ALS Abstracts 3

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Is dental amalgam safe for humans? The opinion of the scientific committee of the European Commission.
            (Mutter, 2011) Download
It was claimed by the Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR)) in a report to the EU-Commission that "....no risks of adverse systemic effects exist and the current use of dental amalgam does not pose a risk of systemic disease...". SCENIHR disregarded the toxicology of mercury and did not include most important scientific studies in their review. But the real scientific data show that:(a) Dental amalgam is by far the main source of human total mercury body burden. This is proven by autopsy studies which found 2-12 times more mercury in body tissues of individuals with dental amalgam. Autopsy studies are the most valuable and most important studies for examining the amalgam-caused mercury body burden.(b) These autopsy studies have shown consistently that many individuals with amalgam have toxic levels of mercury in their brains or kidneys.(c) There is no correlation between mercury levels in blood or urine, and the levels in body tissues or the severity of clinical symptoms. SCENIHR only relied on levels in urine or blood.(d) The half-life of mercury in the brain can last from several years to decades, thus mercury accumulates over time of amalgam exposure in body tissues to toxic levels. However, SCENIHR state that the half-life of mercury in the body is only "20-90 days".(e) Mercury vapor is about ten times more toxic than lead on human neurons and with synergistic toxicity to other metals.(f) Most studies cited by SCENIHR which conclude that amalgam fillings are safe have severe methodical flaws.

Sjuk av amalgam
            (Redhe, 1991) Download
Detta fall har redovisats i min tidigare bok. Orsaken till att jag tar upp det igen är att det har viss principiell betydelse. Man diskuterar huruvida amalgam kan orsaka obotliga, livshotande sjukdomar. Den här fallbeskrivningen kan betraktas som ett inlägg i den debatten.


 

Recovery from amyotrophic lateral sclerosis and from allergy after removal of dental amalgam fillings.
            (Redhe and Pleva, 1994) Download
In the debate about the possible risks with mercury released from dental amalgam fillings, the following two patient cases are a contribution to this case.

Amyotrophic lateral sclerosis after accidental injection of mercury.
            (Schwarz et al., 1996) Download
We describe a case of amyotrophic lateral sclerosis after accidental injection of mercury. While shaking a mercury thermometer, a female nurse plunged it into her left hand. Three and a half years after mercury infiltration, the 38 year old woman was admitted with progressive weakness of the legs. we performed a chelation treatment with dimercaptosuccinic acid. Chelation treatment, as in this patient, has never been successful in amyotrophic lateral sclerosis.

Exposure to environmental toxicants and pathogenesis of amyotrophic lateral sclerosis: state of the art and research perspectives.
            (Trojsi et al., 2013) Download
There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease, is caused by gene--environment interactions. In fact, given that only about 10% of all ALS diagnosis has a genetic basis, gene-environmental interaction may give account for the remaining percentage of cases. However, relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron degeneration leading to ALS, although exposure to chemicals--including lead and pesticides-agricultural environments, smoking, intense physical activity, trauma and electromagnetic fields have been associated with an increased risk of ALS. This review provides an overview of our current knowledge of potential toxic etiologies of ALS with emphasis on the role of cyanobacteria, heavy metals and pesticides as potential risk factors for developing ALS. We will summarize the most recent evidence from epidemiological studies and experimental findings from animal and cellular models, revealing that potential causal links between environmental toxicants and ALS pathogenesis have not been fully ascertained, thus justifying the need for further research.


 

Mitochondrial bioenergetics during the initiation of mercuric chloride-induced renal injury. I. Direct effects of in vitro mercuric chloride on renal mitochondrial function.
            (Weinberg et al., 1982a) Download
Increasing data suggest that mitochondrial dysfunction may be an important early component of nephrotoxin-induced changes in renal cell function and viability. This study was designed to obtain more detailed information about the effects on several basic bioenergetic parameters of the direct interaction of Hg2+ with renal cortical mitochondria in vitro as a necessary prelude to studies of mitochondrial functional changes after treatment with mercuric chloride in vivo. Beginning at a threshold level of 2 nmol of Hg2+/mg of mitochondrial protein, Hg2+ induced marked stimulation of State 4 respiration, mild inhibition of State 3 respiration, and 2,4-dinitrophenol uncoupled respiration, a striking increase in atractyloside-insensitive ADP uptake and stimulation of both basal- and Mg2+-activated oligomycin-sensitive mitochondrial ATPase activity. These effects of Hg2+ could be prevented and reversed by the sulfhydryl reagent dithioerythritol and by albumin but were not affected by Mg2+. Detailed studies on the addition of HgCl2 to the preparation at different stages of the mitochondrial isolation procedure demonstrated that the presence of other proteins decreased mitochondrial Hg2+ binding, that the Hg2+ was not readily washed off the mitochondria by nonprotein-containing solutions, and that prolonged exposure of mitochondria to Hg2+ during the isolation procedure did not markedly alter its functional effects or their reversibility as assessed on the final mitochondrial preparation. These data provide an important basis for critically assessing the changes in function of mitochondria isolated after in vivo treatment with mercuric chloride.

