Hello everybody, you are in for a special treat today. I know you hear me say that a lot, but today is extra special because we're going to go down some really fascinating pathways and Bob's going to share some of the latest research on rantes and platelet activation. And you know Bob from some of my other interviews, I will actually formally introduce him once again in just a minute or two. But first some housekeeping. If you want more information, you can visit my website, jillcarnahan.com. We have literally 10 years of almost weekly articles. So loads and loads and loads of information. They're all free for you to read and peruse and share with your friends, family, or if you're a physician, share with your patients sometimes. I get other doctors who say, yeah, can I use your, you know, blogs as handouts? And I don't mind you share those away. I love it. I love the information. For me, just like Bob today, I know one of our passions in life is just bringing great information. And we actually get a thrill out of studying and learning. So we're the weirdos. We're the nerds. I was the kind of nerd in my class that really loved to read and study and learn.  I'm super excited. If you want products, sometimes we talk about products and services and you can find all of those at drjilhealth.com. And then as you well know, we're over 100 episodes on YouTube, you can subscribe there. And actually if you do that would help me out, give me a review, or you can find us on audio on anywhere you listen to podcasts. So Stitcher and iTunes and Spotify, you name it. You can find all of our episodes there. And we'll try to make this friendly for those auditory listening Bob. So if there's some slide, we're going to do slides, which I know you all love to see, but we'll try to read a few little details. So if you're just listening by audio and not seeing the video, you'll maybe be able to follow along as well. Now, just a warning, we're going to dive deep. We like to go deep into the physiology. So don't worry if it's over your head, there will be some takeaway points, Bob, so good at bringing about kind of the basics. But I know a lot of other doctors, practitioners, healthcare professionals listen to us on this podcast. So for those of you who want to go deep, you're going to go deep today. So let me introduce my friend, Bob.  You may have heard me say this before, but one day I was texting Bob getting ready for our interview. And I just audio text like we do. And it said, Hey, babe, when are we getting on? So then the last time we had a conference, and I sometimes get the honor of introducing Bob, I told the whole audience, babe, you know, his, his nickname is babe. So hey, babe, and good morning. And great to see you today. And then the whole audience at the conference, I think you got a lot of Hey, babes, right, Bob? So we love to joke and laugh about that. And so that was very funny. And the name is a little bit stuck. So sometimes that's how Siri goes. Anyway, without further ado, Bob Miller is a traditional naturopath specializing in the field of genetic specific nutrition. He's earned his naturopath degree at Trinity School of Natural Health and his board certified through the ANMA in 93 Open Tree of Life practice and served as traditional naturopath for 25 years. For the past several years, he's been engaged exclusively with nutritional genetic variants and related research and specializing in nutritional support for those with chronic Lyme disease. And as we'll talk today, many other chronic infections and toxic triggers. Bob, I just want to say I always love having you on because it stimulates my learning. I learn new things. We go back and forth and I'll be like, Oh, I'm seeing this in practice. Do you think this relates to literally in real time? I feel like often we're making great discoveries. I feel like one of the things you're leading us is with your background and pathways, you can really pull these together. And you've got a team of researchers doing a lot of the work as well. And I just love how you pulled this together. And what we're doing is, if any of you know about research, I just talked to a patient the other day who had a mold litigation case, and he was talking about how in the legal system, he's trying to prove that his daughter was sick from mold. And it's almost impossible because what happens is what's the standard of care in medicine right now is 20 years old. So what we're doing in medicine right now as the standard is very, very old as far as research, what you and I are doing and what we love to do is push the envelope, get the research out there. Because what happens is this, just like I talked to my patient, he brought all kinds of studies about toxicity and health. And he could prove it because the research was up to date with what he was seeing in his daughter. But when he came in the court of law, he was trying to prove what what does medicine say. And sadly, while I love allopathic medicine, what medicine says is very delayed. So the research right now in 20 or 30 years that might be standard of care. And what I love about framing this conversation is we are on the cutting bleeding edge of what does the data show about pathways. And we're actually saying, could this be part of the issue? We're not saying that we have a for sure drug or supplement that's been studied 20 years. But we're saying, looking at this pathways, this makes sense. And this may be contributing. And I love being on the cutting edge because what I see Bob and I know you do is miracles, because we're pushing the envelope and doing things that we feel are very safe with patients that might be brand new. And we're making a difference. And I love being here with you, because I know some of the information especially today is going to be on that cutting edge for these complex chronic conditions, we've been seeing infections and toxins for decades, I've been doing this 20 years, this is not new. But the pandemic has really accentuated the need for chronic lenses to view infections and toxins.  All of a sudden, we're seeing on a new level the patients who need our help. So without further ado, I'm going to let you share your screen and dive right in. Oh, sorry, one more thing, because I pulled an article and I was like, I was reading this last week and I talked to one of my friends, we had a game night the other night and the talk was on blood viscosity. Can you imagine a Dr. Jill's house game night is all about, you know, what else is new in the world. So this article was talking about how the thickness of a blood has a lot to do with morbidity and mortality, meaning like cause of illness and death and symptoms. We know that there's an effect with COVID on this. And we've known for decades that there's an effect with other viruses, other infections, toxins. And today we're specifically talking about the brand taste pathway and platelet activation, but this all has to do with the thickness of your blood. And if you don't think that's relevant, think again, because we're going to show you some amazing evidence. I read in this article and this was profound that over the age of 60, our blood viscosity, regardless of infection or toxin, exponentially increases. And so that's part of the increased risk of stroke and heart attack and all of these things. So I feel like in my expertise right now, this area of learning is going to be one of the most profound things that changes how I practice medicine. So go ahead and show us your slides, Bob. And let's dive right in. Okay, let's get to it. And thank you for that introduction.  And I'm so excited to present this because this is mind boggling what we're going to look at. And of course you always mention this is educational, informational only. We're not practicing medicine, telling anyone how to diagnose or treat any disease. And I think people have seen this slide before, but I plugged it in again. The platelet activation, the 3D chest pain, played underwater because there's so many factors that played together with this. So we're going to be talking today about platelet activation in aggregation. So I found this cool little chart. So let's talk first about what platelets are.  They float around in our blood and they just kind of are there.   So you know, Dr. Joe, one of the things we've talked about in every review we've done here, we've talked about that many of the things we're talking about are helpful unless they're excessive. That theme just keeps coming up for us. And the same way with your blood clotting. Without this, at least a little cut, you bleed to death. Excessive, that's where you get the blood clots. And then you're more prone to heart attacks and strokes. And Bob, just on that line, what I'm seeing in clinical practice, I'm actually starting to test patients for coagulation deficits in the blood, a huge panel. What's interesting, and most of them who have issues, they have not only bleeding issues, but clotting issues both at the same time. So this is very relevant because it's at Goldilocks, you can have some severe issues and you can actually be hypercoagulable and hypercoagulable, meaning you can clot easier, but also bleed easier at the same time. Different pathways. Interesting. Alright, here's some blood clot 101. I think most people know this, but just in case they don't. It's a massive blood that forms when platelets, proteins and cells stick together. And then, as we said, your body forms a blood clot to stop the bleeding. Then your body usually breaks down and removes the clot, but sometimes they form or they shouldn't. Your body makes too many or the blood clots don't break down like they should. And this can cause health problems for us. They can form and travel to the blood vessels in the limbs, lungs, brain, heart and kidneys. Deep vein thrombosis, I'm sure people have heard about that, deep vein. Pulmonary embolism is another problem, or they can affect ischemic stroke, heart attack, kidney problems, kidney failure, and pregnancy related problems. Here's an article we always like to say that everything we talk about is peer-reviewed studies. And this talks about arteriohypercoagulability as a cause of stroke in adults. Now, this I found very fascinating. The deadly type of stroke increasing among younger and middle-aged adults. And this was just published, you can see here, February 4th of this year. And this was in the American Heart Association Journal stroke. It said, new cases of debilitating an often deadly type of stroke that causes bleeding in