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2 episodes with il1
2 episodes with il1
3 episodes with il1
2 episodes with il1
Eno is joined by Eric Samulski of Rotoworld to talk about a busyyyy weekend of news. A lot of call-ups, injuries and moves this weekend. Also, they talk about where the money went in some of the moves of the weekend.Rundown4:57- Jac Caglianone called up by KC9:40- Corbin Burnes is hurt14:57- Mookie Betts fractures toe20:54- Varsho & Santander on the IL for Toronto24:27- Mick Abel is back for Philly28:15- Eovaldi heads to the IL35:20- Yordan Álvarez return delayed43:45- Coby Mayo gets called back up47:10- Cole Young called up by Seattle56:05- Possible moves for the Giants?57:15- Rockies make a move at 1B58:12- Jobe heads to the IL1:00:14- Where the Money WentFollow Eno on Bluesky: @enosarris.bsky.socialFollow DVR on Bluesky: @dvr.bsky.sociale-mail: ratesandbarrels@gmail.comJoin our Discord: https://discord.gg/FyBa9f3wFeSubscribe to The Athletic: theathletic.com/ratesandbarrelsHosts: Eno SarrisWith: Eric SamulksiExecutive Producer: Brian Smith Hosted on Acast. See acast.com/privacy for more information.
Go to http://shadyrays.com and use code TALKIN for 35% off polarized sunglasses.Download the DraftKings Sportsbook app and use promo code JMBASEBALLCorona. La Playa Awaits. Be sure to get yours athttps://OrderCorona.comUse code TALKIN2025 for 10% off your next SeatGeek order*: https://seatgeek.onelink.me/RrnK/TALK.... Sponsored by SeatGeek. *Restrictions apply. Max $20 discountCoach Trev and Talkin' Jake talk about how the Dodgers just keep coming back and winning, what's going on with Juan Soto, what the Blue Jays getting back to .500 means and more!0:00 Intro2:40 NL Burn6:00 NL Standings8:30 Diamondbacks / Dodgers13:00 Phillies / Rockies14:00 Tigers / Cardinals17:20 Royals / Giants20:10 Reds / Pirates21:45 Cubs / Marlins23:10 Orioles / Brewers24:10 Braves / Nationals24:40 AL Burn28:36 AL Standings31:10 What's up with Juan Soto?33:40 Mets / Red Sox37:20 Rangers / Yankees38:40 Padres / Blue Jays44:00 Angels / A's48:10 Guardians / Twins49:40 Astros / Rays54:00 Standout Performances1:04:00 En Fuego1:10:00 Batters who are struggling1:12:40 Heading to the IL 1:13:30 Back from IL1:14:11 Awards1:25:00 Jake's in on Mariners in the West
Use code TALKIN2025 for 10% off your next SeatGeek order*: https://seatgeek.onelink.me/RrnK/TALKIN2025. Sponsored by SeatGeek. *Restrictions apply. Max $20 discountDownload the DraftKings Sportsbook app and use promo code JMBASEBALLCorona. La Playa Awaits. Be sure to get yours athttps://OrderCorona.comBook your next trip at https://www.bestwestern.com Coach Trev and Talkin' Jake talk about how awesome Rivalry weekend was, Jose Alvarado getting busted for PED's, Angel's sweep of the Dodgers and more! 0:00 Intro2:00 AL Burn7:15 AL Standings8:30 Astros / Rangers13:44 Mets / Yankees19:00 Nationals / Orioles23:05 Cardinals / Royals27:30 Braves / Red Sox30:35 Tigers / Blue Jays36:00 NL Burn42:00 NL Standings43:15 Mariners / Padres47:39 A's / Giants50:45 Pirates / Phillies51:00 Jose Alvarado suspended55:00 Twins / Brewers1:00:05 Guardians / Reds1:03:30 Standout Performances1:08:50 En Fueego1:14:47 Batters who are struggling1:17:30 Going on the IL1:19:50 Awards1:34:20 Austin Barnes and Chris Taylor released
Download the DraftKings Sportsbook app and use promo code JMBASEBALLBook your next trip at https://www.bestwestern.comCorona. La Playa Awaits. Be sure to get yours athttps://OrderCorona.com.Use code TALKIN2025 for 10% off your next SeatGeek order*: https://seatgeek.onelink.me/RrnK/TALKIN2025. Sponsored by SeatGeek. *Restrictions apply. Max $20 discountCoach Trev and Talkin' Jake break down the latest series throughout MLB including, if the Reds are a true contender, the Padres being the scariest team in baseball, can Aaron Judge hit at a .400 average throughout the season and more!0:00 Intro3:00 NL Burn5:00 NL Standings7:20 Diamondbacks vs Mets13:00 Cardinals vs Reds18:13 Cubs vs Pirates19:18 Nationals vs Phillies22:00 Giants vs Padres26:33 AL Burn30:00 AL Standings34:00 Royals vs Rays37:25 Twins vs Guardians39:45 Jose Ramirez is insane 250/25041:25 Tigers vs Astros46:40 A's vs Rangers49:00 Yankees vs Orioles & Red Sox vs Blue Jays53:46 Standout performances1:02:00 En Fuego1:10:20 Batters who are struggling1:12:10 Injured list updates1:13:55 Returning from IL1:14:25 Awards
Use code TALKIN2025 for 10% off your next SeatGeek order*: https://seatgeek.onelink.me/RrnK/TALKIN2025. Sponsored by SeatGeek. *Restrictions apply. Max $20 discountCorona. La Playa Awaits. Be sure to get yours athttps://OrderCorona.com.Download the DraftKings Sportsbook app and use promo code JMBASEBALLBook your next trip at https://www.bestwestern.comCheck out Warehouse Challenges! https://www.youtube.com/@warehousechallengesTalkin' Jake and Coach Trev break down the weekend recap and discuss the wild walk-off's from the weekend, the red hot Tigers, Nolan Arenado doing Nolan Arenado like things and more!0:00 Intro3:00 AL Burn6:30 AL Standings8:00 Orioles / Tigers13:00 Devin Williams outed as closer16:10 Red Sox / Guardians18:00 Astros / Royals20:25 Angels / Twins22:07 Marlins / Mariners25:00 White Sox / A's26:50 NL Burn30:00 NL Standings32:55 Braves / Diamondbacks35:55 Phillies / Cubs38:29 Mets / Nationals44:00 Brewers / Cardinals46:20 Pat Murphy over managing?49:44 Pirates / Dodgers & Giants / Rangers52:11 Dodgers depth neds to figure it out56:11 Standout Performances1:02:30 En Fuego1:04:50 Batters who are struggling1:07:20 Players on IL1:09:50 Awards
Go to http://shadyrays.com and use code TALKIN for 35% off polarized sunglasses.Download the DraftKings Sportsbook app and use promo code JMBASEBALLBook your next trip at https://www.bestwestern.comUse code TALKIN2025 for 10% off your next SeatGeek order*: https://seatgeek.onelink.me/RrnK/TALKIN2025. Sponsored by SeatGeek. *Restrictions apply. Max $20 discount Coach Trev and Talkin' Jake talk Mets dominance over Phillies, Cubs being an issue in the NL, Astros starting to take off, Tigers series win and more!0:00 Intro3:00 NL BURN6:28 NL Standings13:00 Mets / Phillies17:00 Cardinals / Braves19:00 Rays / Diamondbacks22:23 Dodgers / Cubs24:00 Orioles / Nationals & Reds / Marlins25:00 AL Burn30:00 AL Standings32:00 Yankees / Guardians35:00 Blue Jays / Astros38:45 Padres / Tigers44:00 Mariners / Red Sox46:55 Rest of AL48:30 Rangers / Athletics51:05 Standout Performances1:00:15 En Fuego1:03:30 Players who are struggling1:05:10 IL update1:06:10 Returning from IL1:06:10 Awards
What do you know about Steve Jobs, the legendary co-founder of Apple, who created one of the greatest gadgets of our time? Turns out, he was a man of mystery, and in the most literal sense of the word. Just think about it, he'd been driving a car around Silicon Valley without a license plate for years on end! That meant breaking the law, which requires all passenger vehicles to have tags. Some believed that he did it just because he could. Call it a rebellious spirit if you want. Or maybe he wanted to protect his privacy by any means possible. Someone even came up with the theory that it was the font on the plate that he didn't like. After all, he was a perfectionist in every way, so maybe he really thought an ugly plate would ruin his beautiful car. Other videos you might like: I Adopted Rich People's Habits, See How My Life Changed • I Adopted Rich People's Habits, See H... 12 Signs of High Intelligence You Probably Have • 12 Signs of High Intelligence You Pro... Why “C” Students Are More Successful Than “A” Students • Why “C” Students Are More Successful ... TIMESTAMPS: Did he have an arrangement with the local police?
Ilala Metals Ltd (proposed code: IL1) managing director Richard Henning joins Proactive's Tylah Tully to discuss the company's Initial Public Offering (IPO) to raise $5 million, with the option to accept up to a further $3 million in oversubscriptions. The funds will support ongoing exploration and initial drilling at the Serule Uranium Project in Botswana, advancement of the Central Copper Project in the country's prolific Kalahari Copper Belt and exploration at other uranium projects in Botswana. Following completion of the IPO, Ilala Metals plans to list on the Australian Securities Exchange (ASX) in September this year. It holds 100% stakes in multiple copper and uranium leases in Botswana, covering 13,177 square kilometres and a lithium-tantalum project in Namibia. The Serule Project, adjacent to Lotus Resources' Letlhakane Uranium Project, has shown promising results, with 1,062 metres of drilling completed and analysis pending. The Central Copper Project has also progressed, with a recent magnetic survey extending coverage to the entire dome target area, identifying structural targets for further exploration. The company has been hard at work over the past year and with plenty of news flow to come, is set for a strong last quarter of 2024. #ProactiveInvestors #IlalaMetals #ASX #IPO #Uranium #Copper #Botswana #ASXListing #Exploration #MiningInvestment #KalahariCopperBelt #Lithium #Tantalum #MineralResources #Drilling #GreenEnergy #InvestmentOpportunity #MiningIndustry #ResourceDevelopment #SustainableMining #UraniumExploration #CopperExploration #invest #investing #investment #investor #stockmarket #stocks #stock #stockmarketnews
In this episode, we dive deep into understanding the flu, its global impact, and effective strategies for recovery. As we explore effective recovery strategies from the flu, it's crucial to consider liver health. Liver Prime, a comprehensive liver detox supplement, plays a pivotal role in supporting your body's natural detoxification process, crucial for flu recovery. Discover the benefits of Liver Prime and how it can enhance your healing journey. https://www.mswnutrition.com/products/liver-prime Show Notes: Sleep for Flu Recovery: The role of IL1 in sleep regulation and influenza virus response: [https://www.sciencedirect.com/science/article/abs/pii/S0889159114005108] Impact of sleep apnea on influenza-associated SARI: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9109977/] Acute sleep disruption and inflammation: [https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00195-0/fulltext] The importance of sleep in clearing metabolic waste: [https://www.nature.com/articles/s42003-021-02825-4] N-Acetyl Cysteine (NAC) for Flu Recovery: Efficacy of NAC in acute respiratory distress syndrome: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398034/] NAC's inhibition of influenza A virus replication: [https://www.sciencedirect.com/science/article/abs/pii/S000629520900728X] NAC's role in improving flu symptoms: [https://erj.ersjournals.com/content/erj/10/7/1535.full.pdf] Adrenal Gland Support during Flu Recovery: Benefits of sauna sessions for respiratory system dysfunctions: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916915/] The influence of viral infections on the endocrine system: [https://www.ncbi.nlm.nih.gov/books/NBK568565/] Lymphatic Drainage for Flu Recovery: Lymphatic function's role in lung health: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10043242/] Vitamin D3 for Flu Recovery: Historical use of vitamin D3 in infectious disease treatment: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855046/] Vitamin D's association with reduced risk of acute respiratory illness and influenza: [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3649720/] As we conclude our discussion on flu recovery, remember that a holistic approach, including liver health, is key. Liver Prime offers a targeted way to support your liver, aiding in detoxification and overall wellness during recovery. To learn more and to incorporate this crucial supplement into your recovery plan, visit https://www.mswnutrition.com/products/liver-prime
In S3E5 Mike welcomes his musical good buddy James Park onto the podcast where they discuss their mutual love of college hoops, music, the performance art form that is pub trivia and then take a deep (dish) dive on one of their favorite forms of sustenance: pizza.Follow the podcast on Twitter: @friendsofmikedEmail the podcast at talkingfriendship@gmail.comKey moments from the pod: 0:30: Mike welcomes listeners to S3E5 featuring Mike's good buddy James Park.1:30: Mike corrects a major pronunciation error he personally made in Episode 4.5 of Season 3.3:00: Mike talks about what's going on with him, which essentially doubles as a quick recap of Season 3 so far, including a reference to a recent walkabout he took in his neighborhood, and a hearty thank you to the listener community.6:15: Mike then identifies a classic (literally) song that features an instrument James knows really, really well in the violin as a tribute to James.10:30: Mike welcomes James Park into the virtual podcast studio.11:35: James gives his life story, Mike brings up a touchy subject about how the NCAA left his hometown. James then talks about his passion for music and the violin and why Ann Arbor is a great town for music.17:20: James talks about his oldest and dearest friend (the infamous Rob/Robert) and the guys prove a math equation on friendship.22:45: The guys talk about the last time they saw each other (spoiler alert: it was watching America's national pastime).26:00: The guys trace the origin of their friendship back to a single event, a very orderly but also fun work party in 2016 and what Mike was wearing to that party (a tuxedo tracksuit).29:30: Mike and James talk a bit about their shared passion for the sport of college hoops, with James' loyalties lying with a bird and Mike's with a mammal. They also get into a piece of memorabilia in Mike's basement pub that requires a trigger warning for James before he sees it. 35:10: The guys then break down one of their all time favorite activities known as Pub Trivia/Pub Quiz and how their team Prune Tracy (EAT YOUR PRUNES!!) became legends in the late 2010's around the Eastern Michigan trivia scene.40:40: James throws down the infamous “7 Day Trivia Challenge” to Mike and he…..accepts!44:00: The guys discuss one of their favorite shared foods (a little known delicacy known as pizza), how they fell in love with it, then break down their favorite pizza places they've ever been to. The discussion covers a ton of ground on “pie”, including discussing why New Haven, CT is known as a pizza hotbed, where Mike would get pizza before school dances, where James would get pizza with friends while playing music and why they both love Chicago pizza.48:00: Pizzeria Uno, Overland Park, Kansas49:50: Bricks Pizza, Chicago, IL52:15: Frist Campus Center on the campus of Princeton University in Princeton, NJ54:20: Little Caesars, Allen Park, MI (includes a non-sequitur from James on an amazing Japanese TV show called “Old Enough”)59:00: Koronet Pizza, New York, NY1:02:30: Buddy's Pizza, Dearborn, MI1:05:20: Modern Apizza, New Haven, CT1:11:20: Frank Pepe's, New Haven, CT1:13:30: Pequod's, Chicago, IL1:17:00: James then drops some knowledge as to how to keep a friendship going.1:19:00: James updates the listeners on what he's excited about coming up in his life.1:21:00: Mike takes James through the (not so) Rapid Fire segment, including talking about when James' favorite music venues, his top feature of living in Ann Arbor, MI (spoiler alert: it's not the roads), the trivia topic he feels most comfortable answering (including how he used to con his mom to get Little Debbie snacks in order to learn about US Presidents), and where he'd love to travel to soon that he's never been to.
http://www.patreon.com/thenomikishow » We need your help to keep providing free videos! Make sure to click Like & Subscribe! And we encourage you to join us on Patreon as a Patron for as low as $5/month! Varun Nikore is Executive Director of AAPI Victory Alliance, and previously was with the AAPI Victory Fund.» https://twitter.com/VarunNikore» https://linktr.ee/aapivictoryallianceBenjamin Dixon is host of The Benjamin Dixon Morning Show & podcast.» https://twitter.com/BenjaminPDixon» https://youtube.com/thebenjamindixonshow» https://patreon/thebpdshowImani Oakley: Candidate for Congress in NJ's 10th District» https://twitter.com/ImaniOakleyNJ10» https://oakleyforcongress.comDr. Stephany Spaulding: Organizer, Civil Rights Activist, and Educator running for Congress in Illinois' 1st District» https://twitter.com/drstephanyrose» https://spauldingforcongress.comNomiki is LIVE » Wed & Fri: 8p ET / 5p PT TNS swag » http://www.TheNomikiShow.comFind Nomiki on:Twitter: http://www.twitter.com/NomikiKonst » http://www.twitter.com/TheNomikiShow IG: https://www.instagram.com/thenomikishow» https://www.instagram.com/nomikikonstYouTube: https://www.youtube.com//TheNomikiShowFacebook: https://www.facebook.com/nomikikonstMusic Credits: Ohayo by Smith The Mister https://smiththemister.bandcamp.com Smith The Mister https://bit.ly/Smith-The-Mister-YT Free Download / Stream: https://bit.ly/_ohayo Music promoted by Audio Library https://youtu.be/bzCw4RyFqHo Mi-Lo by Smith The Mister https://smiththemister.bandcamp.com Smith The Mister https://bit.ly/Smith-The-Mister-YT Free Download / Stream: https://bit.ly/mi-lo Music promoted by Audio Library https://youtu.be/--4tHbTT97g
Join us for Side B of the Hurt Bird Bath discussion on this week's new episode of The Umphreys "WOW" Show! This time, Rob Turner & Jimmy Knowledge are joined by Josh Colky from Umphreak's Anonymous. The trio will discuss what versions of this iconic Umphrey's McGee song placed in their bronze, silver and gold medal spots.Josh Colky: 3. 02/19/04 - Theater of Living Arts — Philadelphia, PA2. 12/31/08- The Auditorium Theatre — Chicago, IL1. 03/16/06 - La Boule Noir — Paris, France Jimmy Knowledge: 3. 06/03/05- The Barrymore Theatre — Madison, WI2. 05/22/03- The Vogue Theatre — Indianapolis, IN1. 07/13/07- Ogden Theatre, Denver, CO Rob Turner: 3. 02/24/06- The Pageant — St. Louis, MO2. 10/29/14- Forum Theatre — Binghamton, NY1. 12/03/04- Variety Playhouse — Atlanta, GA Listen to Side A: https://the-umphreys-wow-show-with-rob-turner-jimmy-knowledge.simplecast.com/episodes/episode-1-hurt-bird-bath-side-aContact the Umphreys "WOW" show: umwowshow@gmail.comWall of "WOW": https://datcmediacompany.com/wall-of-%22wow%22-wednesdayWhere you can find the hosts on Twitter:The Umphrey's "WOW" show: https://twitter.com/umWOWshowJimmy Knowledge: https://twitter.com/UMfactsRob Turner: https://twitter.com/RsTnerDropped Among This Crowd Podcast Episode 189: https://droppedamongthiscrowdpod.simplecast.com/episodes/a-conversation-with-rob-turner-jimmy-knowledge-announcing-the-umphreys-wow-showWhere you can find this week's guest: Twitter: https://tinyurl.com/3ppkutecInstagram: https://tinyurl.com/2srze4u2Facebook: https://tinyurl.com/ye25uwkzDATC Media Company: https://datcmediacompany.comDropped Among This Crowd Podcast: https://droppedamongthiscrowdpod.simplecast.comCrooked Conversations: https://datcmediacompany.com/some-variations-2Email: droppedamongthiscrowdpod@gmail.comDATC Media Instagram: DATC Media Company (@datcmediacompany) • Instagram photos and videosDATC Media Facebook: (5) Dropped Among This Crowd Media | FacebookDATC Media: (1) DATCMediaCompany (@DatcMedia) / Twitter"Dropped Among This Crowd" Official Store: https://datcmediacompany.com/datc-store
An introduction to your host, what the podcast will be about (integrative medicine & psychedelics) and a primer on evidenced based medicine.0:00 - Bio, Mary Ella Wood, DOUndergrad: Point Loma Nazarene University, San Diego, CAMedical School: Alabama College of Osteopathic Medicine, Dothan, ALResidency: General Surgery, Danbury Hospital, Danbury, CTResidency: Family Medicine, West Suburban Medical Center, Oak Park, IL1:06 - Journey to Integrative Medicine3:50 - What is Integrative Medicine?4:25 - Psychedelics5:08 - Podcast Format6:50 - Evidenced Based Medicine
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
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.
