Identifying Triggers for Gluten Sensitivity

Is it greed, ignorance or an attempt to make things better, that is poisoning our population?

The August 14^th, 2010 issue of Science News, reported that a research team, led by gastroenterologist Robert Anderson of the Walter and Eliza Hall Institute of Medical Research in Parkville, Australia, had identified the triggers for celiac disease (gluten sensitivity).

Since the Sound Health Research Institute often evaluates clients who exhibit gluten sensitivity and a myriad of associated diseases, it was clear that this information needed to be added to our databases. I decoded the three proteins as BioAcoustic biofrequencies (biomarkers) and was immediately involved in an avalanche of novel data.  The metabolic pathways distorted by these proteins are multifaceted and link with nearly all systems of the human body; causing immune distortion and acute cellular inflammation.

The article listed only three proteins, w-5 gliadin (wheat), g-3 hordein (barley) and g secalins (rye) that were responsible for the production of the specific anti-gliadin antibody reactions.  These proteins, which were responsible for the allergic reactions, are associated with grain glutens from which they derive.

Patent records indicated the grains are clones developed in a laboratory by Monsanto.

This may indicate that the present-day epidemic of gluten sensitivities/allergies stem from man-manipulated grains.  These gluten-containing, allergic causing, grain clones are being used to create foods that we eat every day; bread, cereals, crackers, pastry, seasonings, even some chips contain wheat.  As I developed the BioAcoustic correlations I was aghast with the realization of how thoroughly our health is being negatively influenced by these genetically modified foods.

Further investigation revealed that the cloned genes contained two substitutions that distorted the way the body processes two sulfur rich amino acids: proline and glutamine. This allergy creating substitutions result in the non-methylation of these two amino acids.

Glutamine distortions seem to be the most destructive.  The enzyme required to utilize glutamine is glutamate decarboxylase (GAD).  Glutamate is a key molecule in cellular metabolism and the most abundant excitatory neurotransmitter in the vertebrate nervous system.

In mammals, GAD exists in two isoforms encoded by two different genes-

GAD1 and GAD2 are expressed in the brain where GABA is used as a neurotransmitter, GAD2 is also expressed in the pancreas and has been associated with diabetes.

This led to an evaluation of the GAD genomes and what happens when these genes are activated:

Glutamate decarboxylase aka glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation (part of the process of breaking down for use by the body) of glutamate to GABA (gamma aminobutyric acid) and CO₂.

GABA is a natural tranquilizer and an important inhibitory neurotransmitter that helps regulate neuron activity of the body’s nano sensors.  Starting with the GAD enzyme response and moving toward GABA along with the active form of B6, these Nano transmitters of the body are created and regulated.  The movement of electrical energy and hence magnetic potential within the body are controlled by these Nano transmitters.

GAD uses PLP (pyridoxal 50-phosphate) as a cofactor.

PLP was granted a patent by the US government patent office to the Canadian company, Medicare.  PLP is now under the control of the pharmaceutical industry and is often associated with blood clotting issues, migraines, neural disorders and seizures.

Nano transmitters produced in conjunction with GAD metabolism directly show associations with these diseases: diabetes, autism, arthritis, Parkinson’s, AL,S Multiple Sclerosis, joint pain and deterioration, auditory disorders, Celiac Disease, Cohn’s, Irritable Bowel syndrome, diverticulitis, schizophrenia,  bipolar and anxiety disorders, aspartame sensitivity, MSG reactions, Lupus, Fibromyalgia, depression, seizures, brain signaling, the use of calcitonin (cancer related), histidine function (seasonal allergies), cellular inflammation and vaccination reactions.

Glutamate is an analogue frequency of aspartame and is part of MSG (mono-sodium glutamate).

James Oschman in his publication, Energy Medicine, states that cells emit frequency based signals as a request for needed biochemicals to gather at the site of the cell. Since Glutamate and Aspartame are the analog frequencies, this may explain why Aspartame has been implicated in so many muscle and joint disorders.

These observations are based on the mathematical matrix of biological BioAcoustics developed over the last twenty years.  The system allows for the evaluation of items associated with the body in terms of numeric Mathways.   I expect this information will be the impetus that opens the world to the potential of BioAcoustic Biology and the hope of allowing access to Self-Health care; even after the fact.

Is it greed, ignorance or an attempt to make things better, that is poisoning our population? Is Math as Medicine our hope for the future?

July 2, 2017 –       AFTERTHOUGHT

Wheat has been identified as a major lectin (ANTINUTRIENT) that can cause significant digestive upset. Humans are unable to digest lectins efficiently. *Research shows lectins bind to cells on the gut wall causing a range of issues including immune dysfunction and inappropriate cell growth.

The lectins in wheat are phytohemagglutinins which cause the issues with the digestion of wheat. I’m wondering if plant phytohemagglutinins that cause digestive lectin upset are the same or similar to the hemagglutinin added to vaccines since they both seem to cause the same issues.

 

 

References:

