in Hospitals, Nursing Homes and Hospices using topical ammonia oxidizing bacteria
Skin and wound infections involving antibiotic resistant organisms are serious problems in medical care. Hospitals and nursing homes present difficult infection control challenges because diverse patients carry different organisms and presenting different immune system status. The large influx of patients, staff, visitors and supplies, with diverse resident microorganisms ensures that a hospital is an open system in terms of microbiology. It is suggested that introducing and maintaining a dominant population of autotrophic ammonia oxidizing bacteria in the hospital and patient environment may significantly reduce hospital transmitted infections while also reducing selection for antibiotic resistance.
The conventional approach to infection control is the liberal use of soap and detergents to remove soil, use of chemical disinfectants [1] including oxidants such as bleach, iodine and hydrogen peroxide; cell membrane disruptants such as alcohols, cationic surfactants and phenolics and the rare and judicious use of antibiotics. Antibiotics are agents which interfere with a microorganism's internal metabolism in a fairly specific way (as opposed to non-specific oxidants and membrane disruptants). Some antimicrobial agents are being used indiscriminately such as triclosan, which inhibits lipid synthesis in target organisms.[2] Use of triclosan containing cleaning products does lead to increased resistance of exposed microorganisms to triclosan and also to other antibiotics [3] (the therapeutic and statistical significance of this is complex, a single resistant clone may be medically significant even if most clones stay susceptible). Use of antibacterial household products does not reduce the incidence of disease symptoms. [4]
Antibiotics should be used sparingly because use eventually leads to antibiotic resistance. Every time an antibiotic is used, organisms are exposed to different levels as the administered dose is absorbed, transported throughout the body, and finally metabolized or excreted. If the exposure level is less than the toxic dose, the organism will survive and if resistant will pass that resistance down to its descendents. Non-target non-pathogenic organisms can develop resistance, and this can be transferred to pathogens via plasmids. Even non-antibiotic disinfectants, such as pine oil can cause broader resistance to antibiotics through upregulation of multi-drug resistance pathways. [5] These are ATP powered transporters which excrete target compounds including antibiotics. Upregulation of these efflux pathways can cause broad spectrum resistance to many antibiotics and chemical disinfectants. [6]
In addition to the problem of resistance, killing all microorganisms including non-pathogens leaves those niches completely open for the next organism that appears. Re-inoculation of surfaces cannot be avoided because microorganisms are ubiquitous in the environment and on patients. An adult human contains more bacterial cells than human cells. [7] Mostly in the gut, but every surface exposed to the external environment including the skin, mouth, gut all have characteristic resident microorganisms. The resident commensal microbiota is a normal part of what protects against infection by pathogenic organisms. When that normal flora is disrupted, as with systemic antibiotics, the now empty niche can be colonized by pathogens, as for example a yeast infection following antibiotics.
Many pathogenic organisms can survive long term on dry inert surfaces, days, weeks and even months. [8]
I am working with organisms previously unrecognized as commensal Autotrophic Ammonia Oxidizing Bacteria (AOB). AOB are widely known in the environment, where they perform the first step in the process of nitrification, the oxidation of ammonia to nitrite. They are found in virtually all soils and all sources of water including ground, surface and sea water. I have found that AOB live on the external surfaces of many eukaryotes, where they provide a first line of defense in keeping those organisms from acquiring surface infections.
AOB are obligate autotrophs. They derive ATP only from oxidation of ammonia into nitrite and are incapable of deriving ATP from oxidation of organic compounds. There has been no report of an infection with any of these organisms and it is likely that an infection is not possible. They produce no toxins, and have no transporters to excrete them. They are slow growing with optimum doubling times of ~10 hours. They are incapable of growth on any media used to isolate pathogens.
The major product of commensal AOB is nitrite, produced from ammonia in sweat or bodily secretions. Acidified nitrite is a very potent anti-microbial and has been shown to kill antibiotic resistant organisms such as MRSA and VRE. [9] The normal pH of the skin is about 4, sufficiently acid that nitrite disproportionates to NO and NO2 and sufficiently acid that nitrite has potent antimicrobial effects. AOB are virtually completely resistant to nitrite, acidified nitrite, NO, even NO2 at levels that would be acutely toxic to other organisms (e.g. 600 ppm NO, 100 ppm NO2) [10]. Acidified nitrite is synergistically (~100x) toxic to some organisms in the presence of H2O2 and lactate. [11] Lactic acid bacteria are a large class of commensal organisms, particularly on the skin and vagina where some of the most persistent produce H2O2 [12], and because they lack hemes are fairly resistant to NOx toxicity. It is our hypothesis that AOB are natural human commensal organisms, and in conjunction with Lactic acid bacteria provide a first line of defense against skin pathogens for humans and for many eukaryotes.
AOB are associated with corrosion of natural stone, particularly calcareous stone. [13] The mechanism seems to be production of low pH via oxidation of ammonia to nitrite, the low pH then traps more ammonia from the atmosphere and the low pH causes loss of NO/NOx. Too low a pH reduces NH3 availability to the bacteria, too high a pH causes loss to the atmosphere. The growth rate is higher on calcareous rock likely because as the rock dissolves it releases trace minerals needed for growth. The only substrates needed are ammonia, CO2, O2 and minerals.
While NO/NOx species are broadly antimicrobial, the main mechanism for preventing surface infection may not one of organism death (which organisms can evolve resistance to) but rather disruption of quorum sensing (evolved resistance to disruption of quorum sensing is much more difficult and may necessitate loss of pathogenicity). .
Many microorganisms communicate by what is called quorum sensing. [14] Organisms producing a specific chemical which diffuses away, but when a sufficient number of clones of the organism are present the local concentration builds to a level that triggers a change to a different phenotype. Usually this transition is associated with the expression of virulence factors, adherence, toxins, exporters, proteases, biofilm formation. If these virulence factors are not expressed, the organism remains non-virulent even if it is a virulent strain. Virulence factors can only cause disease if they are expressed. Even transient interference with quorum sensing blocks formation of abscesses by Staphylococcus aureus. [15]
Gram-negative bacteria often use acyl homoserine lactones as quorum sensing compounds. Some eukaryotes interfere with these signals as part of their defense against infection. These interference mechanisms include oxidation [16] by hypochlorite, superoxide and NOx, and displacement by halogenated furanones. [17]
Nitric oxide is a signaling molecule used by some biofilm formers to transition from a biofilm phenotype to a planktonic type. That is, low NO triggers the transition to form a biofilm and high NO inhibits it. Bacteria in biofilms are much more resistant to antimicrobial agents both antibiotics and antiseptics. The inhibitory concentration in a biofilm is higher sometimes by more than a factor of 500. [18] Many infections particularly persistent infections are characterized by the formation of biofilms [19] which is not surprising because therapeutic doses cannot be arbitrarily increased to counter the increased resistance of biofilms. Nitrite inhibited the formation of biofilms by Staphylococcus aureus and Staphylococcus epidermidis, and caused dissociation of biofilms already formed. [20] When formation of quorums sensing compounds is blocked, even agents that are virulent pathogens exhibit reduced dissemination and reduced mortality. [21] The main virulence factor of Staphylococcus epidermidis is formation of a biofilm and this is triggered through quorum sensing. [22]
An advantage of the AOB as commensal organism suppressing heterotrophic pathogenic organisms is that AOB have very simple genomes [23] and an almost complete inability to metabolize organic compounds. It is quite likely that they would be extremely slow to evolve resistance to antibiotic compounds (if at all) because they lack precursor metabolic pathways that can be adapted to metabolizing them. If they are unable to evolve resistance, they would be unable to transmit that resistance via a plasmid to a pathogen. Because they grow ~30 times slower (10 hours vs. 20 minutes), if they could evolve resistance they would do so much slower (if at all).
It is expected that AOB are safer than the lactobacilli which are commonly consumed in large quantities as yogurt and which are specifically used as probiotics. [24] Very rarely liver abscesses and endocarditis has been attributed to lactobacilli strains which have been indistinguishable from those used by the patients as food. [25] These associations are thought to be opportunistic infections rather than primary infections. [26] Introduction of some Lactic acid bacteria into nude athymic mice does not cause illness. In any case AOB don't excrete any proteases to degrade structural proteins and are unable to metabolize animal products if they did (unlike Lactic acid bacteria). AOB are obligate aerobes and so can't colonize the gut. The only place they can live is on the external skin, where they can live long term (years) subsisting only on natural secretions (unpublished data). During long term growth on human skin AOB do suppress other bacteria including bacteria that cause body odor (unpublished data).
Many pathogens express urease which hydrolyzes urea into ammonia raising the pH of infected skin and tissues. If this ammonia were oxidized into nitrite by AOB, they would lower the pH. If the skin did become infected, any infectious organisms would metabolize proteins into amino acids and then deaminate them releasing ammonia. An AOB biofilm would oxidize that ammonia into nitrite and NO, killing or inhibiting the organism. The pH of the site where the infection is would be high due to the ammonia released. The pH dependence of surface tension (lower at high pH) would wick those fluids to regions of low pH, where the AOB are turning the cation (ammonium) into an anion (nitrite). This is thought to be a major factor on the skin where natural pH gradients distribute sweat to regions of highest AOB activity. The lowest pH that AOB can attain is limited by the availability of ammonia (ionized ammonium is not metabolized) and the decomposition of nitrous acid. A pH below 4 cannot be generated by AOB.
I have been growing these bacteria in an organic free media simulating human sweat, distilled water plus minerals and ammonia. The only source of organic is what the AOB fix from CO2 utilizing the ATP they derive by oxidizing the ammonia to nitrite. The growth media ends up being about 40 mM in nitrite, perhaps 20 times levels observed in vivo in human saliva (2 mM) [27]. Human saliva naturally contains nitrite derived from nitrate concentrated 10x over plasma levels in saliva then reduced to nitrite by tongue commensal bacteria. This nitrite is a normal part of the antimicrobial system of the mouth and gut. [28] Mice and rats have survived for years on drinking water containing 5,000 ppm sodium nitrite (72 mM) [29].
In a hospital or nursing home setting there are many surfaces which cannot be sterilized. The surface in closest proximity to a patient's wound is the patient him/herself. Patients cannot be sprayed with disinfectant for a variety of reasons, and no disinfectant is self-renewing the way a natural biofilm is. An agent that was completely natural, sufficiently mild, odorless, which actively suppressed bacteria via mechanisms which did not lead to resistance and was self-renewing could be a useful addition to normal infection control procedures. One method of use might be to spray the patient down after bathing. Another use might be to apply to surfaces after cleaning. Perhaps applying to surfaces not cleaned as regularly, the undersides of beds, walls, floors. Perhaps applying to bedding and garments.
A major problem is incontinence and skin injury due to ammonia from hydrolysis of urea in urine. AOB oxidize ammonia to nitrite, suppressing the heterotrophic bacteria that hydrolyze urea to ammonia. Formation of nitrite lowers pH, turning toxic ammonia into non-toxic ammonium. The pH can't get below about 5-6 because the availability of ammonia goes down (they don't utilize ammonium). NO and nitrite are vasodilators and would be expected to increase circulation in affected regions. The NO/NOx level can't get to locally toxic levels because hyperemia occurs first which then carries the NO/NOx away.
This is an approach that may have some advantages for in patient long term care.
[1] McDonnell G, Russell AD. Antiseptics and disinfectants: activity, action, and resistance. Clin Microbiol Rev. 1999 Jan;12(1):147-79. Review. Erratum in: Clin Microbiol Rev 2001 Jan;14(1):227.
[2] McMurry LM, Oethinger M, Levy SB. Triclosan targets lipid synthesis. Nature. 1998 Aug 6;394(6693):531-2.
[3] Aiello AE, Marshall B, Levy SB, Della-Latta P, Larson E. Relationship between triclosan and susceptibilities of bacteria isolated from hands in the community. Antimicrob Agents Chemother. 2004 Aug;48(8):2973-9.
[4] Larson EL, Lin SX, Gomez-Pichardo C, Della-Latta P. Effect of antibacterial home cleaning and handwashing products on infectious disease symptoms: a randomized, double-blind trial. Ann Intern Med. 2004 Mar 2;140(5):321-9.
[5] Moken MC, McMurry LM, Levy SB. Selection of multiple-antibiotic-resistant (mar) mutants of Escherichia coli by using the disinfectant pine oil: roles of the mar and acrAB loci. Antimicrob Agents Chemother. 1997 Dec;41(12):2770-2.
