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.

BioMed Central (BMC) Musculoskeletal Disorders2012 13:162 Pierre Balthazard, Pierre de Goumoens, Gilles Rivier, Philippe Demeulenaere,Pierluigi Ballabeni, Olivier Dériaz KEY POINTS FROM THIS ARTICLE: The aim of this study was to assess whether manual therapy (MT) has animmediate analgesic effect, and to compare the lasting effect on functional disabilityof MT plus AE to sham therapy (ST) plus AE. This is the first controlled study toassess the efficacy of spinal manipulation/mobilization followed by specific activeexercises. 1) Recent clinical recommendations still propose active exercises (AE) for chronicnon-specific low back pain (CNSLBP). 2) Current evidences suggest that manual therapy (MT) induces an immediateanalgesic effect through neurophysiologic mechanisms at peripheral, spinal andcortical levels. [Key Point] 3) Randomization: Patients in this study selection were aged 20 to 65 years with non-specific low backpain with or without leg symptoms, for a period between 12 and 26 weeks. Theyhad no radiologic abnormalities other than degenerative disease.22 patients were assigned to manual therapy plus active exercise.20 patients were assigned to sham therapy (dysfunctional ultrasound) plus activeexercise. Active exercise was started in the clinical setting and was eventually performed at home.Eight therapeutic sessions were delivered over 4 to 8 weeks.Patients were evaluated at each session, before and after treatment, at week 8 andagain at 3 and 6 months using standard measurement outcomes, which included: * Visual Analogue Scale (VAS) for pain intensity * Oswestry Disability Index (ODI) for disability 4) MT intervention induced a better immediate analgesic effect. 5) MT + AE induced lower disability (-7.1, ODI) and lower pain (-1.2, VAS). 6) This study confirmed the immediate analgesic effect of MT over ST. Followedby specific active exercises, it reduces significantly functional disability and tends toinduce a larger decrease in pain intensity, compared to a control group. 7) These results confirm the clinical relevance of MT as an appropriatetreatment for CNSLBP. 8) These authors propose that CNSLBP and its clinical presentations andmanifestations may be linked to alterations in neuro-cortical function. Theneurophysiologic mechanisms at cortical level should be investigated morethoroughly for MT. [Key Point] 9) Randomized controlled trials reported that manual therapy is more effectiveon physical function, mental health, physical disability and/or pain than nointervention, sham manipulation, light exercises or general active exercises. 10) Manual therapy may interfere with the neuromuscular, autonomic andendocrine responses, produce a placebo effect and/or alter the patientspsychological state. [Key Point] 11) The manual therapy consisted of: A)) Passive intervertebral movements with postero-anterior pressure applied onpainful or stiffed vertebral segment(s) with the patient lying prone. AND/OR B)) A muscle-energy technique using a hold-relaxed technique on an iliumdysfunction with the patient side lying. AND/OR C)) High velocity, low amplitude rotational-lateral flexion dynamic thrust(manipulation) performed on a stiffed vertebral segment(s) with the patient sidelying. 12) The active exercise consisted of: A)) Educational information on low back anatomy and biomechanics and ways toprotect the spine during activities of daily. B)) 2 home mobility exercises (supine pelvic tilt and low back lateral flexion), tobe performed twice a day, 2 sets of 10 repetitions. C)) After the 3rd or 4th session, the recommendation of home exercises changesto stretching and motor control exercises. D)) Mobility exercises during the 8 therapeutic sessions to improve patientsspinal range of motion. E)) Passive stretching exercises for the spine, hamstring, iliopsoas, rectusfemoris, and piriformis. F)) Strengthening exercises for weak superficial trunk muscles. 13) For MT/ST intervention, the immediate effect of intervention was in favor ofmanual therapy over detuned ultrasound, with a greater decrease in pain level. 14) The main original result of this study is that manual therapy, immediatelyfollowed by active exercise, accelerates reduced disability in CNSLBP patients. 15) The analgesic effect of MT combined with exercises can be efficient todecrease pain for CNSLBP. The analgesic effect of manual therapy (i.e., theimmediate effect) may allow the patient to perform better/more accurate activeexercises. 16) The present study confirms the immediate analgesic effect of manual therapyfor CNSLBP. Followed by specific active exercises, it significantly reduces functionaldisability and tends to induce a larger decrease in pain intensity, compared to acontrol group. 17) CNSLBP is largely characterized by structural, functional and neurochemicalcortical modifications. [Key Point] 18) Improving the knowledge of the precise neurophysiologic mechanisms ofmanual therapy at cortical level seems essential in order to validate the choice ofthis therapy for CNSLBP. 19) For CNSLBP, the use of spinal manipulation/mobilization is favorablyrecommended. COMMENTS FROM DAN MURPHY Since both manual therapy and sham therapy (dysfunctional ultrasound) were bothfollowed with active exercise, the clear conclusion for CNSLBP treatment is: 1) Manual therapy is a lot better than sham therapy. 2) Manual therapy is a lot better than exercise (since the same exercises wereperformed by the sham dysfunctional ultrasound group). Importantly, these authors contend that CNSLBP involves alterations in neurocorticalfunction, and that manual therapy can improve this neuro-cortical function. Importantly, these authors acknowledge that manual therapy affects autonomicand endocrine responses, a key point for chiropractors.

