Podcasts about monocytes

Hello Friend, Have you ever been told, “Your blood tests are normal,” but deep down you know something isn't right? It's one of the most frustrating things to hear, especially when you're dealing with fatigue, brain fog, or other unexplained symptoms. Here's the truth: those “normal” lab results might still hold valuable clues about your health—if you know where to look. Your CBC panel, a test you've probably already had done, includes five key markers that can reveal so much about what's really going on inside your body. In this week's episode of Functional Medicine for Christian Women, I break down the CBC differential and explain how Neutrophils, Lymphocytes, Eosinophils, Basophils, and Monocytes can provide insight into your immune function, inflammation, and even chronic stress. I'll show you why this simple test is often the best starting place for uncovering the root cause of your symptoms—and how you can use it to take the first step toward feeling better. In health, Lacy Lain, FMCHC, LEHP P.S. If you've ever felt dismissed by conventional doctors, I made this episode with you in mind. Let's start finding the answers your body is trying to tell you. What's Next? Book Your Free Consultation: Sick Of Feeling Like Junk, Know Something's Not Right, Yet You're Told By Your Doctors That Your Labs Are “Normal”... Connect with Lacy: Apply to work with Lacy 1:1 (two spots now open!) The Stronger Collective App Learn more by clicking here. Related Episodes You Might Enjoy: 42. Why Am I Always Tired? Common Causes of Chronic Fatigue in Working Women 27. Why Career-Driven Women Should Care About Blue Zones, Air Quality, and Houseplants for Better Indoor Air 45. Unlock Your Energy: How Hormones Could Be the Key to Fixing Your Fatigue 33. Bandaid Solutions vs Functional Solutions in Women's Health 47. How NAD+ Can Help Exhausted Women Regain Their Energy Naturally - Disclaimer: Our life and health coaches do not diagnose, treat, prevent, or cure any disease or condition. Nothing we share with our clients is intended to substitute for the advice, treatment, or diagnosis of a qualified licensed physician. Lacy Lain, FMCHC may not make any medical diagnoses or claim, nor substitute for your personal physician's care. It is the role of Lacy Lain and her Practitioners to partner with their clients to provide ongoing support and accountability in an opt-in model of self-care and should be done under the supervision of a licensed physician. These platforms share personal experiences and provides education. Interaction on these platforms does not constitute a doctor/patient relationship.

View the Show Notes For This Episode Dr. James Lavalle discusses Metaflammaging with Dr. Ben Weitz. [If you enjoy this podcast, please give us a rating and review on Apple Podcasts, so more people will find The Rational Wellness Podcast. Also check out the video version on my WeitzChiro YouTube page.] Podcast Highlights In this episode of the Rational Wellness Podcast, host Dr. Ben Weitz engages in a comprehensive discussion with Dr. James LaValle, an internationally recognized clinical pharmacist and nutritionist. They delve into the concept of metaflammation—metabolic inflammation—and its impact on health and aging. Dr. LaValle shares his personal journey into integrative and functional medicine, his work with athletes and professional teams, and his development of the Metabolic Code. He also discusses the significance of various biomarkers for assessing health, the role of GLP-1 agonists in obesity and diabetes management, and the potential benefits and concerns surrounding peptides. Additionally, they cover the importance of lifestyle changes, stress management, and innovative health technologies in promoting longevity and well-being.   00:00 Introduction to the Rational Wellness Podcast 00:29 Meet Dr. James LaValle: A Journey in Integrative Medicine 05:26 The Metabolic Code and Personalized Care 06:33 The Role of Lifetime in Promoting Wellness 07:31 Understanding Biomarkers and Metabolic Health 18:02 The Impact of GLP-1s and Lifestyle Changes 27:12 Concerns and Considerations with GLP-1s 31:05 Inflammation Markers: Mean Platelet Volume and Neutrophil Lymphocyte Ratio 31:42 Understanding Metabolic Inflammation 32:09 The Role of Basophils and Cortisol in Inflammation 32:25 Neutrophils, Lymphocytes, and Immune System Stress 33:27 Monocytes and Macrophages: Indicators of Inflammation 36:12 The Importance of Urinary pH and Kidney Health 37:47 Root Causes of Obesity: Genetics, Environment, and Nutrient Deficiencies 39:14 The Impact of Prescription Drugs on Weight Gain 39:49 Magnesium Deficiency and Metabolic Syndrome 40:54 The Problem with Ultra-Processed Foods 42:36 The Importance of Personal Health Responsibility 44:11 Exploring Peptides and Their Benefits 48:54 Innovations in Longevity and Health Supplements 54:22 The Science Behind Synapsin and RG3 58:45 Conclusion and Final Thoughts   Dr. James Lavalle is an internationally recognized clinical pharmacist and a board certified clinical nutritionist for close to 40 years and he is the author of more than 20 books including, “Cracking the Metabolic Code.”  He has lectured for more than a decade for the American Academy of Anti-Aging Medicine.   Jim has served thousands of patients using his "Metabolic Model for Health" through his integrative health practice, LaValle Metabolix in Orange County, CA.   James is best known for his expertise in personalized integrative therapies uncovering the underlying metabolic issues that keep people from feeling healthy and vital.  His website is JimLavalle.com.  To find out more about his nutrition products that he has developed, including Synapsin, please go to MetabolicElite.co.   Dr. Ben Weitz is available for Functional Nutrition consultations specializing in Functional Gastrointestinal Disorders like IBS/SIBO and Reflux and also Cardiometabolic Risk Factors like elevated lipids, high blood sugar, and high blood pressure.  Dr. Weitz has also successfully helped many patients with managing their weight and improving their athletic performance, as well as sports chiropractic work by calling his Santa Monica office 310-395-3111.

