Podcasts about Galectin

Join Dr. Jill Carnahan and special guest Ruby Tischoff as they uncover the Role of Galectin-3 in Breakthrough Strategies for Mold and Environmental Illness! Galectin-3 is a protein that has garnered attention for its involvement in various pathological conditions, including inflammatory cascades, hyperactivation, and fibrosis. Dr. Jill Carnahan and guest Ruby Tischoff will explain how targeting Galectin-3 can be a game-changer for individuals suffering from mold illness and other environmental sensitivities. Key Points  ✅ Galectin-3 as a Central Driver of Chronic Inflammation and Toxic Load: Ruby explained how galectin-3 acts as a pro-inflammatory lectin that contributes to chronic illness by promoting fibrosis, immune dysregulation, and cellular "trapping" of toxins like mycotoxins and lipopolysaccharides (LPS). It also facilitates pathogen persistence through biofilm formation and immune evasion, making it a critical target in addressing environmental illness. ✅ Modified Citrus Pectin (PectiSol) as a Clinically Studied Galectin-3 Blocker: The conversation highlighted how PectiSol binds and inhibits galectin-3, disrupting its pathological effects while enhancing cellular communication, immune modulation, and safe detoxification. Peer-reviewed research supports its efficacy in reducing toxic body burden, preventing biofilm-associated infections, and improving outcomes in fibrotic and oncologic conditions. ✅ Supporting Sensitive Patients through Gentle, Targeted Detox: Discussed the importance of tailoring detoxification protocols for environmentally sensitive individuals. Ruby emphasized that by lowering galectin-3, PectiSol helps reduce inflammatory cascades, Herxheimer reactions, and immune hyperactivation, thereby allowing for a more gradual and well-tolerated detoxification process. Ruby Tischoff, FDN-P Ruby Tischoff, FDN-P is a functional diagnostic nutrition practitioner and natural health expert with over 25 years of experience in integrative medicine and nutraceutical science. Ruby has worked closely under the clinical mentorship of renowned physician Isaac Eliaz, MD, and is a recognized expert in the fields of galectin-3 research and therapeutic targeting, safe detoxification, and nutritional science, among other areas. Ruby's commitment as a FDN-P emphasizes addressing root causes rather than masking symptoms, through strategic, individualized integration of leading-edge solutions grounded in evidence-based practices and outstanding clinical success. ecoNugenics  ecoNugenics supplements are rooted in a blend of science and real-world results. Their premium, physician-crafted formulas feature ingredients backed by 200+ peer-reviewed studies and 30 years of clinical use. Gut Health Detox Reset Program: https://econugenics.com/pages/detox-reset-sales-2025 

Dr. Myriah Hinchey is a naturopathic physician who specializes in the treatment of tick-borne diseases, including Lyme disease. Her focused practice and dedication to this specific area of medicine has allowed her to develop deep knowledge and understanding of the complexities surrounding chronic Lyme and other tick-borne diseases. Dr. Hinchey has treated thousands of patients with chronic tick-borne disease and has encountered a wide range of presentations and challenges associated with these conditions. Her clinical experience, combined with ongoing research and study, as well as overcoming her own battle with chronic tick-borne disease contributes to her authority in this field.Furthermore, Dr. Hinchey has stayed up-to-date with the latest research, treatment protocols, and emerging therapies (allopathic/ prescription and natural/ herbal) related to chronic Lyme disease. She has collaborated with other experts in the field and attends several conferences and professional events each year to expand her knowledge and refine her approach to patient care as well as educate other medical professionals on her unique approach to healing tick-borne disease, using herbal and lifestyle medicine. She is a member of and frequent speaker at the International Lyme and Associated Diseases Society (ILADS) and a member of and frequent lecturer at the Medical Academy of Pediatric Special Needs (MAPS).Topics covered in this episode:Functional Medicine Micronutrient Food Sensitivity Detoxification Biofilms Galectin 3 Lyme DiseaseBiofilms on Immune System SurveillanceHerxheimer Reaction Inflammatory CascadePectin (Pactosol)Immune System Dysregulation To learn more about Dr. Myriah Hinchey and her work, head over to https://econugenics.com/collections/pectasol__________________________________________________________We hope you enjoyed this episode. Come check us out at www.lindseyelmore.com/podcast.Become a supporter of this podcast: https://www.spreaker.com/podcast/the-lindsey-elmore-show--5952903/support.

In this bonus episode, Dr. Joel Kahn sits down with Dr. Isaac Eliaz, a renowned clinician and researcher based in California, to discuss Galectin-3 and its critical role in heart health. The conversation kicks off with a brief Hebrew exchange between Dr. Kahn and Dr. Eliaz, who hails from Israel, before diving into the science behind Galectin-3. Galectin-3 is a regulatory protein heavily involved in chronic inflammation and has been linked to the development of numerous conditions, including heart disease. Elevated levels of Galectin-3 are often observed in both acute and chronic heart failure, playing a pivotal role in the inflammatory pathways that lead to myocardial tissue remodeling after injury.  At the Kahn Center, Galectin-3 blood levels are routinely measured as part of our comprehensive approach to heart health. Tune in to learn more about how this protein impacts the heart and the latest insights into managing inflammation to protect cardiovascular health.

Good morning from Pharma and Biotech Daily: the podcast that gives you only what's important to hear in Pharma and Biotech world.Novo Nordisk's weight loss drug, cagrisema, failed to meet investor expectations of achieving 25% weight loss, causing the stock to plummet. Galectin's stock also tumbled after its lead asset missed the primary endpoint in a phase IIb/III trial. On a positive note, Ionis' Tryngolza became the first FDA-approved therapy for familial chylomicronemia syndrome. GSK posted mixed survival data for the Jemperli/Zejula combo in first-line ovarian cancer treatment. Intelligencia AI accurately predicted high-potential biotechs before the ASH conference, showcasing the reliability of its AI-driven methodology. Overall, the biopharma industry is seeing a mix of successes and setbacks in various drug developments and approvals.

In today's episode, host Chris Duffin dives deep into the fascinating world of cognitive enhancement with special guest Anthony Castor. We'll explore a range of nootropic peptides and supplements designed to boost brain function, resilience, and overall well-being. Chris and Anthony discuss such potent peptides as C Max and Celnac, revealing their roles in cognitive enhancement, neuroprotection, and stress resistance. We'll learn about Synapsin's ginsenoside RG3, and its anti-aging properties, and the intriguing nootropic properties of NewPEPT. Listen as Anthony shares personal anecdotes about using compounds like Dihexa for synapse formation and modafinil for enhancing wakefulness and cognitive performance. Throughout the conversation, we'll also delve into the science behind these compounds, examining their neurotransmitter modulation, neuroprotection, and practical applications for high-stress jobs, shift work, and productivity boosts. Additionally, we'll cover lifestyle practices that complement these cognitive enhancers, emphasizing the importance of sleep, hydration, and a balanced diet.   This episode of the ARCHITECT of RESILIENCE podcast is available on Apple, Spotify & YouTube, and is sponsored by  @marekhealth : Performance. Longevity. Optimization.

This week we get to dive into the mysteries of longevity and discover how to outsmart chronic disease with Dr. Isaac Eliaz, a trailblazer in the realm of holistic health. In this episode, we journey through Dr. Eliaz's remarkable transition from Western medicine to the wisdom of Eastern practices, revealing how such an eclectic background has shaped his approach to wellness. Prepare to be enthralled by his insights into the 'survival paradox' and its profound implications on our health, as we discuss the delicate balance between our biological fight or flight mechanisms and their unintended consequences in modern life.We look at the new science behind aging with a discussion that could redefine your understanding of what it means to live a long, healthy life. Dr. Eliaz pulls back the curtain on galectin-3, a protein that may hold the key to aging and longevity. Learn how the levels of this protein correlate with inflammation and fibrosis, which could potentially shorten our lifespan, and how centenarians mystify us with their low galectin-3 levels. From regenerative medicine to epigenetic reprogramming, this episode connects the dots between our lifestyle choices and the inner workings of our cells, offering a blueprint for reversing the aging process and revitalizing our health.We conclude with a heart-to-heart on the emotional and physical healing powers of the heart as Dr. Eliaz illuminates the profound influence our emotions have on gene expression and overall health. This final segment is a testament to the heart's role not just in love and poetry, but as an instrumental organ in combating disease and fostering a nourishing environment where our cells can flourish. https://dreliaz.org/Please support this podcast by checking out our sponsors:Siphox Health, at-home health testing for all (15% off with this link):https://pathlongevity.com/Prolon, maker of the Fasting Mimicking Diet (20% off with this link):https://prolonlife.com/Lufkin Reverse Aging Revolution Summit June 20-22, 2024 https://robertlufkinmdcom.ontralink.com/t?orid=49&opid=2 Live video broadcast every Tuesday and Thursday at 11:45 am pst on X, Facebook, LinkedIn, Twitch, and Youtube to a loyal audience of over 400,000 followers. Also available as an audio podcast on Apple Podcasts, Spotify, Google Podcasts, Stitcher, Pandora, iHeartRadio, and and everywhere quality podcasts can be found. *** CONNECT WITH DR ROB ON SOCIAL MEDIA *** Web: https://robertlufkinmd.com/X: https://x.com/robertlufkinmdYoutube: https://www.youtube.com/robertLufkinmdInstagram: https://www.instagram.com/robertlufkinmd/LinkedIn: ...

References Front Immunol. 2020; 11: 591803 Am J Gastroenterol. 2004 Nov;99(11):2147-9. Biochem Biophys Res Commun. 2005 Dec 16;338(2):1031-6 Front Immunol. 2019 Jun 7;10:1309. FASEB J. 2021 May; 35(5): e21439. Hildegard von Bingen 1150.- "Canticles Of Ecstasy --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

How do pesticides and herbicides impact our gut health? Here to discuss leaky gut and inflammation is a pioneer in the field of integrative medicine, Dr. Isaac Eliaz.   Dr. Isaac Eliaz is not only an integrative medical doctor, he's also a licensed acupuncturist, researcher, product formulator, and expert on detoxification.    Have you heard about Galectin-3, the 'survival protein' that increases bacterial imbalances and drives up other inflammatory proteins in the body?   Dr. Eliaz shares on this as well as some of his unique formulations for detoxifying glyphosate and supporting the healing of the gut wall. This is a fascinating episode as we learn about the worst toxins affecting our health today - and what we can do about it.    Please share this content with someone who may reap the benefits of learning more about leaky gut and inflammation. This information has the potential to change someone's life. Thank you!   In This Episode:   What are the worst toxins impacting our health today? How we are surrounded by glyphosate How pesticides are made in toxic solutions. How glyphosate affects the human body How glyphosate can lead to thyroid cancer and chronic kidney disease The Survival Paradox Protein Why Galectin-3 blockers are the most important supplements we can take Appreciating how the 100 trillion microorganisms in our gut are helping us Is there a test for Galectin-3? The role that Galectin-3 plays in our gut What is the optimal range for Galectin-3? How you really want to be 'under 10' when testing for Galectin-3 What is citrus pectin? How can it help? Understanding our body's inflammatory response to binders Understanding how leaky gut is a response to our environment How modified citrus pectin breaks the biofilm and absorbs the toxins Dr. Isaac Eliaz shares some of his formulations to combat the effects of glyphosate Visit drisaaceliaz.org to find out more Last words of inspiration: because everything changes, everything is possible This podcast is sponsored by ShopC60.com. C60 is a powerful, Nobel Prize-winning antioxidant, that helps to optimize mitochondrial function, fights inflammation, and neutralizes toxic free radicals!   I'm a big fan of using C60 in conjunction with your keto and intermittent fasting lifestyle to support your immune system, help your body detox, and increase energy and mental clarity.    My favorite C60 products for Keto & IF lifestyles include C60 Purple Power in Organic MCT Coconut Oil (you can add this to your coffee) and their delicious Sugar-Free C60 Gummies (made with allulose and monk fruit)!   If you are over the age of 40, and you'd like to kick fatigue and brain fog to the curb this year, visit shopc60.com and use the coupon code “JOCKERS” for 15% OFF  and start taking back control over your health today!   Vitamin C is a critical compound when it comes to supporting the immune system. It's also really good for your skin - and for your energy!   Paleovalley's Essential C Complex is a really powerful, pure Vitamin C supplement. Unlike most Vitamin C supplements, it contains zero synthetic ingredients. In fact it's made from three of the most potent Vitamin C sources on Earth!    Get a stronger immune system, healthier skin, and more energy today! Check out Paleovalley's Essential C Complex at paleovalley.com/jockers    “If you look at pesticides: they are made in very toxic solutions. 'Soups' that are not regulated." -Dr. Isaac Eliaz   Subscribe to the podcast on: Apple Podcast Stitcher Spotify PodBean  TuneIn Radio   Resources: Visit https://shopc60.com/jockers - Use code “JOCKERS” to get 15% off! Paleovalley's Essential C Complex - visit paleovalley.com/jockers  Connect with Dr. Isaac Eliaz: Website - https://dreliaz.org/ Book  - The Survival Paradox: Reversing the Hidden Cause of Aging and Chronic Disease - Kindle edition by Eliaz, Isaac. Health, Fitness & Dieting Kindle eBooks @ Amazon.com EcoNugenics (products) - ecoNugenics   Connect with Dr. Jockers: Instagram – https://www.instagram.com/drjockers/ Facebook – https://www.facebook.com/DrDavidJockers YouTube – https://www.youtube.com/user/djockers Website – https://drjockers.com/ If you are interested in being a guest on the show, we would love to hear from you! Please contact us here! - https://drjockers.com/join-us-dr-jockers-functional-nutrition-podcast/

*Covid vaccine linked to increased all cause mortality *Elon Musk's experience with Covid vaccination *7 medicinal plants for covid-19 prevention & treatment *Covid mandates begin in Texas *Psychiatric illnesses among the vaccinated *Bivalent Booster Protection drags to near zero says CDC *DNA contamination fragments in Pfizer Covid vaccines *Can matcha or green tea fight off covid? *Covid-19 vaccine may trigger rheumatic inflammation diseases *Covid repeated times can have an outsize effect on Blacks. *Covid vaccine could harm gut, leading to brain fog & autoimmune diseases *Galectin-3 and the key to relieving covid symptoms *Protective Covid nasal sprays *Benefits of Vitamin D for sepsis acquired by covid *HV-1 variant *FDA safety signal for covid vaccine among toddlers *FDA issues alert on dosage for covid vaccine for kids *1 in 3 covid vaccine recipients suffered neurological side effects *Sore arm after covid vaccine could indicate severe complications

Dr. Myriah Hinchey is a naturopathic physician who specializes in the treatment of tick-borne diseases, including Lyme disease. Her focused practice and dedication to this specific area of medicine has allowed her to develop deep knowledge and understanding of the complexities surrounding chronic Lyme and other tick-borne diseases. Dr. Hinchey has treated thousands of patients with chronic tick-borne disease and has encountered a wide range of presentations and challenges associated with these conditions. Her clinical experience, combined with ongoing research and study, as well as overcoming her own battle with chronic tick-borne disease contributes to her authority in this field.Furthermore, Dr. Hinchey has stayed up-to-date with the latest research, treatment protocols, and emerging therapies (allopathic/ prescription and natural/ herbal) related to chronic Lyme disease. She has collaborated with other experts in the field and attends several conferences and professional events each year to expand her knowledge and refine her approach to patient care as well as educate other medical professionals on her unique approach to healing tick-borne disease, using herbal and lifestyle medicine. She is a member of and frequent speaker at the International Lyme and Associated Diseases Society (ILADS) and a member of and frequent lecturer at the Medical Academy of Pediatric Special Needs (MAPS).Topics covered in this episode:Functional Medicine Micronutrient Food Sensitivity Detoxification Biofilms Galectin 3 Lyme DiseaseBiofilms on Immune System SurveillanceHerxheimer Reaction Inflammatory CascadePectin (Pactosol)Immune System Dysregulation To learn more about Dr. Myriah Hinchey and her work, head over to https://econugenics.com/collections/pectasol__________________________________________________________This podcast is brought to you by ecoNugenics. You'll hear us discuss both PectaSol Modified Citrus Pectin and GlyphoDetox — some powerful natural support for today's most critical areas of health. We've partnered with ecoNugenics to offer you 20% off PectaSol Modified Citrus Pectin and GlyphoDetox with code LINDSEY15, learn more here: https://econugenics.link/lindseyelmore.__________________________________________________________We hope you enjoyed this episode. Come check us out at www.lindseyelmore.com/podcast.This show is part of the Spreaker Prime Network, if you are interested in advertising on this podcast, contact us at https://www.spreaker.com/show/5952903/advertisement

Achieving quality sleep is essential, and for our listeners looking to improve their rest, remember to use the discount code Kahn10 at Symphony Natural Health for savings on Herbatonin and the maca products highlighted in last week's episode. In this week's episode of Heart Doc VIP, Dr. Joel Kahn covers three diverse mini-topics: the importance of lifestyle choices, the impact of exercise, and how Galectin-3 levels can predict frailty—a subject that we delved into in a previous podcast episode dated 12/23/22. For those interested in managing Galectin-3 levels, modified citrus pectin is available for purchase at Dr. Joel Kahn's Store. The spotlight of this episode is on three traditional Chinese therapies—Tongxinluo (TXL), DanShen, and Fo-ti—that are largely unfamiliar to U.S. healthcare professionals. Dr. Kahn discusses a groundbreaking new study focusing on the use of TXL in heart attack survivors and the significant reductions in adverse outcomes, including mortality. Join us as we explore these exciting treatment options and their potential benefits for heart health.