the brain have been increasing in the U.S., growing at an even faster rate on young younger to middle-aged adults than older ones. 11% increase over the past decade. And again, it was just published in a journal. So something's going on that's causing this to occur. I'll be honest, this is an area we're just starting to research. And until I started digging into this, I had no idea that platelets carried serotonin. Fascinating. Platelets transport serotonin at a high concentration in dense granules and release it upon activation. Besides the clotting, serotonin influences a variety of immune functions. Fascinating. Serotonin levels are elevated in autoimmune disease such as asthma, RA, and during tissue regeneration after ischemia. Pacific antagonism of serotonin receptors appears to improve survival after a heart attack or sepsis. And they're saying in conclusion, targeting immune modulatory effects of platelet serotonin may provide novel therapeutic options for common health problems. So I was really stunned by this that your platelets carry serotonin and we don't quite yet understand the relationship between that and serotonin in the brain. It's very complex. And I just had a conversation recently with a psychiatrist who said it's now being believed that the SSRIs are somehow impacting this and helping it in some way. So absolutely fascinating. Bob, I have a comment on that because flu boxing, which has been used at times for long COVID, I won't go into the details of that, but I looked at several articles and it has to do with the hemoxygenase, which you'll talk about today, I'm sure. And these have to be hemoxygenase agonist, I believe. I may be saying that wrong. But there's a correlation with especially that particular SSRI and hemoxygenase. So let's make it known when we talk about that later, it may come to play. Yes, absolutely. Now platelets do not synthesize serotonin, but they acquire it from specialized cells in the GI tract. However, the serotonin secreted from platelets may have a role in platelet aggregation and therefore clot formation. And serotonin may have vasoconstrictive properties. So I used to always think of serotonin as the happy thing for the brain, but it's much more than that. Elevated plasma levels of serotonin have been found in hypertension and thrombosis. So a lot to learn on this. So we could probably do a half hour, 45 minute talk on that someday. But for right now, we're just hitting the highlights here. Now, here is what we're going to talk about today.  So this is a map. And just for those who are new to this, these purple ovals are enzymes. Your DNA makes the enzymes. And we can have what are called genetic mutations or SNPs where that enzyme most of the time is underactive, but sometimes overactive.  Here's an enzyme called TNFA, tumor necrosis factor. And this is the first time we've spoken about this in our many interviews. I think this is what, number eight or number nine? I believe Dr. Joseph. Yeah, we have a, yeah, if you want to listen to any of those, they're all on YouTube. We've got some great ones. So tumor necrosis factor kicks in, perhaps when we have some mycotoxins or clostridia, even Bartonella and any source of lipopolysaccharides, gram negative bacteria. They stimulate tumor necrosis factor. Is that a good thing? Sure. And if anybody's listened to us before, you know what the next sentence is, unless it's overactive. And interestingly, you can have a genetic mutation on TNFA that makes it over respond. I know we've spoken before about the HFE gene. And when this is mutated, we can absorb a little bit more iron. When people get two copies of this, they many times have what's called hemochromatosis, but very common in the English, Irish and Askenazi Jewish to have one copy of this, which causes you to absorb a little bit more iron. And that also stimulates tumor necrosis factor alpha. What we've been clinically observing in our health coaching is that when people have an upregulation of TNFA and the HFE, these folks have many times lots of inflammation that no one can seem to resolve. Bob, I know that well because I'm a carrier and I just want to mention for those of you listening, this is something you can ask your doctor to test. You can test iron and iron studies. I always recommend that I test that in all my patients just to check if there's iron excess in your blood. But you can also ask for the hemochromatosis gene. It's a very easy test to perform. Insurance may or may not cover it.  And of course, Bob, your genetics will do the same. So it doesn't. But if someone just wants to ask a regular doctor, hemochromatosis genetics are not difficult to order. Absolutely. Very common in the English and the Irish. A funny story behind that, the reason the Irish came to America was because of potato famines. So by natural selection, the women who had this gene, the absorbed more iron, that made them healthy enough to have babies during times of famine. Isn't that fascinating? Wow. Yeah. So that stimulates the NF Kappa B, which is another inflammatory enzyme. That stimulates NOx, NADPH oxidase. And we did a whole recording on this. I'm going to talk a little bit about CERT1, CERT2N1, which calms these guys down. And we did a whole show in Interleukin 6, how that stimulates it. Now, something that's being talked about quite a bit is mast cells.  Again, they're our friends. They're there to help us if we have an infection. But I'm sure anyone who's paying attention to the health situation now, they're constantly hearing about mast cell activation, where the mast cells are becoming excessive. And when they become excessive, that's when they can be harmful. Dr. Jill, in your work, I mean, what percentage of your patients do you think have excess mast cell production? Yeah, Bob, I was going to comment because this is becoming a bigger and bigger issue. Almost all, now I see mostly complex chronic patients which have Lyme or mold or some other infectious load or chronic fatigue. And I would say at least 50%, maybe upwards of 70% have mast cell issues as part of their clinical picture. Sure. And probably when you started, it was probably not seen very much at all. No. In fact, I'll just tell you, 20 years ago in medical school, we were talking about mastocytosis, which is a blood cell disorder in the bone marrow, almost like a proliferative, kind of like a pre-cancerous type of condition. We hardly ever, that's considered a zebra, which means it's really rare. And we didn't even get taught about mast cell activation, which is more a normal number of mast cells that are overactive. And now we know that environmental triggers, toxins, infections, et cetera, some of the things we'll talk about today are triggers to those mast cells. And the fact that I'm seeing more and more and more of that tells us, tells me our load of infections and toxins is getting really high in the environment. Absolutely. I should also mention that mercury induces NFKappa B, COX2 and INOS, and glyphosate stimulates NFKappa B, that's roundup. Then of course, the mast cells make histamine. By the way, we did a whole show on histamine. Now, this is new information here, Dr. Jill. I would advise everybody really watch the video we did on INOS. And we actually called it the Carnahan reaction, where the INOS enzyme, which makes a lot of nitric oxide to kill pathogens, gets upregulated. And it gets upregulated when we have virus, bacteria, or fungus, which is a good thing unless overactive. INOS inhibits INOS, that's endothelial nitric oxide, which is circulatory. So if anyone's ever heard of renods or rainods, that's where you have cold hands and feet, or just general circulatory problems in general, many times we don't have endothelial nitric oxide, because the INOS inhibits the INOS. And as we'll talk about later, there are genetic mutations that cause the INOS to be upregulated. We'll get to that later. And Bob, maybe some people, if they didn't hear, I'll just do one minute or 30 seconds here, because my story, which Bob helped me figure out was, I always called ketomium, one of the molds that I had been exposed to in the past, the narcoleptic mold, because when I would get exposed to this mold, I'd literally like pass out, I'd have to lay down, my blood pressure would be 85 over 55, I couldn't sustain physician upright. And I talked to Bob one day, and we were trying to figure out what might be going on, and he looked at my genetics, and I happen to have a very rare combination of upregulation of that INOS too. So what was happening for me was massive vasodilation, almost like if you're in septic shock, where your circulation opens so wide up, you can't get pressure to the brain when you're upright. So we kind of figure that out, and that's thus the name. But I wanted to mention, at the same time with those symptoms, sometimes I would have actually like either cold hands or feet, or achy legs, which indicated that INOS 3 was being downregulated. So it all kind of made sense when we talked about it. Absolutely. So glad we found that for you. And that's, as we said, that's why we call it the carnahan reaction. I have a couple slides to explain it when we get there. Aluminum, mercury, uranium, plastics, and I think someday we're going to look back and see a big oops over all the plastics in the way it's getting down into micro particles, electromagnetic fields, high fructose, corn syrup, gluten, glyphosate, all stimulate the INOS enzyme. I think some people are probably having an aha moment at this point, because look what INOS does. It activates platelets, and INOS will calm it down. So remember that slide we showed you how the platelets get activated. Then they create something called ranties, and that's the next slides we're going to go over. So hold on to that term here, ranties. That's really the crux of what we're talking about here today. So that INOS stimulates the platelets. Now on the other hand, when tumor necrosis factor gets upregulated, it will stimulate an enzyme called cox2, and cox2 will cause the body to take arachidinogad, which is one of the fats, and pull it out of the cell membrane and go down a pathway where it stimulates something called thromboxane A2, and once again stimulates and activates the platelets. Now also, you'll notice up here, superoxide, peroxanitrite. I think way early we did a video on peroxanitrite. We talked about EMF, the calmodulant comes from EMF, lipopolysaccharides, histamine, mTOR. All of those stimulate the phospholipase A2 enzyme to pull out this arachidinog