BUFFALO, NY- August 7, 2024 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science), Volume 16, Issue 14 on July 26, 2024, entitled, “mTORC1 activation in presumed classical monocytes: observed correlation with human size variation and neuropsychiatric disease.” In this new study, researchers Karl Berner, Naci Oz, Alaattin Kaya, Animesh Acharjee, and Jon Berner from Woodinville Psychiatric Associates, Virginia Commonwealth University, University of Birmingham, University Hospitals Birmingham, and MRC Health Data Research UK, aimed to measure phosphorylated p70S6K, a marker for mTORC1 activity, in individuals with psychiatric disease to determine whether phosphorylated p70S6K could predict medication response. Their results showed that mTORC1 activity correlated highly with classical biometrics (height, macrocephaly, pupil distance) and specific neuropsychiatric disease profiles (anxiety and autism). “Our data suggest that human variability of mTORC1 gain of function observed during the differentiation of stem-like monocytes into vascular tissue-resident macrophages correlates with physical size, subsets of neuropsychiatric disease, and clinical ketamine or rapamycin response.” DOI - https://doi.org/10.18632/aging.206033 Corresponding author - Jon Berner - jonbernermd@gmail.com Video short - https://www.youtube.com/watch?v=EXzX6CjtAHc Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.206033 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, ketamine, lithium, monocyte, mTORC1, rapamycin About Aging-US The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population. The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.) Please visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM

The CBC (complete blood count) with differential is the most common lab test performed on patients. Practitioners often look at the ranges indicated in the CBC. However, they don't look closely at the five critical markers that can tell what's happening inside the patient's body.Learning how to read blood work better is essential to providing quality care. Becoming a Functional Blood Work Specialist is possible no matter how simple or complex your background is. Today, I share how some practitioners elevated their practice by incorporating functional blood work into their treatment package. I also discuss the five markers inside this standard blood test to help you discover the gold inside your patient's CBC.Open enrollment for the 90-day Functional Blood Work Specialist Program is happening now. I'd be honored to have you join this cohort. We start and end together, so you'll need to decide before February 29th is over. We begin March 1st. Get all the details and become certified at drkylieburton.com/90“No matter how simple your background is or how complex your background is, the blood work your patients have is loaded with gold.”- Dr. Kylie BurtonIn This Episode:What is the CBC?What is the WBC, and what do the numbers mean?What are Neutrophils?What are Lymphocytes?What are Monocytes?What are Basophils and Eosinophils?Why join the 90-Day Functional Blood Work Specialist Program?Resources:Join the 90-day Functional Blood Work Specialist Program - https://drkylieburton.com/90day/Learn How to Read the Blood Work Your Clients Already Have in a Better Way - https://drkylieburton.com/cbc-live/Why Are My Labs Normal? By Dr. Kylie Burton - https://drkylieburton.com/product/why-are-my-labs-normal/Connect with Dr. Kylie:Website - https://drkylieburton.com/Instagram - https://www.instagram.com/drkylieburton/Facebook - https://web.facebook.com/drkylieburton/YouTube - https://www.youtube.com/channel/UCdqJbAS6ocKydcjNiDQoauw

In this episode of Health411, host Dr. Jonathan Karp and producer Josh Brewer discuss a recent article regarding chronic alcohol use and its subsequent effects on the immune system.

Overview White Blood Cells Normal Value Range Pathophysiology Special considerations Abnormal values (high) Abnormal values (low) Nursing Points General Normal value range WBC 4500-10000/mcL Differential Neutrophils 40-60% Bands 3-5% >8% indicates signal to WBC for more production Infection or inflammation is severe Eosinophils 1-4% Basophils 0.5-1% Lymphocytes 20-40% Monocytes 2-8% Pathophysiology WBC Formed in the bone marrow Responsible for responding to foreign invaders Creating antibodies (immunity) Phagocytosis (eating bacteria or fungi) Multiple types with different purposes Neutrophils – inflammation and first response to invader Eosinophils – Inflammation Allergic response Parasites Basophils Inflammation Allergic response Lymphocytes Create antibodies Recognize antigens Destroy cells T Cells B Cells Natural Killer cells Monocytes Macrophages Engulf and destroy invaders Indicative of infection Special considerations Lavender top tube Will commonly be submitted for Complete Blood Count with differential Abnormal lab values Increased White Blood Cell count (leukocytosis) Infection Inflammation Trauma/Stress Pregnancy Asthma Allergic Reaction Decreased lab values (leukopenia) Systemic Lupus Erythematosus (SLE)/Rheumatoid arthritis Cancers Chemotherapy/Radiation Medications Neutropenic precautions Masks Gloves Wash hands Consider yourself infectious Prevent spread of infection to the patient Assessment Consider the overall WBC count plus abnormalities in differential Evaluate patient Signs or symptoms of: Trauma Inflammation Infection Therapeutic Management Antibiotic therapies where indicated by infection (followed by cultures to determine efficacy of antibiotics) Anti-inflammatories for inflammation Provide neutropenic precautions when necessary Nursing Concepts Lab Values Infection Control Patient Education Educate patient on the finishing any antibiotics completely. Do not stop prior, even if the patient says they are feeling better.

Long Covid is on the rise, yet most people are still left struggling to recover.Is it even possible??In this week's episode, Evie and Toréa had the opportunity to interview Halina Kowalski to dive into the details of how she recovered from Long Covid! Listen in on this unique approach that Halina used to put her symptoms into remission. Her background as a mental health clinical researcher primed her ability to research and discover the latest scientists and doctors looking at Long Covid. Discover her unique trifecta approach combining precision medicine, functional medicine and the use of contrast therapy to resolve her long illness.Let's begin! About Halina KowalskiHalina Kowalski is a mental health professional & clinical researcher with an insatiable thirst for learning ancient healing methods and practices from all cultures and peoples. Her studies led me down a path and quest to learn the traditional healing methods of her own Latvian ancestry. She discovered, by no coincidence, she had already been deeply drawn to the Latvian-Baltic tradition of sauna (pirts) that incorporates wild foraged plants and herbs into the heat and steam ritual of sacred mind/body/spirit healing. Her role as a researcher allowed her to piece together a combination of precision medicine, functional medicine and these ancient healing practices to place her own long covid into remission.Timestamps00:00 Overcoming Long Covid with a Trifecta Approach05:43 Helina's Long Covid journey13:15 incellDx by Dr. Bruce Patterson15:38 The Immune Signature of Long-Haul Covid17:25 The Theory on Spike Protein17:55 Monocytes that evade senolysis (cell death) 23:17 Telemedicine with covidlonghaulers.com26:25 Incorporating functional medicine into the healing process31:24 Effects of Cold Exposure against Covid-1937:47 Where to find Helina and gathersaunahouse.comResources MentionedDr Bruce Patterson https://www.ifm.org/about/profile/bruce-patterson-md/incellDx https://incelldx.com/Covid Long Haulers https://www.covidlonghaulers.com/homeMaraviroc and Long Covid https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9944830/Connect with Halina @ Gather Website: https://www.gathersaunahouse.com/Instagram: https://instagram.com/gather_saunahouseConnect with ToréaWebsite: https://www.torearodriguez.com/Instagram: https://www.instagram.com/torearodriguez/Connect with EvieWebsite: https://holisticallyrestored.com/Instagram: https://www.instagram.com/holisticallyrestored/Join the Optimized Wellness Community:...