Summary: My tenacious interlocutor returns to discuss his lively Street Epistemology Discord server engagements that occurred in the interim. I do some more "messaging" than normal in this one, likely in response to them asking me questions. Watch video of talk here: https://youtu.be/HQWeRF0OBG4 Note: I found in interesting how "importance" of the claim was being viewed differently by both parties here. The students seem to be using it as "needed" while I seem to be viewing it as "fantastic." If only I had asked something like, "Are you saying that, the more necessary a claim is to a person, the more likely the attestations of others from a long time ago are true?", or something to that effect. IL2 at one point asks, "What happens to me?," as if that should be a factor in assessing the truth of a claim. I was later reminded about a discussion I had about differences in adjective meanings, like we might see with a word like "important" or "extraordinary". In their view, it seems, if a claim is "important" to them personally (like "Jesus rose from the dead," it's less likely someone would lie or be mistaken about the claim, and therefore you can accept what they stated as true to a high degree of confidence. Whereas from my perspective (and perhaps others who might be more skeptically-minded) we see "importance" as a biasing factor to control for; the more important or impactful one might find a claim to them personally is a reason to apply more—not less—scrutiny to the supporting reasons. Check out Pinecreek on YouTube and his more advanced "Flying Man" ( https://youtu.be/2ZNiCpeF_Jg?t=4789 ) example, which is further along than I was here with my off-the-cuff car metaphor in 2019. I'd like to see this idea of how we might be using adjectives differently explored further in future SE discussions. Location: San Antonio, Texas Recorded: 25 November 2019 Released: 27 May 2021 Anthony's Social Media: https://linktr.ee/magnabosco Street Epistemology Resources: https://tinyurl.com/abm-se-resources Street Epistemology Communities: https://tinyurl.com/abm-se-community Street Epistemology Discord Server: https://discord.gg/sKap3zM (recommended) Street Epistemology Survey: https://se-survey.web.app/en Skip ahead to a desired point in the talk: -- Intro: 00:01 Carolina: 00:16 Best Entrance Ever: 00:44 Interruption: 01:05 Start: 03:07 Opting Out: 03:32 Staying Cool?: 07:44 Faith: 08:07 Testing: 12:49 Peace Out: 14:28 Elon's Tesla: 18:14 What Happens to Me?: 20:36 Handshakes: 24:40 Have a Blessed Day: 24:55, 26:30 Equipment Change: 25:09 Closing Thoughts: 25:47 Consent: 26:58 Get Right Back in There: 27:39 End Screen: 27:42 Bonus Footage: 28:05 -- Note: Add 35 seconds to these timestamps if listening to the podcast version of this talk. Audio correction provided by Philipp Grzemba. Intro Music '19th Floor' by Bobby Richards, provided by YouTube. Audio Clip: 'Say Good Night' by Joakim Karud, Unported— CC BY-SA 3.0 Music provided by Jim Rhodes, with Dan Harris on lap steel. Links to References in Video: IL1's YouTube Channel: https://www.youtube.com/channel/UCuhe7b8v1lgHQCppxEEI_uw Watch 1st talk w/IL1: https://youtu.be/DBBW-ZUjKEM Watch 2nd talk w/IL1: https://youtu.be/w3bu-yc8sRI Watch 3rd talk w/IL1: https://youtu.be/HQWeRF0OBG4 Watch more faith talk: https://youtu.be/hxDD3sajaxw (How Faith Ends) Watch talk w/Jenna (ACA Host): https://youtu.be/S_0JhCv1mTs Mistakes: Please let me know if you spot any. Recorded w/Go-Pro. Edited w/PowerDirector. The views addressed here are mine and mine alone, and are not necessarily shared by members of my family and friends. The intro and outro of this episode was narrated by AZ.
Oliver Schöndorfer, a UI Designer and Typographer, who helps developers improve their websites through pimped typography joins Ari Koponen on the Frontend Greatness podcast to talk about "Better Web Typography." Oliver's YouTube Channel “Pimp my Type”: http://pimpmytype.com Newsletter with weekly font recommendations for web and app design: https://pimpmytype.com/newsletter In this episode: - How can you make typography on the web better? - Choosing fonts for your next web project - Using variable fonts to improve typography and performance --- Episode Notes Social - Oliver's Twitter: https://twitter.com/glyphe - Pimp My Type: http://pimpmytype.com - Ari's Twitter: https://twitter.com/apkoponen Show Notes - Web Almanac - Fonts: https://almanac.httparchive.org/en/2020/fonts/ - "5 steps to faster web fonts": https://iainbean.com/posts/2021/5-steps-to-faster-web-fonts/ - Prevent Faux Fonts: https://alistapart.com/article/say-no-to-faux-bold/ - Avoid Google Fonts: https://wicki.io/posts/2020-11-goodbye-google-fonts/ - Rasmus Anderssons (@rsms): https://twitter.com/rsms - The "Il1 ag" rule. Oliver's Recommendations - Zack Leatherman: https://twitter.com/zachleat - "Web Typography" by Richard Rutter: https://www.amazon.co.uk/Web-Typography-designing-typography-responsive/dp/099566420X - Typography.guru on YouTube: https://www.youtube.com/typographyguru
As the powerhouse of the cell, mitochondria are associated with producing energy. However, studies regarding the function of mitochondria suggest that it does way more than powering the cell. In this episode, Dr Elizabeth Yurth discusses the function of the mitochondria in our overall health. For instance, it signals the nucleus to repair the damage done by oxidative stress. Furthermore, the role of mitochondria is also to facilitate improvement in metabolism. Dr Elizabeth also explains how increasing butyrate levels in your gut microbiome is beneficial. This stimulates your mitochondria to release PGC-1α and NPK. As a result, it will have a greater capacity to eliminate waste and harmful substances in the cell. Additionally, we discuss fat tissue, blood sugar levels and metabolism. If you want to know more about the function of mitochondria and how it informs your overall health, this episode is for you. Listening to this podcast will also help you understand your digestive health. 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Health Optimisation and Life Coaching If you are struggling with a health issue and need people who look outside the square and are connected to some of the greatest science and health minds in the world, then reach out to us at support@lisatamati.com, we can jump on a call to see if we are a good fit for you. If you have a big challenge ahead, are dealing with adversity or are wanting to take your performance to the next level and want to learn how to increase your mental toughness, emotional resilience, foundational health and more, then contact us at support@lisatamati.com. Order My Books My latest book Relentless chronicles the inspiring journey about how my mother and I defied the odds after an aneurysm left my mum Isobel with massive brain damage at age 74. The medical professionals told me there was absolutely no hope of any quality of life again, but I used every mindset tool, years of research and incredible tenacity to prove them wrong and bring my mother back to full health within 3 years. Get your copy here: https://shop.lisatamati.com/collections/books/products/relentless. For my other two best-selling books Running Hot and Running to Extremes chronicling my ultrarunning adventures and expeditions all around the world, go to https://shop.lisatamati.com/collections/books. Lisa’s Anti-Ageing and Longevity Supplements NMN: Nicotinamide Mononucleotide, a NAD+ precursor Feel Healthier and Younger* Researchers have found that Nicotinamide Adenine Dinucleotide or NAD+, a master regulator of metabolism and a molecule essential for the functionality of all human cells, is being dramatically decreased over time. What is NMN? NMN Bio offers a cutting edge Vitamin B3 derivative named NMN (beta Nicotinamide Mononucleotide) that is capable of boosting the levels of NAD+ in muscle tissue and liver. Take charge of your energy levels, focus, metabolism and overall health so you can live a happy, fulfilling life. Founded by scientists, NMN Bio offers supplements that are of highest purity and rigorously tested by an independent, third party lab. Start your cellular rejuvenation journey today. Support Your Healthy Ageing We offer powerful, third party tested, NAD+ boosting supplements so you can start your healthy ageing journey today. Shop now: https://nmnbio.nz/collections/all NMN (beta Nicotinamide Mononucleotide) 250mg | 30 capsules NMN (beta Nicotinamide Mononucleotide) 500mg | 30 capsules 6 Bottles | NMN (beta Nicotinamide Mononucleotide) 250mg | 30 Capsules 6 Bottles | NMN (beta Nicotinamide Mononucleotide) 500mg | 30 Capsules Quality You Can Trust — NMN Our premium range of anti-ageing nutraceuticals (supplements that combine Mother Nature with cutting edge science) combat the effects of ageing, while designed to boost NAD+ levels. Manufactured in an ISO9001 certified facility Boost Your NAD+ Levels — Healthy Ageing: Redefined Cellular Health Energy & Focus Bone Density Skin Elasticity DNA Repair Cardiovascular Health Brain Health Metabolic Health My ‘Fierce’ Sports Jewellery Collection For my gorgeous and inspiring sports jewellery collection ‘Fierce’, go to https://shop.lisatamati.com/collections/lisa-tamati-bespoke-jewellery-collection. Here are three reasons why you should listen to the full episode: Understand that the function of mitochondria is not only to produce energy but also to enhance cell growth and healing. Learn about the effect of butyrate and antibiotics on the mitochondria, as well as the diet and activities to boost mitochondrial performance. Find out more about the function of the mitochondria in regulating stress, blood glucose and ageing. Resources Gain exclusive access and bonuses to Pushing the Limit Podcast by becoming a patron! Harness the power of NAD and NMN for anti-ageing and longevity with NMN Bio. Listen to my other Pushing the Limits Episodes: #183: Sirtuins and NAD Supplements for Longevity with Dr Elena Seranova #187: How to Slow Down Ageing and Promote Longevity with Dr Elizabeth Yurth #189: Understanding Autophagy and Increasing Your Longevity with Dr Elena Seranova Connect with Dr Elizabet Yurth: Instagram Boulder Longevity Institute — Learn more about research-based longevity medicine developed by Dr Elizabeth Yurth. Sign up at the Human Optimization Academy to access resources on taking control of your health! Mitozen’s Pro ByoMax™ – Probiotic / Butyrate Suppository Episode Highlights [06:33] What Is the Mitochondria? The mitochondria are bacteria classified as anaerobic organisms. Humans have a symbiotic relationship with the mitochondria. With their help, we can survive outside water and air. Mitochondria also have their own genome. You inherit them from your mother. The communication between the nucleus and the mitochondria is imperative to our health. [11:00] The Function of Mitochondria In theories of ageing, mitochondria produce free radicals damageing our DNA. The mitochondria release mitochondrial peptides when activated by oxidative stress. These mitochondrial peptides are messages sent to the nucleus to signal it to heal your body. When the mitochondria are stressed, it also activates the unfolded protein response (UPR). The UPR either gets rid of bad protein through autophagy or fixes them. Tune in for more details about how the mitochondria initiate growth and healing. [17:05] Damage in the Cells The body tries to get rid of dysfunctional proteins. You need to be careful of the amount of antioxidants you take. Taking too much may inhibit your body's response to bad proteins. You should take your body through a cycle. You go through an autophagy phase where you clear out the bad cells. Then, you go through the growth phase, where you induce more toxic stress. In doing so, you can initiate growth and healing. [19:32] Mitochondria Permeability Transition Pore (MPTP) This pore is a gate that opens and closes the mitochondria. As you grow old or when you are in worse health, it stays open longer. Then, it allows bad stuff to go in and out more often. Melatonin keeps the pores closed most of the time. Spermidine also induces mitochondrial biogenesis by restoring this pore structure. Antibiotics like minocycline may have some very significant benefits to your cell health. [23:14] The Effects of Butyrate on the Gut Microbiome Your microbiome is most affected by butyrate. To consume antibiotics and probiotics, you first have to keep butyrate in your microbiome. Higher levels of butyrate may also help the cell, specifically the mitochondria. It improves aerobic metabolism. High butyrate also regulates your PGC-1α gene to improve your aerobic endurance. Sick people usually replenish butyrate by doing rectal suppositories. To know more about the full effects of butyrate, listen to the full episode. [32:33] Relationship Between the Function of Mitochondria and Gut Microbiome Butyrate increased the PGC-1α and NPK in the mitochondrial level. As a result, your oxidative capacity is restored, and the mitochondria become healthier. After inducing autophagy and getting rid of the bad stuff, Dr Yurth restricts the food consumption of her patients. Then, she will use spermidine at a higher dose. At this stage, the mitochondrial peptides released will induce the nucleus to have a healthier genome. [36:57] The Effects of Melatonin Melatonin also affects the mitochondrial permeability transition pore (MPTP). Interleukin-1 beta (IL1β) causes damage to mitochondria. High dose melatonin blocks IL1β. Melatonin also creates a homeostatic reaction in the mitochondria. It’s therefore anti-cancer. High dose melatonin also restores your circadian rhythm. When you should take it depends on your genes. 20 mg is a high dose of melatonin. This dosage is for people with cancer. [42:18] The Importance of Mitochondrial Peptides Mitochondrial peptides like the SS-31 helps the endoplasmic reticulum to be healthy. Exercise helps induce mitochondrial peptides. MOTS-c as a drug is an alternative for people who can’t exercise. You can also produce MOTS-c when you exercise. MOTS-c helps with glucose metabolism, fat loss, turning white fat to brown fat, and overall metabolism. [44:44] Why Brown Adipose Tissue Is Metabolically Active When babies are born, they need something to keep them warm. Brown adipose tissue is functional for heat production and burns calories. White fatty tissues are more common as you get older. It only coats your organs and provides little benefits. Butyrate can convert white fat to brown fat, which can help you boost your metabolism. Fat is also metabolically active. Men who are fatter convert their testosterone into estrogen. Dr Yurth emphasises that a good diet and quality exercise is worthless without looking at hormones. Listen more to learn about how hormones affect your metabolism. [54:20] Regulating Blood Sugar As your blood glucose rises, you will feel temporary stress which is good for you. However, long-term high levels of glucose in your blood are damageing. Dr Yurth mentioned the benefits of continuous glucose monitoring (CGM). Go for a walk after a meal to regulate spikes in your sugar levels. Chromium and cinnamon help maintain blood glucose. However, the positive effects rely on genetics. A recent study revealed that eating protein before carbohydrates shows a lower blood glucose and insulin level. [1:00:36] Enzymes and Breaking Down Proteins Evidence shows that the dysfunction of the metabolic process starts in bile acids. In treating neuromuscular weakness or building muscle, you should focus on your digestive enzymes. Integrate mass proteases and lipases into your meals. Dr Yurth reiterates the importance of keeping your gut microbiome healthy through consuming butyrate. Good bacteria such as probiotics, which are anaerobes, will not survive the colon site. If you don’t have a healthy gut lining, your immune system will see probiotics as foreign materials. This can cause a histamine response. 7 Powerful Quotes from the Episode ‘I'm gonna make the case that actually every single disease, from cancer, to cardiovascular disease, everything related to ageing, osteoporosis, everything comes down to mitochondrial dysfunction.’ ‘I’m just a big advocate with diet, and with exercise, with everything, everything's done cyclically. Because we want to go through phases all the time where we're getting rid of bad stuff and then regrowing.’ ‘We’re able to use the butyrate for fatty acid oxidation and actually improve aerobic metabolism.’ ’As you're learning, the gut is everything. And now we're learning it may even be imperative to the mitochondria.’ ‘I think what it's going to come down to when we look at this mitochondria, it's not going to be trying to figure out what is my perfect dose of antioxidants. It's gonna be figuring out how do I get that mitochondria with the pores, letting the good stuff in and letting the bad stuff out?’ ‘What it's really trying to get across is just, you know, sensible stuff, we just did a thing you know, about just taking a walk after dinner, right?’ ‘That little bit of stress, like I said, what you know, what doesn't kill you makes you stronger.’ About Dr Elizabeth Yurth Elizabeth Yurth, MD, is the Medical Director and co-founder of the Boulder Longevity Institute. This institute was established in 2006. Dr Yurth is double board-certified in Physical Medicine & Rehabilitation and Anti-Ageing/Regenerative Medicine. She also has a Stanford-affiliated Fellowship in Sports and Spine Medicine. Here, Dr Yurth specialises in Sports, Spine, and Regenerative Medicine. Additionally, she also has a dual-Fellowship in Anti-Aging and Regenerative Medicine (FAARM) and Anti-Aging, Regenerative and Functional Medicine (FAARFM) through the American Academy of Anti-Aging Medicine (A4M). Dr Yurth serves as a faculty member in SSRP (Seeds Scientific Research and Performance) with 25 mastermind physician fellows. Here, she allows herself to stay abreast and teach others in the emerging field of cellular medicine. An active athlete herself, Dr Yurth has worked with numerous sports teams at both the collegiate and professional levels. At present, she works as a consultant for high-level athletes from across the country. She aims to aid them in recovery and optimise performance. Dr Yurth resides in Boulder, Colorado, with her husband and five children. To know more about Dr Yurth’s work, visit Boulder Longevity Institute and connect with her on Instagram. Enjoyed This Podcast? If you did, be sure to subscribe and share it with your friends! Post a review and share it! If you enjoyed tuning in, then leave us a review. You can also share this with your family and friends so they can learn more about mitochondrial health and include butyrate in their diets. Have any questions? You can contact me through email (support@lisatamati.com) or find me on Facebook, Twitter, Instagram and YouTube. For more episode updates, visit my website. You may also tune in on Apple Podcasts. To pushing the limits, Lisa Full Transcript Of The Podcast Welcome to Pushing The Limits, the show that helps you reach your full potential with your host, Lisa Tamati, brought to you by lisatamati.com. Lisa Tamati: Lisa Tamati your host here at Pushing The Limits. Super excited that you're here with me again today. Thanks for tuning in. I do love and appreciate your loyalty. And I would love to hear from you. If you've got something to say about the podcast, you’ve got some comments and questions about some of the topics that we have raised, please do reach out to us. We love hearing from our listeners. And if you can give us a rating and review if you're enjoying the content, that really really helps the show. We've also got our Patron VIP premium membership now open. If you love our show, if you love what we do, what we stand for our values, our principles, the work that we put into this podcast, which we've been doing now for five and a half years, without any money or any—just for the love of it and for the passion of it. If you want to help support us and keep us going and want to get a whole lot of premium membership benefits, then head over to patron.lisatamati.com. I would love you to join our VIP tribe. That's patron.lisatamati.com. For the price of about a coffee a day or a little bit more, you can be involved. There's two tiers in there, with different levels of premium member benefits. And we would love you to join us there. So if you can please do. Now today's superstar is Dr Elizabeth Yurth. And if you follow the podcast, you might have remember that name because she was on just a few weeks ago. And she is now one of my favorite teachers. I have been learning from her at the Bone Longevity Institute of Human Optimization Academy. And she is a brilliant teacher, and a brilliant orthopaedic surgeon and longevity expert. And she offers the world's most advanced research-based health care. And it's all customised to you. And the information that we're going to share with you today—today's topic if you like, is all around mitochondrial health. Now we do deviate a little bit because as we do in these conversations, we go off on a few tangents. But it is really all about understanding what your mitochondria are, why you need to know about it, how to keep them healthy, because these little bacteria if you like, and these little powerhouses of our cells are absolutely crucial to health and longevity. And Dr Yurth says that the mitochondria, she thinks, are at the very basis of all diseases. So when these little guys go awry, that's when diseases come into play. And everything from cancer, chronic fatigue, to all of the diseases right across the spectrum can be affected by mitochondrial health. So we do a bit of a deep dive into that today. So I hope you enjoy this session with Dr Elizabeth Yurth. She's a lady who walks the talk. She's an incredibly amazing person, athlete, orthopaedic surgeon. She loves this. She breathes it the way she loves, as you know, in complete alignment with what she also teaches, so make sure you check out all her links in the show notes. Right. Now before we go over to the show. Just want to also let you know about our NMN, our supplements. They’re longevity and anti-ageing supplement. We are into longevity. We are into health span. We are into increasing our lifespan and healthspan. So if you want to get into having—to boosting your NAD levels in your body, we've recently done a couple of episodes with Dr Elena Seranova on this topic, then head over to nmnbio.nz. And grab your NMN supplements over there to get your longevity regime underway. And in today's podcast, we talk a little bit about this. We talk also about spermidine, which we've also mentioned in other podcasts. There are some amazing compounds out there that are going to help us stay healthier and longer. And there's a lot of techniques and things that we can actually engage in. We don't have to be passive bystanders to our ageing, we can do things about it, we can slow it down, and even reverse it in some places. So I hope you enjoy this episode. So do check out my Longevity Supplement over at nmnbio.nz. And enjoy today's show with Dr Elizabeth Yurth. Lisa: Well, hi everyone and welcome back to Pushing The Limits. Super excited to have another wonderful guest that we've actually had on before and back by popular demand. That was a very, very popular episode. So I have Dr Elizabeth Yurth with me. Hi, Dr Yurth, how are you doing? Dr Elizabeth Yurth: Lisa, thank you for having me again. I love being with you. Lisa: Oh, it's just that, our last episode was just so full of information that I've had it on repeat going, for me, because there's so much in there and so many people have written and have been asking questions. So I want to get started by saying if after this interview, you