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Prostaglandin D2 suppresses human NK cell function via signaling through D prostanoid receptor

Discussion in 'Other Health News and Research' started by nanonug, Nov 5, 2012.

  1. nanonug

    nanonug Senior Member

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    Mil Med. 2012 Jan;177(1):113-7.
    Mast cell activation syndrome masquerading as agranulocytosis.

    Afrin LB.
    Source

    Section of Hematology/Oncology, Medical Service, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29401, USA.
    Abstract

    Acquired agranulocytosis is a rare, life-threatening disorder. The few known causes/associations usually are readily identifiable (e.g., drug reaction, Felty syndrome, megaloblastosis, large granular lymphocytic leukemia, etc.). We report a novel association with mast cell disease. A 61-year-old morbidly obese man developed rheumatoid arthritis unresponsive to several medications. Agranulocytosis developed shortly after sulfasalazine was started but did not improve when the drug was soon stopped. Other symptoms across many systems developed including hives and presyncope. Marrow aspiration and biopsy showed only neutropenia. Serum tryptase was mildly elevated; urinary prostaglandin D2 was markedly elevated. Other causes were not found. Mast cell activation syndrome (MCAS) was diagnosed. Oral antihistamines, montelukast, and cromolyn were unhelpful; aspirin was initially felt contraindicated. Imatinib immediately increased neutrophils from 0% to 25% but did not help symptoms; subsequent addition of aspirin increased neutrophils further and abated symptoms. Different presentations of different MCAS patients reflect elaboration of different mediators likely consequent to different Kit mutations. Mast cells (MCs) help regulate adipocytes, and adipocytes can inhibit granulopoiesis; thus, a Kit-mutated MC clone may have directly and/or indirectly driven agranulocytosis. MCAS should be considered in otherwise idiopathic agranulocytosis presenting with comorbidities best explained by MC mediator release.
    PMID: 22338992
  2. nanonug

    nanonug Senior Member

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    Biochem Pharmacol. 2007 Jun 30;74(1):107-17. Epub 2007 Mar 30.
    PGD2 metabolism in plasma: kinetics and relationship with bioactivity on DP1 and CRTH2 receptors.

    Schuligoi R, Schmidt R, Geisslinger G, Kollroser M, Peskar BA, Heinemann A.
    Source

    Medical University Graz, Institute of Experimental and Clinical Pharmacology, Universit├Ątsplatz 4, 8010 Graz, Austria. rufina.schuligoi@meduni-graz.at <rufina.schuligoi@meduni-graz.at>
    Abstract

    Prostaglandin (PG)D(2), an important mediator in allergic diseases, is rapidly transformed in plasma to active metabolites that bind and activate two distinct receptors, DP1 and CRTH2. Since the rate of PGD(2) degradation and the bioactivity of the resulting metabolites are still unclear, the aim of our study was to analyze the kinetics and biological effects of PGD(2) metabolites formed in plasma. Eosinophil shape change was taken as a parameter of chemotactic activation mediated by CRTH2 whereas inhibition of platelet aggregation served as a measure of DP1 activity. PGD(2) was degraded in plasma with an apparent half-life of approximately 30 min, accompanied by a loss of potency in inhibiting platelet aggregation as well as inducing eosinophil stimulation. Incubation of PGD(2) in plasma for 120 min caused an increase in the IC(50) for platelet aggregation by a factor of 6.5 and an increase of the EC(50) for eosinophil shape change by a factor of 7.2. However, tandem mass spectrometry analysis showed that incubation of PGD(2) in plasma for 120 min resulted in clearance of PGD(2) of more than 92%, which was mirrored by a continuous formation of Delta(12)-PGD(2) and Delta(12)-PGJ(2), whereas only small amounts of 15d-PGD(2) and 15d-PGJ(2) were detected. Interestingly, a rapid degradation of PGD(2) was also observed in serum, which was not prevented by pepsin digestion of serum preceding the addition of PGD(2). Therefore, despite extensive non-enzymatic metabolization of PGD(2) in plasma, its biological activity with respect to DP1 and CRTH2 is maintained through the formation of bioactive metabolites.
  3. alex3619

    alex3619 Senior Member

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    So far as I am aware all eicosanoids are local. I am not aware of any exceptions. PGD2 in tissue has a half life of six seconds. It cannot travel far. Even getting into the blood takes too long. Eicosanoids are cell to cell hormones. They are not endocrine hormones.