Peter Schmidt, MD; Thomas E. Mayer, MD; Robert Drescher, MD, MAFrom the Department of Neuroradiology, Institute of Radiology, University HospitalJena, Jena, Germany The purpose of this study was to evaluate the normal anatomical variability of thealar ligaments in asymptomatic individuals with 3-T magnetic resonance imaging(MRI) and to compare the findings with standard 1.5-T examinations. Thirty-sixparticipants underwent 3-T and 1.5-T MRIs. Alar ligament MRI findings wereanalyzed with regard to the features detectability, signal intensity compared with muscle tissue, homogeneity, shape, spatial orientation, and symmetry.Evaluated images were coronal T2-weighted MRI with a slice thickness, 0.8 mm. KEY POINTS FROM THIS STUDY: 1) Rupture of the alar and transverse ligaments due to whiplash injury can leadto upper cervical spine instability and subsequent neurological deterioration. 2) Delineation of the alar ligaments was significantly better on 3-T images. 3) This study demonstrates that high-field 3-T MRI provides better visualizationof the alar ligaments compared with 1.5-T MRI. The higher signal-to-noise ratioallows detection of small signal changes. 4) Approximately 25% of whiplash-injured patients experience prolongedmorbidity, with little prospect of complete resolution of pain and other symptoms. 5) 24-70% of whiplash-injured patients suffer from long-term symptoms. 6) Up to 16% [of whiplash-injured patients] remain severely impaired manyyears after the accident, which interferes with their activities of daily living. 7) The alar ligaments are considered an important ligamentous craniocervicalstructure for the integrity and stability of the craniocervical junction. Due to the lackof a disk and the horizontal nature of the facet joints, the stability of theatlantoaxial joint depends mainly on ligaments and muscles. 8) The most important function of the alar ligaments is the limitation of axialrotation, and they are most vulnerable when the head is rotated and flexed. 9) Magnetic resonance imaging (MRI) is the modality of choice to visualizeanatomy and pathology of the alar ligaments because of its high tissue contrast andmultiplanar imaging capability. 10) 9.7% of the alar ligaments were difficult to detect on 3-T MRI compared with55.6% on 1.5-T MRI. 11) This study demonstrates that reliable assessment of alar ligaments by meansof MRI can be achieved and that high-field 3-T MRI provides better visualization ofthe alar ligaments compared with 1.5-T MRI. 12) A 2009 study reported that high signal changes of the alar and transverseligaments are common in whiplash-associated disorders and unlikely to representage-dependent degeneration. 13) These authors note that the studies that claim there is no significance to alarligament signal abnormality and chronic whiplash symptoms were performed on a1.5-T MRI. They suggest that the findings and conclusion would most likely bedifferent had the authors used a 3.0-T MRI unit. 14) Alar ligament imaging is difficult because of their subtle structures andvariable orientation. T2 contrast is helpful to differentiate the ligamentousstructures of the spine from surrounding fatty tissue and muscles, as well as fromcerebrospinal fluid. 15) The higher signal-to-noise ratio of 3-T MRI compared with 1.5-T MRI allowsfor the detection of small signal changes of a ligament, which at 1.5 T will likely notovercome the noise threshold. [Key Point] 16) High-field 3-T MRI is a valuable diagnostic tool for imaging of the alarligaments because of its excellent delineation of these ligaments compared withstandard 1.5-T MRI. 17) High-field 3-T MRI increases the reliability and accuracy of alar ligamentlesion classification. COMMENTS FROM DAN MURPHY: Alar ligament integrity is of critical importance to both upper cervical chiropractorsand to chiropractors managing whiplash injuries. A number of studies we havereviewed indicate that: 1) Alar ligaments are specifically injured in motor vehicle collisions. 2) Injured alar ligaments are primarily responsible for chronic whiplashsymptoms, especially post-traumatic headaches. This study clearly points out that 3.0-T MRI has more diagnostic accuracy than dothe standard 1.5-T MRI units.

