. Enhanced production of recombinant Escherichia coli glutamate decarboxylase through optimization of induction strategy and addition of pyridoxine.

    PubMed

    Su, Lingqia; Huang, Yan; Wu, Jing

    2015-12-01

    This report describes the optimization of recombinant Escherichia coli glutamate decarboxylase (GAD) production from engineered E. coli BL21(DE3) in a 3-L fermentor. Investigation of different induction strategies revealed that induction was optimal when the temperature was maintained at 30°C, the inducer (lactose) was fed at a rate of 0.2 g L(-1)h(-1), and protein expression was induced when the cell density (OD600) reached 50. Under these conditions, the GAD activity of 1273.8 U mL(-1) was achieved. Because GAD is a pyridoxal 5'-phosphate (PLP)-dependent enzyme, the effect of supplementing the medium with pyridoxine hydrochloride (PN), a cheap and stable PLP precursor, on GAD production was also investigated. When the culture medium was supplemented with PN to a concentration of 2mM at the initiation of protein expression, and then again 10h later, the GAD activity reached 3193.4 U mL(-1), which represented the highest GAD production ever reported. PMID:26364229

  19. 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. PMID:25863827

  20. Profile of agomelatine and its potential in the treatment of generalized anxiety disorder

    PubMed Central

    Levitan, Michelle Nigri; Papelbaum, Marcelo; Nardi, Antonio Egidio

    2015-01-01

    Background Although many generalized anxiety disorder (GAD) patients respond to the available pharmacological treatments, nearly half of them do not present the expected results. Besides, the side effects associated to some drugs have a negative impact on treatment adherence. Therefore, the aim of this review was to report the clinical profile of agomelatine, a selective melatonergic MT1/MT2 receptor agonist with serotonin 5-HT2c receptor antagonist activities, as a potential pharmacological option in the treatment of GAD. Methods We performed a literature review regarding studies that evaluated the use of agomelatine in GAD treatment. Results Two short-term, double-blinded studies and one prevention-treatment trial evaluated the efficacy of agomelatine in the treatment of GAD. Agomelatine was associated with higher rates of clinical response and remission, when compared to placebo. In addition, the long-term use of agomelatine decreased the risk of relapse of anxiety symptoms, even for the severely ill patients. Besides, the tolerability was satisfactory with the absence of discontinuation symptoms, as observed in previous studies. Conclusion The efficacy and tolerability profiles of agomelatine in the treatment of GAD were good. However, the scarce number of trials, the small sample sizes, and the use of patients without any comorbid conditions were some limitations that impaired the generalization of the results in the general population. Nevertheless, agomelatine is an attractive off-label option in the treatment of GAD that needs more conclusive evidences to establish its role in future guidelines. PMID:25999720

  1. The Relationship between Perceived Discrimination and Generalized Anxiety Disorder among African Americans, Afro Caribbeans and non-Hispanic Whites

    PubMed Central

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

    2010-01-01

    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 3,570 African Americans, 1,438 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. PMID:21041059

  2. Neurostructural abnormalities associated with axes of emotion dysregulation in generalized anxiety

    PubMed Central

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

    2015-01-01

    Background Despite the high prevalence of generalized anxiety disorder (GAD) and its negative impact on society, its neurobiology remains obscure. This study characterizes the neurostructural abnormalities associated with key symptoms of GAD, focusing on indicators of impaired emotion regulation (excessive worry, poor concentration, low mindfulness, and physiological arousal). Methods These domains were assessed in 19 (16 women) GAD patients and 19 healthy controls matched for age and gender, using questionnaires and a low demand behavioral task performed before and after an induction of perseverative cognition (i.e. worry and rumination). Continuous pulse oximetry was used to measure autonomic physiology (heart rate variability; HRV). Observed cognitive and physiological changes in response to the induction provided quantifiable data on emotional regulatory capacity. Participants underwent structural magnetic resonance imaging; voxel-based morphometry was used to quantify the relationship between gray matter volume and psychological and physiological measures. Results Overall, GAD patients had lower gray matter volume than controls within supramarginal, precentral, and postcentral gyrus bilaterally. Across the GAD group, increased right amygdala volume was associated with prolonged reaction times on the tracking task (indicating increased attentional impairment following the induction) and lower scores on the ‘Act with awareness’ subscale of the Five Facets Mindfulness Questionnaire. Moreover in GAD, medial frontal cortical gray matter volume correlated positively with the ‘Non-react mindfulness’ facet. Lastly, smaller volumes of bilateral insula, bilateral opercular cortex, right supramarginal and precentral gyri, anterior cingulate and paracingulate cortex predicted the magnitude of autonomic change following the induction (i.e. a greater decrease in HRV). Conclusions Results distinguish neural structures associated with impaired capacity for cognitive

  3. 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

  4. Glutamatergic or GABAergic neuron-specific, long-term expression in neocortical neurons from helper virus-free HSV-1 vectors containing the phosphate-activated glutaminase, vesicular glutamate transporter-1, or glutamic acid decarboxylase promoter

    PubMed Central

    Rasmussen, Morten; Kong, Lingxin; Zhang, Guo-rong; Liu, Meng; Wang, Xiaodan; Szabo, Gabor; Curthoys, Norman P.; Geller, Alfred I.

    2009-01-01

    Many potential uses of direct gene transfer into neurons require restricting expression to one of the two major types of forebrain neurons, glutamatergic or GABAergic neurons. Thus, it is desirable to develop virus vectors that contain either a glutamatergic or GABAergic neuron-specific promoter. The brain/kidney phosphate-activated glutaminase (PAG), the product of the GLS1 gene, produces the majority of the glutamate for release as neurotransmitter, and is a marker for glutamatergic neurons. A PAG promoter was partially characterized using a cultured kidney cell line. The three vesicular glutamate transporters (VGLUTs) are expressed in distinct populations of neurons, and VGLUT1 is the predominant VGLUT in the neocortex, hippocampus, and cerebellar cortex. Glutamic acid decarboxylase (GAD) produces GABA; the two molecular forms of the enzyme, GAD65 and GAD67, are expressed in distinct, but largely overlapping, groups of neurons, and GAD67 is the predominant form in the neocortex. In transgenic mice, an ∼9 kb fragment of the GAD67 promoter supports expression in most classes of GABAergic neurons. Here, we constructed plasmid (amplicon) Herpes Simplex Virus (HSV-1) vectors that placed the Lac Z gene under the regulation of putative PAG, VGLUT1, or GAD67 promoters. Helper virus-free vector stocks were delivered into postrhinal cortex, and the rats were sacrificed 4 days or 2 months later. The PAG or VGLUT1 promoters supported ∼90 % glutamatergic neuron-specific expression. The GAD67 promoter supported ∼90 % GABAergic neuron-specific expression. Long-term expression was observed using each promoter. Principles for obtaining long-term expression from HSV-1 vectors, based on these and other results, are discussed. Long-term glutamatergic or GABAergic neuron-specific expression may benefit specific experiments on learning or specific gene therapy approaches. Of note, promoter analyses might identify regulatory elements that determine a glutamatergic or GABAergic

  5. Islet glutamic acid decarboxylase modified by reactive oxygen species is recognized by antibodies from patients with type 1 diabetes mellitus

    PubMed Central

    Trigwell, S M; Radford, P M; Page, S R; Loweth, A C; James, R F L; Morgan, N G; Todd, I

    2001-01-01

    The generation of an autoimmune response against islet beta-cells is central to the pathogenesis of type 1 diabetes mellitus, and this response is driven by the stimulation of autoreactive lymphocytes by components of the beta-cells themselves. Reactive oxygen species (ROS) have been implicated in the beta-cell destruction which leads to type 1 diabetes and may modify beta-cell components so as to enhance their immunogenicity. We investigated the effects of oxidation reactions catalysed by copper or iron on the major beta-cell autoantigen glutamic acid decarboxylase (GAD). Lysates of purified rat islets were exposed to copper or iron sulphate with or without hydrogen peroxide or ascorbic acid. Immunostaining showed that these treatments generated high molecular weight covalently linked aggregates containing GAD. These are not formed by intermolecular disulphide bonds between cysteine residues since they cannot be resolved into monomeric form when electrophoresed under extreme reducing conditions. There was no modification of insulin or pro-insulin by ROS. The same oxidative changes to GAD could be induced in viable islet cells treated with copper sulphate and hydrogen peroxide, and thus the modifications are not an artefact of the catalysed oxidation of cell-free lysates. Sera from patients with type 1 diabetes and stiffman syndrome containing GAD antibodies reacted predominantly with the highest molecular weight modified protein band of GAD: normal human sera did not precipitate GAD. Thus, oxidatively modified aggregates of GAD react with serum antibodies of type 1 diabetes patients and some SMS patients: this is consistent with oxidative modifications of autoantigens being relevant to the pathogenesis of type 1 diabetes. PMID:11703367

  6. Islet glutamic acid decarboxylase modified by reactive oxygen species is recognized by antibodies from patients with type 1 diabetes mellitus.

    PubMed

    Trigwell, S M; Radford, P M; Page, S R; Loweth, A C; James, R F; Morgan, N G; Todd, I

    2001-11-01

    The generation of an autoimmune response against islet beta-cells is central to the pathogenesis of type 1 diabetes mellitus, and this response is driven by the stimulation of autoreactive lymphocytes by components of the beta-cells themselves. Reactive oxygen species (ROS) have been implicated in the beta-cell destruction which leads to type 1 diabetes and may modify beta-cell components so as to enhance their immunogenicity. We investigated the effects of oxidation reactions catalysed by copper or iron on the major beta-cell autoantigen glutamic acid decarboxylase (GAD). Lysates of purified rat islets were exposed to copper or iron sulphate with or without hydrogen peroxide or ascorbic acid. Immunostaining showed that these treatments generated high molecular weight covalently linked aggregates containing GAD. These are not formed by intermolecular disulphide bonds between cysteine residues since they cannot be resolved into monomeric form when electrophoresed under extreme reducing conditions. There was no modification of insulin or pro-insulin by ROS. The same oxidative changes to GAD could be induced in viable islet cells treated with copper sulphate and hydrogen peroxide, and thus the modifications are not an artefact of the catalysed oxidation of cell-free lysates. Sera from patients with type 1 diabetes and stiffman syndrome containing GAD antibodies reacted predominantly with the highest molecular weight modified protein band of GAD: normal human sera did not precipitate GAD. Thus, oxidatively modified aggregates of GAD react with serum antibodies of type 1 diabetes patients and some SMS patients: this is consistent with oxidative modifications of autoantigens being relevant to the pathogenesis of type 1 diabetes. PMID:11703367

  7. Rab-family GTPase regulates TOR complex 2 signaling in fission yeast

    PubMed Central

    Tatebe, Hisashi; Morigasaki, Susumu; Murayama, Shinichi; Zeng, Cui Tracy; Shiozaki, Kazuhiro

    2010-01-01

    Summary Background From yeast to human, TOR (Target Of Rapamycin) kinase plays pivotal roles in coupling extracellular stimuli to cell growth and metabolism. TOR kinase functions in two distinct protein complexes, TOR complex 1 (TORC1) and 2 (TORC2), which phosphorylate and activate different AGC-family protein kinases. TORC1 is controlled by the small GTPase Rheb, but little is known about TORC2 regulators. Results We have identified the Ryh1 GTPase, a human Rab6 ortholog, as an activator of TORC2 signaling in the fission yeast Schizosaccharomyces pombe. Mutational inactivation of Ryh1 or its guanine nucleotide exchange factor compromises the TORC2-dependent phosphorylation of the AGC-family Gad8 kinase. In addition, the effector domain of Ryh1 is important for its physical interaction with TORC2 and for stimulation of TORC2 signaling. Thus, GTP-bound Ryh1 is likely to be the active form stimulatory to TORC2–Gad8 signaling. Consistently, expression of the GTP-locked mutant Ryh1 is sufficient to promote interaction between TORC2 and Gad8 and to induce Gad8 hyper-phosphorylation. The loss of functional Ryh1, TORC2 or Gad8 brings about similar vacuolar fragmentation and stress sensitivity, further corroborating their involvement in a common cellular process. Human Rab6 can substitute Ryh1 in S. pombe and therefore, Rab6 may be a potential activator of TORC2 in mammals. Conclusions In its GTP-bound form, Ryh1, an evolutionarily conserved Rab GTPase, activates TORC2 signaling to the AGC kinase Gad8. The Ryh1 GTPase and the TORC2–Gad8 pathway are required for vacuolar integrity and cellular stress resistance in S. pombe. PMID:21035342

  8. [Treatment of generalized anxiety: new pharmacologic approaches].

    PubMed

    Boulenger, J P

    1995-01-01

    First defined as a residual diagnostic category in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM), Generalized Anxiety Disorder (GAD) was until recently one of the least studied and least clearly conceptualized of the anxiety disorders. The clinical definition of GAD has however improved up to the fourth edition of the DSM where the disorder is now characterized as a chronic state of apprehensive expectation and uncontrollable worry concerning multiple daily life events or activities and accompanied with at least 3 symptoms belonging to a list of six common manifestations of psychic or motor tension. Clinical research demonstrating the stability and the specificity of somatic symptoms clearly support the validity of the diagnosis of GAD despite possible difficulties in the differential diagnosis with other chronic conditions or axis II disorders such as dysthymia or mixed anxiety-depressive disorder. After benzodiazepines (BZD) and 5-HT1A agonists like buspirone, several other types of new anxiolytic drugs have been developed for the treatment of GAD. Partial agonists at GABA-BZD receptor sites may offer the advantage of a better efficacy vs side-effects ratio over classical BZDs; however, systematic comparative clinical trials will have to demonstrate the clinical relevance of the encouraging results obtained with these drugs, at the experimental level, during studies in healthy volunteers and during the first placebo-controlled trials. Furthermore, the recent description of GABA-receptor's subunits clearly suggest that the development of drugs acting at this level and devoided of psychomotor or withdrawal side-effects is a target that is worth pursuing. On the other hand, the development of 5-HT2 and 5-HT3 antagonists is also of interest for the treatment of GAD since it could provide new anxiolytic drugs without these side-effects and thus easier to administer on a long-term basis corresponding to the chronicity of GAD

  9. Healthcare utilization and costs in patients beginning pharmacotherapy for generalized anxiety disorder: a retrospective cohort study

    PubMed Central

    2011-01-01

    Background Patterns of healthcare utilization and costs in patients beginning pharmacotherapy for generalized anxiety disorder (GAD) have not been well characterized. Methods Using a large US health insurance database, we identified all patients with evidence of GAD (ICD-9-CM diagnosis code 300.02) who initiated pharmacotherapy with medications commonly used to treat GAD (eg, selective serotonin reuptake inhibitors [SSRIs], venlafaxine, benzodiazepines) between 1/1/2003 and 12/31/2007. We examined healthcare utilization and costs over the 12-month periods preceding and following date of initial receipt of such therapy ("pretreatment" and "follow-up", respectively). Patients with incomplete data were excluded. Results A total of 10,275 patients met all study inclusion criteria. Forty-eight percent of patients received SSRIs; 34%, benzodiazepines; and 6%, venlafaxine. SSRIs and venlafaxine were about three times more likely to be used on a long-term basis (> 90 days) than benzodiazepines (p < 0.01). In general, levels of healthcare utilization were higher during follow-up than pretreatment. Mean (SD) total healthcare costs increased from $4812 ($10,006) during pretreatment to $7182 ($22,041) during follow-up (p < 0.01); costs of GAD-related pharmacotherapy during follow-up were $420 ($485). Conclusions More than one-half of patients initiating pharmacotherapy for GAD receive either SSRIs or venlafaxine. Levels of healthcare utilization and costs are greater in the year following initiation of therapy than in the immediately preceding one. PMID:22151689

  10. 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. PMID:26644273

  11. 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. PMID:27442922

  12. 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. PMID:25563942

  13. Anti-glutamic acid decarboxylase antibody positive neurological syndromes.

    PubMed

    Tohid, Hassaan

    2016-07-01

    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 calledhyperexcitability 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

  14. Rumination predicts heightened responding to stressful life events in major depressive disorder and generalized anxiety disorder.

    PubMed

    Ruscio, Ayelet Meron; Gentes, Emily L; Jones, Jason D; Hallion, Lauren S; Coleman, Elizabeth S; Swendsen, Joel

    2015-02-01

    Although studies have documented heightened stress sensitivity in major depressive disorder (MDD) and generalized anxiety disorder (GAD), the mechanisms involved are poorly understood. One possible mechanism is the tendency to ruminate in response to stress. We used ecological momentary assessment to study ruminative thoughts after stressful events in 145 adults with MDD, GAD, comorbid MDD-GAD, or no psychopathology. Diagnosed individuals reported more event-related rumination than controls, even after adjusting for event stressfulness. Rumination was equally common in MDD and GAD and was especially severe among comorbid cases. More rumination immediately after the event predicted poorer affect, more maladaptive behavior, and more MDD and GAD symptoms at the next signal, even when pre-event levels of these variables were controlled. Rumination mediated, but did not moderate, the association of stress with affect and with symptoms. Stress-related rumination was more deleterious for diagnosed than healthy individuals, more intense for more severe clinical cases, and more persistent for cases with a greater temperamental vulnerability for emotional disorders. These results implicate rumination as a mechanism of stress sensitivity and suggest pathways through which it may maintain depression and anxiety in everyday life. PMID:25688429

  15. Genes in the GABA Pathway Increase in the Lateral Thalamus of Sprague-Dawley Rats During the Proestrus/Estrus Phase.

    PubMed

    Umorin, Mikhail; Stinson, Crystal; Bellinger, Larry L; Kramer, Phillip R

    2016-05-01

    Pain can vary over the estrous cycle as a result of changes in estradiol concentration but the mechanism causing this variation is unclear. Because the thalamus is important in pain control, gene expression in the lateral thalamus (ventral posteromedial, ventral posterolateral, reticular thalamic nuclei) was screened at different phases of the estrous cycle. Gene expression changes in Sprague-Dawley rats were further analyzed by real-time PCR and ELISA and plasma estradiol levels were measured by RIAs at different phases of the estrous cycle. Our results indicated that both the RNA and protein expression of glutamate decarboxylase 1 and 2 (GAD1, GAD2), GABA(A) receptor-associated protein like 1 (GABARAPL1), and vesicular GABA transporter (VGAT) significantly increased in the lateral thalamus when plasma estradiol levels were elevated. Estradiol levels were elevated during the proestrus and estrus phases of the estrous cycle. Estrogen receptor α (ERα) was observed to be co-localized in thalamic cells and thalamic infusion of an ERα antagonist significantly reduced GAD1 and VGAT transcript. GAD1, GAD2, GABARAPL1, and VGAT have been shown to effect neuronal responses suggesting that attenuation of pain during the estrous cycle can be dependent, in part, through estradiol induced changes in thalamic gene expression. PMID:26388520

  16. Effect of cross-linker glutaraldehyde on gastric digestion of emulsified albumin.

    PubMed

    Del Castillo-Santaella, Teresa; Maldonado-Valderrama, Julia; Molina-Bolivar, Jose Antonio; Galisteo-Gonzalez, Francisco

    2016-09-01

    Human serum albumin (HSA) has been shown to be an ideal protein for nanoparticle preparation. These are usually prepared by using cross linker agents such as glutaraldehyde (GAD). Liquid lipid nanocapsules (LLN) constitute a new generation of nanoparticles more biocompatible and versatile for oral delivery of lipophylic drugs. The first barrier that an orally administered formulation must cross is the gastrointestinal tract. Hence, it is crucial to address the impact of gastrointestinal digestion on these structures in order to achieve an optimal formulation. This study evaluates the effect of gastric digestion on HSA emulsions structured with GAD as a model substrate for the preparation of LLN. This is done by SDS-PAGE, emulsion microstructure, and interfacial tension techniques. Our results demonstrate that the cross- linking procedure with GAD strongly inhibits pepsin digestion by formation of inter- and/or intramolecular covalent bonds between substrate amino acids. Emulsification of HSA also protects from gastric digestion probably by the orientation of the HSA molecule, which exposes the majority of pepsin cleaving sites preferably to the hydrophobic part of the oil-water interface. In this emulsified HSA, cross-linking with GAD at the interface promotes structural modifications on the HSA interfacial layer, restricting the access of pepsin to cleavage sites. We identify interfacial aspects underlying enzymatic hydrolysis of the protein. Assuring that HSA-GAD structures resist passage through the gastric compartment is crucial is important towards the rational design of oral delivery systems and the first step to get the complete digestion profile. PMID:27341303

  17. Abnormal Functional Connectivity of the Amygdala-Based Network in Resting-State fMRI in Adolescents with Generalized Anxiety Disorder

    PubMed Central

    Liu, Wen-jing; Yin, Da-zhi; Cheng, Wen-hong; Fan, Ming-xia; You, Mei-na; Men, Wei-wei; Zang, Li-li; Shi, Dian-hong; Zhang, Fang

    2015-01-01

    Background We aimed to investigate the disruptions of functional connectivity of amygdala-based networks in adolescents with untreated generalized anxiety disorder (GAD). Material/Methods A total of 26 adolescents with first-episode GAD and 20 normal age-matched volunteers underwent resting-state and T1 functional magnetic resonance imaging (fMRI). We analyzed the correlation of fMRI signal fluctuation between the amygdala and other brain regions. The variation of amygdala-based functional connectivity and its correlation with anxiety severity were investigated. Results Decreased functional connectivity was found between the left amygdala and left dorsolateral prefrontal cortex. An increased right amygdala functional connectivity with right posterior and anterior lobes of the cerebellum, insula, superior temporal gyrus, putamen, and right amygdala were found in our study. Negative correlations between GAD scores and functional connectivity of the right amygdala with the cerebellum were also observed in the GAD adolescents. Conclusions Adolescents with GAD have abnormalities in brain regions associated with the emotional processing pathways. PMID:25673008

  18. Generalized Wind Turbine Actuator Disk Parameterization in the Weather Research and Forecasting (WRF) Model for Real-World Simulations

    NASA Astrophysics Data System (ADS)

    Marjanovic, N.; Mirocha, J. D.; Chow, F. K.

    2013-12-01

    In this work, we examine the performance of a generalized actuator disk (GAD) model embedded within the Weather Research and Forecasting (WRF) atmospheric model to study wake effects on successive rows of turbines at a North American wind farm. These wake effects are of interest as they can drastically reduce down-wind energy extraction and increase turbulence intensity. The GAD, which is designed for turbulence-resolving simulations, is used within downscaled large-eddy simulations (LES) forced with mesoscale simulations and WRF's grid nesting capability. The GAD represents the effects of thrust and torque created by a wind turbine on the atmosphere within a disk representing the rotor swept area. The lift and drag forces acting on the turbine blades are parameterized using blade-element theory and the aerodynamic properties of the blades. Our implementation permits simulation of turbine wake effects and turbine/airflow interactions within a realistic atmospheric boundary layer flow field, including resolved turbulence, time-evolving mesoscale forcing, and real topography. The GAD includes real-time yaw and pitch control to respond realistically to changing flow conditions. Simulation results are compared to SODAR data from operating wind turbines and an already existing WRF mesoscale turbine drag parameterization to validate the GAD parameterization.

  19. A pilot study of the effects of chronic paroxetine administration on hippocampal N-acetylaspartate in generalized anxiety disorder.

    PubMed

    Mathew, S J; Price, R B; Shungu, D C; Mao, X; Smith, E L P; Amiel, J M; Coplan, J D

    2010-08-01

    The neural basis of generalized anxiety disorder (GAD) is poorly characterized. The effect of chronic administration (12 weeks) of paroxetine, a selective serotonin reuptake inhibitor, on N-acetylaspartate (NAA), a marker of neuronal viability, was evaluated in adults with GAD using proton magnetic resonance spectroscopic imaging ((1)H MRSI) at 1.5 T. We hypothesized that, pretreatment abnormalities in hippocampal NAA/creatine (NAA/Cr) would normalize with symptomatic improvement. Nine GAD patients (mean age = 41.7 year; 4 females) received 12 weeks of open-label paroxetine treatment, flexibly dosed up to 60 mg/day. Clinical outcome was assessed with the Hamilton Anxiety Rating Scale (HAM-A). Multislice ( 1)H MRSI scans were performed at unmedicated baseline and following 6 and 12 weeks of treatment. Ten untreated healthy volunteers (HVs) (mean age = 37.1 year; 4 females) received scans at the same intervals. All patients achieved remission (HAM-A GAD patients showed persistently lower levels of bilateral hippocampal NAA/Cr (17.7% mean decrease; Cohen's d = 1.29) that were maintained across all three time points, despite marked symptom improvement. This pilot study failed to support an association between a hippocampal neuronal marker and anxiolytic response to paroxetine, and suggests further investigation of potential trait-like hippocampal abnormalities in GAD. PMID:19204062

  20. Humoral and cellular autoimmune responses in stiff person syndrome.

    PubMed

    Lohmann, Tobias; Londei, Marco; Hawa, Mohammed; Leslie, R David G

    2003-09-01

    Stiff person syndrome (SPS) is a chronic autoimmune disease associated with humoral and cellular immune responses to glutamic acid decarboxylase (GAD) 65. Another chronic autoimmune disease, type 1 diabetes (T1D), is also associated with autoimmune responses to this antigen, but T1D patients develop SPS only extremely rarely and only a third of SPS patients develop T1D (mostly mild manifestations in adulthood). In a previous study, we described important differences between T1D and SPS in the autoimmune response to GAD 65: (1) T cells of SPS patients recognize epitopes in the middle of GAD 65 (amino residues 81-171 and 313-403), whereas patients with T1D preferentially recognize another middle (161-243) and a C-terminal region (473-555); and (2) GAD antibodies (Abs) were nearly exclusively of the Th1-associated IgG1 type in T1D, whereas SPS patients had both Th1- and Th2-associated IgG4 and IgE GAD Abs. These differences were not simply related to different HLA alleles. Fine epitope mapping revealed further distinct T cell epitopes in both diseases despite similar HLA background. Therefore, a single autoantigen can elicit different immune responses causing distinct chronic autoimmune diseases possibly related to a Th1 or Th2 bias of the disease. PMID:14592879

  1. Rumination Predicts Heightened Responding to Stressful Life Events in Major Depressive Disorder and Generalized Anxiety Disorder

    PubMed Central

    Ruscio, Ayelet Meron; Gentes, Emily L.; Jones, Jason D.; Hallion, Lauren S.; Coleman, Elizabeth S.; Swendsen, Joel

    2015-01-01

    Although studies have documented heightened stress sensitivity in major depressive disorder (MDD) and generalized anxiety disorder (GAD), the mechanisms involved are poorly understood. One possible mechanism is the tendency to ruminate in response to stress. We used ecological momentary assessment to study ruminative thoughts following stressful events in 145 adults with MDD, GAD, comorbid MDD-GAD, or no psychopathology. Diagnosed individuals reported more event-related rumination than controls, even after adjusting for event stressfulness. Rumination was equally common in MDD and GAD and was especially severe among comorbid cases. More rumination immediately after the event predicted poorer affect, more maladaptive behavior, and more MDD and GAD symptoms at the next signal, even when pre-event levels of these variables were controlled. Rumination mediated, but did not moderate, the association of stress with affect and with symptoms. Stress-related rumination was more deleterious for diagnosed than healthy individuals, more intense for more severe clinical cases, and more persistent for cases with a greater temperamental vulnerability for emotional disorders. These results implicate rumination as a mechanism of stress sensitivity and suggest pathways through which it may maintain depression and anxiety in everyday life. PMID:25688429

  2. Nitrogen dioxide formation in the gliding arc discharge-assisted decomposition of volatile organic compounds.

    PubMed

    Bo, Zheng; Yan, Jianhua; Li, Xiaodong; Chi, Yong; Cen, Kefa

    2009-07-30

    To apply gliding arc discharge (GAD) plasma processing to volatile organic compounds (VOCs) emission control, the formation of NO(2) as an undesired byproduct needs to be addressed. Comparative results of effluent temperature and product concentrations between experiment and thermodynamic equilibrium calculation show that the NO(2) formation in dry air GAD is totally out of thermodynamic equilibrium. Meanwhile, obvious NO (A(2)Sigma+)) and N(2)(+) (B(2)Sigma(u)(+)) are detected as the major reactive species in the dry air GAD plasma region. These results suggest that the thermal (or Zeldovich) NO(x) formation mechanism is not significant in GAD system, while the energy level and the density of electrons in the plasma region will severely influence the NO(2) formation. The presence of 500 ppm VOCs in the feed gases shows a limiting influence on the NO(2) formation, which is in the order of aromatic hydrocarbon (C(6)H(6) and C(7)H(8))>straight-chain hydrocarbon (C(4)H(10) and C(6)H(14))>halogenated hydrocarbon (CCl(4)). The influences of VOCs chemical structure, supply voltage, feed gas humidity, and reactor geometry on NO(2) formation are investigated, and the results correspond to above mechanism analysis. Based on the above, the possible pathways of the inhibition of NO(2) formation in GAD-assisted VOCs decomposition process are discussed. PMID:19153003

  3. 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. PMID:26241663

  4. Deficiency of the 65 kDa isoform of glutamic acid decarboxylase impairs extinction of cued but not contextual fear memory.

