"Would those who say 'it cannot be done' kindly not interrupt those who are doing it.

"

[Chinese proverb]

Introduction ========= Wondro was the trade name of a herbal medicine manufactured and marketed in the first half of the twentieth century. Thousands of testimonial letters were received spanning such a wide cross section of humanity and ailments that either these individuals were suffering from a shared mass psychosis or there is a common denominator to disease that has gone unrecognized. This document investigates Wondro from a biochemical perspective to examine why it might have had such beneficial results for so many different diseases. It also explores a simple alternative protocol based upon the proposed mode of action for Wondro and the features of Wondro that increased its efficacy. Both Wondro and its proposed alternative "do no harm". They are benign substances without side effects. However, if the theories considered herein are correct, then they may produce amazing results in intractable cases by allowing the body to heal itself. The contents of some of the letters (circa 1930's) are published in a separate document "Wondro Testimonials Pamphlet". The work "Astrophysiology...and Yeast" investigates how Wondro (or its alternative protocol) could integrate into a comprehensive strategy for improved well-being. See "RELATED WORKS". This a work in progress. Check the "REVISION HISTORY" section for the latest updates.

CAUTION: Although the techniques and supplementation protocols described herein are minimalist by design, a qualified health practitioner should always be consulted before making any significant changes to your daily regimen to ensure that they are compatible with your own personal medical profile.

[2012-07]

[Note: This work may be freely quoted and copied unchanged with attribution to the source.]

CONTENTS Cover page quote ............................................... Introduction .................................................... Contents ........................................................ List of figures ................................................. 2 3 4 6

Wondro -- Snake Oil or Miracle Cure? ............................ 12 Wondro for One .................................................. 14 Wondro Alternative Protocol ..................................... 18 Just A Teaspoon Of Sugar ........................................ 20 Daily Toxic Spill ............................................... 21 Starvation Diet? ................................................ 23 Sulphur Sulphur Everywhere ...................................... 25 Pseudo Heavy Metal .............................................. 28 Carnosine ....................................................... 30 Message From MMS? ............................................... 31 Acetaldehyde -- Liquid Or Vapor? ................................ 33 Scavenger Hunt .................................................. 37 -- Enolate Ion and Crotonaldehyde ............................. 37 -- Dimethyl Fumarate .......................................... 37 -- Quinones ................................................... 39 -- Coenzyme Q10 ............................................... 39 -- Vitamin K .................................................. 41 -- Lapachol (Pau D'arco) ...................................... 41 -- Progesterone ............................................... 41 -- Prednisone ................................................. 45 -- Humic Acids (Dirt for Dessert) ............................. 47 -- An Apple A Day ............................................. 49 -- Acetaldehyde Scavenger Attributes .......................... 51 -- Wondro ..................................................... 54 Soda Pop Stow-Away .............................................. 61 Signposts Of Disease ............................................ 73 Bridge Across The Chasm ......................................... 74 Geepers Creepers (GPCRs) ........................................ 77 Not So Tight Junctions .......................................... 80 Slow Death By Strangulation ..................................... 82 Deep Throat ..................................................... 85 Mostly Mucus .................................................... 87 Pulmonary Peroxidosis ........................................... 90 Toxic Soup ...................................................... 94 When The Backup Fails .......................................... 101 Neural Short Circuits .......................................... 103 Enzyme Killer .................................................. 105 -- Choline Acetyl Transferase ................................ 105 -- Glucosamine Phosphate N-acetyl Transferase ................ 105

Cellular Mayhem ................................................. -- Prostaglandins ............................................. -- DNA Repair ................................................. To Go Or Not To Go .............................................. Hair Trigger Allergies .......................................... Catecholamines In Chaos ......................................... Tryptophan Starvation ........................................... Caught In A Loop ................................................ Reactive Oxygen Species ......................................... Double-Edged Sword .............................................. Rear-View Mirror ................................................ Autism .......................................................... Friendly Giant .................................................. Acetaldehyde Game ............................................... Cellular Electron Ping-Pong ..................................... -- Nicotinamide ............................................... -- Tryptophan ................................................. -- OPK and NAD+/NADH Balance .................................. -- Light Therapy and NAD+/NADH Balance ........................ -- Bipolar Disorder ........................................... -- Lithium Carbonate .......................................... -- Valpromide ................................................. -- Carbamazepine .............................................. -- Lamotrigine ................................................ -- Topiramate ................................................. Oddball Amino Acid .............................................. Dr. Jekyll and Mr. Acetaldehyde ................................. -- Amyloid Plaques ............................................ -- Spermatozoa Acrosomes ...................................... -- Mercury Inhibition of Aldehyde Dehydrogenase ............... -- Albumin Binding ............................................ -- Autoimmunity Activation .................................... -- Iodine Depletion ........................................... -- Necrotizing Enterocolitis .................................. -- Fibrosis ................................................... Fate Of Wondro .................................................. End Of Illness? ................................................. INDEX

109 109 109 110 112 114 119 126 127 131 136 141 144 147 152 152 156 156 158 158 158 160 160 163 163 167 170 170 170 170 172 172 172 172 172 173 174

LIST OF FIGURES Wondrenic Acid ......................................... Front Cover Wondro/Laxico ................................................... 13 Wondro Before Heating ........................................... 15 Wondro After Heating ............................................ 15 Acetaldehyde .................................................... 16 Linolenic Acid .................................................. 16 Wondrenic Acid .................................................. 17 Wondrenic Acid + Acetaldehyde ................................... 17 Wondro Alternative Protocol ..................................... 19 Candida Albicans (Budding Phase) ................................ 24 Candida Albicans (Hyphal Phase) ................................. 24 Sulphur, Sulphur Everywhere ..................................... 26 EDTA chelation .................................................. 29 Carnosine ....................................................... 29 Carnosine + Acetaldehyde ........................................ 29 Acetaldehyde, Carbon Dioxide, Water ............................. 34 Acetaldehyde Hydrogen-Bonding With Water ........................ 34 Hydrated Acetaldehyde (1,1-ethanediol) .......................... 34 Acetaldehyde + Resonance-stabilized Enolate Ion ................. 38 Ach Enolate + 3-Hydroxy Butanal ................................. 38 Crotonaldehyde .................................................. 38 Candida Albicans, Acetaldehyde, Crotonaldehyde .................. 38 Nucleophilic Attack On Methyl Formate ........................... 40 Dimethyl Fumarate ............................................... 40 Acetaldehyde + Dimethyl Fumarate ................................ 40 Fumaric Acid .................................................... 40 1,4-Benzoquinone ................................................ 42 Acetaldehyde + 1,4-Benzoquinone ................................. 42 Coenzyme Q10 .................................................... 43 Lovastatin ...................................................... 43 Menadione ....................................................... 44 Phylloquinone ................................................... 44 Menaquinone ..................................................... 44 Lapachol ........................................................ 44 Progesterone .................................................... 46 Prednisone ...................................................... 46 Acetylsalicylic Acid (Aspirin) .................................. 46 Typical Humic Acid .............................................. 48 Fulvic Acid ..................................................... 48 An Apple A Day Keeps The Doctor Away! ........................... 50 Phloridzin ...................................................... 50 Phloretin ....................................................... 50 Phloroglucinol .................................................. 50 Acetaldehyde Protonation Carbocation ............................ 52 Phloroglucinol Tautomerism ...................................... 52

Acetaldehyde Cross-linking to Ethylidene-diphloroglucinol ....... Ethanol Acetaldehyde Acetic Acid ................................ Tannic Acid ..................................................... Epigallocatechin Gallate ........................................ Quercetin ....................................................... Resveratrol ..................................................... Acetaldehyde Relative Size ...................................... Alpha-Linolenic Acid ............................................ Linoleic Acid ................................................... Alpha-Wondrenic Acid ............................................ Acetaldehyde Ring-Forming Condensation Reaction ................. 1,8-diaminonaphthalene .......................................... 3,4-diaminobenzoic acid ......................................... Anthranilamide .................................................. Allantoin ....................................................... Salicylanilide .................................................. Salicylamide .................................................... Malonamide ...................................................... 3-mercapto-1,2-propanediol ...................................... 2,3-diaminopyridine ............................................. 1,2-diaminoanthraquinone ........................................ Biuret .......................................................... 2-amino-2-methyl-1,3-propanediol ................................ 4,5-dihyroxy-2,7-naphthalene disulfonic acid disodium salt ...... 4-amino-3-hydroxybenzoic acid ................................... 1,2-diaminocyclohexane .......................................... N-acetylglycinamide ............................................. Arginine ........................................................ Asparagine ...................................................... Aspartic acid ................................................... Cysteine ........................................................ Serine .......................................................... 5-amino-1,3,3-trimethylcyclohexylamine .......................... Dimethylaminoterephthalate ...................................... Glycine ......................................................... Methylanthranilate .............................................. Octadecanamide .................................................. Piperazine ...................................................... Stearylamine .................................................... Formaldehdye and Acetaldehyde ................................... Disulphide Bond in Lipoic Acid .................................. Lipoic Acid + Acetaldehyde ...................................... G Protein-Coupled Receptor (GPCR) ............................... GPCR Disulphide Linkage .........................................

52 53 53 53 53 53 55 55 55 55 63 63 63 63 63 65 65 65 65 65 65 67 67 67 67 67 67 69 69 69 69 69 69 71 71 71 71 71 71 75 76 76 78 78

Tight Junctions ................................................. 81 Thyroid and Parathyroid Glands .................................. 83 Acetaldehyde Autoxidation to Peracetic Acid ..................... 91 Diacetyl Peroxide ............................................... 91 Acetic Anhydride ................................................ 91 Hydrogen Peroxide ............................................... 91 Tartrazine, Carmoisine, Sunset Yellow ........................... 95 Anthocyanidins .................................................. 96 Sodium Bisulphite ............................................... 97 Sodium Bisulphite + Acetaldehyde ................................ 97 Acetyl-Sulphate ................................................. 97 Cholesterol Sulphate ............................................ 97 Cysteine + Acetaldehyde ......................................... 99 NMTCA (N-nitroso-2-methylthiazolidine-4-carboxylic acid) ........ 99 Methionine ..................................................... 101 Homocysteine ................................................... 101 Acetyl-CoA and Acetaldehyde .................................... 106 Acetylcholine .................................................. 106 N-acetyl-D-glucosamine 6-phosphate ............................. 107 PGF2-alpha ..................................................... 107 PGE2 ........................................................... 107 Guanine ........................................................ 107 Methylguanine .................................................. 107 O6-methylguanine-DNA-transferase ............................... 107 Serotonin ...................................................... 111 Serotonin + Acetaldehyde ....................................... 111 Histamine ...................................................... 113 Histamine + Acetaldehyde ....................................... 113 Dopamine ....................................................... 115 Dopamine + Acetaldehyde ........................................ 115 Norepinephrine ................................................. 116 Norepinephrine + Acetaldehyde .................................. 116 Monoamine Oxidase .............................................. 117 Serotonin Catabolism ........................................... 117 Tryptophan / N-formyl-kynurenine ............................... 120 Norharmane ..................................................... 120 Tryptophan + Acetaldehyde (3-MTBC) ............................. 120 Reactive Oxygen Species ........................................ 128 Cysteine / Cystine ............................................. 129 N,S-diacetyl-L-cysteine ........................................ 129 Hydroxyl Radical Abstraction of Hydrogen Atom .................. 132 Lipid Peroxide ................................................. 132 Lipid Hydroperoxide ............................................ 132 Malondialdehyde ................................................ 132

Glutathione .................................................... Glutathione Disulphide ......................................... Acetaldehyde and Methylmercury ................................. Acetaldehyde Polarization ...................................... Acetaldehyde and Water ......................................... Mammalian Metallothionein ...................................... Acetaldehyde and Pyridoxal-5'-phosphate ........................ Enzyme Lysine Residue Pyridoxal-5'-phosphate Schiff Base ....... Enzyme Lysine Residue Acetaldehyde Schiff Base ................. Folic Acid ..................................................... Acetaldehyde Schiff Base Formation ............................. Acetaldehyde + Folic Acid ...................................... Cobalamin (Vitamin B12) ........................................ Acetamide ...................................................... Ethylidene-N-N-diacetamide ..................................... Urea ........................................................... Ethylidene-diurea .............................................. Niacin ......................................................... Nicotinamide ................................................... Acetaldehyde Nicotinamide Schiff Base Formation ................ Ethylidene-N,N'-dinicotinamide ................................. Nicotinamide Adenine Dinucleotide .............................. NAD+/NADH Oxidation/Reduction Reaction ......................... Acetaldehyde NAD+ Schiff Base Formation ........................ Tryptophan To Niacin Backdoor Synthesis Pathway ................ Lithium Carbonate .............................................. Valpromide ..................................................... Valpromide + Acetaldehyde ...................................... Carbamazepine .................................................. Carbamazepine + Acetaldehyde ................................... Lamotrigine .................................................... Lamotrigine + Acetaldehyde ..................................... Topiramate ..................................................... Topiramate + Acetaldehyde ...................................... Serine ......................................................... Cysteine ....................................................... Selenocysteine ................................................. Acetaldehyde Frog ..............................................

133 133 137 137 139 139 145 145 145 148 148 148 149 149 149 151 151 153 153 153 153 155 155 155 157 159 159 159 161 161 162 162 164 164 168 168 168 171

REVISION HISTORY 2012-07-31 Initial release. 2012-08-01 ...Toxic Soup p. 94 2012-08-13 ...Comparative Toxicogenomics Database p. 21 ...induction of tolerance to acetaldehyde p. 22 ...Mostly Mucus p. 87 ...Cysteine + Acetaldehyde (MTCA) p. 98 ...MAO/Serotonin catabolism pps. 114-115 2012-08-22 ...When The Backup Fails p. 101 ...Cys/CySS redox potential pps. 127-130 ...Double-Edged Sword p. 131 2012-09-02 ...Rear-view Mirror p. 136 ...Autism p. 141 2012-09-19 ...hydrogen peroxide pps. 31-32 ...Pulmonary Peroxidosis p. 90 ...Friendly Giant p. 144 ...Oddball Amino Acid p. 167 2012-10-01 ...Scavenger Hunt p. 37 2012-10-14 ...Acetaldehyde -- Liquid Or Vapor? p. 33 ...Soda Pop Stow-Away p. 61 2012-11-27 ...An Apple A Day p. 49 ...Tryptophan Starvation p. 119 ...Acetaldehyde Game p. 147 ...Cellular Electron Ping-Pong p. 152 2012-12-20 ...Bipolar Disorder p. 158

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ONLINE LINK INFO "Wondro -- Inside Out" www.scribd.com/doc/101099776 http://www.epubbud.com/book.php?g=7D42SJH6 http://dl.dropbox.com/u/57134457/wio/index.html RELATED WORKS "Astrophysiology and Yeast" www.scribd.com/doc/74090699 www.epubbud.com/book.php?g=7JQU45V8 http://dl.dropbox.com/u/57134457/aay/index.html "Wondro Testimonials Pamphlet" www.scribd.com/doc/76584628 www.epubbud.com/book.php?g=W4S59AQF http://dl.dropbox.com/u/57134457/wtp/index.html ACKNOWLEDGMENTS Jmol: Java viewer for chemical structures in 3D -- www.jmol.org

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Wondro -- Snake Oil or Miracle Cure? ============================= During the first half of the 1900's a father and son team of entrepreneurial pioneers undertook to manufacture and market a substance that had been encountered in Scotland on a trip overseas in 1918. It consisted of flax seed oil and sulphur chemically combined with heat to form a black viscous liquid that was named "Harris' Wonder Health Restorer", a name that was subsequently shortened to "Wondro". In its time it was immensely popular and they received world-wide testimonials from individuals who had experienced almost miraculous improvement from diseases that had previously been considered to be incurable. Although it had a particularly pungent, characteristic odor which made it somewhat unpleasant to take on a spoon, this did not deter those who found relief from their various ailments. With the dubious promise of disease eradication associated with the introduction of antibiotic medications and more stringent regulations regarding the manufacture and distribution of such remedies, Wondro was finally discontinued, much to the disappointment of its many avid proponents who consumed it daily. This particular substance had not been unknown to the medical science of its time as references to similar concoctions called "balsam of sulphur" and "sulphurated linseed oil" have been found in "Dunglison, R., Medical Lexicon, A Dictionary of Medical Science, 1866" and "Griffith, R. E., A Universal Formulary: Preparing And Administering Officinal and Other Medicines, 1874". These documents make no mention of the mode of its action. With the publication of the acetaldehyde hypothesis (C. O. Truss, 1984) further research into this substance has illuminated some possibilities as to why it was so effective. The yeast Candida Albicans exists as a commensal parasite in the alimentary mucosa of human hosts. It is capable of producing acetaldehyde via the decarboxylation of pyruvate formed from sugar and carbohydrates in food intake. Acetaldehyde (see figure "Acetaldehyde") is an organic molecule but miniscule in size in comparison to other biological structures. Carbonyl (C=O) groups are electrophilic because of the electron density shift towards the oxygen atom. This polarizes the molecule and makes it highly reactive towards exposed sulphydryl and amine groups. Acetaldehyde is recognized as a carcinogenic immunosuppressive neurotoxin. Although the exact chemical structure of Wondro is not known, flax oil has a high content of unsaturated linoleic and linolenic fatty acids. These contain double bond carbon to carbon linkages (see figure "Linolenic Acid") in the backbone of the fatty acid. These double bonds create a bend in the physical shape of the fatty acid molecule and make flax oil a liquid at room temperature as opposed to something like butter where the fatty acid chain is saturated. When elemental sulphur and flax oil are combined with heat, it has been proposed that the unsaturated components of the flax oil are vulcanized (see figure "Wondrenic Acid"). In essence the sulphur links into the fatty acids at the double bond junctures. This changes the color and viscosity of the resulting compound from a mixture of yellow sulphur and liquid flax oil to a black slippery substance with a viscosity that increases in proportion to the amount of sulphur used in the reaction. Ingestion of this elixir would result in an alimentary mucosal coating of nucleophilic sulphur-rich fatty acid molecules in an area of the body known for yeast overgrowth. Any acetaldehyde produced by yeast in this region would rapidly combine irreversibly with the sulphurated molecules forming thioester bonds (see figure "Wondrenic Acid + Acetaldehyde") and be unavailable for further interference with normal body metabolism. The fact that Wondro alone, in the absence of any other therapies, could "cure" a variety of diseases has profound implications upon the potential etiology of many, as yet, perplexing conditions. Other sulphurbearing compounds such as N-acetyl-cysteine, lipoic acid, methyl-sulphonyl-methane (MSM) have also been found to be beneficial in numerous disease conditions suggesting a common mode of action related to the presence of the sulphur moiety. Excess unrestrained acetaldehyde alone could be responsible for the manifestation of a host of diverse diseases with the symptoms as varied as the genetic vulnerability of the individuals involved. Wondro was labeled a "blood purifier" and if all that it did was prevent acetaldehyde generated by yeast in the alimentary canal from reaching the bloodstream, then it was true to its claims.

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13

Wondro For One ============= The herbal medicine Wondro, or balsam of sulphur (as it was known to medical science in the late 1800's) is an incredibly simple substance. Heat elemental sulphur and flax oil together so that the sulphur combines with the oil (a form of vulcanization, see cover figure "Wondrenic Acid"). As such it is a compound rather than a mixture such as sulphur and molasses where the sulphur remains in suspension in the sugary goo. Both were used for remedial purposes but those who had used both claimed superior results from Wondro as compared to the sulphur and molasses concoction. Given the availability of pharmaceutical "Precipitated Sulphur, USP" and health food store supplemental "Flax Oil", the resulting compound should not be difficult to make. Since the oil/sulphur mixture is potentially flammable and emits a pungent odor when heated, it is best to limit the risk and smell by making it in single dose quantities only.

WONDRO FOR ONE precipitated sulphur, USP (1/2 tsp) flax oil (2 tbsp)

Measure the oil into a small glass ramekin. Add the powdered sulphur and mix with a milk frother so that the sulphur is well-distributed throughout the oil (see figure "Wondro Before Heating"). Place a glass lid over the ramekin and microwave on high for 5 minutes or until the oil has changed color from a yellowy mixture into a brownish-black viscous liquid (see figure "Wondro After Heating"). Cool and consume on a tablespoon or from an egg cup. If you follow a "make one for tomorrow, take the one made yesterday" procedure, then you don't have to wait for it to cool. A drop of oil of thyme [1] or oil of garlic may be added to the Wondro before consumption to add a known antifungal to the compound. Uncombined elemental sulphur is a potential irritant -- handle with caution. Do NOT use industrial grade linseed oil -- this may be laced with toxic drying agents. Wondro itself does not necessarily cause burping but if foods are consumed that do there may be the return of the accompanying odor experienced when it was consumed. This was considered a minor annoyance to those who were in the dire straits of disease. The only other side effect of regular consumption is a slight tingling sensation when exposed to full sunshine. The consistency of the compound will thicken if more sulphur is used. The residue from the bottom of the large vats in which Wondro used to be made was not discarded. It was mixed into a base of beeswax and marketed as a "Black Ointment" salve for external sores. It was a bit messy and smelly, of course, but highly effective in facilitating the healing process and preventing secondary infections. Thousands upon thousands of favorable testimonials were received covering such a vast diversity of conditions that one cannot but wonder if all of these were not related to a common causality. The commensal yeast acetaldehyde hypothesis (C. O. Truss, The Missing Diagnosis, 1976) may provide this link. The primary site for yeast colonization is the alimentary mucosa and that is where Wondro was active. Its viscous consistency and attractive electronegative sulphur atoms as binding sites would provide an alimentary mucosal coating to intercept any acetaldehyde released by the yeast before it migrated into the bloodstream. This would eliminate the plethora of metabolic interference events resulting from exposure to this vile molecule (see "Dr. Jekyll and Mr. Acetaldehyde"). Now that more is understood about the mode of action of Wondro, an alternative protocol that is easier to make (no heating) and easier to take (odorless) has been proposed (see "Wondro Alternative Protocol"). [1] Braga PC et al. "Thymol inhibits Candida albicans biofilm formation and mature biofilm", Intl Journal of Antimicrobial Agents, Volume 31, Issue 5, Pp. 472-477, May 2008. http://www.ncbi.nlm.nih.gov/pubmed/18329858

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Wondro Before Heating (Yellow)

Wondro After Heating (Black)

15

Acetaldehyde

Linolenic acid (omega-3)

16

Wondrenic Acid

Wondrenic Acid + Acetaldehyde

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Wondro Alternative Protocol ====================== As good as Wondro was in its time, it may be possible to concoct an alternative based upon its mode of action. OBJECTIVES: sulphur must be present as an attractive irreversible binding site for acetaldehyde [Elemental sulphur exists as a tight octatomic ring. This may not provide as much of an externally attractive electronegative profile for acetaldehyde binding as a sulphur atom that is part of another molecular structure. This would explain why the results obtained with Wondro (a sulphur-bearing compound) were superior to "sulphur and molasses" (a mixture). Elemental uncombined sulphur is also a potential irritant to mucous membranes.] consistency of the delivery mechanism should be able to persist in the intestinal villi [Something that is water soluble may not persist long enough to be available for binding when the yeast releases its acetaldehyde. Ideally the substance should be able to coat the external membrane of the budding yeast cells as well.] heating should be avoided [When anything containing essential fatty acids is heated with sulphur, the unsaturated carbon atoms are vulcanized. Although the result may be biologically neutral and not harmful, the health benefits of the essential fatty acids are lost.] easy and quick to prepare [A single dose of Wondro requires 5 minutes of microwave heating time and a few minutes of cooling time before it can be ingested.] palatable for ingestion [Wondro has a distinctive odor and flavor that some may find difficult to adjust to.] PROPOSED WONDRO ALTERNATIVE: 2 tbsp cold-pressed flax oil 2 x 500 mg timed-release N-acetyl-L-cysteine (RESBID) Pour the oil into the egg cup, add the powdered contents of two opened capsules and whiz with a milk frother to emulsify. Consume in the morning before eating. The result is a suspension of combined sulphur atoms (part of a conditionally-essential amino acid derivative) in healthy essential fatty acids that will coat the alimentary surfaces and yeast membranes where it would be immediately available for acetaldehyde binding. There may, of course, be some trade off in efficacy here. Each sulphurated linoleic fatty acid (omega-6) molecule (Wondreic acid) potentially has two sulphur-rich acetaldehyde binding sites and each sulphurated linolenic fatty acid (omega-3) molecule (Wondrenic acid) potentially has three, while N-acetyl-L-cysteine (see figure "Sulphur, Sulphur Everywhere") has only one per molecule (see computations in "Just A Teaspoon of Sugar"). While the alternative protocol may be sufficient for an ongoing "maintenance" program, the original sulphurated flax oil may be more effective initially. They are compatible and may be consumed together, morning and evening, for instance, to capitalize on the merits of both.

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Wondro Alternative Protocol -- NAC Emulsified in Flax Oil

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Just A Teaspoon Of Sugar ==================== We're not just talking about a few acetaldehyde molecules here and there. To put things into perspective let's see what happens in the worst case scenario if budding yeast in the gut gets a hold of and metabolizes an entire teaspoon of sugar (sucrose). In one teaspoon of sugar (1 tsp sucrose X 4 g / tsp X 1 mol / 342.3 g X 6.02 x 10^23 molecules / mol) equals about 7 x 10^21 molecules of sucrose. There is one molecule of glucose for each molecule of sucrose and each molecule of glucose yields two molecules of pyruvate which can be metabolized by pyruvate decarboxylase in yeast into one molecule of acetaldehyde and one molecule of carbon dioxide (the gas/bloating symptom). Hence for one teaspoon of sugar (7 x 10^21 X 1/1 X 2/1 X 1/1) equals 14,000,000,000,000,000,000,000 molecules. There are potentially 14 sextillion molecules of acetaldehyde (about 1 gram) that can be released from Candida Albicans yeast cells for each teaspoon of sugar that they are fed! Twenty-five percent of the ingested sugar may emerge from the reaction as a harmful substance. Each and every one of these acetaldehyde molecules that isn't apprehended can cause damage to the body in any number of different ways, some of which are described in more detail in subsequent chapters. The single dose Wondro formula uses about 1/2 teaspoon (5 grams) of elemental sulphur. Assuming that the heating process combines all of the available sulphur into the unsaturated fatty acid bonds in the flax oil (5 g S X 1 mol / 32.065 g X 6.02 x 10^23 atoms / mol) equals about 94 x 10^21 or 94 sextillion atoms of "combined" sulphur in the resulting compound. About 50% of these (47 sextillion) may be available for acetaldehyde binding. This supposition is supported by a naturally occurring process in the body in the pyruvate dehydrogenase reaction portion of the citric acid cycle where acetyl-coenzyme A is formed (see figure "Lipoic Acid + Acetaldehyde"). As an intermediate step in this reaction, acetaldehyde breaks into the disulphide bond in lipoic acid. This may be very similar to what happens to the sulphurated fatty acids in flax oil when they encounter acetaldehyde in the gut. It is important to note here that although the body does indeed use the acetaldehyde molecular configuration in the production of acetyl-coenzyme A, it only does so when acetaldehyde is "immobilized" safely within an enzyme. It doesn't allow it to float freely in the cellular milieu. The intent of a good acetaldehyde scavenger, then, would be to similarly immobilize rogue molecules of acetaldehyde released in unexpected locales. As a comparison, the suggested Wondro alternative protocol uses two 500 mg capsules (1 gram) of Nacetyl-L-cysteine which may yield up to (1 g NAC X 1 mol / 163.19 g X 6.02 x 10^23 molecules / mol) equals about 3.7 x 10^21 or 3.7 sextillion atoms of sulphur in the emulsion, since there is one sulphur atom per molecule of NAC with all of these potentially available for acetaldehyde binding. Based on these calculations the Wondro formulation would be at least 10 times as potent an acetaldehyde scavenger as the NAC emulsion but the NAC emulsion is easier to make (no heating) and to take (odorless).

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Daily Toxic Spill ============ Let's suppose that individuals resident in a certain community started to manifest the following rather nebulous profile of symptoms: Chronic pain throughout the muscles and tendons or any soft tissues of the body Chronic malaise general feeling of discomfort, fatigue, and illness Brain fog state of forgetfulness and confusion Chronic infections Gastrointestinal complaints (diarrhea, constipation, bloating, gas, heartburn, indigestion) Food allergies Dizziness Migraines and/or headaches Visual disturbances Mood swings, depression, and/or anxiety Nervous system malfunctions burning extremities, numbness, tingling, paralysis Environmental analysis teams would be called in to look for the source of a possible toxic spill that had migrated into the water table because this is indicative of heavy metal poisoning. Hair analysis and urinalysis might turn up nothing suspect. Mass psychogenic illness, perhaps? But wait...there had been a recent derailment of train cars carrying a colorless pungent, woody odor liquid identified to be acetaldehyde. The size, shape, and polarized nature of this molecule allow it to behave as if it were a heavy metal ion with the same symptomatic profile without readily revealing its presence to analysis. Pause for a moment and consider the effects of a commensal organism (Candida Albicans) capable of producing and releasing acetaldehyde into its environment, i.e. your body, on a daily basis... The hazardous material data sheets for acetaldehyde drive home just how dangerous this stuff is. It is highly flammable, reactive, and poses a health hazard in the industrial workplace unless utmost precautions are exercised in its handling [1,2]. Acetaldehyde is so highly reactive that it is difficult to trace, especially in the body. However, in the presence of thiamine-pyrophosphate and acetyl-coenzyme A it reacts to form a stable metabolite called 2,3-butanediol. 2,3-butanediol has been found in the urine of humans in "apparently unrelated disease states" [3]. It has also been found in the urine of premature babies indicative of "abnormal colonisation of neonates" [4]. The Comparative Toxicogenomics Database (CTD) is a public resource that promotes understanding about the interaction of environmental chemicals with gene products, and their effects on human health. This wealth of expanded chemical-gene-disease data continues to help users generate testable hypotheses about the molecular mechanisms of environmental diseases [5]. If there is any lingering doubt about the ability of acetaldehyde to precipitate and participate in disease processes, check out the more than one thousand cross-indexed entries between "Acetaldehyde and Disease" listed in the reference: http://ctdbase.org/detail.go?type=chem&acc=D000079&view=disease

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To make matters even worse, the "pulsed low dosage" exposure profile of acetaldehyde emission from Candida Albicans may be inducing a tolerance to acetaldehyde. This means that the normal acetaldehyde scavenging and neutralization mechanisms may not be responding adequately to its presence, thus increasing its downstream toxicity potential [6]. [1] "Right to Know -- Hazardous Substance Fact Sheet (Acetaldehyde)" http://nj.gov/health/eoh/rtkweb/documents/fs/0001.pdf [2] "Acetaldehyde Health and Safety Guide (World Health Organization, Geneva, 1994) http://inchem.org/documents/hsg/hsg/hsg90_e.htm [3] Casazza et al., "Short chain diol metabolism in human disease states", Trends Biochem Sci. 1990 Jan;15(1):26-30. http://www.ncbi.nlm.nih.gov/pubmed/2107613 [4] Mills et al., "Urinary excretion of 2,3-butanediol and acetoin by babies on a special care unit", Clin Chim Acta. 1989 Jan 13;179(1):51-9. http://www.ncbi.nlm.nih.gov/pubmed/2920442 [5] Davis AP et al., "The Comparative Toxicogenomics Database: update 2011.", Nucleic Acids Res. 2011 Jan;39(Database issue):D1067-72. Epub 2010 Sep 22. http://www.ncbi.nlm.nih.gov/pubmed/20864448 [6] Crouch JY et al., "Inhibition of rat liver transaminases by low levels of acetaldehyde and the pharmacologic effects of B6 vitamers.", Biochem Pharmacol. 1989 Oct 15;38(20):3431-7. http://www.ncbi.nlm.nih.gov/pubmed/2818634

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Starvation Diet? ============ The numbers in "Just A Teaspoon of Sugar" are scary. And since yeast likes to metabolize simple sugars, producing acetaldehyde in the process, trying to starve the yeast out of existence in your system by depriving it of the sugar that it likes and needs might seem like a reasonable approach. In fact, sugar cravings are one of the indicative signs that there is an overgrowth of yeast on board, intercepting what the body needs for its own energy requirements. If a significant proportion of sucrose in the diet emerges as acetaldehyde, reducing the amount of raw material for yeast metabolism is certainly a factor in recovery. However, too strict a diet in this regard may be counterproductive. It is impossible to remove the yeast from your system by simply starving it to death. You will be a casualty before it is. Candida Albicans is an incredibly robust and versatile organism. Fungi, in general, being totally reliant on other hosts for their energy requirements, have become adept at finding ideal environments, waiting out times of short supply, and migrating to other locales in search of their sustenance. When nutrients are not forthcoming, Candida Albicans can go dormant for extended periods waiting, or it can shift from a budding phase to a hyphal growth mode secreting the enzyme phospholipase (cf. bee stings and spider bites) to burrow its way through tissue (see figures "Candida Albicans -- Budding Phase and Candida Albicans -- Hyphal Phase"). It cannot be overemphasized that the individuals who described their experiences in the Wondro testimonials pamphlet did not implement any strict dietary protocols to achieve their personal remarkable results. In fact a good many commented upon how much their appetites had improved and how much more they were enjoying their food. All they did was consume a daily dosage of sulphurated flax oil, which in light of what is now known, looks like a highly efficient acetaldehyde scavenger. This focuses the spotlight on this toxin as perhaps being the most significant factor of yeast metabolism in the etiology of a wide variety of disease states. Since we now have a much clearer idea of where this toxin is coming from (commensal yeast) and how this yeast manages to increase its stake in the body (antibiotic selective removal of intestinal bioflora, for example), we should be able to do at least as well, hopefully better, at managing yeast overgrowth and its deleterious effects. Any effective yeast abatement protocol must at least attempt to: scavenge and neutralize any acetaldehyde being produced stop the production/release of acetaldehyde from the yeast remove any tolerance to free acetaldehyde that the body may have acquired reactivate the body's own innate immune response to reduce yeast populations supply the necessary resources to the innate immune system to perform this task reduce the level of viable yeast cells capable of producing acetaldehyde repopulate the gut with beneficial bacteria for competitive exclusion Furthermore, it should be able to do these things without too severe a dietary regimen and without side effects that prevent the protocol from being continued indefinitely. Such a protocol and the reasoning behind each step are presented in the reference ("Astrophysiology...and Yeast -- Minimalist Approach to the Yeast Problem / Yeast Abatement Protocol").

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CDC Image #3192

Candida Albicans (Budding Phase)

Candida Albicans (Hyphal Phase)

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Sulphur Sulphur Everywhere ====================== If the results obtained from a daily protocol of Wondro were a consequence of acetaldehyde scavenging and its proficiency at this task was due to the presence of sulphur atoms in the vulcanized fatty acids of flax oil, then we might expect to find other sulphur-bearing compounds that also demonstrate the "panacea effect" for a variety of conditions. Compare the amount and position of the sulphur atoms (the yellow balls in the figures "Sulphur, Sulphur Everywhere") and note that more than a few show up in herbal remedies and diets. Chronic exposure to acetaldehyde is so potentially deleterious that the body starts to fail at its weakest points conditioned by the cumulative level of daily exposure (a function of dietary sugar content and yeast colonization population), the physical location(s) of the yeast colonies emitting the toxin, and inherent genetic vulnerabilities. Although there may be a nebulous array of common symptoms, each individual may eventually develop a different diagnosed "disease" with a known label. This could explain why something like Wondro could provide such dramatic results for such a wide variety of supposedly incurable conditions. The relief that the body receives from the reduction of continuous toxic stress allows it to restore its own balance and heal itself. Yeast is an incredibly complex, polymorphic, highly adaptable organism. The ability of Candida Albicans to insert itself into the bioflora of the human body and remain there indefinitely is a delicate balancing act between providing for its own needs and modulating the immune response of its host without killing off its sugar-daddy. Precisely how it has been accomplishing this has remained elusive. But here is where the Wondro testimonials (See "RELATED WORKS") may provide a useful clue. They are not medical research but they do represent an ad hoc clinical trial of sorts that demonstrated the results of introducing a substance with a mode of action limited to what now appears to be acetaldehyde scavenging and nothing more. At the time of its popularity little was known about the disease-causing potential of yeast or acetaldehyde. Wondro was described as a "blood purifier" that rested on the merits of its results alone. In light of the current investigation, given its ability to prevent acetaldehyde (truly a "monkey-wrench-in-the-works" molecule) from migrating into the blood stream and causing cumulative systemic failure, the original description was amazingly close. The acetaldehyde production of Candida Albicans metabolism is something that sets it apart from other yeast species. This may also be what allows this organism to entrench itself and potentially precipitate a slow but relentless downward spiral of its host into disease. It also explains why acetaldehyde-chelating substances (especially those with exposed sulphur atoms) have a historical lore of being cure-alls for apparently unrelated diseases. While this may appear to clear away a lot of confusion and provide some optimism regarding intractable chronic illnesses, due caution is necessary. Just because a substance can chelate or neutralize acetaldehyde does not necessarily mean that it doesn't have other toxic effects of its own. Elemental sulphur itself, of course, has the most yellow balls and was the active ingredient in the folk remedy "Sulphur and Molasses". However, in this configuration, the sulphur is tightly bound to itself in an octatomic ring and may not provide as attractive a binding site for acetaldehyde as some of the other structures. It is also irritating in its elemental form to mucous membranes. Lipoic acid can cross the bloodbrain barrier and if it is carrying chelated mercury when it does this, this sensitive area can be disrupted. Horseradish contains allyl isothiocyanate with a salient sulphur presence but in large doses is considered to be a potential abortifacient. Is sulphurated flax oil or a stand-in (N-acetylcysteine emulsified in flax oil) truly an ideal solution? Possibly, but this too needs to be subjected to the clinical scrutiny of this day and age to ensure that its effects are fully understood.

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Sulphur, Sulphur Everywhere

Elemental Sulphur

Wondreic Acid

N-acetylcysteine

Lipoic Acid

Grapefruit Mercaptan

Garlic Diallyl Disulphide Horseradish Allyl Isothiocyanate

Methylsulphonylmethane (MSM)

Dimethyl Sulphoxide (DMSO)

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The affinity of acetaldehyde for sulphur is actually used by the body in its aldehyde dehydrogenase enzymes that convert it into harmless acetic acid via a cysteine residue present at the active site. Although not part of the enzyme, magnesium proximity is a cofactor in enzyme efficiency. If aldehyde dehydrogenase systems are running close to saturation, then magnesium depletion from other critical functions with accompanying deficiency symptoms (loss of concentration, muscle cramping, rage) may also be problematic. Although aldehyde dehydrogenases are present in cells throughout the body, the major concentration is in the liver used primarily for the detoxification of ingested alcohol. The liver of most people is prepared to handle acetaldehyde as a byproduct of alcohol metabolism within reasonable limits, the two enzymes alcohol and aldehyde dehydrogenase working in tandem. But when acetaldehyde is released by yeast in the gut and directly into the cerebrospinal fluid near the blood brain barrier, it is like ingesting a timedrelease daily dose of the highly reactive poison, something that pushes normal aldehyde scavenging to its limits. Also, since these are regions where acetaldehyde release is unexpected, there may be too much exposure time for it to be effectively neutralized. Red blood cells have been shown to be able to perform "catch and release" transport of acetaldehyde to all parts of the body [1]. Genetic deficiencies of certain types of aldehyde dehydrogenase are linked to a higher incidence of esophageal and oropharyngolaryngeal cancers [2] and to increased risk for late onset Alzheimer's [3]. Homeopathic sulphur is indicated in many conditions, possibly because of its ability to shift the morphology of yeast away from the budding cells that produce acetaldehyde (see "Astrophysiology...and Yeast -- Fungal Polymorphism and Homeopathy"). Sulphur-rich hot springs have long been touted as beneficial therapy for many disorders. Both the aroma and tactile contact with sulphur may factor into reducing yeast-based acetaldehyde production.

