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.
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.
Wednesday, April 16, 2008
Delusional Nonsense
As a scientist concerned about the rampant disinformation being put out on the web, and as someone very concerned about scientific literacy and the education of children to be scientifically literate, I feel I must blog about the travesty of disinformation being put out by Ben Stein and the Discovery Institute.
I interrupt my regular blogging to post the obligatory links of Ben Stein's movie aka the crappy Creationist movie (oops I mean expelled the movie aka Intelligent Design or ID movie) Expelled to the Expelled Exposed web site. PZ Myers has many of the details.
Evolution is one of the scientific theories that there is the most evidence for. The largest amount of evidence is in the DNA of living organisms. Every bit of the DNA that has been analyzed so far is completely consistent with evolution and with common descent. Just as DNA testing is extremely reliable for determining relatedness of children to their parents, it is also reliable in determining relatedness of more distant relatives. Even very distant relatives to humans, such as E. coli.
I interrupt my regular blogging to post the obligatory links of Ben Stein's movie aka the crappy Creationist movie (oops I mean expelled the movie aka Intelligent Design or ID movie) Expelled to the Expelled Exposed web site. PZ Myers has many of the details.
Evolution is one of the scientific theories that there is the most evidence for. The largest amount of evidence is in the DNA of living organisms. Every bit of the DNA that has been analyzed so far is completely consistent with evolution and with common descent. Just as DNA testing is extremely reliable for determining relatedness of children to their parents, it is also reliable in determining relatedness of more distant relatives. Even very distant relatives to humans, such as E. coli.
Saturday, April 5, 2008
I am Kathleen
I am Kathleen
All that is necessary for the triumph of evil is for good men to do nothing. Edmund Burke
We must, indeed, all hang together or, most assuredly, we shall all hang separately. Benjamin Franklin
Kathleen Seidel over at Neurodiversity has been subpoenaed by the lawyer representing Lisa Sykes in her lawsuit against Glaxo-SmithKline, Wyeth, Inc. and Bayer Pharmaceuticals Corporation.
I see this as an example of the typical bullying behavior that many NTs exhibit toward ASDs. It is an action designed only to hurt, not to derive any benefit from. Ms. Seidel doesn't have any information that would be of any actual use in the lawsuit. This is a purely punitive action to try and hurt her. I see this as the worst type of behavior. It is only destructive and can have no positive effects. It is always easier to destroy than to create. It is very unfortunate that our society rewards such destructive behaviors. Bullies such as Mr. Shoemaker can only do their dirty work against small groups. Divide and conquer. Bullies from the Mercury Militia have made death threats against vaccine researchers. This is just more of the same. It may have the imprimatur of being "legal", in the same sense that everything is "legal" if you are not caught. Being "legal" doesn't make it right.
Normally I blog about nitric oxide physiology and its connection to autism spectrum disorders. Most of those blogs are about a year ago. My research indicates that low NO is the real cause of the symptoms of ASDs. Low NO does explain every symptom of the ASDs. My most recent blog on ASDs and nitric oxide discusses the resolution of autism symptoms with fever. It is clearly due to higher NO from iNOS. I don't like getting involved in politics because that involves trying to get other people to do things. I prefer to focus on what I can do. I know that is the typical ASD mind-set. Situations like this are upsetting to me because I perceive an injustice which can only be corrected if people who are NT can be convinced to do "the right thing".
This subpoena is clearly an injustice. When I observe an injustice, I begin to think about what I can do to stop the injustice and to prevent the injustice from ever happening again to anyone else. A number of lawyers have blogged about how this incident is an injustice. So far, none of them (to my knowledge) have done anything to stop this injustice and to prevent an injustice like this from happening in the future. It would seem that our legal system is not set up to do things like that, and the people who control the legal system (that would be lawyers) don't want to change the legal system to prevent injustices like this from happening because that would limit the power that they have over non-lawyers.
