 Hey everybody, we're live today and I know some of you have been waiting for this interview since the last little snippet we did last month. I am so excited to be here again with my good friend Bob Miller. We always have so much fun diving into pathways and trying to figure things out and this pathway in particular has a lot of personal relevance. You can see from the title, the crony and reaction we're going to talk all about how that's affected me personally and how I've had some really massive insights and breakthroughs by understanding this pathway in my own personal health, and how Bob and I have worked together already probably on almost a half a dozen patients in conversing and finding this pathway is actually more common than we thought Bob will dive in and tell you all the fun and fascinating information that he's been working on. If you do that, just a little background, you can find all of my blogs literally 10 plus years of content at JillCarnahan.com all free. So if you want to know more about mold or environmental toxicity or benzene or any sort of topic lime and co-infections it's all there. If you want any products you can find those at drjilhealth.com. So if we ever mentioned any of those, you can find them there. On the YouTube channel JillCarnahan MD you can find all of these interviews if you have missed any of them live video and Bob and I have a whole it's this probably our half a dozen mark here. I think we're on number six so there's lots of great content there. You can also find me anywhere you listen to podcasts so YouTube or Stitcher and you can listen there in your car if you're walking if it's easier. So that's the background. I told Bob today I want to get right in. I don't want to waste a lot of time. If you want to listen to my other interviews with Bob you can get a formal introduction. He's just a genius at putting together pathways and he does a lot of work in our field with teaching practitioners and we're going to talk about the certification course at the end that if you want to know more you can join him will give you links will give you all that information. But without further ado Bob let's jump right into the Carnahan reaction. Absolutely I've been looking forward to this for a long time and I think a lot of people are going to have quite a few aha moments as we go through this today. This screen share here. And I think we're seeing the scene the screen correct. Yeah perfect looks great. And as the title says the Carnahan reaction. And of course this is not giving medical advice this is just educational and informational. So we're going to be talking about nitric oxide pH 4 super oxide and then how that can get out of balance and caused by environmental and genetic factors that cause it to go wrong. Here's a real brief what we're going to look at what in us is in us is what could be potentially negative consequences of excess in us. So we're going to be talking about environmental stimulators something called Nassan coupling why that's so dangerous. And we're going to have a little more emphasis today on BH4 tetra hydra baroptim. The consequences of inadequate BH4. We'll touch on high fructose corn syrup and aspartame. And then what we're talking about today the Carnahan reaction. And at the very end we're going to tell you about how health professionals can take our certification course and we'll have a Dr. Jill coupon code that will save you $100. So I want to thank a couple people, Matthew, Beth, Mariam, the Kay Rippy folks who have contributed to this work. These are folks that that help with the research. Now we're going to very quickly go through nitric oxide because we know our other video we talked about this so we're going to burn through this pretty quickly. It's a very simple molecule. It's one item of nitrogen one of oxygen. But it's now regarded as one of the most significant molecules in the body. Absolutely crucial to your well being. Here's what it does. It acts as a vasodilator causing the blood vessels to expand stimulates the brain helps men with erectile function and impedance increases energy supports wound healing supports the immune system. And it's a signaling molecule present in the cardiovascular and nervous system so incredibly important molecule. Nobel Prize 1998 given to three gentlemen for their research as it relates to cardiovascular health. And I'm not going to read this because there's too many here and we're short on time, but what we might be able to do Dr. Jill is a PDF these slides link these. So for people who really want to look at these carefully they, they can we can give you a link for that. I love that so everyone stay tuned because wherever you're listening to this I will be sure and include a special link where you can download these slides. Now let's look at how nitric oxide is made. So I'm going to slide over another little map here, and don't panic this isn't as bad as it looks. Okay, so there's a substance called BH four that's right here in the middle. It's made with oxygen, something called NADPH and amino acids called arginine to make nitric oxide. It's all accomplished by the NOS three enzyme or endothelial nitric oxide. Now, on the other hand, when we are faced with a pathogen when we are faced with bacteria virus fungus or parasite. INOS kicks in says, Oh, we got a problem here. Same procedure, but makes more of it to kill the pathogen. The problem arises when this gets carried away. Get tissue damage or organ dysfunction. And we're going to go through these. I won't read these now, but over here are the environmental factors and these last two internal factors that will stimulate. Also of note, you know, many people are dealing with mold and we'll talk about your experience a little bit later. Clostridium mold, Bartonella, their sources of lipopolysaccharides that stimulate NADPH oxidase, mass cells, histamine in the INOS enzyme. So I'm speculating, but I think the reason this mutation probably got popular is because there was probably somewhere in time that there might have been virus fungus and parasites. And this was actually helpful. Yeah. However, now what's happening to us is we have all these environmental factors stimulating it. Then something else comes along and it gets carried away. Now, if anybody saw our video before, we focused on the INOS up regulation. We've been doing a lot of research and everything we said is true. We're going to put a little more focus on BH4 depletion. Because what happens is if we use up this BH4, we're running off of BH2. And if we're running off BH2, we make superoxide a nasty, nasty free radical. And then that makes something called peroxynitride that may further inhibit the BH4 and we're on one little merry-go-round here. And then we also want to talk a little bit. This was new. We didn't have this last time. We've mapped out the whole pathway of how we make BH4. How it's dependent upon something called guanitine triphosphate from the Krebs cycle. And then how we need folate and genetic mutations here could impact it as well. So we'll get into that as we move along, but that's the big picture. So, as we said, BH4, oxygen, arginine, heme, NADPH. And specifically for the nitric oxide that helps circulation, NAS3. Interestingly, there's one RS number. Here it is 3918226. Wild means it's the one that's the most useful. T meaning the risk that it's less useful. And then mutations on the T, either heterozygous or homozygous, will cause less than optimal nitric oxide production. So if somebody has a 23 and me or they do know the functional genomic, they can look at this and if they have one or two T's, they may have less nitric oxide production. The endothelial nitric oxide. Interesting. And Bob, just to clarify, you're going to go into this in detail, but most of the mutations that we're going to talk about actually increase production. Is this the unique one that actually decreases? Is that kind of why you're bringing it to the attention? Well, yes. This is the one that's the NAS3. Got it. Got it. Okay. So NAS3 is the one that helps us have circulation. NAS2 is the one we're concerned about being upregulated. Okay. So again, just to clarify just because I think the listener will understand too. So on the circulatory fit, this will