    PubMed

    Sangha, Susan; Narayanan, Rajeevan T; Bergado-Acosta, Jorge R; Stork, Oliver; Seidenbecher, Thomas; Pape, Hans-Christian

    2009-12-16

    Extinction procedures are clinically relevant for reducing pathological fear, and the mechanisms of fear regulation are a subject of intense research. The amygdala, hippocampus, and prefrontal cortex (PFC) have all been suggested to be key brain areas in extinction of conditioned fear. GABA has particularly been implicated in extinction learning, and the 65 kDa isoform of glutamic acid decarboxylase (GAD65) may be important in elevating GABA levels in response to environmental signals. Extinction of conditioned fear was examined in Gad65(-/-) mice while recording local field potentials from the amygdala, hippocampus, and PFC simultaneously while monitoring behavior. Gad65(-/-) mice showed generalization of cued fear, as reported previously, and impaired extinction of cued fear, such that fear remained high across extinction training. This endurance in cued fear was associated with theta frequency synchronization between the amygdala and hippocampus. Extinction of contextual fear, however, was unaltered in Gad65(-/-) mice when compared with wild-type littermates. The data imply that GAD65 plays a critical role in regulating cued fear responses during extinction learning and that, during this process, GABAergic signaling is involved in modulating synchronized activity between the amygdala and hippocampus. In view of the more pronounced effect on cued versus contextual fear extinction, these influences may rely more on GABAergic mechanisms in the amygdala. PMID:20016086

  5. 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. PMID:26731173

  6. 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. PMID:26459843

  7. Mindfulness and self-compassion in generalized anxiety disorder: examining predictors of disability.

    PubMed

    Hoge, Elizabeth A; Hölzel, Britta K; Marques, Luana; Metcalf, Christina A; Brach, Narayan; Lazar, Sara W; Simon, Naomi M

    2013-01-01

    Generalized anxiety disorder (GAD) is a condition characterized by worry and physiological arousal symptoms that causes significant disabilities in patients' lives. In order to improve psychotherapeutic interventions, a careful characterization of the deficiencies of this population as well as factors that ameliorate disability is crucial. Variables that have not traditionally been the focus of research should be considered, such as trait mindfulness and self-compassion. We investigated whether GAD patients would report lower mindfulness and self-compassion levels than healthy stressed individuals. Eighty-seven GAD patients and 49 healthy controls completed the Five Facet Mindfulness Questionnaire, the Self-Compassion Scale, and measures of anxiety. Patients with GAD also completed the Sheehan Disability Scale. Results showed that GAD patients had lower mindfulness and self-compassion than healthy stressed controls, and both were negatively correlated with levels of anxiety, worry, and anxiety sensitivity. In patients, mindfulness was a better predictor of disability than actual anxiety symptom scores. These findings highlight that in the presence of anxiety symptoms, mindfulness can be a factor that helps protect against feeling disabled by the disorder. The findings thereby add an important variable to the characterization of this disorder and should be taken into consideration for future treatment development. PMID:24174978

  8. 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

  9. 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. PMID:24797176

  10. 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. PMID:23017406

  11. 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

  12. Respiratory sensory gating measured by respiratory-related evoked potentials in generalized anxiety disorder

    PubMed Central

    Chan, Pei-Ying S.; Cheng, Chia-Hsiung; Hsu, Shih-Chieh; Liu, Chia-Yih; Davenport, Paul W.; von Leupoldt, Andreas

    2015-01-01

    The perception of respiratory sensations plays an important role both in respiratory diseases and in anxiety disorders. However, little is known about the neural processes underlying respiratory sensory perception, especially in patient groups. Therefore, the present study examined whether patients with generalized anxiety disorder (GAD) would demonstrate altered respiratory sensory gating compared to a healthy control group. Respiratory-related evoked potentials (RREP) were measured in a paired inspiratory occlusion paradigm presenting two brief occlusion stimuli (S1 and S2) within one inspiration. The results showed a significantly greater S2/S1 ratio for the N1 component of the RREP in the GAD group compared to the control group. Our findings suggest altered respiratory sensory processing in patients with GAD, which might contribute to altered perception of respiratory sensations in these patients. PMID:26217278

  13. 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. PMID:27345596

  14. 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. PMID:26493392

  15. A Contemporary View of Applied Relaxation for Generalized Anxiety Disorder

    PubMed Central

    Hayes-Skelton, Sarah A.; Roemer, Lizabeth

    2013-01-01

    Applied Relaxation (AR), originally developed by Lars-Göran Öst, is a long standing, efficacious treatment for generalized anxiety disorder (GAD). While newer treatments are continuing to be developed, AR remains one of the most efficacious treatments for GAD. However, AR has received less in-depth attention more recently, particularly in terms of potential mechanisms of action. This paper is written to honor the development and history of AR and to highlight the ways that it has continued to be adapted. In this paper, the AR treatment strategies are presented, which include: noticing early signs of anxiety, learning relaxation skills, and applying relaxation at the first sign of anxiety. Then, additional adaptations to AR are presented along with recommendations of how AR may be enhanced by understanding potential mechanisms of change. Finally, recommendations are made for the continued evolution of AR as a powerful and efficacious treatment for GAD. PMID:23731329

  16. Immunohistochemical evidence for colocalization of gamma-aminobutyric acid and serotonin in neurons of the ventral medulla oblongata projecting to the spinal cord.

    PubMed

    Millhorn, D E; Hökfelt, T; Seroogy, K; Oertel, W; Verhofstad, A A; Wu, J Y

    1987-04-28

    Fluorescence immunohistochemistry was used to analyze the medulla oblongata of colchicine-treated rats that had been incubated with guinea pig antibodies to serotonin (5-HT) and either rabbit or sheep antibodies to glutamic acid decarboxylase (GAD). Numerous cells in the rostral ventrolateral medulla in the region of nucleus raphe magnus were immunostained for either 5-HT or GAD. A substantial number of neurons showed positive immunoreactivity for both substances, and were most frequently observed in the lateral aspect of nucleus raphe magnus. In addition, a number of the 5-HT/GAD-containing neurons were retrogradely labelled with Fast blue dye that had been injected into the thoracic spinal cord. This work provides evidence for colocalization of the classical neurotransmitters 5-HT and GABA in single cells of the ventral medulla oblongata, some of which project to the spinal cord. PMID:3555707

  17. Adding a Motivational Interviewing Pretreatment to Cognitive Behavioral Therapy for Generalized Anxiety Disorder: A Preliminary Randomized Controlled Trial

    PubMed Central

    Westra, Henny A.; Arkowitz, Hal; Dozois, David J.A.

    2009-01-01

    Seventy six individuals with a principal diagnosis of generalized anxiety disorder (GAD) were randomly assigned to receive either an MI pretreatment or no pretreatment (NPT), prior to receiving CBT. Significant group differences favoring the MI-CBT group were observed on the hallmark GAD symptom of worry and on therapist-rated homework compliance, which mediated the impact of treatment group on worry reduction. Adding MI pretreatment to CBT was specifically and substantively beneficial for individuals with high worry severity at baseline. There was evidence of relapse at 6-month follow-up for high severity individuals who received MI-CBT, but significant moderator effects favoring the high severity MI-CBT group were again apparent at 12-months post-treatment. Pending replication in a more controlled test, these findings suggest that MI may be a promising adjunct to CBT for GAD for those of high severity, a group which has been less responsive to CBT in past research. PMID:19665347

  18. 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. PMID:23470116

  19. Correlation between the level of microRNA expression in peripheral blood mononuclear cells and symptomatology in patients with generalized anxiety disorder.

    PubMed

    Chen, Sheng-Dong; Sun, Xin-Yang; Niu, Wei; Kong, Ling-Ming; He, Ming-Jun; Fan, Hui-Min; Li, Wan-Shuai; Zhong, Ai-Fang; Zhang, Li-Yi; Lu, Jim

    2016-08-01

    This study investigated the correlation between the level of microRNA expression in peripheral blood mononuclear cells (PBMCs) and symptomatology in patients with generalized anxiety disorder (GAD). MicroRNA array was performed in peripheral blood mononuclear cells (PBMCs) obtained from GAD patients with gender, age, ethnicity-matched healthy controls. Then real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to verify the top 7 miRNAs with the highest fold-change values in 76 GAD patients and 39 healthy controls. It demonstrated that 5 miRNAs showed significantly differences in expression levels (P<0.01). These 5 GAD-associated miRNAs were finally selected into our study to analyze the association between the plasma level of miRNAs expression and symptomatology scores in Hamilton Anxiety Scale (HAMA). Results showed that the level of miR-4505 and miR-663 was negatively correlated with the total HAMA scores in GAD patients (r=0.2228, r=0.264 P<0.05). MiR-663 was selected into the regression equation of HAMA total scores and psychic anxiety symptomatology scores, and it could explain 5.3% of the HAMA total scores and 15.3% of the anxiety symptomatology scores. This study analyzed preliminarily possible circulating miRNAs expression changes in GAD patients, and the expression level of miR-663 highly correlated with psychic anxiety symptoms, further molecular mechanism of which needs to be explored. PMID:27423364

  20. Adult Attachment as a Moderator of Treatment Outcome for Generalized Anxiety Disorder: Comparison Between Cognitive–Behavioral Therapy (CBT) Plus Supportive Listening and CBT Plus Interpersonal and Emotional Processing Therapy

    PubMed Central

    Newman, Michelle G.; Castonguay, Louis G.; Jacobson, Nicholas C.; Moore, Ginger A.

    2016-01-01

    Objective To determine whether baseline dimensions of adult insecure attachment (avoidant and anxious) moderated outcome in a secondary analysis of a randomized controlled trial comparing cognitive–behavioral therapy (CBT) plus supportive listening (CBT + SL) versus CBT plus interpersonal and emotional processing therapy (CBT + I/EP). Method Eighty-three participants diagnosed with generalized anxiety disorder (GAD) were recruited from the community and assigned randomly to CBT + SL (n = 40) or to CBT + I/EP (n = 43) within a study using an additive design. PhD-level psychologists treated participants. Blind assessors evaluated participants at pretreatment, posttreatment, 6-month, 12-month, and 2-year follow-up with a composite of self-report and assessor-rated GAD symptom measures (Penn State Worry Questionnaire, Hamilton Anxiety Rating Scale, Clinician’s Severity Rating). Avoidant and anxious attachment were assessed using self-reported dismissing and angry states of mind, respectively, on the Perceptions of Adult Attachment Questionnaire. Results Consistent with our prediction, at all assessments higher levels of dismissing styles in those who received CBT + I/EP predicted greater change in GAD symptoms compared with those who received CBT + SL for whom dismissiveness was unrelated to the change. At postassessment, higher angry attachment was associated with less change in GAD symptoms for those receiving CBT + I/EP, compared with CBT + SL, for whom anger was unrelated to change in GAD symptoms. Pretreatment attachment-related anger failed to moderate outcome at other time points and therefore, these moderation effects were more short-lived than the ones for dismissing attachment. Conclusions When compared with CBT + SL, CBT + I/EP may be better for individuals with GAD who have relatively higher dismissing styles of attachment. PMID:26052875

  1. 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. PMID:25149863

  2. Heart rate and autonomic response to stress after experimental induction of worry versus relaxation in healthy, high-worry, and generalized anxiety disorder individuals.

    PubMed

    Fisher, Aaron J; Newman, Michelle G

    2013-04-01

    Generalized anxiety disorder (GAD) is the most commonly occurring anxiety disorder and has been related to cardiovascular morbidity such as cardiac ischemia, sudden cardiac death, and myocardial infarction. Both GAD and its cardinal symptom - worry - have been shown to promote muted physiological reactivity in response to laboratory and ecological stressors. Importantly, no study to date has examined the concurrent and relative contributions of trait and state worry within healthy controls, (non-clinical) high trait-worry controls, and GAD participants. The present study examined heart rate (HR), respiratory sinus arrhythmia (RSA), and salivary alpha-amylase (sAA) responses to laboratory stress during and following the experimental induction of worry versus relaxation in healthy controls (n=42), high trait worriers (n=33) and participants with GAD (n=76). All groups exhibited increased HR and decreased RSA in response to the stressor, with no differences by condition. Baseline sAA significantly moderated HR and RSA reactivity, such that higher sAA predicted greater increases in HR and decreases in RSA. There was a significant group by baseline sAA interaction such that in GAD, higher baseline sAA predicted decreased change in sAA during stress, whereas higher baseline sAA predicted greater sAA change in healthy controls. High-worry controls fell non-significantly between these groups. The present study provides additional evidence for the effect of worry on diminished HR stress response and points to possible suppression of adrenergic sympathetic stress responses in GAD. PMID:23384513

  3. Comparison of the hemodynamic effects of gasless abdominal distention and CO2 pneumoperitoneum during incremental positive end-expiratory pressure.

    PubMed

    Woolley, D S; Puglisi, R N; Bilgrami, S; Quinn, J V; Slotman, G J

    1995-01-01

    Laparoscopy is used increasingly in managing critically ill patients. Carbon dioxide (CO2) pneumoperitoneum is used during these procedures. The increased intra-abdominal pressure of CO2 pneumoperitoneum, however, can affect cardiopulmonary performance adversely. Recently, gasless abdominal wall distention has been introduced as an alternative to CO2 pneumoperitoneum. The purpose of this study was to compare the hemodynamic effects of gasless abdominal distention (GAD) with those of CO2 pneumoperitoneum during mechanical ventilation with positive end-expiratory pressure (PEEP). Six anesthetized, paralyzed, mechanically ventilated adult swine were monitored with pulmonary artery and arterial catheters at incremental values of PEEP (0-20 cm H2O, by 5, Control) and then allowed to return to baseline hemodynamic status at 0 cm H2O PEEP. The animals were then randomly assigned to receive either CO2 pneumoperitoneum at 15 mm Hg intra-abdominal pressure (PNEUMO) or GAD (equal to anterior abdominal wall displacement of CO2) and PEEP was reapplied. The animals were allowed to return to hemodynamic baseline and PEEP was reapplied with the alternate method of abdominal wall distention. A complete hemodynamic profile and arterial/mixed venous blood gas measurements were monitored at each value of PEEP. With GAD, central venous pressure (CVP), pulmonary artery pressure (PAP), pulmonary capillary wedge pressure (PCWP), and PaCO2 were significantly reduced, compared to PNEUMO, and PaO2 was increased. Cardiac index was higher in GAD versus PNEUMO at baseline, but was lower for GAD at PEEP levels above 10 cm H2O. These results indicate that in its net effect, GAD does not exacerbate the adverse hemodynamic effects of PEEP.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7830409

  4. 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

  5. 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. PMID:26125602

  6. Adiponectin ameliorates the apoptotic effects of paraquat on alveolar type II cells via improvements in mitochondrial function

    PubMed Central

    HE, YARONG; ZOU, LIQUN; ZHOU, YAXIONG; HU, HAI; YAO, RONG; JIANG, YAOWEN; LAU, WAYNE BOND; YUAN, TUN; HUANG, WEN; ZENG, ZHI; CAO, YU

    2016-01-01

    Previous studies have demonstrated that excessive reactive oxygen/nitrogen species (ROS/RNS)-induced apoptosis is an important feature of the injury to the lung epithelium in paraquat (PQ) poisoning. However the precise mechanisms of PQ-induced dysfunction of the mitochondria, where ROS/RNS are predominantly produced, remain to be fully elucidated. Whether globular adiponectin (gAd), a potent molecule protective to mitochondria, regulates the mitochondrial function of alveolar type II cells to reduce PQ-induced ROS/RNS production remains to be investigated. The current study aimed to investigate the precise mechanisms of PQ poisoning in the mitochondria of alveolar type II cells, and to elucidate the role of gAd in protecting against PQ-induced lung epithelium injury. Therefore, lung epithelial injury was induced by PQ co-culture of alveolar type II A549 cells for 24 h. gAd was administrated to and removed from the injured cells in after 24 h. PQ was observed to reduce cell viability and increase apoptosis by ~1.5 fold in A549 cells. The oxidative/nitrative stress, resulting from ROS/RNS and disordered mitochondrial function were evidenced by increased O2−., NO production and reduced mitochondrial membrane potential (ΔΨ), adenosine 5′-triphosphate (ATP) content in PQ-poisoned A549 cells. gAd treatment significantly reversed the PQ-induced cell injury and mitochondrial dysfunction in A549 cells. The protective effects of gAd were partly abrogated by an adenosine 5′-monophosphate-activated protein kinase (AMPK) inhibitor, compound C. The results suggest that reduced ΔΨ and ATP content may result in PQ-induced mitochondrial dysfunction of the lung epithelium, which constitutes a novel mechanism for gAd exerting pulmonary protection against PQ poisoning via AMPK activation. PMID:27220901

  7. The role of cannabinoid 1 receptor expressing interneurons in behavior

    PubMed Central

    Brown, Jacquelyn A.; Horváth, Szatmár; Garbett, Krassimira; Schmidt, Martin J.; Everheart, Monika; Gellért, Levente; Ebert, Philip; Mirnics, Károly

    2013-01-01

    Schizophrenia is a devastating neurodevelopmental disorder that affects approximately 1% of the population. Reduced expression of the 67-kD a protein isoform of glutamic acid decarboxylase (GAD67), is a hallmark of the disease, and is encoded by the GAD1 gene. In schizophrenia, GAD67 downregulation occurs in multiple interneuronal subpopulations, including the cannabinoid receptor type 1 positive (CNR1+) cells, but the functional consequences of these disturbances are not well understood. To investigate the role of the CNR1-positive GABA-ergic interneurons in behavioral and molecular processes, we employed a novel, miRNA-mediated transgenic mouse approach. We silenced the Gad1 transcript using a miRNA engineered to specifically target Gad1 mRNA under the control of Cnr1 bacterial artificial chromosome. Behavioral characterization of our transgenic mice showed elevated and persistent conditioned fear associated with an auditory cue and a significantly altered response to an amphetamine challenge. These deficits could not be attributed to sensory deficits or changes in baseline learning and memory. Furthermore, HPLC analyses revealed that Cnr1/Gad1 mice have enhanced serotonin levels, but not dopamine levels in response to amphetamine. Our findings demonstrate that dysfunction of a small subset of interneurons can have a profound effect on behavior and that the GABA-ergic, monoamine, and cannabinoid systems are functionally interconnected. The results also suggest that understanding the function of various interneuronal subclasses might be essential to develop knowledge-based treatment strategies for various mental disorders including schizophrenia and substance abuse. PMID:24239560

  8. 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

  9. The slow Wallerian degeneration gene, WldS, inhibits axonal spheroid pathology in gracile axonal dystrophy mice.

    PubMed

    Mi, Weiqian; Beirowski, Bogdan; Gillingwater, Thomas H; Adalbert, Robert; Wagner, Diana; Grumme, Daniela; Osaka, Hitoshi; Conforti, Laura; Arnhold, Stefan; Addicks, Klaus; Wada, Keiji; Ribchester, Richard R; Coleman, Michael P

    2005-02-01

    Axonal dystrophy is the hallmark of axon pathology in many neurodegenerative disorders of the CNS, including Alzheimer's disease, Parkinson's disease and stroke. Axons can also form larger swellings, or spheroids, as in multiple sclerosis and traumatic brain injury. Some spheroids are terminal endbulbs of axon stumps, but swellings may also occur on unbroken axons and their role in axon loss remains uncertain. Similarly, it is not known whether spheroids and axonal dystrophy in so many different CNS disorders arise by a common mechanism. These surprising gaps in current knowledge result largely from the lack of experimental methods to manipulate axon pathology. The slow Wallerian degeneration gene, Wld(S), delays Wallerian degeneration after injury, and also delays 'dying-back' in peripheral nervous system disorders, revealing a mechanistic link between two forms of axon degeneration traditionally considered distinct. We now report that Wld(S) also inhibits axonal spheroid pathology in gracile axonal dystrophy (gad) mice. Both gracile nucleus (P < 0.001) and cervical gracile fascicle (P = 0.001) contained significantly fewer spheroids in gad/Wld(S) mice, and secondary signs of axon pathology such as myelin loss were also reduced. Motor nerve terminals at neuromuscular junctions continued to degenerate in gad/Wld(S) mice, consistent with previous observations that Wld(S) has a weaker effect on synapses than on axons, and probably contributing to the fact that Wld(S) did not alleviate gad symptoms. Wld(S) acts downstream of the initial pathogenic events to block gad pathology, suggesting that its effect on axonal swelling need not be specific to this disease. We conclude that axon degeneration mechanisms are more closely related than previously thought and that a link exists in gad between spheroid pathology and Wallerian degeneration that could hold for other disorders. PMID:15644421

  10. Association between a polymorphism of the 65K-glutamate decarboxylase gene and insulin-dependent diabetes mellitus

    SciTech Connect

    Kure, S.; Aoki, Y.; Narisawa, K.

    1994-09-01

    Autoimmunity against 65K-glutamate decarboxylase (GAD65), one of two forms of the {gamma}-aminobutyric acid-synthesizing enzyme, is commonly associated with insulin-dependent diabetes mellitus (IDDM). To study the predisposing effect of the GAD65 genotype on IDDM, we performed a case-control study screening an association between a newly-identified GAD65 polymorphism and IDDM in the Japanese population. The identified polymorphism was a microsatellite that was located in an intron near the 3{prime} end of the GAD65 gene consisting of variable numbers of a (CA)-dinucleotide repeat. We amplified the polymorphic region by polymerase chain reaction, and, for each individual in the control group (n=254) and the IDDM group (n=108), determined a pair of (CA)-repeat numbers, each number derived from one or the other of their alleles. In both groups we found 13 allelic variants with different repeat numbers, ranging from 19 to 31 repeats of the (CA) dinucleotide. The most frequent allelic variant in the IDDM group was 20 repeats; (CA){sub 20}. A higher frequency of a genotype containing two (CA){sub 20} alleles (p=0.005) was observed in the IDDM group (41.7%) compared with the control group (26.8%). Odds ratio (a 95% confidence interval) for a heterozygote or a homozygote of (CA){sub 20} versus a subject without (CA){sub 20} was 1.2 (0.66-2.25) and 2.23 (1.18-4.21), respectively. No significant association was observed between the (CA)-repeat genotype and the appearance of anti-GAD antibodies in the patients whose duration of the diabetes was less than 4 years (n=35). Therefore, genetic variations in GAD65 appears to be associated with IDDM susceptibility.

  11. 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

  12. Confirmational identification of Escherichia coli, a comparison of genotypic and phenotypic assays for glutamate decarboxylase and beta-D-glucuronidase.

    PubMed Central

    McDaniels, A E; Rice, E W; Reyes, A L; Johnson, C H; Haugland, R A; Stelma, G N

    1996-01-01

    Genotypic and phenotypic assays for glutamate decarboxylase (GAD) and beta-D-glucuronidase (GUD) were compared for their abilities to detect various strains of Escherichia coli and to discriminate among other bacterial species. Test strains included nonpathogenic E. coli, three major groups of diarrheagenic E. coli, three other non-coli Escherichia species, and various other gram-negative and -positive bacteria found in water. The genotypic assays were performed with hybridization probes generated by PCR amplification of 670- and 623-bp segments of the gadA/B (GAD) and uidA (GUD) genes, respectively. The GAD enzymes catalyze the alpha-decarboxylation of L-glutamic acid to yield gamma-aminobutyric acid and carbon dioxide, which are detected in the phenotypic assay by a pH-sensitive indicator dye. The phenotypic assay for GUD involves the transformation of 4-methylumbelliferyl-beta-D-glucuronide to the fluorogenic compound 4-methylumbelliferone. The GAD phenotypic assay detected the majority of the E. coli strains tested, whereas a number of these strains, including all representatives of the O157:H7 serotype and several nonpathogenic E. coli strains, gave negative results in the GUD assay. Both phenotypic assays detected some but not all strains from each of the four Shigella species. A strain of Citrobacter freundii was also detected by the GUD assay but not by the GAD assay. All E. coli and Shigella strains were detected with both the gadA/B and uidA probes. A few Escherichia fergusonii strains gave weak hybridization signals in response to both probes at 65 degrees C but not at 68 degrees C. None of the other bacterial species tested were detected by either probe. These results were consistent with previous reports which have indicated that the GAD phenotypic assay detects a wider range of E. coli strains than does the GUD assay and is also somewhat more specific for this species. The genotypic assays for the two enzymes were found to be equivalent in both of

  13. γ-Amino-butyric acid (GABA) receptor subunit and transporter expression in the gonad and liver of the fathead minnow (Pimephales promelas).

    PubMed

    Biggs, Katie; Seidel, Jason S; Wilson, Alex; Martyniuk, Christopher J

    2013-09-01

    γ-Amino-butyric acid (GABA) is the major inhibitory neurotransmitter in the vertebrate central nervous system. GABA receptors and synthesizing enzymes have also been localized to peripheral tissues including the liver, oviduct, uterus and ovary of mammals but the distribution and role of GABA in peripheral tissues of fish has not been fully investigated. The objectives of this study were to (1) determine if mRNA encoding GABA synthesizing enzymes (glutamic acid decarboxylase 65 and 67; gad65 and gad67), GABA transporters, and GABAA receptor subunits are localized to liver and gonad of fathead minnow (Pimephales promelas) (FHM) (2) investigate the effects of GABA on ovarian 17β-estradiol (E2) production, and (3) measure transcript responses in the ovary after in vitro incubation to GABA. Real-time PCR assays were developed for gad65, gad67, vesicular GABA transporter (vgat) and GABA transporter 1 (gat1), and select GABAA receptor subunits (gabra1, gabra5, gabrb1, gabrb2, gabrg1, gabrg2). All transcripts were localized to the brain as expected; however transcripts were also detected in the liver, ovary, and testis of FHMs. In the female liver, gad65 mRNA was significantly higher in expression compared to the male liver. Transcripts for gad67 were the highest in the brain>gonad>liver and in the gonads, gad67 was significantly higher in expression than gad65 mRNA. In the liver and gonad, the relative abundance of the subunits followed a general trend of gabrb1>gabrb2=gabrg1=gabrg2>gabra1=gabra5. To explore the effects of GABA in the ovary, tissue explants from reproductive female FHMs were treated with GABA (10(-10), 10(-8) and 10(-6)M) for 12h. GABA had no significant effect on 17β-estradiol production or on mRNA abundance for genes involved in ovarian steroidogenesis (e.g., 11βhsd, cyp17, cyp19a). There was a significant decrease in estrogen receptor 2a (esr2a) mRNA with 10(-10)M GABA. This study begins to investigate the GABA system in non-neural tissues of

  14. 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

  15. 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

  16. 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…

  17. Antiallodynic effect of tianeptine via modulation of the 5-HT7 receptor of GABAergic interneurons in the spinal cord of neuropathic rats.

    PubMed

    Lin, Hai; Heo, Bong Ha; Kim, Woong Mo; Kim, Yong Chul; Yoon, Myung Ha

    2015-06-26

    Although tianeptine, an atypical antidepressant has been reported to have antinociceptive effects, the mode of action is different from that of tricyclic antidepressants despite structural similarities. We examined the antiallodynic effect of intrathecal tianeptine in neuropathic pain rats and determined the involvement of 5-hydroxytryptamine type 7 (5-HT7) receptor of the GABAergic interneurons in the spinal cord. Neuropathic pain was induced by spinal nerve ligation (SNL). After observation of the effect from intrathecal tianeptine, a 5-HT7 receptor antagonist (SB-269970) was administered intrathecally 10 min before delivery of tianeptine, to determine the contribution of spinal 5-HT7 receptor on the activity of tianeptine. GAD expression and GABA concentrations were assessed. Intrathecal tianeptine dose-dependently attenuated mechanical allodynia in SNL rats. Pre-treatment with intrathecal SB-269970 reversed the antiallodynic effect of tianeptine. Both GAD65 expression and the GABA concentration in the spinal cord were decreased in neuropathic rats but were increased by tianeptine. Additionally, 5-HT7 receptor and GAD65 were co-localized in the spinal cord. Intrathecal tianeptine reduces neuropathic pain. 5-HT7 receptor of the GABAergic interneurons together with GAD65 plays a role in the activity of tianeptine at the spinal cord level. PMID:25982324

  18. Gravity-assisted drainage imaging in the assessment of pediatric hydronephrosis

    PubMed Central

    Acker, Matthew R.; Clark, Roderick; Anderson, Peter

    2016-01-01

    Introduction: As early detection of hydronephrosis increases, we require better methods of distinguishing between pediatric patients who require pyeloplasty vs. those with transient obstruction. Gravity-assisted drainage (GAD) as part of a standardized diuretic renography protocol has been suggested as a simple and safe method to differentiate patients. Methods: Renal scans of 89 subjects with 121 hydronephrotic renal units between January 2004 and March 2007 were identified and analyzed. Results: Of all renal units, 65% showed obstruction. GAD maneuver resulted in significant residual tracer drainage in eight renal units, moderate drainage in 12 renal units, and some improvement in 40 units after the GAD maneuver. Of the eight renal units with significant residual tracer drainage, only two proceeded to pyeloplasty. After pyeloplasty, nine children had improved time to half maximum (T1/2 Max) and 13 were unchanged. Conclusions: Our study was limited due to its retrospective design and descriptive analyses, but includes a sufficient number of subjects to conclude that GAD as part of a diuretic renography protocol is an effective and simple technique that can help prevent unnecessary surgical procedures in pediatric patients. PMID:27217854

  19. 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…

  20. Genetic and Environmental Contributions to Common Psychopathologies of Childhood and Adolescence: A Study of Twins and Their Siblings

    ERIC Educational Resources Information Center

    Ehringer, Marissa A.; Rhee, Soo Hyun; Young, Susan; Corley, Robin; Hewitt, John K.

