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Novel Disease Paradigm Produces Explanations for a Whole Group of Illnesses A Common Causal Etiologic Mechanism for Chronic Fatigue Syndrome Multiple Chemical Sensitivity Fibromyalgia and Posttraumatic Stress Disorder Martin L. Pall Professor of Biochemistry and Basic Medical Sciences Washington State University martinpallwsu.edu5093351246 Specific web pages Multiple Chemical Sensitivity Chronic Fatigue Syndrome Fibromyalgia These four illnesses chronic fatigue syndrome CFS multiple chemical sensitivity MCS fibromyalgia FM and posttraumatic stress disorder PTSD often occur together in the same individuals they are comorbid and share many symptoms in common 115. Gulf War syndrome is a combination of all four 1620. These four illnesses also share a common pattern of case initiation 1521 Each is often initiated that is started by a shortterm stressor only to be followed by chronic illness that typically lasts for years and often for life. These various similarities and overlaps among these four have led many scientists to suggest that they may share a common etiology cause however they have been uncertain what the cause may be. I will call these four illnesses multisystem illnesses following the lead of some others and will challenge here the claims they are unexplained and that even their symptoms are unexplained. Indeed my goal for this web page is to provide a detailed explanation for their overall mechanism and provide a proposed mechanism for many of the symptoms and signs that they share. Therapy should be based on downregulating the overall mechanism. In web pages linked to this one I will discuss some specific features of each of these illnesses and how each of these specific features may be generated by this same basic mechanism. This web site outlines the understanding of these illnesses that is documented in great detail in my forthcoming book 21.ShortTerm Stressors and the Cycle They InitiateThe stressors implicated in the initiation of these illnesses 21 are summarized in Table 1.Table 1 Illnesses Initiated by Short Term Stressors IllnessStressorsChronic fatigue syndrome Viral infections bacterial infections physical trauma severe psychological stress carbon monoxide exposure organophosphorus pesticide exposure ciguatoxin exposure toxoplasmosis protozoan infection Multiple chemical sensitivity Volatile organic solvent exposure organophosphoruscarbamate pesticide exposure organochlorine pesticide exposure pyrethroid pesticide exposure Fibromyalgia Physical trauma particularly head and neck trauma viral infections bacterial infections autoimmune diseases secondary fibromyalgia severe psychological stress Posttraumatic stress disorder Severe psychological stress physical head trauma The stressors most commonly involved in the initiation of each type of illness are indicated in bold face. These 12 diverse stressors can all act to increase the levels of the compound nitric oxide in the body 152127. Eight of these have been shown to increase nitric oxide in animal models andor in humans. The other four ciguatoxin severe psychological stress organochlorine pesticides and pyrethroid pesticides have all been shown to initiate a response that leads to increased NMDA receptor activity and it is known that increased NMDA receptor activity produces increased levels of nitric oxide and its oxidant product peroxynitrite. Thus all 12 can produce a common biochemical response and the consequent increase in nitric oxide may explain the common roles of these stressors in initiating cases of these chronic illnesses. How can a shortterm increase in nitric oxide produce chronic illness that typically lasts for years and often for life? It may be argued that it may act through its oxidant product peroxynitrite to initiate a vicious cycle mechanism which is responsible for the chronic illness. In other words we have an initial cause one or more shortterm stressors and then an ongoing cause of chronic illness vicious cycle. The cycle that is proposed to be responsible is diagrammed in Figure 1 152128.Fig. 1 legend. Vicious NOONOO cycle diagram. Each arrow represents one or more mechanisms by which the variable at the foot of the arrow can stimulate the level of the variable at the head of the arrow. It can be seen that these arrows form a series of loops that can potentially continue to stimulate each other. An example of this would be that nitric oxide can increase peroxynitrite which can stimulate oxidative stress which can stimulate NF kB which can increase the production of iNOS which can in turn increase nitric oxide. This loop alone constitutes a potential vicious cycle and there are a number of other loops diagrammed in the figure that can collectively make up a much larger vicious cycle. The challenge according to this view in these illnesses is to lower this whole pattern of elevations to get back into a normal range. You will note that the cycle not only includes the compounds nitric oxide superoxide and peroxynitrite but a series of other elements including the transcription factor NF kB oxidative stress five inflammatory cytokines in box upper right all three different forms of nitric oxide synthases iNOS nNOS and eNOS and two neurological receptors the vanilloid receptor