Paul D. Giles, DO, MS, Kendi L. Hensel, DO, PhD, Christina F. Pacchia, PhD, MichaelL. Smith, PhD: From the Department of Integrative Physiology, University of NorthTexas Health Science Center. BACKGROUND FROM DAN MURPHY: Heart rate variability (HRV) is the variation in the time interval between heartbeats.It is largely under the control of the autonomic nervous system.The parasympathetic influence lengthens HRV via the release of acetylcholine bythe vagus nerve (slowing the heart rate).The sympathetic influence shortens HRV via the release of epinephrine andnorepinephrine (accelerating the heart rate). Vagal and sympathetic nerve activity constantly interact; under resting conditions,vagal tone prevails. KEY POINTS FROM THIS STUDY: 1) Osteopathic manipulative treatment (OMT) focusing on the upper cervicalspine is theorized to affect the function of the vagus nerve and thereby influencethe parasympathetic branch of the autonomic nervous system. 2) This study was designed to determine the acute effect of upper cervical spinemanipulation on cardiac autonomic control as measured by heart rate variability. Itused 19 healthy, young adult subjects underwent cervical osteopathic manipulationand sham manipulation. Six minutes of electrocardiographic data were collectedbefore and after each intervention, and heart rate variability was assessed. 3) Study exclusion factors included:hypertension, caffeine consumption within 4 hours, tobacco use within 48 hours,history of cardiovascular disease, neuropathic disorders, unexplained episodes ofsyncope, and any musculoskeletal signs/symptoms. 4) The anatomical relationship of the efferent vagus nerve to the musculoskeletal structures at the occiput lends credence to the hypothesis thatosteopathic manipulative treatment at this location, such as suboccipitaldecompression, could affect vagal functions. 5) Previous studies have shown that manual therapies can affect vagal function. 6) Cervical manipulation may have direct effects on the parasympatheticnervous system. 7) Decompression of the occipito-atlantal junction, a technique that focuses ontreating an articular compression between the occiput and the atlas, may improveconditions relating to the path of the vagus as it exits the skull. 8) Because of the proximity of the vagus to the musculoskeletal structures inthe suboccipital region, it is plausible that local inflammation, edema, musclehypertonicity or spasm, or other somatic dysfunctions could cause either a chemicalor compressive effect on the vagus, thereby affecting its optimum function. 9) Since the vagus plays a significant role in the autonomic control of heartrate, it is therefore also plausible that if optimum performance of the vagus isimpeded by dysfunction in the surrounding structures, its ability to contributeeffectively to the autonomic control of heart rate might also be affected. 10) The manipulation protocol involved the treatment of the subjects posteriorcervical musculature by using kneading and stretching. The kneading force wasapplied perpendicular to the long axis of the muscle. The stretching was aseparation of the origin and insertion of a muscle. This soft tissue treatment wasperformed for about 5 minutes. Then occipital-atlas decompression was applied for 2 – 3 minutes by using the index fingers to contact the occiput as near to theoccipital condyles. The sham treatment placed the fingers near the occipitalcondyles, but no tension was applied in any direction, for about 8 minutes. 11) Heart rate variability is used to assess changes in autonomic control of heartrate under a variety of conditions including with manual therapies. Heart ratevariability was measured as an index of autonomic control. 12) The changes in the frequency domain indices of heart rate variability wereconsistent with an enhanced parasympathetic control associated with the OMTtreatment. 13) These data demonstrate that suboccipital decompression, a soft tissuemanipulative technique, can affect indices of heart rate variability. 14) Many forms of manipulative medicine have been theorized to affect theautonomic nervous system, and it has been espoused that this can include bothstimulatory and inhibitory effects on the respective branches of the autonomicnervous system. 