Podcasts about bh4

For this episode, we discuss the roles and sensitivity of mitochondria with Dr. Richard Frye, MD, PhD. Dr. Frye received an MD and a PhD in Physiology and Biophysics from Georgetown University. He is board certified in Pediatrics, Neurology with special competence in Child Neurology, and as a Certified Principal Investigator. In addition, he has a Masters in Biomedical Sciences and Biostatistics from Drexel University. Dr. Frye has over 300 publications in leading journals and book chapters.Dr. Frye shares many figures during the conversation so the listener can follow along.Dr. Richard Frye https://drfryemdphd.comRossingnol Medical Center Facebook https://www.facebook.com/RossignolMedicalCenterNeurological Health Foundation https://neurologicalhealth.orgHealthy Child Guide https://neurologicalhealth.org/the-guide-5/Daylight Computer Company https://daylightcomputer.com?sca_ref=8231379.3e0N25Wg3wuse "autism" in the discount code for $25 coupon.This is the future of tech.Chroma Light Therapy https://getchroma.co/?ref=autismuse "autism" for a 10% discount,0:00 Dr. Richard Frye0:58 Daylight Computer Company5:17 Chroma Light Devices8:27 History of Leucovorin; low risk, high reward; Folate Receptor Alpha (FRa)10:25 Blood Brain Barrier; Folate; CSF (cerebral spinal fluid)14:04 DNA, RNA; MTHFR (Methylenetetrahydrofolate reductase)17:34 Cerebral Folate deficiency; BH4, Placenta & Womb23:35 Folate deficiency & Autism26:21 Clinical Studies & Data29:28 Folate & Mitochondria; Cerebral Folate Antibodies; White Matter Findings (!)34:45 Cerebral Folate deficiency & Ranges; Autistic Phenotypes: Language, Communication, & Behaviors40:45 Language & Communication; Self-Injurious Behaviors; Hyperactivity, Agitation; Treatment duration42:53 Folate Autoantibodies & Maternal Health & Markers45:30 Studies & Behavioral outcomes; inflammation & thyroid findings46:58 Neural development; Language connections, white matter tracts & distal connections48:53 Leucovorin for different severity/levels of Autism; Spinal Bifida51:08 Preparing for pregnancy53:50 Transgenerational aspects of Folate Autoantibodies Research; Prenatal Care & Awareness59:32 Guidance & SupportX: https://x.com/rps47586Hopp: https://www.hopp.bio/fromthespectrumYT: https://www.youtube.com/channel/UCGxEzLKXkjppo3nqmpXpzuAemail: info.fromthespectrum@gmail.com

Opening Exercise: The audio will lead you through a series of moves from the beginning of a game. At a certain point, one player will make a mistake and it'll be your job to find the move to punish it. To learn more about Don't Move Until You See It and get the free 5-day Conceptualizing Chess Series, head over to https://dontmoveuntilyousee.it/conceptualization PGN for today's exercise: 1. d4 Nf6 2. c4 e6 3. Nf3 Bb4+ 4. Nc3 b6 5. Bg5 Bb7 6. a3 Bxc3+ 7. bxc3 h6 8. Bh4 d6 9. e3 Nbd7 10. Bd3 g5 11. Bg3 Ne4 12. Qc2 f5 13. O-O Qf6 14. Nd2 Nxd2 15. Qxd2 h5 16. h3 h4 17. Bh2 g4 18. hxg4 h3 19. gxh3 Rxh3 20. f4 Qh4 21. Rf2 Nf6 22. gxf5 Ng4 23. Rff1 { Black to move. Checkmate in two moves. } * And the answer is... 23... Rg3+ (23... Qg3+ 24. Bxg3 Rh1#) 24. Bxg3 Qh1#

For decades, we've been told that our DNA is a fixed blueprint—an unchangeable code that dictates our health and lifespan. But what if that's only half the story? Sharon Hausman-Cohen, a physician, researcher, and genomics expert at IntellxxDNA, joins Dave to reveal the cutting-edge science of genetic optimization—how understanding your DNA can unlock longer life, better brain function, and even protection from chronic disease. Forget the old-school genetic reports that left you with useless percentages. The new frontier of precision genomics goes beyond risk factors to actionable insights, showing you exactly how to turn on your body's most powerful longevity genes and turn off the pathways driving inflammation, cognitive decline, and disease. What You'll Learn in This Episode: • Why genetics alone don't determine your future—and how to use epigenetics to control your health • The truth about MTHFR, APOE4, and other “bad” genes—are they actually harming you? • How genetic reports can predict and eliminate brain fog, fatigue, and pain • The hidden genetic reasons behind ADHD, depression, and anxiety—and how to fix them • Why some people age faster—and the one longevity gene that determines your biological age • Cutting-edge breakthroughs in DNA-based biohacking—is it possible to edit your genes for peak performance? This is the future of personalized medicine. By understanding your own genetic blueprint, you can stop guessing and start making the precise changes that will optimize your energy, brainpower, and lifespan! ** Visit IntellxxDNA at https://intellxxdna.com/asprey/ When you go to the website to find a clinician please select “human upgrade/longevity” as the type of consult to get specialized biohacking clinicians! ** SPONSORS -Timeline | Head to https://www.timeline.com/dave to get 10% off your first order. -Leela Quantum Tech | Head to https://leelaq.com/DAVE for 10% off. Resources: • Dave Asprey's New Book - Heavily Meditated: https://daveasprey.com/heavily-meditated/ • IntellxxDNA Website: https://intellxxdna.com/asprey/ • 2025 Biohacking Conference: https://biohackingconference.com/2025 • Danger Coffee: https://dangercoffee.com • Dave Asprey's Website: https://daveasprey.com • Dave Asprey's Linktree: https://linktr.ee/daveasprey • Upgrade Collective – Join The Human Upgrade Podcast Live: https://www.ourupgradecollective.com • Own an Upgrade Labs: https://ownanupgradelabs.com • Upgrade Labs: https://upgradelabs.com • 40 Years of Zen – Neurofeedback Training for Advanced Cognitive Enhancement: https://40yearsofzen.com Timestamps: • 00:00 – Intro • 02:00 – The Role of Genetics in Longevity • 03:37 – Gene Variants & Cognitive Health • 05:58 – Epigenetics vs. Genetics • 08:21 – Genomics & Pain Management • 09:26 – Breakthroughs in Genetic Research • 12:33 – The Future of Genomic Medicine • 14:27 – How to Use Genomic Reports • 38:25 – Mitochondria & Longevity • 42:40 – BH4 & Mental Health • 43:42 – Folinic Acid & Brain Function • 44:37 – Genomics & Autism • 46:06 – Personalized Medicine • 56:00 – APOE4 & Alzheimer's Risk • 59:44 – Genetics & Heart Health • 01:04:54 – The Future of Precision Medicine • 01:20:23 – Conclusion & Next Steps See Privacy Policy at https://art19.com/privacy and California Privacy Notice at https://art19.com/privacy#do-not-sell-my-info.

Opening Exercise: The audio will lead you through a series of moves from the beginning of a game. At a certain point, one player will make a mistake and it'll be your job to find the move to punish it. To learn more about Don't Move Until You See It and get the free 5-day Conceptualizing Chess Series, head over to https://dontmoveuntilyousee.it/conceptualization PGN for today's exercise: 1. e4 e5 2. Nf3 Nc6 3. Bc4 Bc5 4. O-O Nf6 5. d3 d6 6. Bg5 h6 7. Bh4 g5 8. Bg3 h5 9. Nxg5 h4 10. Nxf7 hxg3 11. Nxd8 Bg4 12. Qd2 Nd4 13. Nc3 { What is the best move for Black? } * And the answer is... 13... Nf3+ 14. gxf3 Bxf3

Dr Maja Risager Nielsen and Dr François Feillet discuss pregnancy in PKU and two different papers looking at the outcomes in pregnancies with and without BH4 treatment. The impact of phenylalanine levels during pregnancy on birth weight and later development in children born to women with phenylketonuria Maja Risager Nielsen, et al https://doi.org/10.1002/jimd.12600 Efficacy and safety of sapropterin before and during pregnancy: Final analysis of the Kuvan® Adult Maternal Paediatric European Registry (KAMPER) maternal and Phenylketonuria Developmental Outcomes and Safety (PKUDOS) PKU-MOMs sub-registries François Feillet, et al https://doi.org/10.1002/jimd.12724

Listener feedback link: https://form.jotform.com/240459204544050 Kunwar Jung-KC and Alba Tristán-Noguero discuss tyrosine hydroxylase deficiency and explain how the tyrosine hyodroxylase cofactor, BH4, has shown early therapeutic potential in human neurons and a knock-in mouse model. Tetrahydrobiopterin (BH4) treatment stabilizes tyrosine hydroxylase: Rescue of tyrosine hydroxylase deficiency phenotypes in human neurons and in a knock-in mouse model Kunwar Jung-KC, Alba Tristán-Noguero, et al https://doi.org/10.1002/jimd.12702

Opening Exercise: The audio will lead you through a series of moves from the beginning of a game. At a certain point, one player will make a mistake and it'll be your job to find the move to punish it. To learn more about Don't Move Until You See It and get the free 5-day Conceptualizing Chess Series, head over to https://dontmoveuntilyousee.it/conceptualization PGN for today's exercise: d4 f5 2. Bg5 h6 3. Bh4 c5 4. e3 Qb6 5. b3 Nf6 6. dxc5 * And the answer is... Qb4+ { forking the king and bishop }

Opening Exercise: The audio will lead you through a series of moves from the beginning of a game. At a certain point, one player will make a mistake and it'll be your job to find the move to punish it. To learn more about Don't Move Until You See It and get the free 5-day Conceptualizing Chess Series, head over to https://dontmoveuntilyousee.it/conceptualization PGN for today's exercise: 1. d4 f5 2. Bg5 h6 3. Bh4 g5 4. e4 gxh4 And the answer is... 5. Qh5#

Question: Is whole food vitamin C superior to natural because it is part of a tyrosinase complex? Short Answer: Vitamin C is nearly ubiquitously distributed in plant tissues, and is never bound to any enzyme as a structural complex. Vitamin C promotes absorption of iron from plant foods, inhibits copper absorption, and de-loads copper from ceruloplasmin, which may play a role in distributing copper to tissues. Vitamin C is not capable of destroying ceruloplasmin. These functions follow directly from vitamin C as an electron donor and there is no evidence whatsoever that whole food vitamin C behaves differently in these respects than synthetic vitamin C. However, daily needs in most contexts are 2-400 milligrams of vitamin C per day, which is below the dose shown to potentially cause problems with copper. Getting this from whole foods or whole food supplements is better than using synthetic vitamin C because it avoids GMO corn and Chinese synthetics and provides a host of other beneficial constituents alongside the vitamin C. This is a clip from a live Q&A session open to CMJ Masterpass members. In addition to this episode, you can access two other free samples using this link: https://chrismasterjohnphd.substack.com/p/questions-on-hair-trace-mineral-analysis In that batch of free episodes you will also find the answer to this question: Is Hair Mineral Testing Useful?  What's the Deal With Seed Oils? If you want to become a Masterpass member so you can participate in the next live Q&A, or so you can have access to the complete recording and transcript of each Q&A session, you can save 10% off the subscription price for as long as you remain a member by using this link to sign up: https://chrismasterjohnphd.substack.com/qanda Learn more about the Masterpass here: https://chrismasterjohnphd.substack.com/about This snippet is from the June 16, 2023 AMA. The full recording and transcript is reserved for Masterpass members. Here is a preview of what's included: Butyrate for Hashimoto's? What else? What in the comprehensive nutritional screening is helping to interpret lactate/pyruvate and ketone ratios? Is the solution to a respiratory chain disorder to take Niagen? If I have high manganese on an HTMA, do I need to detox? Should CFS patients target reducing their serum BH4? What to do about low alkaline phosphatase? If my glucose spikes above 140, should I eat fiber and take ACV before the meal, eat cinnamon with the meal, chew slowly, and move for ten minutes after my meals? Difficulty getting Quest to do the lactate/pyruvate ratio correctly. Is 38 milligrams of niacinamide enough to rule out niacin deficiency as a cause of low NAD+? How does optimizing body composition help optimize energy metabolism? Can impaired energy metabolism make someone fatter? Is monounsaturated fat the best fat? Manganese followup. Do you need to stop taking biotin before a biotin test? What in "a bunch of supplements" flip the lactate/pyruvate ratio from high to low? NAD infusions, yay or nay? Why do I feel better after a warm shower, even better than after sunshine? Should I cut back on vitamin A if I have toxicity symptoms but cutting back makes me get sick? Do home blood drop tests have to be pricked at the finger? Is it true that my boyfriend was just born a night owl? How much eating out is too much? When measuring ketones, lactate, and glucose at home to optimize energy metabolism, what time of day should we take the measurements? Here's a link to the full AMA: https://chrismasterjohnphd.substack.com/p/recording-and-transcript-of-the-june-a55  

Lectura y comentarios sobre el artículo: “Guía de consenso para el diagnóstico y tratamiento de las deficiencias de tetrahidrobiopterina (BH4)” que desmenuza trastornos neurometabólicos caracterizados por deficiencias de los metabolitos de BH4: monoamina, dopamina, serotonina entre otras.

Question: What Is the Real Issue With Seed Oils? Short Answer: The main issue with seed oils is that they present an oxidative liability. They do not acutely cause oxidative stress, but their polyunsaturated fatty acids (PUFAs) are more vulnerable than any other macronutrient to oxidative damage. Oxidative stress can increase because of nutrient deficiencies, toxins, infections, other sources of inflammation, alcohol, or smoking, and it will inevitably increase as a function of aging. As oxidative stress increases, more PUFAs in the tissues mean more damage. At least 0.6 milligrams of vitamin E should be gotten per gram of PUFA in the diet, but vitamin E cannot fully protect against PUFA, so their intake should be moderated to the very low levels needed, as obtained by eating fatty fish once or twice a week, eating eggs daily, and eating 4-8 ounces of liver per week. Additional secondary problems with them include residual solvents and heat damage prior to intake, but the main issue is that we do not want to increase our tissue PUFA content more than needed. This is a clip from a live Q&A session open to CMJ Masterpass members. In addition to this episode, you can access two other free samples using this link: https://chrismasterjohnphd.substack.com/p/questions-on-hair-trace-mineral-analysis In that batch of free episodes you will also find the answer to this question: Is Hair Mineral Testing Useful? Is Whole Food Vitamin C Really Different? If you want to become a Masterpass member so you can participate in the next live Q&A, or so you can have access to the complete recording and transcript of each Q&A session, you can save 10% off the subscription price for as long as you remain a member by using this link to sign up: https://chrismasterjohnphd.substack.com/qanda Learn more about the Masterpass here: https://chrismasterjohnphd.substack.com/about This snippet is from the June 16, 2023 AMA. The full recording and transcript is reserved for Masterpass members. Here is a preview of what's included: Butyrate for Hashimoto's? What else? What in the comprehensive nutritional screening is helping to interpret lactate/pyruvate and ketone ratios? Is the solution to a respiratory chain disorder to take Niagen? If I have high manganese on an HTMA, do I need to detox? Should CFS patients target reducing their serum BH4? What to do about low alkaline phosphatase? If my glucose spikes above 140, should I eat fiber and take ACV before the meal, eat cinnamon with the meal, chew slowly, and move for ten minutes after my meals? Difficulty getting Quest to do the lactate/pyruvate ratio correctly. Is 38 milligrams of niacinamide enough to rule out niacin deficiency as a cause of low NAD+? How does optimizing body composition help optimize energy metabolism? Can impaired energy metabolism make someone fatter? Is monounsaturated fat the best fat? Manganese followup. Do you need to stop taking biotin before a biotin test? What in "a bunch of supplements" flip the lactate/pyruvate ratio from high to low? NAD infusions, yay or nay? Why do I feel better after a warm shower, even better than after sunshine? Should I cut back on vitamin A if I have toxicity symptoms but cutting back makes me get sick? Do home blood drop tests have to be pricked at the finger? Is it true that my boyfriend was just born a night owl? How much eating out is too much? When measuring ketones, lactate, and glucose at home to optimize energy metabolism, what time of day should we take the measurements? Here's a link to the full AMA: https://chrismasterjohnphd.substack.com/p/recording-and-transcript-of-the-june-a55  

Question: How useful is hair trace mineral analysis (HTMA) for nutritional testing? Short Answer: Hair trace mineral analysis is included as an optional add-on in the comprehensive nutritional screening from Testing Nutritional Status: The Ultimate Cheat Sheet, because it can capture data for some ultra-trace minerals for which there are no better-validated tests, and it might capture a pattern that might not be picked up as quickly with blood work, such as a mineral transport issue. However, its utility is limited by the fact that hair mineral content is not well validated as a test for any specific mineral, is generally anti-validated when there is enough science on a mineral (such as zinc, where hair zinc does not go down in deficiency), and should not be used as a central piece of data without corroboration from other more well-validated tests, which exist for most of the nutrients. This is a clip from a live Q&A session open to CMJ Masterpass members. In addition to this episode, you can access two other free samples using this link: https://chrismasterjohnphd.substack.com/p/questions-on-hair-trace-mineral-analysis In that batch of free episodes you will also find the answer to this question: What's the Deal With Seed Oils? Is Whole Food Vitamin C Really Different? If you want to become a Masterpass member so you can participate in the next live Q&A, or so you can have access to the complete recording and transcript of each Q&A session, you can save 10% off the subscription price for as long as you remain a member by using this link to sign up: https://chrismasterjohnphd.substack.com/qanda Learn more about the Masterpass here: https://chrismasterjohnphd.substack.com/about This snippet is from the June 16, 2023 AMA. The full recording and transcript is reserved for Masterpass members. Here is a preview of what's included: Butyrate for Hashimoto's? What else? What in the comprehensive nutritional screening is helping to interpret lactate/pyruvate and ketone ratios? Is the solution to a respiratory chain disorder to take Niagen? If I have high manganese on an HTMA, do I need to detox? Should CFS patients target reducing their serum BH4? What to do about low alkaline phosphatase? If my glucose spikes above 140, should I eat fiber and take ACV before the meal, eat cinnamon with the meal, chew slowly, and move for ten minutes after my meals? Difficulty getting Quest to do the lactate/pyruvate ratio correctly. Is 38 milligrams of niacinamide enough to rule out niacin deficiency as a cause of low NAD+? How does optimizing body composition help optimize energy metabolism? Can impaired energy metabolism make someone fatter? Is monounsaturated fat the best fat? Manganese followup. Do you need to stop taking biotin before a biotin test? What in "a bunch of supplements" flip the lactate/pyruvate ratio from high to low? NAD infusions, yay or nay? Why do I feel better after a warm shower, even better than after sunshine? Should I cut back on vitamin A if I have toxicity symptoms but cutting back makes me get sick? Do home blood drop tests have to be pricked at the finger? Is it true that my boyfriend was just born a night owl? How much eating out is too much? When measuring ketones, lactate, and glucose at home to optimize energy metabolism, what time of day should we take the measurements? Here's a link to the full AMA: https://chrismasterjohnphd.substack.com/p/recording-and-transcript-of-the-june-a55

