Stephanie Seneff, Robert M. Davidson and Jingjing Liu This article is 27 pages long and has 121 references November 7, 2012; 14; pp. 2227-2253 BACKGROUND FROM DAN MURPHY: FROM Salway, Metabolism at a Glance, Blackwell, 2004: Glutathione is a tripeptide that is formed from glutamate, cysteine and glycine. Glutathione protects cells against oxidative damage. Glutathione conjugates with toxins and drug metabolites to form water-soluble products for excretion. FROM Dan, an over simplication: Vaccine producers have a problem. Using a weakened live virus increases risk of giving the person the disease. Using a completely dead virus does not work very well unless the vaccine is coupled with something that ramps up the immunological response, an adjuvant, such as mercury or aluminum. The problem is that these adjuvants, like mercury or aluminum are extremely toxic to the nervous system, especially the developing nervous system of a child. This is further complicated by the fact that the blood-brain barrier is not fully complete until after many such vaccines are administered (around age 2 or so). KEY POINTS FROM THIS ARTICLE: 1) The Vaccine Adverse Event Reporting System (VAERS) is a surveillance system implemented by the U.S. government, which allows doctors and/or patients to report any adverse reactions observed in association with vaccines. 2) Autism (ASD) is a condition characterized by impaired cognitive and social skills, associated with compromised immune function. The incidence is alarmingly on the rise, and environmental factors are increasingly suspected to play a role. 3) This paper investigates word frequency patterns in the U.S. Centers for Disease Control (CDC) VAERS database. Results provide strong evidence supporting a link between autism and the aluminum in vaccines. A literature review showing toxicity of aluminum in human physiology offers further support. [Key Point] 4) Mentions of autism in VAERS increased steadily at the end of the last century, during a period when mercury was being phased out, while aluminum adjuvant burden was being increased. [Key Point] 5) After 2000, vaccines have been associated with increased cellulitis, seizure, depression, fatigue, pain and death, which are also significantly associated with aluminum-containing vaccines. 6) These authors propose that children with the autism diagnosis are especially vulnerable to toxic metals such as aluminum and mercury due to insufficient serum sulfate and glutathione. [Key Point] 7) A strong correlation between autism and the MMR (Measles, Mumps, Rubella) vaccine is also observed, which may be partially explained via an increased sensitivity to acetaminophen given to control fever. [Key Point] 8) While it has been suggested that the observed increase in [Autism] rates may be due mainly to a change in diagnosis criteria, the actual criteria have changed very little from 1943. 9) The fact that ASD rates have been rapidly increasing over the last two decades strongly points to an environmental component. [Key Point] 10) The ASD community has maintained a long-standing conviction that vaccination plays a causative role in ASD, an idea that has been vehemently denied by the vaccine industry. 11) A study published in 2011 has confirmed a positive correlation between the proportion of children who received vaccinations in each state over the interval from 2001 to 2007 and the incidence of autism or speech and language impairment. For each 1% increase in vaccination rate, 680 additional children were diagnosed with autism or speech delay. [Key Point] 12) In 2012, we proposed that a causative factor in autism is an inadequate supply of cholesterol sulfate, both in utero and postnatally. Cholesterol sulfate synthesis in the skin is catalyzed by sun exposure. We hypothesized that autism may be induced by a combination of inadequate dietary sulfur and insufficient sun exposure to the skin, for both the mother and the child. [Key Point] [We have reviewed a number of studies linking low glutathione levels to autism: glutathione contains the sulfur containing amino acid cysteine] [We have reviewed a number of studies linking low vitamin D levels to autism: insufficient sun exposure causes low levels of vitamin D] 13) In autism there is a consistent deficiency in glutathione, an important sulfurbased antioxidant that plays a role in detoxifying aluminum. [Key Point] 14) Cysteine is the rate-limiting amino acid in the synthesis of glutathione and sulfate. 15) ASD individuals have reduced levels of glutathione, cysteine, and sulfate, impeding the detoxification and excretion of mercury. 16) Glutathione and sulfate are essential for the detoxification of xenobiotics and commonly administered drugs like acetaminophen in the liver. [Glutathione attaches to toxins so that the body can eliminate them. Acetaminophen 3 {like in Tylenol} is a toxin and depletes body stores of glutathione during detoxification, leaving inadequate levels of glutathione to detoxify toxins metals, like mercury and/or aluminum, etc. in vaccines] 17) Cholesterol sulfate deficiency provides an explanation for the link between autism, acetaminophen, asthma, and eczema. 18) Many children with autism have a low amount of serum glutathione. 19) Increased use of antibiotics leads to an alteration in gut flora which impairs the ability to detoxify toxic metals like mercury. 20) Vitamin D deficiency has been hypothesized to be a risk factor for autism. The over-zealous application of sunscreen is strongly implicated in autism, not only because sunscreen interferes with the production of vitamin D3 and cholesterol sulfate but also because it often contains aluminum, particularly the high Sun Protection Factor (SPF) sunblock products. [Wow] 21) Aluminum, due in part to its +3 ionic charge, is highly toxic to biological systems. [Key Point] There are no known life forms that utilize aluminum in any biological systems. 22) Autistic children accumulate aluminum that would almost certainly interfere with neuron function through these mechanisms: A)) Absorption through the skin because of poorly developed epidermis barrier. B)) As a consequence of their serum sulfate deficiency that leads to an impaired ability to dispose of aluminum. C)) Due to their increased permeability of the blood brain barrier. 23) It has recently been proposed that aluminum, commonly used in vaccines as an adjuvant, may be the most significant factor in adverse reactions, and, furthermore, that the nervous system is especially vulnerable to aluminum toxicity. 