Podcasts about il6

Welcome back to another week & another episode of Rinse & Repeat Radio!For this week's episode - I will be taking over the whole hour with new music from Chris Lake, Disco Lines, Odd Mob, & more.Make sure to subscribe for new music every Wednesday on both Apple Podcasts & Mixcloud.Episode 263- Turn it up!Upcoming dates & more - www.cazesthedj.comInstagram/TikTok/Twitter - @cazesthedj***Tracklisting***1.) Chris Lake & Abel Balder - Ease My Mind (Odd Mob Remix)2.) Chris Lake, Green Velvet - Deceiver (ROSEDRiiVE Remix)3.) OMNOM & Marco Strous - Everyone's Your Friend4.) Low Steppa, Capri (UK) - Got The Funk5.) Disco Lines, Tinashe - No Broke Boys6.) Rihanna x Prospa - BBHMM (Cazes 'Don't Stop' Edit)7.) Sebastian Ingrosso & Steve Angello feat. Namasenda - No Enemies8.) Moby, BLONDISH, Kiko Franco  - Natural Blues9.) Disclosure & Sam Smith x Chris Lorenzo x GT_Ofice, Matthew Topper & Robbie Rosen - Latch (Cazes 'Appetite' Edit)10.) Avicii & Nicky Romero x Luke Alexander - I Could Be The One (Cazes 'Hypnotic' Edit)11.) Nicole Moudaber & Castion - Get Back12.) Chris Lake - Savana 13.) CID - Party Jumpin14.) Green Velvet , Chris Lake - Percolator (Mikey Barreneche & Giometrik Edit)15.) Jack Orley - Swing Yo Hip (feat Siena Liggins) 16.) Zillamatic, Cazes - NaughtyUpcoming Dates6/13 - Good Night John Boy - Chicago, IL6/14 - Good Night John Boy - Cleveland, OH6/15 - Azure Day Party @ Ciel - Washington, DC6/28 - M. Bird - Tampa, FL

Welcome back to Rinse And Repeat Radio! On this week's guest mix we have Icon out of Houston, TX.You can catch Icon rockin every weekend as some of the coolest spots in the city as well as all around the country.He took over the first half of the episode with a guest mix including a bunch of his favorite records, remixes, edits, & more.Episode 262 turn it up! **Tracklisting**** Icon Guest Mix **1.) Lupe Fiasco Ft. Mathew Santos Vs. M83 Vs. Morten - Superstar (Icon 'Midnight City' X ‘Timeless' Edit)2.) Hugel, J Balvin & Ellie Goulding Ft Topic, Arash & Daecolm - I Adore You (Purari Remix) 3.) Soulja Boy Vs. Biscits - Turn My Swag On (Rick Wonder 'Freak' Edit)4.) Bart Skils & Layton Giordani - Deadly Valentine 5.) Tame Impala - Let It Happen (Ship Wrek Remix)6.) Chris Lake & Abel Balder - Ease My Mind (Odd Mob Extended Remix)7.) Lola Young & Christian Nielsen - Messy Firefly (Corey Craig Edit) 8.) Rels B -  Un Rodeoooo (Icon Remix) 9.) Celeda, Jesus Fernandez, Karl8 & Andrea Monta - The Underground 10.) The Prodigy - Funky Shit (James Hype Edit) 11.) Mau P - People Talk People Sing 12.) Parisi & Daniel Allan - Man Down13.) Cid - Pass Out** Cazes Mix**14.) Alok, Laszewo, A$ap Rocky - Highjack (Right Back)15.) Cid - Party Jumpin'16.) Tony Dark Eyes - Drippin17.) Cat Dealers, Makj, Faiolli - I'm A Man18.) Omnom & Marco Strous - Everyone's Your Friend 19.) Acraze - Telephone Ringin'Upcoming dates & more - www.cazesthedj.comInstagram/TikTok/Twitter - @cazesthedjUpcoming Dates6/6 - Ayu Dayclub - Las Vegas, NV6/7 - Komodo Lounge - Dallas, TX6/13 - GoodNight John Boy - Chicago, IL6/14 - GoodNight John Boy - Cleveland, OH6/15 - Azure Day Party - Washington, DC

Welcome back to Rinse And Repeat Radio! On this week's guest mix we have return guests the Deux Twins out of Los Angeles, CAYou can catch the Deux Twins rockin' at some of the coolest spots all around the country like XS (Las Vegas), Zouk (LA), and so much more.They took over the first half of the episode and put together a mix just for us including a bunch of their originals, remixes, edits, & more.Episode 261 turn it up! **Tracklisting**** Deux Twins Guest Mix **1.) Tommy Richman - Actin Up (Deux Twins Remix)2.) Chris Lake - Toxic3.) Deux Twins - Id4..) Faed - Talkin Sh*t5.) Sidepiece - Lick 6.) Charli Xcx - Guess (Deux Twins Remix)7.) Travis Scott - Antidote (Deux Twins Remix)8. Playboi Carti - Evil Jordan (Hills Remix)9. Glo Rilla - Tgif (Deux Twins Remix)10.) Zillamatic & Cazes - Naughty11. 2 Chainz - Watch Out (Deux Twins Remix) 12.) Chris Lake - I Want You13. Tommy Richman - Million Dollar Baby (Deux Twins Remix)14. Chrystal - The Days (Relo ‘Midnight City' Remix)** Cazes Mix **15.) Prospa - Don't Stop16.) Tony Romera - Time To Move17.) Esse - Detroit18.) Cajmere Ft. Dajae - Brighter Days (Alok, Santti & Ruddek Remix)19.) Discip - Mind Games20.) Sidepiece - Lick21.) Luis Torres - Love At The RaveUpcoming dates & more - www.cazesthedj.comInstagram/TikTok/Twitter - @cazesthedjUpcoming Dates6/6 - Ayu Dayclub - Las Vegas, NV6/7 - Komodo Lounge - Dallas, TX6/13 - GoodNight John Boy - Chicago, IL6/14 - GoodNight John Boy - Cleveland, OH6/15 - Azure Day Party - Washington, DC

Welcome back to another week & another episode of Rinse & Repeat Radio!For this week's episode - I will be taking over the whole hour with new music from Prospa, FAED, Acraze & more.Make sure to subscribe for new music every Wednesday on both Apple Podcasts & Mixcloud.Episode 260- Turn it up!Upcoming dates & more - www.cazesthedj.comInstagram/TikTok/Twitter - @cazesthedj***Tracklisting***1.) CASSIMM - I Like It2.) DJ S.K.T - Deeper3.) Acraze - Telephone Ringin4.) InntRaw - Bye Bye Bye5.) Tony Romera - Time To Move6.) Prospa - Don't Stop7.) Sebastian Ingrosso & Steve Angello feat. Namasenda - No Enemies8.) FAED - TALKIN SH*T9.) Lady Gaga - Abracadabra (MAKJ Remix)10.) Chris Lake & Ragie Ban - Toxic11.) Discip - Serotonine12.) Crespo - Lose Control13.) Cassian, SCRIPT, Belladonna (ofc) - Where I'm From14.) Swedish House Mafia x KREAM - Save The World (Cazes 2025 Edit)15.) Pendulum - The Island Pt.1 (SQU4RE Bootleg)Upcoming Dates6/6 - Ayu Dayclub - Las Vegas, NV6/7 - Komodo Lounge - Dallas, TX6/13 - GoodNight John Boy - Chicago, IL6/14 - GoodNight John Boy - Cleveland, OH6/15 - Azure Day Party - Washington, DC

Cancer cachexia isn't just weight loss—it's a hijacking of motivation

W tym odcinku zagłębiamy się w świat kanabichromenu (CBC) – jednego z mniej znanych, ale niezwykle obiecujących fitokanabinoidów. Naszym gościem jest Izabela Piątek, współwłaścicielka Polskiej Grupy Kapitałowej 3H, ekspertka od badań i rozwoju w branży konopnej. Dowiesz się, dlaczego CBC nazywany jest „czarnym koniem” w leczeniu depresji, jak działa na układ nerwowy, skórę oraz stany zapalne.Porozmawiamy także o jego potencjale w terapii bólu migrenowego, nowotworów i problemów jelitowych. Ale to nie wszystko – Izabela Piątek zdradza kulisy produkcji kosmetyków konopnych, radzi, jak rozpoznać wysokiej jakości ekstrakty i unikać oszustów na rynku.Jeśli interesuje Cię, jak nauka odkrywa tajemnice konopi oraz jakie są perspektywy rozwoju tej branży, ten odcinek jest dla Ciebie. Przygotuj się na sporą dawkę wiedzy, ciekawostek i praktycznych wskazówek. Włącz i posłuchaj już teraz!

With wineries, outdoor adventures, historical markers, and friendly small towns, Southern Illinois is truly a hidden gem that is totally worth checking out. Today, Stevie is joined by Jessica Baine from the Caffeine Until Cocktails blog, who talks about the Shawnee National Forrest, things to do in the Fall, and much more when it comes to visiting Souther Illinois. Show Notes ⬇️ Published on 9/20/24 Timecodes0:00 - Intro2:07 - What About Southern Illinois Makes it a Unique Place to Visit and Explore?2:48 - More About the Shawnee National Forrest3:54 - Garden of the Gods and What its Like to Explore it5:27 - Historical Markers in Jackson County, IL6:41 - Wineries in Jackson County, IL7:39 - Top Things to do in the Fall in Southern Illinois10:22 - Ava, IL12:04 - Effingham, IL14:04 - Southern Illinois Towns are Hidden Gems15:25 - Murphysboro, IL17:49 - Stay Connected with Caffeine until Cocktails20:18 - Jessica Baine is a Student of Travel Check Out These Southern Illinois Blogs from Caffeine Until Cocktails101 Things to do in Southern IllinoisHistorical Markers in Jackson County, IllinoisJackson County Wineries: Southern Illinois TourismTop 9 Fall Activities: A Guide to Fall in Southern IllinoisWelcome to Ava, IllinoisSummer in Effingham, IllinoisHow to Spend One Day in Murphysboro, ILFollow Caffeine Until Cocktails on Instagram or PinterestExplore Group Experience to Learn how to Build your Travel Tribe

US-based biotech company Priovant Therapeutics is dedicated to developing novel therapies for autoimmune diseases with high morbidity and few available treatment options. The company's lead asset, brepocitinib, is a dual selective inhibitor of TYK2 and JAK1. Through dual TYK2/JAK1 inhibition, brepocitinib suppresses key cytokines linked to autoimmunity—including type I IFN, type II IFN, IL6, IL12, and IL23—with a single, targeted therapy. Brepocitinib has generated positive data in seven phase 2 studies with oral once-daily administration. It is currently being evaluated in a phase 3 program for dermatomyositis and is entering a phase 3 program for non-infectious uveitis.This week on the podcast we have a conversation with Priovant's CEO Benjamin Zimmer about dermatomyositis, non-infectious uveitis, current treatments, potential options, and how brepocitinib is making a difference. 00:55-02:34: About Priovant02:34-06:38: What are dermatomyositis and non-infectious uveitis?06:38-08:35: What are the current treatments?08:35-12:32: What is brepocitinib?12:32-15:36: Are there other treatments in development? 15:36-17:50: What is your relationship with Pfizer?17:50-20:48: Brepocitinib clinical trials20:48-24:06: Future plans and timeline24:06-27:59: Finding patients for clinical trials27:59-29:19: Future opportunities Interested in being a sponsor of an episode of our podcast? Discover how you can get involved here! Stay updated by subscribing to our newsletter

Thank you Space City! Houston, We Love You!Alex meets Adriano's mother and makes a plea for her religion. Madelein breaks down when Luke hesitates while visiting a wedding venue. Kyle gets an STD test as Ani looks to a friend for advice. Shawn plans a big surprise for Alliya.---6/2 Phoenix,AZ6/5 Columbus, OH6/6 Indianapolis,IN6/7 Chicago, IL6/12 Atlanta,GA 6/13 Charlotte, NC Hosted on Acast. See acast.com/privacy for more information.

Not even the thunderstorm in Dallas can stop the boys! Thank you Dallas and Ft Worth, Sissies! Episode Title: S8 Ep11: "Weeping Beauty"Angela learns the fate of Michael's visa. Patrick presents Thais with the worst birthday gift. Gino's actions push Jasmine over the edge. Ashley decides to protect her finances. Liz and Ed try to move on. Emily wants to meet Kobe's ex. Loren has an emotional homecoming.See Y'all on the road!5/31 Houston,TX6/2 Phoenix,AZ6/5 Columbus, OH6/6 Indianapolis,IN6/7 Chicago, IL6/12 Atlanta,GA 6/13 Charlotte, NC Hosted on Acast. See acast.com/privacy for more information.

Ever wondered why some people seem to avoid sickness effortlessly, while others catch every bug in the vicinity? It turns out, luck and genetics may both play a role. In this episode, we uncover the secrets of the IL6 gene, responsible for coding interleukin 6 (IL-6), a crucial immune messenger.  Discover how certain variants of the IL6 gene, such as rs1800795, are linked to higher or lower IL-6 levels, affecting immunity and susceptibility to infections. But the story doesn't end there – we explore other variants like rs1800796, connecting genetic makeup to conditions like acne, longevity, muscle recovery, and inflammatory diseases. Is your IL6 gene making you ill, or is it your genetic strength?

Is gay retirement different? Do LGBTQ+ folks need their own retirement communities? Do some already exist and if so where?Did you know that queer people are going back into the closet as we age? That's according to an August 2023 Salon article. That's in part because of the 508 anti-LGBTQ+ laws at the state-level throughout the country, per the ACLU.That makes retirement and retirement housing more unaffordable for us - increasing the pink tax.That's why you're listening to Queer Money episode #470 because we're kicking off our new Gay Retirement 101 series.Today, we're sharing our favorite LGBTQ+ retirement communities10 of our favorite places for LGBTQ+ individuals tolive in retirement1. Pueblo Manor in Apache Junction, AZ2. Triangle Square in Hollywood, CA3. A Place for Us in Cleveland, OH4. Rainbow Vista in Gresham, OR5. Town HallApartments in Chicago, IL6. Fountaingrove Lodge in Santa Rosa, CA7. Wilton Manors, FL8. The Residences atSeashore Point in Provincetown, MA9. Village Hearth Cohousing in Durham, NC 10. Birds of a Feather in Village of Pecos, NMFor the resources and to connect with our guests, get the show notes at: https://queermoneypodcast.com/subscribe Follow us:Queer Money Instagram Queer Money YouTubeQueer Money on TiktokDownload your FREE Queer Money Kickstarter a 9-step Guide to Kickstart Your Journey to Financial Independence

Take 10 with Tim – September 15, 2023 @ 8 am1.Word association on each of these recently called up kida.Ronny Mauriciob.Maysn Winnc.Jordan Wicksd.Jasson Domingueze.Connor Phillipsf.Evan Carterg.Pete Crow-Armstrong2.What one or two surprise players have been making a difference for you down the stretch?3.Let's look at the MLB races4.Heston Kerjstad gets the call after Ryan Mountcastle goes out with a shoulder injury. Any interest?5.Have we seen the last at-bat for Shohei Ohtani for the season? He hasn't played since September 3rd. He's out with an oblique, but of course the Angels didn't put him on the IL6.I just finished writing the Pittsburgh Pirates minor league system. While I like the system very much, I've liked it for the past few years. But their players have just not performed. Hayes, Contreras, End Rodriguez, Mitch Keller, and Henry Davis.a.They look great in the minor leagues and then underperform once they get promoted to the Majors.7.Give me on hitter that you will target for this weekend's FAAB?8.Give me one pitcher that you will target for this weekend's FAAB?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/3306394/advertisement

A new research paper was published in Aging (Aging-US) Volume 15, Issue 14, entitled, “Inhibiting NLRP3 signaling in aging podocytes improves their life- and health-span.” The decrease in the podocyte's lifespan and health-span that typify healthy kidney aging cause a decrease in their normal structure, physiology and function. The ability to halt and even reverse these changes becomes clinically relevant when disease is superimposed on an aged kidney. NLRP3 [nod-like receptor protein 3] expression is increased in podocytes of mice with advanced age and contributes to their damage. “However, the functional consequence of increased levels of NLRP3 in aged podocytes is unknown.” In this new study, researchers Natalya Kaverina, R. Allen Schweickart, Gek Cher Chan, Joseph C. Maggiore, Diana G. Eng, Yuting Zeng, Sierra R. McKinzie, Hannah S. Perry, Adilijiang Ali, Christopher O'Connor, Beatriz Maria Veloso Pereira, Ashleigh B. Theberge, Joshua C. Vaughan, Carol J. Loretz, Anthony Chang, Neil A. Hukriede, Markus Bitzer, Jeffrey W. Pippin, Oliver Wessely, and Stuart J. Shankland from the University of Washington, Cleveland Clinic Foundation, National University Hospital Singapore, University of Pittsburgh, University of Michigan, and the University of Chicago hypothesized that reducing NLRP3 signaling earlier at middle-age improves overall podocyte health and slows down healthy podocyte aging in mice. “To this end, we performed a comprehensive analysis of inflammasome signaling including pharmacological and genetic NLRP3 loss-of-function approaches.” RNA-sequencing of podocytes from middle-aged mice showed an inflammatory phenotype with increases in the NLRP3 inflammasome, signaling for IL2/Stat5, IL6 and TNF, interferon gamma response, allograft rejection and complement, consistent with inflammaging. Furthermore, injury-induced NLRP3 signaling in podocytes was further augmented in aged mice compared to young ones. The NLRP3 inflammasome (NLRP3, Caspase-1, IL1β IL-18) was also increased in podocytes of middle-aged humans. Higher transcript expression for NLRP3 in human glomeruli was accompanied by reduced podocyte density and increased global glomerulosclerosis and glomerular volume. Pharmacological inhibition of NLRP3 with MCC950, or gene deletion, reduced podocyte senescence and the genes typifying aging in middle-aged mice, which was accompanied by an improved podocyte lifespan and health-span. Moreover, modeling the injury-dependent increase in NLRP3 signaling in human kidney organoids confirmed the anti-senescence effect of MC9950. Finally, NLRP3 also impacted liver aging. “In summary, our results demonstrate for the first time that aging podocytes acquire an inflammatory phenotype, which include the NLRP3 inflammasome and which is consistent with inflammaging.” DOI - https://doi.org/10.18632/aging.204897 Corresponding authors - Oliver Wessely - wesselo@ccf.org, and Stuart J. Shankland - stuartjs@uw.edu Keywords - aging, kidney, podocyte, NLRP3 inflammasome, reporter About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ For media inquiries, please contact: MEDIA@IMPACTJOURNALS.COM

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.31.551394v1?rss=1 Authors: Fernandez-Gonzalez, A., Mukhia, A., Nadkarni, J., Willis, G., Reis, M., Zhumka, K., Vitali, S., Liu, X., Galls, A., Mitsialis, S. A., Kourembanas, S. Abstract: Objective: Macrophages play a central role in the onset and progression of vascular disease in pulmonary hypertension (PH) and cell-based immunotherapies aimed at treating vascular remodeling are lacking. This work evaluates the effect of pulmonary administration of macrophages modified to have an anti-inflammatory/pro-resolving phenotype in attenuating early pulmonary inflammation and progression of experimentally induced PH. Approach and Results: Mouse bone marrow derived macrophages (BMDMs) were polarized in vitro to a regulatory (M2reg) phenotype. M2reg profile and anti-inflammatory capacity were assessed in vitro upon lipopolysaccharide (LPS)/interferon-{gamma} (IFN{gamma}) restimulation, before their administration to 8- to 12- week-old mice. M2reg protective effect was tested at early (2 to 4 days) and late (4 weeks) time points during hypoxia (8.5% O2) exposure. Levels of inflammatory markers were quantified in alveolar macrophages and whole lung, while PH development was ascertained by right ventricular systolic pressure (RSVP) and right ventricular hypertrophy (RVH) measurements. Bronchoalveolar lavage (BAL) from M2reg-transplanted hypoxic mice was collected, and its inflammatory potential tested on naive BMDMs. M2reg macrophages demonstrated a stable anti-inflammatory phenotype upon a subsequent pro-inflammatory stimulus by maintaining the expression of specific anti-inflammatory markers (Tgf{beta}, Il10 and Cd206) and downregulating the induction of proinflammatory cytokines and surface molecules (Cd86, Il6 and Tnf). A single dose of M2regs attenuated the hypoxic monocytic recruitment and perivascular inflammation. Early hypoxic lung and alveolar macrophage inflammation leading to PH development was significantly reduced and, importantly, M2regs attenuated RVH, RVSP and vascular remodeling at 4 weeks post treatment. Conclusion: Adoptive transfer of M2regs halts the recruitment of monocytes and modifies the hypoxic lung microenvironment, potentially changing the immunoreactivity of recruited macrophages and restoring normal immune functionality of the lung. These findings provide new mechanistic insights on the diverse role of macrophage phenotype on lung vascular homeostasis that can be explored as novel therapeutic targets. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.12.548684v1?rss=1 Authors: Pranty, A. I., Wruck, W., Adjaye, J. Abstract: Bilirubin induced neurological damage (BIND), which is also known as Kernicterus, occurs as a consequence of defects in the bilirubin conjugation machinery, thus resulting in unconjugated bilirubin (UCB) to cross the blood brain barrier (BBB) and accumulation. Severe hyperbilirubinemia can be caused by a mutation within the UGT1A1 encoding gene. This mutation has a direct contribution towards bilirubin conjugation leading to Kernicterus as a symptom of Crigler Najjar Syndromes (CNS1, CNS2) and Gilbert syndrome, which results in permanent neurological sequelae. In this comparative study, we used human induced pluripotent stem cells (hiPSCs) derived 3D-brain organoids to model BIND in vitro and unveil the molecular basis of the detrimental effects of UCB in the developing human brain. hiPSC derived from healthy and CNS patients were differentiated into day 20 brain organoids, these were then stimulated with 200nM UCB. Analyses at 24 and 72 hrs post-treatment point at UCB induced neuro-inflammation in both cell lines. Transcriptome and associated KEGG and Gene Ontology analyses unveiled activation of distinct inflammatory pathways such as cytokine cytokine receptor interaction, MAPK signaling, calcium signaling, NFkB activation. Furthermore, both mRNA expression and secretome analysis confirmed an upregulation of proinflammatory cytokines such as IL6 and IL8 upon UCB stimulation. In summary, this novel study has provided insights into how a human iPSC derived 3D-brain organoid model can serve as a prospective platform for studying the etiology of BIND Kernicterus. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

DrBeen#26 Near Infrared Light Therapy Reduces Inflammation Ep 26: Near Infrared Light Therapy Reduces Inflammation Near infrared light therapy reduces inflammatory mediators by 50% and IL6 by 80%. Let's review. DrBeen: Medical Education Onlinehttps://www.drbeen.com/ FLCCC | Front Line COVID-19 Critical Care Alliancehttps://covid19criticalcare.com/ URL list from Thursday, Sep. 15 2022 Infrared light therapy relieves TLR-4 dependent hyper-inflammation of the type induced by COVID-19 - PMChttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451450/ Not scientific but interesting article about heat-shock proteins and infrared.Infrared Sauna Use And Heat Shock Proteinshttps://saunas.org/infrared-sauna-use-and-heat-shock-proteins/ Some more referencesNear-infrared spectroscopy - Wikipediahttps://en.wikipedia.org/wiki/Near-infrared_spectroscopy Near Infrared (NIR) Light Therapy of Eye Diseases: A Review - PMChttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738953/#:~:text=NIR%20and%20LEDs%20light%20can,modify%20biological%20functions%20of%20cells. Sep 15, 2022 at 10:13 PMRed Light Therapy vs. Infrared Saunahttps://youtu.be/vwgLlYcYZ_4 Red/near-infrared irradiation therapy for treatment of central nervous system injuries and disorders - PubMedhttps://pubmed.ncbi.nlm.nih.gov/23492552/ The Benefits of Near-Infrared Light Therapyhttps://platinumtherapylights.com/blogs/news/near-infrared-light-therapy Near-Infrared Light and Skin: Why Intensity Matters - Abstract - Challenges in Sun Protection - Karger Publishershttps://www.karger.com/Article/Abstract/517645 The effect of red-to-near-infrared (R/NIR) irradiation on inflammatory processes - PubMedhttps://pubmed.ncbi.nlm.nih.gov/31170016/#:~:text=Introduction%3A%20Near%2Dinfrared%20(NIR,blood%20flow%20and%20tissue%20oxygenation. Near-infrared light reduces glia activation and modulates neuroinflammation in the brains of diet-induced obese mice | Scientific Reportshttps://www.nature.com/articles/s41598-022-14812-8 Near-infrared light reduces β-amyloid-stimulated microglial toxicity and enhances survival of neurons: mechanisms of light therapy for Alzheimer's disease | Alzheimer's Research & Therapy | Full Texthttps://alzres.biomedcentral.com/articles/10.1186/s13195-022-01022-7 Infrared light therapy relieves TLR-4 dependent hyper-inflammation of the type induced by COVID-19 - PMChttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8451450/ What Is Near-Infrared Light? - StoneLockhttps://stonelock.com/what-is-near-infrared-light/#:~:text=Infrared%20Light%20(IR)%20is%20the,past%20what%20we%20can%20see. Toll-like receptor 4 - Wikipediahttps://en.wikipedia.org/wiki/Toll-like_receptor_4 NF-κB - Wikipediahttps://en.wikipedia.org/wiki/NF-%CE%BAB Lipopolysaccharidehttps://en.wikipedia.org/wiki/Lipopolysaccharide Disclaimer:This video is not intended to provide assessment, diagnosis, treatment, or medical advice; it also does not constitute provision of healthcare services. The content provided in this video is for informational and educational purposes only.Please consult with a physician or healthcare professional regarding any medical or mental health related diagnosis or treatment. No information in this video should ever be considered as a substitute for advice from a healthcare professional. covid 19dr beenflcccinflammationinfrared light therapy

Eno and DVR discuss some of the biggest risers -- and a few fallers -- among starting pitchers from the first month of the season. Rundown0:45 Jacob deGrom Returns to the IL6:23 Nathan Eovaldi's First Month in Texas13:51 Dustin May's Rise Up Eno's Rankings18:50 Freddy Peralta's Velo Returns; Pitch Mix is Strong23:08 Jesús Luzardo's Step Forward in Miami26:26 Joe Ryan New Arsenal28:54 Zac Gallen's Continued Dominance31:20 Other Big Movers44:10 JP Sears: Sneaky Fallback Add From April?50:30 Hunter Brown's First 50 MLB Innings57:04 Big Fallers in the RankingsFollow Eno on Twitter: @enosarrisFollow DVR on Twitter: @DerekVanRipere-mail: ratesandbarrels@theathletic.comSubscribe to The Athletic at $1/month for the first year: theathletic.com/ratesandbarrelsSubscribe to the Rates & Barrels YouTube channel: https://www.youtube.com/c/RatesBarrelsThis episode is brought to you by BetterHelp. Give online therapy a try at betterhelp.com/rates and get on your way to being your best self.Head to factor75.com/rates40 and use code RATES40 to get 40% off your first box. Hosted on Acast. See acast.com/privacy for more information.