    2006-01-01

    We report findings based on analyses of self-reports of six common adolescent psychopathologies (attention deficit/hyperactivity disorder, ADHD; conduct disorder, CD; oppositional defiant disorder, ODD; generalized anxiety disorder, GAD; separation anxiety disorder, SAD; and major depressive disorder, MDD) in a sample of 1,162 male and female…

  1. The Relation between Early Maladaptive Schemas, Depression, and Generalized Anxiety among Adults Seeking Residential Treatment for Substance Use Disorders

    PubMed Central

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

    2015-01-01

    Objective Previous research has shown that early maladaptive schemas (EMS) play an important role in substance use, depression, and anxiety. However, little work has 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. Method We used pre-existing patient records of adults diagnosed with a substance use disorder from a residential substance use treatment facility (N = 122). Results 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). Conclusions 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. PMID:26099037

  2. Reduced white matter integrity and its correlation with clinical symptom in first-episode, treatment-naive generalized anxiety disorder.

    PubMed

    Wang, Wei; Qian, Shaowen; Liu, Kai; Li, Bo; Li, Min; Xin, Kuolin; Sun, Gang

    2016-11-01

    The purpose of this study was to explore white matter microstructural alterations in the patients with generalized anxiety disorder (GAD) using diffusion tensor imaging (DTI) technique, and to assess neural associations with the symptom severity. Twenty-eight first-episode, treatment-naive GAD patients without co-morbidities and 28 matched healthy controls underwent DTI acquisition and clinical symptom assessments. Tract-based spatial statistics (TBSS) was used to analyze white matter microstructural abnormalities in patients with GAD, as well as their associations with clinical symptom scores in a voxel-wise manner. Compared to controls, patients showed decreased fractional anisotropy (FA) values in 7 clusters of white matter in bilateral uncinate fasciculus, body of corpus callosum, left middle cingulum (cingulate gyrus), bilateral anterior thalamic radiation and corona radiate, right anterior limb of internal capsule, bilateral inferior frontal-occipital fasciculus, bilateral superior and inferior longitudinal fasciculus, and increased mean diffusivity and radial diffusivity in widespread white matter regions. Reduced FA values in right uncinate fasciculus, left cingulum bundle showed significantly negative correlations with clinical symptom severity for Hamilton anxiety Rating Scale scores. Our findings suggest microstructural abnormalities in uncinate fasciculus and cingulum bundle play key roles in the underlying neural basis of GAD. PMID:27515289

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

    PubMed Central

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

    2015-01-01

    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. PMID:26245488

  4. 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…

  5. 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…

  6. 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...

  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. Surface plasmon resonance biosensor detects the downstream events of active PKCbeta in antigen-stimulated mast cells.

    PubMed

    Tanaka, Maiko; Hiragun, Takaaki; Tsutsui, Tomoko; Yanase, Yuhki; Suzuki, Hidenori; Hide, Michihiro

    2008-06-15

    Surface plasmon resonance (SPR) biosensors detect large changes of angle of resonance (AR) when RBL-2H3 mast cells are cultured on a sensor chip and stimulated with antigen. However, the detail of molecular events that are responsible for such large changes of AR remained unknown. In this study, we investigated the relationship between intracellular signaling events induced by antigen and the change of AR, by genetic manipulation of intracellular signaling molecules; spleen tyrosine kinase (Syk), src-like adaptor protein (SLAP), linker for activation of T cells (LAT), growth-factor-receptor-bound protein 2 (Grb2), Grb2-related adaptor protein (Gads), and isotypes of protein kinase C (PKC). RBL-2H3 mast cells overexpressing dominant-negative Syk or SLAP, which both interfere with active Syk, exhibited only minimal increase of AR in response to antigen stimulation. Likewise, the interference of the activation of LAT and Gads, by expressing dominant-negative LAT and Gads, respectively, resulted in nearly complete suppression of the antigen-induced increase of AR. The cells overexpressing PKCs, apart from PKCbeta, showed a reduced extent of increase of AR in response to antigen stimulation. Moreover, the introduction of the small interfering RNA targeted against PKCbeta suppressed the antigen-induced increase of AR. These results indicate that the activation of Syk, LAT, Gads, and subsequent PKCbeta is indispensable for the antigen-induced increase of AR of mast cells detected by SPR biosensors. PMID:18339533

  9. 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…

  10. 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…

  11. 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…

  12. 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…

  13. 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).…

  14. 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…

  15. 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…

  16. 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…

  17. 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…

  18. 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…

  19. 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). Analyses…

  20. 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).…

  1. 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…

  2. 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.…

  3. 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…

  4. 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…

  5. 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…

  6. 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

  7. 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)…

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

    PubMed Central

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

    2016-01-01

    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. PMID:26822065

  9. 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…

  10. CONFIRMATIONAL IDENTIFICATION OF ESCHERICHIA COLI, A COMPARISON OF GENOTYPIC AND PHENOTYPIC ASSAYS FOR GLUTAMATE DECARBOXYLASE AND B-D-GLUCURONIDASE

    EPA Science Inventory

    Genotypic and phenotypic assays for glutamate decarboxylase (GAD) and B-D-glucuronidase (GUD) were compared for their abilities to detect various strains of Escherichia coli and to discriminate among other bacterial species. Test strains included nonpathogenic E.coli, three major...

  11. Genetics Home Reference: Coats plus syndrome

    MedlinePlus

    ... Additional NIH Resources (2 links) National Eye Institute: Diagram of the Eye National Eye Institute: Retinal Detachment ... 1101/gad.222893.113. Citation on PubMed or Free article on PubMed Central Crow YJ, McMenamin J, ...

  12. Paradoxical cardiovascular effects of implementing adaptive emotion regulation strategies in generalized anxiety disorder.

    PubMed

    Aldao, Amelia; Mennin, Douglas S

    2012-02-01

    Recent models of generalized anxiety disorder (GAD) have expanded on Borkovec's avoidance theory by delineating emotion regulation deficits associated with the excessive worry characteristic of this disorder (see Behar, DiMarco, Hekler, Mohlman, & Staples, 2009). However, it has been difficult to determine whether emotion regulation is simply a useful heuristic for the avoidant properties of worry or an important extension to conceptualizations of GAD. Some of this difficulty may arise from a focus on purported maladaptive regulation strategies, which may be confounded with symptomatic distress components of the disorder (such as worry). We examined the implementation of adaptive regulation strategies by participants with and without a diagnosis of GAD while watching emotion-eliciting film clips. In a between-subjects design, participants were randomly assigned to accept, reappraise, or were not given specific regulation instructions. Implementation of adaptive regulation strategies produced differential effects in the physiological (but not subjective) domain across diagnostic groups. Whereas participants with GAD demonstrated lower cardiac flexibility when implementing adaptive regulation strategies than when not given specific instructions on how to regulate, healthy controls showed the opposite pattern, suggesting they benefited from the use of adaptive regulation strategies. We discuss the implications of these findings for the delineation of emotion regulation deficits in psychopathology. PMID:22218164

  13. Are there specific metacognitive processes associated with anxiety disorders in youth?

    PubMed

    Bacow, Terri Landon; May, Jill Ehrenreich; Brody, Leslie R; Pincus, Donna B

    2010-01-01

    While Wells' metacognitive model of generalized anxiety disorder (GAD) posits that certain metacognitive processes, such as negative meta-worry (negative beliefs about worry), are more strongly associated with symptoms of GAD than other anxiety disorders in adults, research has yet to determine whether the same pattern is true for younger individuals. We examined the relationship between several metacognitive processes and anxiety disorder diagnostic status in a sample of 98 youth aged 7-17 years. Twenty youth with GAD were compared with similarly sized groups of youth with obsessive-compulsive disorder (OCD, n = 18), social phobia (SOC, n = 20), separation anxiety disorder (SAD, n = 20), and healthy controls who were not patients (NONP, n = 20) using a self-report measure of metacognition adapted for use with young people in this age range (Metacognitions Questionnaire for Children). Contrary to expectations, only one specific metacognitive process was significantly associated with an anxiety disorder diagnosis, in that the controls endorsed a greater degree of cognitive monitoring (self-reported awareness of one's thoughts) than those with SAD. In addition, there was a trend indicating that nonpatients scored higher than youth with GAD on this scale. These surprising results suggest potentially differing patterns in the relationships between symptoms and metacognitive awareness in anxious youth, depending on the type of anxiety disorder presentation. PMID:22110332

  14. Aberrant regional neural fluctuations and functional connectivity in generalized anxiety disorder revealed by resting-state functional magnetic resonance imaging.

    PubMed

    Wang, Wei; Hou, Jingming; Qian, Shaowen; Liu, Kai; Li, Bo; Li, Min; Peng, Zhaohui; Xin, Kuolin; Sun, Gang

    2016-06-15

    The purpose of this study was to investigate the neural activity and functional connectivity in generalized anxiety disorder (GAD) during resting state, and how these alterations correlate to patients' symptoms. Twenty-eight GAD patients and 28 matched healthy controls underwent resting-state functional magnetic resonance (fMRI) scans. Amplitude of low-frequency fluctuation (ALFF) and seed-based resting-state functional connectivity (RSFC) were computed to explore regional activity and functional integration, and were compared between the two groups using the voxel-based two-sample t test. Pearson's correlation analyses were performed to examine the neural relationships with demographics and clinical symptoms scores. Compared to controls, GAD patients showed functional abnormalities: higher ALFF in the bilateral dorsomedial prefrontal cortex, bilateral dorsolateral prefrontal cortex and left precuneus/posterior cingulate cortex; lower connectivity in prefrontal gyrus; lower in prefrontal-limbic and cingulate RSFC and higher prefrontal-hippocampus RSFC were correlated with clinical symptoms severity, but these associations were unable to withstand correction for multiple testing. These findings may help facilitate further understanding of the potential neural substrate of GAD. PMID:27163197

  15. Decreased hair cortisol concentrations in generalised anxiety disorder.

    PubMed

    Steudte, Susann; Stalder, Tobias; Dettenborn, Lucia; Klumbies, Elisabeth; Foley, Paul; Beesdo-Baum, Katja; Kirschbaum, Clemens

    2011-04-30

    Previous research examining hypothalamic-pituitary-adrenal (HPA) axis activity in generalised anxiety disorder (GAD) has suggested a general hypercortisolism. These studies have mostly relied on salivary, plasma or urinary assessments, reflecting cortisol secretion over short time periods. The current study utilised the novel method of cortisol assessment in hair to obtain a retrospective index of cortisol secretion over a prolonged period of time. Hair cortisol levels were determined in 15 GAD patients and in 15 age- and gender-matched controls. In addition, participants collected six saliva samples (on awakening, +30 min, 12:00, 16:00, 20:00 h and at bedtime) on two consecutive weekdays for the assessment of the diurnal cortisol profile. Results revealed significantly lower (50-60%) cortisol levels in the first and second 3-cm hair segments of GAD patients compared to those of controls. No significant between-group differences were seen in diurnal cortisol profiles. The hair cortisol findings tentatively suggest that under naturalistic conditions GAD is associated with hypocortisolism. If corroborated by future research, this demonstrates the important qualities of cortisol measurement in hair as an ecologically valid, retrospective index of long-term cortisol secretion and as a marker for psychiatric disorders associated with hypo- or hypercortisolism. PMID:20889215

  16. 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. PMID:26460536

  17. 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…

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

    PubMed

    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

  19. Transcriptional regulation of glutamic acid decarboxylase in the male mouse amygdala by dietary phyto-oestrogens.

    PubMed

    Sandhu, K V; Yanagawa, Y; Stork, O

    2015-04-01

    Phyto-oestrogens are biologically active components of many human and laboratory animal diets. In the present study, we investigated, in adult male mice with C57BL/6 genetic background, the effects of a reduced phyto-oestrogens intake on anxiety-related behaviour and associated gene expression in the amygdala. After 6 weeks on a low-phyto-oestrogen diet (< 20 μg/g cumulative phyto-oestrogen content), animals showed reduced centre exploration in an open-field task compared to their littermates on a soybean-based standard diet (300 μg/g). Freezing behaviour in an auditory fear memory task, in contrast, was not affected. We hypothesised that this mildly increased anxiety may involve changes in the function of GABAergic local circuit neurones in the amygdala. Using GAD67(+/GFP) mice, we could demonstrate reduced transcription of the GAD67 gene in the lateral and basolateral amygdala under the low-phyto-oestrogen diet. Analysis of mRNA levels in microdissected samples confirmed this regulation and demonstrated concomitant changes in expression of the second glutamic acid decarboxylase (GAD) isoform, GAD65, as well as the anxiolytic neuropeptide Y. These molecular and behavioural alterations occurred without apparent changes in circulating oestrogens or testosterone levels. Our data suggest that expression regulation of interneurone-specific gene products in the amygdala may provide a mechanism for the control of anxiety-related behaviour through dietary phyto-oestrogens. PMID:25650988

  20. Pregabalin for the treatment of patients with generalized anxiety disorder with inadequate treatment response to antidepressants and severe depressive symptoms.

    PubMed

    Olivares, José M; Álvarez, Enrique; Carrasco, José L; Pérez Páramo, María; López-Gómez, Vanessa

    2015-09-01

    To evaluate the effectiveness of pregabalin in patients with resistant generalized anxiety disorder (GAD) and severe depressive symptoms, we carried out a post-hoc analysis of a multicenter, prospective, and observational 6-month study. We included patients who were at least 18 years old, fulfilled the Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for GAD, showed inadequate responses to previous courses of antidepressant treatment, had Montgomery-Asberg Rating Scale scores of at least 35, had not received pregabalin previously, and were prescribed pregabalin upon entry into this study. We included 1815 patients fulfilling the DSM-IV criteria for GAD, and 133 (7.3%) fulfilled the selection criteria for these analyses. Ninety-seven percent of the patients received pregabalin (mean dose: 222 mg/day) in combination with other psychotropics. The Hamilton Anxiety Scale total score was reduced by a mean of 20.3 points (95% confidence interval, 22.1-18.4) (57.2% reduction) at month 6. Pregabalin also ameliorated comorbid depressive symptoms, with a reduction in the mean score of the Montgomery-Asberg Rating Scale of 22.3 points (95% confidence interval, 24.2-20.4) (56.6% reduction). Our results suggest that pregabalin, as part of a combination regimen with antidepressants and/or benzodiazepines, might be effective for the treatment of patients with GAD who have shown inadequate response to previous antidepressants and have severe depressive symptoms. PMID:26111356

  1. 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…

  2. What Do Childhood Anxiety Disorders Predict?

    ERIC Educational Resources Information Center

    Bittner, Antje; Egger, Helen L.; Erkanli, Alaattin; Costello, E. Jane; Foley, Debra L.; Angold, Adrian

    2007-01-01

    Background: Few longitudinal studies of child and adolescent psychopathology have examined the links between specific childhood anxiety disorders and adolescent psychiatric disorder. In this paper we test the predictive specificity of separation anxiety disorder (SAD), overanxious disorder (OAD), generalized anxiety disorder (GAD), and social…

  3. 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…

  4. 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

  5. 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. PMID:26822065

  6. 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. Parents…

  7. Virtual reality in the treatment of generalized anxiety disorders.

    PubMed

    Gorini, Alessandra; Pallavicini, Federica; Algeri, Davide; Repetto, Claudia; Gaggioli, Andrea; Riva, Giuseppe

    2010-01-01

    Generalized anxiety disorder (GAD) is a common anxiety disorder characterized by 6 months of "excessive anxiety and worry" about a variety of events and situations. Anxiety and worry are often accompanied by additional symptoms like restlessness, being easily fatigued, difficulty concentrating, irritability, muscle tension and disturbed sleep. GAD is usually treated with medications and/or psychotherapy. In particular, the two most promising treatments seem to be cognitive therapy and applied relaxation. In this study we integrated these approaches through the use of a biofeedback enhanced virtual reality (VR) system used both for relaxation and controlled exposure. Moreover, this experience is strengthened by the use of a mobile phone that allows patients to perform the virtual experience even in an outpatient setting. This paper describe the results of a controlled trial (NCT00602212) involving 20 GAD patients randomly assigned to the following groups: (1) the VR and Mobile group (VRMB) including biofeedback; (2) the VR and Mobile group (VRM) without biofeedback; (3) the waiting list (WL) group. The clinical data underlined that (a) VR can be used also in the treatment of GAD; (b) in a VR treatment, patients take advantage of a mobile device that delivers in an outpatient setting guided experiences, similar to the one experienced in VR. PMID:20543266

  8. 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…

  9. Disability and health-related quality of life in outpatients with generalised anxiety disorder treated in psychiatric clinics: is there still room for improvement?

    PubMed Central

    2011-01-01

    Objective We assessed the impact of generalised anxiety disorder (GAD) on disability and health-related quality of life in outpatients treated in psychiatric clinics via a secondary analysis conducted in 799 patients from a cross-sectional study of prevalence of GAD in psychiatric clinics. Methods Patients were allocated into two groups: follow-up (15.7%) and newly diagnosed patients (84.3%), and were administered the Hamilton Anxiety Scale (HAM-A), Clinical Global Impressions Scale (CGI), Sheehan Disability Scale (SDS), and 36-item short form structured quality of life questionnaire (SF-36) scales. Results The newly diagnosed group showed higher significant intensity of anxiety (56.9% vs 43.0% (HAM-A >24)), psychiatrist's CGI Severity (CGI-S) scores (4.2 vs 3.7), and perceived stress according to SDS (5.7 vs 5.2). They also showed lower scores in mental health-related quality of life: 25.4 vs 30.8. Statistical differences by gender were not observed. GAD was shown to have a significant impact on patient quality of life and disability, with a substantial portion having persistent, out of control symptoms despite treatment. Conclusions These results suggest that there is still room for improvement in the medical management of patients with GAD treated in psychiatric clinics. PMID:21401940

  10. Is the Resolution Style "Exiting Statements" Related to Adolescent Problem Behavior?

    ERIC Educational Resources Information Center

    Wijsbroek, Saskia A. M.; Hale, William W., III; Van Doorn, Muriel D.; Raaijmakers, Quinten A. W.; Meeus, Wim H. J.

    2010-01-01

    This study examined the association between the adolescents' conflict resolution style "exiting statements" (i.e., the expression of the adolescent' desire to minimize or end the contact with his or her parents) in parent-adolescent conflicts with self-rated adolescent GAD symptoms and delinquency symptoms of 1313 adolescents. A multi-group,…

  11. Training-induced changes in the expression of GABAA-associated genes in the amygdala after the acquisition and extinction of Pavlovian fear

    PubMed Central

    Heldt, Scott A.; Ressler, Kerry J.

    2008-01-01

    Previous work suggests the γ-aminobutyric acid (GABA)ergic system may be dynamically regulated during emotional learning. In the current study we examined training-induced changes in the expression of GABAA-related genes and the binding of GABA receptor radioligands in the amygdala after the acquisition and extinction of Pavlovian fear. Using in situ hybridization, we examined the expression pattern changes of mRNAs for GABAergic markers in the lateral, basolateral and central subdivisions of the amygdala in C57Bl/6J mice. These markers included GABA-synthesizing enzymes (GAD67 and GAD65), major GABAA receptor subunits (α1, α2, α3, α5, β2 and γ2) and the expression of mRNAs that are involved in a variety of GABA-related intracellular processes, including GABA transporter-1 (GAT1), GABAA receptor-associated protein and the GABAA clustering protein, gephyrin. With fear conditioning, we found decreased mRNA levels of α1, α5 and GAD67, as well as deceased benzodiazepine binding in the amygdala. Fear extinction induced an increase in mRNA levels of α2, β2, GAD67 and gephyrin, as well as a decrease in GAT1. Together, these findings indicate that the acquisition of fear induced a downregulation of mRNA markers related to a decrease in amygdala GABAergic function, whereas the acquisition of fear extinction produced an upregulation of GABAergic markers related to enhanced GABAergic transmission. PMID:18088283

  12. Cognitive Behavioral Treatment for Older Adults with Generalized Anxiety Disorder: A Therapist Manual for Primary Care Settings

    ERIC Educational Resources Information Center

    Stanley, Melinda A.; Diefenbach, Gretchen J.; Hopko, Derek R.

    2004-01-01

    At least four academic clinical trials have demonstrated the utility of cognitive behavior therapy (CBT) for older adults with generalized anxiety disorder (GAD). These data may not generalize, however, to more heterogeneous and functionally impaired patients and the medical settings in which they typically receive care. A recent pilot project…

  13. A fluorescence-coupled assay for gamma aminobutyric acid (GABA) reveals metabolic stress-induced modulation of GABA content in neuroendocrine cancer.

    PubMed

    Ippolito, Joseph E; Piwnica-Worms, David

    2014-01-01

    Pathways involved in the synthesis of the neurotransmitter gamma-aminobutyric acid (GABA) have been implicated in the pathogenesis of high grade neuroendocrine (NE) neoplasms as well as neoplasms from a non-NE lineage. Using The Cancer Genome Atlas, overexpression of the GABA synthetic enzyme, glutamate decarboxylase 1 (GAD1), was found to be associated with decreased disease free-survival in prostate adenocarcinoma and decreased overall survival in clear cell renal cell carcinomas. Furthermore, GAD1 was found to be expressed in castrate-resistant prostate cancer cell lines, but not androgen-responsive cell lines. Using a novel fluorescence-coupled enzymatic microplate assay for GABA mediated through reduction of resazurin in a prostate neuroendocrine carcinoma (PNEC) cell line, acid microenvironment-induced stress increased GABA levels while alkaline microenvironment-induced stress decreased GABA through modulation of GAD1 and glutamine synthetase (GLUL) activities. Moreover, glutamine but not glucose deprivation decreased GABA through modulation of GLUL. Consistent with evidence in prokaryotic and eukaryotic organisms that GABA synthesis mediated through GAD1 may play a crucial role in surviving stress, GABA may be an important mediator of stress survival in neoplasms. These findings identify GABA synthesis and metabolism as a potentially important pathway for regulating cancer cell stress response as well as a potential target for therapeutic strategies. PMID:24551133

  14. Sensory-Derived Glutamate Regulates Presynaptic Inhibitory Terminals in Mouse Spinal Cord.

    PubMed

    Mende, Michael; Fletcher, Emily V; Belluardo, Josephine L; Pierce, Joseph P; Bommareddy, Praveen K; Weinrich, Jarret A; Kabir, Zeeba D; Schierberl, Kathryn C; Pagiazitis, John G; Mendelsohn, Alana I; Francesconi, Anna; Edwards, Robert H; Milner, Teresa A; Rajadhyaksha, Anjali M; van Roessel, Peter J; Mentis, George Z; Kaltschmidt, Julia A

    2016-06-15

    Circuit function in the CNS relies on the balanced interplay of excitatory and inhibitory synaptic signaling. How neuronal activity influences synaptic differentiation to maintain such balance remains unclear. In the mouse spinal cord, a population of GABAergic interneurons, GABApre, forms synapses with the terminals of proprioceptive sensory neurons and controls information transfer at sensory-motor connections through presynaptic inhibition. We show that reducing sensory glutamate release results in decreased expression of GABA-synthesizing enzymes GAD65 and GAD67 in GABApre terminals and decreased presynaptic inhibition. Glutamate directs GAD67 expression via the metabotropic glutamate receptor mGluR1β on GABApre terminals and regulates GAD65 expression via autocrine influence on sensory terminal BDNF. We demonstrate that dual retrograde signals from sensory terminals operate hierarchically to direct the molecular differentiation of GABApre terminals and the efficacy of presynaptic inhibition. These retrograde signals comprise a feedback mechanism by which excitatory sensory activity drives GABAergic inhibition to maintain circuit homeostasis. PMID:27263971

  15. 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…

  16. Survival and expression of acid resistance genes in Shiga toxin-producing Escherichia coli acid adapted in pineapple juice and exposed to synthetic gastric fluid

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aims: The aim of this research was to examine relative transcriptional expression of acid resistance (AR) genes, rpoS, gadA and adiA, in O157:H7 and non-O157 Shiga toxin-producing Escherichia coli (STEC) serotypes after adaptation to pineapple juice (PJ) and subsequently to determine survival with e...

  17. GABA-shunt enzymes activity in GH3 cells with reduced level of PMCA2 or PMCA3 isoform

    SciTech Connect

    Kowalski, Antoni

    2011-08-12

    Highlights: {yields} Suppression of PMCA2 or PMCA3 slows down proliferation of GH3 cells. {yields} PMCA2 suppression lowers the activity of GABA-shunt enzymes. {yields} PMCA3 suppression increases the expression of glutamate decarboxylase 65. {yields} PMCA2 and PMCA3 function appears to be linked to regulation of GABA metabolism. -- Abstract: GABA ({gamma}-aminobutyric acid) is important neurotransmitter and regulator of endocrine functions. Its metabolism involves three enzymes: glutamate decarboxylase (GAD65 and GAD67), GABA aminotransferase (GABA-T) and succinic semialdehyde dehydrogenase (SSADH). As many cellular processes GABA turnover can depend on calcium homeostasis, which is maintained by plasma membrane calcium ATPases (PMCAs). In excitable cells PMCA2 and PMCA3 isoforms are particularly important. In this study we focused on GABA-metabolizing enzymes expression and activity in rat anterior pituitary GH3 cells with suppressed expression of PMCA2 or PMCA3. We observed that PMCA3-reduced cells have increased GAD65 expression. Suppression of PMCA2 caused a decrease in total GAD and GABA-T activity. These results indicate that PMCA2 and PMCA3 presence may be an important regulatory factor in GABA metabolism. Results suggest that PMCA2 and PMCA3 function is rather related to regulation of GABA synthesis and degradation than supplying cells with metabolites, which can be potentially energetic source.

  18. Millon multiaxial personality patterns differentiate depressed and anxious outpatients.

    PubMed

    Freeman, A M; Kablinger, A S; Rolland, P D; Brannon, G E

    1999-01-01

    Ninety-three patients, including 47 patients with Generalized Anxiety Disorder (GAD) and 46 patients with Major Depression (MD), were entered into recent clinical trials. Clinicians acknowledge that during the initial screening process, clear separation between depressed and anxious patients may be difficult. By using the DSM-IV criteria, the Hamilton Depression and Anxiety Scales, and a variety of other structured evaluations, patients were divided into the two diagnostic groups. The Millon Multiaxial Inventory (MCMI-III) was administered to all 93 patients as part of their initial assessment, but was not used in the diagnostic decision making process or in assignment to a particular clinical study. Upon completion of these studies, the Millon data were analyzed utilizing a cutoff score of 75, conforming to previous studies. Statistically significant differences in Millon personality patterns between MD and GAD patients included dependent, obsessive-compulsive, self-defeating, and borderline traits. Patients exhibiting dependent, self-defeating, and borderline patterns were statistically more likely to be included in clinical trials of MD rather than GAD. Also, patients with MD were more likely to disclose clinical information and exhibit self-critical behavior when compared to those with GAD. These results suggest that the MCMI-III may detect personality differences between anxious and depressed outpatients presenting for clinical trials. PMID:10569130

  19. Hypoxia regulates glutamate metabolism and membrane transport in rat PC12 cells.

    PubMed

    Kobayashi, S; Millhorn, D E

    2001-03-01

    We investigated the effect of hypoxia on glutamate metabolism and uptake in rat pheochromocytoma (PC12) cells. Various key enzymes relevant to glutamate production, metabolism and transport were coordinately regulated by hypoxia. PC12 cells express two glutamate-metabolizing enzymes, glutamine synthetase (GS) and glutamate decarboxylase (GAD), as well as the glutamate-producing enzyme, phosphate-activated glutaminase (PAG). Exposure to hypoxia (1% O(2)) for 6 h or longer increased expression of GS mRNA and protein and enhanced GS enzymatic activity. In contrast, hypoxia caused a significant decrease in expression of PAG mRNA and protein, and also decreased PAG activity. In addition, hypoxia led to an increase in GAD65 and GAD67 protein levels and GAD enzymatic activity. PC12 cells express three Na(+)-dependent glutamate transporters; EAAC1, GLT-1 and GLAST. Hypoxia increased EAAC1 and GLT-1 protein levels, but had no effect on GLAST. Chronic hypoxia significantly enhanced the Na(+)-dependent component of glutamate transport. Furthermore, chronic hypoxia decreased cellular content of glutamate, but increased that of glutamine. Taken together, the hypoxia-induced changes in enzymes related to glutamate metabolism and transport are consistent with a decrease in the extracellular concentration of glutamate. This may have a role in protecting PC12 cells from the cytotoxic effects of glutamate during chronic hypoxia. PMID:11259512

  20. DNA fragmentation is increased in non-GABAergic neurons in bipolar disorder but not in schizophrenia

    PubMed Central

    Buttner, Ned; Bhattacharyya, Sujoy; Walsh, John; Benes, Francine M.

