NOTE: Dr. Shaw spoke on Sat. Nov. 7th at
SPEC Hall, Vancouver - we will have a video of his presentation posted
soon.
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Journal of Neuromolecular Medicine, 2007, Petrik and Shaw
Journal of Inogranic Biochemistry, 2009 in press, Shaw and Petrik
Key points:GWS: epidemiology link to AVA vaccine,
our literature search and what we found/didn't find
our experiments and interpretations.
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Neurodegenerative
Diseases: Neurotoxins as Sufficient Etiologic Agents
Christopher A. Shaw1, 2, 4 Contact Information and Gunter U. Huglinger3
(1) Department of Ophthalmology, University of British Columbia,
Vancouver, BC, Canada
(2) Department of Experimental Medicine and the Neuroscience Program,
University of British Columbia, Vancouver, BC, Canada
(3) Experimental Neurology, Philipps University, 35033 Marburg, Germany
(4) Neural Dynamics Research Group, 828 W. 10th Ave, V5Z 1L8 Vancouver,
BC, Canada
Received: 9 June 2007 Accepted: 9 October 2007 Published online: 6
November 2007
Abstract
A dominant paradigm in neurological disease research is that the
primary etiological factors for diseases such as Alzheimer?s (AD),
Parkinson?s (PD), and amyotrophic lateral sclerosis (ALS) are genetic.
Opposed to this perspective are the clear observations from
epidemiology that purely genetic casual factors account for a
relatively small fraction of all cases. Many who support a genetic
etiology for neurological disease take the view that while the
percentages may be relatively small, these numbers will rise in the
future with the inevitable discoveries of additional genetic mutations.
The follow up argument is that even if the last is not true, the events
triggered by the aberrant genes identified so far will be shown to
impact the same neuronal cell death pathways as those activated by
environmental factors that trigger most sporadic disease cases. In this
article we present a countervailing view that environmental neurotoxins
may be the sole sufficient factor in at least three neurological
disease clusters. For each, neurotoxins have been isolated and
characterized that, at least in animal models, faithfully reproduce
each disorder without the need for genetic co-factors. Based on these
data, we will propose a set of principles that would enable any
potential toxin to be evaluated as an etiological factor in a given
neurodegenerative disease. Finally, we will attempt to put
environmental toxins into the context of possible
genetically-determined susceptibility.
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Aluminum
hydroxide injections lead to motor deficits and motor neuron
degeneration
Christopher A. Shawa, b, c, Corresponding Author Contact Information,
E-mail The Corresponding Author and Michael S. Petrikc
aDepartments of Ophthalmology and Visual Sciences, University of
British Columbia, Vancouver, British Columbia, Canada
bExperimental Medicine, University of British Columbia, Vancouver,
British Columbia, Canada
cGraduate Program in Neuroscience, University of British Columbia,
Vancouver, British Columbia, Canada
Received 17 April 2009;
revised 26 May 2009;
accepted 29 May 2009.
Available online 20 August 2009.
Abstract
Gulf
War Syndrome is a multi-system disorder afflicting many veterans of
Western armies in the 1990?1991 Gulf War. A number of those afflicted
may show neurological deficits including various cognitive dysfunctions
and motor neuron disease, the latter expression virtually
indistinguishable from classical amyotrophic lateral sclerosis (ALS)
except for the age of onset. This ALS ?cluster? represents the second
such ALS cluster described in the literature to date. Possible causes
of GWS include several of the adjuvants in the anthrax vaccine and
others. The most likely culprit appears to be aluminum hydroxide. In an
initial series of experiments, we examined the potential toxicity of
aluminum hydroxide in male, outbred CD-1 mice injected subcutaneously
in two equivalent-to-human doses. After sacrifice, spinal cord and
motor cortex samples were examined by immunohistochemistry.
Aluminum-treated mice showed significantly increased apoptosis of motor
neurons and increases in reactive astrocytes and microglial
proliferation within the spinal cord and cortex. Morin stain detected
the presence of aluminum in the cytoplasm of motor neurons with some
neurons also testing positive for the presence of hyper-phosphorylated
tau protein, a pathological hallmark of various neurological diseases,
including Alzheimer?s disease and frontotemporal dementia. A second
series of experiments was conducted on mice injected with six doses of
aluminum hydroxide. Behavioural analyses in these mice revealed
significant impairments in a number of motor functions as well as
diminished spatial memory capacity. The demonstrated neurotoxicity of
aluminum hydroxide and its relative ubiquity as an adjuvant suggest
that greater scrutiny by the scientific community is warranted.