References Luigi Boccherini: Symphony Op. 12 No. 4 in D Minor JCI Insight. 2016 Nov 17; 1(19): e87748 Front Immunol. 2023; 14: 1149366 Adv Biol Regul.2019 Jan;71:41-54. Int. J. Mol. Sci. 2019, 20(6), 1505 --- Send in a voice message: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/message Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support

Commentary by Dr. Iacopo Fabiani

Welcome to another exciting episode of Heart Doc VIP with Dr. Joel Kahn! This week, we delve into the fascinating realm of healthy aging, healthspan, and longevity. Join us as we explore a groundbreaking project led by tech entrepreneur Bryan Johnson, who is on a mission to reverse the aging process, optimize his health, and share his program developed by a team of 30 advisors. In a recent meeting, Dr. Kahn had the privilege of discussing Bryan Johnson's innovative approach with him. One aspect that deserves applause is Mr. Johnson's decision to adopt a whole-food vegan diet, which aligns perfectly with Dr. Kahn's philosophy. To discover more about this remarkable project, including its details and results, make sure to visit the website: blueprint.bryanjohnson.co/#blueprint-starter-guide. But wait, there's more! In a flashback to our December 22, 2022, episode titled "The Survival Paradox and Galectin-3," Dr. Kahn has gone the extra mile to secure a fantastic offer for our loyal listeners. We've arranged an exclusive 15% discount on the line of products discussed in that particular episode. Just use the code KAHN15 when you visit the following website: econugenics.link/shop-kahn. Tune in to this exciting episode of Heart Doc VIP with Dr. Joel Kahn, where we delve into the fascinating world of healthy aging, Bryan Johnson's groundbreaking project, and an incredible discount on cutting-edge products. It's time to prioritize your health and well-being!

Show notes and links: https://www.chrisbeatcancer.com/dr-isaac-eliaz-the-survival-paradox-galectin-3-modified-citrus-pectin-and-integrative-cancer-therapy

In this episode, Isaac Eliaz together with Evan Hirsch, talk about Modified Citrus Pectin, Galectin-3, Long Covid & Chronic Fatigue.   Dr. Isaac Eliaz is a leading expert in the field of integrative medicine, specializing in cancer, detoxification, immunity, and complex conditions. He is a respected physician, researcher, best-selling author, educator, and mind-body practitioner. Dr. Eliaz partners with leading research institutes including Harvard, National Institutes of Health (NIH), Columbia, and others, to co-author studies on integrative therapies for cancer, heavy metal toxicity, and others. He is founder and Medical Director of Amitabha Medical Clinic in Santa Rosa, CA, where he has pioneered the use of therapeutic apheresis as an adjunctive blood filtration treatment for detox and chronic degenerative conditions.   To learn more about Dr. Isaac Eliaz, please visit: https://www.dreliaz.org/opt-in/   For more information about Dr. Evan and his program, Click Here.   Prefer to watch on Youtube? Click Here.   Please note that any information in this episode is for educational purposes only and does not constitute medical advice.

In this episode, I am speaking with Isaac Eliaz, MD, a leading expert in integrative medicine, specializing in cancer detoxification, immunity, and complex chronic conditions. We will discuss his recent book, The Survival Paradox, the Galectin-3 pathway, hormesis, and more.  In this podcast, Dr. Eliaz and I discuss:  The Survival Paradox and what it means to you Galectin-3 and the critical role it plays in low energy levels and chronic illness The best compound to lower Galectin-3 levels How hormesis is a key factor in preventing disease and fatigue Why meditation and letting go is critical for healing

Reduce systemic damage and start feeling better!  Join leading expert in integrative medicine, Dr. Isaac Eliaz, as he describes the protein Galectin 3, its ancient role in survival, and how it affects your current lifestyle. Dr. Eliaz specializes in cancer, detoxification, immunity, and complex conditions, and brings special insight on how lowering Galectin 3 levels can benefit longevity and health. Listen to this episode to start living a longer and more vibrant life! For show notes, visit  https://fivejourneys.com/podcasts/decrease-inflammation-by-lowering-galectin-3/  Follow us on Instagram at https://www.instagram.com/fivejourneyspodcast/  Read the first two chapters of “The Survival Paradox” book for FREE at https://www.dreliaz.org/opt-in/ Get 15% OFF with the Promo Code “WTRUBOW15” at https://www.dreliaz.org/ and https://econugenics.com/

What's the first thing that goes on your mind when  you think of disease?In this episode, Kashif is joined by Dr. Isaac Eliaz, a pioneer in the field of integrative medicine since the early 1980s. Dr. Isaac specialized on mind-body medicine, cancer, detoxification and immune health.There is a different way of looking at disease, and exploring this new paradigm involves looking into what drives inflammation, fibrosis, and immune dysregulation -- hallmarks of the issues that biohackers want to address. When these issues are understood properly, there's a way of healing perfectly and stopping the fire that burns everything in our bodies.Kashif and Dr. Isaac discuss the aforementioned issues and also ways on how to solve them. They emphasized that going back to the root cause in more aspects than one such as finding one's trauma can lead to healing not just your individual self but also your ancestors. Kashif and Dr. Isaac also dived deeper into discussing Galectin 3, a protein that binds inflammatory compounds, and how it can be battled with Pectasol. Besides these, here are the talking points brought about throughout the episode:Aging, and what makes chronic infectionsInflammation as the body's response to a problemTypes of body responses: sympathetic and parasympathetic response response, fight and flight response, survival and heart responseDifference between a good and stressful environmentPectasol and how it absorbs toxins like the overproduction of the galectin-3 proteinMultigenerational healingQuantum EntanglementConceptual HealingYou may learn more from Dr. Isaac by checking out the following:Survival Paradox, a book authored by Dr.Isaac, on AmazonDr. Isaac Eliaz' website: dreliaz.orgUnlock your infinite healing potential by ordering your copy of the Survival Paradox and getting yourself a bottle of  PectaSol formulated by Dr. Isaac Eliaz today! Avail of a 15% discount by using the code KKHAN15 on https://econugenics.com/pages/pectasol-kashif-khan?utm_source=kashifkhanunpilled&utm_medium=affiliate&utm_campaign=pectasollander_aff&utm_term=kashifkhanunpilled_pectasollander&a_aid=Unpilled&a_bid=65fd5200Follow Kashif Khan to receive updates on the UNPILLED Podcast!This episode may also be streamed on YouTube.

Lectins are a family of proteins that bind to carbohydrates found throughout the plant and animal kingdoms. Some people, unfortunately, think of the healthiest foods on the planet, legumes, as plant sources of lectins to avoid. Not true. This week, Dr. Kahn talks about a lectin made by humans, galectin-3. The paradox is that this compound, measured on a simple lab test, is helpful at low doses but causes inflammation and scarring of at least the heart and kidneys. Modified citrus pectin blocks galectin-3 and is available as a capsule or powder developed by Isaac Eliaz, MD. A new sponsor this week is medicinemanplantco.com and discount code Kahn10 on The Blood Pressure Pill. Try it.

Dr. Isaac Eliaz discusses the sources of toxicity and how it contributes to chronic disease.  He shares his expertise on detox and how toxicity creates illness. He shares his approach based on decades of experience reversing illness. And he explains the paradox that how we are designed to survive can become the barrier to our healing. He has so much to share. Don't miss this 2 part interview.Key takeaways2:23     Dr. Eliaz's background3:28     His research on the Galectin 37:45 The Survival Paradox9:52     Inflammation and cortisol14:01 Modified Citrus Pectin17:49   The gut21:32 Recalibration with Apheresis therapy25:10 Can you avoid pesticides?You probably have heard a lot about ozone therapy by now. Our guests mention it quite a bit on the podcast.If you are healing chronic illness or biohacking for optimal health, Simply O3 will make getting started with ozone therapy super easy.  Go to SimplyO3.com or call (844) 655-2524. Use code FIX to get 10% off! You can find Dr. Isaac Eliaz herewww.dreliaz.orgThe Survival Paradoxeconugenics.com

Dr. Isaac Eliaz discusses the sources of toxicity and how it contributes to chronic disease.  He shares his expertise on detox and how toxicity creates illness. He shares his approach based on decades of experience reversing illness. And he explains the paradox that how we are designed to survive can become the barrier to our healing. He has so much to share. Don't miss this 2 part interview. Key takeaways2:23     Dr. Eliaz's background3:28     His research on the Galectin 37:45     The Survival Paradox9:52     Inflammation and cortisol14:01   Modified Citrus Pectin17:49   The gut21:32   Recalibration with Apheresis therapy25:10   Can you avoid pesticides?You probably have heard a lot about ozone therapy by now. Our guests mention it quite a bit on the podcast.If you are healing chronic illness or biohacking for optimal health, Simply O3 will make getting started with ozone therapy super easy.  Go to SimplyO3.com or call (844) 655 2524. Use code FIX to get 10% off! You can find Dr. Isaac Eliaz herewww.dreliaz.orgThe Survival Paradoxeconugenics.com

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.04.515043v1?rss=1 Authors: Roman-Fernandez, A., Mansour, M., Kugeratski, F. G., Anand, J., Sandilands, E., Galbraith, L., Rakovic, K., Freckmann, E. C., Cumming, E. M., Park, J., Nikolatou, K., Lilla, S., Shaw, R., Strachan, D., Mason, S., Patel, R., McGarry, L., Katoch, A., Campbell, K., Nixon, C., Miller, C. J., Leung, H. Y., Le Quesne, J., Norman, J. C., Zanivan, S. R., Blyth, K., Bryant, D. M. Abstract: The glycocalyx component and sialomucin Podocalyxin (PODXL) is required for normal tissue development by promoting apical membranes to form between cells, triggering lumen formation. Elevated PODXL expression is also associated with metastasis and poor clinical outcome in multiple tumour types. How PODXL presents this duality in effect remains unknown. We identify an unexpected function of PODXL as a decoy receptor for Galectin-3 (GAL3), whereby the PODXL-GAL3 interaction releases GAL3 repression of integrin-based invasion. Differential cortical targeting of PODXL, regulated by ubiquitination, is the molecular mechanism controlling alternate fates. Both PODXL high versus low surface levels occur in parallel subpopulations within cancer cells. Orthotopic intraprostatic xenograft of PODXL-manipulated cells or those with different surface levels of PODXL define that this axis controls metastasis in vivo. Clinically, interplay between PODXL-GAL3 stratifies prostate cancer patients with poor outcome. Our studies define the molecular mechanisms and context in which PODXL promotes invasion and metastasis. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

On this episode of the Menopause Reimagined Podcast, Andrea Donsky, Nutritionist (16+ years), Menopause Educator and Menopause Researcher speaks with Dr. Isaac Eliaz, a Physician, Researcher, and Best-Selling Author. His in-depth training in Western medicine and research, Traditional Asian medicine, and complementary healing modalities has earned him recognition as a leader in integrative wellness and medicine. On this episode you'll learn how inflammation affects your overall health, especially during perimenopause and menopause, and how a simple solution can help reduce the inflammation in your body.Here are some of the highlights Andrea and Dr. Eliaz discussed:00:58 The research Dr. Eliaz has focused on throughout his career and how he integrates different modalities of medicine02:17 The power of citrus fruit and citrus pectin03:15 The Survival Paradox and its connection with inflammation and fibrosis05:30 The definitions of inflammation and fibrosis08:40 Explanation of Galectin-3, organ dysfunction, and how it works synergistically with other treatments12:27 How Galectin-3 changes as we age and why supplementing is important14:30 Inflammation in perimenopause and menopause15:05 Memory, neuroinflammation and Galectin-317:28 Other research in cancer, kidney disease, sepsis, and removal of pesticides19:00 More discussion on pesticides22:10 Detoxification in perimenopause and menopause25:15 Reactive vs responsive transformation of health26:20 Blood sugar effects, insulin resistance,  diabetes, and kidney disease relationship with Galectin-330:15 Testing for Galectin-3 levels and autoimmune conditions32:40 PectaSol formulas and how it can help. The differences between active phase and maintenance phase40:40 Does PectaSol count towards fiber in our diet?41:30 The properties of pectin42:30 Summarizing of how we can affect the quality and quantity of our life44:15 Mind-body connection and it's importance to feeling wellLinks:Buy PectaSol & get a 15% discount. Use code: TRY15ECO. The Survival Paradox: Reversing the Hidden Cause of Aging and Chronic Disease by Dr. Isaac Eliaz: https://amzn.to/3wykJB8Dr. Eliaz's products are available here. ====== 