    2007-01-01

    Apoptosis is thought to contribute to neuronal loss in bipolar disorder and schizophrenia, although empiric evidence in support of this idea has been lacking. In this study, we investigated whether or not apoptosis is associated with GABAergic interneurons in the anterior cingulate cortex in schizophrenia (n = 14) and bipolar disorder (n = 14) when compared to normal controls (n = 14). A double-labeling technique using the Klenow method of in situ end-labeling (ISEL) of single-stranded DNA breaks was combined with an in situ hybridization localization of mRNA for the 67 kiloDalton (kDa) isoform of glutamate decarboxylase (GAD67) and applied to the anterior cingulate cortex of 14 normal controls, 14 schizophrenics, and 14 patients with bipolar disorder matched for age and postmortem interval. An increase in Klenow-positive, GAD67-negative nuclei was observed in layer V/VI of patients with bipolar disorder, but not schizophrenics. Klenow-positive cells that were also positive for GAD67 mRNA did not show differences in either patient group. Conclusions: This is the first demonstration that there is more DNA fragmentation in cells showing no detectable GAD67 mRNA in patients with bipolar disorder than in schizophrenics or controls. These findings suggest that non-GABAergic cells may be selectively vulnerable to oxidative stress in patients with bipolar disorder. PMID:17442540

  1. 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…

  2. 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. PMID:27050932

  3. Developmental Trajectories of Auditory Cortex Synaptic Structures and Gap-Prepulse Inhibition of Acoustic Startle Between Early Adolescence and Young Adulthood in Mice.

    PubMed

    Moyer, Caitlin E; Erickson, Susan L; Fish, Kenneth N; Thiels, Edda; Penzes, Peter; Sweet, Robert A

    2016-05-01

    Cortical excitatory and inhibitory synapses are disrupted in schizophrenia, the symptoms of which often emerge during adolescence, when cortical excitatory synapses undergo pruning. In auditory cortex, a brain region implicated in schizophrenia, little is known about the development of excitatory and inhibitory synapses between early adolescence and young adulthood, and how these changes impact auditory cortex function. We used immunohistochemistry and quantitative fluorescence microscopy to quantify dendritic spines and GAD65-expressing inhibitory boutons in auditory cortex of early adolescent, late adolescent, and young adult mice. Numbers of spines decreased between early adolescence and young adulthood, during which time responses increased in an auditory cortex-dependent sensory task, silent gap-prepulse inhibition of the acoustic startle reflex (gap-PPI). Within-bouton GAD65 protein and GAD65-expressing bouton numbers decreased between late adolescence and young adulthood, a delay in onset relative to spine and gap-PPI changes. In mice lacking the spine protein kalirin, there were no significant changes in spine number, within-bouton GAD65 protein, or gap-PPI between adolescence and young adulthood. These results illustrate developmental changes in auditory cortex spines, inhibitory boutons, and auditory cortex function between adolescence and young adulthood, and provide insights into how disrupted adolescent neurodevelopment could contribute to auditory cortex synapse pathology and auditory impairments. PMID:25759333

  4. Adsorption Behavior of Heat Modified Soybean Oil via Boundary Lubrication Coefficient of Friction Measurements

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The frictional behaviors of soybean oil and heat modified soybean oils with different Gardner scale viscosities as additives in hexadecane have been examined in a boundary lubrication test regime (steel contacts) using Langmuir adsorption model. The free energy of adsorption (delta-Gads) of various...

  5. Filling in the Gaps in the Catalog of Cancer Genes - TCGA

    Cancer.gov

    Dr. Gad Getz and his group at the Broad Institute of MIT and Harvard identifies 33 new cancer-causing genes and finds that the catalog of cancer genes is far from complete. Learn more about the current cancer genome landscape in this Case Study.

  6. Cognitive Vulnerability in Patients with Generalized Anxiety Disorder, Dysthymic Disorder and Normal Individuals

    PubMed Central

    Al-Ghorabaie, Fateme Moin; Noferesti, Azam; Fadaee, Mahdi; Ganji, Nima

    2016-01-01

    Aim: The purpose of this study was to assess cognitive vulnerability and response style in clinical and normal individuals. Method: A sample of 90 individuals was selected for each of the 3 groups of Generalized Anxiety disorder, Dysthymic disorder and normal individuals. They completed MCQ and RSQ. Results: Results analyzed by MANOVA and post hoc showed significant differences among groups. Dysthymic group and GAD reported higher scores on cognitive confidence compared to the normal group. Individuals with GAD showed highly negative beliefs about need to control thought, compared to the other groups, but in cognitive self-consciousness they have no differences with the normal group. In regard to uncontrollability, danger and positive beliefs, GAD group had higher levels than the other groups. Although normal and GAD group didn’t show any significant differences in response style, there was a significant difference between Dysthymic group and other groups in all response styles. Discussion: Beliefs and meta-cognitive strategies can be distinguished between clinical and non clinical individuals. Also, findings support the Self-Regulatory Executive Function model. PMID:27045393

  7. 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. PMID:26825550

  8. Generalized anxiety disorder and major depressive disorder comorbidity: an example of genetic pleiotropy?

    PubMed

    Gorwood, P

    2004-02-01

    Generalized anxiety disorder (GAD) and major depressive disorder (MDD) are the most common type of anxiety-mood comorbidity. Up to 80% of subjects with lifetime GAD also have a comorbid mood disorder during their lifetime. Many hypotheses have been raised to explain such high comorbidity. Pleiotropy, i.e. a single genetic mutation explains (apparently) different disorders, is one of them and is hereby reviewed. Importance and reliability of GAD and MDD comorbidity (1); Evidence in favour of co-aggregation of GAD and MDD within families (the risk of one disorder in a proband increasing the risk for the other in relatives) (2); substantial heredity for both disorders according to twin studies with evidence for genetic correlation of unity between the two disorders (3); existence of numerous mechanisms (4) potentially linking the two disorders to common vulnerability genes, are all in accordance with such a hypothesis. Some examples of potentially shared mechanisms (such as CRF dysregulation or abnormal transcription factors) and possible common vulnerability genes (for example, the serotonin transporter gene) are given to highlight the pleiotropy hypothesis. PMID:14969778

  9. Decreased choline and creatine concentrations in centrum semiovale in patients with generalized anxiety disorder: relationship to IQ and early trauma.

    PubMed

    Coplan, Jeremy D; Mathew, Sanjay J; Mao, Xiangling; Smith, Eric L P; Hof, Patrick R; Coplan, Paul M; Rosenblum, Leonard A; Gorman, Jack M; Shungu, Dikoma C

    2006-06-30

    We have demonstrated, using proton magnetic resonance spectroscopy imaging ((1)H-MRSI), elevations of N-acetyl-aspartate/creatine (NAA/CR) in right dorsolateral prefrontal cortex (DLPFC) in patients with generalized anxiety disorder (GAD) in comparison to healthy volunteers. A recent study indicates that the volume of prefrontal cortical white matter may be disproportionately increased in man in comparison to other primate species, with evolutionary implications. We therefore re-analyzed the identical scans with a specific focus on the centrum semiovale (CSO) as a representative region of interest of cerebral white matter. The central hypothesis was, in accordance with our gray matter findings, that patients with GAD, in comparison to healthy controls, would exhibit either an increase in NAA in CSO, or alternatively demonstrate reductions in concentrations of choline (CHO)-containing compounds and/or creatine+phosphocreatine (CR). MRSI scans that were obtained from an earlier [Mathew, S.J., Mao, X., Coplan, J.D., Smith, E.L., Sackeim, H.A., Gorman, J.M., Shungu, D.C., 2004. Dorsolateral prefrontal cortical pathology in generalized anxiety disorder: a proton magnetic resonance spectroscopic imaging study. American Journal of Psychiatry 161, 1119-1121] sample of 15 patients with GAD [6 with early trauma (ET)] and 15 healthy age- and sex-matched volunteers were analyzed further for CSO metabolite alterations. Self-reported worry was scored using the Penn State Worry Questionnaire (PSWQ) and intelligence was assessed using the Wechsler Abbreviated Scale of Intelligence (WASI). Serial multislice/multivoxel MRSI scans had been performed on a 1.5-T MRI. Using absolute quantification methods for metabolite concentrations, we examined NAA, CHO and CR. GAD patients without ET exhibited bilaterally decreased concentrations of CHO and CR in CSO in comparison to healthy volunteers, whereas GAD patients with ET were indistinguishable from controls. In patients with GAD, high IQ

  10. Cholera Toxin B Subunit Linked to Glutamic Acid Decarboxylase Suppresses Dendritic Cell Maturation and Function

    PubMed Central

    Odumosu, Oludare; Nicholas, Dequina; Payne, Kimberly; Langridge, William

    2012-01-01

    Dendritic cells are the largest population of antigen presenting cells in the body. One of their main functions is to regulate the delicate balance between immunity and tolerance responsible for maintenance of immunological homeostasis. Disruption of this delicate balance often results in chronic inflammation responsible for initiation of organ specific autoimmune diseases such as rheumatoid arthritis, multiple sclerosis and type I diabetes. The cholera toxin B subunit (CTB) is a weak mucosal adjuvant known for its ability to stimulate immunity to antigenic proteins. However, conjugation of CTB to many autoantigens can induce immunological tolerance resulting in suppression of autoimmunity. In this study, we examined whether linkage of CTB to a 5 kDa C-terminal protein fragment of the major diabetes autoantigen glutamic acid decarboxylase (GAD35), can block dendritic cell (DC) functions such as biosynthesis of co-stimulatory factor proteins CD86, CD83, CD80 and CD40 and secretion of inflammatory cytokines. The results of human umbilical cord blood monocyte-derived DC - GAD35 autoantigen incubation experiments showed that inoculation of immature DCs (iDCs), with CTB-GAD35 protein dramatically suppressed levels of CD86, CD83, CD80 and CD40 co-stimulatory factor protein biosynthesis in comparison with GAD35 alone inoculated iDCs. Surprisingly, incubation of iDCs in the presence of the CTB-autoantigen and the strong immunostimulatory molecules PMA and Ionomycin revealed that CTB-GAD35 was capable of arresting PMA + Ionomycin induced DC maturation. Consistant with this finding, CTB-GAD35 mediated suppression of DC maturation was accompanied by a dramatic decrease in the secretion of the pro-inflammatory cytokines IL-12/23p40 and IL-6 and a significant increase in secretion of the immunosuppressive cytokine IL-10. Taken together, our experimental data suggest that linkage of the weak adjuvant CTB to the dominant type 1 diabetes autoantigen GAD strongly inhibits DC

  11. KCC2 expression supersedes NKCC1 in mature fiber cells in mouse and rabbit lenses

    PubMed Central

    Kasinathan, Chinnaswamy

    2015-01-01

    Purpose Na-K-Cl cotransporter 1 (NKCC1) and K-Cl cotransporter 2 (KCC2) have fundamental roles in neuron differentiation that are integrated with gamma-aminobutyric acid (GABA) and glutamate receptors, GABA synthesized by GAD25/65/67 encoded by GAD1/GAD2 genes, and GABA transporters (GATs). Cells in the eye lens express at least 13 GABA receptor subunits, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl D-aspartate (NMDA) glutamate receptors, GAD1/GAD2, GAT1–4 and vGAT, and NKCC1. NKCC1:KCC2 ratios determine the switch in GABA actions from trophic/growth promoting early in development to their classic inhibitory roles in adult neurons. Lens epithelial cells cover the anterior surface and differentiate to elongated fiber cells in the lens interior with comparable morphology and sub-cellular structures as neurons. NKCC1 is expressed before KCC2 in neuron development and increases cell chloride, which stimulates differentiation and process formation. Subsequently, KCC2 increases and extrudes cell chloride linked with maturation. KCC2 has an additional structural moonlighting role interacting with F-actin scaffolding in dendritic spine morphogenesis. We examined KCC2 versus NKCC1 spatial expression in relation to fiber cell developmental status within the lens. Methods Immunofluorescence and immunoblots were used to detect expression in mouse and rabbit lenses. Results NKCC1 was restricted to peripheral elongating lens fiber cells in young adult mouse and rabbit lenses. Lens KCC2 expression included the major KCC2b neuronal isoform and was detected in interior fiber cells with decreased NKCC1 expression and localized at the membranes. Lens expression of RE-1 silencing transcription factor (REST) regulated KCC2 is consistent with GAD1 and GAD2, several GABA and glutamate receptor subunits, miR-124, and other REST-regulated genes expressed in lenses. Conclusions NKCC1 in peripheral elongating fiber cells is superseded by KCC2 expression in

  12. Clinical Spectrum of Stiff Person Syndrome: A Review of Recent Reports

    PubMed Central

    Sarva, Harini; Deik, Andres; Ullah, Aman; Severt, William L.

    2016-01-01

    Background “Classic” stiff person syndrome (SPS) features stiffness, anti-glutamic acid decarboxylase (anti-GAD) antibodies, and other findings. Anti-GAD antibodies are also detected in some neurological syndromes (such as ataxia) in which stiffness is inconsistently present. Patients with otherwise “classic” SPS may either lack anti-GAD antibodies or be seropositive for others. Hence, SPS cases appear to fall within a clinical spectrum that includes conditions such as progressive encephalomyelitis with rigidity and myoclonus (PERM), which exhibits brainstem and autonomic features. We have compiled herein SPS-spectrum cases reported since 2010, and have segregated them on the basis of likely disease mechanism (autoimmune, paraneoplastic, or cryptogenic) for analysis. Methods The phrases “stiff person syndrome”, “PERM”, “anti-GAD antibody syndrome”, and “glycine receptor antibody neurological disorders” were searched for in PubMed in January 2015. The results were narrowed to 72 citations after excluding non-English and duplicate reports. Clinical descriptions, laboratory data, management, and outcomes were categorized, tabulated, and analyzed. Results Sixty-nine autoimmune, 19 paraneoplastic, and 13 cryptogenic SPS-spectrum cases were identified. SPS was the predominant diagnosis among the groups. Roughly two-thirds of autoimmune and paraneoplastic cases were female. Anti-GAD antibodies were most frequently identified, followed by anti-amphiphysin among paraneoplastic cases and by anti-glycine receptor antibodies among autoimmune cases. Benzodiazepines were the most commonly used medications. Prognosis seemed best for cryptogenic cases; malignancy worsened that of paraneoplastic cases. Discussion Grouping SPS-spectrum cases by pathophysiology provided insights into work-up, treatment, and prognosis. Ample phenotypic and serologic variations are present within the categories. Ruling out malignancy and autoimmunity is appropriate for suspected

  13. An Open Trial of Emotion Regulation Therapy For Generalized Anxiety Disorder and Co-Occurring Depression

    PubMed Central

    Mennin, Douglas S.; Fresco, David M.; Ritter, Michael; Heimberg, Richard G.

    2015-01-01

    Background Although CBT is efficacious for a wide variety of psychiatric conditions, relatively fewer GAD patients achieve high endstate functioning as compared to patients receiving CBTs for other disorders. Moreover, GAD trials that utilized patient samples without prominent depression have tended to report that effect sizes for depressive outcomes were small or diminished to pre-treatment levels in the follow-up period. Emotion Regulation Therapy (ERT) integrates principles from traditional and contemporary cognitive behavioral treatments with basic and translational findings from affect science to offer a blueprint for improving intervention by focusing on motivational, regulatory, and contextual learning mechanisms. Method The purpose of this investigation was to provide initial support for the efficacy of ERT in an open trial of patients with GAD and co-occurring depressive symptoms. Twenty-one patients received a 20-session version of ERT delivered in weekly individual sessions. Standardized clinician ratings and self-report measures were assessed at pre-, mid-, and post-treatment as well as at three- and nine-month follow-ups. Intent-to-treat analyzes were utilized. Results GAD patients, half with comorbid major depression, evidenced statistically and clinically meaningful improvements in symptom severity, impairment, quality of life, and in model-related outcomes including emotional/motivational intensity, mindful attending/acceptance, decentering, and cognitive reappraisal. Patients maintained gains across the three and nine month follow-up periods. Conclusions These findings, although preliminary, provide additional evidence for the role of emotion dysregulation in the onset, maintenance, and now treatment of conditions such as GAD and co-occurring depressive symptoms. PMID:25945946

  14. Generalized Anxiety Disorder and Social Anxiety Disorder, but Not Panic Anxiety Disorder, Are Associated with Higher Sensitivity to Learning from Negative Feedback: Behavioral and Computational Investigation

    PubMed Central

    Khdour, Hussain Y.; Abushalbaq, Oday M.; Mughrabi, Ibrahim T.; Imam, Aya F.; Gluck, Mark A.; Herzallah, Mohammad M.; Moustafa, Ahmed A.

    2016-01-01

    Anxiety disorders, including generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic anxiety disorder (PAD), are a group of common psychiatric conditions. They are characterized by excessive worrying, uneasiness, and fear of future events, such that they affect social and occupational functioning. Anxiety disorders can alter behavior and cognition as well, yet little is known about the particular domains they affect. In this study, we tested the cognitive correlates of medication-free patients with GAD, SAD, and PAD, along with matched healthy participants using a probabilistic category-learning task that allows the dissociation between positive and negative feedback learning. We also fitted all participants' data to a Q-learning model and various actor-critic models that examine learning rate parameters from positive and negative feedback to investigate effects of valence vs. action on performance. SAD and GAD patients were more sensitive to negative feedback than either PAD patients or healthy participants. PAD, SAD, and GAD patients did not differ in positive-feedback learning compared to healthy participants. We found that Q-learning models provide the simplest fit of the data in comparison to other models. However, computational analysis revealed that groups did not differ in terms of learning rate or exploration values. These findings argue that (a) not all anxiety spectrum disorders share similar cognitive correlates, but are rather different in ways that do not link them to the hallmark of anxiety (higher sensitivity to negative feedback); and (b) perception of negative consequences is the core feature of GAD and SAD, but not PAD. Further research is needed to examine the similarities and differences between anxiety spectrum disorders in other cognitive domains and potential implementation of behavioral therapy to remediate cognitive deficits. PMID:27445719

  15. Generalized Anxiety Disorder and Social Anxiety Disorder, but Not Panic Anxiety Disorder, Are Associated with Higher Sensitivity to Learning from Negative Feedback: Behavioral and Computational Investigation.

    PubMed

    Khdour, Hussain Y; Abushalbaq, Oday M; Mughrabi, Ibrahim T; Imam, Aya F; Gluck, Mark A; Herzallah, Mohammad M; Moustafa, Ahmed A

    2016-01-01

    Anxiety disorders, including generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic anxiety disorder (PAD), are a group of common psychiatric conditions. They are characterized by excessive worrying, uneasiness, and fear of future events, such that they affect social and occupational functioning. Anxiety disorders can alter behavior and cognition as well, yet little is known about the particular domains they affect. In this study, we tested the cognitive correlates of medication-free patients with GAD, SAD, and PAD, along with matched healthy participants using a probabilistic category-learning task that allows the dissociation between positive and negative feedback learning. We also fitted all participants' data to a Q-learning model and various actor-critic models that examine learning rate parameters from positive and negative feedback to investigate effects of valence vs. action on performance. SAD and GAD patients were more sensitive to negative feedback than either PAD patients or healthy participants. PAD, SAD, and GAD patients did not differ in positive-feedback learning compared to healthy participants. We found that Q-learning models provide the simplest fit of the data in comparison to other models. However, computational analysis revealed that groups did not differ in terms of learning rate or exploration values. These findings argue that (a) not all anxiety spectrum disorders share similar cognitive correlates, but are rather different in ways that do not link them to the hallmark of anxiety (higher sensitivity to negative feedback); and (b) perception of negative consequences is the core feature of GAD and SAD, but not PAD. Further research is needed to examine the similarities and differences between anxiety spectrum disorders in other cognitive domains and potential implementation of behavioral therapy to remediate cognitive deficits. PMID:27445719

  16. Antigen-specific immunomodulation for type 1 diabetes by novel recombinant antibodies directed against diabetes-associates auto-reactive T cell epitope.

    PubMed

    Dahan, Rony; Gebe, John A; Preisinger, Anton; James, Eddie A; Tendler, Mark; Nepom, Gerald T; Reiter, Yoram

    2013-12-01

    The trimolecular complex composed of autoreactive T-cell receptor, MHC class II, and an autoantigenic peptide plays a central role in the activation of pathogenic Islet-specific CD4+ T cells in type 1 diabetes (T1D). We isolated and characterized novel antibodies against autoreactive T-cell epitopes associated with T1D. Our antibodies mimic the specificity of the T-cell receptor (TCR), while binding MHC class II/peptide complexes in an autoantigen peptide specific, MHC-restricted manner. The isolated TCR-like antibodies were directed against the minimal T-cell epitope GAD-555-567 in the context of the HLA-DR4-diabetic-associated molecule. A representative high-affinity TCR-like antibody clone (G3H8) enabled the detection of intra- and extra-cellular DR4/GAD-555-567 complexes in antigen presenting cells. I561M single mutation at the central position (P5) of the GAD-555-567 peptide abolished the binding of G3H8 to the DR4/GAD complex, demonstrating its high fine TCR-like specificity. The G3H8 TCR-like antibody significantly inhibited GAD-555-567 specific, DR4 restricted T-cell response in vitro and in vivo in HLA-DR4 transgenic mice. Our findings constitute a proof-of-concept for the utility of TCR-like antibodies as antigen-specific immunomodulation agents for regulating pathogenic T-cells and suggest that TCR-like antibodies targeting autoreactive MHC class II epitopes are valuable research tools that enable studies related to antigen presentation as well as novel therapeutic agents that may be used to modulate autoimmune disorders such as T1D. PMID:24090977

  17. Differential alterations of resting-state functional connectivity in generalized anxiety disorder and panic disorder.

    PubMed

    Cui, Huiru; Zhang, Jie; Liu, Yicen; Li, Qingwei; Li, Hui; Zhang, Lanlan; Hu, Qiang; Cheng, Wei; Luo, Qiang; Li, Jianqi; Li, Wei; Wang, Jijun; Feng, Jianfeng; Li, Chunbo; Northoff, Georg

    2016-04-01

    Generalized anxiety disorder (GAD) and panic disorder (PD) are most common anxiety disorders with high lifetime prevalence while the pathophysiology and disease-specific alterations still remain largely unclear. Few studies have taken a whole-brain perspective in the functional connectivity (FC) analysis of these two disorders in resting state. It limits the ability to identify regionally and psychopathologically specific network abnormalities with their subsequent use as diagnostic marker and novel treatment strategy. The whole brain FC using a novel FC metric was compared, that is, scaled correlation, which they demonstrated to be a reliable FC statistics, but have higher statistical power in two-sample t-test of whole brain FC analysis. About 21 GAD and 18 PD patients were compared with 22 matched control subjects during resting-state, respectively. It was found that GAD patients demonstrated increased FC between hippocampus/parahippocampus and fusiform gyrus among the most significantly changed FC, while PD was mainly associated with greater FC between somatosensory cortex and thalamus. Besides such regional specificity, it was observed that psychopathological specificity in that the disrupted FC pattern in PD and GAD correlated with their respective symptom severity. The findings suggested that the increased FC between hippocampus/parahippocampus and fusiform gyrus in GAD were mainly associated with a fear generalization related neural circuit, while the greater FC between somatosensory cortex and thalamus in PD were more likely linked to interoceptive processing. Due to the observed regional and psychopathological specificity, their findings bear important clinical implications for the potential treatment strategy. Hum Brain Mapp 37:1459-1473, 2016. © 2016 Wiley Periodicals, Inc. PMID:26800659

  18. GABA Signaling and Neuroactive Steroids in Adrenal Medullary Chromaffin Cells

    PubMed Central

    Harada, Keita; Matsuoka, Hidetada; Fujihara, Hiroaki; Ueta, Yoichi; Yanagawa, Yuchio; Inoue, Masumi

    2016-01-01

    Gamma-aminobutyric acid (GABA) is produced not only in the brain, but also in endocrine cells by the two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67. In rat adrenal medullary chromaffin cells only GAD67 is expressed, and GABA is stored in large dense core vesicles (LDCVs), but not synaptic-like microvesicles (SLMVs). The α3β2/3γ2 complex represents the majority of GABAA receptors expressed in rat and guinea pig chromaffin cells, whereas PC12 cells, an immortalized rat chromaffin cell line, express the α1 subunit as well as the α3. The expression of α3, but not α1, in PC12 cells is enhanced by glucocorticoid activity, which may be mediated by both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). GABA has two actions mediated by GABAA receptors in chromaffin cells: it induces catecholamine secretion by itself and produces an inhibition of synaptically evoked secretion by a shunt effect. Allopregnanolone, a neuroactive steroid which is secreted from the adrenal cortex, produces a marked facilitation of GABAA receptor channel activity. Since there are no GABAergic nerve fibers in the adrenal medulla, GABA may function as a para/autocrine factor in the chromaffin cells. This function of GABA may be facilitated by expression of the immature isoforms of GAD and GABAA receptors and the lack of expression of plasma membrane GABA transporters (GATs). In this review, we will consider how the para/autocrine function of GABA is achieved, focusing on the structural and molecular mechanisms for GABA signaling. PMID:27147972

  19. Hippocampal GABAergic interneurons coexpressing alpha7-nicotinic receptors and connexin-36 are able to improve neuronal viability under oxygen-glucose deprivation.

    PubMed

    Voytenko, L P; Lushnikova, I V; Savotchenko, A V; Isaeva, E V; Skok, M V; Lykhmus, O Yu; Patseva, M A; Skibo, G G

    2015-08-01

    The hippocampal interneurons are very diverse by chemical profiles and rather inconsistent by sensitivity to CI. Some hippocampal GABAergic interneurons survive certain time after ischemia while ischemia-sensitive interneurons and pyramidal neurons are damaged. GABAergic signaling, nicotinic receptors expressing α7-subunit (α7nAChRs(+)) and connexin-36 (Cx36(+), electrotonic gapjunctions protein) contradictory modulate post-ischemic environment. We hypothesized that hippocampal ischemia-resistant GABAergic interneurons coexpressing glutamate decarboxylase-67 isoform (GAD67(+)), α7nAChRs(+), Cx36(+) are able to enhance neuronal viability. To check this hypothesis the histochemical and electrophysiological investigations have been performed using rat hippocampal organotypic culture in the condition of 30-min oxygen-glucose deprivation (OGD). Post-OGD reoxygenation (4h) revealed in CA1 pyramidal layer numerous damaged cells, decreased population spike amplitude and increased pair-pulse depression. In these conditions GAD67(+) interneurons displayed the OGD-resistance and significant increase of GABA synthesis/metabolism (GAD67-immunofluorescence, mitochondrial activity). The α7nAChRs(+) and Cx36(+) co-localizations were revealed in resistant GAD67(+) interneurons. Under OGD: GABAA-receptors (GABAARs) blockade increased cell damage and exacerbated the pair-pulse depression in CA1 pyramidal layer; α7nAChRs and Cx36-channels separate blockades sufficiently decreased cell damage while interneuronal GAD67-immunofluorescence and mitochondrial activity were similar to the control. Thus, hippocampal GABAergic interneurons co-expressing α7nAChRs and Cx36 remained resistant certain time after OGD and were able to modulate CA1 neuron survival through GABAARs, α7nAChRs and Cx36-channels activity. The enhancements of the neuronal viability together with GABA synthesis/metabolism normalization suggest cooperative neuroprotective mechanism that could be used for increase in

  20. Noise-induced hearing loss is correlated with alterations in the expression of GABAB receptors and PKC gamma in the murine cochlear nucleus complex

    PubMed Central

    Kou, Zhen-Zhen; Qu, Juan; Zhang, Dong-Liang; Li, Hui; Li, Yun-Qing

    2013-01-01

    Noise overexposure may induce permanent noise-induced hearing loss (NIHL). The cochlear nucleus complex (CNC) is the entry point for sensory information in the central auditory system. Impairments in gamma-aminobutyric acid (GABA)—mediated synaptic transmission in the CNC have been implicated in the pathogenesis of auditory disorders. However, the role of protein kinase C (PKC) signaling pathway in GABAergic inhibition in the CNC in NIHL remains elusive. Thus, we investigated the alterations of glutamic acid decarboxylase 67 (GAD67, the chemical marker for GABA-containing neurons), PKC γ subunit (PKCγ) and GABAB receptor (GABABR) expression in the CNC using transgenic GAD67-green fluorescent protein (GFP) knock-in mice, BALB/c mice and C57 mice. Immunohistochemical results indicate that the GFP-labeled GABAergic neurons were distributed in the molecular layer (ML) and fusiform cell layer (FCL) of the dorsal cochlear nucleus (DCN). We found that 69.91% of the GFP-positive neurons in the DCN were immunopositive for both PKCγ and GABABR1. The GAD67-positive terminals made contacts with PKCγ/GABABR1 colocalized neurons. Then we measured the changes of auditory thresholds in mice after noise exposure for 2 weeks, and detected the GAD67, PKCγ, and GABABR expression at mRNA and protein levels in the CNC. With noise over-exposure, there was a reduction in GABABR accompanied by an increase in PKCγ expression, but no significant change in GAD67 expression. In summary, our results demonstrate that alterations in the expression of PKCγ and GABABRs may be involved in impairments in GABAergic inhibition within the CNC and the development of NIHL. PMID:23908607

  1. How different is the time-averaged field from that of a geocentric axial dipole ? Making the best of paleomagnetic directional data using the statistical Giant Gaussian Process approach.