lower nitric oxide, which could be a disadvantage because we need that basal dilation in the circulatory system. But the NOS2, a lot of the mutations are upregulated, which causes the reactive oxygen and all of those things that you just talked about. Absolutely. Now I'm going to make this very short because there are people that are a lot more qualified to speak on this than I am. And perhaps that'd be an interesting guest for you sometime, but I just want to mention that, you know, this is the pathway we're talking about with nitric oxide. There's another one called the nitrate pathway. And the L-Arginine pathway is pH dependent, oxygen dependent. This one isn't. Interestingly, arugula is one of the highest sources of nitrates. Wow. What happens is when we get nitrates, they'll turn into nitrites, and nitric oxide. So there is a plan B here, also spinach, celery, butter lettuce, bok choy, beets, and kale. What we have to have is bacteria on the tongue that provides the nitrate reductases. That's why sometimes using mouth washes and fluoride toothpaste, whitening could degrade this. And antibiotics and anti-fungals could also decrease it as well. So this is an additional pathway that could bring nitric oxide in. You know, the good nitric oxide. And what's interesting, and I just learned this from Beth Shirley. Nitrates and nitrates recouples the NOS. We'll talk about that later. It inhibits these enzymes. We don't have to read them. It gets complicated, but they're inflammatory. Supports antioxidants, SOD, catalyst, CERT-1. And this GTP, that is at the beginning of the, of the phase to make BH4 in an enzyme called heme oxygenase that helps us break down heme properly. So some food choices there could be a big part of it. Now here's where we really want to get into today, the INOS. Remember I said INOS is what comes to your rescue to kill pathogens. And Bob, if I could really quick comment on the diet, because people are practically speaking, this is one of the reasons why leafy greens are such a core part of a healthy diet. No matter what you're doing, paleo, keto, vegan, anywhere in between, I always say a plant-based diet is still the best, no matter who you are, what you're doing. And you can do that with keto. You can do that with, it just means that plants primarily are still such a powerful source of nutrition. And this is just one more reason why leafy greens in particular are powerhouses. And if you don't have leafy greens as part of your diet, you're missing out, it's so crucial. I think if I had to pick one element of a healthy diet, of course there's never one. Leafy greens are right up there at the top. Absolutely, absolutely. Now let's get into INOS here. So as we said, INOS is crucial for our immune defense. So INOS generates a very high amount of nitric oxide to fight bacteria, virus, fungal. INOS 3 is the one that makes little puffs of it to dilate your blood vessels. When we get total elimination of it, it increases susceptibility to various infections. On the other hand, excessive has been associated with many health concerns. You know, as you've said, Dr. Jill, we've spoken many times and we keep coming back to, you know, Goldilocks and the three bears, not too much, not too little. And that balance, not too little, not too much, is so critical and almost no matter what we're talking about. So not enough INOS, we don't kill pathogens. Too much, we can cause damage. It is. And you and I have talked, again, if you're listening out there, methylation has been a hot topic for several years now. And you and I, Bob, have talked all the time about how everybody is like, oh, methylation, let's do this, or NAD, let's do this. And so people go kind of crazy with the NAD precursors or methylated folate or methylated B12. But if you are in a process and you're really toxic or your genetics are not ready for that load, a lot of times these things make people worse. And this is one of the reasons why it's that happy medium, just really quick and then yet when I first was diagnosed with breast cancer after that was realizing I was deficient in methylated Bs, I went pretty crazy on getting methylated folate and methylated B12. And it was really horrendous because my body was not ready for that. So just, I love that. I wanted to reiterate to those of you are listening, if you're getting excited about methylated Bs or you have MTHFR, you have a NADPH deficiency and you're getting NAD, some of these things too much is not a good thing. Absolutely. One of my favorite sayings is when the house is burning down, you don't paint the walls and build the lawn. Yes. So good. Yeah, we have to put out the fire. Now, this is a period, you know, as I said, in a literature review, I mean, people will notice, we're just bringing up peer-reviewed literature. This isn't just somebody's opinion. Excess production of nitric oxide appears to be linked to tissue damage and organ dysfunction, even when we get something like septic shock. Now, here's another one as it relates to the autoimmune thyroid. The enhanced expression of INOS in autoimmune thyroiditis suggests that nitric oxide synthase plays an important role in the inflammatory phenomena observed in this disease. Alzheimer's, what a serious problem that's becoming to be. Yeah. Here's a peer-reviewed study. INOS seems to be a major instigator of the beta amyloid deposition in disease progression. Their conclusion in a vision of INOS may be a therapeutic option in Alzheimer's disease. Clearly, we have to do more research into this. Now, as we talked about when you've got too much superoxide that's made, it combines with nitric oxide to make peroxanitrite. We're going to talk about that a little bit because more research is now showing peroxanitrite may not be as bad as we thought, but you'll still see differing opinions on this. But in this article, cellular generation of peroxanitrite may contribute to the carcinogenesis and tumor progression by weakening key cellular defense enzymes such as anacetyl-transferase-1. And Bob, I just want to comment because 20 years ago, 25 years old, I had breast cancer and part of my journey in helping patients has been, why did this happen at 25 to me? And I think of many, many, many things. One of them is poor detox glutathione transferases and the pesticide exposure as a farm girl being raised in that environment. This INOS, which we'll talk about, I've got some real specific deficiencies in the genetics there. And I think that was part of the factor, this reactive oxygen. And I've got a lot of issues with absorption and methylation of B12. So all of these things together and there's more, but those are just a few of the pearls with the genetics that now allows me to understand things like why would someone like me who is living a healthy lifestyle get cancer at 25 years old? Absolutely. Well, we have part of the answers in what we're talking about. Here's an article inhibiting INOS improves triple negative breast cancer. Our relationship in gastric cancer, the expression of INOS and VEGF are closely related to tumor angiogenesis and are involved in the advancement and the lymph node metastasis. Here we're talking about colon cancer, INOS expression and tyrosine nitration, maybe an indicator of cancer development and progression in colitis and colon cancer. And of course, part of your story was Crohn's disease, I believe as well. Yes, yes, exactly. It makes a lot of sense now. Yes, high levels of INOS expression and ovarian tumors are associated with a greater risk of disease, relapse and patient death. Real quick thought as you're going, I love these thoughts that just pop up. So you talked about LPS earlier. LPS is the coding of bacteria and you correlated it with not only, we talk a lot about the gut microbiome and this leakage of the coding of the bacteria into the immune system through a permeable gut and it's a massive trigger for Crohn's disease, cancer, even mood disorders and sleep disorders. So back to my story, the chemotherapy caused massive permeability and LPS from the gut was one of those triggers that caused the Crohn's disease. So then we look back at this INOS and LPS being a trigger there, again in my personal story that LPS had a big role, I think. Absolutely, yes. Here