and the NMDA receptor.We are now calling this cycle the NOONOO cycle based on the structures of nitric oxide NO and peroxynitrite ONOO but pronounced no oh no! One of the features of the NOONOO cycle that may not be obvious from Fig. 1 is that mitochondrial energy metabolism dysfunction is an integral part of the cycle. It is known that peroxynitrite attacks a number of the components of mitochondria inhibiting their ability to generate energy in the form of ATP 212325. Several of these components are certain proteins known as ironsulfur proteins and have key roles in the generation of energy in mitochondria and are inactivated by peroxynitrite. Nitric oxide and superoxide can also inhibit energy metabolism in mitochondria as well 2125. The lowered energy metabolism has important roles in the NOONOO cycle leading to increased NMDA activity and increased levels of intracellular calcium Ca 2. Lowered energy metabolism may also lead to lowered ability of the impacted cells to recover from the impact of other elements of the cycle.There are 22 different mechanisms represented by the arrows in the NOONOO cycle of which 19 are wellaccepted biochemistry 21. The other 3 are less well documented but have been reported in apparently reliable studies. Overall there is extensive evidence supporting the individual mechanisms of the NOONOO cycle and what needs to be questioned is its physiological relevance to these multisystem illnesses.Five PrinciplesThere are five principles underlying the NOONOO cycle as an explanatory model of these illnesses 21 the first two of which we have already discussedShort term stressors that initiate cases of multisystem illnesses act by raising nitric oxide synthesis and consequent levels of nitric oxide and its oxidant product peroxynitrite. Initiation is converted into a chronic illness through the action of vicious cycle mechanisms through which chronic elevation of nitric oxide and peroxynitrite and other cycle elements is produced and maintained. Symptoms and signs of these illnesses are generated by elevated levels of nitric oxide andor other important consequences of the proposed mechanism i.e. elevated levels of peroxynitrite or inflammatory cytokines oxidative stress and elevated NMDA and vanilloid receptor activity. Because the compounds involved nitric oxide superoxide and peroxynitrite have quite limited diffusion distances in biological tissues and because the mechanisms involved in the cycle act at the level of individual cells the fundamental mechanisms are local. Therapy should focus on downregulating NOONOO cycle biochemistry. Ill discuss examples of principle 3 later on this web page as well on the specific pages dedicated to three of these illnesses multiple chemical sensitivity chronic fatigue syndrome and fibromyalgia. The fourth principle is a very important one. Because the compounds involved nitric oxide peroxynitrite and superoxide have relatively short half lives in biological tissues and because the mechanisms of the cycle act at the cellular level the basic mechanism of the cycle is local. Consequently the cycle may severely impact one tissue of the body but an adjacent tissue may be largely unimpacted. Thus because the tissues impacted by the cycle may vary from one patient to another this easily explains why the symptoms and signs of illness vary so much from one patient to another. This variability in symptoms and signs has been one of the great puzzles of these multisystem illnesses and it is easily resolved by the NOONOO cycle mechanism. I am not saying that there are no systemic changes in these illnesses but rather that the main changes are local.The fifth principle is the most important one for the sufferers of these illnesses and for the dedicated physicians and other health care providers who are trying to effectively treat them. We need to lower the NOONOO cycle biochemistry for effective treatment treating symptoms will never be very effective because symptomatic treatment does not get at the basic cause of illness. I will argue below that we do have five effective treatment protocols each using multiple agents that downregulate NOONOO cycle biochemistry.Elevation of NOONOO Cycle Elements in the Chronic Phase of IllnessThe chronic phase of these multisystem illnesses the only phase that can usually be studied in humans is typically studied years or decades after the initiation of illness. Nevertheless where NOONOO cycle elements have been studied they have been reported to be elevated. Clearly one needs to explain how these may be elevated years after the initiation of illness and the NOONOO cycle mechanism provides such an explanation. Among the cycle elements that have been studied are oxidative stress nitric oxide synthesis inflammatory cytokine levels lower mitochondrialenergy metabolism NMDA activity and vanilloid activity. Peroxynitrite itself has not been studied but its elevation can be inferred from the elevation of nitric oxide synthesis and of oxidative stress. Some of these elements have only been studied in some multisystem illnesses. For example vanilloid activity has only been studied to my knowledge in FM and in MCS being apparently elevated in both. Inflammatory cytokines have only been studied in CFS FM and in PTSD but not in MCS however it is