There are many research studies that are consistent with and/or support the efficacy of the Defeat Autism Now! (DAN!) approach. DAN! refers to a safe, biomedical approach to the treatment of autistic children and adults. I would like to thank Teresa Binstock for compiling and summarizing the following compilation of research studies.
Bernard Rimland, Ph.D.
Director, Autism Research Institute
Teresa Binstock
Researcher in Developmental &
Behavioral Neuroanatomy
binstock@peakpeak.com
P.O. Box 1788 Estes
Park, CO 80517
View [Adobe pdf file] Teresa Binstock's mini-DAN! Power Point presentation (Nov. 2004) - Auburn, Alabama.
Controversies: thimerosal and MMR – cites 1-36
Intestinal Pathologies – cites 37-65
vMV in PBMCs, as variant SSPE – cites 66-72
MMR: MV antibodies in autism– cites 73-77
vMV, MV impair immunity – cites 78-83
MV & Vitamin A – cites 84-97
Vitamin A & IgA, sIgA – cites 88b-88h
Autism, malnutrition, flora – cites 98-106
Gastrointestinal miscellany – cites 107-112
Glutathione – cites 113-125
Tylenol depletes GSH – cites 126-129
GSH & thimerosal – cites 130-134
Chorioamnionitis, fetal, placental – cites 135-142
Colic, cow’s milk allergy in breast fed infants – cites 143-149
Chronic Diarrhea of Infancy – cites 150-153
Recurrent otitis & GSH– cites 154-160
Gluten hypersensitivity, bacteria – cites 161-171
Gluten neuropathologies – cites 172-176
Gluten immunologics, ataxia – cites 177-181
Chelation – cites 182-194
Viruses – cites 195-203
Probiotics – cites 204-213
Immune impairments in autism– cites 214-223
Methylcobalamin (mB12) – cites 224-239
Nutritional Therapy & Violent Behavior -- cite 240
Epileptiform pattern in autism – cites 241-246
Amino acids & epileptiform activity – cites 247- 253
Autism Treatment Evaluation Checklist (ATEC) - cite 254
New Autism Epidemiology Study - whole article free online – cite 255
1: Parker SK et al. Thimerosal-containing vaccines and autistic spectrum disorder: a critical review of published original data. Pediatrics. 2004 Sep;114(3):793-804.
2: Andrews N et al. Thimerosal exposure in infants and developmental disorders: a retrospective cohort study in the United kingdom does not support a causal association. Pediatrics. 2004 Sep;114(3):584-91.
3: Heron J, Golding J; ALSPAC Study Team. Thimerosal exposure in infants and developmental disorders: a prospective cohort study in the United kingdom does not support a causal association. Pediatrics. 2004 Sep;114(3):577-83.
4. Madsen KM et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med. 2002 Nov 7;347(19):1477-82.
5. Geier MR, Geier DA. Thimerosal does not belong in vaccines. 8 September 2004
http://pediatrics.aappublications.org/cgi/eletters/114/3/584
6. Carol Stott et al. MMR and
Autism in Perspective: The Denmark Story
http://www.jpands.org/vol9no3/stott.pdf
7. G.S. Goldman; F.E.Yazbak. An Investigation of the Association Between MMR Vaccination and Autism in Denmark. http://www.jpands.org/vol9no3/goldman.pdf
8a. CDC quote from p22: Bernard/Safeminds presentation to
IOM, Oct 21, 2004
http://www.safeminds.org/iomvsd21oct04presentation.pdf
8b. Summary of CDC 1999 findings, p96-7 in: Neurodevelopmental disorders following thimerosal-containing childhood vaccines... Geier DA, Geier MR, in DAN! Conference Proceedings, Fall 2004, p95-101.
In 1999, the CDC intiated study designed to review the medical records of hundreds of thousands of children in the CDC's Vaccine Safety Datalink (VSD). The VSD is a massive databse that tracks the medical records of hundreds of thousands of patients belonging to seven major health maintenance organizations.
"In the initial analysis of the VSD database conducted by Dr. Thomas Verstraeten, [then] a CDC researcher, in the fall of 1999, showed statistically significantly large increased risks for neurodevelopmental disorders following additional doses of thimerosal... The following are [sic] a brief sampling of some of effects observed:”
autism = 7.62 (95% Confidence Interval (CI) = 1.84-31.5)
autism = 11.35 (95% CI = 2.70-47.76)
specific disorders of sleep of non-organic origin = 4.98 (95% CI = 1.55-15.94)
specific disorders of sleep of non-organic origin = 4.64 (95% CI = 1.12-19.25)
phase-disruption of 24-hour sleep-wake cycle = 53.64 (95% CI = 3.23-892.10)
somnambulism or night terrors = 5.76 (95% CI = 1.38-24.05)
attention deficit without mention of hyperactivity = 6.38 (95% CI = 1.56-26.09)
attention deficit with mention of hyperactivity = 8.29 (95% CI = 2.03-33.89)
developmental speech or language disorder = 2.09 (95% CI = 1.08-4.03)
other developmental speech or language delay = 2.32 (95% CI = 1.20-4.48)
unspecified delay in development = 2.08 (95% CI = 1.03-4.19)
[the above data] among children receiving > 25 micrograms ethylmercury from
thimerosal at age 1 month in comparison to children receiving 0 micrograms of
ethylmercury at age 1 month;
attention deficit disorder = 2.88 (95% CI = 1.05-7.88) and
attention deficit disorder = 2.84 (95% CI = 1.03-7.85), and
coordination disorder = 18.26 (95% CI = 5.65-59.01)
among children receiving > 75 micrograms of ethylmercury
from thimerosal in comparison to children receiving < 12.5 microgram from
thimerosal at age 3 months; and
autism = 2.15 (95% CI = 1.04-4.43) and
among children receiving increases of 7.5-10 micrograms of thimerosal over 1
month, in comparison to children receiving less than 5 micrograms of
ethylmercury from thimerosal over 1 month [9-10].
"Additionally, studies were conducted in 2000 by CDC to evaluate the
dose-response effects of thimerosal on childhood neurodevelopmental disorders
based upon evaluation of the VSD database [11]. It was found that there
were statistically significant
relationships between increasing exposures to thimerosal and the following
outcomes, including:
(1) for two months of age, an unspecified developmental delay, which has its
own ICD-9 code.
(2) Exposure at three months of age, Tics.
(3) Exposure at six months of age, language and speech delays, which are two
separate ICD-9 codes.
(4) Exposure at one, three and six months of age, the entire category of
neurodevelopmental delays, which includes all of these plus a number of other
disorders (i.e., including autism)."
[9.] Email from Thomas Verstraeten to Robert Davis and Frank Destefano. Nov 29,
1999. Obtained under FOIA by SafeMinds.
[10.] Email from Thomas Verstraeten to Robert Davis and Frank Destefano.Dec 17,
1999. Obtained under FOIA by SafeMinds.
8c. The Truth behind the Vaccine Coverup. Russell Blaylock MD. Sep 12 2004
http://sydney.indymedia.org/front.php3?article_id=45874&group=webcast
Excerpt: “It all started when a friend of mind sent me a copy of a letter from Congressman David Weldon, M.D. to the director of the CDC, Dr Julie L. Gerberding, in which he alludes to a study by a Doctor Thomas Verstraeten, then representing the CDC, on the connection between infant exposure to thimerosal-containing vaccines and neurodevelopmental
injury. In this shocking letter Congressman Weldon referrers to Dr. Verstraeten's study which looked at the data from the Vaccine Safety Datalink and found a significant correlation between thimerosal exposure via vaccines and several neurodevelopmental disorders including tics, speech and language delays, and possibly to ADD.
“Congressman Weldon questions the CDC director as to why, following this meeting, Dr. Verstraeten published his results, almost four years later, in the journal Pediatrics to show just the opposite, that is, that there was no correlation to any neurodevelopmental problems related to thimerosal exposure in infants…”
8d. Original in-house CDC study is online. Verstraeten et al 2000, unpublished; obtained via FOIA
http://factsformedia.com/factsformedia/thimerosalstudy.pdf
9a. Excerpts from CDC’s in-house conference: Thimerosal sequelae
http://www.nationalautismassociation.org/library/IOM%20Simpsonwood%20in%20bold.pdf
9b. Blaylock R, MD. The
thimerosal coverup – a thorough delineation of CDC, FDA knowledge about
thimerosal circa 1999.
http://sydney.indymedia.org/front.php3?article_id=45874&group=webcast
10a. House Subcommittee Hearing transcripts: Truth Revealed: New Scientific Discoveries Regarding Mercury in Medicine and Autism. September 08, 2004
http://reform.house.gov/WHR/Hearings/EventSingle.aspx?EventID=1311
10b. Testimony of Lyn Redwood, RN, MSN; President; Safeminds
http://reform.house.gov/UploadedFiles/Testimony Redwood.pdf
10c. Analysis and critique of the CDC’s handling of the thimerosal exposure assessment based on Vaccine Safety Datalink (VSD) information. Safeminds, 2003.
http://www.momsonamissionforautism.org/index/VSD.SafeMinds.critique.pdf
10d. NoMercury.org – an information resource about thimerosal
11. Verstraeten T, Davis RL, DeStefano F et al. Safety of thimerosal-containing vaccines: a two-phased study of computerized health maintenance organization databases. Pediatrics. 2003 Nov;112(5):1039-48. Erratum in: Pediatrics. 2004 Jan;113(1):184.
12. Geier MR, Geier DA. Neurodevelopmental disorders after thimerosal-containing vaccines: a brief communication. Exp Biol Med 2003 228(6):660-4 PMID 12773696
“We were initially highly skeptical that differences in the concentrations of thimerosal in vaccines would have any effect on the incidence rate of neurodevelopmental disorders after childhood immunization. This study presents the first epidemiologic evidence, based upon tens of millions of doses of vaccine administered in the United States, that associates increasing thimerosal from vaccines with neurodevelopmental disorders.”
13. Geier DA, Geier MR. An assessment of the impact of thimerosal on childhood neurodevelopmental disorders. Pediatr Rehabil. 2003 6(2):97-102 PMID 14534046
“The [thimerosal] dose-response curves showed increases in odds ratios of neurodevelopmental disorders from both the VAERS and US Department of Education data closely linearly correlated with increasing doses of mercury from thimerosal-containing childhood vaccines and that for overall odds ratios statistical significance was achieved. Similar slopes and linear regression coefficients for autism odds ratios in VAERS and the US Department of Education data help to mutually validate each other.”
14. Geier DA, Geier MR. A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosal-containing childhood vaccines on the population prevalence of autism. Med Sci Monit. 2004 Mar;10(3):PI33-9. Epub 2004 Mar 01.
15. Geier MR, Geier DA. Autism and thimerosal-containing vaccines: analysis of the Vaccine Adverse Events Reporting System (VAERS). IOM presentation, Feb 9, 2004.
Slides: http://www.iom.edu/view.asp?id=18392
Audio: http://www.iom.edu/view.asp?id=19120
16. Geier & Geier. Parents' worries about thimerosal in vaccines are well founded!
http://pediatrics.aappublications.org/cgi/eletters/112/6/1394
[An excellent summary & rebuttal of pro-thimerosal articles.]
17. Baskin DS et al. Thimerosal induces DNA breaks, caspase-3 activation, membrane damage, and cell death in cultured human neurons and fibroblasts. Toxicol Sci. 2003 Aug;74(2):361-8. Epub 2003 May 28. PMID: 12773768
18. David Baskin, M.D. Relation of Neurotoxic Effects of Thimerosal to Autism. IOM presentation, Feb 9, 2004. Audio only: http://www.iom.edu/view.asp?id=19124
19. Pichichero ME et al. Mercury concentrations and metabolism in infants receiving vaccines containing thiomersal: a descriptive study. Lancet. 2002 30;360(9347):1737-41. PMID 12480426
“Interpretation: Administration of vaccines containing thiomersal does not seem to raise blood concentrations of mercury above safe values in infants.” [But see cite 20]
20. Waly M et al. Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosal. Mol Psychiatry. 2004 Apr;9(4):358-70. PMID: 14745455
“Our findings outline a novel growth factor signaling pathway that regulates MS activity and thereby modulates methylation reactions, including DNA methylation. The potent inhibition of this pathway by ethanol, lead, mercury [at nanomolar levels described by Pichichero et al), aluminum and thimerosal suggests that it may be an important target of neurodevelopmental toxins.”
21. Richard C. Deth, Ph.D. Effects of Mercury on Methionine Synthase: Implications for Disordered Methylation in Autism DAN! 2003 Philadelphia
http://64.202.182.52/powerpoint/dan2003/RichardDeth.htm
22a. Mady Hornig, M.D Etiologic factors and pathogenesis of autism: evidence from clinical studies and animal models. IOM presentation Feb 9 2004 Audio only: http://www.iom.edu/view.asp?id=19108
22b. Mady Hornig, PhD: Testimony to House Subcommittee Sept 8 2004
http://reform.house.gov/UploadedFiles/Testimony Hornig.pdf
23. Westphal GA et al. Homozygous gene deletions of the glutathione S-transferases M1 and T1 are associated with thimerosal sensitization. Int Arch Occup Environ Health. 2000 Aug;73(6):384-8. PMID: 11007341
24: Muller M et al. Inhibition of the human erythrocytic glutathione-S-transferase T1 (GST T1) by thimerosal. Int J Hyg Environ Health. 2001 Jul;203(5-6):479-81. PMID: 11556154
25. Westphal GA et al. Thimerosal induces micronuclei in the cytochalasin B block micronucleus test with human lymphocytes. Arch Toxicol. 2003 Jan;77(1):50-5. Epub 2002 Nov 06. PMID: 12491041
26. Havarinasab S et al. Dose-response study of thimerosal-induced murine systemic autoimmunity. Toxicol Appl Pharmacol. 2004 194(2):169-79. PMID: 14736497
“The autoimmune syndrome induced by thimerosal is different from the weaker and more restricted autoimmune reaction observed after treatment with an equipotent dose of methylmercury.”