is information on INOS and osteoarthritis. People can look at the slides if they want to read all the for the detail. If you're joining us late we are going to put a link to the slides so that you can get these as a PDF. Here is for the respiratory and vascular system. So what we're going to be talking about here is COVID. Now, of course, we're not seeing there's any cure that we're providing here or cure, but this is interesting that what they're saying here and this is a peer reviewed study, showed up in HubMed, in the journal Nitric Oxide, implications of COVID on the INOS and INOS activity, consequences for the respiratory and vascular system. Look at this slide. When COVID hits you hard and the antiviral effects come in, that can be a consequence of the severe lung inflammation as it suppresses the INOS, the blood clots. So again, we're not saying this is a cure or prevention, but may explain why some people are more impacted by COVID, because the INOS is getting up-regulated by the virus, going too far, causing the blood clots. Now, interesting. We've been talking about all of this and here's an article that says data are accumulating on a protective effect of high output nitric oxide synthesis and a protective stress response and simultaneously aids in down-regulating the pro-inflammatory response. So it's like, uh-oh, Bob, you just made an argument that the INOS is the problem. Now you're saying that it may not be, and of course this information came from some of the researchers who were talking to me and saying, this is being reevaluated. So I'm not taking a position on it, but the question is who is the real villain? Now, everything we've said so far is correct. The up-regulation of INOS is a problem, so we're not saying but here's the scientific debate. Is the inflammation from the nitric oxide or the superoxide created with the nitric oxide? Or we'll talk a little later about NOS uncoupling. So it almost just becomes a scientific argument, not as much something that we need to be concerned about, but all of this that we've talked about might be the superoxide rather than the nitric oxide. So this will probably be hotly debated for years. So this really gave me this quote. When you see firemen of fire, are they the cause of the fire? It's an association versus causation, Bob. We know this in research, right? I love that you're bringing this up, because it's really, as you look at that list that you showed earlier, I'm sure we're going to dive into of causes. Usually someone like me or our patients, they have other reasons that are having massive inflammation, and this just makes that absolutely. So, you know, maybe someday this will be definitively, you know, in all the conferences they're talking about, clearly the INOS is elevated. No one's debating that. The question is, is it the INOS making the superoxide more than nitric oxide? Stay tuned. But again, from what we're talking about, it really doesn't much matter because it's causing damage. So there's a saying that's been around for a long time. So if the environment pulls the trigger, here's your free radicals. So let's look at a couple of them. Aluminum, mercury, uranium, plastics. Someday we may have to just do a subject just on... I think we do. It's so... I do these test urinary analysis of metabolites from a couple of different labs in BPA. I would say almost always phthalates in BPA come up for most patients and even patients like myself who are, you know, using really clean beauty and they are ubiquitous. It's really hard. And I always say, you know, those BPA-free plastics, I don't think they're any better. You know, the new versions, I think plastic is plastic is plastic. Please avoid that. And we're polluting the ocean, the water release, we're making a mess. Ethanol, EMF, we'll talk more about that. We spoke about the lime mold, even fluoride. Just found that today. High-fructose corn syrup. We're going to talk about that a little bit. We have a couple slides on that. Glyphosate and then homocysteine if it's high or iron, too high. So let's get into them. Here's a slide on glute. Increased ionos expression has been found in the small intestine of Celiac disease patients during a small-scale clinical analysis. So what they're saying here is the increased urinary nitric oxide products in children with Celiac disease during at least three clinical analysis. And there was increased ionos expression was also reported in the small intestine. In those with Celiac, a gluten-free diet was found to result in a rapid decrease in the plasma nitric oxide and in no products. Now, if anyone's interested in, you know, do we have gluten sensitivity? There's an enzyme called KIA-1109. And when there's one mutation, you're usually gluten-sensitive to that really jacks up the chance of Celiac, not a diagnosis, but a potential. And here we have listed the RS numbers, which is the good one, which is the risk. And you can see by this bar chart that the homozygous only occurs in 2.6 and 2.5 percent of the population, so not very common. But when someone has these, there's a very good chance of gluten is not their friend. Now we're going to talk about microwave and EMF. And here we're talking about more nitric oxide, or more ionos. When exposed to electromagnetic fields. Now, as you said, we let me show you this first. These are some of the genes that are related to the calcium-voltage channels that when mutated allow EMF to push calcium in more strongly and then again make superoxide. And again, we list the four here if anyone ever wants to look them up and see which one is the wild means the good one, the risk is the mutation. But rather than go into it your video number 54, we spoke about EMF. So there they go. They can go back with one hour and 21 minutes. We spoke about EMF. So we go into there with all the pathways so we don't have to repeat it here. So find that video and go back and listen to it. We had fun on that one too. Good. Mercury alone induces NF-Kappa B activation. You know, I probably went through it very quickly, but NF-Kappa B, among other things, stimulates the INOS enzyme. So we all know that Mercury is dangerous for us. We all know that glyphosate more and more information is coming out. It promoted NF-Kappa B that stimulates INOS, also stimulates INOS, other inflammatory markers. And so can you imagine the poor person who has gluten sensitivity, where there's glyphosate sprayed at the beginning and the ending of the crop. These people are in real trouble. Now, there's genetic polymorphisms that are determinants of pesticide toxicity. There's a couple of them listed here, but the ones that's most common is called the PON-1. And that will help take out the pesticides. For this one, that only 1.3% of the population has a heterozygous 0.1 homozygous. So knowing your PON-1 status helps you understand how seriously we should take pesticides. I mean, we all should. But this even makes you more... But those patients in particular, we're really watching, and organic diet is really, there's no other way because you want to prevent it after you're exposed. It's much harder to detoxify. Absolutely. Now, you did a great show with McKay Ripi, and he gets into the to the BPA. It induces the uncoupling of the enos that we'll talk about a little bit later. So it uncouples the NOS-3, which is the good one, and creates the peroxynitrite. I'm not sure which number show that is, but they could easily find it on your YouTube or somewhere else. Listen to the one with McKay Ripi, a great, great video. Ammonia increases the expression and activity of the L-Arginine transporter. I found this absolutely fascinating. And I didn't put slides up for the urea cycle, but there is a genetic pattern that can mean that something called the urea cycle doesn't clear ammonia quite as well. And then that activates NF-Kappa B, which leads to these nitric oxide synthesis and protein nitration. So it's really important to make sure that the urea cycle and ammonia is cleared. And you know, Bob, I do have people who have the smell, their smell ammonia, or they have urinary, that smell in the urine of ammonia. So I do find this not too uncommonly in patients. Absolutely. That old person smell. Yeah. Yeah. Yeah. Hi, Fructose corn