[1] Baraona E et al., "Transport of acetaldehyde in red blood cells.", Alcohol Alcohol Suppl. 1987;1:203-6. http://www.ncbi.nlm.nih.gov/pubmed/3426680 [2] Yokoyama A et al. (August 1998). "Alcohol-related cancers and aldehyde dehydrogenase-2 in Japanese alcoholics". Carcinogenesis 19 (8): 13837. http://www.ncbi.nlm.nih.gov/pubmed/9744533 [3] Ohta S, "Roles of mitochondrial dysfunctions in Alzheimer's disease--contribution of deficiency of ALDH 2", Rinsho Shinkeigaku. 2000 Dec;40(12):1231-3. http://www.ncbi.nlm.nih.gov/pubmed/11464464

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Pseudo Heavy Metal ================ Strictly speaking, chelation therapy is the intravenous administration of chelating agents such as EDTA (ethylenediaminetetraacetic acid) to remove "heavy metals" from the body. There are controversial applications of this technique for other diseases as well with widely differing opinions on the efficacy of such treatments. EDTA works by sequestering a (positive) cation such as lead within an electronegative net so that it is unable to interact with sites in the body that are vulnerable to attack by the heavy metal. Heavy metal ions are miniscule in size. Atomic Radius (10^-12 m.) of Heavy Metals: 119 Arsenic (As) 143 Aluminum (Al) 151 Mercury (Hg) 151 Cadmium (Cd) 175 Lead (Pb) Consider for a moment the acetaldehyde being released by the budding phase of Candida Albicans metabolism [1]. This is an organic (carbon, oxygen, hydrogen) molecule but tiny in comparison to most biological molecular configurations. Spectral data observations place the molecular radius of acetaldehyde somewhere in the 184-237 pm range [2]. These values place the acetaldehyde molecule in the same size range as the heavy metal ions listed above. Carbonyl (C=O) groups are electrophilic (negative-seeking) because of the electron density shift towards the oxygen atom. This makes the carbonyl carbon of acetaldehyde highly reactive towards nucleophilic (positive-seeking) structures. In essence acetaldehyde is a "pseudo-heavy-metal" with similar deleterious consequences to human physiology. Does this imply that acetaldehyde would also be chelated by the electronegative EDTA net (see figure "EDTA Chelation") just as if it were a heavy metal? If so, this would reduce the impact of acetaldehyde (an immunosuppressive, carcinogenic, neurotoxin) and possibly explain the amelioration of symptoms via chelation therapy in diseases where actual heavy metals had not been found in excess. In fact, there are industrial applications where EDTA is used in precisely this manner as a countermeasure to acetaldehyde contamination [3]. If acetaldehyde is the culprit and yeast is its source, is intravenous EDTA chelation the best technique for accomplishing the task of capturing it? --Not necessarily, given that the primary source of acetaldehyde emission is likely in the gut. Allowing acetaldehyde to migrate into the bloodstream gives it more than ample opportunity to be transported throughout the body before it might come into contact with an intravenous chelating agent. A more effective strategy would be first, to intercept it in the gut before it has had a chance to enter the bloodstream and second, to lower the levels of acetaldehyde exposure by reducing yeast levels capable of producing it. [1] Truss C.O., "Metabolic abnormalities in patients with chronic candidiasis: the acetaldehyde hypothesis.", Orthomol Psychiatr 1984; 13:6693. http://orthomolecular.org/library/jom/1984/pdf/1984-v13n02-p066.pdf [2] Lobanov V.V., Electronic and spatial structure of positive and negative molecular ions of acetaldehyde, Theoretical and Experimental Chemistry, 1982, Volume 18, Number 5, Pages 564-569. http://www.springerlink.com/content/f4412p7579733266 [3] US patent 4357461, "Reduction of acetaldehyde generation during polyester production by the addition of EDTA". http://www.surechem.org/index.php?Action=document&docId=454607&db=USPTO

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EDTA Chelation

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Carnosine ======== Since aldehydes are so reactive and potentially damaging to cellular structures it would be surprising if the body did not have multiple techniques for dealing with them. The dipeptide carnosine (see figure "Carnosine") which is highly concentrated in muscle and brain tissues has the ability to scavenge aldehydes formed from the peroxidation of cell membrane fatty acids during oxidative stress. Carnosine can be manufactured in the body by carnosine synthase from the amino acid L-histidine and beta-alanine with meat (beef/lamb) being its main dietary source. The noticeable difference between carnosine and the acetaldehyde scavengers discussed previously is that there are no sulphur atoms in its structure. However, it does have a long "tail" connected to the imidazole ring. One of the proposed structures for the method of aldehyde scavenging is the incorporation of the reactive carbonyl carbon into an additional ring structure formed by the combination of this tail and the aldehyde group via non-enzymatic folding of the tail back onto the original ring. Although acetaldehyde is a much smaller entity than a peroxidized fatty acid, presumably carnosine would react with it as well in a similar manner (see figure "Carnosine + Acetaldehyde"). The reactive carbon (shown as *C) from acetaldehyde has been "herded into a paddock" and is no longer a threat to other molecular structures in the body [1]. Since carnosine has been reported to have beneficial effects in numerous apparently unrelated conditions (autism, epilepsy, Parkinson's, schizophrenia) and since carnosine is a naturally occurring aldehyde scavenger in the body, this adds credence to the premise being explored in this work -- namely that acetaldehyde being emitted from budding yeast (Candida Albicans) metabolism is the underlying driving force in a wide variety of disease processes. It also suggests that the normal aldehyde scavenging and detoxifying mechanisms are overloaded because of acetaldehyde levels far in excess of the body's ability to cope. Normally the body self-regulates the concentration of carnosine with the enzyme carnosinase that splits the dipeptide back into its amino acid constituents. There is a rare autosomal recessive metabolic disorder, carnosinemia, that occurs when there is a deficiency of this enzyme. Severe and potentially debilitating neurological symptoms occur when carnosine levels are too high. The risk associated with excessive carnosine supplementation is that side effects similar to this genetic disorder may be provoked. The ideal acetaldehyde scavenger is a substance that is metabolically benign, sequesters acetaldehyde irreversibly, and can be continued indefinitely in a daily protocol while yeast levels that are the source of the toxin are being reduced by other strategies. [1] Hipkiss, A.R., "Carnosine, a protective anti-ageing peptide?", Intl Journal of Biochemistry & Cell Biology, Volume 30, Issue 8, August 1998, Pages 863868. http://www.sciencedirect.com/science/article/pii/S1357272598000600

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Message From MMS? ================= The oral consumption of MMS (Miracle Mineral Solution) with active ingredient sodium chlorite (household bleach) has apparently been used to treat a wide variety of disease conditions. Sodium chlorite can perform a non-enzymatic Lindgren (Pinnick) reaction [1] with aldehydes converting them into the corresponding carboxylic acid -- in other words, changing acetaldehyde into acetic acid in the gut before the acetaldehyde has migrated to other environs. However, the side effects described for an MMS (sodium chlorite) protocol match those documented for chlorine dioxide poisoning: rapid heart rate, skin irritation, nausea, vomiting. This suggests that the usage of MMS may be producing chlorine dioxide when ingested. The reaction mechanism for an aldehyde and sodium chlorite in an acidic environment produces chlorine dioxide as one of the products: CH3CHO + 3HClO2 CH3CHO acetaldehyde HClO2 chlorous acid -> CH3COOH + HCl + 2ClO2 + H2O CH3COOH acetic acid HCl hydrochloric acid ClO2 chlorine dioxide H2O water

The acetaldehyde is neutralized to harmless acetic acid but chlorine dioxide is a toxic by-product. This is a bit like mixing cleaners when you scrub the toilet bowl. The fact that individuals who have used MMS trade off one set of symptoms (acetaldehyde exposure) for another (ClO2 exposure) may be the elusive evidence that toxic acetaldehyde is indeed being produced by yeast in the body. The chemical structures of sodium chlorite (MMS) and sulphurated flax oil (Wondro) are so different that they must work in different ways. Wondro is more like a net that snares the acetaldehyde, using exposed sulphur atoms as a lure, before it can do any further damage in the body. MMS is reacting with it and turning it into harmless acetic acid but producing toxic chlorine dioxide in the process. The very fact that both remedies appear to work for so many different diseases suggests that: a) a lot of diseases have a common cause and b) there is a link between the modes of action of the two remedies. Since both remedies have a neutralizing effect on acetaldehyde, albeit in different ways, this strongly suggests that acetaldehyde may be the pivotal fulcrum of different illnesses. Another toxic substance that may produce results because of potentially dangerous side reactions is hydrogen peroxide (see "Pulmonary Peroxidosis"). Using this substance in a treatment protocol is a bit like throwing starter fluid onto a smouldering barbecue. There may be some temporary remission or change of symptoms because of the antimicrobial and acetaldehyde neutralizing properties, but this is not something that can be continued in the long term without sustaining collateral damage resulting from both hydrogen peroxide itself and the side reactions that it can precipitate. Hydrogen peroxide (H2O2) will react with acetaldehyde (CH3CHO) in aqueous (H2O) solution producing hydroxy alkyl peroxides [2] such as 1-hydroxyethyl hydroperoxide, CH3CH(OH)OOH, which is unstable and may produce damaging free radical species: CH3CHO + H2O2 <--> CH3CH(OH)OOH Hydrogen peroxide can also react with acetic acid (CH3COOH) to produce peracetic acid (CH3COOOH), an oxidant with similar potency to chlorine dioxide: CH3COOH + H2O2 <--> CH3COOOH + H2O

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Acetic acid is the body's byproduct of acetaldehyde dehydrogenation. Microbes in the body's bioflora also produce acetic acid [3] that would be bioavailable for the hydrogen peroxide reaction to peracetic acid. Peroxides in general are unstable since the oxygen-oxygen chemical bond can easily cleave forming reactive radical species. Not only are they irritating and inflammatory, they are toxic to living cells resulting from the oxidation of proteins, membrane lipids and DNA. Using hydrogen peroxide therapy can easily set the pulmonary peroxidosis cascade in motion as well as bleaching essential organs (such as the liver) if the mixture concentration isn't just right [4]. Since yeast-released acetaldehyde is implicated in so many different disease processes including cancer (see "Cellular Mayhem"), then the strategy of using a toxic substance (sodium chlorite or hydrogen peroxide) to kill the yeast or reduce acetaldehyde exposure by diverting it into another substance will produce results but at what cost -- risky at best, fatal at worst? Now that we know more about the why's and wherefore's of the disease process in relation to yeast and acetaldehyde, there are less risk-prone approaches for addressing the difficulty. It's not an easy task, by any means, but there is a way out of the maze using techniques that can be continued indefinitely [5].

[1] Lindgren et al., "Preparation of Carboxylic Acids from Aldehydes (Including Hydroxylated Benzaldehydes) by Oxidation with Chlorite". Acta Chemica Scandinavica (1973) 27: 888. http://actachemscand.org/doi/10.3891/acta.chem.scand.27-0888 [2] Satterfield et al., "Reaction of Aldehyde and Hydrogen Peroxide in Aqueous Solution",Ind. Eng. Chem., 1954, 46 (5), pp 9981001 http://pubs.acs.org/doi/abs/10.1021/ie50533a049 [3] Henningsson A, "Short-chain fatty acid formation at fermentation of indigestible carbohydrates.", Food & Nutrition Research 2001 Vol 45 http://www.foodandnutritionresearch.net/index.php/fnr/article/view/1801 [4] Pritchett S et al., "Accidental ingestion of 35% hydrogen peroxide", Can J Gastroenterol. 2007 October; 21(10): 665667. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2658134 [5] "Yeast Begone!" in "Astrophysiology... and Yeast", 2011. http://www.scribd.com/doc/74090699 http://www.epubbud.com/book.php?g=7JQU45V8

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Acetaldehyde -- Liquid Or Vapor? ========================== Let's take a closer look at the byproducts of the partial fermentation process being performed by Candida albicans in the body which forms acetaldehyde (the toxin) and carbon dioxide (the gas/bloating symptom) (see "Pushmi-Pullyu" in "Astrophysiology... and Yeast). Why are the boiling points (the temperature at which the liquid form changes into a vapor) so markedly different (see table and figure "Acetaldehyde Carbon Dioxide Water")? Acetaldehyde is larger and heavier than water but has a much lower boiling point. Carbon dioxide is the same molar mass as acetaldehyde and somewhat smaller, but with a drastically lower boiling point. Also, since the boiling point of acetaldehyde is significantly lower than body temperature (37C), one might expect that any acetaldehyde released by yeast in the body would be a gas rather than a liquid, but the actual situation is more complex. The answer to this apparent conundrum lies in how these substances interact with themselves and each other. Molecular structures that are polarized have electron cloud distributions that form slightly positive and slightly negative regions (a dipole) in the molecule. These partial charges create attractive forces between molecules that can hold them together. The stronger the attractive forces between molecules, the more energy required to dissociate them and the higher is the boiling point. Carbon dioxide is linear and centrosymmetric with no electrical dipole. As a non-polar molecule it is easily separated from other carbon dioxide molecules and has a very low boiling point. It is emitted from intestinal yeast metabolism as a gas and remains that way to be expelled by the body. Water exhibits a special type of electrostatic dipole-dipole interaction called a hydrogen bond that is possible because its hydrogen atom is bonded to its highly electronegative oxygen atom. Acetaldehyde is a polar molecule with a dipole moment about 1.5 times greater than water but it cannot hydrogen bond with itself because none of its hydrogen atoms are bonded to its oxygen. The much stronger hydrogen bonds in water make its boiling point much higher than that of acetaldehyde. In an aqueous environment, however, where acetaldehyde and water are mixed, acetaldehyde can hydrogen-bond with water. This suggests that under physiological conditions, even though its boiling point is significantly lower than body temperature, most of the yeast-emitted acetaldehyde will remain in solution and be available for unfavorable reactions with other molecules (see figure "Water HydrogenBonding With Acetaldehyde"). Trace amounts of acetaldehyde in the breath are detectable and considered to be biomarkers for cancer [2]. Aldehydes often have a fragrant aroma and are used in the perfume industry where continuous exposure can lead to skin diseases [3]. Are aldehydes what dogs can smell when they have been trained to identify patients with lung and breast cancers [4]? Studies have shown that acetaldehyde may be released by lung cancer cells themselves [5] suggesting that a chain reaction may be established from yeast-released acetaldehyde-mediated cancer initiation via DNA damage [6], prostaglandin interference, and DNA repair suppression through to cancerous cells emitting additional carcinogenic acetaldehyde (see "Cellular Mayhem"). Water itself in close proximity to acetaldehyde may catalyze its hydration [7] to 1,1-ethanediol where the two molecules are now covalently bonded rather than just hydrogen-bonded (see figure "Hydrated Acetaldehyde"). This is the objective of the acetaldehyde hydration visualization (see "Psychosomatic Nightmare?" in "Astrophysiology... and Yeast"). Hydrated acetaldehyde may spontaneously split back into the reactive aldehyde and water so that this form is not truly a "scavenged" (i.e. permanently neutralized) form for acetaldehyde.

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Acetaldehyde

Carbon Dioxide

Water

Hydrated Acetaldehyde 1,1-ethanediol

Acetaldehyde Hydrogen-Bonding With Water

34

Carbonic anhydrases [8] are zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide to form the bicarbonate ion and protons via the reaction: CO2 + H2O <=> H2CO3 <=> HCO3(-) + H(+) This reaction is the mainstay, not only for the formation of gastric acid in the stomach, but also for the buffering of pH in body fluids where a slightly alkaline environment is suitable for life processes. This enzyme can also accept acetaldehyde as a substrate for hydration [9]. When carbonic anhydrase is deliberately inhibited, patients experience malaise, fatigue, weight loss, depression, anorexia, and loss of libido with accompanying acidosis [10]. If yeast-released acetaldehyde is competing for access to carbonic anhydrase enzymes in the body, then this may create conditions similar to overt enzyme inhibition with metabolic acidosis the result. A lower pH favors the budding form of the yeast [11] dependent upon the availability of glucose [12]. The concentration of hydrogen cations (protons) in body fluids, something that determines its level of acidity, must be tightly regulated otherwise H+ can bind to negatively charged protein centers in structures including, but not limited to, enzymes with functional and structural impairment the consequence. Acidic damage and heavy metal cation damage bear a remarkable resemblance to the deleterious effects inflicted by the polar nature of the acetaldehyde molecule. When equilibrium balancing processes in the body are stretched too far, resulting in metabolic acidosis for instance, often they are too far out of kilter to realign even after the stressors have been removed. In this case OPK (Orthomolecular Psychokinesiology) techniques may be useful, not only in detecting such conditions, but also in giving the body the energetic boost it needs to re-establish the proper homeostasis. In the case of metabolic acidosis, homeopathic visualizations of natrum carbonicum and fluoricum acidum can be used in a teeter-totter fashion along with kinesiology hand grip biofeedback to correct acidosis (see "Homeopathy Without The Pellets" in "Astrophysiology... and Yeast").

[1] Nadykto AB et al., "Uptake of neutral polar vapor molecules by charged clusters/particles: Enhancement due to dipole-charge interaction", JOURNAL OF GEOPHYSICAL RESEARCH, VOL. 108, 4717, 7 PP., 2003 http://www.agu.org/pubs/crossref/2003/2003JD003664.shtml [2] Spanel P et al., "Quantification of trace levels of the potential cancer biomarkers formaldehyde, acetaldehyde and propanol in breath by SIFT-MS", 2008 J. Breath Res. 2/4 http://iopscience.iop.org/1752-7163/2/4/046003 [3] Schubert H, "Skin diseases in workers at a perfume factory", Contact Dermatitis, Vol 55 Issue 2, pages 8183, August 2006 http://onlinelibrary.wiley.com/doi/10.1111/j.0105-1873.2006.00881.x/abstract [4] McCulloch M et al., "Diagnostic accuracy of canine scent detection in early- and late-stage lung and breast cancers.", Integr Cancer Ther. 2006 Mar;5(1):30-9. http://www.ncbi.nlm.nih.gov/pubmed/16484712 [5] Smith D et al., "Quantification of acetaldehyde released by lung cancer cells in vitro using selected ion flow tube mass spectrometry.", Rapid Commun Mass Spectrom. 2003;17(8):845-50. http://www.ncbi.nlm.nih.gov/pubmed/12672140 [6] Matsuda T et al., "Increased DNA damage in ALDH2-deficient alcoholics.", Chem Res Toxicol. 2006 Oct;19(10):1374-8. http://www.ncbi.nlm.nih.gov/pubmed/17040107

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[7] Kurz JL et al., "The Hydration of Acetaldehyde. II. Transition-State Characterization", J. Am. Chem. Soc., 1967, 89 (14), pp 35283537 http://pubs.acs.org/doi/abs/10.1021/ja00990a600 [8] Breton S, "The cellular physiology of carbonic anhydrases." JOP. 2001 Jul;2(4 Suppl):159-64. http://www.ncbi.nlm.nih.gov/pubmed/11875253 [9] Pocker Y et al., "The Catalytic Versatility of Carbonic Anhydrase from Erythrocytes. The EnzymeCatalyzed Hydration of Acetaldehyde.", J. Am. Chem Soc., 1965, 87 (8), pp 18091811 http://pubs.acs.org/doi/abs/10.1021/ja01086a045 [10] Epstein DL et al., "Carbonic anhydrase inhibitor side effects. Serum chemical analysis.", Arch Ophthalmol. 1977 Aug;95(8):1378-82. http://www.ncbi.nlm.nih.gov/pubmed/889513 [11] Buffo J et al., "A characterization of pH-regulated dimorphism in Candida albicans.", Mycopathologia. 1984 Mar 15;85(1-2):21-30. http://www.ncbi.nlm.nih.gov/pubmed/6374461 [12] Pollack JH et al.,"The role of glucose in the pH regulation of germ-tube formation in Candida albicans.", J Gen Microbiol. 1987 Feb;133(2):415-24. http://www.ncbi.nlm.nih.gov/pubmed/3309155

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Scavenger Hunt ============= The polarity of the carbonyl (C=O) in the acetaldehyde molecule makes it highly reactive towards configurations with attractive charge concentrations. Large electronegative sulphur atoms are particularly amenable to bonding (see "Sulphur, Sulphur Everywhere" and "Bridge Across The Chasm"), but when it can't find a sulphur center to glom onto even other carbonyls will do. The simplest illustration of this type of reaction is to consider the potential interaction of two acetaldehyde molecules with each other. Enolate Ion and Crotonaldehyde. Hydrogens adjacent to a carbonyl group are weakly acidic so that the loss of a proton to a hydroxide ion, forming a water molecule, can result in a resonance-stabilized enolate ion (see figure "Acetaldehyde + Resonance-stabilized Enolate Ion"). The nucleophilic properties of the enolate ion and the polar properties of acetaldehyde favor the formation of an aldol, a molecule with both an aldehyde and alcohol group. In the case of two acetaldehyde molecules, the result is 3-hydroxybutanal (see figure "Ach Enolate + 3-Hydroxy Butanal"). The exothermic dehydration of this aldol can result in the formation of an alphabeta unsaturated aldehyde, crotonaldehyde (see figure "Crotonaldehyde"). The overall aldol condensation of acetaldehyde with acetaldehyde is then: 2 CH3CHO --> CH3CH=CHCHO + H2O Since crotonaldehyde retains the aldehyde group of its acetaldehyde parents, the reactivity of this group [1] makes it just as neurotoxic, carcinogenic, and immunosuppressive. It can also participate in the oxidative peroxide cascade described for acetaldehyde (see "Pulmonary Peroxidosis"). Although a byproduct of lipid peroxidation, like malondialdehyde (see "Doubled-Edged Sword") and present in both cigarette and wood smoke, having a potential yeast to acetaldehyde [2] to crotonaldehyde pathway in the body (see figure "Candida Albicans, Acetaldehyde, Crotonaldehyde") makes it much more likely to surface in various disease processes [3] even without reactive oxygen species or environmental exposure. It has been found in neurodegenerative disorders [4] and is a potent irritant in chronic pulmonary disease [5]. Given the predilection of acetaldehyde to react with other carbonyls (including itself) via the nucleophilic (positive-seeking) attack of the acetaldehyde enolate (negative) ion on the slightly positive carbonyl carbon, this opens up an vast array of molecular configurations that may produce beneficial results in a wide variety of conditions. Their ability to interact with yeast-released acetaldehyde because of their available carbonyls may remove free acetaldehyde from the body at the point of contact and be a shared mode of action. Dimethyl Fumarate. When a carbonyl is adjacent to an ether linkage with an oxygen atom, it is an ester. The simplest ester is methyl formate which is subject to the nucleophilic (Nu) attack reaction common to esters (see figure "Nucleophilic Attack On Methyl Formate"). Dimethyl fumarate (BG-12) is a methyl unsaturated double ester (see figure "Dimethyl Fumarate") that has been used to treat psoriasis (since 1959) and recently experimentally for relapse-remitting multiple sclerosis and rheumatoid arthritis with ongoing studies for lupus and cancer.

37

Acetaldehyde

Resonance-stabilized Enolate Ion

Ach Enolate

3-Hydroxybutanal

3-Hydroxybutanal

(Enolate)

Crotonaldehyde

Candida Albicans

Acetaldehyde

Crotonaldehyde

38

The instability of acetaldehyde can lead to acetylation of this structure either via its acetyl radical [6] addition to the double bond of the fumarate ester [7] or nucleophilic attack of its enolate ion on either of the carbonyl carbons. Either way acetaldehyde has been denatured from its aldehyde existence by dimethyl fumarate [8] (see figure "Acetaldehyde + Dimethyl Fumarate"). Given the toxicity profile of free acetaldehyde and its connection to so many disease processes, this would suggest that some of the efficacy of this substance may be a result of this acetaldehyde scavenging ability. The suspected mode of action of dimethyl fumarate is as an immunosuppressive via glutathione (reduced form) depletion [9]. Trying to dampen a hyperactive immune system makes sense if it is really out of control; but if the reason that the immune system is malfunctioning is a result of yeast-released acetaldehyde, then the immunosuppressive aspects of dimethyl fumarate are an unnecessary and undesirable impediment to the body's normal metabolism. Deliberate depletion of glutathione can severely impair the body's ability to cope with reactive oxygen species (see "Reactive Oxygen Species" and "Double-Edged Sword"). There are other aspects to the fumarate configuration that suggest it may be active because of its interaction with commensal yeast colonization. It has antifungal properties [10] and is commonly used to kill molds that may cause furniture or shoe leather to deteriorate during storage and transportation. In this regard, so many cases of skin allergy, acute eczema and skin burns resulting from contact with DMF have been reported that it has been banned for usage in this manner by the European Commission [11]. It was also identified as the potent contact sensitizer antagonist in a severe dermatitis epidemic [12]. The connection to acetaldehyde is also found in the usage of fumaric acid (see figure "Fumaric Acid") in hangover remedies. Although fumaric acid is an intermediate in the citric acid cycle and used as a food additive, therapy with its ester derivatives is associated with side effects [8] including flushing, diarrhea, transaminase elevation, lymphocytopenia, eosinophilia, and disruption of kidney function. Quinones. When the hydrogen atom joined to a carbonyl (C=O), something that is the distinguishing feature of an aldehyde, is another carbon-containing side group instead, then the structure is known as a ketone. A quinone contains a pair of ketones on a cyclic ring. Quinones are particularly interesting from an acetaldehyde perspective because they occur frequently in nature and in vital body nutrients. One of the simplest quinone structures is 1,4-benzoquinone (see figure "1,4-Benzoquinone"). In the case of a quinone undergoing an acylation with acetaldehyde, the acetyl group can add either to one of the carbonyl oxygens [14] or to a carbon beside this group [15] (see figure "Acetaldehyde + 1,4Benzoquinone"). Quinone derivatives have been shown to lower blood and liver acetaldehyde levels suggesting that some type of acylation of this nature may be favorable in the body [16]. With quinone structures being a potential acetaldehyde sink, then it might be expected that critical substances that are based upon quinone backbones may be subject to interference from yeast-released acetaldehyde. Coenzyme Q10. Coenzyme Q10 (ubiquinone) is a vital part of the body's energy metabolism at the aerobic cellular respiration level (see figure "Coenzyme Q10"). Its function is coupled to the energy storing molecule ATP (Adenosine-5'-triphosphate) with the most energy-demanding organs (heart, liver, and kidney) having commensurately high CoQ10 concentrations. Acetaldehyde interference with the quinone carbonyls of CoQ10 could introduce a significant deficit in the body's energy metabolism with chronic fatigue the result.

39

Nucleophilic Attack On Methyl Formate

Dimethyl Fumarate

Acetaldehyde + Dimethyl Fumarate

Fumaric Acid

40

Although CoQ10 can be biosynthesized in the body, it requires sufficient acetyl-CoA, something whose production depends upon an enzyme-bound acetaldehyde to lipoic acid interaction that may also be subject to rogue acetaldehyde interference (see figure "Lipoic Acid + Acetaldehyde"). The body's CoQ10 status can also be impacted by statin-type drugs that block HMG Co-A reductase in the mevalonate pathway shared by both CoQ10 and cholesterol synthesis. Interestingly, although not a quinone, lovastatin, has carbonyl esters that may provide binding sites for acetaldehyde (see figure "Lovastatin"). Since there are several possible pathways for acetaldehyde interference with cholesterol levels (see "Slow Death By Strangulation" and "Toxic Soup") the acetaldehyde scavenging potential of a statin could in part be an "off-label" reason why statins appear to normalize cholesterol metabolism. Unfortunately, statins carry a heavy burden of side effects, either because of, or in addition to, their impact on CoQ10 production [17]. Vitamin K. All of the structurally similar, fat-soluble vitamins known as vitamin K are derivatives of a quinone ring structure. Vitamin K is utilized in the blood coagulation process as well as for maintenance of bone and other tissue. Menadione (vitamin K3) is a synthetic compound that has vitamin K activity (see figure "Menadione"). The naturally occurring forms, phylloquinone (vitamin K1) and menaquinone (vitamin K2) have longer sidechain tails than the synthetic form (see figures "Phylloquinone" and "Menaquinone"). The potential effectiveness of supplemental phylloquinone and menaquinone in the treatment of osteoporosis and arterial calcification [18] suggest that acetaldehyde disruption of these essential quinones may play a causal role in these disease conditions. Synthetic menadione has a higher toxicity profile [19] than its counterparts with their long lipophilic tails. Lapachol (Pau D'arco). Lapachol from Pau D'arco used to make Taheebo tea is a quinone (see figure "Lapachol"). Some of its effectiveness in treating a variety of disease states, including yeast infections, may result from its acetaldehyde scavenging ability. Short side-chain quinones, however, as noted previously for menadione (vitamin K3), have a toxicity profile that makes them unfavorable for supplementation [20]. If the statin lovastatin, used to modulate cholesterol metabolism, may actually achieve results via the acetaldehyde scavenging ability of its carbonyl esters in the molecule (see figure "Lovastatin") rather than by its expected mode of action, are there other endogenous or exogenous substances that may also have peripheral effects because of salient carbonyl groups in their configurations? Progesterone. The ability of the carbonyl ketones in the female hormone progesterone (see figure "Progesterone") to remove free acetaldehyde from circulation may provide some protection against interference with other vital substances such as CoQ10 and vitamin K. Cyclic hormonal fluctuations [21] and pregnancy [22] certainly predispose the female metabolism to elevated colonization levels by Candida albicans, a source of acetaldehyde [23]. If progesterone is removing some of the toxic background acetaldehyde being emitted by budding yeast metabolism, then one might expect acetaldehyde-related interference to increase subsequent to menopause when progesterone levels drop drastically. Vitamin K, a quinone which may be a target for acetaldehyde interference, is required for the gammacarboxylation of osteocalcin, a bone-related protein circulating in the blood. Circulating levels of undercarboxylated osteocalcin are higher in postmenopausal women resulting in increased risk for fractures [24]. This is thought to be a result of inadequate vitamin K nutritional status. However, vitamin K quinones, denatured by interaction with acetaldehyde that is no longer being scavenged by progesterone, could produce the same effects as an overt nutritional deficiency.

41

1,4-Benzoquinone

Acetaldehyde + 1,4-Benzoquinone

42

Coenzyme Q10 (Ubiquinone)

Lovastatin

43

Menadione

Phylloquinone (Vitamin K1)

Menaquinone (Vitamin K2)

Lapachol

44

Unlike the other fat-soluble vitamins, bodily stores of vitamin K are quickly depleted [25], and a rapid onset of deficiency is possible. As a result the body's vitamin K status is exquisitely sensitive to anything that may be interfering with its molecular configuration. Genetically deficient aldehyde dehydrogenase activity is linked to impairment of osteoblastogenesis [26]. Chronic pulsed low-dosage exposure to acetaldehyde, even when aldehyde dehydrogenase activity is normal, can create the same deleterious effects as impaired aldehyde disposal. This implies that circulating yeast-released acetaldehyde levels could lead to osteoporotic degradation [27] independently, even with or without the proposed protective effects of progesterone. Even as estrogen-related compounds contribute to increased background yeast levels [28] that may persist even after menopause, there are other clues that progesterone may be acting in ways other than its usual function. The remission of nerve myelin deterioration, characteristic of multiple sclerosis, during pregnancy when progesterone levels are high and the usage of dimethyl fumurate to alleviate this same disease suggest some link between these two compounds and the disease process. Although current thought is looking at autoimmunity and immunosuppressive connections between therapeutic substances, could the common factor be something completely different -- the ability of these molecular configurations to bind acetaldehyde and remove its toxic presence? Advanced invasive candidiasis is not a prerequisite for exposure to toxic acetaldehyde. Even "commensal" levels of colonization can provide exposure levels capable of precipitating diseases as varied as the genetically susceptibility of the individuals involved. Candida antibody studies have already shown a correlation between the presence of candida species antibodies and multiple sclerosis [29]. Prednisone. Prednisone is a glucocorticoid precursor, hepatically transformed into prednisolone, used in diverse indications: asthma, COPD, CIPD, rheumatic disorders, allergic disorders, ulcerative colitis/Crohn's disease, adrenocortical insufficiency, cancer-associated hypercalcemia, thyroiditis, laryngitis, tuberculosis, lipid pneumonitis, multiple sclerosis, nephrotic syndrome, myasthenia gravis, lupus, migraines,... a long list indeed! There are three carbonyls exposed in this molecule (see figure "Prednisone") that would provide binding sites for acetaldehyde. Would something else that scavenged acetaldehyde provide relief in all of these different conditions? One of the arguments used against "cure-all" herbals is that it is impossible for a single substance to be effective in so many different conditions. But prednisone is an example of a substance with just that profile -- but burdened with major side effects as well [30]. Drugs and the bioactive substances of herbal remedies converge at the molecular level and are indistinguishable, having both favorable modes of action and adverse side effects. Even the common prostaglandin synthesis inhibitor, aspirin, has an ester side chain carbonyl (see figure "Acetylsalicylic Acid -- Aspirin") that acetaldehyde might find attractive. Given that acetaldehyde is going to be a factor in everyone with a yeast load and that yeast is virtually universally carried by everyone at some level or another, some of the therapeutic effects of aspirin may be a result of its acetaldehydebinding ability. Its ability to lower acetaldehyde levels slightly after alcohol consumption suggests that it may have a partial action in this manner [31]. Consuming massive amounts of aspirin to try and combat acetaldehyde release is not a viable strategy, however, because of its impact upon essential prostaglandin metabolism and known toxicity risks [32] associated with high intake levels. Just because a naturally occurring substance is classified as a "herb" doesn't mean that it doesn't incur side effects like drugs extracted or designed in a lab. On the other hand, not all "side effects" of a drug are necessarily non-beneficial. Sometimes drugs that are specifically designed to attack a particular enzymatic pathway may have beneficial "off-label" effects because of other interactions.

45

Progesterone

Prednisone

Acetylsalicylic Acid (Aspirin)

46

Humic Acids (Dirt for Dessert). Consider the structures of the naturally occurring substances humic and fulvic acids with respect to the frequency and availability of carbonyl (C=O) structures in any of quinones, esters, or ketone linkages (see figures "Typical Humic Acid" and "Fulvic Acid"). Humic substances are the major organic constituents of soil with fulvic acids the lower molecular weight and higher oxygen content components. Geophagy is the practice of eating dirt driven by compulsion. If the veritable smorgasbord of carbonyls in these substances are binding acetaldehyde, then the remission of yeast-released acetaldehyde aggravation may be a motivating force in this disorder similar to the paradoxical acetaldehyde cravings experienced by alcoholics (see "Acetaldehydism" in "Astrophysiology... and Yeast"). Since colloidal fulvic acid also has antimicrobial properties [33], it might be expected to display antifungal aspects as well [34]. Large cluster-type molecules can demonstrate chelating activity where other substances are sequestered by intermolecular forces without actually forming a covalent or ionic bond. The heavy metal chelating properties of humic acids [35] might provide an alternate mechanism for preventing acetaldehyde from interacting with its surroundings. Since acetaldehyde has the size, shape, and electrophilic nature of a heavy metal ion (see "Pseudo Heavy Metal"), substances that chelate heavy metals might also be expected to sequester acetaldehyde and reduce its deleterious effects on the body (see "Rear-View Mirror"). However, if humic/fulvic acids fall into this class, some due caution must be exercised in the ingestion of substances that either provide minerals or can chelate them. Firstly, some substances may appear to be excellent nutritional mineral sources but upon closer scrutiny carry some undesirable excess baggage. A case in point, hijiki is a distinctive, almost black, shredded seaweed, that is used mainly as an appetizer or starter in some Japanese restaurants. Hijiki is also sold for use in soups and salads and some vegetarian and vegan dishes where seaweed is an ingredient. Analysis of this particular type of seaweed found that it had much higher levels of the heavy metal inorganic arsenic than other seaweeds such as arame, kombu, nori, and wakame which had none. Although this particular contaminant is impossible to avoid completely, some foodstuffs seem to accumulate it much more readily than others and should be avoided [36] in excess. Secondly, if a substance is not necessarily a mineral source but is a good heavy metal chelator, then depending upon its source and production, it may come with heavy metals already in place that might get released into the body. Fulvic acid isolated from the environment or produced from the oxidation of coal or lignite is inappropriate for supplementation since such preparations may contain high levels of heavy metals and potentially toxic elements. However, there are other techniques that can produce an ingestible form of carbohydrate-derived fulvic acid [37] . And thirdly, a heavy metal chelator that grabs minerals without letting them go may interfere with the absorption of essential metals such as copper and zinc. This may not necessarily be an impediment providing that the chelator is consumed at times other than normal food intake. However, attempting to utilize such a substance therapeutically as an acetaldehyde scavenger implies that it needs to be consumed at the time of maximum acetaldehyde release when the yeast is fermenting dietary carbohydrates -- a conflict of constraints. There is a arresting pattern here that unifies the observation that apparently unrelated diseases respond to the same medication (e.g. psoriasis, multiple sclerosis, lupus, cancer) for unknown reasons. When acetaldehyde is put into the picture suddenly all of the paths of the maze converge upon the ability of structurally diverse substances to react with and prevent acetaldehyde from inflicting a cascade of damage elsewhere. Most of the substances considered thus far have adverse effects or potential risks that make their continuous usage ill-advised so the quest now becomes a "scavenger hunt" for a substance that can perform this with minimal collateral damage.

47

Typical Humic Acid

Fulvic Acid

48

An Apple A Day. Why single out an apple from all of the other fruits and vegetables in our dietary rainbow? Phloridzin and phloretin are flavonoids, a class of polyphenolic compounds that used to be referred to as vitamin P, occurring in many plants that form part of the human diet. Phloridzin and phloretin (see figure "Phloridzin and Phloretin") occur primarily in apples [38] with varying concentration depending on many factors such as the condition of cultivation, harvest and storage/processing of the apples [39]. Since these compounds have been shown to have the ability to scavenge reactive dicarbonyl species [40], a closer look at the polyphenolic ring of phloretin (see figure "Phloroglucinol") is warranted in relation to acetaldehyde. Deprotonation and protonation of acetaldehyde can result in reactive ionic species. The deprotonation of acetaldehyde forming the enolate anion with a negative carbon atom has already been described in regards to the formation of crotonaldehyde from the condensation of two acetaldehyde molecules (see "Scavenger Hunt / Enolate Ion and Crotonaldehyde"). If the electronegative oxygen atom of acetaldehyde captures a proton, then a carbocation containing a positive carbon atom can be formed (see figure "Acetaldehyde Protonation Carbocation"). The ability of acetaldehyde to form either an anion (-) or a cation (+) depending upon the pH of the surrounding milieu demonstrates why it is so highly reactive with other molecular configurations. This is both bad news and good news The bad news is that acetaldehyde can be rapidly damaging to essential body structures and enzymes with a wide diversity of disease processes the result. The good news is that many different kinds of molecular configurations can serve as acetaldehyde scavengers to prevent this kind of damage providing that the right substances are ingested so as to be available where and when the yeast is releasing this toxin. Given the connection between yeast-released acetaldehyde and disease processes, this explains why there are so many different "cure-alls" that appear to have beneficial effects for so many different conditions. Recognizing their common mode of action is an important step in giving individuals healing choices that maximize the benefits and minimize the risk. Although the ultimate goal is to reduce the actual production of acetaldehyde by the elimination of viable budding yeast cells, the stranglehold exerted by yeast-released acetaldehyde must first be broken so that other techniques aimed at yeast abatement may succeed. The electrophilic carbocation is ideal for ethylidene bridge cross-linking condensation (water-releasing) reactions of nucleophilic configurations. Phloroglucinol exists in an equilibrium state between its two tautomers (see figure "Phloroglucinol Tautomerism") where migration of a proton is accompanied by the switch of a double bond to a single one. We have already seen that acetaldehyde finds quinones attractive for binding (see "Scavenger Hunt / Quinones").The addition of a third hydroxyl/ketone electrondonating group in the meta configuration of phloroglucinol can generate electron-rich nucleophilic centers at the unsubstituted carbon sites [41]. This means that molecular structures containing polyphenolic rings similar to phloroglucinol are prime candidates for cross-linking reactions via the carbocation intermediate form of acetaldehyde (see figure "Acetaldehyde Cross-linking to Ethylidene-diphloroglucinol"). Ethylidenelinked products usually undergo polycondensation; the initial products evolve with a high degree of polymerization that finally precipitate and give rise to dimers, trimers, and tetramers of polyphenols in different structural forms [42]. Ethanol, acetaldehyde, and acetic acid are so closely related in structure via oxidation/reduction reactions that the wine industry is quite familiar with the occurrence of all three of these substances in varying amounts in their products (see figure "Ethanol Acetaldehyde Acetic Acid"). The acetaldehyde crosslinking of polyphenols that occur in wine has been well-studied and documented [43]. Since the polyphenols that occur in wine and other foods are far more complex than the illustration of cross-linking shown above for phloroglucinol, the resulting structures are also more involved. For example, consider the structure of tannic acid found in tea and wine (see "Tannic Acid"). Regardless of the molecular complexity, once acetaldehyde has formed an ethylidene bridge in these polyphenols, it has lost its aldehyde reactivity and its potential for inappropriate disease-causing reactions with other molecules in the body has been neutralized.

49

"An apple a day keeps the doctor away!"

Phlorizdin

Phloretin

Phloroglucinol

50

If acetaldehyde emanating from yeast metabolism isn't scavenged, then the consequences can be dire indeed. DNA adducts or interstrand cross-links formed from reactive carbonyl species such as acetaldehyde, malondialdehyde, and crotonaldehyde can prohibit the transitory separation of complementary DNA strands and interfere with the replication and transcription processes of DNA, something that is fundamentally and critically essential to the health and well-being of each and every cell in the body. In a study which tested several bioactive phenolic compounds for their potential to prevent interstrand cross-links in calf thymus DNA, it was found that phloretin (but not phloridzin) was effective in preventing DNA cross-links by quenching acetaldehyde providing that it reacted with the acetaldehyde before it had a chance to form an adduct with DNA [44]. Orally consumed phloridzin is nearly entirely converted into phloretin by hydrolytic enzymes in the small intestine [45]. This may provide a clue as to why apples stand out above other polyphenol-containing foods which have some beneficial effects but where the rings contain only two hydroxyl groups rather than three (see figures "Quercetin" and "Resveratrol"). The same study also observed that epigallocatechin gallate (see figure "Epigallocatechin Gallate") (found in green tea) could prevent DNA cross-links even after the formation of acetaldehyde adducts with DNA strands. Note that both epigallocatechin gallate and phloretin have benzenetriol rings while quercetin and resveratrol have at most benzenediol rings. In relation to wine-fault (spoilage) the taste of acetaldehyde is described as green apple-like, grassy, sour and metallic. The association with green apples is indicative of the fact that this fruit actually contains small amounts of acetaldehyde [46]. It is interesting that an aromatherapy technique for dealing with headaches is to cut a green apple in half and sniff it. The implications here are that acetaldehyde (emanating from yeast) may have something to do with the headache symptoms and that exposure to a vaporous dilution of this substance relieves the acetaldehyde aggravation of brain biochemistry. This is similar to the postulated motivational influence for alcohol cravings that increase the concentration of acetaldehyde in the liver (see "Acetaldehydism" in "Astrophysiology... and Yeast") where the energetic (homeopathic) signal of acetaldehyde may result in a down-regulation of acetaldehyde production by Candida albicans throughout the body. Acetaldehyde Scavenger Attributes. What makes something an "ideal" acetaldehyde scavenger? Acetaldehyde is so reactive that almost anything it bumps into in the body can function as a de facto acetaldehyde scavenger. The problem with this is that the intended function of an essential structure or substance is then compromised by the presence of the acetaldehyde adduct. Introducing exogenous substances that react with acetaldehyde runs the risk, just like any drug, of their side effects either before or after acetaldehyde interaction. The question also arises as to whether the scavenger itself should have antifungal properties. Since Candida albicans doesn't acquiesce when antifungally challenged, shifting from budding cells to invasive hyphal cells and increasing acetaldehyde emission in other sub-colonies throughout the body, it is probably better initially if the scavenger is not an antifungal. Then the oral scavenging step can be separated from the yeast-challenging aspects of the protocol (see "Minimalist Approach to the Yeast Problem" and "Yeast Abatement Protocol" in "Astrophysiology... and Yeast") without setting off the symptom-shifting cascade that appears when the yeast is aggravated. Mopping up acetaldehyde before it comes into contact with anything essential allows the body to recover from the continuous exposure to this toxin and to prepare for the more arduous task of actually reducing the yeast colonization levels. Individuals with a long history of chronic disease may need this time to rebuild sufficient stamina to continue with the remaining steps of the protocol.