reported that chemical exposure can increase such cytokine levels. In general where data are available elements of the NOONOO cycle appear to be elevated in the chronic phase of multisystem illnesses 152128.Three Generic Types of Evidence for the Existence of the NOONOO CycleThere are three generic types of evidence that is evidence not linked to any specific diseasesupporting the existence of the NOONOO cycle reviewed in my book ref 21. One is a series of studies showing that treatment with two drugs known to act to increase nitric oxide levels can produce increases in nitric oxide synthesis. These two drugs nitroglycerine and nitroprusside are both known to chemically break down and one of the break down products is nitric oxide. They are reported to lead to increased nitric oxide synthesis in the body due to the action of all three nitric oxide synthases. This provides evidence for a vicious cycle leading to increased nitric oxide synthesis via all three synthases but does not provide evidence for any of the other elements of the NOONOO cycle. A second type of generic evidence is from studies of hyperalgesia the process that produces excessive perception of pain. It has been shown that all of the elements of the NOONOO cycle are involved in the generation of excessive pain hyperalgesia. It is difficult to see how all of these elements can be involved here unless they are linked together by such a cycle as the NOONOO cycle. What is surprising is that cycle elements are elevated both in the painful tissues and also in that region of the spinal cord that is involved in pain processing the dorsal horn regions of the spinal cord. Thus two types of regions of the body appear to have NOONOO cycle elevation in hyperalgesia. One of the consequences of these mechanisms is that it provides a simple explanation for the excessive pain in these multisystem illnesses NOONOO cycle elevation produces chronic pain through the same mechanisms previously documented in hyperalgesia.The third type of generic evidence for the cycle reviewed in my book is the finding that NMDA stimulation leads to increased activity for essentially all of the elements of the NOONOO cycle. NMDA stimulation is known to allow the flow of calcium ions Ca 2 into the cytoplasm of the cell leading in turn to stimulation of the two nitric oxide synthases that are calciumdependent nNOS and eNOS. Thus two cycle elements are elevated initially intracellular calcium and nitric oxide but this leads to elevation of the other cycle elements as well. All the major elements of the NOONOO cycle are reported to be elevated following NMDA stimulation 21. This provides evidence that the NOONOO cycle or something very similar to it can act in living cells in response to NMDA stimulation.Shared Symptoms and Signs Found in Multisystem Illnesses In Chapter 3 in my book 21 I look at a 17 distinct symptoms and signs that are found in several of these multisystem illnesses and several of these were discussed in an earlier paper 23. Most of these are often found in all four of these illnesses although there are some which have only been studied in two or three of them. Most of these only occur in some patients reflecting the high variability of symptoms and signs that was discussed above. Many people have repeatedly claimed that these symptoms and signs are unexplained but that is no longer true. In my book and in some cases in an earlier paper 23 I present a number of plausible mechanisms by which these symptoms and signs can be generated by NOONOO cycle elements. These are presented as plausible mechanisms not as established mechanisms in these illnesses. Several of these are listed in Table 2Table 2 Plausible Mechanisms for Symptoms and Signs of Multisystem Illnesses Symptom or sign Plausible mechanismLearning and memory dysfunction Excessive levels of nitric oxide in brain energy metabolism dysfunction in brain due to peroxynitrite nitric oxide and superoxide Fatigue Energy metabolism dysfunction in brain due to peroxynitrite nitric oxide and superoxide Chronic excessive pain Hyperalgesia mechanisms due to all of the elements of the NOONOO cycle Anxietypanic attack Excessive NMDA activity in the amygdala of the brain Brain PET scan abnormalities Energy metabolism dysfunction leading to lowered fluorodeoxyglucose transport in the brain changes in blood flow produced by nitric oxide peroxynitrite and isoprostanes Brain SPECT scan abnormalities Changes in accumulation of probe molecule due to lowered reduced glutathione in brain which is produce in turn by peroxynitritecaused oxidative stress Immune NKcell dysfunction Produced by oxidant damage and specifically by elevated levels of superoxide Depression Increased nitric oxide in brain Sleep disturbance Produced by elevated levels of inflammatory cytokines increased nitric oxide and increased NF kB activity Orthostatic intolerance Two possible mechanisms both involving nitric oxide nitric oxide effects on autonomic nervous system activity and also local nitric oxidemediated vasodilation Irritable bowel syndrome Nitric oxide and vanilloid effects on GI tract function Food allergies Peroxynitritemediated intestinal hyperpermeability leading to increased food antigen absorption and immune response to such antigens Evidence for each of