“This pathway depicts the diverse metabolic fates and roles that glutamate plays in the body. As seen from this diagram, glutamate can serve as a precursor or substrate molecule for many compounds. For instance, glutamate can be generated from glutamine with the concomitant production of ammonia through the action of the enzyme glutaminase. Glutamate can also be oxidatively deaminated through glutamate dehydrogenase to produce 2oxoglutarate and ammonia. Additionally, glutamate can be generated from alanine or aspartate in combination with 2-oxoglutarate using the enzyme transaminase. The resulting byproducts (pyruvate and oxaloacetate) are key components in glycolysis, gluconeogenesis and the TCA cycle. Glutamate and proline metabolism are also connected. In particular, 1-pyrroline-5carboxylate is a biosynthetic metabolite that is synthesized from proline by the enzyme pyrroline-5-carboxylate reductase and converted into the amino acid glutamate by the enzyme 1-pyrroline-5-carboxylate dehydrogenase. Glutamate also plays an important role in the body’s disposal of excess nitrogen through the reaction catalyzed by glutamate dehydrogenase, which converts glutamate and NADP into 2-oxoglutarate, NADPH and ammonia. The ammonia is then excreted predominantly as urea. Glutamate can also participate with glutamine and ATP in the synthesis of several other phosphorylated compounds such as carbamoyl phosphate, phosphoribosylamine and glucosamine 6-phosphate. These molecules can serve as precursors for purine and polysaccharide metabolism. Another enzyme, glutamate-cysteine ligase (GCL), will conjugate glutamate and glycine with cysteine to produce glutathione, a key redox regulatory molecule in the cell. Glutamate also serves as the precursor for the synthesis of the neurotransmitter known as GABA (gamma-Aminobutyric acid) in GABA ergic neurons. This reaction is catalyzed by glutamate decarboxylase (GAD), which is most abundant in the cerebellum and pancreas. Glutamate also serves as the most abundant fast excitatory neurotransmitter in the mammalian nervous system. At chemical synapses, glutamate is stored in vesicles. Nerve impulses trigger release of glutamate from the pre-synaptic cell. The glutamate then travels across the synapse, binding to glutamate sensitive receptors such as NMDA receptors on the post-synaptic cell, activating the cell.”

Science News, August 14th, 2010; Vol. 178 #4 (P 8), Separating wheat from chaff in celiac disease.

NATHAN SEPPA. 2010. Separating wheat from chaff in celiac disease. [ONLINE] Available at: https://www.sciencenews.org/article/separating–wheat–chaff–celiac–disease. [Accessed 11 July 2017].

 

Alessio Fasano. 2009. Celiac Disease Insights: Clues to Solving Autoimmunity Study of a potentially fatal foodtriggered disease has uncovered a process that. [ONLINE] Available at: https://www.scientificamerican.com. [Accessed 11 July 2017].

 

Editor. 2017. http://www.absoluteastronomy.com/topics/glutamic_acid. [ONLINE] Available at: http://www.absoluteastronomy.com. [Accessed 11 July 2017].

 

Editor. 2017. http://www.absoluteastronomy.com/topics/glutamate_decarboxylase. [ONLINE] Available at: http://www.absoluteastronomy.com. [Accessed 11 July 2017].

 

Alexandra Rowles, RD. 2017. 6 Foods That Are High in Lectins. [ONLINE] Available at: https://authoritynutrition.com. [Accessed 11 July 2017].

Reference Article Abstracts 

GAD and Diabetes The Diabetic Antigen Glutamic Acid Decarboxylase (GAD 65) in the Human Peripheral Blood

G.P. Tilza, b, J. Dausseta, M. Wiltgenc

International Archives of Allergy and Immunology – Vol 152, No 2, 2010 http://content.karger.com/ProdukteDB/produkte.asp?Doi=265540

Int Arch Allergy Immunol 2010; 152:184-194 (DOI: 10.1159/000265540)

Abstract

Background: Glutamic acid decarboxylase (GAD 65) is a diabetes-associated antigen which is generally considered to be strictly intracellular. In order to better understand autoimmunity, this study demonstrates the appearance of GAD 65 in the peripheral human blood and presents implications for the diagnosis and therapy of some autoimmune diseases. Methods: The GAD 65 molecules are detected by their interaction with monoclonal antibodies labeled with dyes in an experimental setup with fluorescence correlation spectroscopy (FCS). These interactions result in changes in Brownian motion measured as fluorescence fluctuations. Sera from 153 patients with diabetes mellitus type 1 and controls were investigated. To enable the representation of the molecule as a model for further discussions, we present structural visualizations of its hydrophobic properties, leading to possible interactions with the cell membrane lipids and epitope locations. Results: The GAD65 antigen could be measured with a sensitivity of 2.65 µg/ml in ‘clean systems’ resulting from spiking experiments and human sera. The GAD 65 antigen could be identified in 8 patient sera: 4 children with diabetes mellitus type 1 and 4 adults initially taken as controls but who retrospectively showed signs of autoimmunity. Conclusion: We conclude that these findings are of significance for the concept of autoimmunity, i.e. in an initial step the immune system is primed by its accessibility to GAD 65. Our experimental results may also be important for the therapy of diabetes mellitus type 1 and other autoimmune diseases by the passive administration of GAD 65 antibodies.

Copyright © 2009 S. Karger AG, Basel

GAD and Diabetes/Calcitonin:

GAD and Calcitonin – Calcitonin is a 32–amino-acid peptide with a … Calcitonin is a hormone that participates in calcium and phosphorus metabolism.   BioAcoustically calcitonin is a major player in the role of how the body handles cancer threat.

Immunohistochemically staining of alternate consecutive sections revealed numerous glutamate decarboxylase-like immunoreactive Purkinje cells that also contained calcitonin gene-related peptide.

It can be postulated that acetylcholine, γ-aminobutyric acid, dopamine, calcitonin gene-related peptide, enkephalins and dynorphins (whose coexistence with choline acetyltransferase and enkephalins has been previously described immunocytochemically) coexist in lateral efferent neurons.

Title: Diabetes mellitus decreases the expression of calcitonin-gene related peptide, gammaamino butyric acid and glutamic acid decarboxylase in human pancreatic islet cells.

Al-Salam S, Hameed R, Parvez HS, Adeghate E.

Department of Pathology, Faculty of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.

Abstract

OBJECTIVES: The pattern of distribution of calcitonin-gene related peptide (CGRP), a neuropeptide, gamma-aminobutyric acid (GABA), a neurotransmitter and GABA-converting enzyme, glutamic acid decarboxylase (GAD) in the pancreas of diabetic patients was investigated to determine whether diabetes mellitus influences the expression of these biological transmitters.

METHODS: Pancreatic tissue samples retrieved, during pancreatectomy, from cancer patients with and without Type 2 diabetes were paraffin embedded. The expression of CGRP, GABA and GAD was examined in pancreatic tissue using immunofluorescence techniques.