51

Acetaldehyde

Protonation

Carbocation

Phloroglucinol Tautomerism

Acetaldehyde Cross-linking to Ethylidene-diphloroglucinol

52

Ethanol

Acetaldehyde

Acetic Acid

Tannic Acid

Epigallocatechin Gallate

Quercetin

Resveratrol

53

The general rule, then, of acetaldehyde scavenging is to find a non-toxic, non-essential substance with the following characteristics: attractive irreversible binding site(s) for acetaldehyde minimal biochemical side effects both before and after acetaldehyde binding mode of delivery that allows it to come into contact with and persist in areas of potential yeast-released acetaldehyde minimal intrinsic antifungal properties so as not to provoke the yeast into an invasive morphic phase shift neither an enzyme inhibitor (i.e. designer drug) nor an enzyme accelerator (i.e. nutrient) no interference with nutrient absorption The motivation here is that if acetaldehyde reacts with the scavenger (i.e. antidote to the yeast's venom), it doesn't react with anything else and since yeast-released acetaldehyde appears to be the upstream cause of so many different downstream disease states, then removing its dangerous aldehyde properties at the point of release will have an ameliorating effect on all of the body's metabolism. Since acetaldehyde itself is so reactive, there are many diverse substances that will combine with it. This may be why there are so many different substances that produce results across a variety of disease states (see also "Sulphur, Sulphur Everywhere"). Satisfying all of the stated constraints while at the same time trying to reduce the source of acetaldehyde production is a non-trivial task. Specificity of the antidote is crucial -- ideally acetaldehyde and nothing else. Even the usage of increased quantities of the amino acid cysteine, which binds readily to acetaldehyde to form a thiazolidine (see "Toxic Soup") may precipitate unexpected problems in down-regulated uptake absorption pathways leading to "acquired nutrient absorption disorder" (see "Pseudo Deficiences" in "Astrophysiology... and Yeast") and paradoxical deficiency symptoms. If acetaldehyde finds the highly electronegative oxygen attached to a carbonyl an attractive binding site, then the larger and more electronegative sulphur is an even better target. The comparable sizes (see figure "Acetaldehyde Relative Size") between acetaldehyde and the heavy metal mercury atom demonstrate why the polarized acetaldehyde molecule can wreak just as much havoc in the body as a heavy metal mercury cation. (Experimental spectral data [47,48] with adjustments for bonding, etc. place the acetaldehyde molecule slightly larger than shown but still in the same size range.) Both oxygen and sulphur are in the same group (16) in the periodic table. One might expect the next chalcogen, selenium, to be an even better bait for acetaldehyde and this is likely true except that selenium compounds are so highly reactive that they are too dangerous to even consider. Although the body does utilize the specialized amino acid selenocysteine in rapid turnover enzymes such as glutathione peroxidase, it synthesizes this "on-demand" rather than keeping a free pool in the cells (see "Odd-ball Amino Acid"). Wondro. Sulphurating alpha-linolenic acid by heating flax oil (see figures "Alpha-Linolenic Acid" and "Linoleic Acid") with a small amount of elemental sulphur (see "Wondro For One") creates a molecular configuration where the sulphur has reacted into the double-bond carbon-to-carbon linkages (see figure "AlphaWondrenic Acid"). Variations on the distribution and saturation of sulphur sites is possible depending upon the quantity of sulphur used in the reaction. A similar structure, wondreic acid, with potentially two disulphide linkages could be expected to be formed from the linoleic acid constituent of flax oil.

54

Oxygen Atom

Sulphur Atom

Acetaldehyde Molecule

Mercury Atom

Acetaldehyde Relative Size

Alpha-Linolenic Acid (omega-3)

Linolenic Acid (omega-6)

Alpha-Wondrenic Acid

55

How does this substance fare when assessed against the above criteria for an acetaldehyde scavenger? The disulphides in this structure would be very attractive and irreversible binding sites for acetaldehyde, sparing any other reactive sites or substances in the body from this toxin. Disulphides are common structural elements in many biological configurations so that this molecule, in and of itself, would not be unusual or reactively threatening to other human enzymes or tissue. But since it doesn't occur naturally in the body in this form, introducing it doesn't interfere with any active processes, one way or another. This means that it should act as a highly specific acetaldehyde trap without side effects. Other than the pungent characteristic odor, those who took it noticed a slight tingling effect upon exposure to direct sunlight. The mechanism for this was not known but it was not particularly bothersome, nor did it develop into anything beyond that. The oily viscous consistency of the vulcanized fatty acid allowed it to persist in an aqueous environment by coating epithelial tissue and yeast membranes, essentially both ready and waiting to intercept released acetaldehyde. It didn't appear to be an intrinsic antifungal since there were no yeast backlash reactions experienced (something quite noticeable even with garlic supplementation). The results that were obtained by those who felt compelled to share their experience (see RELATED WORKS "Wondro Testimonials Pamphlet") were so dramatic across such a wide cross-section of disease states that the biochemical connections between yeast, acetaldehyde and disease as explored in this work are echoed in their personal accounts of recovery. A slightly simpler version (odorless and without heating) that attempts to mimic the effects of Wondro using a flax oil emulsion has been proposed and consumed with favorable results on a daily basis for several months without any negative repercussions (see "Wondro Alternative Protocol"). It contains less combined sulphur and may not be quite as effective as the wondrenic/wondreic acid version. At the biochemical level, the slightest shift of the position of an atom in a structure can change something that is benign and helpful in the body into something that is toxic. Leaving no stone unturned while searching for the ideal acetaldehyde scavenger is an important step in the journey to understanding and solving this problem.

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[1] "Aldehydes" in "Reactive Group Data sheets", CAMEO Chemicals. http://cameochemicals.noaa.gov/react/5 [2] Gainza-Cirauqui ML et al., "Production of carcinogenic acetaldehyde by Candida albicans from patients with potentially malignant oral mucosal disorders.", J Oral Pathol Med. 2012 Aug 22. http://www.ncbi.nlm.nih.gov/pubmed/22909057 [3] "Crotonaldehyde + Disease" from: Davis AP et al., "The Comparative Toxicogenomics Database: update 2011.", Nucleic Acids Res. 2011 Jan;39(Database issue):D1067-72. Epub 2010 Sep 22. http://ctdbase.org/detail.go?type=chem&acc=C012796&view=disease [4] Kawaguchi-Niida M et al., "Crotonaldehyde accumulates in glial cells of Alzheimer's disease brain.", Acta Neuropathol. 2006 May;111(5):422-9. Epub 2006 Mar 15. http://www.ncbi.nlm.nih.gov/pubmed/16538519 [5] Moretto N et al., "alpha,beta-Unsaturated aldehydes contained in cigarette smoke elicit IL-8 release in pulmonary cells through mitogen-activated protein kinases.", Am J Physiol Lung Cell Mol Physiol. 009 May;296(5):L839-48. http://www.ncbi.nlm.nih.gov/pubmed/19286926 [6] Nakao LS et al., "Metabolism of acetaldehyde to methyl and acetyl radicals: in vitro and in vivo electron paramagnetic resonance spin-trapping studies.", Free Radic Biol Med. 2000 Oct 15;29(8):721-9. http://www.ncbi.nlm.nih.gov/pubmed/11053773 [7] Chudasama V et al., "Hydroacylation of alpha,beta-unsaturated esters via aerobic C-H activation." Nat Chem. 2010 Jul;2(7):592-6. http://www.ncbi.nlm.nih.gov/pubmed/20571580 [8] Wiley RH et al.,"Gamma-Radiation-Induced Addition of Aldehydes to Esters of Maleic, Fumaric, and Acetylenedicarboxylic Acids", J. Org. Chem., 1960, 25 (6), pp 903904 http://pubs.acs.org/doi/abs/10.1021/jo01076a006 [9] Lehmann JC et al., "Dimethylfumarate induces immunosuppression via glutathione depletion and subsequent induction of heme oxygenase 1.", J Invest Dermatol., 2007 Apr;127(4):835-45. http://www.ncbi.nlm.nih.gov/pubmed/17235328 [10] Huhtanen CN et al., "Antifungal Properties of Esters of Alkenoic and Alkynoic Acids", Journal of Food Science, Vol. 49 Iss. 1, p. 281, January 1984. http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2621.1984.tb13726.x/abstract [11] Chemical Inspection & Regulation Service, "DMF Testing | Directive 2009/251/EC (DMF)", 2009. http://www.cirs-reach.com/Testing/Dimethyl_Fumarate_DMF_Testing.html [12] Rantanen T, "The cause of the Chinese sofa/chair dermatitis epidemic is likely to be contact allergy to dimethylfumarate, a novel potent contact sensitizer.", Br J Dermatol., 2008 Jul;159(1):218-21. http://www.ncbi.nlm.nih.gov/pubmed/18503603 [13] Nugteren-Huying WM et al., "[Fumaric acid therapy in psoriasis; a double-blind, placebo-controlled study]., Ned Tijdschr Geneeskd 1990 Dec 8;134(49):2387-91. http://www.ncbi.nlm.nih.gov/pubmed/2263264 [14] Molina MT et al., "N-Heterocyclic Carbene-Catalyzed Monoacylation of 1,4-Naphthoquinones with Aldehydes", J. Org. Chem., 2009, 74 (24), pp 95739575 http://pubs.acs.org/doi/abs/10.1021/jo902235h

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[15] Waske PA et al.,"Photoacylations of 2-substituted 1,4-naphthoquinones: a concise access to biologically active quinonoid compounds", Tetrahedron Letters Vol 47 Issue 8, 20 February 2006, Pages 13291332 http://www.sciencedirect.com/science/article/pii/S0040403905027292 [16] Hobara N et al., "Quinone derivatives lower blood and liver acetaldehyde but not ethanol concentrations following ethanol loading to rats.", Pharmacology. 1988;37(4):264-7. http://www.ncbi.nlm.nih.gov/pubmed/2848265 [17] Golomb BA et al., "Statin adverse effects : a review of the literature and evidence for a mitochondrial mechanism." Am J Cardiovas Drugs 2008;8(6):373-418. http://www.ncbi.nlm.nih.gov/pubmed/19159124 [18] Adams J et al., "Vitamin K in the treatment and prevention of osteoporosis and arterial calcification.", Am J Health Syst Pharm. 2005 Aug 1;62(15):1574-81. http://www.ncbi.nlm.nih.gov/pubmed/16030366 [19] Tzeng WF et al., "The role of lipid peroxidation in menadione-mediated toxicity in cardiomyocytes.", J Mol Cell Cardiol. 1995 Sep;27(9):1999-2008. http://www.ncbi.nlm.nih.gov/pubmed/8523459 [20] Felicio AC et al., "Fetal growth in rats treated with lapachol.", Contraception. 2002 Oct;66(4):289-93. http://www.ncbi.nlm.nih.gov/pubmed/12413627 [21] Kalo-Klein A et al., "Candida albicans: cellular immune system interactions during different stages of the menstrual cycle.", Am J Obstet Gynecol. 1989 Nov;161(5):1132-6. http://www.ncbi.nlm.nih.gov/pubmed/2686440 [22] Nohmi T et al., "Suppression of anti-Candida activity of murine neutrophils by progesterone in vitro: a possible mechanism in pregnant women's vulnerability to vaginal candidiasis.", Microbiol Immunol. 1995;39(6):405-9. http://www.ncbi.nlm.nih.gov/pubmed/8551972 [23] Gainza-Cirauqui ML et al., "Production of carcinogenic acetaldehyde by Candida albicans from patients with potentially malignant oral mucosal disorders.", J Oral Pathol Med. 2012 Aug 22. http://www.ncbi.nlm.nih.gov/pubmed/22909057 [24] Szulc P et al., "Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women.", J Clin Invest. 1993 Apr;91(4):1769-74. http://www.ncbi.nlm.nih.gov/pubmed/8473517 [25] Suttie JW et al., "Vitamin K deficiency from dietary vitamin K restriction in humans.", Am J Clin Nutr. 1988 Mar;47(3):475-80. http://www.ncbi.nlm.nih.gov/pubmed/3348159 [26] Huang QY et al., "Genetics of osteoporosis.", Mol Genet Metab. 2006 Aug;88(4):295-306. http://www.ncbi.nlm.nih.gov/pubmed/16762578 [27] Hoshi H et al., "Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis.", J Bone Miner Res. 2012 Sep;27(9):2015-23. http://www.ncbi.nlm.nih.gov/pubmed/22508505 [28] Tarry W et al., "Candida albicans: the estrogen target for vaginal colonization.", J Surg Res. 2005 Dec;129(2):278-82. http://www.ncbi.nlm.nih.gov/pubmed/16111702

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[29] Benito-Leon J et al., "Association between multiple sclerosis and Candida species: evidence from a case-control study", European Journal of Clinical Microbiology & Infectious Diseases Volume 29, Number 9 (2010), 1139-1145. http://www.ncbi.nlm.nih.gov/pubmed/20556470 [30] Kauh E et al., "Prednisone affects inflammation, glucose tolerance, and bone turnover within hours of treatment in healthy individuals.", Eur J Endocrinol. 2012 Mar;166(3):459-67. http://www.ncbi.nlm.nih.gov/pubmed/22180452 [31] Truitt EB Jr et al., "Aspirin attenuation of alcohol-induced flushing and intoxication in Oriental and Occidental subjects.", Alcohol Alcohol Suppl. 1987;1:595-9. http://www.ncbi.nlm.nih.gov/pubmed/3426738 [32] Temple AR, "Acute and chronic effects of aspirin toxicity and their treatment.", Arch Interm Med. 1981 Feb 23;141(3 Spec No):364-9. http://www.ncbi.nlm.nih.gov/pubmed/7469627 [33] van Rensburg CE et al., "An in vitro investigation of the antimicrobial activity of oxifulvic acid.", J Antimicrob Chemother. 2000 Nov;46(5):853. http://www.ncbi.nlm.nih.gov/pubmed/11062218 [34] Sherry L et al., "Carbohydrate Derived Fulvic Acid: An in vitro Investigation of a Novel Membrane Active Antiseptic Agent Against Candida albicans Biofilms.", Front Microbiol. 2012;3:116. Epub 2012 Mar 29. http://www.ncbi.nlm.nih.gov/pubmed/22479260 [35] Gao K et al., "Interaction between peat, humic acid and aqueous metal ions", Environmental Geochemistry and Health, Vol 21, No. 1 (1999), 13-26. http://www.springerlink.com/content/vk1n34g77p384216 [36] Food Standards Agency, "Consumers Advised Not To Eat Hijiki Seaweed", 2010. http://www.food.gov.uk/news-updates/news/2010/aug/hijikiseaweed#.UFzDjK7Z2So [37] Gandy JJ et al., "Phase 1 clinical study of the acute and subacute safety and proof-of-concept efficacy of carbohydrate-derived fulvic acid." Clin Pharmacol. 2012;4:7-11. http://www.ncbi.nlm.nih.gov/pubmed/22427734 [38] Escarpa A et al., "High-performance liquid chromatography with diode-array detection for the determination of phenolic compounds in peel and pulp from different apple varieties.", J Chromatogr A. 1998 Oct 9;823(1-2):331-7. http://www.ncbi.nlm.nih.gov/pubmed/9818410 [39] Spanos GA et al., "Influence of processing and storage on the phenolic composition of apple juice", J. Agric. Food Chem., 1990, 38 (7), pp 15721579 http://pubs.acs.org/doi/abs/10.1021/jf00097a031 [40] Shao X et al., "Apple polyphenols, phloretin and phloridzin: new trapping agents of reactive dicarbonyl species.", Chem Res Toxicol. 2008 Oct;21(10):2042-50. http://www.ncbi.nlm.nih.gov/pubmed/18774823 [41] Zhu Q et al., "Natural Polyphenols as Direct Trapping Agents of Lipid Peroxidation-Derived Acrolein and 4-Hydroxy-trans-2-nonenal", Chem. Res. Toxicol., 2009, 22 (10), pp 17211727. http://www.ncbi.nlm.nih.gov/pubmed/19743801

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[42] Es-Safi NE et al., "Studies on the acetaldehyde-induced condensation of (-)-epicatechin and malvidin 3-O-glucoside in a model solution system.", J Agric Food Chem. 1999 May;47(5):2096-102. http://www.ncbi.nlm.nih.gov/pubmed/10552502 [43] Saucier C et al., "First Evidence of Acetaldehyde-Flavanol Condensation Products in Red Wine", Am. J. Enol. Vitic 1997 vol. 48 no. 3 370-373 http://www.ajevonline.org/content/48/3/370.abstract [44] To Tsz-kin James, "Protective effects of some bioactive phenolic compounds against DNA adduct formation and interstrand cross-links caused by reactive carbonyl species in chemical models.", University of Hong Kong, 2011. http://dx.doi.org/10.5353/th_b4608455 [45] Crespy V et al., "Bioavailability of phloretin and phloridzin in rats.", J Nutr. 2001 Dec;131(12):322730. http://www.ncbi.nlm.nih.gov/pubmed/11739871 [46] Power FB et al., "The Odorous Constituents Of Apples. Emanation Of Acetaldehyde From The Ripe Fruit.", J. Am. Chem. Soc., 1920, 42 (7), pp 15091526 http://pubs.acs.org/doi/abs/10.1021/ja01452a029 [47] Kilb R.W. et al., "Calculation of energy levels for internal torsion and overall rotation. 2. CH3CHO type molecules. Acetaldehyde spectra," J. Chem. Phys., 26, No. 6, 1695-1703 (1957). http://jcp.aip.org/resource/1/jcpsa6/v26/i6/p1695_s1 [48] Lobanov V.V., "Electronic and spatial structure of positive and negative molecular ions of acetaldehyde", Theoretical and Experimental Chemistry, 1982, Volume 18, Number 5, Pages 564-569 http://www.springerlink.com/content/f4412p7579733266

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Soda Pop Stow-Away ================= One of the problems associated with using polyesters such as poly(ethylene terephthalate) (PET) for beverage containers is the generation of acetaldehyde during the melt processing of the polyester. Although the quantities involved are not a toxicity concern, over time such contamination can alter the flavor of the contents of the container. One technique for dealing with this problem is to incorporate acetaldehyde scavenging additives during production that react to form water and an organic byproduct that does not affect the taste of the beverage nor discolor the container. A suite of potential additives have been examined in this regard [1]. By design, additives were chosen that have sterically situated functional groups X and Y such as amine (NH2 and NHR), hydroxyl (OH), carboxyl (CO2H), amide (CONH2 and CONHR), sulfonamide (SO2NH2), or thiol (SH) that upon condensation with acetaldehyde form a stable 5- or 6-membered ring after the release of a water molecule (see figure "Acetaldehyde RingForming Condensation Reaction"). Although these substances may be safe to use in an industrial application as described in the reference, many are orally toxic and not appropriate to even consider as ingested acetaldehyde scavengers. Then why document them here in a medical context? The similarities and differences in molecular structures between these substances is a invaluable resource for comparison with known drugs and herbals that appear to be effective across a wide spectrum of diseases. If a commonality with a substance in this list is found that suggests that acetaldehyde binding may be occurring, then this may imply that yeast-released acetaldehyde is playing a role in the development of a disease of unknown origin. Also, if a particular disease is characterized by the malfunction of a certain biochemical pathway in the body because of enzyme failure or diversion of critical substances away from necessary byproducts, then scrutiny of the structures of the biochemical participants in the pathway (see "Acetaldehyde Game") may reveal a structural commonality with a substance in this list that is known to form a complex with acetaldehyde. Again this would implicate acetaldehyde as a factor in the disease. Some of the scavengers examined are biological substances (eg. arginine, asparagine, cysteine). The fact that they have been shown here to form complexes with acetaldehyde indicates that commensal yeast may already be interfering with their supply and absorption resulting in deficiency conditions relating to their particular functions in the body. And finally, there is always the possibility that a scavenger that has been tested in an industrial setting may be biologically compatible, suitable, and ideal for therapeutic usage. Information on the biological activities of small molecules has been centralized by the National Center for Biotechnology Information into a massive database PubChem with data on 100 million substances and 200 million bioactivities [2]. Of particular interest to this study for any given substance are the additional links in PubChem to "Biomedical Effects and Toxicity" and "Literature". Information in this section may also contain links to the National Cancer Institute's Yeast Anticancer Drug Screen [3] where tens of thousands of compounds have been methodically screened for their potential to inhibit the growth of yeast strains altered in DNA damage repair or cell cycle control [4]. As important as finding molecular configurations with anti-cancer properties may be in the treatment of malignancies, if cancer as a disease is a disruption in metabolic cellular regulation, repair, and destruction processes, then the administration of anti-cancer drugs alone will not correct the imbalance in the body that allowed the cancer to initiate and persist or to reappear. There is no doubt that acetaldehyde is a carcinogenic substance. Chronic exposure to this toxin emanating from commensal Candida albicans fermentation of dietary carbohydrates may set the stage for downstream carcinogenic processes. This being true, then just as much effort needs to be expended in finding ways of dealing with the upstream cause of cancer as well as the downstream consequences.

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The compounds tested in the industrial search for an acetaldehyde scavenger in the processing of melted polyester are itemized herein with notes and links to the PubChem database. They are listed in decreasing order of efficacy (i.e. ring-forming reactivity with acetaldehyde) for the specific tests performed. The relative performance is indicated by the number of asterisks in the note from 0 to 4. From the diversity of structural arrangements that show ring closure reactivity with acetaldehyde, it should be glaringly obvious why this substance is so dangerous in the body. It can react with and incapacitate just about any biological configuration it encounters. CAUTION: This information is for reference only. Unless specifically stated to the contrary, all of these substances should be considered to be potentially toxic and not appropriate for therapeutic management of yeast-released acetaldehyde. The configurations with profiles that have the most potential for more testing in their possible physiological roles as acetaldehyde scavengers are methyl anthranilate (cf. grape diet cure) and 3-mercapto-1,2propanediol (monothioglycerol).

List of Industrial Acetaldehyde Scavengers Tested ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ (See figures of the same names as each of the compounds.) 1,8-diaminonaphthalene Notes: ring closure condensation reaction with acetaldehyde (****). http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=68067&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ 3,4-diaminobenzoic acid Notes: ring closure condensation reaction with acetaldehyde (****). http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=69263&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ Anthranilamide Notes: ring closure condensation reaction with acetaldehyde (***). http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6942&loc=ec_rc ~~~~~~~~~~~~~~~~~~~ Allantoin Notes: ring closure condensation reaction with acetaldehyde (***). Allantoin is present in botanical extracts of the comfrey plant and urine from cows and most mammals. It is used topically in many cosmetics and skin care products. Because uric acid may be oxidized to allantoin by various reactive oxygen species, it is postulated that uric acid functions as an antioxidant in human bodily fluids [5]. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=204&loc=ec_rcs

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Acetaldehyde Ring-Forming Condensation Reaction

1,8-diaminonaphthalene

3,4-diaminobenzoic acid

Anthranilamide

Allantoin

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~~~~~~~~~~~~~~~~~~~ Salicylanilide Notes: ring closure condensation reaction with acetaldehyde (***). Derivatives of salicylanilide have a variety of pharmacological uses with antibacterial and antifungal activities. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6872&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ Salicylamide Notes: ring closure condensation reaction with acetaldehyde (***). Salicylamide is a non-prescription drug with analgesic and antipyretic properties used in a manner similar to aspirin. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5147&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ Malonamide Notes: ring closure condensation reaction with acetaldehyde (***). Side to side carbonyls in an ester configuration are present in dimethyl fumarate which is being investigated in relation to relapse-remitting multiple sclerosis (see "Scavenger Hunt"). http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=7911 ~~~~~~~~~~~~~~~~~~~ 3-mercapto-1,2-propanediol Notes: ring closure condensation reaction with acetaldehyde (**). Monothioglycerol is classified as an antioxidant, an antimicrobial, a cosmetic agent, a stimulator of wound healing, and as a jelly in atrophic rhinitis [6]. The effectiveness of monothiogycerol in rhinitis may result from its ability to quench yeast-released acetaldehyde before it initiates a cascade of peroxidation (see "Pulmonary Peroxidosis"). http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=7291&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ 2,3-diaminopyridine Notes: ring closure condensation reaction with acetaldehyde (**). http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=9956&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ 1,2-diaminoanthraquinone Notes: ring closure condensation reaction with acetaldehyde (**). http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=15652&loc=ec_rcs

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Salicylanilide

Salicylamide

Malonamide

3-mercapto-1,2-propane diol

2,3-diaminopyridine

1,2-diaminoanthraquinone

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~~~~~~~~~~~~~~~~~~~ Biuret Notes: ring closure condensation reaction with acetaldehyde (**). Biuret is the result of condensation of two molecules of urea. It is used as a non-protein nitrogen source in ruminant feed. The "Biuret Test" is a chemical test used for detecting the presence of peptide bonds, for diagnosis of hyperproteinuria for example. Biuret reagent is so-named, not because it contains biuret, but because of its reaction to the peptide-like bonds in the biuret molecule. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=7913&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ 2-amino-2-methyl-1,3-propanediol Notes: ring closure condensation reaction with acetaldehyde (**). http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=1531&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ 4,5-dihyroxy-2,7-naphthalene disulfonic acid disodium salt Notes: ring closure condensation reaction with acetaldehyde (**). Also known as disodium chromotropate. The chromotropic acid method can be used to determine the concentration of formaldehyde in ambient air samples. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=67220&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ 4-amino-3-hydroxybenzoic acid Notes: ring closure condensation reaction with acetaldehyde (**). This is a derivative of paraaminobenzoic acid (PABA) which is an intermediate in the bacterial synthesis of folate. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=137566&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ 1,2-diaminocyclohexane Notes: ring closure condensation reaction with acetaldehyde (*). This has a medical use as a carrier ligand in oxaliplatin, a platinum-based antineoplastic agent used in cancer chemotherapy. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4610&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ N-acetylglycinamide Notes: ring closure condensation reaction with acetaldehyde (*). This is a derivative of the amino acid glycine.

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Biuret

2-amino-2-methyl-1,3-propanediol

4,5-dihyroxy-2,7-naphthalene disulfonic acid disodium salt

4-amino-3-hydroxybenzoic acid

1,2-diaminocyclohexane

N-acetylglycinamide

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http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=75800&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The following substances were found to be capable of forming 5- or 6-member rings upon condensation with acetaldehyde but were thermally unstable under the conditions of the industrial process in question (heating with polyester at 150 C for 45 min). This is far beyond the most extreme of physiological conditions and these substances should not be ruled out based only upon their thermal instability in this particular application. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Arginine Notes: ring closure condensation reaction with acetaldehyde. Arginine is a conditionally non-essential amino acid that participates in protein biosynthesis in the body. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6322&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ Asparagine Notes: ring closure condensation reaction with acetaldehyde. Asparagine is a non-essential amino acid that participates in protein biosynthesis in the body. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=6267&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ Aspartic acid Notes: ring closure condensation reaction with acetaldehyde. Aspartic acid is a non-essential amino acid that participates in protein biosynthesis in the body. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5960&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ Cysteine Notes: ring closure condensation reaction with acetaldehyde. Cysteine is a non-essential amino acid that participates in protein biosynthesis in the body. It can be biosynthesized from serine and methionine. An acetaldehyde-scavenging formulation called Acetium is currently being marketed in Finland and Germany (see "Toxic Soup" and "When The Backup Fails"). http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5862&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ Serine Notes: ring closure condensation reaction with acetaldehyde. Serine is a non-essential amino acid that participates in protein biosynthesis in the body. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5951&loc=ec_rcs

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Arginine

Asparagine

Aspartic acid

Cysteine

Serine

5-amino-1,3,3-trimethylcyclo hexylamine

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~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The following substances were tested as additives but found to be incapable of forming 5- or 6-member rings upon condensation with acetaldehyde. They are included here for comparison with the structures that do form rings. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 5-amino-1,3,3-trimethylcyclohexylamine Notes: no ring closure condensation reaction with acetaldehyde. No PubChem database entry. ~~~~~~~~~~~~~~~~~~~ Dimethylaminoterephthalate Notes: no ring closure condensation reaction with acetaldehyde. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=79336 ~~~~~~~~~~~~~~~~~~~ Glycine Notes: no ring closure condensation reaction with acetaldehyde. Glycine is a non-essential amino acid that participates in protein biosynthesis in the body. It is also a neurotransmitter. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=750&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ Methylanthranilate Notes: no ring closure condensation reaction with acetaldehyde. Although there was no ring closure byproduct in this application, methyl anthranilate is used in the perfume industry to form Schiff bases with aldehydes. Since methyl anthranilate occurs naturally in Concord grapes, its formation of a Schiff base with acetaldehyde may provide the basis for Johanna Brandt's "grape diet" cure by functioning as an acetaldehyde scavenger. The steric proximity of the electron-rich ester may favor and stabilize the formation of the resulting configuration (see also figure "Acetaldehyde + Methylanthranilate"). http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=8635&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ Octadecanamide Notes: no ring closure condensation reaction with acetaldehyde. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=31292&loc=ec_rcs

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Dimethylaminoterephthalate

Glycine

Methylanthranilate

Octadecanamide

Piperazine

Stearylamine

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~~~~~~~~~~~~~~~~~~~ Piperazine Notes: no ring closure condensation reaction with acetaldehyde. Piperazine is used as an anthelmintic for paralyzing parasites. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4837&loc=ec_rcs ~~~~~~~~~~~~~~~~~~~ Stearylamine Notes: no ring closure condensation reaction with acetaldehyde. Stearylamine in liposomes is being investigated for inhibition of the growth of the protozoan parasites. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=15793&loc=ec_rcs

[1] Rule et al., "Method To Decrease The Acetaldehyde Content Of Melt-Processed Polyesters", US Patent 6274212, 2001. http://www.google.com/patents/US6274212?printsec=abstract#v=onepage&q&f=false [2] National Center for Biotechnology Information, "PubChem Bio Assay / Compound / Substance Database", 2004. http://pubchem.ncbi.nlm.nih.gov [3] National Cancer Institute, "NCI Yeast Anticancer Drug Screen Database", 2002. http://dtp.nci.nih.gov/yacds [4] Hobeck S et al., "The FHCRC/NCI Yeast Anticancer Drug Screen" in "Yeast as a Tool in Cancer Research", 2007, 315-346, DOI: 10.1007/978-1-4020-5963-6_12 http://www.springerlink.com/content/jg57235741j2471k [5] Lagendijk et al., "The Determination of Allantoin, a Possible Indicator of Oxidant Status, in Human Plasma", J Chromatogr Sci (1995) 33 (4): 186-193. http://chromsci.oxfordjournals.org/content/33/4/186.abstract [6] Rowe et al., "Monothioglcerol" in "Handbook of Pharmaceutical Excipients", Sixth Edition, Pharmaceutical Press, 2009.

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Signposts Of Disease ================= Google Earth is a virtual globe, map and geographical information program that allows you to travel the world from your computer screen with satellite imagery, maps, terrain, 3D buildings, street views and much more. You perceive a realistic visualization of the world and its features. It would be nothing less than incredible if a technique existed for zooming in on the body to find the most likely places that disease might strike? Far-fetched, impossible -- maybe -- but perhaps not as fanciful as it sounds? The toxic metabolite acetaldehyde produced by the yeast Candida Albicans, a commensal parasite carried by human hosts, is difficult to detect because it consists of organic atoms in a compact configuration that reacts quickly with other molecules, blending into the background landscape. Aldehydes such a formaldehyde are used as fixation preservatives to stop enzymatic processes and stiffen cellular membranes. Chronic exposure to acetaldehyde produced in vivo may actually be "embalming a living host" (see figure "Acetaldehyde Frog"). If it can't be easily found in its simplest reactive form, then where has it gone? Fuchsin or rosaniline hydrochloride is a magenta dye stemming from the work of Lauth (1861), Schiff (1866) and Gomori (1950). It is used in the the histological staining of body tissue. Aldehyde fuchsin has the amazing property of staining some of the very same molecular groups that are prone to reaction with acetaldehyde itself, especially cellular surface structures that have attractive binding sites exposed. Aldehyde-fuchsin has been shown to have an affinity for tissues with highly sulphated mucopolysaccharides and also those with a high content of cystine. The common feature in all of these instances appears to be a sulphur moiety. Sulphur is a relatively large, highly electronegative atom in the organic schema. Its electron cloud and associated charge can be redistributed temporarily by its surroundings, exhibiting valence states of 2 or 4 or 6, so that utilitarian functions such as elasticity, motion, and stickiness are possible. More often than not it is found in a cysteine residue in an enzymatic reaction pocket designed to hold a substrate just long enough for the atomic reconfiguration specific to the enzyme to be carried out and the enzyme product ejected -- transient metabolite binding. Since acetaldehyde is a tiny electrophilic molecule, it finds sulphur atoms very attractive and binds irreversibly when it encounters an exposed sulphur moiety. This gums up the intended function of the sulphur atom and associated structures with the result that elasticity, motion, or enzymatic reaction rates are impaired or inhibited completely. Once in place, acetaldehyde will degrade and denature these tissues, possibly creating an autoimmune response to the resulting configurations, eventually leading to disease, organ failure and death. Since aldehyde fuchsin will bind to and stain the same sulphur-rich tissue structures that are attractive to acetaldehyde, mapping out those tissues in the body that are stained by aldehyde fuchsin provides a window to those areas most likely to be vulnerable to acetaldehyde exposure. Aldehyde-fuchsin produces staining of beta cell granules of the islets of Langerhans, keratin, elastic fibres, mast cell granules, hyaline cartilage, goblet cells, thyroid colloid, agentaffine cell granules, acrosomes of spermatozoa, gastric chief cells, beta cells of the pancreatic islets, certain hypophyseal beta granules, pituitary granules/cells, tonsil epithelial cells -- a veritable smorgasbord of binding sites. Depending upon the genetic propensity of an individual to disease, the level of acetaldehyde being produced by commensal yeast loads, the viability of innate aldehyde scavengers such as aldehyde dehydrogenases and carnosine, and the blood-borne distribution of acetaldehyde in its reactive form to various parts of the body; the metabolic dysfunctions that could result from in vivo production of acetaldehyde alone are numerous and diverse. Is this why substances that scavenge and neutralize acetaldehyde effectively are labeled as miraculous panaceas in a host of diseases?

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Bridge Across The Chasm ==================== Disulphide bonds are found in the body wherever strength, flexibility, elasticity, or stickiness are required in protein structures. They may also be used as signalling switches to switch on or off processes such as secretion. They are a highly conserved structural element of G Protein-Coupled (GPCR) and ligand-gated ion channel receptors, something crucial to the fundamental integrity of biochemical communication in the body between secretory organs and cells and from cell to cell. Disulphide bonds even play a role in hair dressing. Hair straightening or a permanent wave involves breaking down the disulphide bonds between hair structural proteins using a chemical solution. Some hair relaxers contain formaldehyde for this very purpose. But formaldehyde is a known toxic carcinogen with adverse side effects even when used externally. Acetaldehyde is only slightly larger than formaldehyde and shares a similar toxic profile (see figure "Formaldehyde and Acetaldehyde"). As robust as disulphide linkages are, being resistant to both heat and water, when an aldehyde such as formaldehyde or acetaldehyde comes into contact with a disulphide linkage, the disulphide bridge is broken irreversibly by the formylation or acetylation, respectively, of one of the sulphur atoms and the reduction (addition of hydrogen) of the other (see figure "Disulphide + Acetaldehyde Before/After"). Think of a long rope bridge across a deep gorge that has been ruptured in the middle. There is no longer any connection between the opposite sides of the chasm. In essence both the structure and functionality of the protein (tissue or enzyme or receptor) containing the critical disulphide bridge has been compromised. Wondro (sulphurated flax oil) likely has several disulphide linkages on each of the fatty acids that has been vulcanized by heating during its production process (see figure "Wondrenic Acid"). Wondreic (from linoleic) and wondrenic (from linolenic) acid disulphide bonds serve no functional purpose in the body. However, they are irresistible targets for acetaldehyde produced in the throat and the gut by budding yeast metabolism (see figure "Wondrenic Acid + Acetaldehyde"). Once acetaldehyde has broken into a disulphide linkage it loses its reactivity and cannot escape. Its potential threat to other critical body structures has been neutralized. By sacrificing its own disulphide bonds, Wondro is able to block any damage that its captured acetaldehyde molecules might have inflicted throughout the body. Furthermore, because Wondro is a "useless" molecule in the body, this doesn't deprive it of anything essential in the process. The inescapable corollary to this is that all of the diverse conditions that Wondro was used for with beneficial results may have been related to acetaldehyde toxicity -- making Candida Albicans a common denominator of illness -- something that C. O. Truss was trying to tell us back in 1984. It is important to note that an acetaldehyde scavenger such as Wondro does not repair damage done by previous acetaldehyde exposure. Acetaldehyde that has already linked itself to other structures in the body loses its reactivity and remains there as collateral damage of yeast metabolism. But an acetaldehyde scavenger can prevent further damage from additional acetaldehyde being released by yeast metabolism -- something that happens whenever the yeast is fermenting pyruvate from carbohydrates in the diet (see "Just A Teaspoon of Sugar"). By reducing the cumulative stress incurred from chronic acetaldehyde exposure, an acetaldehyde scavenger allows the body's own considerable recuperative processes to function unimpeded by this toxin. To be effective the acetaldehyde scavenger must also be present in the areas of yeast colonization to be useful. Hence, there may be some latency time between the commencement of such a protocol and actual remission of symptoms. Some chronic conditions may have taken years to develop. It is not unreasonable to not see definitive results until after one or two months on the protocol. This is why it is so critical that the acetaldehyde scavenging substance have no side effects of its own so that it may be continued indefinitely if desired.

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Formaldehyde

Acetaldehyde

Before...

Disulphide Bridge

Acetaldehyde

After...

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Disulphide Bond in Lipoic Acid

Lipoic Acid + Acetaldehyde

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Geepers Creepers (GPCRs) ====================== There are over two hundred different types of cells comprising the trillions of cells that make up the human body, each with its own specific function. At any given time an individual cell may contain over ten billion proteins of at least ten thousand different types of the estimated over one hundred thousand different kinds of proteins in the human body. Orchestrating the production, function, and disposal of such a vast array of shapes and sizes is a mammoth task. Part of a cell's job is to maintain its own integral function while working in harmony with the other cells in the body. It needs to know what is happening and what is expected of it at any given time. Cells are quite particular about what they let inside with their semi-permeable membranes taking up what is needed and rejecting (keeping outside) substances that are not. One of the mechanisms that is used in this regard is an integral membrane protein called a G ProteinCoupled Receptor (GPCR). These are specialized proteins that are interwoven into the cell's membrane and pass "messages" but not "molecules" from the extra-cellular environment into the intra-cellular milieu. Part of this protein is outside of the cell and part of it is inside (see figure "G Protein-Coupled Receptor"). Messenger molecules (hormones) fit like a hand in a glove into the unique protein shape that is available externally. This triggers an actual conformational rearrangement (physical shifting) of the amino acid constituents of the GPCR precipitating a biochemical cascade of events on the inside of the cell that are specific to the type of messenger and cell. Other molecules that do not fit into the glove cannot do this. It is a bit like a doorbell that responds to a certain fingerprint only. As an example, consider one of the largest endocrine glands, the thyroid. This gland produces hormones that control the metabolism of almost every tissue in the body including how they use energy, make proteins, and their sensitivity to other hormones. Thyroid hormones even regulate cholesterol homeostasis by exerting control over its production and catabolism. The thyroid is induced to produce its hormones by the binding of thyroid-stimulating hormone (TSH), produced by the pituitary gland, to TSH receptors (GPCR's) in the membranes of thyroid cells. This sends a signal from the "outside" of the thyroid cell to the "inside" that activates the thyroid cell to produce and send out its own messenger molecules (hormones) to other cells which, in turn, have receptors that recognize the thyroid messengers. High levels of circulating levels of TSH (as measurable via a thyrotropin blood test) are often indicative of an under-active thyroid gland that is not responding adequately to TSH stimulation. The downstream consequences of the interruption of the receptor communication system for TSH alone can be devastating and this is just one of a host of GPCR-type receptors found in the various types of cells throughout the body. It is already known that G protein-coupled receptors are involved in many diseases. The actual methodology surrounding a GPCR is quite complex and not fully understood even yet but consider for a moment a common feature of all GPCR's that is essential to their bio-mechanical function. The extracellular loops shown in the figure contain two highly-conserved cysteine residues that form a disulphide bond (see figure "GPCR Disulphide Linkage") that is essential to the shape and function of the receptor. "Highly-conserved" in genetic terms indicates that despite differences in types of these receptors across cells and species in the evolutionary chain, the disulphide bridge remains a constant feature in all of the variants -- in other words, a critical component of the underlying mechanism. Acetaldehyde has an affinity for disulphide bonds. The best acetaldehyde scavengers are substances with an S-S bond incorporated into their molecular structure. In fact the body uses this very affinity in its own production of acetyl-coenzyme A, a necessary component of the citric acid cycle. It decarboxylates pyruvate to form acetaldehyde and moves this into the proximity of a disulphide bond in lipoic acid. The disulphide bond is cleaved by the acetaldehyde and the enzyme subsequently transfers the acetyl group from the acetaldehyde/lipoic conjugate to coenzyme A forming acetyl-coenzyme A (see figures "Lipoic Acid" and "Lipoic acid + acetaldehyde").

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G Protein-Coupled Receptor (GPCR)

GPCR Disulfide Linkage

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But, it does this under the strict control of an enzyme where the acetaldehyde is always safely immobilized within the constraints of the enzyme. It never allows the acetaldehyde to float freely in the cellular milieu. Acetaldehyde produced and emitted by yeast metabolism is not subject to such constraints. These rogue molecules pass freely through the intestinal walls and can hitch rides on red blood cells to be released later wherever the blood flows [Baraona E et al., op. cit.]. GPCR proteins may be more than one thousand atoms (hundreds of amino acids) in length whereas acetaldehyde molecules (that are commensurate in size and behaviour to heavy metal ions) are even smaller than the amino acids that comprise the GPCR protein. This means that rogue acetaldehyde molecules would have no problem drifting into the receptor pockets which are in the extracellular region and attacking the -S-S- disulphide bridge that stabilizes the GPCR. If acetaldehyde cleaves this bond, it is highly unlikely that the signalling nature of a receptor damaged in this manner will continue to function correctly. Either the hormonal ligand that usually fits into the receptor pocket will not dock properly or the conformational shift will not occur even if it does. Think of trying to open or close a door with a screw driver jammed into the hinge or a door where the hinge is broken completely. Although different cells perform different tasks and respond to different external messaging substances (peptides, hormones, etc.), their GPCR receptors all share this common mechanism for triggering a response inside a cell. Unrestrained acetaldehyde molecules have the ability to push the entire hormonal communications network into chaos! Consider once again the thyroid example. If acetaldehyde has damaged the GPCR receptors of thyroid cells, they will no longer respond to the TSH coming from the pituitary gland. The T3 and T4 hormones usually produced by the thyroid will dwindle and the negative feedback loop that suppresses TSH production when T4 levels are high will not engage. Circulating levels of TSH will remain high and symptoms of hypothyroidism will manifest. We now have a commensal perpetrator (Candida Albicans) capable of producing a weapon (toxic acetaldehyde) that can inflict calamity on vital protein structures (enzymes, receptors, structural tissue components) at a level that encompasses all different cellular specificities, more often than not leading to chronic, if not fatal diseases. Furthermore, treatment protocols that focus on removing the source of the toxin (yeast abatement) and/or sequestering it (acetaldehyde scavenging) before it can run rampant throughout the body produce dramatic results in patients with apparently unrelated diseases.