KSQD 5-31-2023: Stress raises glucocorticoids and inflammation in the gut, thus causing irritable bowel syndrome; Mosquitos are attracted to terpenes in many soaps, but repelled by those with coconut oil; Editorial about gender selection and the altering of sexual development

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.28.530459v1?rss=1 Authors: Bavykina, V., Avino, M., Husain, M. A., Zimmer, A., Parent-Roberge, H., Khalil, A., Brunet, M. A., Fulop, T., Laurent, B. Abstract: Background. Alzheimer's disease (AD) is the most common form of dementia with the symptoms gradually worsening over the years. However, the driving pathological processes occur well before the appearance of symptoms. AD patients display signs of systemic inflammation, suggesting that it could precede the well-established AD hallmarks. We recently showed that the innate immune response in the form of monocyte activation is detectable at the pre-clinical stage. Objectives. Our goal here is to characterize changes of gene expression in peripheral blood monocytes from patients at different stages of AD progression and validate potential biomarkers for a better prognosis and diagnosis of AD clinical spectrum. Results. We performed a whole transcriptome analysis on monocytes purified from healthy subjects, Mild Cognitive Impairment (MCI) and AD patients, and established the list of genes differentially expressed in monocytes during the disease evolution. We observed that, in the top 500 genes differentially expressed, a majority of these genes were upregulated (65%) during AD progression. These genes are mainly involved in chemokine/cytokine-mediated signaling pathways. We further confirmed several biomarkers by quantitative PCR and immunoblotting and showed that they are often deregulated at pre-clinical stages of the disease (MCI stage), supporting the hyperactivation of monocytes in MCI patients. Perspectives. Our findings provide evidence that the pre-clinical stage of AD can be detected in monocytes using a specific set of biomarkers, highlighting the importance to study the early innate immune response in AD. Our results open the possibility to use these biomarkers with different diagnostic methodologies to better predict and efficiently treat AD. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.12.520033v1?rss=1 Authors: Wu, Y., Huang, J., Ding, N., Lu, M., Wang, F. Abstract: Non-obstructive azoospermia is the most serious cause of male infertility. The testis has a special immunological environment, but the relationship between immune cells in the testicular microenvironment is still unclear. Therefore, it is urgent to identify the interaction mechanism and molecular determinants of immune cells in the testicular microenvironment. To further elucidate the etiology of azoospermia and provide a reference for the treatment of azoospermia. The GSE145467 and GSE9210 datasets were analyzed by Limma package, and then the differential genes were analyzed by enrichment analysis and protein-protein interaction analysis. In addition, we combined single-cell analysis(scRNA) to identify immune cell types and verified the expression of Hub genes in these immune cells. Finally, CellChat was used for cell-to-cell communication analysis. We found the distribution of immune cells in the microenvironment of Y chromosome AZF region microdeletions (AZFa_Del), idiopathic NOA (iNOA), and Klinefelter syndrome (KS) was significantly different from that of normal adults, especially monocytes/macrophages. In normal subjects, monocytes/macrophages mainly played the role of the signal source, while in patients with azoospermia, monocytes/macrophages mainly received signals from other immune cells. Monocytes/macrophages in AZFa_Del, iNOA, and KS communicated with other immune cells mainly through MDK-LRP1, PTN-NCL, and MDK-NCL ligand-receptor pairs respectively. Our research provides new ideas for the pathogenesis and treatment of azoospermia. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

In this week's episode, we will review a study that cell-free hemoglobin S was found to induce high levels of pro-inflammatory cytokine production in monocytes. The effect is mediated by Toll-like receptor 4, or TLR4, suggesting intriguing therapeutic possibilities for sickle cell disease.  Secondly, germinal center B cells with aberrant expression profiles undergo independent clonal evolution in the microenvironment of angioimmunoblastic T-cell lymphoma. New findings published in Blood elucidate mechanisms of disease pathogenesis and uncover a new potential target for treatment. Finally, an upfront combination of three immunosuppressive agents was highly effective and well tolerated in patients with acquired hemophilia A. Although prospective studies are needed, the triple regimen could be an attractive treatment option, particularly for elderly and frail patients.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.28.514304v1?rss=1 Authors: Sirkis, D. W., Warly Solsberg, C., Johnson, T. P., Bonham, L. W., Sturm, V. E., Lee, S. E., Rankin, K. P., Rosen, H. J., Boxer, A. L., Seeley, W. W., Miller, B. L., Geier, E. G., Yokoyama, J. S. Abstract: Background: Emerging evidence from mouse models is beginning to elucidate the brain's immune response to tau pathology, but little is known about the nature of this response in humans. In addition, it remains unclear to what extent tau pathology and the local inflammatory response within the brain influence the broader immune system. Methods: To address these questions, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from carriers of pathogenic variants in MAPT, the gene encoding tau. Results: Analysis of ~181,000 individual PBMC transcriptomes from MAPT pathogenic variant carriers (n = 8) and healthy non-carrier controls (n = 8) demonstrated striking differential expression in monocytes and natural killer (NK) cells. We observed a marked reduction in the expression of CX3CR1 - the gene encoding the fractalkine receptor that is known to modulate tau pathology in mouse models - in monocytes and NK cells. We also observed a significant reduction in the abundance of nonclassical monocytes and dysregulated expression of nonclassical monocyte marker genes, including FCGR3A. Finally, we identified reductions in TMEM176A and TMEM176B, genes thought to be involved in the inflammatory response in human microglia. We confirmed differential expression of select biologically relevant genes dysregulated in our scRNA-seq data using droplet digital PCR as an orthogonal technique for quantitative validation. Conclusions: Our results suggest that human peripheral immune cell expression and abundance are modulated by tau-associated pathophysiologic changes. CX3CR1 and nonclassical monocytes in particular will be a focus of future work exploring the role of these peripheral signals in additional tau-associated neurodegenerative diseases. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