acid. So here's pathway number two that can stimulate platelets and the ranties. Now, pathway number three, we did a video where we talked about the home cycle on interleukin-6. Again, interleukin-6 is a cytokine. It's our friend unless it's overactive. So you can have genetic mutations in IL-6, or you can have multiple environmental factors that stimulate IL-6. I encourage you to watch our video on that. Stimulates superoxide, more mast cells, more histamine. Histamine stimulates ranties. Ranties stimulates mast cells. We've got a little bit of a- It's just cycle, Bob. I call that, right? Absolutely. Then superoxide, mast cells, and histamine stimulate what's called the renin angiotensin system, where we make angiotensin II that'll cause aldosterone that can cause high blood pressure, but angiotensin II stimulates ranties. Then finally, we all know the benefits of the omega-3 fatty acids, and your fish oils, and they're your good fats, and then you have your bad fats. There's enzymes called the fatty acid desaturases and ELOVL II that end up making something called protections and resolvents, and they will inhibit that activation of the platelets. Now, we have slides and peer reviewed studies, but that is basically what we're going to tell you today, how environmental toxins, combined with genetic weakness, can cause this pathway to be upregulated. We can also have multiple things that can cause this pathway to be upregulated, and here in our clinic, we've been doing a lot of measuring of the omega-3s, and then also, here's a urine test that you can measure from BoxA and A2. Are you finding that I'm sure you do look at some folks' omega-3s and 6s in arachidic acid? Yeah. Finding those had a balance just a bit. Thanks. I was going to mention that because again, try to put, if you're listening to a practical application, you can get omega testing through Genova diagnostics, through grape planes, and the thromboxane A2. Bob, where can that be tested through the urine? Do you know what lab? Yes. We can maybe put that in one of the links, and I think people can go there on their own if they want. We'll put that in the link. Yeah, because if you have a... Oh, go ahead. Sorry, Bob. Go ahead. Go right ahead. It's called what? Oh, it's called inflammation test, chronic inflammation test. Yeah, we'll get the link. That way, we don't have to worry about it. So, the hang tie will be sure and link those, but you can ask your doctor. I mean, you maybe need a functional doctor who understands this, but even Quest and LabCorp have omega panels. So, this is not something that's outside the reach of the normal physician to order for you. And I was going to mention those protectants and resolvents. Would that include SPMs and DHA or those? Yeah, SPMs. Yeah. Yeah, there's two companies that make them. And they're getting quite a bit of attention in the fellow medicine world that we'll get to this. If this pathway doesn't work, you can just jump right down here and take the protections and resolvents to calm things down. I have seen that be very powerful in either right post-COVID, long COVID, and in myself. And now, of course, it makes sense why. So, SPMs, I'll put links to some of those brands in the chat here or if you're listening anywhere else as well. Sure. And if anyone would like this chart to study it, just go to nutrigenicresearch.org slash research download. We don't ask for your email. There's no charge. There's no catch. You can download the PDF if you'd like to dig into this. All right. Now, we're going to talk about antibodies. What an interesting name. Regulated upon activation, normal T cells expressed and secreted. Wow. That's quite the name here. Or also called CCL5. It's a pro-inflammatory mediator of the cytokine chemokine family. Here's the key point. Regulates the mobilization and survival of immune inflammatory cells from the bloodstream into tissues and other areas of injury infection. Can that be a good thing? Sure. When it's excessive, can it be a bad thing? Of course. So, here they're saying sustained production is associated with several detrimental effects such as heart disease, liver disease, viral infection. Treatments that interfere with rantees are associated with improved outcomes. Now, there's many things that will stimulate the rantees. For our discussion today, we're looking at the platelets because the activated platelets stimulate the rantees. As we said, look what rantees stimulates, histamine secretion by mass cells, IgE and IgG production by lymphocytes, activation and proliferation of the natural killer cells. It recruits T cells, macrophages, asana fills, and basa fills to sites of inflammation. Again, necessary for our survival, but harmful in excess. Now, we're going to just go through these slides pretty quick. We're not going to read them in any detail, but just so people understand what is some medical literature that says what's related to rantees. And by the way, Dr. Jill, I think we're just scratching the surface. I mean, I just keyed a few things and found some things, and I'm sure there's a whole lot more. For the liver, it mediates attic injury and promotes fibrosis. So, if somebody's got liver disease going on, rantees in excess can be a problem. Autism spectrum disorder. In a study of young autistic patients, rantees and other chemokines are shown to be higher when compared with typically developing children. And of course, keyword here is hypothesis, that older chemokine levels are involved in autism spectrum disorder. I think it would be inappropriate to say, yeah, this is the issue, but it's probably one of the contributing factors. So they're saying chemokine plasma levels could be potential biomarkers for autism. Inflammation. Fundamental role in histamine and serotonin generation and cell function. This study was on eczema, and the rantees played a role in the ongoing chronic inflammation of a topic eczema and reflected the severity of the disease. Heart disease. Chemokines like rantees control the recruitment of leukocytes within the vascular wall, essential in the development of the plaque formation. What they did is they did a little study. They took something that knocked down rantees, and it was shown to reduce the progression of the heart disease. So this study is saying keyword potentially new therapeutic strategy. Inflammatory bowel disease. Crohn's disease. So as you know, Dr. Jill, that's something that you were trying to figure out while you were struggling with it. And they're saying here the frequency of the rantees was greatest in severely inflamed tissue. And they were saying significant redundancy in the generation of these signals in chronic inflammation. And it was infrequent in normal colon. So it tears to be higher in inflammatory bowel disease. Now, this is interesting. You spoke about COVID in 10 terminally old critical COVID-19 patients. Refound elevations of interleukin 6 and rantees. And then what they did is they took a, this was like a trial. This is a, blocks the rantees going into the receptor sites. And they noticed a significant decrease in the COVID plasma virus after using that drug. So there is research going on. And there is a doctor, Dr. Bruce Patterson, who put out a paper. It's still not peer reviewed yet. It's in preprint. But he's saying that COVID is really a rantees disease. Probably a little more complex than that, but clearly seems to be elevated in people with COVID. Children with RSV infections have increased CCL5 protein levels in both the upper and lower airway secretions. And it correlates positively with the disease severity. Here we're talking about prostate cancer. The rantees seems to be elevated in prostate cancer as well. And here's just a little chart that shows when we have obesity and too much adipose tissue. And then we get the inflammation, heart disease, liver issues, and beta cell degeneration in the pancreas. Rantees being one of the players that causes all of that. Now, what are some things that stimulate rantees? So what we're saying is that platelets function as the cells that promote immunity inflammation, but they do stimulate rantees. So if our platelets get too activated, they will stimulate rantees. Lime disease. And this is one area that we'd like to study. I'm hoping to be able to get lots of people with lime disease to measure their rantees. But they discovered that Borrelia appears to be a strong inducer of those chemokines. And as we know, some people get lime disease. They don't even know they had it. Others do one round of antibiotics. They're fine. And others are studying for years. They are dealing with all the massive inflammation. And they see the best doctors. They get the best antibiotics. They do all the herbal things. And they still continue to struggle. Those are the chronic lime individuals. And one of the things we need to research is how much the stimulation of rantees may be a factor. We don't know yet, but that's an area of research that we need to look at. Now, rantees stimulation is also related to NF Kappa B. The strength of rantees has been shown to be highly dependent on the pre-existence of NF Kappa B. And then here it says also iron has been shown to serve as a direct agonist means it stimulates NF Kappa B, tumor necrosis factor, alpha promoter activity, and the release of the TNF alpha protein. So once again, that iron in excess kicks this all off. And again, just observing clinically observing those who have mycotoxins, lime, up regulation of TNFA and over absorption of the iron are the ones that are just debilitated by their Lyme disease. I'm sure you see that as well.  