Down syndrome, vaccinations and genetic susceptibility to injury
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Down syndrome, vaccinations and genetic susceptibility to injury
What does the research show?
Laurette Janak Autism One May 2009 Email: laurette.janak@verizon.net
Overview
Description of Down syndrome Down syndrome autism prevalence Down syndrome and mercury sensitivity Down syndrome & mitochondrial dysfunction Cancer and vaccines; is there a connection? Down syndrome and aluminum sensitivity One-size-fits-all philosophy Vaccines and immune overload Scenario for DS injury from vaccines Future directions of study
Common knowledge about DS
• • • • • • • • Characteristic facial features Learning challenges Immune system deficiencies Mitochondrial dysfunction Adverse reaction to some pharmaceuticals High occurrence of celiac disease Diabetes Advanced aging with early development of Alzheimer’s disease or dementia • A 15-20 fold increased risk of leukemia
Genetics of Down syndrome
Extra chromosome 21
Why shed light on DS at an autism conference?
• Medical literature shows autism within the DS population to be in the range of 5-11% (1) • Much is known about the genetics, biochemistry and neurology of DS.
Why shed light on DS at an autism conference?
• Can we learn anything about why the unique genetics of DS increase the risk for the occurrence of autism?
• Can this knowledge then be applied toward understanding an autism risk within the general population?
Subjectivity verses Objectivity
It’s just down syndrome. It’s down syndrome and autism.
Neuroanatomic correlates of autism and stereotypy in children with Down Syndrome (Neuroreport. 2008 Apr 16;19(6):653-6) Included MRIs of 15 children with DS, 15 children with DS-ASD and 22 controls. DSM-IV criteria was used for ASD diagnosis. Aberrant Behavior Checklist (ABC)
Irritability Lethargy Stereotypy (repetitive movements) Hyperactivity Inappropriate speech
Mean ABC scores
Irritabili ty Lethargy Stereotypy Hyperactiv ity Inappropri ate speech Total score
All DS 7.1 9.3 6.9 11.7 1.5 36.4
DS only 2.3 2.5 0.7 4.7 0.1 10.2
DS-ASD 11.9 16.1 13.1 18.7 2.9 62.7
MRI findings
Brain volumes were significantly decreased in DS versus controls. A distinguishing feature of significantly more white matter in the brainstem and cerebellum of DSASD children compared to DS alone.
This pattern resembles that seen in children with autism alone. Increased white matter correlated with the ABC stereotypy subscale score.
Subjectivity verses Objectivity
It’s just down syndrome. It’s down syndrome and autism.
Chicken or the Egg
Autism
Oxidative stress
Early oxidative stress in amniotic fluid of pregnancies with Down syndrome
Clin Biochem. 2007 Feb;40(3-4):177-80
Tested the hypothesis that oxidative stress occurs early in DS pregnancies Measured Isoprostanes (IPs) in the amniotic fluid of DS pregnancies as a marker of free radical damage to lipids A 9-fold increase in IPs was found in the amniotic fluid of pregnancies with DS fetuses
Early oxidative stress in amniotic fluid of pregnancies with Down syndrome.
Clin Biochem. 2007 Feb;40(3-4):177-80
• Oxidative stress occurs early in a DS pregnancy and appears to “predispose patients to oxidative injury that begins in utero, as a result of gene loading.”
• Oxidative stress begins in-utero in DS. Oxidative stress is implicated in neurodegenerative disorders. • What happens if an infant with DS is exposed to things that worsens their oxidative stress? • What types of exposures could do this?
Glutathione Utilization
Over expressed in Down syndrome
Cysteine (glycine, glutamate)
SOD
H2O2
GPx
L
GST
GSH
GR
Detoxification of drugs and chemicals
Up-regulated by metal exposure
H2O
GSSG
GSH: glutathione GSSG: oxidized glutathione GR: glutathione reductase GPx: glutathione peroxidase
GST: glutathione transferase SOD: superoxide dismutase H2O2: hydrogen peroxide
A major
Notes on glutathione in antioxidant made
the body
Has antiviral properties Removes heavy metals from the body Is needed for detoxification of many chemicals and pharmaceutical drugs Protects against DNA & mitochondrial damage Found to be low in children with DS
IOM 2004
With respect to the hypothesis that there may be a subgroup of children who are genetically more sensitive to the toxic effects of thimerosal (a mercury preservative found in vaccines), the IOM had this to say:
“This hypothesis cannot be excluded by epidemiological data from large population groups that do not show an association between a vaccine and an adverse outcome. Depending upon the frequency of the genetic defect, a rare event caused by genetic susceptibility could be missed even in large study samples.”
Before
Studies showed that the overexpression of SOD and increased oxidative stress occurs in Down syndrome Heavy metals (including mercury) increase oxidative stress and upregulates SOD
2004 IOM declaration
After
Before
Studies showed decreased levels of GSH in DS
•J Pediatr. 2003 May;142(5):583-5. •Am J Hum Genet. 2001 Jul;69(1):88-95.
After
Mercury and other metals deplete GSH in a dosedependent manner
•Immunopharmacol Immunotoxicol. 1993 Mar-Jun;15(2-3):273-90.
2004 IOM declaration
Before
An animal model of DS which showed decreased GSH in hippocampal neurons stated: –“Additional lowering of GSH levels led to enhanced cell death…..Based on these results we suggest that a GSH level which is decreased under a specific threshold by increased consumption, reduced synthesis or lack in precursor contributes to cell loss and neurodegeneration in Down syndrome.”