27. Vojdani A, Pangborn JB et al. Infections, toxic chemicals and dietary peptides binding to lymphocyte receptors and tissue enzymes are major instigators of autoimmunity in autism. Int J Immunopathol Pharmacol. 2003 Sep-Dec;16(3):189-99. PMID: 14611720
28. Holmes AS, Blaxill MF, Haley BE. Reduced levels of mercury in first baby haircuts of autistic children. Int J Toxicol. 2003 Jul-Aug;22(4):277-85. PMID: 12933322
“Hair mercury levels in the autistic group were 0.47 ppm versus 3.63 ppm in controls, a significant difference. The mothers in the autistic group had significantly higher levels of mercury exposure through Rho D immunoglobulin injections and amalgam fillings than control mothers. Within the autistic group, hair mercury levels varied significantly across mildly, moderately, and severely autistic children, with mean group levels of 0.79, 0.46, and 0.21 ppm, respectively.”
29. Boyd Haley, Ph.D. Reduced Levels of Mercury in First Baby Haircuts of Autistic Children. IOM presentation, Feb 9 2004.
Slides: http://www.iom.edu/view.asp?id=18394
Audio: http://www.iom.edu/view.asp?id=19128
30: Boyd Haley, Ph.D. Nucleotides and Mercury DAN! 2003 Philadelphia
http://64.202.182.52/powerpoint/dan2003/Haley.htm
31. L-W. Hu et al. "Neutron Activation Analysis of Hair Samples for the Identification of Autism", Transactions of the American Nuclear Society, Vol. 89, November 16-20, 2003.
32. Bernard S, Enayati A, Redwood L, Roger H, Binstock T. Autism: a novel form of mercury poisoning. Med Hypotheses. 2001 Apr;56(4):462-71. PMID: 11339848
33. Bernard S, Enayati A, Roger H, Binstock T, Redwood L. The role of mercury in the pathogenesis of autism. Mol Psychiatry. 2002;7 Suppl 2:S42-3. PMID: 12142947
34. Excerpts from CDC’s in-house conference: Thimerosal sequelae
http://www.nationalautismassociation.org/library/IOM%20Simpsonwood%20in%20bold.pdf
35. Congressman, Dr. Weldon's letter to the CDC director,
available at:
http://momsonamissionforautism.org/Autism_Central/Dr_Weldon_Responds.shtml
36a. IOM presentation of Congressman Dave Weldon, M.D.
http://www.nationalautismassociation.org/pdf/Weldon.pdf
36b. Doctors must prescribe without all the facts. Dr. Darshak Sanghavi, Children's Hospital
and Harvard Medical School. sanghavi@post.harvard.edu October 12, 2004
http://www.boston.com/news/globe/health_science/articles/2004/10/12/doctors_must_prescribe_without_all_the_facts/
37. D'Eufemia P et al. Abnormal intestinal permeability in children with autism. Acta Paediatr. 1996 Sep;85(9):1076-9. PMID: 8888921
“We determined the occurrence of gut mucosal damage using the intestinal permeability test in 21 autistic children who had no clinical and laboratory findings consistent with known intestinal disorders. An altered intestinal permeability was found in 9 of the 21 (43%) autistic patients, but in none of the 40 controls.”
38. Reichelt KL, Knivsberg AM. Can the pathophysiology of autism be explained by the nature of the discovered urine peptides? Nutr Neurosci. 2003 Feb;6(1):19-28. PMID: 12608733
39. Mercer ME, Holder MD. Food cravings, endogenous opioid peptides, and food intake: a review. Appetite. 1997 Dec;29(3):325-52. PMID: 9468764
40a. Lucarelli S et al. Food allergy and infantile autism. Panminerva Med. 1995 Sep;37(3):137-41. PMID: 8869369
“The aim of the present study has been to verify the efficacy of a cow's milk free diet (or other foods which gave a positive result after a skin test) in 36 autistic patients. We also looked for immunological signs of food allergy in autistic patients on a free choice diet. We noticed a marked improvement in the behavioural symptoms of patients after a period of 8 weeks on an elimination diet and we found high levels of IgA antigen specific antibodies for casein, lactalbumin and beta-lactoglobulin and IgG and IgM for casein. The levels of these antibodies were significantly higher than those of a control group which consisted of 20 healthy children.”
40b. Iacono G et al. Chronic constipation as a symptom of cow milk allergy. J Pediatr. 1995 Jan;126(1):34-9. PMID: 7815220
“Twenty-seven consecutive infants (mean age, 20.6 months) with chronic "idiopathic" constipation were studied to investigate the possible relation between constipation and cow milk protein allergy (CMPA). The infants were initially observed on an unrestricted diet, and the number of stools per day was recorded. Subsequently the infants were put on a diet free of cow milk protein (CMP) for two periods of 1 month each, separated by two challenges with CMP. During the CMP-free diet, there was a resolution of symptoms in 21 patients; during the two consecutive challenges, constipation reappeared within 48 to 72 hours. In another six patients the CMP-free diet did not lead to improvement of constipation. Only four of the patients who improved on the CMP-free diet had concomitant symptoms of suspected CMPA, but a medical history of CMPA was found in 15 of the 21 patients cured and in only one of the six patients whose condition had not improved (p < 0.05); in addition, in 15 of the 21 cured patients, results of one or more laboratory tests (specific IgE, IgG, anti-beta-lactoglobulin, circulating eosinophils) were positive at the time of diagnosis, indicating hypersensitivity, compared with one of the six patients whose condition did not improve (p < 0.05). The endoscopic and histologic findings at the time of diagnosis showed proctitis with monocytic infiltration in two patients cured with the CMP-free diet; after 1 month on this diet, they were completely normal. We conclude that constipation in infants may have an allergic pathogenesis.”
40c. Iacono G et al. Intolerance of cow's milk and chronic constipation in children. N Engl J Med. 1998 Oct 15;339(16):1100-4. PMID: 9770556
BACKGROUND: Chronic diarrhea is the most common gastrointestinal symptom of intolerance of cow's milk among children. On the basis of a prior open study, we hypothesized that intolerance of cow's milk can also cause severe perianal lesions with pain on defecation and consequent constipation in young children. METHODS: We performed a double-blind, crossover study comparing cow's milk with soy milk in 65 children (age range, 11 to 72 months) with chronic constipation (defined as having one bowel movement every 3 to 15 days). All had been referred to a pediatric gastroenterology clinic and had previously been treated with laxatives without success; 49 had anal fissures and perianal erythema or edema. After 15 days of observation, the patients received cow's milk or soy milk for two weeks. After a one-week washout period, the feedings were reversed. A response was defined as eight or more bowel movements during a treatment period. RESULTS: Forty-four of the 65 children (68 percent) had a response while receiving soy milk. Anal fissures and pain with defecation resolved. None of the children who received cow's milk had a response. In all 44 children with a response, the response was confirmed with a double-blind challenge with cow's milk. Children with a response had a higher frequency of coexistent rhinitis, dermatitis, or bronchospasm than those with no response (11 of 44 children vs. 1 of 21, P=0.05); they were also more likely to have anal fissures and erythema or edema at base line (40 of 44 vs. 9 of 21, P<0.001), evidence of inflammation of the rectal mucosa on biopsy (26 of 44 vs. 5 of 21, P=0.008), and signs of hypersensitivity, such as specific IgE antibodies to cow's-milk antigens (31 of 44 vs. 4 of 21, P<0.001). CONCLUSIONS: In young children, chronic constipation can be a manifestation of intolerance of cow's milk.
41. Arnold GL et al. Plasma amino acids profiles in children with autism: potential risk of nutritional deficiencies. J Autism Dev Disord 2003 33(4):449-54. PMID: 12959424
“No amino acid profile specific to autism was identified. However, children with autism had more essential amino acid deficiencies consistent with poor protein nutrition than an age/gender matched control group. There was a trend for children with autism who were on restricted diets to have an increased prevalence of essential amino acid deficiencies and lower plasma levels of essential acids including the neurotransmitter precursors tyrosine and tryptophan than both controls and children with autism on unrestricted diets.”
42. Chauhan V et al. Alteration in amino-glycerophospholipids levels in the plasma of children with autism: a potential biochemical diagnostic marker. Life Sci 2004 Feb 13;74(13):1635-43. PMID: 14738907
“the levels of AGP [amino-glycerophospholipids] were found to be significantly increased in the plasma of children with autism as compared to their non-autistic normal siblings.”
43. Knivsber AM et al. Reports on dietary intervention in autistic disorders. Nutr Neurosci. 2001;4(1):25-37. PMID: 11842874
“…Gluten and/or casein free diet has been implemented to reduce autistic behaviour, in addition to special education, since early in the eighties. Over the last twelve years various studies on this dietary intervention have been published in addition to anecdotal, parental reports. The scientific studies include both groups of participants as well as single cases, and beneficial results are reported in all, but one study. While some studies are based on urinary peptide abnormalities, others are not. The reported results are, however, more or less identical; reduction of autistic behaviour, increased social and communicative skills, and reappearance of autistic traits after the diet has been broken.”
44. Karyn Seroussi -- Dietary Intervention for Autism DAN! 2003 Philadelphia
http://64.202.182.52/powerpoint/dan2003/KarynSeroussi.htm
45. ARI’s Parent Ratings Data
http://www.autismresearchinstitute.com/treatment/form34q.htm
http://www.autismresearchinstitute.com/treatment/form34q.pdf
46: Wakefield AJ et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet. 1998 28;351(9103):637-41. PMID: 9500320
47: Ashwood P et al. Intestinal lymphocyte populations in children with regressive autism: evidence for extensive mucosal immunopathology. J Clin Immunol. 2003 Nov;23(6):504-17. PMID: 15031638
“At all sites, CD3(+) and CD3(+)CD8(+) IEL as well as CD3(+) LPL were significantly increased in affected children compared with developmentally normal noninflamed control groups (p<0.01) reaching levels similar to inflamed controls. In addition, two populations--CD3(+)CD4(+) IEL and LP CD19(+) B cells--were significantly increased in affected children compared with both noninflamed and inflamed control groups including IBD, at all sites examined (p<0.01). Histologically there was a prominent mucosal eosinophil infiltrate in affected children that was significantly lower in those on a gluten- and casein-free diet, although lymphocyte populations were not influenced by diet.The data provide further evidence of a pan-enteric mucosal immunopathology in children with regressive autism that is apparently distinct from other inflammatory bowel diseases.”
48: Wakefield AJ. Enterocolitis, autism and measles virus. Mol Psychiatry. 2002;7 Suppl 2:S44-6. PMID: 12142948
49: Wakefield AJ. The gut-brain axis in childhood developmental disorders. J Pediatr Gastroenterol Nutr. 2002 May-Jun;34 Suppl 1:S14-7. PMID: 12082381
50. Binstock T. Anterior insular cortex: linking intestinal pathology and brain function in autism-spectrum subgroups. Med Hypotheses 2001 57(6):714-7. PMID: 11918432
“Numerous parents and some physicians report that an autistic child's attention and language improve in response to treatments which eliminate certain dietary antigens and/or which improve intestinal health. For at least some autism-spectrum children, the link between intestinal pathology, attention, and language may derive from shared neuroanatomic pathways within the anterior insular cortex (aIC); from a neurotrophic virus such as herpes simplex (HSV) migrating within afferents to the insular cortex; and/or from synaptic exhaustion in the aIC as induced by chronically inappropriate neuronal activity in the enteric nervous system and/or its vagal efferents.”
51: Torrente F et al. Small intestinal enteropathy with epithelial IgG and complement deposition in children with regressive autism. Mol Psychiatry. 2002;7(4):375-82, 334.
PMID: 11986981
“Most strikingly, IgG deposition was seen on the basolateral epithelial surface in 23/25 autistic children, co-localising with complement C1q. This was not seen in the other conditions. These findings demonstrate a novel form of enteropathy in autistic children, in which increases in mucosal lymphocyte density and crypt cell proliferation occur with epithelial IgG deposition. The features are suggestive of an autoimmune lesion.”
52. Uhlmann V et al. Potential viral pathogenic mechanism for new variant inflammatory bowel disease. Mol Pathol. 2002 Apr;55(2):84-90. PMID: 11950955
“AIMS: A new form of inflammatory bowel disease (ileocolonic lymphonodular hyperplasia) has been described in a cohort of children with developmental disorder. This study investigates the presence of persistent measles virus in the intestinal tissue of these patients (new variant inflammatory bowel disease) and a series of controls by molecular analysis… RESULTS: Seventy five of 91 patients with a histologically confirmed diagnosis of ileal lymphonodular hyperplasia and enterocolitis were positive for measles virus in their intestinal tissue compared with five of 70 control patients. Measles virus was identified within the follicular dendritic cells and some lymphocytes in foci of reactive follicular hyperplasia. The copy number of measles virus ranged from one to 300,00 copies/ng total RNA. CONCLUSIONS: The data confirm an association between the presence of measles virus and gut pathology in children with developmental disorder.”