This week, please join author Andrew Chapman and Guest Editor Harvey White as they discuss the article "Coronary Artery and Cardiac Disease in Patients With Type 2 Myocardial Infarction: A Prospective Cohort Study." Dr. Carolyn Lam: Welcome to Circulation on 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. Dr. Greg Hundley: And I'm Dr. Greg Hundley, Associate Editor and Director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Greg Hundley: Well, Carolyn, this week's feature on April 19th refers to coronary artery and cardiac disease in patients with type two myocardial infarction. And we will have more to learn about that, but how about we grab a cup of coffee and get started with some of the other articles in the issues. Dr. Carolyn Lam: Please? You first. Dr. Greg Hundley: Thanks Carolyn. So Carolyn, this team investigated the observational and causal associations of 90 cardiovascular proteins, which were measured using affinity based proteomic assays to estimate their association with incident heart failure. And so to accomplish this, the team, led by Dr. Thomas Lumbers from University College of London, utilized a fixed effect meta-analysis of four population-based studies comprising a total of 3,000 plus participants with 732 heart failure events. Now, the causal effects of heart failure associated proteins were then investigated by Mendelian randomization using CIS protein, quantitative loci, genetic instruments identified from genome-wide association studies or GWAS and over 30,000 individuals. Dr. Carolyn Lam: Wow! Big study, important stuff. So what did they find? Dr. Greg Hundley: Right Carolyn, several things. So 44 of 90 proteins were positively associated with the risk of incident heart failure. Now, among these eight proteins had evidence of a causal association with heart failure that was robust to multiverse sensitivity analysis. Higher CSF1, Galectin-3 and KIM-1 or kidney injury molecule one were positively associated with the risk of heart failure, whereas higher adrenomedullin chitinase-3 like-protein-1, cathepsin L1, and fibroblast growth factor 23, and matrix metalloproteinase 12 were protective. And so Carolyn in summary, the team identified 44 circulating proteins that were associated with incident heart failure of which eight showed evidence of a causal relationship, and seven were identified as being drugable, including adrenomedullin, which represents a particularly promising drug target. Dr. Greg Hundley: Additionally, Carolyn, this is a really interesting study as the teams approach demonstrates a tractable roadmap for the triangulation of population genomic and proteomic data for the prioritization of therapeutic targets for complex human diseases. Dr Carolyn Lam: Wow! Super cool. Yeah, indeed the methodology is significant there too. Thanks Greg. Well, this next paper deals with hypertrophic cardiomyopathy and we know that familial hypertrophic cardiomyopathy is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. But how exactly is the dysregulated sarcomeric force production sensed and how does that lead to pathological remodeling? Dr. Carolyn Lam: Well, today's authors and they are Dr. Qyang from Yale University School of Medicine and colleagues gained insights from a severe phenotype of an individual with hypertrophic cardiomyopathy and a second genetic alteration in a sarcomeric mechanosensing protein. They derived cardiomyocytes from patient specific induced pluripotent stem cells and developed robust, engineered heart tissues to study human cardiac mechanobiology at both cellular and tissue levels. They further used computational modeling for muscle contraction and rescue of disease phenotype via gene editing and pharmacological interventions to identify a new mechanotransduction pathway in hypertrophic cardiomyopathy. Dr. Greg Hundley: Wow, Carolyn! Tell us more about this new pathway. Dr. Carolyn Lam: The study presents a novel biomechanical mechanism by which enhanced myofilament contractile force generation due to sarcomeric mutations, destabilize the muscle limb protein Z-disc mechanosensory complex, and this leads to disinhibition of calcineurin nuclear factor of activated T-cells or NFAT signaling and consequently leads to hypertrophy. Normalization of hypercontractile force in proband cardiomyocytes either with gene editing approaches or with ectomyosin crossbridge inhibitor mavacamten, resulted in an increase in Muscle Lim Protein levels, a decrease in that calcineurin and fat activity and a rescue from the hypertrophic cardiomyopathy defects. Dr. Carolyn Lam: The authors provided evidence that the common Muscle Lim Protein W4R variant is an important modifier that worsens the disease severity of hypertrophic cardiomyopathy, but alone does not appear sufficient to cause disease. All in all, these data established a foundation for developing innovative mechanism-based treatments for hypertrophic cardiomyopathy that stabilize the Z-disc Muscle Lim Protein mechanosensory complex. Dr. Greg Hundley: Oh, wow Carolyn! What a really nice mechanistic study and important new information too. Well, Carolyn, my next paper comes to us from Dr. Anthony Rosenzweig, Massachusetts General Hospital at the Harvard Medical School and Carolyn the LV myocardium increases in mass in response to pathological as well as physiological stimuli. The former or pathologic hypertrophy, often proceeds cardiomyocyte loss and heart failure. The latter or physiologic, paradoxically protects the heart enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. Now, while long non-encoding RNAs are important in cardiac development and disease associated with pathologic hypertrophy, less is known about their roles in physiologic hypertrophy or cardiomyogenesis. Dr Carolyn Lam: Oh, interesting! So what did these authors find about link RNAs and physiologic hypertrophy? Dr Greg Hundley: Right, Carolyn. So in this study of mice, the authors identified exercise regulated cardiac link RNAs termed lncExACT and lncExACT1 was evolutionarily conserved and decreased in exercised hearts, but increased in experimental heart failure. Cardiac lncExACT1 over expression caused pathological hypertrophy and heart failure while lncExACT1 inhibition induced physiologic hypertrophy and cardiomyogenesis protecting against cardiac fibrosis and dysfunction. Dr. Greg Hundley: Now, lncExACT1 functioned by regulating microRNA 222 calcineurine signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCH2 over expression in zebra fish induced pathological hypertrophy and impaired cardiac regeneration promoting scarring after this injury. In contrast mirroring DCH2 deletion, induced physiological hypertrophy and promoted cardiomyogenesis. Dr. Carolyn Lam: Oh, wow, Greg! Okay. Could you wrap it up for us? What's the take home message? Dr. Greg Hundley: You bet, Carolyn. These studies identify that lncExACT1 DCHS2 is a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1 DCHS2 acts as a master switch, toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the benefits of exercise. Dr Carolyn Lam: Oh, thank you, Greg. Well, also in this issue is an In-Depth paper by Dr. Luesebrink on “Percutaneous Transvalvular Micro Exhale Flow Pump Support in Cardiology.” There's a Research Letter by Dr. Shekhar on “Age and Racial or Ethnic Disparities in Pediatric Out-of-Hospital Cardiac Arrest.” Dr. Greg Hundley: Right, Carolyn. Well, Carolyn from the mailbag, we have a Letter to the Editor from Dr. Gronda entitled “The Failing Heart and SGLT2 inhibitor Renal Effects: Are They Mutually Engaged in Business?” We also have from Dr. Viskin, an ECG challenge entitled “Sinus Node Dysfunction with a Nice Twist.” And finally, Carolyn, there's a Perspective piece from Dr. Schulman entitled “The Price and Quality of the Generic Pharmaceutical Market.” Well, how about at Carolyn we get on our feature discussion involving type two myocardial infarction. Dr. Carolyn Lam: Yay! Let's go. Dr. Greg Hundley: Well, listeners, welcome to our feature discussion on this April 19th and we have with us today, Dr. Andrew Chapman from Edinburg, Scotland and Dr. Harvey White from Auckland, New Zealand. Welcome gentlemen. And we'll start with you, Andrew. First, could you describe for us some of the background information that went into the preparation of your study? Dr Andrew Chapman: Good morning and good evening and thank you very much for the invitation. So type two myocardial infarction is an interesting diagnosis. It was first introduced in around 2007 in recognition that patients could have heart injury when they were in hospital with other problems that led to an imbalance in myocardial oxygen supply, or an unmet need in myocardial oxygen demand, without the presence of atherothrombotic coronary artery disease. We don't know a great deal about these patients. Dr. Andrew Chapman: There have been a number of observational cohort studies, including from ourselves in Scotland, which have demonstrated the outcomes for this patient group are poor. We know only around one-third of patients with type two MI, survive to five years after diagnosis. And we also know, and previously demonstrated from patients in Scotland that those with underlying coronary artery disease actually had the worst outcomes and were at increased risk of future myocardial infarction events due to plaque rupture. So we hypothesized that patients with type two myocardial infarction may have failed a physiological stress test due to another illness and we wanted to investigate what the prevalence of underlying coronary artery disease and/or structural heart disease was, using a panel of different imaging modalities. Dr. Greg Hundley: And so Andrew tell us the hypothesis that you wanted to address? Dr. Andrew Chapman: So we believed that observational evidence suggested that coronary artery disease was important in patients with type two myocardial infarction and we felt that this was increasing their susceptibility to these events. Our primary hypothesis was that the majority of patients with type two myocardial infarction would have underlying coronary artery disease, which was previously quiescent undetected. Dr. Greg Hundley: Tell us a little bit about the study design and the study population that you use to answer this question. Dr. Andrew Chapman: Demand MI is to our knowledge, the first prospective observational cohort study in which patients who were in hospital with evidence of myocardial injury, so a raised cardiac troponin, were screened for the presence of supplier demand imbalance and the clinical diagnosis of type two MI. Now, in those patients that we were able to recruit, we did obviously have important exclusion criteria, but we designed a series of different investigations depending on individual patient risk factors and the appropriateness of such, but the primary goal was to undertake coronary angiography, ideally using an invasive coronary angiogram, which would allow us to undertake additional testing, such as plaque imaging and pressure wire study, to look for the functional consequences of stenosis. In those not fit for an invasive angiogram, we undertook CT coronary angiography. And in all patients we undertook structural imaging and we aimed to do cardiac MRI in all. Due to the coronavirus pandemic and for other reasons, we used echocardiography where MRI was not available. Dr. Greg Hundley: And so the total number of subjects here was how many? Dr. Andrew Chapman: We recruited 100 patients with a clinical diagnosis of type two myocardial infarction. Dr. Greg Hundley: Very good. And so now, Andrew, what were your results? Dr. Andrew Chapman: It's a really fascinating study, obviously, in my opinion. So we recruited 100 patients with a clinical diagnosis of type two myocardial infarction who had evidence of supplier demand and balance, a raised cardiac troponin concentration and evidence of symptoms and/or signs of myocardial ischemia. So in line with the universal definition criteria. Of 100 patients after undertaking coronary imaging, we reclassified the diagnosis in seven. Dr. Andrew Chapman: In five patients, we found that there was evidence of either plaque rupture or a stent thrombosis. And in two patients, we found evidence of myocarditis and stress cardiomyopathy respectively. The first principle finding is that actually despite careful characterization and really detailed screening, we were correct in 93 of 100 patients and we got the diagnosis wrong in seven. The principle hypothesis related to the prevalence of coronary artery disease and this was, as alluded to, undertaking with invasive and noninvasive imaging. But overall, the prevalence of coronary artery disease was 68% of those with type two myocardial infarction and this was obstructive in 30%. Dr. Andrew Chapman: We also undertook structural imaging as mentioned. We observed evidence of left ventricular systolic dysfunction in 34% of patients, of around a third, and perhaps most surprisingly, although we had a clear diagnosis of myocardial infarction in these patients, we only found imaging evidence of in part pattern late gadolinium enhancement, which is considered the gold standard for its diagnosis of myocardial infarction. We only observed that in 42%, which raises some interesting questions. Dr. Andrew Chapman: One of the principle clinical findings of the study is that these underlying conditions of coronary artery disease and left ventricular impairment, both of which are readily treatable with secondary prevention. These conditions were previously unrecognized in 60% of patients and only one-third were on appropriate evidence-based treatment, which gives me some cause for optimism, that there may be a role here for targeted treatment, which could plausibly, plausibly impact on outcomes. Dr. Greg Hundley: And Andrew, just a clarification point, maybe a subgroup analysis, any differences in your findings in regarding men versus women? Dr. Andrew Chapman: Excellent question. And in most studies of type two myocardial infarction, it's thought that this condition is more prevalent in women than men, but undoubtedly in all observational cohorts, there is selection bias as you will only diagnose a type two myocardial infarction if a clinician requests to test troponin in the first place. In our study, interestingly, we recruited more men than women. We had 56% men and we did not find any differences by sex in our analysis. Dr. Greg Hundley: Well listeners, what an excellent description from Dr. Chapman. A very interesting study. And we now want to turn to one of our editors, guest editors, Dr. Harvey White, and Harvey, we want to thank you for your work here with us at the American Heart Association and Circulation, and you receive many articles to review. What attracted you to this particular article and how do we put in context, these results with others that have been published pertaining to type two myocardial infarction? Dr. Harvey White: Thanks, Greg, it's a pleasure to work for Circulation. This paper is very close to my heart because I introduced the typing system in 2007 and it had minimal support and people said, "Why do we need a typing system? We've got killer class and Canadian class and you've done a troponin release system as well". And people stood up and then I laid out the type one plaque rupture. We know the pathophysiology and we know the treatment. Type two, I'd worked on beta blockers, supply and demand and I thought we should define the pathophysiology and define the treatment. That's 2007, which is 15, 16 years ago. And Andrew's paper is really lovely. As I said, it's close to my heart and he inches things forward. I've written an editorial, which I call "Zooming in on the enigmas of type two MI" and enigma means mystery or it's unclear, uncertain. Dr. Harvey White: And that's for sure we don't have full support for the diagnosis. It's become very practical, used in clinical trials and clinically, but we don't know how to manage it and we don't know how to define the groups. Andrew and colleague study is very nice. It's prospective and it has set out to define the coronary artery disease. I've tried for about 10 years to subdivide type two and to those without coronary disease and those with coronary disease. And you could also have a type C, which hasn't been investigated or unknown. And Andrew has answered one of the enigmas and it's really interesting. Large proportion, normal coronary arteries, diagnosis was changed a little bit based on the finding of thrombus. We're challenged with that finding because all MIs have thrombus at PM and really type one should be ruptured plaque. But Andrew changed the diagnosis in a few where one was an OTC, a marvelous case with marvelous pictures, changed the diagnosis. So I like the study and I like the findings. Thanks. Dr. Greg Hundley: Very nice. Well, Andrew, what a perspective and listeners getting just to listen to Dr. White is really quite exciting for me. Andrew, what do you see as the next study to be performed in this sphere of research? Dr. Andrew Chapman: I think we've gone some way to provide some insights into the underlying pathophysiology of this condition and these coexistent conditions of coronary artery disease and left ventricular impairment, which might increase an individual's susceptibility to a type two myocardial infarction. The question is what can we do about it and does targeted treatment with secondary prevention therapies for coronary disease and treatment for heart failure left ventricular impairment, does that improve outcomes? Dr. Andrew Chapman: The next study for me is clear. The next study for me, needs to be a randomized controlled trial, whereby patients with type two myocardial infarction are randomized to current best practice or risk stratification by a cardiologist with an interest in this condition, followed by targeted investigation for coronary disease and LV impairment and thereafter treatment as appropriate. This will be a trial of a complex intervention. I'm very grateful that we've received funding in Scotland already for this pilot phase of this trial, which we've called Targets Type Two and we'll begin recruitment for that trial in August of this year. Dr. Andrew Chapman: I must acknowledge colleagues in this area are looking at coronary disease and type two myocardial infraction. Professor Derek Chew is leading a study called Act Two, which is already recruiting and that will also provide invaluable information as to the prevalence of coronary disease and the potential benefits of treatment of that coronary disease in patients with this condition. Dr. Greg Hundley: And Harvey. How about your, what is your perspective in terms of the next series of studies perhaps that need to be performed in this space? Dr. Harvey White: There's a number and I like very much, Andrew's suggestion. The study that we're doing is randomizing to angiography or not angiography working with Derek Chew. I think all patients with MI should have coronary angiography. It's simple, it takes about 10 minutes. There's obviously some contraindications, but the information as Andrew has pointed out is really so useful. He found dissection, he found an embolus. Normal coronary arteries that in my view changes the management. Whether you should do an angiogram is very important. Randomization to various treatments. That's important. I would like to get more information about the objective evidence of type two MI, the criteria for low hemoglobin, shortness of breath, low blood pressure, high blood pressure, and so forth. There's a lot to do. As Andrew pointed out, the outcome may be worse than type one that's becoming more common and I think these studies will be very, very important. Dr. Greg Hundley: Very nice well listeners. We want to thank Dr Andrew Chapman as lead investigator and Dr Harvey White as guest editor for bringing us this study using advanced imaging of patients with type two myocardial infarction, which identified coronary artery disease in two-thirds and left ventricular dysfunction in one-third, and also highlighting that unrecognized and untreated coronary or cardiac disease occurs in many patients with type two MI and gives us pause for thought on a series of studies that may be performed in the future. Dr. Greg Hundley: Well, on behalf of Carolyn and myself, we want to wish you 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, 2022. 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, please visit AHAjournals.org.

There is an urgent need for prognostic tools that can accurately predict the outcomes of patients undergoing treatment for breast cancer. Dr Fatima Rehman and her colleagues investigated the relationship between breast cancer prognosis and the secretion of a biological marker called Galectin-3 to drive forward the development of optimised treatment regimes. This work was conducted at Shaukat Khanum Memorial Cancer Hospital and Research Centre in Pakistan.

The episode and this conversation is sponsored by HistoIndex. This specific conversation focuses on ways and AI-assistive technologies and analyses can improve our abilities to assess efficacy in drugs that treat advanced fibrosis and cirrhosis.For this extrasode, HistoIndex Chief Scientific Officer Dean Tai joins Quentin Anstee, Mazen Noureddin, Joern Schattenberg and Roger Green to discuss how AI-based algorithms can support improved analysis of ballooned hepatocyte changes both in advanced fibrosis and cirrhosis patients.The rest of the conversation probes how this work will affect diagnosis and drug development, what other tests panelists can foresee and areas where Histoindex is looking to create new algorithms and improve existing ones.This conversation starts with Histoindex Chief Scientific Officer Dean Tai discussing the approach his company takes to AI-assisted hepatopathology. Dean starts by discussing briefly how staining, which is extremely helpful when the goal is to define the individual patient, becomes one more source of error in the more quantitative approach necessary for drug trials. He goes on to point out that while they can achieve 90% success in reproducing an individual coder's result using AI, their goal is to achieve 99% success. He finishes by defining the goal as "majority-agreed hepatocytes," hepatocytes where 5 or more of the 9 pathologists in the initial exercise agreed that a hepatocyte had ballooned. As Dean puts it, with ballooned hepatocytes, "you are really trying to identify bad apples from all apples," not "oranges from apples."In explaining the Histoindex approach, Dean describes some pathologists as "under-callers" who identify relatively few ballooned cells and others as "over-callers" who identify far more cells. The primary difference between the two groups was how large they needed a cell to be before they classed it as "ballooned."Because these differences were systematic and structural, Quentin questions whether we can ever "train" consistent responses. He suggests that consistency will grow for a while but then coders will revert more to their historical patterns. In response to a question from Mazen, Quentin goes on to note that the number of pathologists necessary to validate a ballooned cell will vary inversely with the number of cells identified. For example, a model based on 7-member agreement produces results that are more specific, less sensitive. A model based on 3-member agreement would produce more sensitivity, less specificity. As a result, the team settled on 5 (majority of 9) as the best-rounded number. Mazen responds that for drug trials, being more specific is preferable because it creates a better chance for the drug to appear efficacious when it is.The panelists go on to note that this tool is extremely helpful today in Phase 2, but not in Phase 3 and Dean explains some of the concepts Histoindex is working on to support future use in Phase 3 trials.At that point, the conversation shifts to having Mazen discuss his work in cirrhosis. Going back through historic work, and particularly separate work from Drs. Garcia-Tsao and Younossi, Mazen identified three features to track: septal thickness, nodular features and fibrosis area (the SNOF score). Using these metrics Mazen sought data from the Galectin trials because these were among the few trials that measures portal pressures. The Galectin data allowed researchers to correlate these kinds of measures to a 20% change in portal pressures. This score wound up being reliable in detecting portal hypertension and in two particularly pivotal measures: detecting presence of varices and changes of greater than 20% in portal pressures.