With great power comes great responsibility. If the legal profession is unwilling to be responsible with the power that society has granted it, then society must take that power away from it.
I am beginning to understand why NTs are so hard for ASDs to communicate with. NTs have a very strong "theory of mind", that matches the "theory of mind" of the other NTs. This "theory of mind" greatly facilitates communication between NTs, however it also greatly limits the types of things that can be communicated or even thought about. Anthropomorphic feelings about emotions, feelings, motivations, wants, needs, desires, etc. these are the "currency" of the NT theory of mind. Facts and logic are much more difficult for NTs. For NTs, anthropomorphic feelings usually "trump" facts and logic. The opposite is true for ASDs. ASDs can accept this (because it is factually correct). NTs can't accept this because they have a "theory of mind" need to feel that their "theory of mind" is based on facts and logic. NTs simply can't accept that some of their most basic assumptions are based not on facts and logic, but on arbitrary feelings they have no control over. This is obvious in some individuals, Creationists for example. All humans have it to some extent, NTs simply have it to a somewhat greater degree. The "theory of mind" of NTs has a lot of hysteresis. Once something is "believed", an NT has a hard time changing that belief even in the face of evidence the belief is false. I am not saying this to be disparaging of NTs. I think that all humans are on the NT/ASD spectrum. There is an inherent trade off of "theory of mind" for "theory of reality". My research indicates that much of that trade-off is programmed in utero. That is what I am working on right now.
I happen to know a lot about the false mercury causes autism idea because I spent a lot of time reading the literature about it. I blogged about it a year ago, there is zero evidence to support a mercury connection to autism and much evidence to show there is no connection. More data has come out since I blogged about it, all of which makes any connection even less likely. The Faroe Islands study on autism showed that even in 750 individuals with mercury levels over 60 nM/L in cord blood there is no excess of autism. The false "mercury causes autism" idea is wasting a great deal of time and resources that could be put to better use. It has already caused the deaths of multiple children. It has caused multiple children to be chelated multiple times. Chelation by succimer is known to cause learning difficulties (presumably via brain damage) all by itself. That mercury does not cause autism is not at all a close scientific all.
It is clear to me that Mr. Shoemaker sent the subpoena solely to injure and intimidate Ms. Seidel. By doing so I think he has committed malpractice. Ms. Seidel was attacked because she posted information about Mr. Shoemaker's financial involvement in the business of the "mercury causes autism" litigation. A "business" that Mr. Shoemaker has made a lot of money at. It is understandable that Mr. Shoemaker would be upset when his shady business dealings and business plans are disclosed. However Mr. Shoemaker's business dealings have nothing to do with Lisa Sykes in her lawsuit against Glaxo-SmithKline, Wyeth, Inc. and Bayer Pharmaceuticals Corporation. The actions of Mr. Shoemaker in issuing the subpoena are mean spirited and contemptible. Ms. Seidel has no connection to the case, had no role in what ever "caused" the autism of the children in the case.
In my opinion Mr. Shoemaker has breached his duty to Ms. Sykes by using her lawsuit as a vehicle to attack Ms. Seidel because of her exposure of his unrelated business dealings. The media circus Mr. Shoemaker has generated surrounding the litigation he is pursuing for multiple clients makes settlement for any particular one of those clients less likely. In his business of vaccine litigation, a media circus may increase the ultimate legal fees that he gets; it does not serve individual clients.
In my opinion the Hannah Poling case was clear malpractice. Why was it included in the Autism Omnibus when it was a table injury? Only to bolster the Autism Omnibus, not to provide relief to Ms. Poling as quickly as possible. The obvious reason is to get increased legal fees, not provide relief for his clients.