24) Vaccine clinical trials often include aluminum in the placebo, at the same or greater concentrations than the amount found in the vaccine. [This is crazy] 25) A highly informative study [Aluminum and Alzheimer’s disease: after a century of controversy, is there a plausible link? Journal of Alzheimers Disease: 2011] reviews the relationship between aluminum toxicity and Alzheimer’s disease. It also discusses issues the aluminum burden in children’s vaccines. It was pointed out that children today receive a cumulative aluminum burden from vaccines that may exceed the FDA limit by a factor of 50. [Wow!] 26) The vaccine industry has a difficult task in designing vaccines that are both safe and effective. The use of weakened but live pathogens can lead to vaccineinduced disease in children with an impaired immune system, yet debris from dead pathogens may not always cause a sufficient reaction to induce the required for protection against future exposure. Therefore the vaccine industry increasesimmunologic success in using vaccines with dead pathogens by adding adjuvants such as [very toxic] aluminum. 27) Also, adding aluminum or mercury to vaccines increases the stability of the antigen for long-term storage. 28) Glass contains aluminum oxide. When mercury in vaccines began to be phased out in the late 1990s, they began storing them in glass vials, yet aluminum can be leached out of the glass vial and the rubber stopper during storage. 29) Aluminum is one of the most common elements on Earth, yet no biological system has yet found a use for it. Its +3 charge makes it extremely destructive in water-based biological systems. 30) Aluminum is a known neurotoxin and there is no safe level. The central nervous system is particularly susceptible to the deleterious effects of aluminum. 31) Exposure to low concentrations of aluminum sulfate may be associated with Alzheimer’s disease. [This is the stuff municipalities put in water to filter it; aluminum sulfate causes debris to clump for easy removal, but aluminum sulfate residuals remain. Aluminum sulfate is often called alum.] 32) Aluminum exposure induces significant reactive oxygen species (ROS), even more than mercury (7X more) or lead (3X more). [Wow] 33) Aluminum damages the mitochondria, causing impaired ATP synthesis and excess production of reactive oxygen species. 34) Mercury [and aluminum] has a great predilection for bonding to reduced sulfur atoms, especially those in thiol-containing molecules such as glutathione, cysteine, homocysteine, and albumin. 35) Methylmercury is eliminated by binding to bio-organic sulfates. Newborns are much more susceptible to mercury toxicity than adults. 36) Impaired disposal of mercury and aluminum is due to insufficient glutathione. 37) Mercury builds up to toxic levels and further reduces sulfate bioavailability in the child with autism. 38) The measles, mumps, and rubella (MMR) vaccine may be contributing to the increased prevalence of autism. Unlike many vaccines, MMR contains neither thimerosal nor aluminum. MMR is often administered simultaneously with DTaP, an aluminum-containing vaccine. The synergistic and cumulative effects of multiple vaccines would likely lead to nonlinear enhancement of adverse events. 39) In the U.S., thimerosal still appears in several vaccinations given to young children, including Hep-B and HiB Titer. Aluminum is present in several of the vaccines, for example, Hep-B, PREVNAR, all of the DTaP formulations, and H1N1 flu vaccine multidose vials. 40) Recent published studies seriously addresses the question of the safety of aluminum adjuvants in vaccines, pointing out the neurotoxicity of aluminum. 41) There is a three-fold increased risk to autism associated with neonatal administration of Hepatitis B (Hep-B) vaccine prior to 1999, compared with either no vaccination or a delay until after the first month of age. Notably, Hep-B contains both aluminum and mercury. 42) Several researchers have reported increased frequencies of either sudden death or other health crises such as anaphylaxis or cardiorespiratory problems in association with vaccines. 43) Adults given the Hepatitis B vaccine show a significant number of adverse reactions. 44) Adults show profound adverse reaction to multiple vaccinations containing aluminum, including debilitating muscle pain and weakness associated with chronic fatigue syndrome and myofascitis. 45) MMR is significantly more likely to be associated with autism. MMR contains neither aluminum nor mercury. An interesting theory relating the MMR vaccine to ASD involves a proposed toxic reaction to the acetaminophen (paracetamol) administered to control fever following vaccination. [Key Point] 46) Acetaminophen may mediate oxidative stress and neurotoxicity in autism. 47) An impaired ability to metabolize toxic substances via a sulfation pathway contributes to autism. If the MMR vaccine is administered simultaneously with DTaP, an aluminum-containing vaccine (as is often the case), then the acetaminophen would likely interfere with the childs ability to dispose of the aluminum. [Key Point] 48) Hep-B is administered usually within 24 hours of birth, and most definitely in the first two months of life, and HiB Titer is administered three or four times before the age of 15 months. These two vaccinations would thus cause an accumulation of mercury and aluminum along with a depletion of the bioavailability of sulfate prior to the MMR vaccine in the vulnerable child, leaving them more susceptible to an infection arising from the live virus administered in MMR, and a subsequent dose of Tylenol (acetaminophen) to curb fever. 49) In the U.S., aluminum was allegedly phased in at the same time that mercury was phased out. [Key Point] 50) If the current CDC immunization schedule is followed, babies are injected with nearly 5 mg of aluminum by 18 months of age. 51) Symptoms associated with aluminum-containing vaccines include: fatigue, seizure, blister, cellulitis, pain, swelling, injection site macule, insomnia, injection site reaction, infection, depression, and uveitis. 52) The increased sensitivity to aluminum in the population is possibly due to a synergistic effect of cumulative exposure to multiple [vaccine] toxins. 53) When MMR fever is treated with acetaminophen, it becomes toxic to the brain of the child predisposed toward autism because of their inability to dispose of it. 54) Acetaminophen would also deplete sulfate needed to detoxify aluminum in any concurrent aluminum-containing vaccine such as DTaP. 55) In 1991, the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control (CDC) recommended that all infants be injected with the first dose of hepatitis B vaccine at birth. Since Hep-B contains both mercury and aluminum, and since it is administered at birth, it is likely to be a major factor contributing to the steady rise in autism-related events in the latter half of the 1990’s. The practice of requiring Hep-B administration at birth is likely to be extremely dangerous to children who are born with a sulfur deficiency. 