When your blood results are “normal” what does that really mean given that the average person is overweight, sick and expected to die of one of the diseases of civilisations? This is why if you don't feel well then you might need to take things into your own hands by learning how to read your bloods and identify autoimmune signs before you're too far down the rabbit hole.On this episode we reveal:Why most doctors miss the signs of autoimmune diseaseThe 4 steps to begin recovering from autoimmune diseaseHow to read your own blood work and supplementing vitamin D***Join the Busy Mum's Facebook Group here: https://mattylansdown.com/BusyMothersFBgroup ***SOCIAL MEDIA--DR. KYLIE BURTONWebsite: https://drkylieburton.com/InstagramTiktok--MATTY LANSDOWNJoin the Busy Mum's Facebook Group: >>HERE

TWiV explains why this season's influenza vaccine is not protecting against mild to moderate disease caused by H3N2 virus, and that antibody-dependent entry of SARS-CoV-2 into monocytes is a major contributor to severe COVID-19. Hosts: Vincent Racaniello, Dickson Despommier, Rich Condit, and Amy Rosenfeld Subscribe (free): Apple Podcasts, Google Podcasts, RSS, email Become a patron of TWiV! Links for this episode Seasonal influenza vaccine effectiveness (MMWR) Properties of a dominant H3N2 variant (bioRxiv) Scott Henley on influenza vaccine growth in eggs (TWiV 480) Fc receptor dependent entry of SARS-CoV-2 into monocytes (Nature) Timestamps by Jolene. Thanks! Weekly Picks Dickson – Ketanji Brown Jackson confirmed to US Supreme Court Amy – Some threats just keep coming in waves Rich – Lady Bird Johnson Wildflower Center Vincent – Martijn Doolaard Listener Picks Ann – Immunological memory to SARS-CoV-2 infection and vaccines Chris – Isoplexis Intro music is by Ronald Jenkees Send your virology questions and comments to twiv@microbe.tv

SHR # 2786:: Kefir: Post-workout Drink for Cancer Survivors - Dr. Peter Smoak, Ph.D. - Cancer is one of the most prevalent diseases affecting society today, with just over 1.8 million new cancer cases projected for the year 2020 in the United States alone. An underlying cause of cancer is unresolved inflammation. Monocytes are part of the innate immune response which plays an important role in the initiation of inflammation in the body, especially in the presence of pathogenic bacteria. . Elevated numbers of inflammatory monocytes are associated with tumor cell survival and metastasis. Chemotherapy and radiation are two of the most effective and commonly used cancer treatments; however, both are associated with monocytopenia and increases in the proportion of inflammatory monocytes (8, 9) in concert with major disturbances of the microbiome. The number and strains of probiotic species play an important role in determining their survival in the human gut and large numbers of highly diverse microbial gut populations have the potential to provide significant health benefits. Kefir is a fermented milk beverage that differs from other fermented milk products in that it is started by a culture containing a robust quantity and combination of many different bacteria and yeast species bound together in an exopolysaccharide matrix. Given the potential for kefir to improve the health of cancer survivors, this study examined the effects of 12 weeks of kefir consumption on body size and composition, cardiovascular fitness, muscular strength, measures of depression, fatigue, quality of life, gastric distress, biomarkers of gut dysbiosis, whole body inflammation, and monocyte phenotype and function in a population of cancer survivors enrolled in a structured exercise program. http://shrnetwork.biz/mag get $200 worth of free gifts from November 1st through the 30th use code SHR10.

This podcast is a summary of article "Monocytes and Macrophages in Kidney Transplantation and Insights from Single Cell RNA-Seq Studies" by Andrew Malone.