want to talk to Dr Yurth and one of her team at the Border Longevity Institute, you can do that even when you're in New Zealand or Australia, you can do teleconsults. And yeah, so if you are facing some difficult health problem, and you really want some help, make sure you do that. And we'll have all the links in the show notes and so on. And before we get underway, there is a Bold Longevity of—what is it called, optimisation? Dr Yurth: Human Optimization Academy, right? Yeah, from the Border Longevity site, or just go to bliacademy.com and sign up. But you guys have definitely signed up for that we actually are trying to really put together tons—and all the information you guys need to try. And you'll have one place where you can go get all of these things that we talked about, and all the things that Lisa talks about, and really be able to learn about them. Because as we know, doctors don't really learn this stuff very well. So you guys have to do it yourself. And so we're trying to give you a place to do. It's coming from a very experienced... Lisa: Yeah, and if you want on the latest, so make sure bli.academy.com. And I'll put that in the show notes too guys, so you can find it. Now today's subject is mitochondria, one of Dr Yurth’s favorite subjects. Okay, for starters, what is a mitochondria? Dr Yurth: What's really so cool about mitochondria, right, is they're actually they were actually their own little bacteria. So they invaded us back when we were threatened to kind of moving from an anaerobic to an aerobic environment. So when we went from sort of anaerobic organisms to actually living in air, we couldn't do it. And so these little bacteria got into the cells, and they formed a symbiotic relationship, so that we could survive outside of water and air. And so they were responsible for us being able to move out of the ocean and into an air or an aerobic environment. Well, they're actually their own little organism. Right? I mean, that that is weird, right? That we have this essential part of our cell. Now our essential part of survival is actually its own organism. And it was a one celled organism, it gone to formed a symbiotic relationship, it allowed the bacteria to survive living inside ourselves. And if we allowed ourselves to survive, so amazing. And that's why they're so unique is that they actually contain a whole genome that is separate from your nuclear genome, right? So they have a mitochondrial genome that's completely different. And it's only inherited from your mother. So that mitochondrial genome is not inherited from your father at all. It's probably one of the reasons your mother's health at the time, because even though the mitochondria has its own genome, that genome is impacted by things you do. So if I have a baby, and I'm super unhealthy, I've altered that mitochondrial genome. And then I've transferred that mitochondrial genome only from me—the dad was great and doing everything right—to my children. So that's one of the... Lisa: So that’s the epigenetic…. Because I'm just about to go through IVF, as I said before, very interesting for me. So even though I'm going to have an egg donor... Dr Yurth: You wanna make sure she’s healthy, right? Lisa: Yeah, she's just—she is, and we've got her on everything. Her DNA is coming into the egg, but actually, my mitochondria will be a part of this baby, if we have one. Dr Yurth: So you will alter—so basically, she's, you're going to be, the baby will have her mitochondrial DNA. But because you will be growing this baby, you will be altering that mitochondrial DNA by epigenetic influences that you're doing, right. So now you're going to be changing some of that DNA structure, or the genome of that mitochondria by things you're doing. The mitochondria, so even though it's coming in, and again, you want her to come in with this great mitochondrial DNA in the first place. Right? So we want this good genome in the first place, which is why you do want her to be healthy and fit and all those things. And younger. But then you know all about the epigenetics, and so you're going to be potentially altering some of that, too. So that's one of the really amazing things. Now, what we used to think is, all the mitochondria did was do oxidative phosphorylation, and make energy, make ATP. And that's what they did. They were our energy powerhouse. That's all we ever learned, right? High school was like, ‘Oh, the powerhouse of the cell’. So we now know, they do a whole lot more than that. So they're not just responsible for aerobic metabolism, and making ATP. So they're not just energy production. And in fact, there's the communication back and forth between the nucleus of ourselves and these mitochondrial DNA that's imperative to health. Well, I'm gonna make the case that actually every single disease, from cancer, to cardiovascular disease, everything related to ageing, osteoporosis, everything comes down to mitochondrial dysfunction. Lisa: Wow. So this is pretty– Dr Yurth: It's imperative and, and you're gonna start reading more about this, is that the key to fixing our health is going to be fixing the mitochondria. And we've already figured out like, you know, you I know you're big into NAD that, improving NAD and I know you have a product that does that. And that is— that's critical, right? To mitochondrial health. We know that's critical to mitochondrial health. But there's more to that story. And the big thing is that is that piece of communication, that mitochondria sends messages out to the nucleus, and the nucleus sends messages back to the mitochondria. Lisa: Okay, so what are these messages that they’re sending backwards and forwards? And why does this have to do with the function of the mitochondria itself? Dr Yurth: Well, there's, as the body goes through the oxidative phosphorylation pathway, that Krebs cycle, that cycle that makes energy, right. And we know that we create these free radicals. And that's been one of the big theories of ageing is this free radical theory of ageing, that mitochondria produce all these free radicals, as free radicals overwhelm the body, they damage cells, and we get damaged tore into our DNA? Hmm. Lisa: So we all thought that antioxidants would be the answer, recommended… Dr Yurth: Right. We just take a bunch of antioxidants into the mix, and you're going to be great, because now, all those free radicals, you're not going to have any damage. The problem is that we know that there's been this—the mitochondria has a very, has a way to handle this oxidative stress. So there's a few things that happen. Obviously, stress is really critical to the mitochondria’s health. So as it creates these free radicals, and and it's rust by things, it actually produces what are called mitochondrial peptides. So it has its own genome, right, that's now been activated by this stress. And it creates these—its own peptides that no other structure in your body can produce. So it's producing these little chains of amino acids. And there's quite a few being developed now or that or that we were learning about, but the sort of the three main ones that we kind of have a pretty good knowledge about right now are something called MOTS-c. There's another one called humanin, and another one called SS-31. And those are what—the SS-31s, and a group of them are called small humanin-like peptides or SHLPs. Those peptides, so once the mitochondria is stressed, it encodes this DNA to say, ‘Oh, you need to go out there and tell the nucleus to do some good stuff’. So these mitochondrial peptides now go outside of the mitochondria, and they tell the nucleus to to heal things and get stronger and do better. And then that sends messages back to the mitochondria. So that stress, that oxidative stress actually, it's just like, you know, what doesn't kill you makes you stronger. Lisa: And actually it’s a fact on this. Dr Yurth: It’s really a fact that mitochondria health, that these medical peptides are imperative to health. In fact, humanin which were first developed actually was looking like a cure for Alzheimer's. And it may be really—well, it may be actually very, very baffling here, but very, very helpful in dementias and a lot of other diseases. We know that higher levels of humanin, people who live to be a hundred and above have much higher levels of humanin, so we know that these mitochondrial peptides, the higher they are, the healthier you are. No mitochondrial stress. If I just impound my body with antioxidants all the time, then I'm actually probably doing some damage. So cancer, right, so where—now again there, I can also overwhelm, right? There's also another response, the mitochondria have, it's called the UPR, unfolded protein response. So as the mitochondria are stressed, and these damaged proteins that are produced when we're under stress, right, we get damaged or proteins, that's where we're kind of linking that to Parkinson's and Alzheimer's and some of the plaques that form... Lisa: The tau proteins and things. Dr Yurth: Yeah, yep. When the mitochondria is stressed, it actually sends messages out to the nucleus to activate what's called the UPR, the unfolded protein response. A little protein response actually takes these bad proteins and it strings them back out and makes them normal. Or it says, ‘These guys are so damaged. Let's just get rid of that mitochondria and initiate basically autophagy or mitophagy, eliminates the bad mitochondria that are too damaged. There's too many damaged proteins. We've overwhelmed the unfolded protein response’. Now it initiates this response to kill off the bad mitochondria. See, if I'm just now taking a ton of antioxidants. Maybe I've blocked this response to get rid of all these bad proteins. Right. And I'm actually inducing more of these bad, abnormal proteins that are going to cause damage. Lisa: I've talked on a couple of episodes with Dr Elena Seranova about—who is a molecular biologist on autophagy. And I think we talked about it too last time. So that's getting rid of the damaged proteins in the cells or in the mitochondria itself, getting rid of it. And we talked about fasting last time and how critical fasting is for autophagy in getting rid of these bad proteins and clearing things out. So if we—so you're saying we can overwhelm this protein, and what do you call unfolding... Dr Yurth: Unfolded protein response, UPR. Lisa: Yeah, we can overwhelm it with too many antioxidants and actually stop it... Dr Yurth: Stop the UPR from being activated. So now we don't actually kill it, we don't actually—either fix the damaged protein or get rid of the cells that are too damaged. Lisa: Wow, okay. And so in this is this two-way communication between the mitochondria and the DNA, this is the nucleus of the cell. This is all within the—if we picture a big, nice fat round cell, and inside, you've got thousands of mitochondria per cell. And you've got the actual nucleus, which has that nice double helix, you see in the graph– Dr Yurth: Where all the DNA is. Lisa: –where the DNA, your code for life is– Dr Yurth: Right. Lisa: And these are talking backwards and forwards to each other to keep the health of the cell good. And then when we do autophagy, or mitophagy, we're getting rid of the damaged parts of the proteins that have been damaged through—is this through, so the damage that occurs in the cells is happening because of DNA breaks? And what are toxins and things like that, right? Dr Yurth: Exactly, these reactive oxygen species that you know, they're starting to damage the DNA too much inside the mitochondria and creating abnormal proteins. Right? So now we've created these dysfunctional proteins that are going to do damage, so the body tries to get rid of them. And it's not, I'm not gonna say there's no place for antioxidants, right? But what you have to be careful of, is sort of cycling through phases where you're off of your antioxidants, and maybe inducing more autophagy, right. So we now want a little more oxidative stress to induce this healing response to give the cell some stress, and then maybe going on antioxidants for a little while to make sure that we don't ever have too many. Lisa: Yeah, if you've gotten a lot of antioxidants, or sorry, or oxidative stress, because maybe you're exercising a heck of a lot or you've had an infection, or you've got something other high stress... Dr Yurth: You eat like crap, or you're fat or… Then you might need extra antioxidants. And just to support the baseline of your functional health. But even those people, right, need them off and on, they should not be constantly. They should do phases, right? They should cycle it. I'm just a big advocate with diet, with exercise with everything, everything's done so quickly. Because we want to go through phases all the time, where we're getting rid of bad stuff, and then regrowing and getting rid of bad stuff and regrowing. Right? It’s just like cleaning your house. You got to get rid of all the crap, but then you're gonna… Lisa: Bring the new groceries. Dr Yurth: Yeah, right. It's get cluttered again. And then you got to go clean it all out again, and things get cluttered again. Yeah, I mean, that's the world's clutter wouldn't happen, but it does, right. Even the most pristine non hoarder person, there's still clutter that happens, and you still have to do your spring clean outs. And that's—so I like to think about the body in the same way, you know, going into the spring clean outs where you go through a big autophagy phase where you're fasting, we're using hydro spermidine, where you're using things that will help to really clear out all the bad cells, all these damage, mitochondria that are producing too many reactive oxygen species, right? And then going through growth phases, where where I'm now maybe I'm inducing a little bit more toxic stress, I'm exercising harder, I'm lifting more weights, I'm running more, right, I'm inducing more oxidative stress. Maybe I'm eating more calories during that time. Now there's more oxidative stress cells a little bit stressed that actually initiate some growth and some healing. Right. And then I can do the same thing over and over again. But there's really interesting new research leads when you kind of look at ‘Okay, well, how does this all make sense’? So it's probably going to come down more to this. This is what's called the MPTP or mitochondrial permeability transition pore. And what they've now found is that that's probably where we need to focus is this little pore is letting stuff in back and forth through the mitochondria. So the right amount of things get through. So we know this little pore opens and closes. As we're in worse health, or older, it stays open longer, allowing more bad things to go In and out. So it's designed to open periodically, closed periodically. So for brief periods. So what a lot of focus now is on anti-ageing. And mitochondrial health is focusing a little bit on this mitochondrial transition pore. In fact, there's a really cool study just came out where they're actually taking out these mitochondria and actually changing the pore structure for treating cancer. So they can actually make the pores in these cancer cells more permeable, so they can get drugs with a little nanobot that's poking holes in the mitochondria. But on our home base, is what we really would rather do is keep these little mitochondrial transition pores closed most of the time, let them open periodically. So there's some interesting things that do that, melatonin does that? Oh, so higher dose melatonin seems to work primarily on this pore to actually regulate keeping it closed more often. So it’s spermidine, that's one way spermidine induces cellular or mitochondrial biogenesis is by restoring this pore structure. Lisa: And we're big into augmenting spermidine. I've just got my first shipment, I'm working on getting that down here guys. Dr Yurth: Spermidine is kind of amazing. Because it really is so good for mitophagy, getting rid of bad mitochondria, but also mitochondrial biogenesis probably because it does focus a little bit more on this pore. Making more mitochondria, right. Right, make more mitochondria, we need more mitochondria. The other thing interesting, I don't know how many of—how you or your listeners have looked at things like minocycline, right? Antibiotic, we always think antibiotics are bad, right? Yeah. Well, interestingly, minocycline and doxycycline. And minocycline is a little bit better, probably actually has a very nice anti-ageing effect, used periodically, to actually close off these pores, and let the cell kind of develop and grow more than mitochondria grow more. So minocycline has a really distinct effect on the mitochondrial transition pore as well, for this permeability pore. So there are a few simple things that you can use, and I like. Lisa: And it doesn't want your good microbes and stuff when you take them. Dr Yurth: You know, definitely antibiotics have the downside of changing the gut microbiome. And we know that there's downsides to that, which is why you're not going to stem minocycline all the time. But like anything, it appears to have some very significant benefits in our cell health. So by doing that, maybe twice a year, doing like a 10-day course of minocycline, you can actually restore cell health. Now, after that, do you have to really work on gut health? Probably depends on how bad your gut is. So if my gut is super healthy, it's probably gonna regenerate, divide, right? Otherwise, it would, I have a lot and I know you're really interested in some gut microbiome stuff. Because you're gonna be a really—you're gonna see a really big connection coming up here soon between the gut microbiome and mitochondria even. But we know the gut microbiome is most affected by butyrate. So using tributyrate, which is sort of pre-butyrate that can turn to be right in your intestine. So if I had somebody on an antibiotic, do I throw—I'm just gonna throw probiotics into the mix? Well, no, because the probiotics aren't gonna survive. So what you have to do is first throw butyrate into the mix. Remember what the good bacteria in our gut do that we eat fiber? The anaerobic bacteria. Turn that fiber into butyrate. Butyrate has all these far reaching effects. Number one, it's imperative for the colonocytes, the colon cells to be healthy, that's what they—that's what they use for energy is butyrate. So they're different from your other cells, they use butyrate for energy. So when they use butyrate, for energy, I have these nice healthy colonocytes, they create a nice anaerobic environment where my anaerobes can thrive. And they can make more butyrate. And you have this nice cycle. But butyrate has some really interesting effects. There was a great study for your distance runners using butyrate to increase performance. Because higher levels of gut butyrate also seemed to help the cell, the mitochondria, and actually produce you actually, were able to use the butyrate for fatty acid oxidation and actually improve aerobic metabolism by having higher levels of butyrate. Lisa: Was it like yeah, the athletes with keto. Yeah, because butyrate is like, isn't butter got butyrate in it? Or am I? Butyrate, butter. Dr Yurth: Oh, butter. So butter does have butyrate in it, yes. So you can even increase butyrate by eating a whole lot of butter. You'd be—so your medium chain triglycerides, the short chain fatty acids do have butyric acid in them. The problem with when you eat butyric acid, when you eat butyrate, it doesn't really reach this lower intestine very well. Okay, and so even though it has some benefits, probably some other places, you really have to get the gut bacteria. And so the only way to really get butyrate to the lower intestine is either to take a pre-butyrate form, which is I like tributyrin, one has research behind it, or to use it rectally. So that's the other thing you can do is use it rectally. Lisa: Okay, then that gets direct into the colon and then can get the right to the cells there. Dr Yurth: Yeah, and this actually has a genetic—do you remember your PGC alpha gene? So when you get hired to get butyrate, you actually upregulate PGC alpha. And that's one of the things that improves aerobic endurance in your long distance athletes. You can actually—they did a study with butyrate on improving endurance in sort of your distance runners, your higher level endurance athletes, and besides, it's significant improvements. Also in race horses. Same thing. So butyrate does affect mitochondria in other places, including skeletal muscle, and around that. So there is this big connection that we're just learning about between the gut microbiome and mitochondria. So if I'm going to put somebody into minocycline. I'm going to also make sure I have them on tributyrate so I'm keeping that nice anaerobic metabolism going. I'm making sure I'm getting butyrate to myself. Now I've repaired the mitochondria. I've given it another source to work better. And I'm going to have overall better endurance, better health, better aerobic metabolism. Better Vo2max. Lisa: Yeah, wow, that's just crazy. So butyrate—but if we just taking butyric acid or in through butter or that type of thing. Brother just arrived in the background. It’s all good. Podcast life. At least the cat’s not running from down as well. So butyric acid, when I take it in the form of say medium chain triglycerides or butter and stuff, it's not going to help my colonocytes and my colon, but I still get through to the mitochondria and help. Dr Yurth: Yeah. I mean, there's significant benefits to it, but you really want to replenish the butyrate in the lower intestine, where you really need that for overall health. You really have to either do it rectally, or take it as a pro butyrate or a pre-butyrate form or tributyrin– Lisa: Tributyrin. I'll put that in the links. Dr Yurth: You know what is interesting, my patients who have the worst, now are the sickest, like I take care tributyrate. I have no problems with it. I'm fine. I feel good and most people. But if you're sick or not well or have a bad gut and you take it, you'll feel pretty miserable. Because you actually can't turn it into butyrate very well and it actually causes a lot of GI distress. So some of those really sick people the only way to replenish butyrate first is to do a rectal suppository. So you can get rectal suppositories of butyrate right. You do like a high dose, like two grams of a rectal suppository, butyrate, replenish the butyrate then you throw like a spore probiotic or probiotic and now I've created this nice anaerobic environment I've replaced the good bacteria. Now actually they do fine as a maintenance with the tributyrate now that I've restored the gut health. For people who are not well, and I'll tell you, if any of you patients or your people, you talk to your clients, you talk to them use him take tributyrin, and they get they're like, ‘Oh, I'm nauseous, I can't take it’, or ‘Gives me diarrhea’, but it's because they have a bad gut and you've got to work, you know, right? Yeah. So tells you, right, that you need to replenish the butyrate. And again, the only way to do is rectally. Lisa: Can you buy that as a consumer without a doctor who's until…. Dr Yurth: But there is a company and I don't know that, here in the US that's called MitoZen. That does make a pro-butyrate, it's a suppository. It's a two-week course, you have a high dose butyrate and it's actually pretty cool as a spore biotic mixed in. So I use that product a lot. It's on the pricey side like all this stuff. But I really find like a two week course of it. People do pretty well. All you do is two weeks of it, and then you can get them into the oral much less expensive form. The rectal butyrate smells