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Not So Tight Junctions ================= Many of the Wondro testimonials (circa 1930's) spoke of relief from "stomach troubles" that were chronic and apparently intractable. It has been well established that increased intestinal permeability (leaky gut) is associated with the pathology of numerous diseases: inflammatory and infectious bowel diseases such as Crohn's and ulcerative colitis, chronic inflammatory arthritides, acne, psoriasis, dermatitis, herpetiformis, eczema, urticaria, irritable bowel syndrome, autism to name just a few. Is leaky gut the cause, an effect, or a consequence of something common to all of these conditions? In a sense the gastrointestinal tract from mouth to anus can be considered to be "outside" of the body with special structures (intestinal walls) and processes (digestion) in place to allow it to select what it needs and dispose of everything else as waste. The "inside" of the body is a much more controlled environment that needs to be protected from the ingested material being processed and disposed of. This is maintained by cells that are conformed in "tight junction" interactions where their membranes are sealed together by multiple strands of special protein complexes that form a barrier that is virtually impermeable to fluids (see figure "Tight Junctions"). Acetaldehyde inhibits the enzyme protein tyrosine phosphatase (PTP), possibly by blocking the conserved cysteine (sulphur-containing) residue at the active site. PTPs are a group of enzymes that remove phosphate groups from phosphorylated tyrosine residues on proteins. The unimpeded action of PTPs are a necessary part of the formation/maintenance of epithelial tight junctions. These tight junction structures seal the intestinal walls so that they are impermeable to macromolecules and fluids. Acetaldehyde exposure, as studied in relation to alcoholism where it is a known toxic byproduct of excess alcohol consumption, can result in the disassembly of the proteins in the junctional complex [1,2]. In other words, acetaldehyde can punch holes in the intestinal wall = leaky gut syndrome! Acetaldehyde that stems from ethanol metabolism appears in the liver where aldehyde dehydrogenase enzymes are prepared to cope with it (within reasonable concentration limits) and turn it into harmless acetic acid. Acetaldehyde that is released in the gut by yeast metabolism immediately adjacent to the intestinal cells forming the tight junction complexes is a surprise to the body that it cannot deal with. Tight junctions are also critical in maintaining the integrity of the blood-brain barrier that restricts access of substances to the brain extracellular fluid. A breakdown of the blood-brain barrier is associated with diseases such as meningitis, epilepsy, multiple sclerosis, Alzheimer's, and HIV encephalitis. [1] Atkinson KJ, Rao RK, "Role of protein tyrosine phosphorylation in acetaldehyde-induced disruption of epithelial tight junctions", AJP - GI June 1, 2001 vol. 280 no. 6 G1280-G1288. http://ajpgi.physiology.org/content/280/6/G1280.full [2] Basuroy et al., "Acetaldehyde disrupts tight junctions and adherens junctions in human colonic mucosa: protection by EGF and L-glutamine", Am J Physiol Gastrointest Liver Physiol. 2005 Aug;289(2):G367-75. Epub 2005 Feb 17. http://www.ncbi.nlm.nih.gov/pubmed/15718285

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Tight Junctions

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Slow Death By Strangulation ====================== One of the reasons it has taken so long to start to unravel this murder mystery is that we have underestimated the abilities of this nemesis. It is not in the yeast's best interests to engage the innate immune system. Although it is a struggle between equals with the yeast often winning a skirmish [1], precious fungal energy and resources are expended in the process. It is preferable from a yeast perspective to remain "below the radar" and bud away within certain self-imposed thresholds so that it doesn't dispose of its host or engage in outright battle with the immune system. In most cases it succeeds with this strategy and only in severely immunocompromised individuals does its truly pathogenic nature emerge. Even then it is considered to be a consequence of disease rather than a cause. Each and every anecdotal and historical clue may help in formulating a strategy of recovery. Anything with 94 sextillion atoms of sulphur for every two tablespoon dosage (see "Just A Teaspoon Of Sugar") is going to have a rather pungent odor, even if the sulphur is buried in the fatty acids of flax oil. At some point in its production history in the first half of the twentieth century the mode of Wondro marketing was changed from a liquid to gel capsules for this very reason. In capsules it was more convenient to carry (e.g. for railroad workers) and to take (no messy spoon and less odor). Although it still appeared to work, there was a lingering perception amongst those who made it and took it that it just wasn't just quite as effective in this form. This is the first clue... Furry teeth syndrome is something that has been reported after binge drinking or even eating a Caesar salad with a particularly potent garlic dressing. Something related to the alcohol or the garlic-infused liquid has shifted the commensal balance so that yeast colonization profiles are altered toward the mouth. This is the second clue... Dr. William G. Crook in his 1980's book, "The Yeast Connection", was convinced after treating many patients that candidiasis and thyroid abnormalities were related. Whenever symptoms occur simultaneously, however, there is always the "chicken and egg" debate about which came first. Does Candida Albicans cause impairment of thyroid function or does low thyroid activity allow yeast to take hold? So yeast and the thyroid interaction is the third clue... Is there a connection here? Assuming that Wondro worked its magic by scavenging acetaldehyde and that the acetaldehyde is emanating from the sugar metabolism of commensal yeast, then the historical change in efficacy could be explained by the fact that the capsules missed the initial portion of the alimentary canal -- the esophageal lining! This implies that a significant proportion of the acetaldehyde to blood stream poisoning of the body may occur from this region even before the stomach and intestines because commensal yeast finds this region an ideal colonization locale. Here it is "first in line" for ingested nutrients prior to the rather harshly acidic environment of the stomach. Anal itching and a coated tongue are biomarkers for yeast overgrowth -- from mouth to anus. Ingestion of an antifungal such as the garlic in the salad dressing, which coats the esophageal lining on the way to the stomach, may precipitate an avoidance maneuver shift of the yeast in this area away from the antifungal, that is, towards the mouth (tongue and teeth) with the furry teeth syndrome the net result. Although alcohol doesn't kill Candida Albicans the yeast doesn't like it in its external environment [2,3]. Hence the binge drinking may similarly shift the commensal focus from the throat to the mouth and teeth. As for the third clue, what is situated immediately adjacent to the esophageal region missed by capsules but not by liquids? The thyroid gland is located in the neck wrapped around the esophagus (see figure "Thyroid and Parathryoid Glands")! This endocrine gland produces hormones that control the metabolism of almost every tissue in the body including how they use energy, make proteins, and their sensitivity to other hormones.

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The acetaldehyde that is released by budding yeast metabolism in the esophageal lining is such a small molecule that it should have no trouble diffusing across the esophageal lining and right into the proximity of the thyroid gland. Even if the barrier proves difficult it can disrupt the tight junctions that seal the lining and punch its way through (see "Not So Tight Junctions"). The thyroid gland produces and releases its hormones in response to circulating levels of "thyroid-stimulating-hormone" (TSH) released by the pituitary gland. The TSH molecule alerts thyroid cells that more of their T3 and T4 hormones are needed by docking in a thyroid cell TSH receptor, an integral membrane protein called a G Protein-Coupled Receptor (see "Geeper Creepers"). These types of receptors may be exquisitely sensitive to rogue molecules of acetaldehyde. The damage to the structurally and functionally essential disulphide bridge inflicted upon the receptor by acetaldehyde (see "Bridge Across the Chasm") may be sufficient to stop the receptor from responding to the TSH signals to produce thyroid hormones. When thyroid hormones are low, the immune system becomes sluggish and is less able to respond to yeast cells that are inhabiting the body [4]. Yeast levels increase with more acetaldehyde production which further impairs thyroid function and a vicious cycle is in place. Here is where the yeast must limit its own virulence (possibly via quorum-sensing of its own acetaldehyde release) to ensure that it doesn't dispose of its host too quickly. By colonizing the esophageal lining adjacent to the thyroid, Candida Albicans is able to exert a considerable amount of "host control" including but not limited to reining in the immune response to its presence. Since hypothyroidism and hyperlipidemia go hand in hand, the major contributor to high cholesterol levels in the bloodstream may be the interference of acetaldehyde with the TSH receptors of the thyroid. The output of thyroid hormone is critical to both the production and catabolism of cholesterol [5]. This is supported by the observation that individuals treated with thyroid replacement hormones such as synthroid usually show improvement in cholesterol levels without additional treatment with inhibitors such as statins [6]. All of these three clues point to the conclusion that yeast colonization in the esophagus, something that often reveals its presence as a coated tongue, furry teeth, or in its advanced infectious state as thrush, literally has a "stranglehold" on the metabolism of the body through its ability to impair thyroid function. This has implications for any yeast abatement protocol in terms of the delivery mechanism of both acetaldehyde scavengers and antifungal agents. Capsules may not be the best mode for either... [1] Scherwitz C, Martin R, "The phagocytosis of Candida albicans blastospores and germ tubes by polymorphonuclear leukocytes", Dermatologica, 1979;159(1):12-23. http://www.ncbi.nlm.nih.gov/pubmed/383529 [2] Pollack JH, Hashimoto T, "Ethanol-induced Germ Tube Formation in Candida albicans", Microbiology December 1985 vol. 131 no. 12 3303-3310. http://mic.sgmjournals.org/content/131/12/3303.short [3] Zeuthen ML et al., "Ethanol Tolerance and the Induction of Stress Proteins by Ethanol in Candida albicans", Microbiology May 1988 vol. 134 no. 5 1375-1384. http://mic.sgmjournals.org/content/134/5/1375.short [4] Schaefer JS et al., "Immunological regulation of metabolisma novel quintessential role for the immune system in health and disease", January 2011 The FASEB Journal vol. 25 no. 1 29-34. http://www.fasebj.org/content/25/1/29.full [5] Field FJ et al., "The effect of hypothyroidism and thyroxine replacement on hepatic and intestinal HMGCoA reductase and ACAT activities and biliary lipids in the rat.", Metabolism. 1986 Dec;35(12):1085-9. http://www.ncbi.nlm.nih.gov/pubmed/3784912 [6] Mishkel MA et al., "Hypothyroidism, an important cause of reversible hyperlipidemia.", Clinica Chimica Acta, Volume 74, Issue 2, 17 January 1977, Pages 139151. http://www.sciencedirect.com/science/article/pii/0009898177902157

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Deep Throat ========== If the esophageal region adjacent to the thyroid gives Candida Albicans both a niche for prime nutrient access and a degree of host control through acetaldehyde-mediated suppression of thyroid function (see "Slow Death by Strangulation"), then there should be other biomarkers of its colonization in this region. Sore throats are a common occurrence with a preponderance of emergency department instances of throat-related cases in every year. The most common cause is viral infection. But what makes the throat and adjacent tonsils so vulnerable to infection? If acetaldehyde in the gut can disrupt the tight junctions proteins in the intestinal wall leading to "leaky gut", then yeast-released acetaldehyde in the esophagus could similarly alter the epithelial permeability in this sensitive region leading to "leaky throat" with inflammation, soreness, and susceptibility to infection (classic symptoms of sore throat) the result (see "Not So Tight Junctions"). A connection between the integrity of tight junction proteins and the common condition of acid reflux has also been established [1]. A sneeze is an autonomic reflex used by the body as a first line of defense in an attempt to physically clear invading material including viral activity from the respiratory passages. Budding activity of yeast and release of acetaldehyde will increase after the consumption of certain foods. If there is yeast-induced acetaldehyde irritation in the esophageal tissues potentially leading to loss of tight junction integrity, is acid reflux a similar autonomic response to attempt to eliminate the pathogenic behaviour by exposing whatever is causing the damage to the acidic environment of the stomach? Recent studies have demonstrated a role for the tonsils in the production of immune system T-cells [2], elevating the utility of these often-infected and often-removed lymph nodes at the top of the throat from just passive blocking of inhaled or ingested pathogens to an active participation in the systemic biochemistry of the immune system. Aldehyde fuchsin intensely stains tonsil tissue [3] indicating that these endothelial cells would be exquisitely sensitive to attack by acetaldehyde molecules released by budding yeast metabolism. This model of yeast-produced, acetaldehyde-mediated disruption of both the tight junction proteins in the lining of the esophagus and of the epithelial cells of the tonsils may explain why steeped garlic tea, an antifungal (i.e. anti-yeast), is a frequently recommended home remedy for sore throats. Furthermore, it elucidates why a liquid acetaldehyde scavenger such as Wondro or emulsified NAC is more efficacious than an encapsulated one (something that bypasses this vulnerable region completely on its way to the stomach). There are conflicting reports on the web about the usage of garlic as a home remedy for heartburn. For some it seems to be a trigger and for others the answer to their quest for relief. Assuming that yeast in the throat and esophagus has something to do with the condition, we may be able to rationalize both types of experience. Remember that we are not dealing with a passive organism here. Yeast is prepared to fight when antifungally challenged (e.g. by garlic). One of the ways it does this is to shift morphology from a budding yeast into an invasive hyphal form (see figures "Candida Albicans -- Budding/Hyphal Phase") that is capable of penetrating human cellular membranes by expressing one or more of the enzymes in the phospholipase group [4], something that is also found in snake venom and bee stings. For epithelial cells already damaged and sensitized by acetaldehyde emitted by yeast in this region, this type of invasive penetration may exacerbate the damage already in place and be an additional trigger for acid reflux. Several sore throat remedies have a sweet component such as honey (e.g. olive oil, lemon, and honey) that may be included for this very reason -- to entice yeast back into its budding form. The long-term problem with this is that the yeast goes back to producing acetaldehyde which is deleterious to the tight junction proteins that seal the esophageal lining.

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Therein lies the catch-22 host-control enigma that exists with yeast colonization. If you give it what it wants, it can damage the body (budding phase acetaldehyde toxicity symptoms). But, if you don't give it what it wants, it can shift strategies and damage the body some more (hyphal phase phospholipase degradation of tissue), perhaps with symptoms that were worse than before. This may be why novel combinations such as honey, garlic and apple cider vinegar for heartburn are popular. Adding an acetaldehyde scavenger to the liquid mixture might make it even more effective.

[1] Asaoka D. et al., "Altered localization and expression of tight-junction proteins in a rat model with chronic acid reflux esophagitis", J Gastroenterol. 2005 Aug;40(8):781-90. http://www.ncbi.nlm.nih.gov/pubmed/16143882 [2] McClory S. et al., "Evidence for a stepwise program of extrathymic T cell development within the human tonsil", J Clin Invest. 2012;122(4):14031415. http://www.jci.org/articles/view/46125 [3] Sunami-Kataoka et al. "Chondroitin sulfate proteoglycan at the basal lamina beneath high endothelial cells in human palatine tonsils: a light and electron microscopic study using the cationic colloidal iron method.", Arch Histol Cytol. 2001 Dec;64(5):535-43. http://www.ncbi.nlm.nih.gov/pubmed/11838713 [4] Niewerth M, Krting HC, "Phospholipases of Candida albicans.", Mycoses. 2001 Nov;44(9-10):361-7. http://www.ncbi.nlm.nih.gov/pubmed/11766099

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Mostly Mucus ===========

Mucus, the slippery gelatinous secretion covering epithelial cells in the respiratory, gastrointestinal, urogenital, visual, and auditory systems of the body, can be considered to be a part of the innate immune system. One of its primary functions is protection against infectious agents such as fungi, bacteria, and viruses. In areas exposed to the external environment such as the airways it also traps foreign particles and expels them via continuous flow towards the digestive tract where they can be excreted. Sneezing and coughing are secondary more violent forms of expulsive processes that occur when the normal flow of mucus is interrupted or insufficient to deal with a perceived threat. Mucus has lubricating and protective properties as well that are utilized in the digestive tract to assist the passage of food down the esophagus and to shield the lining of the stomach from the highly acidic environment that occurs during digestion. Ear infections occur when the movement of mucus through the Eustachian tube draining the middle ear is impaired sufficiently to allow trapped fluid to become a breeding ground for infectious agents. The smaller size and horizontal positioning of the Eustachian tube in children is such that they are more prone to infection in this region. Since continuous movement of mucus is vital to its function there are body organelles that are found in the areas where it abounds to assure that this occurs. Motile cilia are specialized protuberances from cells adjacent to mucus-secreting cells that beat in an asymmetric but coordinated waves to accomplish this movement (see figure "Motile Cilia"). Cilia are about 10 micrometers in length with a beating frequency that provides continuous unidirectional movement of the slime blanket of mucus above them at about 10 mm per minute. Any impairment of this motion can result in increased occurrence of infection in the regions where this mucociliary transport system is an integral part. A mature ciliated cell may have up to 200 cilia. Each cilium is composed of a concentric cylinder of microtubule proteins around a central bridge with fibrous ridges and radial spokes that provide structural stability. Within this sheath are many tiny nanomachine protein motors called dyneins that synchronously slide one microtubule structure against the other until the overall cellular protuberance is stretched and bent first in one direction and then another with the result being a form of repeating whiplash motion (see figure "Cilium Ultrastructure"). The dynein motors (see figure "Dynein Molecular Strutting Motor") are protein structures that actually physically walk along tracks in the microtubules (think of a back-packer hiking along railroad tracks stepping from one railroad tie to the next). The motors are powered by the conversion of chemical energy stored in ATP (Adenosine Triphosphate) to mechanical energy (protein "leg" movement) via the enzyme dynein ATPase which converts ATP to ADP (Adenosine Diphosphate), releasing energy with the dephosphorylation. Mucociliary transport systems in the respiratory tract (lower and upper, sinuses, Eustachian tube, middle ear) and fallopian tubes are vital to the well being of these regions but also provide suitable habitats for onboard yeast colonization. Budding yeast cells range in size from 5 to 10 micrometers in diameter commensurate with the length of a motile cilium. This means that budding yeast cells can anchor themselves quite nicely into the inter-cilia gaps underneath the mucus layer. Although the composition of mucus spans a wide variety of substances including enzymes, immunoglobulins, inorganic salts, and proteins, a major constituent is mucin composed glycoproteins that can provide a food source for yeast metabolism.

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Motile Cilia

Cilium Ultrastructure

Dynein Molecular "Strutting" Motor

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The yeast Candida Albicans has a nasty habit of interfering with host mechanisms designed to eradicate it -- evolution has tuned it well in this regard with the mucociliary transport system being no exception to the rule. The mucociliary environment is ideal from a yeast perspective except for one thing...the continuous movement which is trying to clear it from the area, thus disrupting its ability to form stable colonies. However, acetaldehyde emitted from the budding yeast phase [1] can inhibit dynein ATPase [2], form protein adducts with the microtubule tracks that the dynein motors traverse [3] and slow down, perhaps even stop, the beating of the cilia that propel the mucus! It has been demonstrated that antibiotic therapy is a major risk factor for increased levels of yeast colonization [4] and also that yeast is present in the region of the middle ear [5]. Since yeast-emitted acetaldehyde can interfere with the mucociliary transport system responsible for draining and clearing the Eustachian tube and since the efficient functioning of this process is essential for keeping this region clear from all types of pathogens, this provides a connection between antibiotic therapy, yeast-released acetaldehyde, and persistent recurrent ear infections, especially in children where the size and orientation of this channel render it more vulnerable to infection. If the rising yeast levels are not addressed concurrently with the antibiotic therapy targeting the ear infection, then a vicious cycle of increasing acetaldehyde mucociliary transport interference is in place that will also increase the probability of reinfection. [1] Truss C.O., "Metabolic abnormalities in patients with chronic candidiasis: the acetaldehyde hypothesis.", Orthomol Psychiatr 1984; 13:6693. http://orthomolecular.org/library/jom/1984/pdf/1984-v13n02-p066.pdf [2] Sisson JH et al.,"Acetaldehyde-mediated cilia dysfunction in bovine bronchial epithelial cells.", Am J Physiol. 1991 Feb;260(2 Pt 1):L29-36. http://www.ncbi.nlm.nih.gov/pubmed/1825452 [3] Tuma DJ et al., "Acetaldehyde and microtubules.", Ann N Y Acad Sci. 1991;625:786-92. http://www.ncbi.nlm.nih.gov/pubmed/2058934 [4] Wey SB et al., "Risk factors for hospital-acquired candidemia. A matched case-control study.", Arch Intern Med. 1989 Oct;149(10):2349-53. http://www.ncbi.nlm.nih.gov/pubmed/2802900 [5] Cohen SR et al., "Otitic candidiasis in children: an evaluation of the problem and effectiveness of ketoconazole in 10 patients.", Ann Otol Rhinol Laryngol. 1990 Jun;99(6 Pt 1):427-31. http://www.ncbi.nlm.nih.gov/pubmed/2350126

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Pulmonary Peroxidosis ================== Acetaldehyde will react with atmospheric oxygen (autoxidation) to form the peroxide peracetic acid (see figure "Acetaldehyde and Peracetic Acid"). Peracetic acid is a strong oxidant with a reduction potential similar to that of the bleaching agent chlorine dioxide (see "Message from MMS"). It is used in applications requiring chlorine-free bleaching sequences [1] and for dental sterilization [2] where it can inhibit the growth of Candida Albicans. Its potency is underscored by its usage in conjunction with hydrogen peroxide for anthrax spore decontamination [3]. The product peracetic acid can further react with additional acetaldehyde to form the highly shock sensitive and explosive diacetyl peroxide [4] which can degrade into acetic acid and the flammable and irritating acetic anhydride [5] (see figures "Diacetyl peroxide" and "Acetic anhydride"). Hydrogen peroxide also has the oxygen to oxygen bond that characterizes oxidizing agents used as disinfectants (see figure "Hydrogen Peroxide"). Peracetic acid (CH3COOOH) can be formed in an acidic environment by the reaction of acetic acid (CH3COOH) with hydrogen peroxide (H2O2): CH3COOH + H2O2 <--> CH3COOOH + H2O When peracetic acid formed by the atmospheric oxidation of acetaldehyde degrades it can split via the above reversible reaction into acetic acid and hydrogen peroxide. This means that yeast-released acetaldehyde has the potential for spawning trace amounts of diacetyl peroxide, acetic anhydride, and hydrogen peroxide in the body in addition to the peracetic acid from autoxidation. Peroxides in general are unstable since the oxygen-oxygen chemical bond can easily cleave forming reactive radical species. Not only are they irritating and inflammatory, they are toxic to living cells resulting from the oxidation of proteins, membrane lipids and DNA. Organic compounds can even ignite on contact with concentrated peroxides. [If levels are elevated in just the "right" amounts and locales, could this be the ignition source [6] for rare but inexplicable cases of spontaneous human combustion?] Occupational exposure to exogenous sources of these chemicals confirms their toxicity, as in the case of occupational asthma induced by pulmonary mucous membrane irritation by a peracetic-hydrogen peroxide sanitizing mixture [7]. Aerosolized acetaldehyde, even in the absence of its peroxide derivatives, is capable of inducing histamine-mediated bronchostriction in asthmatics [8]. When acetaldehyde dehydrogenase-2 genotype differences create an abnormality in the handling of acetaldehyde as an intermediate of alcohol metabolism, incidence of alcohol-induced asthma increases [9]. Smooth muscle contraction, regulated by G-Protein-Coupled-Receptors (GPCRs) (see "Geepers Creepers") is often aberrant in pulmonary diseases [10]. Lung disorders such as asthma, adult respiratory distress syndrome (ARDS) and chronic obstructive pulmonary disease (COPD) are all characterized by increased levels of hydrogen peroxide in expired breath condensates [11]. Although the increased presence of H2O2 has a strong correlation to the severity of these disease, it has been attributed to the byproducts of the inflammatory process; in other words, a consequence rather than a cause of the distress. Although phagocytic immune system cells do utilize hydrogen peroxide and free radical species in their destruction of pathogens including yeast cells [12], the production of these dangerous substances is restricted to lysosomes that normally prevent exposure of the extracellular environment to peroxides. The autoxidation route from yeast-released extracellular acetaldehyde to peracetic acid to hydrogen peroxide is not limited by any such constraints. It produces a host of toxic derivatives along the way that have the same effect as spraying disinfectant into the lungs on a daily basis, something that would increase the sensitivity of the epithelial tissues to any airborne allergens or irritants.

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Consider again the initial reaction presented in this section, acetaldehyde plus inhaled oxygen yielding peracetic acid. If either of the concentrations of the reactants on the left side of the reaction increases, this can be expected to increase the output of the product, peracetic acid. The amount of acetaldehyde depends upon the level of yeast colonization and the intake of dietary simple carbohydrates. Any increase of inhaled oxygen in the presence of acetaldehyde should also raise the output of peracetic acid. Exercise-induced asthma [13] is triggered after at least several minutes of vigorous, "aerobic" activity with normal nasal breathing supplemented by mouth-breathing. But such activity can be expected to increase the exposure of yeast-released acetaldehyde in the mouth and esophageal region to inhaled oxygen with the dispersion of the peroxide byproducts into the airways -- pulmonary peroxidosis. The resulting caustic cocktail then triggers the inflammatory response in the irritated tissues. But if everyone has yeast, and yeast releases acetaldehyde, why doesn't everyone develop pulmonary complications? The potential may be there in everyone, but genetics again plays a role. Genetic variants of GSDMB/ORMDL3 [14], proteins involved in the apoptosis of epithelial cells and the unfolded protein response, respectively, are associated with the susceptibility to the hyperresponsiveness of asthma. Whether pulmonary symptoms manifest before other types of symptoms is a function of the amount of acetaldehyde being released, of where it ends up, and the genetic vulnerability (innate scavenging potential and tolerance threshold) of each individual . Although the reactivity of acetaldehyde means that little of it is left in its native form, when you start to look really hard for its traces in relation to disease, a veritable stampede of footprints emerge where it has trampled all over the body's biochemistry. Why has it taken so long to realize this...especially when medical doctors like Truss and Crook started to sound the alarm more than 30 years ago?

[1] Brasileiro LB et al., " The use of peracids in delignification and cellulose pulp bleaching.", Qum. Nova [online]. 2001, vol.24, n.6, pp. 819-829. ISSN 0100-4042. http://dx.doi.org/10.1590/S0100-40422001000600020 [2] Stopiglia CDO et al., "Microbiological evaluation of peracetic acid for disinfection of acrylic resins.", Rev. Odonto Ciencia (Online) vol.26 no.3 Porto Alegre 2011 http://dx.doi.org/10.1590/S1980-65232011000300008 [3] US EPA, "Anthrax spore decontamination using hydrogen peroxide and peroxyacetic acid", 2007 http://www.epa.gov/opp00001/factsheets/chemicals/hydrogenperoxide_peroxyaceticacid_factsheet.htm [4] Chemical Book, "Acetyl Peroxide" http://www.chemicalbook.com/ChemicalProductProperty_EN_CB6256911.htm [5] Bawn et al., "The oxidation of acetaldehyde in solution. Part I.The chemistry of the intermediate stages", Trans. Faraday Soc. 1951,47, 721-734 http://pubs.rsc.org/en/content/articlelanding/1951/tf/tf9514700721 [6] Doruntz et al., "Low temperature ignition of acetaldehyde/oxygen mixtures initiated by organic peroxides adsorbed on the surface of a reaction vessel", Combustion and Flame, Volume 69, Issue 3, September 1987, Pages 251255 http://www.sciencedirect.com/science/article/pii/0010218087901180 [7] Cristofari-Marquand E et al., "Asthma caused by peracetic acid-hydrogen peroxide mixture.", J Occup Health. 2007 Mar;49(2):155-8. http://www.ncbi.nlm.nih.gov/pubmed/17429174 [8] Myou S et al., "Aerosolized acetaldehyde induces histamine-mediated bronchoconstriction in asthmatics.", Am Rev Respir Dis. 1993 Oct;148(4 Pt 1):940-3. http://www.ncbi.nlm.nih.gov/pubmed/7692778

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[9] Takao A et al., "Correlation between alcohol-induced asthma and acetaldehyde dehydrogenase-2 genotype.", J Allergy Clin Immunol. 1998 May;101(5):576-80. http://www.ncbi.nlm.nih.gov/pubmed/9600491 [10] Deshpande DA et al., "Targeting G protein-coupled receptor signaling in asthma.", Cell Signal. 2006 Dec;18(12):2105-20. http://www.ncbi.nlm.nih.gov/pubmed/16828259 [11] Loukides S et al., "Elevated levels of expired breath hydrogen peroxide in bronchiectasis.", Am J Respir Crit Care Med. 1998 Sep;158(3):991-4. http://www.ncbi.nlm.nih.gov/pubmed/9731036 [12] Lehrer RI, "Antifungal effects of peroxidase systems.", J Bacteriol. 1969 Aug;99(2):361-5. http://www.ncbi.nlm.nih.gov/pubmed/5817553 [14] Kang MJ et al., "GSDMB/ORMDL3 variants contribute to asthma susceptibility and eosinophilmediated bronchial hyperresponsiveness.", Hum Immunol. 2012 Sep;73(9):954-9. http://www.ncbi.nlm.nih.gov/pubmed/22732088

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Toxic Soup ========= The singular possibility that the commensal yeast Candida Albicans may be releasing toxic acetaldehyde during its own metabolic processing of dietary carbohydrates (sugar is a simple carbohydrate) requires a complete rethinking of the initiation and manifestation of disease processes. Everything that is ingested, digested, absorbed and excreted has the opportunity of reacting with this molecule and producing something else in the process that may be deleterious to well being. And if this isn't enough, the toxin itself can leech its way through the intestinal walls and take a ferry ride on red blood cells to distant oases far from its origin. Coloration with both synthetic and natural dyes represents a major part of the food processing and marketing industry, primarily for aesthetic reasons enhancing the perceived flavor that arises from the mental association of a particular color with an expected sensory experience. The link between synthetic food dyes and disease has been given much regulatory attention with the result that some dyes have been delisted and banned from commercial usage. Let's take a look at some of the known offenders that cause the most allergic and intolerance reactions to see if there is a common feature that might make them targets for acetaldehyde interaction (see figures "Tartrazine", "Carmoisine", and "Sunset Yellow"). The ones here are all azo compounds which incorporate the functional group R-N=N-R'. Note also that they all have NaSO3 exposed side chains. Now compare these structures with some natural pigments called anthocyanins which are derivatives of anthocyanidins with pendant sugars (see figures "Anthocyanidins" and "Anthocyanidin Side Chains"). In the assortment of side chains of these natural pigments, which aren't typically associated with the same severity of allergic reactions, there are no SO3 R groups! Consider, then, one of the simplest structures which does contain this configuration, sodium bisulphite, a preservative (see figure "Sodium Bisulphite"). What happens when the sulphite structure common to sodium bisulphite and the food coloration azo compounds come into contact with acetaldehyde? The carbonyl electrophilic carbon finds the nucleophilic sulphur or oxygen an attractive binding site for acetylation (see figures "Sodium Bisulphite + Acetaldehyde" and "Acetyl-sulphate"). A variety of "pseudoallergic" responses have been attributed to ingestion of these food dyes and preservatives: anxiety, migraine, clinical depression, blurred vision, itching, general weakness, heatwaves, feeling of suffocation, purple skin patches, irritability, hyperactivity, restlessness, sleep disturbance, diarrhea, vomiting, urticaria. But the mechanisms of why certain sensitized individuals react in this manner have remained elusive. If people are not, in fact, reacting to the substances themselves but a metabolite of the substance's reaction with acetaldehyde, then this could explain why some food colorings are more allergy-prone than others and why some individuals are more vulnerable. Drug delivery experiments have shown that acetylation increases the bioavailability of orally ingested molecular configurations [1]. This implies that a much higher concentration of acetylated food dye molecules could potentially migrate into the bloodstream than if they remained in their native (unmodified) form. Once in the bloodstream of sensitized individuals, the immune system would respond to these invasive chemicals as allergens. And, even if the response is not a classic IgE mediated one, the potential pseudo-allergens are being delivered to cells throughout the body as if the food dye had been injected rather than ingested. The temporal release profile of acetaldehyde in areas where it is able to come into contact with and produce the sensitizing byproducts is not only a function of the reactivity of the coloring or preservative with acetaldehyde, but also a function of the temporal agenda of a "creature" with its own evolutionary arsenal of host-control techniques. The level of yeast colonization in certain critical areas, the morphic phase of the yeast at the time of exposure to nutrients, the kind of nutrients that are presented, and other concomitant food intake (such as antifungals) that vary from one individual to another and from one meal to the next all need to be factored into the model.

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Tartrazine (E102) (FD&C Yellow #5)

Carmoisine (E122) - (FD&C Red #3)

Sunset yellow (E110) (FD&C Yellow #6)

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Anthocyanidins

Anthocyanidin Side Chain Substitutions

(From: http://en.wikipedia.org/wiki/Anthocyanin)

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Sodium Bisulphite

Sodium Bisulphite + Acetaldehyde

Acetyl-sulphate

Cholesterol Sulphate

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Avoiding the identifiable substances that trigger potentially debilitating reactions, something that is learned through a tedious process of trial and error, is certainly a positive step. However, this may not be addressing the underlying problem. If the budding phase yeast-released acetaldehyde isn't reacting with the food coloring or preservative, then it will be reacting with something else. And these other reactions may be less obvious but just as harmful in the longer term. This can make the cause and effect chain murky at best. Hyperactivity, for example, is not just a simple matter of a reaction to a food coloring. Although food coloring may trigger this condition, there are other biochemical pathways subject to acetaldehyde interference that may also produce the same symptoms. Once a particular molecular structure has surfaced in relation to the formation of acetaldehyde adducts, it is always instructive to search for other essential configurations in the body that might also be subect to attack in a similar manner. If the dots connect with the research of others with respect to disease, then a clearer picture of what is actually transpiring may emerge. Cholesterol sulphate is a multifunctional sulpholipid (see figure "Cholesterol Sulphate") that is abundant in human plasma. When looking for chance encounters with rogue acetaldehyde molecules; proximity, reactivity, and concentration all are factors in the likelihood of interactions. What happens subsequently, as a result of these misconfigured biological structures, is as complex and confusing as the chaotic array of diseases that remain a conundrum to modern medical science. The salient NaO3S feature of this molecule is quite similar to the side chains of the synthetic food coloring agents. The amphiphilic nature of cholesterol sulphate, arising from its negative charge, means not only that it can travel freely in the bloodstream, but also that it might also be an attractive target for acetylation in encounters with acetaldehyde. Such an interaction would remove the cholesterol sulphate molecules thus violated from their vital roles in human metabolism. A deficiency of cholesterol sulphate in association with disease states is just beginning to be explored [2]. Another possible repercussion of this might be an increase of circulating cholesterol levels as the body attempts to compensate for the lossage. Given the affinity of acetaldehyde for sulphur, it wouldn't be surprising to find interference with the sulphating mechanisms that are responsible for generating the abundant store of circulating cholesterol sulphate. If acetaldehyde is binding to dietary intake of the sulphur-bearing amino acids methionine and cysteine, for instance, then this can create disruption in all of the body's sulphur-dependent metabolic pathways including the generation of taurine, the antioxidant glutathione, and sulphate ions. This may provide a clue as to why intracellular levels of cysteine and glutathione are depressed significantly in children diagnosed with autism [3]. The amino acid L-cysteine condenses with acetaldehyde to form a stable thiazolidine called 2Methylthiazolidine 4-carboxylic acid (MTCA) via a Schiff base intermediate [4] (see figure "Cysteine + Acetaldehyde"). Usage of additional cysteine to compensate for this interference, associated with high alcohol intake, has been explored [5]. The non-prescription supplement Acetium [6] produced by the Finnish company Sartorius Biohit utilizes this reaction as an acetaldehyde scavenger in the stomach. In the presence of dietary nitrates and nitrites, such as are used in the food processing industry for meat preservation, curing, and coloration; MTCA may be nitrosated to produce N-nitroso-2-methylthiazolidine 4-carboxylic acid (NMTCA) detectable in human urine [7] (see figure "NMTCA"). Nitrosamines are putative carcinogens [8] but vitamin C has been shown to have a protective effect [9]. Usage of cysteine as an acetaldehyde scavenger in a capsule for the yeast-released toxin has the potential drawback of missing the critical esophageal region adjacent to the thyroid (see "Slow Death By Strangulation") and needs to be cofactored with sufficient ascorbate to reduce the potential side reaction to NMTCA. As with all toxic interactions it is imperative not only that the toxin (in this case, unsequestered acetaldehyde) be safely scavenged by side-effect-free molecular policemen patrolling the toxic soup, but also that the source of the toxin (i.e. the yeast Candida Albicans) be addressed at the same time.

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Cysteine + Acetaldehyde

N-nitroso-2-methylthiazolidine -4-carboxylic acid

NMTCA

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[1] Ogiso T et al., "Enhancement of the oral bioavailability of phenytoin by N-acetylation and absorptive characteristics.", Biol Pharm Bull. 1998 Oct;21(10):1084-9. http://www.ncbi.nlm.nih.gov/pubmed/9821815 [2] Seneff S. et al., "Might cholesterol sulfate deficiency contribute to the development of autistic spectrum disorder?", Med Hypotheses. 2012 Feb;78(2):213-7. Epub 2011 Nov 17. http://www.ncbi.nlm.nih.gov/pubmed/22098722 [3] Suh JH et al., "Altered Sulfur Amino Acid Metabolism In Immune Cells of Children Diagnosed With Autism", Science Publications (2008). http://en.scientificcommons.org/46275754 [4] Yamshita K et al., "Acetaldehyde Removal from Indoor Air through Chemical Absorption Using LCysteine", Int J Environ Res Public Health. 2010 September; 7(9): 34893498. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954559 [5] Salaspuro V et al., "Removal of acetaldehyde from saliva by a slow-release buccal tablet of Lcysteine", Int J Cancer 2002 Jan 20;97(3):361-4. http://www.ncbi.nlm.nih.gov/pubmed/11774289 [6] "Acetium capsule reduces the amount of carcinogenic acetaldehyde in stomach" http://www.acetium.com [7] Ohshima H et al., "Occurrence in human urine of new sulphur-containing N-nitrosamino acids Nnitrosothiazolidine 4-carboxylic acid and its 2-methyl derivative, and their formation.", J Cancer Res Clin Oncol. 1984;108(1):121-8. http://www.ncbi.nlm.nih.gov/pubmed/6746703 [8] Lin JK, "Nitrosamines as potential environmental carcinogens in man.", Clin Biochem. 1990 Feb;23(1):67-71. http://www.ncbi.nlm.nih.gov/pubmed/2184959 [9] Lu SH et al., "Urinary excretion of N-nitrosamino acids and nitrate by inhabitants of high- and low-risk areas for esophageal cancer in Northern China: endogenous formation of nitrosoproline and its inhibition by vitamin C.", Cancer Res. 1986 Mar;46(3):1485-91. http://www.ncbi.nlm.nih.gov/pubmed/3943105

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When The Backup Fails ================== The unique attributes of the sulphur atom show up in many diverse areas (see "Signposts of Disease"). There are only two amino acids that contain sulphur: cysteine and methionine. Dietary cysteine is a potential target for direct acetaldehyde attack (see figure "Cysteine + Acetaldehyde"). The position of the sulphur atom in methionine (see figure "Methionine") does not appear to be as attractive a target for acetaldehyde binding as it is for cysteine [1]. This implies that dietary methionine could take up some slack in relation to acetaldehyde-mediated cysteine disruption. Cysteine is classed as a semi-essential amino acid for this very reason, that it can usually be synthesized by the human body from methionine. However, this pathway is not fully developed in children [2] making them more vulnerable to aberrations in cysteine metabolism [3]. The functional pathway from methionine to cysteine involves conversion of the intermediate homocysteine (see figure "Homocysteine") into cystathionine using the enzyme cystathionine-beta-synthase with pyridoxal-phosphate as a cofactor. However, pyridoxal-phosphate is an aldehyde and the carbonyl group similarity in acetaldehyde may interfere with this step in the pathway from methionine to cysteine [4]. Excess homocysteine that can't make the transition to cysteine should be recycled back to methionine via the enzyme methionine synthase with vitamin B12 as a cofactor, but acetaldehyde inhibits this transition as well by forming an inhibiting covalent adduct with the enzyme [5]. With cysteine essentially functioning as an acetaldehyde scavenger, the methionine that the body is using to try and rebuild dwindling cysteine reserves gets stuck as homocysteine and can't go forward or back. This is supported by the association of hyperhomocysteinemia with alcoholism [6] where acetaldehyde is a known by-product of alcohol metabolism in the liver. Although homocysteine is not an amino acid, it looks like one. The structural similarities between the intermediate homocysteine and methionine can create problems for protein synthesis with the result that excess levels of homocysteine are cytotoxic [7]. In this model, not only does yeast-released acetaldehyde interfere directly with cysteine, it also blocks the secondary pathways from methionine to cysteine and from homocysteine back to methionine, producing an accumulation of a toxic substance in the process. The body's sulphur-based metabolism is now officially in big trouble!