British Society for Rheumatology Young Investigator Award winner Dr Zixing Tian (University of Manchester, UK) joins Dr Steven Zhao to discuss the work behind the winning abstract 'No difference in risk of myocardial infarction among patients receiving either IL6 or TNF inhibitors for rheumatoid arthritis', and the implications for future research. This abstract was presented at the rheumatoid arthritis oral abstract session at British Society for Rheumatology Annual Conference 2023 and is available here. Thanks for listening to Talking Rheumatology Research! Join the conversation on Twitter using #TalkingRheumResearch, tweet us @RheumJnl, or find us on Instagram. Want to read more rheumatology research? Explore Rheumatology and Rheumatology Advances in Practice.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.19.537428v1?rss=1 Authors: Pryce Roberts, A., Dec, K., Tyrrell, V., O'Donnell, V. B., Harwood, A. J., Williams, J. Abstract: Sporadic Alzheimer's disease is the leading cause of dementia worldwide and the Apolipoprotein-E4 allele (APOE) is the strongest genetic risk factor but despite its importance, its role in disease pathogenesis is incompletely understood. The APOE gene encodes Apolipoprotein E (ApoE). Astrocytes are the main source of ApoE in the central nervous system (CNS) and are essential for homeostasis in health and disease. In response to CNS insult, a coordinated multicellular inflammatory response is triggered causing reactive astrogliosis with changes in astrocytic gene expression, cellular structure and function. Using a human embryonic stem-cell line with the neutral APOE33 genotype, we used CRISPR Cas-9 gene-editing technology to create isogenic APOE lines with an APOE44 genotype. We developed a modified protocol designed to produce quiescent astrocytes and then stimulated them to induce an astrogliotic A1 phenotype. Several potentially pathological APOE44-related phenotypes were identified in both quiescent cells and reactive A1 astrocytes including significantly decreased phagocytosis and impaired glutamate uptake in APOE44 astrocytes. There were also key differences in the inflammatory profiles of APOE33 and APOE44 astrocytes characterised by significantly decreased secretion of IL6, IL8 and several oxylipins in APOE44 quiescent astrocytes. In A1 astrocytes there was a pro-inflammatory phenotype in APOE44 astrocytes with increases in GRO, ENA78, IL6 and IL8, a decrease in IL10 as well as significant differences in oxylipin expression suggestive of a defect in their immunomodulatory function. As TNF- induced signaling in astrocytes is driven by Nuclear factor kappa B (NF-{kappa}B) we investigated the proteins of this pathway and found significantly higher levels of the p65 and I{kappa}B sub-units in both quiescent and A1 APOE44 astrocytes. This suggests that perturbation of NF-{kappa}B signaling may contribute to the damaging cell phenotypes that we observe and provides a new direction for targeted disease therapeutics. Given the large numbers of existing drugs that act on the NF-{kappa}B pathway, this could be realised in a relatively short timeframe. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.12.532316v1?rss=1 Authors: Ullah, K., Ai, L., Li, Y., Liu, L., Zhang, Q., Pan, K., Humayun, Z., Sitikov, A., Su, Q., Zhao, Q., Sharp, W. W., Fang, Y., Wu, D., Liao, J. K., Wu, R. Abstract: Rationale: Cardiac microvascular leakage and inflammation are triggered during myocardial infarction (MI) and contribute to heart failure. Hypoxia-inducible factor 2 (Hif2) is highly expressed in endothelial cells (ECs) and rapidly activated by myocardial ischemia, but whether it has a role in endothelial barrier function during MI is unclear. Objective: To test our hypothesis that the expression of Hif2 and its binding partner aryl hydrocarbon nuclear translocator (ARNT) in ECs regulate cardiac microvascular permeability in infarcted hearts. Methods and Results: Experiments were conducted with mice carrying an inducible EC-specific Hif2-knockout (ecHif2-/-) mutation, with mouse cardiac microvascular endothelial cells (CMVECs) isolated from the hearts of ecHif2-/- mice after the mutation was induced, and with human CMVECs and umbilical-vein endothelial cells transfected with ecHif2 siRNA. After MI induction, echocardiographic assessments of cardiac function were significantly lower, while measures of cardiac microvascular leakage (Evans blue assay), plasma IL6 levels, and cardiac neutrophil accumulation and fibrosis (histology) were significantly greater, in ecHif2-/- mice than in control mice, and RNA-sequencing analysis of heart tissues from both groups indicated that the expression of genes involved in vascular permeability and collagen synthesis was enriched in ecHif2-/- hearts. In cultured ECs, ecHif2 deficiency was associated with declines in endothelial barrier function (electrical cell impedance assay) and the reduced abundance of tight-junction proteins, as well as an increase in the expression of inflammatory markers, all of which were largely reversed by the overexpression of ARNT. We also found that ARNT, but not Hif2, binds directly to the IL6 promoter and suppresses IL6 expression. Conclusions: EC-specific deficiencies in Hif2 expression significantly increase cardiac microvascular permeability, promote inflammation, and reduce cardiac function in infarcted mouse hearts, and ARNT overexpression can reverse the upregulation of inflammatory genes and restore endothelial-barrier function in Hif2-deficient ECs. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.06.527377v1?rss=1 Authors: Yin, Z., Wu, L., Zhang, Y., Sun, Y., Chen, J. W., Subudhi, S., Ho, W., Lee, G. Y., Wang, A., Gao, X., Ren, J., Zhu, C., Zhang, N., Ferraro, G. B., Muzikansky, A., Zhang, L., Stemmer-Rachamimov, A., Mao, J., Plotkin, S. R., Xu, L. Abstract: Patients with Schwannomatosis (SWN) overwhelmingly present with intractable, debilitating chronic pain. There are no effective therapies to treat SWN. The drivers of pain response and tumor progression in SWN are not clear. The pain is not proportionally linked to tumor size and is not always relieved by tumor resection, suggesting that mechanisms other than mechanical nerve compression exist to cause pain. SWN research is limited by the lack of clinically-relevant models. Here, we established novel patient-derived xenograft (PDX) models, dorsal root ganglia (DRG) imaging model, and combined with single-cell resolution intravital imaging and RNASeq, we discovered: i) schwannomas on the peripheral nerve cause macrophage influx into the DRG, via secreting HMGB1 to directly stimulate DRG neurons to express CCL2, the key macrophage chemokine, ii) once recruited, macrophages cause pain response via overproduction of IL-6, iii) IL-6 blockade in a therapeutic setting significantly reduces pain but has modest efficacy on tumor growth, iv) EGF signaling is a potential driver of schwannoma growth and escape mechanism from anti-IL6 treatment, and v) combined IL-6 and EGFR blockade simultaneously controlled pain and tumor growth in SWN models. Our findings prompted the initiation of phase II clinical trial (NCT05684692) for pain relief in patients with SWN. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.26.525731v1?rss=1 Authors: Crosson, T., Bhat, S., Wang, J.-C., Salaün, C., Roversi, K., Herzog, H., Rafei, M., Blunck, R., Talbot, S. Abstract: Nociceptor neurons play a crucial role in maintaining the body's equilibrium by detecting and responding to potential dangers in the environment. However, this function can be detrimental during allergic reactions, since vagal nociceptors can contribute to immune cell infiltration, bronchial hypersensitivity, and mucus imbalance, in addition to causing pain and coughing. Despite this, the specific mechanisms by which nociceptors acquire pro-inflammatory characteristics during allergic reactions are not yet fully understood. In this study, we aimed to investigate the molecular profile of airway nociceptor neurons during allergic airway inflammation and identify the signals driving such reprogramming. Using retrograde tracing and lineage reporting, we identified a class of inflammatory vagal nociceptor neurons that exclusively innervate the airways. Using an ovalbumin mouse model of airway inflammation, we found that these neurons undergo significant reprogramming characterized by the upregulation of the NPY receptor Npy1r, along with Il6. A screening of asthma-driving cytokines revealed that IL-13 drives part of this reprogramming, including Npy1r overexpression via the JAK/STAT6 pathway, while IL-1{beta} induces IL-6 expression and release. Additionally, we observed that sympathetic neurons release NPY in the bronchoalveolar fluid of asthmatic mice, which limits the excitability of nociceptor neurons. In summary, allergic airway inflammation reprograms airway nociceptor neurons to acquire a pro-inflammatory phenotype, characterized by the release of IL-6, while a compensatory mechanism involving NPY1R limits nociceptor neurons' activity. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.21.521533v1?rss=1 Authors: Montgomery-Song, A., Ashraf, S., Santerre, P., Kandel, R. Abstract: Senescence, particularly in the nucleus pulposus (NP) cells, has been implicated in the pathogenesis of disc degeneration, however, the mechanism(s) of annulus fibrosus (AF) cell senescence is still not well understood. Both TNF and H2O2, have been implicated as contributors to the senescence pathways, and their levels are increased in degenerated discs when compared to healthy discs. This the objective of this study is to identify factor(s) that induces inner AF (iAF) cell senescence Under TNF exposure, at a concentration that can induce senescence in NP cells, bovine iAF cells did not undergo senescence, indicated by their ability to continue to proliferate as demonstrated by Ki67 staining and growth curves and lack of expression of the senescent markers, p16 and p21. Unlike iAF cells, NP cells treated with TNF accumulated more intracellular ROS and secreted more H2O2. Following TNF treatment, only iAF cells had increased expression of the superoxide scavengers SOD1 and SOD2 whereas NP cells had increased NOX4 gene expression, an enzyme that can generate H2O2. Treating iAF cells with low dose H2O2 (50 M) induced senescence, however unlike TNF, H2O2 did not induce degenerative-like changes as there was no difference in COL2, ACAN, MMP13, or IL6 gene expression or number of COL2 and ACAN immunopositive cells compared to untreated controls. The latter result suggests that iAF cells have distinct degenerative and senescent phenotypes. To evaluate paracrine signalling, iAF and TNF-treated NP cells were co-cultured. In contact co-culture the NP cells did induce iAF senescence. Thus, senescent NP cells may secrete soluble factors that induce degenerative and senescent changes within the iAF. This may contribute to a positive feedback loop of disc degeneration, and these processes could include H2O2 and cytokines (TNF). Further studies will investigate if human disc cells respond similarly. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.25.513730v1?rss=1 Authors: Rossi, M., Anerillas, C., Idda, M. L., Munk, R., Shin, C. H., Donega, S., Tsitsipatis, D., Herman, A. B., Martindale, J. L., Yang, X., Piao, Y., Mazan-Mamczarz, K., Fan, J., Ferrucci, L., De, S., Abdelmohsen, K., Gorospe, M. Abstract: Senescent cells release a variety of cytokines, proteases, and growth factors collectively known as the senescence-associated secretory phenotype (SASP). Sustained SASP contributes to a pattern of chronic inflammation associated with aging and implicated in many age-related diseases. Here, we investigated the expression and function of the immunomodulatory cytokine BAFF (B-cell activating factor), a SASP protein, in multiple senescence models. We first characterized BAFF production across different senescence models, including senescent human diploid fibroblasts (WI-38, IMR-90) and monocytic leukemia cells (THP-1), and tissues of mice induced to undergo senescence. We then identified IRF1 (interferon response factor 1) as a transcription factor required for promoting BAFF mRNA transcription in senescence. We discovered that suppressing BAFF production decreased the senescent phenotype of both fibroblasts and monocyte-derived THP-1 cells, overall reducing IL6 secretion, SA-{beta}-Gal staining, and {gamma}-H2AX accumulation. Importantly, however, the influence of BAFF on the senescence program was cell type-specific: in monocytes, BAFF promoted the early activation of NF-{kappa}B and general SASP secretion, while in fibroblasts, BAFF contributed to the production and function of TP53 (p53). We propose that BAFF is elevated across senescence models and is a potential target for senotherapy. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Video: Scientist Carl Sagan testifying to the U.S. Senate in 1985 on the greenhouse effect: (2:00) WEF: The Most Evil Business in the World – Samuel Leeds (10:49) Israel caught hiding BOMBSHELL Pfizer   Frequent nut consumption associated with less inflammation Brigham and Women's Hospital, September 1, 2022 In a study of more than 5,000 people, investigators from Brigham and Women's Hospital have found that greater intake of nuts was associated with lower levels of biomarkers of inflammation, a finding that may help explain the healthbenefits of nuts. The results of the study appear in the American Journal of Clinical Nutrition. “Population studies have consistently supported a protective role of nuts against cardiometabolic disorders such as cardiovascular disease and type 2 diabetes, and we know that inflammation is a key process in the development of these diseases,” said corresponding author Ying Bao, MD, ScD, an epidemiologist in BWH's Channing Division of Network Medicine. “Our new work suggests that nuts may exert their beneficial effects in part by reducing systemic inflammation.” Previously Bao and her colleagues observed an association between increased nut consumption and reduced risk of major chronic diseases and even death, but few prospective cohort studies had examined the link between nut intake and inflammation. In the current study, the research team performed a cross-sectional analysis of data from the Nurses' Health Study, which includes more than 120,000 female registered nurses, and from the Health Professionals Follow-Up Study, which includes more than 50,000 male health professionals. The team assessed diet using questionnaires and looked at the levels of certain telltale proteins known as biomarkers in blood samples collected from the study participants. They measured three well-established biomarkers of inflammation: C-reactive protein (CRP), interleukin 6 (IL6) and tumor necrosis factor receptor 2 (TNFR2). After adjusting for age, medical history, lifestyle and other variables, they found that participants who had consumed five or more servings of nuts per week had lower levels of CRP and IL6 than those who never or almost never ate nuts. In addition, people who substituted three servings per week of nuts in place of red meat, processed meat, eggs or refined grains had significantly lower levels of CRP and IL6. Peanuts and tree nuts contain a number of healthful components including magnesium, fiber, L-arginine, antioxidants and unsaturated fatty acids such as α-linolenic acid. Researchers have not yet determined which of these components, or if the combination of all of them, may offer protection against inflammation, but Bao and her colleagues are interested in exploring this further through clinical trials that would regulate and monitor diet. “Much remains unknown about how our diet influences inflammation and, in turn, our risk of disease,” said Bao. “But our study supports an overall healthful role for nuts in the diet and suggests reducing inflammation as a potential mechanism that may help explain the benefits of nuts on cardiometabolic diseases.” Blueberry extract could help fight gum disease and reduce antibiotic use Laval University (Quebec), September 2, 2022 Gum disease is a common condition among adults that occurs when bacteria form biofilms or plaques on teeth, and consequently the gums become inflamed. Some severe cases, called periodontitis, call for antibiotics. But now scientists have discovered that wild blueberry extract could help prevent dental plaque formation. Their report in ACS' Journal of Agricultural and Food Chemistry could lead to a new therapy for periodontitis and a reduced need for antibiotics. Many people have had some degree of gum inflammation, or gingivitis, caused by dental plaque. The gums get red and swollen, and they bleed easily. If left unchecked, the condition can progress to periodontitis. The plaque hardens into tartar, and the infection can spread below the gum line and destroy the tissue supporting the teeth. To treat this condition, dentists scrape off the tartar and sometimes have to resort to conventional antibiotics. But recently, researchers have started looking at natural antibacterial compounds to treat gum disease. Daniel Grenier and colleagues wanted to see if blueberry polyphenols, which work against foodborne pathogens, could also help fight Fusobacterium nucleatum, one of the main species of bacteria associated with periodontitis. In the lab, the researchers tested extracts from the wild lowbush blueberry, Vaccinium angustifolium Ait., against F. nucleatum. The polyphenol-rich extracts successfully inhibited the growth of F. nucleatum, as well as its ability to form biofilms. It also blocked a molecular pathway involved in inflammation, a key part of gum disease. The researchers say they're developing an oral device that could slowly release the extract after deep cleaning to help treat periodontitis. Meat consumption contributing to global obesity University of Adelaide, August 11, 2022 Should we be warning consumers about over-consumption of meat as well as sugar? That's the question being raised by a team of researchers from the University of Adelaide, who say meat in the modern diet offers surplus energy, and is contributing to the prevalence of global obesity. “Our findings are likely to be controversial because they suggest that meat contributes to obesity prevalence worldwide at the same extent as sugar,” says Professor Maciej Henneberg. “In the analysis of obesity prevalence across 170 countries, we have found that sugar availability in a nation explains 50% of obesity variation while meat availability another 50%. After correcting for differences in nations' wealth (Gross Domestic Product), calorie consumption, levels of urbanization and of physical inactivity, which are all major contributors to obesity, sugar availability remained an important factor, contributing independently 13%, while meat contributed another 13% to obesity. “While we believe it's important that the public should be alert to the over-consumption of sugar and some fats in their diets, based on our findings we believe meat protein in the human diet is also making a significant contribution to obesity,” Professor Henneberg says. “There is a dogma that fats and carbohydrates, especially fats, are the major factors contributing to obesity,” Mr You says. “Whether we like it or not, fats and carbohydrates in modern diets are supplying enough energy to meet our daily needs. Because meat protein is digested later than fats and carbohydrates, this makes the energy we receive from protein a surplus, which is then converted and stored as fat in the human body.” “Nevertheless, it is important that we show the contribution meat protein is making to obesity so that we can better understand what is happening. In the modern world in which we live, in order to curb obesity it may make sense for dietary guidelines to advise eating less meat, as well as eating less sugar,” he says. Study suggests possible link between artificial sweeteners and heart disease French National Institute for Health and Medical Research, September 7, 2022 A large study of French adults published by The BMJ today suggests a potential direct association between higher artificial sweetener consumption and increased cardiovascular disease risk, including heart attack and stroke. The findings indicate that these food additives, consumed daily by millions of people and present in thousands of foods and drinks, should not be considered a healthy and safe alternative to sugar, in line with the current position of several health agencies. Artificial sweeteners are widely used as no- or low-calorie alternatives to sugar. They represent a $7.2 billion (£5900m; €7000m) global market and are found in thousands of products worldwide, particularly ultra-processed foods such as artificially sweetened drinks, some snacks, and low calorie ready meals. Several studies have linked consumption of artificial sweeteners or artificially sweetened beverages (ASB) to weight gain, high blood pressure, and inflammation. To investigate this further, a team of researchers at the French National Institute for Health and Medical Research (Inserm) and colleagues drew on data for 103,388 participants (average age 42 years; 80% female) of the web-based NutriNet-Santé study, launched in France in 2009 to investigate relations between nutrition and health. Dietary intakes and consumption of artificial sweeteners were assessed by repeated 24-hour dietary records and a range of potentially influential health, lifestyle, and sociodemographic factors were taken into account. A total of 37% of participants consumed artificial sweeteners, with an average intake of 42.46 mg/day, which corresponds to approximately one individual packet of table top sweetener or 100 mL of diet soda. The researchers found that total artificial sweetener intake was associated with an increased risk of cardiovascular disease (absolute rate 346 per 100,000 person years in higher consumers and 314 per 100,000 person years in non-consumers). Artificial sweeteners were more particularly associated with cerebrovascular disease risk (absolute rates 195 and 150 per 100,000 person-years in higher and non-consumers, respectively). Aspartame intake was associated with increased risk of cerebrovascular events (186 and 151 per 100,000 person-years in higher and non-consumers, respectively), while acesulfame potassium and sucralose were associated with increased coronary heart disease risk (acesulfame potassium: 167 and 164 per 100,000 person-years; sucralose: 271 and 161 per 100,000 person-years in higher and non-consumers, respectively). Your soap and toothpaste could be messing with your microbiome University of Chicago, September 2, 2022 Antimicrobial chemicals found in common household products could be wreaking havoc with people's guts, according to a research paper out this week in the journal Science. Triclosan is an antibacterial compound used in soaps, detergent and toothpaste, as well as toys and plastics. It was originally only used in hospitals, but it found its way into homes as Americans became more germ-phobic. (However, recent studies have found it no more effective at killing bacteria than plain soap. ) Now, there are growing concerns about the possible negative effects of the chemical on human health and the environment. According to the US Food and Drug Administration (FDA), animal studies have shown that the chemical can act as a hormone disruptor. A 2008 study found traces of triclosan in the urine of 75% of the participants – some as young as six. The chemical has also been found in more than half of freshwater streams in the US. Disturbing the human microbiome has been “linked to a wide array of diseases and metabolic disorders, including obesity, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS) and behavioral and metabolic disorders,” wrote the paper's authors, Alyson L Yee and Jack A Gilbert. Yee and Gilbert also suggested that exposure to triclosan could be even more detrimental to the health of developing fetuses and newborns than to adults. A 2014 New York University study found that gut disruptions in early infancy could have lasting negative effects on immune and brain development. Triclosan could also be contributing to antibiotic resistance, which scientists believe is caused by the overuse of antimicrobials in humans and animals. There are partial bans of the chemical in the European Union and in Minnesota, and the FDA says it will continue reviewing the chemical for its safety. Exposure to phthalates could be linked to pregnancy loss Peking University, September 2, 2022 A new study of more than 300 women suggests that exposure to certain phthalates — substances commonly used in food packaging, personal-care and other everyday products — could be associated with miscarriage, mostly between 5 and 13 weeks of pregnancy. The research, appearing in the ACS journal Environmental Science & Technology, is the first epidemiological study on non-work-related exposure to phthalates to provide evidence for the possible link among a general population. Out of concern over the potential health effects of phthalates, the U.S. has banned six of these substances from use in certain products made for young children. But many are still included as ingredients in paints, medical tubes, vinyl flooring, soaps, shampoos and other items. Research on phthalates has shown that long-term exposure to low levels of some of these compounds harms lab animals' health and can increase their risk for pregnancy loss. Additionally, at least one study found that female factory workers exposed to high levels of phthalates through their work were at a higher risk for miscarriage. But there is little epidemiological evidence of phthalates' effects on pregnancy among women with non-occupational exposure. Jianying Hu, Huan Shen and colleagues wanted to find out if there might be a link. The researchers tested urine samples from 132 women who had miscarriages and 172 healthy pregnant women in China. They found pregnancy loss was associated with higher levels of urinary phthalate metabolites from diethyl phthalate (DEP), di-isobutyl phthalate (DiBP) and di-n-butyl phthalate (DnBP). Although this doesn't prove that phthalates cause pregnancy loss, the study suggests an association exists that the researchers say should be studied further.

Gut Immune Body Brain Axis.Dr Gundry:Leaky Gut, gut microbiome and dietRenowned Cardiovascular Surgeon who realised that all he was doing was treating thesymptoms so he studied the underlying causes.The lining of the gut is one cell thickAs bacteria break down the gut that is when ageing startsIbuprofen or roundup disastrous the bacteria populationSkin is a mirror of the lining of the gutJoints do not naturally wear out.Animal model C Elegans as bacteria begin to break down the wall of the gut that is whenageing starts105 year old people have a diverse set of bugs identical to a healthy 30 year old. It is notattacking the wall of the gut.Ecermansia musinophilia. Lives in the mucous layer whose job is to trap lectins plantproteins looking for sugar molecules and to protect the wall of the gut from harmful bacteria.Ecermansia musinophilia eats mucus which in turn makes more mucus.Metformin works by increasing mucous and this change in bacteria makes some peoplehave mild diarrhoea as the bacteria change.If we damage this lining eg ibuprofen or food with roundup destroys the bacteria populationand gut lining.Glyocosade an antibacterial damages Ecermansia Musinophilia even though it does notdirectly affect human cells.Antibiotics in food or direct prescription eg ladies who take low dose for UTI have a higherincidence of heart disease.Heart disease is an autoimmune disease starting in the gut.Cholesterol is an innocent bystander which gets sucked into the inflamed wall of a bloodvessel.Infants with heart transplants have coronary artery disease with pathology identical withtypical coronary artery disease.Lectins which are a foreign protein which can stick to sugar molecules on the surface ofblood vessels are the cause of atherosclerosis and removing lectins reduces those markers.Lectins are one of the plant defence systems. Sticky proteins that look for specific sugarmolecules to stick to which insights an inflammtory response.Joints do not normally wear out. Usually you can find bacterial particles in the joint fluid ofarthritisBecauseLectins broke down the wall of the gut. 65% of the immune system is behind the wall of thegut because the gut is where the outside word gets through. A reason why we store fat inthe gut is to provide energy to the immune system. Similarly fat on the outside ofatherosclerotcic blood vessles correlates with the severity of inflammation.Fat is not the cause . It is there because of the inflammation and the inflammation is theredue to the leaky gut.The immune system responds to antigens on bacteria of viruses. Lectins have antigens withcross reactivity with other proteins in the body. Eg thyroid.Nightshade vegetables or peanutsLectins disrupt the microbiome and break up the lining of the gut allowing entry by lectinsand by bacteria or bacterial particles.Hence if you inject a bacterial lipopolysaccharide into a person you can induce septic shock.Alzheimers Parkinsons is neuroinflammation.Most amyloid is produced by bacteria in the gut. Therefore 40 billion dollars invested inantiamyloid drugs has been a waste because amyloid is produced by the amyloid producingbacteria inthe gut fet by western diet. Then the amyloid has to get through the wall of the gut.Once they get through the gut wall and goto the brain it will produce more amyloid.Cholesterol and amyloid coexist in dementia in those with the apoE gene.The apo E gene codes for a carrier molecule because it is less efficient at transportingcholesterol. It cannot get out of the cell after it has been attracted by inflammation.Faecal microbial transplant:1970s broad spectrum antibiotics came out which made it much quicker to treat infectionsbut it also wiped out the gut bacteria. Normally 10000 species of bacteria.Pseudomembranous colitis was caused by Clostridium Difficile over growing. Initial studydone from the faeces of medical students.Faecal enemas treated the pseudomembranous colitis.Meat with animals treated by antibiotics can also cause problems.60% of faeces is bacteriaOral microbiome and cloud of bacteria around us –Holobiome . This defines our personalspace.Kissing is a human and ape characteristic. Exchanging oral microbiome. Bacteria decidewhether the other person's bacteria are compatible with them.Women have a gut feeling because they are more capable of listening to their microbiome. We inherit our microbiome from our mother. All of the mitochondria are involved with bacteriainherited from our mother. Bacteria communicate to their ‘sisters 'ie the body's mitochondria.Autism: kids have a different microbiome than ‘normal'The placental microbiome is important in educating the foetal immune system.Oral faecal transplants for 6 weeks in autistic kids. Almost immediately 50% autismsymptoms reduced.Ecermansia like tubers, mushrooms, -study in Asia find 90% reduction in Alzheimers withtwo cups of mushrooms a week.Inulin containing compounds eg chicory, radicchio, jerusalem artichoke.Exercise women who exercise routinely from midlife have a 90% reduction in Alzheimers. Inthose who get AD it happens 11 years later. Housework can be important part of exercise.Meditation and yoga also changes the gut microbiome.Lymph system in the brain in deep sleep -early in the sleep cycle-shrinks by 20% and thesebad proteins are squeezed out. You need a 3-4 hour window between sleep and dinnerbecause blood flow diverts to the gut.Olive oil /walnuts / mediterranean low fat diet: first two groups improved memory after 5years. 3rd group lost memoryThose with CVD had a 30% reduction in events, the low fat group continued CVS events.Polyphenos in olive oil grow proteinsTMAO is made by gut bacteria primarily from animal protein especially choline eg egg yolkand carnitine . TMAO damages blood vessels. Polyphenols in certain olive oil and red winebalsamic vinegar that paralyse enzyme systems in the bacteria so they do not make TMAO.However the logical error here is that eggs which are high in choline are not associated withincreased morbidity.Vitamin D at least 5000 units a day . Almost all cancer patietns and autoimmune pateitnshave low vitamin D. HIgher your VItamin D the longer your telomere. Stem cells in the gutare simulated by vitamin D.VItamin CLectins are present in most plant foods but especially high in:legumes, such as beans, lentils, peas, soybeans, and peanutsnightshade vegetables, such as tomatoes and eggplantdairy products, including milkgrains, such as barley, quinoa, and riceThe Roll of Inflammation in Depression and FatigueFrontiers In Immunology:CH Lee 2019:Immune system link to depression first noticed with immunotherapy eg INFa (which activates an inflammatory antiviral response) for Hepatitis C : associated with raised proinflammatory cytokines and depression and fatigue.20% of patients treated with INFa developed depression which resolved on discontinuationbut also increased the risk of depression in future.Also people with higher IL6 aged 9 were more likely to have depression aged 18 in a dosedependent manner.Innate immune system seems to be lower in depression eg NK cells and also less antiinflammatory regulatory T cells whereas inflammatory monocytes are activated.There is commonality in immune activation from autoimmune disorder such as multiplesclerosis or immune reactions in sepsis.Antidepressants reduce inflammation while a higher baseline level of inflammation predicts apoorer treatment response.People with depression have been shown to have higher inflammatory markers which canbe used to predict treatment efficacy and future recurrences of depression.Elevated inflammatory markets eg TNFa after an MI disrupt the blood brain barrier causingdepression.Inflammatory changes in the brain with raised TNFa in the hippocampus and striatumprecede development of depressive symptoms.Neurogenesis is inhibited by the kynurenine pathway which is rescued by both inhibitors ofthis pathway and traditional antidepressants.TNFa also increases glutamate release causing exocytotic damage to surroundingsneurones.Conditions associated with chronic immune activation such as asthma, atopy, diabetes mMS, RhA, SLE are all associated with raised levels of depression eg 36% of asthma havedepression who also had higher TNFa than those who were not depressed. 75% in RhAMS up to 50% risk of depression.Acute inflammation with sepsis also causes depression and raises the risk of depression infuture which in animal models can be reduced by using steroid during the acute sepsis.Antidepressants reduce inflammatory markers perhaps SNRI more effective than SSRI andalso ECT adds in return to normal of NK activity.Directly reducing the immune response eg anti TNF a or Caspase Inhibitors have beenshown to reduce depression. Rituximab which is an antibody that targets and depletes Bcells in the treatment of RhA also reduces depression.Aspirin can reduce depression but can also reduce the effect of an SSRI.

VIDEOS: 1. The Anti-Smartphone Revolution – (13:23) ColdFusion 2. Gravitas Plus: Explained: The China-Taiwan conflict (9:11)   HEALTH NEWS Astonishing effects of grapes, remarkable potential for health benefits Frequent nut consumption associated with less inflammation Body posture affects how oral drugs absorbed by stomach [why not supplements too?]  Lifting Weights Beats Out Cycling, Swimming For Vegans Wanting Stronger Bones Perfectionism Linked To Burnout At Work, School And Sports, Research Finds  Mindfulness Therapy Better Than Antidepressants Astonishing effects of grapes, remarkable potential for health benefits Western New England University, August 8, 2022 Recent studies released by Dr. John Pezzuto and his team from Western New England University show “astonishing” effects of grape consumption and “remarkable” impacts on health and on lifespans. Published in the journal Foods, one study showed that adding grapes in an amount equal to just under two cups of grapes per day to a high-fat diet, typically consumed in western countries, yielded reductions in fatty liver and extended lifespans.  Noting that these studies add an entirely new dimension to the old saying ‘you are what you eat,' Pezzuto, who has authored over 600 scientific studies, said that the work with grapes showed actual changes in genetic expression. “That is truly remarkable.” Adding grapes to a high-fat diet also increased levels of antioxidant genes and delayed natural death.  Acknowledging that it is not an exact science to translate years of lifespan from a mouse to a human, Pezzuto said that his best estimate is the change observed in the study would correspond to an additional 4-5 years in the life of a human. Another study by Dr. Pezzuto and his team published in the journal Antioxidants, reported that grape consumption altered gene expression in the brain and had positive effects on behavior and cognition that were impaired by a high-fat diet.  Frequent nut consumption associated with less inflammation Brigham and Women's Hospital, August 1, 2022 In a study of more than 5,000 people, investigators from Brigham and Women's Hospital have found that greater intake of nuts was associated with lower levels of biomarkers of inflammation, a finding that may help explain the health benefits of nuts. The results of the study appear in the American Journal of Clinical Nutrition. “Population studies have consistently supported a protective role of nuts against cardiometabolic disorders such as cardiovascular disease and type 2 diabetes, and we know that inflammation is a key process in the development of these diseases,” said corresponding author Ying Bao, MD, ScD, an epidemiologist in BWH's Channing Division of Network Medicine. “Our new work suggests that nuts may exert their beneficial effects in part by reducing systemic inflammation.” In the current study, the research team performed a cross-sectional analysis of data from the Nurses' Health Study, which includes more than 120,000 female registered nurses, and from the Health Professionals Follow-Up Study, which includes more than 50,000 male health professionals. The team assessed diet using questionnaires and looked at the levels of certain telltale proteins known as biomarkers in blood samples collected from the study participants. They measured three well-established biomarkers of inflammation: C-reactive protein (CRP), interleukin 6 (IL6) and tumor necrosis factor receptor 2 (TNFR2). After adjusting for age, medical history, lifestyle and other variables, they found that participants who had consumed five or more servings of nuts per week had lower levels of CRP and IL6 than those who never or almost never ate nuts. In addition, people who substituted three servings per week of nuts in place of red meat, processed meat, eggs or refined grains had significantly lower levels of CRP and IL6. Peanuts and tree nuts contain a number of healthful components including magnesium, fiber, L-arginine, antioxidants and unsaturated fatty acids such as α-linolenic acid.  Body posture affects how oral drugs absorbed by stomach [why not supplements too?]  Johns Hopkins School of Medicine, August 8, 2022 A common, economic, and easy method of administering drugs is orally, by swallowing a pill or capsule. But oral administration is the most complex way for the human body to absorb an active pharmaceutical ingredient, because the bioavailability of the drug in the gastrointestinal tract depends on the medication's ingredients and the stomach's dynamic physiological environment. In Physics of Fluids, researchers from Johns Hopkins School of Medicine employ a biomimetic in-silico simulator based on the realistic anatomy and morphology of the stomach—a “StomachSim”—to investigate and quantify the effect of body posture and stomach motility on drug bioavailability. “”When the pill reaches the stomach, the motion of the stomach walls and the flow of contents inside determine the rate at which it dissolves. The properties of the pill and the stomach contents also play a major role. Stomach contents, motility, and gastric fluid dynamics all play a role in a drug's bioavailability, and stomach contractions can induce pressure and generate complex pill trajectories. This results in varying rates of pill dissolution and nonuniform emptying of the drug into the duodenum and, sometimes, gastric dumping in the case of modified-release dosage. The modeling appears to be the first of its kind to couple gastric biomechanics of posture with pill movement and drug dissolution to quantify an active pharmaceutical ingredientpassing through the pylorus into the duodenum. The model enabled the researchers to calculate and compare the emptying rate and the release of a dissolved active pharmaceutical ingredient into the duodenum for a variety of physiological situations. Lifting Weights Beats Out Cycling, Swimming For Vegans Wanting Stronger Bones Medical University of Vienna (Austria), August 2, 2022 When it comes to bone health, a new study finds people on a plant-based diet should grab the dumbbells. Researchers in Austria have found that lifting weights is the best form of exercise for vegans – trumping cycling and swimming. The team found that vegans who do resistance training once a week – such as machine-work, free weights, or bodyweight resistance – have stronger bones than plant-based eaters who do other forms of exercise. The new study, published in the Journal of Clinical Endocrinology & Metabolism, found vegans who did resistance training had similar bone structure to omnivores — people who eat both meat and vegetables. For at least five years, authors followed 43 men and women on a plant-based diet and 45 men and women who eat meat as well. “Our study showed resistance training offsets diminished bone structure in vegan people when compared to omnivores.” Perfectionism linked to burnout at work, school and sports, research finds  York St. John University (UK), July 31, 2022 Concerns about perfectionism can sabotage success at work, school or on the playing field, leading to stress, burnout and potential health problems, according to new research published by the Society for Personality and Social Psychology.  In the first meta-analysis of the relationship between perfectionism and burnout, researchers analyzed the findings from 43 previous studies conducted over the past 20 years. It turns out perfectionism isn't all bad. One aspect of perfectionism called “perfectionistic strivings” involves the setting of high personal standards and working toward those goals in a pro-active manner. These efforts may help maintain a sense of accomplishment and delay the debilitating effects of burnout, the study found.  The dark side of perfectionism, called “perfectionistic concerns,” can be more detrimental when people constantly worry about making mistakes, letting others down, or not measuring up to their own impossibly high standards, said lead researcher Andrew Hill, an associate professor of sport psychology at York St. John University in England. Previous research has shown that perfectionistic concerns and the stress they generate can contribute to serious healthproblems, including depression, anxiety, eating disorders, fatigue and even early mortality. The study was published online in the Personality and Social Psychology Review. The study found that perfectionistic concerns had the strongest negative effects in contributing to burnout in the workplace, possibly because people have more social support and clearly defined objectives in education and sports. A student can be rewarded for hard work with a high grade, or a tennis player can win the big match, but a stellar performance in the workplace may not be recognized or rewarded, which may contribute to cynicism and burnout.  “People need to learn to challenge the irrational beliefs that underlie perfectionistic concerns by setting realistic goals, accepting failure as a learning opportunity, and forgiving themselves when they fail,” Hill said. “Creating environments where creativity, effort and perseverance are valued also would help.”  Mindfulness Therapy Better Than Antidepressants University of Exeter (UK), July 31, 2022  Antidepressants are big business.  But for the same money, and without the side effects, a little mindfulness can do the same job.  A new study from the University of Exeter in the UK suggests that mindfulness-based cognitive therapy (MBCT) is just as good as drugs – and maybe even better   MBCT is a structured training program for the mind and body.  It was developed to help people deal with repeated bouts of depression.  It teaches them skills to recognize and respond constructively to the thoughts and feelings associated with relapse.  In other words, it helps patients re-focus their thoughts as a way to avoid falling back into depression. Prior studies have shown that MBCT reduces the risk of relapse or recurrence of depression by about 34% compared to usual care or placebo.  B The research published in The Lancet  followed a group of 424 depressed patients for two years. The patients had all suffered three or more previous major depressive episodes.  And they were all taking a maintenance course of antidepressants. The MBCT group attended eight group therapy sessions in which they learned mindfulness practices and cognitive-behavioral skills, and participated in group discussions.   After two years, relapse rates were worse in the drug group.  The drug group relapsed at the rate of 47% compared to only 44% for the mindfulness group.  The researchers concluded that MBCT may be an effective alternative to antidepressants for prevention of depressive relapse with no significant difference in cost. And it may be a good alternative for people who choose not to use drugs.  But they also suggested MBCT was more beneficial than drugs in preventing relapses in patients who were at highest risk of relapse especially those who reported severe childhood abuse.