RESULTS: CGRP, GABA and GAD were observed in many cells located in the central as well as the peripheral regions of pancreatic islet. The expression of CGRP, GABA and GAD decreased dramatically in pancreatic islet cells of diabetic patients compared to control. CGRP and GABA co-localized with glucagon in some pancreatic islet cells of both normal and diabetic patients. The pattern of distribution of CGRP, GABA and GAD in normal and Type 2 diabetic patients was similar to that of insulin.

CONCLUSION: The number of human pancreatic islet cells expressing CGRP, GABA and GAD decreased significantly after the onset of Type 2 diabetes. These neuropeptides and neurotransmitters may play a role in the regulation of pancreatic beta cell function.

PMID: 20010500 [PubMed – indexed for MEDLINE]

GAD and Autoimmune Diabetes

J Diabetes Sci Technol. 2009 March; 3(2): 320–330.

Published online 2009 March.

The Role of Immunomodulation Therapy in Autoimmune Diabetes

Johnny Ludvigsson, M.D., Ph.D.

for the Linköping Diabetes Immune Intervention Study Group

Division of Pediatrics and Diabetes Research Centre, Department of Clinical and Experimental Medicine, Linköping University, Sweden

Correspondence to: Johnny Ludvigsson, M.D., Ph.D., Department of Clinical and Experimental

Medicine, Division of Pediatrics and Diabetes Research Centre, Faculty of Health Sciences,

Linköping University, SE-581 85 Linköping, Sweden; email address Johnny.ludvigsson@lio.se

Funding: These studies have been supported by the Swedish Research Council, the Swedish

Child Diabetes Foundation (Barndiabetesfonden), the NovoNordisk Foundation, Diamond Medical, the Söderbergs Foundation, the County Council of Östergötland, and the Regional Research Fund of Southeast Sweden (FORSS).

Disclosure: Diamyd Medical has sponsored the phase-2 trial on GAD (Diamyd) treatment and supported the mechanistic studies. There is no other connection to Diamyd Medical, and therefore there exists total independence in research. I have in recent years also had funding from NovoNordisk for studies on antibodies toward insulin analogs and honoraria for lectures from NovoNordisk, Sanofi-Aventis, and Eli Lilly.

 Abstract

Type 1 diabetes (T1DM) is characterized by loss of virtually all endogenous insulin secretion. If residual insulin secretion is preserved, this will lead to improved metabolic balance, less acute and late complications, improved quality of life, and, in case of pronounced improvement of residual insulin secretion, complete remission and even cure of the disease.

Immune suppression or immune modulation have been demonstrated as a proof of principle to stop/decrease the destructive process and thereby preserve beta-cell function. Several methods to save residual beta-cell function have been tried for more than three decades with little or no evidence of efficacy. Positive effects have been seen mainly in adult patients but have been minimal or absent in children with diabetes. Furthermore, the safety of these immune interventions and/or their benefit to risk relationships have not been found to justify clinical use.

More specific immune modulation with anti-CD3 monoclonal antibodies has resulted in more encouraging postponement of C-peptide decline, but with frequent and serious adverse effects. Still more promising are the autoantigen therapies, of which glutamic acid decarboxylase (GAD) vaccination has shown significant preservation of residual insulin secretion in 10–18-year-old type 1 diabetes patients with recent onset. Efficacy was most impressive in the subgroup of patients with diabetes of short duration (<3 months). The treatment was simple, well tolerated, and showed no treatment-related adverse events. If these results can be confirmed, there is a realistic hope that GAD vaccination, perhaps in combination with vaccinations with other autoantigens and/or other therapies, will result in remission for some patients. The prospects of cure and prevention of T1DM will become less remote.

Keywords: autoantigen treatment, C-peptide, glutamic acid decarboxylase vaccination, immune intervention, immunomodulation, type 1 diabetes  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2771520/?tool=pubmed

Physiol Res. 2004;53(3):279-86.

Anti-GAD-positive patients with type 1 diabetes mellitus have higher prevalence of autoimmune thyroiditis than anti-GAD-negative patients with type 1 and type 2 diabetes mellitus.

http://www.ncbi.nlm.nih.gov/pubmed/15209535

H, Perusicová J, Hill M, Sterzl I, Vondra K, Masek Z.

Third Department of Medicine, General University Hospital, First Faculty of Medicine, Charles

University, Prague, Czech Republic. hanabarova@seznam.cz

Abstract

The aim of our study was to evaluate antibodies against thyroglobulin (anti-TG) and thyroid peroxidase (anti-TPO) – markers of autoimmune thyroiditis – in several groups of adult patients with type 1 and type 2 diabetes mellitus (DM). We were particularly interested whether the presence of thyroid antibodies is related to the positivity of glutamic acid decarboxylase antibodies (anti-GAD). We found elevated anti-GAD in 46 % (97/210) patients with type 1 DM. All patients with type 2 diabetes were anti-GAD-negative. At least one thyroid antibody (anti-TG and/or anti-TPO) was found in 30 % (62/210) patients with type 1 DM and 27 % (22/83) type 2 diabetes patients. The patients with type 1 DM were further grouped according to their antiGAD status. The anti-GAD-positive patients had a higher prevalence of anti-TG antibodies than the anti-GAD-negative patients (25 % vs. 12 %, p=0.03) as well as anti-TPO antibodies (32 % vs. 12 %, p<0.001). At least one thyroid antibody was detected in 39 % (38/97) of anti-GAD-positive but only in 21 % (24/113) of anti-GAD-negative patients with type 1 DM (p=0.006). No significant difference in the frequency of thyroid antibodies was found between anti-GADnegative patients with type 1 and type 2 DM (21 % vs. 27 %, p=0.4). The groups with or without thyroid antibodies in both type 1 and type 2 diabetic patients did not differ in actual age, the age at diabetes onset, duration of diabetes, body mass index or HbA1c level. Patients with elevated thyroid antibodies had significantly higher levels of TSH than those without thyroid antibodies (1.86 vs. 3.22 mIU/l, p=0.04 in type 1 DM; 2.06 vs. 4.89 mIU/l, p=0.003 in type 2 DM). We conclude that there is a higher frequency of thyroid-specific antibodies in anti-GADpositive adult patients with type 1 DM than in anti-GAD-negative patients or in patients with type 2 DM. Patients with or without thyroid antibodies do not differ in age, DM onset and duration, BMI or HbA1c. Thyroid antibodies-positive patients have higher levels of thyroid stimulating hormone (TSH).  PMID: 15209535 [PubMed – indexed for MEDLINE]