[1] Yamashita K et al., "Acetaldehyde Removal from Indoor Air through Chemical Absorption Using LCysteine.", Int J Environ Res Public Health. 2010 September; 7(9): 34893498. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2954559 [2] Imura K et al., "Amino acid metabolism in pediatric patients.", Nutrition. 1998 Jan;14(1):143-8. http://www.ncbi.nlm.nih.gov/pubmed/9437700 [3] Bradstreet JJ et al., "Biomarker-guided interventions of clinically relevant conditions associated with autism spectrum disorders and attention deficit hyperactivity disorder.", Altern Med Rev. 2010 Apr;15(1):15-32. http://www.ncbi.nlm.nih.gov/pubmed/20359266 [4] Lumeng L, "The role of acetaldehyde in mediating the deleterious effect of ethanol on pyridoxal 5'phosphate metabolism.", J Clin Invest. 1978 Aug;62(2):286-93. http://www.ncbi.nlm.nih.gov/pubmed/27531 [5] Barak AJ et al., "Methionine synthase. a possible prime site of the ethanolic lesion in liver.", Alcohol. 2002 Feb;26(2):65-7. http://www.ncbi.nlm.nih.gov/pubmed/12007580 [6] Carvo ML et al., "Hyperhomocysteinemia in chronic alcoholism: relations to folic acid and vitamins B(6) and B(12) status.", Nutrition. 2000 Apr;16(4):296-302. http://www.ncbi.nlm.nih.gov/pubmed/10758367 [7] Jakubowski H, "Molecular basis of homocysteine toxicity in humans.", Cell Mol Life Sci. 2004 Feb;61(4):470-87. http://www.ncbi.nlm.nih.gov/pubmed/14999406

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Methionine

Homocysteine

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Neural Short Circuits ================ Nerve impulses continuously flash throughout the body's neural network at speeds up to 100 meters/second allowing split second action/reaction mechanisms to cope with changes in the surrounding environment. A petite mal or grand mal episode can disrupt this coordinated process with a seizure that may last from a few seconds up to several minutes. Neurons in the network talk to each other via neurotransmitters that either excite neuronal firing (glutamate) or inhibit impulse firing (gamma-aminobutyric acid or GABA). Although there are several different aspects to the pathology of epilepsy, let's consider for a moment the specific situation of neurotransmitter receptor malfunction to see if at least one mechanism may be related to acetaldehyde toxicity. GABA receptors are transmembrane proteins in neurons that respond to GABA molecules. Some of these receptors are ligand-gated ion channels and others are G protein-coupled receptors (GPCRs). Glutamate similarly can activate receptors in both of these classes that are specific to its molecular configuration. GPCR receptors containing structurally and functionally critical disulphide bridges may be exquisitely sensitive to rogue molecules of acetaldehyde (see "Geepers Creepers"). Although structurally distinct from GPCRs, ligand-gated ion channel receptors are characterized by a loop formed by a disulphide bond between two cysteine (Cys) residues in a highly conserved (i.e. critical) region of the receptor. The fact that acetaldehyde is both attracted to and capable of disrupting disulphide bonds (see "Bridge Across The Chasm") has been demonstrated by the staining of disulphide-rich tissues by aldehyde fuchsin, something that glues itself to the molecular configurations that react with its aldehyde group [1] and by the increase of sulphydryl (-SH) content in proteins rich in disulphide linkages when exposed to acetaldehyde [2]. This implies that rogue molecules of acetaldehyde may attack the critical disulphide trigger mechanisms of both the GPCR-type and CYS-loop-type receptors in both GABA and glutamate responsive neuronal cells. The result may be like a machine gun that won't fire because its trigger is broken or that is continuously firing because its trigger is jammed -- something that manifests as an epileptic fit. If this model of epilepsy has merit, then there should be confirmation of reduction of episodic seizures by protocols that either scavenge acetaldehyde and/or reduce its production from yeast via antifungal action. The ketogenic diet is a high-fat, low-carbohydrate, adequate-protein diet that was popular in the 1920's and 1930's for the control of epilepsy. It is referred to as a "starvation" diet because it limits the intake of carbohydrates that would normally be converted into glucose to such an extent that the body is forced to burn fats for fuel instead (ketogenesis). Often the diet includes a large proportion of medium-chain triglycerides (MCTs) from sources such as coconut oil. The mode of action of the ketogenic diet is unknown... However, from the perspective of this investigation, not only will the reduction in the amount of available glucose in the ketogenic diet result in less acetaldehyde emission from yeast metabolism (see "Just A Teaspoon Of Sugar"), but medium-chain triglycerides such as those in coconut oil are antifungal [3], something that would reduce the yeast levels emitting acetaldehyde. Acetaldehyde scavengers such a N-acetyl cysteine have proven to be been effective in some cases of epilepsy [4]. Since users of Wondro back in the 1920's-1950's could restore a healthy equilibrium by ingesting an acetaldehyde scavenger alone without any dietary restrictions, this suggests that for some types of epilepsy, at least, an integrated "yeast abatement protocol" (see "Astrophysiology ...and Yeast") might be able to replace the ketogenic diet with similar favorable results minus the severity of the dietary regimen (see "Starvation Diet?").

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[1] Bock P, "Elaunin fibres in the basement membrane of sweat gland secretory coil are rich in disulfidegroups.", Experientia [1979, 35(4):538-539]. http://ukpmc.ac.uk/abstract/MED/108134 [2] Matsumoto H et al., "Effect of Bisulfite and Acetaldehyde on the Disulfide Linkage in Wheat Protein.", 1960, Cereal Chem 37:710 - 720. http://www.aaccnet.org/publications/cc/backissues/1960/Documents/CC1960a77.html [3] Bergsson G et al., "In Vitro Killing of Candida albicans by Fatty Acids and Monoglycerides.", Antimicrob. Agents Chemother. November 2001 vol. 45 no. 11 3209-3212. http://aac.asm.org/content/45/11/3209.full [4] Hurd RW et al., "Treatment of four siblings with progressive myoclonus epilepsy of the UnverrichtLundborg type with N-acetylcysteine.", Neurology. 1996 Nov;47(5):1264-8. http://www.ncbi.nlm.nih.gov/pubmed/8909441

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Enzyme Killer =========== Enzymes are folded protein conglomerations that facilitate the production of certain molecules required by the body from raw materials that are already present. They are three-dimensional structures that attract and hold the raw material molecules just long enough in just the right orientation for the new product to form. Shape, charge, and fluid dynamic motion may all play a role in bringing the raw materials together under ideal conditions so that the product can emerge. Enzymes are fast workers, capable of catalyzing several million reactions per second. An enzyme inhibitor is a substance that prevents a particular enzyme or class of enzymes from performing their specific tasks with the effect that the concentration of desired product is substantially reduced or eliminated even when the raw materials for the enzyme are available. Some enzyme inhibitors work by binding irreversibly into the enzyme reaction pocket, thus preventing the raw materials from assuming their required positions for the reaction to occur. Some essential molecular configurations required in the body are so complex that several intermediate steps, each with a different enzyme, are necessary before the desired product is formed. Inhibition of any one of the enzymes in the pathway can prevent the formation of the end-product. Acetaldehyde is such a small electrophilic molecule that it can easily drift into enzyme reaction pockets, latch itself onto a reactive protuberance, and remain there, thus rendering the enzyme, attacked in this way, useless. The product concentration of the enzymes inhibited in this manner may drop so low that deficiency symptoms start to manifest even when adequate reserves of the raw materials are available. Acetaldehyde will preferentially disable enzymes that are keyed to working with structures that are similar to its own shape and atomic configuration. As examples, consider just two of a host of enzymes in metabolic pathways that may be subject to acetaldehyde interference. Choline Acetyl Transferase. Acetylcholine is a significant neurotransmitter in both the peripheral and central nervous systems responsible for a host of functions including but not limited to mental concentration, memory, and sleep patterns. Acetylcholine is synthesized in the body from dietary choline and acetyl-coenzyme A, a derivative of vitamin B5, by the enzyme choline acetyltransferase. Acetaldehyde has been shown to inhibit the production side but not the degradation side of acetylcholine thus creating a deficit in this neurotransmitter. Compare the structures of acetyl-CoA (a necessary precursor of acetylcholine) and acetaldehyde in the figure "Acetyl-CoA and Acetaldehdye". The H3C-C=O- portions of these two molecules are identical! Furthermore, it is the enzymatic "transfer" of this structure that transforms choline into acetylcholine (see figure "Acetylcholine"). If rogue molecules of acetaldehyde are contaminating the enzyme reaction pockets at the sites designed to hold acetyl-CoA in place for the acetyl transfer, then the enzyme becomes dysfunctional and acetylcholine can no longer be produced by the affected enzymes. Reduced activity of acetylcholinetransferase has been clinically demonstrated in patients with Alzheimer's disease. It might also be the source of the "brain fog" so commonly reported by individual with yeast overgrowth. Is this why coconut oil, an antifungal, that can disrupt yeast cell membranes has anecdotal reports about improving these conditions -- because it reduces the amount of acetaldehyde being released by budding yeast cells that would subsequently be available for enzymatic interference with the production of this essential neurotransmitter?

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N-acetyl-D-glucosamine 6-phosphate

PGF2-alpha

PGE2

Guanine

O6-methylguanine

O6-methylguanine-DNA-transferase
From: what-when-how.com/molecular-biology

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Glucosamine-Phosphate N-acetyltransferase. Human joints are bone-to-bone junctions that require special lubricants to reduce friction and provide shock absorption. Synovial fluid in the joint cavities contains hyaluronic acid, a large gooey molecule, that is capable of providing such protection. If the buffering capability of synovial fluid is impaired, then inflammation and joint pain are the result. Hyaluronic acid, itself is composed of long linked chains of D-glucuronic acid and D-Nacetylglucosamine. A critical step in the production of D-N-acetylglucosamine is the transfer of an acetyl group, again from acetyl-CoA, to D-glucosamine 6-phosphate catalyzed by glucosamine-phosphate Nacetyltransferase, producing N-acetyl-D-glucosamine 6-phosphate (see figure of the same name). See the familiar H3C-C=O- structure at the lower right hand corner of the molecule. This comes from acetyl-CoA in a manner very similar to the production of acetylcholine but in a different enzyme with a different starting molecule. If free acetaldehyde also contaminants this enzyme, again because of its similarity in shape to acetyl-CoA, then the downstream production of N-acetyl-D-glucosamine and ultimately of hyaluronic acid would be impaired. One doesn't have to dig too deeply to find attempts to compensate for the failure of this pathway, given the popularity and availability of glucosamine sulphate supplements on the market for arthritic conditions. Is this why acetaldehyde scavengers, such as sulphurated flax oil (Wondro), had such amazing results with a wide variety of arthritic conditions -- by ensnaring the acetaldehyde being released by yeast cells before it could interfere with the maintenance of synovial fluid? The enzymes described above are just two of a much larger class of acetyl transferase enzymes, all of which may be subject to acetaldehyde inhibition. And this type of attack is not the only way that acetaldehyde can interfere with essential body processes. The fact that there are so many different vulnerable biochemical loci may explain why candidiasis syndrome has such a confusing symptomatic profile with a wide variety of different illnesses responding to yeast abatement protocols.

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Cellular Mayhem ============= The carcinogenic aspects of acetaldehyde as a metabolite of alcohol and as a constituent of tobacco smoke have already been established in the medical research journals. With a commensal yeast (Candida Albicans) in the picture releasing acetaldehyde as a part of its metabolism, this places virtually everyone at risk to acetaldehyde toxicity, not just drinkers and smokers. Acetaldehyde is so highly reactive that there may be many different biochemical pathways by which this occurs but consider the following two possibilities: prostaglandins and DNA repair.

Prostaglandins. Prostaglandins are cell-to-cell regulatory substances produced to stimulate a variety of body processes in a delocalized (non-organ-specific) fashion. Two such inter-cellular molecules are PGF2-alpha and PGE2. PGF2-alpha stimulates cellular repair growth and PGE2 suppresses it (see figures "PGF2-alpha" and "PGE2"). Dietary deficiencies of essential fatty acids favor the production of PGF2-alpha over PGE2. Acetaldehyde can further exacerbate this imbalance by inhibiting the action of PGE2 but not PGF2-alpha. This means that cellular proliferation stimulated by localized emission of PGF2-alpha may not be adequately controlled by the corresponding suppressor prostaglandin PGE2. Look closely at the two structures in the figures and consider that they act by fitting into cellular receptors keyed to the difference in their atomic configurations. The crucial difference is in the upper left-hand corner of each molecule. Notice that the prostaglandin PGE2 responsible for shutting down cellular proliferation stimulated by PGF2-alpha has a C=O instead of the C-OH group that is present in PFG2alpha. But again this C=O is similar to the configuration of the much smaller molecule acetaldehyde. Consider what happens to a cell with acetaldehyde stuck in its receptor for PGE2. It would no longer be responsive to the cellular proliferation dampening effects of PGE2 because PGE2 can't dock there to exert its controlling influence. Cellular reproduction out of control = cancer!

DNA Repair. Guanine is one of the four DNA bases fundamental to all lifeforms (see figure "Guanine"). O6methylguanine is a methylated (CH3) damaged form of guanine that is dangerous because it can cause DNA mutations which may be carcinogenic (see figure "O6-methylguanine"). O6-methylguanine-DNAtransferase is a suicide enzyme that can repair the damaged form of guanine by sacrificing itself in the process (see figure "O6-methylguanine-DNA-transferase"). Acetaldehyde also finds the cysteine active site in this enzyme attractive (because of the exposed sulphydryl) and irreversibly acetylates it. Since this is a "single-use" enzyme each acetaldehyde molecule that attacks an MGMT enzyme molecule in this manner makes it dysfunctional for DNA repair [1] and significantly reduces the availability of active repair enzymes. Dysfunctional DNA repair = cancer! [1] Krokan H et al.,"Cytotoxicity, thiol depletion and inhibition of O6-methylguanine-DNA methyltransferase by various aldehydes in cultured human bronchial fibroblasts.", Carcinogenesis. 1985 Dec;6(12):1755-9. http://www.ncbi.nlm.nih.gov/pubmed/4064250

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To Go Or Not To Go ================ Biogenic amines are life-essential substances that the body creates internally for diverse purposes. The monoamine subclass contains a single amino group connected to an aromatic ring by a two-carbon chain (-CH2-CH2-). A prime example is serotonin which plays a major role in regulating intestinal movements, mood, appetite, sleep, memory, and learning (see figure "Serotonin"). Note the long tail terminated by the NH2 group. We have seen this configuration before in the discussion on carnosine (see "Carnosine"). The Pictet-Spengler reaction is a condensation reaction of this type of configuration with an aldehyde that effects a ring closure even at physiologic conditions (i.e. spontaneously within the body). The acetaldehyde reaction with carnosine is just such a Pictet-Spengler reaction that allows the body to scavenge reactive aldehydes before they inflict damage. However, since serotonin also has this structure, we might expect serotonin exposed to acetaldehyde to form a Pictet-Spengler reaction product (see figure "Serotonin + Acetaldehyde"). In fact, this is exactly what happens with the result being a beta-carboline called 6-hydroxy-1-methyl1,2,3,4-tetrahydro-beta-carboline (6-OH-MTBC). But this isn't serotonin anymore, ever again! The serotonin levels that are essential to metabolic function will be depleted in proportion to the amount of acetaldehyde that comes into contact with serotonin. By reacting with acetaldehyde in the gut, serotonin may be filling in as an acetaldehyde scavenger but it has more important things to do. Introducing something like Wondrenic or Wondreic acid into the mixture, that really has nothing better to do, takes the pressure off the biochemical substances that are critical. Irritable bowel syndrome (IBS) is a common gastrointestinal disorder of unknown origin. Although there are no structural or pathologic abnormalities present, people suffering from IBS experience altered bowel habits, frequently suffering from constipation, diarrhea, or alternating episodes of both. Since serotonin is involved in intestinal motility, a disorder of its function at the molecular level is suspected in this condition [1]. About 90% of the body's serotonin content is located in the gut, the primary colonization site for yeast. In essence, the serotonin in the gut is acting as a scavenger of acetaldehyde released from Candida Albicans but at the expense of its vital role in intestinal motility. As a consequence of its depletion the body may up-regulate its production but since acetaldehyde release from the yeast is sporadic and dependent upon dietary intake, the net result may be such an imbalance in serotonin levels that there is vacillation between episodes of diarrhea and constipation. [1] Gershon MD, "Serotonin and its implication for the management of irritable bowel syndrome.", Reviews in Gastroenterological Disorders [2003, 3 Suppl 2:S25-34]. http://ukpmc.ac.uk/abstract/MED/12776000

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Serotonin

Serotonin + Acetaldehyde

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Hair-Trigger Allergies ================ One of the reasons that yeast-induced acetaldehyde toxicity presents such a confusing symptomatic profile is that its high reactivity means that it can affect multiple physiologically competing processes in different ways. Consider histamine for example. This is a biogenic amine involved in the inflammatory response of the immune system especially with respect to allergens that bind to mast cells and trigger its release. A runny nose and water eyes are classic symptoms of a histamine-mediated allergic reaction. There is also a Pictet-Spengler reaction here that might be expected to deactivate this biogenic amine in a fashion similar to that postulated for serotonin depletion in the gut (see figures "Histamine" and "Histamine + Acetaldehyde"). However, acetaldehyde by itself is a potent stimulator of histamine release from mast cells [1] and an inhibitor of the enzyme, diamine oxidase, that degrades histamine from its active form [2]. These factors may predominate in the case of histamine to create higher, rather than lower, levels of ambient histamine in conjunction with impaired pathways that are supposed to clear it once it has been released. Histamine intolerance is an acquired condition in which the body reacts to histamine in foods (e.g. red wine, soy sauce) also suggesting dysfunction of the pathways that dispose of this biogenic amine. Typical symptoms include headache, diarrhea, migraine, running or inflamed nasal passages, asthma bronchiale and arrhythmia, hypotension, urticaria and dysmenorrhoea [3]. Both doctors C.O. Truss (Missing Diagnosis, 1976) and W. G. Crook (The Yeast Connection, 1983) were allergy specialists before they began to focus on the interrelationship between yeast and disease. They found that many of their allergy patients responded to yeast reduction therapy, something that addresses the source of the toxin. The acetaldehyde-mediated disruption of histamine metabolism may be one of the mechanisms that increases an individual's sensitivity to allergy-prone substances.

[1] Kawano T et al., "Acetaldehyde induces histamine release from human airway mast cells to cause bronchoconstriction.", Int Arch Allergy Immunol. 2004 Jul;134(3):233-9. Epub 2004 Jun 1. http://www.ncbi.nlm.nih.gov/pubmed/15178893 [2] Zimatkin SM et al., "Alcohol-histamine interactions.", Alcohol Alcohol. 1999 Mar-Apr;34(2):141-7. http://www.ncbi.nlm.nih.gov/pubmed/10344773 [3] Maintz L et al., "Histamine and histamine intolerance.", Am J Clin Nutr May 2007 vol. 85 no. 5 11851196. http://www.ajcn.org/content/85/5/1185.full

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Histamine

Histamine + Acetaldehyde (4-methyl spinaceamine)

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Catecholamines In Chaos ==================== Dopamine is a catecholamine neurotransmitter involved in brain biochemistry that may play a role in the disease processes of Parkinson's, schizophrenia, and attention deficit hyperactivity disorder (ADHD). It is synthesized within cells in the body, mainly from the non-essential amino acid L-tyrosine, but can also be formed from the essential amino acid L-phenylalanine. Its Pictet-Spengler condensation product with acetaldehyde is salsolinol (see figures "Dopamine" and "Dopamine + Acetaldehyde"). Salsolinol is a neurotoxin involved in the apoptosis of dopaminergic neurons. This implicates the production of acetaldehyde by Candida Albicans as a possible precursor to the development of Parkinson's disease in genetically predisposed individuals [1]. Dopamine binds to and activates a group of receptors called the dopamine receptors to mediate its physiological effects in the body. The dopamine receptors are a series of five G protein-coupled receptors (GPCRs), something that also may be vulnerable to acetaldehyde interference (see "Geepers Creepers"). Therapeutic treatment with L-DOPA, a precursor to the catecholamines dopamine, norepinephrine, and epinephrine, may may be effective by compensating for the loss of dopamine through its interaction with acetaldehyde. Normally, catecholamine levels are tightly regulated by their synthesis/degradation pathways so the introduction of L-DOPA dosage levels that are too high may trigger some serious side effects including hypotension, arrhythmias, nausea, gastrointestinal bleeding, disturbed respiration, hair loss, disorientation and confusion, emotional stress, and psychotic episodes. Another catecholamine, norepinephrine, formed from dopamine is also vulnerable to Pictet-Spengler attack by acetaldehyde (see figures "Norepinephrine" and "Norepinephrine + Acetaldehyde") forming 4hydroxy salsolinol. It plays a major role in blood pressure and heart rate regulation, especially during the fight-or-flight response where, in conjunction with epinephrine, it stimulates increased heart rate, release of glucose from energy stores, increased blood flow to skeletal muscle, and increased oxygen supply to the brain. As if the unscheduled diversion of critical biogenic amines into beta-carbolines and isoquinolines isn't enough trouble already, there are other aspects to these substances that can be disrupted as well by yeast-released acetaldehyde. Most unrestrained aldehydes in the body are thugs. They beat up whatever they come into contact with. [Pyridoxal (a form of vitamin B6) and retinal (a precursor to retinol -- vitamin A) are exceptions but even these are kept under close enzymatic supervision.] Aldehyde scavengers such as carnosine and aldehyde converters such as aldehyde dehydrogenase patrol to make sure that dangerous aldehydes are kept under control. This is especially important in reactions where the body creates an aldehyde as a byproduct of one of its own enzymatic processes. The enzyme monoamine oxidase (MAO) is used to regulate the levels of monoamine neurotransmitters and neuromodulators by removing the bioactive profile of these substances through their oxidation to an aldehyde(!) (see figure "MAO Oxidation of Monoamines"). For example, the concentration of serotonin is controlled by its breakdown into 5-hydroxyindole acetaldehyde by monoamine oxidase (see figure "Serotonin Catabolism"). Although the R-CHO aldehyde by-product molecules are much larger than acetaldehyde, they are just as reactive and can participate in neurodegenerative processes such as spawning free radicals [2], creating protein adducts, or forming isoquinoline alkaloid derivatives (neurotoxins) [3]. The potential for oxidative stress and other types of damage is increased if the aldehyde degradation products of the biogenic amines are not dealt with quickly and adequately.

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Dopamine

Dopamine + Acetaldehyde (salsolinol)

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Norepinephrine

Norepinephrine + Acetaldehyde (4-hydroxy-salsolinol)

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MAO Oxidation of Monoamines

Serotonin Catabolism

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With an endogenous source of acetaldehyde production arising from the fermentative degradation of carbohydrates by Candida Albicans, on-board systems for coping with the aldehydes generated by MAO may already be saturated and overloaded. Hence, there exists the potential for damage, not only from the unexpected yeast-released acetaldehyde itself, but also from the aldehydes generated by MAO in the normal regulation of monoamine levels. There are just too many aldehyde molecules in the line-up waiting for service and things get ugly! These unprocessed aldehydes may further react with the biogenic amines creating more beta-carbolines and isoquinolines, thus reducing the levels of necessary neurotransmitters again. However, since betacarbolines [4] and isoquinolines [5] are themselves inhibitors of monoamine oxidase, they can disrupt the bio-regulation of normal biogenic amine degradation leading to a confusing state of either too much or too little of a vital neurotransmitter, depending upon the mode of acetaldehyde interference predominant at any given moment, something influenced by the voracious metabolic appetite of yeast for carbohydrates. [1] Epp LM, Mravec B, "Chronic polysystemic candidiasis as a possible contributor to onset of idiopathic Parkinson's disease.", Bratisl Lek Listy 2006; 107(6-7): 227-230. http://www.bmj.sk/2006/107067-01.pdf [2] Pena-Silva RA et al., "Serotonin produces monoamine oxidase-dependent oxidative stress in human heart valves", Am J Physiol Heart Circ Physiol. 2009 Oct;297(4):H1354-60.. http://www.ncbi.nlm.nih.gov/pubmed/19666839 [3] Marchitti SA et al., "Neurotoxicity and Metabolism of the Catecholamine-Derived 3,4Dihydroxyphenylacetaldehyde and 3,4-Dihydroxyphenylglycolaldehyde: The Role of Aldehyde Dehydrogenase", Pharmacological Reviews, June 2007 vol. 59 no. 2 125-150. http://www.ncbi.nlm.nih.gov/pubmed/17379813 [4] Kim H et al., "Inhibition of monoamine oxidase A by beta-carboline derivatives", Arch Biochem Biophys. 1997 Jan 1;337(1):137-42. http://www.ncbi.nlm.nih.gov/pubmed/8990278 [5] Bembenek ME et al., "Inhibition of monoamine oxidases A and B by simple isoquinoline alkaloids: racemic and optically active 1,2,3,4-tetrahydro-,3,4-dihydro-, and fully aromatic isoquinolines", J Med Chem. 1990 Jan;33(1):147-52. http://www.ncbi.nlm.nih.gov/pubmed/2296014

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Tryptophan Starvation ================= C. albicans has established a niche in reality that it controls extremely well to provide for its needs. It is rarely found in the environment outside of a mammalian host and even when it is, it can usually be traced back to contamination or contact. It positions itself in nutrient-rich zones just waiting to be fed and emits molecules to manipulate the immune system's response or non-response to its presence as it sees fit. Its long history of interaction with the specific mammalian cell types that it encounters in its chosen habitat is reflected by a staggering list of point-counterpoint scenarios [1]: biosynthesis of perfect counterfeit immunomodulating molecules resolvin E1 [2] and prostaglandin E2 [3] suppression of lymphocyte maturation and function [4] cell-wall-mediated inhibition of phagocytosis by macrophages [5] degradation of immunoglobulins, complement and extracellular matrix by multiple secreted aspartyl proteases [6] emission of tissue-invasive phospholipases [7] reduction of reactive oxygen species production by macrophages and neutrophils [8] inhibition of release of nitric oxide from macrophages [9] aberrant acidic lysosomal compartmentalization after phagocytosis [10] white-opaque phase variant suppression of neutrophil-chemotactic peptides [11] selective induction of apoptosis (cellular suicide) in a variety of cells including neutrophils [12], macrophages [13], and human sperm cells (infertility) [14] tetrad of mechanisms (induced endocytosis, direct invasion, intercellular junction passage, leukocyte transport) for penetration of endothelial or epithelial barriers [15], including the blood-brain barrier [16] cell wall remodelling to suit environmental substrate [17] utilization of multiple alternate non-fermentable carbon sources in glucose-poor conditions [18] subversion of nutritional (iron-limiting) immunity by active acidification of local environment [19] to liberate essential iron from transferrin [20], ferritin [21], and hemoglobin adaptive prediction for coping with changing environmental stressors [22] formation of mixed colony biofilms with organisms such as Staphylococcus epidermidis with mutually advantageous resistance to antimicrobial agents [23] Now that we understand a bit more about the profile of this perpetrator and what it is capable of doing, perhaps we can look for an answer to the question why C. albicans releases toxic acetaldehyde into its environment, instead of reducing it to alcohol or oxidizing it to acetate (see "Pushmi-Pullyu" in "Astrophysiology... and Yeast").

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Tryptophan

N-formyl-kynurenine

Norharmane

Tryptophan + Acetaldehyde (3-MTBC)

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Tryptophan starvation is an antimicrobial technique used by the body to rid itself of invasive organisms [24]. It is especially effective against microbes, such as Toxoplasma gondii, that require tryptophan as an essential amino acid scavenged from host cells [25]. The tryptophan starvation sequence is initiated by interferon-gamma released by various immune system cells when they encounter a problem. For example, oral epithelial cells, a part of the innate immune system barriers to infection, can respond to C. albicans growth by secreting interferon-gamma [26]. Interferon-gamma induces the production of the enzyme indoleamine 2,3-dioxygenase (IDO) in many cell lines. This enzyme is the rate-limiting step in the catabolism of the amino acid tryptophan into N-formylkynurenine (see figure "Tryptophan / N-formyl-kynurenine"). The antiparasitic and cytotoxic efficacy of tryptophan starvation at inducing apoptosis (cellular-suicide) has been demonstrated in morphologic studies with DNA analysis in ME180 (human epidermoid carcinoma) cells [27]. T helper cells (Th cells) are a type of white blood cell of the body's adaptive immune system, involved in maximizing the cidal activity of phagocytes. Th17 cells are a subset of this class that produce interleukin 17 (IL-17), an immunostimulatory cytokine that possesses multiple proinflammatory functions, such as recruiting neutrophils, activating neutrophil/macrophage phagocytosis activity, and inducing beta-defensin release. Th17 and IL-17 are regarded as an important component in host defense against fungal infections [28]. In response to this threat C. albicans can downregulate the secretion of host IL-17 by inhibiting the IDO catabolism of tryptophan [29], actively shifting the balance of tryptophan metabolism and thwarting the tryptophan-starvation-mediated host Th17 response [30]. The beta-carboline norharmane is a known IDO inhibitor (see figure "Norharmane"). When acetaldehyde and tryptophan collide, they can undergo a non-enzymatic Pictet-Spengler condensation reaction to form 3-carboxy-1-methyl-1,2,3,4-tetrahydro-beta-carboline (3-MTBC) (see figure "Tryptophan + Acetaldehyde"). Is the beta-carboline 3-MTBC also an IDO inhibitor? If it is, then suddenly we have an evolutionary reason for C. albicans releasing acetaldehyde into its extracellular environment and the technique by which it scuttles the body's tryptophan starvation anti-microbial maneuver. Since acetaldehyde released anywhere can reach the bloodstream and be transported throughout the body [31], this also introduces the potential for systemic disruption of tryptophan metabolism at sites other than those being colonized by C. albicans. The consequences of this go far beyond the localized struggle between yeast and the immune system at mucosal sites! The self versus non-self recognition process is crucial to any organism with immune system cells capable of inflicting lethal damage to other cells. IDO is one of the key players in this process [32]. Regulatory T cells (Tregs) are a subpopulation of T cells which modulate the immune system by dampening T cell activity after an infectious episode and maintaining tolerance to self-antigens. In other words, they are essential to prevent the body from attacking itself (autoimmunity). Tregs are especially important during pregnancy to prevent the mother's immune system from attacking the foetus, a common cause of miscarriage [33]. The tryptophan starvation pathway, mediated by the enzyme IDO which shunts tryptophan into kynurenine, is a critical step in the production of Tregs [34] which in turn quench the immune system post-infection to ensure that autoimmunity is not a deleterious consequence. The dual role of IDO induction as both an antimicrobial effector and an immunosuppressor dampening Tcell activation and IFN-gamma production is something of a paradox unless tryptophan limitation is a more severe microbial deterrent than it is to T cells. Then under "ideal" conditions this allows IDO to act as an antimicrobial agent prior to its immunomodulatory effects. A similar incongruity appears with IDO in relation to its tumour-protective and tumour-destructive properties [35].

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However, the commensal presence of C. albicans skews this precarious balancing act, with the potential impairment of the IDO tryptophan to kynurenine pathway necessary for Treg immunostabilization after infection not just manifesting when the body is actively targeting the yeast. The ongoing pulsed lowdosage acetaldehyde exposure resulting from the unique fermentation pathway of C. albicans means that the immune system is also continuously vulnerable. Hence, when an infectious agent, such as hepatitis C for example, results in immune system activation, then even after resolution of the viral infection, the inadequacy of the corresponding immune system downregulation phase means that the onset of an autoimmune condition, such as rheumatoid arthritis [36], is much more likely in individuals with a high background yeast load. The same argument applies not just to rheumatoid arthritis but to all of the conditions with an autoimmune component (e.g. encephalomyelitis [37], multiple sclerosis [38], diabetes [39], systemic lupus erythematosus [40]). Furthermore, even when the current yeast levels are low, since C. albicans appears to depend upon a certain amount of pressure from the host immune system to keep it in check, then any infectious assault which diverts immune system resources away from this containment will result in an increase in the yeast load and acetaldehyde emission levels -- something which sets the stage for problems in the future. Similarly, implementation of a steroidal immunosuppressive regimen may also allow yeast levels to increase with more acetaldehyde emission and more IDO inhibition. This would exacerbate the autoimmune condition and create a self-defeating loop of higher and higher dosage requirements attempting to quench the immune system irregularities, even with the potential off-label acetaldehyde scavenging abilities of steroids (see "Scavenger Hunt -- Prednisone"). This model also validates the dramatic results documented in the historical Wondro testimonials pamphlet (see "Related Works"), where remission of arthritic conditions was a common theme. By functioning as an upstream scavenger of acetaldehyde emitted from yeast cells, the sulphurated fatty acids in the flax oil limited the contact of acetaldehyde with a plethora of vulnerable reaction points including, but not limited to, enzymatic pathways such as the IDO tryptophan to kynurenine shunt. Invasive organisms such as C. albicans do not acquiesce to attempts from any level, whether an exogenous drug or an endogenous immune system tactic, to expunge them from their comfortable niche. Fungi, in particular, represent the reversion of certain primitive plant life to the prechlorophyll levels of parasitic bacteria. This means they have all of the advanced adaptive genetic machinery of a plant that is now directed at establishing and sustaining their parasitic presence within a suitable host.

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[06] Naglik JR et al., "Candida albicans secreted aspartyl proteinases in virulence and pathogenesis.", Microbiol Mol Biol Rev. 2003 Sep;67(3):400-28. http://www.ncbi.nlm.nih.gov/pubmed/12966142 [07] Naglik JR et al., "Differential expression of Candida albicans secreted aspartyl proteinase and phospholipase B genes in humans correlates with active oral and vaginal infections.", J Infect Dis. 2003 Aug 1;188(3):469-79. http://www.ncbi.nlm.nih.gov/pubmed/12870130 [08] Wellington M et al., "Live Candida albicans suppresses production of reactive oxygen species in phagocytes.", Infect Immun. 2009 Jan;77(1):405-13. http://www.ncbi.nlm.nih.gov/pubmed/18981256 [09] Schroppel K et al., "Suppression of type 2 NO-synthase activity in macrophages by Candida albicans.", Int J Med Microbiol. 2001 Mar;290(8):659-68. http://www.ncbi.nlm.nih.gov/pubmed/11310444 [10] Fernandez-Arenas E et al., "Candida albicans actively modulates intracellular membrane trafficking in mouse macrophage phagosomes.", Cell Microbiol. 2009 Apr;11(4):560-89. http://www.ncbi.nlm.nih.gov/pubmed/19134116 [11] Geiger J et al. "Release of a potent polymorphonuclear leukocyte chemoattractant is regulated by white-opaque switching in Candida albicans.", Infect Immun. 2004 February; 72(2): 667677. http://pubmedcentralcanada.ca/articlerender.cgi?artid=1050620 [12] Rotstein D et al., "Phagocytosis of Candida albicans induces apoptosis of human neutrophils.", Shock. 2000 Sep;14(3):278-83. http://www.ncbi.nlm.nih.gov/pubmed/11028543 [13] Abe S et al., "Suppression of anti-Candida activity of macrophages by a quorum-sensing molecule, farnesol, through induction of oxidative stress.", Microbiol Immunol. 2009 Jun;53(6):323-30. http://www.ncbi.nlm.nih.gov/pubmed/19493200 [14] Rennemeier C et al., "Microbial quorum-sensing molecules induce acrosome loss and cell death in human spermatoza.", Infect Immun. 2009 November; 77(11): 49904997. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2772518 [15] Zhu W et al., "Interactions of Candida albicans with epithelial cells.", Cell Microbiol. 2010 Mar;12(3):273-82. http://www.ncbi.nlm.nih.gov/pubmed/19919567 [16] Jong AY et al., "Traversal of Candida albicans across human blood-brain barrier in vitro.", Infect Immun. 2001 July; 69(7): 45364544. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC98530 [17] Park H et al., "Transcriptional responses of candida albicans to epithelial and endothelial cells.", Eukaryot Cell. 2009 Oct;8(10):1498-510. http://www.ncbi.nlm.nih.gov/pubmed/19700637 [18] Ramirez MA et al., "Mutations in Alternative Carbon Utilization Pathways in Candida albicans Attenuate Virulence and Confer Pleiotropic Phenotypes.", Eukaryot Cell. 2007 February; 6(2): 280290. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797957

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[19] Almeida RS et al., "The hyphal-associated adhesin and invasin Als3 of Candida albicans mediates iron acquisition from host ferritin.", PLoS Pathog. 2008 Nov;4(11):e1000217. http://www.ncbi.nlm.nih.gov/pubmed/19023418 [20] Knight SA et al., "Iron acquisition from transferrin by Candida albicans depends on the reductive pathway.", Infect Immun. 2005 Sep;73(9):5482-92. http://www.ncbi.nlm.nih.gov/pubmed/16113264 [21] Almeida RS et al., "Candida albicans iron acquisition within the host.", FEMS Yeast Res. 2009 Oct;9(7):1000-12. http://www.ncbi.nlm.nih.gov/pubmed/19788558 [22] Mitchell A etl al., "Adaptive prediction of environmental changes by microorganisms.", Nature. 2009 Jul 9;460(7252):220-4. http://www.ncbi.nlm.nih.gov/pubmed/19536156 [23] Adam B et al., "Mixed species biofilms of Candida albicans and Staphylococcus epidermidis.", J Med Microbiol. 2002 Apr;51(4):344-9. http://www.ncbi.nlm.nih.gov/pubmed/11926741 [24] Leonhardt RM et al., "Severe Tryptophan Starvation Blocks Onset of Conventional Persistence and Reduces Reactivation of Chlamydia trachomatis", Infect Immun. 2007 November; 75(11): 51055117. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2168275 [25] Miller CM et al., "The immunobiology of the innate response to Toxoplasma gondii.", Int J Parasitol. 2009 Jan;39(1):23-39. http://www.ncbi.nlm.nih.gov/pubmed/18775432 [26] Rouabhia M et al., "Interleukin-18 and Gamma Interferon Production by Oral Epithelial Cells in Response to Exposure to Candida albicans or Lipopolysaccharide Stimulation", Infect Immun. 2002 December; 70(12): 70737080. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC133048 [27] Konan KV et al., "Treatment of ME180 cells with interferon-gamma causes apoptosis as a result of tryptophan starvation.", J Interferon Cytokine Res. 1996 Sep;16(9):751-6. http://www.ncbi.nlm.nih.gov/pubmed/8887061 [28] Zelante et al., "Th17 Cells In Fungal Infections" in "Th17 Cells in Health and Disease" 2011, pp 299317. http://rd.springer.com/chapter/10.1007/978-1-4419-9371-7_16 [29] Bozza S et al., "A crucial role for tryptophan catabolism at the host/Candida albicans interface.", J Immunol. 2005 Mar 1;174(5):2910-8. http://www.ncbi.nlm.nih.gov/pubmed/15728502 [30] Cheng SC et al., "Candida albicans dampens host defense by downregulating IL-17 production.", J Immunol. 2010 Aug 15;185(4):2450-7. Epub 2010 Jul 12. http://www.ncbi.nlm.nih.gov/pubmed/20624941 [31] Baraona E, "Transport of acetaldehyde in red blood cells.", Alcohol Alcohol Suppl. 1987 1987;1:2036. http://www.ncbi.nlm.nih.gov/pubmed/3426680

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[32] Curti A et al., "The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology.", Blood. 2009 Mar 12;113(11):2394-401. http://www.ncbi.nlm.nih.gov/pubmed/19023117 [33] Guerin LR et al., "Regulatory T-cells and immune tolerance in pregnancy: a new target for infertility treatment?", Hum Reprod Update. 2009 Sep-Oct; 15(5): 517535. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2725755 [34] Mezrich JD et al., "An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells.", J Immunol. 2010 Sep 15;185(6):3190-8. http://www.ncbi.nlm.nih.gov/pubmed/20720200 [35] Dubener W et al., "Antimicrobial and immunoregulatory effector mechanisms in human endothelial cells. Indoleamine 2,3-dioxygenase versus inducible nitric oxide synthase.", Thromb Haemost. 2009 Dec;102(6):1110-6. http://www.ncbi.nlm.nih.gov/pubmed/19967141 [36] Hirohata S et al., "Development of rheumatoid arthritis after chronic hepatitis caused by hepatitis C virus infection.", Intern Med. 1992 Apr;31(4):493-5. http://www.ncbi.nlm.nih.gov/pubmed/1633356 [37] Sakurai K et al., "Effect of indoleamine 2,3-dioxygenase on induction of experimental autoimmune encephalomyelitis.", J Neuroimmunol. 2002 Aug;129(1-2):186-96. http://www.ncbi.nlm.nih.gov/pubmed/12161035 [38] Kwidzinski E et al., "Indolamine 2,3-dioxygenase is expressed in the CNS and down-regulates autoimmune inflammation.", FASEB J. 2005 Aug;19(10):1347-9. http://www.ncbi.nlm.nih.gov/pubmed/15939737 [39] Grohmann U et al., "A defect in tryptophan catabolism impairs tolerance in nonobese diabetic mice.", J Exp Med. 2003 Jul 7;198(1):153-60. http://www.ncbi.nlm.nih.gov/pubmed/12835483 [40] Pertovaara M et al., "Indoleamine 2,3-dioxygenase activity is increased in patients with systemic lupus erythematosus and predicts disease activation in the sunny season", Clin Exp Immunol. 2007 November; 150(2): 274278. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219350

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Caught In A Loop ============== Tryptophan is one of the twenty standard amino acids. Although it isn't a biogenic amine like the ones discussed previously (e.g. serotonin, histamine, dopamine), it is also vulnerable to attack by acetaldehyde in a Pictet-Spengler ring closure reaction (see figure "Tryptophan + Acetaldehyde"). The resulting compound (3-carboxy-1-methyl-1,2,3,4-tetrahydro-beta-carboline) can no longer participate in any of the amino-acid related functions of its parent tryptophan. Since tryptophan is an essential amino acid in the human diet, it is subject to deficiency by both dietary inadequacy (e.g. pellagra) or biochemical processes (such as reaction with acetaldehyde) that denature its structure. Tryptophan is the only amino acid with a double ring in its configuration. It is the precursor for the synthesis of the neurotransmitter serotonin (5-hydroxtryptamine) (see figure "Serotonin"), melatonin (Nacetyl-5-methoxytryptamine), and when dietary intake of niacin is inadequate, of nicotonic acid as well. The nicotinic acid connection with respect to acetaldehyde may be important because of the dependence of aldehyde dehydrogenase upon NAD(+) in the reaction that converts acetaldehyde (CH3CHO) into harmless acetic acid (CH3COOH). NAD (nicotinamide adenine dinucleotide), a derivative of nicotinic acid (vitamin B3) is a coenzyme electron acceptor in the reaction: CH3CHO + NAD(+) + H20 -> CH3COOH + NADH + H(+) This provides several points of potential interference from excess yeast-released acetaldehyde with tryptophan metabolism in the body: by direct condensation with tryptophan, itself; by condensation with its biogenic amine, serotonin; by the possible diversion of tryptophan into the production of NAD to support elevated levels of aldehyde dehydrogenase, and by depletion of normal downstream products of tryptophan (e.g. melatonin) because of exhaustion of tryptophan supplies. Although both tryptophan and NAD/NADH mechanisms have been implicated in disease states such as obsessive compulsive disorder (OCD) and bipolar affective disorder (BAD), results are inconclusive, possibly because of the complex interactions of the processes involved. See the reference ("Astrophysiology...and Yeast -- Sick or Not?") for orthomolecular psychokinesiology (OPK) techniques that may be useful for both testing and rebalancing these affected pathways once the impact of acetaldehyde exposure has been limited.