Please join author Milton Packer and Associate Editor Justin Ezekowitz as they discuss the Perspective "Heart Failure and a Preserved Ejection Fraction: A Side-by-Side Examination of the PARAGON-HF and EMPEROR-Preserved Trials." Dr. Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the Journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National Heart Center. Dr. Greg Hundley: And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia. Dr. Carolyn Lam: Greg, it really is so great to be back with you chatting about the papers here in the Journal. Thank you for going solo and for just being the greatest partner on earth. Thank you for that. For everyone listening in, we are back with some gusto and especially with this feature discussion today. You are not going to want to miss it. We are talking to Dr. Milton Packer as well as Dr. Justin Ezekowitz. We are going to compare PARAGON and EMPEROR-Preserved trials in heart failure with preserved ejection fraction. A really interesting discussion you're not going to want to miss, but now let's start with some papers in today's issue. I'd like to start, please. Dr. Greg Hundley: You bet. Dr. Carolyn Lam: Greg, you know the optimal duration of antiplatelet therapy in patients with high bleeding risk with or without oral anticoagulation after coronary stenting? Well, that still remains a question. Today's paper is a pre-specified subgroup analysis of the MASTER DAPT trial and reports on the outcomes of patients with or without an oral anticoagulation indication in this study. Dr. Greg Hundley: Right, Carolyn. Remind us. What was the MASTER DAPT trial? What did it test? Dr. Carolyn Lam: Ah. MASTER DAPT investigated an abbreviated or one-month versus a non-abbreviated or three to 12-month dual antiplatelet therapy and a stopping of antiplatelet therapy at six months strategy after coronary stenting in an all-comer population at high bleeding risk. Dr. Greg Hundley: Carolyn, what did this subgroup analysis of outcomes in patients with and without oral anticoagulation show? Dr. Carolyn Lam: At 12 months of follow-up, ischemic and net risk did not differ with abbreviated versus non-abbreviated anti-platelet regimens in both subgroups, although significantly fewer clinically relevant bleeding events occurred in the group without an oral anticoagulation indication. Whereas only numerically fewer bleeding events occurred in the group with an oral anticoagulation indication that did not reach statistical significance. This subgroup analysis from the MASTER DAPT trial really adds additional evidence that dual antiplatelet therapy beyond one month in patients with or without an indication for oral anticoagulation really has no benefit and only increases bleeding risk. Dr. Greg Hundley: Oh, very important finding, Carolyn. Great research. Well, Carolyn, how the extracellular matrix microenvironment modulates the contractile phenotype of vascular smooth muscle cells and confers vascular homeostasis really remains elusive. Thus, these investigators led by Professor Wei Kong at Peking University applied protein-protein interaction network analysis to explore novel extracellular matrix proteins associated with the vascular smooth muscle cell phenotype. Dr. Carolyn Lam: Huh. Interesting. What did they find, Greg? Dr. Greg Hundley: Right, Carolyn. By combining an in-vitro and an in-vivo genetic mice vascular injury model, they identified nidogen-2, a basement membrane glycoprotein, as a key extracellular matrix protein for maintenance of vascular smooth muscle cell identity. Nidogen-2 exerted its protective function via direct interaction and modulation of Jagged1-Notch3 signaling. Dr. Carolyn Lam: Wow! Nidogen-2 and Jagged1-Notch3. I always learn so much. What are the clinical implications, Greg? Dr. Greg Hundley: Right, Carolyn. Perhaps targeting nidogen-2 to precisely modulate Jagged1-Notch3 signaling, well, that may provide novel therapeutic strategy for atherosclerosis and post-injury restenosis. Dr. Carolyn Lam: Very nice. Well, in the next paper, we discuss inflammation in heart failure. We know that inflammation contributes to the pathogenesis of heart failure, but there is limited understanding of inflammation's potential benefits. Interesting, huh? Well, these authors, Dr. Wollert and colleagues from Hannover Medical School in Germany, identified an adaptive crosstalk between inflammatory cells and cardiomyocytes that protects against persistent afterload stress-induced heart failure in mice. Monocytes and macrophages produced myeloid-derived growth factor in the pressure overloaded myocardium to augment SERCA2a expression in cardiomyocyte's calcium cycling and contractility. Myeloid-derived growth factor plasma concentrations were also found to be elevated in patients with aortic stenosis and to decline after aortic valve implantation indicating that pressure overload also triggers myeloid-derived growth factor release in humans. Dr. Greg Hundley: Carolyn, really informative preclinical science, but what are the clinical implications? Dr. Carolyn Lam: Ah. These observations molecularly defined a feature of the inflammatory response to hemodynamic overload that protects against heart failure development. Inflammation's beneficial trade therefore need to be considered when developing inflammation as a therapeutic target in heart failure. All of this is really discussed in a lovely editorial entitled Inflammation and Heart Failure: Friend or Foe? That's by Drs. Hajjar and Leopold. Dr. Greg Hundley: Great job, Carolyn. Well, my next paper focuses on resistant hypertension. Carolyn, although lifestyle modifications generally are effective in lowering blood pressure among patients with unmedicated hypertension or those treated with one to two antihypertensive agents, the value of exercise and diet for lowering blood pressure in patients with resistant hypertension is unknown. To address this, Professor James Blumenthal and co-authors at Duke University Medical Center enrolled 140 patients with resistant hypertension with an average age of 63 years, 48% women, 59% black, 31% diabetes, and 21% with chronic kidney disease and randomly assigned them to A, a four-month cardiac rehab center-based program of lifestyle modification. We're going to call that C-LIFE, consisting of dietary counseling, behavior and weight management, and exercise. Or number 2 or the B, a single counseling session providing standardized education and physician advice. We'll call that SEPA. Dr. Greg Hundley: The primary endpoint was clinic measured systolic blood pressure. Secondary endpoints included 24-hour ambulatory blood pressure and selective cardiovascular disease biomarkers including baroreflex sensitivity to quantify the influence of baroreflex on heart rate; high-frequency heart rate variability to assess vagally-mediated modulation of heart rate; flow-mediated dilation to evaluate endothelial function; and pulse wave velocity to assess arterial stiffness; and then finally left ventricular mass to characterize left ventricular structure and remodeling. Dr. Carolyn Lam: Wow! That is a very, first of all, important clinical question. Then also, just very intricate methodology in assessing this. What did they find? Dr. Greg Hundley: Right, Carolyn. Between-group comparisons revealed that the reduction in clinic systolic blood pressure was greater in C-LIFE compared with SEPA. Next, 24-hour ambulatory systolic blood pressure also was reduced in C-LIFE with no change in SEPA. Then next, compared with SEPA, C-LIFE resulted in greater improvements in baroreflex sensitivity, high-frequency heart rate variability, and flow-mediated dilation. There was no between-group differences in pulse wave velocity or LV mass. Dr. Greg Hundley: Carolyn, diet and exercise can lower blood pressure in patients with resistant hypertension. When delivered in a cardiac rehabilitation setting, a four-month program of diet and exercise as adjunctive therapy, results in a significant reduction in clinic and ambulatory blood pressure, and improvement in selected cardiovascular disease biomarkers. Dr. Carolyn Lam: Wow! Really nice, Greg. Okay. Well, looks like we're all going to round up already with what else there is in today's issue. Let me start. There's an exchange of letters between Drs. Fang and Vinceti regarding the article Blood Pressure Effects on Sodium Reduction: Dose-Response Meta-analysis of Experimental Studies. Dr. Greg Hundley: Right, Carolyn. I've got a few things in the mail bag. First, Professor Anker has a Research Letter regarding the Kidney Function After Initiation and Discontinuation of Empagliflozin in Heart Failure Patients With and Without Type 2 Diabetes: Insights From the EMPERIAL Trials. Dr. Gerstenfeld has an ECG challenge entitled Atrioventricular Block with Narrow and Wide QRS: The Pause That Refreshes. Then lastly, Dr. Donald Lloyd-Jones has an AHA update regarding the American Heart Association's focus on primordial prevention. Well, Carolyn, I can't wait to hear this fantastic feature discussion with you and Dr. Packer. How about we jump to that? Dr. Carolyn Lam: Great. Let's go, Greg. Dr. Carolyn Lam: Because side-by-side exam of PARAGON and EMPEROR is like side-by-side of... Dr. Justin Ezekowitz: You can compare our new and our old prime minister much like your paper did. Dr. Milton Packer: Yeah, yeah. Dr. Justin Ezekowitz: There are [crosstalk] and it could be viewed until they perform in the broader world how it goes. You don't quite know. Dr. Milton Packer: The only problem is you can't do a head-to-head comparison of the old prime minister and the new prime minister. Dr. Justin Ezekowitz: That is true except that the head-to-head comparison includes excellent care by both the new and the old. I think that comparison's going to be pretty equal. I think we can case-control that one. Dr. Carolyn Lam: I really liked that that was politically correct because we are recording. Everybody, welcome to the feature discussion. I am here with Dr. Milton Packer from Baylor and he really needs no introduction. We're discussing heart failure with preserved ejection fraction. As well as our associate editor, Dr. Justin Ezekowitz from University of Alberta. Hence, in case anybody's wondering, we were talking about the Canadian elections. Let's just launch straight into it, a side-by-side comparison of PARAGON and EMPEROR-Preserved. Dr. Packer... Milton, if I may, what in the world drove you to do this? Dr. Milton Packer: My God. Oh, my God. Yes. Dr. Carolyn Lam: Tell us about what drove you to do this and please, if you could just summarize the results. Dr. Milton Packer: Well, let me just say from the outset that this was a commentary, not an original research article. Dr. Carolyn Lam: Yes. Dr. Milton Packer: The commentary was motivated by two very straightforward observations. We had two large scale outcome trials of two different drugs in heart failure with a preserved ejection fraction. I was privileged to serve as you were, Carolyn, on the leadership committees of both trials. It's not as if we have involvement in only one trial. We have involvement in both trials and we are very proud of that involvement. Dr. Milton Packer: One trial came in with a effect size of