these is presented in my book 21.It can be seen from Table 2 that a diverse group of shared symptoms and signs can be generated via known mechanisms from elements of the NOONOO cycle providing plausible mechanisms for such symptom generation. Thus these symptoms and signs should no longer be considered to be unexplained. I will consider how what are viewed as unique symptoms of signs of MCS CFS or FM may be generated on the web pages dedicated to each of these individual illnesses. TherapyThe fifth principle of the NOONOO cycle is that therapy should focus on downregulating NOONOO cycle biochemistry. In other words lower the cause of illness. Let me state at the outset that I am a Ph.D. not an M.D. and nothing here should be viewed as medical advice. There are several challenges to therapies aimed at lowering NOONOO cycle biochemistry. The first of these is that we need to stop doing things that upregulate this biochemistry and there are various stressors that upregulate this biochemistry therefore are of obvious concern. The second is that the complexity of the NOONOO cycle makes it difficult to downregulate and makes it likely that we will need to use multiple agents in order to be effective in such downregulation. We dont have a magic bullet to treat these illnesses and may have to rely therefore on complex combinations of agents each of which may produce an incremental improvement by lowering aspects of the cycle mechanism. The third is that peroxynitrite the most central element in the NOONOO cycle is difficult to effectively scavenge in vivo and therefore approaches based solely on scavenging peroxynitrite may not be expected to be effective. Lets consider the first of these challenges. Such stressors as chemical exposure in MCS excessive exercise in CFS and psychological stress especially in PTSD should be avoided to have any expectation of effective therapy. Each of these stressors are expected to upregulated NOONOO cycle activity in these individual illnesses. Foods to which individuals have developed food allergies should be avoided as antibodyantigen reactions cause tissues to increase nitric oxide synthesis. Excitotoxins can stimulate NMDA activity and upregulate NOONOO cycle biochemistry and should therefore be avoided. Excitoxins include monosodium glutamate aspartame and possibly certain other flavorings such as hydrolyzed vegetable proteins.In Chapter 15 of my book I consider 30 different agents or classes of agents that are available today and are predicted to downregulate NOONOO cycle biochemistry and are predicted therefore to be potentially useful therapeutic agents. I will add a 31 st such agent that was suggested to me by Dr. Jacob Teitelbaum. Each of these are listed in the long table that follows.Table 3 Agents Predicted to DownRegulate NOONOO Cycle Biochemistry Agent or class Mechanisms EvidenceTocopherolstocotrienols Chain breaking antioxidants. Gammatocopherol may have special role in peroxynitrite scavenging and tocotrienols are reported to have special roles in protecting from excitoxicity Ascorbate Chain breaking antioxidant may also scavenge peroxynitrite helps to regenerate other antixoxidants CT Coenzyme Q10 Stimulates mitochondrial function scavenges peroxynitrite lowers NMDA activity CT selenium Antioxidant properties selenium compounds are peroxynitrite scavengers replete deficiencies carotenoids Scavenge peroxynitrite in membranes flavonoids Complex group of phenolic antioxidants with multiple and variable functions chain breaking antioxidants lower NF kB activity scavenge peroxynitrite superoxide and nitric oxide allow regeneration of other antioxidants CT TMG choline SAMe others Compounds with methyl groups attached to positively charged nitrogens or sulfurs act to relieve reductive stress CT Carnitine acetyl carnitine Improved transport of fatty acids into mitochondrion for energy metabolism and regeneration of mitochondrial inner membrane others? CT phospholipids May allow regeneration of oxidized mitochondrial inner membrane lipids phosphatidyl choline may act to lower reductive stress CT? Hydroxocobalamin B 12 Potent nitric oxide scavenger limited uptake when taken orally other forms of B 12 may act as precursor but with probable lower efficacy. CT Vitamin B 6 pyridoxal phosphate Lowers excitoxicity by improving balance between glutamate and GABA COA Riboflavin and also 5phosphate May increase glutathione reductase activity and thus increase reduction of oxidized glutathione Other B vitamins Improve energy metabolism replete deficiencies Reduced glutathione and precursors Reduced glutathione not effective taken orally precursors should probably be limited in dosage used. Most important antioxidant synthesized in body many functions. COA alipoic acid Helps restore reduced glutathione antioxidant activity regenerate other antioxidants lowers NF kB activity quality of supplements seems to be quite variable Mg 2 Magnesium acts to lower NMDA activity improve energy metabolism replete deficiencies CT Zn 2 Mn 2 Cu 2 Precursors of superoxide dismutases antioxidant activity replete deficiencies doses should be modest riluzole Lowers glutamate release excitoxicity taurine Lowers excitoxicity NF kB activity iNOS induction Ca 2 NMDA antagonists gabapentin Lower excessive NMDA activity lower