Psalm 23 Video: https://www.youtube.com/watch?v=AIrS3h7cH_A BOOK: The Survival Paradox https://amzn.to/3AkKkOL Modified Citrus Pectin https://amzn.to/33xG02N Medical Center, Amitabha Medical Clinic in Santa Rosa, CA: www.amitabhaclinic.com      

Dr. Isaac Eliaz begins his work from a place of contemplation. “Nothing is solid. Nothing stays the same,” he tells host Dr. Rishi Desai. He has focused in part on Galectin-3, which he calls the survivor protein, for its role shielding cells that decide “I'm not going to die”—cancerous cells. Yet, whether he's operating at the level of one of the 50 trillion cells in a human body, or at the level of the human those cells constitute, Dr. Eliaz understands himself as basically treating an inability to accept change. He calls it the “survival paradox.” The idea has been central to a career devoted to the integration of the scientific and the holistic—a career in which Dr. Eliaz has incorporated Buddhist practice into his pioneering research, oncology, and more. Tune in to hear what makes the heart fundamentally different from other organs, why some doctors get worse over time, and why healing means more than simply getting rid of a disease.

Professor Peter Szodoray og forskerteamet han leder har avdekket sentrale mekanismer som styrer aktivering av kroppens immunceller.Denne forskningen kan få stor betydning for utvikling av vaksiner og behandling av blodkreft. Nøkkelen ligger i Galectin 1 - et lite protein med svært viktige oppgaver. Forskerteamet har vist at å fremme dannelsen av Galectin 1 kan bidra til å stimulere immunsystemet, og en hemming av proteinet kan bekjempe autoimmune sykdommer og leukemi. Peter Szodoray tror dette kan bidra til å utvikle nye legemidler mot kronisk lymfatisk leukemi. See acast.com/privacy for privacy and opt-out information.

Jörn Schattenberg and Mazen Noureddin join the Surfers to discuss five recently-reported or ongoing clinical trials in NASH cirrhosis. The reviews focus on study findings and their implications, but also on the methods used to conduct each trial and the implications of these designs on generalized learning and ability to move beyond the biopsy.Stephen Harrison leads the group in discussing recent results from NASH cirrhosis trials, including the REVERSE trial with obeticholic acid, the FALCON 2 trial with pegbelfermin and a post-hoc analysis of Galectin Therapeutics' Phase 2 trial for belapectin. The group also discussed ongoing trials including the FGF-21 efruxifermin, the FGF-19 aldafermin, the Galectin-3 inhibitor belapectin and the combination agent trial from Gilead Sciences. Along the way, Terns Pharma CEO Sen Sundaram joins from the audience to ask whether the name "cirrhosis" is the most appropriate way to define the disease, given all that we are learning. This session takes a deep look at cirrhosis, with focus on clinical trials, disease pathology and patient management.

Reversing the Hidden Cause of Aging and Chronic Disease  with Dr. Isaac Elias, MD   Dr. Isaac Eliaz is an integrative physician, licensed acupuncturist, researcher, author, formulator, and frequent guest lecturer. He has been a pioneer in integrative medicine research since the early 1980s, with numerous peer-reviewed publications substantiating his innovative protocols. Dr. Eliaz is Founder and Medical Director of Amitabha Medical Clinic in Santa Rosa, California, an integrative health center specializing in cancer, immune function, and inflammatory conditions. He is regarded as a leading expert in the field of Galectin-3 research. His book "The Survival Paradox: Reversing the Hidden Cause of Aging and Chronic Disease” has just been released.   www.survivalparadox.com www.dreliaz.org 

People with type 2 diabetes are at high risk of developing NASH, increasing their risk of poor outcomes. However, the only way to confirm a diagnosis of NASH is through liver biopsy, so how can we help identify people with NASH? This episode examines the currently available approaches to identifying NASH with Professor Arun Sanyal. For more free education, visit the DKIP website, follow us on Twitter (@dkipractice) or connect on LinkedIn. References: European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016 Jun;64(6):1388-402. doi: 10.1016/j.jhep.2015.11.004. Epub 2016 Apr 7. PMID: 27062661. Chalasani N, et al. The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328-357 Disclosures: Professor Arun Sanyal discloses: Consulting advisor: Conatus, GenFit, Gilead, malinckrodt, Pfizer, Salix, Boehringer Ingelhiem, Immuron, Intercept, Novartis, Bristol Myers, Merck, Hemoshear, Lilly, Novo Nordisk, Terns, Galectin, Sequana, Fractyl, Amra, Albireo, Sanofi, Jannsen, Takeda, Northsea, Owl, Poxel, 89 Bio, Siemens, Ngm Bio, Perspectum, Astra Zeneca, Biocellvia, Regeneron, Genentech, Roche, Madrigal, Inventiva, Albireo, Covance, Prosciento, Histoindex, Path Ai Research grants: Conatus, Gilead, Echosense-sandhill, Malinckrodt, Immuron, Boehringer Ingelhiem, Novartis, Bristol Myers, Merck, Lilly, Novo Nordisk, Fractyl, Owl, Second Genome, Siemens, Madrigal, Inventiva, Covance Royalties: Elsevier, Uptodate Stock: Sanyal Bio, Exhalenz, Akarna, Genfit, Hemoshear, Durect, Indalo, Tiziana, Rivus This independent educational activity is supported by an educational grant from Novo Nordisk A/S. The educational content has been developed by Liberum IME in conjunction with an independent steering committee; Novo Nordisk A/S has had no influence on the content of this education.

Naim Alkhouri, Ian Rowe and GenFit Global Diagnostics Leader Suneil Hosmane join Louise Campbell and Roger Green to review presentations from Day Two at the 4th Global NASH Congress.On April 29, over 175 NASH stakeholders from across the globe met virtually to hear 20 presentations from leaders in academia and industry. SurfingNASH selected 9 presentations to discuss in a session recorded right after the conference concluded. When  the five panelists got together, the discussion extended to 90 minutes...too long for a single episode.Episode 22 features Naim Alkhouri and Louise Campbell discussing featured presentations on genomics, transcriptomics and the genetics of precision medicine, plus a review of belapectin and non-hepatologist awareness of and commitment to treat NASH and NAFLD.  The conversation features deep dives into drug development and debates on the proper public health strategy for treating NAFLD patients. Stimulating...engaging..."can't miss."HEP Dynamics will publish the rest of the Day Two reviews in Episode 23 on Saturday, May 1.

Commentary by Dr. Douglas Mann

What happens when sheep become resistant to antiparasitic drugs? Do ancient breeds of sheep hold the key to understanding immune systems? How are animals being used to advance human medicine? What is Galectin-11 and how does it affect parasites? What ways can technology assist in farm management? How are we using virtual reality to help our students study parasites?This week our experts in the field, Professor David Piedrafita, Dr Sarah Preston and Dr Danielle Auldist, explore these questions and what the jobs of the future may look like...To learn more about our Bachelor of Veterinary and Wildlife Science, or if you have any questions about this episode, you can get in touch with us on Instagram, LinkedIn, Facebook and Twitter.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.05.136226v1?rss=1 Authors: Martineau, E., Arbour, D., Vallee, J., Robitaille, R. Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motoneurons in a motor-unit (MU) dependent manner. Glial dysfunction contributes to numerous aspects of the disease. At the neuromuscular junction (NMJ), early alterations in perisynaptic Schwann cell (PSC), glial cells at this synapse, may impact their ability to regulate NMJ stability and repair. Indeed, muscarinic receptors (mAChR) regulate the repair phenotype of PSCs and are overactivated at disease-resistant NMJs (Soleus muscle) in SOD1G37R mice. However, it remains unknown whether this is the case at disease-vulnerable NMJs and whether it translates into an impairment of PSC-dependent repair mechanisms. We used Soleus and Sternomastoid muscles from SOD1G37R mice and performed Ca2+-imaging to monitor PSC activity and used immunohistochemistry to analyze their repair and phagocytic properties. We show that PSC mAChR-dependent activity was transiently increased at disease-vulnerable NMJs (Sternomastoid muscle). Furthermore, PSCs from both muscles extended disorganized processes from denervated NMJs and failed to initiate or guide nerve terminal sprouts at disease-vulnerable NMJs, a phenomenon essential for compensatory reinnervation. This was accompanied by a failure of numerous PSCs to upregulate Galectin-3 (MAC-2), a marker of glial axonal debris phagocytosis, upon NMJ denervation in SOD1 mice. Finally, differences in these PSC-dependent NMJ repair mechanisms were MU-type dependent, thus reflecting MU vulnerability in ALS. Together, these results reveal that neuron-glia communication is ubiquitously altered at the NMJ in ALS. This appears to prevent PSCs from adopting a repair phenotype, resulting in a maladapted response to denervation at the NMJ in ALS. Copy rights belong to original authors. Visit the link for more info

What is Galectin-3 and how is it connected to disease? Galectin-3 (Gal-3) is a protein that modulates an array of biochemical processes in the body and is becoming increasingly implicated in the development of a multitude of diseases, including cancer, fibrosis, and metabolic diseases. But what if there was a way to lower levels of Galectin-3 with a natural compound? Today we welcome clinician and researcher, Dr Isaac Eliaz who shares with us his research on modified citrus pectin (MCP) and how, through influencing Gal-3, it has the potential to be applied to a broad range of inflammatory diseases. Dr Eliaz also discusses his passion for the profound effects of mind-body medicine practices, including how meditation can influence Gal-3 and improve wellbeing. Find today's show notes and transcript here: https://www.fxmedicine.com.au/podcast/galectin-3-new-target-inflammation-dr-isaac-eliaz *****DISCLAIMER: The information provided on FX Medicine is for educational and informational purposes only. The information provided is not, nor is it intended to be, a substitute for professional advice or care. Please seek the advice of a qualified health care professional in the event something you learn here raises questions or concerns regarding your health.*****