    To increase the PGD2 half life for testing you need a cell free sample, or perhaps instant freezing with nitrogen or something. That means you must spin a blood sample and then rush to analyze the plasma.You do not have a lot of time. The thirty minutes quoted was for a cell free sample I suspect, you would have to read the methods section of the full paper to be sure. You spin the blood to remove cells to do the test so far as I am aware. Also plasma is not a place where PGD2 would be most active. Its a cell to cell hormone, and most active in closely packed tissues according to what I currently understand. Now it is possible the quoted figure for plasma is correct, but then the cell concentration is low. Its a mostly cell free medium. It still tells you nothing about brain or tissue specific PGD2 concentrations, plasma is globally averaged by the flow of blood. Its a pool.

    Yes, serum and urinary PGD2 tests do not make sense in the manner you claim. They are a degraded temporally and spatially averaged measure. They tell you something about global effects, but nothing about local or temporally limited ones.

    Study African Sleeping Sickness to look at what short term highly elevated PGD2 does. In this case its a pathogen making it (a parasite). High levels of PGD2 is closely associated with loss of consciousness.

    Eicosanoids due to their short half lives are continually produced by cells when required. Those cells are also a major factor in the degradation of eicosanoids, though being fat hormones they are very vulnerable to heat, oxidative stress etc.

    What that last paper implied was that degraded metabolites of PGD2 are more persistent. I am still not sure what this means, it would require additional research.

    Bye, Alex
  4. nanonug

    nanonug Senior Member

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    I honestly don't know how to interpret this. In what way do they make sense, then?

    MCAS is a multi-system, therefore global, disorder. It is exactly the global nature of MCAS and the mediators responsible for symptoms one is interested in testing for.

    It's funny you mention this as this is exactly one of my symptoms: an overwhelming and unavoidable need to sleep after meals. It feels like propofol (I had an upper endoscopy and a colonoscopy recently and remember how one falls asleep in less than a second.)

    Yes, it implied that but it also stated PGD2's half-life in plasma.

    The fact is that labs use urinary PGD2 as a diagnostic marker, including a "normal" range. Given that these tests are used in clinical practice (I have done one myself) leads me to believe that they measure what they purport to measure. At least, until proof to the contrary.

    Here is the blurb on Inter Science Institute website (this is the one my golden sample got sent):
    Prostaglandin D2 (PG D2), urine. In particular, it says, "Prostaglandin D2 is excreted directly into the urine [...] Prostaglandin D2 production and circulating levels are drastically suppressed by aspirin and indomethacin. Urine Prostaglandin D2 levels give an integrated picture of Prostaglandin D2 production over a 24 hour period minimizing the effect of diurnal variation and episodic secretion."
  5. alex3619

    alex3619 Senior Member

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    Hi nanonug, tests like blood tests and urine tests make sense in that they demonstrate a general increase in prostaglandins such as PGD2. This tells you something is wrong, it gives clues as to the symptoms and possible causes, but does not specifically identify the exact mechanism or tissue distribution or timing.

    I first became interested in PGD2 many years ago in relation to sleep disorders. Its half life in plasma is longer than tissue because there are no cells to absorb and degrade it, but even so it disappears reasonably fast. I am less sure about the relevance of the metabolites as I have never investigated them.

    PGD2 is indeed excreted into the urine. Most of that is from the kidneys I supect, due to the half life. However, this is a still a guide. Some information is better than no information.