[6] Poole K. Efflux-mediated antimicrobial resistance J. Antimicrob. Chemother., July 1, 2005; 56(1): 20 - 51.
[7] Xu J, Gordon JI. Inaugural Article: Honor thy symbionts. Proc Natl Acad Sci U S A. 2003 Sep 2;100(18):10452-9.
[8] Kramer A, Schwebke I, Kampf G. How long do nosocomial pathogens persist on inanimate surfaces? A systematic review. BMC Infect Dis. 2006 Aug 16;6:130.
[9] Rao A, Jump RL, Pultz NJ, Pultz MJ, Donskey CJ. In vitro killing of nosocomial pathogens by acid and acidified nitrite. Antimicrob Agents Chemother. 2006 Nov;50(11):3901-4.
[10] Schmidt I, Hermelink C, van de Pas-Schoonen K, Strous M, op den Camp HJ, Kuenen JG, Jetten MS. Anaerobic ammonia oxidation in the presence of nitrogen oxides (NO(x)) by two different lithotrophs. Appl Environ Microbiol. 2002 Nov;68(11):5351-7.
[11] Kono Y, Shibata H, Adachi K, Tanaka K. Lactate-dependent killing of Escherichia coli by nitrite plus hydrogen peroxide: a possible role of nitrogen dioxide. Arch Biochem Biophys. 1994 May 15;311(1):153-9.
[12] Vallor AC, Antonio MA, Hawes SE, Hillier SL. Factors associated with acquisition of, or persistent colonization by, vaginal lactobacilli: role of hydrogen peroxide production. J Infect Dis. 2001 Dec 1;184(11):1431-6.
[13] Mansch R, Bock E. Biodeterioration of natural stone with special reference to nitrifying bacteria. Biodegradation. 1998;9(1):47-64.
[14] Schauder S, Bassler BL. The languages of bacteria. Genes Dev. 2001 Jun 15;15(12):1468-80. Review.
[15] Wright JS 3rd, Jin R, Novick RP. Transient interference with staphylococcal quorum sensing blocks abscess formation. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1691-6.
[16] Rothfork JM, Timmins GS, Harris MN, Chen X, Lusis AJ, Otto M, Cheung AL, Gresham HD. Inactivation of a bacterial virulence pheromone by phagocyte-derived oxidants: new role for the NADPH oxidase in host defense. Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13867-72.
[17] Hentzer M, Riedel K, Rasmussen TB, Heydorn A, Andersen JB, Parsek MR, Rice SA, Eberl L, Molin S, Høiby N, Kjelleberg S, Givskov M. Inhibition of quorum sensing in Pseudomonas aeruginosa biofilm bacteria by a halogenated furanone compound. Microbiology. 2002 Jan;148(Pt 1):87-102.
[18] Olson ME, Ceri H, Morck DW, Buret AG, Read RR. Biofilm bacteria: formation and comparative susceptibility to antibiotics. Can J Vet Res. 2002 Apr;66(2):86-92.
[19] Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: a common cause of persistent infections. Science. 1999 May 21;284(5418):1318-22. Review.
[20] Schlag S, Nerz C, Birkenstock TA, Altenberend F, Götz F. Inhibition of staphylococcal biofilm formation by nitrite. J Bacteriol. 2007 Nov;189(21):7911-9.
[21] Lesic B, Lépine F, Déziel E, Zhang J, Zhang Q, Padfield K, Castonguay MH, Milot S, Stachel S, Tzika AA, Tompkins RG, Rahme LG. Inhibitors of pathogen intercellular signals as selective anti-infective compounds. PLoS Pathog. 2007 Sep 14;3(9):1229-39.
[22] Xu L, Li H, Vuong C, Vadyvaloo V, Wang J, Yao Y, Otto M, Gao Q. Role of the luxS quorum-sensing system in biofilm formation and virulence of Staphylococcus epidermidis. Infect Immun. 2006 Jan;74(1):488-96.
[23] Chain P, Lamerdin J, Larimer F, Regala W, Lao V, Land M, Hauser L, Hooper A, Klotz M, Norton J, Sayavedra-Soto L, Arciero D, Hommes N, Whittaker M, Arp D. Complete genome sequence of the ammonia-oxidizing bacterium and obligate chemolithoautotroph Nitrosomonas europaea. J Bacteriol. 2003 May;185(9):2759-73.
[24] Boyle RJ, Robins-Browne RM, Tang ML. Probiotic use in clinical practice: what are the risks? Am J Clin Nutr. 2006 Jun;83(6):1256-64; quiz 1446-7.
[25] Sipsas N, Zonios D, Kordossis T. Safety of Lactobacillus strains used as probiotic agents. Clin Infect Dis 2002; 34:1283–4 .
[26] Ishibashi N, Yamazaki S. Probiotics and safety. Am J Clin Nutr. 2001 Feb;73(2 Suppl):465S-470S.
[27] Pannala AS, Mani AR, Spencer JP, Skinner V, Bruckdorfer KR, Moore KP, Rice-Evans CA. The effect of dietary nitrate on salivary, plasma, and urinary nitrate metabolism in humans. Free Radic Biol Med. 2003 Mar 1;34(5):576-84.
[28] Dykhuizen RS, Frazer R, Duncan C, Smith CC, Golden M, Benjamin N, Leifert C. Antimicrobial effect of acidified nitrite on gut pathogens: importance of dietary nitrate in host defense. Antimicrob Agents Chemother. 1996 Jun;40(6):1422-5.
[29] National Toxicology Program. Toxicology and carcinogenesis studies of sodium nitrite (CAS NO. 7632-00-0) in F344/N rats and B6C3F1 mice (drinking water studies). Natl Toxicol Program Tech Rep Ser. 2001 May;495:7-273.
Showing posts with label skin disease. Show all posts
Showing posts with label skin disease. Show all posts
Thursday, June 5, 2008
Sunday, May 25, 2008
Is the secret to good health in a bowl of cherries?
In a word, no. As we all know the secret to good health is NO.
I received a question regarding a product that mentions specific antioxidant activity against peroxynitrite. Rather than leave the answer as a comment I am posting it as a blog. I looked at the CherryActive website and while their product may have abundant antioxidants of certain (and uncharacterized) types there is no compelling evidence on their website or in the literature that consuming supplemental antioxidants (of any type) has any positive health value and some modest evidence that modest levels supplemental antioxidants are actually harmful.
Cherries as a unique neutraceutical? Unlikely at best.
Even supposing that supplemental antioxidants had good effects, the only place those good effects could occur would be inside cells at the sites of free radical formation. Ingested antioxidants must survive digestion in the stomach and gut, be absorbed through the gut into the blood stream, be transported through the portal system, be metabolized by the liver (most likely) and then distributed by the blood stream throughout the body in exactly the correct amounts of each type of antioxidant in each different tissue compartment simultaneously. Is there any evidence that such things might occur with intact cherry antioxidants from this specific type of cherry? (I say intact because that is what the in vitro tests of cherry juice measured, antioxidant capacity before digestion and absorption, not afterward.) Not really. Perhaps it could happen with antioxidants that human physiology evolved to work best with, but such evolution would take a long time, many generations. For specific antioxidants to be a continuous and integral part of the human diet for many generations, those antioxidants could not be unique to a single food type which would only be available in the "wild" for a short period while in season (perhaps 1 month out of the year for cherries).
The only way humans could evolve physiology adapted to cherries as the ideal source of specific and unique antioxidants would be if the lack of the ability to utilize cherry antioxidants produces such a detriment to survival and reproduction that humans who could utilize those antioxidants had a substantial advantage. There certainly has been no report of the kinds of adverse effects from not consuming cherries that would be required to provide sufficient evolutionary pressure for humans to evolve a physiology that matched the phytochemical profile of cherries, particularly not a particular type of cherries. In any case, cherries were domesticated pretty recently, in Europe, Asia and North America (not Africa where most of human evolution occurred).
Free radicals, peroxynitrite, and superoxide: They say it like it is a bad thing.
They cite an article on NO and peroxynitrite (with the author's name misspelled). The article is a pretty good review; however the authors don't seem to appreciate the (extreme) importance of the location of the formation of superoxide to the location of the formation of peroxynitrite. Superoxide is a charged anion (as is peroxynitrite). Lipid membranes block anions very well. Superoxide can't pass through a lipid membrane except through an anion channel. Virtually all superoxide is generated inside of vesicles and is isolated from the cytoplasm by a lipid membrane. Mitochondria do generate a lot of superoxide, but it is vectorally produced to the inside of the inner matrix. There are 2 lipid membranes confining the superoxide, and the mitochondrial potential (~140 mV) keeps anions inside too. Superoxide (as superoxide) can't get out of mitochondria while the potential is intact and/or while the membranes are intact. Superoxide is dismutated to H2O2 and that being uncharged can diffuse out. Acute effects of superoxide or peroxynitrite in mitochondria would be expected to be confined to the inner matrix. Peroxynitrite does decompose producing NO2 which is uncharged and so can diffuse through the lipid membranes. NO2 could diffuse out, but NO2 is quite reactive and so can't diffuse very far. Nitration of mitochondrial proteins not in the inner matrix might be mediated through NO2. There might be a number of important control mechanisms utilizing nitration of mitochondrial proteins with NO2. Nitration of mitochondrial proteins is known to be important. The detailed mechanisms of that are still mostly unknown.
The other main sites of superoxide production are microsomes where a lot of metabolism of xenobiotic (and non-xenobiotic) chemicals takes place utilizing the cytochrome P450 enzymes. In microsomes too, the superoxide is vectorally produced to the inside of the vesicle. Cytochrome P450 enzymes are involved in a great many synthetic operations in the body. That is how cholesterol is synthesized, also steroids, and also how many toxins are rendered less toxic (and sometimes more toxic). Virtually all of the P450 enzymes are highly uncoupled, that is they make a lot of superoxide. Mitochondria only make a few percent superoxide from the O2 they consume, the P450 enzymes make a lot more, in some cases as much as 50% of the O2 consumed ends up as superoxide. This superoxide is important in the regulation of the activity of the P450 enzymes.
Normally the P450 enzymes are inhibited by NO. NO binds to the active site where O2 binds and prevents O2 from binding and beginning the reaction. Normally there is a little activity, so that electrons trickle through and generate enough superoxide to keep the NO level in balance. When the P450 enzyme becomes activated, the superoxide level goes up, the NO level goes down, and the activity of the P450 enzyme goes up, metabolizing what ever normal or xenobiotic chemical needs metabolizing. The pulse of superoxide and other free radicals produced by that the pulse of metabolic activity has important regulatory effects.
The oxidation of xenobiotic chemicals is called Phase I of the drug metabolizing process. This is followed by Phase II of the drug metabolizing process where the oxidation products are tagged with molecules that make them excretable. This includes glutathione, sulfate and even glucose. Glutathione and glucose tag the chemical for excretion in the bile, sulfate tags it for excretion in the urine.
The free radicals and electrophiles produced during the Phase I process cause the expression of the Phase II genes which then detoxify those oxidation products by conjugating them so they can be excreted. There is considerable thought that a significant part of the observed health effects of different phytochemicals in food is due to their metabolism by the P450 system, the normal generation of superoxide and other free radicals, and the stimulation of the Phase II system by those free radicals. It may be the production of free radicals rather than the destruction of free radicals that is mechanism by which fruits and vegetables are protective (if they actually are protective which is not clear). There have actually been no blinded studies of food intake on health.
In vitro, peroxynitrite is only observed when there is near stoichiometric production of superoxide and NO. When either is in several fold excess, peroxynitrite and effects attributed to peroxynitrite are not observed. In other words the problem of peroxynitrite (if is actually is a problem) is likely due to either not enough superoxide or not enough NO, rather than from too much of either. The association of nitrated proteins with adverse health states may be an effect not a cause. Peroxynitrite only occurs when the quantities are essentially equal and equal production occurs for extended periods of time. To me that sounds more like a signaling problem, that the "signal" of peroxynitrite wasn't high enough to switch physiology hard enough to get it back into the "good" state of either excess NO or excess superoxide. If that is the case, blocking peroxynitrite signaling would be a bad thing and would exacerbate peroxynitrite problems.