 

GAD and Autism

Acta Neuropathological

Volume 113, Number 5, 559-568, DOI: 10.1007/s00401-006-0176-3

Original Paper

Title: Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications

Jane Yip, Jean-Jacques Soghomonian and Gene J. Blatt

Abstract

The recent identification of decreased protein levels of glutamate decarboxylase (GAD) 65 and 67 isoforms in the autistic cerebellar tissue raises the possibility that abnormal regulation of GABA production in individual neurons may contribute to the clinical features of autism. Reductions in Purkinje cell number have been widely reported in autism. It is not known whether the GAD changes also occur in Purkinje cells at the level of transcription. Using a novel approach, the present study quantified GAD67 mRNA, the most abundant isoform in Purkinje cells, using in situ hybridization in adult autistic and control cases. The results indicate that GAD67 mRNA level was reduced by 40% in the autistic group (P < 0.0001; two-tailed t test), suggesting that reduced Purkinje cell GABA input to the cerebellar nuclei potentially disrupts cerebellar output to higher association cortices affecting motor and/or cognitive function. These findings may also contribute to the understanding of previous reports of alterations in the GABAergic system in limbic and cerebro cortical areas contributing to a more widespread pathophysiology in autistic brains.

 

GAD and Multiple Sclerosis (MS) and Aspartame  The Connection Between MS and Aspartame

http://www.truthinlabeling.org/Blaylock–AspartameAndMultipleSclerosisNeurosurgeon%27sWarning.html

By Russell L. Blaylock, MD

Neurosurgeon

6-7-4

Recently, much controversy has surrounded a claim that aspartame may produce an MS-like syndrome. A current review of recent peer-reviewed scientific studies has disclosed a pathophysiological mechanism to explain this connection. As far back as 1996 it was shown that the lesions produced in the myelin sheath of axons in cases of multiple sclerosis were related to excitatory receptors on the primary cells involved called oligodendroglia. Recent studies have now confirmed what was suspected back then. The loss of myelin sheath on the nerve fibers characteristic of the disease is due to the death of these oligodendroglial cells at the site of the lesions (called plaques). Further, these studies have shown that the death of these important cells is as a result of excessive exposure to excitotoxins at the site of the lesions.

Normally, most of these excitotoxins are secreted from microglial immune cells in the central nervous system. This not only destroys these myelin-producing cells it also breaks down the blood-brain barrier (BBB), allowing excitotoxins in the blood stream to enter the site of damage. Aspartame contains the excitotoxin aspartate as 40% of its molecular structure. Numerous studies have shown that consuming aspartame can significantly elevate the excitotoxin level in the blood. There is a common situation during which the excitotoxin exposure is even greater. When aspartate (as aspartame) is combined in the diet with monosodium glutamate (MSG) blood levels are several folds higher than normal. With the BBB damaged, as in MS, these excitotoxins can freely enter the site of injury, greatly magnifying the damage. So, we see that dietary excitotoxins, such as aspartame and MSG, can greatly magnify the damage produced in multiple sclerosis. Likewise, excitotoxins have been shown to break down the BBB as well.

Of equal concern is observation that we know that about 10% of the population (based on autopsy studies of elderly) have MS lesions without ever developing the full-blown disease, a condition called benign MS. A diet high in excitotoxins, such as aspartame, can convert this benign, subclinical condition into full-blown clinical MS. The amount of excitotoxins consumed in the average American diet is considerable, as shown by several studies. In addition, the toxin methanol is also in the aspartame molecule. Methanol is an axon poison. Combined toxicity of the aspartate and the methanol adds up to considerable brain toxicity and can convert benign, subclinical MS into full-blown MS. Once the MS becomes full-blown, further consumption of excitotoxins magnifies the toxicity, increasing disability and death.

Recent studies have also shown that even single exposures to these food-based excitotoxins can produce prolonged worsening of neurological lesions. In addition, it has been demonstrated that autoimmune reactions (as occur with MS) greatly magnify the toxicity of aspartate and glutamate (the excitotoxins). We also know liquid forms of excitotoxins are significantly more toxic because of rapid absorption and higher blood levels. In the face of this connection between excitotoxicity and the pathophysiology of MS, it would be ludicrous to allow further use of this excitotoxin containing sweetener.

 

References:

1. Sannchez-Gomez MV, Malute C. AMPA and kainate receptors each mediate excitotoxicity in oligodendroglial cultures. Neurobiology of Disease 6:475-485, 1999

 

2. Yoshika A, et al. Pathophysiology of oligodendroglial excitotoxicity, J Neuroscience Research 46: 427-437, 1996.

 

3. Singh P, et al. Prolonged glutamate excitotoxicity: effects on mitochondrial antioxidants and antioxidant enzymes. Molecular Cell Biochemistry 243: 139-145, 2003.

 

4. Leuchtmann EA, et al. AMPA receptors are the major mediators of excitotoxin death in mature oligodendrocytes. Neurobiology of Disease 14:336-348, 2003.

 

5. Takahashi JL, et al. Interleukin1 beta promotes oligodendrocyte death through glutamate excitotoxicity. Annal Neurology 53: 588-595, 2003.