15) The data in our study consistently point to an effect of suboccipitaldecompression to moderately enhance parasympathetic control of heart rate and/orshift the sympatho-vagal balance to a more predominant vagal control. These 3effects were associated with a slowing of heart rate accompanying suboccipital decompression. 16) This study shows changes in the heart rate variability indices relating to areduced sympathetic and enhanced parasympathetic control. [Key Point] 17) The suboccipital decompression used in this study caused significant changesconsistent with an enhanced parasympathetic control of heart rate. 18) This study demonstrates that suboccipital manipulative decompression canaffect heart rate variability. This effect is consistent with potential changes in thecontrol of heart by the parasympathetic nervous system. These data support the hypothesis that upper cervical spine manipulation can acutely affect measures ofheart rate variability in healthy individuals. COMMENTS FROM DAN MURPHY The bottom-line conclusion of this study is that upper cervical spine mechanicalfunction is influenced by upper cervical spine manipulation, which in turn influencesthe vagus parasympathetic control of the heart.These authors suggest that the mechanism whereby upper cervical spinalmanipulation influences the vagus nerve and therefore the balance ofparasympathetic and sympathetic control of the heart is mechanical.We have reviewed 2 other articles with the same conclusions (upper cervical spinemechanical function is influenced by upper cervical spine manipulation, which inturn influences the vagus parasympathetic control of the heart), but with a differentmechanism. Their mechanism is that upper cervical spine mechanoreceptorsneurologically fire to the medullary Nucleus Intermedius which then fires to theNucleus Tractus Solitarius (a sensory nucleus of the vagus nerve in the medulla),which in turn influences cardiorespiratory function. Interestingly, both studies favorably mention chiropractic upper cervical adjusting to influence blood pressure: Article Review #13-08 The Neurochemically Diverse Intermedius Nucleus of the Medulla as a Source ofExcitatory and Inhibitory Synaptic Input to the Nucleus Tractus SolitariiThe Journal of Neuroscience; August 1, 2007; 27(31); pp. 8324-8333.Ian J. Edwards, Mark L. Dallas, Sarah L. Poole, Carol J. Milligan, Yuchio Yanagawa,Gabor Szabo, Ferenc Erdelyi, Susan A. Deuchars, and Jim Deuchars Article Review #3-11: The intermedius nucleus of the medulla: A potential site for the integration ofcervical information and the generation of autonomic responses.Journal of Chemical Neuroanatomy; November 2009, 38, pp. 166 – 175.Ian J. Edwards, Susan A. Deuchars, Jim Deuchars

Journal of Neurotrauma January 30, 2013 [ebub] Hasadsri L MD; Wang BH, MD;, PhD; Wang BH MD; Lee JV PhD; Erdman JW PhD;Llano DA MD, PhD; Wszalek T PhD; Sharrock MF BSc First author is from the Department of Neurosurgery, University of Illinois College ofMedicine. This article has 190 references KEY POINTS FROM THIS ARTICLE: 1) Traumatic Brain Injury (TBI) is a global public health epidemic. 2) In the US more than 3 million people sustain a TBI annually. 3) TBI may cause motor and sensory deficits and lead to severe cognitive,emotional, and psychosocial impairment, crippling vital areas of higher functioning. 4) TBI is the signature injury in wounded soldiers in Iraq and Afghanistan. 5) TBI may have a devastating impact on athletes playing contact sports. 6) There has been little progress in developing effective TBI interventions. 7) Nutritional intervention may provide a unique opportunity to enhance theneuronal repair process after TBI. 8) The two omega-3 fatty acids that are most promising for their neurorestorativecapacities in TBI are docosahexaenoic acid (DHA) and eicosapentaenoicacid (EPA). 9) Chronic repetitive sub-concussive head impacts may also result incumulative long-term deleterious effects. 10) Long-term health disorders associated with TBI include: A)) Post-traumatic stress disorder (PTSD) B)) Neurodegenerative diseases (Alzheimer’s disease or Parkinsonism) C)) Neurocognitive deficits D)) Psychosocial health problems (e.g., binge drinking, major depression,impairment of social functioning and ability to work, suicide) E)) Epilepsy F)) Pain G)) Other alterations in personality or behavior 11) Nutritional intervention, such as supplementation with n-3 (also known asomega-3) fatty acids, may be of therapeutic benefit in acute injury to the brain. 