53. Wakefield AJ et al. Review article: the concept of entero-colonic encephalopathy, autism and opioid receptor ligands.Aliment Pharmacol Ther 2002 16(4):663-74. PMID 11929383
54. Furlano RI et al. Colonic CD8 and gamma delta T-cell infiltration with epithelial damage in children with autism. J Pediatr. 2001 Mar;138(3):366-72. PMID: 11241044
“OBJECTIVES: We have reported colitis with ileal lymphoid nodular hyperplasia (LNH) in children with regressive autism. The aims of this study were to characterize this lesion and determine whether LNH is specific for autism. METHODS: Ileo-colonoscopy was performed in 21 consecutively evaluated children with autistic spectrum disorders and bowel symptoms. Blinded comparison was made with 8 children with histologically normal ileum and colon, 10 developmentally normal children with ileal LNH, 15 with Crohn's disease, and 14 with ulcerative colitis. Immunohistochemistry was performed for cell lineage and functional markers, and histochemistry was performed for glycosaminoglycans and basement membrane thickness. RESULTS: Histology demonstrated lymphocytic colitis in the autistic children, less severe than classical inflammatory bowel disease. However, basement membrane thickness and mucosal gamma delta cell density were significantly increased above those of all other groups including patients with inflammatory bowel disease. CD8(+) density and intraepithelial lymphocyte numbers were higher than those in the Crohn's disease, LNH, and normal control groups; and CD3 and plasma cell density and crypt proliferation were higher than those in normal and LNH control groups. Epithelial, but not lamina propria, glycosaminoglycans were disrupted. However, the epithelium was HLA-DR(-), suggesting a predominantly T(H)2 response. INTERPRETATION: Immunohistochemistry confirms a distinct lymphocytic colitis in autistic spectrum disorders in which the epithelium appears particularly affected. This is consistent with increasing evidence for gut epithelial dysfunction in autism.”
55. O'Leary JJ et al. Measles virus and autism. Lancet. 2000 Aug 26;356(9231):772. PMID: 11085720
56. Wakefield AJ et al. Enterocolitis in children with developmental disorders. Am J Gastroenterol. 2000 Sep;95(9):2285-95. PMID: 11007230
“OBJECTIVE: Intestinal pathology, i.e., ileocolonic lymphoid nodular hyperplasia (LNH) and mucosal inflammation, has been described in children with developmental disorders. This study describes some of the endoscopic and pathological characteristics in a group of children with developmental disorders (affected children) that are associated with behavioral regression and bowel symptoms, and compares them with pediatric controls. METHODS: Ileocolonoscopy and biopsy were performed on 60 affected children (median age 6 yr, range 3-16; 53 male). Developmental diagnoses were autism (50 patients), Asperger's syndrome (five), disintegrative disorder (two), attention deficit hyperactivity disorder (ADHD) (one), schizophrenia (one), and dyslexia (one). Severity of ileal LNH was graded (0-3) in both affected children and 37 developmentally normal controls (median age 11 yr, range 2-13 yr) who were investigated for possible inflammatory bowel disease (IBD). Tissue sections were reviewed by three pathologists and scored on a standard proforma. Data were compared with ileocolonic biopsies from 22 histologically normal children (controls) and 20 children with ulcerative colitis (UC), scored in an identical manner. Gut pathogens were sought routinely. RESULTS: Ileal LNH was present in 54 of 58 (93%) affected children and in five of 35 (14.3%) controls (p < 0.001). Colonic LNH was present in 18 of 60 (30%) affected children and in two of 37 (5.4%) controls (p < 0.01). Histologically, reactive follicular hyperplasia was present in 46 of 52 (88.5%) ileal biopsies from affected children and in four of 14 (29%) with UC, but not in non-IBD controls (p < 0.01). Active ileitis was present in four of 51 (8%) affected children but not in controls. Chronic colitis was identified in 53 of 60 (88%) affected children compared with one of 22 (4.5%) controls and in 20 of 20 (100%) with UC. Scores of frequency and severity of inflammation were significantly greater in both affected children and those with UC, compared with controls (p < 0.001). CONCLUSIONS: A new variant of inflammatory bowel disease is present in this group of children with developmental disorders.”
60. Wakefield AJ, Montgomery SM. Autism, viral infection and measles-mumps-rubella vaccination. Isr Med Assoc J. 1999 Nov;1(3):183-7. PMID: 10731332
61. Wakefield AJ. MMR vaccination and autism. Lancet. 1999 Sep 11;354(9182):949-50. PMID: 10489978
62a. Horvath K et al. Gastrointestinal abnormalities in children with autistic disorder. J Pediatr. 1999 Nov;135(5):559-63. PMID: 10547242
“OBJECTIVES: Our aim was to evaluate the structure and function of the upper gastrointestinal tract in a group of patients with autism who had gastrointestinal symptoms. STUDY DESIGN: Thirty-six children (age: 5.7 +/- 2 years, mean +/- SD) with autistic disorder underwent upper gastrointestinal endoscopy with biopsies, intestinal and pancreatic enzyme analyses, and bacterial and fungal cultures. The most frequent gastrointestinal complaints were chronic diarrhea, gaseousness, and abdominal discomfort and distension. RESULTS: Histologic examination in these 36 children revealed grade I or II reflux esophagitis in 25 (69.4%), chronic gastritis in 15, and chronic duodenitis in 24. The number of Paneth's cells in the duodenal crypts was significantly elevated in autistic children compared with non-autistic control subjects. Low intestinal carbohydrate digestive enzyme activity was reported in 21 children (58.3%), although there was no abnormality found in pancreatic function… CONCLUSIONS: Unrecognized gastrointestinal disorders, especially reflux esophagitis and disaccharide malabsorption, may contribute to the behavioral problems of the non-verbal autistic patients…”
62b. Horvath K, Perman JA. Autism and gastrointestinal symptoms. Curr Gastroenterol Rep. 2002 Jun;4(3):251-8. PMID: 12010627
63. Horvath K, Perman JA. Autistic disorder and gastrointestinal disease. Curr Opin Pediatr. 2002 Oct;14(5):583-7. PMID: 12352252
“High prevalence of histologic abnormalities in the esophagus, stomach, small intestine and colon, and dysfunction of liver conjugation capacity and intestinal permeability were reported. Three surveys conducted in the United States described high prevalence of gastrointestinal symptoms in children with autistic disorder. Treatment of the digestive problems may have positive effects on their behavior.”
64. Quigley EM, Hurley D. Autism and the gastrointestinal tract. Am J Gastroenterol. 2000 Sep;95(9):2154-6. PMID: 11007210
65. Tim Buie, M.D. Presentation at 2003 DAN!, Philadelphia.
http://64.202.182.52/powerpoint/dan2003/TimothyBuie.htm
66. Kawashima H et al. Detection and sequencing of measles virus from peripheral mononuclear cells from patients with inflammatory bowel disease and autism. Dig Dis Sci. 2000 Apr;45(4):723-9. PMID 10759242
“One of eight patients with Crohn disease, one of three patients with ulcerative colitis, and three of nine children with autism, were positive. Controls were all negative. The sequences obtained from the patients with Crohn's disease shared the characteristics with wild-strain virus. The sequences obtained from the patients with ulcerative colitis and children with autism were consistent with being vaccine strains. The results were concordant with the exposure history of the patients. Persistence of measles virus was confirmed in PBMC in some patients with chronic intestinal inflammation.”
67. Jeff Bradstreet, M.D. A Case-control Study of Mercury Burden in Children with Autistic Disorders and Measles Virus Genomic RNA in Cerebrospinal Fluid in Children with Regressive Autism. IOM presentation, Feb 9, 2004.
Slides: http://www.iom.edu/view.asp?id=18578
Audio: http://www.iom.edu/view.asp?id=19130
68. 48a: Valsamakis A et al. Altered virulence of vaccine strains of measles virus after prolonged replication in human tissue. J Virol. 1999 73(10): 8791-7. PMID 10482633
http://jvi.asm.org/cgi/reprint/73/10/8791.pdf
69. Binstock T. Intra-monocyte pathogens delineate autism subgroups. Med Hypotheses. 2001 Apr;56(4):523-31. PMID 11339860
70. Garg RK. Subacute sclerosing panencephalitis.Postgrad Med J. 2002 Feb;78(916):63-70. PMID 11807185.
71. Neuroprogressive disease of post-infectious origin: a review of a resurging subacute sclerosing panencephalitis (SSPE). Ment Retard Dev Disabil Res Rev. 2001;7(3):217-25. PMID: 11553938
72. Gascon GG. Subacute sclerosing panencephalitis. Semin Pediatr Neurol. 1996 Dec;3(4):260-9. PMID: 8969008
73. Geier DA, Geier MR. A comparative evaluation of the effects of MMR immunization and mercury doses from thimerosal-containing childhood vaccines on the population prevalence of autism. Med Sci Monit. 2004 Mar;10(3):PI33-9. Epub 2004 Mar 01. PMID: 14976450
“These studies have shown that there is biological plausibility and epidemiological evidence showing a direct relationship between increasing doses of mercury from thimerosal-containing vaccines and neurodevelopmental disorders, and measles-containing vaccines and serious neurological disorders. It is recommended that thimerosal be removed from all vaccines, and additional research be undertaken to produce a MMR vaccine with an improved safety profile.”
74. Vijendra K. Singh, Ph.D. Autism, Vaccines, and Immune Reactions. IOM presentation, Feb 9, 2004.
Audio only: http://www.iom.edu/view.asp?id=19132
75. Singh VK, Jensen RL. Elevated levels of measles antibodies in children with autism. Pediatr Neurol. 2003 Apr;28(4):292-4. PMID: 12849883
“Virus-induced autoimmunity may play a causal role in autism. To examine the etiologic link of viruses in this brain disorder, we conducted a serologic study of measles virus, mumps virus, and rubella virus. Viral antibodies were measured by enzyme-linked immunosorbent assay in the serum of autistic children, normal children, and siblings of autistic children. The level of measles antibody, but not mumps or rubella antibodies, was significantly higher in autistic children as compared with normal children (P = 0.003) or siblings of autistic children (P <or= 0.0001). Furthermore, immunoblotting of measles vaccine virus revealed that the antibody was directed against a protein of approximately 74 kd molecular weight. The antibody to this antigen was found in 83% of autistic children but not in normal children or siblings of autistic children. Thus autistic children have a hyperimmune response to measles virus, which in the absence of a wild type of measles infection might be a sign of an abnormal immune reaction to the vaccine strain or virus reactivation.”
76. Singh VK et al. Abnormal measles-mumps-rubella antibodies and CNS autoimmunity in children with autism. J Biomed Sci. 2002 Jul-Aug;9(4):359-64. PMID 12145534
“Autoimmunity to the central nervous system (CNS), especially to myelin basic protein (MBP), may play a causal role in autism, a neurodevelopmental disorder. Because many autistic children harbor elevated levels of measles antibodies, we conducted a serological study of measles-mumps-rubella (MMR) and MBP autoantibodies. Using serum samples of 125 autistic children and 92 control children, antibodies were assayed by ELISA or immunoblotting methods. ELISA analysis showed a significant increase in the level of MMR antibodies in autistic children. Immunoblotting analysis revealed the presence of an unusual MMR antibody in 75 of 125 (60%) autistic sera but not in control sera. This antibody specifically detected a protein of 73-75 kD of MMR. This protein band, as analyzed with monoclonal antibodies, was immunopositive for measles hemagglutinin (HA) protein but not for measles nucleoprotein and rubella or mumps viral proteins. Thus the MMR antibody in autistic sera detected measles HA protein, which is unique to the measles subunit of the vaccine. Furthermore, over 90% of MMR antibody-positive autistic sera were also positive for MBP autoantibodies, suggesting a strong association between MMR and CNS autoimmunity in autism. Stemming from this evidence, we suggest that an inappropriate antibody response to MMR, specifically the measles component thereof, might be related to pathogenesis of autism.”
77. Singh VK et al. Serological association of measles virus and human herpesvirus-6 with brain autoantibodies in autism. Clin Immunol Immunopathol 1998 89(1):105-8. PMID: 9756729
“Considering an autoimmunity and autism connection, brain autoantibodies to myelin basic protein (anti-MBP) and neuron-axon filament protein (anti-NAFP) have been found in autistic children. In this current study, we examined associations between virus serology and autoantibody by simultaneous analysis of measles virus antibody (measles-IgG), human herpesvirus-6 antibody (HHV-6-IgG), anti-MBP, and anti-NAFP. We found that measles-IgG and HHV-6-IgG titers were moderately higher in autistic children but they did not significantly differ from normal controls. Moreover, we found that a vast majority of virus serology-positive autistic sera was also positive for brain autoantibody: (i) 90% of measles-IgG-positive autistic sera was also positive for anti-MBP; (ii) 73% of measles-IgG-positive autistic sera was also positive for anti-NAFP; (iii) 84% of HHV-6-IgG-positive autistic sera was also positive for anti-MBP; and (iv) 72% of HHV-6-IgG-positive autistic sera was also positive for anti-NAFP. This study is the first to report an association between virus serology and brain autoantibody in autism; it supports the hypothesis that a virus-induced autoimmune response may play a causal role in autism.“
78. Hussey GD et al. The effect of Edmonston-Zagreb and Schwarz measles vaccines on immune response in infants. J Infect Dis. 1996 Jun; 173(6): 1320-6 PMID: 8648203
The effects of measles immunization on immune responses in infants and the roles of vaccine strain and age of immunization are not known. Eighty-eight children were immunized at 6 or 9 months of age with the Edmonston-Zagreb (EZ) or Schwarz (SW6, SW9) strain of measles vaccine… Therefore, measles immunization resulted in suppression of lymphoproliferation, which was most evident in infants with the highest antibody responses and most immune activation.”
79. Auwaerter PG et al. Changes within T cell receptor V beta subsets in infants following measles vaccination. John Hopkins University School of Medicine, Baltimore, MD 21287, USA. Clin Immunol Immunopathol 1996 79(2): 163-70. PMID: 8620622
“Measles produces immune suppression which contributes to an increased susceptibility to other infections. These data suggest that [vaccinal and wild-type] measles virus may affect immune responses in part by altering the T cell receptor repertoire.”
80. Schneider-Schaulies S, ter Meulen V. Triggering of and interference with immune activation: interactions of measles virus with monocytes and dendritic cells. Viral Immunol. 2002;15(3):417-28. PMID: 12479392
81. Measles virus suppresses cell-mediated immunity by interfering with the survival and functions of dendritic and T cells. J Exp Med 1997;186:813-23
82. Sonoda S, Nakayama T. Detection of measles virus genome in lymphocytes from asymptomatic healthy children. J Med Virol 2001 65(2):381-7 PMID: 11536248
“In 83 individuals immunized with measles vaccine, the vaccine strain genome was detected in 10 (71.4%) of 14 recipients whose PBMC were obtained within 2 months of vaccination.”