    NASA Astrophysics Data System (ADS)

    Hulot, G.; Khokhlov, A.; Johnson, C. L.

    2012-12-01

    It is well known that the geometry of the recent time-averaged paleomagnetic field (TAF) is very close to that of a geocentric axial dipole (GAD). Yet, numerous numerical dynamo simulations show that some departures from such a simple geometry is to be expected, not least because of the heterogeneous thermal core-mantle boundary conditions that the convecting mantle imposes on the geodynamo. Indeed, many TAF models recovered from averaging lava flow paleomagnetic directional data (the most numerous and reliable of all data) would suggest this is the case. However, assessing the significance of such minor departures from the GAD is particularly challenging, because non-linear directional data are sensitive not only to the time-averaged component of the field, but also to its time fluctuating component, known as the paleosecular variation (PSV). This means that in addition to data errors, PSV also must be taken into account when assessing any lava flow directional data based claims of departures of the TAF from the GAD. Furthermore, because of limited age information for these data , it is necessary to assess departures from the GAD by resorting to a statistical approach. We report recent progress using an approach we have suggested and further developed (Khokhlov et al., Geophysical Journal International, 2001, 2006) to test the compatibility of combined time-averaged (TAF) and paleosecular variation (PSV) field models, against any lava flow paleomagnetic database, asssuming that these TAF and PSV models are defined within the Giant Gaussian Process statistical framework. In particular we will show how sensitive statistical measures of the compatibility of a combined set of TAF and PSV models with a given directional database can be defined. These measures can be used to test published TAF and PSV models with updated 0-5 Ma lava flow paleomagnetic data sets. They also lay the groundwork for designing inverse methods better suited to seek the minimum required

  2. Social Skills and Social Acceptance in Children with Anxiety Disorders.

    PubMed

    Scharfstein, Lindsay A; Beidel, Deborah C

    2015-01-01

    Whereas much is known about the deficits in social behaviors and social competence in youth with social anxiety disorder (SAD), less is known about those characteristics among youth with generalized anxiety disorder (GAD). This study aimed to better elucidate the social repertoire and peer acceptance of youth with SAD and youth with GAD, relative to normal control (NC) youth. The sample consisted of 58 primarily Caucasian children, ages 6 to 13 years: 20 SAD (12 female), 18 GAD (12 female), and 20 NC (9 female). Diagnoses were based on Anxiety Disorders Interview Schedule for DSM-IV: Children and Parent Versions interviews. A multimodal assessment strategy included parent and child reports, observer ratings of social performance, computer-based analysis of vocal qualities of speech, and peer ratings of likeability and friendship potential. Whereas self- and parental report did not differentiate the two diagnostic groups, differences on observable behaviors were apparent. Children with SAD exhibited anxious speech patterns, extended speech latencies, a paucity of speech, few spontaneous vocalizations, and ineffective social responses; they were perceived by peers as less likeable and socially desirable. Children with GAD had typical speech patterns and were well liked by their peers but displayed fewer spontaneous comments and questions than NC children. Parent and child reports are less sensitive to what could be important differences in social skill between youth with SAD and GAD. Direct observations, computer-based measures of speech quality, and peer ratings identify specific group differences, suggesting the need for a comprehensive evaluation to inform treatment planning. PMID:24819443

  3. GABA Signaling and Neuroactive Steroids in Adrenal Medullary Chromaffin Cells.

    PubMed

    Harada, Keita; Matsuoka, Hidetada; Fujihara, Hiroaki; Ueta, Yoichi; Yanagawa, Yuchio; Inoue, Masumi

    2016-01-01

    Gamma-aminobutyric acid (GABA) is produced not only in the brain, but also in endocrine cells by the two isoforms of glutamic acid decarboxylase (GAD), GAD65 and GAD67. In rat adrenal medullary chromaffin cells only GAD67 is expressed, and GABA is stored in large dense core vesicles (LDCVs), but not synaptic-like microvesicles (SLMVs). The α3β2/3γ2 complex represents the majority of GABAA receptors expressed in rat and guinea pig chromaffin cells, whereas PC12 cells, an immortalized rat chromaffin cell line, express the α1 subunit as well as the α3. The expression of α3, but not α1, in PC12 cells is enhanced by glucocorticoid activity, which may be mediated by both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). GABA has two actions mediated by GABAA receptors in chromaffin cells: it induces catecholamine secretion by itself and produces an inhibition of synaptically evoked secretion by a shunt effect. Allopregnanolone, a neuroactive steroid which is secreted from the adrenal cortex, produces a marked facilitation of GABAA receptor channel activity. Since there are no GABAergic nerve fibers in the adrenal medulla, GABA may function as a para/autocrine factor in the chromaffin cells. This function of GABA may be facilitated by expression of the immature isoforms of GAD and GABAA receptors and the lack of expression of plasma membrane GABA transporters (GATs). In this review, we will consider how the para/autocrine function of GABA is achieved, focusing on the structural and molecular mechanisms for GABA signaling. PMID:27147972

  4. Age-related gene expression change of GABAergic system in visual cortex of rhesus macaque.

    PubMed

    Liao, Chenghong; Han, Qian; Ma, Yuanye; Su, Bing

    2016-09-30

    Degradation of visual function is a common phenomenon during aging and likely mediated by change in the impaired central visual pathway. Treatment with GABA or its agonist could recover the ability of visual neurons in the primary visual cortex of senescent macaques. However, little is known about how GABAergic system change is related to the aged degradation of visual function in nonhuman primate. With the use of quantitative PCR method, we measured the expression change of 24 GABA related genes in the primary visual cortex (Brodmann's 17) of different age groups. In this study, both of mRNA and protein of glutamic acid decarboxylase (GAD65) were measured by real-time RT-PCR and Western blot, respectively. Results revealed that the level of GAD65 message was not significantly altered, but the proteins were significantly decreased in the aged monkey. As GAD65 plays an important role in GABA synthesis, the down-regulation of GAD65 protein was likely the key factor leading to the observed GABA reduction in the primary visual cortex of the aged macaques. In addition, 7 of 14 GABA receptor genes were up-regulated and one GABA receptor gene was significantly reduced during aging process even after Banjamini correction for multiple comparisons (P<0.05). These results suggested that the dysregulation of GAD65 protein might contribute to some age-related neural visual dysfunctions and most of GABA receptor genes induce a clear indication of compensatory effect for the reduced GABA release in the healthy aged monkey cortex. PMID:27196061

  5. Reductions in the diurnal rigidity of anxiety predict treatment outcome in cognitive behavioral therapy for generalized anxiety disorder.

    PubMed

    Fisher, Aaron J; Newman, Michelle G

    2016-04-01

    Generalized anxiety disorder (GAD) is a chronic and disabling disorder which is characterized by worrisome mentation about future outcomes. Because the evocative stimuli in GAD are largely internally derived, the feared outcomes contained in worry episodes can be invoked - and responded to - regardless of external context. We hypothesized that individuals with GAD would be entrained to internally-regulated, fixed patterns of anxiety on a day-to-day basis and that successful therapeutic intervention would serve to mitigate this entrainment. Thus, the present study examined the constructs of flexibility and rigidity as they apply to the daily fluctuation of anxious symptoms in individuals with GAD. We aimed to demonstrate that an apparently variable system can be conceptualized as rigid when the variability maps onto stable and predictable periodic oscillations. Sixty-nine individuals completed cognitive-behavioral treatment for GAD. Average age was 36.62 years (SD = 11.56), and participants were mostly Caucasian (89.5%) and female (68.4%). Daily-diary data indicating level of anxiety on a 0 to 100-point scale and collected four times per day were subjected to spectral analysis in order to determine the spectral power attributable to daily oscillations - which was related to the degree of rigidity in daily anxiety. Diurnal rigidity decreased throughout therapy and the degree to which rigidity was reduced significantly predicted reliable change at post-treatment. Thus, symptom rigidity can be conceptualized as stable periodic fluctuation and is discernible from other metrics of volatility in repeated measures data. Moreover, diurnal rigidity is significantly reduced during treatment, facilitating flexible responding to environmental demands. PMID:26953959

  6. Housing quality, housing instability, and maternal mental health.

    PubMed

    Suglia, Shakira Franco; Duarte, Cristiane S; Sandel, Megan T

    2011-12-01

    Poor housing conditions and residential instability have been associated with distress among women; however, this association could be the result of other social factors related to housing, such as intimate partner violence (IPV) and economic hardship. We examined associations of housing conditions and instability with maternal depression and generalized anxiety disorder (GAD) while accounting for IPV and economic hardship in the Fragile Families and Child Wellbeing Study (N = 2,104). In the third study wave, interviewers rated indoor housing quality, including housing deterioration (e.g., peeling paint and holes in floor) and housing disarray (e.g., dark, crowded, and noisy). Mothers reported whether they had moved more than twice in the past two years, an indicator of housing instability. A screening for depression and GAD was obtained from questions derived from the Composite International Diagnostic Interview-Short Form in the second and third study waves. IPV and economic hardship were assessed through questionnaire. In this sample, 16% of women were classified as having probable depression and 5% as having probable GAD. In adjusted analyses, mothers experiencing housing disarray (odds ratio [OR], 1.3 [95% confidence interval (CI), 1.0, 1.7]) and instability (OR, 1.4 [95% CI, 1.2, 2.3]) were more likely to screen positive for depression. In addition, those experiencing housing instability were more likely to screen positive for GAD (OR 1.9 [95% CI, 1.2, 3.0]) even after adjusting for other social factors. No associations were noted between housing deterioration and maternal mental health. Similar associations were noted when incident cases of probable depression and GAD were examined. Housing instability and disarray, but not deterioration, are associated with screening positive for depression and generalized anxiety among women regardless of other social stressors present in their lives. Housing could potentially present a point of intervention to prevent

  7. Introduction of Dr. Andrew V Schally

    PubMed Central

    Mendoza-Valdés, Arturo

    2015-01-01

    I first met Dr. Andrew V Schally (PhD, MDhc (Multi), DSc, Distinguished Medical Research Scientist, U.S. Department of Veterans Affairs Professor of Pathology and Department of Medicine,
Miller School of Medicine, University of Miami, Miami, Florida, USA) many years ago, probably around the beginning of the 1990's in one of his visits to Mexico City (Figure 1). He has many friends in my country since some of the investigations that led to the development of the LHRH agonists were made in a couple of Mexican hospitals in collaboration with some outstanding Mexican physicians that I will mention later. In that time, I was the head of the Department of Urology of the Mexican National Cancer Institute and our Director, Dr. Jaime de la Garza, invited him for a meeting. I was surprised by his humbleness, intelligence and easy going personality, in spite of being a Nobel Prize scientist. PMID:26112485

  8. Nicotine worsens the severity of nephropathy in diabetic mice: implications for the progression of kidney disease in smokers

    PubMed Central

    Hua, Ping; Feng, Wenguang; Ji, Shaonin; Raij, Leopoldo

    2010-01-01

    Epidemiological studies have established the role of cigarette smoking as a risk factor in the progression of chronic kidney disease, including diabetic nephropathy. We have previously reported that nicotine promotes mesangial cell proliferation and hypertrophy via activation of nonneuronal nicotinic acetylcholine receptors and that nicotine worsens renal injury in a model of acute glomerulonephritis (Jaimes E, Tian RX, Raij L. Am J Physiol Heart Circ Physiol 292: H76–H82, 2007; Jaimes EA, Tian RX, Joshi M, Raij L. Am J Nephrol 29: 319–326, 2009). These studies were designed to test the hypothesis that nicotine worsens renal injury in db/db mice, a well-established model of diabetic nephropathy, and that reactive oxygen species play an important as mediators of these effects. For these studies, nicotine (100 μg/ml) was administered in the drinking water to control and db/db mice for 10 wk. Blood pressure was measured by the tail-cuff method, and urine was collected for proteinuria. At death, kidneys were collected for histology and molecular biology. The administration of nicotine did not result in significant changes in blood pressure or blood glucose and resulted in cotinine levels similar to those found in the plasma of smokers. In diabetic mice, the administration of nicotine significantly increased urinary protein excretion (1-fold), glomerular hypertrophy, and mesangial area (∼20%). These changes were accompanied by significant increases in NADPH oxidase 4 (∼30%) and increased nitrotyrosine and Akt expression. In vitro, we determined that nicotine has additive effects to high glucose on reactive oxygen species generation and Akt phosphorylation in human mesangial cells. These findings unveil novel mechanisms that may result in the development of novel strategies in the treatment and prevention of diabetic nephropathy in smokers. PMID:20685820

  9. Glutamic Acid Decarboxylase 65 and Islet Cell Antigen 512/IA-2 Autoantibodies in Relation to Human Leukocyte Antigen Class II DR and DQ Alleles and Haplotypes in Type 1 Diabetes Mellitus ▿

    PubMed Central

    Stayoussef, Mouna; Benmansour, Jihen; Al-Jenaidi, Fayza A.; Said, Hichem B.; Rayana, Chiheb B.; Mahjoub, Touhami; Almawi, Wassim Y.

    2011-01-01

    The frequencies of autoantibodies against glutamic acid decarboxylase 65 (GAD65) and islet cell antigen (ICA) 512/IA-2 (512/IA-2) are functions of the specific human leukocyte antigen (HLA) in type 1 diabetes mellitus (T1D). We investigated the association of HLA class II (DR and DQ) alleles and haplotypes with the presence of GAD and IA-2 autoantibodies in T1D. Autoantibodies were tested in 88 Tunisian T1D patients and 112 age- and gender-matched normoglycemic control subjects by enzyme immunoassay. Among T1D patients, mean anti-GAD antibody titers were higher in the DRB1*030101 allele (P < 0.001), together with the DRB1*030101/DQB1*0201 (P < 0.001) and DRB1*040101/DQB1*0302 (P = 0.002) haplotypes, while lower anti-GAD titers were associated with the DRB1*070101 (P = 0.001) and DRB1*110101 (P < 0.001) alleles and DRB1*070101/DQB1*0201 (P = 0.001) and DRB1*110101/DQB1*030101 (P = 0.001) haplotypes. Mean anti-IA-2 antibody titers were higher in the DRB1*040101 allele (P = 0.007) and DRB1*040101/DQB1*0302 (P = 0.001) haplotypes but were lower in the DRB1*110101 allele (P = 0.010) and the DRB1*110101 (P < 0.001) and DRB1*110101/DQB1*030101 (P = 0.025) haplotypes. Multinomial regression analysis confirmed the positive association of DRB1*030101 and the negative association of DRB1*110101 and DQB1*030101, along with the DRB1*070101/DQB1*0201 and DRB1*110101/DQB1*030101 haplotypes, with anti-GAD levels. In contrast, only the DRB1*040101/DQB1*0302 haplotype was positively associated with altered anti-IA-2 titers. Increased GAD65 and IA-2 antibody positivity is differentially associated with select HLA class II alleles and haplotypes, confirming the heterogeneous nature of T1D. PMID:21490167

  10. Glutamic acid decarboxylase 65 and islet cell antigen 512/IA-2 autoantibodies in relation to human leukocyte antigen class II DR and DQ alleles and haplotypes in type 1 diabetes mellitus.

    PubMed

    Stayoussef, Mouna; Benmansour, Jihen; Al-Jenaidi, Fayza A; Said, Hichem B; Rayana, Chiheb B; Mahjoub, Touhami; Almawi, Wassim Y

    2011-06-01

    The frequencies of autoantibodies against glutamic acid decarboxylase 65 (GAD65) and islet cell antigen (ICA) 512/IA-2 (512/IA-2) are functions of the specific human leukocyte antigen (HLA) in type 1 diabetes mellitus (T1D). We investigated the association of HLA class II (DR and DQ) alleles and haplotypes with the presence of GAD and IA-2 autoantibodies in T1D. Autoantibodies were tested in 88 Tunisian T1D patients and 112 age- and gender-matched normoglycemic control subjects by enzyme immunoassay. Among T1D patients, mean anti-GAD antibody titers were higher in the DRB1*030101 allele (P < 0.001), together with the DRB1*030101/DQB1*0201 (P < 0.001) and DRB1*040101/DQB1*0302 (P = 0.002) haplotypes, while lower anti-GAD titers were associated with the DRB1*070101 (P = 0.001) and DRB1*110101 (P < 0.001) alleles and DRB1*070101/DQB1*0201 (P = 0.001) and DRB1*110101/DQB1*030101 (P = 0.001) haplotypes. Mean anti-IA-2 antibody titers were higher in the DRB1*040101 allele (P = 0.007) and DRB1*040101/DQB1*0302 (P = 0.001) haplotypes but were lower in the DRB1*110101 allele (P = 0.010) and the DRB1*110101 (P < 0.001) and DRB1*110101/DQB1*030101 (P = 0.025) haplotypes. Multinomial regression analysis confirmed the positive association of DRB1*030101 and the negative association of DRB1*110101 and DQB1*030101, along with the DRB1*070101/DQB1*0201 and DRB1*110101/DQB1*030101 haplotypes, with anti-GAD levels. In contrast, only the DRB1*040101/DQB1*0302 haplotype was positively associated with altered anti-IA-2 titers. Increased GAD65 and IA-2 antibody positivity is differentially associated with select HLA class II alleles and haplotypes, confirming the heterogeneous nature of T1D. PMID:21490167

  11. Quetiapine monotherapy in acute treatment of generalized anxiety disorder: a systematic review and meta-analysis of randomized controlled trials

    PubMed Central

    Maneeton, Narong; Maneeton, Benchalak; Woottiluk, Pakapan; Likhitsathian, Surinporn; Suttajit, Sirijit; Boonyanaruthee, Vudhichai; Srisurapanont, Manit

    2016-01-01

    Background Some studies have indicated the efficacy of quetiapine in the treatment of generalized anxiety disorder (GAD). Objective The purpose of this study was to systematically review the efficacy, acceptability, and tolerability of quetiapine in adult patients with GAD. Methods The SCOPUS, MEDLINE, CINAHL, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched in April 2015. All randomized controlled trials (RCTs) of GAD were considered to be included in this meta-analysis. All RCTs of quetiapine in GAD patients providing endpoint outcomes relevant to severity of anxiety, response rate, remission rate, overall discontinuation rate, or discontinuation rate due to adverse events were included. The version reports from suitable clinical studies were explored, and the important data were extracted. Measurement for efficacy outcomes consisted of the mean-changed scores of the rating scales for anxiety, and response rate. Results A total of 2,248 randomized participants in three RCTs were included. The pooled mean-changed score of the quetiapine-treated group was greater than that of the placebo-treated group and comparable to selective serotonin reuptake inhibitors (SSRIs). Unfortunately, the response and the remission rates in only 50 and 150 mg/day of quetiapine-XR (extended-release) were better than those of the placebo. Their response and remission rates were comparable to SSRIs. The rates of pooled overall discontinuation and discontinuation due to adverse events of quetiapine-XR were greater than placebo. Only the overall discontinuation rate of quetiapine-XR at 50 and 150 mg/day and the discontinuation rate due to adverse events of quetiapine-XR at 50 mg/day were comparable to SSRIs. Conclusion Based on this meta-analysis, quetiapine-XR is efficacious in the treatment of GAD in adult patients. Despite its low acceptability and tolerability, the use of 50–150 mg/day quetiapine-XR for adult GAD patients may be

  12. The MD Blues: Under-Recognized Depression and Anxiety in Medical Trainees

    PubMed Central

    Dhamoon, Mandip S.; Lander, Sarah; Dhamoon, Amit S.

    2016-01-01

    Background Mental health disease is under recognized in medical professionals. Objective To screen medical students (MS), residents and fellows for major depressive disorder (MDD) and generalized anxiety disorder (GAD) under the new era of work hour reform with age-matched controls from a large representative cross-sectional survey. Methods We conducted an anonymous online survey at a medical university in 2013–2014. We incorporated the Patient Health Questionnaire 2 (PHQ-2) to screen for MDD and the generalized anxiety disorder scale (GAD-7) to screen for GAD, along with additional questions on life stressors and academic performance. We compared these results to age-matched controls from the National Health and Nutrition Examination Survey (NHANES) database. Results 126 residents/fellows and 336 medical students participated voluntarily. 15.1% and 15.9% of postgraduates as well as 16.4% and 20.3% of MS screened positive for MDD and GAD, respectively. When compared to national estimates, the prevalence of a positive screen for MDD was over five-fold higher in medical trainees compared to age-matched controls (16% vs. 2.8%, p<0.0001). Similarly, the prevalence of a positive screen for GAD was over eight-fold higher in medical trainees (19% vs. 2.3%, p<0.0001).The prevalence was consistently higher within age strata. 33.3% of postgraduates and 32% of MS believe there is a significant impact of depression or anxiety on their academic performance. For stress relief, one fifth of residents/fellows as well as MS reported alcohol use. Conclusions The stresses of medical education and practice may predispose trainees to psychopathological consequences that can affect their academic performance and patient care. The current study showed a significantly higher rate of MDD and GAD positive screens in medical trainees than the prevalence in an age-matched U.S. population, despite significant work hour reform for medical trainees. Increased awareness and support services are

  13. Yoga-Enhanced Cognitive Behavioral Therapy (Y-CBT) for Anxiety Management: A Pilot Study

    PubMed Central

    Khalsa, Manjit K.; Greiner-Ferris, Julie M.; Hofmann, Stefan G.; Khalsa, Sat Bir S.

    2014-01-01

    Cognitive behavioral therapy is an effective treatment for generalized anxiety disorder (GAD), but there is still room for improvement. The aim of the present study was to examine the potential benefit of enriching cognitive behavioral therapy (CBT) with Kundalini Yoga (Y-CBT). Participants consisted of treatment resistant clients at a community mental health clinic. A total of 32 participants enrolled in the study and 22 completed the program. After the Y-CBT intervention, pre-post comparisons showed statistically significant improvements in state and trait anxiety, depression, panic, sleep, and quality of life. Results from this preliminary study suggest that Y-CBT may have potential as a promising treatment for those suffering from GAD. PMID:24804619

  14. Things that Go Bump in the Night: Frequency and Predictors of Nightmares in Anxious and Nonanxious Children.

    PubMed

    Reynolds, Katharine C; Alfano, Candice A

    2016-01-01

    Frequency and predictors of nightmares among children 7-11 years old with generalized anxiety disorder (GAD; n = 42) and no diagnosis (n = 44) were examined using both prospective and retrospective child and parent reports. Both children with GAD and their parents reported significantly more nightmares than controls based on retrospective reports, but the groups did not differ when nightmares were assessed daily across a one-week prospective period. Females reported more nightmares than males according to prospective assessment only. Controlling for sex and group, child sleep anxiety and presleep somatic arousal predicted parent but not child report of nightmares. Results suggest both clinically anxious youth and their parents overestimate the occurrence of nightmares, yet factors influencing retrospective accounts appear to differ across informants. PMID:26406387

  15. (/sup 3/H)muscimol binding sites increased in autopsied brains of chronic schizophrenics

    SciTech Connect

    Hanada, S.; Mita, T.; Nishino, N.; Tanaka, C.

    1987-01-19

    (/sup 3/H)muscimol binding and glutamic acid decarboxylase (GAD) activity in the prefrontal cortex and caudate nucleus of autopsied brains from 19 chronic schizophrenics and 17 control subjects were investigated. In the schizophrenics, saturation analysis with varying concentrations of (/sup 3/H)muscimol revealed an increase in the number GABA/sub A/ receptors, but there was no significant difference in the affinity. In addition, the enhancement of (/sup 3/H)muscimol binding by diazepam was significantly greater in schizophrenics than in controls. GAD activity did not differ between controls and schizophrenics. The possibility that GABAergic mechanisms might play a role in case of chronic schizophrenia should be given further attention.

  16. Cognitive behavioral treatment for older adults with generalized anxiety disorder. A therapist manual for primary care settings.

    PubMed

    Stanley, Melinda A; Diefenbach, Gretchen J; Hopko, Derek R

    2004-01-01

    At least four academic clinical trials have demonstrated the utility of cognitive behavior therapy (CBT) for older adults with generalized anxiety disorder (GAD). These data may not generalize, however, to more heterogeneous and functionally impaired patients and the medical settings in which they typically receive care. A recent pilot project suggested the potential benefits of a new version of CBT for GAD among older patients in primary care. The manual developed and tested in this pilot project is presented here. Treatment components include motivation and education, relaxation skills, cognitive therapy, problem-solving-skills training, exposure exercises, and sleep-management-skills training. Procedures are designed to be administered flexibly to maximize attention to individual patient needs. Examples of session summaries, patient handouts, and homework forms are provided. PMID:14710708

  17. Effect of dopaminergic denervation and transplant-derived reinnervation on a marker of striatal GABAergic function.

    PubMed

    Segovia, J; Meloni, R; Gale, K

    1989-07-24

    Solid grafts of dopamine-containing fetal mesencephalon were placed adjacent to the striatum of rats with 6-hydroxydopamine lesions of ascending dopaminergic projections. These grafts resulted in a significant, although partial, reversal of the lesion-induced increase in striatal glutamic acid decarboxylase (GAD) when measured 3-4 months after the lesion. These results suggest that the grafted neurons can partly restore inhibitory control over striatal GABA neurons. In the same rats, the grafts partially reversed apomorphine-induced turning although amphetamine-induced turning was nearly abolished. It is likely that both apomorphine-induced behavior and striatal GAD activity reflect the sustained chronic influence of the graft on target neurons in striatum. PMID:2505886

  18. Thought-action fusion across anxiety disorder diagnoses: specificity and treatment effects.

    PubMed

    Thompson-Hollands, Johanna; Farchione, Todd J; Barlow, David H

    2013-05-01

    Thought-action fusion (TAF) is a cognitive error that has been frequently investigated within the context of obsessive-compulsive disorder (OCD). However, evidence suggests that this error may also be present in disorders other than OCD, indicating that TAF is related to higher order factors rather than a specific diagnosis. We explored TAF in a sample of patients with mixed diagnoses undergoing treatment with a transdiagnostic CBT protocol. Elevated TAF levels at baseline were not specific to patients with OCD. However, the presence of any generalized anxiety disorder (GAD) diagnosis was unexpectedly the strongest predictor of likelihood TAF. Likelihood TAF, a particular component of TAF, was reduced after transdiagnostic treatment, and this reduction was not affected by the presence of a GAD diagnosis. Results indicate that TAF is responsive to treatment and should be assessed and, perhaps, treated in disorders beyond OCD. PMID:23595095

  19. Resolving Ambiguity in Emotional Disorders: The Nature and Role of Interpretation Biases.

    PubMed

    Hirsch, Colette R; Meeten, Frances; Krahé, Charlotte; Reeder, Clare

    2016-03-28

    People with emotional disorders, such as social anxiety disorder (SAD), generalized anxiety disorder (GAD), and depression, demonstrate a consistent tendency, or bias, to generate negative interpretations of ambiguous material. This is different from people without emotional disorders who tend, in general, to make positive interpretations of ambiguity. If central components of an emotional disorder have high levels of inherent ambiguity (e.g., concern about the negative perceptions of others in SAD, or worry in GAD), then interpretive bias may have a causal maintaining role, and this has been demonstrated in studies using cognitive bias modification techniques. This research has also shown that interpretation biases combine with other cognitive processes, such as imagery and memory, which could exacerbate distress. Psychological interventions will benefit from effectively targeting negative interpretations, and future experimental research can inform ways to improve facilitation of more benign inferential processing to maximize amelioration of key components of emotional disorders. PMID:27019398

  20. The power of positive thinking: Pathological worry is reduced by thought replacement in Generalized Anxiety Disorder

    PubMed Central

    Eagleson, Claire; Hayes, Sarra; Mathews, Andrew; Perman, Gemma; Hirsch, Colette R.

    2016-01-01

    Worry in Generalized Anxiety Disorder (GAD), takes a predominantly verbal form, as if talking to oneself about possible negative outcomes. The current study examined alternative approaches to reducing worry by allocating volunteers with GAD to conditions in which they either practiced replacing the usual form of worry with images of possible positive outcomes, or with the same positive outcomes represented verbally. A comparison control condition involved generating positive images not related to worries. Participants received training in the designated method and then practiced it for one week, before attending for reassessment, and completing follow-up questionnaires four weeks later. All groups benefited from training, with decreases in anxiety and worry, and no significant differences between groups. The replacement of worry with different forms of positive ideation, even when unrelated to the content of worry itself, seems to have similar beneficial effects, suggesting that any form of positive ideation can be used to effectively counter worry. PMID:26802793

  1. Persistent Suppression of Type 1 Diabetes by a Multicomponent Vaccine Containing a Cholera Toxin B Subunit-Autoantigen Fusion Protein and Complete Freund's Adjuvant

    PubMed Central

    Dénes, Béla; Fodor, István; Langridge, William H. R.