–Brain Res 1997 Aug 15;765(2):313-8
After
2004 IOM declaration
Before
Animal models and human studies have found cholinergic dysfunction in DS
•Eur J Neurosci. 2000 Sep;12(9):3259-64. •Brain Res. 1994 Sep 26;658(1-2):27-32. •Neurosci Lett. 1997 Feb 7;222(3):183-6.
After
Exposure to mercury can induce cholinergic dysfunction
•J toxicol Sci 1979 Nov;4(4):351-62 •Res Commun Chem Pathol Pharm 1980 Nov;30(2):381-4 •Brain Res Dev Brain Res 1995 Mar 16;85(1):96-109
2004 IOM declaration
Before Other abnormalities that are noted in DS and may be impacted by mercury exposure include:
•Calcium dysregulation •Alterations in glutamate metabolism •Autoimmune disorders •Leukemia 2004 IOM declaration
After
Before
Despite all that was known about both DS and the mechanisms by which mercury induces toxicity… I have been unable to find any study that has investigated the toxic effects of thimerosal in individuals with DS.
After
2004 IOM declaration
Before
After
A 2004 in-vitro animal study investigated thimerosal’s effect on cells suffering from oxidative stress induced by hydrogen peroxide (H2O2); a situation similar to that found in DS:
–The toxicity of thimerosal was, “greatly augmented when the cells suffered oxidative stress induced by (H2O2).” Toxicol In Vitro
2004 Oct;18(5):563-9.
2004 IOM declaration
The BIG Question
• Does this mean mercury exposure in DS individuals causes autism?
– not necessarily
BUT…
Another BIG Question
• Should such a damaging agent be given to a DS population, all of whom are at high risk for neurodegeneration and Alzheimer’s ?
November 9, 2007
U.S. Government conceded a vaccineautism case in the Court of Federal Claims
Vaccinations aggravated an underlying mitochondrial disorder resulting in features of
Media Mitochondrial Puppets disorders are
rare!
Mitochondria in DS
It is extremely well documented that Down syndrome individuals have mitochondrial dysfunction. The nature of this dysfunction is multi-factorial & includes:
Impaired mitochondrial enzyme activities
Cytochrome oxidase (complex IV) Isocitrate dehydrogenase (Krebs cycle enzyme) Decreased protein levels of complex I Decreased gene expression of ATPase6 (effects functioning of complex V)
Mitochondria in DS
Accumulation of toxic free radicals begins in-utero.
Clin Biochem. 2007 Feb;40(3-4):177-80
Studies on fetal DS brain and in fetal DS amniocytes demonstrate mitochondrial dysfunction occurs prior to birth.
J Neural Transm Suppl. 2001;(61):109-16. Mol Cells. 2003 Apr 30;15(2):181-5.
More Questions
• Are vaccines also aggravating the underlying mitochondrial dysfunction in children with DS? • Could this explain the vastly higher incidence of autism among children with DS?
Mitochondria in DS/ASD
• DS mitochondria have a lower mitochondrial membrane potential which, is “underlying the presence of an increasing susceptibility of these organelles to damaging agents”.
– FEBS Lett. 2007 Feb 6;581(3):521-5.
Cristae - the site of the electron transport chain Matrix- the site of the citric acid cycle
CAN THIMEROSAL BE ONE OF THESE “DAMAGING AGENTS”?
Mitochondria and Thimerosal
• Thimerosal induces programmed cell death via the mitochondrial pathway by inducing oxidative stress and depletion of glutathione (GSH).
– Genes Immun 2002 Aug;3(5):270-8
thimerosal
Does dose make the poison
GSH
GSH
GSH
GSH
GS H
thimerosal
GS
H
GSH
GSH
Glutathione (GSH) protects against thimerosal induced apoptosis (cell death)
Genes Immun 2002 Aug;3(5):270-8
GSH
GSH
Cell Death
thimerosal
GSH
SAME DOSE of thimerosal as in previous slide!
Lower GSH in DS leaving cells more vulnerable to toxins
GSH
QuickTimeª and a decompressor are needed to see this picture.
Low glutathione levels can make people more sensitive to DNA damage from a variety of mutagenic environmental exposures.
Illuminating Cancer in DS and Autism
• Cancer in DS and ASD – Children with DS have a 15-20 fold increased occurrence of leukemia. – Individuals with autism have an increased mortality from cancer.
• J Autism Dev Disord 2001 Dec;31(6)569-76
» (this was a small study)
– “We have seen the co-occurrence in families of autism and leukemia”
– NIH Autism Research Network
http://www.autismresearchnetwork.org/AN/IACC/wfAim.aspx?Aim=4
Illuminating Mercury as a Mutagen
• It has been clearly demonstrated that mercury at low levels is a mutagen. • The mutagenic property of mercury has been shown to be causally related to its ability to induce H2O2.
• Environ Mol Mutagen 1998;31(4):352-61
• Therefore: children with low glutathione may be at higher risk for cancer from exposure to heavy metals and other environmental toxins.
Illuminating Metal DNA Damage in DS “The mechanism of carcinogenesis in Down syndrome could be explained by our findings: SODs enhance metal-mediated DNA damage induced by H2O2. We conclude that SODs may increase the frequency of mutations due to oxidative DNA damage in cells, increasing carcinogenic potential.”
» FEBS Lett. 2001 Apr 27;495(3):187-90.
Illuminating Mercury and Leukemia
• Biological mechanisms are consistent with epidemiology studies showing an increased mortality from leukemia with exposure to mercury.
– Age standardized cancer mortality ratios in areas heavily exposed to
• N.Int Arch Occup Environ Health. 2007 Aug;80(8):679-88.