bad. One of my patients, like ‘All my dogs are following me everywhere’. Other people—when you're doing I don't think other people can smell it on you but you can kinda smell it when you do it. It’s kind of like urine. Some people don't like the smell of, I don't mind the smell of that, but some people say they don't like the smell of that either. Lisa: Okay, men and tributyrate, so if he’s not really sick, so if they’re really sick. So if you've got something like Crohn's disease, or IBS, or something– Dr Yurth: Those people you wanna do the rectal, and they do amazing. I will tell you, they do amazing. There's a big stage just coming out with Crohn's being a mitochondrial disorder, too. It's got mitochondrial disorder, but IBS, your SIBO patients, you put them on the rectal butyrate, two weeks so that they do absolutely amazing. Honestly, it's incredible how well they do in a lot of illnesses. I mean, it's been our go to for a whole lot of different disorders. And it's amazing how well it works. As you're learning the gut is everything. And now we're learning it may even be imperative to the mitochondria. Lisa: So how does it connect with mitochondria? So that piece here I've sort of like, haven't quite got in my head. How does—like you said, mitochondria are the basis of health, because they are the ones that are producing the energy for the cell, talking to the nucleus, they're causing this cascade of different events in the cell. They're actually producing ATP, which is our energy. So if you look at things like say, as you get older, your EGFR goes down, your function of your kidneys, in other words, starts to deteriorate. And this is, as an ultra endurance athlete, we smash the crap out of my kidneys with rhabdomyolysis a hundred times. I've had real battles getting my EGFR back up and managed it to quite a good degree, but it's still a problem. And as we get older, we sort of lose about 1% a year they say, of kidney function. So then it’s just another example of it's actually the mitochondria that in this case, and the kidney cells that are not able to do their energy production to do what the kidney cells should be doing. So how can we reverse that train and get our kidneys working in this case, or our brain or in another case, or heart cells? All of these areas are affected by the mitochondrial function. And how does that link connect to the gut situation? Dr Yurth: So it connects to the butyrate because what butyrate does, at the mitochondrial level, is increases PGC-1 alpha and AMPK. And so you're, you're inducing on a genetic basis, a better oxidative capacity, right? So you're restoring the oxidative capacity to the cell, the mitochondria healthier. And so it's really working—the butyrate and searching fatty acids are really working on a genetic level, probably primarily at PGC-1alpha, I think we'll probably find more and more because this is very new. But it looks like that PGC-1 alpha is where it's happening is a very distinct effect on mitochondria. And then the AMPK through the ACC pathway. So basically, I think, if you think about it, probably from your training and everything, think about it as an epigenetic influence changing genetic output, right. So that's probably where the short term fatty acids are working in terms of mitochondrial health, I think there's going to be more to that story. You're right, kidney disease brain to these, everything comes down to we have to have mitochondrial health. So exactly what you said, first, have a healthy gut, let's replace the butyrate. Because we know that that's important for those pathways, then, what we have to do is go through phases where we really induce mitophagy. That's where you're fasting and your spermidine comes in, right. So we've got to basically induce, get rid of all the bad mitochondria. So that's gonna induce mitophagy right. So get rid of all the bad stuff. And then we want to do more of a build up phase. So what I'll do is all patients go through different courses, 6-12 weeks of really kind of more real time food restrictions, and using spermidine at a higher dose, and I'll get them sort of clean slate right. Now I want to regrow and that's where I want to actually regrow in. So I'm gonna have them now, get a little bit less out of eat a little bit more a little less calorie deficit, I want to create a little bit of oxidative stress because now I'm going to induce those humanin-like peptides, those mitochondrial peptides, my MOTS-c, SS-31, the small humanin-like peptides, humanin itself. So we know that those are so imperative for ageing, and that when those peptides are released, they induce your nucleus to have a healthier genome. So now I'm going to have everything else be healthier, because it's going to send messages back to the mitochondria, mitochondria is going to be healthy, but then that's gonna get overwhelmed after a while. So then we go back into our, you know. So when you think of things that way, always that sort of breakdown-cleanup, breakdown-cleanup, kind of an easier way to live right? Don't get bored. Always live in this super restricted capacity. Lisa: Especially with calorie restriction and things. Dr Yurth: Yeah, like caloric restriction and right eating very low calories. Yeah. Lisa: It makes you miserable too. Dr Yurth: That’s right. And so when you can tell—when you tell people listen, I want you to do this for 12 weeks, and then we're gonna let you kind of, you know, have a little me, I'm not gonna tell them go eat cake, but we're gonna be able to, you know, do a little bit more and go through growth phases. And people feel better, and they look better and they have more muscle mass, if you're always in that AMPK state right, that break down, but not really break down state but that more longevity stat, more catabolic state more, yeah. Which is good for longevity, right? But when you look at those people, they always look so healthy. I'll look at someone's people. And you're like, I mean, sometimes they don't have much muscle mass, their hair is thinner. So we do want to go through these phases where we allow the body to kind of grow a little bit, right, especially if you want some muscle, we know that muscle is imperative to health. And thenI think we're sort of in the long term now they've got the mitochondria in this good homeostatic balance state where I've gotten it, but how do I keep that reactive oxygen species as low as possible? That's going to be where you look at them. That mitochondrial transitional pore, where, how do I keep that balance? And I think that's where maybe a lower dose spermidine every day, like one or two tablets every day of spermidine but I love melatonin for that purpose. Lisa: I wanted to come back to melatonin. So I understood like melatonin—I was a little bit hesitant to take melatonin because it can change or can fix your circadian rhythms and so on. But after listening to you a couple of times talking about melatonin, why is it not a problem then? Do we take it at nighttime? And what sort of dosages do we need to take? Dr Yurth: It’s interesting. I mean, we will dose—so for my osteoarthritis patients who have, for instance, high levels, most patients who have diffuse arthritis, or degenerative discs have very high levels of a cytokine called interleukin 1 beta. Interleukin 1 beta is very damaging in mitochondria, that's probably one of the reasons you get cell death and, and your chondrocytes all die off. So one of the things we know blocks interleukin 1 beta is higher dose melatonin. We also know that that's very anti-cancer, right? Probably for the same reason it's creating this balance, this homeostatic reaction in the mitochondria. So I actually like, in those patients, high dose melatonin, a high dose melatonin sounds interesting. Unlike the lower dose melatonin, it sometimes actually has more of a stimulating effect. But it actually does help restore your own circadian balance at a higher dose. I have a lot of people who take it in the morning, because if they take it at night, they actually are stimulated by it. If you take in the morning, they're sleepy at bedtime, and they sleep through the night. While I'm working with your own. Your super charismatic nucleus and tinea, we're kind of brain level, a kind of balance you back out. Lisa: So what sort of level is like, I'm at the moment, just me personally, anecdotally, I'm taking a five milligram dose of melatonin at night time to optimise my sleep. And is that a low dose? Is that or is that a high? Yeah, what is the high dose? Dr Yurth: So high dose is like 20 milligrams. We use the high doses in our people who have osteoarthritis primarily, cancer, we use high dose melatonin, especially your breast cancer patients will use high dose melatonin. So we'll use that, you know, as a trigger adjunct. Not always, you really have to kind of work with people, there's people who do great take in at night. One of my sons does great, it's 20 milligrams of melatonin at night. Sleeps through the night and wake up early in the morning. Me, I actually take it in the morning. If I take it at night, I'm wide awake all night. But if I take in the morning, I have a really nice, good sleep with good deep sleep on my Oura ring. I get a good hour and a half of deep sleep. So it seems very different in different people and how it's interacted. And I'm sure that has to do a lot with kind of genetic, what are your clock genes? So I think that that probably has a little bit of a genetic influence. And I do have people who just don't follow—can only tolerate very low dose. You know, but we're finding more and more reasons to be very cautious with oh, you don't really want to take more than three to five milligrams of melatonin. Yeah, really finding that the higher doses seem to have a very advantageous effect on... Lisa: Without putting your body clock out. You're super right. Dr Yurth: Actually, potentially really benefiting your body clock, your circadian rhythm, which is critically important. And right now, that's one of the sort of easy things we can do that we know is going to be working. And as I said, I think what—it's going to come down to when we look at this mitochondria, it's not going to be trying to figure out what is my perfect dose of antioxidants. It's gonna be figuring out how do I get that mitochondria with the pores, letting the good stuff in, letting the bad stuff out? Yeah, in the right sequence because we know that, for instance, cancer cells that port stays open all the time. There's this very imbalance in this other mitochondria are really getting all this stuff all the time. So we know that a huge factor to health is trying to restore this normal port. I think that we're—there's a drug that's coming out. I can't remember the name of it. Yeah, I can't remember the name of it, but that will probably be actually really, if we can get it will be actually really interesting. It's actually coming out for the treatment of ALS. But that looks like it might be really helpful for that pore. Lisa: They’re shutting the mitochondrial pore. Dr Yurth: Yeah, I mean, if that will be something we can get. I don't know. But we'll find more things. Like I said, I think minocycline is a really nice thing to go to, like twice a year, I'll use a 10-day minocycline course, really benign. Lisa: Minocycline. How do you spell it? Dr Yurth: So, minocycline, M-I-N-O-C-Y-C-L-I-N-E. Cheap antibiotics. I mean, it's like a $10 antibiotic. Right. And that has, but it has really—and it's been looked at in the anti-ageing field for a while, but we kind of weren't so clear of its effect on the mitochondria. Well, now we actually have found it's actually working on this pore, to actually balance out and keep the pore closed more, which is what you really want. When we're young, the pore is not open as much as it does when we’re old, there's less bad stuff coming through the mitochondria. Lisa: So itis getting porous, isn't it? So basically, the membrane is getting porous. Dr Yurth: Exactly, that's probably where—like some of the mitochondria peptides like SS-31, which was the cardia lipid membrane, which helps them that endoplasmic reticulum inside the mitochondria to be healthy. So that's why peptides like that are so beneficial. Lisa: Yeah, yeah. And there's lots of, you know, we can't get these fancy peptides, unfortunately, that easily. The caveolae pan is an enzyme that is a very important enzyme for us. It's a stabilising enzyme, isn't it? So, we want more of this and this is what one of these peptides is right. And so hopefully, there's going to be more research around that and more drugs even coming out around that. Dr Yurth: Yeah, and remember that one of the ways we induce some of these mitochondrial peptides is exercise. Right? MOTS-c is a little bit of stress for our body, right and so it reduces the mitochondria to produce some of these mitochondrial peptides. MOTS-c which is kind of considered exercise in a bottle because you can actually give at least mice you can give them MOTS-c— basically this mitochondrial peptide and it acts just like exercise. Lisa: Exercise hermetic. Dr Yurth: Yeah. So it's very cool. Of course, it's very expensive and... But way cheaper to go exercise, but it's a nice thing to offer people who can't exercise for some reason. Like, you'll have an injury or elderly people who are just so sarcopenic and trying to get them to do anything until you build a little bit of muscle is almost impossible. So things like that are going to be really nice in that realm as peptides like MOTS-c. There's a whole company here that is actually just working on these mitochondrial peptides as drugs for treating things like this. Right now, we know that one of the best ways to produce MOTS-c is to exercise, stimulates your mitochondria to be a little stressed. Mitochondria produces more MOTS-c. MOTS-c helps with glucose metabolism, it helps with fat loss, it helps with turning white fat into brown fat helps. It helps with kind of overall aero metabolism. Lisa: Just briefly on that. What is white fat versus brown adipose tissue, you know, brown fat? And why is brown metabolically active? Dr Yurth: Yeah, so you know, white fats what—that fat we get as we get older and you know, it's really doing nothing beneficial. Brown fat is what little kids have, right? Brown fats—we look at babies or you look at little kids and they have that little chubbiness. Well, that's usually brown fat. Why? You know, maybe boys made fun because I'm always cold and so I'm way overdressed. My kids, but little kids don't get nearly as cool. We don't have to like them quite so bundled up as we do, because they're really covered with brown fat, which is metabolically active, that's what it was designed for. And when you're born you have this brown fat, you can stay warm. I mean, really, we were meant for survival, right? These babies who are born, they need something to keep them you know. Also there when you were caveman and you were just laying there in the cave, you survived. So brown fat is metabolically active, it's helping for warmth and heat production. It's actually burning calories. White fat is what we get as we get older and we just eat too much and we sit around too much. And all it does is coat our organs and do nothing beneficial. So brown fat actually you can convert white adipose to brown adipose, so you can turn it into metabolically active tissue. Then you're actually going to be able to burn more calories and you'll be way more metabolically active. You actually want brown fat. You can convert white fat to brown fat. You know, and that's probably does come down to—that's one of the things that when you looked at butyrate it was one of the places that butyrate actually worked was actually helping to convert more brown fat and white fat. So there was a big problem putting people on butyrate can really help with fat loss using butyrate and if you're overweight people who are all have metabolic their guts are horrible. Yeah, uterine those patients can really help with fat loss. Lisa: I just had Dr Austin Perlmutter on you know, probably… And he was talking about the white fat cells, the visceral fat cells having not a consciousness but they have an ulterior motive to keep themselves alive. So they seem that all these—make you hungrier, send out inflammatory compounds and so on to make sure that they stay alive. They end up killing the host in the end. But like a cancer cell, they although they have their own agenda independent of what was actually healthy for your body. So they don't want you to do fasting. They don't want you to do any of these things, because they're not going to get knocked off. Dr Yurth: Yeah, I mean, fat is metabolically active too. Remember it converts—fat cells have—they convert testosterone to estrogen. So men who are fatter will start converting all their testosterone into estrogen. So it's one of the places that that we have, you know, aromatase is inside fat cells. White men tend to have bigger breasts, and you know, is that fat cells actually are converting very mostly into this bad estrogen. So even your testosterone, you put them on testosterone, a lot of them just convert it to estrogen. Lisa: Wow. So that's independent of your innate genetic pathway for your hormones. Dr Yurth: Fat cells have aromatase. Fat cells have aromatase. Lisa: Oh, wow, that's—I didn't realise that. I mean, I thought your genetic pathway was your genetic pathway. And you'll be converting your testosterone to estrogen is more if you have that genetic predisposition. Dr Yurth: It's certainly genetic there. But yes, that fat guys have breasts, right? You look at breasts because they're very estrogenic. And so if you try and get—if you take some of your overweight males, and you put them on testosterone without using things to block estrogen or getting rid of fat first, then you just keep making more estrogen, making more fat. They’re making it worse, right? Lisa: So okay, so it's not just to do with your genetic pathway, but also to do with how much fat you have. And the more fat tissue the more estrogenised you’ll be. That's in the new—okay. So that's why. Because you see, a lot of young people nowadays are thinking over probably growing up with less quality food than what we grew up with in our generation, seem to be more estrogenised and have more of these issues, and the actual body shape, the phenotype, the way it secretes, is this more estrogenised than past generations? Dr Yurth: We're seeing a lot of twenty-year olds who come in, who have high estrogen levels, low testosterone levels. I think drugs have to do with that, too. I mean, here in Colorado, we have legal marijuana, which is unfortunately not very good for testosterone. Lisa: Oh, wow. I didn’t know that either. Marijuana is not good for testosterone. Dr Yurth: It's not good for testosterone levels at all. And then our food, right, bisphosphonates all these things that are so we're seeing this you know, these really young guys with testosterone levels that that you're a god awful. Lisa: And then estrogen levels higher than the... Dr Yurth: Estrogen levels that are high, right? Lisa: Yeah, I just did my estrogen levels and my—I know mine are low because I'm going through menopause and so on. And I was looking at my husband's and I was thinking, ‘Oh, it was about…’ Dr Yurth: You do start good to see that right. You start to see that these men—these older man look like woman, it switches. Yeah. You know, and they start taking on more female build, right? They get the bigger breasts and bigger bellies and they start getting this more female build to them. Lisa: I mean, I've had lots of things so that it's not it's you, going the other way and there's testosterone is good and bad. Yeah, that is what you see in older and older men is that tendency to go and eat. It's really really hard to get testosterone replacement therapy or hormone replacement therapy for men or—for woman a little bit easier. They've seen you know, the doctor seems... I am willing to give it to woman but well, this integrated medical fraternity for bioidentical hormone replacement? And, you know, it's so easy... Dr Yurth: It kind of kills me because I get this—we're putting together this course called what to fix for us to kind of help people. In this journey of getting healthy, what do I do? Because I'm overwhelmed. And as I was putting together, I was like, ‘Okay, well, you start with exercise’. And that's it. No, actually, you kind of have to start with hormones. Because if I take somebody who has no testosterone, and no hormones, they have no progesterone, so they can't sleep, they have no testosterone, this is both men and women. So you know that their joints hurt, because there's progesterone receptors on joints, they've no testosterone. So trying to get them to go into the gym, and is impossible. So for me to say, follow a good diet, do exercise without replacing hormones. It's really kind of not right, right. I mean, as I was putting together a talk, I said, you know, actually, the first thing I do is get these people hormone stabilised, because then I'm going to go to motivate another, their testosterone levels are good, they feel m
In this episode, I interview the NIH team who brought you VEXAS! Hear different points of view of this disease, how it was discovered, clinical presentations, as well as where this research could lead. Then, we wrap up with Dr. Kastner’s historical take on autoinflammatory disorders! Intro :11 In this episode :12 Big thanks to Peter Grayson, MD, MSc 2:07 About our guests 2:30 The interview 5:10 How did VEXAS come about? 5:37 You had an idea of where to start looking? 6:58 What should rheumatologists know about ‘somatic mutation’? 12:31 Do you think this could be a clue to other conditions? 13:37 Can you tell us about some of the unique aspects that we see in these patients with MDS that make them atypical? 17:14 How’s the clinician going to see or note the vacuoles? 18:53 Do we have kind of a pathway for how the vacuoles are forming based on what we know about ubiquitization or is that unclear? 20:51 What’s going to raise the antenna that this isn’t “run of the mill x disease”? 23:33 How, in your experience, have patients responded to diagnoses being changed? 37:15 Where does everyone see the therapy going for this condition in the future? 41:15 Do we think that with this approach that this is going to “reshuffle the deck” of what we call certain diseases from multiple different specialties over the next decade? 44:02 Would you mind walking us through a little bit about FMF and how the different variants you saw led to further discoveries? 49:46 What was known about IL1 at the time? How did that knowledge of IL1 come along? 52:53 It’s such a true honor to have you all on 57:42 David Beck, MD, PhD, is a genetics fellow at the NIH. He can be reached at david.beck@nih.gov. Marcella A. Ferrada, MD, is Lawrence Shulman scholar at NIAMS. She can be reached at ferradama@mail.nih.gov. Peter Grayson, MD, MSc, is head of the Vasculitis Translational Research Program at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and associate director of the NIAMS fellowship program. He can be reached at peter.grayson@nih.gov. Dan Kastner, MD, PhD, is an NIH distinguished investigator in the Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch; director in the Division of Intramural Research; and head of the Inflammatory Skin Disease Section at the National Human Genome Research Institute. We’d love to hear from you! Send your comments/questions to Dr. Brown at rheuminationspodcast@healio.com. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum Disclosures: Beck, Brown, Ferrada, Grayson and Kastner report no relevant financial disclosures.