56) Aluminum in these vaccines administered to young children may be even more toxic than the mercury. 57) The autistic child cannot adequately detoxify acetaminophen. 58) ASD is a condition characterized by a serum deficiency in sulfur metabolites, particularly the sulfate anion, which results in an inability to safely dispose of mercury, aluminum, and acetaminophen. [Key Point] 59) While the autism community has focused on the mercury in thimerosal as the main culprit in vaccines, our studies with the VAERS database have identified aluminum and acetaminophen as being likely even more damaging than mercury. Because of the sulfur deficiencies, aluminum, mercury and acetaminophen likely accumulate in the autistic brain, leading to further damage. [Key Point] 60) We hypothesize that this unanticipated consequence is due to simultaneous increases in the aluminum content, attributed to an increased number of required vaccines, intentional addition of aluminum to achieve an adjuvant effect, as well as the likely further accumulation of aluminum as a consequence of leaching, given the new practice of storage in individual glass vials with rubber stoppers. 61) Oral antibiotics dramatically inhibit mercury excretion to 10% of normal levels. [Important] 62) Further aluminum exposure comes from aluminum in skin products such as high SPF sunscreen, particularly for the child whose barrier function is defective due to inadequate cholesterol sulfate and filaggrin in the epidermis. Other potential sources of aluminum are aluminum flocking agents in municipal water supplies, aluminum leaching from aluminum baby formula cans, and aluminum in the human milk supply to the breastfeeding infant, absorbed by the mother from sunscreen, antiperspirants, antacid medications, cooking utensils, etc. 63) The high fever associated with a reaction to MMR led to the administration of acetaminophen, whose safe disposal, like that of aluminum, depends on an adequate serum supply of bio-sulfates. The frequent presence of concurrent aluminum-containing vaccines would contribute synergistically to toxicity. 64) We hypothesize that the fever associated with MMR results in the administration of acetaminophen, which, in conjunction with the intense immune response to live viruses, becomes toxic to the vulnerable child. 65) Both women of childbearing age and children should be encouraged to consume foods that are rich in sulfur and to spend considerable time outdoors without sunscreen on sunny days. It might be prudent to implement a screening test for sulfate and/or glutathione concentration in the blood prior to administration of an aluminum-containing vaccine, and to waive the vaccine or consider a nonaluminum-containing alternative if sulfate or glutathione levels are insufficient. 66) The practice of including aluminum in the so-called placebo in vaccine trials should be abolished, so that the effects of aluminum adjuvant can be formally measured in a premarket phase. 67) Based upon our statistical research of the VAERS database, we would encourage the vaccine industry to consider omitting aluminum adjuvant doping of all vaccines for both children and adults. 68) Neuronal damage due to aluminum penetration into the nervous system may be a significant factor in autism. The fact that mentions of autism rose steadily concomitant with significant increases in the aluminum burden in vaccines, is highly suggestive. 69) Autism may be linked to other environmental toxins, like herbicides or pesticides, or aluminum in other products such as antiperspirants and antacids. 70) We observed a strong correlation between the MMR vaccine and autism, which we suggest could be explained by the effects of acetaminophen. 71) We propose that simple corrective measures such as increased sunlight exposure and decreased use of sunscreen may help protect a child from a severe reaction to aluminum-containing vaccines, but we also feel that the vaccine industry should find a way to reduce or even eliminate the aluminum content in vaccines.

Clinical Infectious Diseases 2009; Vol. 49; No. 9: pp. 1405-1410 Karen M. Starko In February 1919…Edward’s fever kept getting higher and higher…aspirin…was given to him by the 1/2-handful over and over…Edward sweated through his mattress…Dr.…could not save his patient. Clella B. Gregory, Pandemic Influenza Storybook, US Department of Health and Human Services 1) The Flu of 1918 – 1919 had a very high case-fatality rate, especially among young adults. Early deaths exhibited extremely wet, sometimes hemorrhagic lungs. 2) The hypothesis presented herein is that aspirin contributed to the incidence and severity of viral pathology, bacterial infection, and death, because physicians of the day were unaware that the regimens (8.0 – 31.2 g per day) produce levels associated with hyperventilation and pulmonary edema. Aspirin overdose causes pulmonary edema. 3) In 1918 there was a spike of official recommendations for toxic regimens of aspirin immediately before the October 1918 death spike. Today, aspirin regimens recommended in 1918 are known to be toxic. 4) In 1918, the US Surgeon General, the US Navy, and the Journal of the American Medical Association recommended use of aspirin just before the October death spike. If these recommendations were followed, and if pulmonary edema occurred in 3% of persons, a significant proportion of the deaths may be attributable to aspirin. 5) The 1918 – 1919 influenza pandemic showed unprecedented overall mortality. Deaths in the United States peaked with a sudden spike in October 1918. The spike in Flu deaths during the fall of 1918 may have been linked to Salicylate. 6) The hypothesis presented herein is that salicylate therapy for influenza during the 1918 – 1919 pandemic resulted in toxicity and pulmonary edema, which contributed to the incidence and severity of early ARDS-like lungs, subsequent bacterial infection, and overall mortality. Pharmacokinetic data indicate that the aspirin regimens recommended for the Spanish influenza predispose to severe pulmonary toxicity. 7) A confluence of events created a perfect storm for widespread salicylate toxicity. The loss of Bayer’s patent on aspirin in February 1917 allowed many manufacturers into the lucrative aspirin market. Official recommendations for aspirin therapy at toxic doses were preceded by ignorance of the unusual nonlinear kinetics of salicylate (unknown until the 1960s), which predispose to accumulation and toxicity; tins and bottles that contained no warnings and few instructions; and fear of Spanish influenza, an illness that had been spreading like wildfire. 