– Cancer mortality in Minamata disease patients exposed to methylmercury through fish diet.
• J Epidemiol. 1996 Sep;6(3):134-8.
Poster Presentation April 9, 2002
American Association for Cancer Research Annual Meeting (2)
Suggested mechanism
Epidemiologica l association of Hep B vaccine and risk of acute lymphocytic leukemia.
Thimerosal
Thimerosa l Hep B vaccine Leukemi a
?
• 167 matched case-control pairs from the Northern California Childhood Leukemia study diagnosed 1995-1999 (3) • OR = 2.6 for 3 or more doses of Hep B vaccines • OR = 5.0 for 3 or more doses of Hep B vaccine during infancy • Thimerosal free Hep B vaccines became available in Fall 1999
– MMWR July 21, 2000 / 49(28); 642,651
Safety of immunization and adverse events following vaccination against hepatitis B.
J Hepatol. 2003;39 Suppl 1:S83-8.
• “…the safety of hepatitis B vaccine has repeatedly been under attack.” • By claims of being associated with: RA, diabetes, MS, “and more recently lymphoblastic leukemia.”
Following the thread of science
Int J Epidemiol. 2005 Oct;34(5)
• “Receiving three or more doses of hepatitis B vaccines during infancy appears to be associated with an increased risk of overall leukemia and ALL among children who were born in or before 1995, but the associations were only of borderline significance.” OR = 1.8 • Thimerosal vs thimerosal free Hep B not considered
Following the thread of science
Int J Epidemiol. 2007 Feb;36(1):110-6
• • • •
Childhood leukemia diagnosed 2003-2004 in France 53.8 % of the cases were 4 years old or less at time of diagnosis Likely that many received thirmerosal free Hep B No association found
1999 thimerosal free Hep B introduced in U.S.
2002 OR = 5.0 for 3 or more in infancy OR = 2.6 for 3 or more case cohort (1995-1999)
2005 OR = 1.8 on or before 1995 OR = 1.08 (after 1995 ) Case cohort (1995-2002)
2007 No association
Glutathione and Mild Infections
Common childhood illness such as ear infections (otitis media) and tonsillitis: serum antioxidant vitamins levels of glutathione (GSH) malondialdehyde - a marker of oxidative stress
Cemek et al. 2005
Vaccination during Mild Illness
• In 1996, JAMA reported it is safe to give MMR to children who presented with mild illnesses such as upper respiratory infection, otitis media and diarrhea.
• (King GE et al., 1996)
– Position supported by the American Academy of Pediatrics (AAP).
Glutathione and Measles
• Viral infections such as measles can decrease GSH and other antioxidants.
• Cemek et al. 2007
• CAN THE MEASLES VACCINE DO THE SAME?
Measles Vaccine and Glutathione
• I could not find a study with respect to measles vaccination and glutathione. • Then how do we know measles vaccine is not causing damage especially when given during a course of mild illness in susceptible children such as children with DS who already have low GSH?
DNA Repair in DS
• Individuals with DS have poor DNA repair mechanisms. • So viral DNA damage can be more problematic in persons with DS.
QuickTimeª and a decompressor are needed to see this picture.
Measles Viral Damage in DS
• “…to gain insight into the relation between Down’s syndrome and leukemia, we have compared the incidence of chromosomal breakage in lymphocytes and a QuickTimeª from children with Down’s syndrome and those from decompressor normal children before and after measles areinfection.” to see this picture. needed • “Patients with Down’s syndrome show more chromosomal breaks after virus infection than do normal control subjects.”
• Pediat Res 7: 582-587 (1973) Higurashi
What We Knew Then…
Chromosomal breaks have been documented in patients receiving attenuated measles vaccines. – “Breakage here was of the same type as seen with the clinical disease.”
• Am J Hum Genet. 1966 Jan;18(1):81-92
Reconfirmed vaccine breakage in both DS and typical children.
Ilyinskikh NN 1981
QuickTimeª and a decompressor are needed to see this picture.
Vaccines and Chromosomal Damage
“…study on the effects of the vaccines on the hereditary material of the inoculated organisms is very meager, although it is directly concerned with human health.”
“…the chromosomes of male mice are comparatively more susceptible to aberration on exposure to measles vaccine than that of the female mice.”
Int J hum Genet, 3(1): 51-58 2003
Of Mice and Men
QuickTimeª and a decompressor are needed to see this picture.
• Clastogenicity of “rubella vaccine in mouse bone marrow, recorded here, is in agreement with the earlier reports on the induction of chromosomal breaks in human embryonic cell cultures.”
• Int J hum Genet, 3(1): 51-58 2003
More Study Needed
• “Further study is essential to unveil the exact mechanism of the clastogenic action of different vaccines on the hereditary materials of the inoculated organisms.” Int J
Genet, 3(1): 51-58 (2003)
• DO UPCOMING VACCINES UNDERGO TESTING ON THE CLASTOGENIC PROPERTIES OF THE VACCINE PRIOR TO PUBLIC RELEASE?
•
sanofi pasteur
Influenza Virus Vaccine, H5N1
HIGHLIGHTS OF PRESCRIBING INFORMATION
http://www.fda.gov/cber/label/h5n1san041707LB.pdf
Safety and effectiveness have NOT been established in pregnant or lactating women, and in pediatric and geriatric populations. Each dose contains 50 ug mercury; you get 2 doses over a 28 day time frame. The clinical trials used an “investigational” vaccine that did NOT contain any mercury.
• “There are no data to assess the concomitant administration of Influenza Virus Vaccine, H5N1, with other vaccines.” • “Influenza Virus Vaccine, H5N1, has NOT been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.”