about 13% on its primary endpoint with a borderline P-value. A second trial, EMPEROR-Preserved, came in with a 21% reduction and its primary endpoint with a really small and persuasive P-value. The two patient populations in the two trials were really amazingly similar. We wanted to understand why it was 21% in one trial and persuasively so and why it appeared to be smaller in the PARAGON trial with sacubitril/valsartan. We thought, well, maybe that difference was related to how endpoints were defined or maybe that difference was related to the influence of ejection fraction. The reason we got excited about that was that as almost everyone knows, PARAGON found an influence of ejection fraction on the effect of sacubitril/valsartan in patients with HFpEF. We found an influence of ejection fraction on the effect of empagliflozin in HFpEF in EMPEROR-Preserved. We wanted to understand whether that influence was similar in the two trials. Dr. Milton Packer: Just to make life simple, PARAGON had created certain cut points for ejection fraction. They had presented and previously published in Circulation endpoints based on those cut points of ejection fraction. All we did was we used their endpoints and their cut points, and we put the two trials side by side. We did not do a statistical comparison of the effect size. There're actually no P-values in the whole commentary. But what we wanted to see was: Was the shape of the ejection fraction influence relationship similar or different in the two trials? Well, very simple. In PARAGON, as has been reported, there was a linear relationship: as ejection fraction increased, the effect of sacubitril/valsartan got smaller. In EMPEROR-Preserved, there was also an attenuation at a highest ejection fraction, but the relationship wasn't linear. It was like a hockey stick. It was flat and then went up at an ejection fraction over 62.5, which was the cut point that PARAGON used. Dr. Milton Packer: When we compared patients between the low 40s and the low 60s, the effect size in empagliflozin appeared to be larger than the effect size of sacubitril/valsartan in that ejection fraction group using the same endpoints. In fact, for hospitalizations for heart failure, which is really what SGLT2 inhibitors do, it was twice as great with empagliflozin in EMPEROR-Preserved than with sacubitril/valsartan in PARAGON-HF. We thought this was really interesting. We put the pictures up side by side. We wrote a commentary and Circulation was so kind to accept it. Dr. Carolyn Lam: Oh, but Milton, you were very, honestly as always, very clever to have done this analysis. But if I could reiterate a few things for the audience, which is very important. First of all, as you rightly first pointed out, it's a perspective piece. It is not a head-on comparison with P-values. It could not be. Let's just also give the audience a bit of background in that PARAGON included patients with an ejection fraction of 45% and above. EMPEROR-Preserved was above 40. PARAGON looked at total heart failure hospitalizations and cardiovascular death as a primary outcome. EMPEROR looked at first cardiovascular death or heart failure hospitalization. Dr. Carolyn Lam: Let's just remember the designs were different. Of course in the comparison, PARAGON compared sacubitril/valsartan versus valsartan. I like the way you very carefully wrote in your study that it was more a study of neprilysin inhibition since it's sacubitril/valsartan against valsartan and it was empagliflozin versus placebo. We know that it's important to state that as a basis. Then really important to say to everybody out there, pick up our journal. You must look at this bigger. I myself have already cited it at least twice already, Milton, because people will just naturally ask that. "Are the results different because of ejection fraction or different endpoints?" What you did there in that beautiful figure is that you tried as best as you can to match it up in terms of ejection fraction bins and match it up in terms of hospitalizations. There. I just wanted to state those few things, but I'm really- Dr. Milton Packer: Oh, no. No. Carolyn, you're 100% right. That's why there are couple of things. I just want to underscore what you said because I think your points were spot on. First of all, we really lined up the endpoints and the ejection fraction. We tried our best to compare apples and apples. It would not have been a useful exercise for us to compare different endpoints and different ejection fraction subgroups. But I just want to make sure that everyone understands: I'm a big fan of sacubitril/valsartan and I'm a big fan of neprilysin inhibition. As you know, both PARADIGM-HF and PARAGON-HF weren't really tests of sacubitril/valsartan; they were tests of neprilysin inhibition. They were great tests at that. PARAGON in particular was a great test of that. We're comparing neprilysin inhibition and SGLT2 inhibition. Dr. Milton Packer: But here's my most important point: we do not want people to choose one over the other. That was not the intent. We think that there are data in patients with certain ejection fractions, let's say between 40 and 60, I'm just creating a range, where both interventions are appropriate. Now I understand there are cost considerations and I don't want to minimize that, but we are not suggesting that anyone prefer one drug over the other. All we wanted to do was we wanted to ask the question: Since the effect size in one trial seemed to be different than the effect size in the other trial, what were the ejection fraction subgroups that represented that difference? We found that the patients with ejection fractions greater than 60, 65% did not contribute to that difference. It was the patients with lower ejection fractions that contributed to the difference. I hope that's helpful. Dr. Carolyn Lam: Ah. That's wonderful. Justin, have you recovered from the talk about the Canadian elections? Dr. Justin Ezekowitz: Oh. I have indeed. Dr. Carolyn Lam: I'm on swinging. Dr. Justin Ezekowitz: I have indeed. Thanks for recognizing that Canada just had a major election we carried out in six weeks. But, Milton, I really enjoyed reading this. Maybe I can just ask you about two elements within this perspective piece, which is number 1, what's incredibly concordant is a lack of difference across cardiovascular death for both agents in both trials regardless of the trial differences and the potential differences in patient populations recruited; that's number 1. It's incredibly flat for cardiovascular death. Dr. Justin Ezekowitz: But number 2 is there is a danger in comparing trials even non-statistically. That's often a pitfall we get into, but we have to put some frame of reference on that. What is the one or two key things you think differ between PARAGON and EMPEROR-Preserved that you say, "You really need to look at these trials differently"? Those two questions came to mind when looking at this great figure that you produced. Dr. Milton Packer: Okay. The first question is so much easier and that is that these drugs don't reduce cardiovascular deaths. Full stop. It's really interesting because sacubitril/valsartan reduces cardiovascular death in people with ejection fractions of 40% or less, but not in patients with ejection fraction greater than that. The primary effect is heart failure hospitalizations. Empagliflozin didn't reduce cardiovascular death even in patients with the ejection fraction less than 40% or greater than 40%. What we're really, really talking about two drugs where the major effect is a reduction in heart failure hospitalizations. That comes out whether you do the analysis as time-to-first-event or total heart failure hospitalizations. Dr. Milton Packer: Of course, we're looking forward to the DELIVER trial with dapagliflozin. My own personal expectation is they're going to come out with a very striking effect on heart failure hospitalizations and not on cardiovascular deaths. Cardiovascular deaths in patients with HFpEF is really... It's a hard goal because only half of the deaths are cardiovascular. These patients have so many comorbidities that influence prognosis. The other thing, which is really important, is that heart failure hospitalizations only represented 18% of all hospitalizations in these patients; it's really small. I think of empagliflozin as being a treatment of the heart failure of HFpEF, not a treatment for HFpEF. I hope that makes sense. Justin, what was your second question? Dr. Justin Ezekowitz: Absolutely. Dr. Milton Packer: Oh, the differences between- Dr. Justin Ezekowitz: Yeah. Thank you, Milton. Dr. Milton Packer: Okay. There's always differences between two trials. As I said before, Carol and I were involved in both trials. They were done slightly at different times. They didn't overlap. Remember that the cut points in the two trials, one was 40%, one was 45%, really didn't matter to our analysis because we corrected for that in our ejection fraction subgroups. I was actually really much more impressed by the similarities than by the differences, but here's the catch. HFpEF is an incredibly heterogeneous disease. When we look at baseline characteristics, we're looking at means, medians, percentages. We're not picking up on any heterogeneity and there's a lot of heterogeneity. I actually think that HFrEF is a reasonably homogeneous disease. I think HFpEF is an incredibly diverse disease with a whole host of different disorders. What I'm amazed by is that we actually got an effect size that was greater than 20% in an all-comers HFpEF analysis. Dr. Milton Packer: But in all honesty, Justin, it wasn't really all-comers. We excluded people with BMIs over 45. There are a lot of patients who are obese and had BMIs greater than 45 who have HFpEF. By the way, especially in Texas. I didn't say that. We didn't enroll those patients. In all honesty, if I had to do it all over again, I would have. By the way, PARAGON didn't enroll them either. Dr. Carolyn Lam: Well, this is an incredible conversation. I know that we could just do a whole hour of chatting about what this implies for the higher ejection fraction, what this implies for how we should be treating heart failure. I don't even dare to ask for some last words maybe from both Justin and Milton, but recognizing that the time is short, anything else to add? Dr. Milton Packer: I think Justin should do last words. Dr. Justin Ezekowitz: Well, let me summarize by saying there is a hockey stick. We love hockey sticks in Canada. A simple and an excellent comparison. I think people should really look at that figure to understand it, but do not undertreat your patients with HFpEF and look at these with a grain of salt. Thanks for joining us, Milton. Thanks, Carolyn. Dr. Milton Packer: Thank you so much. Dr. Carolyn Lam: On behalf of Greg and I, you've been listening to Circulation on the Run. Thank you so much for joining us today and don't forget to tune in again next week. Dr. Greg Hundley: This program is copyright of the American Heart Association 2021. The opinions expressed by speakers in this podcast are their own and not necessarily those of the editors, or of the American Heart Association. For more, visit ahajournals.org.