response to chemical exposure in MCS CT Inosine Increases uric acid pools which scavenges in turn peroxynitrite breakdown products may also act to speed recovery of ATP pools possible downside may include increased mast cell activity Long chain omega3 fatty acids Lower iNOS induction lower NF kB activity replete deficiencies CT Agents that lower NF kB activity Lower NF kB activity COA? Curcumin Similar of flavonoids in actions Algal supplements Rich in antioxidants CT Hyperbaric O 2 treatment May act via hydrogen peroxide to induce synthesis of tetrahydrobiopterin and therefore decrease NOS uncoupling CT Minocycline tetracyclines Lowers iNOS induction NMDA activity creatine Lowers excitotoxicity Lowers vanilloid activity Panax ginseng? Guaifenesin? Expected to lower vanilloid activity COA? carnosine Reported peroxynitrite scavenger unusual antioxidant TRH Lowers NMDA activity Dribose Increases recovery of ATP pools after energy metabolism dysfunction may increase reduction of oxidized glutathione COA Evidence is listed as being clinical trial evidence CT or clinical observationsanecdotal evidence COA or none based solely on studies of CFS MCS FM or closely related illnesses. It can be seen from Table 3 that there are many different agents that are promising candidates for therapy. Most of them are nutritional supplements. There is some evidence for efficacy of individual agents based on clinical trials CT or from clinical observations andor anecdotal evidence COA but in most cases the individual agents where they seem to be effective have relatively modest effectiveness. The suggestion is that combinations of these agents may be much more effective than individual agents. This combination therapy has been the approach taken by five different physicians in developing their treatment protocols and such combination therapy approaches appear to be the most promising of all therapeutic approaches for treatment of these illnesses.Five physicians have developed complex treatment protocols for these multisystem illnesses. Three of these have focused on the treatment of chronic fatigue syndrome or closely related fatiguing illness one on both chronic fatigue syndrome and fibromyalgia and one on chemically sensitive patients. Each of these protocols uses from 14 to 18 different agents or classes of agents that are predicted to downregulate NOONOO cycle biochemistry! While two of these protocols Teitelbaums and Cheneys contain substantial numbers of agents not obviously related to the NOONOO cycle each contains many agents predicted to downregulate the cycle. The treatment protocols are outlined in the lists that followDr. Paul Cheney has developed his treatment protocol based on clinical observations and has honed it over the past two decades of treatment of chronic fatigue syndrome patients. He advises trying to avoid things that exacerbate the NOONOO cycle mechanism some of the same things that I discussed above. Specifically he suggests attenuating GI tract problems by such strategies as going on a low food allergen diet minimizing environmental chemical exposure and also minimizing inflammatory diseases such as around the teeth. The agents that I list are followed in some cases by comments on how they may actthose comments are mine not Cheneys.High dose hydroxocobalamin B12 injections potent nitric oxide scavenger Whey proteinglutathione precursor Guaifenesinvanilloid antagonist? NMDA blockers Magnesiumlowers NMDA activity Taurineantioxidant and acts to lower excitotoxicity including NMDA activity GABA agonistsGABA acts as an inhibitory neurotransmitter to lower NMDA activitythese include the drug neurontin gabapentin Histamine blockersmast cells which release histamine are activated by both nitric oxide and vanilloid stimulation Chapter 7 and may therefore be part of the cycle mechanism Betaine hydrochloride HClBetaine lowers reductive stress the hydrochloride form should only be used in those with low stomach acid. Betaine trimethylglycine is also listed separately in the protocol description Antioxidants listed as followsFlavonoids including bioflavonoids olive leaf extract organic botanicals hawthorn extract Vitamin E forms not listed Coenzyme Q10acts both as antioxidant and to stimulate mitochondrial function alipoic acid Selenium Omega3 and 6 fatty acids Melatoninas an antioxidant that may act in the brain Pyridoxal phosphateimproves glutamateGABA ratio Folic acidlowers uncoupling of nitric oxide synthases Cheney prescribes for his patients a total of 18 distinct agents or classes of agents each of which can be viewed as downregulating aspects of the NOONOO cycle. I would argue that this in not just coincidental that it argues in support of the NOONOO cycle mechanism.Dr. Jacob Teitelbaum has published placebocontrolled trial data supporting the efficacy of one version of his protocol 2930 something none of these other physicians has done. It seems to be effective on both chronic fatigue syndrome and fibromyalgia patients. I am going to describe a recent version of his complex protocol focusing on what may be the central parts of the protocol the parts described as nutritional treatments and mitochondrial energy treatments. The last agent in the list Dribose was added to the protocol recently personal communication.Daily