    Indomethacin is potentially a powerful drug to treat CFS or ME but needs to be treated with caution. I think aspirin is a bad idea in CFS or ME due to increase damage to the gut lining. I dont think its coincidental that indomethacin can prevent death from alcohol poisoning, given that alcohhol induces a massive release of free arachidonic acid, which will be rapidly converted to eicosanoids.

    Mast cells are a connective tissue cell type. They reside primarily under the skin and in mucosal layers. That is why they react to chemicals, and what they are for. They are part of the early warning system. I do not know what makes PGD2 in the brain. I doubt it would be mast cells or similar, but I could be wrong: the brain may have its own type of mast cell.

    Mast cells are thus primarily spread throughout external barriers to the body, they are not omnipresent inside the body. Given the very short range of the PGD2 this might call into question exactly what they can affect. I am looking into this. I do note I have found reference to mast cells in the spleen, which implies they may also be present in lymph nodes. The thin muscle that surrounds the gut mucosa also has mast cells, its like a second layer of defence.

    Then there are papers like this:

    "http://www.ncbi.nlm.nih.gov/pubmed/11727255
    Hum Pathol. 2001 Nov;32(11):1174-83.
    Mast cell distribution and activation in chronic pancreatitis.

    Esposito I, Friess H, Kappeler A, Shrikhande S, Kleeff J, Ramesh H, Zimmermann A, B├╝chler MW.
    Source

    Department of Visceral and Transplantation Surgery, Institute of Pathology, University of Bern, Inselspital, Bern, Switzerland.
    Abstract

    Chronic pancreatitis (CP) is characterized by mononuclear inflammatory cell infiltration and replacement of the destroyed parenchyma by fibrous tissue. Recently, mast cells have been implicated in chronic inflammatory processes with fibrous tissue deposition. [...deleted...] The total number of mast cells was significantly higher in CP than in the normal pancreas (P < .0001) and correlated positively with the extent of fibrosis and the intensity of inflammation. Immunoglobulin E (IgE)-dependent mast cell activation was higher in CP than in the normal pancreas. [...deleted...] These results suggest that mast cells, activated by an IgE-dependent mechanism and/or by an SCF-c-kit autocrine loop, are a relevant component of the inflammatory infiltrate in CP, independent of the underlying cause. Their localization near degenerating acini and regenerating ducts might indicate that they play a crucial role in tissue destruction and remodeling in CP."

    See the link for the full abstract. Mast cell disorders like this are because mast cells have infiltrated the tissue possibly due to inflammation. The damage is local.

    In doing further reading it appears that various agents can stimulate PGD2 synthesis in the lining of the brain. See for example: http://www.ncbi.nlm.nih.gov/pubmed/1508957

    PGD2 in the brain is produced mainly by an alternate pathway, called Beta-trace. This protein is secreted into the CSF and then induces PGD2 .synthesis apparently.

    I think this topic is important. It ties into three issues I am investigating - circadian disorders, LPS and gamma delta T cells.

    Nanonug, you might find this particularly interesting:

    http://www.ane.pl/pdf/6044.pdf
    NMDA receptors and nitric oxide regulate prostaglandin D2 synthesis in the rabbit hippocampus in vivo

    It turns out the brain can make large quantities of PGD2 all on it own, and the conditions under which it does so appear to be the same as other conditions associated with ME like NO and NMDA activation.

    I keep finding references to the enzyme beta trace that makes PGD2 in the brain being glutathione dependent. I am still looking.

    Bye, Alex
  6. nanonug

    nanonug Senior Member

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    PGD2 is highly specific for mast cell activation. It is for this reason it is used as a diagnostic tool for mast cell activation disorders. As such, an abnormal elevation in serum or urinary levels is a very reliable indicator of MCAD.

    MCAD is able to pretty much affect every single system in the body. It makes no sense to think that PGD2 would be or kidney origin. Look at Table 1 on this document: "Polycythemia From Mast Cell Activation Syndrome: Lessons Learned."

    If PGD2 has an elimination half-life of 30 minutes in plasma, I would say it can affect pretty much anything in the body.
  7. alex3619

    alex3619 Senior Member

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    Hi Nanonug, you are not addressing the points I made.