Our 2019 Cade Prize winners, Greg Hudalla and Ben Keselowsky, have invented a new way to control inflammatory diseases such as arthritis. The method uses natural enzymes to suppress inflammation at the source, without the harmful side effects of medications. Ben, a native of Tampa and a graduate of the University of South Florida, always enjoyed science and math and was inspired by his high school physics teacher. Greg, originally from Chicago, became interested in medicine after a serious knee accident at 18 ended his collegiate athletic career. *This episode was originally released on May 22, 2019.* TRANSCRIPT: Intro: 0:01 Inventors and their inventions. Welcome to Radio Cade a podcast from the Cade Museum for Creativity and Invention in Gainesville, Florida. The museum is named after James Robert Cade , who invented Gatorade in 1965. My name is Richard Miles. We’ll introduce you to inventors and the things that motivate them, we’ll learn about their personal stories, how their inventions work and how their ideas get from the laboratory to the marketplace. Richard Miles: 0:39 Weekend warriors rejoice, your bad knees are about to get better. That is if the breakthrough by our guests today becomes widely available. People suffering from arthritis will have a brighter future. And before I mangle any more metaphors, welcome my guests, Greg Hudalla and Ben Keselowsky, both professors in biomedical engineering at the University of Florida. Welcome Greg and Ben . Ben Keselowsky: 0:57 Hi. Greg Hudalla: 0:57 Hi. Richard Miles: 0:58 So this is actually personal for me because I’ve been a lifelong runner and just last year found out I have osteoarthritis, a word I couldn’t even pronounce six months ago, much less define. So in between icing my knee and stretching, spending a lot of time at the physical therapist office, I come across your application of the Cade Prize. And so after the show, you’ll both lay hands on me and I’ll be good to go, right? It’s simple, a few needles might be evolved , right ? So let’s explain for our listeners in simple terms, what is the problem that you’re trying to solve? And how does your invention do that? Ben Keselowsky: 1:29 Our mission is to control inflammatory disease and we’re motivated by the fact that inflammation underlies the onset, the progression and the pain associated with numerous diseases that affect millions of people. And so osteoarthritis is one of these that we’re particularly interested in, in the U.S. 13% of the population is afflicted. That’s over 40 million people with direct healthcare costs of over $80 billion per year. Current technologies include steroids and antibodies, and they’re injected into the bloodstream and they’re distributed throughout the body. And they’re associated with terrible side effects, including infection, lymphoma, diabetes, and weight gain. And our technology works at the site of inflammation and it uses natural mechanisms that suppress inflammation. And so, we use an enzyme called IDO, Indoleamine dioxygenase, it breaks down an essential amino acid, tryptophan, into its product [inaudible] . And those two mechanisms, the local depletion of tryptophan and production of [inaudible] work together to quiet down inflammation. And so being able to suppress that inflammation allows tissue to return to healthy function. Greg Hudalla: 2:51 So the key challenge for us when we began developing this technology was coming up with a strategy to place IDO at the site action and have it persist There for a useful duration of time. Um , so if you were to say, inject the drug directly into the tissue of interest, it would be gone within minutes to hours. So you don’t really get a lot of activity or efficacy from a drug. Richard Miles: 3:14 Greg, if I can interrupt that’s the current standard of care, right? That’s what most people do though. They’ll go in, for instance, with osteoarthritis, they’ll go in to get a shot of what is a cortisone or something like that, right? Greg Hudalla: 3:22 Right.Yeah, so they’ll either get a topical treatment right on the surface of the skin, in which case the steroid can penetrate into the joint and have some effect, or they’ll get a localized injection, or they’ll have say an intravenous infusion of drug that’s coursing throughout the entire body. So, what we sought to do was develop an approach by which you can inject the drug into the tissue site, and it would persist as opposed to diffusing away and losing action at the site of interest. So to do this, we developed a technology that we’ve dubbed GATOR, which stands for Galectin Anchors for Therapeutic Enzyme Retention. Specifically, we link IDO our therapeutic enzyme to galectin three, a protein that binds to sugars that decorate every tissue within your body by binding to tissue sugars. Galectin three anchors IDO at the site of injection. So this prevents the diffusion of the drug through the tissue. And this gives us a much longer duration of action of drug at the site of interest. So for example, our version 1.0 of IDO GATOR persists at the injection site for upwards of seven days. Whereas again, conventional drugs say if we were to inject IDO into the tissue directly, it would be gone within minutes to hours. So in terms of moving the technology forward, we have demonstrated preclinical efficacy of IDO GATOR, and a couple of models. So the first is osteoarthritis as was alluded to at the onset of our show today. Um, in these cases, we’ve been able to demonstrate that injection of IDO GATOR into the joint that’s afflicted with osteoarthritis will reduce pain that’s sensed by the host. It will also tamp down inflammation, which in turn will prevent further progression of the disease. And a striking sort of observation here is that injection of IDO GATOR can restore normal gait in the patients . So a patient that’s experienced some degree of limping that limp will be diminished following injection of the drug into the joint. The other space where we have really exciting data is in the area of periodontal disease. So a non resolving chronic inflammation in a tooth. And what we’ve demonstrated to date is that by injecting IDO, IDO GATOR into the site of disease, that again, we can suppress inflammation as a result of turning down that inflammation. We can prevent the bone loss, that’s a hallmark of the disease, which would ultimately lead to the need for the tooth to be extracted or removed. So by getting ahead of the inflammation, we’re not getting ahead of the disease progression Richard Miles: 5:42 So far, I’m loving this. I mean, it sounds like great news. And I neglected mention at the top of the show that to , to congratulate you on advancing from the Cade Prize, sweet 16 round to the final four round. So congratulations to both of you. -Thank you very much. Tell me, does your current research indicate, is there the possibility that you could extend this even beyond say seven days? And is there also the possibility that you mentioned there would be like in the case of say knees, injections, is there a topical patch or application possibility in this? Greg Hudalla: 6:11 Yeah, so I’ll touch on the first question, which is, is there a way to extend the duration? So we haven’t demonstrated it yet with IDO G, but we have developed a model platform in which we can achieve residence time or duration of action, upwards of about 14 to 17 days at the injection site. So in order to do this, we play sort of a biochemistry trick. So most of your listeners are probably familiar with Velcro, right? And Velcros two material surfaces that interact through a series of hooks and eyes, right? And if you were in a vision , one hook interacting with one eye, you can pull it apart pretty easily, but as you start to link multiple hooks and eyes together, you significantly strengthened the interaction at that interface, the interaction between the two pieces of Velcro. So what we do essentially, as we increase the number of galectin three binding sites, and we take our protein of interest or therapeutic interest say IDO, and now, instead of linking it to one copy of our galectin three anchor, we can link it to two or three or four copies of our collecting three anchor. And so this acts in a census molecular Velcro now, instead of having one site of interaction, you have multiple sites of interaction by adding these sites of interaction together, you can strengthen the anchoring phenomenon that we see occur. And so again, we can go from our flagships seven day formulation to formulations that should persist for weeks at the injection site . Richard Miles: 7:29 So before we talk about the commercial path that you’d like to see this travel, let’s talk a little bit about the approval process, right? Because what little I know of medical drugs of any sort of medical devices, there’s this very long convoluted FDA approval process that lasts like 100 years, right ? Roughly right . Maybe 98. It’s just going to be tough to get through the approval process. Ben, you want to take a stab at that? Greg Hudalla: 7:49 So as you mentioned, this would classify as a drug. And so with that comes some unique challenges in the FDA translation space. So first maybe a bit of history. So our therapeutic is an enzyme and enzymes are actually the first class of proteins that were pursued as biologic drugs. So as early, as about the 1950s, when scientists first started developing a real handle on what enzymes do and the roles that they play, and then being able to extract them from living systems, they were really attractive drug candidates because they catalyze reactions they’ll speed, a reaction up they’re essential for basically every biological reaction that happens in our bodies. And so the idea is that unlike a small molecule in which you deliver a very high dose, in principle, you can deliver a little bit of enzyme and it will go a very long way because it will continue acting on drugs fast forward about 30 years into the future, and enzymes have been outpaced by biologic drugs that we hear a lot more about. And some things like monoclonal antibodies. And the reason why is because of the fact that a little bit of enzyme goes a long way. If they leave the site of intended action, they can catalyze reactions offsite, and this can lead to unwanted side effects. So again, that was one of the major drivers behind our anchoring technology now onto the sort of translational efforts or the , what we see as the translational path for IDO GATOR, one of the benefits of our system. So let me remind everyone that what our technology is really based on is what we know of sort of a peanut butter and jelly or chocolate and peanut butter. We take a really promising enzyme drug, and we link it to this anchoring domain, galectin three. And so we’ve taken two proteins and we’ve physically stuck them together to make a new molecule , um , on some level that presents a series of challenges. But the benefit here is that IDO is a protein that’s expressed within our bodies . So we’re naturally tolerant to that enzyme being around galectin three is also a protein that is expressed within our bodies. So we’re naturally tolerant to galectin three being around. So we envision from a safety profile, that IDO of galectin three will be relatively safe from the perspective of it’s tolerance by your immune system. The other benefits of our system that sort of speak to this safety features are that because we’re delivering IDO GATOR locally, we can significantly reduce the dose. So even if a little bit of drug does leave the site of intended action and get into circulation, move into another tissue, the amount of enzyme that’s, there is so low that it’s unlikely to have significant side effects that one might experience if they were to deliver the same drug systemically. So, from the perspective of the molecule itself and sort of entry into the human space, we see those as being real advantages. There’s one more unique feature of our technology that I want to touch on too , which sets it apart from a lot of biologics that go through the preclinical pipeline and then try to make the transition into the clinical or human use space. And that is that galectin three, the anchoring domain in our technology interacts with sugars that are decorating human tissues, but these sugar molecules are conserved from mouse to man. So what that means is , is in principle, there will be no re-engineering of the drug that’s required. So your listeners may have heard of humanized antibodies in the past. So this is an antibody that’s raised in an animal host. And then the domain that’s necessary for binding to sites in our tissue is maintained. It’s moved over from the animal antibody into a human antibody to make it safer, make it more tolerated within human systems. We wouldn’t need to go through that process. So we see on one level, a clearer translation from the preclinical studies that we’re doing now into the clinical space, but we also see this as another potential business opportunity. And that is that we could in theory, use this same therapeutic in veterinary medicine applications. So osteoarthritis, periodontal disease, the two spaces in which we’ve been evaluating efficacy now , um , are things that afflict companion pets all the time, right? My dogs have had teeth extracted because of , of periodontal disease. And I know of a significant number of friends who have dogs and cats that’s that have experienced osteoarthritis in their hips and their knees. As they get older, they receive a lot of the same conventional treatments that humans do, injections of steroids or injections of antibodies because of the fact that both IDO and the galectin three anchoring domain are conserved across mammalian species and the mechanisms by which they work are conserved across mammalian species. We really think there’s an opportunity here to translate into the vet product space first, and then use that to really springboard into the human clinical use. Richard Miles: 12:13 So let’s talk about the business side a bit. Now, could you describe for me what sort of your game plan is now? I mean, are you both going to quit your jobs? One of you clean out your garage? You’ll be for like Steve Wasnic was next Steve jobs, right. You’ll be mixing enzymes in the basement or is there a different, a better path available? Ben Keselowsky: 12:27 Yeah. So this gets into the question of what is it that people should do when they’re trying to start a new company, and it’s really about finding the right team. So finding the right team members and that’s where we’re at. So, we are looking for business people. We’re looking for investing partners to really help drive this forward with vision, with experience. This is the stage we’re at. We’re trying to find partners to help drive this forward. Richard Miles: 12:54 Oh , so still very early stage. Do you have patents on this technology? Ben Keselowsky: 12:57 We’re pending. Yes, we do. We’re very lucky to have excellent support from the office of technology licensing here at UF, and we are pursuing patents in U.S., Canada, Europe, Japan, and Australia and Australia. Thank you. Richard Miles: 13:11 So one of the things our listeners find interesting, at least I find it interesting is the personal backgrounds of the inventors that we have on the show. So Ben, maybe starting with you, if you could talk a little bit about where you’re from, what were some of your early influences? How’d you end up in North central Florida doing some research? Ben Keselowsky: 13:26 Sure. Yeah. So I am born and raised in Florida from Tampa. Richard Miles: 13:31 So you’re a long way from home, right? Ben Keselowsky: 13:33 95 miles or something. That’s right. So growing up in Tampa, I went to USF and studied there. And then I moved all the way up North to Atlanta for grad school and then moved back down to Tampa. So I was, Richard Miles: 13:44 Winters were too cold for up there? Ben Keselowsky: 13:45 Yes, they dragged on and on in Atlanta. So I was very happy to get my family close. We love the small college town. You have mentioned. We were just across the street at the festival. And so we enjoyed the small college town and UF is a fantastic place to be. Our department is centrally located with the health sciences, the teaching hospital, the veterinary medicine, the rest of engineering. We have a really great location where we are in . Fantastic. Richard Miles: 14:13 Did you always want to go into an engineering or science related field? What were you like as a kid? Were you a good student? Teacher’s pet? Spill the beans here. Ben Keselowsky: 14:20 I really quite enjoyed science and math. And my dad was a retired mechanical engineer, worked at TECO Tamp Electric Cooperative. He’d take me to the power plant and show me the boilers and everything that , how it works and teach me how combustion engines work. So, yeah, I was pretty nerdy and enjoyed things like that. It was basically told I’m doing well in this. I should think about engineering. That was your parents telling you that teachers telling you that was my father. Um, and actually in high school, I looked up to my physics teacher a lot. He was fantastic. Terry Adams, he made things very fun. And the group in the class had a lot of fun trying to learn these concepts together and really enjoy the creativity and the teamwork, which is fantastic. Greg and I came together on this chocolate and peanut butter concept just by chatting because we’re right next door . Our offices are running door to each other, but growing up, I was kind of did well in math and science and enjoyed it a lot. I enjoyed the arts too, but now kind of my outlet is the creativity with science and technology. Richard Miles: 15:27 Greg, your turn, were you the sort of kid that we’re dissecting frogs when you’re three years something, tell us about your upbringing. Greg Hudalla: 15:33 So I grew up in and then just outside of Chicago. So I’m a bit farther away from home. I did my undergrad at the Illinois Institute of technology and then grad school in Wisconsin so much like Ben made a pretty short commute from home. And then I moved back to Chicago and my entire family, my entire extended family is still in the greater Chicago land area. So when I left for Madison and then came back, they thought, all right , you’ve done it. You’ve seen the world. You know , there’s Chicago, it’s the greatest city on earth. Richard Miles: 15:57 Wisconsin, how much further can you go? I mean come on. Greg Hudalla: 16:00 And then , uh , Ben was on the hiring committee when I was applying for jobs and University of Florida popped up on my radar. And you could sort of hear the needle scratch if you will, or the tire squeal in the minds of all of my family members, as I tried to explain to them that we were going to pick up and move to Gainesville, but you know, it’s been great. It’s a quintessential American college town and it’s been a really terrific experience in the few years that I’ve been here. So getting back to a little bit of my sort of pre academic time. So I was always a good student, but when I went to college, I didn’t really have a clear vision of what it was that I wanted to do. So, I’m the son of an iron worker and a court reporter. And for them, college was a big deal putting my brother and I into school and seeing us through to the finish line was a huge deal for the two of them. But I was flexible. And like I said, sort of lacking vision when I first went to college. And so my freshman year I was actually a college athlete. So I was playing on the university soccer team and three games into my freshman year. I suffered an injury to my knee that resulted in a significant amount of cartilage. So damage on the, about the size of a silver dollar cartilage had detached from my femur. So I’m in 18, 19 year old kid. At this point in time, I went from pretty much not having osteoarthritis to having extremely advanced osteoarthritis, Richard Miles: 17:16 So this really is personal for you. Greg Hudalla: 17:17 30 seconds. Right? And so when we went to the orthopedic surgeon, the suggestion at the time was we have to take the cartilage out and we’re probably going to need to give you a total knee replacement. And again, I’m a 19 year old kid at this point in time, Richard Miles: 17:30 Not the typical knee replacement surgery candidate . Greg Hudalla: 17:32 Exactly. Right? And this is the early two thousands when total knee replacements don’t have a particularly long lifespan . And so insurance wasn’t happy. My parents weren’t happy. I wasn’t happy. The surgeon wasn’t happy. And so initially they had done a microfracture procedure to try and restore , uh , send me the cartilage that was still relatively healthy at the site. And some time was put into, let’s try to find an alternative approach, some other way to deal with this. And so maybe six to nine months later, we’re meeting with the orthopedic surgeon. And he says, I think you’re a good candidate for a brand new technology. It’s technology known as Carticel that was pioneered by Genzyme in which they take a biopsy of cartilage cells from a healthy site in your body. And they send them out to a lab. They grow them up and they reimplant those cells back into your tissue . So it’s a way to save the joint, save the bone, and ideally provide me a longer timeframe before I might need a total knee replacement. Now I’m 18 or so 19 years out from this procedure. And I still have my original knee, but it was at that moment, that was when the light bulb went off for me. And I said, I want to know who does this right? Who develops technologies like this ? What career path do you follow? Where you can work on things where you can have this sort of impact on someone’s quality of life. And that was when I was introduced to the world of biomedical engineering. And from that moment forward, I said, this is what I want to do. I’m going to study engineering, go to graduate school. And ultimately I want to be running my own academic research lab somewhere. Richard Miles: 18:55 Wow, that’s an amazing moment of clarity for an 18 year old. So refresh my memory. This would result of a hit on the field, or how did this happen? Greg Hudalla: 19:02 Yeah, so I, Richard Miles: 19:03 So you need to go back and thank that guy who took you out, right? Like, oh he gave me direction. Greg Hudalla: 19:07 So it was me that, you know, the fault is entirely on me. I remember going in for the slide tackle and feeling the moment of pain and thinking, this is it, this is what’s happened. What’s going on. It was a game changing experience. Richard Miles: 19:17 So the two of you are still in the thick of your academic careers. And I realized I have to talk to you . You’re you’re older than I thought you were. I think part of it’s by the time you hit your mid fifties, everybody looks young, right? So I was going to say, well, you don’t have much experience to share, but clearly you actually do, in terms of wisdom for younger academics or younger entrepreneurs. And you probably have already gotten this question or you certainly will get it more and more. And that is how did you do it? You can tell us a secret of taking a research and commercializing it. And I understand you’re still at the very beginning of that path, but what are some of the lessons you feel you’ve learned already being in academia for a good while now, and as you see the transition, perhaps of either a new life or a new path for your research commercial market, what are the sorts of things that you would do again, Ben, we can start with you and what are the things that you would not do again? Ben Keselowsky: 20:03 So right now, what we’re trying to do with this technology is very early. And so really the advice of team building is paramount finding the right people. We’re still making those efforts. And so the Cade contest has been fantastic and it’s motivated us to really push on that more and more, and to keep going out for more and more activities like that. And I think that’s just expanding your contact base and trying to make more and more interactions until you find just the right match. So in this venture, we’re still working on that. I’m trying to answer your specific question . Richard Miles: 20:41 Okay. Anything else you want to dispense wisdom on? And just life advice, you know, you don’t have to come up with the smart answers, but it’s funny. Sometimes people have had either very positive or sort of horrific experiences along the way, but it sounds like you all have had a fairly stable, happy research careers to date. Ben Keselowsky: 21:02 It’s a lot of work, keeping your head up, having a group of people that you can rely on to keep you going and commiserate with is critical. So on the commercial side, I’m also a cofounder of a small company called One Vacs LLC. And they’re still also working on finding the right business partners and investors and things like that. They have been quite successful with the people that have been working there. Greg Marshall, is he person there and he’s been getting SBI. Ours is getting NIH funding through small business grants. So I think that that’s a fantastic pathway that startup companies can take as well. But it’s independent from finding the right business partners and you have to do both those things to be successful. Richard Miles: 21:47 Greg how about you, aside from going out and getting banged up on the sports field as a path to advancement, what else would you share in terms of lessons learned? Greg Hudalla: 21:54 I think a lot of us approach this with a vision of what we want to do. There’s a finish line there. And I think the important part is figuring out how to move along that path. Really the first step in that process is identifying the technology. So I’ll be the first one to admit when I started my academic career, I had no idea that this is where my research was going to go at galectin three and galactans are a family of proteins that I’ve studied in my research for a number of years now. But it really wasn’t until a day that I remember very fondly of leaning against the door jam of Ben’s office. And him kind of complaining to me and me complaining about various things. And he said, I’ve got this enzyme that I think is a really terrific candidate for therapeutic. I just don’t know how to get it where I want it to go. And he said, could we do something like this? Could we modify it in this way or modified in that way? He’s like all of my conventional approaches have tried and I just keep destroying the enzyme. I can’t maintain its activity. And I was just kind of standing there daydreaming. And I remember saying, well, we work with on this family of carbohydrate binding proteins, nobody’s really asked if we could use this as a way to localize it a protein at a site of interest. Let’s take a shot at this and see what happens. And now, you know, we’re three or four years down the road. We not only have demonstration that the concept works, but we’ve started moving it into developing this new drug that we think actually has potential to impact the quality of life of many people, the world over. And so for me, that’s the thing that I would encourage people to not lose sight of the opportunity that’s in front of you and listen to the people around you and take what you know, and try to find ways to move what you know, into new spaces. That’s really what innovation is, right? It’s not about inventing something new from scratch, right? I had a student a number of years ago, use the analogy of putting wheels on a suitcase for many years, we lugged suitcases around. So your cases are fantastic tool. As soon as someone put wheels on the suitcase, right? That innovation of taking two technologies that have been around for a very, very long time and blending them together. It revolutionized the way that we travel for me, that’s at the crux of really doing something interesting and exciting and novel. It’s not about finding something fundamentally new it’s on some level, taking things that already exist and finding ways to repurpose them and opportunities to interact with amazing colleagues like Ben and the other people around me at UF have opened my eyes to opportunities that again, when I started my career, I didn’t have the foresight and I didn’t know that this was what my path would look like. Richard Miles: 24:18 So you guys are gonna have to remember and write down these origin stories. Cause after you’ve sold Gator for billions of dollars, you both have yachts and multiple houses gonna need some sort of anchor of humility and touching Greg and Ben. I can already tell there’s a great team dynamic here. I think you guys are gonna do quite well. And thank you very much for coming on Radio Cade, I hope to have you back as guests for an update. Ben Keselowsky: 24:38 Thank you so much. Greg Hudalla: 24:38 Yes. Thanks a lot. Richard Miles: 24:40 I’m Richard Miles. Outro: 24:43 Radio Cade would like to thank the following people for their help and support Liz Gist of the Cade Museum for coordinating and vendor interviews. Bob McPeak of Heartwood Soundstage in downtown Gainesville, Florida for recording, editing and production of the podcasts and music theme. Tracy Collins for the composition and performance of the radio Cade theme song featuring violinist, Jacob Lawson and special thanks to the Cade Museum for Creativity and Invention located in Gainesville, Florida.