In this episode, Nurse Doza discusses the topic of bloating and provides tips on how to reduce it. Bloating is a common issue, with nearly 40% of the general population reporting experiencing it. Nurse Doza encourages listeners to take note of their own symptoms and do their own research to find strategies that work for them. This episode aims to empower listeners to take action and find relief from bloating.   00:00 START 02:29 Tips to reducing bloat. 07:40 Elimination diet and bloating. 10:38 Gut and brain interaction. 13:52 L-glutamine supplementation and gut health. 17:48 Support your liver. 21:10 Supporting the liver 23:41 Depression and Serotonin Production. 28:08 Digestive issues and processed foods. 30:39 Serotonin and mood support.   Elevate your mood naturally with Bliss. Our carefully formulated supplement is designed to support neurotransmitter production, ensuring a balanced and joyful life. Before diving into the episode, don't forget to click the link and explore how Bliss can transform your everyday experiences. https://www.mswnutrition.com/products/bliss/?ref=nursedoza 1. Diet and Bloating Examine your diet to identify potential causes of bloat. Low Fermentable Oligo-, Di- and Mono-saccharides And Polyols (FODMAP) Diet is highly recommended for treating IBS symptoms¹. IBS diagnosis is based on the Rome IV criteria, highlighting the relation of abdominal pain with defecation and changes in bowel habits¹. A significant percentage of IBS patients, especially women, associate their symptoms with food intake. Bloating and abdominal pain are the most frequent complaints¹. Commonly reported dietary triggers include carbohydrates, fatty foods, coffee, alcohol, and hot spices¹. Gluten can disrupt bowel barrier functions, especially in certain patients akin to celiac individuals¹. Excessive fructose intake exacerbates NAFLD markers² and can disturb the intestinal barrier, intensifying liver inflammation and fructose conversion into fatty deposits³. ¹ ² ³ 2. Gut Health and Bloating Address gut health to alleviate bloating. DGBIs encompass conditions like IBS, reflux hypersensitivity, and functional dyspepsia⁴. Several factors, including past infections and psychological conditions, can lead to DGBIs⁴. Disorders of gut–brain interaction or FGIDs are recognized as microbiota–gut–brain abnormalities prevalent worldwide⁵. Gut microbiota is susceptible to changes due to varying factors like diet and psychological state⁵. Methanogenic microbes in the colon can lead to slowed gut transit and constipation due to serotonin depletion⁵. ⁴ ⁵ 3. Bloodwork and Bloating Seek bloodwork to identify underlying causes. hs-CRP is linked with NAFLD⁶. IBS has been found to predict higher hs-CRP levels⁷. Elevated ALT is often observed in IBS patients⁸. Excessive gas correlates significantly with liver steatosis and heightened ALT levels⁹. ⁶ ⁷ ⁸ ⁹ 4. Liver Health and Bloating Support the liver for better digestion. IBS symptoms like abdominal pain and bloating can also indicate NAFLD¹⁰. Cholecystitis can lead to abdominal bloating¹¹. The gallbladder isn't essential for a healthy life¹¹. ¹⁰ ¹¹ 5. Mood, Serotonin, and Bloating Maintain a balanced mood and serotonin levels to manage bloating. Serotonin has diverse intestinal functions¹². IBS might be associated with serotonin dysfunction affecting gut motility¹². Changes in serotonin levels can be addressed with specific medications for symptom relief¹³. Essential components for serotonin synthesis include tetrahydrobiopterin (BH4) and pyridoxine (vitamin B6)¹⁴. ¹² ¹³ ¹⁴ As you've learned today, neurotransmitter balance plays a crucial role in our overall well-being. Why not support your body's natural balance with Bliss? Click on the link to discover how this transformative supplement can amplify your health journey. https://www.mswnutrition.com/products/bliss/?ref=nursedoza  

Question: How much iron can we absorb at once? Short Answer: High-dose iron will produce more total absorbed iron, but will also leave more in the gut, which could cause constipation or disturb the gut microbiome. If desperate for quick relief, 200 milligrams per day of iron taken in the morning will work faster than lower doses or the same dose taken in the afternoon. For most people, however, I believe it is best to start with 18 milligrams of iron, and only increase it to 27 or 36 milligrams, or higher, if needed. If it is difficult to raise iron with a supplement, try eating a temporary carnivore diet that includes egg yolks but not whites, or at least try taking your iron with a breakfast that matches this description. This is a clip from a live Q&A session open to CMJ Masterpass members. In addition to this episode, you can access two other free samples using this link: https://chrismasterjohnphd.substack.com/p/questions-on-vitamin-d-sulfate-synthesis  In that batch of free episodes you will also find the answers to these questions: Is It Important to Get Vitamin D Sulfate Specifically From the Sun? What cofactors are needed to synthesize and recycle BH4? If you want to become a Masterpass member so you can participate in the next live Q&A, or so you can have access to the complete recording and transcript of each Q&A session, you can save 10% off the subscription price for as long as you remain a member by using this link to sign up: https://chrismasterjohnphd.substack.com/qanda Learn more about the Masterpass here: https://chrismasterjohnphd.substack.com/about This snippet is from the February 15, 2023 AMA. The full recording and transcript is reserved for Masterpass members. Here is a preview of what's included: Is It Important to Get Vitamin D Sulfate Specifically From the Sun? What cofactors are needed to synthesize and recycle BH4? What nutrients are important for long-term PPI use? For how long does transferrin saturation respond to recent iron-rich food? Muscle spasms: creatine, creatinine, sodium, and potassium. Hematologists ignore iron saturation. How to detox arsenic? Could folic acid supplements impair BH4 recycling? How to increase butyrate? More on hematologists and transferrin saturation. Here's a link to the full AMA: https://chrismasterjohnphd.substack.com/p/recording-and-transcript-of-the-february  Access the show notes, transcript, and comments here.

Question: What cofactors are needed to synthesize and recycle BH4? Short Answer: Zinc, magnesium, potassium, and niacin are the cofactors needed for the synthesis and recycling of BH4. Folate and methylation are not involved, though high-dose folate or folic acid could hypothetically hurt BH4 recycling since both are recycled by dihydrofolate reductase (DHFR). This is a clip from a live Q&A session open to CMJ Masterpass members. In addition to this episode, you can access two other free samples using this link: https://chrismasterjohnphd.substack.com/p/questions-on-vitamin-d-sulfate-synthesis In that batch of free episodes you will also find the answers to these questions: Is It Important to Get Vitamin D Sulfate Specifically From the Sun? How Much Iron Can We Absorb At Once? If you want to become a Masterpass member so you can participate in the next live Q&A, or so you can have access to the complete recording and transcript of each Q&A session, you can save 10% off the subscription price for as long as you remain a member by using this link to sign up: https://chrismasterjohnphd.substack.com/qanda Learn more about the Masterpass here: https://chrismasterjohnphd.substack.com/about This snippet is from the February 15, 2023 AMA. The full recording and transcript is reserved for Masterpass members. Here is a preview of what's included: Is It Important to Get Vitamin D Sulfate Specifically From the Sun? How Much Iron Can We Absorb At Once? What nutrients are important for long-term PPI use? For how long does transferrin saturation respond to recent iron-rich food? Muscle spasms: creatine, creatinine, sodium, and potassium. Hematologists ignore iron saturation. How to detox arsenic? Could folic acid supplements impair BH4 recycling? How to increase butyrate? More on hematologists and transferrin saturation. Here's a link to the full AMA: https://chrismasterjohnphd.substack.com/p/recording-and-transcript-of-the-february  Access the show notes, transcript, and comments here.

Question: Is it important to get vitamin D sulfate specifically from the sun? Short Answer: It is important to get morning outdoor sunlight as close to every day as possible for your circadian rhythm, and to get some exposure to unprotected sunlight during the day when UV is available, but at doses less than needed to cause reddening, and it is equally important to always avoid burning. There are many reasons for this, and the cholesterol sulfate hypothesis — to which the vitamin D sulfate hypothesis is peripheral — is an interesting and worthy hypothesis but should not be the final arbiter of your sun exposure habits. This is a clip from a live Q&A session open to CMJ Masterpass members. In addition to this episode, you can access two other free samples using this link: https://chrismasterjohnphd.substack.com/p/questions-on-vitamin-d-sulfate-synthesis In that batch of free episodes you will also find the answers to these questions: What cofactors are needed to synthesize and recycle BH4? How Much Iron Can We Absorb At Once? If you want to become a Masterpass member so you can participate in the next live Q&A, or so you can have access to the complete recording and transcript of each Q&A session, you can save 10% off the subscription price for as long as you remain a member by using this link to sign up: https://chrismasterjohnphd.substack.com/qanda Learn more about the Masterpass here: https://chrismasterjohnphd.substack.com/about This snippet is from the February 15, 2023 AMA. The full recording and transcript is reserved for Masterpass members. Here is a preview of what's included: What cofactors are needed to synthesize and recycle BH4? How Much Iron Can We Absorb At Once? What nutrients are important for long-term PPI use? For how long does transferrin saturation respond to recent iron-rich food? Muscle spasms: creatine, creatinine, sodium, and potassium. Hematologists ignore iron saturation. How to detox arsenic? Could folic acid supplements impair BH4 recycling? How to increase butyrate? More on hematologists and transferrin saturation. Here's a link to the full AMA: https://chrismasterjohnphd.substack.com/p/recording-and-transcript-of-the-february

The Chess Angle is sponsored by Chessable. Check out a list of our favorite courses! This episode is a primer on the Nimzo & Queen's Indian Defenses for adult improvers and club-level players. These two openings can be used as a complete system against 1. d4. Fighting for control of the e4-square is a major theme. Lines discussed include the following:NIMZO-INDIAN:Rubenstein Variation with 4...b6: 1. d4 Nf6 2. c4 e6 3. Nc3 Bb4 4. e3 b6 5. Bd3 Bb7 (5. Nge2 Ne4!) 6. Nf3 Ne4!Classical Variation with 4...0-0: 1. d4 Nf6 2. c4 e6 3. Nc3 Bb4 4. Qc2 0-0 5. a3 Bxc3+ 6. Qxc3 Ne4! 7. Qc2 f5Leningrad Variation: 1. d4 Nf6 2. c4 e6 3. Nc3 Bb4 4. Bg5 h6 5. Bh4 c5 6. d5 d6Samisch Variation with 4. a3: 1. d4 Nf6 2. c4 e6 3. Nc3 Bb4 4. a3 Bxc3 5. bxc3 and Black can begin an attack on the weak c4-pawn (...Nc6-a5, ...b6, ...Ba6, etc.)QUEEN'S INDIAN:Main Line:  1. d4 Nf6 2. c4 e6 3. Nf3 b6 4. g3 Bb7 5. Bg2 Be7 6. 0-0 0-0 7. Nc3 Ne4! 8. Qc2 Nxc3 9. Qxc3 (9. Ng5?? Nxe2! 10. Qxe2 Bxg2 11. Qh5 h6 -+) c5 (9...Be4 is also good in the main line)Petrosian System with 4. a3:  1. d4 Nf6 2. c4 e6 3. Nf3 b6 4. a3 Bb7 5. Nc3 d5! (stopping 6. d5 by White)Errata: When discussing odds & ends,  I mentioned that you can sometimes trick your opponent into playing the French Defense after 1. d4 e6! 2. e4 d5. I said 2. ...e5 by mistake (though I suspect most of you knew what I meant). RECOMMENDED RESOURCES:Starting Out: The Nimzo-Indian (Amazon)Starting Out: The Queen's Indian (Amazon)The Fierce Nimzo-Indian by WFM Maaike Keetman (Chessable)Our links:WebsiteTwitterYouTubeFacebookE-mail: info@thechessangle.comThe Amazon links above are affiliate links, which earn us a commission on qualifying purchases. This helps support the podcast at no additional cost to you.

Summary   Hello and welcome to episode #19!   This is Ralph Sanchez and today I'll be talking the outcomes of two recent studies that investigated the potential use of Viagra and Cialis in the risk reduction for late-onset Alzheimer's disease (LOAD).   I was in part inspired to provide an overview on these two recent studies as they are cautionary tales on how many studies do not include the interrelated factors that are essential in arriving to an integrated assessment and analysis that serves their very premise— which is, does this or that work in a potential solution to something else?   Does Viagra or Cialis offer any proposed solution to the risk for LOAD and dementia?   Well today, I'll be adding a great deal of information—the missing pieces to the puzzle as it were—with regard the pathways by which Viagra and Cialis may or may not work, and many other complimentary or natural alternatives that play a similar role in maintaining and optimizing a healthy cardiovascular and cerebrovascular system.   First, let me provide a little insight as to the molecular pathways in which drugs like Viagra and Cialis function, and why they may be considered as repurposed drug candidates for the treatment or in the risk reduction for LOAD.   Viagra (sildenafil) and Cialis (tadalafil) are Phosphodiesterase-5 inhibitors (PDE5is) which fall into a class of drugs that are normally prescribed to men to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS).   PDE5is can have a profound effect on cardiovascular health and PDE5is mediate their benefits by inhibiting the breakdown of a molecule, cyclic GMP (cyclic 3′,5′ guanosine monophosphate).   Cyclic GMP (cGMP) is an intracellular and second messenger molecule that modulates many downstream pathways, including significant effects in vasorelaxation—the ability of your blood vessels to dilate and expand as needed.   The vascular effect that is enabled by PDE5i-induced vasodilation is a pivotal pathway in vascular homeostasis and a healthy heart-brain axis.   And that vasodilation effect is how PDE5is improve and treat ED.   There is a lot more to that vasodilation benefit mediated by PDE5i therapy  which I'll get to here soon.   So on to a brief description of the two recent studies on Viagra and Cialis, and so much more that was not included in those studies that will provide a crucial insight into how you can improve your vascular health and reduce your risk for LOAD.   NIH Studies First, a recent (2021)National Institutes of Health (NIH) funded study reported a risk reduction benefit of 69% for Alzheimer's disease (AD) in users of Viagra (Sildenafil).   The analysis simply compared Viagra users to those who did not take it, and the study was focused on a screen of drugs that could potentially be repurposed in the risk reduction for AD in aging individuals.   In a similar and second NIH funded study published this year (2022) titled— Drug Repurposing for Effective Alzheimer's Medicines—(DREAM), the NIH analyzed data from Medicare beneficiaries that were treated with Viagra and Cialis.   The NIH team compared people with pulmonary arterial hypertension (PAH) treated with Viagra and Cialis over those with PAH on another class of drugs (endothelin receptor antagonists) used to treat pulmonary hypertension.   And note that PAH is a term that refers to high blood pressure in the blood vessels leading from the heart to the lungs   Yes, PDE5is are also prescribed to patients to reduce blood pressure in PAH, and off-label use of PDE5 inhibitors (PDE5is) is used to treat cardiovascular diseases, Raynaud's disease and women with female sexual arousal disorder.   The average age of patients included in the DREAM study “was 74 years (range 65–96 years), and 69% were women.”   Notably, studies have shown that in women, "PDE5 inhibitor efficacy is estrogen dependent in female heart disease."   The DREAM PDE5i study rationale for focusing on patients with PAH and treated with PDE5is, Viagra or Cialis, for the new study analysis over those individuals on another class of antihypertensive drugs was attributed to the odds that the two groups were  "more likely to have people with similar characteristics".   In comparing those two pulmonary hypertension groups in the DREAM study the research team concluded that they "observed no evidence for a reduced risk of Alzheimer's disease and related dementia with phosphodiesterase-5 inhibitors"—Viagra or Cialis.   Bottom line, two differences in the design and outcomes as the Viagra study was favorable while the DREAM study was not. Fair enough.   However, there is much more to this story that was not included in the two studies, which includes an important benefit for heart and brain health that is only in part mediated by PDE5i therapy.   And we begin with nitric oxide— a vital molecule produced in your body and brain that not only impacts many potential benefits to your health, it can also be a component in deleterious oxidative stress reactions that are very damaging to your body and brain.   Nitric Oxide Nitric oxide (NO) was first discovered in 1772 but it was not until 1987 that it was identified as an important signaling molecule that played a vital role in endothelium-dependent vasodilation in mammals.   A few years later, in 1992, the journal Science nominated nitric oxide as the “Molecule of the Year” due to its role as a fundamental signaling agent in cardiovascular health and function.   In the body and brain, NO can be synthesized by two distinct pathways.   First, endogenous nitric oxide (NO) can be synthesized from the amino acid L. arginine (L-arginine-NO-synthase pathway) which is the initial upstream driver of cGMP activation in vasodilation.   Remember that we started this overview by emphasizing the role of PDEis in blocking the degradation of cGMP.   However, NO signaling is where cGMP activation begins.   Additionally, another amino acid—L. citrulline—is metabolized from arginine and can be utilized in regeneration of arginine.   Both amino acids are at the center of many studies which showcases their metabolism in vasodilation pathways.   Nitric oxide may be also be derived from the intake and metabolism of foods rich in nitrate (nitrate–nitrite–nitric oxide pathway).   Vegetables such as beets, celery, arugula and spinach, and fruits (e.g., strawberries) supply approximately 80%—85% of dietary nitrates in individuals that consume such foods regularly.   Indeed, those foods are not only a terrific source of nitrate, they also are rich in many types of polyphenols which are key nutrients in protecting against oxidative stress pathways associated with nitric oxide metabolism.   Many of you listening in or reading the transcript have likely become familiar with supplements using beets, or arginine and citrulline and other synergistic ingredients that have been heavily marketed to athletes as performance enhancers.   In a clinical setting, these NO enhancing products are often used for ED and cardiovascular health support.   Drugs (organic nitrates) are also well-known NO donors (e.g., nitroglycerin, amyl nitrite).   Thus, NO can be produced from the precursors L. arginine and L. citrulline, or nitrates and nitrites that are either derived from foods, supplements and drugs.   Another important understanding in all of this is that oral and gut bacteria convert dietary nitrate (NO3) to nitrite (NO2), and in the acidic stomach nitrite is further reduced to nitric oxide.   NB, antiseptic mouthwashes inhibit nitrate to nitrite metabolism by eradicating oral bacteria, and proton pump inhibitors (PPIs) and antacids suppress stomach acid and nitrite to NO metabolism.   To recap NO is an essential signaling and vasodilatory molecule secreted by vascular endothelial cells, which stimulates the production of cGMP (NO/cGMP Pathway) via activation of the receptor for cGMP— soluble guanylate (guanylyl) cyclase (sGC).   Another important point about NO in women is that estrogen (E2) increases NO synthesis.   Thus, the estrogen-NO dynamic is vital in vascular relaxation and endothelial-dependent vasodilation in women and should be included in any risk assessment for cardiometabolic and dementia risk in perimenopause or the earliest stage of menopause.   In contrast, cardiovascular disease (CVD) risk factors such as excess belly fat, high blood pressure, insulin resistance and type 2 diabetes, glycation and chronic inflammation (inflammageing) disrupts endothelial function, promotes arterial stiffness, and blunts the synthesis of NO.   Studies have shown that ED occurs in approximatelym35% to 75% of men with type 2 diabetes, and related studies have concluded that ED predicts future cardiovascular events.   Additionally, CVD risk factors upregulate the formation of an arginine metabolite—ADMA (asymmetric dimethylarginine)—that inhibits vascular NO production (eNOS uncoupling).   ADMA impairs vascular endothelial function and increases vascular oxidative stress (NO-ONOO cycle), and elevated ADMA has been linked to CVD in many studies. See image below.   A useful assessment in analyzing the underlying factors associated with cardiometabolic disease such as atherosclerosis is the serum arginine/ADMA ratio which provides information on arginine bioavailability for production of NO.   So, to summarize, the integrity of NO-sGC-cGMP Pathway is critical to signaling and vasodilation mechanisms that are essential to blood flow and vascular/endothelial homeostasis.   Healthy endothelial function and NO levels is critical in the normal function of many vital organ systems including the cardiovascular and cerebrovascular system (neurovascular system), and the respiratory and renal systems.   Indeed, a healthy endothelium is a fundamental cornerstone to living younger, longer.   For a more thorough overview of the neurovascular system, please listen in to episode #16 titled: “Brain Detoxification-Part 1-The Role of the Blood Brain Barrier and The Glymphatic System” here on this channel.   NO-PDE5i Brain Benefits But what about the role of PDE5is in all of this?   Is there a role for PDE5i therapy in preventing cognitive decline?   Would the PDE5i—sildenafil, or other PDE5 inhibitors, impart the same benefits on brain and cognitive health as healthy levels of NO does?   Previous studies have shown that low dose sildenafil activates signaling pathways which suppresses the processing and generation of beta-amyloid and tau protein aggregates.   Additionally, PDE5 inhibition mediated benefits include: induces cellular antioxidant levels, blunts neuroinflammation, and stimulates the production of new mitochondria (mitochondrial biogenesis) Now, is there a world where the combined therapy of NO and PDE5i therapy exists?   Only a handful of recent studies have shown that supplemental citrulline or arginine therapy in combination with a PDE5 inhibitors could be a synergistic and therapeutic alternative to PDE5i monotherapy for severe ED and pulmonary hypertension.   Overall, combination therapy was superior to monotherapies.   No such combination studies that investigated PDE5 inhibitors with citrulline or arginine therapy in the risk for late-onset Alzheimer's disease (LOAD) have been undertaken.   Bottom line, given the lack of research that includes the multiple pathways of NO metabolism and its role in endothelial function, the investigation into Viagra or any other PDE5i in the risk reduction for LOAD is grossly incomplete.   And that answers the unfinished Viagra and Cialis story as a viable treatment for cognitive impairment or Alzheimer's as the NIH studies on Viagra and Cialis just did not go deep enough into interrelated mechanisms that intersect with the PDE5 enzyme.   However, key nutrients, nutraceuticals and herbs are well-known NO precursors and PDE5 inhibitors, and they also protect against the upregulation of NO and the pro-inflammatory pathways and oxidative stress cascades associated with excess NO production.   Without a doubt, dietary, nutrient and botanical/herbal extracts are vital interventions in an optimal heart-brain health protocol.   More on that below after this brief overview on the glycocalyx.   The Glycocalyx (preview) I must add that any overview on NO in vascular and endothelial health is incomplete without an overview on the glycocalyx—a gel-like thin protective layer covering present on endothelial cells which maintains the endothelial barrier.   In fact, almost every cell in the human body, including bacteria, are covered by a glycocalyx layer.   And yes, the role of a glycocalyx layer in bacteria is another story.   The degradation of the endothelial glycocalyx layer in aging and cardiovascular disease significantly reduces endothelial cell production of NO, and collectively these interactions are a major and underlying factor in cardiovascular AND neurovascular disease.   I have been closely following the emerging research with regard to the glycocalyx over the past 5 years, and the evidence that you cannot have a healthy-heart-brain axis without a vibrant endothelial glycocalyx is compelling.   Case in point, the recent studies that have demonstrated the importance of the glycocalyx in vascular/endothelial health have established a new and critical insight into the treatment and potential reversal of atherosclerosis.   Nutrition-Diet (preview) A host of nutrients, nutraceuticals and herbs are well-known NO precursors and PDE5 inhibitors.   First, apart from arginine and citrulline, vitamin C, E and D are core nutrients in NO-mediated endothelium-dependent relaxation.   Recently, vitamin K2-MK-7 studies have also been linked to enhanced NO-dependent endothelial function.   Glutathione has been shown to be an essential and protective antioxidant in modulating NO reactivity and protecting against the damaging NO-ONOO cycle.   Glutathione and glutathione-based enzymes detoxifies peroxynitrite (ONOO)—a reactive nitrogen species, and improves nitric oxide bioavailability and endothelial function.   And, tetrahydrobiopterin (BH4) is a key enzymatic cofactor required for the synthesis of several neurochemicals—serotonin, dopamine and NO.   Additionally, polyphenols and in particular flavonoids, are the most the most frequently reviewed and studied phenolic NO precursors and PDE5 inhibitors, and they support the integrity of the glycocalyx structure and function.   So many nutrients  to make a case for including the phytoestrogenic benefits of many flavanoids, but here is an abbreviated list of the most cited plant/herbal derivatives and nutrients: Resveratrol Quercetin Catechins, epicatechin (e.g.,green tea) Pine bark (Pycnogenol®) and grape seed extracts (GPSE) Isoflavones (e.g. genistein) Hawthorne (Crataegus species) Icariin (Epimedium brevicornum) Aged garlic extracts Pomegranate extracts Gingko biloba Black ginger (kaempferia parviflora) Xanthones (Anaxagorea luzonensis) And, all the nitrate/flavanoid-rich foods including beets, spinach/leafy greens, and celery, pomegranate, berries, cherries, citrus, garlic, dark chocolate and many others.   Of course, a low-carbohydrate Mediterranean diet or Mind Diet lifestyle is rich in polyphenols and other heart and brain health nutrients.   In addition, exercise training and caloric restriction promotes NO activity and endothelium-dependent vasodilation through activation of eNOS.   Additional points covered in this episode's audio file…   NO Synthesis (preview) Now, I'll briefly describe how NO is synthesized as there are principal pathways that illustrate key and elemental features of NO metabolism—good and bad.   The NO-cGMP pathway is in part regulated by the activity of a family of enzymes—nitric oxide synthases that regulate nitric oxide (NO) synthesis.   There are three NOS enzyme synthases—neuronal (nNOS), endothelial (eNOS), and inducible (iNOS).   iNOS driven NO production is associated with immune system responses to various stimuli such as infections, and NO can either function as a regulator of such responses, or excessive production of NO by iNOS can upregulate those pathways in a destructive manner.   Nitric Oxide-S-nitrosylation (preview) I want to add another important feature of NO metabolism with regard to the risk for LOAD.   And that is the physiological and pathophysiological role of another NO reaction that takes place in the body and brain which is termed S-nitrosation, or S-nitrosylation.   I was not planning on adding this to this episode, but a recent research study just published reported that a S-nitrosylation pathway was a risk factor in Alzheimer's disease in women.   S- nitrosylation is the bonding of NO to sulfur compounds on amino acids such as cysteine.   In a recent study finding reported on just a few days ago—December 14, 2022, the elevated S-nitrosylation modification of an immune system protein known as complement component C3 (SNO C3) was present at much higher (six-fold) levels in the brains of women who had died of Alzheimer's, compared to men who had died with the disease.   The postmortem brain research that was conducted at Scripps Research and Massachusetts Institute of Technology (MIT) also reported that declines in estrogen, which normally serves as a neuroprotective hormone, was likely a strong factor in the generation of the SNO-C3 form of complement C3.   Cured Meats (preview) Another key factor to weigh into this overview with regard to diet, nitrates, nitrites and NO, are cured meats.   In fact, some of you may be anticipating this section of the  overview by now as there is considerable concern and media dissemination of the potentially deleterious role of nitrates and nitrites used in various types of processed meat products such as bacon, sausages and other “deli meats”.   In fact, many studies have explored the risk of nitrate and nitrite added to various foods as their metabolism under certain conditions can potentially convert into a toxic nitrosamines (N-nitroso compounds)   That's it for this summary and as always, thank you for listening in or taking the time to read the summary . Please do listen in to hear the rest of the story. God bless and goodbye.   BrainDefend® Ralph Sanchez, MTCM, CNS, D.Hom. https://www.TheAlzheimersSolution.com   https://www.facebook.com/TheAlzheimersSolution/ https://www.linkedin.com/in/ralph-sanchez/ https://www.instagram.com/alzheimers_solution/ https://twitter.com/RalphSanchez        