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Reactive Oxygen Species ==================== Oxygen is a mainstay in the metabolism of most lifeforms on this planet. But processes such as combustion (e.g. forest fires) and oxidation (e.g. rusting) demonstrate that oxygen may have a destructive aspect as well. Reactive oxygen species in the body are unstable molecular forms of oxygen containing unpaired valence shell electrons that make them highly reactive with the surrounding cellular environment (see figure "Reactive Oxygen Species"). Such potentially dangerous configurations are used by the immune system to ruthlessly ravage invaders. One of the body's primary defense mechanisms against yeast is the reactive oxygen respiratory burst of innate immune system neutrophils that use the enzyme myeloperoxidase to produce hypochlorous acid (HOCl) from hydrogen peroxide (H2O2) and chloride anion (Cl-). In the presence of hydrogen peroxide and either potassium iodide, sodium chloride, or potassium bromide, purified human myeloperoxidase is rapidly lethal to several species of Candida [1]. The rate of disappearance of iodine from the wrist pulse point (see "Astrophysiology...and Yeast -- Yeast Abatement Protocol") is often an indicator of how active this neutrophil pathway is in relation to onboard yeast colonization. However, oxidative stress resulting from excess reactive oxygen species in the body can damage DNA, RNA, lipids, and proteins. Since oxidative stress is implicated in the pathogenesis of numerous different diseases, supplementation with antioxidants and free radical scavengers is an attempt to counteract these effects. But are the elevated levels of reactive oxygen species a cause, an effect, or a parallel consequence of the disease process? Acetaldehyde has been well studied in relation to its role in alcohol consumption. Its presence in the body can increase the concentrations of reactive oxygen species [2]. Although the body has numerous mechanisms for keeping reactive oxygen species in check (glutathione, ascorbate, vitamin E, catalase, superoxide dismutase, etc.), chronic daily exposure to acetaldehyde being emitted by budding yeast (Candida Albicans) metabolism may overload these protective pathways. This means that the potential exists for extensive downstream damage not only from acetaldehyde itself, but also from the reactive oxygen species that it spawns. Acetaldehyde is so reactive, in and of itself, that it is rarely found in isolation but it does leaves a trail of damage in the body's biochemical profile. Are there non-hepatic pathways resulting from yeast-released acetaldehyde that may lead to ROS accumulation in other cells in the body? ROS within a cell are a natural consequence of oxygen-based aerobic respiration in the mitochondrial power plants [3] that keep the cell supplied with its biochemical energy source ATP (adenonsine triphosphate). Cells are miniature factories carrying out dynamic chemical reactions on a continuous basis. Reduction-oxidation (redox) reactions involve the change in "oxidation" state of the reactants, either via a gain of electrons (reduction) or a loss of electrons (oxidation). Since electrons are neither being created nor destroyed in the cellular processes there must be an equal number of electrons gained and electrons lost. Cells maintain pools of several redox couples such as cystine/cysteine, NAD+/NADH, NADP+/NADPH, and the oxidized and reduced forms of glutathione and metalloenzymes that can serve as electron acceptors or donors to ensure that electron transfer can occur in an efficient and balanced manner. When theses pools are inadequate or imbalanced, then the cell enters a state of "oxidative stress" since it can no longer perform its necessary chemical reactions that comprise its unique functions in the body. Cystine is the oxidized form of two amino acid cysteine molecules joined by a disulphide bond (see figure "Cysteine / Cystine"). The cystine/cysteine redox couple is the predominant low-molecular-weight thiol/disulphide pool found in plasma. It is possible to measure the redox potential (in millivolts) of the plasma thiol/disulphide redox pool. In healthy adults this is centered at approximately -80mv while in disease states it may become oxidized (less cysteine) to between -62 to -20 mv [4]. Inadequate dietary intake and absorption of sulphur-bearing amino acids can shift the redox potential towards the oxidized state associated with disease [5]. Oxidized extracellular Cys/CySS also can stimulate the generation of intracellular reactive oxygen species (ROS) [6].

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Cysteine

Cystine

N,S-diacetyl-L-cysteine

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Acetaldehyde in the gut can react with dietary cysteine to form a thiazolidine (see "Toxic Soup" and figure "Cysteine + Acetaldehyde"). Cystine with its disulphide bond (see "Bridge Across The Chasm" and figure "Disulphide Bridge") may be subject to side reactions with acetaldehyde that alter its structure as well, releasing a cysteine that can be attacked by acetaldehyde and a hybrid structure such as N,S-diacetyl-Lcysteine (see figure "N,S-diacetyl-L-cysteine"). With this kind of disruption in progress, acetaldehyde can influence the status of the thiol/disulphide redox plasma pool and indirectly exert a deleterious impact on every cell in the body that depends upon this vital resource, even without actually coming into contact with the cells in question! Diseases that have a genetic component but late onset may eventually manifest because of a gradual shift of the Cys/CySS redox potential until the vulnerable cells are no longer able to cope with the cumulative increasing oxidative stress. Parkinson's disease [7], amyotrophic lateral sclerosis (ALS) [8], and Leber hereditary optic neuropathy [9] all have connections to reduced capacity for dealing with oxidative stress. The as-yet unrecognized factor that triggers these diseases may the ongoing exposure to acetaldehyde from increasing "commensal" yeast colonization in the body, something that can shift the redox potential to a critical point where the cells in the body are no longer able to deal with the ROS associated with normal function. This oxidative-stress-to-disease point may be different in each individual. Monitoring the redox potentials of the various redox couple pools, plasma Cys/CySS in particular, over time could provide an indication of both possible movement towards disease and the efficacy of therapeutic strategies (such as acetaldehyde scavengers and yeast reduction protocols) aimed at dealing with acetaldehyde toxicity.

[1] Lehrer RI, "Antifungal Effects of Peroxidase Systems", J Bacteriol. 1969 August; 99(2): 361365. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC250023 [2] Novitskiy G. et al., "Effects of ethanol and acetaldehyde on reactive oxygen species production in rat hepatic stellate cells.", Alcohol Clin Exp Res. 2006 Aug;30(8):1429-35. http://www.ncbi.nlm.nih.gov/pubmed/16899047 [3] Turren JF, "Mitochondrial formation of reactive oxygen species.", J Physiol 2003 Oct 15;552(Pt 2):33544. http://www.ncbi.nlm.nih.gov/pubmed/14561818 [4] Ramierez A et al., "Extracellular cysteine/cystine redox potential controls lung fibroblast proliferation and matrix expression through upregulation of transforming growth factor-beta", AJP - Lung Physiol October 2007 vol. 293 no. 4 L972-L981. http://ajplung.physiology.org/content/293/4/L972.full [5] Nkabyo YS et al.,"Thiol/disulfide redox status is oxidized in plasma and small intestinal and colonic mucosa of rats with inadequate sulphur amino acid intake.", J Nutr. 2006 May;136(5):1242-8. http://www.ncbi.nlm.nih.gov/pubmed/16614411 [6] Zhu JW et al., "Extracellular cysteine (Cys)/cystine (CySS) redox regulates metabotropic glutamate receptor 5 activity.", Biochimie. 2012 Mar;94(3):617-27. Epub 2011 Sep 22. http://www.ncbi.nlm.nih.gov/pubmed/21964032 [7] Grasbon-Frodl EM et al.,"Analysis of mitochondrial targeting sequence and coding region polymorphisms of the manganese superoxide dismutase gene in German Parkinson disease patients.", Biochem Biophys Res Commun. 1999 Feb 24;255(3):749-52. http://www.ncbi.nlm.nih.gov/pubmed/10049782 [8] Valentine JS et al., "Misfolded CuZnSOD and amyotrophic lateral sclerosis.", Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3617-22. Epub 2003 Mar 24. http://www.ncbi.nlm.nih.gov/pubmed/12655070 [9] Qi X et al., "Optic neuropathy induced by reductions in mitochondrial superoxide dismutase.", Invest Ophthalmol Vis Sci. 2003 Mar;44(3):1088-96. http://www.ncbi.nlm.nih.gov/pubmed/12601034

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Double-Edged Sword ================ A healthy body needs healthy cells and the health of each and every individual cell depends upon what is happening within and without at the biochemical level. Aerobic organisms, which derive their energy from the reduction of oxygen, play a dangerous game if they are unable to deal with the small amounts of superoxide anion (O2-), hydroxyl radical (OH), and hydrogen peroxide (H2O2) that arise during the electron ping-pong performed by mitochondria (see "Reactive Oxygen Species"). A closer look at this area is warranted in relation to aldehydes. The hydroxyl radical is the most reactive of these species. It likes to swipe hydrogen atoms from polyunsaturated fatty acids (the initiation step) to return to a stable state as a water molecule (see figure "Hydroxyl Radical Abstraction of Hydrogen Atom"). The purloined hydrogen atom leaves the lipid with a carbon-centered unpaired electron that can attract molecular oxygen in the peroxidation (oxygen uptake) step forming a lipid peroxide (see figure "Lipid Peroxide"). But this configuration is still unstable and the lipid peroxyl radical can second another hydrogen atom from another lipid in the propagation step forming a lipid hydroperoxide (see figure "Lipid Hydroperoxide"). Although not a radical species, this configuration is conformationally unstable and can split the lipid into another lipid radical, a lipid fragment and aldehydes such as malondialdehyde (see figure "Malondialdehyde"). If acetaldehyde is a dagger with a highly reactive carbonyl group that can damage body tissue, DNA, enzymes, and other chemical compounds; then malondialdehyde is twice as deadly with two carbonyls in a tiny molecule. This double-edged sword has no beneficial aspect. Whereas acetaldehyde can latch onto things and slice things and change them into something else, malondialdehyde can not only do this but also also cross-link structures creating tangles and log jams that are beyond rescue. The detectable levels of malondialdehyde in a cell are a measure of oxidative stress [1]. Since the pathway to malondialdehyde described produces spinoff radical species along the way, each of these can initiate another similar pathway resulting in a chain reaction that can rapidly get out of control. If the cellular redox pools and enzymes responsible for maintaining order amidst the chaos cannot intercept the ROS and quench the deleterious cascade, the cell must consider more drastic measures to ensure that its insanity doesn't spread. Apoptosis is the rapid disintegration of a cell into bite-sized chunks that can be assimilated and disposed of by macrophages -- a form of self-programmed cellular suicide. Death of a cell by trauma (necrosis) can spill harmful contents (such as reactive aldehydes) into the extracellular environment. Apoptosis, on the other hand, produces encapsulated cell fragments that phagocytic cells are able to engulf and quickly remove before the contents of the cell can cause damage to surrounding cells. More than 50 billion cells per day may undergo apoptosis in an average human adult with higher rates in individuals with degenerative diseases associated with oxidative stress [2]. The status of the extracellular cysteine/cystine (Cys/CySS) redox pool is closely coupled to the competence of the major intracellular antioxidant redox system, glutathione/glutathione disulphide (GSH/GSSG). Glutathione is a tripeptide made up of the three amino acids glutamate, cysteine, and glycine (see figures "Glutathione" and "Glutathione Disulphide"). Of the three constituents, dietary cysteine, that contributes the critical sulfhydryl group, is the most likely rate-limiting step for the synthesis of glutathione within the cell. Glutathione not only participates directly in the neutralization of reactive oxygen species (ROS), it also assists other antioxidants such as vitamins C and E by returning them to their reduced (active) forms. Although acetaldehyde doesn't appear to react directly with glutathione [3], it does react with its precursor amino acid cysteine (see "Toxic Soup") and a glutathione metabolite cysteinylglycine to form thiazolidinecarboxylic acid derivatives. It can also interfere with the backup supply pathway from dietary methionine to cysteine (see "When The Backup Fails"). This means that acetaldehyde released by yeast has the potential for clobbering both of the vital sulphur-based redox pools: Cys/CySS and GSH/GSSG.

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Hydroxyl Radical Abstraction of Hydrogen Atom

Lipid Peroxide

Lipid Hydroperoxide

Malondialdehyde

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Glutathione

Glutathione Disulphide

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Although there is some control over cellular ROS exerted by redox pools from outside the cell [4], in order to establish its own redox pools inside a cell, the cell must first transport the necessary molecules through its membrane and into the intracellular milieu. Since the systemic availability of oral glutathione (GSH) is negligible [5], the vast majority of it must be manufactured intracellularly and since cysteine is the limiting resource in this regard, cellular uptake of plasma cysteine is essential. Cystine is a ubiquitous disulphide of back-to-back cysteine molecules generated from cysteine by an oxidase on extracellular surfaces [6]. The oxidative stress-inducible cystine/glutamate antiporter system transports one molecule of cystine, the oxidized form of cysteine, through the cellular membrane in exchange for one glutamate molecule which is released into the extracellular space [7]. The cystine molecule inside the cell can then supply two cysteine molecules for glutathione biosynthesis. When cystine uptake by the cystine/glutamate antiporter system is inhibited [8] or impaired, creating a void in the antioxidant defenses of a cell, this leads ultimately to an accumulation of toxic ROS in the cell and eventual cellular death [9]. Since the toxic levels of ROS lipids in a cell associated with impaired cystine availability will spawn malondialdehyde this implies that not only are acetaldehyde and malondialdehyde both tiny, look-alike deadly aldehydes [10] but also that there is a chain of causation from yeast-released acetaldehyde through disruption of sulphur redox pools to the accumulation of malondialdehyde in cells, a sign of oxidative stress that usually heralds the death knell of the cell. Whether directly or indirectly, not only does acetaldehyde accelerate the rate of cell death [11] but it retards the rate of replacement [12] leading to chronic wasting away of body tissue, all the while hiding under the cover of increased oxidative stressors. Many diseases of unknown origin are associated with oxidative stress biomarkers [13,14]. In fact it is a rare disease state indeed that isn't associated with abnormalities in the redox pools. But instead of being a consequence of whatever abnormality is occurring, perhaps this redox pool insufficiency is the driving force. Even in the absence of apparent illness, the rapidity of the aging process is linked to redox pool competence [15]. Given the high reactivity of acetaldehyde and its pulsed low-dosage appearance whenever yeast ferments carbohydrates, any and all of the pathways explored in this work may contribute toward the downward spiral of the host into disease. However, the impairment of the redox status of every cell in the body is going to be at least a major, if not the most significant, factor in conditions of progressively chronic failure. Given the criticality of dietary sulphur metabolism in this regard and given the affinity of acetaldehyde for binding to sulphur-bearing structures, it should no longer be so surprising that Wondro produced beneficial results in so many apparently unrelated diseases. By sacrificing its metabolically useless disulphide bonds to irreversible binding with acetaldehyde, it allowed the function of critically essential sulphur pathways to return to normal, thereby reducing the overall load of oxidative stress on each and every cell, and permitting the body to heal itself. [1] Valenzuela A, "The biological significance of malondialdehyde determination in the assessment of tissue oxidative stress." Life Sci. 1991;48(4):301-9. http://www.ncbi.nlm.nih.gov/pubmed/1990230 [2] "Malondialdehyde + Disease", From: Davis AP et al., "The Comparative Toxicogenomics Database: update 2011.", Nucleic Acids Res. 2011 Jan;39(Database issue):D1067-72. Epub 2010 Sep 22. http://ctdbase.org/detail.go?view=disease&type=chem&acc=D008315 [3] Kera Y et al., "Conjugation of acetaldehyde with cysteinylglycine, the first metabolite in glutathione breakdown by gamma-glutamyltranspeptidase.", Agents Actions. 1985 Oct;17(1):48-52. http://www.ncbi.nlm.nih.gov/pubmed/2867670 [4] Imhoff Br et al., "Extracellular redox status regulates Nrf2 activation through mitochondrial reactive oxygen species." Biochem J. 2009 Dec 10;424(3):491-500 http://www.ncbi.nlm.nih.gov/pubmed/19778293

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[5] Witschi A et al., "The systemic availability of oral glutathione.", Eur J Clin Pharmacol. 1992;43(6):6679. http://www.ncbi.nlm.nih.gov/pubmed/1362956 [6] Jones DP et al., "Cysteine/cystine couple is a newly recognized node in the circuitry for biologic redox signaling and control.", FASEB J. 2004 Aug;18(11):1246-8. http://www.ncbi.nlm.nih.gov/pubmed/15180957 [7] Conrad M et al., "The oxidative stress-inducible cystine/glutamate antiporter, system x (c) (-) : cystine supplier and beyond.", Amino Acids. 2012 Jan;42(1):231-46. http://www.ncbi.nlm.nih.gov/pubmed/21409388 [8] Dixon SJ et al., "Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death.", Cell, Vol 149(5), 1060-1072, 25 May 2012 http://www.ncbi.nlm.nih.gov/pubmed/22632970 [9] Banjac A et al., "The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death.", Oncogene. 2008 Mar 6;27(11):1618-28. Epub 2007 Sep 10. http://www.ncbi.nlm.nih.gov/pubmed/17828297 [10] Wyatt TA et al., "Malondialdehyde-acetaldehyde adducts decrease bronchial epithelial wound repair.", Alcohol. 2005 May;36(1):31-40. http://www.ncbi.nlm.nih.gov/pubmed/16257351 [11] Menegola E et al., "Acetaldehyde in vitro exposure and apoptosis: a possible mechanism of teratogenesis." Alcohol. 2001 Jan;23(1):35-9. http://www.ncbi.nlm.nih.gov/pubmed/11282450 [12] Zimmerman BT et al., "Mechanisms of acetaldehyde-mediated growth inhibition: delayed cell cycle progression and induction of apoptosis.", Alcohol Clin Exp Res. 1995 Apr;19(2):434-40. http://www.ncbi.nlm.nih.gov/pubmed/7625579 [13] Perez YG et al., "Malondialdehyde and sulfhydryl groups as biomarkers of oxidative stress in patients with systemic lupus erythematosus.", 2012 Aug;52(4):658-660. http://www.ncbi.nlm.nih.gov/pubmed/22885431 [14] Pampliega O et al.,"Increased expression of cystine/glutamate antiporter in multiple sclerosis.", J Neuroinflammation. 2011 Jun 3;8:63. http://www.ncbi.nlm.nih.gov/pubmed/21639880 [15] Droge W, "Aging-related changes in the thiol/disulfide redox state: implications for the use of thiol antioxidants.", Exp Gerontol. 2002 Dec;37(12):1333-45. http://www.ncbi.nlm.nih.gov/pubmed/12559403

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Rear-View Mirror ============= Industrial waste-water methylmercury was eventually identified as the the cause of the devastating neurological symptoms in Minamata, Japan that appeared starting in 1956. Afflicted individuals had mercury levels in hair samples that were hundreds of times greater than for the average of those living outside of the affected region. The ultimate toxicity of this organic heavy metal compound is not disputed as other incidents around the world (Niigata, Japan 1965; Basra, Iraq 1971) involving methylmercury exposure have resulted in similar mass poisonings with a high fatality rate. Methylmercury has a chemical formula of CH3Hg+. Since it is a positively charged cation, it will combine with anions such as chloride, hydroxide and nitrate. Ingested methylmercury also has a high affinity for sulphur-containing compounds such as the amino acid cysteine [1] and proteins/peptides displaying cysteine residues where it forms a covalent bond with the sulfhydryl group. Acetaldehyde (CH3CHO) also finds cysteine and associated sulfhydryls irresistible [2]. The structures of these two substances side by side highlight their size and shape similarities (see figures "Acetaldehyde" and "Methylmercury"). Acetaldehyde is not a cation like methylmercury. However, as a result of the higher electronegativity of oxygen than carbon in the acetaldehyde molecule, the carbonyl group is polarized. The carbon atom has a partial positive charge, and the oxygen atom has a partial negative charge (see figure "Acetaldehyde Polarization"). This renders acetaldehyde highly reactive towards a wide variety of attractive groups in a fashion that might mimic the heavy metal cations. The relatively small hydrogen atom connected to the carbonyl carbon presents little steric hindrance to the formation of complexes at this carbon site. This prolific reactivity is emphasized by the many classes of reactions that occur involving acetaldehyde [3]: 1,2-additions with nucleophilic reagents yielding two-carbon extended secondary alcohols aldol condensation with wide variety of enolates including itself Mannich reactions for Schiff base formation Pictet-Spengler ring-forming reactions Lindgren (Pinnick) oxidation to carboxylic acid mixed Tishchenko dismutation reactions with itself to form paraldehyde (a trimer) and metaldehyde (a tetramer) autoxidation with oxygen to paracetic acid Baeyer-Villiger oxidation with paracetic acid to carboxylic acid Friedel-Crafts acetylation of quinones Stetter nucleophile-catalyzed conjugate addition to a Michael acceptor producing a dicarbonyl Cannizarro disproportionation to acetic acid and ethanol Prins reaction with alkenes (olefins) and alkynes AngeliRimini reaction with sulfonamides even with water to form a hydrate (see figure "Acetaldehyde and 1,1-ethanediol")

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Acetaldehyde

Methylmercury

Acetaldehyde Polarization

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Not all of these reactions occur within the body but even a subset of the list above is enough to provide unrestrained acetaldehyde with more than ample opportunities for disruption of whatever aspects of the body's biochemistry that it happens to come into contact with. Both acetaldehyde and methylmercury can be scavenged by the body's innate chelating cysteine-rich metallothioneins [4,5]. Note the abundance of (yellow) sulphur atoms in the structure (see figure "Mammalian Metallothionein") However, the competence of this system may become overloaded when toxic exposure is chronic or high and is dependent upon dietary intake and absorption of sulphur-bearing amino acids, something that can be disrupted by either acetaldehyde or methylmercury (see "Toxic Soup" and "When The Backup Fails"). Methyl mercury has a high affinity for the selenohydryl group and selenide [6]. This can create an intracellular selenium deficiency for selenoenzymes where selenium appears in a cysteine residue instead of sulphur (as part of the 21st proteinogenic amino acid selenocysteine). Even normal functioning of mitochondrial cellular energy processes can result in the appearance of reactive oxygen species (see "Reactive Oxygen Species"). One of the major responsibilities of the cellular glutathione redox pool (GSH/GSSG) is ensuring that these damaging species do not accumulate. The main reaction catalyzed by glutathione peroxidase is: 2 GSH + H2O2 ---> GS-SG + 2 H2O which neutralizes hydrogen peroxide back to water, and a related pathway catalyzed by phospholipidhydroperoxide glutathione peroxidase: 2 GSH + Lipid Hydroperoxide ---> GS-SG + Lipid + 2 H20 returning the dangerous lipid hydroperoxide to its lipid state before it can split into another free radical and malondialdehyde. The biological importance of clearing cells of reactive oxygen species before they have a chance to accumulate is underscored by the fact that glutathione peroxidase is a selenocysteine-dependent enzyme. This increases its reaction rate throughput substantially in comparison to enzymes containing ordinary sulphur-based cysteine. But, even when sulphur-containing glutathione is amply available in its reduced form (GSH), methylmercury can impair these reactions by rendering glutathione peroxidase [7] (and other seleno-enzymes) non-functional via a post-transcriptional error for selenocysteine which is in short supply [8]. This leads to intolerable levels of oxidative stress within the contaminated cells followed by cellular dissociation (apoptosis) and potentially fatal outcomes. Fortunately, acetaldehyde exposure does not lead to this type of rapid catastrophic collapse of the glutathione redox sufficiency [9]. However, the similarities between symptomology in candidiasis syndrome, acetaldehyde poisoning, and heavy metal toxicity (see "Daily Toxic Spill") and the size, shape and polar nature commonalities of acetaldehyde in relation to methylmercury suggest that there are some common pathways under duress in each of these conditions. The ability of yeast-released acetaldehyde to disrupt sulphur-based metabolism and erode both the Cys/CySS and GSH/GSSG redox pools leading to increasing levels of oxidative stress has already been explored (see "Reactive Oxygen Species" and "Double-Edged Sword"). Since the seleno-enzyme glutathione peroxidase is the major toxicity attack point for methylmercury, perhaps both acetaldehyde and methylmercury contribute to the downward spiral of an organism into disease mediated by increased oxidative stress but on different time scales (years in the case of low-dose yeast-released acetaldehyde acetaldehyde and weeks/months in the case of acute methylmercury exposure).

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Acetaldehyde

1,1-ethanediol

Mammalian Metallothionein

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Another difference to factor into this model is that there are other scavenging mechanisms for aldehydes (e.g. aldehyde dehydrogenase, carnosine) that can reduce the impact of acetaldehyde. Even in the case of methylmercury poisoning there is a silent latency symptom-free period between the time of first exposure and the manifestation of identifiable neurological symptoms [10]. Since iodothyronine deiodinases involved in the activation and deactivation of thyroid hormones are also seleno-enzymes, then methylmercury exposure could be expected to interfere with thyroid hormone function [11], something capable of impacting every cell in the body. Acetaldehyde also appears to be capable of disrupting thyroid metabolism, possibly by TSH receptor interference (see "Deep Throat"). In situations where there is combined exposure to both methylmercury (even in trace amounts) and yeastreleased acetaldehyde, there may be a synergistic deleterious effect via competition for the resources in the body designed to deal with this type of toxicity (see "Autism"). [1] Roos DH et al., "Complex methylmercury-cysteine alters mercury accumulation in different tissues of mice.", Bas Clin Pharmacol Toxicol. 2010 Oct;107(4):789-92. http://www.ncbi.nlm.nih.gov/pubmed/20486922 [2] Medina VA et al., "Covalent binding of acetaldehyde to hepatic proteins during ethanol oxidation.", J Lab Clin Med. 1985 Jan;105(1):5-10. http://www.ncbi.nlm.nih.gov/pubmed/3968465 [3] Encyclopedia of Reagents for Organic Synthesis, "Acetaldehyde" http://www.wiley.com/legacy/wileychi/eros/acetaldehyde.html [4] Hao Q et al., "Aldehydes release zinc from proteins. A pathway from oxidative stress/lipid peroxidation to cellular functions of zinc.", FEBS J. 2006 Sep;273(18):4300-10. Epub 2006 Aug 23. http://www.ncbi.nlm.nih.gov/pubmed/16930132 [5] Yao CP et al., "Metallothioneins attenuate methylmercury-induced neurotoxicity in cultured astrocytes and astrocytoma cells.", Ann N Y Acad Sci. 1999;890:223-6. http://www.ncbi.nlm.nih.gov/pubmed/10668428 [6] Sugiura Y et al., "Selenium protection against mercury toxicity: high binding affinity of methylmercury by selenium-containing ligands in comparison with sulphur-containing ligands.", Bioinorg Chem. 1978 Aug;9(2):167-80. http://www.ncbi.nlm.nih.gov/pubmed/698281 [7] Franco JL et al., "Methylmercury neurotoxicity is associated with inhibition of the antioxidant enzyme glutathione peroxidase.", Free Radic Biol Med. 2009 Aug 15;47(4):449-57. Epub 2009 May 18. http://www.ncbi.nlm.nih.gov/pubmed/19450679 [8] Usuki F et al., "Post-transcriptional defects of antioxidant selenoenzymes cause oxidative stress under methylmercury exposure.", J Biol Chem. 2011 Feb 25;286(8):6641-9. Epub 2010 Nov 24. http://www.ncbi.nlm.nih.gov/pubmed/21106535 [9] Pivetta LA et al., "Acetaldehyde does not inhibit glutathione peroxidase and glutathione reductase from mouse liver in vitro.", Chem Biol Interact. 2006 Feb 25;159(3):196-204. Epub 2006 Jan 4. http://www.ncbi.nlm.nih.gov/pubmed/16387289 [10] Weiss B et al., "Silent latency periods in methylmercury poisoning and in neurodegenerative disease.", Environ Health Perspect. 2002 Oct;110 Suppl 5:851-4. http://www.ncbi.nlm.nih.gov/pubmed/12426145 [11] Kwada J et al., "Effects of organic and inorganic mercurials on thyroidal functions.", J Pharmacobiodyn. 1980 Mar;3(3):149-59. http://www.ncbi.nlm.nih.gov/pubmed/6451681

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Autism ====== Although much attention has been given to the role of heavy metals in the etiology of autism [1], there is considerable controversy and less than definitive results in this regard. Since there are cases of autism where there has been no detectable level of mercury exposure, either environmentally, through mercury fillings, or the vaccine preservative thiomersal [2]; this is used as an argument that mercury doesn't cause autism. However, enzymatic biochemical pathways that are linked to diseases aren't particular about what is interfering with them in relation to manifestations of the disorder, only that they have been inhibited or impaired. This means that mercury may be one of many causes of autism that block certain critical metabolic pathways that are essential to maintaining the mental alertness that is being compromised. Since mercury does seem to trigger this condition in some individuals, we should be looking for other entities that are also onboard which might share its disruptive profile. Mercury is a heavy metal, a highly electrophilic positive cation that likes to bind to exposed sulfhydryl groups. It can easily drift into and damage cysteine residue enzymatic reaction pockets because of its miniscule size. This behaviour can interfere with critical biochemical pathways by shutting down the enzymes responsible for maintaining them. In a lineup of potential perpetrators (see figures "Acetaldehyde" and "Methylmercury"), acetaldehyde (the pseudo heavy metal) also matches this profile. This is something that everybody is coping with in one way or another as a byproduct of yeast fermentation of carbohydrates with the dosage dependent upon yeast colonization levels. But if everyone has yeast and acetaldehyde can cause autism, then why doesn't everyone have it? This is where the genetic predisposition comes in. Symptoms from chronic acetaldehyde exposure don't manifest until dosage levels and damage approach disease thresholds. Then each individual begins to display a "known" disease based upon the weakest link in their unique genetic profile. Monozygotic twins are much more likely to develop similar autistic disorders than dizygotic twins [3]. So now we have at least two potential causative agents, mercury and acetaldehyde, sharing similar molecular profiles that may be responsible for the autistic suite of symptoms. What is worse is that they may have a synergistic deleterious effect when combined by competing for the resources in the body designed to deal with this type of toxicity. The body has a natural heavy metal chelator in the form of the protein metallothionein [4]. If an individual is fortunate enough to have low background yeast levels, then they may be able to cope with mercury exposure within reasonable limits without showing any adverse effects -- these are the children who get vaccinated (even with thiomersal-preserved products) and are just fine. However, if an individual has a high background yeast level with acetaldehyde emissions that are saturating their metallothionein competence [5], then any incremental exposure to mercury will set off a cascade of negative consequences, possibly including the autism reported subsequent to vaccinations if they are genetically predisposed to this condition. The thionein apoprotein of metallothionein has an abundance of sulfhydryl cysteine residues (see figure "Metallothionein") that function as snares for the reactive oxygen species and toxic metals that can bind to them. Sulfur loci available for binding are also prominent in the proposed structure and mode of action of Wondro (see figures "Wondrenic Acid" and "Wondrenic + Acetaldehyde"). Metallothionein is something that the body has to make via protein synthesis from amino acids with a dependence upon dietary cysteine (or methionine). Both of these amino acid absorption and production pathways are subject to decimation by excess levels of acetaldehyde (see "Toxic Soup" and "When The Backup Fails"). In other words, functional metallothionein may be in short supply because of limited cysteine availability, something that has also been described in relation to autism [6]. As well, the molecules of this precious protein that there are may be just barely coping with daily levels of acetaldehyde exposure.

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This is a recipe for disaster when even the minutest levels of mercury are incrementally added to the mixture. An exposure dosage that would normally be tolerated cannot be scavenged by the underproduced and overloaded metallothionein protective mechanism and spills its toxic presence into critical enzymatic interference. If this trauma concomitantly compromises the immune system's back-pressure on current yeast loads because of neutrophil impairment by mercury [7], then the yeast population may ratchet higher to another tolerance level with a higher daily dosage of acetaldehyde release. Subsequently, even after any detectable levels of mercury have been eliminated [8], the autistic spectrum disorder may persist because of the increased acetaldehyde levels. Mercury (the actual heavy metal), which was the initial trigger of the symptoms may have waned but acetaldehyde (the pseudo heavy metal) remains a daily occurrence. Disruption of serotonin metabolism is common in autism [9] and the monoamine oxidase pathway that regulates the concentration of this neurotransmitter is exquisitely sensitive to acetaldehyde and its metabolites (see "Catecholamines In Chaos"). If the heavy-metal mimicking effects of acetaldehyde are a major factor in the etiology of autism, then we should find situations where autism appears because of treatments that result in higher yeast loads, even in the absence of overt mercury contamination. One such commonality is the prevalence of autism in conjunction with antibiotic treatment for otitis media [10] (see "Mostly Mucus"). If autism is a genetically modulated disorder related to interference with enzymatic sulfhydryl metabolism, precipitated by mercury (via either dental amalgam or thiomersal) and/or yeast-released acetaldehyde exposure, then together with ensuring that mercury contamination is no longer an issue, the treatment focus should be shifted to acetaldehyde scavenging and yeast abatement so that the crucial impacted metabolic pathways may resume normal function.

[1] Desoto MC et al., "Sorting out the spinning of autism: heavy metals and the question of incidence.", Acta Neurobiol Exp (Wars). 2010;70(2):165-76. http://www.ncbi.nlm.nih.gov/pubmed/20628440 [2] Blaxill MF et al., "Thimerosal and autism? A plausible hypothesis that should not be dismissed.", Med Hypotheses. 2004;62(5):788-94. http://www.ncbi.nlm.nih.gov/pubmed/15082108 [3] Bailey A et al., "Autism as a strongly genetic disorder: evidence from a British twin study.", Pschol Med. 1995 Jan;25(1):63-77. http://www.ncbi.nlm.nih.gov/pubmed/7792363 [4] Coyle P et al., "Metallothionein: the multipurpose protein.", Cell Mol Life Sci. 2002 Apr;59(4):627-47. http://www.ncbi.nlm.nih.gov/pubmed/12022471 [5] Hao Q et al., "Aldehydes release zinc from proteins. A pathway from oxidative stress/lipid peroxidation to cellular functions of zinc.", FEBS J. 2006 Sep;273(18):4300-10. Epub 2006 Aug 23. http://www.ncbi.nlm.nih.gov/pubmed/16930132 [6] Suh JH et al., "Altered Sulfur Amino Acid Metabolism In Immune Cells of Children Diagnosed With Autism", Science Publications (2008). http://en.scientificcommons.org/46275754 [7] Worth RG et al., "Mercury inhibition of neutrophil activity: evidence of aberrant cellular signalling and incoherent cellular metabolism.", Scan J Immunol. 2001 Jan;53(1):49-55. http://www.ncbi.nlm.nih.gov/pubmed/11169206

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Friendly Giant =========== A precious few aldehydes in the body are essential to its function. Compared to acetaldehyde, pyridoxal (the active form of vitamin B6) is a large cyclic molecule with the aldehyde group as a side chain (see figure "Acetaldehyde and Pyridoxal-5'-phosphate). The high reactivity of the carbonyl group present is exploited to advantage in pyridoxal phosphate (PLP) dependent enzymes. Although essential to amino group transfer, decarboxylation, interconversion, and sundry manipulation of amino acids, the reactivity of this "friendly giant" must be held in abeyance until it is needed. It has been shown that while acetaldehyde has no effect on the synthesis of pyridoxal phosphate, it may accelerate its degradation by displacing this co-enzyme from binding proteins which protect it against hydrolysis [1]. Acetaldehyde has thus assumed another deleterious role by interfering with cellular reserves of a vital nutritional component . This can lead to deficiency symptoms which are indistinguishable from an actual paucity of dietary intake. One of the cellular detoxification pathways for acetaldehyde is oxidation via the enzyme aldehyde dehydrogenase which emits acetic acid. Although normally considered to be a harmless molecular configuration relative to its parent aldehyde, accumulation of this weak acid, when acetaldehyde levels are high and chronic, can upset the pH balance of the cell [2]. Even the acetate itself may have a negative impact on PLP-based enzymes. Acetate has been shown to inhibit the recombination of PLP with glutamate apodecarboxylase [3]. When a cargo ship docks with the space station it must approach and latch with the hatch at just the right angle and alignment so that a good seal is obtained, its cargo can be transferred, and it can be dispatched for the return journey. Something similar happens within enzymes in the body where molecules temporarily attach themselves to latch points in the protein structure so that the desired chemical reaction may occur. If the substrates cannot position themselves properly within the enzyme, the chemical reaction that is essential just won't happen. A common "latch" point in many of the diverse enzymes that utilize PLP as a cofactor is the amino group of an active site lysine amino acid. The aldehyde portion of PLP forms a Schiff base (carbon-nitrogen double bond) with the lysine residue (see figure "Enzyme Lysine Residue Pyridoxal-5'-phosphate Schiff Base"). In the cellular "inner space" small freely floating molecules of acetaldehyde have no problems drifting into reaction pockets of enzymes. For PLP reactive enzymes, they can form the Schiff base with the lysine residues, prevent PLP from assuming its requisite position in the enzymes and effectively render the enzymes useless [4] (see figure "Enzyme Lysine Residue Acetaldehyde Schiff Base"). Structural ejection mechanisms that would normally recycle the enzyme for another reaction may not be able to remove the tiny acetaldehyde molecules which remain there as permanent inhibitors of the enzymatic pathways. In the space station analogy, think of a small piece of space junk getting stuck in the cargo bay seals preventing a uniform docking maneuver. The aldehyde commonality between acetaldehyde and PLP means that not only can acetaldehyde create a deficiency state of PLP even in the presence of adequate dietary intake, it can shut down enzymatic PLP-dependent pathways even when PLP is sufficiently available as a co-factor. Deficiency symptoms can then be expected to manifest that may respond to higher than normal intake of B6, something that attempts to compensate for this disruption. However, even the conditions that appear to be associated with a B6 deficiency may not be completely resolved by B6 supplementation alone. This confusion arises since the disruptive influence of acetaldehyde includes but is not limited to PLP. Acetaldehyde is interfering with other essential biochemical functions as well. This is why scavengers (such as Wondro) that intercept the acetaldehyde before it has had a chance to attack vulnerable pathways or antifungals (such as garlic) that reduce the production of acetaldehyde or energetic signals (such as homeopathic sulphur) that shift yeast from its budding fermentative state appear to achieve superior results in a wide variety of conditions. They are working at the upstream source of the difficulty,

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Acetaldehyde

Pyridoxal-5'-phosphate

Enzyme Lysine Residue Pyroxidal-5'-phosphate Schiff Base

Enzyme Lysine Residue Acetaldehyde Schiff Base

145

rather than downstream at the level of the deficiency symptoms. Chasing the symptoms using drugs or nutritional supplements only provides temporary relief since the sporadic low-dosage acetaldehyde exposure continues uninterrupted. The Enzyme Commission [5] list of PLP-dependent activities [6] is hundreds of entries in length. Of these pathways each and every one that is present in the body is a potential candidate for acetaldehydemediated PLP interference. As well, since many PLP-dependent enzymes are working at the level of amino (fundamental building blocks of proteins) group transfer and conversion, a critical precursor step in a multi-step pathway may be impaired. This means that the subsequent enzymatic processes may also be affected even though they are not specifically dependent upon PLP themselves. PLP deficiency has been causally implicated in several clinical disorders in the alcoholic patient, including peripheral neuropathy [7], convulsions [8], sideroblastic anemia [9], and liver disease [10]. Acetaldehyde is an intermediate in the hepatic enzymatic breakdown of ingested alcohol but even low levels of yeastreleased acetaldehyde may be just as, or even more, damaging because of the locales where it is released by colonizing yeast cells. [1] Lumeng L, "The Role of Acetaldehyde in Mediating the Deleterious Effect of Ethanol on Pyridoxal 5'Phosphate Metabolism", J Clin Invest. 1978 August; 62(2): 286293. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC371765 [2] Roe et al., "Perturbation of Anion Balance during Inhibition of Growth of Escherichia coli by Weak Acids", J Bacteriol. 1998 February; 180(4): 767772. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC106953 [3] Fonda ML, "The effect of anions on the interaction of pyridoxal phosphate with glutamate apodecarboxylase.", Archi Biochem Biophys. 1975 Oct;170(2):690-7. http://www.ncbi.nlm.nih.gov/pubmed/242264 [4] Mauch TJ et al., "Covalent binding of acetaldehyde selectively inhibits the catalytic activity of lysinedependent enzymes.", Hepatology. 1986 Mar-Apr;6(2):263-9. http://www.ncbi.nlm.nih.gov/pubmed/2937708 [5] Moss GP, "Enzyme Nomenclature", School of Biological and Chemical Sciences, Queen Mary University of London. http://www.chem.qmul.ac.uk/iubmb/enzyme/ [6] Ibid., "pyridoxal" http://www.googlesyndicatedsearch.com/u/queenmary?q=pyridoxal&hl=en&hq=inurl:www.chem.qmul.ac. uk/iubmb/enzyme&ie=UTF-8&prmd=ivns&ei=GMdGUP6lKcfhiwLd54HoAQ&start=10&sa=N [7] Dellon AL et al., "Experimental model of pyridoxine (B6) deficiency-induced neuropathy.", Ann Plast Surg. 2001 Aug;47(2):153-60. http://www.ncbi.nlm.nih.gov/pubmed/11506323 [8] Lerner AM et al., "Association of pyridoxine deficiency and convulsions in alcoholics.", Proc Soc Exp Biol Med. 1958 Aug-Sep;98(4):841-3. http://www.ncbi.nlm.nih.gov/pubmed/13591361 [9] Hines JD et al., "Studies on the pathogenesis of alcohol-induced sideroblastic bone-marrow abnormalities.", N Engl J Med. 1970 Aug 27;283(9):441-6. http://www.ncbi.nlm.nih.gov/pubmed/5434110 [10] Labadarios et al., "Vitamin B6 deficiency in chronic liver disease--evidence for increased degradation of pyridoxal-5'-phosphate.", Gut. 1977 January; 18(1): 2327. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1411256

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Acetaldehyde Game ================ Let's play a combination game of "pictionary" and "find Waldo" to see if we can transfer the information gained from the side-trip into industrial acetaldehyde scavenging (see "Soda-Pop Stowaway") to good use in a medical context. In this game we'll be looking for molecular group similarities (the pictionary part) that might provide attractive binding sites for acetaldehyde (Waldo). Although folic acid (vitamin B9) is an essential dietary requirement of everyone, it is particularly important during pregnancy where deficiencies are linked to fetal neural tube defects involving the brain and spinal cord [1] (see figure "Folic Acid"). A prominent and recurrent feature of the industrial acetaldehyde scavengers examined previously is the presence of the amino group (-NH2) where the nitrogen provides an attractive binding site (e.g. 1,8diaminonaphthalene). Does folic acid have an exposed amine group that might be vulnerable to interaction with acetaldehyde? Indeed, acetaldehyde may form a Schiff base (C=N) with the trailing amine (without cyclization in this case). "Waldo" (aka acetaldehyde) has attached itself to the end of the folic acid molecule (see figure "Acetaldehyde + Folic Acid"). Acetaldehyde has been caught interfering with the enzymatic cofactor roles of vitamins before in the case of pyridoxal (vitamin B6) where it has the potential for forming a Schiff base with the lysine residue amino attachment point for the vitamin in several different enzymes (see "Friendly Giant"). This time, by forming a Schiff base with folic acid itself, it can also interfere with the critical functions of this vitamin. If acetaldehyde gums up either the structure of an enzyme or the structure of a critical substrate that is supposed to fit into a reaction pocket, then the result is the same: a dysfunctional biochemical pathway. Since the body uses folate to synthesize DNA, repair DNA, and methylate DNA, this provides yet another link from acetaldehyde exposure to dis-regulation of cellular maintenance and ultimately to cancer [2] (see "Cellular Mayhem"). Even when dietary or supplementary folate intake is adequate, a high commensal yeast load releasing acetaldehyde may result in a functional folate deficiency. As well as fetal defects and cancer, this could lead to glossitis (inflammation of the tongue), diarrhea, depression, confusion, and anemia. Folate deficiency that manifests even when classical measurement of blood concentrations, peripheral blood, and bone marrow examinations appear to be normal is recognized in alcoholic patients where high acetaldehyde levels are associated with the incomplete metabolism of ethanol [3]. When acetaldehyde is metabolized by xanthine oxidase (a molybdenum-based enzyme) it can generate the superoxide anion reactive oxygen species capable of cleaving folate [4] (see "Reactive Oxygen Species"). Since folic acid and cobalamin are closely coupled, both in their functionality and deficiency symptoms consider the configuration of the largest and most structurally complex vitamin (see figure "Cobalamin"). Note that there are six amide side groups (-CONH2) surrounding a cobalt-containing ring. This amide group also appears in the list of industrial acetaldehyde scavengers (e.g. salicylamide and malonamide). One of the simplest amides, acetamide (see figure "Acetamide") reacts with acetaldehyde to form ethylidene-N,N-diacetamide [5] (see figure "Ethylidene-N,N-diacetamide"): CH3CHO + 2 CH3CONH2 --> (CH3CONH)2CHCH3 + H2O This suggests that any one or all of the amide side chains of cobalamin (like red-wigglers angling for bass) could become targets of acetaldehyde attack with loss of vitamin B12 structure and activity potential. Cobalamin plays a role in brain and nervous system functioning, fatty acid synthesis and energy production, and like folate is involved in DNA synthesis and regulation. Early biomarkers of B12 deficiency include teeth clenching and myoclonic jerking including tics, twitches, and "sleep starts". No fungi, plant, nor animal can synthesize this vitamin, making it particularly vulnerable to deficiency in restrictive or nonsupplemented diets that avoid foods containing B12 from a bacterial source.