Dr Paul Wang:                   Welcome to the monthly podcast, On the Beat for Circulation: Arrhythmia and Electrophysiology. I'm Dr Paul Wang, editor in chief, with some of the key highlights from this month's issue.                                                 In our first paper, in a single‐center observational cohort study, Owen Donnellan and Associates compared arrhythmia recurrence rates in morbidly obese patients who underwent prior bariatric surgery, with those of non-obese patients following atrial fibrillation ablation. In addition to morbidly obese patients who did not undergo bariatric surgery, they matched 51 morbidly obese patients' body mass index, 40 kilograms per meter squared, who had undergone prior bariatric surgery in a two to one manner with 102 non-obese patients, and 102 morbidly obese patients without bariatric surgery on the basis of age, gender, and timing of atrial fibrillation ablation. From the time of bariatric surgery to ablation, bariatric surgery was associated with a significant reduction in BMI. 47.6 to 36.7 and reduction in systolic blood pressure, 145 to 118, P < 0.001.                                                 During a mean follow up of 29 months following ablation, recurrent arrhythmia occurred in 10 out of 51 or 20 patients in a bariatric surgery group, compared to 25 out of 102 patients, 24.5% in a non-obese group, and 56 out of 102 or 55% in the non-bariatric surgery morbidly obese group. No procedural complications were observed in the bariatric surgery group. In our next paper, Martin Andreas and Associates examined whether noninvasive, low-level, transcutaneous electrical stimulation of the greater auricular nerve reduced the risk of postoperative atrial fibrillation, in a pilot of patients undergoing cardiac surgery. After cardiac surgery, electrodes were applied in the triangular fossa of the ear. Stimulation, amplitude 1-million-amp frequency, one Hertz for 40 minutes, followed by a 20-minute break, was performed for up to two weeks after cardiac surgery. Patients were randomized into sham, N equals 20 or treatment group, N equals 20, for low- level, transcutaneous electrical stimulation. Patients receiving low-level, transcutaneous stimulation had a significant reduced incidence of postoperative atrial fibrillation. Four out of 20, compared to controls 11 out of 20. P equals 0.02.                                                 The median duration of postoperative atrial fibrillation was comparable between the treatment group and control group. No effect on low-level stimulation on CRP or IL-6 levels was detectable. In our next paper, Kazuki Iso and Associates examine whether the vagal response phenomenon is common to patients without atrial fibrillation. Continuous, high- frequent stimulation of the left atrial ganglion and plexus was performed in 42 patients, undergoing ablation for atrial fibrillation. In 21 patients undergoing ablation for left-sided accessory pathway, the high frequency stimulation, 20 Hertz at 25 milliamps of 10 millisecond pulse duration, was applied for five seconds at three sites within the presumed anatomical area of each of the five major left atrial ganglion plexus, for a total of 15 sites per patient. The authors define vagal response to high frequency stimulation, as prolongation of the R interval by > 50% in comparison to the mean pre-high-frequency stimulation RR interval, average over 10 beats.                                                 In active ganglion plexus areas, is areas in which vagal response was elicited. Overall, more active ganglion plexi or GP areas were found in the atrial fibrillation group patients, than in the non-atrial fibrillation group patients. And in all five major GPS, the maximum R interval during high-frequency stimulation was significantly prolonged in atrial fibrillation patients. After multivariate adjustment, association was established between the total number of vagal response sites and the presence of atrial fibrillation. The authors concluded that the significant increase in vagal responses elicited in patients with atrial fibrillation, compared to responses in non-atrial fibrillation patients, suggests that the vagal responses is to hypercan stimulations, reflect an abnormally increased ganglion plexi activity, specific to atrial fibrillation substrates.                                                 In our next paper, Vidal Essebag and Associates combine the data from the Bruise Control One and Two studies to evaluate the effect of concomitant antiplatelet therapy on clinically significant hematomas, and to understand the relative risk of clinically significant hematomas in patients treated with DOAC versus continued Warfarin. The Bruise Control study demonstrated that perioperative Warfarin continuation, reduced clinically- significant hematomas by 80%, compared to Heparin bridging. 3.5% versus 16%. Bruise Control Two observed a similarly low risk of clinically-significant hematomas when comparing continued versus interrupted direct oral anticoagulant. 2.1% in both groups. A total of 1,343 patients were included in Bruise Control One and Bruise Control Two, the primary outcome for both trials with clinically-significant hematomas. There are 408 patients identified as having continued either a single or dual antiplatelet agent at the time of device surgery. Anti-platelet use versus non-use was associated with clinically-significant hematomas in 9.8% versus 4.3%. P less than 0.001 and remained a strong independent predictor with multi-variate adjustment. Odds ratio 1.965, however, multivariate analysis adjusting for anti-platelet use, there was no significant difference in clinically-significant hematomas observed between direct oral anticoagulant use, compared with continued Warfarin.                                                 In our next paper, Markus Rottmann and associates examine the relationship between activation slowing during sinus rhythm, and vulnerability for reentry, and correlated the areas with components of the circuit. In a porcine model of healed infarction, of 15 swine, nine had inducible ventricular tachycardia, 5.2 per animal. While in six swine, VT could not be induced despite stimulation from four RV and LV sites at two drive trains in six extra stimuli down to refract refractoriness. Infarcts with ventricular tachycardia had a greater magnitude of activation slowing, during sinus rhythm, a minimal endocardial activation velocity cutoff, less than 0.1 meters per second. Differentiated inducible from non-inducible infarctions. P equals 0.15. Regions of maximal endocardial slowing during the sinus rhythm corresponded to the VT isthmus. Area under the curve equals 0.84 while bystander sites exhibited near normal activation during sinus rhythm. VT circuits were complex, with 41.7 exhibiting discontinuous propagation with intramural bridges of slow conduction in delayed quasi -simultaneous endocardial activation. Regions forming the VT isthmus borders had facts or activation during sinus rhythm, while regions forming the inner isthmus were activated faster during ventricular tachycardia.                                                 In our next paper, Mary Rooney and Associates sought to define the prevalence of subclinical atrial fibrillation in a community-based elderly population, and to characterize subclinical atrial fibrillation and the incremental diagnostic yield of four versus two weeks of continuous ECG monitoring. They conducted a cross-sectional analysis within the community- based, multi-centered observational atherosclerosis risk in communities. Erik Study, using visit five, 2016 to 2017 data. The 2,616 Erik Study participants who wore a lead-less ambulatory ECG monitor for up to two weeks were age 79 years, 42% men and 26% black. In its subset, 386 participants without clinically-recognized atrial fibrillation wore the monitor twice, each time for two weeks. They characterize the prevalence of subclinical atrial fibrillation, atrial fibrillation detected without clinically recognized atrial relation. Over two weeks of monitoring and the diagnostic yield of four versus two weeks, the authors found that the prevalence of subclinical atrial relation was 2.5%. the prevalence of subclinical each relation was 3.3% among white men, 2.5% among white women, 2.1% among black men and 1.6% among black women.                                                 Subclinical A Fib was mostly intermittent, 75%. Among those with intermittent subclinical atrial fibrillation, 91% had an AF burden of less than or equal to 10%, during the monitoring period. In a subset of 386 patients without clinical atrial fibrillation, 78% more subclinical atrial fibrillation was detected by four weeks versus two weeks of ECG monitoring. In this study, the prevalence of subclinical A Fib was lower than previously reported. And monitoring beyond two weeks provided substantial incremental diagnostic yield.                                                 In our next study, Rafael Ramirez and Yoshio Takemoto and Associates investigated arrhythmic mechanisms of Ranolazine in sheet models, in paroxysmal and persistent atrial fibrillation. Paroxysmal atrial fibrillation was maintained during acute stretch and persistent atrial relation was induced by long-term atrial tachypacing. Isolated Langendorff-perfused sheet parts were optically mapped. In paroxysmal atrial fibrillation, Ranolazine 10 micromolar reduced dominance frequency from 8.3 to 6.2 Hertz. P less than 0.01, before converting to sinus rhythm, decreased singularity point density for 0.07 to 0.039 and left atrial epicardium and prolonged atrial fibrillation cycling. Road or duration tip trajectory in variants of Afib cycle lengths were unaltered. In persistent atrial fibrillation, Ranolazine reduced dominance frequency, prolonged atrial fibrillation cycle length, increased the variance of atrial fibrillation cycling and had no effect on singularity point density, and failed to convert atrial fibrillation to sinus rhythm. Doubling the Ranolazine concentration or supplementing with Dofetilide failed to convert persistent atrial fibrillation to sinus rhythm.                                                 In computer simulations or rotors, reducing the sodium current decreased dominant frequency, increased tip meandering, and produce vortex shedding upon wave interaction with un-excitable regions. Thus, the authors concluded that paroxysmal atrial fibrillation and persistent atrial relation respond differently to Ranolazine. Cardioversion in the paroxysmal atrial fibrillation can be attributed partly to decrease dominant frequency and singularity point density and prolongation of atrial fibrillation cycling. In persistent atrial fibrillation, increased dispersion of atrial-like cycle length and likely vortex shedding, contributes to rotor formation, compensating for any rotor loss, and may underline the inefficacy of Ranolazine to terminate persistent atrial fibrillation.                                                 In our next paper, Pyotr Platonov and Associates assess the risk of atrial fibrillation and its relationship to Long-QT syndrome genotype, and the long-term prognosis in Long-QT syndrome patients. Genotype- positive patients with Long-QT syndrome. 784 with LQT1. 746 with LQT2, and 233 with LQT3, were compared with 2043 genotype-negative family members. In patients followed from birth to 60 years, LQT3 patients had an increased risk of atrial fibrillation compared to genotype-negative family members. Hazard ratio 6.62. While neither LQT1 or LQT2 demonstrated increased atrial fibrillation risk. After the age of 60 years, LQT2 patients had significant lower risk of atrial fibrillation compared with genotype-negative controls. Hazard ratio of 0.07. Atrial fibrillation was a significant predictor of cardiac events in LQT3 patients, through the age of 60. Hazard ratio, 5.38. The authors concluded that there's an increased risk of early-age atrial fibrillation in LQT3 patients and a protective effect of LQT2 genotype, resulting in a decreased risk of atrial fibrillation after the age of 60.                                                 In our next paper, Julia Ramírez and Associates evaluated the cardiovascular prognostic value of T-waves morphology restitution in 55,222 individuals undergoing an exercise stress test in the UK biobank, and identify any genetic contribution. They found that 1,743 or 3.2% of individuals had a cardiovascular event. T-wave morphology restitution during recovery from exercise was significantly associated with cardiovascular events. Hazard ratio 1.11. Independent of clinical variables and other ECG markers, T-wave morphology restitution during recovery from exercise was also associated with all-cause mortality. Hazard ratio 1.1. And ventricular arrhythmias, hazard ratio 1.16. They identified 12 genetic loci, in total for T-wave morphology restitution during exercise, in T wave morphology restitution during recovery, of which nine are associated with another ECG marker. Individuals with the top 20% of T-wave morphology restitution during recovery, genetic risk scores, were significantly more likely to have a cardiovascular in the full UK biobank. 5.3% than individuals in the bottom percent, a 20% hazard ratio of 1.07.                                                 We have two other research letters in a special report. Wassim Mosleh, Sharma Kattel report that Galectin-3 is a predictor of mortality after cardiac arrest. In the next research letter, Jerry Jez and Associates report on remotely-navigated ablations in ventricular myocardium, that result in acute lesion-size, comparable to force sensing manual navigation. In a special report, Sohaib Virk and Saurabh Kumar report on a meta-analysis of remote magnetic versus manual catheter navigation for atrial fibrillation ablation. That's it for this month. We'll hope that you'll find the journal to be the go-to place for everyone interested in the field. See you next time. This program is copyright, American Heart Association 2019.  

Dr. Isaac Eliaz discusses Galectin 3, a crucial Survival Protein, which can be managed with Modified Citrus Pectin, with Dr. Ben Weitz. [If you enjoy this podcast, please give us a rating and review on Itunes, so more people will find The Rational Wellness Podcast. Also check out the video version on YouTube at https://www.youtube.com/user/weitzchiro/] […]

Commentary by Dr. Valentin Fuster

Dr. Mark Houston will take you on a journey of your heart health that will leave you spellbound. Dr. Houston lectures for A4M, the Anti-Aging Certification Coursefor MDs. Dr. Houston has been training medical doctors in functional cardiology for over 30 years. Dr. Houston and Dr. Berkson are colleagues, lecture together, are friends, and Dr. Mark is also Dr. Lindsey’s doc! Dr. Mark Houston is a renowned “iconic functional cardiologist”, looking deeper under the “hood” of your heart than most heart or even hypertension doctors ever would. He has been in practice for 44 years bringing together the best state-of-the-art traditional western medicine with natural medicine, functional medicine and metabolic medicine. You’ll hear all these words defined. You will learn how Dr. Houston’s approach integrates the whole person‚ mind, body and spirit. You will be shocked at the in-depth manner in which he evaluates the heart, the lining of your blood vessels and even blood pressure analysis. He leaves no stone unturned.  In this show you will learn: What is functional cardiology? Why do so few cardiologists do this? Why there is a huge difference between different functional cardiologists? How an exam at Dr. Houston’s clinic might differ from an exam at a typical cardiology clinic. Why Dr. Houston tests the ApoC3 gene, what it does, and if it’s out of balance how to fix it. Why you may wantyour blood pressure checked for 24-hours especially at night. What is “nocturnal hypertension”? What is the calcium score test? Why run a blood gene panel on the genes that influence heart health? What test evaluates the “flexibility” or “stiffness” of the lining of your blood vessels? Why use fish oil supplements and which kind are the best? Why recommend nutraceuticals? Why a wise healer uses that which works, not just runs yearly blood tests and tells you all is fine even when you still don’t feel well? What about stents, statins and more!   USA Todaywrote that Dr. Houston is the Most Influential Doctor in both Hypertension and Hyperlipidemia. Houston was named one of America’s Top Physicians in 2008 and 2009.   Learn how a patient of Dr. Berkson’s went to many expert cardiologists who did not find the answer, but Dr. Houston found it in the first visit and fixed it. Books By Doctor Houston What Your Doctor May Not Tell You About Hypertension What Your Doctor May Not Tell You About Heart Disease Nutritional & Integrative Strategies in Cardiovascular medicine The Handbook of Hypertension You will hear a bit about these molecules of mass destruction, too: Galectin 3 TMAO Cystatin C ADMA - Asymmetric dimethylarginine. SDMA - Symmetric dimethylarginines   Contact Dr. Houston’s Office In Nashville, TN. http://hypertensioninstitute.com/  