8) From the 1950s to the 1980s, thousands of deaths among children following influenza and other infections (eg, Reye syndrome) were unexplained until studies identified aspirin as the major contributor. 9) Salicylates cause immediate lung toxicity and may predispose to bacterial infection by increasing lung fluid and protein levels and impairing mucociliary clearance. 10) The occurrence of pulmonary edema in humans with salicylate intoxication is well documented. 11) The pathology of the early 1918 Flu deaths is consistent with aspirin toxicity. Autopsy reports by pathologists of the day describe: * Extremely wet and sometimes hemorrhagic lungs. * The amount of lung tissue actually pneumonic seemed too little in many cases to explain death by pneumonia. * A thin, watery, bloody liquid in the lung tissue, like the lungs of the drowned, as well as pleural exudates with small hemorrhages unlike those seen in any other form of acute pneumonia. * The brain was quite regularly swollen. * The kidneys were regularly the seat of cloudy swelling. * The liver had superficial fatty change. These pathology findings are consistent with aspirin toxicity. 12) Aspirin advertisements in August 1918 and a series of official recommendations for aspirin in September and early October preceded the death spike of October 1918. 13) Bayer’s worldwide efforts had left few places lacking aspirin, and in the US Bayer’s had a giant aspirin factory. 14) Official recommendations for aspirin were issued as follows: * September 13, 1918: by the US Surgeon General * September 26, 1918: by the US Navy * October 5, 1918: by the Journal of the American Medical Association3 15) Aspirin sales more than doubled between 1918 and 1920. The number of deaths in the United States increased steeply, peaking first in the Navy in late September, then in the Army in early October, and finally in the general population in late October. 16) Homeopaths, who thought aspirin was a poison, claimed few deaths. 17) Others may have suspected that aspirin was responsible. On 23 November, 1918, Horder wrote in The Lancet that, for intensely toxic cases…aspirin and all socalled febrifuge drugs must be rigidly excluded from the treatment. 18) In summary, just before the 1918 death spike, aspirin was recommended in regimens now known to be potentially toxic and to cause pulmonary edema and may therefore have contributed to overall pandemic mortality and several of its mysteries. 19) Prospectively, aspirin should be investigated in countries where aspirin is used for influenza.

Annals of Neurology August 2012; Vol. 72; No. 2; pp. 234 – 240 Ellen M. Mowry, MD, Emmanuelle Waubant, MD, PhD, Charles E. McCulloch, PhD,Darin T. Okuda, MD, Alan A. Evangelista, BA, Robin R. Lincoln, BS, Pierre-AntoineGourraud, PhD, Don Brenneman, BA, Mary C. Owen, NP, Pamela Qualley, MA,Monica Bucci, MD, Stephen L. Hauser, MD, Daniel Pelletier, MD Primarily from the Multiple Sclerosis Center, Department of Neurology, University ofCalifornia at San Francisco KEY POINTS FROM THIS STUDY: 1) These authors sought to determine whether vitamin D status is associatedwith developing new T2 lesions or contrast-enhancing lesions on brain magneticresonance imaging (MRI) in relapsing multiple sclerosis (MS). 2) EPIC is a 5-year longitudinal MS cohort study at the University of California atSan Francisco. Participants had clinical evaluations, brain MRI, and blood drawsannually. The authors adjusted for age, sex, ethnicity, smoking, and MStreatments, annual 25-hydroxyvitamin D levels and subsequent new T2-weighted and gadolinium-enhancing T1-weighted lesions on brain MRI, clinical relapses, anddisability levels (Expanded Disability Status Scale [EDSS]). 3) Each 10 ng/ml higher 25-hydroxyvitamin D level was associated with a 15%lower risk of a new T2 lesion and a 32% lower risk of a gadolinium-enhancinglesion. 4) Each 10 ng/ml higher vitamin D level was associated with lower subsequentdisability [by 53%]. 5) Higher vitamin D levels were associated with lower MS relapse risk. 6) Interpretation: Vitamin D levels are inversely associated with MS activity onbrain MRI. 7) Multiple sclerosis (MS) is an autoimmune disorder occurring in those whopossess or are exposed to a combination of genetic and environmental risk factors. 8) Known MS environmental risk factors include: * cigarette smoking * infection with Epstein – Barr virus * lower vitamin D levels 9) The brain MRI scans were acquired on a 3T unit. 10) Standard vitamin D levels are presented in nanograms per milliliter (ng/ml). 11) The average vitamin D level by year 4 was 5.3 ng/ml higher than atbaseline. Those who reported using vitamin D supplements within the past 12months had an 8.7ng/ ml higher vitamin D level than those who did not. 12) For each 10 ng/ml higher vitamin D level was associated with a 15% lowerrisk of later developing new T2 lesions. 13) Even after adjusting for baseline vitamin D, each 10ng/ml within-personincrease in vitamin D was associated with a much lower risk of developing a new T2lesion [by 33%] 14) Each 10 ng/ml higher vitamin D level was associated with nearly a 1/3reduction in the risk of a subsequent contrast-enhancing lesion. 15) After adjusting for baseline vitamin D, each 10 ng/ml within-person increasein vitamin D was associated with a substantially lower risk of gadolinium-enhancinglesions [by 47%] 16) Higher vitamin D levels were also associated with lower risk of relapse. 17) Each 10 ng/ml higher vitamin D level was associated with a lower disabilityscore. 18) Individuals with higher vitamin D levels are at much lower risk of thesubsequent development of new lesions and of gadolinium-enhancing lesions onbrain MRI, even after accounting for potential confounding factors. Particularlyimportant is that the within-person effect of vitamin D, which is less subject toconfounding at the individual level, is even stronger. 19) Vitamin D levels did appear to be inversely associated with subsequentdisability. 20) Those who were active smokers at entry in the study were at substantiallygreater risk of developing new T2 lesions and clinical relapses throughout the study.Smoking is a relatively well-established risk factor for MS. 21) Our findings provide further support for the role of vitamin D in MSinflammatory activity and for a randomized trial of vitamin D supplementation. COMMENT FROM DAN MURPHY The studies on the benefits of vitamin D just keep coming. Again, we target 50ng/ml for our patients.