 

6. Pitt D, et al Glutamate uptake by oligodendrocytes: implications for excitotoxicity in multiple sclerosis. Neurology 61: 1113-1120, 2003.

 

7. Soto A, et al. Excitotoxic insults to the optic nerve alter visual evoked potentials. Neuroscience 123: 441-449, 2004.

 

8. Blaylock RL. Interactions of cytokines, excitotoxins and reactive nitrogen and oxygen species in autism spectrum disorders. Journal of American Nutraceutical Association 6: 21-35, 2003.

 

9. Blaylock RL. Chronic microglial activation and excitotoxicity secondary to excessive immune stimulation: possible factors in Gulf War Syndrome and autism. Journal American Physicians and Surgeons, Summer, 2004.

Journal of the Neurological Sciences

Volume 47, Issue 3, September 1980, Pages 353-364

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T06–485GFN8–

56&_user=10&_coverDate=09%2F30%2F1980&_rdoc=1&_fmt=high&_orig=search&_origin=sea rch&_sort=d&_docanchor=&view=c&_searchStrId=1466741711&_rerunOrigin=google&_acct=C

000050221&_version=1&_urlVersion=0&_userid=10&md5=9211e8f445dc32e1c0ae2b8fecbaf0 11&searchtype=a

Abnormal glutamic acid metabolism in multiple sclerosis are open

Westall Corresponding Author Contact Information, a, b, Angela Hawkinsa, b, George W. Ellisona, b and Lawrence W. Myersa, b At the Salk Institute, San Diego, CA U.S.A.

by the Multiple Sclerosis Research Clinic, Department of Neurology, UCLA School of Medicine, Los Angeles, CA U.S.A. Received 18 February 1980;  accepted 16 April 1980.

Available online 18 March 2003.

 Abstract

We have found extensive amino acid abnormalities in multiple sclerosis sera. The most consistent abnormality is an elevation in serum glutamate, which is most striking during relapses. The increase in glutamate in the patients does not occur sharply during the onset of the relapse. Instead it appears to rise gradually within a month or two prior to the onset of the clinical relapse, to reach a peak during the relapse and then to slowly decline.

This work was supported by NIH grants NS-12391 and NS-08711.

 

GAD and Irritable Bowel Syndrome

Scand J Gastroenterol. 2007 Nov;42(11):1289-93.

GAD and Gut Motility

Autoantibodies in patients with gut motility disorders and enteric neuropathy.

Törnblom H, Lang B, Clover L, Knowles CH, Vincent A, Lindberg G.

Karolinska Institute, Department of Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden. hans.tornblom@karolinska.se

Abstract

OBJECTIVE: Enteric neuropathy with mild inflammation (ganglionitis) has been described in several motility disorders including irritable bowel syndrome (IBS), enteric dysmotility (ED), slow-transit constipation (STC) and chronic intestinal pseudo-obstruction (CIPO). The purpose of this study was to test the hypothesis that autoantibodies directed against specific neural antigens including ion channels may be associated with this finding.

MATERIAL AND METHODS: Comprehensive routine and immunohistochemical analyses of fullthickness jejunal laparoscopic biopsies were performed on patients fulfilling the international criteria for IBS, ED, STC and CIPO. Patients with ganglionitis had sera screened for specific antibodies to voltage-gated calcium channels (VGCCs) of P/Q- and N-type, voltage-gated potassium channels (VGKCs), glutamic acid decarboxylase (GAD) and neuronal alpha3-AChR by validated immunoprecipitation assays.

RESULTS: Thirty-three patients were included in the study. Two of them, both with IBS, were found to have positive antibody titres. One had anti-VGKC antibodies and one had anti-alpha3AChR antibodies. No antibodies were detected in GAD or VGCCs (case reports presented).

CONCLUSIONS: A small proportion of patients with inflammatory enteric neuropathy have antibodies directed towards neuronal ion channels. The pathogenic role of such antibodies requires determination but may represent a possible aetiology of severe functional symptoms in these groups of patients.

PMID: 17918010 [PubMed – indexed for MEDLINE]

 

GAD and Parkinson’s

European Neurology – Vol 12, No. 1, 1974Brain Glutamic Acid Decarboxylase Activity in Parkinson’s Disease

U.K. Rinne, H. Laaksonen, P. Riekkinen, V. Sonninen

Department of Neurology, University of Turku, Turku

Address of Corresponding Author

Eur Neurol 1974; 12:13-19 (DOI: 10.1159/000114599)

The activity of glutamic acid decarboxylase (GAD), the enzyme involved in formation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), was studied in autopsy brain samples from six parkinsonian patients and 13 controls. There was relatively good postmortem stability of GAD in deep-frozen brain samples over a 3-week period. The activity of GAD was significantly reduced in brain samples of patients with Parkinson’s disease, being about 50&percnt; of that

in controls. Moreover, levodopa treatment showed a tendency to increase the activity of GAD. The results suggest the involvement of GABA neurons in Parkinson’s disease. Copyright © 1974 S. Karger AG, Basel

 

GAD and Parkinson’s/Epilepsy

Neurology. 1971 Oct;21(10):1000-7.

Title: Glutamic acid decarboxylase in Parkinson’s disease and epilepsy.

McGeer PL, McGeer EG, Wada JA.

PMID: 5165300 [PubMed – indexed for MEDLINE]

 

GAD and Aspartame

http://www.google.com/search?ie=UTF–8&oe=UTF–

8&sourceid=navclient&gfns=1&q=Gad+and+celiac#sclient=psy&hl=en&q=Glutamic+acid+Dehyd rogenase+and+aspartame&aq=f&aqi=&aql=&oq=&gs_rfai=&pbx=1&fp=7b3e9e0669ddb0a1

Eur J Clin Nutr. 2008 Apr;62(4):451-62. Epub 2007 Aug 8.

GAD and Aspartame

Direct and indirect cellular effects of aspartame on the brain.

Humphries P, Pretorius E, Naudé H.

Department of Anatomy, University of Pretoria, Pretoria, Gauteng, South Africa.