Sensitive to sulfur foods? Having difficulty detoxing? You might be dealing with this genetic defect. Listen to figure out what CBS mutations are, what causes them, and what impact they have on the body.01:03 - What is CBS mutation?02:53 - What is BH4?04:40 - CBS mutation health issues07:30 - What can you do about it?Trying to find an integrative medicine or functional medicine doctor who understands what you're going through? Lam Clinic does Telemedicine all over the world and is only a phone call away. 1. Educate yourself by visiting our website: www.lamclinic.com2. Call our office at 714-709-8000 to schedule an appointment. FIND US ONLINE HERE: » Website: https://www.lamclinic.com/» Facebook: https://www.facebook.com/lamclinic» Instagram: https://www.instagram.com/lam_clinic/» Tiktok: https://www.tiktok.com/@lamclinic» YouTube: https://www.youtube.com/LAMCLINIC

Vitamin D doesn't link into the methylation cycle, the folate cycle, or even the BH4 pathway so it seems highly unrelated to MTHFR, but is that true? This week we'll explore: Why vitamin D seems to do literally everything in the research The gene SNPs that affect vitamin D Why folate and vitamin D have relationship status "complicated" How folate and vitamin D might have influenced skin pigment in evolution An MTHFR superpower that regards, you guessed it, vitamin D. For the complete show notes, click here. If you want to join the MTHFR community Genetic Rockstars, click here. If you want to take an MTHFR course or get on the list for future courses, click here. --- Send in a voice message: https://anchor.fm/tohealthwiththat/message

Guest: Christina Broderick Christina's Story: Christina Broderick is a mother of 2 special needs children with Autism. Her oldest son has a rare disorder called Phenylketonuria (PKU). Phenylketonuria is a rare disorder where individuals cannot break down the amino acid that make up proteins in our food. As a result, the amino acid Phenylalanine builds up in their blood or brain and can lead to brain damage if accommodations aren't made. Her son was the first PKU diagnosis in over 30 years in her town of Lake Havasu City, Arizona. As a result, resources were limited. In 2010, Christina as a 19-year-old mother struggled to find a formula that was safe to feed her son. The formula she eventually found was very expensive! Christina also didn't have a PKU specialist in her town, so she had to travel frequently typically 3.5-hour drives to Phoenix, AZ to see a specialist and get resources suitable for her son to include testing kits. For awhile all her son could eat was Rice Cereal. Christina was contacted by a representative of NORD (National Organization or Rare Disorders). NORD is a nonprofit 501(c)(3) provides assistance programs to help patients obtain lifesaving or life sustaining medication they could not otherwise afford. These programs provide medication, financial assistance with insurance premiums and co-pays, diagnostic testing assistance, and travel assistance for clinical trials or consultation with disease specialists. NORD helped Christina with resources a variety of resources to include food, gas reimbursement, medications, and funding. NORD also introduced her the company CAMBROOKE, which provides nutrition for those with serious medical disorders like PKU. When Christina's son turned 6. NORD also introduced Christina to a new medication from Biomarin that was initially introduced for diabetic persons. The manufactures believed that this drug would be effective for individuals with PKU and began a study which included Christina's son. The medication Kuvan made by BIOMARIN ended up being effective for her son. NORD's pay for all her son's PKU medications. Christina reports that NORD will provide support for undiagnosed individuals as well. Recap: If you have a child with a rare disorder like PKU, reach out to NORD. NORD provides education support programs, funding, and resources for individuals with rare disorders. Cambrooke provides low protein foods for individuals with PKU BIOMARIN provides medication for individuals with PKU. Regardless of your child's diagnosis, you can become your child's number 1 advocate by reaching out to see what resources may be available out there that will help your family through tough times. Christina works at RISE Services, Inc. Rise Services Inc. provides services that support children, adults, and families throughout Arizona, Utah, Oregon, Texas, and Idaho. https://riseservicesincaz.org NORD https://rarediseases.org/for-patients-and-families/help-access-medications/patient-assistance-programs-2/ NORD Mission Statement: NORD, a 501(c)(3) organization, is a patient advocacy organization dedicated to individuals with rare diseases and the organizations that serve them.  NORD, along with its more than 300 patient organization members, is committed to the identification, treatment, and cure of rare disorders through programs of education, advocacy, research, and patient services. CAMBROOKE https://www.cambrooke.com/ Ajinomoto Cambrooke (formerly Cambrooke Therapeutics an expansion of Cambrooke Foods) was founded in 2000 by Lynn and David Paolella, the parents of two children diagnosed with a rare disease called phenylketonuria (PKU). PKU is one of the few genetic diseases, which is managed almost entirely with nutritional intervention. The Paolellas' goal in forming Cambrooke was simple - to develop improved nutritional therapeutic options for those with serious medical disorders. BIOMARIN https://www.biomarin.com/our-treatments/products/kuvan/ Kuvan® (sapropterin dihydrochloride) Tablets and Powder for Oral Solution is the first FDA-approved medication for phenylketonuria (PKU). Kuvan is a form of BH4, the cofactor of the PAH enzyme, which helps the enzyme break down Phe. Kuvan is to be used in conjunction with a Phe-restricted diet. Subscribe Now & Leave a Review Apple Podcasts, Spotify,  Google Podcast, &  Stitcher Visit our Website www.pureheartstherapy.com Follow Us: Facebook: Pure Hearts Therapy Facebook Group: Autism Family Toolkit Instagram: Purehearts_Therapy

This week's episode features author Philippe Gabriel Steg and editorialist Gregg Stone as they discuss the article "International Observational Analysis of Evolution and Outcomes of Chronic Stable Angina: The Multinational Observational CLARIFY Study." TRANSCRIPT BELOW Dr. Carolyn Lam: Welcome to Circulation the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts, I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore here with my other co-host, a little bird that you can hear I think in the background and then my real co-host, Greg. Dr. Greg Hundley: Thanks so much, Carolyn. Yes, I'm Dr. Greg Hundley. I'm not the bird this week. Associate editor, director of the Pauley Heart Center in Richmond, Virginia. Carolyn, so this week, our feature discussion is really going to be on the importance of stable angina and what that means prognostically. But before we get to that, how about we grab a cup of coffee, talk to our other bird friends and then we jump in and talk about the other papers in the issue. Would you like to go first? Dr. Carolyn Lam: Love it, Greg. Thank you so much. This first paper, very important question. We know that while the 99th percentile is the recommended diagnostic threshold for myocardial infarction, some guidelines also advocate the use of higher troponin thresholds to rule in myocardial infarction at presentation. It's still unclear whether the magnitude or change in troponin concentration can differentiate causes of myocardial injury and infarction in practice. And so today's paper is really important from Dr. Mills from the University Center for Cardiovascular Science Royal Infirmary of Edinburgh in the University of Edinburgh and colleagues. Dr. Carolyn Lam: What they did was a secondary analysis of the high stakes trial of more than 46,000 consecutive patients with suspected acute coronary syndrome. They evaluated the performance of the 99th percentile rule in threshold and thresholds of 64 ng/L and five times the upper reference limit for the diagnosis of type 1 myocardial infarction. They found that troponin concentrations at presentation have a low, positive predictive value for type 1 myocardial infarction and a threshold of 50 times the upper reference limit is required to achieve a positive predictive value of more than 70%. A change in troponin on serial testing only marginally improved positive predictive value for type 1 myocardial infarction over the presenting troponin alone. Dr. Greg Hundley: Interesting, Carolyn. Very important data. What's our take home message here. Dr. Carolyn Lam: Well, troponin concentrations at presentation are insufficient to distinguish type 1 myocardial infarction from other causes of myocardial injury or infarction and should not be used in isolation to guide management decisions in patients with suspected ACS. Consideration of other important clinical factors may be more helpful than any particular rule in threshold to guide initial triage and management. Dr. Greg Hundley: Wow, Carolyn, so really great new data and more data on the utility of these troponin concentrations. Dr. Greg Hundley: Well, my next paper comes from the world of preclinical science and it's from Professor Vladimir Kalinichenko from Cincinnati Children's Hospital Medical Center. Carolyn, as we know, pulmonary hypertension is a common complication in patients with alveolar capillary dysplasia with misalignment of pulmonary veins, a severe congenital disorder associated with mutations in the Foxf1 gene. Now, while the loss of alveolar microvasculature causes pulmonary hypertension in, and we're going to abbreviate this ACDMPV patients, it is unknown whether increasing neonatal lung angiogenesis could prevent pulmonary hypertension and right ventricular hypertrophy in these subjects. Dr. Carolyn Lam: Wow. Wow. Okay. Let's repeat that. ACDMPV stands for alveolar capillary dysplasia and misalignment of pulmonary veins. Really cool stuff. What did they find, Greg? This sounds like a first of its kind study. Dr. Greg Hundley: Right, Carolyn. Thanks. The Foxf1 wild type, S52 mice developed pulmonary hypertension and RV hypertrophy after birth. The severity of pulmonary hypertension in these mice directly correlated with mortality, low body weight, pulmonary artery muscularization and increased collagen deposition in the lung tissue. Second, increased fibrotic remodeling was found in the human ACDMPV lungs. Third, the mouse endothelial cells carrying the S52F Fox1 mutation were used to produce chimeras via blastocyst complementation and to demonstrate that the Foxf1 wild type S52F endothelial cells have a propensity to differentiate into pulmonary myofibroblasts. And then finally, intravascular delivery of nanoparticles carrying Stat3 copy DNA protected the Foxf1 wild type S52F mice from RV hypertrophy and pulmonary hypertension, improved their survival and decreased that fibrotic lung remodeling. Carolyn, nanoparticle therapies increasing neonatal pulmonary angiogenesis may be considered to prevent pulmonary hypertension in alveolar capillary dysplasia with misalignment of pulmonary veins. Dr. Carolyn Lam: Wow, thank you, Greg. Such incredibly hopeful papers here. The next paper identified a key role of a particular amino acid in cardiac aging. Dr. Greg Hundley: Ah, Carolyn, so you didn't ask me the quiz but I guess it's implied here. Okay, I give up. Which amino acid is it? Dr. Carolyn Lam: Spot on, Greg. Well, the answer is phenylalanine. This is an essential amino acid whose levels are regulated by the tetrahydrobiopterin or BH4 dependent rate limiting enzyme, phenylalanine hydroxylase and whose expression is physiologically restricted to the liver and the kidney. Well, co-corresponding authors Dr. Czibik and Derumeaux from Paris, France, hypothesized that phenylalanine plays a causal role in promoting cardiac senescence and dysfunction based on prior evidence from human metabolomics that shed light on a link between amino acids, aging and heart failure, as well as data showing that plasma levels of phenylalanine increase with age and inversely correlate with leukocyte telomere length. In addition, increased serum phenylalanine levels are associated with heart failure. Here, the authors tested their hypothesis in a series of elegant mouse experiments and showed for the first time that a decline in hepatic phenylalanine catabolism was a causal contributor to a rise in systemic levels, leading to cardiac ectopic phenylalanine hydroxylase activity and resultant cardiac aging. Dr. Carolyn Lam: They demonstrated that phenylalanine administration induced a remarkable premature cardiac deterioration in young mice, closely mimicking that of aged mice and leading to cellular senescence in vitro. They identified hepatic phenylalanine catabolism to decline with age in a p21 dependent manner, while demonstrating that p21 deficiency prevented age related cardiac dysfunction. Administration of phenylalanine hydroxylase cofactor BH4 or dietary phenylalanine restriction, both abrogated the age related rise in the plasma levels and reversed age associated cardiac alterations. This study really identifies phenylalanine and its hydroxylase modulation as a potential therapeutic strategy to promote cardiac health and prevent age related cardiac impairment. Amazing, isn't it? Dr. Greg Hundley: Yeah, Carolyn. Really interesting about phenylalanine and while it may impact cardiovascular health and the aging process. Dr. Greg Hundley: Well, I know we've got some other articles in this issue, so how about I'll go and dip into the mailbag first? The first is from Professors Wong and Finn and they're exchanging letters regarding the prior publication entitled, Microthrombi as a Major Cause of Cardiac Injury in COVID-19 and it's a pathologic study. There's a nice Research Letter from Dr. Zhu entitled, “Catheter Based Adrenal Ablation Remits Primary Aldosteronism: A Randomized Medication Control Trial.” There's a Perspective piece from Dr. Stehlik entitled, “The Long and Winding Road to an Effective Left Ventricular Assist Device: The Demise of Medtronic's HVAD.” And then finally a report from Dr. Mehta and colleagues, really Carolyn, thinking about clinicians' wellbeing and addressing global needs for improvements in the healthcare field. And it's a Joint Opinion representing the American College of Cardiology, the American Heart Association, the European Society of Cardiology and the World Heart Federation. Really a nice report on really addressing physician stress in the workplace. Dr. Carolyn Lam: Nice. Well, there's also an ECG Challenge by Dr. Shi entitled, “An Acutely Breathless Patient with Inferior St-Segment Elevation: A Diagnostic Trap.” In Cardiology News, Bridget Kuehn describe studies detailing heart risks for firefighters. Wow, what an interesting issue, but let's go on now to the feature discussion shall we, Greg? Dr. Greg Hundley: You bet. Dr. Greg Hundley: Welcome listeners to our feature discussion. And today we have with us Dr. Gabriel Steg from Paris, France, Universite de Paris. And also Dr. Gregg Stone, an editorialist from Mount Sinai in New York. Welcome gentlemen. And Gabriel, we'll start with you first. Could you describe for us some of the background related to your study and what was the hypothesis that you wanted to test? Dr. Gabriel Steg: Thank you, Greg. As you know, there have been tremendous changes in cardiology over the past 25 years with the advent of effective anti-anginal therapy, with the advent of myocardial revascularization and the dramatic changes produced by widespread availability of percutaneous coronary intervention and finally the availability of evidence based secondary prevention therapies. And there has been really a sea change in the presentation and treatment, management and outcomes of patients with coronary artery disease. And when we started off, we asked ourselves, is angina pectoris really prognostic in patients with stable coronary artery disease? Is the symptom of angina really prognostic? That was the question we tried to address. Dr. Greg Hundley: And Gabriel, what was your study population and your study design? Dr. Gabriel Steg: It was a very simple descriptive design. We use a large international registry of patients with stable coronary artery disease called the CLARIFY registry, which enrolled almost 35,000 patients with stable coronary artery disease and followed them up for five years. Now, how was stable coronary artery disease defined? It was defined as any of the following conditions, a prior MI, more than three months before enrollment, a prior PCI or a CBG, angina pectoris was a demonstration of myocardial ischemia on noninvasive stress testing or finally the presence of a fixed stenosis of the coronary arteries on an angiogram. And you could get any of these criteria. Of course you could have more than one at the same time. And the design was to describe the anginal status at baseline and every year based on investigator reports, not a formal angina questionnaire, as there are several, including the Seattle angina questionnaire. We had a very simple assessment of angina and angina severity based on presence or absence and then Canadian class of angina. Dr. Greg Hundley: Did you follow these individuals too? Did they experience specific events? Dr. Gabriel Steg: Yes. We collected all the cardiovascular hospitalizations events, revascularizations. We followed the medications and we collected the biological results, although there was no core lab but we collected the results of the tests that were done. We essentially aimed was that registry to describe the population, their management and their outcomes over five years. And this is over 40 plus countries. And fortunately does not include any patient from the United States but has a substantial contribution from Canada and Mexico. Dr. Greg Hundley: Very nice. And so what did you find, Gabriel? Dr. Gabriel Steg: Well, the first observation is the prevalence of angina at baseline and it's 22%. We found that in a patient population selected for having stable coronary artery disease, approximately a fifth to a quarter will have anginal symptoms. I don't think that's a major surprise but what was a big surprise to us is that angina resolved very, very substantially, 40% of the patients who had angina at baseline had no longer angina by one year. And what was even more surprising is what caused the resolution of angina. And it was rarely changes in anginal medications, rarely revascularization. It was largely spontaneous. Almost 80% of the patients had spontaneous resolution of angina. And so, yes, it's been known that angina can regress but we did not expect that it would regress that often and that much spontaneously without intervention or need for increasing medications. Dr. Gabriel Steg: And the other aspect is then we looked at what happened for those patients who had angina resolution at one year and what were the subsequent outcomes? And we found they were indistinguishable from those who had no angina at baseline. And then we looked at those patients who had persistent angina at one year or occurrence of angina at one year, despite not having angina at baseline. And again, we found that having angina at one year was detrimental to the longterm prognosis. It's really good that you either not have angina or that your angina resolve. That's really important. Dr. Greg Hundley: Did you find any differences, Gabriel, between men and women? Dr. Gabriel Steg: No. We looked at a variety of subgroups. We looked by criteria for enrollment. We looked across geographic locales. We looked according to the presence or absence of diabetes and sex and other variables and there were really no major differences. The results were remarkably consistent. Dr. Greg Hundley: Very nice. Well listeners, one of the advantages of some of the publications that we pursue at Circulation is the ability to bring in an editorialist. And with us today, we have Dr. Gregg Stone from Mount Sinai in New York. And Gregg, we want to turn to you. How do we put the results of this study in perspective with other studies that have been involved in this sphere of research? Dr. Gregg Stone: Well, thank you, Greg. First off, I'd like to congratulate Gabriel and his colleagues for a tremendous study and thank you and Circulation for offering David Waters and I, the chance to provide our perspectives. I think this study raises a lot of important issues. Angina is kind of like the common cold to cardiologists. We're always dealing with it but it can be very difficult to diagnose. There's typical angina, atypical angina, anginal equivalent disease, non-anginal chest pain, et cetera. And we've learned in the last several years or decade that the etiology of angina can be very complex. It's not just epicardial coronary disease. There can be microvascular disease, macro or microvascular spasm and other causes. I think that we have to, when we're thinking of angina, we have to try to understand the mechanism and know whether or not it's really due to at least epicardial coronary artery disease, which is the type of disease that may respond to revascularization. Dr. Gregg Stone: In this regard, both David and I were struck with the fact that the CLARIFY even though a very large population, is a very mature population of patients with coronary disease, who I believe were diagnosed at least approximately seven years ago, most had undergone a prior revascularization therapy, about 50% ahead of myocardial infarct and the minority interestingly had inducible ischemia. We wondered is this real angina? Is this true angina that these patients are having? Because they've been effectively revascularized. In contrast, I was one of the co-principal investigators of the ISCHEMIA trial, which was a very different population because we took only with exercise induced moderate or severe ischemia. And while we excluded most patients with class three or four angina because we know those patients basically don't tolerate medical therapy without frequent crossovers. We found that in our trial, angina was more persistent and was substantially reduced by revascularization, by an interventional approach. Much more so than in the medical therapy arm. I think that it really does depend on the patient population and the likelihood of which the angina is due to true inducible ischemia that may respond to a revascularization approach. Dr. Greg Hundley: Very nice. And so Gabriel, want to turn back to you, what do you think is the next study that really needs to be performed in this space? Dr. Gabriel Steg: Well, I think it's really in line with Dr. Stone's comments. I think that what we need to do is to have a much more formal prospective assessment of a broader population of patients with angina using formalized questionnaire, such as the Seattle angina questionnaire, which allow a much better and thorough characterization of the presence, type and severity of symptoms and to look across the whole spectrum of patients with and without myocardial ischemia and look at the prognostic importance of the symptoms. I think that teasing out the relationship between the anginal symptoms, their severity, myocardial ischemia and outcomes is really critical to our interpretation of the series of recent trials, the last of which being ISCHEMIA, which have revolutionized our thinking regarding management of coronary artery disease. And we're still somewhat in the dark as to how to incorporate that information relative to the symptoms and outcomes of our patients. And I think we still have a lot of work to do in that respect. Dr. Greg Hundley: Very Good. And Gregg, do you have anything to add to that? Dr. Gregg Stone: Yeah. I would certainly echo Gabriel's comments. In addition, I think we have to think of angina as a collection of different diseases. And we have to do a better job at trying to understand the mechanisms underlying angina. First, we have to be able to determine whether it's really cardiac in origin versus non-cardiac. And then second, we have to understand again, whether it's coming from epicardial coronary disease, microvascular disease or other mechanisms. We've just been struck in even many of our simple stent studies, how often patients redevelop angina after treatment with no re-stenosis whatsoever, suggesting that many of them may have other etiologies of angina. I think these studies to me are very important because they really highlight, yes how much we've learned but how much more work there still is to do for us to be able to effectively diagnose and treat these patients. Dr. Greg Hundley: Well listeners, we want to thank both Dr. Gabriel Steg, the author of this paper and also Dr. Gregg Stone, who provided his editorial expertise, in bringing us information from these 32,000 plus individuals from the CLARIFY registry, of patients with stable coronary artery disease and helping us answer really two questions regarding the presence of angina. One, both that angina may resolve spontaneously and then second, persistent angina is associated with future cardiovascular events. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, I want to thank our speakers and then also wish everyone a great week and we will catch you next week on the run. Dr. Greg Hundley: This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more, visit ahajournals.org.  