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Folic Acid (Vitamin B9)

Acetaldehyde Schiff Base Formation

Acetaldehyde + Folic Acid

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Cobalamin (Vitamin B12)

Acetamide

Ethylidene-N,N-diacetamide

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By tapping into the energy field involved in the absorption, transport, and delivery of nutrients in the body, an OPK (Orthomolecular Psychokinesiology) test with a kinesiology hand grip can tell you non-invasively in a few seconds whether either B9 or B12 or both are deficient (see "Deficient Or What?" and "PseudoDeficiencies" in "Astrophysiology... and Yeast"). Whether we have realized it or not; yeast, acetaldehyde and disease have been enmeshed for eons. This means that a host of somewhat unorthodox remedial techniques may have arisen by trial and error for dealing with this conceptual triad. Urophagia is the consumption of urine and urine therapy has been used by many cultures throughout history for medicinal purposes. All amino acids are nitrogen-containing substances. Numerous pathways in the body lead to the urea cycle which produces urea as a disposal technique for excess nitrogen and ammonia (NH3) that can raise cellular pH values to toxic levels. Urea is a symmetrical amide (see figure "Urea"). Our game's pictionary skills might suggest that this substance would also be a good candidate for reaction with acetaldehyde -- this is true. Acetaldehyde will react with both amine groups of urea to form ethylidenediurea [6] where "Waldo" is now sandwiched between two urea molecules and has lost its aldehyde reactivity (see figure "Ethylidene-diurea"). CH3CHO + 2 NH2CONH2 <--> NH2CONH-CH(CH3)-NHCONH2 + H2O Although the ingestion of urine may provide some relief from yeast-released acetaldehyde via the ethylidenediurea reaction, there are numerous negative aspects associated with this practice. Considering that the body has carefully accumulated and solubilized the contents of urine for removal, putting these waste byproducts back into the system may not only upset the body's hydration balance but also reintroduce toxins and pathogens that should have been excreted. However, the message from MMS and hydrogen peroxide (see "Message From MMS?") and dirt (see "Scavenger Hunt -- Dirt For Dessert") and now urea is that the healing aspects of these potentially toxic substances could be attributed to their interactions with yeast-released acetaldehyde and that there are better ways of dealing with the problem (for instance, see "Scavenger Hunt / An Apple A Day." for ethylidene cross-linking of polyphenols). [1] Pitkin RM, "Folate and neural tube defects.", Am J Clin Nutr. 2007 Jan;85(1):285S-288S. http://www.ncbi.nlm.nih.gov/pubmed/17209211 [2] Homann N et al., "Microbially produced acetaldehyde from ethanol may increase the risk of colon cancer via folate deficiency.", Int J Cancer. 2000 Apr 15;86(2):169-73. http://www.ncbi.nlm.nih.gov/pubmed/10738242 [3] Gimsing P et al., "Vitamin B-12 and folate function in chronic alcoholic men with peripheral neuropathy and encephalopathy.", J Nutr. 1989 Mar;119(3):416-24. http://www.ncbi.nlm.nih.gov/pubmed/2537891 [4] Shaw S et al., "Cleavage of folates during ethanol metabolism. Role of acetaldehyde/xanthine oxidasegenerated superoxide.", Biochem J. 1989 Jan 1;257(1):277-80. http://www.ncbi.nlm.nih.gov/pubmed/2537625 [5] Noyes et al., "AldehydeAmide Condensation. I. Reactions between Aldehydes and Acetamide", J. Am. Chem. Soc., 1933, 55 (8), pp 34933494 http://pubs.acs.org/doi/abs/10.1021/ja01335a085 [6] Ogata et al., "Kinetics of the Condensation of Urea with Acetaldehyde", J. Org. Chem., 1965, 30 (5), pp 16361639 http://pubs.acs.org/doi/abs/10.1021/jo01016a076

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Ethylidene-diurea

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Cellular Electron Ping-Pong ===================== Electron ping-pong (the transfer of electrons between substances) is so germane to the life biochemistry of organisms that numerous redox (reduction/oxidation) pools are maintained by the body to facilitate the supply and demand for electrons. Reducing agents are electron donors, losing electrons to become oxidized while oxidizing agents are electron acceptors, gaining electrons to become reduced. Antioxidants, such as ascorbate (vitamin C), are reducing agents that help prevent inappropriate oxidation which can spawn free radical chain reactions that are damaging to the body. It has been suggested in this work that the apparent requirement for excessive amounts of supplementary antioxidants in so many cases is a consequence of the the disruption of the balance of paired-substance redox pools by the acetaldehyde released by C. albicans when it is fermenting carbohydrates (see "Reactive Oxygen Species -- Cysteine/Cystine" and "Double-Edged Sword -- Glutathione/Glutathione Disulphide"). Another significant resource in this regard is nicotinamide adenine dinucleotide, a coenzyme used in balancing the redox requirements of cellular respiration via the NAD+/NADH redox pool.

Nicotinamide. Niacin and nicotinamide are both forms of vitamin B3, precursors to NAD (see figures "Niacin" and "Nicotinamide"). Based upon the experience gained in spotting an acetaldehyde scavenger (see "The Acetaldehyde Game") which molecular configuration, niacin or nicotinamide, would be more likely to react with acetaldehyde? Remembering the amide structure of urea which formed ethylidene-diurea with acetaldehyde, in a like fashion, acetaldehyde may form a Schiff base with nicotinamide (see figure "Acetaldehyde Nicotinamide Schiff Base Formation") or cross-link two nicotinamide molecules to give a dinicotinamide (see figure "Ethylidene-N,N'-dinicotinamide"). In either case acetaldehyde has lost its dangerous aldehyde reactivity. Although this protects other body structures and processes, it has also denatured some of the body's precious vitamin B3 resources which, in extreme situations, may lead to a deficiency condition, pellagra. Pellagra, with a long list of symptoms including diarrhea, dermatitis, and dementia, was a scourge in the world until the 1930's when its association with niacin deficiency was established. Since acetaldehyde is also reacting with just about anything it comes in contact with, an advanced recognizable B3 deficiency state because of the nicotinamide reaction is unlikely except when the diet is severely deficient as well. This may be why the treatment of arthritis [1], hyperactivity [2] and schizophrenia [3] with megadoses of nicotinamide and niacin (which is converted into nicotinamide in the body) by Abram Hoffer back in the 1950's was met with so much criticism. A deficiency condition requiring such high dosages would be rare. However, from the perspective of this study, in the cases that Hoffer treated with this nutrient, the excess nicotinamide may have been functioning as an acetaldehyde scavenger rather than in its role as as essential vitamin. In retrospect, this implicates a connection between these apparently unrelated diseases with acetaldehyde and its yeast source as the common factor. This shouldn't come as a surprise given the reactivity of acetaldehyde elucidated in this work. Cellular respiration, involving the oxidation of sugar, amino acids, or fatty acids in the presence of molecular oxygen, takes place in every cell of the body to charge the cellular "batteries", molecules of adenosine triphosphate (ATP) which can release their stored energy later and in other places to accommodate a cell's daily routine of activities. The fundamental activity of cellular respiration is dependent upon the vitamin B3 derivative coenzyme nicotinamide adenine dinucleotide, NAD+, which facilitates the required exchange of electrons in redox reactions (see figure "Nicotinamide Adenine Dinucleotide").

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Niacin

Nicotinamide

Acetaldehyde Nicotinamide Schiff Base Formation

Ethylidene-N,N'-diacetamide

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Since chemical reactions involve movement of electrons in both directions between different molecular configurations, this coenzyme is found in two forms in cells: NAD+ is an oxidizing agent, accepting electrons from other molecules to become reduced; and NADH, a reducing agent which can subsequently donate its electrons by becoming oxidized. The cellular ping-pong between these two agents is an ongoing and critical part of many chemical reactions in the body (see figure "NAD+/NADH Reduction/Oxidation Reaction) and a regulated NAD+ to NADH ratio, the redox state, is crucial for overall stability of an organism. We have already explored what might happen to the exposed amide and amine groups on cobalamin (B12) and folic acid (B9) in relation to acetaldehyde exposure. NAD+ and related coeznyme NAD(P)+, which has an additional phosphate group on the adenine ribose ring, contain both an exposed amide and an exposed amine group that may be attractive to acetaldehyde (see figure "Acetaldehyde NAD+ Schiff Base Formation"). The body's own superfamily of nineteen aldehyde dehydrogenase enzymes [4], for shifting harmful aldehydes to their corresponding carboxylic acids, are NAD(P)+ dependent with an aldehyde-binding sulphur atom in a cysteine residue at the active site. CH3CHO + NAD(+) + H2O --> CH3COOH + NADH + H(+) Aldehydes which aren't handled adequately can react both locally and remotely through diffusion or transportation to other sites. When aldehyde dehydrogenase activity is impaired or genetically dysfunctional, then numerous diseases related to their cytotoxic, mutagenic, or carcinogenic attributes may manifest [5]. Studies on other organisms indicate that alcohol and aldehyde dehydrogenase activity are closely coordinated, something that minimizes the cellular exposure time to free aldehydes [6]. Spontaneous appearance of acetaldehyde emanating from yeast cells must be somewhat of a shock to the body with the result that its innate ability to scavenge it soon enough and rapidly enough is overloaded and in need of assistance. What it does manage to process will push the NAD+/NADH ratio towards the reduced form. Additionally, the appearance of rogue acetaldehyde molecules reacting with amide/amine groups on NAD+/NADH may further corrupt and skew the redox state of the body. This is something which could prevent the optimal functioning of all aldehyde dehydrogenase pathways in the body. In other words, even if the acetaldehyde emitted by yeast doesn't actually reach the cells in an area of the body where a disease like cancer is a potential threat, it may disrupt the body's redox state (NAD+/NADH ratio) sufficiently to indirectly increase the risk of disease everywhere. Although nicotinamide supplementation can help rectify the NAD+/NADH balance [7] and potentially scavenge acetaldehyde by binding directly to it, it may not be the best choice for an acetaldehyde scavenger. The megadose quantities required for effective scavenging may interfere with its alter ego as a nutrient, i.e. megadose quantities can inappropriately accelerate enzymatic pathways and lead to an imbalance of cofactor depletion in a manner similar to the use of megadose antioxidant supplementation for scavenging free radicals (see "Daily Apple Snack" in "Astrophysiology... and Yeast"). Given the staggering capability of yeast for production and emission of acetaldehyde (see "Just A Teaspoon Of Sugar") and the fact that each molecule of this toxin has the potential for inflicting damage, then the situation assumes a statistical probabilistic nature. Increasing the concentration of an ingested substance, any ingested substance, that harmlessly binds to acetaldehyde, reduces the probability of toxin-mediated damage to other critical areas and hence relieves the stressors that are leading to disease. This would explain why the results obtained by Hoffer were dependent upon megadose quantities of nicotinamide far above the normal nutritional requirements. The level of scavenging required, of course, is related to the yeast load emitting the toxin -- the less yeast, the less emitted acetaldehyde, and the less scavenging that is necessary.

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Nicotinamide Adenine Dinucleotide

NAD+/NADH Oxidation/Reduction Reaction

Acetaldehyde NAD+ Schiff Base Formation

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Tryptophan. The NAD+/NADH balance is so critical that the body has a backdoor pathway for the production of vitamin B3, niacin, the precursor to NAD+. The liver can convert the dietary essential amino acid tryptophan to niacin in a multi-step pathway with support from cofactors riboflavin, pyridoxal and iron (see figure "Tryptophan To Niacin Backdoor Synthesis Pathway"). Right out of the starting gate in this sequence there is a potential problem when C. albicans levels are too high. The beta-carboline formed by the Pictet-Spengler condensation reaction of acetaldehyde with tryptophan (see figure "Tryptophan + Acetaldehyde -- 3-MTBC") can not only remove the raw material amino acid, but also inhibit the enzyme indoleamine 2,3-dioxygenase (IDO). Removing tryptophan is on a one to one basis (one acetaldehyde, one lost tryptophan) but the enzyme inhibition potentially has a much greater impact. Although one betacarboline may inhibit one IDO, one IDO enzyme is responsible for converting a host of tryptophan substrates (see "Enzyme Killer"). The overall effect is that the backdoor niacin synthesis pathway may be blocked or severely impaired. Tryptophan is such a key player in so many critical biochemical pathways, including the neurotransmitter serotonin and the neurohormone melatonin, that any interference with its reactions results in a cascade of consequences. The autoimmune disease ramifications of IDO inhibition in relation to the prevention of tryptophan starvation of T-cells, something absolutely necessary for immune system quiescence postinfection, have already been explored (see "Tryptophan Starvation"). With the potential blockage of the tryptophan to niacin pathway by acetaldehyde, there are now at least five different ways in which acetaldehyde from C. albicans can interfere with the NAD+/NADH balance: aldehyde dehydrogenase processing of acetaldehyde requires a NAD+ to NADH shift, potentially skewing the balance when acetaldehyde levels are high acetaldehyde can form a Schiff base with the amide group and denature nicotinamide, a precursor to NAD+ acetaldehyde can form Schiff bases with the exposed amine and amide groups of NAD+/NADH directly removing either of the pair from the redox pool 3-MTBC (the tryptophan/acetaldehyde beta-carboline) diminishes the availability of the essential amino acid tryptophan used in the backdoor pathway from tryptophan to niacin, something required to replenish a depleting NAD+/NADH redox pool, especially when vitamin B3 intake is insufficient even when tryptophan is available, 3-MTBC can inhibit the IDO enzyme which converts it to N'-formylkynurenine, the first step In the backdoor pathway from tryptophan to niacin

OPK and NAD+/NADH Balance. Orthomolecular Psychokinesiology (OPK) techniques for using muscle strength as a biofeedback indicator of dynamic nutrient activity in the body (see "Orthomolecular Psychokinesiology" in "Astrophysiology and Yeast") are not only applicable to the raw materials (vitamins and minerals) currently being sought after and utilized. Any biochemical process in the body can be queried through visualization to determine its status. The NAD+/NADH balance is no exception. Adjust the hand grip so that it can just be compressed. Then visualize, in turn, NAD+ and NADH, and compress the squeezer for each to see if you get stronger or weaker. If both NAD+ and NADH are balanced, as they should be, then neither should return an easier-to-compress result. If one returns a stronger response and the other a weaker, then there may be a problem.

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Tryptophan To Niacin Backdoor Synthesis Pathway

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When NAD+ is too low mood symptoms include depression and anxiety; but when NAD+ is too high the symptoms shift to agitation and mania -- a form of bipolar disorder. Normally, the ratio of this redox pool is so closely regulated that both NAD+ and NADH are available on demand. However, if a situation arises which upsets the balance beyond a certain threshold, especially when acetaldehyde levels are interfering with the re-stabilizing processes, then the body appears to have a problem re-establishing the appropriate equilibrium. It overcompensates, shifting first into a state with too much NAD+ and then into too much NADH, either at one extreme or the other. The amazing aspect of OPK is that it is often possible to rectify this balance using a visualization alone without any additional supplementation. Again adjust the hand grip so that it can just be compressed. Then continue to compress it, visualizing each of NAD+ and NADH in turn like a seesaw, until each returns a harder-to-compress result. The sensation is a bit like pumping up a deflated bicycle tire until you can feel a consistent feedback pressure for both. Mood symptoms should respond almost immediately. The energetics of what is transpiring are not well understood. However, the fact that symptomatic improvement occurs very rapidly indicates that the body already has the necessary resources required to correct the imbalance. It is almost as if the imbalance is not being recognized as such until the visualizations superimpose a psychic homeopathic signal onto the body's energy field, thus alerting it to the fact that its biochemistry is out of kilter. A similar phenomenon has been noticed in regards to absorption kinetics from the gastrointestinal tract. One prodromal biomarker for insufficient vitamin B3 availability in the body is under-arm wetness even in the absence of physical exertion. This may surface after the intake of a large proportion of foods with high vitamin A content, e.g. fish, without adequate B-vitamin support. Often this can be the result of an absorption imbalance that can be rectified just by OPK testing for the deficiency without additional supplementation (see "Pseudo Deficiencies" in "Astrophysiology and Yeast"). Adjust the hand grip so that it can just be compressed. Then squeeze it, thinking of niacin, and continue to do so until the apparent tension in the hand grip increases. If this does not occur within a few compression tests, then additional supplementation of vitamin B3 may be required.

Light Therapy and NAD+/NADH Balance. A cautionary note on the usage of the natural light therapy device Litebook website [8] indicates that, in some cases, mania ("periods of abnormally and persistently elevated, expansive or irritated mood") may be experienced after exposure to the intense LED light. OPK testing has shown that this corresponds to elevated levels of NAD+ in relation to the NAD+/NADH balance. This imbalance is less likely to occur if the light source is positioned so that the light impinges upon the eyes from above instead of from below. This suggests that the angle of incidence of the light is just as an important factor in the biochemistry involved as the light itself. Since sunlight shines from above in the sky, mimicking the positioning of exposure is just as important as the wave length and brightness composition of the source.

Bipolar Disorder. If the yeast-disrupted NAD+/NADH balance model of bipolar disorder has merit, then there should be confirmation obtainable by examining the current molecular therapeutic techniques prescribed for this condition. Bipolar therapy uses mood stabilizing substances in an attempt to reverse the manic or depressive episodes.

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Lithium Carbonate

Valpromide (Depamide)

Valpromide + Acetaldehyde

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Lithium Carbonate. Lithium carbonate has been used to treat depression since 1886 (see figure "Lithium Carbonate"). The polar nature of acetaldehyde allows the formation of coordination complexes with metal cations such as lithium [9] and when acetaldehyde has formed its enolate ion (see "Scavenger Hunt -- Enolate Ion") it may combine with lithium to form the lithium enolate of acetaldehyde [10] (see figure "Lithium Acetaldehyde Enolate"). A multi-layer oxygen scavenging film with neutralizing compounds for by-products such as reactive aldehydes is described in an industrial patent [11]. Carbonates of Group IA and IIA elements are considered to be suitable for trapping acids, alcohols, and aldehydes. Lithium carbonate would fall into this category. Therapeutic administration of lithium carbonate could lead to the disappearance of acetaldehyde from its damaging form via any or all of these pathways. Carbonate ions, CO3(--), are also efficient catalysts for the aldol condensation of carbonyl compounds [12]. Since an acetaldehyde to acetaldehyde aldol condensation can lead to crotonaldehyde (see "Scavenger Hunt -- Crotonaldehyde"), this is not necessarily beneficial since crotonaldehyde is still harmful to biological systems [13]. Lithium has also been shown to be able to trigger dissociation of C. albicans [14] and to suppress the morphogenesis and growth of this yeast [15]. This would reduce the levels of acetaldehyde released by its fermentation process (see "Pushmi-Pullyu" in "Astrophysiology... and Yeast"). Lithium is a highly reactive hydrophilic substance with reported side effects including diabetes mellitus, depression, weight gain, type 2 diabetes mellitus, drug interaction, tremor, nausea, anxiety, vomiting [16]. Other side effects may include diarrhea, drowsiness, tinnitus, polyuria and thirst. Valpromide. Valpromide (Depamide) is a carboxamide (see figure "Valpromide") used in the treatment of epilepsy and some affective disorders. Reported side effects include fall, drug interaction, thrombocytopenia, malaise, hypotension, tachycardia, respiratory distress, pyrexia [17]. The amide group is an attractive binding point for acetaldehyde as we have seen previously (see "SodaPop Stowaway" and "Acetaldehyde Game"). We might expect valpromide to neutralize acetaldehyde via the formation of a Schiff base (see figure "Valpromide + Acetaldehyde"). This would be an off-label action of this drug reducing the impact of acetaldehyde on the NAD+/NADH balance. Carbamazepine. Carbamazepine (Tegretol) is another anticonvulsant and mood-stabilizing drug (see figure "Carbamazepine") used for epilepsy and bipolar disorder as well as trigeminalneuralgia. Its off-label usage includes attention-deficit hyperactivity disorder (ADHD), schizophrenia, phantom limb syndrome, complex regional pain syndrome, paroxysmal extreme pain disorder, neuromyotonia, intermittent explosive disorder, borderline personality disorder, and post-traumatic stress disorder. The fact that it is used for such a wide suite of off-label conditions strongly hints of a hitherto unrecognized commonality between these conditions -- acetaldehyde toxicity perhaps? Reported side effects include convulsion, pyrexia, dizziness, nausea, vomiting, rash, somnolence, drug interaction, headache, pain [18]. Both valproic acid and carbamazepine are linked to neurodevelopmental problems including spina bifida when used during pregnancy [19]. It might also be expected to couple with acetaldehyde (see figure "Carbamazepine + Acetaldehyde"). The reduction of acetaldehyde levels by both valproic acid and carbamazepine is not an unknown effect and has actually been studied in relation to alcoholic post-intoxication syndrome normalization of biogenic amines including adrenaline, noradrenaline, dopamine, serotonin (tryptophan derivative), 5-hydroxyindoleacetic acid and histamine in the brain and blood [20] (see "Catecholamines In Chaos" and "Caught In A Loop").

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Carbamazepine (Tegretol)

Carbamazepine + Acetaldehyde

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Lamotrigine

Lamotrigine + Acetaldehyde

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Lamotrigine. Lamotrigine is an anticonvulsant drug (see figure "Lamotrigine") used in the treatment of epilepsy and bipolar disorder with off-label usage for depression. Possible side effects include dizziness, drowsiness, headache, blurred/double vision, loss of coordination, shaking (tremor), nausea, vomiting, upset stomach, depression, suicidal thoughts/attempts, or other mental/mood problems, rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, and trouble breathing [21]. Lamotrigine has two amine side chains available for acetaldehyde binding (see figure "Lamotrigine + Acetaldehyde").

Topiramate. Topiramate is a sulfonamide anticonvulsant (see figure "Topiramate"). used to treat epilepsy and bipolar disorder. It is most frequently prescribed for migraines. Common side effects of topiramate are tiredness, dizziness, coordination problems, nervousness, nausea, weight loss, confusion, speech problems, changes in vision or double vision, eye pain, tingling or prickling sensation in hands and feet, difficulty with memory, and sensory distortion [22]. Electron-rich sulfonamides react readily with acetaldehyde (see figure "Topiramate + Acetaldehyde"). ~~~~~~~~~~ This investigation strongly suggests that at least some, if not all, of the effectiveness of the known treatments for bipolar disorder are related to their ability to scavenge acetaldehyde or to impair its production from C. albicans [23]. If this is the case, then an alternate treatment regimen aimed directly at these causative agents could provide similar improvement and control without the side effects associated with many of the drug-based therapies. Many drugs are designed to target particular enzymatic pathways with the intent of inhibiting those that are apparently out of control. This runs the risk of side effects that occur because of the introduction of a foreign substance that has other biochemical interactions besides those intended. Not all of these are necessarily deleterious. If the drug has a side chain that is attractive for acetaldehyde binding, then the effects of this toxin and its downstream consequences will be reduced. In clinical trials this off-label effect may provide false positive confirmation that a drug is actually acting as expected with symptoms responding favorably, but for other reasons. Vitamins, minerals, and amino acids, on the other hand, tend to stimulate enzymatic pathways but, in large non-nutritional dosages, can also create peripheral symptoms because of cofactor depletion. Again if the nutrient (e.g. nicotinamide or cysteine) has a molecular configuration that renders acetaldehyde benign, then beneficial effects may ensue. Other substances that do not fall into either of these clinical categories (e.g. MMS or hydrogen peroxide) can also produce results by neutralizing acetaldehyde but at the risk of their own toxic profiles. Wondrenic/wondreic acids (sulphurated linolenic/linoleic acids) were neither drugs nor nutrients and appear to function as acetaldehyde scavengers without enzymatic inhibition or over-stimulation. The common factor in all of these scenarios is the interaction of the substance with acetaldehyde before this toxin has had a chance to react with something else essential to bodily function. As the list of conditions whose biochemical profiles can be traced back to acetaldehyde toxicity gets longer and longer, it should be obvious by now that this commensal yeast problem is more than just something experienced by a subset of immunocompromised humanity.

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Topiramate

Topiramate + Acetaldehyde

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Truss was right [24] -- C. albicans is at the root of a global acetaldehyde pandemic aggravated by the exponential increase in the use of antibiotics without a concomitant fungistatic protocol! Given the multifaceted disruptive influences of acetaldehyde on all bodily functions, including the immune system, prior cumulative exposure to this toxin may be one of the reasons that antibiotics are indicated in so many situations, something which leads to a vicious cycle of acetaldehyde- and antibiotic-induced immunodegradation. The factors that obfuscate this are first, that this organism can be cultured from asymptomatic individuals and second, that those who do succumb to the cumulative effects of acetaldehyde poisoning do so in a host of different ways manifesting a specifically diagnosable end-disease (or diseases) based upon their level and locale of yeast colonization, their innate acetaldehyde scavenging insufficiency, and in-born genetic vulnerabilities.

[1] Hoffer A, "Treatment of Arthritis by Nicotinic Acid and Nicotinamide", Can Med Assoc J. 1959 August 15; 81(4): 235238. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1831040 [2] Hoffer A, "Letter: Hyperactivity, allergy and megavitamins.", Can Med Assoc J. 1974 November 2; 111(9): 905907. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1955901 [3] Hoffer A et al., "Treatment of schizophrenia with nicotinic acid and nicotinamide.", J Clin Exp Psychopathol. 1957 Apr-Jun;18(2):131-58. http://www.ncbi.nlm.nih.gov/pubmed/13439009 [4] Marchitti SA et al., "Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily.", Expert Opin Drug Metab Toxicol. 2008 Jun;4(6):697-720. http://www.ncbi.nlm.nih.gov/pubmed/18611112 [5] Lindahl R, "Aldehyde dehydrogenases and their role in carcinogenesis.", Crit Rev Biochem Mol Biol. 1992;27(4-5):283-335. http://www.ncbi.nlm.nih.gov/pubmed/1521460 [6] Eisses KT et al., "Dual function of the alcohol dehydrogenase of Drosophila melanogaster: ethanol and acetaldehyde oxidation by two allozymes ADH-71k and ADH-F.", Mol Gen Genet. 1985;199(1):76-81. http://www.ncbi.nlm.nih.gov/pubmed/3158799 [7] Volpi E et al., "Nicotinamide counteracts alcohol-induced impairment of hepatic protein metabolism in humans.", J Nutr. 1997 Nov;127(11):2199-204. http://www.ncbi.nlm.nih.gov/pubmed/9349848 [8] Litebook A new generation of light therapy http://www.litebook.com/Support/litebook-usage-information.html [9] Blint RJ, "Competitive Coordination of Lithium Ion", J. Electrochem. Soc. 1997 volume 144, issue 3, 787-791. http://jes.ecsdl.org/content/144/3/787.abstract

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[10] Lynch TJ et al., "Molecular structure of the lithium enolate of acetaldehyde", J. Org. Chem., 1980, 45 (24), pp 50055006 http://pubs.acs.org/doi/abs/10.1021/jo01312a045 [11] Ching et al., "Oxygen-Scavenging System Including A By-Product Neutralizing Material", US Patent 6057013, 1996. http://www.google.com/patents/US6057013?printsec=abstract#v=onepage&q&f=false [12] Noziere B et al., "Inorganic ammonium salts and carbonate salts are efficient catalysts for aldol condensation in atmospheric aerosols.", Phys. Chem. Chem. Phys., 2010,12, 3864-3872. http://pubs.rsc.org/en/content/articlelanding/2010/cp/b924443c [13] Liu XY et al., "Gene expression profile and cytotoxicity of human bronchial epithelial cells exposed to crotonaldehyde.", Toxicol Lett. 2010 Aug 16;197(2):113-22. http://www.ncbi.nlm.nih.gov/pubmed/20471460 [14] Mickle WA et al., "DISSOCIATION OF CANDIDA ALBICANS BY LITHIUM CHLORIDE AND IMMUNE SERUM", J Bacteriol. 1940 June; 39(6): 633647. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC374604 [15] Martins LF et al., "Lithium-mediated suppression of morphogenesis and growth in Candida albicans.", FEMS Yeast Res. 2008 Jun;8(4):615-21. http://www.ncbi.nlm.nih.gov/pubmed/18373681 [16] Adverse Event Reporting System Database, "LITHIUM Adverse Event Statistics", 2011. http://www.adverse-effects.org/drugs/66626-lithium [17] Adverse Event Reporting System Database, "DEPAMIDE Adverse Event Statistics", 2011. http://www.adverse-effects.org/drugs/33250-depamide [18] Adverse Event Reporting System Database, "TEGRETOL Adverse Event Statistics", 2011. http://www.adverse-effects.org/drugs/33555-tegretol [19] Jentink J et al., "Intrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study.", BMJ. 2010 Dec 2;341:c6581. doi: 10.1136/bmj.c6581. http://www.ncbi.nlm.nih.gov/pubmed/21127116 [20] Mitina LV et al., "The evaluation of the efficacy of carbamazepine and valproic acid in the alcohol postintoxication syndrome based on ethanol and acetaldehyde kinetics and the content of biogenic monoamines.", Farmakol Toksikol. 1991 Sep-Oct;54(5):60-2. http://www.ncbi.nlm.nih.gov/pubmed/1800156 [21] MedicineNet, "Lamotrigine Side Effects", 2012. http://www.medicinenet.com/lamotrigine-oral/page2.htm#SideEffects [22] MedicineNet, "Topiramate Side Effects", 2012. http://www.medicinenet.com/topiramate/page2.htm [23] Gainza-Cirauqui ML et al., "Production of carcinogenic acetaldehyde by Candida albicans from patients with potentially malignant oral mucosal disorders.", J Oral Pathol Med. 2012 Aug 22. http://www.ncbi.nlm.nih.gov/pubmed/22909057 [24] Truss CO, "Metabolic abnormalities in patients with chronic candidiasis: the acetaldehyde hypothesis.", Orthomol Psychiatr 1984; 13:6693. http://orthomolecular.org/library/jom/1984/pdf/1984-v13n02-p066.pdf

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Oddball Amino Acid =============== Selenocysteine is known as the twenty-first proteinogenic amino acid. Its structure is identical to cysteine except that it has the element selenium where sulphur would normally reside [1]. The high reactivity of selenium makes it suitable for rapid turnover enzymes such as glutathione peroxidase that clear cells of reactive oxygen species before they pollute the cellular environment. However, this reactivity also means that no free pool of selenocysteine exists in a cell -- it would be too damaging to the cell. This on-demand synthesis makes this amino acid vulnerable not only to (rare) dietary selenium deficiencies but also to disruptions in the pathway that creates it. Selenocysteine synthesis occurs on a specialized transfer RNA adaptor molecule that incorporates selenium into a serine residue via the pyridoxal-5'-phosphate (PLP)-dependent enzyme selenocysteine synthase prior to the incorporation of this modified amino acid into the target protein (see figures "Serine", "Cysteine", "Selenocysteine"). Since this unusual amino acid has no corresponding direct DNA code, it is selected by the UGA (stop) codon during a special translational sequence. When selenocysteine isn't available, either because of a selenium deficiency or because of selenocysteine synthase failure, translation of a selenoprotein terminates at the UGA codon instead of incorporating the modified amino acid. This results in a truncated, dysfunctional selenoenzyme. Methylmercury can rapidly degrade this pathway by creating an intracellular selenium deficiency (see "Rear-View Mirror"). Pulsed low-dosage exposure to yeast-released acetaldehyde may influence this same pathway incrementally over a longer period but can attack from multiple directions. The potential for acetaldehyde interference involves not only diminishing the amount cysteine available for the synthesis of glutathione itself (see "Toxic Soup", "When The Backup Fails", "Double-Edged Sword") but also inducing a pyridoxal deficiency (see "The Friendly Giant"), as well as possibly interfering with the PLP-dependent enzyme that produces selenocysteine, something essential for the selenoenzyme glutathione peroxidase. Since glutathione peroxidase is the major waste removal system for reactive oxygen species of a cell (see "Rear-View Mirror"), without a functional glutathione peroxidase pathway, a cell is susceptible to accumulation of this kind of nasty garbage culminating in cellular death (apoptosis). Although it might seem that supplementation with glutathione would help in this regard, oral absorption is minimal [2] and even when glutathione itself is available, the pathway won't work if the selenoenzyme that uses it is damaged. The entire subclass of selenoenzymes, even those that do not directly utilize PLP as a cofactor themselves, are still dependent upon PLP because of their requirement for the quirky amino acid selenocysteine, synthesized by the PLP-dependent enzyme selenocysteine synthase. This means that acetaldehyde, through PLP disruption, can indirectly have a negative impact on ALL of the body's selenium metabolism [3]. The iodothyronine deiodinases that activate and deactivate thyroid hormones belong to this class of selenoenzymes. If the T4 and T3 hormones manipulated by these deiodinases are not being regulated properly, hypothyroidism can disrupt gene expression in practically every cell in the body [4]. The mammalian thioredoxin reductases [5] are a family of selenium-containing enzymes involved in the regulation of cellular redox protein thioredoxin and hence are involved in protection against oxidant injury, cell growth and transformation, and the recycling of ascorbate from its oxidized form. Whereas proteins in the extracellular environment or on the cell surface are rich in stabilizing disulfides (the oxidized state) (see "Bridge Across The Chasm"), the inside of the cell abounds with proteins that contain many free sulfhydryl groups (the reduced state). Thioredoxin reductase is responsible for rectifying the cross-linking oxidation of sulphur-bearing proteins inside the cell. Not only does acetaldehyde find free sulfhydryl groups attractive targets for damage, it may interfere with the selenium-based management system that attempts to regulate them [6].

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Cysteine

Selenocysteine

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If an OPK (Orthomolecular Psychokinesiology) test indicates that you are deficient in selenium [7], then Brazil nuts are a particularly good dietary source [8]. Intake should be judiciously monitored (too much is as bad as too little) and reduced when OPK biofeedback indicates that levels have stabilized. There is so much interdependence amongst biochemical systems in the body, that impairment in any one of them can have consequences in a myriad of other pathways. Through its ability to disrupt sulphur metabolism and pyridoxal metabolism, acetaldehyde can impact selenium metabolism as well. Regardless of the starting point you choose when you follow unscavenged acetaldehyde throughout the body's intricate biochemical network, just like "sugar in the gas tank", you end up with dysfunction leading to disease.

[1] Nauser T et al., "Why do proteins use selenocysteine instead of cysteine?", Amino Acids. 2012 Jan;42(1):39-44. Epub 2010 May 13. http://www.ncbi.nlm.nih.gov/pubmed/20461421 [2] Witschi A et al., "The systemic availability of oral glutathione.", Eur J Clin Pharmacol. 1992;43(6):6679. http://www.ncbi.nlm.nih.gov/pubmed/1362956 [3] Kryukov GV et al., "Characterization of mammalian selenoproteomes.", Science. 2003 May 30;300(5624):1439-43. http://www.ncbi.nlm.nih.gov/pubmed/12775843 [4] Wu Y et al., "Gene regulation by thyroid hormone.", Trends Endocrinol Metab. 2000 Aug;11(6):20711. http://www.ncbi.nlm.nih.gov/pubmed/10878749 [5] Arner ES et al., "Physiological functions of thioredoxin and thioredoxin reductase.", Eur J Biochem. 2000 Oct;267(20):6102-9. http://www.ncbi.nlm.nih.gov/pubmed/11012661 [6] Moos PJ et al., "Electrophilic prostaglandins and lipid aldehydes repress redox-sensitive transcription factors p53 and hypoxia-inducible factor by impairing the selenoprotein thioredoxin reductase.", J Biol Chem. 2003 Jan 10;278(2):745-50. Epub 2002 Nov 6. http://www.ncbi.nlm.nih.gov/pubmed/12424231 [7] "Deficient or What?", In Astrophysiology...and Yeast, 2011. http://www.scribd.com/doc/74090699 http://www.epubbud.com/book.php?g=7JQU45V8 [8] Ip C et al., "Bioactivity of selenium from Brazil nut for cancer prevention and selenoenzyme maintenance.", Nutr Cancer 1994;21(3):203-12. http://www.ncbi.nlm.nih.gov/pubmed/8072875

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Dr. Jekyll and Mr. Acetaldehyde ======================== Acetaldehyde is nasty stuff. This work just begins to scratch the surface of potential interactions of unrestrained acetaldehyde molecules within the body. There isn't a biochemical process in the body that cannot be disrupted in one way or another by exposure to acetaldehyde either directly or indirectly. Most chemical reactions in the body are performed under the close scrutiny of enzymes which sequester both the reagents and the products until the appropriate results have occurred. Acetaldehyde emitted by yeast is not subject to these constraints. Not only does it impair the ability of enzymes to function properly but it can alter the substrates used in enzymatic reactions just by bumping into them. The Pictet-Spengler condensation reactions with biogenic amines and some of the ring-bearing amino acids is testament to this. Although its high reactivity means that those areas closest to its release from budding yeast cells will be the first and most affected, once it is in the bloodstream it can reach regions far distant from its origin. Since yeast is with us for the duration, daily prophylaxis with an acetaldehyde scavenger should be as commonplace as teeth brushing. Amyloid plaques. Neurofibrillary tangles in alcoholics result when acetaldehyde binds to epsilon-amino groups of lysine and thiol groups of cysteine exposed on the surface of the tau proteins essential for the assembly and stabilization of cellular microtubule structures. But these amyloid plaques are also found in patients with Alzheimer's disease. Is chronic exposure to acetaldehyde emanating from commensal yeast colonization triggering a similar condition in patients even without excessive alcohol consumption? Spermatozoa Acrosomes. Aldehyde-fuchsin stains spermatozoa acrosomes indicating that this is a likely site for acetaldehyde binding. These organelles are involved in the attachment to the ovum during transfer of nuclear material. If acetaldehyde has gummed up the sticky sulphur atoms during this process, could it contribute to fertilization failure? Mercury Inhibition. Mercury inhibits the aldehyde dehydrogenase enzyme necessary for body cells to detoxify acetaldehyde. Does mercury leeching from fillings prevent the body from coping with an increasing level of acetaldehyde emanating from yeast metabolism? Albumin Binding. Human serum albumin is the most abundant protein in human blood plasma. Albumin transports hormones/fatty acids and buffers pH amongst a host of other tasks. But acetaldehyde binds to an exposed cysteine residue in albumin. Does this prevent this important substance from performing its other critical functions? Autoimmunity Activation. In diabetes type 1A there is an immune-mediated destruction of pancreatic B cells. Aldehyde fuchsin stains pancreatic B cells indicating an attractive binding site for acetaldehyde. Does the binding of Ach to proteins result in production of antibodies to modified proteins so that the immune system targets such aberrant structures including but not limited to pancreatic B cells?

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Iodine Depletion. Acetaldehyde reacts with iodine to form iodoform which removes the iodine ion from enzymatic availability. Since iodination by neutrophils is one of the primary defense mechanisms of the innate immune system against fungal invaders, is the release of acetaldehyde by Candida Albicans, as the perfect parasite, an evolutionary acquired fungal survival mechanism for deliberately suppressing the innate immune system? Necrotizing Entercolitis. NEC in premature infants is almost never seen before oral feedings are initiated and is much less likely in breast-fed than formula-fed babies. Suppose that empirical antibiotic therapy has selectively altered gut flora so that yeast acetaldehyde production increases. This causes acid reflux and spitting-up reactions. When the formula is enhanced with xanthan gum to thicken it to counteract the reflux, this induces a hyphal shift in the yeast without killing it. The phospholipase from the hyphal morphic state dissolves and perforates the intestinal wall leading to tissue necrosis. Fibrosis. Both cartilage and connective tissue are intensely stained by aldehyde-fuchsin indicating a predominance of S-S disulphide bonds in these types of proteins. Sulphur seems to show up in a lot of tissues that need to display certain types of macro molecular behaviours, such as the resilience of cartilage or the stretchiness of connective tissue. If something like acetaldehyde bonds to the sulphur before the disulphide bonds can form then the desired characteristics of the tissue are altered in undesirable ways. This impedes tissue damage repair with scar tissue fibrosis, instead of connective tissue, and bone spurs, instead of cartilage, being the end result.