syrup. We're going to talk about this a little bit. This really came into being around the late 70s, early 80s. And we're going to look back someday and say, oops, to this. Right. It increases the INOS enzyme and it suppresses a very important enzyme called SIRT-1. Hopefully we'll have time to get to that. SIRT-1 is a very related to longevity. We talked about this. The lipopolysaccharides activates NF-Kappa B and then that stimulates the INOS enzyme and other inflammatory cascades. Ethanol is able to up-regulate both cox2 and INOS expression. All right. Now let's look at some of the internal things that are pulling the trigger. Now, Bob, there's many other reasons, but I don't tolerate alcohol well, and I just decided 15 years ago I basically don't drink once a while at a party. I'll have one sip of wine. And I don't mind if I don't miss it, but I'm assuming that probably some of the genetics that I have with the INOS and all this in addition to other things are one of the reasons why I just... Are there any other things that you would think about genetically when someone doesn't tolerate alcohol? Is there a set of aldehyde genetics too? That's part of it too, but I'm also thinking of glutathione. Yes. If you don't re-take your oxidized glutathione back to the reduced, that's another factor. Which is me too. Probably multiple factors. All right, here we go. Hyperglycemia increases INOS in levels inside the body. This is possibly why diabetes is another morbidity that makes COVID outcome worse. Worse, yeah. Here's another one on the medication end products. They induce the INOS enzyme. And of course, when I was young, we used to call it adult onset diabetes. You're usually over 40 and rather overweight. Now children are getting diabetes. Yes. And then obesity. Again, another comorbidity. Obesity causes INOS pathway upregulation. And of course, we are getting fatter all the time. Yeah. Histamine stimulates INOS expression. So the more we create histamine, the more we're going to create excess INOS activity. And so many of these are perfect storm bobs because like our mold exposure, which I deal with so many people with that, is one of the number one things that triggers mast cells. Mast cells then throw out prostaglandin, histamines, et cetera. And those people who have trouble breaking down a different genetic variance, this just adds to the toxic mix. Absolutely. So rather than get into histamine today, go back and listen to interview number 34. Histamine. We had a great time going through all the pathways. So we're just mentioning it today. And if you want to learn more, listen to this interview number 34. Then estrogen upregulates inducible nitric oxide synthase and cox too. And what are we doing? All the plastics. Yeah. So those are called estrogen disruptors. If you all haven't heard of them and pesticides, organophosphates, a lot of chemicals in our environment. And what's interesting really quick toxicology classically will show these levels of toxicology basically here's the level that it causes a toxic effect. When we see these endocrine disruptors they are like sometimes tens and hundreds of times lower levels and they're synergistic with other chemicals. So extremely low levels that are not considered toxic. They exert a hormetic effect that means a hormone like effect on the body and can cause real damage at very low levels. So our classical toxicologist haven't been warning us about this, but we see this, you know, levels that are really low and the environment are still causing massive damage. Absolutely. We've made a mess of things. Now, as you know, anybody who follows the things that I teach for the health professionals, I'm a big fan of NADPH oxidase. Again, this is part of our protection when we're faced with a pathogen of any kind if we didn't have NADPH oxidase we'd be in trouble. It stimulates the mass cells, the histamine, kills the pathogen, but again environmental factors are up regulating it. So since blocking either NF-Kappa B activation or NADPH oxidase is sufficient to present INOS expression, there are now separate targets for therapeutic interventions that modulate INOS expression in sepsis. We'll be talking about that a little bit when we talk about your experience with the mold. Again, we could spend the next 20 minutes talking about NADPH oxidase just go to number 26 and we really dig into environmental factors that are over stimulating the NADPH oxidase. Dr. Gill, when we did all these videos I had no clue that all of these dovetail together. I know it's so amazing Bob, that's a fun thing as we just keep diving deeper and for me what's been so great is I have a lot of ahas about patients that as you know I see a lot of the most complex chronic I love mysteries I love detective work but some of these patients have been ill and have tried everything and it's not a matter of the standard protocol there's no one size fits all and these little pearls where you know genetics are always so powerful and kind of finding out what for you as an individual patient with unique genetics is the thing that's going to be a game changer. Absolutely we got to get away from the pill for the year. Absolutely a protocol. I'm not a protocol kind of doctor I mean yeah we use protocols but they're all individualized. Absolutely they've got to be. Then the NADPH oxidase stimulates interleukin 6 you know and I believe that is still the most watched video on your youtube channel. I think so too. Yeah when I grabbed this some time ago there was 2,500 people that just watched on youtube. That's just real they're amazing that's in addition to your facebook and other yeah yeah we all kinds of and we went almost two hours on that one I know. If you want to see how this all interacts watch that interview on IL-6 we did a great job. That was a really good one and that was so relevant to COVID and cytokines and all the stuff that we've seen. I always say one of the good things that happened with the pandemic is it allowed the average population to understand like cytokines some of these words that you and I talk about and a lot of functionalism thinks about but the average person hadn't been exposed to well now most people have heard the word cytokines and they understand at least the basics of what that is. Absolutely so I believe IL-6 over expression is a huge problem again as we talked about in that video all the things that were exposed to environmentally. Nitrates and nitric oxide actually down-regulate that NOx enzyme so back again to your your diet those dietary nitrates can help calm that puppy down. Now the L-Arginine paradox okay you know if you look at some things on the internet and if you want to boost your nitric oxide you'll see boatloads of supplements that have L-Arginine in them you know the literature is very clear L-Arginine turns into nitric oxide so we tend to think well the more L-Arginine the better and again this is still being researched but again I go back to there can be too little or too much and I'm afraid sometimes we're pushing it a little too much again peer-reviewed study I want to just what I circled here we demonstrated for the first time that increased concentrations of L-Arginine further potentiate INOS-dependent superoxide formation wow we need to really emphasize this because superoxide is one nasty nasty free radical and which further takes us back to the argument it may be the superoxide maybe rather than the INOS but either way that extra nitric oxide combines to make the the combines with superoxide creates this inflammatory process so we need to be thinking a little bit more about superoxide and I've been teaching about superoxide for the last 20 years and but I believe in the last 9 months to more we need to look at superoxide even more strongly because I believe it's more of a problem than we ever anticipated by the by this process right here that we're looking at made by the by the EMF made by the Fenton reaction many ways now that we're making more superoxide than we ever did before now question Bob is this one of those things where you and I both love our hydrogen breathing machines and that's to me this kind of universal thing that neutralizes reactive oxygen is this one of the areas where that would be helpful either