83. Valsamakis A et al. Strains of measles vaccine differ in their ability to replicate in an damage human thymus. J Infect Dis. 2001 Feb 1; 183(3): 498-502. Johns Hopkins University, Baltimore, Maryland, USA. PMID: 11133383
[Question: How would the thymic-damage findings be exacerbated if tested tissues were selected to represent humans with excessively increased susceptibility, eg, an infant with persisting colic and/or persisting otitis?]
84. Yalcin SS et al. The effect of live measles vaccines on serum vitamin A levels in healthy children. Acta Paediatr Jpn. 1998 Aug; 40(4): 345-9. PMID: 9745778
“Serum retinol levels have been shown to be depressed during measles infection. This study aims to demonstrate whether there is any decrease in serum vitamin A level following immunization with live viral vaccine and its relation with vaccine seroconversion in children with measles. Since many children receive measles vaccine alone or in combination with measles-mumps-rubella vaccine, we studied serum vitamin A levels and antibody levels in healthy, well-nourished children before and after immunization with monovalent and combined live attenuated measles vaccine… CONCLUSION: Serum vitamin A levels are reduced following vaccination with monovalent and combined live attenuated measles vaccines.”
85. Vitamin A administered
with measles vaccine to nine-month-old infants does not reduce vaccine
immunogenicity. J Nutr. 1999 Aug; 129(8): 1569-73. PMID 10419992
http://www.nutrition.org/cgi/reprint/129/8/1569.pdf
“Among malnourished infants, the geometric mean titer was significantly greater in the vitamin A group compared to the placebo group (ratio of geometric means, 1.57; 95% confidence interval, 1. 18-2.0), but seroconversion rates did not differ.”
[Comment: note the theoretical implication that malourished children may have lower cell-mediated immunity and thus generate increased antibody immunity. This is consistent with immunity lab-data in many autistic children.]
86. Yalcin SS, Yurdakok K.
Sex-specific differences in serum vitamin A values after measles immunization.
Pediatr Infect Dis J. 1999 Aug; 18(8): 747-8. PMID 10462357
87. Semba RD. Vitamin A and immunity to viral, bacterial and protozoan infections. Proc Nutr Soc 1999 58(3): 719-27. PMID 10604208
“…vitamin A and related retinoids play a major role in immunity, including expression of mucins and keratins, lymphopoiesis, apoptosis, cytokine expression, production of antibody, and the function of neutrophils, natural killer cells, monocytes or macrophages, T lymphocytes and B lymphocytes. Recent clinical trials suggest that vitamin A supplementation reduces morbidity and mortality in different infectious diseases, such as measles, diarrhoeal disease, measles-related pneumonia, human immunodeficiency virus infection and malaria. Immune responses vary considerably during different infections, and the available data suggest that the modulation of immune function by vitamin A may also vary widely, depending on the type of infection and immune responses involved."
88. Molina EL, Patel JA. A to Z: vitamin A and zinc, the miracle duo. Indian J Pediatr. 1996 63(4): 427-31. PMID 10832460
“Dietary micronutrients such as vitamins and trace minerals are known modulators of host immune responses against common pathogens. In this respect, vitamin A and zinc have recently received increased attention. Several in vivo and in vitro studies suggest that vitamin A may be a critical player in the mucosal immune responses in the respiratory and gastrointestinal tracts, particularly in undernourished children. The effect may be mediated primarily by stabilization of the membrane of mucosal epithelial cells, as well as enhanced leukocyte functions. The beneficial effect of vitamin A therapy in reducing measles-associated morbidity and mortality suggests its crucial role in defenses against viral pathogens. Zinc is also known affect leukocyte functions such as phagocytosis and T-lymphocyte-mediated immune responses… Dietary supplementation or therapeutic treatment with vitamin A and zinc may be a cheap yet effective means of preventing or treating infections in highly susceptible populations. Additional studies, however, are required to better define the types of pathogens and the specific human populations that may benefit from such therapy.”
88b. Chandra RK, Wadhwa M. Nutritional modulation of intestinal mucosal immunity. Immunol Invest. 1989 Jan-May;18(1-4):119-26. PMID: 2659508
“Protein-energy malnutrition results in an increased risk of gastrointestinal infection. This can be attributed in part to impaired immune responses. Cell-mediated immunity is decreased as judged by reduced number and function of thymus-dependent lymphocytes, impaired delayed cutaneous hypersensitivity reactions, and decreased production of lymphokines. Concentration of secretory IgA is reduced and there are fewer intraepithelial lymphocytes. Antibody responses following viral vaccine administration are reduced and there is decrease in natural killer cell activity. In addition, the number of bacteria binding to epithelial cells is increased. These changes are observed also in certain selected nutrient deficiencies, such as that of vitamin A. It is suggested that impaired systemic and mucosal immunity contributes to the increased frequency and severity of intestinal infections seen in undernourished individuals.”
88c. Lie C et al. Impact of large-dose vitamin A supplementation on childhood diarrhoea, respiratory disease and growth. Eur J Clin Nutr. 1993 Feb;47(2):88-96. PMID: 8436094
“One hundred and seventy-two 0.5-3.0-year-old children in a mountainous area of northern Hebei Province of China were randomly assigned to a vitamin A supplementation group (n = 98) or a control group (n = 74) for a 1 year double-blind study. Capsules containing 200,000 IU vitamin A and 40 IU vitamin E were given to the children in the experimental group 3 and 9 months after baseline examination. During the 12 month study period, there was a significant reduction in the incidence of diarrhoea (P < 0.01) and respiratory disease (P < 0.01) in the children of the experimental group compared to the control. Risk of diarrhoea and respiratory disease were respectively 2.5 and 3.4 times higher in the control children. Serum retinol and IgA levels of the treatment group were significantly higher than that of control group (P < 0.01) 7 weeks after first supplementation. There was no significant difference in saliva IgA level between groups. No significant differences in growth were observed. It was concluded that supplementation with large doses of vitamin A decreased the incidence and severity of diarrhoea and respiratory disease in these children, possibly through enhanced activity of the immune system, but had no effect on growth over 1 year.”
88d. Sarkar J et al. Vitamin A is required for regulation of polymeric immunoglobulin receptor (pIgR) expression by interleukin-4 and interferon-gamma in a human intestinal epithelial cell line. J Nutr. 1998 Jul;128(7):1063-9. PMID: 9649586
“The secretory immunoglobulin A (IgA) antibody response to infections of mucosal surfaces requires transport of IgA from the basal to apical surface of mucosal epithelial cells by a specific transport protein, the polymeric immunoglobulin receptor (pIgR). We have tested the hypothesis that the vitamin A metabolite all-trans retinoic acid (RA) is required for the regulation of pIgR expression by the cytokines interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) in HT-29 cells… These data indicate that RA strongly interacts with IL-4 and IFN-gamma to regulate pIgR expression in HT-29 cells, suggesting that vitamin A may be required for proper in vivo regulation of IgA transport in response to mucosal infections.”
88e. Nikawa T et al. Vitamin A prevents the decline in immunoglobulin A and Th2 cytokine levels in small intestinal mucosa of protein-malnourished mice. J Nutr 1999 129(5):934-41. PMID: 10222382
“These results suggest that large oral supplements of vitamin A may preserve mucosal IgA level during protein malnutrition, possibly by stimulating Th2 cytokine production and thereby, inducing resistance against infection.”
88f. Aukrust P et al. pal.aukrust@klinmed.uio.no Decreased vitamin A levels in common variable immunodeficiency: vitamin A supplementation in vivo enhances immunoglobulin production and downregulates inflammatory responses. Eur J Clin Invest. 2000 30(3):252-9. PMID: 10692003
“BACKGROUND: Vitamin A has a broad range of immunological effects, and vitamin A deficiency is associated with recurrent infections. Common variable immunodeficiency (CVI) is a group of B-cell deficiency syndromes with impaired antibody production and recurrent bacterial infections as the major manifestations, but the immunological dysfunctions may also include T cells and macrophages. In the present study we examined the possible role of vitamin A deficiency in CVI… CONCLUSION: A considerable subgroup of CVI patients appears to be characterized by low vitamin A levels. Our findings support a possible role for vitamin A supplementation in CVI, perhaps resulting in enhanced immunoglobulin synthesis and downregulated inflammatory responses.
88g. Bjersing JL et al. jan.bjersing@immuno.gu.se Loss of ileal IgA+ plasma cells and of CD4+ lymphocytes in ileal Peyer's patches of vitamin A deficient rats. Clin Exp Immunol. 2002 Dec;130(3):404-8. PMID: 12452829
“Child mortality in diarrhoeal disease is increased significantly by vitamin A deficiency in poor countries. The pathological mechanisms are not known in detail. However, in this paper we report that vitamin A-deficient Wistar rats had much reduced IgA+ plasma cells in the ileal lamina propria (eightfold reduction from 470 cells/mm(2), P = 0.009), as well as a prominent reduction of CD4+ cells in the parafollicular regions of ileal Peyer's patches (reduction from 7200 to 105 cells/mm(2), P = 0.009). IL-2Ralpha-chain (CD25) positive lymphocytes in the ileal Peyer's patches were also reduced significantly in vitamin A deficiency (from 1400 to 300 cells/mm(2), P = 0.009). The density of CD8 cells tended to be increased relative to the control animals (from 5100 to 6000 cells/mm(2), not statistically significant). In conclusion, the marked decrease of lamina propria IgA+ plasma cells may be one cause of the high diarrhoeal mortality in vitamin A deficiency. This, in turn, appears to be related to reduced numbers of activated or regulatory CD4+ T cells in Peyer's patches.
88h. Kim JY, Chung BH. Effects of combination dietary conjugated linoleic acid with vitamin A (retinol) and selenium on the response of the immunoglobulin production in mice. J Vet Sci. 2003 Apr;4(1):103-8. PMID: 12819373
“The dietary effect of conjugated linoleic acid (CLA) on the response of the immunoglobulin (serum and tissue) production in Balb/C mice was examined at three doses: 0 %(control), 0.5% and 1.5%. The combination effects of CLA with vitamin ADE or selenium also were investigated. CLA at 0.5% increased serum immunoglobulin A, G, mesenteric lymph node (MHN) and gut luminal IgA (secretory IgA) levels. However, 1.5% CLA decreased SIgG slightly. CLA both alone and combined with vitamin ADE and selenium did not affect serum IgE. The levels of immunoglobulin concentration in the 0.5% CLA group were higher than those in the 1.5% CLA group. The level of serum IgG in 1.5% CLA combined with selenium was maintained at the same level as that of control. It is considered that overdoses of CLA (1.5%) even depressed the production of immunoglobulin but selenium and/or vitamin inhibited this activity to a certain extent.In this study, dietary CLA increased immunoglobulin production in a dose-dependent manner. Vitamin ADE and Selenium combined with CLA also increased the immunoglobulin production response except serum IgE.
89. D'Souza RM, D'Souza R. Vitamin A for preventing secondary infections in children with measles—a systematic review. J Trop Pediatr. 2002 48(2):72-7. PMID 12022432
90. D'Souza RM, D'Souza R. Vitamin A for treating measles in children. Cochrane Database Syst Rev. 2002;(1):CD001479. PMID 11869601
“REVIEWER'S CONCLUSIONS: Although we did not find evidence that a single dose of 200,000 IU of vitamin A per day was associated with reduced mortality among children with measles, there was evidence that the same dose given for two days was associated with a reduced risk of overall mortality and pneumonia specific mortality. The effect was greater in children under the age of two years.”
91. Madhulika et al. Vitamin A supplementation in post-measles complications. J Trop Pediatr. 1994 Oct;40(5):305-7. PMID 7807628.
The case fatality rate was 16 per cent in those who received VIT.A, while the same was 32 per cent in those who did not receive Vit.A (P < 0.02).”
92. Hussey GD, Klein M. Routine high-dose vitamin A therapy for children hospitalized with measles. J Trop Pediatr. 1993 39(6):342-5. PMID 8133555
Measles is without specific therapy and remains important globally as a cause of childhood death. In controlled studies, high-dose vitamin A therapy (Hi-VAT)—with 400,000 IU vitamin A--has been demonstrated to markedly reduce measles-associated morbidity and mortality.”
93. Butler JC et al. Measles severity and serum retinol (vitamin A) concentration among children in the United States. Pediatrics. 1993 Jun;91(6):1176-81. PMID 8502524
94. Bluhm DP, Summers RS. Plasma vitamin A levels in measles and malnourished pediatric patients and their implications in therapeutics. J Trop Pediatr 1993 39(3):179-82. PMID 8326539
This study has shown that there is a high incidence of baseline hyporetinaemia in these patients. The mean retinol plasma levels return to within normal limits after 8 days of either routine treatment or vitamin A supplementation.”
95. Ogaro FO et al. Effect of vitamin A on diarrhoeal and respiratory complications of measles. Trop Geogr Med. 1993;45(6):283-6. PMID 8116059
“These
findings, along with those from three other trials in Africa, suggest that high
dose vitamin A reduces the severity of complications during measles.”
96. Coutsoudis A et al. Vitamin A supplementation enhances specific IgG antibody levels and total lymphocyte numbers while improving morbidity in measles. Pediatr Infect Dis J. 1992 11(3):203-9. PMID 1565535
These findings reinforce results from animal studies that show that the pathways of vitamin A activity in decreasing morbidity and mortality are partly founded on selective immunopotentiation.”