There is extremely good evidence that free radicals are extremely important signaling molecules that are absolutely essential in the right amounts at the right time in the right place and for the right duration. Free radicals tend to be small, are extremely reactive toward many different molecules, and have a very low background (because they are so reactive). Those properties make free radicals excellent signaling molecules capable of achieving a high signal to noise ratio even at very low levels and with very fast kinetics on a large variety of biological molecules simultaneously over multiple different time scales. The pathways controlled by free radical reactions include just about everything, energy production, gene transcription, the cell cycle, DNA replication, ischemic preconditioning. There are just about no physiological pathways that are not closely coupled to pathways utilizing free radicals as signaling molecules. Those ideal properties of free radicals as signaling molecules also make experiments to understand the signaling pathways those free radicals are involved in very challenging. It is not at all surprising that over evolutionary time organisms would evolve physiology to use such ideal signaling molecules many times, at many places, in many tissue compartments, for many reasons to do many things by many different pathways over many different time scales by many different mechanisms.
Signaling by free radicals as signaling molecules are only going to work well in the media they evolved to work in. That media is quite complex (multiple different phases, i.e. lipid and aqueous of different sizes and compositions), and is different in each tissue compartment (blood, plasma, CFS, cytoplasm, mitochondrial matrix, depot fat, liver, kidney, etc, etc.). Adding different compounds that bind strongly to free radicals (that would be supplemental antioxidants) is virtually certain to perturb that media and interfere with that signaling in complex ways.
All the large, long term double-blind placebo controlled trials of supplemental antioxidants have shown either no effect or a slight negative effect. A good recent meta-analysis summarizing many of those antioxidant trials is in the NEJM. A more recent Cochrane review on the subject (which I have only seen the abstract of) found essentially no benefit from supplemental antioxidants.
To me, that is not at all a surprise. My own feeling is that free radical signaling is too important to organisms for them to allow the background environment that signaling occurs in to be set "at random" by arbitrary (and in the wild highly variable) dietary levels of antioxidants. Humans (and every other organism) didn't evolve for their physiology to be optimized by consuming a certain number of a certain type of cherries (or other specific foods) per day. There simply has to be feedback control(s) that regulate the internal environment(s) the free radical signal(s) propagate in. Oxidative stress is such an important parameter to regulate that organisms "learned" how to regulate their own state of oxidative stress billions of year ago. Bacteria regulate their level of oxidative stress (as does every other organism). Stress response genes, including genes for responding to oxidative stress are among the most highly conserved genes in organisms. Why would we think that humans somehow lost that ability? Especially when there is no evidence that humans have lost it. If a particular human did lose the ability to regulate oxidative stress, death would occur in a few minutes (or less).
There are many compounds in vivo that have antioxidant properties in vitro. The natural modulation of the concentrations of a few dozen such compounds in vivo would be difficult to measure, particularly since the antioxidant properties of these molecules can be different by many orders of magnitude. For example NO is an excellent antioxidant. It has a free electron and reacts with free radicals at near diffusion limited kinetics. It is a better antioxidant than is Vitamin E by about a factor of 5,000.
NO rapidly reacts with peroxidized lipids, quenching the free radical mediated chain reaction. NO reacts with peroxidized lipid radicals considerably faster than does vitamin E (~2E9 M-1 s-1 vs. 5E5), and considerably faster than the propagation reaction (1.3E3). In vitro, 7 nM/min NO was as effective as 50 µM/L α- tocopherol in free radical catalyzed linoleic acid oxidation. Oxidative consumption of α- tocopherol did not occur until NO concentrations fell below ~10 nM/L. The combination of NO and α- tocopherol prevented lipid oxidation better than either alone. A slight increase in the NO level has a much larger effect on antioxidant activity than a much larger increase in Vitamin E levels.
10 nM/L NO is somewhat higher than the normal background (which is around 1 nM/L). 1 nM/L is about 30 parts per trillion by weight. There are no techniques to measure that in vivo on the length and time scales that are important. The only reason we know that the basal level is about that is because at higher levels NO activates sGC and causes local vasodilation which brings in oxyhemoglobin which removes the NO.
Summary antioxidant effects
There is no compelling evidence that supplemental antioxidants of any type have any positive health value. Everything important in physiology is regulated by feedback regulation. Oxidative stress is no exception. Attempting to perturb physiology artificially will simply force it to work harder to maintain the setpoint it is trying to achieve. I think this is the reason why all the large double blind placebo controlled studies show slight negative effects of supplemental antioxidants. Diet choice is a major compensatory pathway by which an organism regulates its state of oxidative stress. When people have high levels of oxidative stress they choose to eat foods with lower levels of antioxidants so the body doesn't need to destroy them metabolically (by generating even more superoxide). Diet choice is an effect of ill health, not the cause.
Gout
They mention that cherries seem to have pharmacological effects at reducing urate levels, and imply (or actually state) that lowering urate levels would be a good thing. They cite a paper that does show an acute lowering of plasma urate levels (funded in part by the California Cherry Advisory Board). The reductions reported in plasma urate are quite small and (in my opinion) not physiologically important. The "normal range" for plasma urate (in females) is 139-393 micromoles/L (serum). The levels measured in this study were all within the normal range, the reduction was small and it was an extremely short study (5 hours). Urinary levels of urate did increase in the cherry group. It isn't clear what is the mechanism for the very modest plasma urate reduction. If it is due to an acute inhibition due to cherry flavonoids, in the longer term (days, weeks, months), there may be compensatory increase in the metabolic systems that produce urate such that there would be no chronic effect, or the chronic effect could be to increase urate levels. If it is increased urinary excretion, levels in the urine are what determine the formation of sodium urate kidney stones. Physiology is inherently non-linear with feedback and hysteresis. The only way to determine if a treatment has a long term effect is to measure the effects of that treatment long term.
Gout is caused by the formation and deposition of crystals of sodium urate. Urate is the terminal metabolite of purines which are heterocyclic nitrogen containing bases used in RNA, DNA, ATP and some other fundamental biochemical pathways. Normally they are ultimately degraded to xanthine and then oxidized by xanthine oxidoreductase into urate. For gout to occur, the solubility of sodium urate crystals has to be exceeded in the relevant tissue compartment and nucleation of sodium urate has to occur. If the sodium urate level is below the solubility limit, further reductions in urate levels will have no preventative effect.
The usual treatment for gout is administration of allopurinol which inhibits xanthine oxidoreductase. A great many natural flavonoids also inhibit xanthine oxidase in vitro. Many natural flavonoids have urate lowering activity in vivo. Hypersensitivity to allopurinol is a significant triggering mechanism for Stevens Johnson Syndrome. The mechanism by which that happens is not understood. I would be concerned that any pharmacologically active compound that inhibits xanthine oxidase might have side effect profiles similar to allopurinol. That includes the unidentified compounds in cherries.
It is not clear that a lower plasma urate level is actually a benefit. There is pretty good evidence of an association of higher plasma urate with a reduced incidence of Parkinson's disease. There may also be a protective effect of urate in a number of diseases (I have only seen the abstract of this), but which is cause and which is effect is not clear. Urate is a pretty good antioxidant itself. Trading an insignificant reduction of the possibility of getting gout for a significant increase in the possibility of getting Parkinson's or Alzheimer's disease isn't a choice that I would make.
Without knowing one's urate status, taking pharmacologically active agents to lower it does not seem prudent to me. If one did need to lower one's urate level, using a compound of known composition, purity, efficacy and side-effect profile produced under controlled conditions seems more prudent to me than using some fruit juice. Allopurinol is generic so it is cheap, most insurance would pay for it with the proper medical indication (which is the only reason you want to take anything pharmacologically active), and you need to have your urate status actually measured by your MD in case that joint pain is actually something more serious.
Muscle damage
The CherryActive website claims
"Research study from University of Vermont and published in the British Journal of Sports Medicine shows that drinking cherry juice can help repair damaged muscle leading to an increased recovery rate from strenuous exercise"
The actual report (funded by Cherrypharm Inc and done by researchers who each own 2.5% equity in Cherrypharm Inc) only talks about symptoms and says:
"Although the results of this study indicate a protective effect of cherry juice, it is not possible to conclude that cherry juice supplementation prevented muscle damage, because only two of four indirect markers of damage showed an effect."
They used a proprietary blend of cherry juice and apple juice.
"The cherry juice blend was prepared by mixing freshly prepared tart cherry juice with commercially available apple juice in a proprietary ratio (Cherrypharm Inc, West Hartford, Connecticut, USA). Frozen tart cultivar Montmorency cherries were used to prepare the cherry juice following standard procedures that simulate industrial processing."
They only used subjective measures of muscle function, how the subjects felt about how their muscles were functioning. They specifically chose to not use objective measures of muscle damage, myoglobin and/or creatine kinase. They rationalize their decision in terms of potential confounding due to unauthorized muscle activity not within the protocol they were testing. Why they considered that objective instrumental measures of muscle injury would be more subject to confounding than subjective measures is not explained. I suspect it has to do with each of them owning 2.5% of Cherrypharm Inc. They suggest that future tests might be run using actual measurements but no future papers have been forthcoming. Either they never did the tests, or they did the tests and did not publish them.
They suggest no plausible mechanism by which consuming a cherry juice apple juice blend would have any effects on muscle damage or healing.
The statements on the CherryActive website are clearly not supported by the research they cite. They are being dishonest to pretend that it does.
Conclusion.
Cherries are a fine and tasty food. I have nothing against cherries, I like cherries and I eat cherries when in season. Moderate consumption of cherries as part of a varied diet is likely no more and no less healthful than moderate consumption of any other fruits and vegetables. Cherries do tend to be somewhat pricy for me even when in season. The cherry products sold by CherryActive are extremely pricy. I see no reason to consume any of CherryActive's products other than as simple foods, and virtually any other source of cherries would be more economical as are many other fruits and vegetables.
I didn't know very much about cherries when I started looking into CherryActive. I suspect that I will keep my cherry intake more moderate primarily because of the xanthine oxidoreductase inhibition effects. An extremely important property of xanthine oxidoreductase is the reduction of nitrate to nitrite and the reduction of nitrite to NO. NO from nitrite is extremely important in many emergency and extreme stress situations. Nitrite is substantially protective against infarcts due to acute ischemia in heart muscle, liver, kidney, brain. Messing with the xanthine oxidoreductase system by inhibiting it with cherries is not something one should do without good reasons. The reasons that CherryActive provide are not good enough for me.
I received a question regarding a product that mentions specific antioxidant activity against peroxynitrite. Rather than leave the answer as a comment I am posting it as a blog. I looked at the CherryActive website and while their product may have abundant antioxidants of certain (and uncharacterized) types there is no compelling evidence on their website or in the literature that consuming supplemental antioxidants (of any type) has any positive health value and some modest evidence that modest levels supplemental antioxidants are actually harmful.
Cherries as a unique neutraceutical? Unlikely at best.
Even supposing that supplemental antioxidants had good effects, the only place those good effects could occur would be inside cells at the sites of free radical formation. Ingested antioxidants must survive digestion in the stomach and gut, be absorbed through the gut into the blood stream, be transported through the portal system, be metabolized by the liver (most likely) and then distributed by the blood stream throughout the body in exactly the correct amounts of each type of antioxidant in each different tissue compartment simultaneously. Is there any evidence that such things might occur with intact cherry antioxidants from this specific type of cherry? (I say intact because that is what the in vitro tests of cherry juice measured, antioxidant capacity before digestion and absorption, not afterward.) Not really. Perhaps it could happen with antioxidants that human physiology evolved to work best with, but such evolution would take a long time, many generations. For specific antioxidants to be a continuous and integral part of the human diet for many generations, those antioxidants could not be unique to a single food type which would only be available in the "wild" for a short period while in season (perhaps 1 month out of the year for cherries).
The only way humans could evolve physiology adapted to cherries as the ideal source of specific and unique antioxidants would be if the lack of the ability to utilize cherry antioxidants produces such a detriment to survival and reproduction that humans who could utilize those antioxidants had a substantial advantage. There certainly has been no report of the kinds of adverse effects from not consuming cherries that would be required to provide sufficient evolutionary pressure for humans to evolve a physiology that matched the phytochemical profile of cherries, particularly not a particular type of cherries. In any case, cherries were domesticated pretty recently, in Europe, Asia and North America (not Africa where most of human evolution occurred).
Free radicals, peroxynitrite, and superoxide: They say it like it is a bad thing.