Yeah, Bob, I couldn't agree more. And I've been watching that iron connection for a while. And I haven't always known all the pathways. I just know, gosh, if you have a carrier state or a full-blown hemochromatosis, you're going to struggle more with inflammation and infections. Here we're just saying once again, mass cells produce the histamine, and then the histamine enhances the production of the rantees. So that we're just showing the literature that shows how the mass cells create the histamine, the histamine then stimulates the rantees. Interesting correlation, until we dug into the literature, we had no idea these were connected. So here again, mycotoxins are sources of lipopolysaccharides, stimulate tumor necrosis factor, and begin this cascade. Clostridia, Bartonella, lipopolysaccharides, mercury, glyphosate. And these are some of the genetic mutations, because the tumor necrosis factor mutations a gain of function. HFE is a gain of function. And we're going to be talking about the certuance, lowered function, and IL-6 gain of function. So the more environmental factors you have, combined genetic mutations, increases the potential for this thing to take off. And then as we said, eventually stimulate the inducible nitric oxide synthase. And we're going to talk a little bit about tumor necrosis factor, and down here is the RS number, that when it is mutated causes to have a gain of function. TNF-alpha is an inflammatory cytokine produced during acute inflammation and is responsible for diverse range of signaling events within the cells, leading to necrosis or apoptosis. Is that a good thing? Sure, unless it's overactive. Increased TNF-along with other genetic and epigenetic factors stimulates PLA2, that's the one that brings out the arachidic acid, that then stimulates thromboxin A2, thus leading to platelet activation and increased ranties. On the other hand, NF-kappa B plays a variety of evolutionary conserved roles. Cytokine belonging to the TNF family induce genes regulating inflammation, cell survival, proliferation, primarily through activation of NF-kappa B. So TNFA stimulates NF-kappa B. And what we're finding is when individuals have a homozygous variant here, these are individuals that are just so inflamed, and they're going from one clinic to another trying to find help. And they're not being very successful because this TNFA is up-regulated over-responding. In response to lipopolysaccharides due to your gram negative sepsis, the monocytes are triggered to produce large quantities of TNFA. Several studies have identified the pathways that are activated by lipopolysaccharides, also including the NF-kappa B. So when you're exposed to these LPSs, both of these get up-regulated. And they're saying the concentration of ranties has been shown to increase due to the addition of the TNFA and the lipopolysaccharides. So you can see how this thing just feeds upon itself. Now we're going to talk about mold. This is a mold test. Ocrotoxin, this many times comes from water damaged buildings, very, very common. This is Goliotoxin. Here's the peer-reviewed study. Ocrotoxin is a natural fungal secondary metabolite, and it triggers significant modulation of interleukin-2 and tumor necrosis factor alpha. So Dr. Jill, how common do you see mold toxicity in the people who come to you who are just really struggling and coming to you because they can't get help elsewhere? Yeah. So Bob, this is a huge thing because a lot of people come, they might know that they have a diagnosis of Borrelia, which is Lyme or Bartonella or some other gut issues. But when I always feel like, first of all, I'm always asking questions about mold, but if they're not getting better on what should be helpful, I always ask and test for mold because what I found is many times that's the factor in their environment that's weakening their immune system and creating additional inflammation that has not been addressed. So I would say very frequently, mold is this hidden factor they don't know about that's making them kind of at a standstill with their health. Absolutely. It's rampant. Now there's a couple of nutrients that inhibit TNFA, and there's probably going to be more, but we scour the literature, black cumin, curcumin, quercetin, and milk thistle. All of those will calm down TNFA. Now, CERT1, I'm finding this to be very, very important. It's part of the CERT1. And if you study longevity, one of the things they're looking at is the CERT1s and how to preserve their activity. We're going to talk more about the CERT1s. For right now, we're going to talk about how they inhibit NADPH oxidase and NFCAPB. It's one of the most well-studied certuands, significant role in development, a marker of cell senitence when the cells die. It decreases during aging, likely due to NAD plus deficiency, decreased levels are found in the aging liver. CERT1 plays a critical role in MAOA, and I have another chart for this, AMPK regulation of foxo, a very important antioxidant called superoxide disputase, the endothelial nitric oxide that we spoke about inhibits NOx, NFCAPB, IDNF1, and M-torum, that stands for mammalian tarotorapamycin, the growth of new cells. Is that important? Sure. When it's excessive, it creates problems because it inhibits what's called autophagy, the cleaning of the cells. We should probably spend more time on this, but high fructose corn syrup inhibits CERT1. We've all known that these artificial sweeteners probably aren't that good for us, but when I learned that it inhibits this CERT1, it was like, oh my goodness, that's a big deal. Resveratrol, quercetin, and caloric restriction may activate CERT1 activity. That's your intermittent fasting. When we deprive the body of nutrients for a little while, M-tor, which is the growth of new cells, says, I don't have any nutrients. Okay, janitors come out and do your job. Then that supports the CERT1. Again, just observing in our health coaching, when people have mutations in CERT1, particularly homozyus, they're really struggling. I'm not going to read all of this. This is way too much, but this just illustrates all of the ways that CERT1 is helpful to us. Perhaps we can put a link to the slides or maybe put a link to this. If somebody really wants to read this, but we're not going to just go through and read all of this, but bottom line is CERT1 is really important for your long-term health. Bob, if I can just put it into layman's terms real quick, because you did a great job of explaining M-tor and autophagy, but I want you listeners to understand that M-tor is stimulated by growth hormone, by peptides that a lot of body bill is used by anabolic steroids, even testosterone or anything like that. There's a lot of people out there using these kinds of things to decrease body fat, increase muscle mass, get into great shape. That's basically pushing the creation of new cells, new muscle, all good. But if you don't have autophagy, autophagy, as Bob said, is the cleanup, which helps prevent cancer cells. We have cells all the time that are going rogue that could become excessively division or causing rapid division. Anything in that realm will cause a proneness to cancer. We need both. I wonder, and we saw with COVID people with higher testosterone on anabolic steroids, any of those realms that were pushing M-tor, they had worse outcomes. In fact, some of the treatments were suppression of testosterone. I just wonder if that was related to the CERT-1, and then you mentioned corn syrup and obviously a standard American diet with lots of fast food, high fructose corn syrup. We know metabolically, if people were a metabolic syndrome, diabetes, obesity, they also fared worse with COVID. Those two things make me wonder if it was related to the CERT-1 genetics here. I believe so. I've wondered the same thing. There is some literature out there that COVID uses M-tor for replication because M-tor replicates and it's like a copy machine. It doesn't matter what you put on the glass, it'll copy it. Healthy cell, cancer cell, and possibly COVID. I observed that as well because sometimes you'd hear about these young men that were dying while somebody 78 years old survived. It's like, well, what's going on there? There's many components to it, but that may be a factor. Now, I really like this slide. CERT-1 supports enos, remember we talked about that earlier, anethylionitric oxide, the healthy blood flow, supports peroxide disc mutase, a very important antioxidant, inhibits NF Kappa B, look at this one, inhibits M-tor, and supports MAOA, which is a clearing of histamine. High fructose corn syrup inhibits resveratrol helps, and in your nitrates also seem to support CERT-1. That's like your arugula and beats and things like that. Here's the RS number, 1277-8366. When it's mutated, that's when that CERT-1 activity may not be as robust as it should be. I would have to say I put that on my top 10 list of SNPs that may have an impact on this from a functional standpoint. Now, we've also spoke about mass cells become overreactive and likely present in 9 to 14% of the population. We're just mentioning here there are enzymes called KIT. There are a couple mutations in the KIT enzymes and there's too many to list that will actually cause the mass cells to be trigger-happy, respond too quickly. Most people know some of this, but we'll just review it a little bit. When the mass cells get activated, you make more histamine or interleukins, stimulates tumor necrosis factor A. I probably on my chart ought to have a line going from the mass cells back to the tumor necrosis factor in another feedback loop. Now, let's talk about histamine. And by the way, Dr. Jill and I did a long interview on histamine. Here's the cliff notes. They can be stimulated by allergens or high histamine foods and when we make histamine, we need cortisol to degrade it. The body makes something called dynaminoxidase. There's an enzyme called histamine and methyltransface, MAOA, and glucuronidation, all of which clear histamine. One of the most common things we see in our health coaching is people have genetic mutations in these enzymes that they don't degrade enough histamine. And then there's another one called histidine decarboxylase that actually takes an amino acid called histidine and turns it into histamine. We're looking through the literature, but there are some that are considered pathological and we are just hypothesizing that they're gain a function, but we're not quite sure. But whenever we see mutations in HDC, many times these folks have high levels of histamine, even confirmed by blood work. What percentage of the folks you see, Dr. Jill, do you think have a histamine problem as one of the things they're dealing with? Yeah, Bob. Again, just like the mast cell activation and all the things that that produces, this is one thing, but it's very, very common. And one thing I was thinking as you were talking is I think it's related to our load. I think that's why things are getting worse because our environmental toxic load, and you've just talked about all kinds of triggers in the environment that can do this. And what it is doing is revealing these deficits and genetics that maybe we're there, but when the load was low, no one noticed. And now that we have more toxins, more chemicals, more glyphosate, more high fructose corn syrup, more stress, more lack of sleep, and I could go on and all of these things affect our ability to deal with the environment. So I think it's exponentially increasing. Absolutely. Yes, for sure. Now, here's a peer reviewed study. Histamine stimulates inaus expression. Now, when we did our talk on the corner hand reaction, we didn't have this piece of information. We didn't know that histamine stimulates the inaus as well. We've had this slide before, but just in this chain of events, we're just saying histamine enhances the production of the rankings. So really encourage you to watch this video. It's our number, your number 34, where we talked about histamine. I mean, that's all we spoke about in that whole talk, 45 minutes on histamine. So we got into the histamine foods, the DAONs, I'm a lot of detail. So if somebody wants to learn, look up number 34. That was a fun interview, Dr. Jill. They've all been fun. Now, we're going to talk about nitric oxide, the miracle molecule. 