Keywords: Aluminum hydroxide; Adjuvant; Neurotoxicity; Gulf War
Syndrome; Amyotrophic lateral sclerosis
Article Outline
1. Introduction
2. Experimental procedures
2.1. Experimental animals
2.2. Adjuvants
2.2.1. Doses
2.3. Behavioural tests
2.4. Histological measurements (Experiment 1)
2.4.1. NeuN and active caspase-3
2.4.2. Choline acetyltransferase (ChAT) and Glial fibrillary acidic
protein (GFAP)
2.4.3. Iba-1
2.4.4. Morin (3,5,7,2′,4′-pentahydroxyflavone, BDH)
2.4.5. Staining for hyper-phosphorylated tau protein
2.5. Microscopy
2.6. Criteria for determination and quantification of labeled cells
2.7. Statistics
3. Results
4. Discussion
5. Abbreviations
Animal ethics approval
Conflict of interest
Acknowledgements
References
Thumbnail image
Fig.
1. Impact of aluminum hydroxide on different levels of spinal cord
(SC). (A and B) ChAT labeling in cervical and thoracic cords,
respectively. (C and D) Normalized cell counts for GFAP labeling of
reactive astrocytes in cervical and thoracic spinal cord, respectively.
In cervical cord, the aluminum hydroxide treated groups showed higher
levels of GFAP labeling with the aluminum alone group achieving
statistical significance. (E) Iba-1 fluorescent labeling in the ventral
horn of mouse lumbar cord showed that aluminum-injected mice had
significantly increased numbers of activated microglia. Data are means
? S.E.M. ***p < 0.001, one-way ANOVA.
View Within Article
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Long-term
persistence of vaccine-derived aluminum hydroxide is associated with
chronic cognitive dysfunction
Maryline
Couettea, c, Marie-Fran?oise Boissea, c, Patrick Maisona, d, 2, Pierre
Brugierese, Pierre Cesaroa, c, Xavier Chevalierf, Romain K. Gherardib,
g, h, Anne-Catherine Bachoud-Levia, c, 1 and Fran?ois-J?r?me Authierb,
g, h, 1, Corresponding Author Contact Information, E-mail The
Corresponding Author
aINSERM, Unite U955, Team 1, Creteil F-94010, France
bINSERM, Unite U955, Team 10, Creteil F-94010, France
cUniversite
Paris 12, Faculte de Medecine, AP-HP, Groupe Henri-Mondor
Albert-Chenevier, Department of Neurology, Creteil F-94010, France
dUniversite
Paris 12, Faculte de Medecine, AP-HP, Groupe Henri-Mondor
Albert-Chenevier, Department of Biostatistics, Creteil F-94010, France
eUniversite
Paris 12, Faculte de Medecine, AP-HP, Groupe Henri-Mondor
Albert-Chenevier, Department of Neuroradiology, Creteil F-94010, France
fUniversite
Paris 12, Faculte de Medecine, AP-HP, Groupe Henri-Mondor
Albert-Chenevier, Department of Rheumatology, Creteil F-94010, France
gUniversite
Paris 12, Faculte de Medecine, AP-HP, Groupe Henri-Mondor
Albert-Chenevier, Department of Histology, Creteil F-94010, France
hReference Center for Neuromuscular Diseases
Garches-Necker-Mondor-Hendaye, Creteil F-94010, France
Received 25 March 2009;
revised 26 June 2009;
accepted 1 July 2009.
Available online 20 August 2009.
Abstract
Macrophagic
myofasciitis (MMF) is an emerging condition, characterized by specific
muscle lesions assessing long-term persistence of aluminum hydroxide
within macrophages at the site of previous immunization. Affected
patients mainly complain of arthromyalgias, chronic fatigue, and
cognitive difficulties. We designed a comprehensive battery of
neuropsychological tests to prospectively delineate MMF-associated
cognitive dysfunction (MACD). Compared to control patients with
arthritis and chronic pain, MMF patients had pronounced and specific
cognitive impairment. MACD mainly affected (i) both visual and verbal
memory; (ii) executive functions, including attention, working memory,
and planning; and (iii) left ear extinction at dichotic listening test.
Cognitive deficits did not correlate with pain, fatigue, depression, or
disease duration. Pathophysiological mechanisms underlying MACD remain
to be determined. In conclusion, long-term persistence of
vaccine-derived aluminum hydroxide within the body assessed by MMF is
associated with cognitive dysfunction, not solely due to chronic pain,
fatigue and depression.
Keywords: Aluminum; Macrophagic myofasciitis; Vaccine; Cognitive
dysfunction; Myopathy
Article Outline
1. Introduction
2. Patients and methods
2.1. Global design of the study
2.2. Participants
2.3. Cognitive assessment
2.3.1. Exploratory analysis
2.3.2. Tests used for prospective analysis
2.3.3. Achievement of neuropsychological profiles
2.4. Statistical analyses
3. Results
3.1. MMF patients: medical history and clinical features (Table 1)
3.2. Case-control study: evidence for specific cognitive dysfunction in
association with MMF
3.3. Cohort study: characterization of MMF-associated cognitive
dysfunction (MACD)
4. Discussion
5. Abbreviations
Disclosure
Acknowledgements
Appendix A. Supplementary material
References
Contact Info:
http://www.neuroscience.ubc.ca/shaw.htm