Commentary by Dr. Valentin Fuster

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. This week's issue provides much long awaited healthcare resource utilization and cost implications in the MOMENTUM 3 randomized controlled trial of a magnetically levitated cardiac pump in advanced heart failure. All of this coming right up after these summaries.                                                 The first original paper this week provides important mammalian data on the acute effects of phosphodiesterase type 1 inhibition on the heart. Now phosphodiesterase type 1, or PDE1, is known to hydrolyze cyclic AMP and cyclic GMP in the heart. However, what's important to understand is that data from rodents may not be applicable to humans because rodents express mostly the cyclic GMP favoring PDE1A isoform, whereas human hearts predominantly express PDE1C isoform which has a balanced selectivity for cyclic AMP and cyclic GMP.                                                 In today's paper, first author Dr Hashimoto, corresponding author Dr Kass from Johns Hopkins University School of Medicine and colleagues, determined the acute effects of PDE1 inhibition on PDE1C expressing mammals, dogs and rabbits, in normal and failing hearts. They found that selective inhibition of PDE1 with ITI-214 induced positive inotropic, lusitropic, chronotropic, and arterial vasodilatory effects in dogs and rabbits. These effects occurred via cyclic AMP modulation and were observed in failing hearts. ITI-214 contractile increase was insensitive to beta adrenergic blockade or heart rate increase, but inhibited in vivo by adenosine receptor inhibition. Furthermore, isolated myocytes revealed differences between PDE1 and PDE3 inhibition. Wherein PDE3 inhibition, augmented beta receptor agonism and calcium transients, whereas PDE1 inhibition enhanced function without calcium increase. These findings have important clinical implications for ITI-214 which has completed phase 1 trials and may provide a novel therapy for heart failure.                                                 We know that macrophages are involved in foam cell formation in atherosclerotic plaques, but our next paper tells us we may now have a way to therapeutically modify this. Co-corresponding authors Dr Wei and Schober from Ludwig Maximilian's University Munich elucidated the role of microRNA generating enzyme Dicer in macrophage activation during atherosclerosis. They showed that Dicer deletion in macrophages accelerated atherosclerosis in mice, along with enhanced inflammatory response and increased lipid accumulation in lesional macrophages. In vitro, alternative activation was limited, whereas lipid filled foam cell formation was exacerbated in Dicer deficient macrophages due to impaired mitochondrial fatty acid oxidative metabolism. MicroRNA biogenesis promoted the degradation of fatty acids by mitochondrial respiration in macrophages, which in turn reduced intracellular lipid storage and limited atherosclerosis. Thus, reducing foam cell formation in atherosclerotic arteries by enhancing energy metabolism through microRNA mediated fatty acid oxidation may be a promising approach for the treatment of atherosclerosis.                                                 The next study evaluates how aortic stiffening relates to resting cerebral blood flow and cerebral vascular reactivity in older adults. First and corresponding author Dr Jefferson from Vanderbilt Memory and Alzheimer's Center and her colleagues studied participants free of clinical dementia, stroke, or heart failure, including 155 older adults with normal cognition and 115 mild cognitive impairment. They found that greater thoracic aortic stiffening quantified by cardiac magnetic resonance was associated with lower cerebral blood flow in cognitively normal older adults. Aortic stiffening was associated with reduced resting cerebral blood flow in the presence of preserved reactivity and associated vasodilatory capacity, particularly among participants without hypertension. ApoE4, a well-known genetic susceptibility risk factor for Alzheimer's disease, modified the results with stronger effects among carriers in the temporal lobes, where Alzheimer's disease pathology is known to first evolve. In summary, greater aortic stiffening related to lower regional cerebral blood flow and higher cerebral vascular reactivity in cognitively normal older adults, especially among individuals with increased genetic predisposition for Alzheimer's disease. Understanding the association between higher aortic stiffness and compromised brain health, including cerebral hemodynamics, may allow for earlier detection and targeted interventions to prevent or mitigate the onset of more serious cerebral vascular damage associated with greater aortic stiffening.                                                 Aortic valve replacement for aortic stenosis is usually timed according to the development of symptoms, but could the timing be too late once irreversible myocardial scar has developed? Co-first authors Drs Musa and Treibel, corresponding author Dr Greenwood from University of Leeds and their colleagues found that in patients with severe aortic stenosis, focal myocardial fibrosis determined by cardiac magnetic resonance imaging was present in over 50% of patients and was associated with a two-fold higher late mortality. Focal scar was independently associated with all cause and cardiovascular mortality, after both surgical and transcatheter aortic valve replacement. In severe aortic stenosis, late gadolinium enhancement appears to be a useful biomarker of left ventricular remodeling, and its presence is associated with worse long-term outcomes following aortic valve intervention. Thus, in severe aortic stenosis, late gadolinium enhancement may be a useful biomarker of left ventricular remodeling, and its presence may be associated with worse long-term outcomes following aortic valve intervention.                                                 The next study suggests that endogenous factor Xa activity may be irrelevant pharmacodynamic marker to guide Edoxaban dosing in future. First author Dr Yin, corresponding author Dr Giugliano from TIMI Study Group, Brigham and Women's Hospital in Boston, and their colleagues, describe the value of endogenous factor Xa activity as a pharmacodynamic marker, linking Edoxaban concentrations and clinical outcomes in the ENGAGE AF-TIMI 48 trial. They showed that the extent of inhibition of endogenous factor Xa activity was influenced by Edoxaban dosing and clinical characteristics, and was associated with both antithrombotic benefit and risk of bleeding. The implications are that this approach of linking endogenous factor Xa activity to clinical outcomes may be used to guide dose selection in future clinical trials, to monitor patients in certain clinical scenarios, or to define the doses of oral factor Xa inhibitors in patients who require precise anticoagulation therapy.                                                 The next paper describes a novel multi-protein complex that plays a critical role in regulating cardiomyocyte survival. First author Dr Zhang, corresponding author Dr Yan from University of Rochester School of Medicine and Dentistry and colleagues, showed that phosphodiesterase 1C is activated by transient receptor potential canonical channel-3 derived calcium, thereby antagonizing adenosine A2 receptor cyclic GMP signaling and promoting cardiomyocyte death or apoptosis. Targeting these molecules individually, or in combination, may represent a compelling therapeutic strategy for potentiating cardiomyocyte survival.                                                 The final paper demonstrates a molecular link between two well-recognized biomarkers of fibrosis, Galectin-3 and Osteopontin. First author Dr Shirakawa, corresponding author Dr Sano from Keio University School of Medicine and their colleagues, showed that Osteopontin was almost exclusively produced by Galectin-3 high CD206 positive macrophages, which specifically appear in the infarct myocardium after a myocardial infarct. The interleukin-10-STAT3 Galectin-3 axis was essential for Osteopontin producing reparative macrophage polarization after myocardial infarction, and these macrophages contributed to tissue repair by promoting fibrosis and clearance of apoptotic cells. These results therefore suggest that Galectin-3 may contribute to reparative fibrosis in the infarct myocardium by controlling Osteopontin levels. And that brings us to the end of this week's summaries, now for a feature discussion.                                                 Left ventricular assist devices have truly revolutionized our management of advanced heart failure. In fact, these devices have allowed us to keep patients not just as a bridge to transplantation, but as destination therapy. The devices get better and better but also more and more expensive, and the problem is, that places a lot of strain on our healthcare systems. A lot of us are crying out for information on the cost effectiveness of these newer devices, and guess what? We have answers this week with our featured paper.                                                 I am delighted to have with us the first and corresponding author Dr Mandeep Mehra from Brigham and Women's Hospital in Boston, Massachusetts, as well as our senior editor Dr Biykem Bozkurt from Baylor College of Medicine in Houston, Texas. Hello, Mandeep and Biykem! I am so pleased to be talking about a subject really close to all our hearts. Mandeep, could you start by maybe sketching out the actual issue, and maybe reminding our audience what's the difference between the different types of left ventricular assist systems that you compared. Dr Mandeep Mehra:       The era of left ventricular assist devices took a major therapeutic shift when we recognized that we could usher in continuous flow devices. These are devices that generate no peripheral pulse, they do not have systole and diastole. And these devices are small in profile, have very few moving parts, and there are several commercially available devices, two in the United States and up to three worldwide, that bear these characteristics.                                                 The HeartMate II device, which is a continuous flow device that flows blood in an axial format. The HeartWare, or HVAD device, which is a centrifugal flow pump, where the blood comes in and then is ejected at a 90 degree angle. The Jarvik 2000 pump that is still used in some areas, in many regions experimentally, and then the new kid on the block, the HeartMate 3 device, which is a centrifugal flow pump with some very unique technological characteristics. Dr Carolyn Lam:                Nice! And now drumroll, please tell us what you found in your brilliant study this week. Dr Mandeep Mehra:       First, I'd like to remind the audience that the MOMENTUM 3 trial which randomized patients to the HeartMate II versus the HeartMate 3 device, was called MOMENTUM 3 and was a two-year study. We presented the pivotal two year trials results in 366 randomized patients earlier this year in The New England Journal of Medicine, and this study showed that the HeartMate 3 was superior on the primary endpoint when compared to the HeartMate II. The primary endpoint was survival, free of a disabling stroke, or the need to replace the pump surgically for a pump malfunction. And much of that, Carolyn, was driven by the need for replacement of the pump because the HeartMate 3 pump has some unique features that reduce its proclivity for pump thrombosis.                                                 The HeartMate 3 pump is a frictionless pump. It's completely, magnetically, dynamically, born in the rotor. It has wider blood flow paths, so we don't see hemolysis with this pump. And this pump also has an artificial intrinsic pulse that has been created, that pulsates the pump in a 40 beats per minute configuration. So this was the primary trial result, and one of the lucky foresights that we had when we designed the trial was to embed, prospectively, economic analysis within this trial. We recognized that the cost effectiveness related issues and cost configurations with these devices would become very, very important as we scale into today's day and age of healthcare transformation. And the paper that is being presented in Circulation this week, really speaks to the health resource utilization and cost outcomes between the two devices.                                                 We found that the HeartMate 3 pump is actually a cost minimization device, and what that means, Carolyn, is that we have become very used to thinking of new technology as providing incremental costs. So we think that, "Oh, well, what incremental costs should society bear for the benefits as we allocate new technology?" And in this particular trial, what we found is that while the costs of the pump itself, the HeartMate II and the HeartMate 3, were kept the same, which means its operational implant costs were the same, pretty much. We found that the HeartMate 3 pump was associated with a reduction in healthcare resource utilization over two years and with a marked decrease in cost. And in fact, our estimate of cost reduction was in the range of about 65 thousand dollars less, compared to the HeartMate II, in favor of the HeartMate 3. Dr Carolyn Lam:                Wow, Mandeep, first of all, congratulations on these remarkable findings. Biykem, I really have to bring you in here. What do you think of the implications of this? Dr Biykem Bozkurt:         First, I would like to congratulate the authors for a very innovative approach. As Mandeep has stated, they prospectively collected very challenging billing data from the hospitals, and then also did a very complex analysis including the VRG, as well as looking at payer reimbursements for public versus private. And did a variety of subgroup analysis, which I thought was quite helpful in sorting out that perhaps the cost effectiveness was concurrent both from the Medicare, the public, as well as the private, or regardless of the intent for destination versus bridge to transplant.                                                 Probably the most important concept when you look at these close analysis is incremental cost effectiveness ratio, per quality of adjusted life year gained. Now, I do realize the current analysis doesn't allow us to infer the ICER benefit or the incremental cost effectiveness, which I think the investigators are planning to do with a thousand and more patients over a course of two years, which is going to be probably the more definitive. But as it currently stands, with what is provided by Dr Mehra and his colleagues is, we're probably reaching that sweet spot of what is construed as the cost effectiveness ratio of a cost.                                                 Let's say 100 thousand dollars over the course of a year, then I would like to ask Mandeep whether on the prediction will reach that threshold of less than 100 thousand dollars. Because the former studies, looking at the ICER ratios, or incremental cost effectiveness ratios for the DT destination therapies, usually we select somewhere around 200 thousand dollars. And I know that usually that is seen as a prohibited cost, and there was a discussion whether we would be able to reduce the cost by about half, either doing index admission and add subsequent hospitalizations. With the data Dr Mehra and his colleagues have shown, it looks like the re-hospitalization cost is about, approximately half, or reduced by 50%. Mandeep, any thoughts on that, on that sweet spot? Dr Mandeep Mehra:       Yeah. I think, Biykem, you have articulated this extraordinarily well. And for the audience, since it's worldwide, I'd like to place a few things in perspective on how to think of economic modeling. First of all, the point I would make is that this is the first prospectively collected data that we have in the field, and as you pointed out, it was very, very difficult to pull this data together and is still very complex. But let's just think about what ICER really is. It all starts with what we consider to be health utility.                                                 For example, Carolyn, Biykem, and me less so, would have a health utility of 1.0, 1.0 means a perfect health utility number. And I know, Carolyn, you and Biykem are absolutely perfect so you would be a 1.0, I probably am not a 1.0. But a patient with advanced heart failure has a health utility of about .4, so that's only 40% of what is perfect. And when we place ventricular assist devices, whether you place the HeartMate 3 or the HeartMate II, the health utility actually jumps up to about .7. So it's not perfect yet, but it moves all the way up there.                                                 The incremental cost effectiveness ratios of implanting a device over time are calculated based on this health utility benefit, compared to the population of advanced heart failure. And the best current estimates of the HeartMate II are that ICER is about 200 thousand dollars, per quality adjusted life years gained, and this has been done by creating what's known as Markov modeling. A lot of that, by the way, is conjecture, it's not real information. It is predicted information, so one has to take that data with a grain of salt.                                                 Here in this health resource analysis for MOMENTUM 3, we actually looked at actual data. There are some estimates used in this analysis as well, where we did not have accurate billing forms available, but we focused on those things where we had very clear knowledge of the cost of outcomes. For example, we did not look at the costs of outpatient follow-up care. We mainly looked at the cost differences of hospitalizations. And what we essentially found here is that just looking at hospitalizations and differences between the two devices, the cost differential, whether it's Medicare which is public [inaudible 00:20:14], or whether it's commercial. It ranges somewhere between 50 to 65 thousand dollars of difference between the two devices.                                                 Now, if you assume that the ICER for the HeartMate II is accurately at about 200 thousand, and you reduce that ICER by about 50 to 60 thousand, the ICER would naturally come into the range of what you would consider to be about 135 thousand to 150 thousand dollars per quality adjusted life years gained for the HeartMate 3, compared to an advanced heart failure population. Once we look at it from that perspective, as Biykem pointed out, we are getting closer and closer to the societal norms.                                                 At one time-point, society used to think of a quality adjusted life years gained cost of 50 thousand dollars as something that would be acceptable to society, and this was seemingly based on the threshold for what dialysis provides in benefit. And now, we recognize that we have to really expand that to somewhere around 100 thousand more logically, or between 100 and 150 thousand for some technologies. The important thing I would say to you is that, that is society dependent. So what the United States considers to be a reasonable ICER, say 100 to 130 thousand dollars per quality adjusted life years gained, may not be the same that Great Britain would look at, or Sweden would look at, or another country would look at. And each country actually creates their own economic value propositions, and this will have to be taken into account as we think about this data as well. Dr Carolyn Lam:                How cleverly and clearly articulated, thank you so much Mandeep. Just one last question for both you and Biykem, what do you think this implies for moving to less and less advanced heart failure with these left ventricular assist device systems? Biykem? Dr Biykem Bozkurt:         It's an ever-expanding field, and as these devices are becoming smaller, lower profile with lesser complications and more affordable, probably the utilization will likely increase as we have been seeing. As you know, even the percutaneous non-durable device used, as well as our mechanical circulatory support durable devices are definitely increasing utilization. And thus, one may wonder not only the bridge to transplantation, but the destination therapy portfolio, or bridge to decision portfolio, may really increase as these devices become safer and more affordable. Dr Carolyn Lam:                Wow, that's amazing. How about you, Mandeep, what do you think? Dr Mandeep Mehra:       Carolyn, I couldn't have said it any better than what Biykem articulated. I do think that at least in the United States, as we reach the thresholds of cost effectiveness that we as a society accept, we will start to see a lot more widespread utilization, particularly for lifelong therapy or so-called destination therapy. I completely agree with that. I think that moving the needle to the less sicker population is still challenging, because there are complications with these devices that make that slightly difficult.                                                 There was a trial called the REVIVE-IT trial that was stopped midstream largely because of concerns about pump thrombosis, and that trial was looking at taking these devices to a less sick NYHA class 3 population and was stopped midstream. Now that the HeartMate 3 has pretty much resolved the issue of pump thrombosis, and even show a halfing in stroke rates with this device over two years, I think that that portfolio of evidence needs to be reopened. I would caution though, that until we have confirmatory randomized data in those less sick populations, the use to that population should still stay restricted. Dr Carolyn Lam:                I don't think anyone could have said it better than both of you. Thank you so much for this very insightful and balanced conversation.                                                 Thank you so much for listening today. You were listening to Circulation on the Run, and don't forget to tune again next week.  

Is galectin-3 a post-MI prognostic biomarker for out times? Also today, postmenopausal estrogen use is down since 2006, watching for substance abuse risks among reservists who have never been deployed, and do free meals for physicians affect opioid prescribing?