1998 won a Nobel Prize for three scientists on the benefit of nitric oxide. It's an incredibly simple molecule, nitrogen and oxygen. However, it's one of the most significant molecules in the body, critical to your well-being. Axis of vasodilator causes the blood vessels to expand, including reducing blood pressure, flow of nutrients to the muscles, improving the efficiency of which ways to remove from the muscles and organs. I mean, if we don't have good blood flow to the liver or kidneys, they're going to struggle. Stimulates the brain helps men with erectile function and impotence. That's why they take Viagra and Cialis to help with nitric oxide, increase energy, support wound healing, and support the immune system. It influences everybody organ, including the lungs, liver, kidney, stomach, genitals, and of course the heart. Again, I'm not going to read this way too many things to just sit here and read, but this just illustrates the importance of nitric oxide. Now, INOS, so what we were talking about all those benefits is endothelial nitric oxide helps circulation. There's another enzyme called INOS inducible nitric oxide. What does it do? It kills virus, bacteria, and pathogens. Is that a good thing? Sure, unless it's overactive. How many times have I said that now, Dr. Jill? I love it. Bob, what's so great about this is our body was created to fight infections and to take care of toxins. Some people get all worried and they're like, oh my gosh, I'm toxic with mold. What am I going to do? Well, guess what? If you get yourself out of the environment, even without supplements, you would probably slowly detox because your body's created. What we're talking about is when the load is too heavy or the infection's too great or our stress is too high. Or as you mentioned, and you're the expert in this realm, is the genetic mutations that make our particular pathway mutated and excessive. So these aren't bad things. They're just too much or too little can be an issue. Absolutely. Back to Goldilocks and the three beers. So INOS generates very high amounts of nitric oxide to fight. Total eliminations has shown to increase the infections. I mean, we wouldn't survive if we didn't have INOS to kill the pathogens. On the other hand, excessive has been associated with many health concerns. It's linked to tissue damage and organ dysfunction. Now, this is a chart that we may have had when we did our video on INOS. And again, I would encourage you to watch that video. But here's the cliff notes. And we sort of alluded to this before. INOS is your endothelial nitric oxide. INOS, the inducible nitric oxide, helps with circulation, kills pathogens. When you've got the histamine or many other things that stimulate this, you can see here, here's the list of mercury, uranium, plastics, ethanol, EMF, high fructose corn syrup, gluten, chlorine and fluoride, Roundup, high homocysteine, iron overload, stimulate the INOS, inhibit the INOS. There's a substance called BH4, tetrahydrobaroptin that's needed to do this. If INOS keeps running too hard, we run out of BH4. And it's called NOS uncoupling that we'll talk about a little bit later. But while we're on the map, I want to show you, when we run out of BH4, we make superoxide free radical. And what we're going to show you in a little while is superoxide stimulates the PLA2 enzyme to make more ranties. And there's a lot that can go wrong here. We're not going into it today, but there are pathways where we make BH4, some of it beginning from the citric acid cycle. Then there's also the folate that comes in here. But when the BH4 gets depleted, BH4 is needed to turn tryptophan into serotonin, tyrosine into aldopa. If this gets severe enough, you're going to have tremors and at real severity, potential Parkinson's, and the phenalanine into tyrosine. So I can't tell you how many people have mood has been boosted when we give them something as simple as royal jelly. They can handle it. And that boost to BH4 and they start making their serotonin. Now this is what we call the carnahan reaction. And we're going to show you that in just a moment here. But firstly, INOS activation and platelet secretion. INOS activation influences platelet secretion. INOS knockout mice have prolonged bleeding time. So in other words, if you don't have the platelets activating, you're going to bleed to death. But in excess, that's when you get the clots. So when we did our recording, Dr. Jolan INOS, we didn't know that INOS actually activates the platelets as well. And this is now talking about the INOS. The activity level of INOS enzymes was significantly lower in patients platelets with coronary thrombosis. So here they're saying this data was consistent with the reduction of the expression levels of INOS in patients with the thrombosis. So INOS causes platelet activation. INOS eases the burden. So that's why that INOS-INOS balance is so important. So here's a peer reviewed study published back in 2021, PubMed, then a medical journal called Nitric Oxide. And they're talking about COVID on INOS and INOS activity. And this simplifies it. This is a chart in a peer reviewed study that appeared in a medical journal. As we create more INOS in an effort to kill the virus, this is where we can get the inflammation. As it pushes down INOS, we get the blood clots. And this is possibly why COVID is causing higher levels of blood clots and strokes. Bob, I'm going to, if you have just a second, I want to share something really interesting. I haven't even showed this to you yet. And I think I can share just one picture and then explain really quick, because something happened to me about a year and a half ago, because you know, I'm the guinea pig. Can you see that picture for one second of my leg on top of the screen if it's coming through? There it goes. I'll take this off so we can go back to your slides. So this is my leg a year and a half ago. And I want to tell you a real quick story that I think relates to this. I all of a sudden out of the blue got a very high fever, 104.5. I've never had that. I have a fever in my life. I suspected COVID. I did not test positive, but we know that sometimes there can be errors in that. And I just stayed home and isolated. So after one test, I just assumed within 24 hours, I developed a blood clot and cellulitis. This is a picture of my leg. I've literally never shared that before. I go back to your screen, but I wanted to show you because I believe I probably had COVID. We don't know for sure. But if that's correct, we know I already have a platelet issue with genetics. And then we also know I have clearly a carnion reaction, which is this increase in INOS. And I believe at that time, whether it was COVID or another virus, it triggered a clot, which triggered a cellulitis. And that was my leg. I needed IV antibiotics to get well from that. Fortunately, I recovered very quickly and no problem. But that's a picture of what can happen with this activation. And I believe this is absolutely related to this INOS pathway and the platelet activation. I want to show you in real life, I've literally experienced this. And I should have probably been hospitalized. Fortunately, I have connections and was able to get home IV antibiotics. But one of my friends was like, Jill, you really need to take this seriously.  And my thought was, huh, I wonder what temperature my brain will melt. So just a story to show people this is real, this can happen. And again, no fear, but I'm the guinea pig. So I got to experience that and understand the INOS pathway on a new level. Wow. That's incredible, Dr. Jill. Wow. Sorry, you went through that.  So I'm not going to read these, but these are all the things that stimulate INOS. So we're wondering why we're seeing more conditions today than we did before. You know, when I was born, it was very little BPA. It was very little an aluminum. We weren't exposed to cell phones. I don't think mold and mycotoxins were as bad. We certainly didn't have high fructose cord era when I was a youngster. We didn't have glyphosate. So all of these things cumulatively, I believe, are having an impact on all of us. But anybody who has genetic weakness gets hit harder, that proverbial canary in the mind. Now, mercury is a stimulator of NF Kappa B. And I'm sure, Dr. Jill, you probably check for heavy metals sometimes and you probably see a fair amount of people with mercury toxicity. I do, especially dentists, unfortunately. Absolutely. Here is glyphosate. This is the Great Plains glyphosate test. And you can see this, for a person, they were just pinning the needle. It inhibits SV, catalase, glutathione peroxidase, as well as reduced glutathione. And look at this. Promoted the expression of NF Kappa B and INOS and tumor necrosis factor alpha. So in this study, they didn't measure rantes, but I think it's not hard to interpolate that if these are high, the rantes is going to be high as well. And Stephanie Senev does a lot of talks on this. So if you just Google her name on YouTube, you can find great talks from her. Have you ever had her as a guest or anyone speak about glyphosate? I have not, Bob. It's a great idea. I know Stephanie well. I love her research. I'm going to ask her to be on. So stay tuned. We'll have her on. Absolutely. She'll be glad to talk about glyphosate. There are a couple of enzymes. I mean, there's more than just this one. But there is an enzyme called PON1. And these are the ones that are evidence-based. And just, again, clinically observing, when we see a lot of twos on here and the people live in a farming community and we measure their glyphosate usually extraordinarily high. So PON1 is related to clearing of