In our little mini-series on MTHFR and neurotransmitters, we'll move on to discuss the relationship between MTHFR and dopamine. We'll talk about: The unlikely first symptoms you might see of low dopamine levels Why banana smoothies might help with dopamine related weight gain (like after you quit smoking) The issue with dopamine receptors And how to boost your levels without drugs. For the complete show notes including links to related concepts (like our post on serotonin, or the BH4 connection) you can click here. If you can't wait to join the MTHFR community, Genetic Rockstars, or take an MTHFR 101 course, click here. Thanks for listening! Don't forget to subscribe or leave a review so other people can find great information to help them on their MTHFR journey a little bit more easily. --- Send in a voice message: https://anchor.fm/tohealthwiththat/message

MTHFR is tangled up with neurotransmitters via its direct link with the BH4 pathway, which is where most neurotransmitters are made. So let's talk about MTHFR and serotonin. This week we'll go over: The surprisingly mixed evidence with serotonin and depression. The first thing you should do to boost serotonin with MTHFR. Low serotonin symptoms you might never think of. Some amazing serotonin boosters that are all natural. Thanks for listening today and if you'd like the complete show notes with links to resources, they're here. Also, if you want to be a Genetic Rockstar too, click here. --- Send in a voice message: https://anchor.fm/tohealthwiththat/message

This month on Episode 22 of the Discover CircRes podcast, host Cindy St. Hilaire highlights four featured articles from the March 5 and March 19 issues of Circulation Research. This episode also features an in-depth conversation with Norberto Gonzalez-Juarbe and Maryann Platt from the J. Craig Venter Institute to discuss their study, Influenza Causes MLKL-Driven Cardiac Proteome Remodeling During Convalescence.   Article highlights:   Carnicer, et al. BH4 Prevents and Reverses Diabetic LV Dysfunction   Kyryachenko, et al. Regulatory Profiles of Mitral Valve   Mangner, et al. Heart Failure Associated Diaphragm Dysfunction   Peper, et al. Identification of McT1 as Caveolin3 Interactor       Dr Cindy St. Hilaire:        Hi, and welcome to Discover CircRes: the podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Dr Cindy St Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh. Today I will be highlighting four articles selected from our March 5th and March 19th issues of Circ Res. After the highlights Drs Norberto Gonzalez-Juarbe and Maryann Platt from the J. Craig Venter Institute are here to discuss their study, Influenza Causes MLKL-Driven Cardiac Proteome Remodeling During Convalescence Dr Cindy St. Hilaire:        The first article I want to share is titled, BH4 Increases nNOS Activity and Preserves Left Ventricular Function in Diabetes. The first author is Ricardo Carnicer, who is also corresponding author alongside Barbara Casadei and they're from University of Oxford in the UK. Cardiomyopathy and heart failure are common complications of diabetes, but the molecular pathology underlying this cardiac dysfunction is not entirely clear. Increased oxidative stress and reduced functioning of both mitochondria and nitric oxide synthase or nNOS have been implicated in diabetic cardiomyopathy. Tetrahydrobiopterin or BH4 is a co-factor necessary for nNOS activity. Dr Cindy St. Hilaire:        And in diabetic patients and animals oxidation of BH4 inactivates nNOS and induces vascular endothelial pathology. But, what happens in the cardiac tissue itself? This group shows that although boosting BH4 levels by genetic or pharmacological means prevented or reversed heart dysfunction in diabetic mice, the status of BH4 oxidation and nNOS function in the heart tissue of diabetic patients and mice, did not actually differ significantly from that of healthy controls. Instead through molecular analysis, they revealed that in diabetic mouse cardiomyocytes boosting BH4 promoted a nNOS dependent increase in glucose uptake, which then preserved the cell’s mitochondrial function. Regardless of the pathways involved, the fact that BH4 reversed diabetic associated cardiac dysfunction in mice suggests the potential for therapies that could be used to lower the risks of such complications in humans as well. Dr Cindy St. Hilaire:        The second article I want to share is titled, Chromatin Accessibility of Human Mitral Valves and Functional Assessment of MVP Risk Loci. The first authors are Sergiy Kyryachenko, Adrien Georges, and Mengyao Yu, and the corresponding author is Nabila Bouatia-Naji from Paris Cardiovascular Research Institute in France. The mitral valve opens and closes to direct a one-way flow of blood from the left atrium to the ventricle. If the mitral valve fails, as in the case of mitral valve prolapse or MVP, blood regurgitation, cardiac arrhythmia, and ultimately heart failure can occur. Dr Cindy St. Hilaire:        With 11 valves from MVP patients and 7 control patients, this group used a highly sensitive chromatin profiling technique called ATAC-Seq to identify regions of the genome with increased accessibility, which indicates transcriptional activity. They found that while diseased and healthy valves had similar chromatin profiles, they differed from those of other heart tissues. Valve specific open chromatin regions were enriched in binding sites for NFATC, a transcription factor known to regulate valve formation. And, specifically in MVP tissues, they found two potential causative sequence variants. These MVP-linked variants exhibited enhancer activity in cultured cells. And for one variant, the team identified the gene target of this variant. In providing the first mitral valve cell chromatin profiles and demonstrating their use and functional analysis of MVP-linked variants, this work supplies a valuable research for mitral valve prolapse evological studies. Dr Cindy St. Hilaire:        The third article I want to share is titled, Molecular Mechanisms of Diaphragm Myopathy in Humans with Severe Heart Failure. The first author is Norman Mangner, and the co-senior authors are Axel Linke and Volker Adams from Dresden University of Technology in Germany. The diaphragm is the primary muscle controlling a person's breathing. This muscle can become weakened during heart failure, which exacerbates symptoms and increases the risk of death. The pathological mechanisms underlying the diaphragm's demise are largely unclear. Studies in animals have pointed to increase reactive oxygen species as a contributing factor, but human studies have been limited. This group evaluated the histological and molecular features of human diaphragm biopsies from both heart failure patients and controls. Dr Cindy St. Hilaire:        The diaphragm samples were collected from 18 heart failure patients, who were undergoing implantation of left ventricular assist devices. And 21 control samples were obtained from patients not having heart failure bypass graft surgery. Compared with the controls, the heart failure diaphragms showed significantly reduced thickness, severe muscle fiber atrophy, increased oxidative stress in the form of protein oxidation, increased proteolysis, impaired calcium handling and mitochondrial abnormalities and dysfunction. Pathological measures also correlated with clinical severity. These data are the first insights into the pathology of heart failure related diaphragm weakness, and this work points to the molecular players that could be targeted for novel treatments. Dr Cindy St. Hilaire:        The last article I want to share before our interview is titled, Caveolin3 Stabilizes McT1-Mediated Lactate/Proton Transport in Cardiomyocytes. The first author is Jonas Peper and the corresponding author is Stephan Lehnart from the Heart Research Center, Göttingen in Germany. Caveolae are invaginations of the plasma membrane, and these structures are involved in endocytosis, signal transduction and other important cellular processes. Caveolin is the key protein component of caveolae and isoforms of Caveolin have been implicated in heart conditions. Mice lacking the isoform CAV1 develop heart failure and genome-wide association studies have been linked to human CAV1 variants with cardiac conduction disease and atrial fibrillation. Rare variants of CAV3 are known to cause hypertrophic cardiomyopathy. However, little is known about the normal or pathological actions of Caveolin in heart cells where caveolae are plentiful. To learn more, this group performed mass spectrometry, immunoprecipitation, and other analysis in cardiomyocyte, and uncovered novel CAV associated proteins, some of which turned out to be isoform specific. Dr Cindy St. Hilaire:        CAV1 interacted specifically with aquaporin while CAV3 was associated specifically with the lactate transporting McT1 protein and the iron transporting TFr1 protein. When the team knocked out the function of CAV3 in stem cells derived from human cardiomyocytes, they found that McT1 had reduced surface expression and function, and that the cells exhibited abnormal de-polarizations. Together the results set the stage for future studies of cardiomyocyte CAV biology, including how CAV variants might contribute to disease pathogenesis. Dr Cindy St. Hilaire:        Today I have with me Drs Norberto Gonzalez-Juarbe and Maryann Platt from the J. Craig Venter Institute, and they're here to discuss their study, Influenza Causes MLKL-Driven Cardiac Proteome Remodeling During Convalescence . And this is in our March 5th issue of Circulation Research. So thank you both for being with me today. Dr Maryann Platt:           Great to be here. Dr Norberto Gonzalez-Juarbe:    Thank you. Dr Cindy St. Hilaire:        So I want to start with influenza mediated cardiac complications. So what are these complications? How prevalent are they in people who catch influenza and who's most affected? Dr Norberto Gonzalez-Juarbe:    So for the last hundred years, we have known that every time there's an epidemic or pandemic from influenza, there's adverse cardiac events that come after you get the disease. During the 1918 pandemic, we could see myocardial damage and about 90% of all people that succumb to the infection, and in the latest epidemics that has been about 40% to 50%, suggesting that the more pandemic the strain of influenza is, the more virulent, the more of these adverse cardiac events we are going to see. So it seems that it is attached to severity of disease. The virus can get to the heart easy, the more severe your disease phenotype is, but it seems that some pandemic strains have a better way to get there of causing more damage than the common epidemic strengths. Dr Cindy St. Hilaire:        That was actually one of my other questions, how does it get to the heart? What's happening there? Do we know much about that? I guess, specifically for flu, but I'm sure in the back of everybody's mind, people are also thinking about SARS-CoV2 too. So how does that kind of pathway work or transportation work? Dr Norberto Gonzalez-Juarbe:    Circulation is going to be the main way it gets there for, for example, if we were to look at COVID then in the heart there's the same receptors for the epithelial cells that are in there, the ACE-2 receptor, that's also in the cardiac tissue and COVID-19 can actually infect cardiomyocytes through that receptor. In terms of influenza, it's basically similar. Some of these receptors are present on the epithelium in the lungs, are also present there and flu can actually infect cardiomyocytes. In our study we also look at some other cell types like endothelial cells and fibroblasts, and we show that there's actually some lower grade infection too. But that's why it's all of these, it starts in the severity of disease, that's the more virus is going to be in your bloodstream, the easier it's going to be to get there. And since the same receptors are present in the heart, so it's going to be easy for the virus to affect the cell. Dr Maryann Platt:           It's not necessarily dependent on age or race or anything it's dependent on how sick you are, for sure. Dr Cindy St. Hilaire:        And by sick, does that directly correlate with viral load of the patients or just their response, an overactive response or something like that? Do we know? Dr Norberto Gonzalez-Juarbe:    I think it's a double edged sword, so it's going to be related to viral load, but also the type of immune responses that you're going to be having, it's going to affect the role of the virus in their heart. In our case we studied way after you cleared the proof from the lungs. So most of the studies that have been out there for a while show, when you're really, really sick, what is happening, but that of your compounding because you have all of these immune responses happening, and the virus is doing its thing. But once you clear the virus from the lungs, your, kind of, immune system settles down. And in our study, we show that even if you clear it from the lungs, the virus is still present in the heart. Dr Cindy St. Hilaire:        So one of the mechanisms that you focused on in terms of how influenza was contributing or leading to cardiac complications, is this process called necroptosis? Can you just maybe give us a primer on what that is, and what it's doing specifically in the cardiomyocytes? Dr Maryann Platt:           Sure. So necroptosis, there's a couple of different ways that cells can die, either under normal circumstances, just maintaining the number of cells in your body or in the case of infection, trying to get rid of the infection. So most commonly, cells will undergo apoptosis, which is programmed cell death, not very inflammatory. And then necroptosis is another way that is highly inflammatory and driven by, initiated by, some of the same molecular cascades, but then affected by a different set of molecules. Dr Cindy St. Hilaire:        Interesting. And so it's really that inflammatory component that is driving pathogenesis in the cardiac tissue then. Dr Maryann Platt:           Yeah. Dr Norberto Gonzalez-Juarbe:    And evolutionarily necroptosis has been shown to help the host against viral infections. Specifically, influenza has proteins that can block apoptosis, which is kind of like the good way of dying. And then the cell has to undergo these other necrotic type of cell death to get rid of viral replication. But while some of these might interact with both pathways, necroptosis effect their molecule. MLKL is the last protein in the pathway. That's the one that actually rupture the cells. So we wanted to prevent that from happening to see if we can actually stimulate something protective by having all of the other good cascade-type molecules still there. Dr Cindy St. Hilaire:        ‘Good’in quotes (laughing). Dr Maryann Platt:           Still dying cells, less bad, not as inflammatory Dr Norberto Gonzalez-Juarbe:    Inflammatory since the heart is this type of organ that any injury will be, more or less, long lasting, and that will have detrimental effects throughout life. Dr Cindy St. Hilaire:        Got it. That's interesting. So can you maybe give us a summary of your experimental design and kind of the groups you were looking at, and a summary of the results? Dr Maryann Platt:           Sure. So we had four different groups of mice, two of them were wild type mice and two were MLKL, all knockout mice, which could not undergo necroptosis. And then each of those genotypes, we had uninfected mice or mice that were infected with flu. And then we monitored long viral titer to see how much infection was there at the lungs. And then after the infections subsided in the lungs, two days after a viral load was undetectable, we sacrificed those animals, collected their hearts. Dr Cindy St. Hilaire:        That's great. So that two day resolution, is that a similar time course with humans, in terms of a pathogenesis of developing cardiac complications? How similar, I mean, mice are never perfect models, but what's good and what's not good about using a mouse as for this model? Dr Norberto Gonzalez-Juarbe:    So, mice are not human right?. So, we are always thinking about that quote, but most of the cardiac events that occurred during these type of infections and similar things have been observed in, for example, pneumococcal infection, which is by streptococcus pneumonia. Most of these adverse cardiac events occur right after you leave the hospital. Those are a specific set of adverse cardiac events that are different from the ones that happen when you are severely infected in the hospital. And these can be arrhythmias and myocardial infarction, and some of these things that can happen up to 10 years after you recover from the pulmonary infection. Dr Norberto Gonzalez-Juarbe:    So our model was designed to see that step of the host trying to retcover. And if there was still something there in the heart, right after you get out of the hospital, that you receive your therapeutics, and you're thinking, 'Oh, I don't have any more flu in my lungs, and I'm recovering', that timeframe right after you get out, you might still have some other things happening in your body, that might determine what happens to your heart. Dr Cindy St. Hilaire:        Interesting. So you may actually be feeling pretty good, but your heart or even possibly other organs are still kind of under the weather, so to speak? Dr Norberto Gonzalez-Juarbe:    Exactly. Dr Maryann Platt:           Exactly. Dr Cindy St. Hilaire:        So in your proteomic analysis, I think you stated it was some, it was just under a hundred proteins were differentially regulated, and a majority were actually in kind of metabolic mitochondrial related pathways. Could you maybe tell us the importance about that? But then also, yes, that was a big chunk of it, but were there any other pathways that were either up or down, that were surprising in your findings? Dr Norberto Gonzalez-Juarbe:    The importance of the major mitochondrial proteins that we found, first that the MLKL knockout, so inhibiting these necrotic cell death actually promoted mitochondrial health. So that first was interesting, because that will suggest that this can be quite therapeutic target in the future. That innovation enhance some proteins that protect the mitochondria and aid in mitochondrial function. And if we think about the heart as our engine, we need energy for an engine to work and mitochondria is that energy resource that we have. And the heart is really relying on these, because if you have a metabolic breakdown in the heart, you get cardiac event. So most of the proteins that were changed upon infection had to do with these specific, important metabolic function of the heart. Some other proteins have to do with cellular signaling mechanisms and calcium homeostasis, all these other things that are important to maintaining homeostasis in the heart thus suggesting that the virus is inducing massive stress in their heart without actively replicating or causing inflammation. Dr Norberto Gonzalez-Juarbe:    And that was very important in our study that we didn’t see these antiviral effects, but at the same time, we saw all of these detrimental metabolic effects. So future studies might be also targeting what viral factors might be actually inducing these metabolic effects in the heart. But we also saw some molecules important for cell death mechanisms that were not necroptosis. Dr Norberto Gonzalez-Juarbe:    Marianne, you can describe some of those. Dr Maryann Platt:           So one third way that cells can die is called pyroptosis. And we actually saw that pyroptosis was also elevated in flu infected mice, in their hearts, suggesting that it might not just be necroptosis. All this inflammation coming from necroptosis is what's driving breakdown of heart function, but also possibly pyroptosis. Dr Cindy St. Hilaire:        The mitochondrial aspect is interesting. In heart failure normally there's the switch from fatty acid oxidation to glycolysis. Does that happen in a shorter or smaller way after flu? And in some patients they just don't recover? Is there a metabolic switch to an infected cardiomyocyte, that is more transient, and then in a subset it turns to permanent? Is that what's happening? Dr Norberto Gonzalez-Juarbe:    Yeah, that is something that we might need to follow up on, since our study was more of a snapshot of that specific time point. It will be good to do follow-up studies where we look at different time points post infection. And even maybe three months after infection, then six months after infection. We have done similar studies with pneumococcal pneumonia, and we have found that cardiac function and metabolic function, it is significantly remodeled, even three months after the pneumonia event. Dr Cindy St. Hilaire:        Interesting. So once it's actually cleared from the lungs, it's still… Dr Norberto Gonzalez-Juarbe:    The heart is still undergoing this injury recovery, which cause scarring process and these leads to reduced cardiac function. Dr Cindy St. Hilaire: So influenza actually, maybe a lot of people know this now, but it was somewhat new to me, I guess, at least a year ago when COVID first started. But influenza like SARS-CoV2 is an enveloped virus. It's a single strand RNA virus. So are these findings specific to this class of viruses, specific to RNA viruses? Or is this something that you think is operative in other types of viruses in terms of causing these cardiac complications? Dr Maryann Platt:           It's certainly possible. I'm not a virologist. (laughs). Dr Cindy St. Hilaire:        Not yet. (laughs). Dr Norberto Gonzalez-Juarbe:    Eventually you'll get there. Dr Maryann Platt:           Yeah, eventually probably. But you know, there have been reports of lots of adverse cardiac events in SARS-CoV too. So it's certainly not just unique to influenza, as far as other types of double stranded RNA viruses. I'm not sure. Dr Norberto Gonzalez-Juarbe:    Yeah, of course Coxsackieviruses viruses have shown inductionof cardiac events. And there's a Review in the New England Journal of Medicine about some of these other pneumonia causing agents, but also all other pathogens that can do some of these events, but it's all clinical observations. So, we think that our study and several others studies that are starting to come out, can induce a shift part of field to look at how some of these major respiratory viruses can induce these adverse cardiac events that we see are highly prevalent, right after the event, like during infection. And importantly, how all the pathogens may synergize. Some pathogens such as RSB, flu, COVID, have synergized with bacteria or other virus one enhancing the ability of the other to cause injury and disease. Dr Norberto Gonzalez-Juarbe:    For example, flu with pneumococcal disease, COVID with assorted grand negative pathogens, and actually influenza also has been shown to cause co-infection. So we don't know how some of these pathogens may synergize in the lungs, but also in other organs, to cause these injury that are going to be long lasting. So we are having the acute problem now with COVID and we had this with the 2009 pandemic flu, but in the next 10 years, five years, we're going to see this equivalent of disease damage, the damage associated with the disease, and we are going to have to explain why people are having these cardiac events, why people are having kidney events or liver damage problem. So we need to better understand not only how RNA viruses do this, and there's actually data shows that COVID is present in the cardiac tissue and can replicate in cardiac cells, but also how they may synergize to potentiate these effects. And how can we prevent all of these from happening? By action, therapies to antivirals, or any other way. Dr Cindy St. Hilaire:        That's a perfect segue to my last question I had. And that is, how can, what you found in the study regarding necroptosis, or even just the base proteins that are involved, is it able to be leveraged either for the development of therapies or perhaps even like a screening method, a biomarker to determine which flu patients might go on to develop cardiac phenotypes? Dr Norberto Gonzalez-Juarbe:    There might be a couple of avenues our study can help create these adjunct therapeutics to anti-virals. So one might be targeting the specific necrotic cell pathways to prevent that titrating that is long-lasting and these can be targeting necroptosis or pyroptosis, and there's FDA approved drugs that we may be able to repurpose to target some of these pathways that have these secondary effects, that can target these pathways. But also the very interesting part for me was that MLKL lesion increased this protein called NNT, which is a major factor of mitochondrial function and ATP production. So if we can improve the ability of the heart function and to protect their mitochondria, then we probably can have more roughly protective response against not only flu, but maybe COVID or other viruses that might also do similar things to the heart. Dr Cindy St. Hilaire:         Or even just other heart failures. That's pretty neat. Dr Norberto Gonzalez-Juarbe:    Exactly. Dr Maryann Platt:           Yeah, exactly. Dr Cindy St. Hilaire:        That's great. Drs Gonzalez-Juarbe and Platt. Thank you so much for joining me today. Congratulations on an excellent study and I'm really looking forward to your future, probably viral related, work. Dr Norberto Gonzalez-Juarbe:    Thank you very much. Dr Maryann Platt:           Thanks. Dr Cindy St. Hilaire:        That's it for our highlights from the March 5th and 19th issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes and Circ. Thank you to our guests, Drs Norberto Gonzalez-Juarbe and Maryann Platt. The podcast is produced by Rebecca McTavish and Ashara Ratnayaka, edited by Melissa Stoner, and supported by the Editorial Team of Circulation Research. Some of the copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire and this is Discover CircRes, your on-the-go source for the most exciting discoveries in basic cardiovascular research.  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.29.226308v1?rss=1 Authors: Joel, I. y., Adigun, T. O., AJIBOLA, A. O., BANKOLE, O. O., OZOJIOFOR, U. O., REMI-ESAN, I. A., SULAIMON, L. A. Abstract: Evading apoptosis is one of the hallmarks of cancer cells, therefore a lot of therapeutic strategies have been developed to induce cell death in these cells. BCL2 family protein governs the intrinsic pathway of cell death. The BCL2 family protein possess both pro and anti-apoptosis members. BCL2 protein, a pioneering member of the anti-apoptosis protein has been implicated in several cancerous cells; with dozens of small-molecule inhibitors developed to inhibit its activity. BCL2 family protein processes BH domains (1-4) for heterodimerization and homodimerization amidst it family members and targeting the BH4 domain is an established new strategy for cancer therapy; however, only BDA366 has been reported so far as a BH4 binding molecule. Using Computer-aided drug discovery techniques (Molecular docking, QM-polarized docking, Induced-fit docking, QM-MM optimization, and QM electronic descriptors) we screened M sample (~ 99,000 compounds) of the SCUBIDOO database to find ligands that interact with the BH4 domain of BCL2 protein with high affinity, we identified 11 putative BH4 specific small molecules with binding affinity ranging from ~ -84kcal/mol to -64kcal/mol with a putative binding hypothesis with BH4 amino acid residues: ASP10, ARG12, GLU13, MET16, LYS17, and HIS20 Copy rights belong to original authors. Visit the link for more info