    "PGD2 is highly specific for mast cell activation. It is for this reason it is used as a diagnostic tool for mast cell activation disorders. As such, an abnormal elevation in serum or urinary levels is a very reliable indicator of MCAD."

    I almost agree, but its not completely relevant. PGD2 is also highly specific for the brain, its the most abundant prostaglandin in the brain, though I think some parts of the brain make much larger quantities than the rest. It also does not survive in whole blood for more than seconds. Sorry, but the only place it can come from in urine, in quantity, are the kidneys or associated vessels. Now PGD2 breakdown products I have almost no knowledge of. If they are measuring those then the results might be different. So any measure at real physiological concentrations would be from the kidneys or associated vessels. Measures of levels from other parts of the body would be so degraded they would not reflect real physiological ranges. That does not mean they will be normal; it means that normal is an artifact of the testing procedure. Tissue biopsises are the only way to be sure of real physiological concentrations. A twenty four hour urine sample is particularly problematic as this would see the majority of PGD2 destroyed even before it was tested.

    This does not mean that small quantities of PGD2 cannot be detected in urine or blood from other sources, particularly in blood. However those concentrations will not reflect real tissue concentrations, or tell you which tissues they are from. Tissue biopsies might but require specialized handling.

    "MCAD is able to pretty much affect every single system in the body. It makes no sense to think that PGD2 would be or kidney origin. Look at Table 1 on this document: "Polycythemia From Mast Cell Activation Syndrome: Lessons Learned."

    I am not and have not argued that PGD2 is only of kidney origin. I argue that the majority found in urine is of kidney or associated vessels origin.

    There are three primary sources of PGD2. The brain and associated spinal nerves via beta trace. The skin, via mast cells. Mucous membranes, via mast cells. Where is one location of such membranes? The urethra and inner lining of kidneys. Most organs also have a very thin mucous membrane around them.

    If you listen to an immunologist they will tell you the primary source of PGD2 is mast cells. If you listen to a neurologist they will tell you PGD2 is abundant in the brain and has nothing to do with mast cells.

    If you are measuring PGD2 in urine, its from those mucous membranes. Now if there were an even release of PGD2 across all tissues, then the kidney associated PGD2 would reflect that, but its only an indicator. If however different tissues have different levels (which is much more likely in my view) then even a normal urinary level might not be reliably able to show there was no abnormality. On a similar line of reasoning, an abnormal PGD2 in urine might indicate mast cell activation in the urethra right back to the kidney.

    "If PGD2 has an elimination half-life of 30 minutes in plasma, I would say it can affect pretty much anything in the body."

    This is wrong. It presumes plasma is eqivalent to whole blood. It isn't. First, the blood is full of cells. Second, the blood vessels are wall to wall cells. Those cells rapidly destroy eicosanoids like PGD2. It is very probable that plasma is used as its deliberately depleted of cells so the half life is longer to enable testing. Draw the blood, spin fast, get rid of the cells by drawing off a sample of the almost cell free plasma. That is why they do plasma testing, not whole blood testing. However, as I have said several times I have little idea of the chemistry of PGD2 metabolites, so can't comment.

    What this means is that blood levels, which are a mixed pool of degraded PGD2 for the whole body, would be much lower than real physiological concentrations. Where is it coming from? Anywhere the blood goes, including the brain which has PGD2 of non-mast cell origin. So its not specific, its a general indicator.

    Furthermore PGD2 in the blood would have a marked circadian variation. The exact point in your sleep cycle it was taken would affect the levels. I do not know enough about the experimental ranges to say what variation that would be, only that it would exist. What is the most powerful natural sleep inducer known to science? PGD2.