    2013-01-01

    Data presented here demonstrate multifunctional vaccination strategies that harness vaccinia virus mediated delivery of a gene encoding an immunoenhanced diabetes autoantigen in combination with complete Freund's adjuvant (CFA) that can maintain safe and durable immunologic homeostasis in NOD mice. Systemic coinoculation of prediabetic mice with recombinant vaccinia virus rVV-CTB::GAD and undiluted or 10-fold diluted CFA demonstrated a significant decrease in hyperglycemia and pancreatic islet inflammation in comparison with control animals during 17–61 and 17–105 weeks of age, respectively. Synergy in these beneficial effects was observed during 43–61 and 61–105 wks of age, respectively. Inflammatory cytokine and chemokine levels in GAD-stimulated splenocytes isolated from vaccinated mice were generally lower than those detected in unvaccinated mice. The overall health and humoral immune responses of the vaccinated animals remained normal throughout the duration of the experiments. PMID:24319466

  2. Aldehyde Dehydrogenase 1a1 Mediates a GABA Synthesis Pathway in Midbrain Dopaminergic Neurons

    PubMed Central

    Kim, Jae-Ick; Ganesan, Subhashree; Luo, Sarah X.; Wu, Yu-Wei; Park, Esther; Huang, Eric J.; Chen, Lu; Ding, Jun B.

    2016-01-01

    Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here we show that GABA corelease in dopamine neurons does not utilize the conventional GABA synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol at binge drinking blood alcohol concentrations and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction. PMID:26430123

  3. A Single-blinded, Randomized Clinical Trial of How to Implement an Evidence-based Treatment for Generalized Anxiety Disorder [IMPLEMENT] — Effects of Three Different Strategies of Implementation

    PubMed Central

    Flückiger, Christoph; Forrer, Lena; Schnider, Barbara; Bättig, Isabelle; Bodenmann, Guy; Zinbarg, Richard E.

    2015-01-01

    Background Despite long-standing calls to disseminate evidence-based treatments for generalized anxiety (GAD), modest progress has been made in the study of how such treatments should be implemented. The primary objective of this study was to test three competing strategies on how to implement a cognitive behavioral treatment (CBT) for out-patients with GAD (i.e., comparison of one compensation vs. two capitalization models). Methods For our three-arm, single-blinded, randomized controlled trial (implementation of CBT for GAD [IMPLEMENT]), we recruited adults with GAD using advertisements in high-circulation newspapers to participate in a 14-session cognitive behavioral treatment (Mastery of your Anxiety and Worry, MAW-packet). We randomly assigned eligible patients using a full randomization procedure (1:1:1) to three different conditions of implementation: adherence priming (compensation model), which had a systematized focus on patients' individual GAD symptoms and how to compensate for these symptoms within the MAW-packet, and resource priming and supportive resource priming (capitalization model), which had systematized focuses on patients' strengths and abilities and how these strengths can be capitalized within the same packet. In the intention-to-treat population an outcome composite of primary and secondary symptoms-related self-report questionnaires was analyzed based on a hierarchical linear growth model from intake to 6-month follow-up assessment. This trial is registered at ClinicalTrials.gov (identifier: NCT02039193) and is closed to new participants. Findings From June 2012 to Nov. 2014, from 411 participants that were screened, 57 eligible participants were recruited and randomly assigned to three conditions. Forty-nine patients (86%) provided outcome data at post-assessment (14% dropout rate). All three conditions showed a highly significant reduction of symptoms over time. However, compared with the adherence priming condition, both resource

  4. Worry and Generalized Anxiety Disorder: A Review and Theoretical Synthesis of Evidence on Nature, Etiology, Mechanisms, and Treatment

    PubMed Central

    Newman, Michelle G.; Llera, Sandra J.; Erickson, Thane M.; Przeworski, Amy; Castonguay, Louis G.

    2016-01-01

    Generalized anxiety disorder (GAD) is associated with substantial personal and societal cost yet is the least successfully treated of the anxiety disorders. In this review, research on clinical features, boundary issues, and naturalistic course, as well as risk factors and maintaining mechanisms (cognitive, biological, neural, interpersonal, and developmental), are presented. A synthesis of these data points to a central role of emotional hyperreactivity, sensitivity to contrasting emotions, and dysfunctional attempts to cope with strong emotional shifts via worry. Consistent with the Contrast Avoidance model, evidence shows that worry evokes and sustains negative affect, thereby precluding sharp increases in negative emotion. We also review current treatment paradigms and suggest how the Contrast Avoidance model may help to target key fears and avoidance tendencies that serve to maintain pathology in GAD. PMID:23537486

  5. Ethnicity, development and gender: Tsáchila indigenous women in Ecuador.

    PubMed

    Radcliffe, Sarah; Pequeño, Andrea

    2010-01-01

    In recent decades, indigenous populations have become the subjects and agents of development in national and international multicultural policy that acknowledges poverty among indigenous peoples and their historic marginalization from power over development. Although the impact of these legal and programmatic efforts is growing, one persistent axis of disadvantage, male–female difference, is rarely taken into account in ethno-development policy and practice. This article argues that assumptions that inform policy related to indigenous women fail to engage with indigenous women's development concerns. The institutional separation between gender and development policy (GAD) and multiculturalism means that provisions for gender in multicultural policies are inadequate, and ethnic rights in GAD policies are invisible. Drawing on post-colonial feminism, the paper examines ethnicity and gender as interlocking systems that structure indigenous women's development experiences. These arguments are illustrated in relation to the case of the Tsáchila ethno-cultural group in the South American country of Ecuador. PMID:21125766

  6. Combined treatment with sitagliptin and vitamin D in a patient with latent autoimmune diabetes in adults

    PubMed Central

    Rapti, E; Karras, S; Grammatiki, M; Mousiolis, A; Tsekmekidou, X; Potolidis, E; Zebekakis, P; Daniilidis, M

    2016-01-01

    Summary Latent autoimmune diabetes in adults (LADA) is a relatively new type of diabetes with a clinical phenotype of type 2 diabetes (T2D) and an immunological milieu characterized by high titers of islet autoantibodies, resembling the immunological profile of type 1 diabetes (T1D). Herein, we report a case of a young male, diagnosed with LADA based on both clinical presentation and positive anti-glutamic acid decarboxylase antibodies (GAD-abs), which were normalized after combined treatment with a dipeptidyl peptidase-4 inhibitor (DPP-4) (sitagliptin) and cholecalciferol. Learning points Anti-glutamic acid decarboxylase antibodies (GAD-abs) titers in young patients being previously diagnosed as type 2 diabetes (T2D) may help establish the diagnosis of latent autoimmune diabetes in adults (LADA). Sitagliptin administration in patients with LADA might prolong the insulin-free period. Vitamin D administration in patients with LADA might have a protective effect on the progression of the disease. PMID:27252860

  7. Highly Sensitive H2S Sensor Based on the Metal-Catalyzed SnO2 Nanocolumns Fabricated by Glancing Angle Deposition

    PubMed Central

    Yoo, Kwang Soo; Han, Soo Deok; Moon, Hi Gyu; Yoon, Seok-Jin; Kang, Chong-Yun

    2015-01-01

    As highly sensitive H2S gas sensors, Au- and Ag-catalyzed SnO2 thin films with morphology-controlled nanostructures were fabricated by using e-beam evaporation in combination with the glancing angle deposition (GAD) technique. After annealing at 500 °C for 40 h, the sensors showed a polycrystalline phase with a porous, tilted columnar nanostructure. The gas sensitivities (S = Rgas/Rair) of Au and Ag-catalyzed SnO2 sensors fabricated by the GAD process were 0.009 and 0.015, respectively, under 5 ppm H2S at 300 °C, and the 90% response time was approximately 5 s. These sensors showed excellent sensitivities compared with the SnO2 thin film sensors that were deposited normally (glancing angle = 0°, S = 0.48). PMID:26134105

  8. Thought-action fusion across anxiety disorder diagnoses: Specificity and treatment effects

    PubMed Central

    Thompson-Hollands, Johanna; Farchione, Todd J.; Barlow, David H.

    2013-01-01

    Thought-action fusion (TAF) is a cognitive error that has been frequently investigated within the context of obsessive-compulsive disorder (OCD). However, evidence suggests that this error may also be present in disorders other than OCD, indicating that TAF is related to higher-order factors rather than a specific diagnosis. We explored TAF in a sample of patients with mixed diagnoses undergoing treatment with a transdiagnostic CBT protocol. Elevated TAF levels at baseline were not specific to patients with OCD. However, the presence of any generalized anxiety disorder (GAD) diagnosis was unexpectedly the strongest predictor of likelihood TAF. Likelihood TAF, a particular component of TAF, was reduced after transdiagnostic treatment, and this reduction was not affected by the presence of a GAD diagnosis. Results indicate that TAF is responsive to treatment and should be assessed and, perhaps, treated in disorders beyond OCD. PMID:23595095

  9. Cognitive-Behavior Therapy (CBT) for Panic Disorder: Relationship of Anxiety and Depression Comorbidity with Treatment Outcome

    PubMed Central

    White, Kamila S.; Barlow, David H.; Shear, M. Katherine; Gorman, Jack M.; Woods, Scott W.

    2009-01-01

    Research evaluating the relationship of comorbidity to treatment outcome for panic disorder has produced mixed results. The current study examined the relationship of comorbid depression and anxiety to treatment outcome in a large-scale, multi-site clinical trial for cognitive-behavior therapy (CBT) for panic disorder. Comorbidity was associated with more severe panic disorder symptoms, although comorbid diagnoses were not associated with treatment response. Comorbid generalized anxiety disorder (GAD) and major depressive disorder (MDD) were not associated with differential improvement on a measure of panic disorder severity, although only rates of comorbid GAD were significantly lower at posttreatment. Treatment responders showed greater reductions on measures of anxiety and depressive symptoms. These data suggest that comorbid anxiety and depression are not an impediment to treatment response, and successful treatment of panic disorder is associated with reductions of comorbid anxiety and depressive symptoms. Implications for treatment specificity and conceptual understandings of comorbidity are discussed. PMID:20421906

  10. Emotional, behavioral, and cognitive factors that differentiate obsessive-compulsive disorder and other anxiety disorders in youth.

    PubMed

    Jacob, Marni L; Morelen, Diana; Suveg, Cynthia; Brown Jacobsen, Amy M; Whiteside, Stephen P

    2012-03-01

    Abstract The current study examined specific emotional, behavioral, and cognitive variables that may distinguish obsessive-compulsive disorder (OCD) from generalized anxiety disorder (GAD), social phobia (SoP), and separation anxiety disorder (SAD) in youth. Youth with OCD (n=26) and other anxiety disorders (ADs; n=31), aged 7-12 years (56.1% males), and their parents participated. The study compared the two anxious groups on levels of emotional, behavioral, and cognitive functioning, as well as impairment associated with the disorder. Results indicated that in comparison to youth with GAD, SoP, or SAD, youth with OCD were found to have poorer emotion regulation skills, as well as greater oppositionality, cognitive problems/inattention, and parent impairment associated with the disorder. The findings suggest that there are unique characteristics of OCD that may differentiate this disorder from other ADs in youth. Potential clinical implications and directions for future research are discussed. PMID:21512917

  11. Investigation of hydrocarbon oil transformation by gliding arc discharge: comparison of batch and recirculated configurations

    NASA Astrophysics Data System (ADS)

    Whitehead, J. Christopher; Prantsidou, Maria

    2016-04-01

    The degradation of liquid dodecane was studied in a gliding arc discharge (GAD) of humid argon or nitrogen. A batch or recirculating configuration was used. The products in the gaseous and liquid phase were analysed by infrared and chromatography and optical emission spectroscopy was used to identify the excited species in the discharge. The best degradation performance comes from the use of humid N2 but a GAD of humid argon produces fewer gas-phase products but more liquid-phase end-products. A wide range of products such as heavier saturated or unsaturated hydrocarbons both aliphatic and aromatic, and oxidation products mainly alcohols, but also aldehydes, ketones and esters are produced in the liquid-phase. The recirculating treatment mode is more effective than the batch mode increasing the reactivity and changing the product selectivities. Overall, the study shows promising results for the organic liquid waste treatment, especially in the recirculating mode.

  12. The cerebellar component of Friedreich’s ataxia

    PubMed Central

    Davis, Ashley N.; Morral, Jennifer A.

    2016-01-01

    Lack of frataxin in Friedreich’s ataxia (FRDA) causes a complex neurological and pathological phenotype. Progressive atrophy of the dentate nucleus (DN) is a major intrinsic central nervous system lesion. Antibodies to neuron-specific enolase (NSE), calbindin, glutamic acid decarboxylase (GAD), and vesicular glutamate transporters 1 and 2 (VGluT1, VGluT2) allowed insight into the disturbed synaptic circuitry of the DN. The available case material included autopsy specimens of 24 patients with genetically defined FRDA and 14 normal controls. In FRDA, the cerebellar cortex revealed intact Purkinje cell somata and dendrites as assessed by calbindin immunore-activity. The DN, however, displayed severe loss of large NSE-reactive neurons. Small neurons remained intact. Labeling of Purkinje cells, basket fibers, Golgi neurons, and Golgi axonal plexuses with antibodies to GAD indicated normal intrinsic circuitry of the cerebellar cortex involving γ-aminobutyric acid (GABA). In contrast, the DN displayed severe loss of GABA-ergic terminals and formation of GAD- and calbindin-reactive grumose degeneration. The surviving small GAD-positive DN neurons provided normal GABA-ergic terminals to intact inferior olivary nuclei. The olives also received normal glutamatergic terminals as shown by VGluT2-reactivity. VGluT1-immunocytochemistry of the cerebellar cortex confirmed normal glutamatergic input to the molecular layer by parallel fibers and the granular layer by mossy fibers. VGluT2-immunoreactivity visualized normal climbing fibers and mossy fiber terminals. The DN, however, showed depletion of VGluT1- and VGluT2-reactive terminals arising from climbing and mossy fiber collaterals. The main functional deficit underlying cerebellar ataxia in FRDA is defective processing of inhibitory and excitatory impulses that converge on the large neurons of the DN. The reason for the selective vulnerability of these nerve cells remains elusive. PMID:21638087

  13. Auditory cortical axons contact commissural cells throughout the guinea pig inferior colliculus.

    PubMed

    Nakamoto, Kyle T; Sowick, Colleen S; Schofield, Brett R

    2013-12-01

    Projections from auditory cortex (AC) affect how cells in both inferior colliculi (IC) respond to acoustic stimuli. The large projection from the AC to the ipsilateral IC is usually credited with the effects in the ipsilateral IC. The circuitry underlying effects in the contralateral IC is less clear. The direct projection from the AC to the contralateral IC is relatively small. An unexplored possibility is that the large ipsilateral cortical projection contacts the substantial number of cells in the ipsilateral IC that project through the commissure to the contralateral IC. Apparent contacts between cortical boutons and commissural cells were identified in the left IC after injection of different fluorescent tracers into the left AC and the right IC. Commissural cells were labeled throughout the left IC, and many (23-34%) appeared to be contacted by cortical axons. In the central nucleus, both disc-shaped and stellate cells were contacted. Antibodies to glutamic acid decarboxylase (GAD) were used to identify GABAergic commissural cells. The majority (>86%) of labeled commissural cells were GAD-immunonegative. Despite low numbers of GAD-immunopositive commissural cells, some of these cells were contacted by cortical boutons. Nonetheless, most cortically contacted commissural cells were GAD-immunonegative (i.e., presumably glutamatergic). We conclude that auditory cortical axons contact primarily excitatory commissural cells in the ipsilateral IC that project to the contralateral IC. These corticocollicular contacts occur in each subdivision of the ipsilateral IC, suggesting involvement of commissural cells throughout the IC. This pathway - from AC to commissural cells in the ipsilateral IC - is a prime candidate for the excitatory effects of activation of the auditory cortex on responses in the contralateral IC. Overall this suggests that the auditory corticofugal pathway is integrated with midbrain commissural connections. PMID:24140579

  14. Increased myocardial ischemia-reperfusion injury in renal failure involves cardiac adiponectin signal deficiency.

    PubMed

    Song, Yanbin; Yu, Qiujun; Zhang, Junyi; Huang, Weidong; Liu, Yi; Pei, Haifeng; Liu, Jingyi; Sun, Lu; Yang, Lu; Li, Congye; Li, Yan; Zhang, Fuyang; Qu, Yan; Tao, Ling

    2014-05-01

    Plasma levels of adiponectin (APN) are significantly increased in patients with renal dysfunction and are inversely related to the risk of cardiovascular mortality. The present study was designed to determine the role of APN in myocardial ischemia-reperfusion (MI/R) injury in mice with renal failure and delineate the underlying mechanisms. Renal failure was induced by subtotal nephrectomy (SN). Human recombinant globular domain of adiponectin (gAd) or full-length adiponectin (fAd) was administered via intraperitoneal injection once daily for 7 consecutive days after SN, and in vivo MI/R was introduced 3 wk later. Both plasma and urinary levels of APN increased significantly in SN mice. Compared with sham-operated mice, cardiac function was significantly depressed, and myocardial infarct size and apoptosis increased in SN mice following MI/R. The aggravated MI/R injury was further intensified in APN-knockout mice and markedly ameliorated by treatment with gAd but not fAd. Moreover, SN increased myocardial NO metabolites, superoxide, and their cytotoxic reaction product peroxynitrite, upregulated inducible NO synthase expression, and decreased endothelial NOS phosphorylation. In addition, SN mice also exhibited reduced APN receptor-1 (AdipoR1) expression and AMPK activation. All these changes were further amplified in the absence of APN but reversed by gAd treatment. The present study demonstrates that renal dysfunction increases cardiac susceptibility to ischemic-reperfusion injury, which is associated with downregulated APN/AdipoR1/AMPK signaling and increased oxidative/nitrative stress in local myocardium, and provides the first evidence for the protective role of exogenous supplement of gAd on MI/R outcomes in renal failure. PMID:24595307

  15. Long-Term Pharmacological Treatments of Anxiety Disorders: An Updated Systematic Review.

    PubMed

    Perna, Giampaolo; Alciati, Alessandra; Riva, Alice; Micieli, Wilma; Caldirola, Daniela

    2016-03-01

    Many aspects of long-term pharmacological treatments for anxiety disorders (AnxDs) are still debated. We undertook an updated systematic review of long-term pharmacological studies on panic disorder (PD), generalized anxiety disorder (GAD), and social anxiety disorder (SAD). Relevant studies dating from January 1, 2012 to August 31, 2015 were identified using the PubMed database and a review of bibliographies. Of 372 records identified in the search, five studies on PD and 15 on GAD were included in the review. No studies on SAD were found. Our review confirms the usefulness of long-term pharmacological treatments for PD and GAD and suggests that they can provide further improvement over that obtained during short-term therapy. Paroxetine, escitalopram, and clonazepam can be effective for long-term treatment of PD. However, further studies are needed to draw conclusions about the long-term benzodiazepine use in PD, particularly for the possible cognitive side-effects over time. Pregabalin and quetiapine can be effective for long-term treatment of GAD, while preliminary suggestions emerged for agomelatine and vortioxetine. We did not find any evidence for determining the optimal length and/or dosage of medications to minimize the relapse risk. Few investigations have attempted to identify potential predictors of long-term treatment response. Personalized treatments for AnxDs can be implemented using predictive tools to explore those factors affecting treatment response/tolerability heterogeneity, including neurobiological functions/clinical profiles, comorbidity, biomarkers, and genetic features, and to tailor medications according to each patient's unique features. PMID:26830881

  16. Development of the GABA-ergic signaling system and its role in larval swimming in sea urchin.

    PubMed

    Katow, Hideki; Abe, Kouki; Katow, Tomoko; Zamani, Alemeh; Abe, Hirokazu

    2013-05-01

    The present study aimed to elucidate the development and γ-amino butyric acid (GABA)-ergic regulation of larval swimming in the sea urchin Hemicentrotus pulcherrimus by cloning glutamate decarboxylase (Hp-gad), GABAA receptor (Hp-gabrA) and GABAA receptor-associated protein (Hp-gabarap), and by performing immunohistochemistry. The regulation of larval swimming was increasingly dependent on the GABAergic system, which was active from the 2 days post-fertilization (d.p.f.) pluteus stage onwards. GABA-immunoreactive cells were detected as a subpopulation of secondary mesenchyme cells during gastrulation and eventually constituted the ciliary band and a subpopulation of blastocoelar cells during the pluteus stage. Hp-gad transcription was detected by RT-PCR during the period when Hp-Gad-positive cells were seen as a subpopulation of blastocoelar cells and on the apical side of the ciliary band from the 2 d.p.f. pluteus stage. Consistent with these observations, inhibition of GAD with 3-mercaptopropioninc acid inhibited GABA immunoreactivity and larval swimming dose dependently. Hp-gabrA amplimers were detected weakly in unfertilized eggs and 4 d.p.f. plutei but strongly from fertilized eggs to 2 d.p.f. plutei, and Hp-GabrA, together with GABA, was localized at the ciliary band in association with dopamine receptor D1 from the two-arm pluteus stage. Hp-gabarap transcription and protein expression were detected from the swimming blastula stage. Inhibition of the GABAA receptor by bicuculline inhibited larval swimming dose dependently. Inhibition of larval swimming by either 3-mercaptopropionic acid or bicuculline was more severe in older larvae (17 and 34 d.p.f. plutei) than in younger ones (1 d.p.f. prism larvae). PMID:23307803

  17. The selective conversion of glutamic acid in amino acid mixtures using glutamate decarboxylase--a means of separating amino acids for synthesizing biobased chemicals.

    PubMed

    Teng, Yinglai; Scott, Elinor L; Sanders, Johan P M

    2014-01-01

    Amino acids (AAs) derived from hydrolysis of protein rest streams are interesting feedstocks for the chemical industry due to their functionality. However, separation of AAs is required before they can be used for further applications. Electrodialysis may be applied to separate AAs, but its efficiency is limited when separating AAs with similar isoelectric points. To aid the separation, specific conversion of an AA to a useful product with different charge behavior to the remaining compounds is desired. Here the separation of L-aspartic acid (Asp) and L-glutamic acid (Glu) was studied. L-Glutamate α-decarboxylase (GAD, Type I, EC 4.1.1.15) was applied to specifically convert Glu into γ-aminobutyric acid (GABA). GABA has a different charge behavior from Asp therefore allowing a potential separation by electrodialysis. Competitive inhibition and reduced operational stability caused by Asp could be eliminated by maintaining a sufficiently high concentration of Glu. Immobilization of GAD does not reduce the enzyme's initial activity. However, the operational stability was slightly reduced. An initial study on the reaction operating in a continuous mode was performed using a column reactor packed with immobilized GAD. As the reaction mixture was only passed once through the reactor, the conversion of Glu was lower than expected. To complete the conversion of Glu, the stream containing Asp and unreacted Glu might be recirculated back to the reactor after GABA has been removed. Overall, the reaction by GAD is specific to Glu and can be applied to aid the electrodialysis separation of Asp and Glu. PMID:24616376

  18. A Transgenic Mouse Line Expressing the Red Fluorescent Protein tdTomato in GABAergic Neurons.

    PubMed

    Besser, Stefanie; Sicker, Marit; Marx, Grit; Winkler, Ulrike; Eulenburg, Volker; Hülsmann, Swen; Hirrlinger, Johannes

    2015-01-01

    GABAergic inhibitory neurons are a large population of neurons in the central nervous system (CNS) of mammals and crucially contribute to the function of the circuitry of the brain. To identify specific cell types and investigate their functions labelling of cell populations by transgenic expression of fluorescent proteins is a powerful approach. While a number of mouse lines expressing the green fluorescent protein (GFP) in different subpopulations of GABAergic cells are available, GFP expressing mouse lines are not suitable for either crossbreeding to other mouse lines expressing GFP in other cell types or for Ca2+-imaging using the superior green Ca2+-indicator dyes. Therefore, we have generated a novel transgenic mouse line expressing the red fluorescent protein tdTomato in GABAergic neurons using a bacterial artificial chromosome based strategy and inserting the tdTomato open reading frame at the start codon within exon 1 of the GAD2 gene encoding glutamic acid decarboxylase 65 (GAD65). TdTomato expression was observed in all expected brain regions; however, the fluorescence intensity was highest in the olfactory bulb and the striatum. Robust expression was also observed in cortical and hippocampal neurons, Purkinje cells in the cerebellum, amacrine cells in the retina as well as in cells migrating along the rostral migratory stream. In cortex, hippocampus, olfactory bulb and brainstem, 80% to 90% of neurons expressing endogenous GAD65 also expressed the fluorescent protein. Moreover, almost all tdTomato-expressing cells coexpressed GAD65, indicating that indeed only GABAergic neurons are labelled by tdTomato expression. This mouse line with its unique spectral properties for labelling GABAergic neurons will therefore be a valuable new tool for research addressing this fascinating cell type. PMID:26076353

  19. Regional metabolic alterations in the hypothalamus of restricted rats

    SciTech Connect

    Beverly, J.L.; Martin, R.J.

    1986-01-01

    Alterations of intermediary and neurotransmitter metabolism in the hypothalamus of rats on restricted intakes have been documented. The rates of fatty acid oxidation (FAO) and glutamic acid decarboxylase (GAD) were measured in hypothalamic sites of restricted or ad libitum fed rats. Female Sprague-Dawley rats (230 g) receiving a semi-purified diet received either ad lib (AL), 3/7 of ad lib as a single meal at 1700 h (R), 3/7 of ad lib by intubation as three equally spaced meals (TF) or ad lib for 3 d followed by 4 d of starvation (S). Rats were sacrificed at 0800 h and the brains quickly removed. FAO: Two 1.0 mm slices were dissected from the hypothalamus and areas corresponding to the VMN, PVN, and DMN removed with a 20 gauge punch. An 18 gauge punch was used to remove MFB/LHA. Bilateral punches were incubated at 37 C for 2 h in Krebs-bicarb. media containing (1-/sup 14/C) palmitate (0.1 ..mu..Ci)/..mu..mole). GAD: The VMN and MFB-LHA were dissected as above. GAD activity was measured in homogenates using L-(/sup 14/C) glutamate (1 /sup +/Ci/..mu..mole) as described by Tappaz et al. (1976). Restriction significantly reduced FAO rates in the MFB/LHA. FAO rate in the VMN was not altered when restriction occurred as a single meal per day (R) but was reduced with restriction as three small meals per day (TF) or a 4 d starvation (S). No differences were noted in PVN or DMN FAO rates. GAD activity did not differ with restriction except in response to starvation in the VMN.

  20. Implementation of a generalized actuator disk wind turbine model into the weather research and forecasting model for large-eddy simulation applications

    SciTech Connect

    Mirocha, J. D.; Kosovic, B.; Aitken, M. L.; Lundquist, J. K.

    2014-01-10

    A generalized actuator disk (GAD) wind turbine parameterization designed for large-eddy simulation (LES) applications was implemented into the Weather Research and Forecasting (WRF) model. WRF-LES with the GAD model enables numerical investigation of the effects of an operating wind turbine on and interactions with a broad range of atmospheric boundary layer phenomena. Numerical simulations using WRF-LES with the GAD model were compared with measurements obtained from the Turbine Wake and Inflow Characterization Study (TWICS-2011), the goal of which was to measure both the inflow to and wake from a 2.3-MW wind turbine. Data from a meteorological tower and two light-detection and ranging (lidar) systems, one vertically profiling and another operated over a variety of scanning modes, were utilized to obtain forcing for the simulations, and to evaluate characteristics of the simulated wakes. Simulations produced wakes with physically consistent rotation and velocity deficits. Two surface heat flux values of 20 W m–2 and 100 W m–2 were used to examine the sensitivity of the simulated wakes to convective instability. Simulations using the smaller heat flux values showed good agreement with wake deficits observed during TWICS-2011, whereas those using the larger value showed enhanced spreading and more-rapid attenuation. This study demonstrates the utility of actuator models implemented within atmospheric LES to address a range of atmospheric science and engineering applications. In conclusion, validated implementation of the GAD in a numerical weather prediction code such as WRF will enable a wide range of studies related to the interaction of wind turbines with the atmosphere and surface.

  1. An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability

    PubMed Central

    Tremolizzo, L.; Carboni, G.; Ruzicka, W. B.; Mitchell, C. P.; Sugaya, I.; Tueting, P.; Sharma, R.; Grayson, D. R.; Costa, E.; Guidotti, A.

    2002-01-01

    Reelin and glutamic acid decarboxylase (GAD)67 expressed by cortical γ-aminobutyric acid-ergic interneurons are down-regulated in schizophrenia. Because epidemiological studies of schizophrenia fail to support candidate gene haploinsufficiency of Mendelian origin, we hypothesize that epigenetic mechanisms (i.e., cytosine hypermethylation of CpG islands present in the promoter of these genes) may be responsible for this down-regulation. Protracted l-methionine (6.6 mmol/kg for 15 days, twice a day) treatment in mice elicited in brain an increase of S-adenosyl-homocysteine, the processing product of the methyl donor S-adenosyl-methionine, and a marked decrease of reelin and GAD67 mRNAs in both WT and heterozygous reeler mice. This effect of l-methionine was associated with an increase in the number of methylated cytosines in the CpG island of the reelin promoter region. This effect was not observed for GAD65 or neuronal-specific enolase and was not replicated by glycine doses 2-fold greater than those of l-methionine. Prepulse inhibition of startle declined at a faster rate as the prepulse/startle interval increased in mice receiving l-methionine. Valproic acid (2 mmol/kg for 15 days, twice a day) reverted l-methionine-induced down-regulation of reelin and GAD67 in both WT and heterozygous reeler mice, suggesting an epigenetic action through the inhibition of histone deacetylases. The same dose of valproate increased acetylation of histone H3 in mouse brain nearly 4-fold. This epigenetic mouse model may be useful in evaluating drug efficacy on schizophrenia vulnerability. Hence the inhibition of histone deacetylases could represent a pharmacological intervention mitigating epigenetically induced vulnerability to schizophrenia in individuals at risk. PMID:12481028

  2. Canadian boreal pulp and paper feedstocks contain neuroactive substances that interact in vitro with GABA and dopaminergic systems in the brain.