Neurobiology of Disease June 30, 2012 [epub] Karlie A. Intlekofer, Carl W. Cotman Institute for Memory Impairments and Neurological Disorders, University ofCalifornia Irvine KEY POINTS FROM THIS ARTICLE: 1) Alzheimer’s disease (AD) afflicts more than 5.4 million Americans and is themost common type of dementia, yet effective drug treatments have not beenidentified. 2) Alzheimer’s disease (AD) affects more than one in eight Americans over theage of 65 and nearly half of those over the age of 85. 3) Today there are about 40 million people with AD (worldwide), and in 2050,AD will soar to over 100 million people. 4) Physical activity enhances learning and memory for people of all ages,including individuals that suffer from cognitive impairment. 5) Physical activity reinstates brain function by enhancing brain-derivedneurotrophic factor (BDNF) and other growth factors that promote neurogenesis,angiogenesis, and synaptic plasticity. 6) Physical activity counteracts age- and AD-associated declines in mitochondrial and immune system function. A growing body of evidence alsosuggests that exercise interventions hold the potential to reduce the pathologicalfeatures associated with AD. 7) Exercise is a powerful stimulus that can reverse the molecular changes thatunderlie the progressive loss of hippocampal function in advanced age and AD. 8) Exercise promotes dynamic changes that facilitate brain function. Exercisepromotes brain health in advancing age and AD. 9) Physical activity is a protective factor against cognitive impairment anddementia. 10) The risk of AD is inversely correlated to levels of daily exercise, even withwalking as little as one mile per day. 11) The leading modifiable risk factor for AD in the United States is physicalinactivity, which increases the relative risk of AD by almost two-fold. 12) Exercise significantly improves cognitive performance, memory and attentionin individuals with cognitive impairment. 13) Exercise slows the rate of cognitive decline. Exercise is a potent strategy toalter the trajectory of cognitive decline. 14) AD patients that undergo 5 to 12 weeks of moderate exercise showenhanced memory and improved performance on neuropsychological tests. 15) Physical activity supports brain health even when initiated after theappearance of AD pathology. 16) Exercise increases BDNF. BDNF plays an important role in synaptic plasticityby promoting long-term potentiation (LTP), a synaptic analog of learning andmemory. 17) Physical activity has been shown to enhance neuronal morphology byincreasing synaptic density and dendritic arborization in the hippocampus. 18) Exercise reverses the decline in neurogenesis that occurs with age and elicitsfavorable effects on neuroplasticity. 19) Exercise increases brain glucose utilization and enhances proliferation leadingto enhanced blood flow. 20) Exercise-induced neural activation in the hippocampus requires enhancedmitochondrial capacity to produce ATP from the oxidative phosphorylation ofglucose. Exercise enhances mitochondrial proliferation and respiration. Thismitochondrial biogenesis greatly enhances metabolic capacity and the expression ofboth nuclear and mitochondrial genes. 21) Mitochondrial DNA has a high mutation rate and limited repair mechanisms.Physical activity attenuates mitochondrial DNA (mtDNA) damage and dysfunction. 22) Exercise improves mitochondrial respiration. The tuning of mitochondrialfunction may be an example of a central mechanism by which exercise protectsagainst cognitive decline. 23) An increase in brain inflammation is a risk factor in cognitive dysfunction.Inflammation is tightly associated with memory deficits in the elderly. Regularmoderate exercise is associated with reduced systemic inflammation.Exercise may alleviate the pro-inflammatory immune responses that characterizeaging. 24) Physical activity may confer enhanced protection from infection. 25) There are three major Apolipoprotein E (APOE) alleles in humans,ε2, ε3 and ε4, but only ε4 is associated with increased risk for AD. At least someof the neural consequences of carrying the ε4 isoform may be overcome by physicalexercise. Those with genetic susceptibility to AD stand to gain the most fromphysical activity. 26) Exercise is an emerging therapeutic strategy that improves the function ofmitochondria, immune system, and can mitigate the neurodegeneration inherent inAD and advancing age. By inducing neurotrophins and growth factors that enhanceneuroplasticity, physical activity can significantly improve hippocampal function to a degree even with advancing age and disease. 27) Exercise has emerged as an efficacious therapeutic strategy that yields broadbenefits to cognitive function.