They cite an article on NO and peroxynitrite (with the author's name misspelled). The article is a pretty good review; however the authors don't seem to appreciate the (extreme) importance of the location of the formation of superoxide to the location of the formation of peroxynitrite. Superoxide is a charged anion (as is peroxynitrite). Lipid membranes block anions very well. Superoxide can't pass through a lipid membrane except through an anion channel. Virtually all superoxide is generated inside of vesicles and is isolated from the cytoplasm by a lipid membrane. Mitochondria do generate a lot of superoxide, but it is vectorally produced to the inside of the inner matrix. There are 2 lipid membranes confining the superoxide, and the mitochondrial potential (~140 mV) keeps anions inside too. Superoxide (as superoxide) can't get out of mitochondria while the potential is intact and/or while the membranes are intact. Superoxide is dismutated to H2O2 and that being uncharged can diffuse out. Acute effects of superoxide or peroxynitrite in mitochondria would be expected to be confined to the inner matrix. Peroxynitrite does decompose producing NO2 which is uncharged and so can diffuse through the lipid membranes. NO2 could diffuse out, but NO2 is quite reactive and so can't diffuse very far. Nitration of mitochondrial proteins not in the inner matrix might be mediated through NO2. There might be a number of important control mechanisms utilizing nitration of mitochondrial proteins with NO2. Nitration of mitochondrial proteins is known to be important. The detailed mechanisms of that are still mostly unknown.
The other main sites of superoxide production are microsomes where a lot of metabolism of xenobiotic (and non-xenobiotic) chemicals takes place utilizing the cytochrome P450 enzymes. In microsomes too, the superoxide is vectorally produced to the inside of the vesicle. Cytochrome P450 enzymes are involved in a great many synthetic operations in the body. That is how cholesterol is synthesized, also steroids, and also how many toxins are rendered less toxic (and sometimes more toxic). Virtually all of the P450 enzymes are highly uncoupled, that is they make a lot of superoxide. Mitochondria only make a few percent superoxide from the O2 they consume, the P450 enzymes make a lot more, in some cases as much as 50% of the O2 consumed ends up as superoxide. This superoxide is important in the regulation of the activity of the P450 enzymes.
Normally the P450 enzymes are inhibited by NO. NO binds to the active site where O2 binds and prevents O2 from binding and beginning the reaction. Normally there is a little activity, so that electrons trickle through and generate enough superoxide to keep the NO level in balance. When the P450 enzyme becomes activated, the superoxide level goes up, the NO level goes down, and the activity of the P450 enzyme goes up, metabolizing what ever normal or xenobiotic chemical needs metabolizing. The pulse of superoxide and other free radicals produced by that the pulse of metabolic activity has important regulatory effects.
The oxidation of xenobiotic chemicals is called Phase I of the drug metabolizing process. This is followed by Phase II of the drug metabolizing process where the oxidation products are tagged with molecules that make them excretable. This includes glutathione, sulfate and even glucose. Glutathione and glucose tag the chemical for excretion in the bile, sulfate tags it for excretion in the urine.
The free radicals and electrophiles produced during the Phase I process cause the expression of the Phase II genes which then detoxify those oxidation products by conjugating them so they can be excreted. There is considerable thought that a significant part of the observed health effects of different phytochemicals in food is due to their metabolism by the P450 system, the normal generation of superoxide and other free radicals, and the stimulation of the Phase II system by those free radicals. It may be the production of free radicals rather than the destruction of free radicals that is mechanism by which fruits and vegetables are protective (if they actually are protective which is not clear). There have actually been no blinded studies of food intake on health.
In vitro, peroxynitrite is only observed when there is near stoichiometric production of superoxide and NO. When either is in several fold excess, peroxynitrite and effects attributed to peroxynitrite are not observed. In other words the problem of peroxynitrite (if is actually is a problem) is likely due to either not enough superoxide or not enough NO, rather than from too much of either. The association of nitrated proteins with adverse health states may be an effect not a cause. Peroxynitrite only occurs when the quantities are essentially equal and equal production occurs for extended periods of time. To me that sounds more like a signaling problem, that the "signal" of peroxynitrite wasn't high enough to switch physiology hard enough to get it back into the "good" state of either excess NO or excess superoxide. If that is the case, blocking peroxynitrite signaling would be a bad thing and would exacerbate peroxynitrite problems.
There is extremely good evidence that free radicals are extremely important signaling molecules that are absolutely essential in the right amounts at the right time in the right place and for the right duration. Free radicals tend to be small, are extremely reactive toward many different molecules, and have a very low background (because they are so reactive). Those properties make free radicals excellent signaling molecules capable of achieving a high signal to noise ratio even at very low levels and with very fast kinetics on a large variety of biological molecules simultaneously over multiple different time scales. The pathways controlled by free radical reactions include just about everything, energy production, gene transcription, the cell cycle, DNA replication, ischemic preconditioning. There are just about no physiological pathways that are not closely coupled to pathways utilizing free radicals as signaling molecules. Those ideal properties of free radicals as signaling molecules also make experiments to understand the signaling pathways those free radicals are involved in very challenging. It is not at all surprising that over evolutionary time organisms would evolve physiology to use such ideal signaling molecules many times, at many places, in many tissue compartments, for many reasons to do many things by many different pathways over many different time scales by many different mechanisms.
Signaling by free radicals as signaling molecules are only going to work well in the media they evolved to work in. That media is quite complex (multiple different phases, i.e. lipid and aqueous of different sizes and compositions), and is different in each tissue compartment (blood, plasma, CFS, cytoplasm, mitochondrial matrix, depot fat, liver, kidney, etc, etc.). Adding different compounds that bind strongly to free radicals (that would be supplemental antioxidants) is virtually certain to perturb that media and interfere with that signaling in complex ways.
All the large, long term double-blind placebo controlled trials of supplemental antioxidants have shown either no effect or a slight negative effect. A good recent meta-analysis summarizing many of those antioxidant trials is in the NEJM. A more recent Cochrane review on the subject (which I have only seen the abstract of) found essentially no benefit from supplemental antioxidants.
To me, that is not at all a surprise. My own feeling is that free radical signaling is too important to organisms for them to allow the background environment that signaling occurs in to be set "at random" by arbitrary (and in the wild highly variable) dietary levels of antioxidants. Humans (and every other organism) didn't evolve for their physiology to be optimized by consuming a certain number of a certain type of cherries (or other specific foods) per day. There simply has to be feedback control(s) that regulate the internal environment(s) the free radical signal(s) propagate in. Oxidative stress is such an important parameter to regulate that organisms "learned" how to regulate their own state of oxidative stress billions of year ago. Bacteria regulate their level of oxidative stress (as does every other organism). Stress response genes, including genes for responding to oxidative stress are among the most highly conserved genes in organisms. Why would we think that humans somehow lost that ability? Especially when there is no evidence that humans have lost it. If a particular human did lose the ability to regulate oxidative stress, death would occur in a few minutes (or less).
There are many compounds in vivo that have antioxidant properties in vitro. The natural modulation of the concentrations of a few dozen such compounds in vivo would be difficult to measure, particularly since the antioxidant properties of these molecules can be different by many orders of magnitude. For example NO is an excellent antioxidant. It has a free electron and reacts with free radicals at near diffusion limited kinetics. It is a better antioxidant than is Vitamin E by about a factor of 5,000.
NO rapidly reacts with peroxidized lipids, quenching the free radical mediated chain reaction. NO reacts with peroxidized lipid radicals considerably faster than does vitamin E (~2E9 M-1 s-1 vs. 5E5), and considerably faster than the propagation reaction (1.3E3). In vitro, 7 nM/min NO was as effective as 50 µM/L α- tocopherol in free radical catalyzed linoleic acid oxidation. Oxidative consumption of α- tocopherol did not occur until NO concentrations fell below ~10 nM/L. The combination of NO and α- tocopherol prevented lipid oxidation better than either alone. A slight increase in the NO level has a much larger effect on antioxidant activity than a much larger increase in Vitamin E levels.
10 nM/L NO is somewhat higher than the normal background (which is around 1 nM/L). 1 nM/L is about 30 parts per trillion by weight. There are no techniques to measure that in vivo on the length and time scales that are important. The only reason we know that the basal level is about that is because at higher levels NO activates sGC and causes local vasodilation which brings in oxyhemoglobin which removes the NO.
Summary antioxidant effects
There is no compelling evidence that supplemental antioxidants of any type have any positive health value. Everything important in physiology is regulated by feedback regulation. Oxidative stress is no exception. Attempting to perturb physiology artificially will simply force it to work harder to maintain the setpoint it is trying to achieve. I think this is the reason why all the large double blind placebo controlled studies show slight negative effects of supplemental antioxidants. Diet choice is a major compensatory pathway by which an organism regulates its state of oxidative stress. When people have high levels of oxidative stress they choose to eat foods with lower levels of antioxidants so the body doesn't need to destroy them metabolically (by generating even more superoxide). Diet choice is an effect of ill health, not the cause.
Gout
They mention that cherries seem to have pharmacological effects at reducing urate levels, and imply (or actually state) that lowering urate levels would be a good thing. They cite a paper that does show an acute lowering of plasma urate levels (funded in part by the California Cherry Advisory Board). The reductions reported in plasma urate are quite small and (in my opinion) not physiologically important. The "normal range" for plasma urate (in females) is 139-393 micromoles/L (serum). The levels measured in this study were all within the normal range, the reduction was small and it was an extremely short study (5 hours). Urinary levels of urate did increase in the cherry group. It isn't clear what is the mechanism for the very modest plasma urate reduction. If it is due to an acute inhibition due to cherry flavonoids, in the longer term (days, weeks, months), there may be compensatory increase in the metabolic systems that produce urate such that there would be no chronic effect, or the chronic effect could be to increase urate levels. If it is increased urinary excretion, levels in the urine are what determine the formation of sodium urate kidney stones. Physiology is inherently non-linear with feedback and hysteresis. The only way to determine if a treatment has a long term effect is to measure the effects of that treatment long term.
Gout is caused by the formation and deposition of crystals of sodium urate. Urate is the terminal metabolite of purines which are heterocyclic nitrogen containing bases used in RNA, DNA, ATP and some other fundamental biochemical pathways. Normally they are ultimately degraded to xanthine and then oxidized by xanthine oxidoreductase into urate. For gout to occur, the solubility of sodium urate crystals has to be exceeded in the relevant tissue compartment and nucleation of sodium urate has to occur. If the sodium urate level is below the solubility limit, further reductions in urate levels will have no preventative effect.
The usual treatment for gout is administration of allopurinol which inhibits xanthine oxidoreductase. A great many natural flavonoids also inhibit xanthine oxidase in vitro. Many natural flavonoids have urate lowering activity in vivo. Hypersensitivity to allopurinol is a significant triggering mechanism for Stevens Johnson Syndrome. The mechanism by which that happens is not understood. I would be concerned that any pharmacologically active compound that inhibits xanthine oxidase might have side effect profiles similar to allopurinol. That includes the unidentified compounds in cherries.
It is not clear that a lower plasma urate level is actually a benefit. There is pretty good evidence of an association of higher plasma urate with a reduced incidence of Parkinson's disease. There may also be a protective effect of urate in a number of diseases (I have only seen the abstract of this), but which is cause and which is effect is not clear. Urate is a pretty good antioxidant itself. Trading an insignificant reduction of the possibility of getting gout for a significant increase in the possibility of getting Parkinson's or Alzheimer's disease isn't a choice that I would make.
Without knowing one's urate status, taking pharmacologically active agents to lower it does not seem prudent to me. If one did need to lower one's urate level, using a compound of known composition, purity, efficacy and side-effect profile produced under controlled conditions seems more prudent to me than using some fruit juice. Allopurinol is generic so it is cheap, most insurance would pay for it with the proper medical indication (which is the only reason you want to take anything pharmacologically active), and you need to have your urate status actually measured by your MD in case that joint pain is actually something more serious.
Muscle damage
The CherryActive website claims
"Research study from University of Vermont and published in the British Journal of Sports Medicine shows that drinking cherry juice can help repair damaged muscle leading to an increased recovery rate from strenuous exercise"
The actual report (funded by Cherrypharm Inc and done by researchers who each own 2.5% equity in Cherrypharm Inc) only talks about symptoms and says:
"Although the results of this study indicate a protective effect of cherry juice, it is not possible to conclude that cherry juice supplementation prevented muscle damage, because only two of four indirect markers of damage showed an effect."
They used a proprietary blend of cherry juice and apple juice.
"The cherry juice blend was prepared by mixing freshly prepared tart cherry juice with commercially available apple juice in a proprietary ratio (Cherrypharm Inc, West Hartford, Connecticut, USA). Frozen tart cultivar Montmorency cherries were used to prepare the cherry juice following standard procedures that simulate industrial processing."