glyphosate. Now, there's others as well. So here's again. Histamine stimulates smooth muscle cells to increase INOS expression. And we'd encourage everybody. I think I just checked the other date. It's still the most watched video in your YouTube where we spoke about interleukin-6. We went on for one hour and 51 minutes. That was a great one. It was so awesome. Yes. So number 42. And little did I realize at the time. You know, it's interesting. We spoke about peroxynitrite, histamine, the carnahan reaction, IL-6, the home cycle, and how all of a sudden it's like they're tying together into this. It's just rather astonishing how it all comes together. Bob, I love that you said that. I kind of want to emphasize we've just been going along learning and these pathways are amazing, but we did not expect for it all to, like you said, like today is really accumulation of all of this and how it comes together. And for me, I'm just first of all amazed at your work. And I want to say that publicly, you so appreciate it. But secondly, just how it all really, really makes sense, doesn't it? Absolutely. I mean, I was kind of blown away when it's like we were talking about those things separately. And it's like, oh my gosh, they all work together. Yes. This ranties. So we kind of alluded to this before, but just another quick slide. You know, when you have enough ph4, the enos makes nitric oxide. If we run out of ph4, we make superoxide. And I'm going to show this very soon. Superoxide stimulates PLA2. Now, this is, there is gain of function mutations in the enos enzymes. That means it's overactive. And then that'll create more superoxide. So here is the common functional enos polymorphisms, the RS2779249, when this is mutated, the good one is the C. And then the bad one is the A. So if you would be CA, that means you have one mutation. If you have an AA, you have two mutations. 4.73 times increased enos expression when you had this genetic mutation. Here's another one, RS2297518. The good one is G. The risk is A. And you can see here that the AA only occurs in 3.9% of the population. It's related to early onset Crohn's disease, ulcerative colitis, inflammatory bowel disease. Increased nitrosat of stress, meaning it's making a peroxanitrite and oxidative stress in the gut. And here is the infamous Carnahan reaction. And Dr. Jill's very brave. She allows us to put her on the Internet. And here's that NOS2 that's upregulated. And this 2 means that mother and father gave her mutation. The other one that's upregulation, mother and father gave her mutation. So that's why we're calling it the Carnahan reaction. And here is what can cause that to happen. Again, these things we mentioned before, the genetics could be the NOS2 being gained. I'm not talking about it today, but there's actually a NOS3 lack of function. If we don't make enough superoxide dismutase, CERT1, as we spoke about, supports the production of superoxide dismutase, helps ENOS. DHFR and QDPR help recycle your BH2 to BH4. And the MTHFR81298 is also involved with making enough BH4. So if you want to get more details on the Carnahan reaction, watch the video on INOS. And we went through it in detail. So I'm hoping Dr. Jill, 100 years from now, they're still talking about the Carnahan reaction. All for the greater good. Absolutely. Now, pathway number two. There's a enzyme called phospholipase A2, PLA2. And what this one does, it takes arachidinic acid from the cell membrane, and that's one of the fats, pulls it out. And I think I'll do a little expansion here. And you can see that peroxide, peroxynitrite, I would encourage you to watch our video on EMF because we get too much chalmalam, lipopolysaccharides, histamine, mTOR, all stimulate PLA2. The adrenal glands make cortical steroids. Ginkgo bilobas and urb, curcumin, CDP choline, all inhibit PLA2. And what can happen is that when we have any of these environmental factors, it'll stimulate the PLA2 to bring the arachidinic acid out. And then tumor necrosis factor can also stimulate the cox1 and cox2 enzymes. And we go down a pathway where we stimulate the TXA enzyme and make thromboxin A2. Now, we don't do this on our software yet, but when we come out with our new chip, we want to make sure we have all the PLA2 enzymes because there might be some that are activated. We want to look at the cox1 and 2. This was an interesting one because this guy takes these inflammatory things and moves them over to make prostacycline, which is actually vasodilative and inhibits the platelet aggregation. Now, one of the things that's interesting is that aspirin and your NSAIDs will actually encourage going over this direction. That's why some people take aspirin, although that's been now said not to because of bleeding, but just to show the action. Aspirin will block coming down here to make the thromboxin A2. And again, then activate the platelets and stimulate the rantes. We're not going to get into it today, but interestingly, collagen epinephrine and INOS and endotensin II stimulate the platelets. But I find this interesting that collagen plays a role in that. We need to dig into that just a little bit more. So here is the importance of the adrenal glands to make the cortisol, and the adrenal glands also knock down the histamine. So this is an important pathway, and that's why you spoke earlier about doing those blood tests, seeing where your arachidic acid is, your arachidic acid EPA. Those are all important markers to look at because that will be pro-inflammatory. So here's a little information on that PLA2, phospholipase A2. It liberates arachidic acid, and then that arachidic acid makes prostaglandins and leukotrides. When rat platelets are incubated with phospholipose A2, thromboxane A2-like activity, prostaglandins are formed, again, pro-inflammatory. Right now there aren't any tests for PLA2. I know Great Plains used to have it, but they couldn't get the regent, and I've talked to them and said, you guys got to get that back, because it's so important to look at this PLA2. All right, here's a quick overview, and this came from the Great Plains website, Bill Shaw. And by the way, Bill Shaw was a pioneer. I mean, he was talking about PLA2 a time ago. When experiencing infections, PLA2 can break down the phospholipids of the membranes, the bacteria, fungus, and parasites. So I saw a recording here, but a good thing, yes. However, inflammation often becomes excessive, and then the same phospholipase that attacks infectious agents may attack the cell membranes, damage or killing those cells. Most common free fatty acid produced by this is arachidatic acid, which can increase the production of mediators of inflammation, which we spoke about, the prostaglandins lucatrines. Superoxide anions could stimulate phospholipase A2, and we've spoken about this many times, particularly EMF, is making more superoxide. If we don't take our oxidized glutathione back to the reduced superoxide, and if you remember when we spoke about the Nossan coupling, what do we make? Superoxide. So I believe superoxide is public enemy number one. Now, again, superoxide is helpful. It kills pathogens, but in excess, a problem. So the products of this phospholipase A2 are brain damaging agents, and may be responsible for mitochondrial damage during oxidative stress. Here we're saying that a study of intestinal cells has shown that tumor necrosis TNFA potential dates the release of arachidic acid. So the more you have that TNFA being upregulated by environmental factors or genetic upregulation, the more you're going to take that phospholipase A2 to stimulate the arachidic acid release. Now, we're going to talk a little bit about that thromboxane A2, and this can be measured, stimulating the platelets, creating rantes. However, these activated platelets can also stimulate something called SCD-40L. We're going to get into that just a little bit. But before we do, there's a lot of talk about how the Mediterranean diet has a lot of health benefits. Oleic acid comes from your olive oil, and that may stimulate this PGI2 enzyme to shunt this inflammatory thing over to prostacycline, which is vasodilative, and also inhibits platelet aggregation. So absolutely fascinating how we've been talking about the Mediterranean diet, the olive oil. We now know the pathway that that can move through. So I was blown away by that one, Dr. Jill. Yeah, unbelievable, and I love olive oil. It's good for us, isn't it? It's often with these pathways. And you know, we do a lot of testing where in the micronutrients and things, I see a surprising number of people who are deficient in oleionic acid. Absolutely. And so if that's the case, a little bit of olive oil might certainly be beneficial. Okay, here's the thromboxin A2. Prostaglandin counterbalances the thrombotic and vasoconstrictive properties of TXA2. This balance can become dysregulated in pathological and physiological situations. So increased activity of thromboxin A2 could be associated with mitochondrial or mitochondrial infarction stroke, arteriosclerosis, and bronchial asthma, pulmonary hypertension, kidney injury, hepatic injury, allergies, angiogenesis, and the growth of cancer cells. When activation of TX, or thromboxin A2 is uncontrolled, there could be pathological consequences. I'm not going to read all of this, but the bottom line here is that activated platelets also express SCD40L. And now we're going to get into that. But first, again, mentioning serotonin. Serotonin is transported by the platelets and released upon activation. This induces constriction of injured blood vessels and enhances platelet aggregation to minimize the blood loss. Interestingly, platelets contain high amounts of serotonin and a dysfunction the serotonin system is involved in the development of several behavior orders. This is just hypothetical, so we're not making any statements here, but it may be involved in depression, anxiety disorders, and self-aggressive disturbances. The platelets are able to take up dopamine and express various dopamine receptors, which could make them an interesting tool to study the underlying mechanisms of schizophrenia. Lots to learn here. We're just in the very beginning stages of understanding this. The platelets store large amounts of serotonin. They're released during the thrombus formation and that creates the clots. But what I found interesting, it induces hydrogen peroxide, H2O2. And if you have overabsorption of iron and you don't clear your hydrogen peroxide, you get hydroxyl radicals that are very