American Journal of Clinical Nutrition December 2012; Vol. 96; No. 6; pp. 1409 – 18 Isabel Drake, Emily Sonestedt, Bo Gullberg, Goran Ahlgren, Anders Bjartell, PeterWallstrom, and Elisabet Wirfalt KEY PONTS FROM THIS STUDY: 1) Dietary carbohydrates have been implicated in relation to prostate cancer. 2) This analysis included 8,128 men aged 45 – 73 y without a history of cancer,cardiovascular disease, or diabetes. After a median follow-up time of 15 y, prostatecancer was diagnosed in 817 men. 3) This study found that overall, total carbohydrates consumption did notincrease the risk for prostate cancer. However there was an increase rate ofprostate cancer as related to the consumption of low-fiber cereals, cake, biscuits,rice, and pasta. 4) A high intake compared with zero consumption of sugar-sweetenedbeverages was associated with increased risk of symptomatic prostate cancer, by38%. 5) Results from this large study with high-validity dietary data suggest that ahigh intake of refined carbohydrates may be associated with increased risk ofprostate cancer. 6) Lifestyle and environmental factors play an important role in prostate cancer. 7) Both insulin and insulin-like growth factor I stimulate prostate cancer growthin vitro and have been associated with prostate cancer risk in epidemiologicstudies. 8) Because one of the most potent stimulants for insulin production iscarbohydrate consumption, it has been proposed that diets high in carbohydratesmay affect prostate cancer risk. 9) The nutrient and food variables investigated in this study were totalcarbohydrates, monosaccharides, sucrose, dietary fiber, whole grains, vegetables,fruit and berries, fruit juices, potatoes, low-fiber cereals, low-fiber bread, high-fiberbread, cakes and biscuits, rice and pasta, sweets and sugar, sugar-sweetenedbeverages, alcohol, calcium, selenium, vitamin E, total protein, red meat, processed meat, total fat, SFAs, PUFAs, fish and shellfish, and dairy products.Other measured variables included BMI, waist circumference, smoking,educational level, and total physical activity. 10) A high intake of cake and biscuits was associated with increased risk of low-riskprostate cancer. 11) A high intake of low-fiber cereals was associated with increased risk of totaland low-risk prostate cancer. 12) A high intake of rice and pasta was associated with increased risk of low riskprostate cancer by 33%. 13) Significantly increased risk of symptomatic prostate cancer was seen for ahigh intake of sugar-sweetened beverages by 41%. 14) Refined carbohydrates (ie, cakes and biscuits, low-fiber cereals, rice andpasta, and sugar-sweetened beverages), may be associated with incident prostatecancer. 15) Although no association was seen with total carbohydrates or sucrose, highintake of sugar-sweetened beverages was shown to be associated with 40%increased risk of symptomatic prostate cancer in our study population. 16) Our findings suggest that high intake of foods typically high in refinedcarbohydrates (including cakes and biscuits, low-fiber cereals, rice and pasta, andsugar-sweetened beverages) may increase risk of this disease. COMMENTS FROM DAN MURPHY Article Review 52-12 indicates that the primary fuel for cancer cells is throughthe very inefficient anaerobic glycolysis pathway; because of this inefficiency,cancer cells require large amounts of carbohydrates to fuel their high energyrequirements. Consequently the authors suggest that cancer cells starve whendietary carbohydrates are sharply restricted. [Is There a Role for Carbohydrate Restriction in the Treatment and Prevention of Cancer? Nutrition and Metabolism; October 2011; 8(75)]The bottom line is that this article adds to the evidence that consumption of refinedcarbohydrates is a cancer risk and should be avoided or minimized. Accompanying Editorial Soft Drinks, Aspartame, and the Risk of Cancer and Cardiovascular DiseaseDagfinn Aune 1) The consumption of sugar-sweetened soft drinks has been associated withexcess weight and an increased risk of type 2 diabetes in systematic reviews andmeta-analyses of the evidence, and these conditions are by themselves related toan increased risk of mortality, cardiovascular disease, some cancers, and other chronic diseases. 2) Sugar-sweetened soft drinks are the primary source of added sugars in theAmerican diet. 3) Artificially sweetened diet soft drinks have been marketed as a healthieralternative due to their lack of calories, but studies have linked them to increasedrisk of type-2 diabetes and cardiovascular disease. 4) In animals, aspartame, is linked to an increased risk of lymphomas,leukemias, and transitional cell carcinomas of the pelvis, ureter, and bladder in adose-dependent manner within ranges that are considered to be safe for humanconsumption. 5) In a 2012 study published in the American Journal of Clinical Nutrition, menconsuming one or more diet sodas per day had a 31% increased risk of nonHodgkinlymphoma (NHL) and a 102% increased risk of multiple myelomacompared with no intake. In the same study, intake of regular sugar-sweetenedsodas was associated with a 66% increased risk of NHL in men. In the same study there was a 42% increased risk of leukemia with a high intake of diet soft drinks.[Apparently, both sugar sodas and diet sodas are bad for health]Intake of aspartame was directly associated with risk of NHL and multiple myelomaand suggestively associated with leukemia in men. 6A) With regard to the mechanism that may explain the findings for diet softdrinks, it is known that aspartame breaks down to methanol, aspartic acid, andphenylalanine if stored near or above room temperature. The cancer risk is greaterin men apparently because men are enzymaticly superior in converting methanol to carcinogenic formaldehyde. 6B) Ironically, alcohol consumption inhibits the enzymatic conversion of methanolto carcinogenic formaldehyde; consequently in men who consumed less than 6 oz.of alcohol/day, there was a 134% increased risk of NHL. [Translation: if onedrinks diet sodas, one should also drink more than 6 oz. of alcoholdaily].