Why You Should Listen: In this episode, you will learn about Galectin-3, biofilms, and the use of modified citrus pectin in chronic health conditions. About My Guest: My guest for this episode is Dr. Isaac Eliaz. Dr. Isaac Eliaz, MD, LAc, MS is an integrative medical doctor, licensed acupuncturist, researcher, product formulator, and frequent guest lecturer. He has been a pioneer in holistic medicine since the early 1980s, and has published numerous peer-reviewed research papers on several of his key integrative health formulas. He is the founder and medical director of Amitabha Medical Clinic in Santa Rosa, California, an integrative health center specializing in cancer and chronic conditions. An expert in using highly strategic, synergistic protocols to address numerous areas of health including metastatic cancer, immunity, digestion, detoxification, diabetes, cardiovascular health and more, Dr Eliaz is also widely regarded as the leading expert in the field of Modified Citrus Pectin research. Along with his clinical practice, Dr. Eliaz is an author and frequent lecturer who presents on his unique approaches to health and healing to practitioners worldwide. Dr. Eliaz is committed to empowering patients, practitioners and those seeking guidance for lasting wellness through education, ongoing research and community building. Key Takeaways: - What is galectin-3 and what problems does it cause? - What is the role of galectin-3 and biofilms? - How might reducing galectin-3 help other treatments to work better? - Can galectin-3 be measured? - How does modified citrus pectin work to bind metals, reduce galectin-3, reduce inflammation, and support immunity? - Is modified citrus pectin a good binder of heavy metals? - What role does modified citrus pectin play in reducing TGFb1, C4a, and MMP9? - Can those with citrus allergies generally use modified citrus pectin? - What is Honokiol and how might it be helpful in supporting health? - How important is stress reduction and meditation in shifting away from a sympathetic-dominant state? - What role do the mental, emotional, and spiritual realms play in chronic illness? Connect With My Guest: http://www.dreliaz.org http://www.econugenics.com Code BHG15 will provide a 15% discount on Econugenics products. Related Resources: http://www.amitabhaclinic.com Interview Date: January 12, 2018 Disclosure: BetterHealthGuy.com is an affiliate of Econugenics. Disclaimer: The content of this show is for informational purposes only and is not intended to diagnose, treat, or cure any illness or medical condition. Nothing in today's discussion is meant to serve as medical advice or as information to facilitate self-treatment. As always, please discuss any potential health-related decisions with your own personal medical authority.

Dr. Ben Weitz interviews Dr. Isaac Eliaz, who discusses Galectin-3, an inflammatory protein measured in the blood, that increases risk of nearly every chronic disease, including heart disease, diabetes, arthritis, cancer, chronic kidney disease, and heart failure. [If you enjoy this podcast, please give us a positive review on Itunes, so more people will find […]

Dr Gabriel Rabinovich meets with ecancertv at AACR 2016 to discuss galectins. Galectin 1, secreted by tumour cells, kills T cells and promotes non-immunogenic tumourous dendritic cell growth. Beyond immune suppression, galectins are also linked to angiogenesis, which further promotes the persistence of the tumour microenvironment. Dr Rabinovich reports on the current trials of galectin targeted therapy, and his upcoming research.

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor that is characterized by abundant tumor stroma and a potent immunosuppressive microenvironment. Further studies to clarify why T cells infiltrate the tumor but are not able to perform effector functions as well as to find new effective therapies to overcome immunosuppression are urgently needed. The aims of the present study were (1) to characterize different murine PDAC tumor models in regard to their utility for studying novel immunotherapeutic approaches, (2) to assess the therapeutic efficacy of a novel bifunctional ppp-siRNA that combines silencing of the immunosuppressive molecule galectin-1 and RIG-I-mediated immune activation in murine PDAC and (3) to characterize the immunosuppressive mechanisms leading to T cell inhibition in the tumor microenvironment. (1) This study revealed that the pancreatic cancer cell line T110299, which was developed from a primary tumor of the KPC mouse model, is a new valuable tool for studying novel treatment strategies for PDAC. The histological appearance of T110299 tumors reflects in many aspects the primary tumors in KPC mice, which harbor mutations in the Kras oncogene and p53, and the human disease with regard to tumor differentiation, extensive tumor stroma development, poor vascularization and expression of immunosuppressive molecules, like indoleamine 2,3-dioxygenase (IDO) and galectin-1 (Gal-1). In contrast, Panc02 tumors were found to have a sarcomatoid architecture with very little tumor stroma. In Panc02 cells, galectin-1 was strongly expressed by the tumor cells, which differs from the situation found in humans, KPC mice and T110299 tumors, where galectin-1 is preferentially expressed in tumor-associated pancreatic stellate cells (PSC). However, expression of the cytosolic helicase RIG-I was functional in Panc02 cells, but defective in T110299 cells. As RIG-I is expressed in all human PDAC cell lines tested, the Panc02 model appears to be better suited to study RIG-I-based immunotherapies (Ellermeier et al., 2013). Thus, the histological and functional characterization of the tumor models in this thesis will allow selecting the best-suited tumor model for addressing specific aspects of immunotherapy. (2) Treatment studies of PDAC were performed with the 5’ppp-modified siRNA molecule ppp-Gal-1 in the orthotopic Panc02 tumor model. The dual activities of this molecule were confirmed in vitro, leading to (i) reduced galectin-1 expression via RNAi; and (ii) production of CXCL10 and IFN-, MHC-I up-regulation and apoptosis of tumor cells via RIG-I activation. Treatment of mice with orthotopic pancreatic tumors with ppp-Gal-1 significantly prolonged survival, as compared to unmodified OH-Gal-1 or control RNA. In addition, 20% of the mice completely rejected their tumors leading to long-term tumor control. Thus, bifunctional 5’ppp-modified siRNA is a promising treatment strategy for PDAC deserving further pre-clinical evaluation. (3) Pancreatic tumor cells employ multiple mechanisms for suppression of T cell responses. This study identified TGF-β and IDO as two potent mechanisms leading to inhibition of T cell proliferation. Minute amounts of PDAC supernatants effectively blocked T cell proliferation induced by CD3 and CD28 triggering. This could be partially prevented by SD-208, a small molecule inhibitor of TGF-β receptor signaling, or by blocking IDO activity with D-1-MT. Interestingly, tumor supernatants induced up-regulation of IDO mRNA expression in T cells. Furthermore, blocking IDO activity in T cells appeared to be more effective than blocking IDO in tumor cells. This leads to a new hypothesis that factors secreted by the tumor cells induce IDO expression in T cells, which in turn leads to auto-intoxication of the T cells via kynurenine production and eventually T cell apoptosis. Further studies confirming this hypothesis are warranted.

Fri, 1 Mar 2013 12:00:00 +0100 https://epub.ub.uni-muenchen.de/22768/1/22768.pdf Buzas, E. I.; Gabius, Hans-Joachim; Falus, A.; Molnar, M. J.; Bovin, N. V.; Kaltner, H.; Nagy, G.; Gordeeva, E.; André, S.; Gal, J.; Srivastava, S. K.; Antal, P.; Pal, Z. ddc:

C-type lectin receptors, their adaptor molecules and S-type lectins (galectins) are involved in the recognition of glycosylated self-antigens and pathogens. However, little is known about the species- and organ-specific expression profiles of these molecules. We therefore determined the mRNA expression levels of Dectin-1, MR1, MR2, DC-SIGN, Syk, Card-9, Bcl-10, Malt-1, Src, Dec-205, Galectin-1, Tim-3, Trem-1, and DAP-12 in 11 solid organs of human and mice. Mouse organs revealed lower mRNA levels of most molecules compared to spleen. However, Dec-205 and Galectin-1 in thymus, Src in brain, MR2, Card-9, Bcl-10, Src, and Dec-205 in small intestine, MR2, Bcl-10, Src, Galectin-1 in kidney, and Src and Galectin-1 in muscle were at least 2-fold higher expressed compared to spleen. Human lung, liver and heart expressed higher mRNA levels of most genes compared to spleen. Dectin-1, MR1, Syk and Trem-1 mRNA were strongly up-regulated upon ischemia-reperfusion injury in murine kidney. Tim3, DAP-12, Card-9, DC-SIGN and MR2 were further up-regulated during renal fibrosis. Murine kidney showed higher DAP-12, Syk, Card-9 and Dectin-1 mRNA expression during the progression of lupus nephritis. Thus, the organ-, and species-specific expression of C-type lectin receptors and galectins is different between mice and humans which must be considered in the interpretation of related studies.

C-type lectin receptors, their adaptor molecules and S-type lectins (galectins) are involved in the recognition of glycosylated self-antigens and pathogens. However, little is known about the species- and organ-specific expression profiles of these molecules. We therefore determined the mRNA expression levels of Dectin-1, MR1, MR2, DC-SIGN, Syk, Card-9, Bcl-10, Malt-1, Src, Dec-205, Galectin-1, Tim-3, Trem-1, and DAP-12 in 11 solid organs of human and mice. Mouse organs revealed lower mRNA levels of most molecules compared to spleen. However, Dec-205 and Galectin-1 in thymus, Src in brain, MR2, Card-9, Bcl-10, Src, and Dec-205 in small intestine, MR2, Bcl-10, Src, Galectin-1 in kidney, and Src and Galectin-1 in muscle were at least 2-fold higher expressed compared to spleen. Human lung, liver and heart expressed higher mRNA levels of most genes compared to spleen. Dectin-1, MR1, Syk and Trem-1 mRNA were strongly up-regulated upon ischemia-reperfusion injury in murine kidney. Tim3, DAP-12, Card-9, DC-SIGN and MR2 were further up-regulated during renal fibrosis. Murine kidney showed higher DAP-12, Syk, Card-9 and Dectin-1 mRNA expression during the progression of lupus nephritis. Thus, the organ-, and species-specific expression of C-type lectin receptors and galectins is different between mice and humans which must be considered in the interpretation of related studies.

C-type lectin receptors and their adaptor molecules are involved in the recognition of glycosylated self-antigens and pathogens. However, little is known about the species-and organ-specific expression profiles of these molecules. We therefore determined the mRNA expression levels of Dectin-1, MR1, MR2, DC-SIGN, Syk, Card-9, Bcl-10, Malt-1, Src, Dec-205, Galectin-1, Tim-3, Trem-1, and DAP-12 in 11 solid organs of human and mice. Mouse organs revealed lower mRNA levels of most molecules compared to spleen. However, Dec-205 and Galectin-1 in thymus, Src in brain, MR2, Card-9, Bcl-10, Src, and Dec-205 in small intestine, MR2, Bcl-10, Src, Galectin-1 in kidney, and Src and Galectin-1 in muscle were at least 2-fold higher expressed compared to spleen. Human lung, liver and heart expressed higher mRNA levels of most genes compared to spleen. Dectin-1, MR1, Syk and Trem-1 mRNA were strongly up-regulated upon ischemia-reperfusion injury in murine kidney. Tim3, DAP-12, Card-9, DC-SIGN and MR2 were further up-regulated during renal fibrosis. Murine kidney showed higher DAP-12, Syk, Card-9 and Dectin-1 mRNA expression during the progression of lupus nephritis. Thus, the organ-, and species-specific expression of C-type lectin receptors is different between mice and humans which must be considered in the interpretation of related studies.

Thu, 20 Oct 2011 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/13596/ https://edoc.ub.uni-muenchen.de/13596/1/Fischer_Isabelle.pdf Fischer, Isabelle

Fri, 12 Dec 2008 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/9425/ https://edoc.ub.uni-muenchen.de/9425/2/Mourad-Zeidan_Alexandra.pdf Mourad-Zeidan, Alexandra ddc:610, ddc:600, Medizinische Fakultät

In der vorliegenden Arbeit wurden mit Hilfe der subtraktiven Proteomanalyse Hirn- und Liquorproben von 20 Suizidopfern und 10 Kontrollpersonen untersucht. Das Ziel war die Identifikation möglicher suizidassoziierter Proteine. Bei den Hirnregionen handelte es sich um den präfrontalen Cortex, die Amygdala, den Hippocampus, den Thalamus und die Hypophyse sowie als Referenzregion das Cerebellum. Es wurden insgesamt 15 Proteine in den Hirnregionen präfrontaler Cortex, Amygdala, Hippocampus, Thalamus sowie ein Protein im Liquor identifiziert, deren Expression sich signifikant zwischen Suizidopfern und Kontrollen unterschied. Obwohl die Methodik primär für die Erfassung quantitativer Expressionsunterschiede sowie für die Proteinidentifikation ausgelegt war, erlaubten zudem die Massenspektren und die identifizierten Peptidsequenzen Annahmen über mögliche posttranslationale Modifikationen sowie deren funktionellen Konsequenzen für die betroffenen Neuronen. Sieben der 16 Proteine waren Komponenten des Intermediärmetabolismus', insbesondere des Glukose- und Energiestoffwechsels: Die Enzyme Fruktose-Bisphosphat-Aldolase C, ATP-Synthase, Alpha Enolase und die Neuronen-spezifische Gamma Enolase sowie die Astrozyten-spezifische Glutamin-Synthetase. Nicht enzymatisch waren Galectin-1 und Neuropolypeptid h3. Die Art der Proteinveränderungen ließ auf mögliche Verluste der enzymatischen Aktivitäten schließen mit der möglichen Folge verminderter Astrozyten-vermittelter Glukoseversorgung, reduziertem Energieumsatzes sowie exzitotoxischer Erhöhung der Glutamatkonzentration. Alle drei Faktoren können letztlich zur Degeneration von Neuronen führen. Fünf Proteine waren Bestandteile des Zytoskelettes: Das Neuronen-spezifische Neurofilament Triplet L Protein, zwei Tubulin-Isoformen, das als Astrozyten-Marker geltende saure fibrilläre Gliaprotein sowie das im Liquor identifizierte Beta Aktin Fragment. Die modifizierten Proteine könnten zu einer Instabilisierung des Zytoskelettes, zu vermindertem axonalem Transport und ebenfalls zum Zelltod führen. Die Expressionsunterschiede in zwei Antioxidationsproteinen (Mangan Superoxid Dismutase und Peroxiredoxin2) sowie die Hochregulation des Hitzeschockproteins Alpha Crystallin wiesen auf ein erhöhtes Aufkommen von oxidativem Streß in den Zellen hin. Zusammengefaßt gaben diese Proteinmodifikationen in den Gehirnen der Suizidopfer Anzeichen von exzitotoxischem, proteolytischem, oxidativem und von Energie-Mangel-Streß. Gestützt durch entsprechende Hinweise aus der Literatur wurde daraus die Hypothese formuliert, daß diesen suizidassoziierten zellulären Streßfaktoren eine Form von psychischem Streß, insbesondere in chronischer Form zugrunde lag. Hierzu wurden Mechanismen vorgeschlagen, über die dauerhafter Streß zu den beschriebenen Expressionsveränderungen beigetragen haben könnte. Bislang wurden diese Mechanismen im Zusammenhang mit Suizidalität nicht untersucht und es ist denkbar, daß sie zusätzlich zu den bekannten Streßsystemen wirksam geworden sind.

Commonly, plant and invertebrate lectins are accepted glycohistochemical tools for the analysis of normal and altered structures of glycans in histology and pathology. Mammalian lectins and neoglycoproteins are recent additions to this panel for the detection of lectin-reactive carbohydrate epitopes and glycoligand-binding sites. The binding profiles of these three types of probes were comparatively analyzed in normal, inflamed and neoplastic large intestine. In normal colonic mucosa the intracellular distribution of glycoconjugates and carbohydrate ligand-binding sites in enterocytes reveals a differential binding of lectins with different specificity and of neoglycoproteins to the Golgi apparatus, the rough and smooth endoplasmic reticulum and the apical cell surface. The accessible glycoligand-binding sites and the lectin-reactive carbohydrate epitopes detected by galectin-1 show the same pattern of intracellular location excluding the apical cell surface. Lectin-reactive carbohydrate epitopes detected by plant lectins of identical monosaccharide specificity as the endogenous lectin {[}Ricinus communis agglutinin-I (RCA-I), Viscum album agglutinin (VAA)], however, clearly differ with respect to their intracellular distribution. Maturation-associated differences and heterogeneity in glycohistochemical properties of epithelial cells and non-epithelial cells (macrophages, dendritic cells, lymphocytes) are found. Dissimilarities in the fine structural Ligand recognition of lectins with nominal specificity to the same monosaccharide have been demonstrated for the galactoside-specific lectins RCA-I, VAA and galectin-1 as well as the N-acetylgalactosamine (GalNAc)-specific lectins Dolichos biflorus agglutinin (DBA), soybean agglutinin (SBA) and Helix pomatia agglutinin in normal mucosa and in acute appendicitis. Acute inflammation of the intestinal mucosa found in acute phlegmonous appendicitis is associated with selective changes of glycosylation of mucin in goblet cells mainly of lower and middle crypt segments resulting in an increase of DBA- and SEA-binding sites in the goblet cell population. Appendicitis causes no detectable alteration of neoglycoprotein binding. In contrast, tumorigenesis of colonic adenoma is characterized by increases in lectin-reactive galactose (Gal; Gal-beta 1,3-GalNAc), fucose and N-acetylglucosamine moieties and by enhanced presentation of respective carbohydrate ligand-binding capacity. This work reveals that endogenous lectins and neoglycoproteins are valuable glycohistochemical tools supplementing the well-known analytic capacities of plant lectins in the fields of gastrointestinal anatomy and gastroenteropathology.