For our Hebrew Bibles we have three main groups of manuscripts to compare: the Masoretic Text group, the Samaritan Pentateuch group, and the Septuagint group.  Each of these groups contain many manuscripts with the Masoretic Text group containing the most.  In this episode of How We Got the Bible, we’re going to look at the Read more about 333 Bible 4 – Determining the Best Hebrew Reading[…]

For our Hebrew Bibles we have three main groups of manuscripts to compare: the Masoretic Text group, the Samaritan Pentateuch group, and the Septuagint group.  Each of these groups contain many manuscripts with the Masoretic Text group containing the most.  In this episode of How We Got the Bible, we’re going to look at the Read more about 333 Bible 4 – Determining the Best Hebrew Reading[…]

Remember, I am a real doctor Eric is a real crna. We do do real medicine. But this show is not intended to diagnose or treat. Please, if you have any issues like rectal bleeding, go to our website, kbmdhealth.com. Download the E book, learn about it, but make sure that you talk to your doctor about it.Ken Brown   All right, here we are with the gut check project, Episode 29 a super special episode because we have a guest co host, Eric Rieger was unavailable. And so we had a guest co host today it is Dr. Doug Won, who's here. Welcome to the studio, my friend.Dr. Won  Thank you so much for having me here. Truly an honor.Ken Brown  Well, I think that this is gonna be a really really cool show. You're doing A lot of functional things you're really big into treating the whole person. Your background, I think is really cool. I am gonna warn you though. I hope you're a pretty smart guy because Eric's a smart guy. You got some big shoes to fill in. So why don't we at least find out like if you're, you know, like where you actually came from and everything. Tell us a little bit about yourself?Dr. Won  Sure. I'm from South Korea, immigrated to Irving, Texas when I was 11 years old and went to elementary, middle school and high school in Irving MacArthur High School, go Cardinals. And then after that, I went to Northwestern University. I majored in biology and biomedical engineering, and then went to medical school at utmb in Galveston, and once I was done with the medical school, pursued orthopedic surgery at Washington University in St. Louis, and did spine surgery fellowship in Michigan, and then came right back to Irving, Texas, to treat my friends and family members and my local community and Irving, the city that I love, I went back to it and been there ever since.Ken Brown  Yeah, you're way smarter than Eric. Yeah. Of course right now he's probably arguing I didn't hear anything about Texas Tech. So you know, so in his mind, you didn't go to Texas Tech. You're not nearly as smart. But I guess you did say a few other things Northwestern, double major biology, biomedical engineering and everything. So, yeah, I think that I think the show is going to be really great. What I want to do with this show today, you have you and I have very similar passions. We're really big into the functional medicine side of things. I want to cover some anti aging stuff. I want to talk about how supplements and nutrients can actually augment a lot of these different things that talk about your past. Now. You are one of the most accomplished orthopedic spine surgeons and I can I have to pick your brain before we even jump in. I was actually talking to a very difficult patient of mine and I wanted to throw out a disease and just see if you've ever dealt with any of this. I believe That we have somebody who is smoldering into ankylosing spondylitis. Now this actually happened to one of our co workers, but now I'm treating somebody who's acting a lot like she did. She spent about two years just sort of, you knew something wasn't right. And then pow it just kind of all popped up. Have you had some experience with autoimmune diseases and stuff like that specifically as ankylosing spondylitis?Dr. Won  Yeah, absolutely. In our spine clinic, we used to see a lot of patients with ankylosing spondylitis. And then also patients who didn't quite have the the conditions, but they were HLA 27 positive, and they were brewing the different types of symptoms and conditions. And then we also deal with because I also deal with lifestyle medicine. We've actually seen a lot of different kinds of patients with autoimmune disease. And what we usually tell patients is that your genetics and genes may load the gun, but you actually pulled the trigger through your nutrition and lifestyle.Ken Brown  i like how you say that. Yeah, totally. So one of the things I just want to get this out of the way that you You're a very accomplished orthopedic surgeon. You're currently involved a little bit of a legal situation that you're appealing. What I think is amazing what you have done is because you have to put your surgical practice on hold for a little bit. Yes, you have shifted, and have still taken on the role of being a doctor, helping people and being an educator, you have not slowed down at all, you are the embodiment of resilience of moving through. I'm super, I think that's really, really neat. And why did you decide to kind of shift gears, I mean, you were going from scalpel. And I get that you have to take a little break from that. But a lot of people like you would just say, I'll use this as a break to go tour the world and say hi to things and you went I'm gonna use this as my opportunity to help more people.Dr. Won  Thank you. You know, helping people and making a big impact was my passion. That is a reason why I went into medicine and went into medicine because you know, my father suffered from back and he had four back surgeries, and his life was ruined for about 30 years with severe pain and in life You come up with so many different challenges. Either you can crumble or or decide to just sit back, and then the life continue to punch you, or you can stand back, you know, stand up again, and continue to move on forward. And what got me going was as long as I can make an impact and help all the patients, and my passion was biohacking, which I've been doing, you know, all my life. And what I realized was that in medical school, we really didn't learn how to cure the disease. We learned to manage the disease. And through this experience, I really learned how to better manage and then in many incidences, and cure the patients, and wanted to continue to make an impact and help patients. That's what gets me going and that's what's getting me up every single morning. And no matter what anybody says, as long as I feel good about you know what I'm doing and continue to practice medicine in different way. Through health coaching, and, you know, even approaching and these days, I also teach a lot of doctors in Africa. How to treat chronic disease.Dr. Won  You teach doctors in Africa?Dr. Won  Yes. Ken Brown  Okay. I got a segway out of that for a second. What? Tell me about that? Dr. Won  Yeah, so I came in contact with a physician who was really into preventive medicine. He's a personal doctor to the president of Cameroon. In Africa right now, they're facing so many different chronic disease. In the past, before the Africa became developed, there was no such thing as heart disease, cancer, diabetes, or obesity. But as the countries are becoming wealthier, and countries are becoming more developed, they're now importing American disease such as heart disease, diabetes, cancer, Alzheimer's, and they obviously can't afford to treat the patients with American medicine. So they're looking for ways to treat the patients naturally, and also the citizens most of the people in Africa are still hesitant about Modern medicine. So we got in contact through a mutual friend. And we decided to teach the the physicians there, how to reverse the disease naturally. And then also importantly, to prevent them.Ken Brown  Wow and so are you doing some sort of zoom with them? Do you have a lecture series? How are you doing this? Dr. Won  Yeah. So every Saturday morning, I connect through them through zoom meeting. Thank goodness for technology. I don't have to physically be in Africa. I would love to visit the continent, sometime soon. When things free up, but utilizing the technology, we provide the lectures, mostly to physicians, but also just about anyone who's interested. And we open it up to the whole community. And at one point, we had people from seven different countries connecting seven different countries in Africa.Ken Brown  Oh, wow. That is that is fantastic. So even before you had to kind of take this little hiatus from actually cutting on people and doing spine surgery, you've been thinking about this for a long time. You've been working towards the changing, changing the disease progress, you made a living for many years taking care of the end problem of people having wearing their bodies down, then you as the spine surgeon go in, and you take away their pain and you help them. But even then you were thinking, and what can we do to prevent this?Dr. Won  Yes. Oh, absolutely. So we've been giving free seminars on how to prevent and reverse chronic disease naturally, for about three years. I initially did not necessarily want to give the seminars myself, I'm not a good public speaker. And so I wanted to set up the infrastructure and then invite one of the physicians to do it. And he did it in a couple of times, but it took him away from the family. And it takes a lot of effort to prepare different topics. So I thought this was so important. And as you know, when we're in medical school, maybe we had an hour or two hours of lectures of nutrition, and how to reverse the disease naturally. Well, actually, we didn't learn anything about how to reverse the disease naturally in medical school. We learn how to just manage the disease. And so once I saw the light, I said, I have to share this information with everyone as many people as possible Ken Brown  Even as a gastroenterologist when I trained as a fellow, it is called the division of gastroenterology and nutrition. And I think we got like, half hour a week on nutrition. I know that it's supposed to a split the title. Gastroenterology and nutrition.Dr. Won  Yeah. And look at the hospital. You know, once I had a patient after a very big surgery, and he had a mild, MI you know, mild heart attack. And the next morning when I went up to the patients for patient had eggs, bacon cheese, for breakfast and lunch, I said, this is wrong, and then go to any hospitals, whether it's Dallas or anywhere else, go to the cafeteria, the hospitals are serving disease causing food in the cafeteria and to the patients. I said this is wrong, right. That is the true crime. And I said, you know, it was one of our mission to to really empower the people and teach me How to Prevent and reverse the disease themselves.Ken Brown  We should do a video where you actually come to my hospital to the doctors lounge. They give free food to the doctors and you walk around that doctors lounge. There's bags of m&ms. I've taken pictures of this. There's m&ms there's, this is really funny. There's actually bowls of like gummy bears. And I'll watch and people will just go by just grab a head. Start eating on the way out. I'm like, there's so many things wrong with that. Not just the food, but a lot of hands been in that bowl.Dr. Won  Yeah, actually, I got in trouble with that one of the hospitals here locally in Dallas I actually took a picture of what they were serving at the doctors lounge and then post it on the social media. Oh, and then I got called into the principal's office. The hospital CEO.Ken Brown  Oh, before we get called into the principal's office, since I'm not good at this part. This is what Eric does real well. One thing disclaimer both Dr. Won and myself are real doctors yet this is not intended to treat anybody or give any medical advice if you have that unusual rash or joint pain or anything, this is not here to cure or treat you. But this could help cure whatever it is or not, or at least reverse what's going on by lifestyle changes, not through medical advice. And the other thing that we always need to do is really give love to our sponsors. Our sponsors Atrantil my baby, my little polyphenol complex, which we're going to get into a lot of stuff about this because Dr. Won is a whole food plant based doctor. And those vegetables all have polyphenols similar to what we have, in Atrantil. And we do know that that actually can work like the Mediterranean diet, and do all different kinds of things. And of course, the KBMD health CBD, I'm a big fan of cannabadial, we get into the science of it, we're going to learn more and more. I don't know if you've gotten too much into that. But the one thing that we talk about a lot because I start meeting scientists, like we have discussed before when you have when doctors say there's no science and then you're meeting the bench researchers that are out there. There's gonna be a field like you're an orthopedic spine surgeon you're a subspecialty of a subspecialty. I'm a gastroenterologist I'm a subspecialty of a sub specialty. I guess yours is sub sub sub because you did spine after orthopedic. Your your next level, even though you didn't go to Texas Tech, we're gonna forgive you for that. Dr. Won  Thank you. Ken Brown  Yeah, that's, this is just for Eric because he gets so upset if we don't discuss that. But even when you're sitting there as a sub sub specialist, we've got all these people with knowledge in other fields, that then you start realizing you could be a sub sub specialist. So I've met researchers that I call Endocannabinoidologists because they understand so much on the molecular basis of the endocannabinoid system, which I think eventually we're going to get to, but I think all of it gets corrected if you eat right and live the right lifestyle. So our little disclaimers go to Atrantil.com or go to KBMdhealth.com and take a look at the CBD. So that's usually a Does that a whole lot smoother? That's not really my...Dr. Won  I think you did great. Ken Brown  We have to get that out of there. So, all right, getting back to you, because I this is a rare opportunity to have somebody with both your background, your your skill set. And now this this continual pursuit, this continual change. I'm very similar to you, I've realized at this stage of my life, that moving forward is what keeps me happy. Always trying to see okay, what what can we do? What can we do for the next thing? What can we do for the next level? I try to always talk about a recent news article or something and I want to bring this up. Not to put you on the spot. Dr. Won, How old are you?Dr. Won  I am 48 years old.Ken Brown  You don't look it 48 years old. Awesome. An article just came out out of the National Bureau of Economic Research, which takes on the myth that life begins at age 40. This is kind of interesting, according to this very large study, that they looked at over 257 different countries, different socio economic stages and all that. Fascinating that you're saying that Africa is now getting these Western diseases Dr. Won  Yes. Ken Brown  So it's it's, it's impervious to everybody. The whole world is having the same crisis that I think we face. We just got there a little quicker than everybody else. Dr. Won  Oh, absolutely.Ken Brown  What they looked at is that there is a U shaped curve for happiness. And as it turns out, it bottoms out at age 47.2. And the reason why I bring this up is that there's a lot of people and they were trying to figure out why is it genetics? Is it that the stressors are too much? Is it that disease start setting in right about then you start realizing your own mortality and all these other things. They don't know exactly why, but they were able to account for education, marital status, all these things. And they did show that although it bottoms out by 48 49, people are able to find their way out and they can usually do it through community and through purpose.Dr. Won   Yes.Ken Brown   So both you and I are beyond that now. So now we're in the happiness zone. And I think that you've done exactly that you got through a little curveball and you're like, I'm just gonna keep moving. and I'm going to do this through community and purpose. And what it sounds like, is that the first thing you did is say, I'm going to give free lectures. Tell me about that.Dr. Won  Yeah, so we've been hosting a free seminar, teaching people how to prevent and reverse their chronic disease, and through whole food plant based nutrition. And there's a it's not just in nutrition itself, but it's a whole lifestyle. And that's why we don't like to call it you know, plant based diet is a plant based nutrition and lifestyle. And what I realized was I started going into plant base once I lost a few of my colleagues to cancer, they're physicians, and I myself, always thought, Hey, you know, there's a chance that I might die from cancer and the reason for that is because I've done a tremendous amount of a minimally invasive surgery and use two interpretive X ray machines and, and got significant amount of radiation exposure.Ken Brown  Just explain real quick, minimally invasive and why you would have to be using an X ray machineDr. Won  So a traditional spine surgery, you would make a big incision, right and then open up the spine, take away the, you know, the fat, the fascia and the muscle and then strip all of them off and gain access to the spine. And the whole concept of minimally invasive surgeries, not disrupting the soft tissue, you would make a very small incision, and then utilizing the X ray machine at the time. Now these days, you can use imaging guidance with minimal amount of radiation. But when we were first starting out 15 years ago, it was the typical X ray machine. We were protected with Lead But still, we got a lot of exposure to radiation. So I used to joke around saying I'll probably die of cancer someday. But what I realized was that I don't want to die of cancer Who does? So I started doing just a lot of research how to prevent cancer. And I just, you know, went through about thousand different papers, scientific papers, I realized we all have cancer cells, every single one of us have cancer, so we have cancer. So when we're diagnosed with cancer is a clinically significant cancer that we which we can prevent In many times and reverse, even the study from the MD Anderson state state study showed that number one cause of a cancer was diet. Number two was the tobacco. Number three is obesity, which leads back to the diet, right? And then the genetics makes up the smallest percentage, you know, no more than five to 10%. So we actually have to controlKen Brown  Use your analogy one more time with a gun. I like that.Dr. Won  Yeah, it is the gene or genetic loads the gun, and then the diet and lifestyle pulls the trigger. And so in that we now with better understanding of epigenetics, that the the genes are like the light switches, depending on our nutrition and lifestyle, we actually have the ability to turn them on and turn them off. So So through that approach, I discovered whole food plant based nutrition, which has worked wonders for me, instantaneously, within six weeks, I lost about you know, 25 pounds, and after age 40. They said if you do exactly the same activities level eat same thing. You're going to gain about a pound or 2 every single year, if you know then within 10 years, that's additional 20 pounds. And so starting 40...Ken Brown  I'm sorry to interrupt. I just want to clarify this one thing you chose to go plant based Whole Foods based on the thousands of articles that you researched. Dr. Won  Yes. Ken Brown  So you were not like watching Netflix and stuff. I'm going to I'm going to follow this what the health diet or I'm going to do the game changers This is based you are not influenced you did it all on your own correct?Dr. Won  Yeah. So I actually did it before all those documentaries came out. And the researchers were there. And and what happened was one of my friends from medical school, he came to visit me at one time and then he gave me a book called China Study. And I thought, maybe because he knew that I was also into business. This was about economics book. I didn't even see the cover. And then I kind of put it in the bookshelf and I forgot about it for a long time. And then once I started doing the research, there's a The China Study kept on coming up. And I said, Wait a minute, I think I have a book called China Study. Written by Dr. Campbell from Cornell, and now pulled it out, read it cover to cover, along with other studies, and then realize you can actually reverse the disease. And this has been the studies been going on, you know, there's been studies since 1950s. And so I was convinced I said, You know what, I'm going to do this for myself. And without even trying at first thing I did was wait is, you know, important, but not the most important thing, but I instantaneously lost 25 pounds. And I was back at the weight when I was in high school. And you haven't seen many you know, you don't most people think there's not too many, you know, overweight or obese Asians? Well, in America, there are plenty not and maybe not in Asia, and I was becoming one of them. And so instantaneously, I was back into my high school weight. And then I started exercising on regular basis, and I felt so much better and now I'm I feel better and stronger than when I was in high school. And until about, you know, three years ago, I couldn't even do a single pull up. And and now I can do quite a bit and my goal is by the time I'm 50 I'm going to be able to do muscle up.Ken Brown  Oh, yeah, yeah, for sure. Well, I got to actually Eric super into CrossFit. So he can teach you the whole technique on that. Dr. Won  That'll be great. Ken Brown  We can sit there and do that. It was on last week's show of the week before we actually discussed the fact that when coke really started penetrating China, that's really when their obesity problems started the high fructose corn syrup and all that Dr. Won  Oh, yeah. Yeah, all the the processed food, right. And then, you know, along with the, you know, meat consumption, and as a developed countries are getting wealthier and wealthier they're eating just like American Standard American Diet, right, all the processed food, all the sugar, all the the, you know, high fat animal products. Even in America, average Americans consume about 250 pounds of animal products every single year, which is a tremendous amount, right? And so, and then the China's Study...Ken Brown  How many pounds? Dr. Won  250 pounds. I thought that's a that's a lot right? That's average Americans since I'm I don't eat any somebody is eating 500 pounds of meat every single year right?Ken Brown  I'm gonna look at that cow and go. I'm gonna eat half of you this year. The whole cow.Dr. Won  That is a tremendous amount. I think they said also during the Superbowl, I don't know how they come up with the numbers. Every every year during the Superbowl people consume about 1.6 billion chicken wings. Oh my god.Ken Brown  1.6 billion chicken wings. Yes. For the for the Super Bowl. Dr. Won  Super Bowl. Ken Brown  All right. Yeah, that is a lot of wingless chickens running around.Dr. Won  Yeah, absolutely. And, and you know that the chicken these days doesn't look anything like the chickens from let's say even hundred years ago, because they're genetically modified, you know, and they have so much more antibiotics. They have so much more chemicals, growth hormones, and so people are so concerned about eating food that's not Genetically modified but most people in America don't know where the food comes from. And they don't really think about it especially when it's in a hamburger or chicken sandwich which they really do need to pay attention whether you're plant based or not, you should really know where your food comes from.Ken Brown  You know, I mean I love having you on here because even as gastroenterologist and even though I think like kind of we want to treat the whole body I've I have not spent that much time really going over the whole diet thing because I naively am like okay, this is the weight I want to be. This is kind of what I want to look like when I'm when I'm at the beach is you know, if I start not seeing the the ABS or we go from that six pack to the four pack to the two pack to the no pack. Then I just start working out more. Yeah. And I got a little rude wake up call. Last week I went to I have a functional medicine practitioner. His name's Kevin Wilson. It's smart wellness now. And you know, they they do real Like deep dive into the blood work so it isn't just HDL LDL, it's you know, it's LDL, C it's Apolipoprotein B, it's all this. And my cholesterol went up. I'm feeling better than I ever felt what? And he's like, yeah, you're doing something wrong, buddy. Yeah, and you know, and quite honestly, I'm pretty much paleo so i don't i don't really do dairy or gluten, but I will mowdown some meat. Got to eat my 500 lbs. So you got me rethinking. So he's given me three months to try and reverse this. So I'm starting a little bit slow and so I'm not I'm gonna start watching your videos for sure. Because I did the thing that most people do. I went and watch Game Changers on Netflix and and which is a very fascinating documentary in the sense that that got more traction than what the health and knives over forks and all those other vegan propaganda ones, because I think that they were talking about performance. Dr. Won  Yes, Ken Brown  What you're describing is exactly that you're you this is not an ethical thing. This is not a a conscious choice. You were like, No, I did my research this, I can be healthier.Dr. Won  Yes. I mean, I did this because for my health, and you know, I always tell people that I want to live until 120 years old, I may have had a better chance if I actually started when I was in my 20s.Ken Brown  You know, that will just be you. And Dave Aspy having tea together because he says the exact same thing on his podcast.Dr. Won  I think he says he wants to live forever. And so I don't know if that's possible yet. But they said he, if you do it, right, the kids who are born today have a potential to live until 150 years oldKen Brown  A hundred and 50 years old, have the potential?Dr. Won  Have the potential. But but the sad thing is the kids you know, between age 10 to 12 years old, what percentage of the kids actually have early signs of atherosclerosis? 75% Ken Brown  What? Dr. Won  75% of the kids between age 10 to 12 years old, have already fatty strix. Ken Brown  No! Dr. Won  They all found that the... Ken Brown  That's nuts there's no way! Dr. Won  Even the fetuses are now showing up. unfortunate event because, you know, whatever, you know, may have happened. But when they do an autopsy on fetus, even the fetus, some of the fetus actually have, you know, some fatty Strix, depending on Mother's, you know, a vascular system. Right? So, you're starting at life already having early signs of cardiovascular disease, what is that? Right? And so when mom said, you know, I'm really, you know, sensitive to listen moms who are pregnant, and then also parents, they have such a difficult, you know, challenges, you know, feeding their kids, but they're not really thinking about what they're serving them, right. And I cringe when I go to a breakfast, and then you know, next table, you know, parents are serving their kids bacon, or hotdogs, and the kids and the food that is known by World Health Organization as a group one carcinogen, right. So I think we need to really step back and educate the public and help them see what they're putting on their, on their table. And when I saw the article where the kids, you know, between 10 and 12 years old, 75% of them had already have signs of, you know, cardiovascular disease. I mean, that's terrible. We're not doing something right. And we spend so much money on managing the disease, which we don't do very well. But and, you know, completely forgetting about preventative medicine because there's no money in preventive medicine. Right? That's that was our mission is to actually go to community and and teach them how to eat properly. And so, so we've done not only lectures at our clinic, but also if anybody wants to hear us talk. We'll go and give a talk. And we've gone down to the south side and then the African American churches to church in Richardson at Methodist, you know, pretty much 99% Caucasian, you know, congregation. Or you know, community centers who wants to learn about...Ken Brown  You still have the guts to go to a nice Korean BBQ establishment and give a talk? I like Korean bbq man!Dr. Won  Yeah, you know, for whatever reason Koreans were known for Korean barbecue, but in Korea actually. Their health is declining like in China because the meat consumption has increased processed food, and then their lifestyle is changing. But you know, they used to be one of the healthiest country in the world, because they were too poor to actually eat meat. It wasn't available. Everyone wants to eat. So if you look at all the countries, all the cities and along the Blue Zones, the the cities that have the most amount of centenarians, most people are poor. So by being rich, yeah, you may have money to spend it, but you're actually ruining your health. Ken Brown  Alright. So I was going to ask you this, and it's a perfect it's a perfect segue right now. So I was talking to one of my patients today that she's going to be a guest here shortly what happens to have Crohn's disease and gives back to the community just like you she works as a counselor and does all this and she happens to be a speech therapist for underprivileged kids with autism. So part of this, you know, they, they send them with the with the school system. And so her and I started talking, I started talking about how last week we did a whole show on a chemical that makes plastic flexible, called DEHP you've been exposed to it a ton as a doctor. So have I that's what IV bags are. That's what the tubing is, all the catheters and tools that we use to be flexible so that we're not puncturing where we don't want to use this chemical dehp. And when you said in utero, they're finding stuff as it turns out in utero, if a if a woman is exposed to it, it just goes to the fetus and causes all kinds of stuff. Dr. Won  Oh, wow. Ken Brown  So what her and I talked about is I'm like man, well, what can what can you do to circumvent this autism at you know, I mean, basically epidemic She's like they're too poor to eat healthy. Dr. Won  Yeah. Ken Brown  So now you just said that when countries were poor, they ate healthier. So let's talk about the cost of, of living your lifestyle. Is it possible if I don't have a high income to eat a plant based whole food diet?Dr. Won  Absolutely. When people are thinking Whole Foods plant based, I think a lot of people get that confused and they think it's vegan. And then and they get meat replacement products, which are actually quite expensive. Right?Dr. Won  So when you do... Ken Brown  This guy did that when he watched game changers and it didn't work out well. Dr. Won  Yeah. Ken Brown  Because I think the either the fillers or the soy or something may be very inflamed. Dr. Won  Yeah. Ken Brown  So I backed off.Dr. Won  So one of the things I really you know, it's also talked to the vegan community is that you know, they've already given up the meat which is the one of the most difficult thing for a lot of people. However, they also need to get away from the processed food because most of the the meat replacement products are processed. So when you're eating a whole food plant based, you are eating non processed or minimally processed food. And so the best place you know, and the best pharmacy is actually with F, you know, FARMACY right Farmacy is in the produce section, that is the medicine, that's where people need to go shop. And so if you get dried beans, it costs pennies, right? Versus, you know, getting ground beef or getting chicken breast. So actually eating whole food plant based can be very, very inexpensive. That's why and along the the Blue Zones, the you know, like nicoya, Costa Rica, Okinawa, Japan, you know, Sardinia, and aquaria. All those countries, all those communities, people were relatively poor, they're not wealthy at all, even especially like nicoya they were eating mostly beans Ken Brown  Where's the Nicoya? Dr. Won  Costa Rica. Ken Brown  Okay. Dr. Won  Yeah. And it's one of the cities and Blue Zones that has the most amount of centenarians, right? And and there were most they're all 98% eating plants because they were too poor to eat