Dr Kim Lauper, from the Division of Rheumatology, Department of Internal Medicine and Department of Medicine, Faculty of Medicine, Geneva University Hospitals, Geneve, Switzerland. Join Professor Peter Nash as he interviews authors of recent notable papers in rheumatology. In this addition Dr Lauper discusses her latest paper; Effectiveness of TNF-inhibitors, abatacept, IL6-inhibitors and JAK-inhibitors in 31 846 patients with rheumatoid arthritis in 19 registers from the ‘JAK-pot' collaboration.

Identificato il processo grazie al quale l'allenamento può ridurre il rischio di contrarre il cancro al colon rallentare la crescita dei tumori.La ricerca giunge dagli scienziati dell'Università di Newcastle che hanno chiarito un processo già noto, relativo al rilascio nel flusso sanguigno dell'interleuchina-6 (IL-6), che aiuta a riparare il DNA delle cellule danneggiate. I risultati sono stati pubblicati sull'International Journal of Cancer e gettano nuova luce sull'importanza di un'attività moderata nella lotta contro una malattia che spaventa tutti, e potrebbe essere la base per sviluppare nuovi trattamenti in futuro.

In this episode Clint is back after a month's hiatus and wants to discuss women not really out here hollering at men. They say they are but you aint really bout it like you say you are.Hoochie Daddy Shorts Playlistshttps://linktr.ee/clintcoleyplaylistsMy Edible Kicked In Ticketswww.myediblekickedin.com6/17 Chicago, IL6/25 Oakland, CA6/26 Portland, OR7/8 Detroit, MI7/9 Buffalo, NY7/15 Richmond, VA7/16 Washington, D.C.7/17 Raleigh, NC7/23 Brooklyn, NY

In this episode Clint is by himself again and today he wants to know why men don't seem to be having fun on dates.Hoochie Daddy Shorts Playlistshttps://linktr.ee/clintcoleyplaylistsMy Edible Kicked In Ticketswww.myediblekickedin.com5/20-22 Kansas City, MO6/9 Milwaukee, WI6/10 Milwaukee, WI6/11 St. Louis, MO6/12 Cleveland, OH6/17 Chicago, IL6/18 Minnesota, MN6/25 Oakland, CA6/26 Portland, OR7/8 Detroit, MI7/9 Buffalo, NY7/15 Richmond, VA7/16 Washington, D.C.7/17 Raleigh, NC7/23 Brooklyn, NY

In this episode Clint is by himself and he is discussing Hoochie daddy season. Time to get right fellas.Hoochie Daddy Shorts Playlistshttps://linktr.ee/clintcoleyplaylistsMy Edible Kicked In Ticketswww.myediblekickedin.com5/20-22 Kansas City, MO6/9 Milwaukee, WI6/10 Milwaukee, WI6/11 St. Louis, MO6/12 Cleveland, OH6/17 Chicago, IL6/18 Minnesota, MN6/25 Oakland, CA6/26 Portland, OR7/8 Detroit, MI7/9 Buffalo, NY7/15 Richmond, VA7/16 Washington, D.C.7/17 Raleigh, NC7/23 Brooklyn, NY

This week, please join author Andrew Stokes as he and Greg Hundley discuss the Research Letter "E-Cigarette Use and Risk of Cardiovascular Disease: A Longitudinal Analysis of the PATH Study (2013–2019)." Dr. Greg Hundley: Well, listeners, welcome to this May 17th issue of Circulation on the Run. And I am Dr. Greg Hundley, associate editor, director of the poly heart center at VCU Health in Richmond, Virginia. And this week, Carolyn is away out on vacation and we are going to go through the summaries together. We have a great feature today on e-cigarette use and the risk of cardiovascular disease. But before we get to that, how about we grab a cup of coffee and jump into some of the other articles in the issue? And the first one comes to us from the world of clinical science and Dr. Jiaqi Huang from the National Cancer Institute. Listeners, the objective of this study was to examine overall and cause-specific mortality in relation to dietary and serum cholesterol, as well as egg consumption through the prospective analysis of 27,000 men in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention or ATBC Study, and also a systematic review and meta-analysis of several other cohort studies. Dr. Greg Hundley: So, what did the investigators find? Well, first, based on 482,000 person-years of follow-up, the authors identified 22,000 deaths, including 9,110 deaths from cardiovascular disease. Now, greater dietary cholesterol and egg consumption were associated with increased risk of overall and cardiovascular disease mortality. Now, second, from the meta-analysis component of the study, overall consumption of one additional 50-gram egg per day was associated with an increased cardiovascular disease risk with a pooled relative risk of 1.04 with a higher risk of cardiovascular disease among those from us cohorts where their pooled relative risk ratio was 1.88, a borderline higher cardiovascular disease risk in European cohorts with a pooled relative risk of 1.05, but not an increased cardiovascular disease risk in the Asian cohorts. So, the results from this study, which includes an updated meta-analysis, suggest that there is support for restricted consumption of dietary cholesterol as really a means to improve long-term health and longevity. Dr. Greg Hundley: Well, let's go to our next article. So, in this next study, we are going to move from cholesterol risk now to salt substitution. And this article comes to us from Professor Maoyi Tian from the Harbin Medical University. Listeners, the Salt Substitute and Stroke Study, or SSaSS is a five-year cluster randomized controlled trial and demonstrated that replacing regular salt with a reduced sodium added or potassium salt substitute reduced the risk of stroke, major cardiovascular events, and premature death among individuals with prior stroke or uncontrolled high blood pressure that lived in rural China. So, this particular study, a substudy, assessed the cost-effectiveness profile of this particular intervention. Dr. Greg Hundley: So, listeners, what did the study find? Well, there was a mean follow-up of 20,995 participants that was conducted a little over four years, and over the period, replacing regular salt with salt substitute reduced the risk of stroke by 14% and the salt substitute group had on average 0.054 more quality-adjusted life years per person. The average costs were lower in the salt substitute group, and this intervention was dominant. That is better outcomes at a lower cost for prevention of stroke as well as for quality-adjusted life-years gained. Now, interestingly sensitivity analyses showed that these conclusions were robust except when the price of the salt substitute was increased to the median and highest market prices identified in China. The salt substitute intervention had a 95% probability of being cost-saving and a greater than 99.9% probability of being cost-effective. A really interesting article. Dr. Greg Hundley: Well, now, let's turn our attention to the world of population science. And in this study, these authors led by Dr. Steven Lubitz from Massachusetts General Hospital performed a Genome-Wide Association Study or GWAS of the QT corrected interval among 84,630 United Kingdom Biobank participants. And they created a polygenic risk score. Now, among 26,976 participants with whole-genome sequencing and electrocardiogram data in the Trans-Omics for Precision Medicine or TOPMed program, they identified 160 carriers of punitive pathogenic, rare variants in 10 genes known to be associated with the QT interval. Dr. Greg Hundley: So, the authors here examined the QTC corrected associations with the polygenic risk score and with rare variants from the TOPMed cohort. So, what did they find? They found 54 independent loci by GWAS in the UK Biobank. 21 loci were novel of which 12 were replicated in TOPMed. The polygenic risk score comprising over a million common variants was significantly associated with the QTC in TOPMed, and carriers of punitive pathogenic rare variants had longer QTC intervals than non-carriers. Now, 23.7% of individuals with a QT corrected of greater than 480 milliseconds carried either a monogenic rare variant or had a polygenic risk score in the top decile. 3.4% for monogenic and 21% for the top decile of the polygenic risk score. Dr. Greg Hundley: So, listeners, the findings of this study indicate that the QTC duration in the population is influenced by both rare variants in genes, underlying cardiac repolarization and polygenic risk, with a sizeable additional contribution from polygenic risk. And therefore, comprehensive assessment of the genetic determinants of QTC prolongation should include incorporation of both polygenic and monogenic risk. Dr. Greg Hundley: Well, listeners, let's turn our attention to the world of preclinical science. And this next article comes to us from Professor Junbo Ge from the Department of Cardiology in Zhongshan Hospital in Fudan University. Well, listeners, after myocardial infarction, cardiac resident macrophages, which are self-maintaining in that they originate from embryonic hematopoiesis are responsible for the efficient clearance and degradation of apoptotic cardiomyocytes. And that process is called efferocytosis. Now, efferocytosis is required for inflammation resolution and tissue repair. However, the underlying molecular mechanisms of this process really remain unknown. Dr. Greg Hundley: So, as such, listeners, these authors sought to identify the mechanisms of the continued clearance and degradation of phagolysosomal cargo by cardiac resident macrophages during myocardial infarction. Well, what did Dr. Ge and colleagues find? Several things. First, they identified legumine as a gene specifically expressed by cardiac resident macrophages, and legumine deficiency resulted in a considerable exacerbation in cardiac function, accompanied with the accumulation of apoptotic cardiomyocytes and a reduced index of in-vivo efferocytosis in the border area of infarcts. Furthermore, the formation of LC3 to dependent phagosome around secondary encountered apoptotic cardiomyocytes was disabled. In addition, legumine deficiency increased infiltration of MHC to high CCR2+ macrophages, and the enhancement of recruitment of MHC to low CCR2+ monocytes with downregulation of anti-inflammatory mediators, such as IL10 and TGF-beta, and upregulation of pro-inflammatory mediators, including interleukin-1-beta, Tumor Necrosis Factor alpha, IL6, and IFN-gamma. Dr. Greg Hundley: So, listeners, in summary, the results of this study directly link efferocytosis to wound healing in the heart and identify legumine as a significant link between acute inflammation resolution and cardiac function after infarction. Well, listeners, also in this issue, we have a wonderful On My Mind feature from Professor Camlet entitled “A Role for the Vascular Endothelium in Post-Acute COVID-19.” Well, next, we're going to head to our feature article on e-cigarette use and the risk of cardiovascular disease. Dr. Greg Hundley: Well, listeners, welcome to our feature discussion today. A very interesting topic. E-cigarette use and the risk of cardiovascular disease. And we have with us today the senior author of this particular manuscript, Dr. Andrew Stokes from the Boston University School of Public Health in Boston, Massachusetts. Welcome, Andrew. Andrew, to get started, can you describe some of the background information pertaining to your study and what was the hypothesis that you wanted to address? Dr. Andrew Stokes: Absolutely, and thank you for having me on the podcast. Despite the increasing popularity of electronic cigarettes, the long-term health effects of habitual e-cigarette use remain unclear. Most of the studies that have been conducted to date are either cross-sectional or they pertain to small clinical samples. The goal of the present study was to develop a longitudinal design to see if e-cigarette use at a point in time was linked to cardiovascular events over a multi-year follow-up period. Dr. Greg Hundley: Very nice. So, your specific hypothesis really pertained to e-cigarette use, correct? Dr. Andrew Stokes: That's right. As a novel product, information on e-cigarette use and its health effects is lacking, and so our goal was to see if e-cigarette use was associated with the incidence of clinical events. Dr. Greg Hundley: And so, can you describe for us your study population and your study design? Dr. Andrew Stokes: Absolutely. Data come from the Population Assessment of Tobacco and Health Study or the PATH Study, which is a nationally representative cohort study of the non-institutionalized population containing five annual waves of self-reported data collected between 2013 and 2019. The initial sample included over 30,000 US adults ages 18 years and older with oversampling of tobacco users. We excluded respondents who were lost to follow-up or who had a previous diagnosis of CVD or were missing baseline exposure information. Ultimately, we ended up with a sample of just over 20,000 individuals. Dr. Greg Hundley: Very nice. And so, what were your study results? Dr. Andrew Stokes: So, we had several key findings. One key finding was that, compared to people who only smoke cigarettes, people who smoke both traditional cigarettes and used e-cigarettes had no significant reduction in risk for heart attack, heart failure, or stroke, nor any cardiovascular disease outcome. This is significant because many e-cigarette users use both e-cigarettes and cigarettes in combination. Very few move to exclusive e-cigarette use. Additionally, we found that those who do move to e-cigarette use exclusively though, representing a very small fraction of the cohort, had some evidence of reduction in cardiovascular harm. However, these results for exclusive e-cigarette users were not statistically significant, indicating that additional studies with longer follow-up will be required before we can make any definitive conclusions about this group. Dr. Greg Hundley: Very nice. And did you notice any discrepancy in your results between either men versus women or between individuals that were younger in age versus those that may say be 50 years or older? Dr. Andrew Stokes: I think both sources of effect modification will be valuable directions for future research. Unfortunately, samples of e-cigarette users are quite small and incident events over follow-up are quite limited. Therefore, the present study did not pursue or explore these types of stratifications. Dr. Greg Hundley: Very good. So, sounds like more research to come forward. Well, Andrew, how do we put your results really in the context with other studies evaluating the harmful effects of e-cigarettes? Dr. Andrew Stokes: Of course. So, we know from toxicological studies that there are many constituents of e-cigarette aerosols that are concerning and have substantial toxicity. We know that the inhalation of e-cigarette aerosols among young healthy adults induce inflammation and oxidative stress. Population-based studies from cross-sectional data sources also suggest evidence of harm. What's needed are more longitudinal studies with longer follow-up periods and more incidence events so we can really parse this risk and identify the magnitude of these harms. Finally, we also need to understand better whether there's any harm reduction potential associated with e-cigarette use. E-cigarettes are currently not an FDA-approved cessation product. Therefore, we do not recommend their use despite preliminary evidence of potential harm reduction. We'll need further evidence before we can make any such conclusions. Dr. Greg Hundley: And Andrew, describe for us, and you've started to already, what series of studies are needed next to be performed in this sphere of research? Dr. Andrew Stokes: Right. So, it's difficult to really identify definitively the effects of e-cigarette use in the absence of randomized control trials. However, we can use observational data with target trial approaches to emulate the clinical trial that we would like to do if we were able to. So, the next step is really to look at transitions across products between cigarette and e-cigarette use and to associate those who switch products, such as from e-cigarettes to cigarettes or vice versa, to see if those switches are associated with any harm or harm reduction. Dr. Greg Hundley: Very good. Any specific racial or ethnic groups or even social determinants of health that may need to be targeted with some of these future studies? Dr. Andrew Stokes: That's a great question. So, what we know so far from preliminary research is that some groups are more likely to switch to e-cigarettes than other groups. Particularly among current combustible cigarette users, the rates of switching do vary by race and ethnicity. Thus, we need further research to understand why these patterns differ across subgroups and what their implications may be for health. Dr. Greg Hundley: Do you foresee any difficulty in trying to enroll participants from those other groups as you plan these studies moving forward? Dr. Andrew Stokes: The advantage of the current research design is that we're using a large secondary data set of survey participants who are enrolled in the Population Assessment of Tobacco and Health study. Therefore, we are not enrolling patients ourselves and the response rates are quite high in these surveys. Dr. Greg Hundley: Well, Andrew, we hear that some of the inhalants that are mixed with the inhaled nicotine can be flavors and perhaps have been approved by the FDA for consumption in the GI tract where, whatever these additives are, you would think might be broken down by the digestive system. But if they're inhaled and get into the lung tissue and the parenchyma, the alveoli, et cetera, do they perhaps have harmful effects that maybe we're not aware of? Dr. Andrew Stokes: Absolutely. E-cigarettes come in thousands of characterizing flavors including sweet flavors, tobacco flavors, and many other miscellaneous flavors. As we saw with the outbreak of lung injury associated with the use of e-cigarettes in 2019, inhaling flavors can have health effects that are unanticipated based on research in the GI tract, and therefore, as a next step in this research, we really need more work to investigate how different flavors are associated with the incidence of clinical events, whether cardiovascular or pulmonary conditions. Dr. Greg Hundley: Very nice. Well, listeners, we want to thank Dr. Andrew Stokes from the Boston University School of Health for bringing us this data from the PATH study, suggesting that combining smoking with e-cigarette use does not reduce cardiovascular events and that quitting both products is needed to ensure overall cardiovascular disease risk reduction. 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. 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.

In this episode Clint discusses Kevin Samuels.Hoochie Daddy Shorts At Night Playlisthttps://linktr.ee/clintcoleyplaylistsMy Edible Kicked In Ticketswww.myediblekickedin.com4/14 Boston, MA4/15 Philadelphia, PA4/20 Memphis, TN4/21 Houston, TX4/22 New Orleans, LA4/28 Syracuse, NY4/29 Toronto, ON5/5 Seattle, WA5/6 Vancouver, BC5/12 Indianapolis, IN5/13 Cincinnati, OH5/20-22 Kansas City, MO6/9 Milwaukee, WI6/10 Milwaukee, WI6/11 St. Louis, MO6/12 Cleveland, OH6/17 Chicago, IL6/18 Minnesota, MN6/25 Oakland, CA6/26 Portland, OR7/8 Detroit, MI7/9 Buffalo, NY7/15 Richmond, VA7/16 Washington, D.C.7/17 Raleigh, NC7/23 Brooklyn, NY

In this episode Clint is alone and discussing why men hate dating so much.After Breakfast Playlisthttps://linktr.ee/clintcoleyplaylistsBreakfast Date Playlist.My Edible Kicked In Ticketswww.myediblekickedin.com4/14 Boston, MA4/15 Philadelphia, PA4/20 Memphis, TN4/21 Houston, TX4/22 New Orleans, LA5/5 Seattle, WA5/6 Vancouver, BC5/12 Indianapolis, IN5/13 Cincinnati, OH5/20-22 Kansas City, MO6/9 Milwaukee, WI6/10 Milwaukee, WI6/11 St. Louis, MO6/12 Cleveland, OH6/17 Chicago, IL6/18 Minnesota, MN6/25 Oakland, CA6/26 Portland, OR7/8 Detroit, MI7/9 Buffalo, NY7/10 Toronto, ON7/15 Richmond, VA7/16 Washington, D.C.7/17 Raleigh, NC7/23 Brooklyn, NY

In this episode Clint is joined by Slink Johnson and they are trying to figure out how men are giving quality penis and not getting rewarded with quality snacks.After Breakfast Playlisthttps://linktr.ee/clintcoleyplaylistsFollow Slink Johnson@slinkjohnsonBreakfast Date Playlist.My Edible Kicked In Ticketswww.myediblekickedin.com4/14 Boston, MA4/15 Philadelphia, PA4/20 Memphis, TN4/21 Houston, TX4/22 New Orleans, LA5/5 Seattle, WA5/6 Vancouver, BC5/12 Indianapolis, IN5/13 Cincinnati, OH5/20-22 Kansas City, MO6/9 Milwaukee, WI6/10 Milwaukee, WI6/11 St. Louis, MO6/12 Cleveland, OH6/17 Chicago, IL6/18 Minnesota, MN6/25 Oakland, CA6/26 Portland, OR7/8 Detroit, MI7/9 Buffalo, NY7/10 Toronto, ON7/15 Richmond, VA7/16 Washington, D.C.7/17 Raleigh, NC7/23 Brooklyn, NY

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In this episode Clint is joined by podcast favorite Louis Gee and they discuss why people are out here dating and only thinking about themselves.After Breakfast Playlisthttps://linktr.ee/clintcoleyplaylistsFollow Louis Gee@lougee83Breakfast Date Playlist.My Edible Kicked In Ticketswww.myediblekickedin.com4/14 Boston, MA4/15 Philadelphia, PA4/20 Memphis, TN4/21 Houston, TX4/22 New Orleans, LA4/28 Syracuse, NY4/29 Toronto, ON5/5 Seattle, WA5/6 Vancouver, BC5/12 Indianapolis, IN5/13 Cincinnati, OH5/20-22 Kansas City, MO6/9 Milwaukee, WI6/10 Milwaukee, WI6/11 St. Louis, MO6/12 Cleveland, OH6/17 Chicago, IL6/18 Minnesota, MN6/25 Oakland, CA6/26 Portland, OR7/8 Detroit, MI7/9 Buffalo, NY7/15 Richmond, VA7/16 Washington, D.C.7/17 Raleigh, NC7/23 Brooklyn, NY

In this episode Clint sits down with his friend, singer and songwriter Steph and they discuss why women want to feel special even if you two just met.After Breakfast Playlisthttps://linktr.ee/clintcoleyplaylistsFollow Steph@soundslikestephBreakfast Date Playlist.My Edible Kicked In Ticketswww.myediblekickedin.com4/14 Boston, MA4/15 Philadelphia, PA4/20 Memphis, TN4/21 Houston, TX4/22 New Orleans, LA4/28 Syracuse, NY4/29 Toronto, ON5/5 Seattle, WA5/6 Vancouver, BC5/12 Indianapolis, IN5/13 Cincinnati, OH5/20-22 Kansas City, MO6/9 Milwaukee, WI6/10 Milwaukee, WI6/11 St. Louis, MO6/12 Cleveland, OH6/17 Chicago, IL6/18 Minnesota, MN6/25 Oakland, CA6/26 Portland, OR7/8 Detroit, MI7/9 Buffalo, NY7/15 Richmond, VA7/16 Washington, D.C.7/17 Raleigh, NC7/23 Brooklyn, NY

In this episode Clint and Tahir Moore teach the fellas how to make a playlist and they have a discussion about the last 2 years have been hard.After Breakfast Playlisthttps://linktr.ee/clintcoleyplaylistsFollow Tahir Moore@tahirmooreBreakfast Date Playlist.My Edible Kicked In Ticketswww.myediblekickedin.com4/14 Boston, MA4/15 Philadelphia, PA4/20 Memphis, TN4/21 Houston, TX4/22 New Orleans, LA4/28 Syracuse, NY4/29 Toronto, ON5/5 Seattle, WA5/6 Vancouver, BC5/12 Indianapolis, IN5/13 Cincinnati, OH5/20-22 Kansas City, MO6/9 Milwaukee, WI6/10 Milwaukee, WI6/11 St. Louis, MO6/12 Cleveland, OH6/17 Chicago, IL6/18 Minnesota, MN6/25 Oakland, CA6/26 Portland, OR7/8 Detroit, MI7/9 Buffalo, NY7/15 Richmond, VA7/16 Washington, D.C.7/17 Raleigh, NC7/23 Brooklyn, NY

In this episode Clint is with fellow comedian and friend Isiah Kelly and they are schooling you on what men discuss among themselves as well as what you need to do on a breakfast date. Playlist belowAfter Breakfast Playlisthttps://linktr.ee/clintcoleyplaylistsFollow Isiah Kelly@isiahkellyBreakfast Date Playlist.My Edible Kicked In Ticketswww.myediblekickedin.com4/14 Boston, MA4/15 Philadelphia, PA4/20 Memphis, TN4/21 Houston, TX4/22 New Orleans, LA4/28 Syracuse, NY4/29 Toronto, ON5/5 Seattle, WA5/6 Vancouver, BC5/12 Indianapolis, IN5/13 Cincinnati, OH5/20-22 Kansas City, MO6/9 Milwaukee, WI6/10 Milwaukee, WI6/11 St. Louis, MO6/12 Cleveland, OH6/17 Chicago, IL6/18 Minnesota, MN6/25 Oakland, CA6/26 Portland, OR7/8 Detroit, MI7/9 Buffalo, NY7/15 Richmond, VA7/16 Washington, D.C.7/17 Raleigh, NC7/23 Brooklyn, NY

In this episode Clint is with fellow comedian and friend Malik S and they finish the conversation about which cities have the best women. Also, how long does someone have to be locked up before you realize that you're single.Follow Malik S@malikscomedyMy Edible Kicked In Ticketswww.myediblekickedin.com4/14 Boston, MA4/15 Philadelphia, PA4/20 Memphis, TN4/21 Houston, TX4/22 New Orleans, LA4/28 Syracuse, NY4/29 Toronto, ON5/5 Seattle, WA5/6 Vancouver, BC5/12 Indianapolis, IN5/13 Cincinnati, OH5/20-22 Kansas City, MO6/9 Milwaukee, WI6/10 Milwaukee, WI6/11 St. Louis, MO6/12 Cleveland, OH6/17 Chicago, IL6/18 Minnesota, MN6/25 Oakland, CA6/26 Portland, OR7/8 Detroit, MI7/9 Buffalo, NY7/15 Richmond, VA7/16 Washington, D.C.7/17 Raleigh, NC7/23 Brooklyn, NY

My Edible Kicked In Ticketswww.myediblekickedin.com4/14 Boston, MA4/15 Philadelphia, PA4/20 Memphis, TN4/21 Houston, TX4/22 New Orleans, LA4/28 Syracuse, NY4/29 Toronto, ON5/5 Seattle, WA5/6 Vancouver, BC5/12 Indianapolis, IN5/13 Cincinnati, OH5/20-22 Kansas City, MO6/9 Milwaukee, WI6/10 Milwaukee, WI6/11 St. Louis, MO6/12 Cleveland, OH6/17 Chicago, IL6/18 Minnesota, MN6/25 Oakland, CA6/26 Portland, OR7/8 Detroit, MI7/9 Buffalo, NY7/15 Richmond, VA7/16 Washington, D.C.7/17 Raleigh, NC7/23 Brooklyn, NY

This week Kate, Henry, John and Mark discuss whether iron supplementation provides real benefits for anemic infants, IL6 antagonists for COVID, inhaled corticosteroids for COVID, and platelet rich plasma for Achilles tendinopathy.