the tabs or the breathing hydrogen that would be helpful and I was hoping to do it today but I was working on slides but I tried to do it every morning and some days I'm like oh I really miss that it's amazing and yeah if you want to know more you can get hydrogen tabs on drjelhealth.com there's a couple brands just look up H2 tabs those are the cheap easy version the machines that Bob and I have unfortunately they're about $5,000 so you may not want to invest in that I love it I use it almost every day absolutely now look at this slide well arginine is a co-factor for nitric oxide synthase it has a specific role in regulating that INOS transcription and expression in other words too much of a good thing yeah now this study really blew me away depleting arginine decreases INOS even under conditions that would up regulate INOS yeah I'm really excited about this now this is fascinating and that's why we perhaps we should do a future show just on arginine and because we're going to show you some really cool stuff here arginine does a lot of things but it will also turn into glutamate which is excitatory which will stimulate interleukin-6 which will stimulate mast cells and histamine also part of the neurotransmitter and can make us anxious so excess glutamate can be a real problem so let's talk really quickly about that because a lot of patients have this question so glutamine is a precursor to glutamate and GABA and some people can go down that pathway too there's been a lot of controversy when I teach there's some of the docs that are like glutamine powder is harmless everybody can take it no problem but in my clinical experience which is not a randomized controlled trial there are definitely some populations that do not do well on glutamine and glycine as well because these pathways can go down the wrong and cause excitatory issues with the brain and nervous system absolutely yeah I think some functional doctors have just gotten a little carried away oh you have a leaky gut let me give you this glutamine this glutamine powder and it actually drives the growth of new cells which is the growth of new cells this is something new that was just introduced to me ADMA and a lot of people have not heard of this and I was rather intrigued and that's why I think we need to do a webinar just on this ADMA and what it can do to us fascinating here's a quick preview proteins get arginine put in them then through methylation ADMA ADMA will inhibit the NOS enzyme to make nitric oxide this gets cleared by something called DDH, DDAH enzyme we're we're working on making a new chip for our genetic testing even all possible I want to make sure we got these guys because we've got to start looking at these yeah but look what happens high cholesterol high blood sugar high homocysteine or smoking inhibits this enzyme more inhibition of nitric oxide this is the good nitric oxide the ENOS so there's a lot to learn here I don't claim to be an expert on this but here you can see your your SAM which comes from methylation that arginine protein we really need to dig into this deeply because what this ADMA does increase risk of arterioscarosis such as increasing age and then high cholesterol hypertension high triglycerides, diabetes insulin sensitivity high homocysteine and renal failure and here's what really caught my attention independent risk factor for arterioscarosis cardiovascular death and all cause mortality ouch it always catches attention when you say all cause mortality I always talk about the gluten and people who have the celiac genetics when they completely eliminate gluten they're all cause mortality goes down by 70% that's dramatic and it's a big deal because these underlying inflammatory processes will lead to many many different mortality types of issues absolutely so stay tuned into this content so here's the reaction between nitric oxide, ADMA and homocysteine and they're suggesting that they have a role in preclampsia fascinating it's naturally produced in the body from arginine found in proteins and completely inhibits arginine utilization by NOS it's been repeatedly associated with a variety of health conditions such as endothelial function and cardiovascular health and then as we said the homocysteine slows down that DDH enzyme and further increases those levels which could have a big part of why elevated homocysteine is such a significant factor in our cardiovascular health interestingly though we need homocysteine to make the cysteine that makes glutathione so here we go again if we didn't have homocysteine we wouldn't have glutathione but it goes too high and we have a problem any thoughts you may not have a lot to say here but just curious if you do on the really low homocysteine like say four or five are those hypermethylators is there any thoughts around that Bob? yeah they may be hypermethylating that you know through either the middle pathway or you know through methylfolated methyl B12 they're over converting might be other reasons as well you know there's a SAM-SOL ratio as well where that comes down through so that could be disrupted so again I think a 3D chess game yes I totally agree so here's some of the interactions it induced nitric oxide production again NF Kappa B and for those who don't know it this is a very strong inflammatory component the NF Kappa B in mice it increased the ionized expression three fold wow it was also found to induce nason coupling increasing the reactive oxygen species and this blew me away depleted intracellular levels of your tetrahydrobaropt and that's the BH4 80% that's a big that's a big deal that's a big deal so you know and what's interesting in our health coaching sometimes I'll say to people is your doctor measure your homocysteine it's ignored and I believe that we really need to be paying attention to this so you know one takeaway is I think everyone should be aware of where their homocysteine is because it's a really important Bob I could not agree more and I'll just say if you're listening here's a few things you want to ask your doc if you haven't checked A1C average blood sugar you should be checking that every year because we just talked about HSCRP non-specific inflammatory marker and other things like immunoglobulin G and really all the immunoglobulins very few doctors are checking those and I can't tell you the number of patients I've diagnosed with immunodeficiencies and it's a very simple these are pretty simple tests to get absolutely so me but this number right here I mean I was like you've got 80% reduction in your tetrahydrobaroptin that's the BH4 we talked about earlier in case many people are confused that's what helps you make nitric oxide rather than superoxide wow amazing how do we calm this puppy down okay vitamin D vitamin D has the potential to prevent oxidative damage by suppressing the INOS enzyme zinc also the zinc limits INOS derived high output NO production in any ethyl cells by inhibiting NFCAP would be dependent INOS expression then lysine may reduce the arginine absorption now they're both absorbed through the same transporters and when we take the lysine the arginine may not be absorbed as much and just about everybody knows about you know how you can use lysine for cold sources yeah yeah so let me just comment clinically so anyone who has frequent cold source for general hobbies either one is the virus taking a decent dose of lysine usually have patients a minimum of a thousand a day sometimes up to two thousand will really inhibit that virus and often prevent you from having breakouts this is a great pearl it's an easy and cheap supplement and as we're going to talk about with Bob this has another effect on INOS it's funny Bob personally I did have cold source after my cancer and so I've always been a lysine for the past 20 years and I know I do really well in it but I didn't know the secret of how lysine is also helpful at preventing that up regulation of INOS and so unbeknownst to me I was doing it for one reason and I was getting benefit from another and after we talked about this I upped my dose and it was pretty powerful yes I mentioned here about that I just for the update and here we are in endotoxic shock here's the last you know bottom line lysine has no effect in the absence