97. Frieden TR et al. Vitamin A levels and severity of measles. New York City. Am J Dis Child. 1992 Feb;146(2):182-6. PMID 1285727
Recent studies show that
vitamin A levels decrease during measles and that vitamin A therapy can improve
measles outcome in children in the developing world. Vitamin A levels of
children with measles have not been studied in developed countries. We
therefore measured vitamin A levels in 89 children with measles younger than 2
years and in a reference group in New York City, NY. Vitamin A levels in
children with measles ranged from 0.42 to 3.0 mumol/L; 20 (22%) were low. Children
with low levels were more likely to have fever at a temperature of 40 degrees C
or higher (68% vs 44%), to have fever for 7 days or more (54% vs 23%), and to
be hospitalized (55% vs 30%). Children with low vitamin A levels had lower
measles-specific antibody levels. No child in the reference group had a low
vitamin A level. Our data show that many children younger than 2 years in New
York City have low vitamin A levels when ill with measles, and that such
children seem to have lower measles-specific antibody levels and increased
morbidity. Clinicians may wish to consider vitamin A therapy for children
younger than 2 years with severe measles…”
98: Susan Owens, DAN! Think-tank presentation. Philadelphia 2003.
99. Finegold SM et al. Gastrointestinal microflora studies in late-onset autism. Clin Infect Dis 2002 35(Suppl 1):S6-S16 PMID 12173102
“Some cases of late-onset (regressive) autism may involve abnormal flora because oral vancomycin, which is poorly absorbed, may lead to significant improvement in these children. Fecal flora of children with regressive autism was compared with that of control children, and clostridial counts were higher. The number of clostridial species found in the stools of children with autism was greater than in the stools of control children. Children with autism had 9 species of Clostridium not found in controls, whereas controls yielded only 3 species not found in children with autism. In all, there were 25 different clostridial species found. In gastric and duodenal specimens, the most striking finding was total absence of non-spore-forming anaerobes and microaerophilic bacteria from control children and significant numbers of such bacteria from children with autism. These studies demonstrate significant alterations in the upper and lower intestinal flora of children with late-onset autism and may provide insights into the nature of this disorder.”
100. Bendel CM. Colonization and epithelial adhesion in the pathogenesis of neonatal candidiasis. Semin Perinatol. 2003 Oct;27(5):357-64. PMID 14626499
“C albicans is the most commonly isolated species in colonized or infected infants. Over the past decade the incidence of both colonization and infection with other Candida species, particularly C parapsilosis, has risen dramatically… Microbial factors also augment colonization, including the ability of Candida to adhere to human epithelium.”
101. Walker WA. Role of nutrients and bacterial colonization in the development of intestinal host defense. J Pediatr Gastroenterol Nutr. 2000;30 Suppl 2:S2-7. PMID 10749395
102. Dai D, Walker WA. Protective nutrients and bacterial colonization in the immature human gut. Adv Pediatr. 1999;46:353-82. PMID 10645469
“The normal human microflora is a complex ecosystem that is in part dependent on enteric nutrients for establishing colonization. The gut microbiota are important to the host with regard to metabolic functions and resistance to bacterial infections. At birth, bacterial colonization of a previously germ-free human gut begins. Diet and environmental conditions can influence this ecosystem. A breast-fed, full-term infant has a preferred intestine microbiota in which bifidobacteria predominate over potentially harmful bacteria, whereas in formula-fed infants, coliforms, enterococci, and bacteroides predominate. The pattern of bacterial colonization in the premature neonatal gut is different from that in the healthy, full-term infant gut… Probiotics and prebiotics modulate the composition of the human intestinal microflora to the benefit of the host. These beneficial effects may result in the suppression of harmful microorganisms, the stimulation of bifidobacterial growth, or both. In the future, control and manipulation of the bacterial colonization… may be a new approach to the prevention and treatment of intestinal infectious diseases of various etiologies.”
103. Orrhage K, Nord CE. Factors controlling the bacterial colonization of the intestine in breastfed infants. Acta Paediatr Suppl. 1999 Aug;88(430):47-57. PMID 10569223
“This article summarizes the published data on the intestinal microflora in breastfed infants published during the last 15 y. Enterobacteria and enterococci are found in high numbers in most infants during the first week of life. Bifidobacteria and Bacteroides spp. are found in increasing numbers at the following weeks. The intestinal microflora in breastfed infants can also be followed by different biochemical parameters. Acetic acid is found in higher concentrations in breastfed than in formula-fed infants. Degradation of mucin starts later in breastfed than in formula-fed infants. The conversion of cholesterol to coprostanol is also delayed by breastfeeding. Geographical differences in the composition of the intestinal microflora in infants have been reported, i.e. enterobacteria, enterococci, bifidobacteria, lactobacilli and bacteroides show different occurrences in developed and developing countries. There are minor differences in the infant's intestinal microflora due to breastfeeding or/and formula feeding.”
104. Belley A et al. Intestinal mucins in colonization and host defense against pathogens. Am J Trop Med Hyg. 1999 Apr;60(4 Suppl):10-5 PMID 10344672
“Intestinal mucins are key components of the first line of host defense against intestinal pathogens. These large glycoconjugates secreted by specialized exocrine goblet cells form viscous gels that trap microorganisms and irritants and limit their diffusion to the intestinal epithelium. Moreover, they allow for colonization by indigenous bacterial flora that prevents attachment of pathogenic microbes. The interaction between microbes and mucins involves mucin carbohydrate side chains and microbial adhesin molecules. Certain microorganisms and disease states may alter mucin biochemistry or expression…”
105. Jarvis WR. The epidemiology of colonization. Infect Control Hosp Epidemiol. 1996 Jan;17(1):47-52. PMID 8789688
“Colonization is the presence of a microorganism in or on a host, with growth and multiplication but without any overt clinical expression or detected immune response in the host at the time it is isolated. Normal colonization in humans begins during the birth process and through subsequent contacts with the inanimate or animate environments until a delicately balanced "normal" flora is established; subsequently, the precise components of this flora evolve. This normal flora, such as coagulase-negative Staphylococcus or Staphylococcus aureus on the skin or Candida albicans in the gastrointestinal tract, vagina, or perineal area, can result in infection when normal body defenses are impaired through underlying disease, immunomodulating therapy, or the use of invasive devices, or when the delicate balance of the normal flora is altered through antimicrobial therapy…”
106. Fitzgerald JF. Colonization of the gastrointestinal tract. Mead Johnson Symp Perinat Dev Med. 1977;(11):35-8. PMID 347190
“The alimentary tract is sterile at birth but colonic colonization is relatively complete by the end of the first week of life. The upper alimentary tract is colonized by microorganisms normally inhabiting the oral cavity. The colon on the other hand appears to be colonized by microorganisms originating in the maternallower alimentary tract. The colonic flora of infants is affected by diet (breast or formula feedings). The presence of a "fecal-type" flora in the proximal small bowel should be considered abnormal…”
107. Edelson SB, Cantor DS. Autism: xenobiotic influences. Toxicol Ind Health. 1998 Jul-Aug;14(4):553-63. PMID 9664646
“The advances in medical technology during the last four decades has provided evidence for an underlying neurological basis for autism. The etiology for the variations of neurofunctional anomalies found in the autistic spectrum behaviors appears inconclusive as of this date but growing evidence supports the proposal that chronic exposure to toxic agents, i.e., xenobiotic agents, to a developing central nervous system may be the best model for defining the physiological and behavioral data found in these populations. A total of 20 subjects (15 males and 5 females) who received a formal diagnosis of autism by a developmental pediatrician, pediatric neurologist, or licensed psychologist were included. The mean age for the sample was 6.35 yrs offnge = 3-12 years)… It is most noteworthy that of the 20 cases examined for this study, 100% of the cases showed liver detoxication profiles outside of normal. An examination of 18 autistic children in blood analyses that were available showed that 16 of these children showed evidence of levels of toxic chemicals exceeding adult maximum tolerance. [Chelation challenge is more accurately instructive.] In the two cases where toxic chemical levels were not found, there was abnormal D-glucaric acid findings suggesting abnormal xenobiotic influences on liver detoxication processes. A proposed mechanism for the interaction of xenobiotic toxins with immune system dysfunction and continuous and/or progressive endogenous toxicity is presented as it relates to the development of behaviors found in the autistic spectrum.
108. Thony B et al. Tetrahydrobiopterin biosynthesis, regeneration and functions. Biochem J. 2000 347 Pt 1:1-16. PMID 10727395
109. Cohen BI. The significance of ammonia/gamma-aminobutyric acid (GABA) ratio for normality and liver disorders. Med Hypotheses. 2002 Dec;59(6):757-8. PMID 12445521
110. Kidd PM Autism, an extreme challenge to integrative medicine. Part: 1: The knowledge base. Altern Med Rev. 2002 Aug;7(4):292-316. PMID: 12197782
“Autism, archetype of the autistic spectrum disorders (ASD), is a neurodevelopmental disorder characterized by socially aloof behavior and impairment of language and social interaction. Its prevalence has surged in recent years. Advanced functional brain imaging has confirmed pervasive neurologic involvement. Parent involvement in autism management has accelerated understanding and treatment. Often accompanied by epilepsy, cognitive deficits, or other neurologic impairment, autism manifests in the first three years of life and persists into adulthood. Its etiopathology is poorly defined but likely multifactorial with heritability playing a major role. Prenatal toxic exposures (teratogens) are consistent with autism spectrum symptomatology. Frequent vaccinations with live virus and toxic mercurial content (thimerosal) are a plausible etiologic factor. Autistic children frequently have abnormalities of sulfoxidation and sulfation that compromise liver detoxification, which may contribute to the high body burden of xenobiotics frequently found. Frequent copper-zinc imbalance implies metallothionein impairment that could compound the negative impact of sulfur metabolism impairments on detoxification and on intestinal lining integrity. Intestinal hyperpermeability manifests in autistic children as dysbiosis, food intolerances, and exorphin (opioid) intoxication, most frequently from casein and gluten. Immune system abnormalities encompass derangement of antibody production, skewing of T cell subsets, aberrant cytokine profiles, and other impairments consistent with chronic inflammation and autoimmunity. Coagulation abnormalities have been reported.”
111. Kidd PM. Autism, an extreme challenge to integrative medicine. Part 2: medical management. Altern Med Rev. 2002 Dec;7(6):472-99. PMID 12495373
“Autism and allied autistic spectrum disorders (ASD) present myriad behavioral, clinical, and biochemical abnormalities. Parental participation, advanced testing protocols, and eclectic treatment strategies have driven progress toward cure. Behavioral modification and structured education are beneficial but insufficient. Dietary restrictions, including removal of milk and other casein dairy products, wheat and other gluten sources, sugar, chocolate, preservatives, and food coloring are beneficial and prerequisite to benefit from other interventions. Individualized IgG or IgE testing can identify other troublesome foods but not non-immune mediated food sensitivities. Gastrointestinal improvement rests on controlling Candida, [parasites and pathogenic bacteria], and using probiotic bacteria and nutrients to correct dysbiosis and decrease gut permeability. Detoxification of mercury and other heavy metals by DMSA/DMPS chelation can have marked benefit. Documented sulfoxidation-sulfation inadequacies call for sulfur-sulfhydryl repletion and other liver p450 support. Many nutrient supplements are beneficial and well tolerated, including dimethylglycine (DMG) and a combination of pyridoxine (vitamin B6) and magnesium, both of which benefit roughly half of ASD cases. Vitamins A, B3, C, and folic acid; the minerals calcium and zinc; cod liver oil; and digestive enzymes, all offer benefit… Current pharmaceuticals fail to benefit the primary symptoms and can have marked adverse effects. Individualized, in-depth clinical and laboratory assessments and integrative parent-physician-scientist cooperation are the keys to successful ASD management.”
112. Kidd PM. An approach to the nutritional management of autism. Altern Ther Health Med. 2003 Sep-Oct;9(5):22-31 PMID 14526708
113. Wang XF, Cynader MS. Astrocytes provide cysteine to neurons by releasing glutathione. J Neurochem. 2000 74(4):1434-42. PMID 10737599
“Cysteine is the rate-limiting precursor of glutathione synthesis. Evidence suggests that astrocytes can provide cysteine and/or glutathione to neurons. However, it is still unclear how cysteine is released and what the mechanisms of cysteine maintenance by astrocytes entail. In this report, we analyzed cysteine, glutathione, and related compounds in astrocyte conditioned medium using HPLC methods. In addition to cysteine and glutathione, cysteine-glutathione disulfide was found in the conditioned medium. In cystine-free conditioned medium, however, only glutathione was detected. These results suggest that glutathione is released by astrocytes directly and that cysteine is generated from the extracellular thiol/disulfide exchange reaction of cystine and glutathione: glutathione + cystine<-->cysteine + cysteine-glutathione disulfide. Conditioned medium from neuron-enriched cultures was also assayed in the same way as astrocyte conditioned medium, and no cysteine or glutathione was detected. This shows that neurons cannot themselves provide thiols but instead rely on astrocytes. We analyzed cysteine and related compounds in rat CSF and in plasma of the carotid artery and internal jugular vein. Our results indicate that cystine is transported from blood to the CNS and that the thiol/disulfide exchange reaction occurs in the brain in vivo. Cysteine and glutathione are unstable and oxidized to their disulfide forms under aerobic conditions. Therefore, constant release of glutathione by astrocytes is essential to maintain stable levels of thiols in the CNS.”
114. Fonnum F, Lock EA. The contributions of excitotoxicity, glutathione depletion and DNA repair in chemically induced injury to neurones: exemplified with toxic effects on cerebellar granule cells. J Neurochem. 2004 Feb;88(3):513-31. PMID: 14720201
“Six chemicals, 2-halopropionic acids, thiophene, methylhalides, methylmercury, methylazoxymethanol (MAM) and trichlorfon (Fig. 1), that cause selective necrosis to the cerebellum, in particular to cerebellar granule cells, have been reviewed… All six compounds decrease cerebral glutathione (GSH), due to conjugation with the xenobiotic, thereby reducing cellular antioxidant status and making the cells more vulnerable to reactive oxygen species. 2-Halopropionic acids and methylmercury appear to also act via an excitotoxic mechanism leading to elevated intracellular Ca2+, increased reactive oxygen species and ultimately impaired mitochondrial function… We propose that a combination of reduced antioxidant status plus excitotoxicity or DNA damage is required to cause cerebellar neuronal cell death with these chemicals. The small size of cerebellar granule cells, the unique subunit composition of their N-methyl-d-aspartate (NMDA) receptors, their low DNA repair ability, low levels of calcium-binding proteins and vulnerability during postnatal brain development and distribution of glutathione and its conjugating and metabolizing enzymes are all important factors in determining the sensitivity of cerebellar granule cells to toxic compounds.”