This month on Episode 18 of the Discover CircRes podcast, host Cindy St. Hilaire highlights four featured articles from the October 23 and November 6 issues of Circulation Research. This episode features an in-depth conversation with Drs Eric Boilard from the Université Laval in Quebec, Canada, and Fadila Guessous from Mohammed VI University of Health Sciences in Casablanca, Morocco regarding their study titled Platelets Can Associate with SARS-Cov-2 RNA and Are Hyperactivated in COVID-19. Article highlights: Feng , et al. No Contribution of EMPs to Endothelium Lin, et al. Step Count and Predicted CVD Risk González-Hernández, et al; Sox17 in Developmental Coronary Arteriogenesis Khawaja, et al; HIV Antiretrovirals Alter Endothelial Activation 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 and today, I'll be highlighting four articles selected from the late October and early November issues of Circ Res. Dr Milka Koupenova, who is a platelet expert at the University of Massachusetts Medical School, will join me to interview Drs. Eric Boilard from the Université Laval in Quebec, Canada, and Fadila Guessous from Mohammed VI University of Health Sciences in Casablanca, Morocco. They're here to discuss their study, Platelets Can Associate with SARS-CoV-2 RNA and are Hyperactivated in COVID-19. Dr Cindy St. Hilaire: The first article I want to share is titled No Evidence for Erythro-Myeloid Progenitor-Derived Vascular Endothelial Cells in Multiple Organs. The first authors are Teng Feng and Zibei Gao, and the corresponding author is Hui Zhang from ShanghaiTech University in Shanghai, China. Dr Cindy St. Hilaire: In the early stages of mammalian embryogenesis, a population of cells called mesoderm-derived angioblasts, gave rise to self-renewing intraembryonic endothelial cells, that go on to populate the entire vasculature of the growing fetus. Recent studies have suggested that there is an additional embryonic source of vascular endothelial cells that is derived from erythro-myeloid progenitor cells, also called EMPs, that are found in organs such as the liver, the lung, the heart, and the hindbrain. Dr Cindy St. Hilaire: Evidence of an EMP cell source for vascular endothelial cells stemmed from the use of mirroring cell lineage tracking models. However, the authors of this study argue that these former conclusions were based on flawed genetic tools. To mark erythro-myeloid progenitor cells, the initial study had used a set of supposedly EMP-specific transgenes. However, transgenes are notoriously leaky, meaning, that cells other than EMPs may have been marked. To more accurately mark EMP derived cells, this study used a reporter that they integrated into the endogenous loci of a gene, CSFR1, which is specifically expressed in EMPs. Using this model, they failed to find any evidence of EMP derived vascular endothelial cells in any organ, thus they consider it unlikely that EMPs give rise to vascular endothelial cells. Knowing the true origin of vascular endothelial cells is essential, as it informs the design, development of treatments, and regenerative medicine approaches for vascular diseases. Dr Cindy St. Hilaire: The second article I want to highlight is titled Association of Habitual Physical Activity with Cardiovascular Disease Risk. First author is Mayank Sardana and the corresponding author is Honghuang Lin, and they're at Boston University School of Medicine. Everybody knows that exercise is very good for overall cardiovascular health and current government guidelines suggest a minimum of 150 minutes of moderate to vigorous exercise per week is necessary to keep hearts healthy. There's an ever-growing interest in the use of smart watches and fitness trackers to assess an individual's activity, and many people believe that 10,000 steps a day is a good health goal. However, it's unknown whether the data obtained from smartwatches actually aligns with cardiovascular health prediction. Dr Cindy St. Hilaire: To address this gap, this study recruited participants from the Framingham Heart Study to wear Apple smart watches for a month. The participants had also undergone a 10 year atherosclerotic cardiovascular disease risk assessment based on their age, sex, cholesterol levels, blood pressure, diabetes diagnosis, and smoking history. The step count and activity data from 903 participants found that for every 1,000 average daily step increases, there was an associated 0.18% reduction in predicted cardiovascular disease risk. This association was weaker but still significant after adjusting for body mass indices. The authors conclude that like other measures of activity, those recorded by smart watches are correlated with better cardiovascular health. Dr Cindy St. Hilaire: The third article I want to share is titled, SOX17 Controls Emergence and Remodeling of Nestin-Expressing Coronary Vessels. The first author is Sara González-Hernández and the corresponding author is Joan Isern, and they're from Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain. The exact signals and mechanisms that regulate coronary vascular development are not fully characterized, yet defining these pathways could provide valuable insights into both life threatening congenital coronary abnormalities as well as the neovascularization process that occurs after myocardial injury. To examine coronary vasculature development in more detail, this team created a transgenic reporter system, which used an enhancer region within the Nestin gene to specifically label mouse coronary artery endothelial cells. Dr Cindy St. Hilaire: Cells were isolated from developing embryos at stages of vessel sprouting and vessel remodeling, embryonic days 13.5 and 17.5 respectively. And transcriptional differences were assessed between coronary and endocardial endothelial cells. They found that the transcription factor SOX17 was more highly expressed in these coronary endothelial cells compared with the endocardial endothelial cells, and that expression of SOX17 increased between these two time points that hearts were collected. Coronary specific deletion of SOX17 in genetically engineered mice lead to severe defects in arterial remodeling, confirming the transcription factor's role in coronary vessel development. The team suggested that perhaps SOX17 could be a future therapeutic target for conditions, where promoting coronary artery regeneration or remodeling might be of clinical benefit. Dr Cindy St. Hilaire: The last article I want to share with you before we switch to our interview is titled, HIV Antivirals Affect Endothelial Activation and Endothelial-Platelet Crosstalk. The first author is Akif Khawaja, and the corresponding author is Michael Emerson from the Imperial College, London. Infection with HIV is not the death sentence that it once was. With a regime of continuous anti-retroviral medications, the disease can be managed for the long term. Now that people with HIV are living longer, it is clear that they are at a greater risk of developing cardiovascular disease, possibly due to the off-target effects of these drugs. One HIV treatment, Abacavir Sulfate or ABC, was found to cause a 90% increase in the relative risk of myocardial infarction. ABC has been proposed to cause endothelial dysfunction, however a mechanism by which this may occur has not been established. To see if anti-retrovirals effect endothelial cell function, this group tested three drugs; ABC, as well as tenofovir alafenamide or tenofovir disoproxil fumarate, TAF and TDF respectively, on human endothelial cells in culture. Dr Cindy St. Hilaire: They found that treatment with ABC, but not TDF or TAF, caused endothelial cells to produce more cell adhesion protein, ICAM-1, and also tissue factor, both of which promote blood clotting. Endothelial-derived microparticles, or EMPs, are a biomarker of vascular dysfunction, and these were produced in the ABC treated cells, not in the TDF or TAF treated cells. These EMPs also promoted the increase of ICAM-1 and tissue factor expression, as well as the activation of platelets which can induce blood clotting. These results suggest that altering HIV treatments to avoid or minimize endothelial damage could help to reduce the cardiovascular disease risk in HIV patients. Dr Cindy St. Hilaire: Today, I'm excited to have with me Drs. Eric Boilard from Université Laval in Quebec, Canada, Fadila Guessous from Mohammed VI University of Health Sciences in Casablanca, Morocco, and they are here to discuss their study, Platelets Can Associate with SARS-Cov-2 RNA and Are Hyperactivated in COVID-19. Also, with me today is Dr Milka Koupenova from the University of Massachusetts Medical Center in Worcester Mass, and she's an expert on platelet virus interactions, and she also wrote the editorial that's accompanying this article in our November 6th issue. So thank you, everyone, for joining me today. Dr Eric Boilard: Thank you for inviting us. I look forward to reading the editorial. Dr Milka Koupenova: I hope you like it Eric. Dr Cindy St. Hilaire: Yeah, we're spanning a lot of time zones and we're actually having a little bit of technical difficulties so hopefully Fadila is going to be able to pop in. We can certainly see her on our Zoom call right now. But with that, we're many months into this pandemic now and it is blatantly clear that COVID does not just present with pulmonary symptoms. Many organ systems can be affected, such as the circulatory and neurological systems, but one thing that connects all the parts of the body is the blood system, and before we get into the details of the study, I would love to hear how this collaboration between Quebec and Morocco happened. And then, could you summarize the major findings? Dr Eric Boilard: We both, in Morocco and in Quebec, we had pretty much the same working hypothesis that platelets may be contributing to the overwhelming inflammation in COVID-19 and why. As you know, in Morocco the pandemic hit before us in Canada, and they had a committee that studied patient samples and studies were going on. Whereas us in Quebec, in fact to be frank, in Quebec City, we didn't really have the first wave even. So we were very excited to evaluate our hypothesis but we had no clues other than the actual virus. We actually were working with the virus and human platelets from healthy individuals, but no samples from patients. Clinicians in Morocco were very willing to contribute and to perform working on patients so that's how Younes Zaid, the first author of the manuscript, and Fadila then contacted us given our past work on platelets and viruses and the collaboration was initiated. Dr Cindy St. Hilaire: That's wonderful. I love hearing about these multi-institute collaborations. Team science is really the future. I think it really elevates everything. Dr Eric Boilard: Despite the fact that the distance and I mean, it was through Zoom, but we've been doing weekly meetings with the two labs since March. Dr Cindy St. Hilaire: So, can you maybe give us a quick summary of the major findings of your study? Then we'll dig into the details of it. Dr Eric Boilard: Sure. When we actually started the work, what we knew about COVID-19 was that the severity was likely due to the overwhelming inflammation due maybe to a cytokine storm, so we knew that. It was reported that patients with COVID-19 had a lower platelet count and although thrombocytopenia in the patients was very mild or modest, and did not require transfusion, at that time, our hypothesis was that platelets could contribute to inflammation and therefore could release cytokines and other molecules from their granules in COVID-19. So it's only a couple of weeks after that became more of use that thrombosis and cardiovascular manifestations could also contribute to morbidity and mortality. Dr Eric Boilard: Our design was to look at platelet activation in vitro. So there were studies where we performed aggregation assays with platelets from COVID-19 patients, some were severe and non-severe. There were assays where we actually evaluated a number of molecules and plasma from the patients. We looked at granular components, like PF4 and serotonin, that were greatly increased in COVID-19, both in non-severe and severe patients. We looked at vesicles, or microparticles, released from platelets that were also increased, and cytokines. We look at up to 42 cytokines, if I remember well, in the plasma of the patients and we also look at these cytokines in the platelets from the patients and we found less cytokines in the platelets when there was inflammations, which may suggest that platelets have released their cytokine cargo. I mentioned that platelets were hyperactivated so they bound better on collagen and they aggregated faster with suboptimal concentration of thrombin. Dr Milka Koupenova: I find this dysregulation of cytokines in the platelets specifically very interesting and the fact perhaps that you see that certain cytokines are decreased in platelets and increased in plasma, basically can suggest that maybe platelets are the ones that are contributing to the overall cytokine storm, as you said. My question for you is, what do you think is the contribution of platelets to the dysregulated immune cell response in immune cell activation during this particular infection? Dr Eric Boilard: That's a good question. There are studies that show that platelets could interact with leukocytes. The leukocytes migrate to organs through lungs in this case, so one possibility is that molecules derive from platelets and cytokines but also their interaction with leukocytes could further promote their migration to lungs or adhesion to vasculature. There are studies that suggest that NETs form in COVID-19 and could contribute thrombosis and NETs can implicate interaction between platelets and neutrophils. Or molecules derived from platelets that are neutrophils so these might be some of their contributions. Dr Milka Koupenova: You are reporting changes of IL-7 in platelets which is particularly interesting because they're responsible for T and B cell development and activation. I was wondering if you could comment on that particular fact and how that may be practically responsible for these responses in these patients that come and present with symptoms. Dr Eric Boilard: Yeah, it's a good question. If we look at the different cytokines that were in platelets, we found that many were reduced. That pointed to their release in COVID-19 and some we had expected, such as some broad factors and there was TGF, CD40 ligands inside the cytokine but we expect that its stored in platelets that was released. That made sense to us. IL7, like you said, it was not really reported in platelets and when we look at the 40... broad area of cytokines using the multiplex, that increased in platelets during COVID-19. So this one was increased. Does it mean that platelets translated but some of it is released but some remain in platelets? We have no explanation for this. Does it impact lymphocytes or B cells? Dr Fadila Guessous: If we go further and in terms of seeing the front they know what was downstream, IL7 production in general does not look like for psychometry, what happens to B cells and T cells in our complex. So we just look at the panel of the 48 cytokines, but we didn't go really further. Dr Cindy St. Hilaire: I kind of have a little bit of a more basic question regarding cytokines and where they're coming from. I'm going to guess it's definitely not known for COVID but in maybe any viral infection that can lead to a cytokine storm, is it known what the relative contributions of cytokines are from the platelets, from the leukocytes, and from inflammatory cells? Is there any evidence of which is the bigger player? I mean I know all the different camps have ideas, but has anyone looked at that? Dr Fadila Guessous: We were talking about this actually with Eric. If I had to rephrase your question, like what's the starting point, right in terms of cytokine storms? Dr Fadila Guessous: We don't know. We don't know because when it started in China, everyone was talking about the big cytokine storm. Everyone was talking about monocytes, about neutrophils, so on and so forth but the platelets we were just saying there was thromboembolism in the lungs, right? But no one was talking about cytokine production by the platelets. I think we were the first ones, Eric please correct me if I'm mistaken, we were the first ones to show, when we started, to show that there was the cytokine release by platelets. How big of the extent of the contribution of platelets to the cytokine storm, we don't know, but we have to figure out first what's the key player? The first one to respond, right? Dr Cindy St. Hilaire: Lots of projects. Dr Fadila Guessous: Well the big question, actually we have this big contribution in terms of the cytokine release and activation of platelets, but is it the starting point? We don't know. Dr Cindy St. Hilaire: I guess related to that, you noted that you saw very little ACE2 expression in the platelets which most people appreciate is the entry mechanism of the virus into the platelets. Can you discuss that a little bit more, maybe explain it a little bit more and what that might mean? Your findings versus what other people have seen versus potential other means of entry? Dr Eric Boilard: Yeah sure. As you mentioned, ACE2 is the putative receptor for the virus so that made sense to us to examine whether the receptor may be expressed by platelets. I don't think we mentioned it but we found that there were some... at least for some patients there were SARS-CoV-2 RNA associated with platelets and that's why in part we look at ACE2 RNA expression by platelets. It seems simple but it wasn't that simple. We were actually using through PCR and different approaches and primers we got different answers using intron-spanning and non-intron-spanning primers from that, the receptor was presented so that in fact we ended up concluding that there was little or no ACE2 RNA in platelets of COVID-19 individuals that we examined but that there was some DNA that could be contaminating, potentially due to extracellular DNA maybe provided by extracellular vesicles[inaudible 00:19:30] or something but either way we're speculating. Dr Eric Boilard: One intriguing aspect of the study is that the SARS-CoV-2 RNA was not found on platelets from every patient, it was only in 20% of them and we unfortunately were not able to look at the RNA of these positive patients to determine whether these patients were positive for ACE2 RNA and potentially in some donor cells in some patients, there might be some levels of expression and we are not excluding this. Dr Eric Boilard: So yeah, you ask whether it was consistent with other studies? There was the study by Manny that was published, in Blood where they also could not find the receptor but our studies contrast with the one that was more recently reported by Zhang in Journal Of Hematology & Oncology. In this study they found in fact that a robust expression of ACE2, both protein and RNA, and it was both in humans and mouse so clearly there's still work to do to determine whether ACE2 is present or not, but there could be other means of interaction between the SARS-CoV-2 and platelets if there is indeed an interaction. We speculated that maybe in some patients there could be antibodies against other coronaviruses, you know the cold, the viruses that give the minor cold symptoms and that in some of the patients these cross-reacting antibodies could promote the interaction with platelets through their receptor for IgG , that could be a means. Dr Eric Boilard: There are other receptors that are expressed by platelets, there's probably several. I'm sure we have a list, but one could be the CD147. It's a receptor that is known to be expressed by platelets and that was suggested to interact with SARS-CoV-2, at least it does interact with SARS-CoV, the first one, CoV-1. So these are potential candidates. So there's work to do. Dr Fadila Guessous: What we found was that in Eric's lab, that you have this 20% of aged people that have this SARS-CoV RNA in place, in 20% of aged people. So should we look only at aged people for this ACE2? If they have the receptor for ACE2, maybe? It's like 20%, only aged. And this 20% of people we investigated, they were only aged. Not other people. So do we... probably, we have to go further and investigate more of this age group for ACE2. . Dr Milka Koupenova: So if I can make a comment, despite the fact if ACE2 was expressed or not, right? Could it explain the profound thrombotic response that you see? What's your take on it? Dr Eric Boilard: Personally, I doubt it. I think the disease starts in the lungs and this is where the damages are made, and that it may expand to blood vessels and then multiple players can then from a place of activation damages themself, the lack of O2 in some patients that are in ICU. And then of course the activation of the other cells, the cytokines themselves. So there are numerous ways I will say that can be to play for activation. In fact, the study by us, the one in Blood, they use plasma from the COVID-19 patient and I would assume there was no actual virus particle in this plasma. And they incubated it with platelets, and platelets were then activated. So there are molecules in COVID-19 that circulate in blood that can activate platelets, and that adds to the vasculature damage trauma. I would think that that could come from principle factors. Dr Milka Koupenova: Which would explain why is it so dysregulated, which brings it to the next question now with a favorite question in the literature. Should we be using antiplatelet drugs? Your opinion, Eric and Fadila? Dr Fadila Guessous: Well with my collaborator, Younes Zaid you know, and first author on this paper, actually they are going for that. They are having small trial giving antiplatelets treatment to a few patients in our lab. You will hear the story. I don't know if Eric will allow me to disclose this? I don't know because Younes is not here, but they are using heparin for now and for the treatment, but now they are trying antiplatelet treatment as a small trial. Dr Milka Koupenova: So when do they give antiplatelet drugs? At what stage of the disease? Dr Cindy St. Hilaire: I think maybe the way to ask the question is: If you were going to use antiplatelet therapy for changing the course of the disease, where do you think is the best time point within the disease, from the day you get infected to symptom presentation and well after that, what time point do you think it's most critical, the platelet function? Dr Fadila Guessous: It's a good question. It's a good question because the trial is done in in our lab and I didn't have insight. What time is the time point. Honestly, I don't have an answer for that in time point. Because I have a... they started the trial- Dr Cindy St. Hilaire: No, but I guess, based on what we know and what you've found in your study, where would you think it's more critical, if we even can speculate on that? Dr Fadila Guessous: Yeah, the symptoms. I would give them from the beginning of the symptoms for me. Because otherwise, when you are in the cytokine storm and you have all this [thromboembolism in the lungs and everything, it's too late. Dr Eric Boilard: And if I can add something. When we think of immune cells or B cells, D cells, we don't say anti-lymphocytes or anti-neutrophil therapy. But when we come to platelets, we think that the molecules that are known to impact some of the platelet activities, we think of aspirin, clopidogrel, coagulation, and we call it anti-platelets but. But platelets, I mean, they can do a lot independently of from vaccine, independently of EDP, and sometimes we forget that they are more than just these poor thrombotic cells and that there are different studies that has been published by different groups and us that found that you can use, for example, COX-1-deficient platelets. So they won't make thromboxane yet, they can make lot of IL1 and be pro inflammatory, although they will not make thromboxane. So we actually use mice where were we use a variety of anti-platelet therapies but yet their platelets were able to come out inflammation so there's no one drug that can get all the platelet functions at once, so it's important to remember that. Dr Cindy St. Hilaire: It sounds like maybe some of them could possibly make things like a cytokine storm almost worse, if we're targeting the wrong anti-activity? Dr Eric Boilard: All depends on how platelets are activated. Whether we are activating a GP pathway, or a nighttime pathway or both at the same time, and the environment where platelets are localized and activated so that they all back the response to this. Dr Cindy St. Hilaire: So you're saying it's complicated. Dr Eric Boilard: Yeah, I think it's not simple. Dr Milka Koupenova: Anything complicated, it's platelets. So in a way I think that perhaps what we need to acknowledge is targeting platelets for whatever response. I completely agree that platelets should be targeted at one point but what drugs should be used, is the question? What specific receptor or what specific response? And if we manage to figure some form of controlling the inflammatory response, that