This is the ninth of a series of short videos on Low dose Medicine and in particular Cytokines. This video introduces the cytokine Interleukin 10. IL10 regulates the reactivity of the organism and inhibits the synthesis of most pro- inflammatory cytokines such as IL1, IL6, IL8, IL12, IL23 and tumor necrosis factor (TNF) and also the Th1 sub populations of T-cells such as IFN-gamma and IL2. IL 10 regulates cell cycles and prevents nitric oxides and oxidative stress, it suppresses metastasis and tumor invasion. Since it inhibits the release of IL 1 and TNF it is able to slow down cartilage erosion. IL-10 can stimulate the synthesis of IgE antibodies and acts synergically with IL 4 to inhibit cell mediated immunity. It also prevents insulin resistance and insulin sensitivity. More information about this and other health topics can be found in my books "Low Dose Medicine" and "Cure Without Side effects" by following these links: ►►►https://amzn.to/3Bbx8fd ►►►https://amzn.to/36iaqDU To check the Low dose Medicine health kit follow this link: ►►►https://kit.co/cureswithoutsideffect/low-dose-medicine This episode is also available as a blog post: https://cureswithoutsideffects.wordpress.com/2021/11/12/cytokines-series-interleukin-10-the-master-anti-inflammatory-cytokine/ DISCLAIMER: Nothing contained in this video is intended nor can be taken to diagnose, treat, or cure any disease. It is for informational purposes only. --- Send in a voice message: https://anchor.fm/cureswithoutsideeffects/message

This month on Episode 28 of Discover CircRes, host Cynthia St. Hilaire highlights four original research articles featured in the August 20th and September 3rd issues of Circulation Research. This episode also features an in-depth conversation with Dr Scott Cameron from the Cleveland Clinic and Dr Milka Koupenova from the University of Massachusetts Medical Center about their study, SARS-CoV-2 Initiates Programmed Cell Death in Platelets.   Article highlights:   Gupta, et al. Electronic Cigarettes and Oxidized Lipids   Bartosova, et al. Glucose Derivative Induced Vasculopathy in CKD   Atmanli, et al. DMD Correction Attenuates Cardiac Abnormalities   Ma, et al. Length Dependent Activation in Porcine Myocardium   Cindy St. Hilaire:        Hi, and welcome to Discover CircRes, the podcast for the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire from the Vascular Medicine Institute at the University of Pittsburgh, and today I will be highlighting articles presented in our August 20th and September 3rd issues of Circulation Research. I also will speak with Dr Scott Cameron from the Cleveland Clinic and Dr Milka Koupenova from the University of Massachusetts Medical Center about their study, SARS-CoV-2 Initiates Programmed Cell Death in Platelets. Cindy St. Hilaire:        The first article I want to share is titled Electronic and Tobacco Cigarettes Alter Polyunsaturated Fatty Acids and Oxidative Biomarkers. The first author is Rajat Gupta and the corresponding author is Jesus Araujo from UCLA. E-cigarettes have surged in popularity in the last decade and while many people switching from traditional cigarettes to smokeless ones view the latter as a safe alternative to smoking tobacco, emerging data shows that E-cigarettes cause adverse effects such as oxidative stress, inflammation and endothelial dysfunction in users. The aerosols produced during vaping contain similar levels of reactive oxygen species, also called ROS, as the vapors of tobacco smoke. However, data on the extent to which E-cigarettes, E-cigarette ROS, influences cardiovascular health is lacking. Cindy St. Hilaire:        To address this, this group recruited 32 chronic users of E-cigarettes, 29 chronic tobacco smokers, and 45 individuals that used neither and they measured their plasma levels of oxidative biomarkers. The team found both similarities and differences between the E-cigarettes and the tobacco users. For example, both smoking groups had increased plasma antioxidant capacity and decreased levels of oxidized linoleic acid compared with the levels seen in non-users, while arachidonic acid levels were raised in tobacco smokers and reduced in E-cigarette users. Overall, however, the biomarker levels were deemed to be intermediate for E-cigarette users between the non-users and the tobacco users. This study suggests that while E-cigarettes carry a lower health risk than tobacco, they are by no means safe.     Cindy St. Hilaire:        The second article I want to share is titled Glucose Derivative Induced Vasculopathy in Children on Chronic Peritoneal Dialysis. The first author is Maria Bartosova and the corresponding author is Claus Schmitt and they're from the University of Heidelberg. Diabetes, high blood pressure and obesity are risk factors for both cardiovascular disease and chronic kidney disease. Worse still, loss of kidney function and even dialysis itself are thought to exacerbate cardiovascular issues. In the case of dialysis, it's thought that high levels of glucose degradation products, or GDPs, in the dialysis fluids can promote the addition of sugar moieties to vascular proteins and lipids causing vascular damage. To investigate this theory, Bartosova and colleagues studied vascular tissue from children with chronic kidney disease receiving dialysis fluids with either high levels or low levels of glucose degradation products and compared these to tissues from children not on dialysis at all. Cindy St. Hilaire:        Proteome and transcriptome analysis of the vessel tissues revealed that compared with patients or no to low GDP fluids, patients receiving high GDP fluids had higher levels of damaging glycation, increased transcription of genes involved in cell death, and decreased transcription of genes involved in cell survival and cytoskeletal reorganization. In line with these findings, vessels from high GDP patients displayed considerable evidence of damage, such as markers of apoptosis, skeletal disintegration and thickened intimas. The results confirmed GDPs can cause vasculopathy and suggest low GDP fluids should be used for dialysis patients. Cindy St. Hilaire:        The next article I want to share is titled Cardiac Myoediting Attenuates Cardiac Abnormalities in Human and Mouse Models of Duchenne Muscular Dystrophy. The first author is Ayhan Atmanli and the corresponding author is Eric Olson from UT Southwestern. Duchenne Muscular Dystrophy, or DMD, affects one in 5,000 baby boys and is caused by mutations in gene for dystrophin, an architectural protein essential for muscle cell integrity. Patients display profound muscle degeneration and weakness, with respiratory and heart muscle dysfunction being a major cause for death. With the recent improvements in respiratory medicine that extend the lives of patients, this group now focused on heart dysfunction and specifically, whether gene editing could mitigate it. The team created induced pluripotent stem cells, or iPSCs, from Duchenne Muscular Dystrophy patient and his healthy brother and showed that gene editing from the DMD cells enabled their development into normal-looking cardiomyocytes with normal contractile function and calcium handling, equivalent to that seen in healthy control cells. The unedited DMD cells, by contrast, did not develop normally. For great clinical relevance, the team edited DMD cells after cardiomyocyte differentiation showing that this reduced their propensity for arrhythmia, compared with that of unedited cells. Cindy St. Hilaire:        Lastly, the team provided evidence to suggest gene editing may improve heart abnormalities in mice with the same mutation. All together the results are proof of principle and support of the development of gene editing therapy as treatment for DMD. Cindy St. Hilaire:        The last article I want to share is titled The Super-Relaxed State and Length Dependent Activation in Porcine Myocardium. The first authors are Weikang Ma and Marcus Henze and the corresponding author is Thomas Irving and they're from the Illinois Institute of Technology. Myofilament length-dependent activation or LDA is the fundamental mechanism coupling the force of the heart's contraction to it's proceeding diastolic volume. In other words, LDA ensures that the more the heart fills, the stronger it contracts. Studies of rodent hearts have given insights into LDA mechanics. However, how it operates in large mammalian hearts is unknown. Using structural and biochemical analysis of pig myocardial fibers, this group found that compared with small stretches of the fibers which were equivalent to small diastolic volumes, long stretches induced greater ATP turnover and greater numbers of cross bridges between myosin and actin filaments which are critical contractile machinery proteins. Cindy St. Hilaire:        Myosin motors can be found in three stages, engaged with actin, unengaged in a disordered, relaxed state but ready to engage, or super-relaxed state where they are essentially switched off. The team showed that as muscle stretch increased, the amount of super-relaxed myosin motors diminished with more myosin motors becoming engaged to enable a stronger contraction. When the fibers were treated with a myosin motor inhibitor, these stretch effects were impaired. In revealing the mechanisms of myofilament length-dependent activation, this study provides a platform for studying cardiomyopathies in which this system goes awry. Cindy St. Hilaire:        So today, Dr Scott Cameron from the Cleveland Clinic and corresponding author of the paper, Dr Milka Koupenova from the University of Massachusetts Medical Center, are both with me to discuss their study, SARS-CoV-2 Initiates Programmed Cell Death in Platelets. And this article is in our September 3rd issue of Circ Research and for full disclosure, the editor of Circ Res, Dr Jane Freedman is also an author on this manuscript. And for full double disclosure, I know Dr Koupenova quite well as we were both graduate students together back in the Ravid Lab at Boston University. However, the full Editorial Board selects these articles, not just me alone and this one is timely, novel, and an amazing story. So thank you both for joining me today. Milka Koupenova:       Thank you for having us. Scott Cameron:           Privileged to be here. Cindy St. Hilaire:        So before we jump into the story that is your paper, can you give us a little bit of background about platelets? I know for years, I guess certainly before Katya's lab, I just thought of platelets as little nucleus-free particles that clot. But we know they are so much more than that. So why are they so important? And how do they function to do more than just stop a bleed? Milka Koupenova:       So this is a great question, Cindy, and I am happy that you alluded exactly to the anucleated nature of platelets. So platelets are cell fragments. They're precursors in the bone marrow, the megakaryocyte. They are the second most abundant blood component after the red blood cells. And traditionally, platelets have been known, as what you pointed out, as these little units that change their conformation once there is some form of a problem with either the vascular, which we have a cut, they come together, they form this clot, and bleeding is prevented. But as we have learned perhaps in the past 20 years that platelets have a profound immune role during various immune processes and infections for different kind of microbes. And particularly relevant to this paper is that we understand that platelets have clearly a role responding to the viruses and activating the immune system. Cindy St. Hilaire:        Yeah, and that was actually my next question. You and Jane are the world-leading experts on platelets and viral responses. So what was known about that interaction, I guess before we started looking at SARS-CoV-2, what was known about that platelet virus or even type of virus interaction? Milka Koupenova:       So SARS-CoV-2 is a RNA virus--respiratory virus that we actually thought similarly to influenza that it mostly stays in the lower respiratory tract where it becomes problematic. However, from our work with influenza, when we saw that in certain patients you actually can detect the virus in platelet. In the beginning of the pandemic, we hypothesized that perhaps, in some people, the virus crosses over into the circulation. And based on our previous studies with influenza, we wanted to see if that indeed is the case. Hence we initiated a study here at UMass with the department head who is also on the paper, Dr Finberg, who is a leading expert in influenza and novel virus and we collected platelets from people to see if we can detect it. And so in the beginning, we were not able to detect SARS-CoV-2 in platelets. So we collected platelets from 17 patients and by qPCR with the primers that the CDC has, for whatever reason I couldn't detect anything. And I was really frustrated because previous reports have shown that about 25%, in some people even 35% of the study population, SARS can be detected. So very interesting observations. Milka Koupenova:       I could see it by immunofluorescence but I couldn't detect the RNA. And the story goes, that I attended a seminar on SARS-CoV-2 and the person was actually referencing a company that started from University of Pitt where you are. Cindy St. Hilaire:        Oh, very nice. Milka Koupenova:       And they do specific, it's called amplicon ARTIC v3 sequencing so they enrich for the SARS-CoV-2 RNA and screen by sequencing. And when we did that, we were able to detect it in all patients. So I freaked out and I said, "Oh my gosh, something is wrong." Milka Koupenova:       And so I sent plasma, and I sent controls, and actually RNA from the virus and you can see beautifully that it's only in platelets. Four of the 17 people actually had RNA in the plasma, but what you can observe in all these people is that the virus is fragmented, meaning it's not infectious. And in a way what this tells us, it suggests that platelets are super important in the removing it from the circulation and they probably serve as a dead-end for the virus because you cannot find virus coming out of platelets and the RNA is chopped off. So what I would say, is that platelets are these amazing little units that serve as removal of the viral RNA for these particular viruses, respiratory viruses that are RNA viruses. Cindy St. Hilaire:        I think that is so interesting. So essentially, they're almost like little composters that are chewing it up and preventing it from spreading in the organism. Milka Koupenova:       Yes, and as a result there is a response. Cindy St. Hilaire:        Scott, probably the most common thing that people know with SARS is that loss of smell, or taste, and things like that, but really that doesn't send anybody to the hospital. So really what are the symptoms of COVID-19 patients that tie in with platelets specifically? I feel like that's a lot of things that we maybe in the public, or on Twitter, and things didn't hear as much about. So really what are those big symptoms linking COVID and platelets and what are the implications of platelet death in the pathogenesis of COVID? Scott Cameron:           So certainly I think several investigators are in the world of now showing that platelets are hyperactivated, Robbie Campbell and Matt Rondina put a really nice paper in Blood last year showing that platelets are hyperactive and there are other investigators who found something similar. And so the question is, what are the symptoms of hyperactive platelets in the SARS-CoV-2 patient? So what most of them would find is shortness of breath or dyspnea, and when they present to the emergency department, and certainly we saw this, the oxygen saturation which should be in the mid to high 90s on room air on an average person, was quite often low. It was in the 80s or 70s, sometimes even the 60s. Scott Cameron:           And the real surprising thing was those are patients that would normally immediately be on a ventilator, but yet they could still be talking to you. And so if you have a platelet that's activated in a hyperthrombotic condition, like SARS-CoV-2, COVID-19, and then that forms a blood clot, you have a situation where the amount of oxygen the patients taking in and the amount of oxygen you're measuring in the artery is quite discrepant and we call that the alveolar arterial or oxygen gradient. So if you've got lots of platelet plugs through the microvasculature, it's going to take up some space the oxygen should be using for diffusing in. And so that would be manifested as shortness of breath and that's certainly one of the biggest tip-offs that a patient might have a blood clot, particularly in the lung. Cindy St. Hilaire:        Some of these symptoms of COVID-19 are really worse in patients with comorbidities, diabetes, obesity and heart failure. Are platelets central to kind of the pathogenesis of those disease or the symptoms of those diseases? I guess the root of my question is, why do the comorbidities of diabetes, obesity, and heart failure make COVID worse? Is it something about those disease states themselves or is there a role for platelet? Scott Cameron:           That's a brilliant question, no one's ever asked that before. And as Dr Koupenova said, I'm a little bit biased too because I firmly believe that in different disease states, the disease educates the platelets so you've got a different platelets phenotype. So focusing on diabetes, we know the platelet phenotype is different in diabetic patients. We know that platelet reactivity seems to be higher through the P2Y12 receptor.  In terms of obesity, it is true, we know that, and this has been published also, and we know that the platelet phenotype is hyperactive in a patient with obesity and so that tells me that, that's a comorbidity that might affect platelet function and also vice versa for that case. And then in terms of why is it affecting males more prominently and more severely than females, well one of the beefs, I guess, that I had is that we treat diseases in women the same as we do in men assuming that the platelet phenotype in disease must be the same, but that's absolutely not true. And that's actually a theme that we have in our lab right now, we know that the behavior of platelets, and how platelets are educated in diseases is not all the same in women as in men and I think it's a huge disservice that we really had to have a pandemic that would make that quite clear to us. Cindy St. Hilaire:        You kind of hit onto something that's really, I think it's now becoming more recognized certainly in the cardiovascular field and that is so many studies are really only on male mice, or only younger or older men, and we are missing not only a huge patient population, but probably some really interesting biology that is distinct. Milka Koupenova:       So expanding on that, we know that in platelets, the toll-like receptors, and we've looked at the expression of all 10 in a study that we published in ATVB in 2015, actually, significantly if you look at Farmingham Heart Study data and the expression of these toll-like receptors they are increased in women versus men. And also, an interesting observation that never got published, once upon a time when I was doing studies with TLR7 mice is that if you inject TLR7 agonists, male mice would have a higher level of reduced platelet count than female mice at the same time points, right? And at that time it wasn't published. Definitely there are differences, but I also want to extrapolate a little bit on what was said at the beginning. We have to understand that when it comes to these comorbidities, everything affects a unit that doesn't have a nucleus, right? And diabetes and obesity have the so called profound, chronic inflammation of cytokines, such as IL6, that keep circulating. These things have effect on platelets. So we have two responses, we have the environment that affects platelets and we have the direct response of the virus that affects platelets. And that cumulative response truly can exhaust them and once they become exhausted, once they release their contents, as we show in this paper, then you're compromising their function and you will be compromising taking out the virus from one side and from the other side you're going to be compromising the environment because all of the content that comes out from a unit that already has free form proteins, it exhibits a true insult on what's being surrounded. So these clots that form in the lung or the platelets that circulate they no longer can be resolved properly. Cindy St. Hilaire:        Yeah. Milka Koupenova:       It's a balance. Cindy St. Hilaire:        Yeah, so really it's like destroying the platelet not only are you destroying the vacuum that has to suck up those particles, you're then just dumping a whole bunch of pro-inflammatory things on all of the endothelial cell vasculature that those platelets are nearby. Cindy St. Hilaire:         Actually that was one thing that I thought you spent a decent portion of the discussion on, and that is the method by which the blood is collected really impacts the outputs you observe in quote unquote platelets. Can you talk about the importance of that because I think that's one thing, certainly as a PhD who's just like, "Oh, yeah. I'm just going to collect blood from my mice and do this thing," how critical is that point in the experiment, in the blood collection? Milka Koupenova:       So I am very adamant when it comes to platelets for the blood to be drawn in citrate. And I have to say that a lot of the studies that you would see in the literature are done using EDTA blood or serum. They all have their importance. I'm not going to dismiss it, but if you want to truly measure what's inside in plasma, versus what's inside in platelets, or what's inside in any cell for that matter, you got to go for citrate. You have to be very careful not to shake the blood. You have to be very careful not to cool down the blood. So the nurses probably hated me because often I would be like, "You can't do this. You can't put it on ice. You can't warm it up to above certain degrees. Everything has to be controlled and done correctly." Milka Koupenova:       And so I had done in the past studies in which I would take plasma from the same patient in EDTA, in citrate and then isolate the RNA, have my tech isolate the RNA, and we send it to a fragment analyzer, and you can see how much more RNA you will get in the EDTA plasma. I'm not even talking about serum. Milka Koupenova:       Serum is a very different thing, then you're definitely going to get platelet content in it, in the serum, right? So it's important to distinguish that perhaps when you're getting EDTA plasma you are looking at a content that could have been inside in platelet and I can't stress enough that when it comes to these particular studies, citrate, dextrose, phosphate is your place to go and be. Cindy St. Hilaire:        So in terms of translational potential, what do your findings suggest about future therapies or targets to investigate as therapy? And is modulating platelets a potential for combating viral infections or mitigating their severity? Milka Koupenova:       Well, Scott and I actually talk a lot about that. Scott Cameron:           That's right. Milka Koupenova:       I personally would say, control the inflammation, never let it go to platelet. Let me back up a little bit, if you have to, you have to, right? But your go to method should be inflammation, if you don't get to the point that you need to control platelets then you're in a better place because it becomes very fickle. From everything that you hear me say, you push it to one side and the balance is destroyed. You deactivate platelets or inhibit platelets well, are they now not able to pick up the virus and then you're now having the virus circulating somewhere. Now, if you don't treat platelets that's also not good. So you're in the very fickle situation if you get to the point that you need to control the activation of platelets and there are trials currently that are trying to look at those things. Scott, I'm going to refer this a little bit more to you because you have done some interesting things with that particular point. Scott Cameron:           No, it's a great question, Milka, and I think that as platelet biologists, nobody more than I wanted it to be true that platelets would be the ultimate target. I mean, clearly patients with SARS-CoV-2 have thrombosis, clearly platelets are activated, so should we inactivate them? That was the whole point of the RECOVERY trial and one of the benefits I'll tell you before I sort of go into that is, working in a large organization like the Cleveland Clinic and we have access to data and lots of it extremely quickly, and so because of that I of course could see how many patients were coming into our hospital with thrombotic events. And I could see what the independent predictors of thrombotic events was and it wasn't the platelet count, sometimes platelet count was low, sometimes it's high in the SARS-CoV-2 patient. And if you took those individuals that were on aspirin, comparing them to those that are not in a propensity match study,  one of the things that we find is that aspirin doesn't seem to affect or improve mortality or the number of blood clots in the patient with SARS-CoV-2. Scott Cameron:           We compared that to all non-steroidal anti-inflammatory medications that patients may have been taking also in a propensity match study just in case it was the mechanism action of the drug, rather than the drug itself, and we found that NSAIDs not only did not protect patients, but they were not necessarily harmful either, which was one of the things that came out at the start of the pandemic. Among, I'll add, the absence of evidence based medicine and a lot of cases where naturally people, including clinicians, were scared and so they were going off label and they were trying a lot of different medications with really not a shred of randomized controlled data. Scott Cameron:           But now that we're 18 months into it, the first and biggest study that came back was the RECOVERY trial, which we were all waiting on, where patients were given aspirin and short term mortality was examined over an observational period of one month. And just like we found in a propensity match study, which is as close as you'll get to a clinical trial in a retrospective manner, the prospect of RECOVERY trial actually showed the curves were almost super imposeable, those that got aspirin versus those that didn't. So I think low dose aspirin clearly is not going to be enough for those patients, but I'll also add that over the observational period of one month they also didn't see a higher incidence of death in those patients. And I think Milka's point is really well taken that you have to remember that as well being an entity of thrombosis, platelets are immunological entities and so you've got to really consider should we be inhibiting them and if you are inhibiting them, I think the time point at which you should inhibit them is what we should examine, not just an all or nothing, inhibited or not. Milka Koupenova:       It's just in our linear brains we prefer to think of it as one straight, linear pathway, but it isn't, and I think platelets are actually a great example of how many pathways are feeding into one tiny fragment and that particular blood cell is inducing this profound response during these infections. Cindy St. Hilaire:        I think most people have heard that angiotensin-converting enzyme 2, also called ACE2 is the receptor of SARS-CoV-2. The virus itself uses it to bind and become internalized into the cell, but there's been some discussion or even some discrepancy of data as to whether platelets truly express ACE2 and if that is the means for the virus to enter the platelets. So can you share with us what is the current state of knowledge about that? Scott Cameron:           Yeah, just as a segue of some of the things that Milka said, I think the preparation of your sample is part of the answer. If you draw in the incorrect tube, if you the tube is not completely filled, and the ratio of citrates to whole blood isn't correct you're going to have discrepant results. If you biomechanically activate the platelets by drawing through a short needle, in a small-bore needle for example, that's going to activate the platelets. If you cool them, it's going to activate them. But then also, depending on how you decide to separate them, we always washed platelets in my lab, we wash them two or sometimes three times, and I can tell you if you use flow cytometer we get one white blood cell for every 12,000 platelets. Scott Cameron:           And some investigators might go one step further and they'll a CD45 depletion set, which is certainly important if you're studying RNA. But one of the issues, as you well know, a CD45 is also on the surface of platelets, so if you start with a low expressing protein and you CD45 deplete them, you are actually going to get a decrease in your platelet yields. I've seen it, I think Milka's seen it, various other investigators have, and you might find yourself at the threshold of what your antibody can detect. It's also variably expressed. If you look at even healthy individuals, some of them have almost none. So if you look at 10 individuals, you might actually find none, but then if you look at another 10, the amount of expression that we see is kind of all over the place. It's not like other receptors where one tends to express a certain amount and that's the way it is in health. ACE2 doesn't seem to be that way for whatever reason. Milka Koupenova:       We were able to detect in some of the people by qPCR, but what was interesting is that from the three primers that I used there was never the same person who we were able to detect all three primers with for that receptor. That tells you that maybe they are changes of one base that is not enough for the primer to detect it, right? That becomes another possibility of not being able to detect. Milka Koupenova:       And so I go to confocal microscopy where I use 100 lens and tons of hours in the microscope room, and Scott is completely right, it's really hard to see it particularly in healthy people. And it starts to pick a little bit more in people with cardiovascular disease or people with COVID that are old. So it's a bit complicated, but the important thing here is, besides the fact that we are detecting ACE2 and we're detecting proteins and I use controls, biological controls to prove that this is the case and it's not just an antibody problem, is that the virus will get picked up by platelets even if you don't have ACE2. That is the take home message from this paper is that the platelet has evolved various mechanisms by which is utilizes getting it inside. It is that important for this virus. This type of virus is not recirculating. In this case, what we observed is that the virus is attached to microparticles that are of platelet origin for that matter. Cindy St. Hilaire:        So really what you're saying, what I'm hearing is the platelet is the superhero of the body. Milka Koupenova:       Definitely. Absolutely. No bias, absolutely. Cindy St. Hilaire:        Unbiasedly, it is a superhero. Well, Dr Cameron and Dr Koupenova, thank you so much not only for this amazing discussion, but for really an elegant, elegant paper that is really bringing to light the complex interaction between SARS-CoV-2 and platelets. So thank you so much for joining me and keep publishing amazing stories like this. Milka Koupenova:       Thank you for having us. Scott Cameron:           Thank you, an honor to be here. Thanks again. Cindy St. Hilaire:        That's it for the highlights from August 20th and September 3rd issues of Circulation Research. Thank you for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Dr Scott Cameron and Dr Milka Koupenova. This podcast is produced by Ashara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Dr Cynthia St. Hilaire, and this is Discover CircRes, your on-the-go source for the most exciting discoveries in basic cardiovascular research. This program is copyright of the American Heart Association, 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors or of the American Heart Association. For more information, please visit ahajournals.org.  

CoQ10 supplementation associated with improved trauma patient outcomes Urmia University of Medical Sciences (Iran) July 23 2021.    Findings from a trial reported on July 12, 2021 in the Journal of Nutritional Science revealed benefits for hospitalized traumapatients who were given supplements that contained coenzyme Q10.  The trial enrolled 40 men and women with traumatic injury and low plasma levels of CoQ10. Participants received a placebo or 400 milligrams CoQ10 daily for seven days. Blood samples collected at the beginning and end of the trial were analyzed for interleukin 6 (IL-6), which may be elevated during inflammation, and the oxidative stress markers malondialdehyde (MDA) and thiobarbituric acid reactive substances (TBARS). Body composition was also assessed at these time points, as well secondary outcomes that included Sequential Organ Failure Assessment (SOFA) and the Glasgow Coma Scale (GCS).  While interleukin-6 levels at the beginning of the study were similar between the CoQ10 and placebo groups at an average of 175.05 pg/mL and 177.82 pg/mL, they were reduced by 76.99 pg/mL in the CoQ10 group and 17.35 pg/mL in the placebo group. MDA values averaged 232.37 picograms per milliliter (pg/mL) and 239.96 pg/mL and were lowered by 88.84 pg/ml among participants who received CoQ10 and by 26.23 pg/mL among those who received a placebo. In comparison with the placebo group, fat free mass, skeletal muscle mass and body cell mass increased among those who received CoQ10. GCS and SOFA scores, and duration of hospital stay, ICU stay and ventilator use also improved among treated patients.  “To date, no randomized clinical trial study has been conducted to evaluate the effect of CoQ10 supplementation in traumatic mechanical ventilated patients and we hypothesized that CoQ10 administration in these patients could have beneficial effects on biochemical and clinical factors,” the authors wrote. “We have shown that CoQ10 could improve some of the clinical and anthropometric parameters in patients with a traumatic injury.”     Nigella sativa (black seed) prevents covid-induced vascular damage, scientists conclude   Oriental Institute of Science and Technology (India), July 27, 2021 New research published in the journal Vascular Pharmacology shows that Nigella sativa, also known as black seed or black cumin, binds to ACE2 in the lungs, effectively stopping the Wuhan coronavirus (Covid-19) from inducing inflammation and vascular damage. Researchers out of India investigated the effects of nigellidine, an indazole alkaloid of black seed, using molecular docking for binding to different angiotensin-binding proteins, as well as the Chinese Virus spike glycoprotein. They found that nigellidine “strongly binds” to the Chinese Virus spike protein at what is known as the hinge region or active site opening, which may in turn hamper its binding to the nCoV2-ACE2 surface. “Nigellidine effectively binds in the Angiotensin-II binding site / entry pocket,” the study explains. “Nigellidine showed strong binding to mono / multi-meric ACE1.” This process of ACE blocking could, the study goes on to suggest, restore angiotensin levels and restrict vasoturbulence in Chinese Virus patients, while the receptor blocking could help to stop resulting inflammation and vascular impairment. “Nigellidine may slow down the vaso-fluctuations due to Angiotensin deregulations in Covid patients,” the paper further explains. “Angiotensin II-ACE2 binding (ACE-value -294.81) is more favorable than nigellidine-ACE2. Conversely, nigellidine-ACE1 binding-energy / Ki is lower than nigellidine-ACE2 values indicating a balanced-state between constriction-dilatation.” Nigellidine also binds to the viral spike proteins, which when taken by Chinese Virus patients, and especially those who fall in the elderly category, could greatly reduce their risk of suffering complications or death. Nigellidine impairs SARS-CoV-2 infection, “cytokine storm” through numerous mechanisms In a related study that was published last year in the journal Europe PMC, researchers learned that nigellidine inhibits the Chinese Virus infection in several other ways. It was discovered early on in the “pandemic” that many of those who tested “positive” for the virus were suffering associated “cytokine storms,” in which their immune systems were over-responding and causing more damage, or even death. Nigellidine was then studied and discovered to possess certain properties that inhibit cytokine storms, as well as impede the SARS CoV-2 virus from causing infection. It is also hepato- and reno-protective, meaning it protects against liver damage. Beyond this, nigellidine was determined to possess unique immunomodulatory and anti-inflammatory characteristics, as well as antioxidant potential strong enough to inhibit important proteins associated with the Chinese Virus. In their quest to uncover possible “drug” candidates to protect patients against hyper-inflammation and other associated problems, the researchers learned that nigellidine – and more than likely other black seed constituents – helps tremendously with preventing negative side effects. Along with nigellicine, nigellidine is found in the seed coat of Nigella sativa. Both of these constituents in their sulfated forms are extremely bioavailable, and along with thymoquinone and dithymoquinone, two other black seed components, they show strong antioxidant, antibacterial, anti-hypertensive, anti-inflammatory and immunomodulatory effects. Black seed extracts have been shown in other experiments to decrease oxidative stress, effectively lowering the risk of inflammation-related diseases. We now know that this includes the Wuhan coronavirus (Covid-19). Black seed is also recognized as a metabolic protector, helping to improve lipid and blood sugar levels. “Most importantly, in SARS CoV-2 infection ACE-2 mediated impairment of aldosterone system may be repaired by,” the study further explains, providing relevant information to the current “pandemic.” “Vasorelaxant and anti-hypertensive function of [black seed] helps in the modulation of renin angiotensin system (RAS) or the diuretic activity, which is one of the major targets of COVID. It might have great protective role during post infective secondary disorder of the peripheral vasculature namely cardiac and renal systems. In most of the instances patients die due to this organ dysfunction/failure in COVID-19 infection.” By quelling inflammation, black seed could save lives from covid Laboratory studies have found that intake of Nigella sativa significantly improves the parameters for hyperglycemia and diabetes control, as well as glycated hemoglobin and insulin resistance. Based on this, experts believe that nigellidine specifically could play an important role in fighting the Chinese Virus by “docking” to the proteins and inflammatory molecules that can cause a cytokine storm – mainly TNF-? receptors such as TNFR1, TNFR2 and IL1R. “In the experimental rat model the source of this drug Nigella sativa; black cumin seed extracts were tested for its role on antioxidant, hepatic and renal status,” the paper states. “This work will help in the urgent therapeutic intervention against COVID-19 global pandemic.” “In the current study, we have decisively shown by molecular modeling that nigellidine can bind in the active sites of several important proteins of SARS CoV 2, several host receptors specific for SARS CoV-2 induced inflammatory markers IL1, IL6, TNF-?. Moreover, the extract from black cumin seed has been shown in experimental rat to be highly antioxidative, hepato- and reno-protective. Further studies are necessary to verify the potential effects of nigellidine in in vivo laboratory experimental animal model.”   Vitamin D supplementation improves recovery time of children with pneumonia at pediatric hospital Cairo University (Egypt), July 20, 2021 According to news reporting originating from Cairo, Egypt, by NewsRx correspondents, research stated, “Despite the well-recognized effect of vitamin D in metabolism and homeostasis, there is now growing interest in its probable association with pneumonia. This study aims to supply vitamin D3 (Cholecalciferol) (100,000 IU) to pneumonic children to minimize the duration of illness and improve their outcome.” Our news editors obtained a quote from the research from Cairo University, “A double-blinded, randomized, placebo-controlled trial was conducted in a Pediatric Cairo University affiliated hospital. An intervention arm (93 children) and a control arm (98 children), who had pneumonia with an insufficient or deficient level of vitamin D and whose parental permission was obtained, were enrolled in the trial. All children were treated with antibiotics according to WHO guidelines. Children were given a single injection of 1 mL of 100,000 IU of vitamin D3 or placebo. Clinical data were recorded every eight hours for all children. Outcomes were assessed 7 days after vitamin D injection. The primary outcome variable was the change in serum level of 25(OH)D, while the secondary outcomes were the medical state of the assigned cases (improvement or death) and duration between enrollment and hospital discharge for improved cases. In the supplementation group, the percentage of patients who suffered either deficient (38.7%) or insufficient levels (61.3%) of 25 (OH)D at day one had significantly decreased in the seventh day to (11.8%) and (52.7%), respectively. Kaplan--Meier plots highlighted that the median time to recover of the placebo group was significantly longer than that of the supplementation group (Log Rank P value < .001). VDD was detected in pediatric critical care children.” According to the news editors, the research concluded: “In pneumonic children with high VDD, it is illustrated that Vitamin D supplementation is accompanied by lowered mortality risk and pSOFA scores, reduced time to recover, and improved PaO2/FiO(2).”   Physical activity could combat fatigue, cognitive decline in cancer survivors University of Illinois, July 26, 2021 A new study indicates that cancer patients and survivors have a ready weapon against fatigue and "chemo brain": a brisk walk. Researchers at the University of Illinois, along with collaborators at Digital Artefacts in Iowa City, Iowa, and Northeastern University in Boston, looked at the association between physical activity, fatigue and performance on cognitive tasks in nearly 300 breast cancer survivors. "The data suggest that being more physically active could reduce two of the more commonly reported symptoms in breast cancer survivors: fatigue and cognitive impairment," said study leader Edward McAuley, a professor of kinesiology and community health at Illinois. "Most people think, 'If I exercise, I'll become tired.' In our study, exercise actually was associated with reduced fatigue, which in turn was associated with better cognitive function." Cognitive impairment, such as memory problems or shortened attention spans, is a common complaint among cancer patients and survivors, and is thought to be similar to decline due to aging. Past Illinois research has explored the effect of physical fitness on age-related cognitive decline, so the researchers wondered whether cancer survivors would respond similarly to exercise. "Other studies of cancer survivors have relied on small samples of cancer survivors, and used self-reporting measures of physical activity and cognitive function, which can be very biased," said postdoctoral researcher Diane Ehlers, the first author of the study, which is published in the journal Breast Cancer Research and Treatment. "What makes our study novel is that we had objective measures for both physical activity and cognitive performance, and a nationwide sample of breast cancer survivors." The researchers worked with Digital Artefacts -- developer of the commercial neuroscience app BrainBaseline - to create an iPad app tailored to this study. The app included questionnaires and activities designed to measure attention, memory and multitasking skills. The researchers also sent each participant an accelerometer to track daily physical activity. "We found that higher levels of daily moderate-to-vigorous physical activity were associated with better performance on the cognitive tasks measuring attention, memory and multitasking," Ehlers said. "What was notable was that physical activity's effect on cognitive performance was mediated by fatigue. This provides evidence that physical activity interventions targeting fatigue in cancer patients and survivors might provide promising models for improving cognitive function as well." Next, the researchers plan to conduct further studies to establish causation and further explore the pathways of how physical exercise improves cognitive performance. They are working with Digital Artefacts to conduct an iPhone-based study and focusing on diverse populations of breast cancer survivors. "The message for cancer patients and survivors is, get active!" Ehlers said. "Even if it's 10-minute bouts of brisk walking. It's not a magical cure-all, but we've seen many benefits of physical activity for cancer patients and survivors."   Cannabidiol promotes oral ulcer healing by inactivating CMPK2-mediated NLRP3 inflammasome Sichuan University (China), July 26, 2021 Xingying Qi, West China Hospital of Stomatology, Sichuan University, Chengdu, China, presented the oral session "Cannabidiol Promotes Oral Ulcer Healing by Inactivating CMPK2-Mediated NLRP3 Inflammasome" at the virtual 99th General Session & Exhibition of the International Association for Dental Research (IADR), held in conjunction with the 50th Annual Meeting of the American Association for Dental Research (AADR) and the 45th Annual Meeting of the Canadian Association for Dental Research (CADR), on July 21-24, 2021. The oral ulcer is a common oral inflammatory lesion with severe pain but little effective treatment is currently available. Cannabidiol (CBD) is recently emerging as a therapeutic agent for inflammatory diseases. However, the underlying mechanisms are not fully elucidated. Qi and colleagues sought to investigate whether and how CBD could play a therapeutic role in the oral ulcer. Oral ulcer models were performed in the tongue of C57BL/6 mice by acid etching or mechanical trauma, followed by CBD local administration. Samples were harvested for macroscopic and histological evaluation. CBD oral spray on acid- or trauma-induced oral ulcers on mice tongues inhibited inflammation, relieved pain and accelerated lesions closure in a dose-dependent manner. The results show that CBD accelerates oral ulcer healing by inhibiting CMPK2-mediated NLRP3 inflammasome activation and pyroptosis, which is mediated mostly by PPARγ in nucleus and partially by CB1 in plasma membrane. This data may shed light on the development of new therapeutic strategies for oral ulcers.   Algal solution: Could Spirulina modify the microbiome to protect against age-related damage? Louvain Drug Research Institute (Belgium), July 25 2021 Spirulina might help protect against age-related liver inflammation by modifying pathways in the microbiome, say researchers. Consumption of spirulina could help protect against hepatic inflammation in the elderly, according to the new animal research published in Nutrients. Belgian researchers carried out tests on mice, which suggest that the algae Spirulina has an impact on the gut microbiota, which in turn activates the immune system in the gut and improves inflammation in the liver that is associated with ageing. Led by senior author Professor Nathalie Delzenne from the Louvain Drug Research Institute in Belgium, the team said oral feeding of Spirulina was found to modulates several immunological functions involving, among others, the TLR4 pathway in old mice. “The fact that its oral consumption can influence both gut immunity and systemic sites, such as the liver, suggests that its immune action is not confined to the gut immune system,” wrote the team – who said the findings open the way to new therapeutic tools “in the management of immune alterations in aging, based on gut microbe-host interactions.” Furthermore, they suggested that improvement of the homeostasis in the gut ecosystem ‘could be essential' during the aging process, “and, in this perspective, dietary manipulation of the gut microbiota of the elderly with Spirulina, may represent a tool for preserving a healthy gastrointestinal microbial community in addition to its beneficial effects on immune function.” Study details Delzenne and colleagues noted that while the possible cardiovascular and immune support benefits of Spirulina have been fairly widely reported, the new study brings a fresh approach by testing whether the effects could be related to a modulation of gut micrbiota. In the trial, young mice aged three months were fed a standard diet, while older mice aged 24 months were fed a standard diet either with or without 5% Spirulina for six weeks. Upton supplementation with Spirulina, the team reported several changes to gut microbiota composition, including an increase in Roseburia and Lactobacillus populations. “Interestingly, parameters related to the innate immunity are upregulated in the small intestine of Spirulina-treated mice,” said the team. “Furthermore, the supplementation with Spirulina reduces several hepatic inflammatory and oxidative stress markers that are upregulated in old mice versus young mice.” Expression of several genetic and biochemical markers of inflammation and immunity were altered by supplementation with Spirulina, said the team. In particular, the transcription factor Foxp3 – involved in the differentiation of T cells into regulatory T cells (Tregs) – and MCP1 were increased due to Spirulina supplementation in old mice. Old mice that consumed Spirulina also showed activation of several immune parameters including Foxp3 in the ileum – suggesting an improvement of the gut immune function upon Spirulina treatment in this segment, said the Belgian researchers. Furthermore, Spirulina supplementation upregulated both TLR2 and TLR4 expression in the ileum of aged mice. “In accordance with these results, a solution of Spirulina (5%) exhibited a TLR4 agonist activity similar to the one reached in old-SP mice, suggesting a direct effect of the Spirulina, itself, on the TLR4 pathway,” they added. Microbiome mechanisms While the positive effect of Spirulina on the microbiome and liver inflammation is clear, the team noted that the mechanism by which the algae could change the composition of the intestinal microbiota remains unanswered. One possible mechanism could be the presence of antimicrobial substances produced by Spirulina, they said. “On the other hand, antimicrobial peptides (AMPs) could be mediators of the nutritional modulation of the gut microbiota.” “In the present study, RegIIIγ and Pla2g2 were increased by the supplementation with Spirulina, suggesting that the host contributes to the reduction and modification of the microbial community by modulating the production of specific AMPs,” they added.