The breath-takingly foolish and inane attempted continued use of the Geiers as "expert witnesses" after multiple courts have rejected them as bogus is now understood. The Geiers and Mr. Shoemaker are business partners. The court cases are simply a vehicle for the Geiers and Mr. Shoemaker to make money from fees. The "facts" of the case don't matter. The "credibility" of the Geiers as witnesses doesn't matter. It is not a surprise to me that Mr. Shoemaker is unethical. Birds of a feather flock together. I am not a lawyer, but I am a scientist, and the Geier's published work verges on fraud. The treatments they have subjected children to are quackery and injurious with no basis in physiology to be helpful. Clearly they don't care about the children being subjected to these treatments. Clearly they don't care about children who will be injured as vaccination rates fall.
To me they are complete slimes. The equivalent of war profiteers. Merchants of death who foster wars so they can sell weapons not caring when women and children die. The equivalent of the merchants who egg on a crowd to burn witches so they can profit by selling torches. Merchants who encourage lynching so they can sell rope. People who profit from the misery that they cause. If I believed in Hell, beyond a doubt these people will end up there.
All that is necessary for the triumph of evil is for good men to do nothing. Edmund Burke
We must, indeed, all hang together or, most assuredly, we shall all hang separately. Benjamin Franklin
Kathleen Seidel over at Neurodiversity has been subpoenaed by the lawyer representing Lisa Sykes in her lawsuit against Glaxo-SmithKline, Wyeth, Inc. and Bayer Pharmaceuticals Corporation.
I see this as an example of the typical bullying behavior that many NTs exhibit toward ASDs. It is an action designed only to hurt, not to derive any benefit from. Ms. Seidel doesn't have any information that would be of any actual use in the lawsuit. This is a purely punitive action to try and hurt her. I see this as the worst type of behavior. It is only destructive and can have no positive effects. It is always easier to destroy than to create. It is very unfortunate that our society rewards such destructive behaviors. Bullies such as Mr. Shoemaker can only do their dirty work against small groups. Divide and conquer. Bullies from the Mercury Militia have made death threats against vaccine researchers. This is just more of the same. It may have the imprimatur of being "legal", in the same sense that everything is "legal" if you are not caught. Being "legal" doesn't make it right.
Normally I blog about nitric oxide physiology and its connection to autism spectrum disorders. Most of those blogs are about a year ago. My research indicates that low NO is the real cause of the symptoms of ASDs. Low NO does explain every symptom of the ASDs. My most recent blog on ASDs and nitric oxide discusses the resolution of autism symptoms with fever. It is clearly due to higher NO from iNOS. I don't like getting involved in politics because that involves trying to get other people to do things. I prefer to focus on what I can do. I know that is the typical ASD mind-set. Situations like this are upsetting to me because I perceive an injustice which can only be corrected if people who are NT can be convinced to do "the right thing".
This subpoena is clearly an injustice. When I observe an injustice, I begin to think about what I can do to stop the injustice and to prevent the injustice from ever happening again to anyone else. A number of lawyers have blogged about how this incident is an injustice. So far, none of them (to my knowledge) have done anything to stop this injustice and to prevent an injustice like this from happening in the future. It would seem that our legal system is not set up to do things like that, and the people who control the legal system (that would be lawyers) don't want to change the legal system to prevent injustices like this from happening because that would limit the power that they have over non-lawyers.
With great power comes great responsibility. If the legal profession is unwilling to be responsible with the power that society has granted it, then society must take that power away from it.
I am beginning to understand why NTs are so hard for ASDs to communicate with. NTs have a very strong "theory of mind", that matches the "theory of mind" of the other NTs. This "theory of mind" greatly facilitates communication between NTs, however it also greatly limits the types of things that can be communicated or even thought about. Anthropomorphic feelings about emotions, feelings, motivations, wants, needs, desires, etc. these are the "currency" of the NT theory of mind. Facts and logic are much more difficult for NTs. For NTs, anthropomorphic feelings usually "trump" facts and logic. The opposite is true for ASDs. ASDs can accept this (because it is factually correct). NTs can't accept this because they have a "theory of mind" need to feel that their "theory of mind" is based on facts and logic. NTs simply can't accept that some of their most basic assumptions are based not on facts and logic, but on arbitrary feelings they have no control over. This is obvious in some individuals, Creationists for example. All humans have it to some extent, NTs simply have it to a somewhat greater degree. The "theory of mind" of NTs has a lot of hysteresis. Once something is "believed", an NT has a hard time changing that belief even in the face of evidence the belief is false. I am not saying this to be disparaging of NTs. I think that all humans are on the NT/ASD spectrum. There is an inherent trade off of "theory of mind" for "theory of reality". My research indicates that much of that trade-off is programmed in utero. That is what I am working on right now.