    PubMed

    Waye, Andrew; Annal, Malar; Tang, Andrew; Picard, Gabriel; Harnois, Frédéric; Guerrero-Analco, José A; Saleem, Ammar; Hewitt, L Mark; Milestone, Craig B; MacLatchy, Deborah L; Trudeau, Vance L; Arnason, John T

    2014-01-15

    Pulp and paper wood feedstocks have been previously implicated as a source of chemicals with the ability to interact with or disrupt key neuroendocrine endpoints important in the control of reproduction. We tested nine Canadian conifers commonly used in pulp and paper production as well as 16 phytochemicals that have been observed in various pulp and paper mill effluent streams for their ability to interact in vitro with the enzymes monoamine oxidase (MAO), glutamic acid decarboxylase (GAD), and GABA-transaminase (GABA-T), and bind to the benzodiazepine-binding site of the GABA(A) receptor (GABA(A)-BZD). These neuroendocrine endpoints are also important targets for treatment of neurological disorders such as anxiety, epilepsy, or depression. MAO and GAD were inhibited by various conifer extracts of different polarities, including major feedstocks such as balsam fir, black spruce, and white spruce. MAO was selectively stimulated or inhibited by many of the tested phytochemicals, with inhibition observed by a group of phenylpropenes (e.g. isoeugenol and vanillin). Selective GAD inhibition was also observed, with all of the resin acids tested being inhibitory. GABA(A)-BZD ligand displacement was also observed. We compiled a table identifying which of these phytochemicals have been described in each of the species tested here. Given the diversity of conifer species and plant chemicals with these specific neuroactivities, it is reasonable to propose that MAO and GAD inhibition reported in effluents is phytochemical in origin. We propose disruption of these neuroendocrine endpoints as a possible mechanism of reproductive inhibition, and also identify an avenue for potential research and sourcing of conifer-derived neuroactive natural products. PMID:24041600

  3. Evaluation of the unique and specific contributions of dimensions of the triple vulnerability model to the prediction of DSM-IV anxiety and mood disorder constructs.

    PubMed

    Brown, Timothy A; Naragon-Gainey, Kristin

    2013-06-01

    The triple vulnerability model (Barlow, 2000, 2002) posits that three vulnerabilities contribute to the etiology of emotional disorders: (1) general biological vulnerability (i.e., dimensions of temperament such as neuroticism and extraversion); (2) general psychological vulnerability (i.e., perceived control over life stress and emotional states); (3) disorder-specific psychological vulnerability (e.g., thought-action fusion for OCD). Despite the prominence of this model, a comprehensive empirical evaluation has not yet been undertaken. The current study used structural equation modeling to test the triple vulnerability model in a large clinical sample (N=700), focusing on vulnerabilities for depression, social phobia, generalized anxiety disorder (GAD), and OCD. Specifically, we examined the incremental prediction of each level of the triple vulnerability model for each disorder, with the following putative disorder-specific psychological vulnerabilities: thought-action fusion (TAF) for OCD, the dysfunctional attitudes (DAS) for depression, and intolerance of uncertainty (IoU) for GAD. In the final model that included all three levels of vulnerabilities, neuroticism had significant direct effects on all four disorder constructs, and extraversion was inversely associated with depression and social phobia. However, perceived control was significantly associated with GAD and OCD only. Of the disorder-specific psychological vulnerabilities, TAF was significantly and specifically related to OCD. In contrast, DAS and IoU were not significant predictors of depression and GAD respectively, instead contributing to other disorders. The results are discussed in regard to structural models of the emotional disorders and the various roles of general and specific vulnerability dimensions in the onset, severity, and temporal course of psychopathology. PMID:23611077

  4. Design and fabrication of a basic mass analyzer and vacuum system

    NASA Technical Reports Server (NTRS)

    Judson, C. M.; Josias, C.; Lawrence, J. L., Jr.

    1977-01-01

    A two-inch hyperbolic rod quadrupole mass analyzer with a mass range of 400 to 200 amu and a sensitivity exceeding 100 packs per billion has been developed and tested. This analyzer is the basic hardware portion of a microprocessor-controlled quadrupole mass spectrometer for a Gas Analysis and Detection System (GADS). The development and testing of the hyperbolic-rod quadrupole mass spectrometer and associated hardware are described in detail.

  5. Epilepsy and hippocampal neurodegeneration induced by glutamate decarboxylase inhibitors in awake rats.

    PubMed

    Salazar, Patricia; Tapia, Ricardo

    2015-10-01

    Glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis, requires pyridoxal phosphate (PLP) as a cofactor. Thiosemicarbazide (TSC) and γ-glutamyl-hydrazone (PLPGH) inhibit the free PLP-dependent isoform (GAD65) activity after systemic administration, leading to epilepsy in mice and in young, but not in adult rats. However, the competitive GAD inhibitor 3-mercaptopropionic acid (MPA) induces convulsions in both immature and adult rats. In the present study we tested comparatively the epileptogenic and neurotoxic effects of PLPGH, TSC and MPA, administered by microdialysis in the hippocampus of adult awake rats. Cortical EEG and motor behavior were analyzed during the next 2h, and aspartate, glutamate and GABA were measured by HPLC in the microdialysis-collected fractions. Twenty-four hours after drug administration rats were fixed for histological analysis of the hippocampus. PLPGH or TSC did not affect the motor behavior, EEG or cellular morphology, although the extracellular concentration of GABA was decreased. In contrast, MPA produced intense wet-dog shakes, EEG epileptiform discharges, a >75% reduction of extracellular GABA levels and remarkable neurodegeneration of the CA1 region, with >80% neuronal loss. The systemic administration of the NMDA glutamate receptor antagonist MK-801 30 min before MPA did not prevent the MPA-induced epilepsy but significantly protected against its neurotoxic effect, reducing neuronal loss to <30%. We conclude that in adult awake rats, drugs acting on PLP availability have only a weak effect on GABA neurotransmission, whereas direct GAD inhibition produced by MPA induces hyperexcitation leading to epilepsy and hippocampal neurodegeneration. Because this degeneration was prevented by the blockade of NMDA receptors, we conclude that it is due to glutamate-mediated excitotoxicity consequent to disinhibition of the hippocampal excitatory circuits. PMID:26354164

  6. A Transgenic Mouse Line Expressing the Red Fluorescent Protein tdTomato in GABAergic Neurons

    PubMed Central

    Besser, Stefanie; Sicker, Marit; Marx, Grit; Winkler, Ulrike; Eulenburg, Volker; Hülsmann, Swen; Hirrlinger, Johannes

    2015-01-01

    GABAergic inhibitory neurons are a large population of neurons in the central nervous system (CNS) of mammals and crucially contribute to the function of the circuitry of the brain. To identify specific cell types and investigate their functions labelling of cell populations by transgenic expression of fluorescent proteins is a powerful approach. While a number of mouse lines expressing the green fluorescent protein (GFP) in different subpopulations of GABAergic cells are available, GFP expressing mouse lines are not suitable for either crossbreeding to other mouse lines expressing GFP in other cell types or for Ca2+-imaging using the superior green Ca2+-indicator dyes. Therefore, we have generated a novel transgenic mouse line expressing the red fluorescent protein tdTomato in GABAergic neurons using a bacterial artificial chromosome based strategy and inserting the tdTomato open reading frame at the start codon within exon 1 of the GAD2 gene encoding glutamic acid decarboxylase 65 (GAD65). TdTomato expression was observed in all expected brain regions; however, the fluorescence intensity was highest in the olfactory bulb and the striatum. Robust expression was also observed in cortical and hippocampal neurons, Purkinje cells in the cerebellum, amacrine cells in the retina as well as in cells migrating along the rostral migratory stream. In cortex, hippocampus, olfactory bulb and brainstem, 80% to 90% of neurons expressing endogenous GAD65 also expressed the fluorescent protein. Moreover, almost all tdTomato-expressing cells coexpressed GAD65, indicating that indeed only GABAergic neurons are labelled by tdTomato expression. This mouse line with its unique spectral properties for labelling GABAergic neurons will therefore be a valuable new tool for research addressing this fascinating cell type. PMID:26076353

  7. Descending projections from auditory cortex to excitatory and inhibitory cells in the nucleus of the brachium of the inferior colliculus

    PubMed Central

    Mellott, Jeffrey G.; Bickford, Martha E.; Schofield, Brett R.

    2014-01-01

    Descending projections from the auditory cortex (AC) terminate in subcortical auditory centers from the medial geniculate nucleus (MG) to the cochlear nucleus, allowing the AC to modulate the processing of acoustic information at many levels of the auditory system. The nucleus of the brachium of the inferior colliculus (NBIC) is a large midbrain auditory nucleus that is a target of these descending cortical projections. The NBIC is a source of several auditory projections, including an ascending projection to the MG. This ascending projection appears to originate from both excitatory and inhibitory NBIC cells, but whether the cortical projections contact either of these cell groups is unknown. In this study, we first combined retrograde tracing and immunochemistry for glutamic acid decarboxylase (GAD, a marker of GABAergic cells) to identify GABAergic and non-GABAergic NBIC projections to the MG. Our first result is that GAD-immunopositive cells constitute ~17% of the NBIC to MG projection. We then used anterograde labeling and electron microscopy to examine the AC projection to the NBIC. Our second result is that cortical boutons in the NBIC form synapses with round vesicles and asymmetric synapses, consistent with excitatory effects. Finally, we combined fluorescent anterograde labeling of corticofugal axons with immunochemistry and retrograde labeling of NBIC cells that project to the MG. These final results suggest first that AC axons contact both GAD-negative and GAD-positive NBIC cells and, second, that some of cortically-contacted cells project to the MG. Overall, the results imply that corticofugal projections can modulate both excitatory and inhibitory ascending projections from the NBIC to the auditory thalamus. PMID:25339870

  8. Benefits of Distinguishing between Physical and Social-Verbal Aspects of Behavior: An Example of Generalized Anxiety.

    PubMed

    Trofimova, Irina; Sulis, William

    2016-01-01

    Temperament traits and mental illness have been linked to varying degrees of imbalances in neurotransmitter systems of behavior regulation. If a temperament model has been carefully structured to reflect weak imbalances within systems of behavior regulation, then in the presence of mental illness, these profiles should exhibit distinct patterns consistent with symptoms of mental illness. In contrast to other temperament models used in studies of anxiety disorders, the Functional Ensemble of Temperament (FET) model differentiates not only between emotionality traits, but also between traits related to physical, social-verbal and mental aspects of behavior. This paper analyzed the predictions of the FET model, which maps 12 functional aspects of behavior to symptoms of generalized anxiety disorder (GAD) as described in the DSM/ICD. As an example, the paper describes a study of the coupling of sex, age and temperament traits with GAD using the FET framework. The intake records of 116 clients in treatment with confirmed diagnosis of GAD in a private psychological practice were compared using ANOVA against records of 146 healthy clients using their scores on the FET-based questionnaire, in age groups 17-24, 25-45, 46-65. Patients with GAD in all age groups reported significantly lower Social Endurance, Social Tempo, Probabilistic reasoning (but not in physical aspects of behavior) and higher Neuroticism than healthy individuals, however, no effects on the scales of Motor Endurance or Tempo were found. These findings show the benefits of differentiation between motor-physical and social-verbal aspects of behavior in psychological assessment of mental disorders. PMID:27014146

  9. Toxoplasma gondii Infections Alter GABAergic Synapses and Signaling in the Central Nervous System

    PubMed Central

    Brooks, Justin M.; Carrillo, Gabriela L.; Su, Jianmin; Lindsay, David S.; Blader, Ira J.

    2015-01-01

    ABSTRACT During infections with the protozoan parasite Toxoplasma gondii, gamma-aminobutyric acid (GABA) is utilized as a carbon source for parasite metabolism and also to facilitate parasite dissemination by stimulating dendritic-cell motility. The best-recognized function for GABA, however, is its role in the nervous system as an inhibitory neurotransmitter that regulates the flow and timing of excitatory neurotransmission. When this pathway is altered, seizures develop. Human toxoplasmosis patients suffer from seizures, suggesting that Toxoplasma interferes with GABA signaling in the brain. Here, we show that while excitatory glutamatergic presynaptic proteins appeared normal, infection with type II ME49 Toxoplasma tissue cysts led to global changes in the distribution of glutamic acid decarboxylase 67 (GAD67), a key enzyme that catalyzes GABA synthesis in the brain. Alterations in GAD67 staining were not due to decreased expression but rather to a change from GAD67 clustering at presynaptic termini to a more diffuse localization throughout the neuropil. Consistent with a loss of GAD67 from the synaptic terminals, Toxoplasma-infected mice develop spontaneous seizures and are more susceptible to drugs that induce seizures by antagonizing GABA receptors. Interestingly, GABAergic protein mislocalization and the response to seizure-inducing drugs were observed in mice infected with type II ME49 but not type III CEP strain parasites, indicating a role for a polymorphic parasite factor(s) in regulating GABAergic synapses. Taken together, these data support a model in which seizures and other neurological complications seen in Toxoplasma-infected individuals are due, at least in part, to changes in GABAergic signaling. PMID:26507232

  10. An Archaeal Glutamate Decarboxylase Homolog Functions as an Aspartate Decarboxylase and Is Involved in β-Alanine and Coenzyme A Biosynthesis

    PubMed Central

    Tomita, Hiroya; Yokooji, Yuusuke; Ishibashi, Takuya; Imanaka, Tadayuki

    2014-01-01

    β-Alanine is a precursor for coenzyme A (CoA) biosynthesis and is a substrate for the bacterial/eukaryotic pantothenate synthetase and archaeal phosphopantothenate synthetase. β-Alanine is synthesized through various enzymes/pathways in bacteria and eukaryotes, including the direct decarboxylation of Asp by aspartate 1-decarboxylase (ADC), the degradation of pyrimidine, or the oxidation of polyamines. However, in most archaea, homologs of these enzymes are not present; thus, the mechanisms of β-alanine biosynthesis remain unclear. Here, we performed a biochemical and genetic study on a glutamate decarboxylase (GAD) homolog encoded by TK1814 from the hyperthermophilic archaeon Thermococcus kodakarensis. GADs are distributed in all three domains of life, generally catalyzing the decarboxylation of Glu to γ-aminobutyrate (GABA). The recombinant TK1814 protein displayed not only GAD activity but also ADC activity using pyridoxal 5′-phosphate as a cofactor. Kinetic studies revealed that the TK1814 protein prefers Asp as its substrate rather than Glu, with nearly a 20-fold difference in catalytic efficiency. Gene disruption of TK1814 resulted in a strain that could not grow in standard medium. Addition of β-alanine, 4′-phosphopantothenate, or CoA complemented the growth defect, whereas GABA could not. Our results provide genetic evidence that TK1814 functions as an ADC in T. kodakarensis, providing the β-alanine necessary for CoA biosynthesis. The results also suggest that the GAD activity of TK1814 is not necessary for growth, at least under the conditions applied in this study. TK1814 homologs are distributed in a wide range of archaea and may be responsible for β-alanine biosynthesis in these organisms. PMID:24415726

  11. Targeted enhancement of glutamate-to-γ-aminobutyrate conversion in Arabidopsis seeds affects carbon-nitrogen balance and storage reserves in a development-dependent manner.

    PubMed

    Fait, Aaron; Nesi, Adriano Nunes; Angelovici, Ruthie; Lehmann, Martin; Pham, Phuong Anh; Song, Luhua; Haslam, Richard P; Napier, Johnathan A; Galili, Gad; Fernie, Alisdair R

    2011-11-01

    In seeds, glutamate decarboxylase (GAD) operates at the metabolic nexus between carbon and nitrogen metabolism by catalyzing the unidirectional decarboxylation of glutamate to form γ-aminobutyric acid (GABA). To elucidate the regulatory role of GAD in seed development, we generated Arabidopsis (Arabidopsis thaliana) transgenic plants expressing a truncated GAD from Petunia hybrida missing the carboxyl-terminal regulatory Ca(2+)-calmodulin-binding domain under the transcriptional regulation of the seed maturation-specific phaseolin promoter. Dry seeds of the transgenic plants accumulated considerable amounts of GABA, and during desiccation the content of several amino acids increased, although not glutamate or proline. Dry transgenic seeds had higher protein content than wild-type seeds but lower amounts of the intermediates of glycolysis, glycerol and malate. The total fatty acid content of the transgenic seeds was 50% lower than in the wild type, while acyl-coenzyme A accumulated in the transgenic seeds. Labeling experiments revealed altered levels of respiration in the transgenic seeds, and fractionation studies indicated reduced incorporation of label in the sugar and lipid fractions extracted from transgenic seeds. Comparative transcript profiling of the dry seeds supported the metabolic data. Cellular processes up-regulated at the transcript level included the tricarboxylic acid cycle, fatty acid elongation, the shikimate pathway, tryptophan metabolism, nitrogen-carbon remobilization, and programmed cell death. Genes involved in the regulation of germination were similarly up-regulated. Taken together, these results indicate that the GAD-mediated conversion of glutamate to GABA during seed development plays an important role in balancing carbon and nitrogen metabolism and in storage reserve accumulation. PMID:21921115

  12. Differential gene expression for glutamic acid decarboxylase and type II calcium-calmodulin-dependent protein kinase in basal ganglia, thalamus, and hypothalamus of the monkey

    SciTech Connect

    Benson, D.L.; Isackson, P.J.; Hendry, S.H.; Jones, E.G. )

    1991-06-01

    In situ hybridization histochemistry, using cRNA probes, revealed a complementarity in the distributions of cells in the basal ganglia, basal nucleus of Meynert, thalamus, hypothalamus, and rostral part of the midbrain that showed gene expression for glutamic acid decarboxylase (GAD) or the alpha-subunit of type II calcium-calmodulin-dependent protein kinase (CAM II kinase-alpha). Cells in certain nuclei such as the thalamic reticular nucleus, globus pallidus, and pars reticulata of the substantia nigra show GAD gene expression only; others in nuclei such as the basal nucleus of Meynert, medial mamillary nuclei, and ventromedial hypothalamic nuclei show CAM II kinase-alpha gene expression only. A few nuclei, for example, the pars compacta of the substantia nigra and the greater part of the subthalamic nucleus, display gene expression for neither GAD nor CAM II kinase-alpha. In other nuclei, notably those of the dorsal thalamus, and possibly in the striatum, GAD- and CAM II kinase-expressing cells appear to form two separate populations that, in most thalamic nuclei, together account for the total cell population. In situ hybridization reveals large amounts of CAM II kinase-alpha mRNA in the neuropil of most nuclei containing CAM II kinase-alpha-positive cells, suggesting its association with dendritic polyribosomes. The message may thus be translated at those sites, close to the synapses with which the protein is associated. The in situ hybridization results, coupled with those from immunocytochemical staining for CAM II kinase-alpha protein, indicate that CAM II kinase-alpha is commonly found in certain non-GABAergic afferent fiber systems but is not necessarily present in the postsynaptic cells on which they terminate. It appears to be absent from most GABAergic fiber systems but can be present in the cells on which they terminate.

  13. Levodopa replacement therapy alters enzyme activities in striatum and neuropeptide content in striatal output regions of 6-hydroxydopamine lesioned rats.

    PubMed

    Engber, T M; Susel, Z; Kuo, S; Gerfen, C R; Chase, T N

    1991-06-21

    The effects of striatal dopamine denervation and levodopa replacement therapy on neuronal populations in the rat striatum were assessed by measurement of glutamic acid decarboxylase (GAD) and choline acetyltransferase (CAT) activities in the striatum, dynorphin and substance P concentrations in the substantia nigra, and enkephalin concentration in the globus pallidus. Rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway were treated for 21 days with levodopa (100 mg/kg/day, i.p., with 25 mg/kg benserazide) on either an intermittent (b.i.d.) or continuous (osmotic pump infusion) regimen and sacrificed following a three day drug washout. In saline-treated control rats, striatal GAD activity and globus pallidus enkephalin content were elevated and nigral substance P content was reduced ipsilateral to the 6-OHDA lesion. Intermittent levodopa treatment further increased GAD activity, decreased CAT activity, restored substance P to control levels, markedly increased dynorphin content, and had no effect on enkephalin. In contrast, continuous levodopa elevated globus pallidus enkephalin beyond the levels occurring with denervation, but had no effect on any of the other neurochemical measures. These results indicate that striatal neuronal populations are differentially affected by chronic levodopa therapy and by the continuous or intermittent nature of the treatment regimen. With the exception of substance P, levodopa did not reverse the effects of the 6-OHDA lesion but, rather, either exacerbated the lesion-induced changes (e.g. GAD and enkephalin) or altered neurochemical markers which had been unaffected by the lesion (e.g. CAT and dynorphin).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1717109

  14. Outcrop Gamma-ray Analysis of the Cretaceous mesaverde Group: Jicarilla Apache Indian Reservation, New Mexico

    SciTech Connect

    Ridgley, Jennie; Dunbar, Robyn Wright

    2001-04-25

    This report presents the results of an outcrop gamma-ray survey of six selected measured sections included in the original report. The primary objective of this second study is to provide a baseline to correlate from the outcrop and reservoir model into Mesaverde strata in the San Juan Basin subsurface. Outcrop logs were generated using a GAD-6 gamma-ray spectrometer that simultaneously recorded total counts, potassium, uranium, and thorium data.

  15. Benefits of Distinguishing between Physical and Social-Verbal Aspects of Behavior: An Example of Generalized Anxiety

    PubMed Central

    Trofimova, Irina; Sulis, William

    2016-01-01

    Temperament traits and mental illness have been linked to varying degrees of imbalances in neurotransmitter systems of behavior regulation. If a temperament model has been carefully structured to reflect weak imbalances within systems of behavior regulation, then in the presence of mental illness, these profiles should exhibit distinct patterns consistent with symptoms of mental illness. In contrast to other temperament models used in studies of anxiety disorders, the Functional Ensemble of Temperament (FET) model differentiates not only between emotionality traits, but also between traits related to physical, social-verbal and mental aspects of behavior. This paper analyzed the predictions of the FET model, which maps 12 functional aspects of behavior to symptoms of generalized anxiety disorder (GAD) as described in the DSM/ICD. As an example, the paper describes a study of the coupling of sex, age and temperament traits with GAD using the FET framework. The intake records of 116 clients in treatment with confirmed diagnosis of GAD in a private psychological practice were compared using ANOVA against records of 146 healthy clients using their scores on the FET-based questionnaire, in age groups 17–24, 25–45, 46–65. Patients with GAD in all age groups reported significantly lower Social Endurance, Social Tempo, Probabilistic reasoning (but not in physical aspects of behavior) and higher Neuroticism than healthy individuals, however, no effects on the scales of Motor Endurance or Tempo were found. These findings show the benefits of differentiation between motor-physical and social-verbal aspects of behavior in psychological assessment of mental disorders. PMID:27014146

  16. Sub-chronic Antipsychotic Drug Administration Reverses the Expression of Neuregulin 1 and ErbB4 in a Cultured MK801-Induced Mouse Primary Hippocampal Neuron or a Neurodevelopmental Schizophrenia Model.

    PubMed

    Li, Cunyan; Tang, Yamei; Yang, Jingjing; Zhang, Xianghui; Liu, Yong; Tang, Aiguo

    2016-08-01

    It has been reported that specific environmental influences during the postpartum period might contribute to the development of schizophrenia (SZ). Administration of MK801 during early development led to persistent brain pathology. Glutamate decarboxylase 1 (GAD67) and parvalbumin (PV), and neuregulin 1 (NRG1)/ErbB4 signaling were closely associated with SZ pathology. We postulated therefore that NMDA receptor antagonists exposure during the postpartum period may be associated with expression dysregulation of some of the SZ candidate proteins. To test this, we used mouse primary hippocampal neurons and neonatal male mice treated with the NMDA receptor antagonist, MK801 at postnatal day 4 (P4) or P7, followed by the treatments of antipsychotic drugs (i.e., olanzapine, risperidone, and haloperidol). The expressions of GAD67, PV, NRG1, and ErbB4 in in vitro and in vivo SZ models were detected with Western blot analysis and immunohistochemistry, respectively. Behavioral tests (locomotion activity, social interaction, novel object recognition and prepulse inhibition) were measured. We found MK801 decreased the expression of GAD67, PV, NRG1 and ErbB4, and induced obvious behavioral alterations, while antipsychotics reversed these alterations. These results suggest that exposure to the NMDA receptor antagonist in early development may lead to long-lasting influence on the expression of specific proteins, such as GAD67, PV, NRG1, and ErbB4. Moreover, our results suggest that rescue of the activation of the NRG1/ErbB4 signaling pathway may be one of the mechanisms by which antipsychotic drugs have an antipsychotic effect. PMID:27097547

  17. Triple Comorbid Trajectories of Tobacco, Alcohol, and Marijuana Use as Predictors of Antisocial Personality Disorder and Generalized Anxiety Disorder Among Urban Adults

    PubMed Central

    Brook, Judith S.; Lee, Jung Yeon; Rubenstone, Elizabeth; Brook, David W.; Finch, Stephen J.

    2014-01-01

    Objectives. We modeled triple trajectories of tobacco, alcohol, and marijuana use from adolescence to adulthood as predictors of antisocial personality disorder (ASPD) and generalized anxiety disorder (GAD). Methods. We assessed urban African American and Puerto Rican participants (n = 816) in the Harlem Longitudinal Development Study, a psychosocial investigation, at 4 time waves (mean ages = 19, 24, 29, and 32 years). We used Mplus to obtain the 3 variable trajectories of tobacco, alcohol, and marijuana use from time 2 to time 5 and then conducted logistic regression analyses. Results. A 5-trajectory group model, ranging from the use of all 3 substances (23%) to a nonuse group (9%), best fit the data. Membership in the trajectory group that used all 3 substances was associated with an increased likelihood of both ASPD (adjusted odds ratio [AOR] = 6.83; 95% CI = 1.14, 40.74; P < .05) and GAD (AOR = 4.35; 95% CI = 1.63, 11.63; P < .001) in adulthood, as compared with the nonuse group, with control for earlier proxies of these conditions. Conclusions. Adults with comorbid tobacco, alcohol, and marijuana use should be evaluated for use of other substances and for ASPD, GAD, and other psychiatric disorders. Treatment programs should address the use of all 3 substances to decrease the likelihood of comorbid psychopathology. PMID:24922120

  18. The Relationship Between the Genetic and Environmental Influences on Common Internalizing Psychiatric Disorders and Mental Well-Being

    PubMed Central

    Myers, John M.; Maes, Hermine H.; Keyes, Corey L. M.

    2011-01-01

    To determine the relationship between the genetic and environmental risk factors for common internalizing psychopathology (IP) and mental well-being (MWB), we examined detailed measures of emotional, social and psychological well-being, and a history of major depression (MD), generalized anxiety disorder (GAD) and panic attacks in the last year, in 1,386 twins from same-sex pairs from the MIDUS national USA sample assessed in 1995 and then again in 2005. Statistical analyses were performed with the Mx program. In the 1995 data, the best fit model contained one substantially heritable common factor for MD, GAD and panic attacks, and one strongly heritable common factor for the three well-being measures. Genetic and environmental risk factors for IP accounted for, respectively, 50 and 5%, of the genetic and environmental influences on MWB. We then constructed, using 1995 and 2005 data, two common factors that reflected temporally stable influences on (i) MD and GAD, and (ii) on emotional and psychological well-being. Genetic and environmental risk factors for the stable liability to IP accounted for 41 and 29% of the stable genetic and environmental influences, respectively, on MWB. This study suggests that genetic risk factors for IP make up 41–50% of the genetic influences on MWB. The overlap of environmental risk factors is more modest. Although low levels of IP on average reflect a high genetic propensity for MWB, other independent genetic influences play an important role in producing good mental health. PMID:21451959

  19. Fine Tuning of Synaptic Plasticity and Filtering by GABA Released from Hippocampal Autaptic Granule Cells.

    PubMed

    Valente, Pierluigi; Orlando, Marta; Raimondi, Andrea; Benfenati, Fabio; Baldelli, Pietro

    2016-03-01

    The functional consequence of γ-aminobutyric acid (GABA) release at mossy fiber terminals is still a debated topic. Here, we provide multiple evidence of GABA release in cultured autaptic hippocampal granule cells. In ∼50% of the excitatory autaptic neurons, GABA, VGAT, or GAD67 colocalized with vesicular glutamate transporter 1-positive puncta, where both GABAB and GABAA receptors (Rs) were present. Patch-clamp recordings showed a clear enhancement of autaptic excitatory postsynaptic currents in response to the application of the GABABR antagonist CGP58845 only in neurons positive to the selective granule cell marker Prox1, and expressing low levels of GAD67. Indeed, GCP non-responsive excitatory autaptic neurons were both Prox1- and GAD67-negative. Although the amount of released GABA was not sufficient to activate functional postsynaptic GABAARs, it effectively activated presynaptic GABABRs that maintain a tonic "brake" on the probability of release and on the size of the readily releasable pool and contributed to resting potential hyperpolarization possibly through extrasynaptic GABAAR activation. The autocrine inhibition exerted by GABABRs on glutamate release enhanced both paired-pulse facilitation and post-tetanic potentiation. Such GABABR-mediated changes in short-term plasticity confer to immature granule cells the capability to modulate their filtering properties in an activity-dependent fashion, with remarkable consequences on the dynamic behavior of neural circuits. PMID:25576534

  20. Four Centuries of the Geocentric Axial Dipole Hypothesis

    NASA Astrophysics Data System (ADS)

    Tauxe, L.; Kent, D. V.