These tests are required if you want to test for inflammation in your body. These tests check for systemic or whole body inflammation. Inflammation is something that you don't want going on in your body. High levels of inflammation in the body increase your risk of developing almost every major disease including autoimmune disease, cancer, heart disease, stroke, and much more. Inflammation has also been associated with accelerated aging! No matter how you look at it, it's not something you want in your body. The good news is that you can test for inflammation in your body by looking at some simple blood tests. These blood tests help identify the presence of both acute and chronic inflammation but they don't tell you WHY the inflammation is present. These tests are so important that I order them in just about every patient that I see. They are especially helpful if you have thyroid problems or just want to stay in optimal health. These tests include: - ESR - CRP - Ferritin - Antibody testing (optional) - IL6, TNFa, and fibrinogen (optional) Learn why these tests are so important and what they mean for you in this video. Download my free thyroid resources here (including hypothyroid symptoms checklist, the complete list of thyroid lab tests + optimal ranges, foods you should avoid if you have thyroid disease, and more): https://www.restartmed.com/start-here/ Recommended thyroid supplements to enhance thyroid function: - Supplements that everyone with hypothyroidism needs: https://www.restartmed.com/product/hy... - Supplement bundle to help reverse Hashimoto's: https://www.restartmed.com/product/ha... - Supplements for those without a thyroid and for those after RAI: https://www.restartmed.com/product/th... - Supplements for active hyperthyroidism: https://www.restartmed.com/product/hy... See ALL of my specialized supplements including protein powders, thyroid supplements, and weight loss products here: https://www.restartmed.com/shop/ Want more from my blog? I have more than 400+ well researched blog posts on thyroid management, hormone balancing, weight loss, and more. See all blog posts here: https://www.restartmed.com/blog/ Prefer to listen via podcast? Download all of my podcast episodes here: https://podcasts.apple.com/us/podcast... Disclaimer: Dr. Westin Childs received his Doctor of Osteopathic Medicine from Rocky Vista University College of Osteopathic medicine in 2013. His use of “doctor” or “Dr.” in relation to himself solely refers to that degree. Dr. Childs is no longer practicing medicine and does not hold an active medical license so he can focus on helping people through videos, blog posts, research, and supplement formulation. To read more about why he is no longer licensed please see this page: https://www.restartmed.com/what-happe... This video is for general informational, educational, and entertainment purposes only. It should not be used to self-diagnose and it is not a substitute for a medical exam, treatment, diagnosis, prescription, or recommendation. It does not create a doctor-patient relationship between Dr. Childs and you. You should not make any changes to your medications or health regimens without first consulting a physician. If you have any questions please consult with your current primary care provider. Restart Medical LLC and Dr. Westin Childs are not liable or responsible for any advice, course of treatment, diagnosis, or any other information, services, or product you obtain through this website or video.

Saw palmetto boosts testosterone synthesis Kyung Hee University (South Korea), June 30 2021.   The June 2021 issue of the Journal of Medicinal Food reported the finding of a beneficial effect for saw palmetto against symptoms of andropause in rats.  "Andropause, the male equivalent of menopause, is the set of symptoms caused by the age-related deficiency in male hormones that begins to occur in men in their late 40s to early 50s," Jeong Moon Yun and colleagues explained. "The symptoms of andropause include physical, psychological, and sexual problems, such as fatigue, increased body fat, decreased muscle strength and sexual function, depression, and memory loss." Dr Yun and associates evaluated the effects of an extract of saw palmetto in Leydig cells (in which testosterone biosynthesis occurs) subjected to oxidative stress and in aged rats. In Leydig cells, the administration of testosterone lowered 5 alpha-reductase (which converts testosterone to dihydrotestosterone) and increased total testosterone.  In rats, one of three doses of saw palmetto extract was administered for four weeks. A control group of animals received no treatment. At the end of the treatment period, saw palmetto supplemented rats had significantly less fat tissue weight gain and total weight gain compared to the controls, without a gain in other tissue weight. Serum triglycerides, total cholesterol and the LDL to VLDL cholesterol ratio were also lower in the supplemented groups. Serum total and free testosterone and sperm counts were higher, and sex hormone binding globulin (SHBG) and 5 alpha-reductase levels were lower in all supplemented groups in comparison with the controls. In tests of muscle endurance, rats that received saw palmetto had longer swimming times compared to the control group.  "We suggest that supplementation of saw palmetto may relieve the symptoms of andropause syndrome, including decreased spermatogenesis and muscle endurance and metabolic syndrome by increasing testosterone biosynthesis and bioavailability," the authors concluded.         Diet rich in omega 3 fatty acids may help reduce headaches Trial provides 'grounds for optimism' for many people with persistent headaches and those who care for them University of North Carolina, July 1, 2021 Eating a diet rich in omega 3 (n-3) fatty acids reduces the frequency of headaches compared with a diet with normal intake of omega 3 and omega 6 (n-6) fatty acids, finds a study published by The BMJ today. Modern industrialised diets tend to be low in omega 3 fatty acids and high in omega 6 fatty acids. These fatty acids are precursors to oxylipins - molecules involved in regulating pain and inflammation. Oxylipins derived from omega 3 fatty acids are associated with pain-reducing effects, while oxylipins derived from omega 6 fatty acids worsen pain and can provoke migraine. But previous studies evaluating omega 3 fatty acid supplements for migraine have been inconclusive. So a team of US researchers wanted to find out whether diets rich in omega 3 fatty acids would increase levels of the pain-reducing 17-hydroxydocosahexaenoic acid (17-HDHA) and reduce the frequency and severity of headaches. Their results are based on 182 patients at the University of North Carolina, USA (88% female; average age 38 years) with migraine headaches on 5-20 days per month who were randomly assigned to one of three diets for 16 weeks.  The control diet included typical levels of omega 3 and omega 6 fatty acids. Both interventional diets raised omega 3 fatty acid intake. One kept omega 6 acid intake the same as the control diet, and the other concurrently lowered omega 6 acid intake. During the trial, participants received regular dietary counseling and access to online support information. They also completed the headache impact test (HIT-6) - a questionnaire assessing headache impact on quality of life. Headache frequency was assessed daily with an electronic diary. Over the 16 weeks, both interventional diets increased 17-HDHA levels compared with the control diet, and while HIT-6 scores improved in both interventional groups, they were not statistically significantly different from the control group.  However, headache frequency was statistically significantly decreased in both intervention groups.  The high omega 3 diet was associated with a reduction of 1.3 headache hours per day and two headache days per month. The high omega 3 plus low omega 6 diet group saw a reduction of 1.7 headache hours per day and four headache days per month, suggesting additional benefit from lowering dietary omega-6 fatty acid.  Participants in the intervention groups also reported shorter and less severe headaches compared with those in the control group. This was a high quality, well designed trial, but the researchers do point to some limitations, such as the difficulty for patients to stick to a strict diet and the fact that most participants were relatively young women so results may not apply to children, older adults, men, or other populations.  "While the diets did not significantly improve quality of life, they produced large, robust reductions in frequency and severity of headaches relative to the control diet," they write.  "This study provides a biologically plausible demonstration that pain can be treated through targeted dietary alterations in humans. Collective findings suggest causal mechanisms linking n-3 and n-6 fatty acids to [pain regulation], and open the door to new approaches for managing chronic pain in humans," they conclude. These results support recommending a high omega 3 diet to patients in clinical practice, says Rebecca Burch at the Brigham and Women's Hospital, in a linked editorial. She acknowledges that interpretation of this study's findings is complex, but points out that trials of recently approved drugs for migraine prevention reported reductions of around 2-2.5 headache days per month compared with placebo, suggesting that a dietary intervention can be comparable or better.  What's more, many people with migraine are highly motivated and interested in dietary changes, she adds. These findings "take us one step closer to a goal long sought by headache patients and those who care for them: a migraine diet backed up by robust clinical trial results."     The Southern diet - fried foods and sugary drinks - may raise risk of sudden cardiac death University of Alabama, June 30, 2021  Regularly eating a Southern-style diet may increase the risk of sudden cardiac death, while routinely consuming a Mediterranean diet may reduce that risk, according to new research published today in the Journal of the American Heart Association, an open access journal of the American Heart Association. The Southern diet is characterized by added fats, fried foods, eggs, organ meats (such as liver or giblets), processed meats (such as deli meat, bacon and hotdogs) and sugar-sweetened beverages. The Mediterranean diet is high in fruits, vegetables, fish, whole grains and legumes and low in meat and dairy. "While this study was observational in nature, the results suggest that diet may be a modifiable risk factor for sudden cardiac death, and, therefore, diet is a risk factor that we have some control over," said James M. Shikany, Dr.P.H., F.A.H.A., the study's lead author and professor of medicine and associate director for research in the Division of Preventive Medicine at the University of Alabama at Birmingham. "Improving one's diet - by eating a diet abundant in fruits, vegetables, whole grains and fish such as the Mediterranean diet and low in fried foods, organ meats and processed meats, characteristics of the Southern-style dietary pattern, may decrease one's risk for sudden cardiac death," he said. The study examined data from more than 21,000 people ages 45 and older enrolled in an ongoing national research project called REasons for Geographic and Racial Differences in Stroke (REGARDS), which is examining geographic and racial differences in stroke. Participants were recruited between 2003 and 2007. Of the participants in this analysis, 56% were women; 33% were Black adults; and 56% lived in the southeastern U.S., which is noteworthy as a region recognized as the Stroke Belt because of its higher stroke death rate. The Stroke Belt states included in this study were North Carolina, South Carolina, Georgia, Tennessee, Alabama, Mississippi, Arkansas and Louisiana. This study is the latest research to investigate the association between cardiovascular disease and diet - which foods have a positive vs. negative impact on cardiovascular disease risk. It may be the only study to-date to examine the association between dietary patterns with the risk of sudden cardiac death, which is the abrupt loss of heart function that leads to death within an hour of symptom onset. Sudden cardiac death is a common cause of death and accounted for 1 in every 7.5 deaths in the United States in 2016, or nearly 367,000 deaths, according to 2019 American Heart Association statistics. Researchers included participants with and without a history of coronary heart disease at the beginning of the study and assessed diets through a food frequency questionnaire completed at the beginning of the study. Participants were asked how often and in what quantities they had consumed 110 different food items in the previous year. Researchers calculated a Mediterranean diet score based on specific food groups considered beneficial or detrimental to health. They also derived five dietary patterns. Along with the Southern-style eating pattern, the analysis included a "sweets" dietary pattern, which features foods with added sugars, such as desserts, chocolate, candy and sweetened breakfast foods; a "convenience" eating pattern which relied on easy-to-make foods like mixed dishes, pasta dishes, or items likely to be ordered as take-out such as pizza, Mexican food and Chinese food; a "plant-based" dietary pattern was classified as being high in vegetables, fruits, fruit juices, cereal, bean, fish, poultry and yogurt; and an "alcohol and salad" dietary pattern, which was highly reliant on beer, wine, liquor along with green leafy vegetables, tomatoes and salad dressing. Shikany noted that the patterns are not mutually exclusive. "All participants had some level of adherence to each pattern, but usually adhered more to some patterns and less to others," he explained. "For example, it would not be unusual for an individual who adheres highly to the Southern pattern to also adhere to the plant-based pattern, but to a much lower degree." After an average of nearly 10 years of follow-up every six months to check for cardiovascular disease events, more than 400 sudden cardiac deaths had occurred among the 21,000 study participants. The study found: Overall, participants who ate a Southern-style diet most regularly had a 46% higher risk of sudden cardiac death than people who had the least adherence to this dietary pattern. Also, participants who most closely followed the traditional Mediterranean diet had a 26% lower risk of sudden cardiac death than those with the least adherence to this eating style. The American Heart Association's Diet and Lifestyle recommendations emphasize eating vegetables, fruits, whole grains, lean protein, fish, beans, legumes, nuts and non-tropical vegetable cooking oils such as olive and canola oil. Limiting saturated fats, sodium, added sugar and processed meat are also recommended. Sugary drinks are the number one source of added sugar in the U.S. diet, according to the Centers for Disease Control and Prevention, and the American Heart Association supports sugary drink taxes to drive down consumption of these products. "These findings support the notion that a healthier diet would prevent fatal cardiovascular disease and should encourage all of us to adopt a healthier diet as part of our lifestyles," said Stephen Juraschek, M.D., Ph.D., a member of the American Heart Association's Nutrition Committee of the Lifestyle and Cardiometabolic Health Council. "To the extent that they can, people should evaluate the number of servings of fruit and vegetables they consume each day and try to increase the number to at least 5-6 servings per day, as recommended by the American Heart Association. Optimal would be 8-9 servings per day. "This study also raises important points about health equity, food security and social determinants of health," he continued. "The authors describe the "Southern Diet" based on the U.S. geography associated with this dietary pattern, yet it would be a mistake for us to assume that this is a diet of choice. I think American society needs to look more broadly at why this type of diet is more common in the South and clusters among some racial, ethnic or socioeconomic groups to devise interventions that can improve diet quality. The gap in healthy eating between people with means and those without continues to grow in the U.S., and there is an incredible need to understand the complex societal factors that have led and continue to perpetuate these disparities." This current research expands on earlier studies on participants from the same national stroke project, REGARDS. In a 2018 analysis, Shikany and colleagues reported that adults ages 45 and older with heart disease who had an affinity for the Southern diet had a higher risk of death from any cause, while greater adherence to the Mediterranean diet was associated with a lower risk of death from any cause. And in a 2015 study, the Southern diet was linked to a greater risk of coronary heart disease in the same population. The large population sample and regional diversity, including a significant number of Black participants, are considered strengths of the REGARDS research project. However, potential limitations of this study include that that dietary intake was based on one-time, self-reported questionnaires, thus, it relied on the participants' memory. Self-reported diet can include inaccuracies leading to bias that could reduce the strength of the associations observed. One usual association that remains unexplained is that among individuals with a history of heart disease, those who most adhered to the sweets dietary pattern had a 51% lower risk of sudden cardiac death than participants who followed that pattern the least. Researchers note that they found "no viable explanation for the inverse association of the sweets dietary pattern with risk of sudden cardiac death in those with a history of coronary heart disease."     5-minute workout lowers blood pressure as much as exercise, drugs 'Strength training for breathing muscles' holds promise for host of health benefits University of Colorado, July 2, 2021 Working out just five minutes daily via a practice described as "strength training for your breathing muscles" lowers blood pressure and improves some measures of vascular health as well as, or even more than, aerobic exercise or medication, new CU Boulder research shows. The study, published June 29 in the Journal of the American Heart Association, provides the strongest evidence yet that the ultra-time-efficient maneuver known as High-Resistance Inspiratory Muscle Strength Training (IMST) could play a key role in helping aging adults fend off cardiovascular disease - the nation's leading killer.  In the United States alone, 65% of adults over age 50 have above-normal blood pressure - putting them at greater risk of heart attack or stroke. Yet fewer than 40% meet recommended aerobic exercise guidelines. "There are a lot of lifestyle strategies that we know can help people maintain cardiovascular health as they age. But the reality is, they take a lot of time and effort and can be expensive and hard for some people to access," said lead author Daniel Craighead, an assistant research professor in the Department of Integrative Physiology. "IMST can be done in five minutes in your own home while you watch TV." Developed in the 1980s as a way to help critically ill respiratory disease patients strengthen their diaphragm and other inspiratory (breathing) muscles, IMST involves inhaling vigorously through a hand-held device which provides resistance. Imagine sucking hard through a tube that sucks back.  Initially, when prescribing it for breathing disorders, doctors recommended a 30-minute-per-day regimen at low resistance. But in recent years, Craighead and colleagues have been testing whether a more time-efficient protocol--30 inhalations per day at high resistance, six days per week--could also reap cardiovascular, cognitive and sports performance improvements. For the new study, they recruited 36 otherwise healthy adults ages 50 to 79 with above normal systolic blood pressure (120 millimeters of mercury or higher). Half did High-Resistance IMST for six weeks and half did a placebo protocol in which the resistance was much lower.  After six weeks, the IMST group saw their systolic blood pressure (the top number) dip nine points on average, a reduction which generally exceeds that achieved by walking 30 minutes a day five days a week. That decline is also equal to the effects of some blood pressure-lowering drug regimens.  Even six weeks after they quit doing IMST, the IMST group maintained most of that improvement. "We found that not only is it more time-efficient than traditional exercise programs, the benefits may be longer lasting," Craighead said. The treatment group also saw a 45% improvement in vascular endothelial function, or the ability for arteries to expand upon stimulation, and a significant increase in levels of nitric oxide, a molecule key for dilating arteries and preventing plaque buildup. Nitric oxide levels naturally decline with age.  Markers of inflammation and oxidative stress, which can also boost heart attack risk, were significantly lower after people did IMST. And, remarkably, those in the IMST group completed 95% of the sessions. "We have identified a novel form of therapy that lowers blood pressure without giving people pharmacological compounds and with much higher adherence than aerobic exercise," said senior author Doug Seals, a Distinguished Professor of Integrative Physiology. "That's noteworthy." The practice may be particularly helpful for postmenopausal women. In previous research, Seals' lab showed that postmenopausal women who are not taking supplemental estrogen don't reap as much benefit from aerobic exercise programs as men do when it comes to vascular endothelial function. IMST, the new study showed, improved it just as much in these women as in men.  "If aerobic exercise won't improve this key measure of cardiovascular health for postmenopausal women, they need another lifestyle intervention that will," said Craighead. "This could be it." Preliminary results suggest MST also improved some measures of brain function and physical fitness. And previous studies from other researchers have shown it can be useful for improving sports performance. "If you're running a marathon, your respiratory muscles get tired and begin to steal blood from your skeletal muscles," said Craighead, who uses IMST in his own marathon training. "The idea is that if you build up endurance of those respiratory muscles, that won't happen and your legs won't get as fatigued." Seals said they're uncertain exactly how a maneuver to strengthen breathing muscles ends up lowering blood pressure, but they suspect it prompts the cells lining blood vessels to produce more nitric oxide, enabling them to relax. The National Institutes of Health recently awarded Seals $4 million to launch a larger follow-up study of about 100 people, comparing a 12-week IMST protocol head-to-head with an aerobic exercise program. Meanwhile, the research group is developing a smartphone app to enable people to do the protocol at home using already commercially available devices. Those considering IMST should consult with their doctor first. But thus far, IMST has proven remarkably safe, they said. "It's easy to do, it doesn't take long, and we think it has a lot of potential to help a lot of people," said Craighead.   Research suggests atheroprotective role for chrysin Fu Jen Catholic University (Taiwan), July 1, 2021 According to news reporting originating from New Taipei, Taiwan, research stated, “Atherosclerosis and its related clinical complications are the leading cause of death. MicroRNA (miR)-92a in the inflammatory endothelial dysfunction leads to atherosclerosis.” Our news editors obtained a quote from the research from Fu Jen Catholic University, “Kruppel-like factor 2 (KLF2) is required for vascular integrity and endothelial function maintenance. Flavonoids possess many biological properties. This study investigated the vascular protective effects of chrysin in balloon-injured carotid arteries. Exosomes were extracted from human coronary artery endothelial cell (HCAEC) culture media. Herb flavonoids and chrysin (found in mint, passionflower, honey and propolis) were the treatments in these atheroprotective models. Western blotting and real-time PCRs were performed. In situ hybridization, immunohistochemistry, and immunofluorescence analyses were employed. MiR-92a increased after balloon injury and was present in HCAEC culture media. Chrysin was treated, and significantly attenuated the miR-92a levels after balloon injury, and similar results were obtained in HCAEC cultures in vitro. Balloon injury-induced miR-92a expression, and attenuated KLF2 expression. Chrysin increased the KLF2 but reduced exosomal miR-92a secretion. The addition of chrysin and antagomir-92a, neointimal formation was reduced by 44.8 and 49.0% compared with balloon injury after 14 days, respectively. Chrysin upregulated KLF2 expression in atheroprotection and attenuated endothelial cell-derived miR-92a-containing exosomes.” According to the news editors, the research concluded: “The suppressive effect of miR-92a suggests that chrysin plays an atheroprotective role.” This research has been peer-reviewed.     False-positive mammogram results linked to spike in anxiety prescriptions Penn State University, July 2, 2021 Women who experience a false-positive mammogram result are more likely to begin medication for anxiety or depression than women who received an immediate negative result, according to a study led by Penn State researcher Joel Segel. The finding highlights the importance of swift and accurate follow-up testing to rule out a breast cancer diagnosis. The study found that patients who receive a false-positive mammogram result are also prescribed anxiety or depression medication at a rate 10 to 20 percent higher than patients who receive an immediate negative result. These prescriptions are new and not continuations of previously prescribed medicines. A false-positive result is one where a suspicious finding on the screening mammogram leads to additional testing that does not end up leading to a breast cancer diagnosis. Additionally, within that group of patients who required more than one test to resolve the false-positive there was a 20 to 30 percent increase in those beginning to take anxiety or depression medications. The increase was particularly noticeable among women with commercial insurance who required multiple tests to rule out a breast cancer diagnosis. "The results suggest that efforts to quickly resolve initially positive findings including same-day follow-up tests may help reduce anxiety and even prevent initiation of anxiety or depression medication," said Segel, assistant professor of health policy and administration at Penn State. This study demonstrates that some women who experience a false-positive mammogram may need additional follow-up care to effectively handle the increased anxiety that may accompany the experience, Segel said. More importantly, from a practitioner standpoint, the study identifies sub-populations who may be most at risk of increased anxiety following a false-positive mammogram, Segel said. Specifically, women whose false-positive result requires more than one follow-up test to resolve, women with commercial insurance who undergo a biopsy, women who wait longer than one week to receive a negative result, and women who are under age 50 may all be at higher risk of experiencing clinically significant anxiety or depression. "Regular breast cancer screening is critical to early detection," Segel said. "Patients should continue to work with their providers to ensure they are receiving guideline-appropriate screening and should follow up with their providers if they experience either anxiety or depression following screening or any type of care." Researchers studied commercial- and Medicaid-claims databases to identify women ages 40 to 64 who underwent screening mammography with no prior claims for anxiety or depression medications. The findings recently appeared in Medical Care.     Thymoquinone in Black Seed oil increases the expression of neuroprotective proteins while decreasing expression of pro-inflammatory cytokines Florida A&M University, June 29, 2021    According to news originating from Tallahassee, Florida, research stated, "Neuroinflammation and microglial activation are pathological markers of a number of central nervous system (CNS) diseases. Chronic activation of microglia induces the release of excessive amounts of reactive oxygen species (ROS) and pro-inflammatory cytokines." Our news journalists obtained a quote from the research from Florida A&M University, "Additionally, chronic microglial activation has been implicated in several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. Thymoquinone (TQ) has been identified as one of the major active components of the natural product Nigella sativa seed oil. TQ has been shown to exhibit anti-inflammatory, anti-oxidative, and neuroprotective effects. In this study, lipopolysaccharide (LPS) and interferon gamma (IFN gamma) activated BV-2 microglial cells were treated with TQ (12.5 mu M for 24 h). We performed quantitative proteomic analysis using Orbitrap/Q-Exactive Proteomic LC-MS/MS (Liquid chromatography-mass spectrometry) to globally assess changes in protein expression between the treatment groups. Furthermore, we evaluated the ability of TQ to suppress the inflammatory response using ELISArray ™ for Inflammatory Cytokines. We also assessed TQ's effect on the gene expression of NFKB signaling targets by profiling 84 key genes via real-time reverse transcription (RT2) PCR array. Our results indicated that TQ treatment of LPS/IFN gamma-activated microglial cells significantly increased the expression of 4 antioxidant, neuroprotective proteins: glutaredoxin-3 (21 fold; p< 0.001), biliverdin reductase A (15 fold; p< 0.0001), 3-mercaptopyruvate sulfurtransferase (11 fold; p< 0.01), and mitochondria] Ion protease (> 8 fold; p< 0.001) compared to the untreated, activated cells. Furthermore, TQ treatment significantly (P < 0.0001) reduced the expression of inflammatory cytokines, IL-2 = 38%, IL-4 = 19%, IL-6 = 83%, IL-10 = 237%, and IL-17a = 29%, in the activated microglia compared to the untreated, activated which expression levels were significantly elevated compared to the control microglia: IL-2 = 127%, IL-4 = 151%, IL-6 = 670%, IL-10 = 133%, IL-17a = 127%. Upon assessing the gene expression of NFKB signaling targets, this study also demonstrated that TQ treatment of activated microglia resulted in > 7 fold down-regulation of several NFKB signaling targets genes, including interleukin 6 (IL6), complement factor B (CFB), chemokine (C-C motif) ligand 3 (CXCL3), chemokine (C-C) motif ligand 5 (CCL5) compared to the untreated, activated microglia. This modulation in gene expression counteracts the > 10-fold upregulation of these same genes observed in the activated microglia compared to the controls. Our results show that TQ treatment of LPS/IFN gamma-activated BV-2 microglial cells induce a significant increase in expression of neuroprotective proteins, a significant decrease in expression inflammatory cytokines, and a decrease in the expression of signaling target genes of the NF kappa B pathway. Our findings are the first to show that TQ treatment increased the expression of these neuroprotective proteins (biliverdin reductase-A, 3-mercaptopyruvate sulfurtransferase, glutaredoxin-3, and mitochondrial Ion protease) in the activated BV-2 microglial cells. Additionally, our results indicate that TQ treatment decreased the activation of the NF kappa B signaling pathway, which plays a key role in neuroinflammation." According to the news editors, the research concluded: "Our results demonstrate that TQ treatment reduces the inflammatory response and modulates the expression of specific proteins and genes and hence potentially reduce neuroinflammation and neurodegeneration driven by microglial activation."

This week the Guys talk about how Ryan got out of the Group stage of IL6, How to develop new players, and look at the new command cards.