meat. And they're living beyond and then they didn't necessarily go to the gym, you know, or CrossFit or 24 Hour Fitness, because they walked every day everywhere, they didn't have cars, right? So they're moving their body every single day. They're eating mostly plant, and because that's all they had available to them. And then they had sense of community and, and they had sense of purpose. And you mentioned purpose earlier, I think that is so critical. You have to have a reason for living, right? You have to have why, as long as you have why, and sense of purpose, no matter what challenges are in front of you, you can overcome them. And that's how powerful human beings are. And if you decide to just give up, that is a failure. And no matter how many mistakes you make, how many, you know, failures and debt that you face, as long as you stand back up, and then continue to, you know, pursue your purpose and your why I think Most people will be very, very happy.Ken Brown  Yeah, I think that you saying that you came at 11 years old, you started your journey, probably not the easiest time in your life.Dr. Won  Not at all, I didn't know how to speak English. And but all our family, you know, including my parents, we worked as a janitors, you know, don't want to get my parents in trouble. But when we're 12,13,14 years old, we used to go help our parents, you know, clean the toilets in the building and then I still pass by one of the buildings we used to clean when I was 14 years old. And and that's what we did as a family. And then they, you know, open to the flea market store. My mother was shot at, you know, twice when she was working at the flea market store when she was being robbed. Right. And luckily, they missed, thank goodness and then where my parents lived after I left for college. There was a drive by shooting at my parents house. They got the wrong House, it was supposed to be the next door. But my parents were asleep. And then fortunately, their windows were shattered. And so, you know, we grew up very humble. And a lot of people think that, you know, you're a doctor, you must have come from a doctor family. That wasn't the case at all. And we live in the government assisted housing. But, you know, our parents always gave us you know, good foundation, and always, you know, taught us to have purpose in life. And that really, you know, sunk in with us for you know, since we were little child Yeah, and, and in always the life force, you know, living the life with purpose, and, and that was our mission.Ken Brown  So, you come over here you go through this kind of hardship. Now, we kind of tongue in cheek, talked about how I hope you're as smart as Eric obviously Eric's a very smart guy. He's my crna and he's he could he's still continues to do whatever he wants to do he has entrepreneurial spirit very, very like minded like us. He's very big into purpose into raising his kids the right way and all that stuff. But your your academic background is super impressive. I mean, you know, just for the average person that says, Oh, that's a doctor. Now there's levels of doctor, there's levels of med schools, you gotta really work to get into some of these places. And I, I'm just so impressed that you basically have to put your career that you were worked so hard to do, and you went awesome. I'm gonna work on this now. I love that. I think that is the coolest thing. And I'm learning for you. So I want to ask you a couple quick questions. Dr. Won  Yes.Ken Brown  Because these are the arguments that I get. So the community that I'm in I'm in fact, I should. We'll we'll talk afterwards, but I've been part of some really cool entrepreneurial groups, where it's just like minded people that all they do is sit around and say don't step on this land mine. I blew off my left, you know, theoretically, in a business sense, I blew up my left foot doing that I wouldn't do that, try this software instead try this thing and you know, you read books and stuff like that. Well, a lot of these people are the Paleo community, and they're really smart people, Chris kresser, Rob Wolf, you know, become friends with them in these groups. And what what I'm hearing is, is that in Kevin Wilson, my doctor is not plant based. He's very big into paleo and all these other things. So a couple curveballs towards you. Dr. Won  Sure. Ken Brown  All right. Let's talk about the thing that I get asked a whole lot. Lectins. So you said Dr. Beans do this, what's your thought on lectins? Do they create and then that's going to lead us into the microbiome and and eventually into your entrepreneurial spirit where you continue to grow? So that's where I want to head with this. But can we talk about lectins real quick?Dr. Won  Yeah, absolutely. I think that's a you know, very interesting topic. And so if you think about the Lectin especially in the beans, no one can eat them being raw. You don't eat dry beans, you can eat it, you can't digest it, and we don't recommend it. Right? Because if you eat it, you're going to get nauseated, you're probably gonna throw up. However, if you cook them properly, right, all the lectins are gone, right? And so lectins are there so that the plants can protect itself and so a little bit it's actually healthy for you because you're stressing your body. However once you cook them... Ken Brown  Hormesis.Dr. Won  Yes, absolutely right.Ken Brown  The term Hormesis means that you stress your body a little bit so it adapts.Dr. Won  YesKen Brown  That's why we exercise that's why we fast that's why we do things.Dr. Won  That's why you know, we get exposed to heat that's why we take cold showers right? Ken Brown  I don't take cold showers. I refuse to go that route. I'll sit in a sauna but I will not do a cold shower.Dr. Won  You should try it you know maybe 10 seconds first and you know 15 seconds in the beginning you hate it. But you'll learn to love it. But the lectins...Dr. Won  We're gonna get to elections really quick. Just Just this reminds me my late father in law passed away a few years ago, we were watching a show on navy seals. And a Navy SEAL actually did a obstacle course, where he first soaked himself in warm water, and then did the course. And then they put him in ice water. And then within a sofigel probe, they show that he dropped his core temperature and then through various Navy SEAL techniques, he raised his core temperature. And so my father in law, this is on Christmas, this is about 10 years ago, goes you know, it's Dallas, it's not that cold, but it's cold enough. It's It was like 30 or 40 or something. He goes, I bet you can't even get in that pool. I went out there with my son and my father in law and I jumped in and like a total weenie jumped out in about 10 seconds. So the whole cold thing I think that's funny, but all right, that's the whole point is is that lectins can do this. Let's get back to lectinsDr. Won  Yeah, so but once you actually properly cooked the meals, yeah, I recommend soaking them at least for eight hours or even 24 hours.Ken Brown  Soaking the beans first?Dr. Won  Yes, soak the beans minimum of eight hours. If you have a pressure cooker you don't need to soak them you just dump it in there and you cook itKen Brown  Do can beans qualify?Dr. Won  The can beans are already cooked so you don't even need to cook it you can just open it and start eating them.Ken Brown  Do you find can beings unhealthy or do you always do whole food? Dr. Won  At the house we have both dry beans and canned beans because to make it a little bit more convenient, right. And the can beans are, the studies have shown that they still retain just as much nutrients. And so when I'm really busy, I would open up a can can beans with the my whole grains and mix them up along with different kinds of spices and then along with different greens, but once you cook the bean most of the lectins are gone. So there's really nothing to worry about. And so you don't need to take Lectin you know, supplements or anything like that. If you properly cook the food, then there's really no issues with lectin and if you think about it, so beans are the most known for lectins right? Every single one of the cities, right? There's one common theme among Blue Zones, five cities that has the most amount of centenarians, right? The research by Dan Buettner from National Geographics every single one of them that the common theme was Beans, beans, beans, beans Ken Brown  Shut up! Really? Dr. Won  Every single one of them there was their main source of protein was their beans.Ken Brown  Dang. And I've actually been avoiding them because I'm trying to you know, I've just kind of go with the no grain thing.Dr. Won  Yeah, so the beans is one of the healthiest thing one can consume. Not only it's a great source of protein, but also it's also has so many fodder nutrients. And I consider them as a superfood really, really cheap. Super food, Ken Brown  What are your favorite beans? Dr. Won  All of them, but we have at the house about 10 different kinds of beans. And then when I make grains I usually mix like black beans, pinto beans, white beans, navy beans, kidney beans, along with let's say buckwheat brown rice, wild black rice, barley, mix them up, and then that's how I make the rice and so rice and beans. I don't you know we definitely avoid any refined grains such as white rice,Ken Brown  Oh you do? Dr. Won  Yeah, I we avoid any kind of white anything that's white right?Ken Brown  Okay, so I hope that helped my wife is listening my wife's Puerto Rican. Dr. Won  Uh huh. Ken Brown  So i mean...beans and rice. Yeah, it's just pretty much it's whatever. I'm like, Honey, what are we having? She's like salmon, and beans and rice.Dr. Won  Yeah. That's good. And you just got to put in some greens.Ken Brown  But but but but you avoid the white rice Dr. Won  White rice. Yeah. So the...Ken Brown  As a Korean you still avoid white rice because we love I mean, that's actually our favorite. If we're going to globalize our cuisine for my family, I got a 15 year old a 13 year old and we essentially eat Japanese in this order. Japanese, Thai, Vietnamese, Chinese almost anytime we get a chance to eat out.Dr. Won  You're inner asian. Ken Brown  I'm we are definitely Yeah, it's a it is it is definitely our favorite cuisine. So we end up eating a lot of rice. Dr. Won  Yeah. So interesting fact is that the, the in Asia, you know, while back the white rice was you know, it's extra process right? So this was actually for aristocrats or the wealthy individuals, all the poor people ate brown rice, which is less processed it's unprocessed. Right? And so the the poor people actually live longer they were healthier than rich people, right? Same thing happened 100 years ago, the rich people ate white bread, right? And then the the poor people ate the whole grain bread. And guess what it was a poor people who are healthier, right? So you know, grains, especially white grains, they're extra processed. And so and also raises your blood sugar level much, much faster and raise you know, increases more insulin production or release of insulin. So we try to avoid anything that's processed. So including the the grains. So if you eat you know, brown rice or you know buckwheat barley, black white rice those are the grains that I would recommend that I say it's whole grains not grains, whole grains, Dr. Won  Whole grains?Dr. Won  whole grain.Ken Brown  Beans, beans, okay lectins get destroyed when they get soaked and then followed by cooking and or canned. Dr. Won  Yes. Ken Brown  And then...Dr. Won  Because canned beans are cooked. Ken Brown  Can can beans are cooked and as far as the grains, so yeah, the This works really well for you. And I know right now that there's, you know what I've seen with diets, especially when people make a living like if they have a book or so I mean, I hung out with Rob wolf, the guy looks amazing. He's been keto for 10 years. And Chris kresser is essentially you know, straight up paleo and, you know, I know his blood work is amazing. We've talked about that. And so there are, you know, the the things that actually work it's not working for me. My doctor just told me that's why I'm like, Oh, yeah, we need to we need to call Doug, I need to I need I need to eat his brain and figure out what's going on here because maybe my genetics, so you use the term epigenetics a little while ago. Explain what epigenetics actually is, because there's some confusion around this.Dr. Won  Yeah. So just to simply put it way I like to explain it is our gene is like a light switch. Right? So we are born with certain genes, unfortunately, for some people, and they may have a greater risk of developing certain type of disease. But just because you carry the gene does not actually mean you're actually going to develop those disease. But there's a lot of external factors, environmental factors, including the cancers, right. And so by a proper nutrition and lifestyle, you actually have the ability to turn the genes on or turn them off. So what that tells us is that you actually have a full control. So you know, like Elizabeth Blackburn who won a Nobel prize from UT Southwestern for discovering telomeres did a study with the Ken Brown  She's the one that discovered telomere races?Dr. Won  Yeah. So along with the telomeres, and that's what she, she won the Nobel Prize,Ken Brown  Did not know that wow, out of here, out of here in DallasDr. Won  Yeah at UT Southwestern. Ken Brown  That's, that's impressive.Dr. Won  So she did the research with Dean Ornish, and they got group of patients who had early stage prostate cancer. And then when they did the genetic study, all the over 500 cancer genes were actually turned on. And then they spent three months changing their diet and lifestyle. And then they did the the genetic study again, all the genes were actually cancer genes were turned off over 550 cancer genes, Uncle genes are turned off. So you only took them three months o so especially prostate cancer, right? Especially if you catch them early stage, you really want to treat them with diet and lifestyle change. They said the the traditional surgery, whether it's a chemo or the surgery does not prolong only one out of 49 people actually live longer after getting traditional, conventional medical treatment.Ken Brown  Well, when you start looking at some of this, I listened to a podcast called medical reversals. It was on Freakonomics, the Freakonomics podcast. And they they actually had some doctors on there. And they and if you look back at all these medical reversals, so basically your doctor says, do this, and then we go, Oh, no, that was wrong, because now we've looked at our cohorts of 10,000 patients over 10 years. We can go on and on about that the estrogen replacement therapy, one of the things that's been brought up and I brought this up to my doctor because my cholesterol is statins and statins have not been shown to improve lifespan. And so the question is, do they actually decrease the incidence of events, but it has not been shown to improve lifespan. So now I start. I'm at that stage in my career in medicine where I'm starting to question so many things. I'm having patients come to me, and well, let's throw this one out with autoimmune disease. And you and I were talking about this I treat a lot of Crohn's disease, ulcerative colitis. I use drugs like Remicade and humera. Have you had any experience with as an orthopedist you're going to be exposed to rheumatoid arthritis, you're going to be exposed to ankylosing spondylitis. Poly arthropathy from these other things. Have you had any wins with using your method?Dr. Won  Absolutely. So some of them are my patients and some of them are attendees to our free seminars. And I gave an example of Denise she gave us a permission to talk about her. And so she came to us suffering from severe rheumatoid arthritis and she's been on multiple medications, even methylstrexate as in the past and humira. And humira costs 25 to $50,000 a year. Right? And one of the side effects is heart failure. And she began to have a severe heart issue. So they had to take her off. And and she she was in severe pain. And so I said, you know, you got nothing to lose. You tried everything else. So why don't you try a whole food plant based nutrition, and that's what she did. She did that. January 1, 2018. Within two months, she was in remission. All the pains were goneKen Brown  On her alright rheumatoid arthritis? Dr. Won  Rheumatoid arthritis. Ken Brown  So rheumatoid arthritis is an autoimmune disease. Autoimmune means you something turns a genetic switch on and your body starts attacking yourself. In gastroenterology, I see it with all sort of colitis, Crohn's disease, celiac disease, autoimmune hepatitis. In your field. You see it with the joints.Dr. Won  With the joints rheumatoid arthritis, but we also I've seen patients with multiple sclerosis, right? And actually, this was another patient who walked in or not walked in, came into the clinic on a wheelchair and had multiple sclerosis. So we actually... Ken Brown  In a wheelchair?Dr. Won  In a wheelchair.Ken Brown  That's very advanced MSDr. Won  It's pretty advanced. And and the patient went whole food plant based, and was six to eight months later, when they came back for a follow up visit. He actually walked out walked in with a cane. So he still had weakness, but it got him off the wheelchair and now he's able to strong enough to actually walk with a cane. Ken Brown  Just diet change? Dr. Won  Just a diet change. And he was off to all the medications and he's not the only one and there's a one lifestyle medicine physician even up in New Jersey, a good friend. She was initially infectious disease doctor and during her residency or fellowship, she woke up one day completely paralyzed. Ken Brown  What? Dr. Won  And that's how she discovered she had multiple sclerosis. And to a point she was walking with a cane and she was bad to get on a wheelchair. And she made the she discovered she read an article about blueberries, right? She said No way. There's no way and this can't be and she starts researching and really realized the autoimmune disease starts from the gut. And she needed to find a way to decrease inflammation. And she needed to once she healed her gut, and she changed her complete, you know, nutrition when whole food plant based. 10 years later, she ran a marathon.Ken Brown  I'm sorry, I don't have any Kleenex. Do you have any Kleenex because I have tears of joy. I just had an orthopedic surgeon say that. Everything starts in the gut. Oh,Dr. Won  Yeah. We think that you know, a lot of the the lifestyle medicine physicians and believe that autoimmune disease may be in a different sort of autoimmune disease, whether it's rheumatoid arthritis, Hashimoto thyroiditis, multiple sclerosis, maybe it disease, it all starts from the gut. And then it manifests to a different disease based on our genetic makeup. And so our treatment method whether it's, you know, lupus, multiple sclerosis, you know, Hashimoto thyroiditis, it's all pretty similar. You know, they may, we may make little bit of a different protocol for them, but overall as a whole food plant based, and many of them improve significantly.Ken Brown  Wow, that is. So we've actually, that's actually a common theme that we talked about, we have brought some people in, but my thing is we've got lots of data to show that when you have an inflammation in your gut, that leads to an inflammatory cascade that can cause this epigenetic phenomenon. And so somebody sitting around listening, so I want to talk about what else you have going on, which means that you've taken it to the next level, but I everything about, about this show and about what we want to do is talk science first. Clearly, you're a brilliant And you know, you're, I'm a, I'm a gut doctor. So you know your s-h-i-t. So I wanted to throw this article out at you because it's fascinating that we can talk disease. And I could sit there and say if you've got rheumatoid arthritis if you got ms if you have anything, but there's also one underlying thing that happens to all of us and you keep talking about the Blue Zones. A recent review article, my little secret weapon will eventually be able to disclose who it is, but she sent me an article yesterday. And with you coming on it is a review article on the new insights for cellular and molecular mechanism of aging and aging related diseases. herbal medicine is a potential therapeutic approach. So in other words, what this title says is, yo we're all aging. And why do you want to load the gun faster than it should be loaded? So what this article looked at is they go into the background A little bit where 900 million people in the world are over the age of 60. Dr. Won  Wow. Ken Brown  And you just pointed out that it doesn't matter where you live now it looks like it's it's pretty much spreading everywhere. So aging, which can be divided into both pathologic and physiologic. So if you are perfectly healthy, you're going to physiologically age if you choose to load your gun faster, that's pathologic aging. And this article gets into really cool geeky science about the complex biological processes and the decline of tissue and origins and structural degeneration and then they go into telomeres and then they go into the fat, a common thing keeps popping up. And it is reactive oxygen species or oxidative stress. Dr. Won  Yes. Ken Brown  So stress at a cellular level, or inflammation at a subtle level leads to aging. Dr. Won  Yes. Ken Brown  So if you didn't care about anything about the fetus having a heart attack or a 10 year old having coronary artery disease, We spend a lot of money trying to look younger. I just got done talking about the other article that said that at age 47, maybe that's when men look in the mirror and go, Oh, I'm I'm there. I don't know. It all comes down to reactive oxygen species. This leads to they can actually get into the actual mechanism. So one of the things I run into that we have discussed, which is I'm sure you've run into because I think your field is a little bit less holistic than gi, which is probably because the gut affects so many things. But I imagine if you're trying to talk to one of your colleagues at a conference and say hey, plant based they probably look at you like what?Dr. Won  Yeah, I'm I don't represent typical look of orthopedic surgeon right? So if you imagine orthopedic surgeon those of you who don't know like in medical school, we are like the cords pedic surgeon smart jocks, right? Everyone's hitting the gym, you know, bone broke me fix. Big guys, ex-thletes, right? And then somehow I snuck in as a nerd, right?Ken Brown  So I have I have a friend who played football for the San Francisco 49 years played at the University of Notre Dame. And we have or he's very good friends with orthopedic surgeon named Brian rhadigan. And he played linebacker for Notre Dame, and if there is ever the avatar of what I thought this guy was just jacked, and you know, and he's an orthopedic surgeon now for Notre Dame. Dr. Won  Wow. Ken Brown  But anyways, yeah, so yeah, you you are talking different than the typical orthopedic surgeon.Dr. Won  Yeah. And so but yeah, but I think even with orthopedics, and also especially in spine, some of our patients, after if they choose to follow our diet and lifestyle modification, they came back even with herniated disc, most of the inflammation was gone, pain was gone, and so they they would cancel the surgery. I said Congratulations, right. And so if I can help patients, that surgery is definitely the last resort.Ken Brown  Say that one more time you got paid to operate and you were happy when you didn't have to operate?Dr. Won  Yeah, absolutely. Because there's plenty of patients who's not following the lifestyle modification and who is in agony, who failed all the conservative treatment, who's going to need the surgery. But you know, what I would love to be able to do is to prove to the medical community that so many of the surgeries and procedures that we do are completely unnecessary, because if people are willing to make the lifestyle modification, if the physicians actually know and teach their patients, how to make the modification, because most of them do not know. Right, then I think, you know, many people can avoid significant surgical procedures, whether it's a cardiac cath open, you know, open heart surgeries, which we know that does not extend anybody's life, right. And same thing with spine surgery. And, you know, orthopedics is a little bit If you break a bone, you broke a bone and you need surgery to fix it right?  Ken Brown  Don't try to hobble into whole foods after that skiing accident.Dr. Won  I don't think that whole foods is  going to fix that broken bone, but it may help you heal faster, but you're probably going to still need surgery. And so that is one of my mission and I get a great enjoyment out of it. And you know, I remember one patient who walked in who had a thoracic herniated disc. And you know, in order to do the surgery, we have to do a thoracotomy. So basically cracking our chest open the compress the lung in order to get to the spine from the front. And I said, you really don't want to have this surgery. We can do it if you want to. However, why don't you give me three months make this changes come back in three months. If it doesn't work, then we'll go ahead and do the surgery. She came back to clinic and three months along with her husband, she lost 40 pounds. He lost 60 pounds, right? And she said her pain was gone. And she said doctor, I don't need your service. anymore awesome congratulations. So I think it is very possible and you know once once you have seen that I just get a kick out of itKen Brown  I'm feeling like a little jerk right now because we did a show on using cell phones while there people around the bathroom doing social media posts and I I told everybody to keep doing that because it creates hemorrhoids so they can come see me. I feel like a jerk. I'm over there encouraging, sit on the toilet longer and make an appointment with me.Dr. Won  That's funny.Ken Brown  Oh, you're making me look bad man. I want to talk about something about this article because I we use the term reactive oxygen species all the time. Now one of the things that they got deep into this article is about a lot of the end origin disease that kills most of us. cardiac disease strokes. dementia. A lot of it comes down to blood vessels. Yes, the endotheliam meaning that as our blood vessels, all this inflammation leads to endothelial dysfunction, and impaired activity and arterial stiffness. And the reason why I bring this up is because I'll plug this the polyphenols and Atrantil we do know that they actually improve the most polyphenols when taken in. There's literature for this. But when we first launched Atrantil we did it strictly for people that bloated and then we had all these people that kept staying on it. And that's when I started backing up because I was looking at one little problem then went, Oh, this is actually it's sad that it's that I'm now learning because all I've been doing is doing plant based, but I started with a pill and now I'm working my way to lifestyle. Yeah, which you're doing lifestyle. And you realized, Hey, I can help people in different ways. So you noticed immediately that endothelium is really important. And when we talked before and you brought me some gifts, I would like to talk about what else you have going on here because very clearly, you have put some serious thought into this. And then I came backwards. I started with a plant based product to treat something and now I'm learning about a plant based lifestyle. Yeah, you did the opposite. You started plant based lifestyle and said, I'm going to produce the best product for that. Yeah. So tell me what you got here.Dr. Won  Yeah, so one of the things that we developed was, is called Neo Nox is a nitric oxide booster,Ken Brown  Neo NoxDr. Won  neo neo, no x, no x, and this product was developed without intention of developing a supplement company. what we realized was as I was doing research, even as a physician, we knew that heart disease was a number one killer, but I didn't realize how severe it was. It is actually the number one killer of both men and women worldwide. Right? And, you know,Ken Brown  Yeah we start seeing once women go into menopause. Yeah, they get the same risk as men.Dr. Won  Yeah, exactly. And, and so and a lot of women just getting neglected and they think it's a man's disease. And but women develop a cardiovascular disease just as much as the guys and, and one in three deaths in us is related to vascular disease. So pretty significant amount. And it all comes down to endotheliam and nitric oxide, what I realized was the most important molecule in our body because it saves endotheliam, and is produced it within our endotheliam. However, as we age, by the time you're 40, you lose about 50% of your ability to produce it. By the time you're 60 you lose about 85% of your ability to produce nitric oxideKen Brown  Say that one more time.Dr. Won  So by the time you're 40, you lose about 50% of your ability to produce nitric oxide, which is the most important molecule in our body.Ken Brown  Why do why do we do that? Dr. Won  So a few things number one is produced in your endotheliam. Right intercellular is basically the inner lining of your artery. And so, as we age, we develop atherosclerosis, we damage the endotheliam. So therefore, we lose the ability to produce the, the nitric oxide, but along with that... Ken Brown  So the inflammatory process damaging the endotheliam does not allow us to produce the one molecule to repair the endotheliam.Dr. Won  Exactly. And so and not only the nitric oxide, is that the strongest vasodilator that lowers of blood pressure, and then also vasodilate the vessels so they're more nutrients and oxygen can be delivered to the end organs, right. It also stimulates the stem cells and activates the stem cells and mobilizes the stem cells, Ken Brown  nitric oxide does? Dr. Won  Nitric oxide, and that's how we really actually got into the nitric oxide because we knew we needed to boost the nitric oxide to our patient when we're doing orthopedic stem cell therapy, right to to help them prevent either You know rotator cuff tendonitis and tear surgeries Ken Brown  We had we had weighed with 10 on our show the orthopedist. Dr. Won  Yeah. Ken Brown  From Fort Worth that had the the Panama stem cell clinic.Dr. Won  Yes. Yeah. Ken Brown  We deep dived into stem cells. That's some cool stuff. Yeah.Dr. Won  And but, but most people are looking for that magic pill. They want the injections, right? And the stem cell therapy, but you need to activate them and people who needed the most are typically 60 Plus, right, sometimes 40 Plus, but most of the patients we have arthritis are 60 Plus, but they can't really activate their stem cells because they don't have any nitric oxide. That's part of the reason why people develop cardiovascular disease. people develop diabetes, right? people develop erectile dysfunction, which is a vascular disease. Right. And so that's, that's why the even Biograph Cialis only works on 50% of the population.Ken Brown  So one of the reasons why game changers has been so much more well received is that they have a whole segment on nighttime boners Yeah. And how eating a plant based diet actually improves erectile dysfunction. Dr. Won  Yes. Ken Brown  And so and not just erectile dysfunction actually improves nocturnal erections I should say. Yeah, boner seems a little bit unprofessional. Dr. Won  You are a doctor.Ken Brown  But um, yeah. So that's, that's one of the things so it's, it's when you talk anti aging or you talk sexual performance, that's what people spend all their money. Yes. They don't sit there and go, Oh, I'm going to have a heart attack. Yeah, when really, it's all the same process. It's all the same thing. The thing that's making you look older, the thing that's making you not perform as well in bed is the exact same that's going to kill you! Dr. Won  Exactly. And, and, you know, the dementia, which are mostly now we're realizing that is a vascular disease also, because you're just not getting enough blood to your brain, right. And so, and also lack of energy, you know, after age 40, everyone's fatigue suffering from fatigue, lack of energy, because  mitochondrial biogenesis is actually initiated by nitric oxide also. So it helps nitric oxide stimulates the production of mitochondria, which is the energy source. Ken Brown  There we go. Yeah, so that's the that's the energy source of every cell. Every cell has a little power plant. Yes, it's called the mito