They only used subjective measures of muscle function, how the subjects felt about how their muscles were functioning. They specifically chose to not use objective measures of muscle damage, myoglobin and/or creatine kinase. They rationalize their decision in terms of potential confounding due to unauthorized muscle activity not within the protocol they were testing. Why they considered that objective instrumental measures of muscle injury would be more subject to confounding than subjective measures is not explained. I suspect it has to do with each of them owning 2.5% of Cherrypharm Inc. They suggest that future tests might be run using actual measurements but no future papers have been forthcoming. Either they never did the tests, or they did the tests and did not publish them.
They suggest no plausible mechanism by which consuming a cherry juice apple juice blend would have any effects on muscle damage or healing.
The statements on the CherryActive website are clearly not supported by the research they cite. They are being dishonest to pretend that it does.
Conclusion.
Cherries are a fine and tasty food. I have nothing against cherries, I like cherries and I eat cherries when in season. Moderate consumption of cherries as part of a varied diet is likely no more and no less healthful than moderate consumption of any other fruits and vegetables. Cherries do tend to be somewhat pricy for me even when in season. The cherry products sold by CherryActive are extremely pricy. I see no reason to consume any of CherryActive's products other than as simple foods, and virtually any other source of cherries would be more economical as are many other fruits and vegetables.
I didn't know very much about cherries when I started looking into CherryActive. I suspect that I will keep my cherry intake more moderate primarily because of the xanthine oxidoreductase inhibition effects. An extremely important property of xanthine oxidoreductase is the reduction of nitrate to nitrite and the reduction of nitrite to NO. NO from nitrite is extremely important in many emergency and extreme stress situations. Nitrite is substantially protective against infarcts due to acute ischemia in heart muscle, liver, kidney, brain. Messing with the xanthine oxidoreductase system by inhibiting it with cherries is not something one should do without good reasons. The reasons that CherryActive provide are not good enough for me.
Saturday, February 16, 2008
Morgellons Disease: A hallucinatory parasitosis due to low NO?
Morgellons Disease (MD) is a complex association of symptoms with several suggested explanations. I will add another explanation, that of low nitric oxide. I think my explanation does fit the reported symptoms somewhat better (and simultaneously) and suggests a treatment (increase NO levels). Low NO as an exacerbating factor is consistent with the symptoms and may provide at least some relief (actual and symptomatic) no matter the ultimate "cause".
The two leading explanations are Delusion of Parasitosis (DoP), and actual infestation with unknown disease organism(s) and/or unknown parasite(s). I will go into the symptoms and how the symptoms can be explained by low NO, and then suggest why low NO in particular would lead to feelings and ultimately belief that parasites are infesting the skin. I think calling it a "delusion" while technically correct (depending on the definition of delusion) may not be helpful in that symptoms which lead patient to that conclusion are quite real and not made up. I think calling it a hallucination would be more accurate and perhaps be perceived as less pejorative to those who experience it. The default conclusion that chronic itching of the skin is caused by parasites may be something that is "hard wired" in our nervous systems. An analogy would be phantom pain in a limb that has been amputated. Are people who experience phantom pain called delusional? If not, then people who experience "phantom parasites" should not be called delusional either. The "hallucination" is not in the peoples' heads, it is in their skin. It is low NO in the skin that causes the itching, low NO in the brain does lead to some clouding of thinking, and also causes fatigue and exercise intolerance.
People have many beliefs based on much less evidence than an itching and crawly feelings on the skin and are not considered "delusional" (by some at least) (think astrology, magic, ghosts, superstitions, religion). Morgellons may be thought of as a "parasitosis of the gaps", a parasitosis consistent with symptoms and all the evidence that the believer (a non expert in physiology and parasites) is aware of, the way some consider a belief in supernatural events non-delusional because they are consistent with all the evidence the believer (a non-expert in science) is aware of.
I think the mechanism is by low NO increasing the "gain" on injury detection pathways until the injury detecting pathways begin detecting injuries that are not there. They are as much phantom injuries as the phantom injuries experience in missing limbs.
Symptoms (other than presence of unknown parasites) are all consistent with low NO. Actual infestation with parasites would be expected to increase NO levels via expression of iNOS following activation of NFkB. That would be expected to increase systemic NO levels and might relieve some of the symptoms consistent with low basal NO. Intestinal worms are an effective treatment for Crohn's disease [1] and also protect against asthma in a mouse model [2]
That the presence of unknown filaments has not been resolved is quite strange to me. It is simply not possible that filaments could be looked at seriously and not identified as being parasitic in nature (if they were). Any worm-like parasite has to have characteristic internal structures. Any serious microscopic look at unknown filaments would necessarily involve potting the filaments in a suitable embedding media and taking slices so the internal structure of any filament could be observed. This would unambiguously show if the fiber was part of a worm. A fiber may remain unidentified, but if it is any type of living organism it has to have internal structures that would be unambiguous. I suppose it is possible that every case where there was an actual parasite the people investigating it have been so incompetent they didn't identify it as being parasitic in nature, but that strains credibility. It is more likely that competent investigators did identify all fibers they observed as non-parasites and diagnosed DoP, patients rejected that diagnosis and went to another health care professional who was unable or unwilling to unambiguously identify the fiber as non-parasitic.
Parasites infesting skin have been a problem for many millions of years. Organisms have evolved many different pathways to detect those parasites and to evoke compensatory responses. Itching and the urge to scratch that itch are a primary parasite reduction mechanism and are mediated through quite complex physiological pathways.[3] Essentially all organisms have this response to parasites, and some plants (such as nettles) have evolved mechanisms to specifically activate them demonstrating itching pathways must come from deep evolutionary time. Attempting to cognitively over ride such deep instinctive responses will be difficult, problematic and highly stressful. The more likely outcome is that cognition will be used to explain the symptoms by generating a plausible "cause", and this is what leads to DoP. The best solution would be to resolve the feelings of itch, which will then resolve any need to cognitively explain them.
Non-human primates spend large amounts of time grooming each other. Presumably much of this is for the removal of parasites. Human skin has much less hair, so parasites are much easier to find and remove.
The symptoms are listed on the website for Morgellons Disease, Morgellons Symptoms. I have a brief (NO explanation) following the symptom.
1. “Filaments:” (hardest to explain, Amyloid and other protein fibrils are generic symptom of proteasome inhibition [4] (and likely low ATP due to low NO too) but length scales of known materials not consistent with posted images (at least 10x scale difference). Contamination with environmental fibers most likely explanation.)
2. Movement sensations: (sequential activation of any sensation along a path on the skin will be interpreted as movement along that path. Low NO induces hypersensitivity of mast cell degranulation might make degranulation self-propagating via diffusible agents, proteases, histamine, ROS or NO.)
3. Skin lesions: (mast cell degranulation can produce lesions, scratching would exacerbate.)
4. Musculoskeletal Effects and Pain: (Pain generic symptom of ATP insufficiency as when muscles are worked to extreme exhaustion.)
5. Aerobic limitation: (low NO leads to fewer mitochondria, low aerobic ATP production rate and exercise intolerance)
6. Cognitive dysfunction: (low NO leads to low ATP, low ATP can invoke acute psychosis, NO mediates functional connectivity in neural networks (my hypothesis), low NO reduce neural network functionality, default mental state is non-cognitive low enough NO will invoke that state.)
7. Emotional effects: (Low NO invokes chronic stress and "fight or flight". Lowers the threshold for stress induced mental and physiological changes).
1. Shifting visual acuity: (light signal transduction in retina via cGMP gated channels. [5] Basal NO sets background level cGMP by basal activation sGC. NO modulates on/off response retinal cells [6]) (common effect of cocaine abuse, alcohol withdrawal, migraine see below)
2. Numerous neurological symptoms and clinical findings: (NO involved in many pathways (hundreds or thousands). Low basal NO affects all NO pathways with no threshold).
3. Gastrointestinal symptoms: (GI tract neuronal control largely via NO. [7]Dysregulated NO will impede normal function, [8]Nitroglycerine potentiates bowel peristalsis and sphincter relaxation [9]) Actual infestation with parasitic worms improves Crohn's Disease symptoms (likely mediated through NO from iNOS).
4. Acute changes in skin texture and pigment:
5. Arthralgias:
Common laboratory abnormalities: elevated cytokines, TNF-alpha, C-reactive protein, low hematocrit, elevated blood glucose, elevated insulin.
(NFkB regulates expression of many cytokines [10], NO inhibits NFkB, so low NO would lead to higher levels of cytokines. Hemoglobin is the sink for NO, NO causes activation HIFa1 which causes expression of erythropoietin increasing hematocrit. Low hematocrit is thus a compensatory response to low NO (my hypothesis). Fewer mitochondria mean more ATP via glycolysis requires increased blood sugar, increased insulin, and induces insulin resistance to allow insulin to get to tissues far from capillary.)
Aerobic limitation: (not enough ATP, not enough O2, not enough NO, not enough mitochondria, not enough glucose)
Aerobic limitation is said to be universal in Morgellons and accompanied by increased resting heart rate. Aerobic limitation is an inability to sustain aerobic production of work and is accompanied by breathlessness. The natural assumption is that breathlessness is caused by insufficient O2. However this is not always the case. For example Chronic Obstructive Pulmonary Disease (COPD) is always accompanied by breathlessness upon even modest exercise. This breathlessness is not relieved by breathing 40% O2. [11]Short burst O2 before and following exercise doesn't increase maximal exercise or reduce recovery times. [12] If breathing O2 neither increases the work that can be performed, nor decreases recovery time then a lack of O2 is not the reason for the breathlessness or the work limitation in the first place. The sensation of "breathlessness" is due to exuberant activation of the urge to breathe. There are 3 known mechanisms, low O2, high CO2 and high S-nitrosothiols. [13] For any of these to be useful in signaling the need to breathe, they must vary within their respective active ranges in the times scales important in breathing, faster than minutes. In the above paper (Stevenson and Calverley), they find that breathing with a nose clip significantly reduced aerobic work production and prolonged recovery times compared to breathing through a mask which allowed nose breathing. [14] They suggest invocation of some sort of "diving reflex", but I think NO from the nasal passages is a more plausible explanation.
The ultimate source of energy for muscle is ATP, supplied by mitochondria, glycolysis or creatinine kinase. Mitochondria are the only aerobic ATP source. Insufficient mitochondria would limit aerobic ATP production. Mitochondria have a limited lifetime and are replaced every night. What triggers mitochondria biogenesis is nitric oxide. [15] Lower NO will then lead to fewer mitochondria. Elevated blood glucose would follow from insufficient mitochondria which would necessitate an increase in the amount of ATP produced by glycolysis. It takes 20 times more glucose to produce the same ATP via glycolysis as via oxidation in mitochondria. Normally cells make ATP from glycolysis and then oxidize the lactate produced to make ATP from oxidation. If ATP from mitochondria is reduced by 5%, it will take twice as much glucose to make up for that ATP via glycolysis. Insufficient mitochondria explain the elevated glucose and elevated insulin. The only way more glucose can be delivered to cells is by increasing blood sugar. Glucose transport into cells is active, mediated by GLUT transporters which are increased by insulin. Lower mitochondria will lead to elevated blood sugar and elevated blood insulin.
Elevated TNF-alpha down regulates eNOS expression and inhibits mitochondria biogenesis. [16] Less than complete replacement of mitochondria will eventually lead to aerobic limitation due to a lack of mitochondria to produce aerobic ATP in the muscles. This may or may not be accompanied by breathlessness. Exertional weakness due to reduce mitochondria would not be correctable via oxygen breathing.
Mitochondria can produce different amounts of ATP. At rest most cellular ATP in muscle is produced by mitochondria. Aerobic ATP production can be increased 10x. This is done by increasing the mitochondrial potential, which increases the driving force for ATP production. It also increases the production of superoxide which serves to pull down the local NO level, disinhibit cytochrome c oxidase and allow O2 to be consumed to a low concentration so a larger concentration gradient develops between the blood vessel and the mitochondria so a larger O2 flux can occur down that concentration gradient. Chronic fatigue syndrome is characterized by reduced oxidative ATP production in muscle. [17] If elevated superoxide levels due to operating mitochondria at higher potentials persists during cycles of mitochondria biogenesis, the low NO produced by mitochondria superoxide is expected to reduce mitochondria biogenesis and make the low mitochondria state self-perpetuating (my hypothesis). A symptom that is consistent with this is a "hypermetabolic state", that is a basal metabolism that is higher than would be expected from lean body mass. I attribute this to fewer mitochondria and a higher mitochondria potential where there is more "slip", where the production of ATP is less efficient. It then takes more substrate and O2 to make the same ATP for basal metabolic needs. A hypermetabolic state is observed in some disorders of too few mitochondria characterized by chronic fatigue including obesity, ALS, [18] liver cirrhosis, [19] COPD. [20] Just about everything that produces a hypermetabolic state is also characterized by fatigue, but not everything that produces fatigue also produces a hypermetabolic state. Why that appears to be the case is something I am still trying to figure out. I think it depends on which tissue compartment is most affected by mitochondria depletion. Muscle can use lipid and so isn't entirely dependant on the liver and kidneys for glucose. The nervous system and immune system are, so a hypermetabolic state in them might cascade to the liver and kidneys and cause a hypermetabolic state there. It might not be just mitochondria potential, but too much lactate and glucose running through the Cori cycle increasing ATP demand in the liver and kidneys.