of the endotoxin and thus appears to act as a selective modulator of INOS activity curcumin has been shown to promote the degradation of INOS of course we all know about that quite popular that is frankincense showed a significant increase in a colitis group both pretreatment and treatment with Auswellia exhibited significantly reduced lipid peroxidation nitric oxide and INOS and showed improvements in the tissue injury with the ulcerative colitis there's something called paractin it's something that's manufactured but it comes from andrographis and it was found to reduce pain and mild to moderate osteoarthritis but it also decreases INOS andrographide has been shown to inhibit INOS expression and it inhibited NOX2 that's one of your NADPH oxidases that we spoke about earlier green tea and black tea are helpful and EGCG was the most active inhibitor of the INOS enzyme now we're going to talk about NOS on coupling then we're going to get into the Carnahan reaction so what happens here is BH4 is needed to take L-arginine and turn it into nitric oxide that's what we showed earlier when it turns into BH2 we make the superoxide and we showed that earlier but here we go BH4 is the central character and that's why I said I'm putting more emphasis on the BH4 so here is the pathway that we make BH4 the de novo pathway and then there's also a salvage pathway where the BH4 turns into BH2 and then we bring it back to BH4 so tetrahydroberoptin we've talked about this but here's more phenylalanine is an amino acid needs to turn into tyrosine not good if that doesn't happen BH4 dependent then we need the tyrosine to turn into L-dopa and many people say is that the problem is that it turns into L-dopa and then we need tryptophan to go into serotonin without serotonin we're depressed and it just appears as though more and more people are getting depressed are you abjuring that as well Dr. absolutely I think there was almost a 400% increase in prescriptions for SSRIs in the last year now granted we've had a pandemic but I don't think that's the only thing I think the toxic load look at this fascinating chart here it is here's that GDP cytoklide hydroxies that comes from the Krebs cycle so if we have anything that's impacting Krebs cycle we're not going to have that GTP, monodine triphosphate that helps you make your BH4 the BH4 turns into BH2 we need to bring it back you spoke about this at length the endothelion nitric oxide but here's the phenylalanine into tyrosine the tyrosine into aldopa the aldopa into dopamine look who's lurking lurking over here reactive oxygen species in inflammation the less BH4 and another merry-go-round that we're on here's a little bit more specific how we make it and in the software in our functional genomic analysis software we just recently put in all the SNPs that are related to the production of BH4 still too early to tell but we're finding that when people have trouble producing they have these strange inflammatory conditions they can't seem to resolve I didn't list all of them but here's one of them and you can see even a heterozygous here only in 1.6% of the people in our software so these are evidence-based SNPs that will be related to the production of the BH4 as we make a new chip in the future we want to make sure we have all these evidence-based ones so we can see if someone's having some difficulty making a BH4 I'm really thinking that we need to be spending more time thinking about BH4 so years ago Amy Yasko has talked a lot about this I don't have a heterozygous on the show but you can find some information there too and this has been a really big thing in the world of autism and the children that have been affected by that and adults too but this has been on the radar a while and we can just continue to learn more and more about biopteran and how important it is I didn't have time to find the slide but I saw some things as I was looking that some autistic children not all but some are really helped considerably by boosting their BH4 I mean clearly autism is very complex and I don't think there's one thing that's going to do but in some instances that can be very helpful and it's much harder to prescribe it it's much harder to get I think a drug company got the rights to produce it I don't know what's happening with that but I used to be able to years ago actually prescribe it and it's much harder to get nowadays and we're hoping that if we see the pathway properly if we slow down the wasting of it and support the production of it and support the recycling of it that may be sufficient in some cases now this is a fascinating quote here it's the intracellular BH4 to BH2 ratio rather than the absolute concentrations of BH4 is the key determinant of Nos3 uncoupling again that BH2 when combined with Nos makes the superoxide which kind of goes to that argument that it may be the superoxide that's the real villain here so stay tuned for that folic acid promotes the recycling of the BH2 to the BH4 and it protects against hypoxia induced pulmonary hypertension by recoupling the Enos so we're working at some nutritional formulas that may do this but it's very complex we want to look at how do you support the guanidine triphosphate how do you support the recycling just a lot to learn there now NADPH is needed for BH4 production number 23 if you want to know how to boost your nitric oxide or your NADPH listen to that pathway and as you know I'm a huge fan of NADPH but I just throw a lot of it at one time you have to make sure you do it judiciously when other things are calm down you do and a real quick pearl on that Bob I learned last year last December I was speaking in Vegas I had a big month and I was like let me do some NAD at that time I was doing subcutaneous injections so almost daily and as you know it requires metal donors to process and I have issues with B12 I need a lot of B12 I require I have all kinds of genetic polymorphisms around B12 so as you can imagine for two weeks I felt amazing I was on top of the world great energy felt perfect and then I crashed and I started getting depressed which is not like me at all and really tired and guess what I completely depleted my metal donors so from now on for me this is the end of one this is with my NAD and I don't do well with too much so some patients out there you don't want to overdo this until you know your genetics absolutely and then why wouldn't we listen to number 16 I think that might be one of the first ones we did where we talked about peroxin nitrite now what happens if we deplete that BH4 okay modulation of NOS2 activity by replacement of BH4 maybe a safe and effective approach to reduce the frequency of atrial arrhythmias during heart failure there's another one tetrahydrobrotin and cardiovascular disease BH4 replacement may help treat hypertension ischemia reperfusion industry cardiac hypertrophy chamber remodeling by restoring the NOS it improves endothelial function by those who smoke who are diabetic, hypertensive those with cholesterol problems coronary artery disease and even with heart failure all of that can be effect of supporting your BH4 but I go a step further and it's like yes supplementing that might be okay but let's stop the wasting of it let's support the recycling of it let's support the making of it and one of my favorite saying is I'd rather have you make it than take it but we have to learn a lot on this love it we need a barbisms file these are good barbisms alright we showed this before are then here you're seeing how folic acid or methylfolate and sammi are part of that BH2 to BH4 much more complex than this this is a rather simple drawing now as I said this is needed for phenylalanine to tyrosine conversion here's a little chart PAH takes phenylalanine which is an amino acid converts it to tyrosine and BH4 and ADPH efficiency here can cause a problem now both people know that when babies are born they take a drop of blood and they look for serious illness that's genetic in nature where they have to have very serious dietary restrictions one of the things I'm hypothesizing just that are we getting like little mini versions of that not severe but mini versions because of our BH4 ADPH just you know one talking to some folks there's some individuals that