specific, what you see, that huge amount of cytokine dysregulation that will be great. But if you're targeting platelet-specific function when it comes to thrombosis, I'm a bit concerned that there has to be an exact time in which that's important. And the reason why is because if you have this damage in the endothelium, as you see reproducing the virus in the endothelial cells, and if platelets are not doing their own function then perhaps a lot more virus is leaking into the circulation. And that could be why you see some patients that have it, some patients that don't have it, which is a question that I want to ask. Dr Milka Koupenova: Why do you think some patients have it and some patients don't have it? And do you think that perhaps as the virus gets processed into a platelet and digested, we are missing a time point? Because we're not taking platelets from patients at the same time after infection. We have no way of doing that. So what is your take on the fact that you have virus in some platelets? And from your study, perhaps, if we rely on the numbers, the people who have more severe symptoms seem to have a little bit more. Correct me if I'm wrong. Dr Eric Boilard: Actually, the older people have more chance of having it but it was not in the more severe people. In fact, even among the non-severe patients, there was 20% of them that had platelets with positive RNA. So that didn't correlate with severity or any outcomes. The only correlation we could identify was age. Dr Milka Koupenova: So do you think that perhaps in older individuals there are problems would be degradation of the virus, and hence they are not initiating the proper response? Dr Eric Boilard: Yeah, potentially. Maybe there's somehow an indication of the virus from the organs and it's a destination or it's not captured fast enough on the first varrier of the immune cells in the lungs. Right now we don't have the evidence that it's actually the virus that is in platelets, right? The RNA and there's still work to determine if the virus is there. Dr Milka Koupenova: So practically, in summary, we don't know what it is. Although, I mean, with a bias, me probably like you, and you're very nice, you're cautious, but I also believe that the virus... and it's a belief. That the virus gets inside of platelets. Dr Fadila Guessous: How, Milka? How? Dr Milka Koupenova: There could be some issue that we don't see, and as Eric says, it's some form of an age factor. There could be other receptors. Platelets are tricky, they don't act like every regular cell so they may have evolved to have other receptors that maybe they are not as functional in the ither cells but they're platelet specific. There is the process that from all these cytokines perhaps, platelets are just sucking in things by micropinocytosis, which has happened. The thing that's important to think and mention is that if a virus is not going into a platelet by receptor-specific mechanism, perhaps it's locating to the wrong compartment, and then not introducing the proper immune response. Perhaps that's the reason of why you're catching it only in 20%. This is all very, very speculative. Dr Eric Boilard: Yeah. And are you putting in a contribution of megakaryocytes] in the lungs where they will burst … Dr Milka Koupenova: Yes. That it. Absolutely, it's quite possible. That's a collaboration then you should perhaps consider with Dr Craig Morrell. Which is very interesting, right? We don't know. We were never able to figure, even with our full studies, we also saw, what is it, four out of 18? So it's like 25% of the platelets had RNA for a flu but when you look what the antibody of the virus you find that a lot more platelets have it. So is it that we're missing some form of a process that the virus quickly gets digested and it initiates a response? I don't know until we get the right tools. But currently we are struggling with tools, practically, to assess that question. Dr Eric Boilard: Yet it's impressive what's been done since March with the Covid. Dr Milka Koupenova: Oh, some of them is good. Some of them is really important science and some of them is questionable that raises more questions. Dr Eric Boilard: Absolutely, yeah. Dr Milka Koupenova I personally think it's very important what your study is showing because it gives a base of truly thinking about how platelets maybe truly acting as an immune cell at the beginning. I know that Eric and I might be a little bit biased when it comes to that, but when does the thrombotic response stop? And when does the immune response stop of a platelet? And is it necessary to stop and to be all together? How do we push one and doesn't stop the other? These are the questions that we in the field truly need to assess and that's what I really like about your study, is that it raises these important questions. Dr Fadila Guessous: Before the call, I was looking at the paper from University of Verona. I mean, I was hoping they will find more answers to the same question that is a favorite from University of Verona, and actually they are also more speculative. They didn't answer the question, the same questions we are asking. Dr Milka Koupenova: Well, until we have the virus on hand, the actual virus, it's a little hard for us. And then the other point is even if you have the virus on hands, you're doing all of these in vitro studies, how do you assess the entire immune response? Can we think of platelets just as platelets without being in cells, right? What is your take on that, Eric or Fadila? Can you think of platelets just as platelets when it comes to mediating a response to a viral infection? Because we think okay we do this particular thing with platelets and then they mediate this and they mediate that, but perhaps the interaction between platelets and all the immune cells at the beginning of the response is super important. And I do struggle sometimes with the assessment of what amount is just platelets and what is the communication between each immune cell and platelet. It's very hypothetical. Dr Eric Boilard: I agree that I see platelets as communicators to other cells. I mean, they're so numerous and there are bags with cytokines and other molecules and RNA and micro RNAs and it can impact for different organs, tissues, cells. The fact that they were activated, even in the non-severe patients, all the non-severe patients we analyzed, platelets were there, they were activated. So there was something going on, although thrombosis was not of use in these patients, so they made plates front row and the front part of the disease and the pathogen as a cell. Dr Milka Koupenova: So is there a way of somehow, as you perceive in your future studies, to get platelets from people who get the virus but don't have any symptoms, and compare their cytokine profile of platelets to what you see? Because we focus so much on the people who get infected, logically, right? But truly to assess what is the difference, if we can figure why those patients are not having this profound response, right? Dr Eric Boilard: Something that we dream of. The fact that collecting platelet from someone who has no symptoms is…Because we, if they have no symptoms, then they don't come to us. They don't stop- Dr Fadila Guessous: They don't show up at the hospital. Dr Milka Koupenova: And so you have to recruit them by tests, right? Because we screen, for instance, our institution screens. But it's hard, right? No one wants to take blood from a… Dr Fadila Guessous: You get this kind of calls, people are asymptomatic, they don't have any symptom, they won't show up at the hospital. We used whatever we had in our recruitment from the hospital. Dr Eric Boilard: In fact, you can maybe go through the transfusion work, the studies on transfusion where they actually collect blood from people and people sign that they have no symptoms when they do give blood. And there are studies from China and more recent ones in France where they then went back to this bags of... these were plasma, but maybe one could do it with platelet concentrates. And then go back to these bags where people had signed they had no symptoms when they gave blood, and screened platelets for RNA and then... but you have dozens of dozens of samples to test, but they are available. And maybe someone could find that many were positive but they were asymptomatic, using transfusion studies, maybe. But recruiting people from outside, asking we want people with no symptoms for… Dr Cindy St. Hilaire: I know we're doing sentinal testing of our students, so. Somehow the group doing that needs to couple with platelets studies. But that was wonderful. Thank you Dr Boilard, Geussous, and Koupenova for joining me today. This has been an amazing interview. It's a wonderful study. Good luck on the future research and thank you for moving the field forward on this. Dr Eric Boilard: Thank you very much for inviting us. It was great and we are pleased to interact with you. Thank you. Dr Milka Koupenova: Very nice to meet you Fadila, Eric. Dr Fadila Guessous: Thank you so much for having us. It's really it's a pleasure to have this interview with you and of course I have to say that really it has been a wonderful collaboration with Eric and Younes in our lab. I am from Casablanca so we had really many people involved in this project and everyone, we worked really, really hard to get this very... I mean, you can see the time, it's from March to now, to get this paper out it was really a big effort. A big effort from the Moroccan side and from Eric's team in Quebec City and so we are really very pleased to have this wonderful collaboration. Thank you so much for having us. Dr Cindy St. Hilaire: That's it for the highlights from the late October and early November 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, Drs. Eric Boilard and Fadila Guessous, as well as Dr Milka Koupenova for co-hosting the interview with me. Dr Cindy St. Hilaire: This podcast is produced by Rebecca McTavish and Ishara Ratnayaka, edited by Melissa Stoner, and supported by the editorial team of Circulation Research. Some of the copy text for the highlighted articles was provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, you're on-the-go source for the most exciting discoveries in basic cardiovascular research.
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
This month on Episode 16 of the Discover CircRes podcast, host Cindy St. Hilaire highlights four featured articles from the August 28 and September 11 issues of Circulation Research. This episode features an in-depth conversation with Drs Andrew Murphy and Michelle Flynn from The Baker Heart and Diabetes Institute at Monash University in Melbourne, Australia regarding their study Transient Intermittent Hyperglycemia Accelerates Atherosclerosis By Promoting Myelopoiesis. Article highlights: Fish, et al. KRAS Mutations Cause Arteriovenous Malformations Ehling, et al. B55a in Vascular Biology Barrett, et al. Platelet Activity and Vascular Health in COVID-19 Furmanik, et al. Nox5 in VSMC Phenotype and Calcification Cindy St. Hilaire: Hi. Welcome to Discover CircRes, the podcast to 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'm going to share with you four articles selected from our late August and early September issues of Circulation Research. I'm also going to speak with Drs Andrew Murphy and Michelle Flynn from The Baker Heart and Diabetes Institute at Monash University in Melbourne, Australia regarding their study Transient Intermittent Hyperglycemia Accelerates Atherosclerosis By Promoting Myelopoiesis. So first, the highlights. The first article I'm sharing with you is titled Somatic Gain of KRAS Function in the Endothelium is Sufficient to Cause Vascular Malformations that Require MEK but not PI 3-Kinase Signaling. First authors are Jason Fish, Carlos Perfecto Flores-Suarez, and Emily Boudreau. And the corresponding authors are Jason Fish and Joshua Wythe, and they're from University of Toronto and Baylor College of Medicine. Arterial venous malformations, or AVMs, are tangles of blood vessels in which the arteries are directly connected to the veins without going through the capillary bed. These are thought to be present from birth and when they occur in the brain, they can cause an array of symptoms such as headaches or seizures, but they are also the leading cause of hemorrhagic stroke in children and young adults. This is because the venous system is not muscularized to respond to the pressure forces that are exerted on arteries. These pressure forces cause distension and eventual leakage at the site of AVMs. Vessel tissue recovered from patients undergoing AVM repair has been shown to contain sematic gain of function mutations in the protein RAS GTPase, which is encoded by the gene, KRAS. However, whether these gain of function mutations directly cause AVMs has not been established. This study now shows that endothelial cells with constitutive expression of gain of function KRAS mutants in mice and zebra fish causes vascular malformations and cranial hemorrhages. Inhibiting a MEK kinase, which is a downstream mediator of RAS signaling, prevented hemorrhages in the mutant KRAS carrying fish. In vitro studies also showed that overactive RAS GTPase protein caused excessive angiogenic behavior of endothelial cells. Together, this work confirms the link between gain of function KRAS mutations and brain AVMs, and suggests that MEK inhibition could be a potential strategy for nonsurgical treatment. The second article I want to share with you is titled B55a/PP2A Limits Endothelial Cell Apoptosis During Vascular Remodeling: A Complimentary Approach To Kill Pathological Vessels. The first author is Manuel Ehling and the corresponding author is Massimiliano Mazzone. And the work was completed at Leuven Center for Cancer Biology in Belgium. Building a mammalian vascular system is a dynamic process that is dependent on both growth of new vessels, as well as the pruning of unwanted ones. But while much is known about molecular mechanisms underlying angiogenesis, comparatively little is understood about the mechanisms regulating vascular pruning. This study discovered that suppression of the protein phosphatase 2 subunit, B55A, is a key protein regulating the pruning process. They found that in mouse vascular development, B55a is widely expressed. However, in adult mice expression is restricted only to sites of active angiogenesis. Deletion of B55a in mice caused death in mid to late stages of embryogenesis as a result of vascular problems that appeared to be due to excessive vessel pruning. Switching off B55a in adult mice when the vascular development is for the most part complete did not cause any apparent problems. They did find though, that inhibition of B55a significantly delayed growth of tumors that form from the injection of cancerous cells. Inhibition of B55a produced tumors with less dense vasculature and reduced metastatic potential. Thus, the author suggests that ramping up blood vessel pruning, be it inhibition of B55a, could be a novel strategy for limiting tumor growth. The next article I want to share is titled Platelet and Vascular Biomarkers Associated With Thrombosis and Death in COVID-19. The first author is Tessa Barrett and the corresponding author is Jeffrey Berger, and they're from New York University. Our knowledge of the complications of COVID-19 is evolving every day. Laboratory testing done to date suggests that approximately 30% of hospitalized COVID-19 patients go on to develop thrombotic events. Platelets are central characters in both arterial and venous thrombosis, and it is known that virus platelet interactions can stimulate a pro-coagulant and inflammatory state during a viral infection. Further, recent studies have reported COVID-19 patients have hyperactive platelets and autopsies of COVID-19 patients exhibit micro and macro thrombi across vascular beds, even in patients without clinical thrombosis. This group then hypothesized that biomarkers of platelet activation are associated with incident thrombosis or death in COVID-19 patients. To test this, they randomly selected 100 COVID-19 positive patients and analyzed banked samples collected on the day of the COVID-19 diagnosis to investigate in vivo platelet activity, as well as vascular health biomarkers. They show for the first time that biomarkers of platelet activation at the time of diagnosis are associated with thrombosis or death in patients hospitalized with COVID-19. Their findings suggest platelet activation mechanisms may contribute to adverse events and highlight the potential role of antiplatelet therapy in this disease. The last article I want to share with you before we switch to our interview is titled Reactive Oxygen-Forming Nox5 Links Vascular Smooth Muscle Cell Phenotypic Switching and Extracellular Vesicle-Mediated Vascular Calcification. The first authors are Malgorzata Furmanik and Martijn Chatrou. And the corresponding author is Leon Schurgers from Maastricht University in The Netherlands. Vascular calcification is an active process regulated by several mechanisms, including vascular smooth muscle cell apoptosis, osteochondral genic transdifferentiation, extracellular vesicle release, and cellular senescence. In healthy adult arteries, smooth muscle cells maintain a contractile phenotype. However, various insults such as oxidative or mechanical stress, can induce smooth muscle cells to lose their contractility and this process of de-differentiation is termed phenotypic switching. And phenotypic switching is thought to precede the development of vascular disease. Patients with conditions such as chronic kidney disease have mineral imbalances in their circulation and also exhibit higher levels of vascular calcification. However, the mechanisms behind these observations are not well defined. This group found that extracellular calcium can enter the smooth muscle cells via extracellular vesicles and this increased cytosolic calcium concentration. Increased calcium induces expression and activity of Nox5 in NADPH oxidase. Activation of Nox5 increased production of reactive oxygen species, which in turn decreased contractile marker expression, and also promoted calcification in vitro. Intracellular calcium signaling also further enhanced extracellular vesicle secretion, and decreased extracellular vesicle uptake. This then promoted the accumulation of extracellular vesicles in the extracellular matrix, which is a mechanism that promotes calcification. Together, these data suggest that mineral imbalances, such as those seen in chronic kidney disease patients, contribute to loss of smooth muscle cell contractility, which promotes osteochondral genic transdifferentiation. For the interview portion today, I have with me Drs Andrew Murphy and Michelle Flynn from the Baker Heart and Diabetes Institute and Monash University in Melbourne Australia. And we're going to be discussing their manuscript titled Transient Intermittent Hyperglycemia Accelerates Atherosclerosis by Promoting Myelopoiesis. But really I like the running title, which is Hyperglycemic Spikes Accelerate Atherosclerosis. So thank you both very much for joining me today. Michelle Flynn: Thanks for having us. Cindy St. Hilaire: So before we start to ‘stalk a bit about what the details of this study is, could you maybe give us a little primer on what you've done that led up to this study? Andrew Murphy: Yeah, so this really was a continuation of a study that began actually when I was in my postdoc in Allan Tall lab and working with Ira Goldberg’s lab with the postdoc Prabhakara R Nagareddy there. We've shown along with Ed Fisher’s group at NYU, that mice that had established atherosclerotic lesions that were then made diabetic, failed to have lesion regression compared to those that were non-diabetic with normalized plasma cholesterol levels. We showed that if we gave an SGLT-2 inhibitor to normalize glucose that regression then started to occur. And then we found that this was primarily driven by myelopoiesis, suddenly increased production of monocytes, which through that entered the plaque. And so from that, that was in the hyperglycemic model which is sort of a very rare patient group these days, because most people are on well-controlled glucosteroid drugs. And really the SGLT-2 inhibitors have been a game changer in that scenario. And what we were trying to do with this study was bring it into a more clinically relevant setting that might show the potential importance of glucose on a much larger population. Cindy St. Hilaire: Excellent. Maybe you could give us an introduction to the link between what's known about diabetes and cardiovascular disease and the interplay? Michelle Flynn: So diabetic and pre-diabetic patients actually account for 65% of all cardiovascular deaths, which really indicates that diabetes itself plays a major factor alongside other things like obesity and hypercholesterolemia. And so we've previously shown that hyperglycemia was actually driving atherosclerosis in a chronic hyperglycemic setting. So given that kind of vascular disease actually affects both diabetic and pre-diabetic patients, we suspected that it may not just be chronic hyperglycemia or really intense hyperglycemia that could be driving this issue. And so what we were actually looking at in this paper was how more transient levels of hyperglycemia, which actually occur quite often in both diabetic patients and pre-diabetic patients, how much this can contribute to cardiovascular disease. Andrew Murphy: I guess this link between poor glucose control and cardiovascular disease is obviously very well established. The interesting part is that HbA1c only predicts part of the risk. If you look at fasting blood glucose, again, that's only partially responsible, but if you look at postprandial or two hour glucose loads, you'll see that that is more predictive of cardiovascular events than the other two measures. And it seems to be a continuum. So even if you are a healthy or non-diabetic individual, you obviously still have those postprandial events and depending how high that goes up is thought to be a predictive of future cardiovascular outcomes. And so obviously that's worse than people with pre-diabetes and then again worse with people that have actual, full blown diabetes. Cindy St. Hilaire: And what is a transient hyperglycemic event? What would do that in maybe you and me who don't have diabetes versus someone who has diabetes or is pre-diabetic? Michelle Flynn: So essentially what we're modeling with this transient hyperglycemia is that postprandial increase in glucose after you have a meal, which in people who have impaired glucose tolerance is going to be more pronounced than in someone who has a normal glucose tolerance. Cindy St. Hilaire: Got it. And so how did you test this in the mice? Michelle Flynn: We did this by developing a novel model of transient hyperglycemia. So we used ordinary wild type mice that weren't diabetic, and we injected them with glucose intraperitoneally, which then increased blood glucose levels in the plasma after about 15 minutes up to about 15 to 20 millimolar. And then after about two hours, this decreased back down to baseline levels. So this was very similar to what you actually see in a postprandial event. And by doing this four times throughout the day, we were able to mimic what you might see in a patient who has had several meals across the day who has impaired glucose tolerance. Andrew Murphy: One other advantage with the model that we used was that we were trying to really isolate the effects of glucose. And so by injecting glucose intraperitoneally in otherwise healthy mice, it bypasses the incretin response, which we know loses efficacy, I guess, in people that are diabetic. And so we were just really mimicking acute glucose rises that would occur after a meal. And then obviously in this wild type mouse the insulin response would then kick in to clear the glucose so it really tests that glucose hypothesis. Cindy St. Hilaire: So it's really digging in deeply on the actual sugar component, not just eating in general or other aspects. So in some of your experiments, or I guess in actually most of them, you show that the injection of glucose, it increased the plaque size in these mice, but it didn't alter the cholesterol levels. So can you explain a bit what's going on there? A little bit about the mechanism you discovered and kind of specifically introducing RAGE and the S100A8 and A9 axis? Michelle Flynn: Yeah, so what we showed was that regardless of cholesterol levels, we were seeing an increase in clot plaque size, and this was actually driven by the monocytes and neutrophils which were increased in the circulation of these mice. And then these are able to infiltrate into the plaque where they promote plaque progression. And what we found was that the increase in monocytes and neutrophils was due to an increase in their production within the bone marrow. And this was in turn due to the signaling by a protein heterodimer of S100A8 and A9, which signals via the receptor RAGE in the bone marrow on the progenitors of these cells, which induces their proliferation and differentiation. And then that produces an increase in the production of those immune