Eur J Clin Nutr. 2009 May;63(5):698-9; author reply 695-8.

Eur J Clin Nutr. 2009 Aug;63(8):1044.

Abstract

The use of the artificial sweetener, aspartame, has long been contemplated and studied by various researchers, and people are concerned about its negative effects. Aspartame is composed of phenylalanine (50%), aspartic acid (40%) and methanol (10%). Phenylalanine plays an important role in neurotransmitter regulation, whereas aspartic acid is also thought to play a role as an excitatory neurotransmitter in the central nervous system. Glutamate, asparagines and glutamine are formed from their precursor, aspartic acid. Methanol, which forms 10% of the broken-down product, is converted in the body to formate, which can either be excreted or can give rise to formaldehyde, diketopiperazine (a carcinogen) and a number of other highly toxic derivatives. Previously, it has been reported that consumption of aspartame could cause neurological and behavioral disturbances in sensitive individuals. Headaches, insomnia and seizures are also some of the neurological effects that have been encountered, and these may be accredited to changes in regional brain concentrations of catecholamines, which include norepinephrine, epinephrine and dopamine. The aim of this study was to discuss the direct and indirect cellular effects of aspartame on the brain, and we propose that excessive aspartame ingestion might be involved in the pathogenesis of certain mental disorders (DSM-IV-TR 2000) and also in compromised learning and emotional functioning.

PMID: 17684524 [PubMed – indexed for MEDLINE]

 

Gad and Anxiety

Mol Psychiatry. 2006 Aug;11(8):752-62. Epub 2006 May 23.

Title: Association between glutamic acid decarboxylase genes and anxiety disorders, major depression, and neuroticism.

Hettema JM, An SS, Neale MC, Bukszar J, van den Oord EJ, Kendler KS, Chen X.

Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA 23298-0126, USA. jhettema@hsc.vcu.edu

Erratum in:

Mol Psychiatry. 2006 Aug;11(8):794.

Abstract

Abnormalities in the gamma-aminobutyric acid (GABA) neurotransmitter system have been noted in subjects with mood and anxiety disorders. Glutamic acid decarboxylase (GAD) enzymes synthesize GABA from glutamate, and, thus, are reasonable candidate susceptibility genes for these conditions. In this study, we examined the GAD1 and GAD2 genes for their association with genetic risk across a range of internalizing disorders. We used multivariate structural equation modeling to identify common genetic risk factors for major depression, generalized anxiety disorder, panic disorder, agoraphobia, social phobia and neuroticism (N) in a sample of 9270 adult subjects from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. One member from each twin pair for whom DNA was available was selected as a case or control based on scoring at the extremes of the genetic factor extracted from the analysis. The resulting sample of 589 cases and 539 controls was entered into a two-stage association study in which candidate loci were screened in stage 1, the positive results of which were tested for replication in stage 2. Several of the six singlenucleotide polymorphisms tested in the GAD1 region demonstrated significant association in both stages, and a combined analysis in all 1128 subjects indicated that they formed a common high-risk haplotype that was significantly over-represented in cases (P=0.003) with effect size OR=1.23. Out of 14 GAD2 markers screened in stage 1, only one met the threshold criteria for follow-up in stage 2. This marker, plus three others that formed significant haplotype combinations in stage 1, did not replicate their association with the phenotype in stage 2. Subject to confirmation in an independent sample, our study suggests that variations in the GAD1 gene may contribute to individual differences in N and impact susceptibility across a range of anxiety disorders and major depression.

 

PMID: 16718280 [PubMed – indexed for MEDLINE]

 

GAD and Arthritis

Ann Rheum Dis. 2008 Jul;67(7):1051-2.

Methotrexate and its effect on the anti-GAD titre in two patients with rheumatoid arthritis and diabetes mellitus.

van Deutekom AW, Nurmohamed MT, Peters MJ, van Eijk IC, Dijkmans BA, Hamann D, Heine RJ, Simsek S.

PMID: 18556448 [PubMed – indexed for MEDLINE]  GAD and Migraines

http://www.bio–medicine.org/medicine–news–1/Migraine–prevention–by–targeting–glutamatereceptors–3F–43945–1/

Migraine prevention by targeting glutamate receptors?

When migraine strikes, because of severe pain, often accompanied by nausea and sensitivity to light and sound, sufferers are effectively disabled for up to 72 hours. Since they are forced to stop what they are doing until the pain and other symptoms subside, migraine causes a significant loss in productivity at work and the personal lives of those affected. Migraineurs especially the 25% of migraineurs who experience more than three migraine attacks per month are looking to drug developers to provide new drugs to prevent migraine attacks before they start. In the U.S. alone, approximately 30 million people suffer from migraines and the cost to employers has been estimated at $13 billion annually in lost productivity. Currently, several types of drugs, like generic beta blockers, calcium channel blockers, tricyclic antidepressants and anti-epileptic drugs, some of which are used off-label, are given to prevent migraines. However, many patients have only a partial response to these products, many of which have troubling side effects. Nevertheless, many migraine patients use existing drugs, illustrating how badly new drugs are needed.

Given the role of glutamate in the pathophysiology of migraine, the future of migraine prophylaxis, may lie in modulating one of the receptors in the glutamate system, mGluR5.

At the forthcoming annual meeting of the American Academy of Neurology in Seattle (April 25 May 2), Addex Pharmaceuticals (SIX: ADXN) will present Phase IIa data on ADX10059, a negative mGluR5 allosteric modulator, which shows efficacy in treating acute migraine attacks and provides evidence that inhibition of this glutamate receptor subtype could play a role in stopping migraine attacks before they start.