115. Ehrhart J, Zeevalk GD. Cooperative interaction between ascorbate and glutathione during mitochondrial impairment in mesencephalic cultures. J Neurochem 2003 86(6):1487-97. PMID: 12950457
“These findings indicate that ascorbate contributes to the maintenance of GSSG/GSH status during oxidative stress through scavenging of radical species, attenuation of GSH efflux and redistribution of GSSG to the formation of mixed disulfides. It is speculated that these events are linked by glutaredoxin, an enzyme shown to contain both dehydroascorbate reductase as well as glutathione thioltransferase activities.”
116. Dringen R, Hirrlinger J. Glutathione pathways in the brain. Biol Chem. 2003 384(4):505-16. PMID: 12751781
“The antioxidant glutathione (GSH) is essential for the cellular detoxification of reactive oxygen species in brain cells. A compromised GSH system in the brain has been connected with the oxidative stress occuring in neurological diseases. Recent data demonstrate that besides intracellular functions GSH has also important extracellular functions in brain. In this respect astrocytes appear to play a key role in the GSH metabolism of the brain, since astroglial GSH export is essential for providing GSH precursors to neurons. Of the different brain cell types studied in vitro only astrocytes release substantial amounts of GSH. In addition, during oxidative stress astrocytes efficiently export glutathione disulfide (GSSG)…. This review focuses on recent results on the export of GSH and GSSG from brain cells as well as on the functions of extracellular GSH in the brain. In addition, implications of disturbed GSH pathways in brain for neurodegenerative diseases will be discussed.”
117. Pastore A et al. Analysis of glutathione: implication in redox and detoxification. Clin Chim Acta. 2003 Jul 1;333(1):19-39. PMID: 12809732
“BACKGROUND: Glutathione is a ubiquitous thiol-containing tripeptide, which plays a central role in cell biology. It is implicated in the cellular defence against xenobiotics and naturally occurring deleterious compounds, such as free radicals and hydroperoxides… Glutathione is a critical factor in protecting organisms against toxicity and disease. This review may turn useful for analysing the glutathione homeostasis, whose impairment represents an indicator of tissue oxidative status in human subjects.”
118. Sheehan D et al. Structure, function and evolution of glutathione transferases: implications for classification of non-mammalian members of an ancient enzyme superfamily. Biochem J. 2001 Nov 15;360(Pt 1):1-16. PMID: 11695986
“The glutathione transferases (GSTs; also known as glutathione S-transferases) are major phase II detoxification enzymes found mainly in the cytosol. In addition to their role in catalysing the conjugation of electrophilic substrates to glutathione (GSH), these enzymes also carry out a range of other functions.”
119. Hayes JD, Strange RC. Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology. 2000 Sep;61(3):154-66. PMID: 10971201
“Two supergene families encode proteins with glutathione S-transferase (GST) activity: the family of soluble enzymes comprises at least 16 genes; the separate family of microsomal enzymes comprises at least 6 genes. These two GST families are believed to exert a critical role in cellular protection against oxidative stress and toxic foreign chemicals. They detoxify a variety of electrophilic compounds, including oxidized lipid, DNA and catechol products generated by reactive oxygen species-induced damage to intracellular molecules. An increasing number of GST genes are being recognized as polymorphic. Certain alleles, particularly those that confer impaired catalytic activity (e.g. GSTM1(*)0, GSTT1(*)0), may be associated with increased sensitivity to toxic compounds…”
120. Droge W, Breitkreutz R. Glutathione and immune function. Proc Nutr Soc. 2000 Nov;59(4):595-600. PMID: 11115795
“The immune system works best if the lymphoid cells have a delicately balanced intermediate level of glutathione. Even moderate changes in the intracellular glutathione level have profound effects on lymphocyte functions. Certain functions, such as the DNA synthetic response, are exquisitely sensitive to reactive oxygen intermediates and, therefore, are favoured by high levels of the antioxidant glutathione. Certain signal pathways, in contrast, are enhanced by oxidative conditions and favoured by low intracellular glutathione levels. The available evidence suggests that the lymphocytes from healthy human subjects have, on average, an optimal glutathione level. There is no indication that immunological functions such as resistance to infection or the response to vaccination may be enhanced in healthy human subjects by administration of glutathione or its precursor amino acid cysteine. However, immunological functions in diseases that are associated with a cysteine and glutathione deficiency may be significantly enhanced and potentially restored by cysteine supplementation...”
121. Functions of glutathione and glutathione disulfide in immunology and immunopathology. FASEB J. 1994 Nov;8(14):1131-8. PMID: 7958618
“Even a moderate increase in the cellular cysteine supply elevates the intracellular glutathione (GSH) and glutathione disulfide (GSSG) levels and potentiates immunological functions of lymphocytes…”
122. Enhancement of tissue glutathione for antioxidant and immune functions in malnutrition. Biochem Pharmacol. 1994 Jun 15;47(12):2113-23. PMID: 8031307
123. Fernandez-Checa JC et al. Oxidative stress: role of mitochondria and protection by glutathione. Biofactors. 1998;8(1-2):7-11. PMID: 9699001
124. N-acetylcysteine. Altern Med Rev. 2000 Oct;5(5):467-71. PMID: 11056417 [No authors listed]
“N-acetylcysteine (NAC) is the acetylated precursor of both the amino acid L-cysteine and reduced glutathione (GSH). Historically it has been used as a mucolytic agent in chronic respiratory illnesses as well as an antidote for hepatotoxicity due to acetaminophen overdose. More recently, animal and human studies of NAC have shown it to be a powerful antioxidant and a potential therapeutic agent in the treatment of cancer, heart disease, HIV infection, heavy metal toxicity, and other diseases characterized by free radical oxidant damage. NAC has also been shown to be of some value in treating Sjogren's syndrome, smoking cessation, influenza, hepatitis C, and myoclonus epilepsy.”
125. Cai J et al. Inhibition of influenza infection by glutathione. Free Radic Biol Med. 2003 Apr 1;34(7):928-36. PMID: 12654482
“Infection by RNA virus induces oxidative stress in host cells. Accumulating evidence suggests that cellular redox status plays an important role in regulating viral replication and infectivity. In this study, experiments were performed to determine whether the thiol antioxidant glutathione (GSH) blocked influenza viral infection in cultures of Madin-Darby canine kidney cells or human small airway epithelial cells. Protection against production of active virus particles was observed at a low (0.05-0.1) multiplicity of infection (MOI). GSH inhibited expression of viral matrix protein and inhibited virally induced caspase activation and Fas upregulation. In BALB/c mice, inclusion of GSH in the drinking water decreased viral titer in both lung and trachea homogenates 4 d after intranasal inoculation with a mouse-adapted influenza strain A/X-31. Together, the data suggest that the thiol antioxidant GSH has an anti-influenza activity in vitro and in vivo. Oxidative stress or other conditions that deplete GSH in the epithelium of the oral, nasal, and upper airway may, therefore, enhance susceptibility to influenza infection.
126. Slattery JT et al. Dose-dependent pharmacokinetics of acetaminophen: evidence of glutathione depletion in humans. Clin Pharmacol Ther 1987 41(4):413-8 PMID 3829578
127. Lauterburg BH, Mitchell JR. Therapeutic doses of acetaminophen stimulate the turnover of cysteine and glutathione in man. J Hepatol. 1987 Apr;4(2):206-11. PMID 3584929
“The data indicate that therapeutic doses of acetaminophen markedly stimulate the rate of turnover of the pool of cysteine available for the synthesis of GSH, most likely due to an increased rate of synthesis of GSH which is required to detoxify the toxic metabolite of acetaminophen. Patients who are not able to respond to a similar demand on their stores of GSH by increasing the synthesis of GSH may be at higher risk of developing hepatic injury from drugs that require GSH for their detoxification.”
128. Spielberg SP. Acetaminophen toxicity in lymphocytes heterozygous for glutathione synthetase deficiency. Can J Physiol Pharmacol 1985 63(5):468-71 PMID 4041989
Heterozygous cells failed to use N-acetylcysteine as efficiently to resynthesize glutathione, and the cells were not protected from acetaminophen toxicity. Heterozygotes may be at increased risk of toxicity from drugs whose metabolites are detoxified by glutathione conjugation.”
129. Depletion of hepatic glutathione in rats impairs phagocytosis in vivo. Arch Toxicol Suppl 1989;13:326-9 PMID 2774956
130. Homozygous gene deletions of the glutathione S-transferases M1 and T1 are associated with thimerosal sensitization. Int Arch Occup Environ Health 2000 73(6):384-8 PMID 11007341
131. Muller M et al. Inhibition of the human erythrocytic glutathione-S-transferase T1 (GST T1) by thimerosal. Int J Hyg Environ Health 2001 203(5-6):479-81. PMID 11556154
132. Corrales F et al. Inhibition of glutathione synthesis in the liver leads to S-adenosyl-L-methionine synthetase reduction. Hepatology 1991 14(3):528-33. PMID 1874498
[Note etiologic connection with thimerosal and methionine synthase, cite 20]
133. Pajares MA et al. Modulation of rat liver S-adenosylmethionine synthetase activity by glutathione. J Biol Chem 1992 267(25):17598-605. PMID 1517209
http://www.jbc.org/cgi/reprint/267/25/17598.pdf
[Note etiologic connection with thimerosal and methionine synthase, cite 20]
134a. Meister A et al. Intracellular cysteine and glutathione delivery systems. J Am Coll Nutr. 1986;5(2):137-51. PMID 3722629
134b. Jill James & colleagues. Thimerosal Neurotoxicity is Associated with Glutathione Depletion: Protection with Glutathione Precursors. Neurotoxicology, in press 2004.
135. Abruptio placentae and chorioamnionitis-microbiological and histologic correlation. Acta Obstet Gynecol Scand. 1999 May;78(5):363-6 PMID 10326877
“Conclusion: The incidence of silent chorioamnionitis (placental membrane culture positivity) is higher in the abruptio placentae.”
136. Clinical chorioamnionitis, elevated cytokines, and brain injury in term infants. Pediatrics. 2002 Oct;110(4):673-80 PMID 12359779
137. Fetal endothelial cells express vascular cell adhesion molecule in the setting of chorioamnionitis. Am J Reprod Immunol 2000 43(5):259-63 PMID 12359779
138. Chorioamnionitis and uterine function. Obstet Gynecol 2000; 95:909-12 PMID: 10831982
“Several small studies have suggested that chorioamnionitis has an inhibitory effect upon labor, characterized by decreased uterine contractility, decreased sensitivity to oxytocin stimulation, and subnormal cervical dilation.” [3 cites]
139. Effect of amniotic fluid bacteria on the course of labor in nulliparous women at term
Obstet Gynecol 68:587-592 1986 PMID: 3763067
[Nulliparous – no prior live births]
“Patients with intraamniotic infection have an increased rate of cesarean delivery… These results support a causal relationship between high-virulence bacteria in the amniotic fluid and poor cervical dilation response to oxytocin…”
“Friedman… studied nulliparous patients with ‘amniotic infection syndrome’ and found that 70.5% had labor dysfunction. More recent reports have confirmed this association and have also identified an increased frequency of cesarean delivery among these women.”
“Koh et al… reported a 43% cesarean section rate in 140 patients with clinical ‘chorioamnionitis.’ “
“Two-thirds of the cesarean sections were performed because of poor progress in labor despite the use of oxytocin…”
140. A fetal systemic inflammatory response is followed by the spontaneous onset of preterm parturition. Am J Obstet Gynecol. 1998 Jul;179(1):186-93
141. Preeclampsia is associated with widespread apoptosis of placental cytotrophoblasts within the uterine wall. Am J Pathol 1999 155(1):293-301 PMID 10393861
142. Maternal periodontal disease is associated with an increased risk for preeclampsia.
Obstet Gynecol. 2003 Feb;101(2):227-31 PMID 12576243
143. Colic in breast-milk-fed infants: treatment by temporary substitution of neocate infant formula. Acta Paediatr 2000 Jul;89(7):795-802
144. Development of cow's milk allergy in breast-fed infants. Clin Exp Allergy 2001 Jul;31(7):978-87
145. Cow's milk allergy in infancy. Curr Opin Allergy Clin Immunol. 2002 2(3):217-25
146. Cow's milk allergy presented with bloody stools from day 1 of life. Eur J Pediatr. 2003 Mar;162(3):214-5
147. Host A. Frequency of cow's milk allergy in childhood. Ann Allergy Asthma Immunol. 2002 Dec;89(6 Suppl 1):33-7. PMID: 12487202
148. Bahna SL. Cow's milk allergy versus cow milk intolerance. Ann Allergy Asthma Immunol. 2002 Dec;89(6 Suppl 1):56-60. PMID: 12487206
149. Magazzu G, Scoglio R. Gastrointestinal manifestations of cow's milk allergy. Ann Allergy Asthma Immunol. 2002 Dec;89(6 Suppl 1):65-8. PMID: 12487208
149b. Iacono G et al. Severe infantile colic and food intolerance: a long-term prospective study. J Pediatr Gastroenterol Nutr. 1991 Apr;12(3):332-5.