cells, which promote plaque progression. Cindy St. Hilaire: Interesting. So it's really independent of kind of the basic thing that everyone thinks about, or I guess as non-scientists think about, is cholesterol. The public really focus on cholesterol, but what your study's showing is there's this whole other glucose mediated immune arm to it. What else does this S100A8-A9 regulate? Andrew Murphy: So S100A8 and A9 has some intracellular roles, which may direct the development of the model itself, but really a lot of its extracellular roles and so on is promoting sterile inflammation, chemotaxis, so activation of local immune cells. And in the context of diabetes and obesity, many of other diseases, it can signal via RAGE, as Michelle said, but it can also signal by TLR4. And so it seems as though in those diseases driven mainly by glucose, such as the modeling of postprandial hyperglycemia or all kinase in general, it will signal via RAGE, but we've also shown in the setting of obesity that it will signal via TLR4 to stimulate things like interleukin 1 beta. We've also had a paper just recently in Circulation with Prabhakara Nagareddy’s group where we've shown post myocardial infarction that prime neutrophils in the heart to eventually release IL1-beta and cause myelopoiesis in that way. Cindy St. Hilaire: Wow, so this is really kind of an early activator of a much bigger immune response, whether it's in atherosclerosis or MI or probably, I don't know, a handful other things, I guess, right? Andrew Murphy: It seems to be really important when neutrophils are involved. So in a setting of an MI, we know that they come into the heart very early and become activated and it really makes them about 40% of the cytosol proteins of the cells. So when it degranulates or lyses, they are kind of neutral, at least in the predominant protein. Cindy St. Hilaire: Okay. So this is released in NETs in NETosis then? Andrew Murphy: That's what we're sort of discovering so far. So I guess all I can say is, stay tuned, this is a story for another day. Cindy St. Hilaire: Okay. That's really interesting though. Andrew Murphy: We haven’t looked in gglucose driven events yet. Cindy St. Hilaire: Yeah and actually one of the interesting things I've learned from your study, I had known about GLUT1 and that GLUT1 was I guess the constituently active of the glucose transporters, but I didn't realize it was so high on neutrophils and that neutrophils were so dependent metabolically on glucose. Can you maybe tell a little bit more about that story? Michelle Flynn: Yes. So the neutrophil itself is actually very highly dependent on glycolysis because it doesn't actually have many mitochondria. So compared to most cells, they have very few mitochondria so they can't really rely upon the oxidative phosphorylation for their general metabolism. And so they predominantly rely on glucose coming into the cell and then being shuttled through glycolysis to generate their energy. And yeah this does seem to be predominantly due to uptake of glucose through GLUT1. Cindy St. Hilaire: And then that excess glucose, the byproduct, is reactive oxygen species and upregulation and this cascade of- Michelle Flynn: Yes, yes that's correct. Cindy St. Hilaire: Okay, great. So currently we use HbA1c as a biomarker for overall kind of glucose regulation in diabetic patients. And based on your studies and perhaps the studies of others, would neutrophil numbers or even S100A8 or A9 be a better metric to figure out where a pre-diabetic or even a healthy patient is in terms of their glucose tolerability? Michelle Flynn: Yeah. That could actually be an interesting marker to look at. Given that neutrophils and S100 are also associated with obesity and diabetes in general, and as well as the risk for cardiovascular disease. So with the progression of diabetes, you could expect that the levels of these would increase as well. Andrew Murphy: We've shown previously when we first discovered that the S100 was important in diabetes, that in the Pittsburgh study with Trevor Orchard's group, he had followed people with type one diabetes for 20 years, that those that did develop a cardiovascular event had a higher S100A8 and A9 levels and that correlated with neutrophils. And so it certainly seems to be a marker of predictive outcomes. And so those that do have poorer glycemic control will have higher neutrophils. That's well known. And so perhaps you're right that probably in combination with HbA1c or things like two hour post glucose challenges, S100A8 and A9 and perhaps neutrophil counts would also be a nice predictive measure of potential cardiovascular outcomes of that person. Cindy St. Hilaire: Wow. That'd be really great because you could then maybe kind of more fine tune and predict which patients might be more or less susceptible to cardiovascular events. Andrew Murphy: That's right. Yeah. I think one other important aspect would be if HbA1c is deemed to be relatively well under control, yet you still have a high level of S100A8 and A9, that perhaps those transient spikes are contributing. You're not picking that up in the HbA1c, which looks like the average over approximately a month. And so that could be a nice way to add value onto that score. Cindy St. Hilaire: Interesting. I didn't realize it was that stable about over a month. All right. So I'm relatively healthy. I'm not pre-diabetic, but if I eat a whole bunch of cake or a whole bunch of ice cream or drink a lot of beer, does that create un me a transient hyperglycemic event that is of the same range we're talking about and what do your findings suggest for people who are relatively healthy and things we should be aware about regarding eating habits and things like that? Andrew Murphy: Yeah. I think it's a really good question. And it's sort of hard to give you an exact answer to that right now. We need to look at that in people, model these sort of same spikes in people, but what we I guess don't know yet, even in the preclinical models is how high and how long does that glucose have to be? And I think that's one of the most important questions first. So is there a danger zone where these neutrophils start be the innate senses of hyperglycemia that start to then release S100A8 and A9 to cause these downstream events? But what our data does show is that if you're doing this, having a binge night or a binge day once a week for your life, then that's probably not going to be a great thing. Cindy St. Hilaire: Yeah. All right. So you need to figure out is one scoop of ice cream okay, but two not so great. Andrew Murphy: Maybe if it's two different flavors it'll be okay. Cindy St. Hilaire: Maybe, right? That's great. So, I mean, is there a way we could potentially therapeutically target this signaling axis or is it too ubiquitous in terms of what it regulates? Is there a way to harness what you've found potentially in the clinic? Michelle Flynn: Yeah, so there's an inhibitor of S100A8 and A9 that prevents its binding to RAGE. It's currently approved as an Orphan Drug for systemic sclerosis in both the US and the UK. And that drug itself, we tested in our preclinical mouse model, and we found that it was in fact able to prevent their production of these immune cells, as well as prevent the accelerated atherosclerosis in response to these transient hypoglycemic spikes. Andrew Murphy: So another sort of line of thinking that we're exploring is that we could actually target neutrophil metabolism itself. And so now we're sort of understanding, are there certain proteins that are more abundantly expressed in neutrophils and not other cells in the body that would regulate glycolysis? I know that might sound a bit of a pie in the sky sort of idea, because glycolytic pathway's quite regulated, but there we have found some proteins that are rich in neutrophils and not other cells that may be responsible for the early steps of glycolysis. And so whether that can be harnessed or not, we'll have to see in the future, but it might be a way of more directly targeting neutrophils rather than approaching that's important in sterile inflammation. Cindy St. Hilaire: That makes sense. That is such a cool idea and this is really such a beautiful story. It's one of those papers that you just read it and it's just such a logical progression, but it's also really interesting and I really appreciated all those bone marrow transplants. I did those in grad school, so well done. It's a beautiful story. And then I'm just really happy that you published it with us. So thank you so much for joining me today. Andrew Murphy: Yeah thanks for having us. Michelle Flynn: Thank you. Cindy St. Hilaire: That's it for highlights from the late August and early September 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 #DiscoverCircRes. Thank you to our guests, Drs Andrew Murphy and Michelle Flynn. This podcast is produced by Rebecca McTavish and Ashara Ratnayaka, edited by Melissa Stoner, and supported by the Editorial Team of Circulation Research. Some of the copy text for the highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire, and this is Discover CircRes, your on-the-go source for the most exciting discoveries in basic cardiovascular research.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.29.166637v1?rss=1 Authors: Kyriatzis, G., Bernard, A., Bole, A., Pflieger, G., Chalas, P., Masse, M., Lecorche, P., Jacquot, G., Ferhat, L., Khrestchatisky, M. Abstract: Neurotensin (NT) acts as a primary neurotransmitter and neuromodulator in the CNS and has been involved in a number of CNS pathologies including epilepsy. NT mediates its central and peripheral effects by interacting with the NTSR1, NTSR2 and NTSR3 receptor subtypes. To date, little is known about the precise expression of the NT receptors in brain neural cells and their regulation in pathology. In the present work, we studied expression of the NTSR2 protein in the rat hippocampus using a model of temporal lobe epilepsy induced by pilocarpine and questioned whether NTSR2 was modulated in conditions of neuro-inflammation. This model is characterized by a rapid and intense inflammatory reaction with a pattern of reactive gliosis in the hippocampus. We show that NTSR2 protein is expressed in hippocampal astrocytes and its expression increases together with astrocyte reactivity following induction of status epilepticus. NTSR2 immunoreactivity is also increased in perivascular astrocytes and their end-feet and is apparent in endothelial cells following induction of status epilepticus. Proinflammatory factors such as IL1{beta} and LPS induced NTSR2 in astrocytes, but also in microglia in vitro. Glial NTSR2 expression showed characteristic immediate early gene response under inflammatory conditions. Treating inflamed glial cells with a vectorized NT analogue decreased NTSR2 expression as well as astrocytic and microglial reactivity. Together, these results suggest that NTSR2 is implicated in astroglial and gliovascular inflammation and that targeting the NTSR2 receptor may open new avenues in the regulation of neuroinflammation in CNS diseases. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.24.162941v1?rss=1 Authors: Singh, V., Beer, A., Kraus, A., Zhang, X., Xue, J., Hermann, D. M., Gunzer, M. Abstract: Background: The newly emerged severe acute respiratory syndrome coronavirus (SARS-CoV-2) has caused a worldwide pandemic of human respiratory disease. Angiotensin-converting enzyme (ACE) 2 is the key receptor on lung epithelial cells to facilitate initial binding and infection of SARS-CoV-2. The binding to ACE2 is mediated via the spike glycoprotein present on the virus surface. Recent clinical data have demonstrated that patients suffering from stroke are particularly susceptible to severe courses of SARS-CoV-2 infection, thus forming a defined risk group. However, a mechanistic explanation for this finding is lacking. Sterile tissue injuries including stroke induce lymphocytopenia and systemic inflammation that might modulate the expression levels of surface proteins in distant organs. Whether systemic inflammation following stroke can specifically modulate ACE2 expression in the lung has not been investigated. Methods: Mice were subjected to transient middle cerebral artery occlusion (MCAO) for 45 min and sacrificed after 24 h and 72 h for analysis of brain and lung tissues. Gene expression and protein levels of ACE2, ACE, IL-6 and IL1{beta} were measured by quantitative PCR and Western blot, respectively. Immune cell populations in lymphoid organs were analyzed by flow cytometry. Results: Strikingly, 24 h after stroke, we observed a substantial increase in the expression of ACE2 both on the transcriptional and protein levels in the lungs of MCAO mice compared to sham-operated mice. This increased expression persisted until day 3 after stroke. In addition, MCAO increased the expression of inflammatory cytokines IL-6 and IL-1{beta} in the lungs. Higher gene expression of cytokines IL-6 and IL-1{beta} was found in ischemic brain hemispheres and a reduced number of T-lymphocytes were present in the blood and spleen as an indicator of sterile tissue injury-induced immunosuppression. Conclusions: We demonstrate significantly augmented ACE2 levels and inflammation in murine lungs after experimental stroke. These pre-clinical findings might explain the clinical observation that patients with pre-existing stroke represent a high-risk group for the development of severe SARS-CoV-2 infections. Our studies call for further investigations into the underlying signaling mechanisms and possible therapeutic interventions. Copy rights belong to original authors. Visit the link for more info
Peak Human - Unbiased Nutrition Info for Optimum Health, Fitness & Living
This is an interview I’ve been looking forward to for years. Dr. Dale Bredesen is shaking up the medical world by showing that Alzheimer’s actually can be prevented, treated, and sometimes even reversed. This is really important to me because my mom is the final stages of Alzherimer’s and I, of course, am doing everything I can to prevent myself from falling to the same fate. I believe the Sapien way of eating and lifestyle is doing just that - setting me up for my best chances at my longest healthspan. You can learn more about this at http://sapien.org/diet Dr. Bredesen and I agree on all the core principles. He really is describing a Sapien diet with his protocol. We’re only at odds with the ratio of plant foods to animal foods. As I’ve posted today on social media, I think people are actually more on the side of animal foods than they think. In the context of a whole foods, low carb diet without refined grains, sugar or vegetable oil, more often than not people are getting the majority of their calories from animal foods without necessarily realizing it. Only people eating Standard American Diets or Mediterranean Diets and the like are getting most of their calories from plant foods from all the empty calories coming from grains and other carbohydrates. Many health figures in this space say things like “a plant heavy diet” or “fill half your plate up with greens” and people take this as being akin to a vegetarian diet. As I showed in my post, a daily intake where about 70% of the plates are filled with plants are actually 92% animal foods by calories. I actually eat this way a lot. This is carnivore adjacent and is part of the Sapien Framework. You’re still getting a ton of flavor, variety, and nutrients from plants (even though they’re not as bioavailable), but you're really getting 90% of your calories from animal foods. So make your own decision on the ratio of plant to animal foods, but from what I’ve found, higher animal foods is more species appropriate for homo sapiens, and is actually what most people avoiding empty calorie, nutrient poor foods are already doing. As always, I didn’t want to press him on this. I don’t invite people on my podcast to tell them I don’t agree with their opinions. I’d love for this to be debated with a moderator at some point, but as long as it’s a 1 on 1 Peak Human podcast I’m letting the guest speak their minds. Here’s a bit of Dr. Bredesen’s extensive resume. He received his undergraduate degree from Caltech and his medical degree from Duke. He served as Resident and Chief Resident in Neurology at UCSF, he was the Director of the Easton Center for Alzheimer’s Disease Research, he’s a Professor in the Department of Molecular and Medical Pharmacology at UCLA School of Medicine, and the Founder of the Buck Institute for Research on Aging. The Bredesen Laboratory studies basic mechanisms underlying the neurodegenerative process, and the translation of this knowledge into effective therapeutics for Alzheimer’s disease and other neurodegenerative conditions, leading to the publication of over 220 research papers. He and his group developed a new approach to the treatment of Alzheimer’s disease, and this approach led to the discovery of subtypes of the disease, followed by the first description of reversal of symptoms in patients with MCI and Alzheimer’s disease, with the ReCODE protocol, published in 2014, 2016, and 2018. His book, The End of Alzheimer’s, is a New York Times Bestseller and has been translated into 29 languages. I’ll largely skip the plugs for today. Everyone listening knows about the Food Lies film on Indiegogo, the Patreon at http://patreon.com/peakhuman and my new grass fed meat company http://NoseToTail.org If you find any value in this podcast or my other content on YouTube or social media channels, please consider supporting me and my projects there. I wish I could really get across how much it means to me. It’s honestly the only way any of this is possible. Thanks so much, and I’ll most likely end season 3 with this episode and come back in a couple weeks with an amazing season 4. Here’s the future legend, Dr. Dale Bredesen. BUY THE MEAT NosetoTail.org Preorder Food Lies: http://indiegogo.com/projects/food-lies-post Support me on Patreon! http://patreon.com/peakhuman SHOW NOTES Dr. Bredesen has been studying the phenomenon of Alzheimer’s Disease (AD) for 3 decades and have published over 200 papers on his research Understanding the fundamental nature of the disease is how we can design an effective treatment His protocol is different because it targets the root cause, not the symptoms like most AD drugs do Humans are extremely complicated and there is no one single therapy that will treat the complexity of AD AD is the result of the brain protecting itself from different insults The protective response in the brain causes the brain to shrink and “retreat” so that there is less for foreign substances (insults) to target Amyloids are antimicrobial, bind to toxins, and change the brain’s response to glucose but when they are overproduced and build up that’s when problems occur Some of the contributors to AD are: chronic inflammation, insulin resistance, glycation damage, toxin exposure, decrease in nutrients, hormones, trophic factors, poor vascular support He has identified and categorized 6 different types of AD: inflammatory, atrophic, glycotoxic, toxic, vascular, and traumatic Paraffin candles produce toxins that damage the brain Most damaging mycotoxins (produced from mold) are the ones you breathe - test your home for molds Go to www.survivingmold.com to learn how to test your home for mold and if you are concerned about mold exposure to learn about what to personally get tested For overall markers you should get tested, you can order tests directly from Dr. Bredesen’s site www.drbredesen.com or go to your doctor and test markers Markers for glycotoxicity: fasted insulin, HbA1c, and fasted glucose Markers for nutrients, hormones, and trophic factors: o Vit. D, pragnenolone, progesterone, estradiol, testosterone, free T3 and free T4 (for thyroid), TSH (thyroid stimulating hormone), and reverse T3 (which is an inhibitor of the effect of your active thyroid hormone) Inflammation markers: HS-CRP, TNF-a, IL6, IL8, IL1-b Don’t wait until it’s too late to check for these things, because AD is preventable Glycotoxicity and how sugar is toxic Humans are not designed to eat sugar Overconsumption of sugar is linked to hypertension, CVD, diabetes, dementia, arthritic, leaky gut, and more Sugar is this generation’s smoking, we will get to a day when we think back to how crazy it was that we were eating this stuff We have biomarkers that will tell you whether AD is creeping up on you, so check early in life because you might not feel sick now, but that doesn’t mean it’s not on its way All these lifestyle and diet changes that you make to prevent AD, apply to so many other modern illnesses If AD runs in your family, you should be interested in prevention AD should be a rare disease APOE4 is the most common genetic risk factor If you have a single copy of APOE4 the risk is ~30% If you have a double copy of APOE4 the risk becomes greater than 50% For people with APOE4, find out early and get on prevention, and you will have a low chance of getting the disease 21st century medicine is about root cause and prevention There is no mono-therapy for AD Look out for symptoms of early cognitive decline like the lack of ability to learn new things, losing organizational skills, not being able to do simple calculations, not being able to find the right word, getting lost in familiar places Don’t shake these off as “senior moments” Basic things everyone can do: optimize insulin sensitivity, follow a low-carb, moderate protein, high (good) fat diet, exercise, get enough sleep, reduce stressors in your life, detox, avoid or fix any gut issues, go into periods of ketosis His diet plan is called “KetoFlex 12/3” “Keto” for going into periods of ketosis “Flex” because it is flexitarian, if you want to be a vegetarian or eat meat you can do either “12” because he wants people fasting for at least 12 hours between dinner and the next day’s first meal “3” because he wants people to finish eating at least 3 hours before they go to sleep The Big Four to avoid: grains, simple carbs, dairy, and lectins He has had amazing success with his patients and has been publishing results since 2014 He has never had someone at risk come in for prevention and develop even mild cognitive impairment (MCI) People who come in with subjected cognitive impairment (SCI) see improvement People who come in with MCI the majority improve People with full-blown AD, some people improve and some people don’t He has had people score zero on cognitive tests that have improved The most important point of all of this is that if you get put on a drug for AD you might get a little bump but you fall back to declining again, his approach targets what is actually causing the decline, the people who get better sustain their improvement Complexity gap between the complexity of the problem (human illness) and the data sets that traditional medical doctors are using to treat them (aka we can’t expect a simple mono-therapy to treat a complex condition) Dr. Bredesen’s daughter is a brain health coach and you can find her at www.siabrainhealth.com His protocol includes sauna for riding the body of toxins We are swimming in an Alzheimer’s soup with the amount of toxins we are exposed to in our modern world Get rid of toxins by sweating (sauna and exercise), high fiber diet, optimizing glutathione levels, filtered water, urination, each one of these gets rid of different things If you have leaky gut, fix that The importance of sleep Current research on macular degeneration His new book coming out “The First Survivors of Alzheimer’s Disease” will be about people’s first-hand stories of people told they had no hope but used his protocol and got better and have kept themselves better The future of medicine will need to look at how humans were evolutionarily designed to live You are not powerless to AD, you have control over it We can reduce the global burden of dementia, we can fight cognitive decline Find Dr. Dale Bredesen at www.drbredesen.com His Facebook page https://facebook.com/drdalebredesen/ BUY THE MEAT NosetoTail.org Support me on Patreon! http://patreon.com/peakhuman Preorder the film here: http://indiegogo.com/projects/food-lies-post Film site: http://FoodLies.org YouTube: https://www.youtube.com/c/FoodLies Sapien Movement: http://SapienMovement.com Follow along: http://twitter.com/FoodLiesOrg http://instagram.com/food.lies http://facebook.com/FoodLiesOrg Theme music by https://kylewardmusic.com/
Jamie is as addicted to Married at First Sight as Angela is to IDTVAngela's friend met a tragic demiseLuke and Kate's marriage may be doomedJamie things Luke is hiding that he's gayAngela knew a couple who eventually got a divorce because the man finally came out as gayJamie screwed up his analogyAngela thinks Luke might be in a relationship A scene from Married at First Sight featuring Luke and KateAngela talks about Grace and FrankieBasically this episode is about not lying; don't try and live a double life because your actions affect other peopleAngela has a workshop on March 30th at the Music Connection in Frankfort, IL1-4pm $35 Email Angela at anewchapterwithangela@gmail.com The workshop is called Make Fear Your FriendIn April, Grant Edmonds and Angela will have a relationship workshop. More info on that in the future.