Even TIME magazine featured a cover in 2004, blaming inflammation for heart attack, stroke, Alzheimer's cancer, and other chronic diseases. Dale Bredesen in his book END OF ALZHEIMER'S, Brad Bale and Amy Doneen in their book BEAT THE HEART GENE, and others have their recommendations for biochemical tests for inflammation. Paul Ridker, MD at Brigham & Women's, is considered by many to be the father of chronic inflammation. He recently made headlines with the CANTOS trial. He looks simply at hsCRP. Bredesen adds albumin amounts and ratios. So do Bale and Doneen. Both added TNF alpha and IL6 previously. Both have also looked at Omega6:3. Bredesen looks at glutathione as well.For more information, contact us at 859-721-1414 or myhealth@prevmedheartrisk.com. Also, check out the following resources: PrevMed's article on inflammation testsPrevMed's websitePrevMed's YouTube channelPrevMed's Facebook page

Podcast summary of articles from the December 2020 edition of the Journal of Emergency Medicine from the American Academy of Emergency Medicine.  Topics include racial disparities in head trauma patients, traumatic brain injury, fever in COVID patients, and board review on cardiopulmonary resuscitation (CPR).  Guest speaker is Dr. Ryan Yavorsky.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.11.377309v1?rss=1 Authors: Ahn, S. B., Kamath, K. S., Mohamedali, A., Noor, Z., Wu, J. X., Pascovici, D., Adhikari, S., Cheruku, H. R., Guillemin, G. J., McKay, M. J., Nice, E. C., Baker, M. S. Abstract: Credible detection and quantification of low abundance proteins from human blood plasma is a major challenge in precision medicine biomarker discovery when using mass spectrometry (MS). Here, we employed a mixture of recombinant proteins in DDA libraries to subsequently detect cancer-associated low abundance plasma proteins using SWATH/DIA. The exemplar DDA recombinant protein spectral library (rPSL) was derived from tryptic digestion of 36 human recombinant proteins that had been previously implicated as possible cancer biomarkers in both our own and other studies. The rPSL was then used to identify proteins from non-depleted colorectal cancer (CRC) plasmas by SWATH-MS. Most (32/36) of the proteins in the rPSL were reliably identified in plasma samples, including 8 proteins (BTC, CXCL10, IL1B, IL6, ITGB6, TGF, TNF, TP53) not previously detected using high-stringency MS in human plasmas according to PeptideAtlas. The rPSL SWATH-MS protocol was compared to DDA-MS using MARS-depleted and post-digestion peptide fractionated plasmas (here referred to as a human plasma DDA library). Of the 32 proteins identified using rPSL SWATH, only 12 were identified using DDA-MS. The 20 additional proteins exclusively identified by using the rPSL approach with SWATH were mostly lower abundance (i.e.,

Can a prognostic score help guide clinical decision-making in COVID-19? Find out about this and more in today's PV Roundup podcast.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.02.364356v1?rss=1 Authors: Mirabella, F., Desiato, G., Mancinelli, S., Fossati, G., Rasile, M., Morini, R., Markicevic, M., Grimm, C., amegandjin, C., Termanini, A., Peano, C., Kunderfranco, P., DiCristo, G., Zerbi, V., Lodato, S., Menna, E., Matteoli, M., Pozzi, D. Abstract: Early prenatal inflammatory conditions are thought to represent a risk factor for different neurodevelopmental disorders, with long-term consequences on adult brain connectivity. Here we show that a transient IL-6 elevation, occurring at vulnerable stages of early neurodevelopment, directly impacts brain developmental trajectories through the aberrant enhancement of glutamatergic synapses and overall brain hyper-connectivity. The IL6-mediated boost of excitatory synapse density results from the neuronautonomous, genomic effect of the transcription factor STAT3 and causally involves the activation of RGS4 gene as a candidate downstream target. The STAT3/RGS4 pathway is also activated in neonatal brains as a consequence of maternal immune activation protocols mimicking a viral infection during pregnancy. By demonstrating that prenatal IL-6 elevations result in aberrant synaptic and brain connectivity through the molecular players identified, we provide a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.16.336065v1?rss=1 Authors: Lenz, M., Eichler, A., Kruse, P., Strehl, A., Rodriguez-Rozada, S., Goren, I., Yogev, N., Frank, S., Waisman, A., Deller, T., Jung, S., Maggio, N., Vlachos, A. Abstract: Systemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL6-Tg(TNFa-eGFP)] confirms that ex vivo LPS administration triggers microglial tumor necrosis factor alpha (TNF) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNF, IL6, IL1{beta}, and IFN{gamma} and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation. Copy rights belong to original authors. Visit the link for more info

Dr. Seeds is quite active all over the web - youtube, peptide groups, reddit, and of course, our own emails answering questions about peptide therapy, to providing information to health issues that have no clear cut answers.There was no way to organize this into topical episodes so we made an Ask Me Anything episode instead.Here we answer the following questions:What kinds of things do you recommend for the folks on the west coast dealing with poor air quality from the wildfires?What kinds of peptide therapies for Ehlers Danlos Syndrome?How about adrenal fatigue, what's your recommendation and stance?Not feeling the effects of Dihexa, what do you recommend?Will ARA-290 increase COVID-19 risk due to decreased cytokines IL6, and IL-12?Any recommendations for atrial fibrillation?I wish we had more time, but we promise to do another one of these episodes. It was fascinating to listen to the approach of Dr. Seeds when dealing with each of these issues.Keep your questions coming, and let's prioritize your health at the top of your list!

For those that develop COVID-19, high cytokine levels like IL-6 have been shown to be associated with a significant risk of ending up on a ventilator. In study after study, who has been successfully lowering these levels for their whole career? Yep, you, the hygiene superstar.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.18.254649v1?rss=1 Authors: Audrain, M., Haure-Mirande, J.-V., Mleczko, J., Wang, M., Griffin, J. K., Fraser, P., Zhang, B., Gandy, S., Ehrlich, M. E. Abstract: Microglial TYROBP (also known as DAP12) has been identified by computational transcriptomics as a network hub and driver in late-onset sporadic Alzheimer's disease (AD) and as an important regulator of the microglial environmental sensing function. TYROBP is the transmembrane adaptor of AD-related receptors TREM2 and CR3, but importantly, TYROBP interacts with many other receptors, and little is known about its roles in microglial action and/or in the pathogenesis of AD. Herein, using dual RNA in situ hybridization and immunohistochemistry, we demonstrate that endogenous Tyrobp transcription is increased specifically in recruited microglia in the brains of wild-type and AD-related mouse models. To determine whether chronically elevated TYROBP might modify microglial phenotype and/or progression of AD pathogenesis, we generated a novel transgenic mouse overexpressing TYROBP in microglia. TYROBP-overexpressing mice were crossed with either APP/PSEN1 or MAPTP301S mice, resulting in a decrease of the amyloid burden in the former and an increase of TAU phosphorylation in the latter. Apolipoprotein E (Apoe) transcription was upregulated in MAPTP301S mice overexpressing TYROBP and transcription of genes previously associated with Apoe, including Axl, Ccl2, Tgfb and Il6, was altered in both APP/PSEN1 and MAPTP301S mice overexpressing TYROBP. Lastly, Tyrobp and Apoe mRNAs were clearly increased in Trem2-null mice in microglia recruited around a cortical stab injury or amyloid-beta deposits. Conversely, microglial Apoe mRNA level was dramatically diminished when Tyrobp was absent. Our results provide compelling evidence that TYROBP-APOE signaling in the microglial sensome does not require TREM2. We propose that activation of a TREM2-independent TYROBP-APOE signaling could be an early or even initiating step in the transformation of microglia from the homeostatic phenotype to the Disease-Associated Microglia (DAM) phenotype. Copy rights belong to original authors. Visit the link for more info

We’ve all heard the advice, ‘eat right and exercise’, but it’s often not clear cut what exercise is best for each individual needs, how long we should exercise, and the timing of exercise. In this week’s episode, we discuss practical ways to keep patients exercising safely and effectively. We talk about things to look at on genetic reports, such as inflammatory markers and polymorphisms that can serve as a predetermination for a higher chance of response and injury. We correspond examples of exercise with certain genetic findings and give our own personal examples of how our lives changed for the better once we applied them to our daily routines. Key Takeaways: [3:32] When we get the right kind and amount of exercise, we get a huge bump in dopamine that can boost our mood and help with attention and focus. However, if we exercise too much or in the wrong way, that can cause stress, trauma, and inflammation to the body. [7:42] Recovery and timing are so important in exercise, as we can become even more inflamed when we push the body after it is already deficient in sleep or healthy cortisol levels. [9:15] Practitioners should speak with their patients about what type of exercise they already enjoy and are called to do because they are more likely to stick with it long term then an exercise they don’t find pleasure in doing. [12:28] Genetic variance may affect someone’s risk for exercise, but should not preclude anyone from doing what they enjoy. [13:10] The top thing we look at with genetics when it relates to exercise is the response to inflammation. When a patient has a risk variant for Interleukin 6 and does intense exercise for around an hour, they really do not do well and could actually feel more tired during the day. Patients with this risk variant may do better walking for an hour or experience better results with a 20-30 minute work out rather than trying to do more intense exercise for a longer duration. Switching to low-moderate intensity workouts, they can recover and possibly reduce the chance of harm from an increased inflammation cascade. [15:06] ACTN3 is a muscle structure gene that tells us about your fast-twitch versus your slow-twitch. If you are a variant for the ACTN3 gene, you may be a better fit for endurance since you are able to get more blood flow to the muscles, and this may explain not feeling your best after interval type exercise. However, if you are practicing HIIT style and loving it, then go on enjoying it. This does not mean the average person has to stop this exercise. Again, referencing the IL-6 genetic variant is important. [16:53] ACE is really about how our muscles respond and how we recover. We tend to find that ACE can tell us if we have more vasoconstriction, where our arteries contract. And that's going to be more for your sprinters and more for the people that need that quick blood flow. These are the patients who are genetically advantaged to go long distances like riding bikes and marathons. [17:51]  PPARGCA1A -this how well we're going to do with aerobic exercise. And so this could be a leverage point and say, "You know what, aerobic exercise is going to be just fine for you. However, you will also want to cross-reference the SNPs to prevent injury associated with aerobic training. [20:11] Exercise done correctly in the right amounts actually lowers our IL6 through the vagal nerve and that dopamine. So we really want them to hit that right amount of exercise, which decreases inflammation and does not increase inflammation. [21:18] The beautiful feature about Pure Genomics is as more polymorphisms are scientifically validated and added to the program, they automatically appear on patients' reports; one test equals a lifetime of information. It’s also easy to correlate genetic information with exercise recommendations. [23:13] LPL is what Dr. Morris calls a ‘leverage points’; they highlight response to glucose metabolism. If somebody is struggling with keeping their blood sugar down with diet alone, knowing their LPL and LIPC variants help show the patient that doing some exercise, 20, 30 minutes each day, can really help with your glucose. [23:53] LPL and ADRB2 are two more leverage points. These variants are related to fat burning as a result of exercise. For these patients, exercise a great way to lose this fat as they have beneficial biology for it. We call these “enhanced benefit SNPs”. [23:13] Not all variants are risk-inducing, which is why the term “risk variant” as applied to genomic testing can be misleading. In PureGenomics, SNPs are now reported as “No Action”, “Enhanced Benefit”, or “Consider Action”. SNPs like LPL, LIPC, and ADRB2 are some of the variants that have an enhanced benefit to the patient. [27:29] COL1A1 & COL5A1 are variants associated with ligament injury susceptibility and MMP3 for Achilles tendon injury susceptibility.  And what all these SNPs show really is that you have problems with collagen and collagen deposition and strength. And so, Dr. Morris says before started an exercise program, you want to reference IL-6 and the injury prevention SNPs, COL1A1, COL5A1, AND MMP3 [33:28] We need to remember that polymorphisms are associated with a risk or a benefit. So even though it says risk variant, there's actually an advantage to having the variant as in the case of the LPL, LIPC, MMP3. This is why PureGenomics moved away from the misleading color coding and clearly marks when there is an advantage to having the ‘risk variant’. Mentioned: Good Medicine Pure Encapsulations PureGenomics Free PureGenomics Business Integration 30-minute consult, schedule yours here Why is the generic advice ‘eat right and exercise’ bad advice? With Dr. Penny Kendall-Reed First things first, Mental Health Feeding on Fear with Morgan Knull of Feed Your Genes Quotes Worth Sharing: “The timing and telling patients they are off the hook is as important as it is for us to help them add movement into their life.” - Kara  Ware[7:29] “Exercise is just like diet - if we don’t give people the right type and the right time, we can cause more inflammation and injury.” -Dr. Nathan Morris [8:30] “We all know, in functional medicine, you always go to the gut, and inflammation starts there.” Dr. Nathan Morris[29:22] “We need to remember that polymorphisms are associated with a risk or a benefit. So even though it says risk variant, there may actually be an advantage to having the variant. Therefore, genes are not good or bad”. Kara Ware [33.28]

Dr. Auwaerter covers the following topics: *Recurrences of COVID-19 symptoms *Hydroxychloroquine study from Michigan *Sarilumab (anti-IL6) monoclonal antibody *Operation Warp Speed update *Differences in mortality rates among States *Nasal vs. nasopharyngeal test accuracy. The post UPDATE 7/8/2020 – COVID-19: Keeping Up With A Moving Target appeared first on DKBmed Radio.

  Vidcast:  https://youtu.be/7Weu0XfSb3c   The monoclonal antibody tocilizumab that is designed to reduce IL-6 and cytokine storms apparently doesn’t for critically ill CoVid19 patients. This the conclusion of a preliminary case series from the University of North Carolina.   Eleven patients with confirmed CoVid19 infections were treated with Actemra.  These patients were either severe or critical and had multiple medical issues including obesity and high blood pressure.     Despite Actemra treatment, all patients experienced significant IL-6 level increases without improvements in their fevers or a reduction in their oxygen requirements.  Two other inflammatory indicators did diminish.   The conclusion: randomized, controlled trials of Actemra must occur before this drug can be widely used.   https://www.medrxiv.org/content/10.1101/2020.05.13.20100404v1.full.pdf   #covid #actemra #tocilizumab #il6 #cytokinestorm  

This month on Episode 12 of the Discover CircRes podcast, host Cindy St. Hilaire highlights three featured articles from the May 8 issue of Circulation Research and gives listeners an inside scoop of the cutting edge ideas in the May 22nd Compendium on Obesity. This episode also features an in-depth conversation with Dr Eduardo Marbán concerning COVID-19 and its effects on the heart.   Article highlights:   Roberts et al.  LYN Regulates Monocyte Heterogeneity and Lifespan Lu, et al. Acute Hyperglycemia Activates CaMKII-ROS Pathway Yan, et al. Epicardium and Atrial Cardiomyopathy Transcript Dr Cindy St. Hilaire: Hi. Welcome to Discover CircRes, the podcast of the American Heart Association's journal, Circulation Research. I'm your host, Dr Cindy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh. Today, I'm going to share with you articles selected from the May 8th issue of Circulation Research as well as give you a hint at the cutting-edge ideas in the May 22nd Compendium on Obesity. We'll also have discussion with Dr Eduardo Marbán from the Smidt Heart Institute at Cedar Sinai Medical Center about his Review on COVID-19 and its effects on heart. So, first the highlights. The first article I'm sharing with you is titled Deep Phenotyping by Mass Cytometry and Single Cell RNA Sequencing reveals LYN Regulated Signaling Profiles Underlying Monocyte Subset Heterogeneity and Lifespan. The first authors are Morgan Roberts and Maunish Barvalia and the corresponding author is Kenneth Harder and they're from the University of British Columbia. Monocytes can be separated into two main groups, conventional monocytes which enter tissues from the bloodstream and differentiate into macrophages, and patrolling monocytes, which developed from conventional monocytes but tend to remain in the blood vessel walls where they can scavenge cells and tissue debris. It's thought that patrolling monocytes help to prevent a range of diseases like atherosclerosis by helping to clean up the vessel walls. Studies in mice harboring genetic mutations in a gene called Nr4a1 cause mice to have less than normal numbers of patrolling monocytes. In these mice, the development of atherosclerosis is exacerbated. In addition to Nr4a1, this group has now identified another factor regulating the survival of patrolling monocytes, the tyrosine kinase LYN, L-Y-N. Genetic deficiency of LYN caused the upregulation of Nr4a1 and other genes involved in patrolling monocytes development and survival. This in turn led to the accumulation of patrolling monocytes in the blood, also in the bone marrow, spleen, and the aorta. Loss of LYN was also protective against atherosclerosis in mouse models of this disease. These results not only provide novel insights into patrolling monocyte biology, but also suggest that targeting LYN could offer novel treatments for diseases like atherosclerosis, where boosting the patrolling monocyte numbers could be beneficial. The second article I want to highlight is titled Hyperglycemia Acutely Increases Cytosolic Reactive Oxygen Species via O-linked GlcNAcylation and CaMKII Activation in Mouse Ventricular Myocytes. The first author is Shan Lu and the corresponding author is Don Bers, and they're from the University of California, Davis. Diabetes affects more than 400 million people worldwide and puts these individuals at a higher risk for developing heart failure. When heart failure does occur, the outcomes for these patients with diabetes are likely to be far worse than for individuals without the diabetic condition. Both heart failure and diabetes have been associated with excessive production of reactive oxygen species and also with increased activation of a protein kinase in the cells of the heart called CaMKII. Both ROS and CaMKII are induced by hypoglycemia, where there is an increased amount of extracellular glucose levels in the blood. This study shows that reactive oxygen species in CaMKII are causally linked. When CaMKII was inhibited or genetically deleted in mouse cardiomyocytes, high extracellular glucose levels were unable to induce reactive oxygen species production, which is what would normally occur. The team also discovered that O-GlcNAcylation post-translational modification of CaMKII is induced by the extracellular glucose and this modification is necessary for the enzyme's reactive oxygen species- boosting effects. Lastly, they found that the enzyme NADPH oxidase 2 or NOX2 was the source of this CaMKII induced reactive oxygen species. This work uncovers the molecular pathway linking hyperglycemia, cardiomyocyte-damaging reactive oxygen species production, and it helps explain why heart failure pathology is exacerbated in diabetic patients. The next article I want to share with you is Reactivation of the Epicardium at the Origin of Myocardial Fibro-Fatty Infiltration During the Atrial Cardiomyopathy. The first author is Nadine Suffee and the corresponding author is Stéphane Hatem and they're from Inserm in Montpellier, France. Fatty tissue surrounding the heart is linked to an increased risk for atrial fibrillation, which is the most common form of arrhythmia. It seems that a combination of fat cells, which are called adipocytes and the fibroblast localized within the heart's epicardium, builds up and expand into the subepicardial layers, and this is a feature that is called fibro-fatty infiltration. These fibro-fatty infiltrations cause disturbances to the electrical rhythms that regulate the heart beating. Although generally quiescent in the adult heart, epicardial cells possess the ability to proliferate and have been shown that they harbor the ability to differentiate into adipocytes and fibroblast. This team hypothesized that the epicardial cells were the source of the damaging fibro-fatty infiltrations. Sure enough, when they looked at human heart sections, they found that within the epicardial layer, there were cells that were expressing fibroblast and adipocyte progenitor cell markers. In culture, these epicardial cells with fibroblast progenitor markers could be differentiated into fibroblasts by treatment with angiotensin II and cells with the adipocyte progenitor markers could be differentiated into adipocytes by treatment with atrial natriuretic peptide. The team also showed that these epicardial fibro-fatty infiltrations occurred in a mouse model of atrial cardiomyopathy. Together this work highlights the pathogenesis of epicardial fibro-fatty infiltrations and suggest a novel model in which to study its progression to AFib. The last thing I want to share with you before we switch to our interview with Dr Marbán is that the May 22nd issue of Circulation Research is our Obesity Compendium. Obesity is a major threat to cardiovascular health worldwide. While early studies focused on body mass index as a generalized measure of obesity and focused on the BMIs relation to cardiovascular disease, studies within the last decade have now tried to more fully understand adipose tissue physiology and the overall impact of obesity on cardiovascular disease. The articles in this compendium are obesity phenotypes, diabetes and cardiovascular diseases, basic mechanisms of diabetic heart disease, leukocyte heterogeneity and adipose tissue including obesity, an eclectic cast of cellular actors orchestrates innate immune responses and the mechanisms driving obesity and the metabolic perturbation, metabolic inflammation and insulin resistance in obesity, genetic insights into the relationship between Type 2 diabetes and coronary heart disease, metabolomics and proteomics in Type 2 diabetes, metabolic and molecular imaging in diabetic cardiomyopathy and treatment of obesity and mitigating metabolic risk. This compendium reflects the collective work of leading investigators in the space of diabetes, cardiometabolic disease, and cardiovascular disease with the ultimate goal of providing a summary of selected aspects of obesity and metabolic physiology central to cardiovascular disease development. So, I have with me here today, Dr Eduardo Marbán, the founder of the Smidt Heart Institute at Cedars-Sinai Medical Center in Los Angeles, California. He's a leading physician scientist in the fields of electrophysiology, cardiac progenitor cells, and next generation cell-free therapeutics. Dr Marbán, thank you very much for taking the time out of your busy schedule to speak with us today about your article COVID-19 and the Heart, which is now freely available on the Circulation Research webpage. Dr Eduardo Marbán: It's my pleasure to talk to you Cynthia. Dr Cindy St. Hilaire: First off, how are you and how are things at your hospital center in LA? Dr Eduardo Marbán: We seem to have dodged the bullet here in the sense that we were pretty progressive in terms of quarantine and stay at home orders. Given that, we seem to have peaked at a level that is very manageable in terms of our surge capacity. So, we feel for those who are worse off, but at least knock on wood here, we seem to be surviving so far. Dr Cindy St. Hilaire: Yeah, that's similar to how we are in Pittsburgh. We shut down about the same time that Philadelphia, who was already surging was shutting down. So, we are feeling safe but still prepared. So, I was extremely excited to read this article because as we know, cardiac injury is happening in between 20% to 30% of the COVID-19 patients and cardiac injury is also the cause of about 40% of the COVID-19 related deaths. So, my first question is, what are the types of cardiac injuries or events that you're seeing in these COVID-19 patients and are there any particular characteristics that the subpopulation of patients shares that's different from non-cardiac injury COVID patients? Dr Eduardo Marbán: What seems to be extremely common in COVID-19 patients is elevations of circulating biomarkers, things like troponin I, troponin T, BNP as an indicator of heart failure, but what's much less certain is whether these biomarker elevations have any clinical significance. At the level of isolated case reports, there's fulminant myocarditis, ventricular tachycardia, arrhythmias, occasional acute coronary syndromes, but there seems to be a disconnect between the almost ubiquitous nature of the circulating biomarker elevations and the relative rarity of clinical events. Dr Cindy St. Hilaire: So, do these patients, do a majority of them have a history of cardiovascular disease or is this all new developments? Do we know? Dr Eduardo Marbán: Underlying cardiovascular disease, diabetes, hypertension, and recently obesity and, of course age, have all been implicated as general risk factors for being critically ill with COVID, but there's no specific indication epidemiologically yet that those with underlying cardiovascular disease have a particular predilection to manifesting worse heart symptoms or signs during COVID-19. It makes sense that that would be the case, but so far, the epidemiology is somewhat more general. Dr Cindy St. Hilaire: When you were first writing this article, I'm sure between then and now we even have more epidemiological data points that are constantly changing. Dr Eduardo Marbán: Since the article was published online on April 7th, I've given four updated versions of the webinar to various audiences. Every time we do so, the slides need to change subtly. It's a very rapidly evolving field. Dr Cindy St. Hilaire: Yeah, that's amazing. In the first SARS outbreak, which was in 2002-2003, scientists discovered that this type of Coronavirus enters the cell by binding to angiotensin converting enzyme II as a receptor. So, ACE2 as it's called. It's not a receptor in the canonical sense of the word, but it's a cell surface enzyme and it's involved in the renin angiotensin aldosterone system, which regulates a handful of cardiovascular homeostatic processes and is quite frankly, rather complicated. So, I don't want to talk specifically about that, but I'm wondering if you could tell us a little bit about what ACE2 is, what cells it's found on, and what that might mean for the implications of this virus and its effects on the cardiovascular system? Dr Eduardo Marbán: Well as you correctly stated, ACE2 is central to cardiac physiology in the sense that it creates the bioactive form of angiotensin. In so doing, its regulation is central to that of blood pressure, human dynamics. What is less appreciated and to me was a bit of a revelation is the fact that it's expressed fairly richly on the surface of epithelial cells of the lung and the SARS-CoV virus family seems to have co-opted the presence of that in order to create a handy sort of hook to get into the cells in the first place. Whether there are broader ranging implications of ACE2 other than the particular mode of entry into the cell for a viral infection is a topic of great speculation at this point. Dr Cindy St. Hilaire: Yeah. In some of my preparation for this and also just my curiosity regarding this virus and the vascular system, when you look at things like the human protein atlas, you can see that ACE2 is highly expressed, not only on the lung epithelial like you say, but they're also expressed on cardiovascular cells in nearly all of the tissue. I'm thinking of cells like the smooth muscle cell and the endothelial cell. Is the virus binding to ACE2 positive cells part of the reason for the cardiac events or these cardiac events secondary to systemic toxicity? So, I guess the real question is, do we know anything about the direct versus the indirect effects of the virus on the heart? Dr Eduardo Marbán: No question in vitro that SARS-CoV can infect cardiac myocytes and most surely almost any other cell that expresses these two on its surface. In vivo, how frequently that happens as opposed to triggering secondary cardiac damage due to the systemic inflammation is uncertain, but I can tell you from the various case reports that have actually analyzed human tissue either at autopsy or an endomyocardial biopsy in cases of fulminant myocarditis, the frequency of direct viral infection seen either by culturing viral particles or more frequently by electron microscopy and visualization of inclusion bodies within cells points to perhaps a third of the cases being due to direct infection and two thirds of the cases likely being due to some bystander effect of systemic inflammation. Dr Cindy St. Hilaire: Interesting. So, are the phenotypes different between those patients where it seems to be direct versus indirect? Does the myocarditis appear similar or the cytokine profiles, anything like that? Dr Eduardo Marbán: There are too few patients to make really good conclusions about whether or not the phenotypes differ greatly when there's direct versus indirect cardiac involvement, but certainly from the literature as it exists now, there's no reason to believe that we could outsmart the clinical picture. They all look pretty much the same from the bedside. Dr Cindy St. Hilaire: So from the first SARS outbreak, do we know anything about the long-term effects of this type of viral infection on the cardiovascular system or on the heart specifically? Dr Eduardo Marbán: Yeah. COVID-19 of course the follow-up is limited to a few months since the first cases probably didn't emerge until late October early November and weren't really recognized as such until late '19 early 2020, but for SARS from the 2002-2003 epidemic, some of the long lasting sequelae are unanticipated and include hypertension, hyperlipidemia, pulmonary fibrosis, avascular necrosis. So, it seems that even when a patient is out of the woods, perhaps they're not really out of the woods in terms of long-term sequelae. We need to be watchful for long-term sequelae in COVID-19 survivors. They're going to be many more of them than there were from the SARS epidemic. Dr Cindy St. Hilaire: So, one of the things that's come out recently, which I've been really mulling about because my background is vascular biology and specifically smooth muscle cells and endothelial cells, but one of the findings is about the later stage or more sick patients. These are patients who are going on ventilators and about 50% of them going on the ventilators are dying and/or just not responding to ventilator therapy as doctors expect. So, just to give a little background about ventilators, they're normally used when a patient's blood oxygen level drops too low. So, normal levels are between 95% and 100%. However, patients with pneumonia or acute respiratory symptoms are put on ventilators sometimes when their oxygen drops below 90%, but some of the COVID-19 patients are exhibiting blood oxygen levels at 70% or sometimes even lower, but they don't have outward signs of distress and they can still hold conversations. So, I'm wondering if you can give me any insight into possibly what's going on there with the lens of vascular remodeling, what might be happening to the vasculature in the lung that is unique to this ventilator response and COVID response? Dr Eduardo Marbán: The observation you described is common that sometimes a patient will be profoundly hypoxemic but chatting away or surfing the internet as if nothing were happening. We're not used to seeing this in other cases of ARDS or viral sepsis where the patient usually is in extremis by the time the blood oxygen levels get that low. It begs the question as to whether perhaps there's something about the cerebral circulation, and this is complete and rampant speculation. Whether there's something about the cerebral circulation that makes it somewhat resistant to the effects of systemic hypoxia, perhaps there's a compensatory vasodilation that occurs that compensates for the otherwise deadly systemic hypoxemia. It would be quite interesting to monitor oxygen tensions within the cerebral parenchyma to test that, but all I can say with any certainty right now is that the clinical observation is robust. We see this not infrequently in patients who in the sort of clinical jargon have no right to look that good. Dr Cindy St. Hilaire: Yeah. Yeah. It's like your numbers, you really have those numbers? Yeah. There's just so many questions. It's really unprecedented. So, I guess we've been talking a lot about the disease itself and the symptoms and the pathogenesis, but I want to switch to ask about potential therapies. There's been several therapies that have been suggested by a variety of people and there's, I don't even know how many clinical trials. I looked a week ago and there's really a great response of pharmaceutical companies and university hospital systems trying what they can with the tools they have. So, things like antivirals, HIV protease inhibitors, inhibitory antibodies, and even antimalarial drugs have been suggested that they could possibly work. So, I'm wondering if you could give us some insight from a cardiovascular standpoint, what are the potential implications or potential adverse side effects of using these different therapies off label and what might that mean for the heart in addition to treating the viral infection? Dr Eduardo Marbán: You're correct in the explosion of clinical trials in this area or at least, clinical interventions. At our IRB, as of today, there are 56 active COVID protocols. Imagine nobody even cared about COVID until mid-February, right? Dr Cindy St. Hilaire: That's just at Cedars-Sinai. Dr Eduardo Marbán: Yeah. Now, we have 56 active protocols. So, not all of those are interventional. Some of them are epidemiological or biomarker studies, but still there's an incredible plethora. You're right, the approaches of targeted anything from the viral infection to the viremia to the downstream consequences of viral infection including the hyper inflammation and cytokine storm. The rationale for anti-malarials is actually fairly thin and resides on in vitro observations that actually were just from February that SARS-CoV-2 infection in vitro is somewhat retarded by exposure to hydroxychloroquine. This didn't come out of the blue. There had been an extensive literature and quite controversial literature, I should say, that anti-malarials might be useful in influenza and other infections. In a very general sense, there was a lot of hype created by early in vitro studies, which turned out to be neutral or in some cases even harmful clinically, but this has led to an almost universal adoption of hydroxychloroquine in patients with COVID-19 coupled sometimes with the antibacterial agent azithromycin for which the rationale is even thinner. There's no reason to believe that an antibacterial per se would help in a viral infection, but azithromycin is said to have antioxidant properties, which may or may not potentiate the effects of hydroxychloroquine, but for sure what they do together is prolong repolarization of the heart and lead to a clinical syndrome known as prolonged QT, which is a known substrate for toxic arrhythmias like polymorphic ventricular tachycardia. So, in prescribing some of these agents, one needs to weigh the uncertain benefits against the very certain risk that they entail. Dr Cindy St. Hilaire: Yeah. I think that's a really important point. I think one of the scary things that has the potential of happening during this crisis is too quick of a jump to conclusions. While there is a need for as rapid a response as possible, we still need to make sure that we're taking in all the scientific information we have and that that science is good and strong. I think one of the things that you mentioned in the Review is the lack of power in some of those initial anti-malarial studies. I think it's really important thing I want to emphasize that it's an emergency, but we still need to make proper good scientific decisions. Dr Eduardo Marbán: Well, one of the problems is that hydroxychloroquine and other agents in some cases, remdesivir and you know, you choose, have gotten so popular and hyped that there's almost no possibility of being an ethical clinical trial because the patients want to be on them. So, it may be easier in some settings than in others, but it's certainly not going to be a trivial thing to sort out the true risk benefit ratio of these drugs in this illness. Dr Cindy St. Hilaire: So right now, doctors and scientists, we're all in crisis mode, but once things settled down, we could really start to sit down and think about more mechanistic questions that might be able to be tested that will really help us flush out our understanding of COVID-19 disease pathogenesis and its effects on the cardiovascular system. So, what do you see after this initial crisis is under control, what do you see as the immediate next questions that basic scientists and translational scientists need to address that can help the next time that this comes again? Dr Eduardo Marbán: First of all, it's quite clear that we've all become consumed by COVID-19 and SARS-CoV-2. We can't think of anything else often. It's really hard to even focus on work from the laboratory that doesn't have to do with SARS-CoV-2 and COVID. It's so ubiquitous in public perception and the way we're living our lives that it just makes it incredibly difficult to think about anything else. I think there's going to be a correction in which we're going to get frankly tired of SARS-CoV-2 and COVID and want to think about other things, but among the lasting questions and the ones that will have greater biological merit above and beyond how to deal with this particular virus and this particular pandemic are the following. What is the role of ACE2 in human biology? Clearly here, there's an experiment of nature in which this surface enzyme has been co-opted for viral entry and a tremendous amount of speculation surrounds the question of whether high ACE2 values are protective and detrimental and ACE inhibitors and angiotensin receptor blockers might be detrimental or beneficial. All of these fundamental mechanisms need to be sorted out and now there's motivation to do so because of the epidemic. Some of this work is easier than others and those institutions that happen to have a BSL-3 level facility for being able to directly study the effects of the virus on various tissues should do so with alacrity because it's a limited resource right now where the number of questions really far exceed the ability to answer them just physically. Another question which I think is going to be motivated by our experience with COVID-19 is that of the mechanisms of cytokine storm and hyper thrombotic states. These are things that characterize the critically ill patient with COVID-19. Dr Cindy St. Hilaire: Can you just explain what is a cytokine storm? What does that exactly mean? Dr Eduardo Marbán: So, patients who are critically ill with COVID-19 manifest a late stage of the illness, which is often fatal, in which circulating levels of various inflammatory biomarkers, interleukin 6, C-reactive protein, ferritin being among them, but basically anything that goes up in an inflammatory state. And some of these appeared not to just be markers of inflammation. Something like C-reactive protein is probably just a biomarker of inflammation, but interleukin 6 for example, is a highly bioactive cytokine that itself probably causes tremendous tissue injury and there's some enthusiasm for the use of anti IL6 antibodies and anti IL6 receptor antibodies to treat the critically ill with some anecdotal dramatic success I should say. So perhaps the cytokine storm isn't just a marker of those who are critically ill, perhaps it's causative. If that presumption is real, then it makes good sense to target the cytokine storm, but from a scientific point of view, what causes it in the first place? How does a viral infection lead to massive production of cytokines and inflammatory biomarkers and how can that be mitigated? One of the ways of dealing with that is by understanding precisely how it happens in the first place and there's not that much literature on it. There's a recent study which I found quite provocative that glucose metabolism and the whole process known as O-GlcNAcylation might actually be a trigger in the production of cytokines during viral infections like COVID-19, but I think understanding how it happens will lead to much more targeted therapeutics and perhaps enable us to eventually divorce the infection from the overreaction. Really what's happening is friendly fire. The body's immune system is turning against itself in a sort of vain effort to control the virus. Sometimes the viremia is actually almost gone by the time that these inflammatory biomarkers increase, and the cytokine storm surges. Dr Cindy St. Hilaire: So, it's almost like the inflammatory response reaches some point beyond which it doesn't need virus anymore. It is just full force feeding forward and causing more damage by itself. Dr Eduardo Marbán: Yeah, exactly. It's almost as if there's an eroding cliff and even though the river may be back down to normal levels, the cliff is still unstable and the whole hillside could come crashing down. Dr Cindy St. Hilaire: Are there long terms effects of that? I wonder how long that would last after the infection or is it only during a viral titer in the system? Dr Eduardo Marbán: Well, you raised yet another interesting question to the extent that patients who have survived SARS- CoV-2 infection develop long-term sequelae, what's the mechanism of those long-term sequelae? Why should patients who are previously well develop hyperlipidemia and hypertension after the infection, if in fact they do, so are any of these related to micro thrombotic events? It's quite conceivable. Dr Cindy St. Hilaire: Great. Well, thank you so very much for taking the time to speak with me today. I don't think I found a ton of answers. I found a lot more questions, but hopefully as this develops and we get it under control, maybe we can talk again and talk about some of those new mechanistic findings and potential therapies. Dr Eduardo Marbán: Absolutely. You're welcome, and I hope you and all the listeners stay safe during this pandemic. Dr Cindy St. Hilaire: You too, and your clinical team. That's it for highlights from the May 10th and May 22nd Obesity Compendium issues of Circulation Research. Thank you so much for listening. Please check out the Circulation Research Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DscoverCircRes. Thank you to our guest, Dr Eduardo Marbán. This podcast is produced by Rebecca McTavish, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, your on-the-go source for the most up-to-date and exciting discoveries in basic cardiovascular research.  