pro-inflammatory. All right, SCD40L. Activated platelets are the major source of SCD40L, which has been implicated in platelet and leukocyte activation. And this SCD40L is involved in inflammation and vascular diseases. So here's the activated platelets stimulating the SCD40L. Now, this is interesting. High early SCD40L levels in trauma patients reflect tissue injury, shock, coagulopathy, and adrenal activation and predict mortality. SCD40L may be involved in trauma-adduced endothelial damage and the blood clotting. Now, here's a chart. When we get the activated platelets, SCD40L is activated. That increases VEGF. We'll talk about that in a little bit. Encourages the growth of tumors. So that's why it's so important that we don't have this elevated. I'm sure, Dr. Joe, you measure VEGF on occasion. Yeah. I was going to say, Bob, and there's some new with Dr. Patterson's research, we can now measure SCD40L with special labs as well. So literally, we're doing panels to look at all of these things now. They're not easily accessible as far as lab request, but they are available to be tested. Absolutely. I'm excited to hear you're doing that, because I think we're going to find that the long haul COVID and possibly even the chronic Lyme disease has increased grantees in SCD40L. Yes. I've been talking to the folks at ILAD about that. Hopefully we can do some research. So these myeloid derived suppressor cells are relatively newly defined that they suppress immune responses. And there's a role of this in solid tumors. It's been extensively characterized as pro tumor in intensive clinical studies, circulating and infiltrating MDSCs at the tumor site. We're associated with poor prognosis in patients with solid tumors. In a study of breast cancer patients, the overall survival of preoperative patients with MDSC levels greater than one with stage four disease was significantly shorter compared to people that had lower than one of them. So what they're saying in this study is that MDSC levels could work as a good plastic indicator, especially in those with advanced breast cancer. VEGF, that is the growth of new cells. I'm sorry about the blood vessels. Is that important? Sure. What happens when someone gets cancer? They need those new blood vessels for it to grow. So they're saying that the inhibition of VEGF induced angiogenesis significantly inhibits tumor growth. Angiogenesis is the growth of the new blood vessels. You know what else, Bob? I'm seeing, as you mentioned, mold can either decrease or increase VEGF, but also Bartonella, which you mentioned as an LPS inducer. I see that commonly abnormally high VEGF with Bartonella as well. Absolutely. This is exciting things that are happening here. Now, we did a whole video on this. We called it the home cycle, where multiple, let me just zoom in here a little bit, multiple endogenous mediators like histamine, dopamine, and eutensin, too. All of these will stimulate interleukin-6, mold in micropoxins, Lyme disease, lipopolysaccharides, EMF, stimulate interleukin-6. When interleukin-6 gets stimulated, we get superoxide through NOx, mast cells, histamine. By the way, we talked about the hemoxygenase calms down the mast cells. Then histamine stimulates ranties. Now, as we talked about in that video, superoxide, mast cells, and histamine stimulate the retinansiotensin system. That will stimulate ansiotensin-1, ansiotensin-2, and the literature is there. Anziotensin-2 stimulates ranties. This is where we spoke at length, that long interview about the importance of IL-6. Again, our friend, unless it's overactive. Yet another third way that we can make too much ranties. I'm not going to read this. These are the SNPs, the genetic mutations that could be involved when they're mutated that would allow this to be more proactive. Again, we showed this before, but again, because this makes the histamine, the mast cells create the histamine. The histamine enhances the production of ranties. Mast cells showcase that the mast cells as an additional renin source. Interestingly, mast cells can stimulate that renin-ansiotensin system that's going to make more interleukin-6 and just keep things moving around. Mast cells could be targeted along with renin-ansiotensin system inhibitors to manage ansiotensin-2 related dysfunctions. The ansiotensin-2 dosterone, which causes you to hold on to sodium and excrete potassium, and that's related to blood pressure and edema. Histamine and renin. Histamine has been shown to stimulate the release of renin, and superoxide activates the renin as well. That's just backing up what we talked about. Here's the peer reviewed study. I'm not going to read it, but the bottom line is that you get this feedback loop when you have superoxide, mast cells, and histamine, and it just feeds upon itself an inflammatory cascade. When we did this video, we had no idea that the ansiotensin-2 stimulated ranties. Again, I'm not going to read this, but this is the home's hypothesis that is related to toxic environmental factors, creating these inflammatory agents, depleting our NADPH, stimulating the renin-ansiotensin system in that positive feedback loop of inflammation. Again, if someone is interested, watch our video number 42. Bob, I've been here listening here, and if you're listening, wherever you're listening, I will include these links. Don't worry about finding them. I'll make sure they're included. Oh, good. Good. When I grabbed, there was 2,900 people who watched it on YouTube. That's amazing. And Bob, I just looked. It's over 3,000 now, so it's all right. Wow. Okay. All right. Here's the one on the NOx pathways, where we explain that home cycle. All right. Now, we're going to wrap up with the Omega-3's Resolvants and Protectants. So, a meta-analysis revealed an association between your polyunsaturated fatty acid supplementation and a reduction in platelet aggregation. High-risk patients with cardiovascular disease or diabetes could benefit from the Omega-3 therapy. Now, this is fascinating. Again, peer-reviewed study, both EPA and DHA, this is the parts of your fish oils when you take them, get incorporated into platelet phospholipids at the expense of arachidinic acid, which may help reduce platelet aggregation via a reduction in the arachidinic acid-derived platelet aggregating pro-coagulant metabolites. EPA competes with AA for that cox enzyme reducing its action on arachidinic acid, and it reduces the formation of that Brombox-A and A2. EPA-DHA also gets incorporated into neutrophils and red blood cells at the expense of linoleic acid and arachidinic acid. It decreases whole blood viscosity and increases red blood cell flexibility, thus likely reducing the risk of thrombosis. Now, what happens is they go through a couple of steps, and I'm going to show you a chart here in a couple moments, where we make what are called Protectants and Resolvants, and they're associated with various beneficial effects and the prevention of various diseases, modulates the immune system, helpful for autoimmune, rheumatoid arthritis, cardiovascular, Alzheimer's, type 2 diabetes, and cancer. Interesting little chart here. When you get tissue injury, you get the acute inflammation, the lipoxins, resolvents, and protectants, complete resolution. If not, you'll get abscesses and scars and chronic inflammation from the prostaglandins and leukotrine. So that's why these are so important to resolve complete resolution when we have the resolvents. And that looks like a duplicate slide. Okay. Now, here's arachidinic acid, and it shows on this chart the different pathways, and we want to map this all out. Genetically and epigenetically we want to map this out, but you can see the arachidinic acid comes down and makes acute inflammation and chronic inflammation. Interestingly, there's a couple of pathways that we've not identified yet. This might be a future show to talk about how we can get that arachidinic acid to come down to be actually helping the resolution of inflammation. So arachidinic acid isn't all bad, but your EPA and DHA, they go down these pathways, and here's where you make their resolvents and protectants. And the standard American diet that I think you alluded to earlier, we're much heavier in the omega-citas and the things that will create the arachidinic acid versus the omega-citas. So just for practical, if you're listening, seed oils, I would really avoid, those are going to be sources, canola oil, all these oils that can become rancid and can produce more arachidinic acid. You want the omega 3s, which is your wild salmon, your fish, and bottom line is you should probably be taking a fish oil. And I like the ones, especially if you have this inflammatory pathway, higher DHA and with SPMs. I actually put a link on this site to mega-omega. There's other ones, but that one happens to have both EPA, DHA, and SPMs all in one. Wow, very impressive. Okay. This resolvent E1 is generated during resolution of inflammation in the human vasculature, and a study has shown new potent agonist specific anti-platelet actions. Now this is a little confusing. Agonist means it helps the anti-platelet actions. These actions could underscore some of the beneficial actions of the EPA in humans. I really like this chart. So here's your omega 6s. And from a genetic standpoint, we are finding that there's enzymes called fads, fatty acid de-saturations. And they're involved with taking your omega 6s, the fads 2, down through to make arachidinic acid. But this is interesting. Omega 6s may use up the available fads 2s. So when we consume our fads 2s, they have to go through multiple steps. And this is a new one that we've just added, ELOVL2, finding it to be very significant. This is what takes your EPA into your DHA. So we can make the protectants and resolvents. What we're observing, when people have a lot of mutations in their fads 1 and fads 2, they have unresolved inflammation. They just can't seem to get to the bottom of why they're in their mid-40s and they hurt all over. Part of it could be that they're not getting down to these protectants and resolvents. Because they will inhibit the platelet aggregation and the ranties. So we have this on our computers. We show this to folks all the time. Why it's important that we get those omega 3s, but more importantly, that we get down through this way. And if we don't, we may need to use those protectants and resolvents to just bypass the weakness here. And Bob, I'm going to tell you something really interesting. I showed you all my leg when it was severely cellulite