have brain fog insomnia and they're seeing some improvement as they stop things like aspartame which is pure phenylalanine so we'll talk about that just briefly there is foods that contain that phenylalanine so if someone's having trouble with beef or lean chicken breast or anything on this list one of the things they may want to start considering is am I having some difficulty turning the phenylalanine in there into the tyrosine and as we said there's a serious issue called PKU that is medically diagnosed but interestingly supplementation with BH4 can drive that activity in some individuals with certain mutations lowering the plasma phenylalanine fascinating Bob again this is something that we may have the answer to this but I'm always thinking as we're talking and we have a lot of patients who have excess dopamine because of gut dysbiosis and that upregulation of some of those pathways would SAME or some of these things drive if they already have too much dopamine do you think you would need to be concerned about that does that make sense it does and I can't say for sure but I think that's an absolutely true because I think we need to be concerned about that. I mean I've seen as many people have bad effects as good effects to I think again in literature you can almost induce a mania in someone who is very very prone to high dopamine so I agree I always tell patients to watch so if you're taking SAME it's a great thing for mood there were studies against all the common SSRIs where 1200 milligrams a day actually outperformed most of the SSRIs however if you're prone to mania insomnia anxiety be very cautious it's absolutely so I think most people know what this is you know it was first approved in 74 only started being used in the late 70s early 80s and it's in so many products we won't read them here but that's why I believe some people just can't handle those it actually even can turn into formaldehyde and these are some of the conditions that are associated with too much aspartame cancer, cardiovascular graves, Alzheimer's stroke dementia we're going to look back some day and say what did we do? what were you doing with these artificial sweeteners? now here we are it's time to introduce the Carnahan reaction we named this after Dr. Jill because for health concerns so why don't you take a few moments and explain to us perhaps what happened with your mold exposure or however this ties into and then we'll explain what the Carnahan reaction is sure so I had a mystery and Bob helped me solve it and so he's so cool to name it after me but what happened was just a few months ago I had some significant mold exposures with ketomium and what was happening was I was having I've always known ketomium for me is I call it the narcoleptic mold and mold to me has personalities because aspergillus penicillum caused more allergic redness a lot of histamine reactions but ketomium and stachy botries some of the really toxic black molds for me personally they caused me to be just out like a light like literally when I get exposure I've got to lay down now I can't even stand up and what happened with these recent significant exposures I was getting these episodes where I almost like completely not black out I'll tell you the symptoms in a moment but almost like lose time I equated it almost like if someone was like an alcoholic which I don't drink alcohol and would lose time and space and have these episodes where they just couldn't function I was having these maybe once a week for a few times in August and September and what would happen is my blood pressure would go down to about 80 over 50 and as you can imagine that's not very compatible with standing up and so I realized it was a drop in blood pressure that would cause me to literally have to lie down and sleep because I couldn't even stand and function and of course with that I would have massive brain fog and exhaustion and I just couldn't even function so Bob and I as we talked and realized that nitric oxide in my genetics was upregulated production and that we know mold would be a trigger the likelihood of what was happening was that my the mold was triggering the nitric oxide to be produced that was a massive vasodilatory effect almost like if you always septic and causing this really low blood pressure and the symptoms that I was experiencing absolutely and that really took a toll on you it did it was a rough one so here it is gain of function mutations in Nos-2 enzymes and then other mutations that's a spelling error there mutations in other enzymes that over-stimulate INOS along with environmental and internal stimulation of Nos-2 creates inflammation from excess nitric oxide or maybe superoxide excess superoxide through Nos-on coupling depletion H4 creating more superoxide and potential disruption of the neurotransmitters so that's what we're calling the Carnahan reaction and I think 100 years from now 200 years from now people will still be studying the Carnahan reaction so this is two of the IS numbers that we found in the INOS based upon literature and I suspect there's going to be more it's 277-9249 the aleleal has been associated with hold on to your hat 4.73 times increased INOS expression that's a lot and there was also increased plasma nitrate and nitrate levels and the heterozygous genotype was associated with increased levels of salivary nitrates and nitrites here it is the wild or the one that's good as a C and risk is an A and you can see only 9.9% of the population in our software that analyzes keep in mind this software as people who are not well so I would imagine among the general public it's even less Bob I want to mention one more little thing that's related as patients listen to this isn't related to the INOS but to me personally years ago I was really high cortisol I've been high cortisol for most of my life and in the last several years after I've done a lot so that I'm more on the realm of normal or low cortisol and I think that having that cortisol slightly deficient also contributed because cortisol will regulate your electrolytes and regulate your blood pressure as well so to me there was part of this perfect storm was clearly the INOS but on top of that why was this different from years ago well now I have a little bit lower cortisol than I used to and I think that on top of it and a whole nother thing I won't go into this but I was taking a medication that was lowering my cortisol even further so I think that again that contributed to the perfect storm of this being a massive drop in causing hypotension sure and keep in mind the cortisol calms down the histamine yes it wasn't doing that that was further stimulating INOS further stimulating interleukinosis more superoxide yeah here is RS2297518 again the allele increased INOS activity and associated with onset of early onset of Crohn's ulcerative colitis in IBD and there is a chart you can see that this only occurs homozygous in 3.9% of the population now here's what happened to Dr. Jill this is you're very brave by the way putting your your genetic information on online here there's a genetic mutation called HFE H63D and that may increase the absorption of iron and you can see here you've got one genetic mutation here and that only occurs in 23.9% of the population homozygous only 2% now if you remember when we looked earlier excess iron stimulates INOS mutations in HMOX they may impact the production of billyverdon that inhibits INOS and some mutations here but here we go those two that we pointed out homozygous on both of them so that just puts you in a position that your INOS enzyme is let's call it trigger happy perhaps that it just likes to overreact over respond now Bob on the good side of this I've been super athletic and good running ability years ago I did track and I did volleyball and did cheerleading and again on the other side of this I probably had some good ability for the athletic performance things that need oxygen to tissues because patients use this it's just going to the extreme that it's a problem absolutely as we spoke about in our first interview many people need to boost their nitric oxide which we do and we're not saying that's a bad thing and when we first talked about it we were trying to figure out is this gain a