“To determine the relationship between infantile colic and cow's milk protein intolerance (CMPI) in formula-fed infants, 70 infants (38 male, 32 female) were selected, with mean age 30.2 ± 21.4 days, with severe colic (duration of crying greater than 4 h per day for 5 days per week). In 50 of the infants in the study group (71.4%) there was a remission of symptoms when cow's milk protein (CMP) was eliminated from the diet. Two successive challenges caused the return of symptoms in all these 50 infants. There was a positive anamnesis for atopy in 9 of 50 of the patients with CMP-related colic and in 1 of 20 of those with non-CMP-related colic (p greater than 0.05). A follow-up period of 18 months' mean duration showed that 22 of 50 (44%) of the infants with CMP-related colic and 1 of 20 (5%) of those with non-CMP-related colic developed an overt alimentary intolerance (p less than 0.02). We conclude that a considerable percentage of the infants with severe colic also have CMPI and that in these cases, dietetic treatment should be the first therapeutic approach.”
150. Chronic protracted diarrhea of infancy: a nutritional disease. Pediatrics. 1983 Dec;72(6):786-800. PMID 6417622
151. Pathogenesis of small-intestinal mucosal lesions in chronic diarrhea of infancy: I. A light microscopic study. J Pediatr Gastroenterol Nutr. 1990 Nov;11(4):455-63. PMID: 2262834
152. Pathogenesis of small-intestinal mucosal lesions in chronic diarrhea of infancy: II. An electron microscopic study. J Pediatr Gastroenterol Nutr 1990 11(4):464-80 PMID 2262835
153. Mehta DI, Blecker U. Chronic diarrhea in infancy and childhood. J La State Med Soc. 1998 Sep;150(9):419-29. PMID 9785754
154. Recent advances in otitis media. 6. Microbiology and immunology. Ann Otol Rhinol Laryngol Suppl. 2002 188:62-81. PMID 11968862
155. Viral-Bacterial Synergy in Otitis Media: Implications for Management. Curr Infect Dis Rep. 2000 Apr;2(2):154-159. PMID: 11095851
156. Chonmaitree T et al. Presence of cytomegalovirus and herpes simplex virus in middle ear fluids from children with acute otitis media. Clin Infect Dis 1992 15(4):650-3 PMID 1330014
157. The common mucosal immune system and current strategies for induction of immune responses in external secretions. J Clin Immunol. 1987 Jul;7(4):265-76. PMID: 3301884
158. IgA antibody-producing cells in peripheral blood after antigen ingestion: evidence for a common mucosal immune system in humans. Proc Natl Acad Sci U S A. 1987 Apr;84(8):2449-53. PMID: 3470804
159. Management of chronic otitis media with effusion: the role of glutathione. Laryngoscope. 2001 Aug;111(8):1486-9. PMID: 11568588
“BACKGROUND: The inflammatory cells documented in chronic otitis media with effusion (OME) spontaneously release oxidants which can induce middle ear (ME) epithelial cell damage. Glutathione (GSH), a major extracellular antioxidant in humans, plays a central role in antioxidant defense. PURPOSE: To evaluate the effects of GSH treatment on chronic otitis media with effusion (OME). SUBJECTS AND INTERVENTION: Sixty children with chronic OME were enrolled, 30 of whom were randomly assigned to the treatment group and 30 to the placebo group. Patients in the treatment group received 600 mg glutathione in 4 mL saline per day subdivided into five 2-minute administrations given by nasal aerosol every 3 or 4 waking hours for 2 weeks. Patients in the control group received 4 mL saline per day following the same procedure as for GSH treatment. RESULTS: Three months after therapy improvement had occurred in 66.6% of patients in the GSH-treated group and in 8% of the control subjects (P <.01). CONCLUSION: On the basis of these results, GSH treatment could be considered for the nonsurgical management of chronic OME.”
160. Cow's milk allergy is associated with recurrent otitis media during childhood. Acta Otolaryngol. 1999;119(8):867-73. PMID 10728925
161. Frick TJ, Olsen WA. Celiac disease and the spectrum of gluten sensitivity. Gastroenterologist. 1994 Dec;2(4):285-92. PMID: 7866735
“Celiac disease is a well-known entity in which intolerance to wheat gluten and related proteins from barley, rye, and oats (collectively known as prolamins) damage intestinal mucosa. New insights into the pathology of the celiac intestinal lesion point to a wider spectrum of gluten sensitivity than previously thought. Recent advances in immunology and genetics have shed light on the underlying mechanisms and risks associated with the disease. Although the classical manifestations are well known, the wide variety of clinical presentations make celiac disease often difficult to diagnose, and the ubiquitous presence of prolamins in the Western diet make treatment challenging.
162. Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology 2001 120(3):636-51. PMID: 11179241
“Celiac disease (CD) is a syndrome characterized by damage of the small intestinal mucosa caused by the gliadin fraction of wheat gluten and similar alcohol-soluble proteins (prolamines) of barley and rye in genetically susceptible subjects. The presence of gluten in these subjects leads to self-perpetuating mucosal damage, whereas elimination of gluten results in full mucosal recovery. The clinical manifestations of CD are protean in nature and vary markedly with the age of the patient, the duration and extent of disease, and the presence of extraintestinal pathologic conditions. In addition to the classical gastrointestinal form, a variety of other clinical manifestations of the disease have been described, including atypical and asymptomatic forms. Therefore, diagnosis of CD is extremely challenging and relies on a sensitive and specific algorithm that allows the identification of different manifestations of the disease. Serologic tests developed in the last decade provide a noninvasive tool to screen both individuals at risk for the disease and the general population…”
163. Catassi C, Fabiani E. The spectrum of coeliac disease in children. Baillieres Clin Gastroenterol. 1997 Sep;11(3):485-507. PMID: 9448912
“Coeliac disease is the life-long intolerance to dietary gluten, usually characterized by severe damage to the small-intestinal mucosa. The widespread use of sensitive diagnostic tools, such as the serum anti-gliadin and the anti-endomysial antibodies, has shown not only that coeliac disease is one of the commonest disorders in Western countries but also that this condition is characterized by a higher degree of clinical variability than previously thought (typical, atypical and silent forms). The existence of a latent-potential coeliac disease and even a gluten-sensitive disease with immunological activation of an otherwise normal small-intestinal mucosa has recently been postulated. An increased prevalence of coeliac disease in a number of other disorders has also been reported in both children and adults. The reasons for such a wide clinical heterogeneity are still poorly understood but are likely to depend on both genetic and environmental factors. Further investigations are required to evaluate the impact of undiagnosed, clinically milder forms of coeliac disease on the well-being of the population.”
164. Murray JA. The widening spectrum of celiac disease. Am J Clin Nutr. 1999 Mar;69(3):354-65. http://www.ajcn.org/cgi/reprint/69/3/354.pdf
165. Sollid LM, Gray GM. A role for bacteria in celiac disease? Am J Gastroenterol. 2004 May;99(5):905-6. {Comment on: Am J Gastroenterol. 2004 May;99(5):894-904.} PMID: 15128358
“The finding of rod-shaped bacteria attached to the small intestinal epithelium of some untreated and treated celiac-disease patients, but not to the epithelium of healthy controls, ignites the notion that bacteria may be involved in the pathogenesis of celiac disease. This editorial discusses this possibility in relation to the current understanding of the molecular basis of this disorder.
166: Forsberg G et al. Presence of bacteria and innate immunity of intestinal epithelium in childhood celiac disease. Am J Gastroenterol. 2004 May;99(5):894-904. PMID: 15128357
167. Tursi A et al. High prevalence of small intestinal bacterial overgrowth in celiac patients with persistence of gastrointestinal symptoms after gluten withdrawal. Am J Gastroenterol. 2003 Apr;98(4):839-43. PMID: 12738465
“OBJECTIVE: Celiac disease is a gluten-sensitive enteropathy with a broad spectrum of clinical manifestation, and most celiac patients respond to a gluten-free diet (GFD). However, in some rare cases celiacs continue to experience GI symptoms after GFD, despite optimal adherence to diet. The aim of our study was to evaluate the causes of persistence of GI symptoms in a series of consecutive celiac patients fully compliant to GFD. METHODS: We studied 15 celiac patients (five men, 10 women, mean age 36.5 yr, range 24-59 yr) who continued to experience GI symptoms after at least 6-8 months of GFD (even if of less severity). Antigliadin antibody (AGA) test, antiendomysial antibody (EMA) test, and sorbitol H2-breath test (H2-BT), as well as sophagogastroduodenoscopy (EGD) with histological evaluation, were performed before starting GFD. Bioptic samples were obtained from the second duodenal portion during EGD, and histopathology was expressed according to the Marsh classification. To investigate the causes of persistence of GI symptoms in these patients, we performed AGA and EMA tests, stool examination, EGD with histological examination of small bowel mucosa, and sorbitol-, lactose-, and lactulose H2-breath tests. RESULTS: Histology improved in all patients after 6-8 months of GFD; therefore, refractory celiac disease could be excluded. One patient with Marsh II lesions was fully compliant to his diet but had mistakenly taken an antibiotic containing gluten. Two patients showed lactose malabsorption, one patient showed Giardia lamblia and one patient Ascaris lumbricoides infestation, and 10 patients showed small intestinal bacterial overgrowth (SIBO) by lactulose H2-BT. We prescribed a diet without milk or fresh milk-derived foods to the patient with lactose malabsorption; we treated the patients with parasite infestation with mebendazole 500 mg/day for 3 days for 2 consecutive wk; and we treated the patients with SIBO with rifaximin 800 mg/day for 1 wk. The patients were re-evaluated 1 month after the end of drug treatment (or after starting lactose-free diet); at this visit all patients were symptom-free. CONCLUSIONS: This study showed that SIBO affects most celiacs with persistence of GI symptoms after gluten withdrawal.
168. Wheat allergy: clinical and laboratory findings. Int Arch Allergy Immunol. 2004 Feb;133(2):168-73. PMID: 14764944
169a. Hadjivassiliou M et al. Does cryptic gluten sensitivity play a part in neurological illness? Lancet. 1996 Feb 10;347(8998):369-71. PMID: 8598704
BACKGROUND: Antigliadin antibodies are a marker of untreated coeliac disease but can also be found in individuals with normal small-bowel mucosa. Because neurological dysfunction is a known complication of coeliac disease we have investigated the frequency of antigliadin antibodies, as a measure of cryptic gluten sensitivity, and coeliac disease in neurological patients. METHODS: Using ELISA, we estimated serum IgG and IgA antigliadin antibodies in 147 neurological patients who were divided into two groups. There were 53 patients with neurological dysfunction of unknown cause despite full investigation (25 ataxia, 20 peripheral neuropathy, 5 mononeuritis multiplex, 4 myopathy, 3 motor neuropathy, 2 myelopathy). The remaining 94 patients were found to have a specific neurological diagnosis (16 stroke, 12 multiple sclerosis, 10 Parkinson's disease, 56 other diagnoses) and formed the neurological control group. 50 healthy blood donors formed a third group. FINDINGS: The proportions of individuals with positive titres for antigliadin antibodies in the three groups were 30/53, 5/94, and 6/50 respectively (57, 5, and 12%). The difference in proportion between group 1 and the combined control groups was 0.49 (95% CI 0.35-0.63). Distal duodenal biopsies in 26 out of 30 antigliadin-positive patients from group 1 revealed histological evidence of coeliac disease in nine (35%), non-specific duodenitis in ten (38%), and no lesion in seven (26%) individuals. INTERPRETATION: Our data suggest that gluten sensitivity is common in patients with neurological disease of unknown cause and may have aetiological significance.
169b. Dietary treatment of gluten ataxia. J Neurol Neurosurg Psychiatry. 2003 Sep;74(9):1221-4. PMID: 12933922 m.hadjivassiliou@sheffield.ac.uk
http://jnnp.bmjjournals.com/cgi/reprint/74/9/1221.pdf
BACKGROUND: Gluten ataxia is
an immune mediated disease, part of the spectrum of gluten sensitivity, and
accounts for up to 40% of cases of idiopathic sporadic ataxia. No systematic
study of the effect of gluten-free diet on gluten ataxia has ever been
undertaken. OBJECTIVE: To study the effect of gluten-free diet on patients
presenting with ataxia caused by gluten sensitivity. METHODS: 43 patients with
gluten ataxia were studied. All were offered a gluten-free diet and monitored
every six months. All patients underwent a battery of tests to assess their
ataxia at baseline and after one year on diet. Twenty six patients (treatment
group) adhered to the gluten-free diet and had evidence of elimination of
antigliadin antibodies by one year. Fourteen patients refused the diet (control
group). Three patients had persistently raised antigliadin antibodies despite
adherence to the diet and were therefore excluded from the analysis. RESULTS:
After one year there was improvement in ataxia reflected in all of the ataxia
tests in the treatment group. This was significant when compared with the
control group. The diet associated improvement was apparent irrespective of the
presence of an enteropathy. CONCLUSIONS: Gluten ataxia responds to a strict
gluten-free diet even in the absence of an enteropathy. The diagnosis of gluten
ataxia is vital as it is one of the very few treatable causes of sporadic
ataxia.
170. Food allergy to wheat: identification of immunogloglin E and immunoglobulin
G-binding proteins with sequential extracts and purified proteins from wheat flour. Clin Exp Allergy. 2003 Jul;33(7):962-70. PMID: 12859454
171. Update on wheat hypersensitivity. Curr Opin Allergy Clin Immunol. 2003 Jun;3(3):205-9. PMID: 12840704
172: Gabrielli M et al. Association between migraine and Celiac disease: results from a preliminary case-control and therapeutic study. Am J Gastroenterol. 2003 Mar;98(3):625-9. PMID: 12650798
“OBJECTIVES: Subclinical celiac disease (CD) has been associated with various neurological disorders, the most common being neuropathy and cerebellar ataxia. The aims of the present study were to assess the following: 1) the prevalence of CD in patients affected by migraine; 2) whether there are regional cerebral blood flow abnormalities in migraine patients with CD compared to migraine patients without CD; and 3) the effects of a gluten free diet in migraine patients with CD. METHODS: A total of 90 patients affected by idiopathic migraine were enrolled, and 236 blood donors were used as controls. Serum IgG antitransglutaminase (TgA) and IgA antiendomysial (EmA) were measured. In positive cases, diagnosis was confirmed endoscopically. A gluten free diet was started in the patients diagnosed with CD, who were followed for 6 months. A single photon emission CT brain study was performed before and after a gluten free diet. RESULTS: Four of 90 (4.4%; 95% CI = 1.2-11.0) migraine patients were found to have CD compared with 0.4% (95% CI = 0.01-2.3) blood donor controls (p < 0.05). During the 6 months of gluten free diet, one of the four patients had no migraine attacks, and the remaining three patients experienced an improvement in frequency, duration, and intensity of migraine. Single photon emission CT studies showed a regional baseline reduction in brain tracer uptake in all four patients. Such reduction in uptake completely resolved at follow-up. CONCLUSIONS: Our results suggest that a significant proportion of patients with migraine may have CD, and that a gluten free diet may lead to a improvement in the migraine in these patients.