    One of the things that interests me about PGD2 is it fits with the arachidonate research I have been looking at for 19 years. If a lot is being produced in one part of the body, and the diet does not have adequate glutathione precursors or omega-6 fatty acids, or there are methylation problems, the cell membranes would become arachidonic acid depleted. At that point you would see some very weird effects if the activation was in all PGD2 producing tissues. Two of those could include hyper- or hypo-somnia. It might also alter consciousness. You would also see weird transient symptoms arise in various apparently unrelated tissues. The are related of course, by the biochemistry not location. Many of those effects would also not be related to PGD2 directly, but to the effect that chronic PGD2 oversynthesis would have on the hundreds of other eicosanoids - the arachidonic acid substrate can be in limited supply.

    If the activation is in a specific tissue, not systemic across membranes, then it could be more constant over time, with fewer of these weird effects.

    Eicosanoids involve complex dynamic interactions, between different pathways and substrates, different locations, and at different times. Its one of the most complex things in biochemistry. After 19 years of looking at this, reading hundreds of papers, studying it at university, reading several books on it, I still get confused. In part this is because a lot of what we need to know is only now starting to be discovered (though in part its because my brain is fubar). A lot of what has been published is also wrong. What is right, what is wrong, and under what circumstances, will eventually be figured out. I don't think we are even close to being there yet.

    Bye, Alex
  8. alex3619

    alex3619 Senior Member

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    Two things I am considering regarding PGD2. The first hypothesis is if you are not sleeping, take evening primrose oil. If you are sleeping too much take fish oil. If you are sleeping just right, eat normally.I have no idea if this is right though, its just a guess, and probably confounded by many other factors.

    I think alcohol might be useful as a drug in ME. However figuring out the rules might be tricky. If someone is sleeping way too much then regular small doses of alcohol will deplete the bodies capacity to make excess PGD2. However in the period immediately after taking alcohol I would expect a sudden increase in eicosanoids including PGD2. So its tricky as I said.

    For the last 19 years I have been taking extra virgin olive oil to combat eicosanoids via mass action and the anti-inflammatory properties of the chemicals in the oil. I think it works, but its not very powerful.

    The gold standard for mast cells disorders, from my limited reading, appears to be tissue biopsy. If mast cell numbers are up on staining, then you have a reliable indicator, but you have to have an idea where to biopsy.
  9. alex3619

    alex3619 Senior Member

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    Another thought, though I really need to catch some shuteye. PGD2 synthesis in the brains of ME patients should be significantly elevated based on the chemistry. This will cause arachidonic acid depletion. Mast cells might, just might (I am speculating) therefore multiply as they are being under supplied with arachidonic acid. I wonder if there is any evidence for or against this? For now I need to get some sleep.
  10. nanonug

    nanonug Senior Member

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    I am not because I consider them irrelevant. You are arguing against a diagnostic tool for MCAD. As such, I am going to continue to believe that the labs and the MCAD researchers know what they are doing. As always, I reserve to change my mind. But I need to see published references.
  11. alex3619

    alex3619 Senior Member

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    I am not arguing against a diagnostic tool at all. I am arguing against a particular interpretation of that diagnostic tool, and interpretation of the results. My analysis is not in conflict with any of the papers you have posted here. Could it be in conflict with other evidence? Of course, but like you I haven't seen it.

    PS Here is a paper detailing kidney synthesis of PGD2:
    http://ep.physoc.org/content/67/3/377.full.pdf

    It seems we were both wrong. The kidneys themselves also make PGD2.
  12. alex3619

    alex3619 Senior Member

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    There is some not very convincing claims that resverotrol blocks PGD2. Does anyone have good evidence for this?

    Something else I am researching is the impact of LPS on PGD2. I think it increases it. Since the body of those with ME has elevated LPS, this will tend to increase PGD2 (though I am also researching something with opposes this, more on that later).
  13. Marco

    Marco Old blackguard

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    This looks fairly sound Alex and the abstract and full paper (at least the first 5 pages) are open access :


    http://www.researchgate.net/publica...in_IL-1beta-stimulated_SK-N-SH_neuronal_cells
  14. alex3619

    alex3619 Senior Member

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    Thank you Marco. Interesting. Since it inhibits mainly COX-2 it will not hurt the gut. Also since COX-2 is more about slow synthesis of arachidonate, and COX-1 is more about fast synthesis of arachidonate, an implication is that there might be a tendency to block long term arachidonate synthesis, but not emergency arachidonate synthesis. I am not sure if this is important, but its somethign to think about.