energy BcomplexB vitamins including high dose B 6 riboflavin thiamine niacin and also folic acid. These fall into four categories that I have listed earlier in the chapter Betaine hydrochloride HCllowers reductive stress hydrochloride form should only be taken by those deficient in stomach acid Magnesium as magnesium glycinate and magnesium malatelowers NMDA activityoften uses magnesium injections aLipoic acidimportant antioxidant helps regenerate reduced glutathione Vitamin B 12 IM injections 3 mg injections does not state whether this is hydroxocobalaminmay act as potent nitric oxide scavenger Eskimo fish oilexcellent source of long chain omega3 fatty acids. Lowers iNOS induction antiinflammatory Vitamin C Grape seed extract flavonoid Vitamin E naturaldoes not state whether this includes gtocopherol or tocotrienols Physicians protein formula used as glutathione precursor Zincantioxidant properties and copperzinc superoxide dysmutase precursor AcetylLcarnitineimportant for restoring mitochondrial function Coenzyme Q10both important antioxidant properties and stimulates mitochondrial function Driboseacts to increase rate of ATP and reduced glutathione regeneration If you consider that the oral B vitamins fall into four categories listed earlier in the chapter Teitelbaum uses a total of 18 agents or classes of agents that are predicted to downregulate the NOONOO cycle in the core part of his treatment protocol. Dr. Garth Nicolson started his scientific career developing the famous SingerNicolson fluid mosaic model of biological membranes a model that is described in essentially all of the standard biochemistry textbooks. He and his colleagues have published on open label trials of a complex proprietary mixture known as NT factor TM apparently designed to improve mitochondrial and thus energy metabolism function. The trials have been on a group of older patients with unexplained chronic fatigue and consequently there is some question whether these patients have CFS. Nevertheless Nicolson and coworkers 3133 report statistically significant improvements in fatigue and in several other changes often found in multisystem disease patients affectivemeaning sensory and cognitivemood. Many of the NT factor components are predicted to lower much of the NOONOO cycle biochemistry. Unfortunately there is no detailed description of the concentrations of the components of the NT factor proprietary mixture. The mixture contains the following components that are predicted to lower NOONOO cycle biochemistry Polyunsaturated phosphatidyl cholinepredicted to lower reductive stress Other phosphatidyl polyunsaturated lipidsthis and the phosphatidyl choline are predicted to help restore the oxidatively damaged mitochondrial inner membrane Magnesiumlowers NMDA activity may aid in energy metabolism Taurineantioxidant activity and lowers excitoxicity including NMDA activity Artichoke extractas flavonoid source? Spirulinabluegreen alga is a highly concentrated antioxidant source Natural vitamin Edoes not tell us whether this includes g tocopherol or tocotrienols Calcium ascorbatevitamin C a Lipoic acidimportant antioxidant key role in regeneration of reduced glutathione but also has role in energy metabolism Vitamin B 6balance glutamate and GABA levels lowers excitotoxicity Niacinrole in energy metabolism Riboflavinimportant in reduction of oxidized glutathione back to reduced glutathione also has important role in mitochondrial function Thiaminrole in energy metabolism Vitamin B 12as nitric oxide scavenger? Folic acidlowers nitric oxide synthase uncoupling The way I have categorized these earlier on this site and in Chapter 15 of my book these agents fall into 15 distinct classes of agents expected to lower NOONOO cycle biochemistry. Dr. Neboysa Nash Petrovic is a South African physician who I believe also has a clinic in England. His CFS treatment protocol 34 has been described as follows I am unsure how current this is Valine and isoleucinebranched chain amino acids known to be involved in energy metabolism in mitochondria and may be expectedtherefore to stimulate energy metabolism modest levels may also lower excitotoxicity Pyridoxine B 6improves balance between glutamate and GABA lowers excitotoxicity Vitamin B 12 in the form of cyanocobalamincyanocobalamin is converted to hydroxocobalamin in the human body but the latter form will be more active as a nitric oxide scavenger since it does not require such conversion Riboflavinhelps reduce oxidized glutathione back to reduced glutathione Carotenoids alphacarotene bixin zeaxanthin and luteinlipid fat soluble peroxynitrite scavengers Flavonoids flavones rutin hesperetin and others Ascorbic acid vitamin C Tocotrienolsforms of vitamin E reported to have special roles in lowering effects of excitotoxicity Thiamine aneurinB vitamin involved in energy metabolism Magnesium Zinc Betaine hydrochloride HCllowers reductive stress hydrochloride form should only be used by those deficient in stomach acid Essential fatty acids including long chain omega3 fatty acids Phosphatidyl serinereported to lower iNOS induction 3536 According to the way I have listed these agents his protocol contains 14 agents or classes of agents predicted to downregulate NOONOO cycle biochemistry. My Own Effort to Develop a Treatment