Think on this • A child with DS who has constitutionally low GSH arrives at the doctors office for her MMR
Think on this
• The child is cleared for vaccination despite having an ear infection
– Ear infections can lower GSH
Think on this
• Measles vaccine can damage DNA – Remember: DS individuals have poor DNA repair mechanisms
QuickTimeª and a decompressor are needed to see this picture.
Think on this
• Instructed to give acetaminophen (Tylenol) to help with pain and/or fever
– Can reduce GSH – Can cause transitory decreases in DNA repair ability
QuickTimeª and a QuickTimeª and a decompressor decompressor are needed to see this picture. are needed to see this picture.
Think on this
• Because this child has DS it is recommended that she have a flu shot. – Flu shots still contain thimerosal
• Can decrease glutathione further
QuickTimeª and a decompressor are needed to see this picture.
Think on this
• Depletion of GSH below a certain threshold has been implicated in the process of neurodegeneration in DS
– Stabel-Burrow et al., 1997
Think on this
• Low GSH is a risk factor for leukemia
– Increased prevalence of leukemia in DS
Bacterial infections, immune overload, and MMR vaccine
Inclusion criteria; hospitalization for:
meningococcal infection septicaemia bacterial meningitis pyogenic arthritis acute osteomyelitis lobar (pneumococcal) pneumonia “Cases in children with additional diagnostic codes indicating an underlying disorder predisposing to bacterial infection, such as immunosuppression, malignancy, cystic fibrosis, congenital heart, defect, or a cerebrospinal fluid shunt were excluded.” Full text available at: http://adc.bmj.com/cgi/reprint/88/3/222
Vaccinated vs. Unvaccinated
• “For the majority of the vaccines in the study, the unvaccinated group was primarily composed of children vaccinated with other vaccines.” • “…using only hospitalization, presumably representing the more severe cases of infectious disease, as our study outcome is a limitation.”
– Childhood Vaccination and Nontargeted Infectious Disease Hospitalization JAMA 2005;294(6):699-705
QuickTimeª and a decompressor are needed to see this picture.
Aluminum containing vaccines and Down syndrome
Facts about aluminum
• In typical healthy people, the gastrointestinal tract excludes greater than 95% of dietary Al.
• Even with normal renal excretion, tissue QuickTimeª and a decompressor are needed to see this picture. accumulation of Al occurs.
Facts about aluminum
• “…infants may be at risk from aluminum toxicity when consuming formula containing > 300 micrograms/L” • Mean aluminum concentrations in milks:
– Breast milk 9.2 ug/L – Soy 534 ug/L – Casein hydrolysate 773ug/L
– J Pediatr Gastroenterol Nutr 1994 Nov; 19(4):377-81
Side note
Breast-feeding reduces risk of:
Acute otitis media Non-specific gastroenteritis Lower respiratory tract infections Atopic dermatitis Asthma (young children) Obesity Type 1 and 2 diabetes Childhood leukemia Sudden infant death syndrome Necrotizing enterocolitis
Evid Rep Technol Assess . 2006 Apr;(134):1-161.
Facts about Aluminum
• The mean aluminum absorption in Alzheimer’s disease (AD) exceeds controls by a factor of 1.64
– Moore PB et al,, 2000
Facts about Aluminum
• The mean aluminum absorption in DS exceeds that of controls by a factor of 6.
– Moore PB et al., 1997
Facts about Aluminum
• “Our findings suggest that it may be prudent to minimize the uptake of Al from the diet of patients who are at high risk of developing Alzheimer-type pathology, in particular DS patients, subjects with a strong family history of AD, and patients who are showing early signs of cognitive decline.”
• Moore PB et al., 1997
Facts about Aluminum
Are DS and AD patients warned about the amount of aluminum used in vaccines? Where are the safety studies on injected aluminum in these populations?
One-size-fits-all?
• Celiac Disease
– Varying prevalence depending on country – 0.3-1% general population – 4.6%-13% in DS
• Hep B Vaccine
– 53.9% of children with untreated celiac are nonresponders to the Hep B vaccine. Park et al 2007 – Response rate of 95% with gluten free diet. Nemes et al 2008
QuickTimeª and a decompressor are needed to see this picture.
• Testing for Celiac in DS
IOM 2004
Epidemiology vs Biological Studies
IOM is correct; you cannot determine subgroups of sensitive persons from large epi studies
The biology of DS is consistent with what the medical literature indicates for increased damage from exposure to mercury, aluminum & viruses. One group of genetically sensitive individuals means it is likely that there are others.
Future directions
» Studies should be conducted by independent researchers with no conflict of interest. » Emphasis should be on biological mechanisms not epidemiology. » DS/autism studies should receive the same level of vigor as those of DS/Alzheimer’s and DS/leukemia.
How confident do I feel that sufficient biological studies have been done on mandatory vaccines?
Thank you for touching my life!
References
• • Carter et al., 2008; Lowenthal et al., 2007; Zafeiriou et al., 2007; Kentet al., 1999 Ma X, Does M, Buffler PA, Wiencke JK. Immunization and risk for childhood leukemia -preliminary results from the Northern California Childhood Leukemia Study, a poster presented at American Association for Cancer Research Annual Meeting, San Francisco, April 9, 2002 Vaccination history and risk of childhood leukaemia.Ma X, Does MB, Metayer C, Russo C, Wong A, Buffler PA.Int J Epidemiol. 2005 Oct;34(5):1100-9 Ramesh C. Choudhury and Pramod K. Sahu Clastogenic Potential of Certain Vaccines on Bone Marrow Cells of Swiss Mice Int J Hum Genet, 3(1): 51-58 (2003)
•
•
Down syndrome, vaccinations and genetic susceptibility to injury
What the research showed
Laurette Janak Autism One May 2009 laurette.janak@verizon.net
Down syndrome, vaccinations and genetic susceptibility to injury
What does the research show?