    As a side note I think that an occasional 1.2 gram dose of resverotrol has improved my circadian issues. Lower doses appear to do nothing.

    The full paper is indeed open access, though you have to click a button to download it, I think they call it external download.
  15. Gypsy

    Gypsy Senior Member

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    I thought I would revive this thread as it is of interest to me, espeically Evening Primrose/GLA and its relation to sleep. @alex3619, your posts on this subject have been very helpful. I Was wondering if you had an opinion on how much Evening Primrose would be helpful? I understand that more is not necessarily better. I just started a supplement called "The Essential Woman" by Barleans oils, which is a combination of Flaxseed and a small amount of Evening Primrose. (This is formulated for PMS type issues) Only has 18 mg- 54 mg of EPO per serving. (If I am reading the label correctly!) Is this a very small amount which is unlikely to do much in terms of sleep (insomnia?) I see that most pills have 1,000 mg. MUCH more. Do you think the Flaxseed oil is a good idea or just go for EPO?I can not tolerate fish oil anymore...it makes my insomnia much worse anyways. completely wired to the max on any fish oil now.I thought that the flaxseed oil may help my dry eyes as well. I use olive oil a few days a week.

    Thank you!
    Last edited: Oct 30, 2013
  16. Gypsy

    Gypsy Senior Member

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    @alex3619 Does it matter if EPO is taken in the morning or night (for sleep?)
    Last edited: Oct 30, 2013
  17. alex3619

    alex3619 Senior Member

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    I would take the EPO with meals, and keep doses low. If its not the problem, and you take too much, it could make your other problems worse. You might start with a minimal dose, even only part of a capsule (prick it with a pin and squeeze a little out) then build up to several capsules. If that doesn't work, or you get more inflammation and maybe headaches, stop taking it. If the inflammation or headaches persist, take some fish oil. Fish oil and EPO do something similar, but EPO leads to sleep inducing pathways and fish oil doesn't, while EPO tends to drive inflammation, and fish oil tends to suppress it. You can of course take both in combination to counter the negative affects, but I would still keep EPO dose low to be sure.

    EPO is not a drug. It works when it merges with the cell membranes. When cells in the brain get enough EPO derivatives: its not EPO itself, nor the GLA (gamma linolenic acid I think) that does the trick, it has to be in place to be metabolized, which means a dose right before sleep may not do much.

    The simplest but slowest way though is to simply get more vegetable oils (cold pressed or from uncooked nuts) into the diet. Again, be careful of high doses of primarily omega-6 vegetable oils, even though cold pressed. It can drive inflammation. I use other oils, primarily cold pressed monounsaturated oils, which have smaller quantities of the omega-6 oils in them. Extra virgin olive oil is the best, but world supply is dodgy - a lot of it sold is fake, or old, or off. Go for a local supplier whenever possible. Macadamia oil is poor as its almost pure monounsaturated, but it makes wicked popcorn and Asian food.
    Last edited: Oct 30, 2013
  18. Gypsy

    Gypsy Senior Member

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    Thanks, Alex! I am surprised that some people are taking up to 3,000 mg a day (not ME folks). I can not take fish oil at all anymore. It causes severe exacerbation of insomnia and anxiety, and actually causes me to itch all over. I don't know if I developed an allergy or what. I took it for years, but no more.

    If you don't mind one more question, what do you think of Flaxseed oil as a fish alternative? I can't figure out if it reduces inflammation or not.
    Little Bluestem likes this.
  19. Valentijn

    Valentijn Activity Level: 3

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    At some point I realized my fish oil had soy in it. I switched to a soy-free brand, and the inflamed scaly red patch on my hand finally went away.

    So the problem might be an ingredient other than the fish oil.
  20. Hip

    Hip Senior Member

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