and probably from platelet aggregation. I did not know this pathway, but I'm pretty intuitive. And I didn't at the time know why I just knew they were anti-inflammatory. I took like four times the recommended dose of SPMs. And it really, those are the resolvents that you're talking about. I took very high doses of these and it really, really helped. And it's no wonder you're showing me the pathway for that. Yeah. So here's the study showing, and this was just published back in 2017. FADS and ELOVL2 may have a role in the differences in omega 3 requirements. So what we're finding is the more ELOVL2 mutations, the more there's a higher need for DHA. And here's the FADS and FADS2. So this one over here means mutation. And you can see this person had a mutation in every one of the FADS1 and they had mutations in most of the FADS2. The people that are really struggling, and we see them every once in a while, homozygous or both parents gave the mutation straight down through. Those are the folks that are really struggling in getting their EPA turned into DHA and making their protectants and resolvents. I would have to put this on my top 10 list of important genetic things to be aware of, because we find this really is involved with those who are struggling. And here's a peer reviewed study. Our results are yet, somebody wants to look it up 953413. Regulates your polyunsaturated fatty acids by altering ELOVL2 expression through the FOXO genes. And again, we're finding that one when combined with tumor necrosis factor, folks are in a lot of inflammation. Here's a study, clinical studies in humans shows that marine omega 3s provide anti-platelets effect. Three grams of omega 3 polyunsaturated fatty acids for four weeks lowered fibrinogen, thrombin and factor 5 levels. And we talked about this before that it's the expense of the arachidinic acid. EPA also competes with arachidinic acid for the COX enzymes reducing its action on AA. If remember the COX enzymes are ones that bring it down and make the thromboxin A2. So they're saying EPA both directly and indirectly reduces the formation of arachidinic acid thromboxin A2 that activates the platelets. Now here there's all kinds of tests out there, this one just happened to come from omega quant. This was a middle aged lady who got COVID and was doing very poorly. Now this was post COVID, but here's her omega 3 index. Should be 8 to 12 percent, three and a half. Then here's the ratio of omega 6 to omega 3s. Should be 3.1 to 5.1 off the chart, 11.9. Arachidinic acid to EPA should be 2.5 to 11.1, 35.1 again off the chart. In my opinion it's important that people know where this is. So talk to your physician, whoever that is, and see if you can see where these are, because it's more important than we ever ever realized. And I mentioned earlier Bob, these are now available on your regular labs. So this is not a functional cash lab, you can get it through Quest or LabCorp or Boston Heart or some of these other labs are it's available. Then here is the test for thromboxane.  No wonder this person was struggling in this case study. So this is the same person that had that arachidinic acid. So the arachidinic acid was stimulating the thromboxane A2 and creating massive inflammation and fatigue and lots of histamine. All right, so what's a potential action plan? And this is a really short list, but a couple practical things you can do. Make sure you're in a mold-free environment, clear mold of an issue. If you work with a functional medicine doctor, see if you have some mold inside you. If there's real concern, see a functional medicine person for heavy metals, glyphosate. Check for Lyme plus Tritia lipopolysaccharides. Consider eliminating high fructose corn syrup, but especially with assert one mutations. Low histamine diet if histamine is an issue. Check what we just talked about here. Maybe consider checking the thromboxane A2. As Dr. Jill mentioned, they're not easy to get, but you can measure Rante's, SCD40L, VEGF, TNF, alpha, IL6. Dr. Jill, are you doing what or consider the long haul panels? Is that what you're doing? That's exactly what I'm doing, correct. And then if you want, you can do your genomic resource test if you want to see if there's any mutations that may worsen the situation. So that's it, other than just a brief commercial to health professionals. If you're a health professional and you'd like to look at all this, we have a genetic test called your functional genomics. The software analyzes everything for you and puts it together and we also have online education. If you're a health professional, you want to try the certification course. Here's where you go, NeutrogenicResearch.TalonLMS.com and you can save $100 with using the coupon code Dr. Jill. And it's not for everyone, it's not for the faint of heart. But for somebody who really wants to dig in and study, it's a good resource for you. If anyone wants to contact our clinic, tonhealth.com. There's our phone number,<PHONE_NUMBER>.  There's the website, functionalgenomicanalysis.com. Yvonne Lucasi and Chrissy Bannon are your helpers. And we have a whole line of nutrients that support the function, freedomtoformulate.com. So we just went through probably a three-day course in an hour, an hour and a half, but there it is. As always, it is so fun. And for those of you who stayed with us the whole time, a lot of you did. I hope you enjoyed it. I know someone commented, I'm glued to my seat. So I know that this is not for everyone, but for those of you who enjoy the pathways and understanding.  That's okay. Sometimes we're overwhelmed too, but get a functional doctor. You can do the testing with Bob's companies that he just put up there with your doctor. And there's lots and lots of solutions out there. I'm just excited, Bob, like we said in the beginning, to bring what we're talking about. A lot of the stuff we're talking about, we see this in clinical practice. We don't yet have hundreds of thousands of people in randomized controlled trials, but this is where science starts, right? We ask the questions. We look at pathways and we make hypotheses. And that's where you're on the leading edge. And I couldn't be more honored to be here with you. So thank you again for sharing. Well, thank you for allowing us to the platform here to bring this out, because it wasn't for you. We'd be sitting here having fun by ourselves, not sharing it with anyone. So I really appreciate your openness to bring this out.  And hopefully your hand reaction will be well known. And if I can go through something to help people, I'm all good with it, like my leg and everything else. So thank you all for listening today. We will be back again. So stay tuned.


Hey fellow buddies. Thanks for watching I'm gonna tell you where they got it what they paid for it and what it sold for. Let's get started


Hi and welcome to the session. I am Shashi and I am going to help you to solve the following question. Question is fill in the blanks in the following table. Given that A is the first term, D is the common difference and An is the nth term of the AP. Given table is this. First of all let us understand the key idea to solve the given question. The nth term An of the AP with first term A and common difference D is given by An is equal to A plus n minus 1 multiplied by N. Let us start with the solution now. First of all we can see in first part we have given A, D and N and we have to find out the nth term. So we know by key idea nth term is given by the formula A plus n minus 1 multiplied by D where A is the first term and D is the common difference. Now this implies An is equal to 7 plus 8 minus 1 multiplied by 3. Here we have substituted the value of An and D from this table. Now we get nth term is equal to 7 plus 7 multiplied by 3 or we can say An is equal to 28. Now this completes the first part of the question. Now in the second part we have to find the value of D that is the common difference and we are given An and the value of N. Now again we know nth term is equal to A plus n minus 1 multiplied by D as we have already read in key idea. Now we have to find the D and we will substitute the values of An, An and N given in the second part to find D. Now we can write 0 is equal to minus 18 plus 10 minus 1 multiplied by D. Now this implies 0 is equal to minus 18 plus 90 or we can say this implies 90 is equal to 18. This further implies D is equal to 18 upon 9 equal to 2. So we get D is equal to 2. Now in the third part we have to find the value of A and we are given the value of common difference that is D, N and An. Now we will use the formula for nth term that is An is equal to A plus N minus 1 multiplied by D. So we know nth term is equal to minus 5, A plus value of N is equal to 18 and value of D is equal to minus 3. So we have substituted for An, N and D. Now this implies minus 5 is equal to A minus 51 and this further implies A is equal to minus 5 plus 51. This implies A is equal to 46. Therefore we get A is equal to 46. Now in the fourth part we are given A, D and An and we have to find the value of N. Now again we will use the formula for nth term and substitute for A, D and N and find the value of N. So we can write An is equal to A plus N minus 1 multiplied by D. Now we know An is equal to 3.6, A is equal to minus 18.9. We have to find N and value of D is 2.5. So we have substituted for An, A and D. Now this implies 3.6 plus 18.9 is equal to 2.5 multiplied by N minus 1. Now this implies 22.5 is equal to 2.5 multiplied by N minus 1. This further implies N minus 1 is equal to 22.5 upon 2.5. Now this implies N minus 1 is equal to 9. This implies N is equal to 9 plus 1 equal to 10. Therefore we get the value of N is equal to 10. Now in the fifth part we are given A, D and N and we have to find the value of N. So again we will use the formula for nth term that is A plus N minus 1 multiplied by D. So we can write An is equal to A plus N minus 1 multiplied by D. Now we have to find N and we will substitute the values of An and D. Now we know An is equal to 3.5 plus 105 minus 1 multiplied by 0. Now this implies An is equal to 3.5 plus 0. This further implies An is equal to 3.5. So we get An is equal to 3.5. So our final answer is for first part An is equal to 28 for second part. Common difference is equal to 2 for third part. A is equal to 46 that is the first term. Then for fourth part N is equal to 10 for fifth part An is equal to 3.5. So this is our required answer. This completes the session. Hope you understood the session. Take care and goodbye.