Laurette Janak Autism One May 2009 Email: laurette.janak@verizon.net
Overview
Description of Down syndrome Down syndrome autism prevalence Down syndrome and mercury sensitivity Down syndrome & mitochondrial dysfunction Cancer and vaccines; is there a connection? Down syndrome and aluminum sensitivity One-size-fits-all philosophy Vaccines and immune overload Scenario for DS injury from vaccines Future directions of study
Common knowledge about DS
• • • • • • • • Characteristic facial features Learning challenges Immune system deficiencies Mitochondrial dysfunction Adverse reaction to some pharmaceuticals High occurrence of celiac disease Diabetes Advanced aging with early development of Alzheimer’s disease or dementia • A 15-20 fold increased risk of leukemia
Genetics of Down syndrome
Extra chromosome 21
Why shed light on DS at an autism conference?
• Medical literature shows autism within the DS population to be in the range of 5-11% (1) • Much is known about the genetics, biochemistry and neurology of DS.
Why shed light on DS at an autism conference?
• Can we learn anything about why the unique genetics of DS increase the risk for the occurrence of autism?
• Can this knowledge then be applied toward understanding an autism risk within the general population?
Subjectivity verses Objectivity
It’s just down syndrome. It’s down syndrome and autism.
Neuroanatomic correlates of autism and stereotypy in children with Down Syndrome (Neuroreport. 2008 Apr 16;19(6):653-6) Included MRIs of 15 children with DS, 15 children with DS-ASD and 22 controls. DSM-IV criteria was used for ASD diagnosis. Aberrant Behavior Checklist (ABC)
Irritability Lethargy Stereotypy (repetitive movements) Hyperactivity Inappropriate speech
Mean ABC scores
Irritabili ty Lethargy Stereotypy Hyperactiv ity Inappropri ate speech Total score
All DS 7.1 9.3 6.9 11.7 1.5 36.4
DS only 2.3 2.5 0.7 4.7 0.1 10.2
DS-ASD 11.9 16.1 13.1 18.7 2.9 62.7
MRI findings
Brain volumes were significantly decreased in DS versus controls. A distinguishing feature of significantly more white matter in the brainstem and cerebellum of DSASD children compared to DS alone.
This pattern resembles that seen in children with autism alone. Increased white matter correlated with the ABC stereotypy subscale score.
Subjectivity verses Objectivity
It’s just down syndrome. It’s down syndrome and autism.
Chicken or the Egg
Autism
Oxidative stress
Early oxidative stress in amniotic fluid of pregnancies with Down syndrome
Clin Biochem. 2007 Feb;40(3-4):177-80
Tested the hypothesis that oxidative stress occurs early in DS pregnancies Measured Isoprostanes (IPs) in the amniotic fluid of DS pregnancies as a marker of free radical damage to lipids A 9-fold increase in IPs was found in the amniotic fluid of pregnancies with DS fetuses
Early oxidative stress in amniotic fluid of pregnancies with Down syndrome.
Clin Biochem. 2007 Feb;40(3-4):177-80
• Oxidative stress occurs early in a DS pregnancy and appears to “predispose patients to oxidative injury that begins in utero, as a result of gene loading.”
• Oxidative stress begins in-utero in DS. Oxidative stress is implicated in neurodegenerative disorders. • What happens if an infant with DS is exposed to things that worsens their oxidative stress? • What types of exposures could do this?
Glutathione Utilization
Over expressed in Down syndrome
Cysteine (glycine, glutamate)
SOD
H2O2
GPx
L
GST
GSH
GR
Detoxification of drugs and chemicals
Up-regulated by metal exposure
H2O
GSSG
GSH: glutathione GSSG: oxidized glutathione GR: glutathione reductase GPx: glutathione peroxidase
GST: glutathione transferase SOD: superoxide dismutase H2O2: hydrogen peroxide
A major
Notes on glutathione in antioxidant made
the body
Has antiviral properties Removes heavy metals from the body Is needed for detoxification of many chemicals and pharmaceutical drugs Protects against DNA & mitochondrial damage Found to be low in children with DS
IOM 2004
With respect to the hypothesis that there may be a subgroup of children who are genetically more sensitive to the toxic effects of thimerosal (a mercury preservative found in vaccines), the IOM had this to say:
“This hypothesis cannot be excluded by epidemiological data from large population groups that do not show an association between a vaccine and an adverse outcome. Depending upon the frequency of the genetic defect, a rare event caused by genetic susceptibility could be missed even in large study samples.”
Before
Studies showed that the overexpression of SOD and increased oxidative stress occurs in Down syndrome Heavy metals (including mercury) increase oxidative stress and upregulates SOD
2004 IOM declaration
After
Before
Studies showed decreased levels of GSH in DS
•J Pediatr. 2003 May;142(5):583-5. •Am J Hum Genet. 2001 Jul;69(1):88-95.
After
Mercury and other metals deplete GSH in a dosedependent manner
•Immunopharmacol Immunotoxicol. 1993 Mar-Jun;15(2-3):273-90.
2004 IOM declaration
Before
An animal model of DS which showed decreased GSH in hippocampal neurons stated: –“Additional lowering of GSH levels led to enhanced cell death…..Based on these results we suggest that a GSH level which is decreased under a specific threshold by increased consumption, reduced synthesis or lack in precursor contributes to cell loss and neurodegeneration in Down syndrome.”