Preclinical experiments and small-scale studies in migraineurs with drugs like ketamine, which acts on glutamate signaling through NMDA receptors (functionally related to mGluR5) and the NMDA antagonist memantine. Contact: Mike Sinclair msinclair@halsin.com

44-207-084-5955

Halsin Partners

Source: Eurekalert

 

GAD and Epilepsy

Clinical and Experimental Medicine

Volume 3, Number 1, 32-36, DOI: 10.1007/s102380300013 http://www.springerlink.com/content/w8y7jkgwbvj66nuq/

Anticardiolipin, glutamic acid decarboxylase, and antinuclear antibodies in epileptic patients

1. Verrotti, R. Greco, E. Altobelli, G. Latini, G. Morgese and F. Chiarelli

Abstract

To explore the hypothesis that raised anticardiolipin antibodies, glutamic acid decarboxylase, and antinuclear antibodies may be associated with epilepsy and/or pharmacoresistance, we studied titers in 74 epileptic patients and 50 controls. Epileptic patients were divided into two groups according to their response to anticonvulsant therapy. Group I included 52 children (30 females and 22 males with a mean age ± SD of 7.0±2.4 years) suffering from different types of epilepsy who were treated with various anticonvulsants. Group II included 22 children (10 females and 12 males with a mean age of 6.2±3.6 years) suffering from therapy resistant epilepsy. We found that the prevalence of anticardiolipin antibodies was significantly higher in epileptic patients than in controls, while there was no significant difference between patients who were seizure free and those with uncontrolled epilepsy. No significant difference was found in glutamic acid decarboxylase antibodies between epileptic children and controls, and between patients who were seizure free and those with uncontrolled epilepsy. A significant difference in the incidence of antinuclear antibodies was found between epileptic children and controls, while no difference was found between well-controlled and drug-resistant epilepsy. In conclusion, the prevalence of anticardiolipin and antinuclear antibodies was higher in patients with epilepsy than in controls. There was no significant difference in serum glutamic acid decarboxylase antibodies between epileptic children and controls, and between patients who were seizure free and those with uncontrolled epilepsy.

Key words Anticardiolipin antibodies – Glutamic acid decarboxylase antibodies – Antinuclear antibodies – Epilepsy

Received: 10 October 2002 / Accepted: 18 February 2003

Correspondence to A. Verrotti

 

 Gad and Schizophrenia

Possible implication of an inosine triphosphate metabolic error and glutamic acid decarboxylase in paranoid schizophrenia are open

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B7G7P–4C4NX88–

NV&_user=10&_coverDate=02%2F28%2F1979&_rdoc=1&_fmt=high&_orig=search&_origin=se arch&_sort=d&_docanchor=&view=c&_searchStrId=1468161504&_rerunOrigin=google&_acct= C000050221&_version=1&_urlVersion=0&_userid=10&md5=efca1e57149a17421722c74fccbb5 d20&searchtype=a

Bernardo S. Vanderheidena, b

A Eastern Pennsylvania Psychiatric Institute, Henry Avenue and Abbottsford Road, Philadelphia, Pennsylvania, 19129 USA

Department of Psychiatry and Human Behavior, Jefferson Medical College, Philadelphia, Pennsylvania 19107 USA

Abstract

A micro method for the determination of l-glutamic acid decarboxylase activity is described. It is based on the direct determination of radioactivity by liquid scintillation counting of paper strips containing the labeled products, following incubation of the enzyme with uniformly [14C] labeled substrate, and subsequent separation of the products by high voltage paper electrophoresis. The method was used to determine the effect of ITP on brain glutamic acid decarboxylase. ITP was found to be inhibitory to the enzyme.

 

The ability to synthetize ITP was demonstrated in cell-free extracts of the human brain cortex and various regions of the cat brain.

Based on these observations, and the fact that a significantly lower erythrocyte ITP pyrophosphohydrolase activity is found among paranoid schizophrenics, a hypothesis is presented linking ITP pyrophosphohydrolase deficiency to paranoid schizophrenia through an accumulation of ITP in brain and its inhibitory effect on glutamic acid decarboxylase.

star, open Preliminary reports of this work were presented at the XII Latin-American Congress of Physiological Sciences, Bogotá, Colombia 1975, and at the 172nd American Chemical Society National Meeting, San Francisco, Calif. 1976.

Biochemical Medicine

Volume 21, Issue 1, February 1979, Pages 22-32

 

Gad and Allergies

Clinical & Experimental Allergy

Volume 40, Issue 5, pages 820–830, May 2010

Title: The role of interleukin-4Rα in the induction of glutamic acid decarboxylase in airway epithelium following acute house dust mite exposure

1. A. Hirota1,
2. Budelsky2,
3. Smith2,
4. Lipsky2,
5. Ellis1,

Y-Y. Xiang3,

W-Y. Lu3,

1. D. Inman1

Article first published online: 12 MAR 2010

Summary

Background Asthma is a disease characterized by airway inflammation, remodeling and dysfunction. Airway inflammation contributes to remodeling, a term that is used to describe structural changes including goblet cell metaplasia (GCM), matrix deposition, and smooth muscle hyperplasia/hypertrophy. GCM has been implicated in asthma mortality by contributing to mucus plugs and leading to asphyxiation. In animal models, this process is highly dependent on IL-13. Recently, we have described an IL-13-dependent up-regulation of a GABAergic signaling system in airway epithelium that contributes to GCM. The mechanism by which IL-13 up-regulates GABA signaling in airway epithelium is unknown.

Objectives To test the hypothesis that IL-4Rα signaling is required for allergen induced upregulation of GABAergic signaling and GCM.

Methods BALB/c mice were exposed to an acute house dust mite (HDM) protocol and received vehicle, anti-IL-4Rα-monoclonal antibody, or control antibody. Outcomes included airway responses to inhaled methacholine (MCh), histology for eosinophilia and GCM, phosphorylated STAT6 levels using immunohistochemistry and immunoblot, and glutamic acid decarboxylase (GAD) 65/67 and GABAAβ2/3 receptor subunit expression using confocal microscopy.