function or loss a function I remember telling you well I don't do well with beats I never take arginine as we went through it it's a gain a function and of course you and your team have proven that to be the case absolutely now as we talked about DHFR is part of the way we get the folate there and this is an evidence based SNP on DHFR so part of making or recycling your BH2 to BH4 could have been compromised right we're going to very quickly talk about CERT1 and then we managed to to get through the slides so CERT1 is a very important enzyme it supports anethylion nitric oxide it supports superoxide disputase it inhibits NOx and NFKB and if you remember I mean we're throwing out a lot of terms but these stimulate inflammation but they also stimulate INOS high fructose corn syrup we can CERT1 however resveratrol and nitrates support CERT1 CERT1 also inhibits mTOR which can be inflammatory which inhibits autophagy and it also supports we just found this recently it also supports the MAOA enzyme which is one of the major ways to clear histamine which as we just said stimulates INOS quick random question Bob the MAO SNPs are they mostly gain or loss of function or do they vary from what we understand they're loss of function okay and here's some of the things the CERT1 is involved with it's involved with obesity associated metabolic diseases cancer, adipose tissue aging, cellular senolence cardiac aging neurodegeneration inflammatory signaling all of these things are related to CERT1 and there is one of them that is related to you know pathogenic when it's mutated I'm not going to read all this we don't have time but if someone looks at the slides all the positive things that CERT1 does so and if you look at the statistics here homozygous is only 1.5% of the population so RS1277 8366 it's an evidence based CERT1 mutation T is the wild or the good one C is the risk so we'll go through this very quickly dry fructose corn syrup I think most people know what that is it's just been around since the late 70s early 80s and which food products contain it it's in everything from soft drinks, canned foods jellies and jams processed snacks, fast food items sauces and salad dressings it is just everywhere and that will inhibit your CERT1 so I put these graphics together today you have a typical breakfast of coffee and donuts so if you put some aspartame in there that's going to increase the phenylalanine that's going to create brain fog low dopamine agitation insomnia if your donut is made out of gluten sprayed with glyphosate on it that's going to stimulate the ionos if you've got some filling in there or the icing that has high fructose corn syrup CERT1 inhibition decreased SOD and enos increased NOx and NFKB NOS uncoupling decreased phenylalanine conversion increases in superoxide increases in ionos if someone would have mutations in ionos or sod mutations BH4, BPAH mutations these people are going to be on fire so when you think about a perfect storm you put some artificial sweetener glyphosate wheat high fructose corn syrup what a combination and Bob I just want to comment people talk about Europe and a lot of times eating there they're less toxic less inflamed one of the reasons if you look at a label of a certain product in the US and then that equivalent same brand same manufacturer in Europe they will not use corn syrup in Europe they will throw it into the American mage products I've seen this over and over again it's amazing because our regulations are not as stringent as Europe and some other countries as well so sadly you really have to become a label reader and just I would just recommend you completely avoid processed foods because you're going to get this everywhere if you're eating processed food absolutely and how many people have coffee and donuts I'm not going to read this this is the whole list of all the mutations that could be contributing factors to the up-regulated INOS all right as we said for if you are a health professional we have an opportunity for you to do some online education I mean people can take it as well but there's no certification I'm not going to read these but these are the modules we have up now overview fentanyl reaction nitric oxide glutamate gut histamine oxalates mass cells NADPH steel NADPH oxidase and these are the videos that are listed here NERV2 and KEEP1 more on NADPH glutathione sod and catalase the search ones that we just talked about phase 3 detox and autophagy we're probably about halfway through we're making them as we go along more modules are added every one to three weeks and all you have to do is go to functionalgenomicanalysis.com right here click on the certification you get the first seven modules for free so what we do is we say to doctors our health professionals try this out see if this is for you because it's not for everybody this is not for the faint of heart you have to want to dive deep right Bob yeah this is in a genetic test and it tells you what to do you have to pay and if you use the code Dr. Jill you'll get $100 off but you can try the first modules first before you even have to do anything and then we do have the functional genomic analysis software we have a supplement line there's the genetic test and there's who does the research so I know a lot of people who are not health professionals if they want to talk to us about health coaching here's our phone number 717-733-2003 toolhealth.com if you're a health professional only this is the software we use for the analysis and Yvonne Lucchese is the executive director and her phone is 717-466-5700 so if someone wants to learn you're there and we're probably hopefully in the spring or summer we may do a conference on the Carnahan reaction where we will spend with doctors probably three days talking about every aspect of this I mean we did a really quick review we did it Bob you are amazing I hope the amount of data you just got through and like 75 absolutely amazing I hope you all listening out there appreciate Bob Miller and what he's bringing I just have such great respect for you Bob and your tireless efforts and what I love too is you just you're genuinely doing out of the good for humanity people and you continue to give and you're so generous with your time with me and with everyone here I mean this is all free this is your time and it's valuable and I know how hard you work there's sometimes a nine o'clock at night and you're just getting done with patients itself it is just I want to publicly thank you for your efforts and myself and many many other physicians are benefiting from your work and your team and all the research and I have so supportive of your educational your courses I completely endorse them and believe in the work that you're doing so if you're a physician or a highly educated consumer who wants to learn more you can join that you can give that link and wherever you listen to this will have those links posted with the code and everything I just can't thank you enough I always enjoy our time I always learn more and so fun and any update for you how you're doing now after all that you've got so much better so much better so I added lysine I got rid of the excess and all the little pieces I think we talked about in our little promo but I was taking tons of glutathione which was oxidizing so I took back got rid of some of that I was doing IVs weekly I stopped that so just let this be a lesson to you this is my lifelong lesson less is more and I'm like that kind of person's like oh I want to fix this I want to do this and so often my downfall is just because I do too much and so if you're listening and you're crashing and you have a ton of problems often with my patients I'm like what can we take out because sometimes it's too much I added a lot more lysine of course I've been avoiding mold I'm doing so much better Bob and thank you for asking and our goal is in 2022 you just laugh and mold yes like it's nothing nearly a flesh wound oh thank you so much thank you and thank you everyone for joining us today I hope you enjoyed it as much as I did please leave comments maybe future topics I know Bob and I are always brewing about what to bring next but as always such a fun time thank you so much Bob my pleasure have a great rest of your day