The Physician and Sportsmedicine November 2012, Volume 40, Issue 4, pp. 73-87 Joseph C. Maroon, MD; Darren B. LePere, BS; Russell L. Blaylock, MD; Jeffrey W.Bost, PAC: This article has 157 references FROM ABSTRACT The incidence of all-cause concussions in the United States is 1.6 to 3.8 millionannually, with the reported number of sport- or recreation-related concussionsincreasing dramatically, especially in youth sports.The use of roadside bombs in Iraq and Afghanistan has propelled the incidence ofconcussion and other traumatic brain injuries to the highest levels ever encounteredby the US military. The wars in Iraq and Afghanistan cause about 300 concussions per month. There is a marked increase in post-concussion syndrome (PCS) and the associatedcognitive, emotional, and memory disabilities associated with the condition.There have been no significant advancements in the understanding or treatment ofPCS for decades. The current management of PCS mainly consists of rest, reduction of sensoryinputs, and treating symptoms as needed.Recently, researchers have proposed that activation of the immune inflammatoryresponse may be an underlying pathophysiology that occurs in those whoexperience prolonged symptoms after a concussion. This immune inflammatoryresponse is known as immunoexcitotoxicity. KEY POINTS FROM THIS ARTICLE: 1) Most traumatic brain injuries (TBIs) are mild traumatic brain injuries (mTBIs)and are often referred to as concussions. These concussions can cause long-termdisability. 2) Most signs and symptoms of a cerebral concussion spontaneously resolvewithin 2 to 7 days, including: * Headache * Nausea * Visual disturbance * Balance abnormalities 3) Up to 15% of concussion individuals may experience prolonged andintractable physical, cognitive, emotional, and/or sleep disturbances that result insevere debilitation the so-called post-concussion syndrome (PCS). Thesesymptoms often result in significant disruption and even withdrawal from school,job, or military activity. 4) Post-concussion syndrome requires at least 3 symptoms for a minimum of 4weeks following a head injury, including: * Headache * Dizziness * Sleep problems * Psychological disturbances * Cognitive disturbances 5) Management of PCS includes rest and reduction of sensory input fromschoolwork, computers, and any processing of new information. 6) In PCS, imaging technology (CT, MRI, diffusion tensor imaging, PET) are lessthan optimal because they do not document changes in brain neurochemistry. 7) Following an impact to the head, a cascade of biochemical, immunological,and excitotoxic events occur, mediated by the innate and adaptive immune systemsin the central nervous system. 8) When a person sustains a TBI, it is well recognized that there is a massiverelease of glutamate and aspartate, primarily from astrocytes and microglia cells,which overstimulate glutamate receptors. This results in an influx of calciumthrough the cellular membrane and subsequent neuronal toxicity and cell death. This is called the excitotoxic reaction, and contributes to PCS and to chronictraumatic encephalopathy (CTE)." 9) Microglia are the macrophages of the brain and spinal cord. In brain injury,the microglia become activated, releasing a series of immune factors, such asreactive oxygen species (ROS), inflammatory prostaglandins, and excitotoxins inthe form of glutamate, aspartate, and quinolinic acid. 10) Immunoexcitotoxicity and microglial activation is central to a number ofneurodegenerative diseases, including Alzheimers disease, Parkinsons disease,amyotrophic lateral sclerosis, and vascular dementia. 11) The lingering symptom of headache, cognitive disturbances, and memoryimpairment of PCS are linked to excitotoxic neurotransmitters and inflammatorycytokines. PCS following TBI may represent a persistent, low-grade, chronicallysmoldering neuroinflammatory response. 12) The short-term symptoms of concussion, such as immediate confusion anddisorientation, usually resolve within minutes to several hours and are probably dueto electrochemical changes. 13) A limited activation immunoexcitotoxicity inflammatory response producesprotracted headaches, fogginess, and poor concentration, which resolve within aweek in most cases. 14) After a concussion it is extremely important to prevent a second injury beforethe brain is completely healed. A second impact initiates brain vasoreactive edemawith resultant severe malignant brain swelling, which if not recognized and treatedpromptly, it may be fatal. 15) A second brain injury before complete recovery accelerates microgliaactivation. The initial injury primes the microglia a state in which microgliaupregulate the production of proinflammatory cytokines. Primed microglia releasesignificantly higher levels of proinflammatory cytokines/chemokines andexcitotoxins than normal, causing prolonged brain immunoexcitotoxicity. 16) Both glutamate and quinolinic acid can produce tau proteins and stimulate β-amyloid accumulation in both Alzheimers disease and in CTE. 17) A number of natural plant products and extracts, such as fish oil, resveratrol,green tea, and curcumin, among others, may offer similar effects in the treatmentof AD and other immunoexcitotoxicity-associated neurodegenerative disorders. These compounds work by suppressing or affecting microglial activation states aswell as the excitotoxic cascade and inflammatory mediators, and promoting therelease and generation of neurotrophic factors essential for CNS healing. 18) Nonsteroidal anti-inflammatory drugs are the most common cause of drug-related morbidity and mortality reported to the US Food and Drug Administrationand other regulatory agencies around the world. 19) Omega-3 essential fatty acids (EFAs), vitamin D3, curcumin, resveratrol andother polyphenols, and magnesium have all been shown to clinically reduceinflammation, reduce microglial activation, affect excitotoxic cell signalingprocesses, and are used worldwide to treat inflammatory-related conditions. 20) The major components of omega-3 EFAs, eicosapentaenoic acid (EPA) anddocosahexaenoic acid (DHA), can inhibit production of proinflammatory eicosanoids. 21) The proinflammatory prostaglandin E2 (PGE2), made from omega-6 EFA(arachidonic acid [AA]) found in all cellular membranes, can be downregulatedthrough competitive inhibition due to the enhanced production of prostaglandin E3(PGE3) from EPA, which is also incorporated into cellular membranes. 