Mitochondrial bioenergetics during the initiation of mercuric chloride-induced renal injury. II. Functional alterations of renal cortical mitochondria isolated after mercuric chloride treatment.
            (Weinberg et al., 1982b) Download
The mitochondrial functional defects occurring in the early stages of nephrotoxic renal injury secondary to mercuric chloride have been characterized. No loss of cellular integrity or major mitochondrial structural alterations occurred within the first 3 h after a subcutaneous injection of 5 mg/kg of HgCl2. At 3 h, levels of Hg2+ in renal cortex and isolated renal cortical mitochondria were 1.87 and 0.72 nmol/mg of protein, respectively. Much evidence suggested that this Hg2+ had reached the mitochondria in situ and not during the isolation process. Mitochondria isolated beginning 1 h after treatment with HgCl2 showed depressed ADP uptake. At 2 h, inhibitions of State 3 and 2,4-dinitrophenol uncoupled respiration were detected. Inhibition of 2,4-dinitrophenol-activated mitochondrial ATPase activity was present when measured on mitochondria isolated at 3 h. These effects were not reversed by 2 mM dithioerythritol, 50 mg/ml of albumin or 5 mM MgCl2. Analysis of the data in the context of information available on the in vitro effects of HgCl2 (Weinberg, J. M., Harding, P. G., and Humes, H. D. (1982) J. Biol. Chem. 257, 60-67) indicated that the mitochondrial functional effects could not be attributed to interaction of the mitochondria with Hg2+ during their isolation. These studies implicate compromised mitochondrial bioenergetic function as one of the earliest intracellular effects of Hg2+ in the production of nephrotoxicity but suggest that the intracellular process involves events in addition to those seen with direct exposure of mitochondria to Hg2+ in vitro.

Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes.
            (Yin et al., 2007) Download
The neurotoxicity of high levels of methylmercury (MeHg) is well established both in humans and experimental animals. Astrocytes accumulate MeHg and play a prominent role in mediating MeHg toxicity in the central nervous system (CNS). Although the precise mechanisms of MeHg neurotoxicity are ill-defined, oxidative stress and altered mitochondrial and cell membrane permeability appear to be critical factors in its pathogenesis. The present study examined the effects of MeHg treatment on oxidative injury, mitochondrial inner membrane potential, glutamine uptake and expression of glutamine transporters in primary astrocyte cultures. MeHg caused a significant increase in F(2)-isoprostanes (F(2)-IsoPs), lipid peroxidation biomarkers of oxidative damage, in astrocyte cultures treated with 5 or 10 microM MeHg for 1 or 6 h. Consistent with this observation, MeHg induced a concentration-dependant reduction in the inner mitochondrial membrane potential (DeltaPsi(m)), as assessed by the potentiometric dye, tetramethylrhodamine ethyl ester (TMRE). Our results demonstrate that DeltaPsi(m) is a very sensitive endpoint for MeHg toxicity, since significant reductions were observed after only 1 h exposure to concentrations of MeHg as low as 1 microM. MeHg pretreatment (1, 5 and 10 microM) for 30 min also inhibited the net uptake of glutamine ((3)H-glutamine) measured at 1 min and 5 min. Expression of the mRNA coding the glutamine transporters, SNAT3/SN1 and ASCT2, was inhibited only at the highest (10 microM) MeHg concentration, suggesting that the reduction in glutamine uptake observed after 30 min treatment with lower concentrations of MeHg (1 and 5 microM) was not due to inhibition of transcription. Taken together, these studies demonstrate that MeHg exposure is associated with increased mitochondrial membrane permeability, alterations in glutamine/glutamate cycling, increased ROS formation and consequent oxidative injury. Ultimately, MeHg initiates multiple additive or synergistic disruptive mechanisms that lead to cellular dysfunction and cell death.