Results Acute HDM exposure resulted in increased airway responses to MCh, lung eosinophilia, STAT6 phosphorylation, elevations in GAD65/67 and GABAAβ2/3 receptor expression, and GCM that were inhibited with anti-IL-4Rα-monoclonal treatment. Control antibody had no effect.

Conclusion The IL-4Rα is required for allergen-induced up-regulation of a GABAergic system in airway epithelium implicated in GCM following acute HDM exposure.

 

 Gad and Stiff Man’s Syndrome

Archives of Neurology – Vol 61, No 6, June 2004  http://archneur.ama–assn.org/cgi/content/full/61/6/902

Anti–Glutamic Acid Decarboxylase Antibodies in the Serum and Cerebrospinal Fluid of Patients with Stiff-Person Syndrome

Correlation with Clinical Severity

Goran Rakocevic, MD; Raghavanpillai Raju, PhD; Marinos C. Dalakas, MD

Arch Neurol. 2004; 61:902-904.

 

GAD and Lupus/Fibromyalgia

Lupus. 2005;14(6):486-8.

Gad and Lupus

Anti-glutamic acid decarboxylase antibodies in a patient with systemic lupus erythematosus and fibromyalgia symptoms

Taylor-Gjevre RM, Gjevre JA.

Division of Rheumatology, Royal University Hospital, University of Saskatchewan, Saskatoon, SK, Canada. r.gjevre@usask.ca

Abstract

We report the case of a 29-year old female nurse with a five-year history of systemic lupus erythematosus (SLE) involving multiple systems and on chronic prednisone therapy. This patient has a coexisting diagnosis of fibromyalgia fulfilling ACR criteria. A recent deterioration in her level of functioning in addition to a flare of her inflammatory disease led to further evaluation. During the course of investigation an anti-glutamic acid decarboxylase antibody was found to be present and significantly elevated. A therapeutic trial of baclofen did result in improvement of her subjective myalgias. We raise the possibility of an autoimmune contribution to myalgic symptoms in a portion of SLE patients.

PMID: 16038114 [PubMed – indexed for MEDLINE]

 

Gad and ALS

Journal of Neurological Sciences – Volume 250, Issue 1, Pages 124-132 (1 December 2006)

GABA A-receptor mRNA expression in the prefrontal and temporal cortex of ALS patients

Susanne Petri Corresponding Author Information email address, Katja Kollewea, Claudia Grotheb, Akira Horic, Reinhard Denglera, Johannes Buflera, Klaus Krampfla

Received 9 March 2006; received in revised form 4 August 2006; accepted 8 August 2006.

Abstract

There is evidence that excitotoxic cell death is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Electrophysiological and histological studies support the pathophysiological concept of an impaired inhibitory, namely GABAergic, control of the motoneurons in the cerebral cortex of ALS patients. Recently, pathological, neuropsychological and functional imaging data have challenged the view that ALS is a disorder restricted to the motor system. The aim of our study was to investigate the expression of the most abundant GABAA-receptor subunit mRNAs and the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) in the prefrontal, temporal, occipital and cerebellar cortex of ALS patients compared to tissue of control persons. We performed in situ hybridization histochemistry (ISH) on human post-mortem cortex sections of ALS patients (n=5) and age-matched controls with no history of neurological disease (n=5).

In the prefrontal and temporal cortex of ALS patients, we detected significantly reduced mRNA expression of the α1-subunit, while the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) was significantly upregulated in these regions. In the occipital and cerebellar cortex, we did not see disease-specific differences of the mRNA expression of the investigated subunits.

 

Gad and Celiac

Frequency of Autoantibodies in Celiac Disease

http://www.celiac.com/articles/22001/1/Frequency–of–Autoantibodies–in–CeliacDisease/Page1.html

Celiac.com 01/29/2010 – A team of researchers recently set out to compare levels of glutamic acid decarboxylase antibody (anti-GAD), islet cell antibody (ICA), thyroperoxidase antibody (anti-TPO), thyroglobulin antibody (anti-TG), antinuclear antibodies (FANA), antibodies to double-stranded DNA (anti-ds DNA), antibody to Sjögren syndrome A antigen (anti-SSA), antibody to Sjögren syndrome B antigen (anti-SSB), Smith antibody (anti-Sm), smooth muscle antibodies (ASMA), and antimitochondrial antibody liver-kidney microsome (AMA-LKM) in patients with celiac disease against healthy control subjects,  and autoimmune hypothyroid patients.

The research team included Erkan Caglar, Serdal Ugurlu, Aliye Ozenoglu, Gunay Can, Pinar

Kadioglu, and Ahmet Dobrucali. They are affiliated variously with Faith Sultan Mehmet Education and Research Hospital, the Cerrahpasa Medical Faculty at the University of Istanbul, and Ondokuz Mayis University in Samsun, Turkey. They studied a total of 31 patients with celiac disease, 34 patients with autoimmune hypothyroidism and 29 healthy subjects.

The team used immunofluorescence to assess anti-SSA, anti-SSB, anti-Sm, anti-ds DNA, antiGAD, anti-TPO and anti-TG were studied by enzyme-Linked Immunosorbent Assay (ELISA), and AMA-LKM, ASMA, ANA and ICA.

Researchers used retrospective analysis to assess clinical data and the results of free thyroxinethyroid stimulating hormone (FT4-TSH). The team used SPSS ver. 13.0 for data analysis, and the χ2 method for comparisons within groups.

They found that the frequency of anti-SSA, anti-SSB, anti-GAD, anti-Sm, anti-ds DNA, AMA-LKM, ASMA, ANA and ICA did not differ significantly between the groups.

They found levels of anti-TPO and anti-TG antibodies to be markedly higher (<0.001) in autoimmune hypothyroid patients as compared with other groups.

Previous studies have shown an increased frequency of autoimmune diseases of other systems in people with celiac disease.  Autoimmune antibodies specific for other autoimmune diseases appeared no more frequent in people with celiac disease.

Source: U.S. National Library of Medicine, National Institutes of Health