Part 4 of how NUTRITION has a HUGE impact on your BRAIN! Everything in your brain is something you ate, something you made from something you ate, or, in a few cases, something your mother ate. Nutrition impacts your mental and emotional health, the function of your five senses, and your conscious and unconscious control over your body movements. Join me as I lead you in a safari through the textbook, “Neuroscience,” pointing out along the way all the interesting connections to nutrition. Listen in for part 2 on the COGNITIVE FUNCTIONS! Mental and emotional health, cognitive performance, and sleep! Ads This episode is brought to you by Ancestral Supplements' "Living" Collagen. Our Native American ancestors believed that eating the organs from a healthy animal would support the health of the corresponding organ of the individual. Ancestral Supplements has a nose-to-tail product line of grass-fed liver, organs, "living" collagen, bone marrow and more... in the convenience of a capsule. For more information or to buy any of their products, go to https://chrismasterjohnphd.com/ancestral This episode is brought to you by Ample. Ample is a meal-in-a-bottle that takes a total of two minutes to prepare, consume, and clean up. It provides the right balance of nutrients needed for a single meal, all from a blend of natural ingredients. Ample is available in original, vegan, and keto versions, portioned as either 400 or 600 calories per meal. I'm an advisor to Ample, and I use it to save time when I'm working on major projects on a tight schedule. Head to https://amplemeal.com and enter the promo code “CHRIS15” at checkout for a 15% discount off your first order.” In this episode, you will find all of the following and more: 00:39 Cliff Notes 12:08 Anatomy of the brain 16:41 The role of the basal ganglia in suppressing the investment of energy in any type of program until there is a worthwhile reason not to suppress it, and how dopamine acts as a signal of value in the basal ganglia via disinhibition 24:56 Why we can view Parkinson’s as fundamentally not a problem with movement but as a problem with a perception of the value of investing energy in controlling movement 28:23 Tonic and phasic dopamine and the importance of COMT-mediated methylation for regulating the tonic level of dopamine 36:34 The importance of GABA in suppressing the programs that dopamine doesn't signal has value in order to make the dopamine signal of value meaningful 37:28 Overview of the autonomic nervous system; the sympathetic nervous system mediates the fight-or-flight response, and the parasympathetic nervous system mediates the rest-and-digest response. 41:11 The roles of acetylcholine and norepinephrine in the autonomic nervous system, and the importance of nitric oxide to the sexual functions of the autonomic nervous system 44:28 Sleep and circadian rhythms, the importance of vitamin A, morning sun exposure, and avoiding blue light at night 48:12 Melatonin synthesis, the importance of vitamin B6, BH4, oxidative stress, vitamin B5, methylation, and tryptophan uptake into the brain 51:10 Why you can't mimic your natural melatonin rhythm with melatonin supplements 52:55 Antidiuretic hormone, the importance of light hygiene for preventing you from getting up to pee in the middle of the night, and why salt might also help 56:14 Whether the timing of carbohydrate, protein, and choline supplements makes a difference for your daytime wakefulness, your nighttime sleepiness, your deep sleep, and your REM sleep 01:00:44 The possibility that glycine and magnesium could help get rid of conditioned fear responses 01:01:30 Thoughts on consciousness; are we a ghost in the machine, or are we just a machine? 01:06:25 The default mode network is fundamentally about our inward, introverted-directed processes, contrasted with the executive control network, which is fundamentally about our relationship to the outside world and our extraverted functions. 01:10:52 How activities that had nothing to do with people skills but allowed me to flex my extroverted muscles, like exploring the outside world on my own, helped me with my people skills 01:16:48 Nutrition cannot replace the cognitive work necessary to have a healthy mindset and life, but nutrition does make it easier to do the right thing for your mental health.