There is some evidence that the skin can also perform glucogenesis. [21] That might make the skin a target organ for a hypermetabolic state. That might explain why the symptoms of itching are common in both liver cirrhosis and end stage kidney failure. The liver and the kidneys are the main sites of gluconeogenesis. If they become compromised, more gluconeogenesis has to be done in other organs, including the skin (no doubt). The specific production of glucose in the skin (g/g tissue) is smaller than in the liver, but the skin is considerably larger than the liver. The skin having the capacity for gluconeogenesis is an advantage in that the skin derives O2 from the external air.
Some instances of chronic fatigue have been associated with a "trigger" by patients (n=134) including an apparent infection (72%), none (17%), surgery/trauma (9%), allergy (2%). [22] Low NO could occur due to rebound from NFkB activation or due to a hypermetabolic state. Some CFS is consistent with an immune system operating at a higher "gain". [23] Individuals with CFS have lower levels of bacterial DNA circulating in their blood than do normal controls. [24]
Infectious diseases most associated with CFS include Q-fever [25] which happens to be an intralysosomal disease. NO specifically inhibits replication of the Q-fever agent. [26]
Skin sensations
Many important immune and sensory functions in the skin are mediated via mast cells. [27] These are cells that contain a variety of chemicals stored in vesicles in the cell which are released upon activation (degranulation) by a number of different stimuli. These chemicals include histamine, leukotrienes, proteases, and cytokines such as TNF-alpha. These chemicals are responsible for many of the acute responses of skin to noxious stimuli including itching (one mechanism via the release of histamine). The itch response to nettles and the plant hairs used as itching powder is due to histamine release due to serotonin in the plant hairs. The use of SSRIs to treat the itching of primary biliary cirrhosis is well documented. [28] Presumably the SSRIs cause a desensitization of the mast cells to serotonin which reduces their activation.
For the relatively sparse distribution of mast cells in the skin to be effective, they must communicate and activation of one cell must lead to activation of adjacent cells (to some extent). To robustly "turn on" the mast cell response and produce hysteresis, there must be positive feedback where some agent released by mast cells during degranulation causes the degranulation of adjacent mast cells. There must also be inhibitory agents released (otherwise the entire skin would become activated). Activation of mast cells does cause what is called "immediate hypersensitivity". The extent of mast cell activation and then deactivation (physical and over time) will depend on the balance of activation and inhibition. Anything that tips that balance more to activation will induce hypersensitivity and inappropriate itching.
NO inhibits mast cell degranulation,[29] protease release [30] and low NO potentiates mast cell histamine release and ROS generation. [31] Low NO will then increase the release of cytokines in skin. Because NO is one of the regulators of mast cell degranulation, low NO will increase the sensitivity of mast cells to every other stimuli that causes degranulation. Mast cells generate ROS but not NO [32]. By generating ROS, mast cells decrease the NO level and so increase the sensitivity of other nearby mast cells to be triggered. This reduced NO level also sensitizes other activities including apoptosis (see below).
Skin contains xanthine dehydrogenase (XDH) and when acted upon by proteases irreversibly forms xanthine oxidase (XO) which makes superoxide which lowers NO levels still more. What deactivates XO is NO in the presence of superoxide which oxidizes the Mo-S reaction center releasing S and forming Mo=O. [33] This deactivated enzyme can be reactivated via sulfurization. Both XO and XDH reduce nitrate to nitrite and nitrite to NO. [34] I divert into XO and XDH chemistry is because of their importance in NO generation in vivo, but also because the main inhibitor of XO and XDH used pharmacologically is allopurinol, which is a leading cause of Stevens Johnson Syndrome. [35] A major mechanism of SJS seems to be some sort of hypersensitive immune reaction in the skin involving soluble fas ligand produced by peripheral blood mononuclear cells. NO involvement is plausible because hypersensitivity to allopurinol is very strongly associated with a specific allele in the Major Histocompatibility Complex, HLA-B*5801. [36] The hypersensitivity does seem to be mediated through peripheral mononuclear blood cells. SJS and the more serious Toxic Epidermal Necrolysis (TEN) can be blocked by human immunoglobulin [37] which blocks the fasL or CD95L apoptosis inducing receptor. This therapy also works in children. [38] It turns out that fas mediated apoptosis is highly regulated by NO, and exogenously applied NO specifically inhibits apoptosis mediated through the fas CD95L pathway and NOS inhibition potentiates apoptosis. [39]
I suspect that SJS and TEN are due in part to high levels of oxidative stress in the skin, sufficient to cause NO depletion which then primes cells expressing the CD95L receptor to be hypersensitive to apoptosis. Virtually all of the xenobiotic chemicals that can produce SJS or TEN are metabolized by the cytochrome P450 enzyme system which is quite uncoupled and so makes significant ROS when it metabolizes substrate. If the basal NO level is not high enough to confine that oxidative stress state to the microsome containing the P450 enzyme, then the oxidative stress state can propagate outside and perturb physiology beyond the microsome. I suspect that this is the mechanism for multiple chemical hypersensitivity. A pathologically low NO level (and NO production rate) which cannot tolerate even tiny amounts of superoxide from activation of the cytochrome P450 system by xenobiotic chemicals.
Mast cells also become hypersensitive activated by low NO and a round of positive feedback makes everything quite dicey for a while. If they release proteases which convert XDH to XO, the level of superoxide will go up and can't go down until the XO is inhibited but that takes NO. [40]
Chronic antibiotic use: Herxheimer reaction?
The use of chronic antibiotic treatment has been reported to improve symptoms associated with MD, and also for what is sometimes called Chronic Lyme Disease (also called post Lyme disease syndrome), which has some similarities to MD.
Bacterial infections are not expected to be controlled by long term antibiotic use. Either the bacteria are non-resistant and will be rapidly cleared, or they are resistant and will be unaffected, or they will develop resistance and the infection will worsen. A long term course of antibiotics is then expected either to have no effect, or to result in a worsening of symptoms as resistance develops.
Target organisms are not the only bacteria resident in the human receiving antibiotics. An adult human is reported to have more bacterial cells than human cells with a biomass of about 1.5 kg. [41] Even long term antibiotic treatment doesn't render the human gut sterile. No doubt many of these bacteria are killed by the antibiotics even when taken chronically. When bacteria are killed during antibiotic treatment, the contents of the dead bacteria spill into the infected tissues and can cause a severe immune reaction, the Jarisch-Herxheimer reaction, [42] originally found during chemotherapy for syphilis.
There are reports that antibiotics have anti-inflammatory properties. What they may be seeing is the effect of antibiotics on commensal bacteria. Either a reduction in inflammatory agents produced by those bacteria, or compensatory rebound by endogenous anti-inflammatory agents to a Jarisch-Herxheimer reaction. NO from iNOS expressed due to a Jarisch-Herxheimer reaction would be an example.
Hallucinations of extreme metabolic states: Cocaine, Alcohol Withdrawal, Migraine, Mania, Euphoric Near Death State (ENDS), Solvent Abuse, Autoerotic Asphyxiation, Drowning
Many of the hallucinatory symptoms of MD seem to be similar to those of extreme metabolic stress. I suspect because all of these states are similar in that they are characterized by low NO. I hypothesize that the reason that people somaticize when under stress is because of the physiology that stress invokes. These are adaptive responses to better cope with and survive what ever caused the stress in the first place.
If you are under stress because you are in a war zone or other dangerous or potentially injurious situation, it would be adaptive if your body was more sensitive to telling you if it was injured so you could deal with it. I suspect the mechanism to do this is by increasing the "gain" on the physiological processes that detect injury to 11. With a high enough gain, those systems will start to "detect" injuries that are not there. This is the physiology of somaticization; increase the "gain" to 11. If you are under "real" stress, such as from being chased by a bear, the "gain" goes to zero, and you completely ignore injury and pain, even those that can cause death.
At the physical endurance limit, during a near death physiological state such as is invoked when running from a bear (where to be caught is certain death) small injuries and even large injuries must be ignored and disregarded if one is to escape and survive. Evolution has configured organisms to enter a euphoric state when under near death physiologic stress. I think that is the source of the euphoria in the manic state. I think that is also the source of the euphoria of the stimulant drugs of abuse, the source of the euphoria of solvent abuse, the source of the euphoria during drowning, the source of the euphoria in autoerotic asphyxiation.
If organisms could easily enter that euphoric state they would do so and would risk death with no survival benefit. Evolution has configured organisms such that there is an aversive state between "normal" and the Euphoric Near Death State (ENDS makes a good acronym). I think that aversive state is what depression is, and is also what the physical symptoms commonly attributed to somaticization are. Aversive feelings your body is producing to try and get you to stop doing what ever it is that is invoking that physiological state.
A major factor in regulating the physiologic responses to stress is the nitric oxide level. A high stress state is a low NO state. Anything that lowers NO levels is going to invoke this state to some extent. With NO being a major regulatory signaling molecule in many stress pathways, a lower basal NO level will increase the gain on all of these pathways.
Cocaine does reduce NO production in endothelial cells. [43] In dogs, cocaine binging lowers NO production and also accelerate pacing induced cardiomyopathy. [44] Blocking nitric oxide synthase increases cardiac hypertrophy and fibrosis. [45]
Cocaine is a stimulant drug of abuse. It also causes and/or exacerbates essentially all of the degenerative diseases, as does methamphetamine abuse which also causes WMH. [46] My hypothesis is that this occurs because cocaine induces the near death metabolic state and so causes the euphoria of the "Euphoric Near Death State" (ENDS), the euphoric state that physiology induces when one is "running from a bear" and to be caught is certain death where an organism must be able to endure any injury short of death in order to survive. I discuss the details of this in my acute psychosis blog. This state induces many delusions, in particular the "runner's high", the delusion that you are not tired and can run forever. A very useful delusion when one is running from a bear and to stop to rest is to be caught and eaten. I think that depression is the generic aversive state that physiology must have between the "normal" state and the "near death metabolic state". If organisms could enter the euphoric state easily, they would, and would run themselves to death without need.
I think the somatic feelings of pain, injury and hypersensitivity to injury of the somaticized state are the somatic equivalents of "depression". The aversive state between "normal" and the ENDS.
The "near death metabolic state" is a low NO state. All organism resources are diverted to the "running from a bear" acute ATP need. Everything else is a luxury that is put off until after "the bear" has been escaped from.
So what are cocaine induced hallucinations? They are usually not associated with acute use, but more with chronic use after several days. They include:
Perceptual hallucinations typified by "cocaine bugs". Described by Freud [47] as "similar to that associated with delirium tremens: “A chronic persecution mania, characterized in my experience by the hallucination of small animals moving in the skin” (p. 172)." [48] Cocaine hallucinations are also characterized as similar to those associated with migraine.
Cocaine use is associated with white matter hyperintensities. [49] Yet women seem to be less affected (perhaps due to increased NO from estrogen). Similarly Acute alcohol withdrawal is associated with white matter hyperintensities. [50] My hypothesis is that this is due to ATP depletion in the brain due to insufficient substrate. During chronic alcohol abuse, the liver is used to oxidize alcohol to acetate and acetate is used as substrate in the brain. During alcohol withdrawal, glucose uptake by the brain increases over a period of several weeks. Presumably reduced glucose metabolism results in reduced ATP availability.
Migraines are also associated with white matter hyperintensities and (as discussed in more detail in my blog on resolution of ASD symptoms with fever). MD perhaps exhibit some of the same visual hallucinatory features as does cocaine (but perhaps milder). However these are acute hallucinatory features generated in the CNS, that are common in migraine, cocaine, alcohol withdrawal and the "light" sometimes reported by people who survive near death from drowning.