Protocol My effort to apply the NOONOO cycle mechanism to the treatment of these multisystem illnesses was in cooperation with Dr. Grace Ziem in Maryland. The history of this collaboration and our respective roles are described in my book. The protocol was developed to try to effectively treat Dr. Ziems chemically sensitive chemically injured patients patients that she does not consider to be MCS patients. Her views on this are described in my book 21 and on her web site 37. The protocol described below is only effective according to Dr. Ziem when her patients minimize chemical exposure consistent with the view that we need to avoid upregulating the NOONOO cycle for these agents to be effective. The protocol as described in my book contains the following agents Nebulized inhaled reduced glutathione Nebulized inhaled hydroxocobalamin some use sublingual Mixed natural tocopherols including g tocopherol Buffered vitamin C Magnesium as malate Four different flavonoid sources Ginkgo biloba extract cranberry extract silymarin and bilberry extract Selenium as seleniumgrown yeast Coenzyme Q10 Folic acid Carotenoids including lycopene lutein and b carotene a Lipoic acid Zinc modest dose manganese low dose and copper low dose Vitamin B 6 in the form of pyridoxal phosphate Riboflavin 5phosphate FMN Betaine trimethylglycine Patients are advised to use environmental controls to reduce exposure to volatile organic solvents pesticides and other irritant chemicals wherever possible. Dr. Ziem finds that her most severely chemically injured patients need to be started on much lower doses of the glutathione and a lipoic acid increasing exposure as they see initial improvement. The therapeutic agents were compounded by Key Pharmacy in Kent Washington which has been calling it their neural sensitization protocol. Key Pharmacy has a web site that lists their email address and phone number and consequently further information can be easily obtained. Dr. Ziem reports four distinct observations about her patients 21 The majority of her patients suffering from reactive airways were placed on this protocol during the first half of 2004 and almost all of them were on it or most of it by spring 2005. Patients coming back to see her report consistent improvement of their symptoms including respiratory symptoms fatigue cognitive function and usually migraine. Improvements were well above those seen with her previous treatment approach. Historically Dr. Ziem has gotten many emergency calls each summer from patients who have become very ill from nearby pesticide spraying. In the summer of 2004 she did not receive any such calls from her patients on the protocol. In the summer of 2005 she received only one such call from a patient on the protocol who was directly exposed to pesticide spray. Two of her patients reported being completely asymptomatic something she had not seen before. These were however still controlling their environment to minimize exposure and still on the protocol. Patients seem to be improving at such a rapid rate that many are no longer coming in regularly to see her. She is now able to take new patients at 10 to 15 times the previous rate. In order to assess the progress of the patients who are no longer coming in Mr. Jim Seymour has contacted 30 such patients and all 30 report substantial improvement in their symptoms. However the majority of them are not on the complete protocol reporting that they are unable to afford it. Seymours subjective assessment is that those on the complete protocol have seen much greater improvement than have those on only part. As of the beginning of 2006 two additional agents are being added to the oral part of the protocol acetylLcarnitine and taurine. We are considering adding one or two flavonoidcontaining extracts that scavenge superoxide. The current protocol then contains 17 different agents or classes of agents that are predicted to downregulate NOONOO cycle biochemistry. Dr. Ziem states in a personal communication 21 that I consider the protocol to be the most significant medical advance ever for chemical injury but it is not a substitute for environmental controls. It does gradually allow patients to be in social environments with fewer symptoms and less severe exacerbation. I have talked with other physicians who have used this protocol with apparent favorable response in their CFS and FM patients. It may be effective therefore in a variety of NOONOO cycle diseases. The Tenth Paradigm of Human Disease What we have been describing here is an etiologic mechanism centered on certain morbid processes which explain the four multisystem illnesses and possibly other diseasesillnesses both prominent and obscure. It argues that the multisystem illnesses are true diseases caused by this mechanism albeit diseases that are highly variable from one individual to another because of the variation of tissue distribution of the underlying biochemistry. They constitute in other words a disease spectrum.The NOONOO cycle mechanism fits into the history of diseases 21 Chapter 14 as shown in Table 4Table 4 Ten Paradigms of Human DiseaseInfectious disease Nutritional deficiency disease such as beri beri or scurvy Genetic diseasethose whose predominant cause is mutation of a specific gene Hormone dysfunction disease