 

ALS Untangled No. 20: the Deanna protocol.
            (ALSUntangled et al., 2013) Download
The Christian Broadcasting Network (CBN) aired a story in November 2012 giving anecdotal informa- tion about the ‘Deanna Protocol’, a regimen of nutri- tional supplementation that has been proposed as a treatment for amyotrophic lateral sclerosis (ALS) (1). Vincent Tedone, a retired orthopedic surgeon, created the protocol for his daughter, Deanna, when she was diagnosed with ALS.

Metabolic therapy with Deanna Protocol supplementation delays disease progression and extends survival in amyotrophic lateral sclerosis (ALS) mouse model.
            (Ari et al., 2014) Download
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and eventual death from respiratory failure. There is currently no cure or effective treatment for ALS. Besides motor neuron degeneration, ALS is associated with impaired energy metabolism, which is pathophysiologically linked to mitochondrial dysfunction and glutamate excitotoxicity. The Deanna Protocol (DP) is a metabolic therapy that has been reported to alleviate symptoms in patients with ALS. In this study we hypothesized that alternative fuels in the form of TCA cycle intermediates, specifically arginine-alpha-ketoglutarate (AAKG), the main ingredient of the DP, and the ketogenic diet (KD), would increase motor function and survival in a mouse model of ALS (SOD1-G93A). ALS mice were fed standard rodent diet (SD), KD, or either diets containing a metabolic therapy of the primary ingredients of the DP consisting of AAKG, gamma-aminobutyric acid, Coenzyme Q10, and medium chain triglyceride high in caprylic triglyceride. Assessment of ALS-like pathology was performed using a pre-defined criteria for neurological score, accelerated rotarod test, paw grip endurance test, and grip strength test. Blood glucose, blood beta-hydroxybutyrate, and body weight were also monitored. SD+DP-fed mice exhibited improved neurological score from age 116 to 136 days compared to control mice. KD-fed mice exhibited better motor performance on all motor function tests at 15 and 16 weeks of age compared to controls. SD+DP and KD+DP therapies significantly extended survival time of SOD1-G93A mice by 7.5% (p = 0.001) and 4.2% (p = 0.006), respectively. Sixty-three percent of mice in the KD+DP and 72.7% of the SD+DP group lived past 125 days, while only 9% of the control animals survived past that point. Targeting energy metabolism with metabolic therapy produces a therapeutic effect in ALS mice which may prolong survival and quality of life in ALS patients.

Deanna Protocol Description 2016
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References

ALSUntangled, Group, et al. (2013), ‘ALS Untangled No. 20: the Deanna protocol.’, Amyotroph Lateral Scler Frontotemporal Degener, 14 (4), 319-23. PubMed: 23638638
Ari, C, et al. (2014), ‘Metabolic therapy with Deanna Protocol supplementation delays disease progression and extends survival in amyotrophic lateral sclerosis (ALS) mouse model.’, PLoS One, 9 (7), e103526. PubMed: 25061944
Mutter, J (2011), ‘Is dental amalgam safe for humans? The opinion of the scientific committee of the European Commission.’, J Occup Med Toxicol, 6 (1), 2. PubMed: 21232090
Redhe, O (1991), ‘Sjuk av amalgam’, Frejavagen, 33 PubMed:
Redhe, O and J Pleva (1994), ‘Recovery from amyotrophic lateral sclerosis and from allergy after removal of dental amalgam fillings.’, Int J Risk Saf Med, 4 (3), 229-36. PubMed: 23511261
Schwarz, S, et al. (1996), ‘Amyotrophic lateral sclerosis after accidental injection of mercury.’, J Neurol Neurosurg Psychiatry, 60 (6), 698. PubMed: 8648348
Trojsi, F, MR Monsurrò, and G Tedeschi (2013), ‘Exposure to environmental toxicants and pathogenesis of amyotrophic lateral sclerosis: state of the art and research perspectives.’, Int J Mol Sci, 14 (8), 15286-311. PubMed: 23887652
Weinberg, JM, PG Harding, and HD Humes (1982a), ‘Mitochondrial bioenergetics during the initiation of mercuric chloride-induced renal injury. I. Direct effects of in vitro mercuric chloride on renal mitochondrial function.’, J Biol Chem, 257 (1), 60-67. PubMed: 6458618
——— (1982b), ‘Mitochondrial bioenergetics during the initiation of mercuric chloride-induced renal injury. II. Functional alterations of renal cortical mitochondria isolated after mercuric chloride treatment.’, J Biol Chem, 257 (1), 68-74. PubMed: 6458619
Yin, Z, et al. (2007), ‘Methylmercury induces oxidative injury, alterations in permeability and glutamine transport in cultured astrocytes.’, Brain Res, 1131 (1), 1-10. PubMed: 17182013