    2004-12-01

    William Gilbert first articulated what has come to be known as the geocentric axial dipole hypothesis. The GAD hypothesis is the principle on which paleogeographic reconstructions rely to constrain paleolatitude. For decades there have been calls for permanent non-dipole contributions to the time averaged field. Recently, these have demanded large contributions of the axial octupole, which, if valid, would call into question the general utility of the GAD hypothesis. In the process of geological recording of the geomagnetic field, ``Earth filters'' distort the directions. Many processes, for example, sedimentary inclination error and random tilting lead to a net shallowing of the observed direction. Therefore inclinations that are shallower than expected from GAD can be explained by recording biases, northward transport, or non-dipole geomagnetic fields. Using paleomagnetic data from the last five million years from well constrained lava flow data allows the construction of a statistical geomagnetic field model. Such a model can predict not only the average expected direction for a given latitude, but also the shape of the distribution of directions produced by secular variation. This allows us to differentiate among the possible explanations for shallow bias. We find no compelling reason to abandon the geocentric dipole hypothesis that has served us well for four centuries.

  1. The role of spinal GABAergic circuits in the control of phrenic nerve motor output

    PubMed Central

    Ghali, Michael G. Z.; Rogers, Robert F.

    2015-01-01

    While supraspinal mechanisms underlying respiratory pattern formation are well characterized, the contribution of spinal circuitry to the same remains poorly understood. In this study, we tested the hypothesis that intraspinal GABAergic circuits are involved in shaping phrenic motor output. To this end, we performed bilateral phrenic nerve recordings in anesthetized adult rats and observed neurogram changes in response to knocking down expression of both isoforms (65 and 67 kDa) of glutamate decarboxylase (GAD65/67) using microinjections of anti-GAD65/67 short-interference RNA (siRNA) in the phrenic nucleus. The number of GAD65/67-positive cells was drastically reduced on the side of siRNA microinjections, especially in the lateral aspects of Rexed's laminae VII and IX in the ventral horn of cervical segment C4, but not contralateral to microinjections. We hypothesize that intraspinal GABAergic control of phrenic output is primarily phasic, but also plays an important role in tonic regulation of phrenic discharge. Also, we identified respiration-modulated GABAergic interneurons (both inspiratory and expiratory) located slightly dorsal to the phrenic nucleus. Our data provide the first direct evidence for the existence of intraspinal GABAergic circuits contributing to the formation of phrenic output. The physiological role of local intraspinal inhibition, independent of descending direct bulbospinal control, is discussed. PMID:25833937

  2. Error-related brain activity in youth and young adults before and after treatment for generalized or social anxiety disorder.

    PubMed

    Kujawa, Autumn; Weinberg, Anna; Bunford, Nora; Fitzgerald, Kate D; Hanna, Gregory L; Monk, Christopher S; Kennedy, Amy E; Klumpp, Heide; Hajcak, Greg; Phan, K Luan

    2016-11-01

    Increased error monitoring, as measured by the error-related negativity (ERN), has been shown to persist after treatment for obsessive-compulsive disorder in youth and adults; however, no previous studies have examined the ERN following treatment for related anxiety disorders. We used a flanker task to elicit the ERN in 28 youth and young adults (8-26years old) with primary diagnoses of generalized anxiety disorder (GAD) or social anxiety disorder (SAD) and 35 healthy controls. Patients were assessed before and after treatment with cognitive-behavioral therapy (CBT) or selective serotonin reuptake inhibitors (SSRI), and healthy controls were assessed at a comparable interval. The ERN increased across assessments in the combined sample. Patients with SAD exhibited an enhanced ERN relative to healthy controls prior to and following treatment, even when analyses were limited to SAD patients who responded to treatment. Patients with GAD did not significantly differ from healthy controls at either assessment. Results provide preliminary evidence that enhanced error monitoring persists following treatment for SAD in youth and young adults, and support conceptualizations of increased error monitoring as a trait-like vulnerability that may contribute to risk for recurrence and impaired functioning later in life. Future work is needed to further evaluate the ERN in GAD across development, including whether an enhanced ERN develops in adulthood or is most apparent when worries focus on internal sources of threat. PMID:27495356

  3. Resting-state neuroimaging studies: a new way of identifying differences and similarities among the anxiety disorders?

    PubMed

    Peterson, Andrew; Thome, Janine; Frewen, Paul; Lanius, Ruth A

    2014-06-01

    This review examines recent functional neuroimaging research of resting-state regional connectivity between brain regions in anxiety disorders. Studies compiled in the PubMed- National Center for Biotechnology Information database targeting resting-state functional connectivity in anxiety disorders were reviewed. Diagnoses included posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), panic disorder (PD), and specific phobia (SP). Alterations to network connectivity were demonstrated in PTSD, GAD, SAD, OCD, and PD in several resting-state investigations. Differences from control subjects were primarily observed in the default mode network within PTSD, SAD, and OCD. Alterations within the salience network were observed primarily in PTSD, GAD, and SAD. Alterations in corticostriatal networks were uniquely observed in OCD. Finally, alterations within somatosensory networks were observed in SAD and PD investigations. Resting-state studies involving SPs as a primary diagnosis (with or without comorbidities) were not generated during the literature search. The emerging use of resting-state paradigms may be an effective method for understanding associations between anxiety disorders. Targeted studies of PD and SPs, meta-analyses of the studies conducted to date, and studies of the impact of specific comorbid presentations, are recommended future research directions. PMID:25007403

  4. Effects of Tityus serrulatus crude venom on the GABAergic and dopaminergic systems of the rat brain.

    PubMed

    Dorce, V A; Sandoval, M R

    1994-12-01

    This study was designed to investigate the effect of T. serrulatus scorpion venom on dopamine (DA) and gamma amino butyric acid (GABA) concentrations in different regions of the brain. The ratio of homovanillic acid (HVA) to DA, and the glutamic acid decarboxylase (GAD) activity were determined following intravenous or intracerebral venom injections. The increase in the HVA/DA ratio in the striatum after i.v. or intrastriatal injection could indicate an increase in DA turnover. One hour after i.v. injection of the venom GAD activity was shown to be decreased in the striatum and hypothalamus. After 24 hr GAD activity increased in the striatum and decreased in the hypothalamus and brain stem. These results could indicate different effects of the venom on the GABA system in different areas of the brain. After intrastriatal injection of the scorpion venom, the animals showed stereotyped behavior and rotation activity. Following intrahippocampal injection, myoclonus and orofacial automatisms, which constitute pro-convulsive signals, were observed. These behavioral alterations could be, at least in part, related to the GABA and dopamine alterations caused by the venom, since stereotypy, circling behavior and convulsions are dependent on dopamine and/or GABA. PMID:7725331

  5. Clergy who experience trauma as a result of forced termination.

    PubMed

    Tanner, Marcus N; Wherry, Jeffrey N; Zvonkovic, Anisa M

    2013-12-01

    Forced termination of clergy is a demeaning and psychologically distressing experience. Clergy who experience a forced termination are subjected to mobbing (psychological harassment) and other activities meant to publicly or privately demean a minister in such a way that they resign their ministry position. In a purposive convenience sample of 55 ministers who had been forcibly terminated, participants scored above the known cut-off score for post-traumatic stress disorder (PTSD) and scored high on a measure of burnout and generalized anxiety disorder (GAD). Forced termination has been anecdotally connected to PTSD and GAD, this project sought to empirically link PTSD and GAD to the forced termination of clergy. This study raises concern for the long-term mental health effects of ministers who have been forcibly terminated and provides implications for future clinical study on this group of clergy. Findings in this research indicate there may be a process to forced termination, which could be developed into a theory on forced termination of clergy. PMID:22278328

  6. Anxiety disorders in ancient Indian literature

    PubMed Central

    Sheth, Hitesh C.; Gandhi, Zindadil; Vankar, G. K.

    2010-01-01

    In western literature, the oldest description of symptoms of PTSD, an anxiety group of disorder, is seen in Homer’s Iliad written around 720 BC. According to Shay, Achilles was suffering from symptoms of PTSD. However, in the Indian literature it was mentioned around 5000 BC. The description of a PTSD-like syndrome is seen in the Ramayana, although it was not described as PTSD or by any other similar name. Ravana’s brother Marrich was having symptoms of PTSD after he was grievously hurt by Lord Rama’s arrow and was almost dead. This traumatic event threatened his physical integrity. He developed all the symptoms of PTSD, like hyper-arousal, re-experiencing the events and avoidance. He also gave up his natural work of harassing the monk and got engaged in meditation and austerities. His symptoms lasted for many years till Lord Rama killed him, while he was masquerading as a golden deer to deceive Sita. In another ancient epic Shrimad Bhagavatam, Maharshi Ved Vyasa described the symptoms of Generalized Anxiety Disorder (GAD). The demon King Kansha developed GAD-like symptoms, when Lord Krishna killed all his demons and threatened to kill him. He developed symptoms of GAD, like excessive worry about the attack from his arch foe Krishna, difficulty in concentration and difficulty in falling asleep. Like Marrich, the symptoms of Kansha also lasted until Lord Krishna killed him. PMID:21180424

  7. Dual mechanisms regulating glutamate decarboxylases and accumulation of gamma-aminobutyric acid in tea (Camellia sinensis) leaves exposed to multiple stresses

    PubMed Central

    Mei, Xin; Chen, Yiyong; Zhang, Lingyun; Fu, Xiumin; Wei, Qing; Grierson, Don; Zhou, Ying; Huang, Yahui; Dong, Fang; Yang, Ziyin

    2016-01-01

    γ-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system. It has multiple positive effects on mammalian physiology and is an important bioactive component of tea (Camellia sinensis). GABA generally occurs at a very low level in plants but GABA content increases substantially after exposure to a range of stresses, especially oxygen-deficiency. During processing of tea leaves, a combination of anoxic stress and mechanical damage are essential for the high accumulation of GABA. This is believed to be initiated by a change in glutamate decarboxylase activity, but the underlying mechanisms are unclear. In the present study we characterized factors regulating the expression and activity of three tea glutamate decarboxylase genes (CsGAD1, 2, and 3), and their encoded enzymes. The results suggests that, unlike the model plant Arabidopsis thaliana, there are dual mechanisms regulating the accumulation of GABA in tea leaves exposed to multiple stresses, including activation of CsGAD1 enzymatic activity by calmodulin upon the onset of the stress and accumulation of high levels of CsGAD2 mRNA induced by a combination of anoxic stress and mechanical damage. PMID:27021285

  8. Distress Tolerance and Pathological Worry: Tests of Incremental and Prospective Relationships.

    PubMed

    Macatee, Richard J; Capron, Daniel W; Guthrie, Whitney; Schmidt, Norman B; Cougle, Jesse R

    2015-07-01

    Pathological worry and generalized anxiety disorder (GAD) have been linked with low distress tolerance (DT), although questions remain including whether this association exists independent of depression and comorbidity, the directionality of the relationship between worry and DT, and DT's nonredundancy with other worry-relevant variables (i.e., emotional reactivity, stressful life events). Further, it is unclear whether DT is merely a correlate of excessive worry or acts as a risk factor for its development. Two independent studies were completed to evaluate these questions. In Study 1, DT was examined in patients with GAD and healthy controls. In Study 2, a nonclinical sample completed baseline measures of DT, negative affect, and worry, as well as daily assessments of these constructs and stressors for 1month. In Study 1, lower DT was associated with GAD diagnosis and greater worry symptoms independent of extent of comorbidity and depressive symptoms. In Study 2, lower baseline DT predicted unique variance in daily worry and increases in worry over time, whereas baseline worry did not predict daily DT or decreases in DT 1month later. Findings suggest that low DT plays a role in excessive worry independent of relevant covariates (i.e., comorbidity, emotional reactivity, stressful life events) and that this relationship is unidirectional. Further, preliminary evidence indicates that low DT may be an overall risk factor for the development of worry, particularly during periods of romantic stress, although further research and replication is required. PMID:26163710

  9. CoinFLP: a system for efficient mosaic screening and for visualizing clonal boundaries in Drosophila.

    PubMed

    Bosch, Justin A; Tran, Ngoc Han; Hariharan, Iswar K

    2015-02-01

    Screens in mosaic Drosophila tissues that use chemical mutagenesis have identified many regulators of growth and patterning. Many of the mutant phenotypes observed were contingent upon the presence of both wild-type and mutant cells in the same tissue. More recently, large collections of RNAi lines or cDNAs expressed under Gal4/UAS control have been used to alter gene expression uniformly in specific tissues. However, these newer approaches are not easily combined with the efficient generation of genetic mosaics. The CoinFLP system described here enables mosaic screens in the context of gene knockdown or overexpression by automatically generating a reliable ratio of mutant to wild-type tissue in a developmentally controlled manner. CoinFLP-Gal4 generates mosaic tissues composed of clones of which only a subset expresses Gal4. CoinFLP-LexGAD/Gal4 generates tissues composed of clones that express either Gal4 or LexGAD, thus allowing the study of interactions between different types of genetically manipulated cells. By combining CoinFLP-LexGAD/Gal4 with the split-GFP system GRASP, boundaries between genetically distinct cell populations can be visualized at high resolution. PMID:25605786

  10. Production of gamma-aminobutyric acid by Streptococcus salivarius subsp. thermophilus Y2 under submerged fermentation.

    PubMed

    Yang, S-Y; Lü, F-X; Lu, Z-X; Bie, X-M; Jiao, Y; Sun, L-J; Yu, B

    2008-04-01

    Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the central nervous system, has several well-known physiological functions and has been applied to the production of many drugs and functional foods. The technology of GABA production via submerged fermentation by Streptococcus salivarius subsp. thermophilus Y2 was investigated in this paper. It indicated that the GABA production was related to the biochemical characteristics of glutamate decarboxylase (GAD) of S. salivarius subsp. thermophilus Y2. After 24 h of fermentation at 37 degrees C, which is the suitable culture conditions for GAD-production, then the culture condition were adjusted to the optimal temperature (40 degrees C) and pH (4.5) for the GAD reaction activity in biotransformation of cells and pyridoxal 5'-phosphate (0.02 mmol/l) were added to the broth at the 48 h, the GABA production was increased up to 1.76-fold, reaching 7984.75 +/- 293.33 mg/l. The strain shows great potential use as a starter for GABA-containing yoghurt, cheese and other functional fermented food productions. PMID:17514494

  11. Implementation of wind turbine parameterizations in a mesoscale-LES nested model framework

    NASA Astrophysics Data System (ADS)

    Chow, Fotini; Marjanovic, Nikola; Mirocha, Jeffrey

    2014-11-01

    Wind turbine performance depends on weather conditions, local topography, and wind turbine spacing, among other factors. Atmospheric simulations can be used to predict wind energy production at increasingly higher resolutions. Turbine models placed within such simulations can be used to investigate turbine operation and performance. This work describes the implementation of generalized actuator disk (GAD) and line (GAL) models into the Weather Research and Forecasting (WRF) mesoscale atmospheric model. WRF can be used in a grid nested configuration starting from the mesoscale (~10 km resolution) and ending with fine scale resolutions (~1-10 m) suitable for large-eddy simulations (LES). At LES scales it becomes possible to resolve both the thrust and torque forces generated on turbines and imparted to the atmosphere using GAD and GAL models. Both models include real-time yaw and pitch control to respond to changing flow conditions. Here, the GAD and GAL are tested for idealized and real model configurations and compared to data from a wind farm. Comparisons are also made that help determine the importance of turbine blade tilt away from the tower and the inclusion of tower and turbine hub drag effects.

  12. Assessment of the Transferability of a Protein Force Field for the Simulation of Peptide-Surface Interactions

    PubMed Central

    Vellore, Nadeem A.; Yancey, Jeremy A.; Collier, Galen; Stuart, Steven J.

    2010-01-01

    In order to evaluate the transferability of existing empirical force fields for all-atom molecular simulations of protein adsorption behavior, we have developed and applied a method to calculate the adsorption free energy (ΔGads) of model peptides on functionalized surfaces for comparison with available experimental data. Simulations were conducted using the CHARMM program and force field using a host-guest peptide with the sequence TGTG-X-GTGT (where G and T are glycine and threonine amino acid residues, respectively, with X representing valine, threonine, aspartic acid, phenylalanine or lysine) over nine different functionalized alkanethiol self-assembled monolayer (SAM) surfaces with explicitly represented solvent. ΔGads was calculated using biased-energy replica exchange molecular dynamics to adequately sample the conformational states of the system. The simulation results showed that the CHARMM force-field was able to represent ΔGads within 1 kcal/mol of the experimental values for most systems, while deviations as large as 4 kcal/mol were found for others. In particular, the simulations reveal that CHARMM underestimates the strength of adsorption on the hydrophobic and positively charged amine surfaces. These results provide a means for force field evaluation and modification for the eventual development and validation of an interfacial force field for the accurate simulation of protein adsorption behavior. PMID:20222735

  13. Local infusion of interleukin-6 attenuates the neurotoxic effects of NMDA on rat striatal cholinergic neurons.

    PubMed

    Toulmond, S; Vige, X; Fage, D; Benavides, J

    1992-09-14

    The potential neuroprotective effects of IL-6 against the excitotoxic neuronal loss induced by N-methyl-D-aspartate (NMDA) have been studied. Infusion into the rat striatum of excitotoxic amounts (250 nmol) of NMDA resulted in a 45% decrease in striatal choline acetyl transferase activity (ChAT; a marker of cholinergic neurons) and glutamate decarboxylase (GAD, a marker of GABAergic neurons) at 2 days post-injection. Co-infusion of 10 U of IL-6 reduced the loss of ChAT activity to 21% but failed to prevent the loss of GAD activity. IL-6 per se, up to the dose of 500 U, failed to affect ChAT or GAD activities. The in vivo effects of IL-6 are not mediated by a direct antagonism of NMDA toxicity, since IL-6 (up to a concentration of 500 and 5000 U/ml, respectively) did not antagonize either the increase in cyclic GMP levels resulting from NMDA receptor activation in cerebellar slices or the glutamate-induced release of lactate dehydrogenase, an index of neurotoxicity, by cultured cortical neurons. These results suggest that the increase in IL-6 levels observed in experimental brain lesions may play a role in the protection and regeneration of cholinergic neurons. PMID:1331914

  14. Genetic engineering techniques for lactic acid bacteria: construction of a stable shuttle vector and expression vector for β-glucuronidase.

    PubMed

    Chang, Shiao-Ming; Yan, Tsong-Rong

    2014-02-01

    The shuttle vector, pUL6erm, was constructed by using a replicon from pL2, a multiple cloning site, colE1 ori, the ori of Gram-negative bacteria from vector pUC19, and the erythromycin resistance gene from pVA838 as a selection marker. pUL6erm could be transformed easily and maintained stably in Lactococcus lactis, Streptococcus thermophilus, Lactobacillus plantarum and Lactobacillus casei. Transformation assays of pUL6erm indicated that it had a narrow host range. β-Glucuronidase was induced in the presence of 0.3 M NaCl and 50 mM glutamate and expressed at 2.4 U mg(-1) with the expression vector (pUL6erm-gadR-GUS) constructed based on pUL6erm carrying β-glucuronidase gene wuth a chloride-inducible (gadR) expression cassette using Pgad as promoter. Therefore, pUL6erm and pUL6erm-gadR-GUS might be a safe and useful genetic tool for the improvement of lactic acid bacteria. PMID:24101246

  15. Patch-Clamp Recordings and Calcium Imaging Followed by Single-Cell PCR Reveal the Developmental Profile of 13 Genes in iPSC-Derived Human Neurons

    PubMed Central

    Belinsky, Glenn S.; Rich, Matthew T.; Sirois, Carissa L.; Short, Shaina M.; Pedrosa, Erika; Lachman, Herbert M.; Antic, Srdjan D.

    2013-01-01

    Molecular genetic studies are typically performed on homogenized biological samples, resulting in contamination from non-neuronal cells. To improve expression profiling of neurons we combined patch recordings with single-cell PCR. Two iPSC lines (healthy subject and 22q11.2 deletion), were differentiated into neurons. Patch electrode recordings were performed on 229 human cells from Day-13 to Day-88, followed by capture and single-cell PCR for 13 genes: ACTB, HPRT, vGLUT1, βTUBIII, COMT, DISC1, GAD1, PAX6, DTNBP1, ERBB4, FOXP1, FOXP2, and GIRK2. Neurons derived from both iPSC lines expressed βTUBIII, fired action potentials, and experienced spontaneous depolarizations (UP states) ~2 weeks before vGLUT1, GAD1 and GIRK2 appeared. Multisite calcium imaging revealed that these UP states were not synchronized among hESC-H9-derived neurons. The expression of FOXP1, FOXP2 and vGLUT1 was lost after 50 days in culture, in contrast to other continuously expressed genes. When gene expression was combined with electrophysiology, two subsets of genes were apparent; those irrelevant to spontaneous depolarizations (including vGLUT1, GIRK2, FOXP2 and DISC1) and those associated with spontaneous depolarizations (GAD1 and ERBB4). The results demonstrate that in the earliest stages of neuron development, it is useful to combine genetic analysis with physiological characterizations, on a cell-to-cell basis. PMID:24157591

  16. Proton/l-Glutamate Symport and the Regulation of Intracellular pH in Isolated Mesophyll Cells 1

    PubMed Central

    Snedden, Wayne A.; Chung, Induk; Pauls, Randy H.; Bown, Alan W.

    1992-01-01

    Addition of l-[U-14C]glutamate to a suspension of mechanically isolated asparagus (Asparagus sprengeri Regel) mesophyll cells results in (a) alkalinization of the medium, (b) uptake of l-[U-14C]glutamate, and (c) efflux of [14C]4-aminobutyrate, a product of glutamate decarboxylation. All three phenomena were eliminated by treatment with 1 millimolar aminooxyacetate. In vitro glutamate decarboxylase (GAD) assays showed that (a) 2 millimolar aminooxyacetate eliminated enzyme activity, (b) activity was pyridoxal phosphate-dependent, and (c) activity exhibited a sharp pH optimum at 6.0 that decreased to 20% of optimal activity at pH 5.0 and 7.0. Addition of 1.5 millimolar sodium butyrate or sodium acetate to cell suspensions caused immediate alkalinization of the medium followed by a resumption of acidification of the medium at a rate approximately double the initial rate. The data indicate that (a) continued H+/l-glutamate contransport is dependent upon GAD activity, (b) the pH-dependent properties of GAD are consistent with a role in a metabolic pH-stat, and (c) the regulation of intracellular pH during H+/l-Glu symport may involve both H+ consumption during 4-aminobutyrate production and ATP-driven H+ efflux. PMID:16668938

  17. Multiple metals exposure and neurotoxic risk in bald eagles (Haliaeetus leucocephalus) from two Great Lakes states.

    PubMed

    Nam, Dong-Ha; Rutkiewicz, Jennifer; Basu, Niladri

    2012-03-01

    In the present study, the authors determined concentrations of several elements (As, Cd, Co, Cu, Cr, Mn, Pb, Sb, Zn) in the brains and livers of 46 bald eagles (Haliaeetus leucocephalus) from two Great Lakes states, Michigan and Minnesota. To explore whether exposures are of neurological concern, the authors assessed their associations with neurochemical receptors (N-methyl-D-aspartate [NMDA] and γ-aminobutyric acid A [GABA(A)]) and enzymes (glutamine synthetase [GS] and glutamic acid decarboxylase [GAD]) that play critical roles in vertebrate neurobehavior and reproduction. For most elements, levels in the livers and brains did not differ between region and gender. Hepatic Pb levels averaged 33.1 ppm (dry wt), 30.4% of all carcasses exceeded proposed avian Pb thresholds (>26.4 ppm), and in 30.8% of the birds examined evidence of Pb pellets or fragments was found. Significant changes in the activities of GS and GAD were related to brain concentrations of several metals (Pb, Cd, Co, Cu, Zn). No relationships were found among any of the nine elements and NMDA or GABA(A) receptor levels. When combined with the authors' previous study on these same eagles that showed Hg-associated alterations in GS, GAD, and NMDA receptor levels, the present research suggests that bald eagles are exposed to various elements, especially Pb and Hg, that are capable of causing changes in GABAergic and glutamatergic neurotransmission. The functional significance of these neurochemical changes warrants attention. PMID:22170515

  18. Structural and functional insight into the carbohydrate receptor binding of F4 fimbriae-producing enterotoxigenic Escherichia coli.

    PubMed

    Moonens, Kristof; Van den Broeck, Imke; De Kerpel, Maia; Deboeck, Francine; Raymaekers, Hanne; Remaut, Han; De Greve, Henri

    2015-03-27

    Enterotoxigenic Escherichia coli (ETEC) strains are important causes of intestinal disease in humans and lead to severe production losses in animal farming. A range of fimbrial adhesins in ETEC strains determines host and tissue tropism. ETEC strains expressing F4 fimbriae are associated with neonatal and post-weaning diarrhea in piglets. Three naturally occurring variants of F4 fimbriae (F4ab, F4ac, and F4ad) exist that differ in the primary sequence of their major adhesive subunit FaeG, and each features a related yet distinct receptor binding profile. Here the x-ray structure of FaeGad bound to lactose provides the first structural insight into the receptor specificity and mode of binding by the poly-adhesive F4 fimbriae. A small D'-D″-α1-α2 subdomain grafted on the immunoglobulin-like core of FaeG hosts the carbohydrate binding site. Two short amino acid stretches Phe(150)-Glu(152) and Val(166)-Glu(170) of FaeGad bind the terminal galactose in the lactosyl unit and provide affinity and specificity to the interaction. A hemagglutination-based assay with E. coli expressing mutant F4ad fimbriae confirmed the elucidated co-complex structure. Interestingly, the crucial D'-α1 loop that borders the FaeGad binding site adopts a different conformation in the two other FaeG variants and hints at a heterogeneous binding pocket among the FaeG serotypes. PMID:25631050

  19. Effects of traditionally used anxiolytic botanicals on enzymes of the gamma-aminobutyric acid (GABA) system.

    PubMed

    Awad, R; Levac, D; Cybulska, P; Merali, Z; Trudeau, V L; Arnason, J T

    2007-09-01

    In Canada, the use of botanical natural health products (NHPs) for anxiety disorders is on the rise, and a critical evaluation of their safety and efficacy is required. The purpose of this study was to determine whether commercially available botanicals directly affect the primary brain enzymes responsible for gamma-aminobutyric acid (GABA) metabolism. Anxiolytic plants may interact with either glutamic acid decarboxylase (GAD) or GABA transaminase (GABA-T) and ultimately influence brain GABA levels and neurotransmission. Two in vitro rat brain homogenate assays were developed to determine the inhibitory concentrations (IC50) of aqueous and ethanolic plant extracts. Approximately 70% of all extracts that were tested showed little or no inhibitory effect (IC50 values greater than 1 mg/mL) and are therefore unlikely to affect GABA metabolism as tested. The aqueous extract of Melissa officinalis (lemon balm) exhibited the greatest inhibition of GABA-T activity (IC50 = 0.35 mg/mL). Extracts from Centella asiatica (gotu kola) and Valeriana officinalis (valerian) stimulated GAD activity by over 40% at a dose of 1 mg/mL. On the other hand, both Matricaria recutita (German chamomile) and Humulus lupulus (hops) showed significant inhibition of GAD activity (0.11-0.65 mg/mL). Several of these species may therefore warrant further pharmacological investigation. The relation between enzyme activity and possible in vivo mode of action is discussed. PMID:18066140

  20. Abnormal hippocampal structure and function in clinical anxiety and comorbid depression.

    PubMed

    Cha, Jiook; Greenberg, Tsafrir; Song, Inkyung; Blair Simpson, Helen; Posner, Jonathan; Mujica-Parodi, Lilianne R

    2016-05-01

    Given the high prevalence rates of comorbidity of anxiety and depressive disorders, identifying a common neural pathway to both disorders is important not only for better diagnosis and treatment, but also for a more complete conceptualization of each disease. Hippocampal abnormalities have been implicated in anxiety and depression, separately; however, it remains unknown whether these abnormalities are also implicated in their comorbidity. Here we address this question by testing 32 adults with generalized anxiety disorder (15 GAD only and 17 comorbid MDD) and 25 healthy controls (HC) using multimodal MRI (structure, diffusion and functional) and automated hippocampal segmentation. We demonstrate that (i) abnormal microstructure of the CA1 and CA2-3 is associated with GAD/MDD comorbidity and (ii) decreased anterior hippocampal reactivity in response to repetition of the threat cue is associated with GAD (with or without MDD comorbidity). In addition, mediation-structural equation modeling (SEM) reveals that our hippocampal and dimensional symptom data are best explained by a model describing a significant influence of abnormal hippocampal microstructure on both anxiety and depression-mediate