12) Omega-3 fatty acids have long been known to play a restorative role inseveral pathways implicated in traumatic insult to the brain. 13) Case studies show great benefit on the use of omega-3s in the acute phase ofsevere head injury. 14) N-3 polyunsaturated fatty acids (PUFAs) are uniquely protective againstdegeneration induced by TBI, and they improve behavioral and cognitive outcomesin patients with TBI. 15) The most important n-3 fatty acids for human health and nutrition aredocosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and alpha-linolenic acid(ALA). 16) Humans can convert a limited amount of ALA into EPA and DHA, butsynthesis of EPA and especially DHA from ALA is insufficient to supplant dietaryintake. [Important, especially for strict vegetarians] 17) DHA comprises more than 50% of brain neuronal membrane phospholipids. 18) Omega-3 fatty acids, especially DHA, are essential for maintaining membranefluidity. DHA is tremendously flexible allowing it to under go rapid interconversionsbetween multiple torsional states, and to readily undergo complex yet minimal energy-requiring conformational changes. [Fluidity] 19) During neuronal stress, both EPA and DHA are released from membranephospholipids and converted into compounds called resolvins, which resolveinflammatory processes, protect against oxidative stress, and maintain synapticintegrity. [Resolvins] 20) In the brain, omega-3s, especially DHA: A)) Increased the size of neurons B)) Increases the complexity of dendritic arboritizations C)) Increased the number of neurons D)) Increases serotonin and acetylcholine receptors E)) Improved attention, task performance, learning, and memory F)) Improves dopamine neurotransmission increases dopamine receptors, whichimproves motivational behavior and emotional functions 21) DHA is neuroprotective, and supplementation significantly amelioratessecondary mechanisms of injury and reduces the number of damaged axons. 22) Supplementation with n-3 fatty acids significantly decrease the productionof reactive oxygen species (ROS) and improve cognitive function. 23) DHA has an essential role in nervous system development and are requiredfor proper synaptogenesis, neural membrane synthesis, and the building offunctionally critical circuits within the brain. 24) DHA deficiency is associated with aging and neurodegenerative conditionssuch as Alzheimers disease, while DHA consumption has been shown to improveperformance on visuospatial learning and memory tasks in patients with age-relatedcognitive decline. 25) Dietary supplementation with omega-3 fatty acids improves functionalrecovery in subarachnoid hemorrhage and stroke. 26) Omega-3 fatty acids in the brain appear be neuroprotective in TBI becausethey protect against inflammation, apoptosis, and oxidative stress mechanisms. 27) TBI causes diffuse axonal destruction, demyelination, and neuronal cell death.This is followed by a secondary wave of disruption in the subsequent hours anddays due to inflammatory responses, excitotoxicity, and oxidative stress. 28) Omega-3 fatty acids mitigate the consequences of several key pathologicalpathways in TBI, such as mitochondrial malfunction, apoptotic cell death,glutamate-triggered excitotoxicity, and injury-induced oxidative stress andinflammation. 29) Omega-3 fatty acids may play a critical role in the restoration of cellularenergetics and repair of neuronal damage after TBI. 30) The production of pro-inflammatory prostaglandins is stimulated by andderived from the release of arachidonic acid (AA) secondary to disruption ofneuronal cell membranes. Arachidonic acid is rapidly converted into potentinflammatory mediators such as prostaglandins and leukotrienes. 31) DHA functions in a neuroprotective capacity, antagonizing the pro-deathsignaling pathways initially triggered by AA. 32) The release of the excitotoxic neurotransmitter glutamate is a destructiveevent following acute traumatic injury in the brain. Excess glutamate causesoveractivation of N-methyl d-aspartate (NMDA) and calcium-permeable AMPAreceptors, leading to a massive influx of Ca++ and the induction of bothprogrammed and necrotic cell death via calcium-dependent proteases. DHA: A)) Reduces glutamate excitotoxicity B)) Downregulates the expression of AMPA receptor subunits C)) Decreases Ca++ influx into the neuron 33) The most detrimental consequence of excess intracellular Ca++ is increasedoxidative stress, a key contributor to the pathophysiologic changes that occur afterTBI. 