  Vidcast:  https://youtu.be/UTAoMbd8BZ4   Interferon Alpha 2 Beta shortens persistence of CoVid19 and suppresses levels of the deadly immune mediators interleukin 6 and C-reactive protein.  University of Toronto investigators report that this interferon which curbed the SARS coronavirus some years ago now helps CoVid patients.   All 77 patients in the trial had moderate pneumonia not requiring intensive care.  Mean time to viral clearance for interferon-treated patients was 21 days versus 28 for the untreated.  Treated patients were also spared a toxic IL-6 spike  and enjoyed lower levels of C-reactive protein.   Let’s hope interferon alpha 2 beta turns out to be a universal coronavirus therapeutic.   https://www.frontiersin.org/articles/10.3389/fimmu.2020.01061/full Early    #covid #pandemic #interferon #il6 #creactiveprotein  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.25.061663v1?rss=1 Authors: Paige, C., Barba-Escobedo, P. A., Mecklenburg, J., Patil, M., Goffin, V., Grattan, D., Dussor, G., Akopian, A. N., Price, T. J. Abstract: Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female but not male mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling. SIGNIFICANCE STATEMENT: Females are more likely to experience chronic pain than males, but the mechanisms that underlie this sexual dimorphism are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice, where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that Prolactin receptor expression in Nav1.8+ neurons was necessary for hyperalgesic priming in female, but not male mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal prolactin receptor. Copy rights belong to original authors. Visit the link for more info

Brianne Barker returns to continue a discussion of the immune response to infection with SARS-CoV-2, including use of steroid, coagulation in some patients, cytokine storm, and vaccines. Hosts: Vincent Racaniello, Stephanie Langel, and Cynthia Leifer Guest: Brianne Barker Subscribe (free): iTunes, Google Podcasts. RSS, email Become a patron of Immune! Links for this episode IL6 as COVID-19 marker for severity (Med Mal Infect) How does COVID-19 kill? (Nature) SARS-CoV-2 protective immunity in macaques (bioRxiv) SARS antibody titers wane (J Immunol) Vaccine roundup (Lab Equip) Lung IgG in SARS injury (JCI Insight) Image credit Time stamps by Jolene. Thanks! Music by Steve Neal. Immune logo image by Blausen Medical. Send your immunology questions and comments to immune@microbe.tv

Daniel Griffin joins TWiV to update on the clinical situation, then we discuss a 382 nucleotide deletion in the SARS-CoV-2 genome, a scenario for emergence of the virus from a bat, followed by answers to listener email. Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, Rich Condit, Kathy Spindler, and Brianne Barker Guest: Daniel Griffin Subscribe (free): iTunes, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode 382 nt deletion in genome of SARS-CoV-2 (bioRxiv) Recombination and mutation leading to SARS-CoV-2 (bioRxiv) Letters read on TWiV 600 Timestamps by Jolene. Thanks! Intro music is by Ronald Jenkees. Send your virology questions and comments to twiv@microbe.tv

Daniel Griffin joins TWiV to update on the clinical situation, then we discuss a 382 nucleotide deletion in the SARS-CoV-2 genome, a scenario for emergence of the virus from a bat, followed by answers to listener email. Hosts: Vincent Racaniello, Dickson Despommier, Alan Dove, Rich Condit, Kathy Spindler, and Brianne Barker Guest: Daniel Griffin Subscribe (free): iTunes, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode 382 nt deletion in genome of SARS-CoV-2 (bioRxiv) Recombination and mutation leading to SARS-CoV-2 (bioRxiv) Letters read on TWiV 600 Timestamps by Jolene. Thanks! Intro music is by Ronald Jenkees. Send your virology questions and comments to twiv@microbe.tv

Doris Cully joins TWiV to discuss inhibition of SARS-CoV-2 in cell culture by ivermectin, followed by continuing analysis of the coronavirus pandemic caused by SARS-CoV-2 including COVID-19 in Nadia the tiger, and prediction of respiratory failure by levels of IL-6. Hosts: Vincent Racaniello, Alan Dove, Rich Condit, and Brianne Barker Guest: Doris Cully Subscribe (free): iTunes, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode Ivermectin inhibits SARS-CoV-2 in cell culture (Antiviral Res) Tiger at NY zoo positive for SARS-CoV-2 (NY Times) IL-6 level predicts respiratory failure in COVID-19 patients (medRxiv) Infection fatality rate for managing pandemic (virology blog) Image credit Timestamps by Jolene. Thanks! Intro music is by Ronald Jenkees. Send your virology questions and comments to twiv@microbe.tv

Doris Cully joins TWiV to discuss inhibition of SARS-CoV-2 in cell culture by ivermectin, followed by continuing analysis of the coronavirus pandemic caused by SARS-CoV-2 including COVID-19 in Nadia the tiger, and prediction of respiratory failure by levels of IL-6. Hosts: Vincent Racaniello, Alan Dove, Rich Condit, and Brianne Barker Guest: Doris Cully Subscribe (free): iTunes, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode Ivermectin inhibits SARS-CoV-2 in cell culture (Antiviral Res) Tiger at NY zoo positive for SARS-CoV-2 (NY Times) IL-6 level predicts respiratory failure in COVID-19 patients (medRxiv) Infection fatality rate for managing pandemic (virology blog) Image credit Timestamps by Jolene. Thanks! Intro music is by Ronald Jenkees. Send your virology questions and comments to twiv@microbe.tv

Nous sommes le mardi 7 avril, il est 18 heures, et le premier ministre britannique, Boris Johnson, est en unité de soin intensif...Le journal quotidien de la pandémie Covid-19 avec le Dr Jean-François LemoineLe billet du jour avec Thierry Borsa :• Le confinement, une contrainte acceptée mais difficile à vivreL'info scientifique du jour avec le Dr Jean-Paul Marre :• Les masques chirurgicaux réduisent la quantité de coronavirus dans les gouttelettes respiratoires et les aérosols pour les coronavirus• Les pays où on porte des masques seraient ceux où il y a le moindre nombre de cas de Covid-19 dépistés par habitantL'info pratique du jour :• L'élévation du taux d'IL-6 est étroitement corrélée à la survenue d'une forme grave de Covid-19, et c'est pour cette raison que des études anti-IL6 sont en cours dans la prévention du SDRA et le SDRAL'interview des experts du jour avec :• Le Dr Michelle Levy-Soussan, responsable de l’unité mobile d’accompagnement et de soins palliatifs à l'hôpital Pitié-Salpêtrière, à Paris, parle de son expérience dans un CHU qui est très concerné par la Covid-19 et ses formes graves• Le Pr Jean-David Bouaziz, dermatologue à l’hôpital Saint-Louis, à Paris, nous parle de signes cutanés particuliers observés désormais au cours de la Covid-19 Voir Acast.com/privacy pour les informations sur la vie privée et l'opt-out.

Brianne Barker joins Immune to discuss the immune response to infection with SARS-CoV-2, including immune respones, pathogenesis, immunopathology and more. Hosts: Vincent Racaniello, Stephanie Langel, and Cynthia Leifer Guest: Brianne Barker Subscribe (free): iTunes, Google Podcasts. RSS, email Become a patron of Immune! Links for this episode ACE2 in oral mucosa (I J Oral Sci) IL6 predictor of COVID-19 death (Int Care Med) Protective immunity to SARS-CoV-2 in nonhuman primates (bioRxiv) Antibody to SARS-CoV wanes (J Immunol) Image credit Time stamps by Jolene. Thanks! Music by Steve Neal. Immune logo image by Blausen Medical. Send your immunology questions and comments to immune@microbe.tv

A big message was sent that WE DO NOT WANT WAR WITH IRAN! On 1/5/2020 at Dandelion Fountain in Naperville, we listed to speakers and protested Trump's hostile international actions. This was Erica Bray Parker's speech who is a delegate candidate for Senator Elizabeth Warren in IL6 for President of the USA. Website -elizabethwarren.com Plans- elizabethwarren.com/plans/ How do you volunteer- elizabethwarren.com/join-us/ Local volunteer information email Linda at - Kmmlinda@aol.com Facebook - facebook.com/ElizabethWarren/ Illinois Facebook group - facebook.com/IllinoisforWarren/ Twitter - twitter.com/ewarren Instagram- instagram.com/ElizabethWarren/ Are you interested in attending or hosting an event - events.elizabethwarren.com/?questionnaire_state=hide

Matt Kalaycio, MD, of the Cleveland Clinic joins Blood & Cancer host David H. Henry, MD, of Pennsylvania Hospital, Philadelphia, to preview the potentially practice changing research that will be reported at the 2019 annual meeting of the American Society of Hematology. Plus, in Clinical Correlation, Ilana Yurkiewicz, MD, of Stanford (Calif.) University, addresses the isolation that comes from dealing with a serious chronic illness, especially around the holidays. *  *  *  Help us make this podcast better! Please take our short listener survey: https://www.surveymonkey.com/r/podcastsurveyOct2019 *  *  *  FDA approves atezolizumab combo as first line for advanced NSCLC Atezolizumab is a monoclonal antibody and is already approved for adults with metastatic NSCLC with disease progression. By Laura Nicolaides The Food and Drug administration as approved atezolizumab in combination with paclitaxel and carboplatin chemotherapy for first-line treatment of adults with metastatic, nonsquamous non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations.  *  *  *  ASH abstracts discussed in the podcast: Abstract 1: Post-transplantation cyclophosphamide after allogeneic hematopoietic stem cell transplantation: Results of the prospective randomized HOVON-96 trial in recipients of matched related and unrelated donors. Abstract 261: Superior survival with post-remission pediatric-inspired chemotherapy compared to myeloablative allogeneic hematopoietic cell transplantation in adolescents and young adults with Ph-negative acute lymphoblastic leukemia in first complete remission: Comparison of CALGB 10403 to patients reported to the CIBMTR. Abstract 322: Nonmyeloablative allogeneic transplantation confers an overall survival benefit with similar nonrelapse mortality when compared with autologous stem transplantation for patients with relapsed follicular lymphoma. Abstract 6: Mosunetuzumab induces complete remissions in poor prognosis non-Hodgkin lymphoma patients, including those who are resistant to or relapsing after chimeric antigen receptor T-cell therapies, and is active in treatment through multiple lines. Abstract LBA-5: Validation of BCL11A as therapeutic target in sickle cell disease: Results from the adult cohort of a pilot/feasibility gene therapy trial inducing sustained expression of fetal hemoglobin using posttranscriptional gene silencing. Abstract LBA-6: Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma: Primary analysis results from the randomized, open-label, phase 3 study Candor. Abstract 1588: A randomized trial of EPOCH-based chemotherapy with vorinostat for highly aggressive HIV-associated lymphomas: Updated results evaluating the impact of diagnosis-to-treatment interval and pre-protocol systemic therapy on outcomes. Abstract 940: Elucidating the role of IL6 in stress erythropoiesis and in the development of anemia under inflammatory conditions. Abstract 57: Patient harm from repetitive blood draws and blood waste in the ICU: A retrospective cohort study. Abstract 59: Impact of iron supplementation on patient outcomes in women undergoing gynecologic procedures: Systematic review and meta-analysis of randomized trials. Abstract 126: Polatuzumab vedotin plus obinutuzumab and lenalidomide in patients with relapsed/refractory follicular lymphoma: Primary analysis of the full efficacy population in a phase Ib/II trial. Abstract 168: Risk of hemorrhage in patient with polycythemia vera exposed to aspirin in combination with anticoagulants: Results of a prospective, multicenter, observational cohort study (REVEAL). Abstract 326: Safety and effectiveness of apixaban, LMWH, and warfarin among venous thromboembolism patients with active cancer: A retrospective analysis using four U.S. claims databases. Abstract 327: Safety and effectiveness of apixaban, LMWH and warfarin among venous thromboembolism patients with active cancer: A subgroup analysis of VTE risk scale. Abstract 566: Phase II study of oral rigosertib combined with azacytidine as first line therapy in patients with higher-risk myelodysplastic syndromes.   For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd Ilana Yurkiewicz on Twitter: @ilanayurkiewicz

Jane Ferguson:                Hello. Welcome to episode 33 of Getting Personal: Omics Of The Heart, your podcast from Circulation: Genomic and Precision Medicine. I'm Jane Ferguson. This episode is from October 2019. Let's get started.                                            First up is a paper from Sébastien Thériault, Yohan Bossé, Jean-Jacques Schott and colleagues from Laval University, Quebec and INSERM in Mont. They published on genetic association analyses, highlight IL6, ALPL and NAV1 as three new susceptibility genes underlying Calcific Aortic Valve Stenosis.                                            In this paper, they were interested in finding out whether they could identify novel susceptibility genes for Calcific Aortic Valve Stenosis, or CAVS, which is a severe and often fatal condition with limited treatment options other than surgical aortic valve replacement. They conducted a GWAS meta-analysis across four European ancestry cohorts comprising over 5,000 cases and over 354,000 controls. They identified four loci at genome-wide significance, including two known loci in LPA and PALMD as well as two novel loci, IL6 which encodes the interleukin six cytokine, and ALPL, which encodes an alkaline phosphatase. They then integrated transcriptomic data from 233 human aortic valves to conduct the transcriptome wide association study and find an additional risk locus associated with higher expression of NAV1 encoding neuron navigator one. Through fine mapping, integrating conservation scores, and methylation peaks, they narrowed down the putative causal variants at each locus identifying one snip in each of PALMD and IL6 as likely causal in addition to two candidates snips at ALPL and three plausible candidate snips in NAV1.                                            Phenome-Wide Association Analysis, or PheWAS of the top candidate functional snips found that the IL6 risk variant associated with higher eosinophil count, pulse pressure and systolic blood pressure. Overall, this study was able to identify novel loci associated with CAVS potentially implicating inflammation and hypertension in CAVS etiology. Additional functional studies are required to further explore these potential mechanisms.                                            Next up is a paper from Elisavet Fotiou, Bernard Keavney and colleagues from the University of Manchester. Their paper entitled Integration of Large-Scale Genomic Data Sources With Evolutionary History Reveals Novel Genetic Loci for Congenital Heart Disease explored the genetic etiology of sporadic non syndromic congenital heart disease using an evolution informed approach. Ohnologs are related genes that have been retained following ancestral whole genome duplication events which occurred around 500 million years ago. The authors hypothesized that ohnologs which were retained versus duplicated genes that were lost were likely to have been under greater evolutionary pressure due to the need to maintain consistent gene dosage. For example, as could occur when the resulting proteins form complexes that require stochiometric balance.                                            Thus, ohnologs may be enriched for genes that are sensitive to dosage. The group analyzed copy number variant data from over 4,600 non syndromic coronary heart disease patients as well as whole exome sequence data from 829 cases of Tetralogy of Fallot. Compared to control data obtained from public databases, there was evidence for significant enrichment in CHD associated variants in ohnologs but not in other duplicated genes arising from small scale duplications. Through this and various other filtering steps to prioritize likely variants, the group was able to identify 54 novel candidate genes for congenital CHD highlighting the utility of considering the evolutionary origin of genes in the search for disease relevant biology.                                            Next, we have a clinical letter entitled Pathological Overlap of Arrhythmogenic Right Ventricular Cardiomyopathy and Cardiac Sarcoidosis from Ashwini Kerkar, Victoria Parikh and colleagues at Stanford University. They describe a case of a 50 year old woman previously healthy and a long distance runner who presented with tachycardia. She was found to have normal left ventricular size but severe right ventricular enlargement and systolic dysfunction. Genetic testing using an Arrhythmogenic Right Ventricular Cardiomyopathy or ARVC panel identified a variant in DSG2. through cascade testing it was found that two of the patient's three children also carried this variant. The patient experienced worsening RV failure and subsequently underwent heart transplantation at age 55. Pathology of the heart showed evidence of cardiac sarcoidosis. There have been some previous reports of overlap in ARVC and cardiac sarcoid pathology but not in cases with a high confidence genetic diagnosis such as this one.                                            This case raises the possibility of shared disease mechanisms underlying ARVC and cardiac sarcoidosis and suggests that therapies aimed at immune modulation may also have utility in ARVC. However, further work is required to test this hypothesis. Our next paper is a perspective piece from Babken Asatryan and Helga Servatius from Bern University Hospital. In Revisiting the Approach to Diagnosis of Arrhythmogenic Cardiomyopathy: Stick to the Arrhythmia Criterion!, they outline the challenges in defining diagnostic criteria for a Arrhythmogenic Right Ventricular Cardiomyopathy or ARVC, given the variable presentation of the disease. Given recent advances in knowledge, particularly in recognizing disease overlap with Arrhythmogenic Left Ventricular Cardiomyopathy or ALVC and Biventricular Arrhythmogenic Cardiomyopathy, a new clinical perspective was warranted. The Heart Rhythm Society updated their recommendations this year to introduce a new umbrella term that better encompasses the spectrum of disease, Arrhythmogenic Cardiomyopathy or ACM. This recommends the arrhythmia criterion Should be used as a first line screening criteria for ACM.                                            This is a broad criteria and a definitive diagnosis of ACM requires exclusion of systemic disorders such as sarcoidosis, amyloidosis, mild carditis, Chagas disease, and other cardiomyopathies. Implementation of this new approach to diagnosis may require more extensive investigation of arrhythmias including the use of ambulatory ECG monitors or cardiac loop recorders. These changes may also affect who's referred for genetic testing, potentially shifting diagnoses towards genotype rather than phenotype based disease classifications. Despite challenges and adopting new approaches, it is hoped that these changes will ultimately serve to improve risk stratification and allow for improved disease management and intervention to prevent sudden cardiac death.                                            We end with a scientific statement chaired by Sharon Cresci and co-chaired by Naveen Pereira with a writing group representing the AHA Councils on Genomic and Precision Medicine, Cardiovascular and Stroke Nursing and Quality of Care and Outcomes Research entitled Heart Failure in the Era of Precision Medicine: A Scientific Statement From the American Heart Association. This paper provides a comprehensive overview of the current state of omics technologies as they relate to the development and progression of heart failure and considers the current and potential future applications of these high throughput data for precision medicine with respect to prevention, diagnosis and therapy of heart failure. They discuss advances in genomics, pharmacogenomics, epigenomics, proteomics, metabolomics, and the microbiome, and integrate the findings from this rapidly developing field as they pertain to new methods to diagnose, treat, and prevent heart failure.                                            And that's it for October. I hope to see many of you at AHA Scientific Sessions in Philadelphia in November and look forward to bringing you more of the best new science next month. Thanks for listening. This podcast was brought to you by Circulation: Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association 2019.  

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. Dr Greg Hundley:             And I'm Dr Greg Hundley, associate editor for Circulation, from the Pauley Heart Center at VCU Health in Richmond, Virginia. Well, Carolyn, our feature article, this issue reminds us of the importance of the physical exam in patients with heart failure and reduced ejection fraction involving those that were enrolled in the PARADIGM-HF. Remember a trial of sacubitril/valsartan versus ACE inhibition in those with a reduced ejection fraction? Can't wait to hear more of the discussion of the importance of that physical exam. Carolyn, how about you talk about your first article? Dr Carolyn Lam:                I will because this first paper reports a novel ventricular tachycardia or VT ablation strategy guided by a voltage independent mapping display during sinus rhythm. Dr Greg Hundley:             Well, Carolyn, since many of us don't do VT ablations every day, how about a little background on this one first? Dr Carolyn Lam:                Substrate modification during sinus rhythm is actually the mainstay ablation strategy for scar related VT. With the recent trend being more extensive ablation, aimed to homogenize the entire scar region. These authors are led by Dr Tung from the University of Chicago Medicine Center for Arrhythmia Care, and colleagues. They had hypothesized that a greater understanding of the nature and characteristics of the scar would be most prone to reentry, may actually improve the precision and yield of ablation. Now, they had previously demonstrated that sites critical for reentrant VT localized to regions of activation slowing during sinus rhythm or so-called deceleration zones rather than regions with latest activation. In the current study, they aim to prospectively assess the outcomes of VT ablation guided primarily by targeting these deceleration zones identified by propagational analysis of ventricular activation during sinus rhythm. Dr Greg Hundley:             Interesting. What did they find, Carolyn? Dr Carolyn Lam:                They studied 120 patients with scar related VT who are prospectively enrolled in the U Chicago VT ablation registry between 2016 and 2018, who underwent 144 ablation procedures for scar related VT. They performed high density mapping during baseline rhythm and identified the deceleration zones which all localized to successful termination sites in 95% of cases. The median total radio frequency application duration was 29 minutes to target the deceleration zone, representing ablation of 18% of the low voltage area. At a mean of 12 months, 70% freedom from VT recurrence was achieved with an overall survival rate of 87%. A novel voltage independent high-density mapping display may further identify the functional substrate for VT during sinus rhythm and guide targeted ablation thus obviating the need for extensive radio frequency delivery. Dr Greg Hundley:             Fantastic, Carolyn.                                                 Well, my first paper is from Professor Mark Nicolls from Stanford University. It's entitled Phenotypically Silent Bone Morphogenic Protein Receptor 2 or Bmpr2 mutations, that predispose rats to inflammation induced pulmonary arterial hypertension by enhancing the risk for neointimal transformation. While being the most common inherited risk factor for pulmonary arterial hypertension, Bmpr2 germ line mutations only result in disease in 20% of mutation carriers. A finding that suggest a second hit is required to elicit vascular pathology. Transgenic mouse models of Bmpr2 mutations were developed in this study to better understand the relationship between these phenotypically silent gene mutations and the predisposition to pulmonary arterial hypertension. Dr Carolyn Lam:                Huh. What did they find Greg? Dr Greg Hundley:             In this new two hit model of disease, Bmpr2 mutant rats subjected to pulmonary inflammation, developed severe pulmonary arterial hypertension with vascular remodeling and the pulmonary arterial endothelial cell transformation that occurred did so in three phases. An initial apoptosis phase induced by exogenous LTB4. Second, a proliferative phase relying on P38 mediated noncanonical TGF-beta signaling. And then finally a terminal inflammatory phase in which pulmonary arterial endothelial cells utilized the canonical TGF-beta pathway, expressed mesenchymal markers and produced LTB4, IL6 and NF-kappa beta signaling molecules. The clinical implications include that in phenotypically silent Bmpr2, haploinsufficient individuals, a second hit of pulmonary inflammation may put them at risk for subsequently developing pulmonary arterial hypertension. And this lung inflammation while usually self-limited may cause durable and inflammatory vascular lesions in these genetically susceptible patients. Dr Carolyn Lam:                Wow, that is super interesting. Thanks Greg for that great summary.                                                 Well, my next paper really looks at the temporal trends in survival after pediatric in hospital cardiac arrest in the United States. This is from Dr Holmberg from Beth Israel Deaconess Medical Center and colleagues who performed an observational study of hospitalized pediatric patients who received CPR from January 2000 to December 2018 and were included in the Get With the Guidelines resuscitation registry. Dr Greg Hundley:             Carolyn, what did they find? Dr Carolyn Lam:                They found that survival has improved for pediatric events requiring CPR in the US with a 19% absolute increase in survival for in hospital pulseless cardiac arrests and a 9% absolute increase in survival for non-pulseless events between 2000 and 2018. However, survival from pulseless cardiac arrest appeared to have reached a plateau following 2010. The increase in survival over time is reassuring and perhaps provides some evidence for the progress of quality improvement efforts. However, given the plateau and survival following 2010, there is a continued need for clinical focus and new interventions to improve outcomes of pediatric in hospital cardiac arrests. And Greg, are you now going to tell us what's in the mailbag? Dr Greg Hundley:             Absolutely Carolyn. Professor Wei, from Harvard, provides a new perspective on using the restricted mean survival time difference as an alternative to the proportional hazards model and hazard ratios for analyzing risk in clinical cardiovascular studies. In another article, Eric Peterson from Duke provides a white paper discussing randomized clinical trials versus EMR extracted data to inform new therapies in cardiovascular disease. And he really reviews what are the issues we need to overcome using these EMR strategies? And on my mind piece from Dr Glenn Levine from Baylor, discusses the role of psychological wellbeing as it relates to cardiovascular disease. And then we have a large series of letters in this issue.                                                 First, Otmar Pfister and Kari Nytrøen, each have letters regarding high intensity interval training. Dong-Vu Nguyen, asked for several points of clarification regarding the utility of BNP assessments in syncope and whether other metrics incorporating clinical information could be useful. There's a corresponding response from Christian Müller from the PRICIPLE study with great discourse. And then finally an important research letter from Dr Rodés-Cabau in Quebec, evaluates the left atrial occlude or thrombus occurrence among eight centers in Canada and in this letter provides data that suggests thrombi can occur in those that have implanted left atrial occluders and raises considerations for anticoagulation of these patients. Great set of letters in this issue of the journal. Dr Carolyn Lam:                Absolutely Greg and thanks for sharing that. Let's go onto our feature discussion. Dr Greg Hundley:             You bet.                                                 Welcome everyone to discussion of our featured article and today we have Senthil Selvaraj from University of Pennsylvania and our own Mark Drazner, associate editor at Circulation from the University of Texas Southwestern and we're going to be discussing some very interesting results regarding the physical exam as they've been generated from the PARADIGM heart failure trial. And remember that's a prospective comparison of an Angiotensin Receptor-Neprilysin inhibitor with an angiotensin converting enzyme inhibitor to determine the impact of those two therapies on all-cause mortality and also morbidity in heart failure. Senthil, welcome to this discussion. We're very excited to have the opportunity to discuss your article and I wonder before we get started, could you tell us a little bit about the background and the hypothesis for why you wanted to perform the study and then afterwards tell us a little bit about the study population and the methods. Dr Senthil Selvaraj:          I think the impetus for this study torn out of the fact that we do the clinical exam so often, and I think like many cardiology clinicians in the community, we perform this so often, but we don't know what the actual impact is of performing the clinical exam. What I wanted to understand and the primary motivation was to really understand what the change in the physical exam meant in terms of subsequent prognosis. Does decreasing congestion actually relate to improved cardiovascular outcomes? I think this is an area that is hard to study by randomized controlled trials. In my opinion I think there is not so much equipoise in performing a trial of decongestion versus no decongestion. I think this is sort of one way that we can understand epidemiologic methods, whether lowering congestion improve outcomes.                                                 I had a number of other interesting analysis. I think the first is we've had a number of studies that have evaluated the physical exam, but I think that an updated analysis in a population receiving contemporary management was particularly important, particularly given the fact that the risk rad versus insignificantly in the past couple of decades essentially related to improvements in therapy. The second is we formed the physical exam in conjunction with a number of other additional forensic markers in the use of validated risk scores that to understand those and have utility above and beyond this. For instance, can I just check a natural aside and will that be doing a physical exam. And I think while that's easier, I don't know that that necessarily is the right thing to do. And that was another motivation. Dr Greg Hundley:             What was your overall study design and your study population? Dr Senthil Selvaraj:          The overall study design was to use the PARADIGM-HF cohort. And in our analysis, we did a time updated analysis, which is different than many other analyses previously done. That means that every single point that a patient goes into a clinical trial visit, we updated their physical exam, possible because the study investigators did perform an exam at each of these visits. And so what we did was we used the physical exam and number of signs of congestion as the time bearing covariate and looked at its relationship to outcomes, but also just as importantly why might think decreasing congestion or changing congestion has really stuck out as very important about to want to feel better. And I anything quantifying that relationship while it's intuitive I think is also very important. Dr Greg Hundley:             And just remind us who's in PARADIGM heart failure? Well what was the study population? And just very quickly the randomization arms? Dr Senthil Selvaraj:          PARADIGM-HF was a randomized controlled international multicenter trial of patients with heart failure ejection fraction which has been defined in this study as less than or equal to 40%, near two, three or four symptoms, elevated natriuretic peptides, depending on the trial compared an angiotensin converting enzyme inhibitor and Angiotensin Neprilysin inhibitor to control valsartan. Dr Greg Hundley:             Tell us what were your study results? And how did they pertain to the outcomes that were gathered in PARADIGM-HF? Dr Senthil Selvaraj:          We first divided our cohort based upon the total number of signs and as might imagine increasing congestion was associated with a number of adverse clinical features. We then looked at the association between the number of signs and the efficacy outcomes, which included a primary composite outcome of time to heart failure, hospitalization as well as cardiovascular mortality and then we individually looked at those as well as all-cause mortality. And as we show in our paper, there was really a striking relationship between time updated times of congestion as well as all of the efficacy adjusted for baseline natriuretic peptides which are available in all of our participants in PARADIGM-HF as well as MAGGIC risk score and New York Heart Association class to get at the question of whether improving congestion, where the relationship congestion above and beyond symptoms is still valid.                                                 The other thing that we did is because we only looked at natriuretic peptides at baseline is that we've formed a sub study where we evaluated, since you had natriuretic peptides during follow-up as well at the one month visit and eight month visit and compare the utility of signs of congestion and outcomes and you can still see that there was a significant relationship in this sub analysis. The participants would complete NP data. We further looked at relationship and congestion and quality of life and there is a significant relationship such that for every sign of congestion that you decrease, there is a five-point increase in KCCQ, the quality of life score which some have considered to be a clinically significant increase in times of congestion.                                                 We also looked at the relationship between the treatment arm and reduction of congestion as sacubitril/valsartan was associated with significant reduction in clinical congestion, which has mirrored its impact on natriuretic peptides as well. And finally to understand whether reducing congestion was actually associated with improved outcomes, we entered both the baseline congestion and change of congestion into models that looked at the relationship with outcomes and found that change of congestion was a very strong predictor of outcomes even after baseline congestion, which we interpreted to mean that reduction in congestion was a mutable factor, and that reducing congestion is actually associated with improved outcomes. Dr Greg Hundley:             Signs of congestion on the physical exam, you had JVD, peripheral edema, rales, and then an S3 and so you're adding those up and making a score. And so when one of those particular findings dropped off in terms of score, that's what you're indicating by change in congestion, is that correct? Dr Senthil Selvaraj:          That's really correct. We analyzed this in two methods. The first is a dichotomous presence of a physical exam science. As you said, the presence or absence of JVD, the presence or absence of a DMO rales and an aspirate. The investigators also graded two of those signs of congestion, which included a DMN rale that we formed a complimentary analysis where we created a sign score where we gave partial credits to gradations of the physical exam and we saw very similar outcomes as well. Dr Greg Hundley:             Mark Drazner at UT Southwestern has done a lot looking at the importance of our physical exam and assessing patients with heart failure. Mark, how do you feel the results of this study compare with previously published works? Dr Mark Drazner:             Thanks Greg. First, always a pleasure to join you on this and I do want to congratulate Dr Selvaraj and his team on this outstanding paper to generate considerable enthusiasm among the editorial team and reviewers I'd say. It's a really interesting study for several fold and you've heard a lot of the important methods by Dr Selvaraj already. I would just highlight there've been a number of previous studies that have looked at markers of congestion from physical exam and showed that they had prognostic utility, but a major question that has been addressed to me personally and I think in the field, does that add any independent information beyond just sending BMPR natriuretic peptide level measurement?                                                 And this analysis here as you've heard, one of the big advances was that they were able to adjust for natriuretic peptide levels and showed that the exam or the markers of congestion did add independent prognostic information. I think that's an important step forward, as is bringing the relevance again about the markers of congestion and prognostic utility to patients being receiving the most modern-day therapy including ARNI therapy, which is unparalleled opportunity because of the PARADIGM trial to look at that question. I think those two are really set this paper. I think this is going to be a standard, this is the standard for assessing prognostic utility congestion in heart failure by far in the literature in my opinion. Dr Greg Hundley:             What we're saying is that our following the patients and identifying these physical exam changes during an initiation of ARNI therapy can be really helpful in determining that particular patient's long-term prognosis. Coming back to both of you, maybe first Mark and then we'll come back to Senthil, what do you see is the next study in this field? Both in terms of new therapies in heart failure and the relationship of physical exam and then also perhaps just briefly some thoughts on ARNI therapy. Dr Mark Drazner:             I think this paper highlights the incredible importance of congestion in modern day therapy. And there are a number of other studies that looked at this recently, including there's an analysis of TOPCAT preserved heart failure showing again congestion being linked to adverse outcomes. I think that question is resolved that even in modern day therapy. The next step in my opinion is to understand why clinical congestion, the pathway from clinical congestion to adverse outcomes. What are the links? Can we target those links to try to interrupt that cycle? And what is the most effective way to achieve decongestion? We heard that now ARNI appears to be a mediator of decongestion and we need more work on that I think. I would say looking at the pathway from congestion to adverse outcomes and then what is the optimal way to decongest our patients. Dr Greg Hundley:             Very good. Senthil, do you have anything to add to that? Dr Senthil Selvaraj:          I think that's great. I completely agree with Dr Drazner on this. I think one question would be to understand truly as Dr Drazner said, the optimal way to decongest patients and so for instance, the way that we have traditionally done this is by increasing diuretic. There are a number of experimental and novel ways that we can decongest patients. I think one unanswered question actually is does increasing a diuretic potentially at the expense of activating the renin angiotensin aldosterone access, actually afford benefit if you decongest patients. It's an analysis that I think is ripe and timely and not been adequately addressed. I think that that would be one potential way to go. And the second is, I think as you mentioned in clinical trials, I think clinical congestion may not be an outcome, a pre-specified outcome of course. But I do think that it is an important outcome aside from just looking at decreases in other surrogate markers such as natriuretic peptides. It's easy to perform. It's collected on many investigator visits during these trials and therefore these are ripe analyses. Dr Greg Hundley:             Listeners, we look forward to speaking with you next week and have a great week. Dr Carolyn Lam:                This program is copyright American Heart Association 2019.  