including those with too much or too little hormone function Serial somatic mutation and selectionvarious types of cancer Ischemic cardiovascular disease Allergies Autoimmune disease Amyloid diseases including prion diseases NOONOO cycle diseases The reported prevalences of multisystem illnesses have been fairly wellstudied in the U.S. at least and they are comparable with the prevalences of the other major disease paradigms shown in bold face. It can be argued that the tenth paradigm NOONOO cycle diseases may well be one of the top four disease paradigms in terms of its overall impact on human health.Could It Be Wrong?Could the NOONOO cycle explanation of multisystem illnesses be wrong? Could this tenth paradigm of human disease be fictional? There are certainly many areas where there are little or no data to support predictions of the cycle model and many others where the data that is available is inadequate to support current standards of evidence. In addition the cycle as outlined in Figure 1 may be oversimplified both because certain aspects of it may be missing in certain tissues and because additional cycle elements are likely to be involved in certain tissues as well. Nevertheless the therapy discussion strongly suggests that the cycle makes very useful predictions in terms of therapy and therefore is sufficiently comprehensive to be a useful predictive model. Let me focus on two important features. Firstly it is the only explanatory model that explains not just one but all of these multisystem illnesses. Consequently it is the only available model to fit the prediction that many scientists have made that these must share a common etiologic mechanism. Secondly the cycle mechanism itself as diagrammed in Figure 1 is based almost entirely on wellestablished biochemical mechanisms. The only thing that is new about it is the assumption that the elements of the cycle fit together as predicted by these mechanisms and constitute therefore a vicious cycle. It is that simple prediction that underlies all of the explanatory power of the model. In the last chapter of my book I list 12 puzzling features of these illnesses that are explained by the NOONOO cycle mechanism including its five underlying principles. None of these had been previously explained and this lack of explanation has been what has led in part to the repeated claims that these are unexplained illnesses. The 12 features explained by the NOONOO cycle are as followsIt provides explanations for the etiology of not just one but all four of these multisystem diseases.It explains their chronic nature. It explains how cases can be initiated by 12 diverse and distinct stressors. It explains the diverse biochemical and physiological properties of the chronic phase of these diseases. It explains how 18 different agents or groups of agents may individually produce reported improvements and how the complex treatment protocols of five different physicians may lead to major improvements in sufferers. It explains 16 of the shared symptoms and signs of these diseases symptoms and signs that have repeatedly been described as being previously unexplained. It explains the symptoms that are specific for each type of disease symptoms that can be explained by the influence of the NOONOO cycle on specific tissues. It explains their high comorbidity with each other. It explains their high comorbidity with such wellaccepted diseases as tinnitus asthma migraine lupus and rheumatoid arthritis. It explains 11 distinct puzzling feature of MCS only one of which was adequately explained previously. It explains the properties of animal models of CFS MCS and PTSD each of which provides evidence in turn supporting a NOONOO cycle etiology. It explains the stunning qualitative and quantitative variation in symptoms from one patient to another. If you take away the central mechanism of the NOONOO cycle as it is described in Figure 1 all of these explanations disappear and we are left with an unstructured list of unexplained observations. It is this stunning fit between observation and prediction that tells us that the basic features of the NOONOO cycle explanatory model cannot be wrong! The NOONOO cycle explanatory model is like an arch where the basic cycle mechanism is the keystone. If you remove the keystone the whole arch collapses into a rubble of scattered stones and it is the complete collapse that tells us how the arch is organized to make a compelling structure. The cycle mechanism which is based on a simple and evident assumption is the keystone that is essential for understanding these multisystem illnesses. Richard Feynman the great 20 th century scientist was called by Omni magazine the smartest man in the world and has also been considered to be a great skeptic. Feynman wrote that It is possible to know when you are right way ahead of checking all the consequences. You can recognize truth by its beauty and simplicity. It is that beauty and simplicity and comprehensiveness that tells us that the NOONOO cycle model is fundamentally right.Specific web pages Multiple Chemical SensitivityChronic Fatigue SyndromeFibromyalgiaHow to Support this ResearchReferences1. Miller CS. 1999 Are we on the threshold of a new theory of disease? 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