173. Gluten sensitivity as a neurological illness. J Neurol Neurosurg Psychiatry. 2002 May;72(5):560-3. PMID: 11971034
http://jnnp.bmjjournals.com/cgi/reprint/72/5/560.pdf
174. Headache and CNS white matter abnormalities associated with gluten sensitivity. Neurology 2001 13;56(3):385-8
“The authors describe 10 patients with gluten sensitivity and abnormal MRI. All experienced episodic headache, six had unsteadiness, and four had gait ataxia. MRI abnormalities varied from confluent areas of high signal throughout the white matter to foci of high signal scattered in both hemispheres. Symptomatic response to gluten-free diet was seen in nine patients.”
175. De Santis A et al. Schizophrenic symptoms and SPECT abnormalities in a coeliac patient: regression after a gluten-free diet. J Intern Med. 1997 Nov;242(5):421-3. PMID: 9408073
“A 33-year-old patient, with pre-existing diagnosis of 'schizophrenic' disorder, came to our observation for severe diarrhoea and weight loss. Use of single photon emission computed tomography, (99mTc)HMPAO SPECT, demonstrated hypoperfusion of the left frontal brain area, without evidence of structural cerebral abnormalities. Jejunal biopsy showed villous atrophy. Antiendomysial antibodies were present. A gluten-free diet was started, resulting in a disappearence of psychiatric symptoms, and normalization of histological duodenal findings and of (99mTc)HMPAO SPECT pattern. This is the first case in which, in an undiagnosed and untreated coeliac patient with psychiatric manifestations, the (99mTc)HMPAO SPECT demonstrated a dysfunction of frontal cortex disappearing after a gluten-free diet.
176. Usai P et al. Frontal cortical perfusion abnormalities related to gluten intake and associated autoimmune disease in adult coeliac disease: 99mTc-ECD brain SPECT study. Dig Liver Dis. 2004 Aug;36(8):513-8. PMID: 15334770
OBJECTIVE: Since brain perfusion abnormalities have been described by single-photon emission computed tomography in some autoimmune diseases, the aim of the present study was to evaluate the incidence of perfusion abnormalities by brain single-photon emission computed tomography in a group of coeliac disease patients, and to investigate whether gluten intake and associated autoimmune diseases may be considered risk factors in causing cerebral impairment. METHODS: Thirty-four adult coeliac patients (16 on a gluten-free diet and 18 on a gluten-containing diet, 18 (53%) with autoimmune diseases) underwent 99mTc-ethyl cysteinate dimer brain single-photon emission computed tomography and qualitative evaluation of brain perfusion was performed together with a semiquantitative estimation using the asymmetry index. Ten subjects on our database, matched for sex, age and ethnic group, who were proved normal by histology of jejunal mucosa (four males and six females; median age 39 years, range 27-55 years), were included as control group. RESULTS: Twenty-four out of 34 patients (71%) showed brain single-photon emission computed tomography abnormalities confirmed by abnormal regional asymmetry index (>5%; range 5.8-18.5%). Topographic comparison of the brain areas showed that the more significant abnormalities were localised in frontal regions, and were significantly different from controls only in coeliac disease patients on unrestricted diet. The prevalence of single-photon emission computed tomography abnormalities was similar in coeliac disease patients with (74%) and without (69%) associated autoimmune disease. CONCLUSIONS: Abnormalities of brain perfusion seem common in coeliac disease. This phenomenon is similar to that previously described in other autoimmune diseases, but does not appear to be related to associated autoimmunity and, at least in the frontal region, may be improved by a gluten-free diet.
177. The humoral response in the pathogenesis of gluten ataxia. Neurology 2002 Apr 23;58(8):1221-6
“The authors assessed the reactivity of sera from patients with gluten ataxia (13), newly diagnosed patients with celiac disease without neurologic dysfunction (24), patients with other causes of cerebellar degeneration (11), and healthy control subjects (17).
“Sera from 12 of 13 patients with gluten ataxia stained Purkinje cells strongly. Less intense staining was seen in some but not all sera from patients with newly diagnosed celiac disease without neurologic dysfunction. At high dilutions (1:800) staining was seen only with sera from patients with gluten ataxia but not in control subjects. Sera from patients with gluten ataxia also stained some brainstem and cortical neurons in rat CNS tissue. Commercial anti-gliadin antibody stained human Purkinje cells in a similar manner… Patients with gluten ataxia have antibodies against Purkinje cells. Antigliadin antibodies cross-react with epitopes on Purkinje cells.”
178. Jarvinen TT et al. Intraepithelial lymphocytes in celiac disease. Am J Gastroenterol. 2003 Jun;98(6):1332-7. PMID: 12818278
OBJECTIVE: The aim of this study was to investigate the value of immunohistochemical characterization of different intraepithelial lymphocytes (IELs) in the diagnostic workup of celiac disease (CD). METHODS: The study involved 928 consecutive adult patients undergoing endoscopy undertaken on suspicion of CD or to ascertain the dietary compliance; the control group consisted of 59 adults who underwent endoscopy because of indigestion. Small bowel mucosal morphology, CD3+, alphabeta+, and gammadelta+ IELs were determined. RESULTS: CD was detected in 138 and excluded in 545 adults. CD3+ and gammadelta+ IELs both showed a sensitivity of 93% for CD; specificity was 73% and 88%, respectively. For alphabeta+ cells, the sensitivity was 83% and specificity, 66%. The mucosal morphology recovered on a gluten-free diet and the densities of different IELs, even gammadelta+ cells, decreased. Only the density of gammadelta+ cells remained elevated compared with controls. CONCLUSIONS: Counting of IELs is recommended in borderline cases where the histology is difficult to interpret. An increase especially in gammadelta+ cells strengthens the probability of CD. However, IELs are not invariably increased in CD.
179. Cataldo F et al. Cytokine genotyping (TNF and IL-10) in patients with celiac disease and selective IgA deficiency. Am J Gastroenterol. 2003 Apr;98(4):850-6. PMID: 12738467
“OBJECTIVE: Selective IgA deficiency (IgAD) and celiac disease (CD) are frequently associated and share the ancestral haplotype human leukocyte antigen (HLA)-8.1, which is characterized by a peculiar cytokine profile. The aim of this study was to evaluate the role of tumor necrosis factor (TNF) and interleukin (IL)-10 alleles in CD and CD-IgAD… CONCLUSIONS: Genetically determined increased production of TNF-alpha and reduction of IL-10 may be relevant for susceptibility to CD, mainly in IgAD, as the different allele expression at TNF and IL-10 loci seems to influence cytokine production profile.
180. Esposito C et al. Expression and enzymatic activity of small intestinal tissue transglutaminase in celiac disease. Am J Gastroenterol. 2003 Aug;98(8):1813-20. PMID: 12907337
“Tissue transglutaminase is more expressed and active in defined areas of the small intestinal mucosa from patients with CD. The presence in the celiac mucosa of proteins able to act as amine-donor substrates suggests that tissue transglutaminase-mediated post-translational modification of proteins cross-linked with gliadin peptides may represent a pathogenic mechanism of CD.”
181. Liu E et al. Fluctuating transglutaminase autoantibodies are related to histologic features of celiac disease. Clin Gastroenterol Hepatol. 2003 Sep;1(5):356-62. PMID: 15017653
“BACKGROUND & AIMS: Asymptomatic children at risk for celiac disease (CD) and seropositive for immunoglobulin A anti-TG autoantibodies (TGAA) may lack small intestinal mucosal changes characteristic of CD. We have followed a group of children with serial testing for TGAA… CONCLUSIONS: In children with TGAA seropositivity, the TGAA level varied over time and a higher titer predicted an abnormal biopsy characteristic of CD. A threshold for biopsy for diagnosis of CD could be set higher for screening-identified cases than for clinically identified cases to decrease the frequency of performing "normal" biopsies.
182: Lonsdale D, Shamberger RJ, Audhya T. Treatment of autism spectrum children with thiamine tetrahydrofurfuryl disulfide: a pilot study. Neuroendocrinol Lett. 2002 Aug;23(4):303-8. PMID: 12195231 dlonsdale@pol.net
“OBJECTIVES: In a Pilot Study, the clinical and biochemical effects of thiamine tetrahydrofurfuryl disulfide (TTFD) on autistic spectrum children were investigated. SUBJECTS AND METHODS: Ten children were studied. Diagnosis was confirmed through the use of form E2, a computer assessed symptom score. For practical reasons, TTFD was administered twice daily for two months in the form of rectal suppositories, each containing 50 mg of TTFD. Symptomatic responses were determined through the use of the computer assessed Autism Treatment Evaluation Checklist (ATEC) forms. The erythrocyte transketolase (TKA) and thiamine pyrophosphate effect (TPPE), were measured at outset and on completion of the study to document intracellular thiamine deficiency. Urines from patients were examined at outset, after 30 days and after 60 days of treatment and the concentrations of SH-reactive metals, total protein, sulfate, sulfite, thiosulfate and thiocyanate were determined. The concentrations of metals in hair were also determined. RESULTS: At the beginning of the study thiamine deficiency was observed in 3 out of the 10 patients. Out of 10 patients, 6 had initial urine samples containing arsenic in greater concentration than healthy controls. Traces of mercury were seen in urines from all of these autistic children. Following administration of TTFD an increase in cadmium was seen in 2 children and in lead in one child. Nickel was increased in the urine of one patient during treatment. Sulfur metabolites in urine did not differ from those measured in healthy children. CONCLUSIONS: Thiamine tetrahydrofurfuryl disulfide appears to have a beneficial clinical effect on some autistic children, since 8 of the 10 children improved clinically. We obtained evidence of an association of this increasingly occurring disease with presence of urinary SH-reactive metals, arsenic in particular.”
182. Lonsdale presentation to DAN! 2003, Philadelphia
http://64.202.182.52/powerpoint/dan2003/Lonsdale.htm
183. A. Holmes, S. Cave, and J.M. El-Dahr. OPEN TRIAL OF CHELATION WITH MES0-2,3-DIMERCAPTO SUCCINIC ACID (DMSA) AND LIPOIC ACID (LA) IN CHILDREN WITH AUTISM. As submitted to IMFAR, June 2, 2001.
“Over 400 patients with autism are currently undergoing treatment for removal of heavy metals. Patients are treated with DMSA alone at doses of 10 mg/kg/dose 3 times a day for 3 days in a row (shorter duration than lead protocol to decrease side effects) with 11 days "off" to allow metals to re-equilibrate. After at least 2 rounds of DMSA alone, the thiol antioxidant lipoic acid (hypothesized to aide in removal of heavy metals across the BBB)is added to each dose of DMSA at 2-3mg/kg/dose. In general, noticeable improvements in language, self-help skills, interaction, and core autistic features are not seen until the patient has been on DMSA with LA for 2-3 months.
“Of patients who have been on DMSA/LA for at least 4 months, these results have been noted on general global assessment by parents, teachers, and MDs: age 1-5yrs(n=40): marked improvement 35%, moderate 39%, slight 15%, none 11%; age 6-12yrs (n=25): marked 4%, moderate 28%, slight 52%, none 16%; age 13-17 (n=16): moderate 6%, slight 68%, none 26%; age 18+ (n=4): slight 25%, none 75%. For example, a boy 5yr 5mo scored in the average range on a one word expressive vocabulary test 10/00 and at age equivalent 8yr 2mo in 3/01 with no change in education or medication other than starting DMSA/LA.
“The majority of children excrete mercury, lead, and other metals, suggesting that there may be a generalized problem with metal metabolism. Side effects include transient increases in hyperactivity, self-stimulatory behavior, and loose stools. Younger children in particular respond well to this therapy with significant improvement in function.”
184. DMSA Chelation efficacy PPT presentation by Jane El-Dahr, M.D.
185. Excellent DAN! PPT Presentations online http://www.autismresearchinstitute.com/dan/dan.htm
186. Lead poisoning treatment--a continuing need (commentary). J Toxicol Clin Toxicol. 2001;39(7):661-3. PMID: 11778663
187. Lightening the lead load in children. Am Fam Physician 2000 62(3):545-54, 559-60 PMID: 10950212
188. Mercury poisoning. Curr Probl Pediatr. 2000 Mar;30(3):91-9. PMID: 10742922
189. Lead poisoning in children. Curr Opin Pediatr. 1997 Apr;9(2):173-7. PMID: 9204246
190. Lead intoxication in children with pervasive developmental disorders. J Toxicol Clin Toxicol. 1996;34(2):177-81. PMID: 8618251
191. Pediatric arsenic ingestion. Am J Emerg Med. 1995 Jul;13(4):432-5. PMID: 7605532
192. Oral chelators for childhood lead poisoning. Pediatr Ann. 1994 23(11):616-9, 623-6. PMID: 7838614
193. Succimer: the first approved oral lead chelator.Am Fam Physician. 1993 Dec;48(8):1496-502. PMID: 8249780
194. The current role of 2,3-dimercaptosuccinic acid (DMSA) in the management of childhood lead poisoning.Drug Saf. 1993 Aug;9(2):85-92. PMID: 8397892