–Brain Res 1997 Aug 15;765(2):313-8
After
2004 IOM declaration
Before
Animal models and human studies have found cholinergic dysfunction in DS
•Eur J Neurosci. 2000 Sep;12(9):3259-64. •Brain Res. 1994 Sep 26;658(1-2):27-32. •Neurosci Lett. 1997 Feb 7;222(3):183-6.
After
Exposure to mercury can induce cholinergic dysfunction
•J toxicol Sci 1979 Nov;4(4):351-62 •Res Commun Chem Pathol Pharm 1980 Nov;30(2):381-4 •Brain Res Dev Brain Res 1995 Mar 16;85(1):96-109
2004 IOM declaration
Before Other abnormalities that are noted in DS and may be impacted by mercury exposure include:
•Calcium dysregulation •Alterations in glutamate metabolism •Autoimmune disorders •Leukemia 2004 IOM declaration
After
Before
Despite all that was known about both DS and the mechanisms by which mercury induces toxicity… I have been unable to find any study that has investigated the toxic effects of thimerosal in individuals with DS.
After
2004 IOM declaration
Before
After
A 2004 in-vitro animal study investigated thimerosal’s effect on cells suffering from oxidative stress induced by hydrogen peroxide (H2O2); a situation similar to that found in DS:
–The toxicity of thimerosal was, “greatly augmented when the cells suffered oxidative stress induced by (H2O2).” Toxicol In Vitro
2004 Oct;18(5):563-9.
2004 IOM declaration
The BIG Question
• Does this mean mercury exposure in DS individuals causes autism?
– not necessarily
BUT…
Another BIG Question
• Should such a damaging agent be given to a DS population, all of whom are at high risk for neurodegeneration and Alzheimer’s ?
November 9, 2007
U.S. Government conceded a vaccineautism case in the Court of Federal Claims
Vaccinations aggravated an underlying mitochondrial disorder resulting in features of
Media Mitochondrial Puppets disorders are
rare!
Mitochondria in DS
It is extremely well documented that Down syndrome individuals have mitochondrial dysfunction. The nature of this dysfunction is multi-factorial & includes:
Impaired mitochondrial enzyme activities
Cytochrome oxidase (complex IV) Isocitrate dehydrogenase (Krebs cycle enzyme) Decreased protein levels of complex I Decreased gene expression of ATPase6 (effects functioning of complex V)
Mitochondria in DS
Accumulation of toxic free radicals begins in-utero.
Clin Biochem. 2007 Feb;40(3-4):177-80
Studies on fetal DS brain and in fetal DS amniocytes demonstrate mitochondrial dysfunction occurs prior to birth.
J Neural Transm Suppl. 2001;(61):109-16. Mol Cells. 2003 Apr 30;15(2):181-5.
More Questions
• Are vaccines also aggravating the underlying mitochondrial dysfunction in children with DS? • Could this explain the vastly higher incidence of autism among children with DS?
Mitochondria in DS/ASD
• DS mitochondria have a lower mitochondrial membrane potential which, is “underlying the presence of an increasing susceptibility of these organelles to damaging agents”.
– FEBS Lett. 2007 Feb 6;581(3):521-5.
Cristae - the site of the electron transport chain Matrix- the site of the citric acid cycle
CAN THIMEROSAL BE ONE OF THESE “DAMAGING AGENTS”?
Mitochondria and Thimerosal
• Thimerosal induces programmed cell death via the mitochondrial pathway by inducing oxidative stress and depletion of glutathione (GSH).
– Genes Immun 2002 Aug;3(5):270-8
thimerosal
Does dose make the poison
GSH
GSH
GSH
GSH
GS H
thimerosal
GS
H
GSH
GSH
Glutathione (GSH) protects against thimerosal induced apoptosis (cell death)
Genes Immun 2002 Aug;3(5):270-8
GSH
GSH
Cell Death
thimerosal
GSH
SAME DOSE of thimerosal as in previous slide!
Lower GSH in DS leaving cells more vulnerable to toxins
GSH
QuickTimeª and a decompressor are needed to see this picture.
Low glutathione levels can make people more sensitive to DNA damage from a variety of mutagenic environmental exposures.
Illuminating Cancer in DS and Autism
• Cancer in DS and ASD – Children with DS have a 15-20 fold increased occurrence of leukemia. – Individuals with autism have an increased mortality from cancer.
• J Autism Dev Disord 2001 Dec;31(6)569-76
» (this was a small study)
– “We have seen the co-occurrence in families of autism and leukemia”
– NIH Autism Research Network
http://www.autismresearchnetwork.org/AN/IACC/wfAim.aspx?Aim=4
Illuminating Mercury as a Mutagen
• It has been clearly demonstrated that mercury at low levels is a mutagen. • The mutagenic property of mercury has been shown to be causally related to its ability to induce H2O2.
• Environ Mol Mutagen 1998;31(4):352-61
• Therefore: children with low glutathione may be at higher risk for cancer from exposure to heavy metals and other environmental toxins.
Illuminating Metal DNA Damage in DS “The mechanism of carcinogenesis in Down syndrome could be explained by our findings: SODs enhance metal-mediated DNA damage induced by H2O2. We conclude that SODs may increase the frequency of mutations due to oxidative DNA damage in cells, increasing carcinogenic potential.”
» FEBS Lett. 2001 Apr 27;495(3):187-90.
Illuminating Mercury and Leukemia
• Biological mechanisms are consistent with epidemiology studies showing an increased mortality from leukemia with exposure to mercury.