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Fate Of Wondro ============ If Wondro was so good, what happened to it? It was a temporal casualty -- ahead of its time. It was forced out of production (1950's) when the emerging antibiotics were supposed to be the magic bullet to bring an end to disease. Part of the review that terminated its production and distribution stated that "there is nothing in this remedy that would do anyone any good." But therein lies its elegant beauty -- a metabolically benign substance that does one thing and one thing only. It scavenges yeast-released acetaldehyde and it does this extremely well without side effects. Even with all of the remarkable advances in medical science, we are still struggling with the symptoms of a vast array of chronic diseases. There was no knowledge then as to how Wondro could possibly work for so many different conditions and testimonials are not medical research. The usage of flax oil was rooted in the historical origins of this remedy but any oil with a high content of unsaturated fatty acids would likely work in this regard. It is the double carbon-to-carbon (unsaturated) bond that is the reaction/insertion point for the sulphur -- a form of vulcanization. The alteration in color and increase in viscosity from flax oil to Wondro supports the assumption that the end-product is a sulphurated form of the original oil constituents. When it was produced in large batches, the sulphur and oil were mixed in 60-gallon stainless steel kettles with intense heat (500-600 F) applied for approximately 1 hour before the reaction occurred. This has not been done since the early 1950's. For a batch larger than single dosage adequate ventilation of the production area is paramount. Both constituents are flammable so due caution is required there as well. The proof of concept experiment to see if it could be made in single dosage quantities used a 900W microwave on HIGH for about 5 minutes. It is immediately obvious when the reaction has occurred because of the color change. A more heat-stable oil will not incorporate as much sulphur as readily and may be too thick in consistency to consume easily (e.g. olive oil). Also there may be other heating/sulphur reaction byproducts in other oils that are not beneficial. Wondro made with flax oil was taken by a wide cross-section of humanity in the first half of the twentieth century without any deleterious consequences. Other healing regimens ("Food Is Your Best Medicine" by H. G. Bieler, 1966) have embraced the theory that "...disease is caused by a toxemia which results in cellular impairment and breakdown" without clearly realizing what it was or where it was coming from. C. O. Truss ("The Missing Diagnosis" 1976) has expanded upon this by giving this toxin a name, "acetaldehyde", and a source "Candida Albicans" so that the nature of the damage can be characterized and rectified. Wondro produced amazing results, but why? Truss's work was brilliant, but where was the proof? Both of these concepts challenged the paradigm of their time to such an extent that they were labeled medical heresy and dismissed as frauds. But now these two ideas (venom/antidote) mesh together so well at the molecular level that they may provide insight into a host of downstream disease states that have baffled even the most sophisticated analysis available to modern medicine. The "Yeast Abatement Protocol" described in the reference "Astrophysiology...and Yeast" integrates acetaldehyde scavenging as the first of a seven-step protocol that is low-key but powerful enough to assist both those struggling with disease and those who are healthy, either in restoring or preserving a state of well-being.

173

End Of Illness? ============ The yeast Candida Albicans is such an incredibly complex, finely-tuned organism that it is difficult to know how to begin to deal with it. It has been able to perpetrate this crime against humanity because of our own ignorance and arrogance regarding its capabilities. It has been viewed as a commensal opportunist -a consequence rather than a cause of disease. In fact, this yeast is an evolutionary doomsday machine that has spawned a global acetaldehyde pandemic for eons. People are being medicated to death now because of the symptoms that it creates without even realizing that it is the cause. Sooner rather than later, an organism that is always found lurking at the scene of the crime needs to be added to the list of suspects. History has foreshadowed the significance of this organism. The Wondro story is a puzzle piece that puts the focus on the acetaldehyde aspect as being one of the pivotal points in this yeast's ability to entrench itself and precipitate chronic illness. Was Wondro a miracle cure? No, acetaldehyde scavenging does not repair damage done by previous acetaldehyde exposure. It merely prevents further damage from subsequent release of this toxin by yeast metabolism and gives the body's own recuperative powers a chance to function unimpeded. Since the source of this toxic substance is now known to be a fungus (the yeast Candida Albicans), then why not just take a course of potent antifungals and be rid of it? There are certainly life-threatening infectious situations in immunosuppressed patients where an antifungal drug such as amphotericin B or fluconazole is imperative. However, the mode of action of antifungal drugs seeks to selectively eliminate fungal cells without targeting human cells and herein lies a problem. Both fungal and mammalian cells are eukaryotes (having a nucleus) and share more similarities at the molecular level than say human cells and bacterial cells that are prokaryotes (without a nucleus). This means that the side effects from antifungal drugs may be almost as devastating to the host cells as they are to the yeast cells that need to be eliminated. Furthermore, if we have learned anything from the indiscriminate use of antibiotics over the past decades, it should be that the organisms that we seek to destroy in this manner do not succumb passively to these threats to their existence. The appearance of antibiotic-resistant bacterial strains attests to this. A guns-blazing approach to attempt to rid everybody of Candida Albicans will surely only result in the development of more antifungal-resistant strains. If this is starting to sound a bit like the "Unified Theory of Disease Causation", that is exactly what it is. At the biochemical level where acetaldehyde exerts its influence, the potential for disruption is staggering, with each individual exposed to chronic toxicity succumbing at their own unique weakest link. As preposterous as this may sound, it is consistent with the observed "panacea effect" where certain substances appear to produce beneficial results in a wide variety of apparently unrelated illnesses in different individuals. Close scrutiny of these substances usually reveals either an antifungal or an acetaldehyde scavenging or an acetaldehyde neutralization profile. Although the symptoms and diseases are as different as night and day, there is a common failure pattern here. The miniscule size of acetaldehyde is allowing it access to places where it shouldn't be and its reactivity is allowing it to bond to configurations where it doesn't belong. And, once it reacts, it remains there, impairing the structure or function of the biological entity that was unfortunate enough to be exposed to it. The fall-out of the failure to recognize the toxic potential of Candida Albicans in the form of its venom, acetaldehyde, is that most treatment regimens of the current day and age are focused upon treating symptoms of disease rather than the cause. The question which we should be asking is not "what diseases are associated with acetaldehyde poisoning" but "what diseases are left that aren't associated with acetaldehyde poisoning?" The Wondro message -- that an amazing variety of apparently unrelated disease processes can respond to something as simple as a daily dose of an exceptionally potent but metabolically benign oral acetaldehyde antidote -- implies that every disease condition that has remained a conundrum to modern medical science should be re-examined from an acetaldehyde toxicity perspective. Even the prognosis of diseases that are well understood and treatable may improve if the impact of this toxin is removed from the background.

174

Index

A
abortifacient, 25 absorption, 47, 54, 61, 100-101, 108, 127, 138, 141, 150, 158, 167 acetaldehyde-chelation, 25 acetamide, 9, 147, 150 acetic, 7-8, 27, 31-32, 49, 80, 90, 126, 136, 144 acetoin, 22 acetyl, 4, 39, 57, 77, 92, 105, 108 acetyl-coa, 8, 41, 105, 108 acetyl-coenzyme, 20-21, 77, 105 acetyl-sulphate, 8, 94 acetylation, 39, 74, 94, 98, 109, 136 acetylcholine, 8, 105, 108 acetylcholinetransferase, 105 acetylglucosamine, 108 acetylsalicylic, 6, 45 acetyltransferase, 105 acid-hydrogen, 92 acne, 80 acrosomes, 5, 73, 170 adenosine, 39, 87, 152 adequate-protein, 103 adherens, 80 adp, 87 affective, 126, 160 agentaffine, 73 alcohol, 27, 35, 37, 45, 47, 51, 59, 80, 82, 90, 98, 101, 109, 112, 119, 124, 127, 130, 135, 146, 154, 165-166, 170 alcohol-histamine, 112

alcohol-induced, 59, 90, 93, 146, 165 alcohol-related, 27 aldehyde-fuchsin, 73, 170, 172 alimentary, 12, 14, 18, 82 allantoin, 7, 62, 72 allergies, 5, 21, 39, 57, 93, 112, 165 allergies-prone, 94, 112 allyl, 25 alpha, 57 alpha-linolenic, 7, 54 alpha-wondrenic, 7, 54 als, 130 aluminum, 28 alzheimer, 27, 57, 80, 105, 170 amide, 61, 147, 150, 152, 154, 156, 160 amine, 12, 61, 110, 112, 114, 118, 126, 147, 150, 154, 156, 160, 163, 170 amino, 5, 7, 10, 18, 30, 54, 66, 68, 70, 77, 79, 98, 100-101, 110, 114, 121, 126-127, 130-131, 135-136, 138, 141-142, 144, 146-147, 150, 152, 156, 163, 167, 169-170 amino-acid, 126 ammonia, 150 amyotrophic, 130 anal, 82 anemia, 146-147 anhydrase, 35-36 anhydride, 8, 90 anthocyanidin, 8, 94 anthocyanin, 94 anthranilamide, 7, 62 anthranilate, 62, 70 anti-cancer, 61 anti-candida, 58, 123 antibiotic, 12, 23, 89, 142, 172

Index

antibiotic-induced, 165 antibiotic-resistant, 174 anus, 80, 82 apoptosis, 92, 114, 119, 121, 123-124, 131, 135, 138, 167 appetite, 23, 110, 118 apple, 4, 6, 10, 49, 51, 59-60, 86, 150, 154 apple-like, 51 ards, 90 arginine, 7, 61, 68 aroma, 27, 33 aromatic, 110, 118 arrhythmia, 112 arsenic, 28, 47 arthritic, 108, 122 arthritides, 80 arthritis, 37, 122, 125, 152, 165 asparagine, 7, 61, 68 aspirin, 6, 45, 59, 64, 122 asthma, 45, 90, 92-93, 112 astrophysiology, 11, 32-33, 35, 47, 51, 54, 103, 119, 150, 154, 160 atp, 39, 87, 127, 152 autism, 5, 10, 30, 80, 98, 100-101, 140-143 autoimmune, 73, 122, 125, 156 autosomal, 30 autoxidation, 8, 90, 136

bioflora, 23, 25, 32 biogenic, 110, 112, 114, 118, 126, 160, 166, 170 biomarker, 33, 35, 82, 85, 134-135, 147, 158 biomarker-guided, 101 bipolar, 5, 10, 126, 158, 160, 163 bisulfite, 104 biuret, 7, 66 blastospore, 84 bleach, 31 bloating, 21 blood, 12, 25, 27, 39, 41, 58, 77, 79, 82, 94, 114, 121, 124-125, 147, 160, 170 blood-borne, 73 blood-brain, 25, 80, 119, 123 bloodstream, 12, 14, 28, 84, 94, 98, 121, 170 bowel, 13, 80, 110 brain, 21, 27, 30, 51, 57, 80, 105, 114, 147, 160 bridge, 4, 37, 49, 74, 77, 79, 84, 87, 103, 130, 167 budding, 6, 18, 20, 23, 27-28, 30, 35, 41, 49, 51, 74, 84-87, 89, 98, 105, 127, 144, 170 burn, 103 burning, 21 burping, 14 burrow, 23 butanal, 6, 37 butanediol, 21-22 butter, 12

B
b-vitamin, 158 backbone, 12 bacteria, 23, 87, 122 bad, 49, 126, 169 baeyer-villiger, 136 balsam, 12, 14 basal, 86 bee, 23, 85 beeswax, 14 benzenediol, 51 benzenetriol, 51 benzoquinone, 6, 39 beta-alanine, 30 beta-carboline, 110, 118, 121, 156 beta-defensin, 121 beta-unsaturated, 57 bicarbonate, 35 biliary, 84 bioavailability, 60, 94, 100 biofilm, 14

C
cadmium, 28 caesar, 82 calcification, 41, 58 canal, 12, 82 cancer, 27, 32-33, 35, 37, 47, 61, 66, 72, 100, 109, 147, 150, 154, 169 cancer-associated, 45 candida, 6, 12, 14, 20-23, 25, 28, 30, 33, 36-37, 41, 45, 51, 57-59, 61, 73-74, 79, 82, 84-86, 89-90, 94, 98, 104, 109-110, 114, 118, 122-124, 127, 166, 172-174 candidiasis, 28, 45, 58, 82, 89, 108, 118, 122, 138, 166 capsule, 13, 18, 20, 82, 84, 98, 100 carbamazepine, 5, 9, 160, 166 carbocation, 6, 49 carbohydrate, 12, 32, 47, 59, 61, 74, 92, 94, 103, 118, 134, 141, 152 carbohydrate-derived, 47, 59 carboline, 110, 121, 126

ii

Index

carbon, 6, 12, 18, 20, 28, 30, 33, 35, 37, 39, 49, 54, 94, 119, 123, 136, 173 carbon-centered, 131 carbon-containing, 39 carbon-nitrogen, 144 carbon-to, 54, 173 carbonic, 35-36 carbonyl, 12, 28, 30, 37, 39, 41, 45, 47, 51, 54, 60, 94, 101, 131, 136, 144, 160 carboxamide, 160 carboxy, 121, 126 carboxyl, 61 carboxylic, 8, 31-32, 98, 100, 136, 154 carcinogen, 12, 27-28, 33, 37, 57-58, 61, 74, 100, 109, 154, 165-166 carmoisine, 8, 94 carnosinase, 30 carnosine, 4, 6, 30, 73, 110, 114, 140 carnosinemia, 30 cartilage, 73, 172 catabolism, 8, 10, 77, 84, 114, 121, 124-125 catecholamine, 5, 114, 142, 160 catecholamine-derived, 118 cation, 28, 35, 49, 54, 86, 136, 141, 160 cavity, 108 cereal, 104 cerebrospinal, 27 channel, 13, 74, 89, 103 charge, 13, 33, 37, 73, 98, 105, 136, 152 chasm, 4, 37, 74, 84, 103, 130, 167 chelation, 6, 25, 28, 47, 138 chemical-gene, 21 chlorine, 31, 90 chlorine-free, 90 chlorite, 31-32 chlorous, 31 cholesterol, 8, 41, 77, 84, 98, 100 choline, 4, 105 chondroitin, 86 chromotropate, 66 cider, 86 cilium, 87, 89 citric, 20, 39, 77 co-enzyme, 144 cobalamin, 9, 147, 154 coconut, 103, 105 codon, 167 coenzyme, 4, 6, 39, 77, 126, 152, 154 cofactor, 27, 101, 144, 147, 154, 163, 167 colitis, 80 colloid, 47, 73, 86 colonic, 80, 130 colony, 14, 21, 25, 39, 41, 45, 51, 58, 74, 82, 84-87, 89, 92, 94, 110, 119, 127, 130, 141, 165, 170

combustion, 90, 92, 127 commensal, 12, 14, 21, 23, 39, 45, 61, 73, 79, 82, 94, 109, 122, 130, 147, 163, 170, 174 compulsive, 126 condensation, 7, 37, 49, 60-62, 64, 66, 68, 70, 72, 110, 114, 121, 126, 136, 150, 156, 160, 166, 170 conjugate, 77, 136 constipation, 13, 21, 110 contamination, 28, 47, 61, 108, 119, 142 contribution, 27 convulsion, 146, 160 copd, 45, 90 coupled-receptor, 90 cravings, 23, 47, 51 crohn, 80 crook, 82, 92, 112 crotonaldehyde, 4, 6, 37, 49, 51, 57, 160, 166 cystathionine, 101 cystathionine-beta, 101 cysteine, 7-10, 12, 27, 54, 61, 68, 73, 77, 80, 98, 101, 103, 109, 127, 130-131, 134, 136, 138, 141, 154, 163, 167, 169-170 cysteine-rich, 138 cystine, 8, 73, 127, 130, 134-135 cytokine, 121, 124

D
d-glucosamine, 8, 108 d-glucuronic, 108 d-n, 108 decarboxylase, 20 decarboxylation, 12, 77, 144 dehydrogenase, 5, 20, 27, 45, 73, 80, 90, 93, 114, 118, 126, 140, 144, 154, 156, 165, 170 depamide, 160, 166 dephosphorylation, 87 depression, 21, 35, 94, 147, 158, 160, 163 deprotonation, 49 dermatitis, 35, 39, 57, 80, 152 dermatologica, 84 detoxification, 27, 30, 144 diabetes, 122, 160, 170 diagnosis, 14, 66, 112, 173 diaminoanthraquinone, 7, 64 diaminocyclohexane, 7, 66 diaminonaphthalene, 7, 62, 147 diaminopyridine, 7, 64 diarrhea, 21, 39, 94, 110, 112, 147, 152, 160 dicarbonyl, 49, 59, 136

iii

Index

diet, 4, 23, 25, 30, 47, 49, 58, 61-62, 70, 74, 92, 94, 98, 101, 103, 105, 109-110, 126-127, 130-131, 134, 138, 141, 144, 147, 152, 156, 167, 169 digestion, 80, 87, 94 dihydro, 118 dihyroxy, 7, 66 dimer, 49 dimethyl, 4, 6, 37, 39, 45, 64 dimethylaminoterephthalate, 7, 70 dinicotinamide, 9, 152 diol, 22 dioxide, 6, 20, 31, 33, 35, 90 dioxygenase, 121, 125, 156 dipeptide, 30 dipole, 33 dipole-charge, 35 dipole-dipole, 33 disease, 3-4, 12, 14, 21-23, 25, 27-28, 30-33, 35, 37, 39, 41, 45, 47, 49, 51, 54, 56-57, 59, 61, 73, 77, 79-80, 82, 84, 90, 92, 94, 98, 101, 105, 112, 114, 118, 124-127, 130-131, 134, 138, 140-141, 146, 150, 152, 154, 156, 165, 169-170, 173-174 disease-causing, 25, 49 disodium, 7, 66 disorder, 5, 10, 27, 30, 37, 45, 47, 54, 57-58, 90, 100-101, 110, 114, 126, 141-143, 146, 158, 160, 163, 166 distilled, 13 disulfonic, 7, 66 disulphide, 7, 9, 20, 54, 74, 77, 79, 84, 103-104, 127, 130-131, 134, 152, 172 disulphide-groups, 104 disulphide-rich, 103 dizygotic, 141 dizziness, 21, 160, 163 dna, 5, 32-33, 35, 51, 60-61, 90, 109, 121, 127, 131, 147, 167 dopamine, 8, 114, 126, 160 drug, 166 dye, 73, 94 dynein, 87, 89 dysmenorrhoea, 112

E
eczema, 39, 80 edta, 6, 28 egg, 14, 18, 82 elasticity, 73-74

elaunin, 104 electron, 5, 10, 12, 28, 33, 57, 73, 86, 126-127, 131, 152, 154 electron-donating, 49 electron-rich, 49, 70, 163 electronegative, 14, 18, 28, 33, 37, 49, 54, 73 electrophilic, 12, 28, 47, 49, 73, 94, 105, 141, 169 element, 47, 56, 74, 160, 167 elemental, 12, 14, 18, 20, 25, 54 elixir, 12 emulsion, 18, 20, 25, 56, 85 encapsulate, 85, 131 encephalitis, 80 encephalomyelitis, 122, 125 end-disease, 165 endocrine, 77, 82 endocytosis, 119 endothelial, 85-86, 119, 123, 125 enolate, 4, 6, 37, 39, 49, 160, 166 enzymatic, 45, 73, 105, 114, 122, 141-142, 144, 146-147, 154, 163, 170, 172 enzyme, 4, 9, 20, 23, 27, 30, 35, 49, 51, 54, 56, 61, 73-74, 77, 79-80, 85, 87, 101, 105, 108-109, 112, 114, 121, 127, 131, 138, 140-141, 144, 146-147, 154, 156, 165, 167, 170 enzyme-bound, 41 enzyme-catalyzed, 36 eosinophilia, 39 epigallocatechin, 7, 51 epilespsy, 30, 80, 103-104, 160, 163 epithelial, 56, 73, 80, 85, 87, 89-90, 92, 119, 121, 123-124, 135, 166 epsilon-amino, 170 esophagus, 27, 82, 84-87, 92, 98, 100 ester, 37, 39, 45, 64, 70 estrogen, 58 estrogen-related, 45 ethanol, 7, 49, 58, 80, 84, 101, 130, 136, 140, 146-147, 150, 165-166 ethanol-induced, 84 ethylenediaminetetraacetic, 28 ethylidene, 49, 150 ethylidene-diphloroglucinol, 7, 49 ethylidene-diurea, 9, 150, 152 ethylidene-linked, 49 ethylidene-n, 9, 147, 152 ethylidenediurea, 150 eustachian, 87, 89 evidence, 146 extracellular, 77, 79-80, 90, 119, 121, 127, 130-131, 134, 167 extrathymic, 86 extremity, 21

iv

Index

F
fat, 12, 18, 20, 25, 30, 32, 56, 74, 82, 103-104, 109, 122, 131, 147, 152, 173 fat-soluble, 41, 45 fatigue, 21, 35, 39 fermentation, 32-33, 61, 122, 134, 141, 160 ferritin, 119, 124 fibres, 73, 104 fight-or, 114 flammable, 14, 21, 90, 173 flavonoid, 49 flavor, 18, 61, 94 flax, 12, 14, 18, 20, 23, 25, 31, 54, 56, 74, 82, 108, 122, 173 flight, 114 fluid, 13, 27, 31, 35, 62, 80, 87, 105, 108 fog, 21, 105 folate, 66, 147, 150 forgetfulness, 21 formaldehyde, 35, 66, 73-74 formylation, 74 friedel-crafts, 136 fuchsin, 73, 85, 103, 170 fulvic, 6, 47, 59 fumarate, 4, 6, 37, 39, 64 fumaric, 6, 39, 57 fungus, 23, 27, 82, 87, 121-122, 124, 147, 172, 174 furry, 82, 84

geophagy, 47 germ, 84 germ-tube, 36 gland, 8, 77, 79, 82, 84, 104 glossitis, 147 glucosamine, 4, 108 glucosamine-phosphate, 108 glucose, 20, 35-36, 59, 103, 114 glucose-poor, 119 glutamate, 103, 130-131, 134, 144, 146 glutathione, 9, 39, 54, 57, 98, 127, 131, 134-135, 138, 140, 167, 169 glycine, 7, 66, 70, 131 glycoprotein, 87 gondii, 121, 124 gpcr, 4, 7, 74, 77, 79, 90, 103, 114 gpcr-type, 77, 103 granule, 73 grape, 62, 70 guanine, 8, 109

H
hair, 5, 21, 74, 114, 136 hair-trigger, 112 headache, 21, 51, 112, 160, 163 heart, 31, 39, 114, 118 heartburn, 21, 85-86 heavy-metal, 142 hemoglobin, 119 hepatic, 84, 130, 140, 146, 165 hepatitis, 122, 125 herbs, 3, 13-14, 25, 45 herpetiformis, 80 hg, 28 high-fat, 103 hijiki, 47, 59 histamine, 8, 112, 126, 160 histamine-mediated, 90, 92, 112 histological, 73 homeopathy, 27, 35, 51, 144, 158 homeostasis, 35, 77 homocysteine, 8, 101 honey, 85-86 hormone, 41, 77, 79, 82, 84, 140, 167, 169 horseradish, 25 http, 166 hyaline, 73 hyaluronic, 108 hydration, 33, 35-36, 150

G
g-protein, 90 gaba, 103 gallate, 7, 51 gamma, 124 gamma-aminobutyric, 103 gamma-carboxylation, 41 gamma-glutamyltranspeptidase, 134 garlic, 14, 56, 82, 85-86, 144 garlic-infused, 82 gas, 21, 33, 169 gastric, 35, 73 gel, 82 gelatine, 13 genetic, 12, 25, 27, 30, 73, 77, 92, 122, 130, 141-142, 165

Index

hydrochloric, 31 hydrochloride, 73 hydrogen, 8, 10, 28, 31-33, 35, 39, 74, 90, 92-93, 127, 131, 136, 138, 150, 163 hydrogen-bond, 33 hydrogen-bonded, 33 hydrogen-bonding, 6, 33 hydroperoxide, 8, 31, 131, 138 hydroxy, 6, 31, 37, 110, 114 hydroxy-trans, 59 hydroxybenzoic, 7, 66 hydroxybutanal, 37 hydroxyethyl, 31 hydroxyl, 8, 51, 61, 131 hyperactivity, 94, 98, 101, 114, 152, 160, 165 hypercalcemia, 45 hyperhomocysteinemia, 101 hyperlipidemia, 84 hyperproteinuria, 66 hyphal, 6, 23, 51, 85-86, 172 hyphal-associated, 124 hypophyseal, 73 hypotension, 112, 114, 160 hypothyroidism, 79, 84, 167

interleukin, 121, 124 intestine, 18, 23, 33, 51, 79-80, 82, 84-85, 94, 110, 130, 172 intravenous, 28 iodothyronine, 140, 167 ion, 4, 6, 21, 28, 35, 37, 39, 47, 49, 59-60, 74, 79, 98, 103, 160, 165, 172 iron, 86, 119, 124, 156 iron-dependent, 135 iron-limiting, 119 irritable, 80, 110 islets, 73 isoquinoline, 114, 118 isothiocyanate, 25 itching, 82, 94

J
joint, 108 junction, 4, 8, 80, 84-85, 108, 119 junctures, 12

I
ibs, 110 ifn-gamma, 121 ige, 94 imidazole, 30 immune, 23, 25, 39, 58, 82, 84-85, 87, 90, 94, 100, 112, 119, 121-122, 125, 127, 142, 156, 165-166, 170, 172 immune-mediated, 170 immunocompromised, 82, 163 immunoglobulin, 87, 119 immunological, 84 immunosuppressive, 12, 28, 37, 39, 45, 122 impermeable, 80 impurity, 13 indigestion, 21 indoleamine, 121, 125, 156 inflammation, 59, 85, 108, 125, 147 inhibitor, 36, 45, 54, 84, 105, 112, 118, 121, 144 innate, 23, 73, 82, 87, 92, 121, 124, 127, 138, 154, 165, 172 inter-cilium, 87 interferon, 124 interferon-gamma, 121, 124

K
keratin, 73 ketogenesis, 103 ketone, 39, 47

L
l-cysteine, 8, 18, 20, 98, 100-101, 130 l-dopa, 114 l-glutamine, 80 l-histidine, 30 l-phenylalanine, 114 l-tyrosine, 114 lamina, 86 lamotrigine, 5, 9, 163, 166 langerhans, 73 lapachol, 4, 6, 41, 58

vi

Index

laryngitis, 45 latency, 74, 140 lateral, 130 laxative, 13 laxico, 13 lead, 28, 33, 39, 45, 127, 138, 144, 147, 150, 152, 154, 160 leaky, 80, 85 leber, 130 lemon, 85 leukocyte, 84, 119, 123 lexicon, 12 ligand, 66, 79, 140 ligand-gated, 74, 103 lindgren, 31-32, 136 lining, 82, 84-85, 87 linoleic, 7, 12, 18, 54, 74 linolenic, 6, 12, 18, 74 linseed, 12, 14 lipid, 8, 32, 37, 45, 58-59, 84, 90, 127, 131, 134, 138, 169 lipoic, 7, 12, 20, 25, 41, 77 liquid, 4, 10, 12, 14, 21, 33, 59, 82, 85-86 lithium, 5, 9, 160, 165-166 lithium-mediated, 166 liver, 22, 27, 32, 39, 51, 58, 80, 101, 140, 146, 156 lovastatin, 6, 41 low-carbohydrate, 103 lubricant, 108 lupus, 37, 45, 47, 122, 125, 135 lymph, 85 lymphocytopenia, 39 lysine, 9, 144, 147, 170 lysine-dependent, 146

M
macromolecule, 80 macrophage, 119, 122-123, 131 magenta, 73 magnesium, 27 mal, 103 malaise, 21, 35, 160 malonamide, 7, 64, 147 malondialdehyde, 8, 37, 51, 131, 134-135, 138 malondialdehyde-acetaldehyde, 135 mao, 114, 118 meat, 30, 98 mediated, 121 melatonin, 126, 156

membrane, 18, 25, 30, 32, 56, 59, 73, 77, 80, 84-85, 90, 104-105, 123, 134 memory, 105, 110, 163 menadione, 6, 41 menadione-mediated, 58 menaquinone, 6, 41 meningitis, 80 menopause, 41, 45 mental, 94, 105, 141 mercapto, 7, 62, 64 mercury, 5, 25, 28, 54, 136, 138, 140-143, 170 metabolism, 12, 22-23, 25, 27-28, 30, 33, 39, 41, 45, 51, 54, 57, 74, 77, 79-80, 82, 84-85, 87, 90, 98, 100-101, 103, 109, 112, 118, 121, 126-127, 134, 138, 140, 142, 146-147, 150, 165, 167, 169-170, 174 metabolite, 21, 73, 94, 109, 131, 134, 142 metal, 4, 21, 28, 35, 47, 54, 59, 79, 136, 138, 141-142, 160 metaldehyde, 136 metalloenzyme, 35, 127 metallothionein, 9, 138, 141-142 methane, 12 methionine, 8, 68, 98, 101, 131, 141 methoxytryptamine, 126 methyl, 6-7, 37, 57, 62, 66, 70, 100, 110, 121, 126, 138 methyl-sulphonyl, 12 methylated, 109 methylguanine, 8, 109 methylguanine-dna, 8, 109 methylmercury, 9, 136, 138, 140-141, 167 methylmercury-cysteine, 140 methylmercury-induced, 140 methylthiazolidine, 8 mevalonate, 41 mg, 18, 20 microtubule, 87, 89, 170 microwave, 14, 18, 173 migraine, 21, 45, 94, 112, 163 milk, 14, 18 minamata, 136 mineral, 31, 47 mitochondria, 27, 58, 127, 130-131, 134, 138 mms, 4, 31, 90, 150, 163 molasses, 14, 18, 25 molybdenum-based, 147 monoamine, 8, 110, 114, 118, 142, 166 monoglyceride, 104 monothioglycerol, 62, 64 monozygotic, 141 morphology, 27, 85 motility, 110 mouth, 80, 82, 92 mouth-breathing, 92

vii

Index

msm, 12 mtca, 10, 98 mucopolysaccharide, 73 mucosa, 12, 14, 57-58, 80, 121, 130, 166 mucous, 18, 25, 90 mucus, 4, 10, 87, 89, 142 mucus-secretion, 87 muscle, 21, 27, 30, 90, 114, 156 mutation, 58, 109, 123 mycoses, 86 myelin, 45 myoclonus, 104

norepinephrine, 8, 114 norharmane, 8, 121 nucleophilic, 6, 12, 28, 37, 39, 49, 94, 136 numbness, 21 nutrient, 23, 39, 54, 82, 85, 94, 150, 152, 154, 156, 163 nutrient-rich, 119

O
obsessive, 126 ocd, 126 octadecanamide, 7, 70 octatomic, 18, 25 ointment, 14 olive, 85, 173 omega, 18, 122 oral, 31, 51, 57-58, 100, 121, 123-124, 134-135, 166-167, 169, 172, 174 organ, 32, 39, 73-74 organism, 21, 23, 25, 85, 121, 138, 154, 165, 174 oropharyngolaryngeal, 27 orthomolecular, 35, 126, 150, 156, 169 osteoblastogenesis, 45, 58 osteocalcin, 41, 58 osteoporosis, 41, 58 oxaliplatin, 66 oxidative, 30, 37, 114, 118, 123, 127, 130-131, 134-135, 138, 140, 142 oxidative-stress, 130 oxygen, 5, 8, 12, 28, 33, 37, 39, 47, 49, 54, 62, 90, 92, 94, 114, 119, 123, 127, 130-131, 134, 136, 138, 141, 147, 152, 160, 167 oxygen-based, 127 oxygen-oxygen, 32, 90 oxygen-scavenging, 166

N
n-acetyl, 4, 8, 12, 18, 20, 103, 108, 126 n-acetylation, 100 n-acetylcysteine, 25, 104 n-acetylglycinamide, 7, 66 n-acetyltransferase, 108 n-diacetamide, 9, 147 n-nitroso, 8 nac, 20, 85 nad, 9, 126, 152, 154, 156, 158 nadh, 126, 154, 156, 158 naphthalene, 7, 66 nausea, 31, 114, 160, 163 nebulous, 21, 25 necrosis, 131, 172 neonate, 21 nervous, 21, 105, 147 neural, 4, 103, 147, 150 neurological, 30, 136, 140 neuromyotonia, 160 neuronal, 103 neurons, 103, 114 neuropathy, 130, 146, 150 neurotoxin, 12, 28, 114 neurotransmitter, 70, 103, 105, 114, 118, 126, 142, 156 niacin, 9, 126, 152, 156, 158 nicotinamide, 5, 9, 126, 152, 154, 156, 163, 165 nitrosamine, 98, 100 nmtca, 8, 98 no-synthase, 123 non-enzymatic, 30-31, 121 non-hepatic, 127 non-organ, 109 non-protein, 66 nonenal, 59

P
paba, 66 pain, 21, 108, 160, 163 panacea, 25, 73, 174 pancreatic, 73, 170 pandemic, 165, 174 para-aminobenzoic, 66

viii

Index

paraldehyde, 136 paralysis, 21 parasite, 12, 72-73, 172 parathyroid, 8 parkinson, 30, 114, 118, 130 pathogen, 82, 85, 89-90, 150 pathology, 80, 103, 110 pellagra, 126, 152 peptide, 30, 66, 79, 119 peptide-like, 66 peracetic-hydrogen, 90 peripheral, 41, 105, 146-147, 150, 163 permeability, 80, 85 peroxidation, 30, 37, 58, 64, 131, 140, 142 peroxidation-derived, 59 peroxidosis, 4, 10, 31-32, 37, 64, 90, 92 peroxyl, 131 phagocytosis, 84, 119, 121, 123 phloretin, 6, 49, 51, 59-60 phloridzin, 6, 49, 51, 59-60 phloroglucinol, 6, 49 phosphatase, 80 phosphate, 4, 8-9, 80, 101, 108, 144, 146, 154, 167 phospholipase, 23, 85-86, 119, 123, 172 phospholipid-hydroperoxide, 138 phosphorylation, 80 phylloquinone, 6, 41 pictet-spengler, 110, 112, 114, 121, 126, 136, 156, 170 pinnick, 31, 136 piperazine, 7, 72 pituitary, 73, 77, 79, 84 pneumonitis, 45 poison, 27 polarize, 12, 21, 33, 54, 136 polycondensation, 49 polyester, 28, 61-62, 68, 72 polyethylene, 61 polymerization, 49 polymorphism, 25, 27 polymorphonuclear, 84, 123 polyphenol, 49 polyphenol-containing, 51 polyuria, 160 powder, 14, 18 prechlorophyll, 122 prednisolone, 45 prednisone, 4, 6, 45, 59, 122 premature, 21, 172 progesterone, 4, 6, 41, 45, 58 propanediol, 7, 62, 64, 66 prostaglandin, 5, 33, 45, 109, 119, 122, 169 protein, 32, 35, 41, 57, 68, 70, 74, 77, 79-80, 82, 84-87, 89-90, 92, 101, 103-105, 114, 127, 140-142, 144, 146, 165, 167, 169-170, 172

protein-coupled, 7, 74, 77, 84, 93, 103, 114 proteoglycan, 86 protocol, 3-4, 6, 14, 18, 20, 23, 25, 30-31, 51, 56, 74, 79, 84, 103, 108, 127, 130, 165, 173 protonation, 6, 49 pseudo-heavy, 28 psoriasis, 37, 47, 57, 80 psychogenic, 21 psychokinesiology, 35, 126, 150, 156, 169 psychosis, 3 pubchem, 61-62, 70, 72 pyrexia, 160 pyridoxal, 9, 101, 114, 144, 146-147, 156, 167, 169 pyridoxal-phosphate, 101 pyruvate, 12, 20, 74, 77

Q
quercetin, 7, 51 quinone, 4, 39, 41, 47, 49, 58, 136

R
radical, 8, 31-32, 39, 90, 127, 131, 138, 152 ramekin, 14 receptor, 7, 74, 77, 79, 84, 93, 103, 109, 114, 125, 130, 140 redox, 10, 127, 130-131, 134-135, 138, 152, 154, 156, 158, 167 redox-sensitive, 169 reductase, 41, 84, 140, 167, 169 reflex, 85 reflux, 85-86, 172 reproduction, 109 resveratrol, 7, 51 retinal, 114 rheumatoid, 37, 122, 125 rhinitis, 64 ribose, 154 ros, 127, 130-131, 134

ix

Index

S
s-diacetyl, 8, 130 salicylamide, 7, 64, 147 salicylanilide, 7, 64 salsolinol, 114 schiff, 9, 70, 73, 98, 136, 144, 147, 152, 154, 156, 160 schizophrenia, 30, 114, 152, 160, 165 sclerosis, 37, 45, 47, 59, 64, 80, 122, 130, 135 secretion, 23, 74, 87, 121 seizure, 103 selenide, 138 selenium, 54, 138, 140, 167, 169 selenium-based, 167 selenium-containing, 140, 167 seleno-enzyme, 138, 140 selenocysteine, 9, 54, 138, 167, 169 selenocysteine-dependent, 138 selenohydryl, 138 semi-permeable, 77 serotonin, 8, 110, 112, 114, 118, 126, 142, 156, 160 skin, 31, 33, 35, 39, 62, 94 sleep, 94, 105, 110, 147 slippery, 12, 87 smelly, 14 smoke, 37, 57, 109 smokers, 109 smorgasbord, 47, 73 snake, 4, 12, 85 sneeze, 85 sodium, 8, 31-32, 94, 127 soluble, 18 solution, 25, 31, 33, 60, 74, 92 somnolence, 160 soreness, 85 specific, 109 spermatozoa, 5, 73, 170 spider, 23 spontaneous, 90, 154 staphylococcus, 119, 124 starvation, 4-5, 10, 23, 103, 119, 121, 124, 156 statins, 41, 84 stearylamine, 7, 72 stomach, 35, 80, 82, 85, 87, 98, 100, 163 strand, 51, 80 sub-colony, 51 substrate, 35, 73, 119, 147 sucrose, 20, 23 sugar, 4, 12, 14, 18, 20, 23, 25, 74, 82, 94, 103, 152, 154, 169 sugar-daddy, 25

sulfonamide, 61, 136, 163 sulphate, 8, 73, 86, 98, 100, 108 sulpholipid, 98 sulphur, 4, 6, 12, 14, 18, 20, 25, 27, 30-31, 37, 54, 56, 73-74, 82, 94, 98, 101, 130, 134, 138, 144, 154, 167, 169-170, 172-173 sulphur-based, 101, 131, 138 sulphur-bearing, 12, 18, 25, 98, 127, 134, 138, 167 sulphur-containing, 80, 100, 136, 138, 140 sulphur-dependent, 98 sulphur-rich, 12, 18, 27, 73 sulphurated, 12, 18, 20, 23, 25, 31, 74, 108, 122, 163, 173 superoxide, 127, 130-131, 147, 150 sweat, 104 synovial, 108 synthase, 30, 101, 125, 167 synthroid, 84

T
tachycardia, 160 tartrazine, 8, 94 tautomer, 49 tea, 41, 49, 51, 85 teeth, 82, 84, 147, 170 tegretol, 160, 166 tendon, 21 terephthalate, 61 tetrahydro, 118 tetrahydro-beta, 110, 121, 126 tetramer, 49, 136 th, 121, 124 thiamine-pyrophosphate, 21 thiazolidine, 54, 98, 130 thioester, 12 thiol, 61, 109, 135, 170 thioredoxin, 167, 169 thirst, 160 throat, 4, 74, 82, 85, 140 throat-related, 85 thrombocytopenia, 160 thrush, 84 thyme, 14 thyroid, 8, 73, 77, 79, 82, 84-85, 98, 140, 167, 169 thyroid-stimulating, 77, 84 thyroiditis, 45 thyrotropin, 77 thyroxine, 84 tight-junction, 86

Index

tinnitus, 160 tissue, 21, 23, 30, 41, 56, 73-74, 77, 79, 82, 85-86, 90, 92, 103, 131, 134, 140, 172 tissue-invasive, 119 to-disease, 130 tobacco, 109 tongue, 82, 84, 147 tonsils, 73, 85-86 topiramate, 5, 9, 163, 166 toxin, 23, 25, 30, 33, 49, 51, 56, 61, 74, 79, 94, 98, 112, 154, 163, 165, 173-174 toxin-mediated, 154 toxoplasma, 121, 124 transaminase, 39 transferase, 4, 8, 105, 108-109 transferrin, 119, 124 transmembrane, 103 treg, 121-122 trigeminalneuralgia, 160 triglyceride, 103 trimer, 49, 136 trimethylcyclohexylamine, 7, 70 triphosphate, 39, 87, 127, 152 truss, 12, 14, 28, 74, 89, 92, 112, 165-166, 173 tryptophan, 5, 8-10, 119, 121-122, 124-126, 156, 160 tryptophan-starvation, 121 tsh, 77, 79, 84, 140 tuberculosis, 45 two-carbon, 110, 136 tyrosine, 80

V
valence, 73, 127 valpromide, 5, 9, 160 venom, 54, 85, 174 villi, 18 vinegar, 86 viral, 85, 122 virulence, 84, 123 viscosity, 12, 14, 56, 173 vitamin, 4, 9, 41, 45, 49, 58, 98, 100-101, 105, 114, 126-127, 144, 146-147, 150, 152, 156, 158 vomiting, 31, 94, 160, 163 vulcanization, 12, 14, 18, 25, 56, 74, 173

W
white-opaque, 119, 123 wine-fault, 51 wondreic, 18, 54, 74, 110 wondrenic, 6, 12, 14, 18, 74, 110, 141 wondro, 3-6, 11-14, 18, 20, 23, 25, 31, 54, 56, 74, 80, 82, 85, 103, 108, 122, 134, 141, 144, 173-174 wwwadverse-effectsorg, 166

U
ubiquinone, 39 ulcerative, 45, 80 unsaturated, 12, 18, 20, 37, 173 urea, 9, 66, 150, 152 urinalysis, 21 urinary, 22, 100 urine, 21, 62, 98, 100, 150 urophagia, 150 urticaria, 80, 94, 112

xi