34) The influx of excess Ca++ into mitochondria increases ROS formation,damaging DNA and proteins, inducing programmed cell death. 35) ROS causes lipid peroxidation on a catastrophic scale, further disruptingneuronal membrane integrity and function. 36) The antioxidant defense mechanisms are relatively scarce in the human brain. 37) Traumatic disruptions in cerebral blood flow causes ATP energy depletion andcollapse of energy-dependent ion transport and active pumps, allowing intracellularCa++ overload. 38) Brain oxidative stress causes inflammation and additional microvasculardamage, secondary ischemia, and neuronal cell death. 39) The sex steroid progesterone reduces cerebral edema and has neuroprotective effects. 40) Multiple clinical trials have shown that high-dose fish oil consumption is safeeven in patients receiving other agents that may increase the risk of bleeding, suchas aspirin and warfarin. 41) DHA at doses up to 6g/d does not have deleterious effects on plateletaggregation or other clotting parameters in normal individuals, and fish oil does notaugment aspirin-induced inhibition of blood clotting. 42) It may be prudent to discontinue high-dose omega-3 supplementation in thesetting of an acute bleeding illness or in patients at high risk for hemorrhagicstroke. 43) PUFAs have high susceptibility to lipid peroxidation which may have apotential carcinogenic role.[This is why I advocate taking antioxidant co-factors] 44) High intake of fish may increase the risk of exposure to environmental toxinsand contaminants such as mercury and polychlorinated biphenyls; purified fish oilsare much safer. 45) Omega-3 fatty acids restore cellular energetics, reduce oxidative stress andinflammation, repair cellular damage, and mitigate the activation of apoptoticprocesses after TBI.

12, 2013; Volume 8; Issue 3; e57945 Ethika Tyagi, Rahul Agrawal, Yumei Zhuang, Catalina Abad, James A. Waschek,Fernando Gomez-PinillaFrom the University of California, Los Angeles (UCLA) KEY POINTS FROM THIS ARTICLE: 1) Post-traumatic stress disorder (PTSD) is a condition in which individualsexposed to trauma develop high levels of anxiety and inability to cope with routineliving conditions. 2) Mild traumatic brain injury (mTBI, cerebral concussion) is a risk factor for thedevelopment of psychiatric illness such as posttraumatic stress disorder (PTSD). 3) The neuropeptide Y1 receptor (NPY1R) is a hallmark of PTSD. 4) Brain-derived neurotrophic factor (BDNF) signaling is disrupted in PTSD.Brain-derived neurotrophic factor (BDNF) is reduced in the plasma of PTSD victimsand has a role in anxiety and depression. 5) This study was done using rats.Rats were given diets either enriched or deficient in omega-3 fatty acids (n-3)during their brain maturation period. All rats were then transitioned to a western diet (WD); when becoming adult they were then subjected to mTBI. 6) TBI resulted in an increase in anxiety-like behavior, increase in NPY1R, anddecrease in BDNF. These effects were more pronounced in the animals exposed toan n-3 deficient diet, and TBI worsened these effects and more prominently incombination with the n-3 deficiency condition. 7) Also, the n-3 deficient diet resulted in a brain inflammatory immunologicalresponse. 8) The western diet, typically maladaptive dietary habit, lowers the threshold forneurological disorders in response to challenges, including mTBI. 9) The balance between brain health and disease is likely dependent on factorsacquired particularly during early life. [Key Point] 10) Dietary factors are surfacing as strong modulators of brain plasticity with thecapacity to alter the course of brain disorders. [Key Point] 11) Adoption of unhealthy dietary habits is increasingly common in the modernsociety, and this may act as a vulnerability factor for neurological disorders. 