The immune system has been all the rage over the past year and half!  So we figured not would be a good time to do a bit of a deep dive!  Today we're going to cover who the major players are in the immune system.  Then, we're going to give you some of our favorite immune system-boosting foods, nutrients, and other actionable steps you can take to keep your immune system in tip-top shape! Don't forget!  Get 40% your first order of Life Boost Coffee by using promo code “AOE40” at lifeboostcoffee.com at checkout! Use this link to streamline the process: https://lifeboostcoffee.com/pages/healthy-coffee-ot2e-jhopkins?oid=1&affid=49Experience the lasting joy of cooking with Xtrema® 100% Pure Ceramic Cookware. Xtrema® redefines the cooking process by combining unparalleled versatility with the peace of mind, knowing that every piece of cookware will never leach chemicals, metal, cadmium, lead, or change the taste of your food.  Get 10% off Xtrema cookware using our code ARTOFEATING at checkout!With Culiraw, guilt-free desserts are possible!  They are made of natural organic ingredients that provide your body with fiber, minerals, vitamins and enzymes, sweetened with dates and agave only.  Use code is “aoepodcast” for 10% discount at checkout!Subscribe to Dr. Esposito's YouTube Channel: https://www.youtube.com/channel/UCHRpZFrFsbJIk5fbNIkj4pQ?sub_confirmation=1 Sign up for our newsletter at evokhealth.com and get our 14 Kick-start Recipes & Kitchen Secrets! Feel free to reach out to us at artofeatingpodcast@gmail.com.  You can also follow us on Instagram @artofeatingpodcast.   To reach your hosts, you can find Dr. Esposito at:Email: drvincentesposito@gmail.comIG: @drvincentespositoTikTok: @drvincentesposito Web: insideouthealthwellness.com You can find Dr. Kali at:Web: drkali.com   IG: @dr.kalind 