– Age standardized cancer mortality ratios in areas heavily exposed to
• N.Int Arch Occup Environ Health. 2007 Aug;80(8):679-88.
– Cancer mortality in Minamata disease patients exposed to methylmercury through fish diet.
• J Epidemiol. 1996 Sep;6(3):134-8.
Poster Presentation April 9, 2002
American Association for Cancer Research Annual Meeting (2)
Suggested mechanism
Epidemiologica l association of Hep B vaccine and risk of acute lymphocytic leukemia.
Thimerosal
Thimerosa l Hep B vaccine Leukemi a
?
• 167 matched case-control pairs from the Northern California Childhood Leukemia study diagnosed 1995-1999 (3) • OR = 2.6 for 3 or more doses of Hep B vaccines • OR = 5.0 for 3 or more doses of Hep B vaccine during infancy • Thimerosal free Hep B vaccines became available in Fall 1999
– MMWR July 21, 2000 / 49(28); 642,651
Safety of immunization and adverse events following vaccination against hepatitis B.
J Hepatol. 2003;39 Suppl 1:S83-8.
• “…the safety of hepatitis B vaccine has repeatedly been under attack.” • By claims of being associated with: RA, diabetes, MS, “and more recently lymphoblastic leukemia.”
Following the thread of science
Int J Epidemiol. 2005 Oct;34(5)
• “Receiving three or more doses of hepatitis B vaccines during infancy appears to be associated with an increased risk of overall leukemia and ALL among children who were born in or before 1995, but the associations were only of borderline significance.” OR = 1.8 • Thimerosal vs thimerosal free Hep B not considered
Following the thread of science
Int J Epidemiol. 2007 Feb;36(1):110-6
• • • •
Childhood leukemia diagnosed 2003-2004 in France 53.8 % of the cases were 4 years old or less at time of diagnosis Likely that many received thirmerosal free Hep B No association found
1999 thimerosal free Hep B introduced in U.S.
2002 OR = 5.0 for 3 or more in infancy OR = 2.6 for 3 or more case cohort (1995-1999)
2005 OR = 1.8 on or before 1995 OR = 1.08 (after 1995 ) Case cohort (1995-2002)
2007 No association
Glutathione and Mild Infections
Common childhood illness such as ear infections (otitis media) and tonsillitis: serum antioxidant vitamins levels of glutathione (GSH) malondialdehyde - a marker of oxidative stress
Cemek et al. 2005
Vaccination during Mild Illness
• In 1996, JAMA reported it is safe to give MMR to children who presented with mild illnesses such as upper respiratory infection, otitis media and diarrhea.
• (King GE et al., 1996)
– Position supported by the American Academy of Pediatrics (AAP).
Glutathione and Measles
• Viral infections such as measles can decrease GSH and other antioxidants.
• Cemek et al. 2007
• CAN THE MEASLES VACCINE DO THE SAME?
Measles Vaccine and Glutathione
• I could not find a study with respect to measles vaccination and glutathione. • Then how do we know measles vaccine is not causing damage especially when given during a course of mild illness in susceptible children such as children with DS who already have low GSH?
DNA Repair in DS
• Individuals with DS have poor DNA repair mechanisms. • So viral DNA damage can be more problematic in persons with DS.
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Measles Viral Damage in DS
• “…to gain insight into the relation between Down’s syndrome and leukemia, we have compared the incidence of chromosomal breakage in lymphocytes and a QuickTimeª from children with Down’s syndrome and those from decompressor normal children before and after measles areinfection.” to see this picture. needed • “Patients with Down’s syndrome show more chromosomal breaks after virus infection than do normal control subjects.”
• Pediat Res 7: 582-587 (1973) Higurashi
What We Knew Then…
Chromosomal breaks have been documented in patients receiving attenuated measles vaccines. – “Breakage here was of the same type as seen with the clinical disease.”
• Am J Hum Genet. 1966 Jan;18(1):81-92
Reconfirmed vaccine breakage in both DS and typical children.
Ilyinskikh NN 1981
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Vaccines and Chromosomal Damage
“…study on the effects of the vaccines on the hereditary material of the inoculated organisms is very meager, although it is directly concerned with human health.”
“…the chromosomes of male mice are comparatively more susceptible to aberration on exposure to measles vaccine than that of the female mice.”
Int J hum Genet, 3(1): 51-58 2003
Of Mice and Men
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• Clastogenicity of “rubella vaccine in mouse bone marrow, recorded here, is in agreement with the earlier reports on the induction of chromosomal breaks in human embryonic cell cultures.”
• Int J hum Genet, 3(1): 51-58 2003
More Study Needed
• “Further study is essential to unveil the exact mechanism of the clastogenic action of different vaccines on the hereditary materials of the inoculated organisms.” Int J
Genet, 3(1): 51-58 (2003)
• DO UPCOMING VACCINES UNDERGO TESTING ON THE CLASTOGENIC PROPERTIES OF THE VACCINE PRIOR TO PUBLIC RELEASE?
•
sanofi pasteur
Influenza Virus Vaccine, H5N1
HIGHLIGHTS OF PRESCRIBING INFORMATION
http://www.fda.gov/cber/label/h5n1san041707LB.pdf
Safety and effectiveness have NOT been established in pregnant or lactating women, and in pediatric and geriatric populations. Each dose contains 50 ug mercury; you get 2 doses over a 28 day time frame. The clinical trials used an “investigational” vaccine that did NOT contain any mercury.