The hallucination of movement in the skin is likely generated in the skin itself, which is why it is not so much an acute hallucination of cocaine use, but one from chronic abuse. It takes a while for energy substrates and then NO in the skin to become depleted. Cocaine causes peripheral vasoconstriction, and so reduces blood flow to the skin. This can cause acute hyperthermia, but if continued chronically would likely lead to energy depletion in the skin.
The skin gets considerable O2 from the external air. [51] Substrates to be oxidized must come from the plasma which flows through the extravascular space. Cocaine induced vasoconstriction wouldn't cause immediate depletion of substrates but if consumption exceeds delivery by the now constricted vasculature eventually energy status of the skin will be compromised. Itching is a natural response by which scratching can increase local flow of lymph in the extravascular space. That will increase convective delivery of substrates. Itching in the context of infection or parasitic infestation of the skin is a way to accelerate lymph flow to lymph nodes so that antigen presenting cells can begin the process of mounting an immune response.
I think I have presented considerably evidence and reasoning that MD is plausibly related to a low NO state in the skin and in some other tissues. The treatment I would suggest to raise that NO would be via topical ammonia oxidizing bacteria. These bacteria are obligate autotrophs and so are unable to derive sustenance by metabolizing animal tissues.
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The two leading explanations are Delusion of Parasitosis (DoP), and actual infestation with unknown disease organism(s) and/or unknown parasite(s). I will go into the symptoms and how the symptoms can be explained by low NO, and then suggest why low NO in particular would lead to feelings and ultimately belief that parasites are infesting the skin. I think calling it a "delusion" while technically correct (depending on the definition of delusion) may not be helpful in that symptoms which lead patient to that conclusion are quite real and not made up. I think calling it a hallucination would be more accurate and perhaps be perceived as less pejorative to those who experience it. The default conclusion that chronic itching of the skin is caused by parasites may be something that is "hard wired" in our nervous systems. An analogy would be phantom pain in a limb that has been amputated. Are people who experience phantom pain called delusional? If not, then people who experience "phantom parasites" should not be called delusional either. The "hallucination" is not in the peoples' heads, it is in their skin. It is low NO in the skin that causes the itching, low NO in the brain does lead to some clouding of thinking, and also causes fatigue and exercise intolerance.
People have many beliefs based on much less evidence than an itching and crawly feelings on the skin and are not considered "delusional" (by some at least) (think astrology, magic, ghosts, superstitions, religion). Morgellons may be thought of as a "parasitosis of the gaps", a parasitosis consistent with symptoms and all the evidence that the believer (a non expert in physiology and parasites) is aware of, the way some consider a belief in supernatural events non-delusional because they are consistent with all the evidence the believer (a non-expert in science) is aware of.
I think the mechanism is by low NO increasing the "gain" on injury detection pathways until the injury detecting pathways begin detecting injuries that are not there. They are as much phantom injuries as the phantom injuries experience in missing limbs.
Symptoms (other than presence of unknown parasites) are all consistent with low NO. Actual infestation with parasites would be expected to increase NO levels via expression of iNOS following activation of NFkB. That would be expected to increase systemic NO levels and might relieve some of the symptoms consistent with low basal NO. Intestinal worms are an effective treatment for Crohn's disease [1] and also protect against asthma in a mouse model [2]
That the presence of unknown filaments has not been resolved is quite strange to me. It is simply not possible that filaments could be looked at seriously and not identified as being parasitic in nature (if they were). Any worm-like parasite has to have characteristic internal structures. Any serious microscopic look at unknown filaments would necessarily involve potting the filaments in a suitable embedding media and taking slices so the internal structure of any filament could be observed. This would unambiguously show if the fiber was part of a worm. A fiber may remain unidentified, but if it is any type of living organism it has to have internal structures that would be unambiguous. I suppose it is possible that every case where there was an actual parasite the people investigating it have been so incompetent they didn't identify it as being parasitic in nature, but that strains credibility. It is more likely that competent investigators did identify all fibers they observed as non-parasites and diagnosed DoP, patients rejected that diagnosis and went to another health care professional who was unable or unwilling to unambiguously identify the fiber as non-parasitic.
Parasites infesting skin have been a problem for many millions of years. Organisms have evolved many different pathways to detect those parasites and to evoke compensatory responses. Itching and the urge to scratch that itch are a primary parasite reduction mechanism and are mediated through quite complex physiological pathways.[3] Essentially all organisms have this response to parasites, and some plants (such as nettles) have evolved mechanisms to specifically activate them demonstrating itching pathways must come from deep evolutionary time. Attempting to cognitively over ride such deep instinctive responses will be difficult, problematic and highly stressful. The more likely outcome is that cognition will be used to explain the symptoms by generating a plausible "cause", and this is what leads to DoP. The best solution would be to resolve the feelings of itch, which will then resolve any need to cognitively explain them.
Non-human primates spend large amounts of time grooming each other. Presumably much of this is for the removal of parasites. Human skin has much less hair, so parasites are much easier to find and remove.
The symptoms are listed on the website for Morgellons Disease, Morgellons Symptoms. I have a brief (NO explanation) following the symptom.
1. “Filaments:” (hardest to explain, Amyloid and other protein fibrils are generic symptom of proteasome inhibition [4] (and likely low ATP due to low NO too) but length scales of known materials not consistent with posted images (at least 10x scale difference). Contamination with environmental fibers most likely explanation.)
2. Movement sensations: (sequential activation of any sensation along a path on the skin will be interpreted as movement along that path. Low NO induces hypersensitivity of mast cell degranulation might make degranulation self-propagating via diffusible agents, proteases, histamine, ROS or NO.)
3. Skin lesions: (mast cell degranulation can produce lesions, scratching would exacerbate.)
4. Musculoskeletal Effects and Pain: (Pain generic symptom of ATP insufficiency as when muscles are worked to extreme exhaustion.)
5. Aerobic limitation: (low NO leads to fewer mitochondria, low aerobic ATP production rate and exercise intolerance)
6. Cognitive dysfunction: (low NO leads to low ATP, low ATP can invoke acute psychosis, NO mediates functional connectivity in neural networks (my hypothesis), low NO reduce neural network functionality, default mental state is non-cognitive low enough NO will invoke that state.)
7. Emotional effects: (Low NO invokes chronic stress and "fight or flight". Lowers the threshold for stress induced mental and physiological changes).
1. Shifting visual acuity: (light signal transduction in retina via cGMP gated channels. [5] Basal NO sets background level cGMP by basal activation sGC. NO modulates on/off response retinal cells [6]) (common effect of cocaine abuse, alcohol withdrawal, migraine see below)
2. Numerous neurological symptoms and clinical findings: (NO involved in many pathways (hundreds or thousands). Low basal NO affects all NO pathways with no threshold).
3. Gastrointestinal symptoms: (GI tract neuronal control largely via NO. [7]Dysregulated NO will impede normal function, [8]Nitroglycerine potentiates bowel peristalsis and sphincter relaxation [9]) Actual infestation with parasitic worms improves Crohn's Disease symptoms (likely mediated through NO from iNOS).
4. Acute changes in skin texture and pigment:
5. Arthralgias:
Common laboratory abnormalities: elevated cytokines, TNF-alpha, C-reactive protein, low hematocrit, elevated blood glucose, elevated insulin.
(NFkB regulates expression of many cytokines [10], NO inhibits NFkB, so low NO would lead to higher levels of cytokines. Hemoglobin is the sink for NO, NO causes activation HIFa1 which causes expression of erythropoietin increasing hematocrit. Low hematocrit is thus a compensatory response to low NO (my hypothesis). Fewer mitochondria mean more ATP via glycolysis requires increased blood sugar, increased insulin, and induces insulin resistance to allow insulin to get to tissues far from capillary.)
Aerobic limitation: (not enough ATP, not enough O2, not enough NO, not enough mitochondria, not enough glucose)
Aerobic limitation is said to be universal in Morgellons and accompanied by increased resting heart rate. Aerobic limitation is an inability to sustain aerobic production of work and is accompanied by breathlessness. The natural assumption is that breathlessness is caused by insufficient O2. However this is not always the case. For example Chronic Obstructive Pulmonary Disease (COPD) is always accompanied by breathlessness upon even modest exercise. This breathlessness is not relieved by breathing 40% O2. [11]Short burst O2 before and following exercise doesn't increase maximal exercise or reduce recovery times. [12] If breathing O2 neither increases the work that can be performed, nor decreases recovery time then a lack of O2 is not the reason for the breathlessness or the work limitation in the first place. The sensation of "breathlessness" is due to exuberant activation of the urge to breathe. There are 3 known mechanisms, low O2, high CO2 and high S-nitrosothiols. [13] For any of these to be useful in signaling the need to breathe, they must vary within their respective active ranges in the times scales important in breathing, faster than minutes. In the above paper (Stevenson and Calverley), they find that breathing with a nose clip significantly reduced aerobic work production and prolonged recovery times compared to breathing through a mask which allowed nose breathing. [14] They suggest invocation of some sort of "diving reflex", but I think NO from the nasal passages is a more plausible explanation.
The ultimate source of energy for muscle is ATP, supplied by mitochondria, glycolysis or creatinine kinase. Mitochondria are the only aerobic ATP source. Insufficient mitochondria would limit aerobic ATP production. Mitochondria have a limited lifetime and are replaced every night. What triggers mitochondria biogenesis is nitric oxide. [15] Lower NO will then lead to fewer mitochondria. Elevated blood glucose would follow from insufficient mitochondria which would necessitate an increase in the amount of ATP produced by glycolysis. It takes 20 times more glucose to produce the same ATP via glycolysis as via oxidation in mitochondria. Normally cells make ATP from glycolysis and then oxidize the lactate produced to make ATP from oxidation. If ATP from mitochondria is reduced by 5%, it will take twice as much glucose to make up for that ATP via glycolysis. Insufficient mitochondria explain the elevated glucose and elevated insulin. The only way more glucose can be delivered to cells is by increasing blood sugar. Glucose transport into cells is active, mediated by GLUT transporters which are increased by insulin. Lower mitochondria will lead to elevated blood sugar and elevated blood insulin.
Elevated TNF-alpha down regulates eNOS expression and inhibits mitochondria biogenesis. [16] Less than complete replacement of mitochondria will eventually lead to aerobic limitation due to a lack of mitochondria to produce aerobic ATP in the muscles. This may or may not be accompanied by breathlessness. Exertional weakness due to reduce mitochondria would not be correctable via oxygen breathing.
Mitochondria can produce different amounts of ATP. At rest most cellular ATP in muscle is produced by mitochondria. Aerobic ATP production can be increased 10x. This is done by increasing the mitochondrial potential, which increases the driving force for ATP production. It also increases the production of superoxide which serves to pull down the local NO level, disinhibit cytochrome c oxidase and allow O2 to be consumed to a low concentration so a larger concentration gradient develops between the blood vessel and the mitochondria so a larger O2 flux can occur down that concentration gradient. Chronic fatigue syndrome is characterized by reduced oxidative ATP production in muscle. [17] If elevated superoxide levels due to operating mitochondria at higher potentials persists during cycles of mitochondria biogenesis, the low NO produced by mitochondria superoxide is expected to reduce mitochondria biogenesis and make the low mitochondria state self-perpetuating (my hypothesis). A symptom that is consistent with this is a "hypermetabolic state", that is a basal metabolism that is higher than would be expected from lean body mass. I attribute this to fewer mitochondria and a higher mitochondria potential where there is more "slip", where the production of ATP is less efficient. It then takes more substrate and O2 to make the same ATP for basal metabolic needs. A hypermetabolic state is observed in some disorders of too few mitochondria characterized by chronic fatigue including obesity, ALS, [18] liver cirrhosis, [19] COPD. [20] Just about everything that produces a hypermetabolic state is also characterized by fatigue, but not everything that produces fatigue also produces a hypermetabolic state. Why that appears to be the case is something I am still trying to figure out. I think it depends on which tissue compartment is most affected by mitochondria depletion. Muscle can use lipid and so isn't entirely dependant on the liver and kidneys for glucose. The nervous system and immune system are, so a hypermetabolic state in them might cascade to the liver and kidneys and cause a hypermetabolic state there. It might not be just mitochondria potential, but too much lactate and glucose running through the Cori cycle increasing ATP demand in the liver and kidneys.
There is some evidence that the skin can also perform glucogenesis. [21] That might make the skin a target organ for a hypermetabolic state. That might explain why the symptoms of itching are common in both liver cirrhosis and end stage kidney failure. The liver and the kidneys are the main sites of gluconeogenesis. If they become compromised, more gluconeogenesis has to be done in other organs, including the skin (no doubt). The specific production of glucose in the skin (g/g tissue) is smaller than in the liver, but the skin is considerably larger than the liver. The skin having the capacity for gluconeogenesis is an advantage in that the skin derives O2 from the external air.