22) CTEs mechanisms of immunoexcitotoxicity and microglia activation arereduced by both EPA and DHA. 23) Docosahexaenoic acid (DHA) constitutes > 25% of brain phospholipids,maintaining membrane integrity, fluidity, excitability, and function. 24) Oral supplementation of DHA for 30 days following TBI significantly decreasesthe number of swollen, disconnected, and injured axons, attenuates glutamateinducedneuronal injury and death. 25) Omega-3 EFAs increase neuronal survival following brain injury by reducingexcitoxicity through inhibition of glutamate-induced neuronal toxicity. 26) Therapeutic EPA+DHA dosing for TBI is a total of 1.5 to 5.0 g per day. 27) Vitamin D significantly promotes immune function and reduces theinflammatory response. 28) Vitamin D can limit the extent of TBI injury by reducing cerebral edema,inflammatory response, necrosis, and apoptosis. Vitamin D decreases glutamate-induced neuronal death. 29) Curcumin is a flavonoid compound found in the Indian spice turmeric. It haspotent anti-inflammatory, antioxidant, and antineoplastic effects. 30) Curcumins anti-inflammatory actions arise from inhiibition of proinflammatory mediators, including cytokines and NF-κB and inhibition of COX-1and COX-2. It may be a comparable alternative to NSAIDs without the unacceptableside effects. 31) Curcumin has been found to prevent apoptosis, as well as decrease edemafollowing TBI and ischemia. 32) The suggested dosage of curcumin supplementation for TBI is 400 to 600 mgtaken 3 times per day. 33) Resveratrol is a plant-based polyphenol antimicrobial. It is a powerfulantioxidant with cardioprotective, antineoplastic, and anti-inflammatory effects. 34) Resveratrol may extend the life span, slow the development of chronicneurodegenerative disease, and improve patient outcome following stroke, cerebralischemia, spinal cord injury, and TBI. 35) Resveratrol is anti-inflammatory by suppressing pro-inflammatory PGE2synthesis, and inhibiting TNF-α- and IL-1β-induced NF-κB activation. 36) Resveratrol significantly reduces glutamate release TBI. 37) Moderate resveratrol wine consumption significantly reduced the risk of ADin population studies. 38) Resveratrol can exist in either the cis- or trans- form, but only the transformis believed to be bioactive. The typical supplementation range is between 50to 500 mg/day. 39) Magnesium is required for > 300 metabolic processes and plays an essentialrole in modulating transmembrane electrical activity. It is also essential forprotein synthesis, energy metabolism, maintenance of ionic gradients, immunesystem regulation, smooth muscle tone, and calcium regulation. 40) Magnesium decline is thought to play a major role in the neuronalpathogenesis following TBI. Its most predominant neuroprotective action is byacting as a noncompetitive inhibitor of NMDA excitotoxicity by receptor blockade orby decreasing glutamate release. 41) About 63% of adult Americans have insufficient magnesium, and especiallythose who use proton pump inhibitors [antacids]. 42) Food sources for magnesium include legumes, nuts, whole grains, and mostvegetables. The recommended dosage of magnesium is approximately 80 to 420mg/day. 43) Green tea is a powerful antioxidant, containing numerous polyphenoliccompounds called catechins, of which epigallocatechin-3 galate (EGCG) is the mostabundant. These polyphenols in green tea are anti-inflammatory, helping preventcardiovascular disease, cancer, and arthritis. 44) The typical recommendation is 3 to 4 cups of green tea per day, or 1 servingof extract, which contains between 300 and 400 mg. 45) These nutritional approaches for TBI and PCS attack the pathophysiology ofthe disorder, shortening its duration, and not just ameliorating the symptoms. 46) By supporting neuronal function and countering key immunoexcitotoxicitymechanisms, non-pharmaceutical treatments may offer an effective alternative fortreating post-concussion syndrome. COMMENTS FROM DAN MURPHY: The suggested natural products to be used to halt the pathophysiological cascade ofTBI and PCS were: * Omega-3s EPA+DHA * Vitamin D3 * Curcumin * Resveratrol * Magnesium * Green Tea (EGCG) Quinolinic acid activates the N-methyl-d-aspartate receptor (NMDAR) and canlead to axonal neurodegeneration. Quinolinic acid is a potent neurotoxin. Quinolinicacid is an excitotoxin in the CNS. Quinolinic acid may be involved in many psychiatric disorders, neurodegenerativeprocesses in the brain, as well as other disorders. Within the brain, quinolinic acid is produced by activated microglia cells andmacrophages. The quinolinic acid produced in microglia is then released and stimulates NMDAreceptors resulting in excitatory neurotoxiticity. Quinolinic acid destabilizes the cytoskeleton of the astrocytes and brain endothelialcells contributing to the degradation of the Blood Brain Barrier. Quinolinic acid reaches pathological levels in response to inflammation in the brain,which activates the microglia and macrophages. High levels of quinolinic acid canlead to hindered neuronal function or even apoptotic death. When inflammation occurs, quinolinic acid is produced in excessive levels. Thisleads to over excitation of the NMDA receptor, which results in an influx of Ca2+into the neuron. High levels of Ca2+ in the neuron trigger an activation ofdestructive enzymatic pathways that degenerate crucial proteins and increase NOlevels, leading to an apoptotic response by the cell, which results in cell death. Glutamate further stimulates the NMDA receptors, thus acting synergistically withquinolinic acid to increase its neurotoxic effect. Increased levels of quinolinic acid are linked to: * Mood disorders * Depression * Schizophrenia * Neurodegenerative conditions * Amyotrophic lateral sclerosis (ALS) * Mitochondria dysfunction * Alzheimer’s disease * Brain ischemia, stroke * Huntington’s disease * Parkinsons disease * Bacterial infections of the CNS * Systemic lupus erythematosus * Traumatic Brain Injury * Cognitive decline with ageing * Other brain infections, including polio, Lyme disease Antioxidants provide protection against the pro-oxidant properties of quinolinic acid.Natural phenols such as catechin hydrate, Curcumin, and epigallocatechin gallate(found in green tea) reduce the neurotoxicity of quinolinic acid.COX-2 [controls the production of pro-inflammatory eicosanoids fromomega-6 fatty acid arachidonic acid] is upregulated in neurotoxic disordersand is associated with increased ROS production.