12) The omega-3 fatty acid docosohexaenoic acid (DHA) is structured inneuronal plasma membranes and crucial for neuronal signaling. Diet is the onlysource of DHA for the brain and subnormal content of DHA has been associatedwith mood disorders in humans, i.e., increased risk of suicide in a populationexposed to trauma. 13) Dietary DHA has been shown to protect against cognitive impairmentfollowing brain trauma. 14) Consumption of DHA is below recommended levels while the consumption ofhigh fat and high sugar is on the raise in the western society, and this hardship has been attributed to increased incidence of psychiatric disorders. [Key Point] 15) Individuals with PTSD have increased brain immune activation with increasedrelease of inflammatory cytokines interleukin-1b (IL-1b) and IL-10. N-3 fatty acidsare also immunomodulatory. 16) Dietary n-3 deficiency results in anxiety-like behavior. 17) Dietary n-3 deficiency reduced NPY1R levels and switching to the WDreduced levels even further. However, prior exposure to dietary n-3supplementation preserved the levels of NPY1R in animals transitioned toWD. 18) TBI reduced the levels of NPY1R greatest in the n-3 deficient diet group. 19) Exposure to TBI reduced levels of BDNF greatest in the n-3 deficient dietgroup. 20) We found that exposure to an n-3 diet during gestation and throughoutmaturation of the brain are crucial for building neural resilience during adulthood.The lack of dietary n-3 during brain maturation worsened the effects of transition toa WD and subsequent TBI on anxiety-like behavior and molecular counterpart. InTBI, the WD enhances inflammation in animals deprived of n-3 during development. 21) Our results showed that effects of mTBI were more pronounced in the n-3deficient animals switched to WD, arguing about the critical role of dietary n-3 toprotect against the development of anxiety like disorders after TBI. 22) Dietary DHA is protective and improves cognitive impairment following TBI. 23) The neuropeptide Y1 receptor (NPY1R) is a marker of PTSD. Adequate levelsof n-3 fatty acids protect against the effects of WD and mTBI, and these effectswere reflected in higher levels of NPY1R. 24) Patients suffering PTSD have lower levels of plasma BDNF. Conditions of n-3deficiency, WD and mTBI reduced BDNF levels, and dietary n-3 offset these effects. 25) The concept of metabolic programming describes the action of a nutritionalstress/stimulus during critical periods of early development on altering anorganisms physiology and metabolism much later in life. The n-3 diet deficiencyduring brain formation and subsequent transition to WD altered brain capacity tosustain insults during adulthood, and clues to understand the molecular basis ofmetabolic programming. Reduced brain levels of n-3 and increased levels of n-6found in may have impaired neuronal signaling and contributed to the protractedmolecular and behavioral plasticity in adulthood. 26) Dietary factors during the developmental period are an environmentalvariable that can have long-term consequences on behavioral and immuneresponses, particularly under challenging conditions. 27) Chronic sugar consumption can lead to protracted plasticity, particular underdeficiency of n-3 fatty acids. [Very Important] 28) Reduced dietary n-3 creates a state of higher immune activity following TBI. Dietary transition with traumatic brain injury may also affect the immune systemduring n-3 deficiency that may interact with pathophysiologic domain relevant tomood regulation. 29) Our results emphasize the powerful action of diet during early life fordetermining later susceptibility to brain insults, involving elements associated withplasma membrane signaling, synaptic plasticity, and immune system. [Key Point] 30) Given the increasing consumption of unhealthy diets in environments withhigh prevalence of brain trauma, diet may be a factor for predisposing towards thedevelopment of disorders like PTSD. 31) The contents of n-3 during gestation and early life influence the vulnerabilityof the brain to future challenges (changes to western diet (WD) or TBI) during adultlife. KEY MESSAGES FROM DAN MURPHY 1) Omega-3 fatty acids, especially EPA and DHA, are critical for optimum brainfunction. 2) In utero and infant dietary omega-3s greatly influence adult brain physiology,including depression, anxiety, schizophrenia, suicide, and PTSD. 3) Supplemental omega-3s are both preventative and therapeutic for TBI andPTSD.