Olá ouvintes do AcademiaCast, neste episódio temos um convidado especial, o médico Dr. Mauricio Bezerra para falar sobre processo inflamatório do organismo. Leia o texto escrito por ele: Fisiologicamente os seres humanos iniciam um processo inflamatório crônico gradativo a partir dos 50 anos de idade. Essa elevação segue uma curva exponencial que vai até o limite de Hayflick que é de 120 anos. O processo inflamatório crônico representado principalmente pela elevação da interleucina 6 (IL6) é o grande responsável pelo aparecimento das doenças crônicas e degenerativas. Uma distinção tem que ser feita entre os dois tipos existentes de inflamação: aguda e crônica. Os sinais flogísticos (edema, dor, rubor, calor e perda de função) são a representação clássica do processo inflamatório agudo. O processo inflamatório agudo é fisiológico e ocorre imediatamente após uma lesão tecidual para iniciar um processo de reparo. Infelizmente o uso disseminado e indiscriminado de antiinflamatórios, anticoagulantes e antibióticos acaba por suprimir a inflamação aguda e estimular o processo inflamatório crônico. O processo inflamatório crônico iniciado precocemente diminui a qualidade e a expectativa de vida, acelerando o processo de envelhecimento. Através da mudança de hábitos alimentares, eliminação do sedentarismo e a utilização de vitaminas, fitoterápicos, antioxidantes e de sais alcalinos específicos trata-se a inflamação crônica de uma forma fisiológica, prevenindo o aparecimento de doenças e restabelecendo a alostase do organismo. Sites e Rede sociais: https://www.instagram.com/marcelofranco.edf/?hl=pt-br https://www.instagram.com/flavio_dias__/?hl=pt-br https://www.instagram.com/clinica_fit_/ https://clinicafit.com.br/ https://www.trainingforhealth.com.br/ https://www.minhamelhorformafisica.com.br/

  This month on the Discover CircRes podcast, host Cindy St. Hilaire highlights three featured articles from recent issues of Circulation Research and talks with Denisa Wagner and Nicoletta Sorvillo about their article on how PAD4 in blood promotes VWF strings and thrombosis. Article highlights: Goodyer et al: ScRNA-seq of the Cardiac Conduction System   Xiong et al: Chemotaxis Mediated Second Heart Field Deployment   Ranchoux et al: Pulmonary Hypertension and Metabolic Syndrome   Rühl et al. Thrombin/APC Response in FVL and FII 20210G>A   Mahmoud et al. LncRNA SMILR’s Mechanism and Therapeutic Potential   Transcript   Cindy St. H:                         Hi, welcome to Discover CircRes, the monthly podcast of the American Heart Association's Journal, Circulation Research. I'm your host, Cindy St. Hilaire, and I'm an assistant professor at the University of Pittsburgh. My goal as host of this podcast is to share with you some highlights from the recent articles published in the August 2nd and August 16th issues of Circulation Research. Cindy St. H:                         After I discuss some highlights, we'll also have an in-depth conversation with Drs. Denisa Wagner and Nicoletta Sorvillo, from Boston Children's Hospital and Harvard Medical School, who are the lead authors of one of the exciting discoveries from the August 16th issue. Cindy St. H:                         The first article I want to share with you today is titled Transcriptomic Profiling of the Developing Cardiac Conduction System at Single-Cell Resolution. The first author is William R. Goodyer, and the corresponding author is Sean Wu. They are both located at the Cardiovascular Institute and the Department of Pediatrics at Stanford University. Cindy St. H:                         Have you ever wondered how your heart beats, and why there's always this glub-glub pattern, and where did it come from? How is the heart able to initiate that pattern, from cells that don't contract to cells that contract? Well, the beating of the heart is regulated by what's called the cardiac conduction system, and this is an area in the heart of specialized cells, and these cells establish the rhythmic beating by coordinating the contraction of the chambers of the heart. Cindy St. H:                         There's several components to the CSS. The sinoatrial node acts as the pacemaker in the right atrium. The arterial ventricle node is the electrical relay that slows down the pulse from the SA node. A His bundle helps to transmit those impulses, and the Purkinjie fibers are the terminus of the electrical signal. Between all of these different components are a heterogeneous population of what are called transitional cells. There are several studies that have linked these somewhat amorphous or heterogeneous transitional cells to different arrhythmic disorders. Cindy St. H:                         For the normal function of the heart, all of these parts must come together, and when they don't, there's severe clinical manifestations such as arrhythmias, like I said, but also you can get decreased cardiac output and even sudden cardiac death. While important, the cells of the CSS are rather elusive, and that's because they're in a relatively small number compared to the rest of the cells in the heart, and there also aren't very clear markers to identify the cells in the CSS. Cindy St. H:                         To address this, Goodyer and colleagues harvested cells from embryonic mouse hearts and performed single-cell RNA sequencing on 22,000 individually barcoded cells. What they were looking for is learning what type of cells they are, but more importantly, they had the goal of identifying what these elusive transitional cells are, and can we find a marker for these cells to study them? And in some, yes. Together, the sequencing and spatial data provided gene expression atlas of the mouse CSS. Hopefully, this atlas will guide future studies into the essential electrical system that regulates the heartbeat. Cindy St. H:                         The next article I'd like to highlight is titled Single-Cell Transcriptomics Reveals Chemotaxis-Mediated Intra-Organ Crosstalk During Cardiogenesis. We're really going to hit you over the head with some single-cell transcriptomics in this month's podcast. The first authors of this article are Halqing Xiong, Yingjie Lou, Yanzhu Yue, Jiejie Zhang and the corresponding author is Aibin He and they're all from the Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine and the Peking-Tsinghua Center for Life Sciences, all at Peking University in Beijing, China. Cindy St. H:                         During development, the mammalian heart originates from two distinct areas in the early embryo and they're called the first heart field and the second heart field. Progenitor cells from these regions give rise to very different structures. From the first heart field comes the atria and the left ventricle, and the second heart field forms the right ventricle and the outflow tract. While we know the outcomes of these different developmental layers, a full understanding of how the first and second heart fields are regulated and how they actually interact with one another is actually lacking a lot of detail and we're not exactly sure how those structures can influence one another. Cindy St. H:                         So to learn more, Xiong and colleagues utilized two different murine models that were engineered to label cells coming from either the first or second heart fields red, and by labeling these cells red, it allows for their very pure isolation and then downstream studying at the single-cell level. So from each of these two models, they collected about 600 red-labeled cells and they collected these cells at four different time points, that were essentially at 12 hour intervals, and they did this starting at embryonic day 7.5, and that's because that's the time point in the mouse where these second and first heart fields are starting to develop. Cindy St. H:                         What they found, by using single-cell RNA sequencing, is that the first heart field cells differentiated into cardiomyocytes, in what they called a gradual, wave-like manner, while the second heart field cells differentiated in what they referred to as a more stepwise, defined pattern. The team also found high expression of migration factor MIF in first heart field cells and they found MIF's receptor CXCR2 in the second heart field progenitor cells. This suggests that perhaps the first heart field cells could regulate the migration of the second heart field cells. Sure enough, blocking MIF- CXCR2 interaction in cultured mouse embryos prevented second heart field cell migration and also prevented normal development of the right ventricular outflow tract structures. So together these results provide insight into both normal heart development and also suggest what might go awry in certain congenital heart malformations. Cindy St. H:                         The next paper I want to highlight is titled Metabolic Syndrome Exacerbates Pulmonary Hypertension due to Left Heart Disease. The first author is Benoit Ranchoux and the corresponding author is Francois Potus, and they are from the Pulmonary Hypertension Research Group at Laval University in Quebec City in Quebec, Canada. The disease pulmonary hypertension can arise from a number of causes, but one of the main drivers of what's called group two pulmonary hypertension is left heart disease. Left heart disease itself is caused by several conditions, such as diastolic dysfunction, aortic stenosis, which is a disease that I study, or mitral valve disease. All of these pathologies result in the left heart not beating efficiently or exerting too much energy. Cindy St. H:                         More than half of all group 2 PH patients also have metabolic syndrome, and metabolic syndrome is a condition that is ever increasing in the modern age, especially in America, and it's characterized by obesity coupled with pathology such as dyslipidemia, type 2 diabetes and high blood pressure. Metabolic syndrome is also marked by elevated levels of the inflammatory cytokine IL6. Rat studies have shown that IL6 can induce proliferation of the pulmonary artery smooth muscle cells and consequently, pulmonary hypertension. Cindy St. H:                         In this study Ranchoux and colleagues pulled together all these different pieces in a rat model and essentially want to test left heart disease coupled with metabolic syndrome coupled with does pulmonary hypertension happen or get worse? What they found was really interesting. Left heart disease was induced in a rat model using super coronary aortic banding and then metabolic syndrome was induced with a high fat diet feeding, or with treatment with Olanzapine, which is a second generation anti-psychotic agent, and it's known to induce metabolic syndrome not only in rats, but also in humans. The data from this paper show that inducing metabolic syndrome in rats coupled with left heart disease resulted in elevated IL6 levels and also greatly exacerbated pulmonary hypertension. Cindy St. H:                         Digging into this mechanism, they found that inhibition of IL6, using either an anti-IL6 antibody or by reducing IL6 secretion from macrophages, using the diabetes drug Metformin, ameliorated the pulmonary hypertension in the rats. They then went on and looked at human samples and they found that IL6 was higher in the lungs of pulmonary hypertension patients and that this IL6 could induce proliferation of human pulmonary artery smooth muscle cells. So together these data suggest that the observation in rats holds true for humans, but further goes on to suggest that perhaps Metformin, which is a well-known, well-used diabetic drug, could perhaps be used for the potential treatment of Group 2 pulmonary hypertension patients.   Cindy St. H:                           In the August 16th issue, we have an article titled Increased Activated Protein C Response Rates Reduce the Thrombotic Risk of Factor V Leiden Carriers but not of Prothrombin 20210G>A Carriers. That is some title. The first authors are Heiko Rühl, and Christina Berens, and Dr Rühl is also the corresponding author, and they are at the Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, in Bonn, Germany. Genetic studies have found two mutations that convey particularly increased risk for venous thrombo-embolism, and VTE is also more commonly referred to as deep vein thrombosis. These mutations are called factor five Leiden mutations, or FVL, and the prothrombin 20210G>A mutation we're just going to call F2. Interestingly, the penetrance of these mutations, or how likely they are to exhibit a phenotype, is variable. Some individuals with mutations never experience deep vein thrombosis, while others experience multiple episodes. Cindy St. H:                         As a group, the FVL carriers produce a higher than normal level of an anticoagulation factor called APC, or activated protein c. They also produce high levels of the pro-coagulation factor thrombin, and the authors of this study wondered if it was the balance, or rather perhaps an imbalance, of these factors that could explain the phenotypic variations in the patients that harbor the same mutation. To test this, they collected 58 patients. 30 were FVL and 28 were F2 carriers, and they injected these patients with clotting factors and examined their response rates. In both of the groups, about half of the individuals had no history of deep vein thrombosis, while the other half had had at least one episode. Cindy St. H:                         The team found that while both types of mutations were associated with increased APC and thrombin levels after coagulant injection compared with a control group, in the FVL group lower APC levels correlated with a much higher risk of deep vein thrombosis. In other words, the FVL carriers who had never experienced deep vein thrombosis produced higher levels of APC. Translating this to the clinic, perhaps APC testing could help identify individuals who are carriers of the FVL mutation and determine which of them are at higher risk due to lower levels of APC. Cindy St. H:                         The last paper we're going to highlight before switching to our interview is titled The Human- and Smooth Muscle Cell Enriched lncRNA, SMILR, Promotes Proliferation by Regulating Mitotic CENPF mRNA and Drives Cell Cycle Progression Which Can Be Targeted to Limit Vascular Remodeling. Now that is a crazy title! We’ve got to limit these names here this is difficult. The first authors are Amira Mahmoud and Margaret Ballantyne and the corresponding author is Andrew Baker, and they're all from Queens Medical Research Institute, BHF Center for Cardiovascular Sciences at University of Edinburgh in Edinburgh, UK. Cindy St. H:                         Before we dive into this article, I think it's important that we give a quick explanation of what is a lncRNA? lncRNA, or L-N-C RNA, stands for long non-coding RNA, and these are described as being transcripts which are made into RNA that are in lengths exceeding 200 nucleotides. So that differs them from micro RNAs or peewee RNAs or snRNAs, and they are classically or, I guess originally, considered not to be translated into protein. However, I think now more and more studies are finding that perhaps they are made into peptide sequences. However it's not fully clear what the function of those sequences are. Similar to micro RNAs, they also harbor regulatory functions that can control cellular functions by helping to fine tune the regulation of gene transcription and translation. Cindy St. H:                         Largely speaking, vascular smooth muscle cells are quiescent, but they can be stimulated to proliferate and migrate following injury to the vessel wall. While such activation of smooth muscle cells is essential for wound healing, these same processes are operative in vascular disease or after a cardiovascular procedure. Often what happens is an excess of proliferation of the smooth muscle cell wall can lead to dangerous occlusion of the blood vessel. The long non-coding RNA, SMILR, was recently identified as a promoter of smooth muscle cell proliferation and now in this article, Mahmoud and colleagues have defined its mechanism of action. Through transcriptome analysis of human smooth muscle cells, in which the levels of SMILR were either modulated to be increased or suppressed, the team found that lncRNA regulated expression of several genes involved in mitosis, or cell division. Furthermore, RNA interaction experiments revealed that the messenger RNA encoding the mitotic centromere protein, CENPF, was a direct interaction partner of SMILR. So just like the suppression of SMILR, the inhibition of CENPF resulted in reduced mitosis of the smooth muscle cells. Cindy St. H:                         The team then went on to show the inhibition of SMILR via RNA interference could block the smooth muscle cell proliferation ex-vivo, and they did this using intact sections of human saphenous vein. These results suggest that targeting this lncRNA could be a potential clinical treatment in situations where vessel occlusion is at risk. Cindy St. H:                       Okay, so now we're going to switch and have our interview with Drs Denisa Wagner and Nicoletta Sorvillo, and we're going to discuss their paper entitled Plasma Peptidylarginine Deiminase IV Promotes VWF-Platelet String Formation and Accelerates Thrombosis after Vessel Injury. Thank you Drs. Wagner and Sorvillo for joining us today. I think a funny thing is that between Nicoletta in Switzerland, me and you on the East coast and my producer on the West coast, I think we're spanning about nine hours of time zones here. Thank you all for taking the time, whatever time of day it is, wherever you are. Dr Wagner:                         Thank you. Cindy St. H:                         I was wondering, Denisa, if you could please introduce yourself and tell us a little bit about your background. Dr Wagner:                         I am a vascular biologist. I was always interested in platelets, endothelial cells, and leukocyte. I started with a background of von Willebrand factor research. Von Willebrand factor is the most important adhesion molecule for platelets and it is stored in endothelial cells as we have found very early on, in an organelle called Weibel-Palade bodies. So my work on this paper is actually related to the first observation I ever made scientifically of showing that von Willebrand factor is released from endothelium. Cindy St. H:                         Wow, that's wonderful. And Nicoletta, could you please introduce yourself and tell us a little bit about your background? Nicoletta:                            I'm Italian, I studied in Italy and I did my PhD in the Netherlands, and I've always worked on inflammation and thrombosis during my PhD. One of the major proteins I was working on is ADAMTS13. That is again a protagonist of our paper. Then I moved to Boston, where I had the pleasure to be able to work in Denisa Wagner's lab, and there I continued working on inflammation and ADAMTS13 and now currently I moved here to Bern and I'm bringing my expertise here, but I moved a little bit towards ischemia and reperfusion injury and transplantation. Cindy St. H:                         Interesting. Wow. Denisa, I want to circle back to this factor being one of the first findings that you worked on. How does it feel to still be working on it? Is it still exciting? Dr Wagner:                         It is nice and it's refreshing to come back to it. I did a lot of stuff in between. We did a lot of adhesion molecule work, leukocyte rolling. We made the early knockouts like b-selectin, p-selectin, and von Willebrand factor knockout as well. So it's fun. And by the way, since Nicoletta said that she was Italian, I am originally Czech, from Prague. Cindy St. H:                         Interesting. I did not know that. And actually, Denisa, I don't know if you remember, but when I was a graduate student in Katya Ravid’s lab, we collaborated with you to use some of this intravital imaging on one of our JCI papers. Dr Wagner:                         Oh right, right. I was wondering where I knew your name from. That's funny. Cindy St. H:                         Yes. Yeah, yeah. So it's wonderful to speak to you again. Really I wanted to interview you because I loved this paper, not only because it was a really interesting mechanism that actually I wasn't very well aware of, this citrullination and also because of the beautiful intravital imaging you could do and then link it to patient disease states. Maybe you can start by telling me what's the clinical unmet need or the question that your paper was trying to address? Nicoletta:                            So Denisa Wagner's lab always has worked on neutrophils and NETs and it has been shown that these NETs are involved in thrombosis. So we were curious what happens when even the enzyme that is important to make these NETs, this extracellular DNA, does when it's in the circulation. And this enzyme is of course PAD4 and it is known that it can modify our [inaudible] residues on protein through this process of citrullination. So we went to see if it could modify plasma proteins and as Denisa already said, an important molecule that initiates thrombotic processes is vWF that can be released during inflammation or when there's a damage to the endothelium .  So we went to see what happens if the enzyme that is involved in removing this vWF that is ADAMTS13 happens if it gets modified by this enzyme path. So our question was more like what happens if you have the release of an enzyme that is normally intracellular? What would happen if it gets outside of the cell? Cindy St. H:                         Interesting. So before we get too deep in the weeds, what is citrullinization and why is it important? What do these modifications do? Nicoletta:                            It changes the charge of a protein. It goes and modifies arginine, and it transforms it into citrulline. It changes the charge of a protein and therefore you can imagine if you change a charge of protein it can change even the structure of a protein and if you change the structure then you can change the function. So this is what this modification can do. Cindy St. H:                         And that's what it's doing on the ADAMTS13? It's essentially altering or inhibiting its function? Nicoletta:                            Yes. What we saw is that we can find these citrullinated residues on ADAMTS13 and we identify them by mass spectrometry and then we saw that if it is modified by citrullination, it loses its activity so it doesn't function anymore. Cindy St. H:                         Interesting. Very neat. Could you talk a little bit about the process of where this is happening naturally and where it goes wrong in a diseased state such as either sepsis or aging or just general clotting? Dr Wagner:                         These neutrophil extracellular traps are generated often more during a disease state when there is either an infection or exacerbated inflammation that would be like in sepsis or for example, in a metabolic disorder like diabetes. So there is a lot more of them being generated. Also, for example, in diabetes, PAD4 is elevated inside the neutrophil four-fold. If it's released from diabetic neutrophils , then there would be really a lot more of it. And in aging also, then a NETosis becomes much more prominent. We have done this only with mice, but I believe that it will be also, unfortunately, the case with humans that old mice make a lot more NETs than young mice. Therefore this is relevant to look. Since thrombosis increases both with aging, the incidence of thrombosis, thrombosis increases with a disease like diabetes or in sepsis, you will have micro thrombosis. We thought it would be interesting to study those processes as well, then. Cindy St. H:                         That's really neat. One of the techniques that you utilize heavily in this paper and several of your papers that I'm familiar with is this intravital imaging or intravital microscopy. Just so people can get a sense of what it is you're actually doing, could you maybe describe what that experiment is? Maybe Nicoletta, you could describe that for us? Nicoletta:                            During intravital microscopy, we are able to image in vivo, a vessel in a live mouse. And in this case we use mice and we can label leukocytes and platelets and then look at them in the vessel in vivo and you can then look for a thrombus forming or you can look at the [inaudible 00:23:43] already had leukocyte rolling and you can see what is happening inside the vessel during a proper blood flow and you can damage the vessel in some cases. In our case, in our paper, we do a ferric chloride injury where we damaged the vessel with ferric chloride and therefor you initiate a thrombus development and you can visualize it in vivo and real time. Cindy St. H:                         Excellent. Yes. And hopefully our listeners will look and see the beautiful pictures because those are some serious clots you get forming in the vessels. Yeah. Yeah. And so the other thing that you did was confirming the modification on ADAMTS13, you use mass spectrometry. How difficult was it to confirm that what you thought was happening was happening using that technique? Nicoletta:                            It was very difficult and challenging, I have to say. Dr Wagner:                         See, I would love to hear more about it because you often read, Oh, then we did mass spec and we got this beautiful whatever. Could you tell us a little bit about the struggles? Nicoletta:                            It was quite a struggle. I mean I think trying to identify such a modification that is very, first of all, novel and it changes the math only of one thousandth it's very difficult. To identify you can confuse it with a deiminasion again because of the increase of mass is the same. And another problem was that ADAMTS13, our plasma protein, is low abundance in plasma compared to other plasma proteins like Fibrinogen, that is very, very much abundant. It was a challenge for this reason. So trying to pinpoint out a small, tiny modification already in a protein that is not so abundant in plasma and therefore we have to use this probe, this Biosyn PG program. And we did this in collaboration with Paul Thompson's lab and we were able to then fish out what was modified by the citrullination, but it was very challenging. We tried several different types of techniques that were different types of approaches before being able to show that in vivo. So in human samples we can find this modification. Dr Wagner:                         Nicoletta grew a lot of gray hair during that period. (laughs) Dr Wagner:                         It took us about a year to figure out how we could detect it in vivo because also some antibodies to ADAMTS13 don't work so well. It's a minor protein, but she figured it out. Cindy St. H:                         Wow. That's amazing. Well, congratulations on that. That's excellent. I guess what I'm wondering now is what are the next steps and what might your findings mean in terms of future potential therapeutic options or treatment strategies for different detrimental thrombotic events? Dr Wagner:                         I think what we have really verified that the PAD4 remains active when it circulates in circulation, when the release, and there are several diseases in which PAD4 levels were found to be elevated, like rheumatoid arthritis and what it means in general. That is PAD4 is actually causing havoc. It is citrullinating probably quite indiscriminately. Several proteins may be finding the exposed parts. Maybe it could have some binding sites, but I think it just affects proteins in general and for some of them like, ADAMTS13, this had a very detrimental effect. So in diseases where there is a lot of PAD4, one has to worry about the consequences of citrullinating things and perhaps spot for inhibitors should be used. What do you think, Nicolleta? Nicoletta:                            I totally agree with you. Yes, I totally agree. I mean PAD4 outside the cell could be dangerous, of course. However, we never know if there's something good that it can do that protects by citrullinating proteins so there's so much more to discover about extracellular PAD4 and its effect on the environment. Dr Wagner:                         However, Nicoletta when she wrote a paper at the end she decided to talk about ADAMTS13 as a therapeutic because both she and I, we are convinced that ADAMTS13 it's a possible future therapeutic and it's already given to patients who are lucky in ADAMTS13 and may be given to patients who have thrombotic events in the future, like stroke or myocardial infarction. And these situations are highly pro-inflammatory. Therefore, we would anticipate that in these situations, NETs, and we know NETs are released and therefore, what Nicolleta suggests at the end, is that introducing together with ADAMTS13 an inhibitor of citrullination would be a good thing so that the protein, the ADAMTS13, remains active in circulation. Cindy St. H:                         Wow. So a two-hit strategy. I mean I can think of a handful of potential diseases this would be good for. You know, patients with sickle cell, there's a lot of NETs released then thrombotic events or even stroke. I mean, do you see that this is a potential mechanism that's common to all thrombotic disease or just kind of specific subsets? Nicoletta:                            All is a big word I think, but I think that there are many disorders where together with a thrombotic event, you can find also low levels or low activity of ADAMTS13 and in many of these disorders, nobody knew really why you have a reduction of ADAMTS13 activity, what is happening? Why do you lose this ADAMTS13? What we believe, but of course further studies are needed, is that maybe in these disorders, what is causing the loss of ADAMTS13 is this release of PAD4 because in stroke or in some DIC sepsis, you can find patients or many patients who do have low levels of ADAMTS13 activity and we believe that it's due to maybe citrullination by PAD4. So in that case, I agree with you maybe then that this therapy can be used in different thrombotic events as you suggested. Cindy St. H:                         So what does PAD4 normally do when it's intracellular? What is its, I guess healthy role, in a cell, if it has one? Nicoletta:                            So what is known now is that it really regulates transcription. So that's very important because it citrullinates transcription factors to facilitate transcription. And what Denisa Wagner's lab has identified is that it's extremely important to form these NETs because it citrullinates histone and allows the unraveling of the chromatin and then the NET release. However, it's extremely interesting. We are very interested to understand what else does it do within the cell. Cindy St. H:                         Interesting. That is so neat. I love this story. Dr Sorvillo and Dr Wagner, thank you so much for joining us and congratulations again on a wonderful paper. Dr Wagner:                         Thank you. Nicoletta:                            Thank you for having us and inviting us. Thank you. Cindy St. H:                         So that's it for the highlights from our August issues of Circulation Research. Thank you for listening. This podcast is produced by Rebecca McTavish and edited by Melissa Stoner and supported by the editorial team of Circulation Research. Copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Cindy St Hilaire and this is Discover CircRes, your source for the most up-to-date and exciting discoveries in basic cardiovascular research.