Some instances of chronic fatigue have been associated with a "trigger" by patients (n=134) including an apparent infection (72%), none (17%), surgery/trauma (9%), allergy (2%). [22] Low NO could occur due to rebound from NFkB activation or due to a hypermetabolic state. Some CFS is consistent with an immune system operating at a higher "gain". [23] Individuals with CFS have lower levels of bacterial DNA circulating in their blood than do normal controls. [24]
Infectious diseases most associated with CFS include Q-fever [25] which happens to be an intralysosomal disease. NO specifically inhibits replication of the Q-fever agent. [26]
Skin sensations
Many important immune and sensory functions in the skin are mediated via mast cells. [27] These are cells that contain a variety of chemicals stored in vesicles in the cell which are released upon activation (degranulation) by a number of different stimuli. These chemicals include histamine, leukotrienes, proteases, and cytokines such as TNF-alpha. These chemicals are responsible for many of the acute responses of skin to noxious stimuli including itching (one mechanism via the release of histamine). The itch response to nettles and the plant hairs used as itching powder is due to histamine release due to serotonin in the plant hairs. The use of SSRIs to treat the itching of primary biliary cirrhosis is well documented. [28] Presumably the SSRIs cause a desensitization of the mast cells to serotonin which reduces their activation.
For the relatively sparse distribution of mast cells in the skin to be effective, they must communicate and activation of one cell must lead to activation of adjacent cells (to some extent). To robustly "turn on" the mast cell response and produce hysteresis, there must be positive feedback where some agent released by mast cells during degranulation causes the degranulation of adjacent mast cells. There must also be inhibitory agents released (otherwise the entire skin would become activated). Activation of mast cells does cause what is called "immediate hypersensitivity". The extent of mast cell activation and then deactivation (physical and over time) will depend on the balance of activation and inhibition. Anything that tips that balance more to activation will induce hypersensitivity and inappropriate itching.
NO inhibits mast cell degranulation,[29] protease release [30] and low NO potentiates mast cell histamine release and ROS generation. [31] Low NO will then increase the release of cytokines in skin. Because NO is one of the regulators of mast cell degranulation, low NO will increase the sensitivity of mast cells to every other stimuli that causes degranulation. Mast cells generate ROS but not NO [32]. By generating ROS, mast cells decrease the NO level and so increase the sensitivity of other nearby mast cells to be triggered. This reduced NO level also sensitizes other activities including apoptosis (see below).
Skin contains xanthine dehydrogenase (XDH) and when acted upon by proteases irreversibly forms xanthine oxidase (XO) which makes superoxide which lowers NO levels still more. What deactivates XO is NO in the presence of superoxide which oxidizes the Mo-S reaction center releasing S and forming Mo=O. [33] This deactivated enzyme can be reactivated via sulfurization. Both XO and XDH reduce nitrate to nitrite and nitrite to NO. [34] I divert into XO and XDH chemistry is because of their importance in NO generation in vivo, but also because the main inhibitor of XO and XDH used pharmacologically is allopurinol, which is a leading cause of Stevens Johnson Syndrome. [35] A major mechanism of SJS seems to be some sort of hypersensitive immune reaction in the skin involving soluble fas ligand produced by peripheral blood mononuclear cells. NO involvement is plausible because hypersensitivity to allopurinol is very strongly associated with a specific allele in the Major Histocompatibility Complex, HLA-B*5801. [36] The hypersensitivity does seem to be mediated through peripheral mononuclear blood cells. SJS and the more serious Toxic Epidermal Necrolysis (TEN) can be blocked by human immunoglobulin [37] which blocks the fasL or CD95L apoptosis inducing receptor. This therapy also works in children. [38] It turns out that fas mediated apoptosis is highly regulated by NO, and exogenously applied NO specifically inhibits apoptosis mediated through the fas CD95L pathway and NOS inhibition potentiates apoptosis. [39]
I suspect that SJS and TEN are due in part to high levels of oxidative stress in the skin, sufficient to cause NO depletion which then primes cells expressing the CD95L receptor to be hypersensitive to apoptosis. Virtually all of the xenobiotic chemicals that can produce SJS or TEN are metabolized by the cytochrome P450 enzyme system which is quite uncoupled and so makes significant ROS when it metabolizes substrate. If the basal NO level is not high enough to confine that oxidative stress state to the microsome containing the P450 enzyme, then the oxidative stress state can propagate outside and perturb physiology beyond the microsome. I suspect that this is the mechanism for multiple chemical hypersensitivity. A pathologically low NO level (and NO production rate) which cannot tolerate even tiny amounts of superoxide from activation of the cytochrome P450 system by xenobiotic chemicals.
Mast cells also become hypersensitive activated by low NO and a round of positive feedback makes everything quite dicey for a while. If they release proteases which convert XDH to XO, the level of superoxide will go up and can't go down until the XO is inhibited but that takes NO. [40]
Chronic antibiotic use: Herxheimer reaction?
The use of chronic antibiotic treatment has been reported to improve symptoms associated with MD, and also for what is sometimes called Chronic Lyme Disease (also called post Lyme disease syndrome), which has some similarities to MD.
Bacterial infections are not expected to be controlled by long term antibiotic use. Either the bacteria are non-resistant and will be rapidly cleared, or they are resistant and will be unaffected, or they will develop resistance and the infection will worsen. A long term course of antibiotics is then expected either to have no effect, or to result in a worsening of symptoms as resistance develops.
Target organisms are not the only bacteria resident in the human receiving antibiotics. An adult human is reported to have more bacterial cells than human cells with a biomass of about 1.5 kg. [41] Even long term antibiotic treatment doesn't render the human gut sterile. No doubt many of these bacteria are killed by the antibiotics even when taken chronically. When bacteria are killed during antibiotic treatment, the contents of the dead bacteria spill into the infected tissues and can cause a severe immune reaction, the Jarisch-Herxheimer reaction, [42] originally found during chemotherapy for syphilis.
There are reports that antibiotics have anti-inflammatory properties. What they may be seeing is the effect of antibiotics on commensal bacteria. Either a reduction in inflammatory agents produced by those bacteria, or compensatory rebound by endogenous anti-inflammatory agents to a Jarisch-Herxheimer reaction. NO from iNOS expressed due to a Jarisch-Herxheimer reaction would be an example.
Hallucinations of extreme metabolic states: Cocaine, Alcohol Withdrawal, Migraine, Mania, Euphoric Near Death State (ENDS), Solvent Abuse, Autoerotic Asphyxiation, Drowning
Many of the hallucinatory symptoms of MD seem to be similar to those of extreme metabolic stress. I suspect because all of these states are similar in that they are characterized by low NO. I hypothesize that the reason that people somaticize when under stress is because of the physiology that stress invokes. These are adaptive responses to better cope with and survive what ever caused the stress in the first place.
If you are under stress because you are in a war zone or other dangerous or potentially injurious situation, it would be adaptive if your body was more sensitive to telling you if it was injured so you could deal with it. I suspect the mechanism to do this is by increasing the "gain" on the physiological processes that detect injury to 11. With a high enough gain, those systems will start to "detect" injuries that are not there. This is the physiology of somaticization; increase the "gain" to 11. If you are under "real" stress, such as from being chased by a bear, the "gain" goes to zero, and you completely ignore injury and pain, even those that can cause death.
At the physical endurance limit, during a near death physiological state such as is invoked when running from a bear (where to be caught is certain death) small injuries and even large injuries must be ignored and disregarded if one is to escape and survive. Evolution has configured organisms to enter a euphoric state when under near death physiologic stress. I think that is the source of the euphoria in the manic state. I think that is also the source of the euphoria of the stimulant drugs of abuse, the source of the euphoria of solvent abuse, the source of the euphoria during drowning, the source of the euphoria in autoerotic asphyxiation.
If organisms could easily enter that euphoric state they would do so and would risk death with no survival benefit. Evolution has configured organisms such that there is an aversive state between "normal" and the Euphoric Near Death State (ENDS makes a good acronym). I think that aversive state is what depression is, and is also what the physical symptoms commonly attributed to somaticization are. Aversive feelings your body is producing to try and get you to stop doing what ever it is that is invoking that physiological state.
A major factor in regulating the physiologic responses to stress is the nitric oxide level. A high stress state is a low NO state. Anything that lowers NO levels is going to invoke this state to some extent. With NO being a major regulatory signaling molecule in many stress pathways, a lower basal NO level will increase the gain on all of these pathways.
Cocaine does reduce NO production in endothelial cells. [43] In dogs, cocaine binging lowers NO production and also accelerate pacing induced cardiomyopathy. [44] Blocking nitric oxide synthase increases cardiac hypertrophy and fibrosis. [45]
Cocaine is a stimulant drug of abuse. It also causes and/or exacerbates essentially all of the degenerative diseases, as does methamphetamine abuse which also causes WMH. [46] My hypothesis is that this occurs because cocaine induces the near death metabolic state and so causes the euphoria of the "Euphoric Near Death State" (ENDS), the euphoric state that physiology induces when one is "running from a bear" and to be caught is certain death where an organism must be able to endure any injury short of death in order to survive. I discuss the details of this in my acute psychosis blog. This state induces many delusions, in particular the "runner's high", the delusion that you are not tired and can run forever. A very useful delusion when one is running from a bear and to stop to rest is to be caught and eaten. I think that depression is the generic aversive state that physiology must have between the "normal" state and the "near death metabolic state". If organisms could enter the euphoric state easily, they would, and would run themselves to death without need.
I think the somatic feelings of pain, injury and hypersensitivity to injury of the somaticized state are the somatic equivalents of "depression". The aversive state between "normal" and the ENDS.
The "near death metabolic state" is a low NO state. All organism resources are diverted to the "running from a bear" acute ATP need. Everything else is a luxury that is put off until after "the bear" has been escaped from.
So what are cocaine induced hallucinations? They are usually not associated with acute use, but more with chronic use after several days. They include:
Perceptual hallucinations typified by "cocaine bugs". Described by Freud [47] as "similar to that associated with delirium tremens: “A chronic persecution mania, characterized in my experience by the hallucination of small animals moving in the skin” (p. 172)." [48] Cocaine hallucinations are also characterized as similar to those associated with migraine.
Cocaine use is associated with white matter hyperintensities. [49] Yet women seem to be less affected (perhaps due to increased NO from estrogen). Similarly Acute alcohol withdrawal is associated with white matter hyperintensities. [50] My hypothesis is that this is due to ATP depletion in the brain due to insufficient substrate. During chronic alcohol abuse, the liver is used to oxidize alcohol to acetate and acetate is used as substrate in the brain. During alcohol withdrawal, glucose uptake by the brain increases over a period of several weeks. Presumably reduced glucose metabolism results in reduced ATP availability.
Migraines are also associated with white matter hyperintensities and (as discussed in more detail in my blog on resolution of ASD symptoms with fever). MD perhaps exhibit some of the same visual hallucinatory features as does cocaine (but perhaps milder). However these are acute hallucinatory features generated in the CNS, that are common in migraine, cocaine, alcohol withdrawal and the "light" sometimes reported by people who survive near death from drowning.
The hallucination of movement in the skin is likely generated in the skin itself, which is why it is not so much an acute hallucination of cocaine use, but one from chronic abuse. It takes a while for energy substrates and then NO in the skin to become depleted. Cocaine causes peripheral vasoconstriction, and so reduces blood flow to the skin. This can cause acute hyperthermia, but if continued chronically would likely lead to energy depletion in the skin.
The skin gets considerable O2 from the external air. [51] Substrates to be oxidized must come from the plasma which flows through the extravascular space. Cocaine induced vasoconstriction wouldn't cause immediate depletion of substrates but if consumption exceeds delivery by the now constricted vasculature eventually energy status of the skin will be compromised. Itching is a natural response by which scratching can increase local flow of lymph in the extravascular space. That will increase convective delivery of substrates. Itching in the context of infection or parasitic infestation of the skin is a way to accelerate lymph flow to lymph nodes so that antigen presenting cells can begin the process of mounting an immune response.
I think I have presented considerably evidence and reasoning that MD is plausibly related to a low NO state in the skin and in some other tissues. The treatment I would suggest to raise that NO would be via topical ammonia oxidizing bacteria. These bacteria are obligate autotrophs and so are unable to derive sustenance by metabolizing animal tissues.
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