In this episode, I discuss the must-know facts about high-yield cytokines and interleukins. Covers TNFa, IL1-6, IL8, IL10 and TGFb. Enjoy! The Med School Phys podcast discusses topics in human physiology. Our primary aim is to help medical students learn/review high yield material for their classes and board exams. Hopefully listeners find that this alternative audio-based learning format works for them. This podcast is intended to be educational and all the information shared herein is publicly available through the internet. Med School Phys is an independent project and currently shares no affiliation with other organizations, companies, or academic institutions.-You can email me questions or constructive feedback at medschoolphys@gmail.com -Check out my book, Read This Before Medical School: https://www.amazon.com/dp/B07YCXZM3X/ref=docs-os-doi_0 -Episode transcriptions can be found at: https://drive.google.com/drive/folders/12QQSFho-ThIIeZuulsblGSnnNL8oJ7ag?usp=sharingDISCLAIMER: All information, content, and materials published by the Med School Phys podcast are for informational purposes only and are NOT intended to serve as a substitute for the consultation, diagnosis, and/or medical treatment of a qualified healthcare provider. Please consult your healthcare provider regarding personal medical decisions.
In this episode, I discuss the must-know facts about high-yield cytokines and interleukins. Covers TNFa, IL1-6, IL8, IL10 and TGFb. Enjoy! The Med School Phys podcast discusses topics in human physiology. Our primary aim is to help medical students learn/review high yield material for their classes and board exams. Hopefully listeners find that this alternative audio-based learning format works for them. This podcast is intended to be educational and all the information shared herein is publicly available through the internet. Med School Phys is an independent project and currently shares no affiliation with other organizations, companies, or academic institutions.You can email me questions or constructive feedback at medschoolphys@gmail.comYou can share a link to our episodes via Spreaker or encourage others to listen on their podcasting app of choice: https://www.spreaker.com/user/medschoolphysFind our Youtube channel at: https://www.youtube.com/channel/UCXEEgC1JZysYsKy9NRYisEQEpisode transcriptions can be found at: https://drive.google.com/drive/folders/12QQSFho-ThIIeZuulsblGSnnNL8oJ7ag?usp=sharingDISCLAIMER: All information, content, and materials published by the Med School Phys podcast are for informational purposes only and are NOT intended to serve as a substitute for the consultation, diagnosis, and/or medical treatment of a qualified healthcare provider. Please consult your healthcare provider regarding personal medical decisions.
Background: Infections and immunological processes are likely to be involved in the pathogenesis of Tourette's syndrome (TS). To determine possible common underlying immunological mechanisms, we focused on innate immunity and studied markers of inflammation, monocytes, and monocyte-derived cytokines. Methods: In a cross-sectional study, we used current methods to determine the number of monocytes and levels of C-reactive protein (CRP) in 46 children, adolescents, and adult patients suffering from TS and in 43 healthy controls matched for age and sex. Tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), soluble CD14 (sCD14), IL1-receptor antagonist (IL1-ra), and serum neopterin were detected by immunoassays. Results: We found that CRP and neopterin levels and the number of monocytes were significantly higher in TS patients than in healthy controls. Serum concentrations of TNF-alpha, sIL1-ra, and sCD14 were significantly lower in TS patients. All measured values were within normal ranges and often close to detection limits. Conclusions: The present results point to a monocyte dysregulation in TS. This possible dysbalance in innate immunity could predispose to infections or autoimmune reactions.
Tierärztliche Fakultät - Digitale Hochschulschriften der LMU - Teil 05/07
Salmonella infections in humans arise through chicken-based food such as eggs, egg-products, or chicken meat. The most common cause for these infections is Salmonella enteritidis, and the aim of this study has been to analyze the early innate immune response of chickens induced via this pathogen. Note that S. enteritidis is a host-adapted serovar, which only causes clinical findings in young chickens during their first week of life; adult chickens do not get sick, but may nevertheless act as inapparent infected carriers. We studied the reaction from the chicken immune system on S. enteritidis, using macrophage cultures as well as tissue samples of infected adult chickens. The gene expression studies were carried out by an “Agilent 4x44K chicken microarray” method. In our in vitro studies, we infected primary macrophages with S. enteritidis for 4 hours, using a MOI of 10. The gene expression studies resulted in the inductions of interleukins (IL1β, IL6, IL12p40, IL18), of chemokines (CCL1, CCL4 (K203), CCL20, CXCL8 (IL8), CXCL13), of some members of the tumor-nekrose-factor-superfamily (TNFSF), and of some toll-like receptors (TLR). Hence the cells have an inflammatory reaction. Particularly prominent were the expression changes of K60 (IL8 homolog), K203 (chCCLi2, MIP-1β), CCL20, and TL1a (TNFSF15). Finally, infected macrophages expressed a group of typical Th1-cytokines, including IL12p40, IL18, and IFN-γ. In further analysis of our data, we focused on cytokines, chemokines, and members of the TNF-superfamily. In the ceca we found similar expression patterns within these three groups as was previously found for them in the macrophages study. In our in vivo studies, we infected chickens that were 8 weeks old and already had a well developed immune system. They were infected in the crop using a dose of 107 salmonella. At 5, 12, 24, and 48 hours of infection, we sampled the ceca and cecal tonsils for the bacterial, histological, and gene expression analyses. Already at 5 hours p.i., we were (for all but one animal) able to isolate bacteria from the ceca-tissue. The bacterial load reached its maximum at 12 hours p.i.. The infection of the cecal-tissues was confirmed in the histology, both by the detection of bacteria and by the occurrence of inflammatory cells. However, using histology, we could not detect any bacteria in cecal tonsils, which suggests that no infection was present in these organs. This suggestion was confirmed in gene expression analyses. When comparing the gene expression studies of cecal tonsils and ceca, the former showed lower counts of differential regulated genes (Tab. 11). Both their count maxima occurred at 12 hour p.i though. Moreover, at this time 41 significant regulated pathways had been identified.. In summary, the in vitro and the in vivo experiment both resulted in an initial inflammatory reaction, as well as in a typical Th1-cytokines reaction. To investigate functional characterisation of named candidate genes, in the first instance CCL20, CXCL8, K60, K203, and TL1a, future analyses of the innate immune response should involve them. This may contribute to a better understanding of the successful defense mechanisms against S. enteritidis in chicken, which may help to contain the amount of salmonellosis in humans.
Traditionally, Crohn's disease has been associated with a Th1 cytokine profile, while Th2 cytokines are modulators of ulcerative colitis. This concept has been challenged by the description of tolerising regulatory T cells (Treg) and by proinflammatory Th17 cells, a novel T cell population characterised by the master transcription factor RORtextgreekgt, the surface markers IL23R and CCR6, and by production of the proinflammatory cytokines IL17A, IL17F, IL21, IL22 and IL26, and the chemokine CCL20. Th17 cells differentiate under the influence of IL1textgreekb, IL6, IL21 and IL23. Recent studies indicate that TGFtextgreekb is essential not only for the development of murine Th17 cells but also for differentiation of human Th17 cells. TGFtextgreekb reciprocally regulates the differentiation of inflammatory Th17 cells and suppressive Treg subsets, with the concomitant presence of proinflammatory cytokines favouring Th17 cell differentiation. Several studies demonstrated an important role of Th17 cells in intestinal inflammation, particularly in Crohn's disease. Genome-wide association studies indicate that IL23R and five additional genes involved in Th17 differentiation (IL12B, JAK2, STAT3, CCR6 and TNFSF15) are associated with susceptibility to Crohn's disease and partly also to ulcerative colitis. Taken together, both Th1 and Th17 cells are important mediators of inflammation in Crohn's disease, although activities previously ascribed to IL12 may be mediated by IL23. Anti-IL12/IL23p40 antibody therapy, which targets both Th1 and Th17 cells, is effective in Crohn's disease. However, the complex relationship between Th1 and Th17 cells has not been completely analysed. This will be of great importance to delineate the specific contributions of these cells to Crohn's disease and other autoimmune diseases.
Cours d’immunologie de 4e année de pharmacie. Les cytokines : TNFalpha, IL1, chimiokines.
Infektionen und postinflammatorische Prozesse scheinen bei einer Untergruppe von Tourette-Patienten ein wichtiger pathogenetischer Faktor zu sein. Einige Studien berichten von Streptokokken- und Mykoplasmeninfektionen im Zusammenhang mit dem Tourette-Syndrom. Auch zeigten sich Erfolge entzündungshemmender und antibiotischer Therapien. Monozyten, Makrophagen und deren proinflammatorische Zytokine spielen eine wichtige Rolle bei der angeborenen Immunität und der ersten Abwehr von Bakterien. Deshalb sollten in dieser Arbeit Monozyten und deren proinflammatorische Zytokine bei Tourette-Patienten im Vergleich zu einer gesunden Kontrollgruppe untersucht werden. Bei 43 Tourette-Patienten und 46 gesunden Kontrollpersonen wurden in einer explorativen, prospektiven Studie Monozyten im Differentialblutbild und Monozytensubpopulationen durchflusszytometrisch bestimmt. Vor diesem Hintergrund erfolgte zusätzlich im Serum die Messung von CRP und Neopterin als Entzündungsparameter, sowie die Bestimmung von monozytären Zytokinen, Rezeptoren, Rezeptorantagonisten wie TNF-α, sTNF-R1 und IL-1-ra. Das lösliche CD14 wurde ebenso als monozytenassoziierter Aktivierungsmarker gemessen. Die Monozyten/nl waren bei Tourette-Patienten im Vergleich zu Gesunden signifikant höher, die Verteilung der Monozytensubpopulationen war in beiden Gruppen nicht unterschiedlich. CRP und Neopterin lagen bei Patienten und Gesunden im Normbereich, waren aber in der Tourette-Gruppe signifikant höher. TNF-α, sCD14 und IL-1-ra-Konzentrationen zeigten sich bei den Tourette-Patienten signifikant niedriger. Trotz höherem CRP und Neopterin bei Tourette-Patienten, was auf eine latente subklinische Entzündungsreaktion hinweisen könnte und im Vergleich zu Gesunden erhöhten Monozytenzahlen, waren weitere primär von Monozyten sezernierte proinflammatorische Zytokine und Aktivierungsmarker wie TNF-α, sCD14 und IL1-ra bei Tourette-Patienten niedriger. Diese Ergebnisse deuten möglicherweise auf eine Störung der Monozytenfunktion bei Tourette-Patienten hin. Die höhere Konzentration der Monozyten/nl könnte als Kompensationsmechanismus gedeutet werden. Eine vermehrte Anfälligkeit für Infektionen wäre dadurch denkbar.
Background/aim: Interleukin 31 (IL31), primarily expressed in activated lymphocytes, signals through a heterodimeric receptor complex consisting of the IL31 receptor alpha (IL31Rtextgreeka) and the oncostatin M receptor (OSMR). The aim of this study was to analyse IL31 receptor expression, signal transduction, and specific biological functions of this cytokine system in intestinal inflammation.Methods: Expression studies were performed by RT-PCR, quantitative PCR, western blotting, and immunohistochemistry. Signal transduction was analysed by western blotting. Cell proliferation was measured by MTS assays, cell migration by restitution assays.Results: Colorectal cancer derived intestinal epithelial cell (IEC) lines express both IL31 receptor subunits, while their expression in unstimulated primary murine IEC was low. LPS and the proinflammatory cytokines TNF-textgreeka, IL1textgreekb, IFN-textgreekg, and sodium butyrate stimulation increased IL31, IL31Rtextgreeka, and OSMR mRNA expression, while IL31 itself enhanced IL8 expression in IEC. IL31 mediates ERK-1/2, Akt, STAT1, and STAT3 activation in IEC resulting in enhanced IEC migration. However, at low cell density, IL31 had significant antiproliferative capacities (p
Background: Intravenous methylprednisolone (IV-MP) is an established treatment for multiple sclerosis ( MS) relapses, accompanied by rapid, though transient reduction of gadolinium enhancing (Gd+) lesions on brain MRI. Intermittent IV-MP, alone or with immunomodulators, has been suggested but insufficiently studied as a strategy to prevent relapses. Methods: In an open, single-cross-over study, nine patients with relapsing-remitting MS (RR-MS) underwent cranial Gd-MRI once monthly for twelve months. From month six on, they received a single i.v.-infusion of 500 mg methylprednisolone ( and oral tapering for three days) after the MRI. Primary outcome measure was the mean number of Gd+ lesions during treatment vs. baseline periods; T2 lesion volume and monthly plasma concentrations of cortisol, ACTH and prolactin were secondary outcome measures. Safety was assessed clinically, by routine laboratory and bone mineral density measurements. Soluble immune parameters (sTNF-RI, sTNF-RII, IL1-ra and sVCAM-1) and neuroendocrine tests ( ACTH test, combined dexamethasone/CRH test) were additionally analyzed. Results: Comparing treatment to baseline periods, the number of Gd+ lesions/scan was reduced in eight of the nine patients, by a median of 43.8% ( p = 0.013, Wilcoxon). In comparison, a pooled dataset of 83 untreated RR-MS patients from several studies, selected by the same clinical and MRI criteria, showed a non-significant decrease by a median of 14% ( p = 0.32). T2 lesion volume decreased by 21% during treatment ( p = 0.001). Monthly plasma prolactin showed a parallel decline ( p = 0.027), with significant cross-correlation with the number of Gd+ lesions. Other hormones and immune system variables were unchanged, as were ACTH test and dexamethasone-CRH test. Treatment was well tolerated; routine laboratory and bone mineral density were unchanged. Conclusion: Monthly IV-MP reduces inflammatory activity and T2 lesion volume in RR-MS.
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