I happen to know a lot about the false mercury causes autism idea because I spent a lot of time reading the literature about it. I blogged about it a year ago, there is zero evidence to support a mercury connection to autism and much evidence to show there is no connection. More data has come out since I blogged about it, all of which makes any connection even less likely. The Faroe Islands study on autism showed that even in 750 individuals with mercury levels over 60 nM/L in cord blood there is no excess of autism. The false "mercury causes autism" idea is wasting a great deal of time and resources that could be put to better use. It has already caused the deaths of multiple children. It has caused multiple children to be chelated multiple times. Chelation by succimer is known to cause learning difficulties (presumably via brain damage) all by itself. That mercury does not cause autism is not at all a close scientific all.
It is clear to me that Mr. Shoemaker sent the subpoena solely to injure and intimidate Ms. Seidel. By doing so I think he has committed malpractice. Ms. Seidel was attacked because she posted information about Mr. Shoemaker's financial involvement in the business of the "mercury causes autism" litigation. A "business" that Mr. Shoemaker has made a lot of money at. It is understandable that Mr. Shoemaker would be upset when his shady business dealings and business plans are disclosed. However Mr. Shoemaker's business dealings have nothing to do with Lisa Sykes in her lawsuit against Glaxo-SmithKline, Wyeth, Inc. and Bayer Pharmaceuticals Corporation. The actions of Mr. Shoemaker in issuing the subpoena are mean spirited and contemptible. Ms. Seidel has no connection to the case, had no role in what ever "caused" the autism of the children in the case.
In my opinion Mr. Shoemaker has breached his duty to Ms. Sykes by using her lawsuit as a vehicle to attack Ms. Seidel because of her exposure of his unrelated business dealings. The media circus Mr. Shoemaker has generated surrounding the litigation he is pursuing for multiple clients makes settlement for any particular one of those clients less likely. In his business of vaccine litigation, a media circus may increase the ultimate legal fees that he gets; it does not serve individual clients.
In my opinion the Hannah Poling case was clear malpractice. Why was it included in the Autism Omnibus when it was a table injury? Only to bolster the Autism Omnibus, not to provide relief to Ms. Poling as quickly as possible. The obvious reason is to get increased legal fees, not provide relief for his clients.
The breath-takingly foolish and inane attempted continued use of the Geiers as "expert witnesses" after multiple courts have rejected them as bogus is now understood. The Geiers and Mr. Shoemaker are business partners. The court cases are simply a vehicle for the Geiers and Mr. Shoemaker to make money from fees. The "facts" of the case don't matter. The "credibility" of the Geiers as witnesses doesn't matter. It is not a surprise to me that Mr. Shoemaker is unethical. Birds of a feather flock together. I am not a lawyer, but I am a scientist, and the Geier's published work verges on fraud. The treatments they have subjected children to are quackery and injurious with no basis in physiology to be helpful. Clearly they don't care about the children being subjected to these treatments. Clearly they don't care about children who will be injured as vaccination rates fall.
To me they are complete slimes. The equivalent of war profiteers. Merchants of death who foster wars so they can sell weapons not caring when women and children die. The equivalent of the merchants who egg on a crowd to burn witches so they can profit by selling torches. Merchants who encourage lynching so they can sell rope. People who profit from the misery that they cause. If I believed in Hell, beyond a doubt these people will end up there.
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