• “There are no data to assess the concomitant administration of Influenza Virus Vaccine, H5N1, with other vaccines.” • “Influenza Virus Vaccine, H5N1, has NOT been evaluated for carcinogenic or mutagenic potential, or for impairment of fertility.”
Think on this • A child with DS who has constitutionally low GSH arrives at the doctors office for her MMR
Think on this
• The child is cleared for vaccination despite having an ear infection
– Ear infections can lower GSH
Think on this
• Measles vaccine can damage DNA – Remember: DS individuals have poor DNA repair mechanisms
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Think on this
• Instructed to give acetaminophen (Tylenol) to help with pain and/or fever
– Can reduce GSH – Can cause transitory decreases in DNA repair ability
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Think on this
• Because this child has DS it is recommended that she have a flu shot. – Flu shots still contain thimerosal
• Can decrease glutathione further
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Think on this
• Depletion of GSH below a certain threshold has been implicated in the process of neurodegeneration in DS
– Stabel-Burrow et al., 1997
Think on this
• Low GSH is a risk factor for leukemia
– Increased prevalence of leukemia in DS
Bacterial infections, immune overload, and MMR vaccine
Inclusion criteria; hospitalization for:
meningococcal infection septicaemia bacterial meningitis pyogenic arthritis acute osteomyelitis lobar (pneumococcal) pneumonia “Cases in children with additional diagnostic codes indicating an underlying disorder predisposing to bacterial infection, such as immunosuppression, malignancy, cystic fibrosis, congenital heart, defect, or a cerebrospinal fluid shunt were excluded.” Full text available at: http://adc.bmj.com/cgi/reprint/88/3/222
Vaccinated vs. Unvaccinated
• “For the majority of the vaccines in the study, the unvaccinated group was primarily composed of children vaccinated with other vaccines.” • “…using only hospitalization, presumably representing the more severe cases of infectious disease, as our study outcome is a limitation.”
– Childhood Vaccination and Nontargeted Infectious Disease Hospitalization JAMA 2005;294(6):699-705
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Aluminum containing vaccines and Down syndrome
Facts about aluminum
• In typical healthy people, the gastrointestinal tract excludes greater than 95% of dietary Al.
• Even with normal renal excretion, tissue QuickTimeª and a decompressor are needed to see this picture. accumulation of Al occurs.
Facts about aluminum
• “…infants may be at risk from aluminum toxicity when consuming formula containing > 300 micrograms/L” • Mean aluminum concentrations in milks:
– Breast milk 9.2 ug/L – Soy 534 ug/L – Casein hydrolysate 773ug/L
– J Pediatr Gastroenterol Nutr 1994 Nov; 19(4):377-81
Side note
Breast-feeding reduces risk of:
Acute otitis media Non-specific gastroenteritis Lower respiratory tract infections Atopic dermatitis Asthma (young children) Obesity Type 1 and 2 diabetes Childhood leukemia Sudden infant death syndrome Necrotizing enterocolitis
Evid Rep Technol Assess . 2006 Apr;(134):1-161.
Facts about Aluminum
• The mean aluminum absorption in Alzheimer’s disease (AD) exceeds controls by a factor of 1.64
– Moore PB et al,, 2000
Facts about Aluminum
• The mean aluminum absorption in DS exceeds that of controls by a factor of 6.
– Moore PB et al., 1997
Facts about Aluminum
• “Our findings suggest that it may be prudent to minimize the uptake of Al from the diet of patients who are at high risk of developing Alzheimer-type pathology, in particular DS patients, subjects with a strong family history of AD, and patients who are showing early signs of cognitive decline.”
• Moore PB et al., 1997
Facts about Aluminum
Are DS and AD patients warned about the amount of aluminum used in vaccines? Where are the safety studies on injected aluminum in these populations?
One-size-fits-all?
• Celiac Disease
– Varying prevalence depending on country – 0.3-1% general population – 4.6%-13% in DS
• Hep B Vaccine
– 53.9% of children with untreated celiac are nonresponders to the Hep B vaccine. Park et al 2007 – Response rate of 95% with gluten free diet. Nemes et al 2008
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• Testing for Celiac in DS
IOM 2004
Epidemiology vs Biological Studies
IOM is correct; you cannot determine subgroups of sensitive persons from large epi studies
The biology of DS is consistent with what the medical literature indicates for increased damage from exposure to mercury, aluminum & viruses. One group of genetically sensitive individuals means it is likely that there are others.
Future directions
» Studies should be conducted by independent researchers with no conflict of interest. » Emphasis should be on biological mechanisms not epidemiology. » DS/autism studies should receive the same level of vigor as those of DS/Alzheimer’s and DS/leukemia.
How confident do I feel that sufficient biological studies have been done on mandatory vaccines?
Thank you for touching my life!
References
• • Carter et al., 2008; Lowenthal et al., 2007; Zafeiriou et al., 2007; Kentet al., 1999 Ma X, Does M, Buffler PA, Wiencke JK. Immunization and risk for childhood leukemia -preliminary results from the Northern California Childhood Leukemia Study, a poster presented at American Association for Cancer Research Annual Meeting, San Francisco, April 9, 2002 Vaccination history and risk of childhood leukaemia.Ma X, Does MB, Metayer C, Russo C, Wong A, Buffler PA.Int J Epidemiol. 2005 Oct;34(5):1100-9 Ramesh C. Choudhury and Pramod K. Sahu Clastogenic Potential of Certain Vaccines on Bone Marrow Cells of Swiss Mice Int J Hum Genet, 3(1): 51-58 (2003)
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Down syndrome, vaccinations and genetic susceptibility to injury
What the research showed
Laurette Janak Autism One May 2009 laurette.janak@verizon.net