  Can you really feel years younger and make unexplained symptoms vanish with the click of a button — the “Airplane Mode” on your cell phone? Investigative health journalist Nicolas Pineault used to think this all sounded like something only crazy people wearing tinfoil hats would say. But the overwhelming amount of independent scientific evidence linking electromagnetic fields (EMFs) from wireless technologies with increased risks of cancer, infertility, insomnia, and depression sure has the uncanny ability to change a man’s mind. His new book "" is a simple and unconventional book that will teach you exactly how to reduce your exposure to this brand new 21st-century pollution without going back to the Stone Age. In it, he covers... -What your smartphone, your wifi router and your microwave oven have in common (page 9) -Why policy makers and scientists all worldwide don’t agree about whether EMFs are dangerous or not (page 21) -Is Electro-Hypersensitivity as popularized in the TV show “Better Call Saul” real? Or is it all psychological? (page 62) -Why carrying a cell phone in your pocket can harm your fertility (201 studies prove it) (page 72) -The 1-click fix to reduce cellphone EMFs by 84% (page 142) -What is safer? Speakerphone, earbuds or a Bluetooth ear piece? (page 155) -The #1 worst source of EMF radiation at home (page 160) -Why baby monitors are worse than smartphones, and better alternatives (page 208) It’s true. The jury is still out about whether cellphone radiation is the new smoking or just a temporary scare. But why take chances? Nicolas Pineault is a health journalist who has published more than 1,500 online articles through a daily newsletter called Nick & Gen’s Healthy Life. In 2017, he authored this unconventional book endorsed by top health authorities such as Dr. Mercola, a book that combines common sense and humor to tackle the very serious topic of electromagnetic pollution and its effects on human health.   During our discussion, you'll discover: -The NO/ONOO (nitric oxide/peroxynitrite) cycle and how research by Dr. Martin Pall shows us why chemicals, heavy metals, mold toxins, sugar and junk food, and a bunch of other inflammatory factors each contribute to increasing our sensitivity to EMFs, (and vice-versa)...[10:00]   -How stimulating a pathway called the "NRF2" pathway can help calm down this cycle and make you less EMF sensitive...[23:00]   -EMF shielded clothes, and why Nicolas is now convinced that they actually work...[25:50] -How you can reduce your phone's radiation by 80% by using just 3G instead of 4G/LTE...[33:45]   -How a handful of meta analyses shatter the skeptics beliefs that EMF's do nothing to human, animal and plant biology...[38:55]   -Why you shouldn't hold a cell phone in your hand (and what to use instead)...[44:00]   -Why you need to be very careful with grounding mats and earthing mats, and a supplement to take at night before you ground or earth...[49:45]   -The mineral magnetite that is found in the body of birds, humans and other animals, and how it reacts with EMF...[57:55]   -The importance of metal free inks and natural pigments in tattoos...[62:25]   -Whether or not bluetooth is an issue compared to Wifi and cell phones...[66:40]   -And much more!   Resources from this episode:     -   -   -   -   -   -   -   -   -   - on how EMFs affect voltage-gated calcium channels - on the NO/ONOO- cycle and how EMFs and chemicals act in synergy   -  which shows how calcium channels are activated after less than 5 seconds of EMF exposure   - where she mentions that up to 33% of the population suffers from mild to moderate symptoms of electro sensitivity   - - -- sauna therapy might act by raising BH4 levels   - -   -   - - , the EMF course for health practitioners I've put together with Dr. Klinghardt, Lynch, Mercola, etc. Live beta launching from Feb 26 to Mar 11. -, Dr. Klinghardt's practice   - -   -   -   -   -   -   - -   -   -   -   Show Sponsors: -Kion Aminos - For for muscle recovery, better cognition, reduced cravings, immunity, try Kion Aminos from GetKion.com. -Four Sigmatic - Go to for 15% off. -Organifi - Go to and use discount code GREENFIELD for 20% off your purchase. Do you have questions, thoughts or feedback for Nicolas or me? Leave your comments below and one of us will reply!  

Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism (IEM) caused by mutations in the phenylalanine hydroxylase (PAH) gene. The molecular mechanism underlying deficiency of the PAH protein is, in most of the cases, loss of function due to protein misfolding. PAH mutations induce disturbed oligomerisation, decreased stability and accelerated degradation of hepatic PAH, a key enzyme in phenylalanine metabolism. Since the development of a phenylalanine-restricted diet in the 1950ies, PKU is a prototype for treatable inherited diseases. About 60 years later, the natural PAH cofactor tetrahydrobiopterin (BH4) was shown to act as a pharmacological chaperone stabilising the misfolded PAH protein. In consequence, BH4 (KUVAN®) was introduced to the pharmaceutical market as an alternative treatment for BH4-responsive PAH deficiency. Therefore, PKU is also regarded as a prototype for a pharmacologically treatable protein misfolding disease. Despite the progress in PKU therapy, knowledge on the molecular basis of PKU and the BH4 mode of action was still incomplete. Biochemical and biophysical characterisation of purified variant PAH proteins, which were derived from patient’s mutations, aimed at a better understanding of the molecular mechanisms of PAH loss of function. We showed that local side-chain replacements induce global conformational changes with negative impact on molecular motions that are essential for physiological enzyme function. The development of a continuous real-time fluorescence-based assay of PAH activity allowed for robust analysis of steady state kinetics and allosteric behaviour of recombinantly expressed PAH proteins. We identified positive cooperativity of the PAH enzyme towards BH4, where cooperativity does not rely on the presence of phenylalanine but is determined by activating conformational rearrangements. In vivo investigations on the mode-of-action of BH4 revealed differences in pharmacodynamics but not in pharmacokinetics between different strains of PAH-deficient mice (wild-type, Pahenu1/1 and Pahenu1/2). These observations pointed to a significant impact of the genotype on responsiveness to BH4. The available database information on PAH function associated with PAH mutations was based on non-standardised enzyme activity assays performed in different cellular systems and under different conditions usually focusing on single PAH mutations. These inconsistent data on PAH enzyme activity hindered robust prediction of the patient’s phenotype. Furthermore, assays on single PAH mutations do not reflect the high allelic and phenotypic heterogeneity of PKU with 89 % of patients being compound heterozygotes. In addition, the knowledge on enzyme function and regulation in the therapeutic and pathologic metabolic context was still scarce. In order to get more insight into the interplay of the PAH genotype, the phenylalanine concentration and BH4 treatment, we performed functional analyses of both, single, purified PAH variants as well as PAH full genotypes in the physiological, pathological and therapeutic context. The analysis of PAH activity as a function of phenylalanine and BH4 concentrations enabled determination of the optimal working ranges of the enzyme and visualisation of differences in the regulation of PAH activity by BH4 and phenylalanine depending on the underlying genotype. Moreover, these PAH activity landscapes allowed for setting rules for dietary regimens and pharmacological treatment based on the genotype of the patient. Taken together, precise knowledge on the mechanism of the misfolding-induced loss of function in PAH deficiency enabled a better understanding of the molecular mode of action of pharmacological rescue of enzyme function by BH4. We implemented the combination of genotype-specific functional analyses together with biochemical, clinical and therapeutic data of individual patients as a powerful tool for phenotype prediction and paved the way for personalised medicine strategies in phenylketonuria.

-MEDICINA, ADDIO DULBECCO: Si è spento oggi a San Diego, Renato Dulbecco, il papa' del progetto genoma umano. Vinse il Premio Nobel per la Medicina nel 1975 per le sue scoperte in materia di interazioni tra i virus tumorali e il materiale genetico della cellula. Era nato a Catanzaro il 22 febbraio del 1914. -OBESITA': Una "manovra dietetica" per risanare i conti pubblici. L'obesita' pesa molto sul bilancio dell'Italia: 8,3 miliardi di euro (circa il 6,7 per cento della spesa pubblica) e' il costo sociale annuo relativo a quel circa 10 per cento della popolazione costituita da quasi 5 milioni di obesi adulti. -MENOPAUSA: L'Universita' del Colorado, ha scoperto che la BH4 o tetraidrobiopterina gioca un ruolo chiave nella salute delle arterie delle donne. L'irrigidimento delle arterie puo' causare ipertensione, ispessimento del ventricolo sinistro e aumento del rischio di ictus, di malattie cardiache e di demenza.

Hintergrund: Die bisherige Klassifikation von Patienten mit HPA unterscheidet nicht BH4-sensitive Defekte der PAH und BH4-sensitive Enzymdefekte bei primären Störungen der BH4-Synthese. Sie wurde kürzlich durch die Beobachtung von BH4-Sensitivität bei Patienten mit Mutationen im PAH-Gen ohne Nachweis eines BH4-Mangels in Frage gestellt. Patienten und Methoden: Bei 38 Patienten mit HPA durch Mutationen im PAH-Gen wurden zur systematischen Erfassung von BH4-Sensitivität der biochemische Phänotyp (kombinierter Phenylalanin-BH4-Belastungstest) und die in vivo Phenylalanin-Oxidationsrate (13C-Phe-Oxidationstest) vor und nach Gabe von BH4 untersucht. Phe-BH4-Belastungstest: Die Phenylalaninkonzentration im Vollblut 15 Stunden nach Gabe von BH4 (20 mg/kg) lag signifikant unter dem Ausgangswert bei 10/10 der Patienten mit milder HPA (Phenylalaninkonzentration im Vollblut ohne Diät < 600 µmol/l; Median 363 µmol/l auf 90 µmol/l, p

Durch die systematische Umsetzung von Lithiumtetrahydroboraten mit verschieden substituierten Pyridin-Liganden gelingt es, Regelmäßigkeiten in den erhaltenen Strukturen zu erkennen. Bei Substitution an der para-Stellung der Pyridinringe ändert sich die Zusammensetzung der Verbindung im Vergleich zu LiBH4ž3 py (1) nicht. Das Tetrahydroborat zeigt m2- oder m3-Koordination zum Lithiumion. Bei einfacher ortho-Substitution der Pyridinringe wird eine Verbindung der Zusammensetzung (LiBH4ž2 L)2 erhalten, in der das Tetrahydroborat über ein 2m1 1, m1 2-Koordinationschema zwei Lithiumatome verbrückt. DFT-Rechnungen bestätigen, dass dieses Dimere sich durch besondere Stabilität auszeichnet. Hingegen wird bei zweifacher ortho-Substitution eine monomere Verbindung der Zusammensetzung LiBH4ž2 L erhalten. Durch die Verwendung von Pyridin als Lösemittel gelingt es, Solvate von Lithiumtetrahydroborat mit den Liganden Ethylendiamin und Diethylentriamin darzustellen. Der Vergleich zwischen den Solvaten des Lithiumtetrahydroborates und Lithiumhalogeniden zeigt, dass nur bei guter Solvatation des Lithiumkations analoge Strukturen vorliegen. Pyridin als Lösemittel eignet sich auch zur Darstellung der Kronenether-Solvate von Natrium- und Kaliumtetrahydroborat. Mit KBH4ž18-Krone-6 (24) gelingt erstmalig eine Einkristallstrukturanalyse eines KBH4-Solvates. Durch Verwendung von 18-Krone-6 kann die Struktur des Kaliumborinats KH2BC5H10 (25) aufgeklärt werden. Da zwischen dem Borinat und dem Kaliumion hauptsächlich ionische Wechselwirkungen auftreten, zeigt es deutlich andere Bindungsparameter als die analoge Zirkonverbindung. Insbesondere ist der Bor-Kohlenstoff-Abstand signifikant länger. Ferner gelangt es, Strukturen von vier Amin-Solvaten des Magnesiumtetrahydroborates zu bestimmen. Dabei zeigt sich, dass das Tetrahydroborat-Ion durch Liganden vom Magnesiumatom verdrängt werden kann. Während in Mg(BH4)2ž3 tBuNH2 (28) der durchschnittliche Magnesium-Bor-Abstand 2.537(2) Å beträgt, wird in Mg(BH4)2ž4 py (30) ein Abstand von 2.988(4) Å gefunden. In [Mg(BzlNH2)6](BH4)2 (31) wird das Tetrahydroborat vollständig von dem Magnesium-Ion verdrängt. Durch den Zusatz von einem Äquivalent Wasser gelingt es, Pyridin mit LiBH4 zu Dihydropyridin zu reduzieren. Ohne Wasserzusatz verhält sich LiBH4 gegenüber Pyridin inert. Das Produkt Lithiumtetrakis(1,4-dihydropyridyl)boratž4 py (32) konnte durch Röntgenstrukturanalyse charakterisiert werden. Es handelt sich um das Bor-Analoge des Landsbury-Reagenz, das Aluminium als Zentralatom enthält. Nach Hydrolyse wird 1,4-Dihydropyridin erhalten. Die Umsetzung von Tetrahydroboraten mit Alkoholen und Carbonsäuren eignet sich nur in wenigen Fällen zur Darstellung substituierter Hydroboraten HnB(OR)4-n - bzw. HnB(O2CR)4-n -. Durch die Reaktion von LiBH4 mit 2,2´-Dihydroxybiphenyl in den sekundären Aminen Piperidin, Morpholin und Pyrrolidin als Lösemittel (Gleichung 35) werden gemischte Borate leicht erhalten. Auch bei der Umsetzung von Alkoholaten mit BH3žthf werden verschiedene, von dem eingesetzten Alkoholat abhängige, Reaktionsprodukte erhalten. Auf diesem Weg gelang es NaBH3NCS darzustellen. Mit NaBH3NCSž15-Krone-5 thf (37) war es erstmals möglich, eine nicht fehlgeordnete Struktur mit dem Anion BH3NCS- zu untersuchen. Wie durch IR- und 14N-NMR-Spektroskopie vorhergesagt, liegt 37 als Isothiocyanato-Komplex vor. Der B-NAbstand wird zu 1.575(5) Å bestimmt. Die durch DFT-Rechnung für das Anion BH3NCS- vorhergesagten Bindungsparameter stimmen gut mit den experimentell erhaltenen überein. Phthalsäure reagiert mit BH3žthf unter Bildung von Phthalatohydroborat. Dies kann als Edukt für die Synthese von Monohydroboraten HBR3 - mit sterisch anspruchsvollen Resten R verwendet werden. Deren Darstellung gelingt für R = tBu, OtBu und NMePh. Doch nur für R = tBu wurden Einkristalle erhalten. Für R = OtBu konnten Kristalle isoliert werden, die neben zwei Zersetzungsprodukten auch NaHB(OtBu)3 enthalten. Die Umsetzung von Nukleophilen mit Catecholboran führte in keinem Fall zu dem erwarteten Monohydroborat. Wird Lithiumpiperidid als Nukleophil verwendet, so gelingt es Li2Cat2BHždmežthf (43) zu isolieren. 43 ist formal als Additionsprodukt des bislithiiertem Catechols mit Catecholboran aufzufassen. Das Auftreten von 43 gibt wertvolle Einblicke in den Mechanismus des Ligandenaustausches. Neben NaHB(OtBu)3 (40) ist 43 bisher das einzige durch Röntgenstrukturanalyse charakterisierte Trialkoholatohydroborat. Die Verbindung Na[CatB(NCS)2] (42), die bei der Umsetzung von Catecholboran mit Natriumthiocyanat als Nebenprodukt auftritt, zeigt ein außergewöhnliches NMR-Spektrum. Sowohl im 11B- als auch im 14N-NMR-Spektrum ist die 1J(11B-14N)-Kopplung aufgelöst. Sie beträgt 24 Hz. Mit 42 gelang es zu erstem mal, eine Verbindung, die diese Kopplung zeigt, zu isolieren und in ihrer Struktur aufzuklären. Die Zusammensetzung des Reagenz BBN-CN, das durch Umsetzung von 9-BBN-H mit Natriumcyanid entsteht, wurde durch 11B-, 13C-NMR-Spektroskopie und Einkristallstrukturanalyse aufgeklärt. Es handelt sich bei 44 um das doppelte Addukt von 9-BBN-H an CN-. Die Umsetzung von Thiocyanat mit 9-BBN-H führt zu dem 1:1 Isothiocyanato-Addukt 45. Die experimentellen Befunde, dass Amide und Alkoholate zur Destabilisierung von substituierten Hydroboraten HnBR4-n - führen, wohingegen Cyanid und Thiocyanat diese stabilisieren, wird durch DFT-Rechnungen bestätigt.