This episode covers monocytes!

Amir Sadighi Akha, M.D., D.Phil., lab section director for Mayo Clinic's Cellular and Molecular Immunology Laboratory, joins this episode of the "Answers From the Lab" podcast. Dr. Sadighi Akha and Bobbi Pritt, M.D., discuss dendritic cell enumeration — a new test offered through Mayo Clinic Laboratories that is the only clinical test of its kind currently available in the U.S.

What Is Immunity? Our bodies have an elaborate system of defense which begins to develop even before we are born. The first few months after birth, the Immune System works overtime to develop codes for thousands and thousands of foreign substances which enter the internal environment of the body. There are two basic defense systems operating in the body simultaneously, namely Non-Specific and Specific. First line, Non-Specific immunity takes place in specialized tissues of the body called Mucosal Tissue. This may be found wherever there is an opening from the outside environment to the internal environment of the body, such as the Ears, Nose, Mouth & Throat, Urinary Tract and the Anal Canal. This Mucosal lining is highly resistant to infection and, in fact, generates Non-Specific Antibodies to destroy many potentially harmful pathogens before they can even enter into the interior of our body. The catch is that mucosal tissue can only do its job in the presence of a nutrient called Vitamin A. When this is deficient the protective factor of mucosal tissue deteriorates rapidly. Those who suffer from repeated infections of their mucosal sites should take note. This Non-Specific defense system, called the Reticuloendothelial System, consists of a variety of semi related cells whose function is to destroy and remove such things as worn out blood cells, bacteria, cancer cells and other foreign chemicals that are potentially dangerous to our delicate biochemistry. Monocytes, large white blood cells, which circulate in the bloodstream, develop into Macrophages, which literally ‘eat up' these invading substances. Other parts of this Non-Specific immunity include sites found in the Spleen, Bone Marrow, Lymph Nodes, and even the Brain. This Non-Specific Immune System functions twenty four hours a day to ensure internal safety. You may be interested to know that each one of us gets Cancer every day of our lives. Cancer cells form due to Free Radical damage to DNA material within specific cells or cell groups. When this occurs, the Immune System recognizes these cells as different from the others and takes a chemical photograph of their composition. This information is then returned to the Thymus Gland where it is analyzed. Once the Immune System determines that this cell is not normal, specific Antibodies are formed to destroy the cells before they can explosively multiply. The final line of defense against disease is what we call the Immune System itself. It is technically referred to as the Specific Defense System because it acts against particular harmful agents and further, has the ability to act quickly against substances new and unfamiliar to itself. This is important since immunity is not general but very selective, meaning that immunity to one disease, say the measles, does not automatically mean we are immune to others.

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

Join Yvonne Brandenburg, RVT, VTS SAIM and Jordan Porter RVT, LVT, VTS SAIM as we talk about: White Blood Cell Basics; what WBCs do and what to look for when WBCs are too high or too low.    Question of the Week How many of you do differentials in your clinics, and what are some of your favorite resources? Leave a comment at https://imfpp.org/episode25   Resources We Mentioned in the Show  IMFPP https://www.internalmedicineforpetparents.com/hematology.html Idexx hematology book:  https://www.amazon.com/gp/product/1893441687/ Small Animal Internal Medicine for Veterinary Technicians and Nurses https://imfpp.org/saimbook  E-Clin Path http://eclinpath.com/hematology/morphologic-features/white-blood-cells/     Thanks so much for tuning in. Join us again next week for another episode!  Get Access to the Technician Treasure Trove  Sign up at https://imfpp.org/treasuretrove    Thanks for listening!  – Yvonne and Jordan 

Dr. Poon's research into the mechanism of cell death reveals that what was long thought a random process actually has signs of regulation. In this podcast, you'll learn: What about the process signifies regulation. What cells release in these extracellular vesicles when they die. Why understanding the process of cell death in disease settings may lead to disease-fighting drugs. Dr. Ivan Poon of La Trobe University is a Senior Research Fellow in biochemistry and genetics. He specializes in extracellular vesicles and cell turnover, or the mechanisms of cell death. In this discussion, he explains his focus on trying to understand what happens when cells die. The amount of energy a cell puts into generating small vesicles, or apoptotic bodies, during turnover is significant. Therefore, he and other researchers are studying why cells invest in this process. While researchers have known the basics of cell death for decades, only recently has this mechanism of cell death process been understood as highly regulated rather than random. Furthermore, each cell type follows a different process. Monocytes, for example, form a string-like protrusion like a beaded necklace that then generates apoptotic bodies.  Most important for Dr. Poon is to understand the molecular mechanism of this process—what controls it. The answers may enable special treatment for diseases including drugs that either inhibit or accelerate cell deaths depending on the process needed to regain health.  For more, see Dr. Poon's page on the La Trobe University web site: https://scholars.latrobe.edu.au/display/ipoon

¡Gracias por escuchar! En este episodio hablaré del papel que juega la inflamación en la generación de dolor en pacientes con osteoartritis. La OA tiene una morbilidad asociada sustancial y constituye un creciente problema de salud pública derivado en gran medida del envejecimiento poblacional. Los síntomas de la OA pueden ser funcionales pero se manifiestan principalmente como dolor y el manejo de la enfermedad se centra principalmente en su control.Agradezco que escuchen este podcast y les recuerdo que se encuentra disponible en el catálogo de iTunes, en Google Play (siendo accesible a través del gestor de podcasts de su dispositivo móvil), así como en Spotify. Agradezco también su retroalimentación en estas plataformas y les pido amablemente que califiquen el podcast ya que esto es importante para su continuado desarrollo.A continuación se enlistan las referencias mencionadas en este episodio: Grace, P. M., Hutchinson, M. R., Maier, S. F. & Watkins, L. R. Pathological pain and the neuroimmune interface. Nat. Rev. Immunol. 14, 217–231(2014).Owens, C. & Conaghan, P. G. Improving joint pain and function in osteoarthritis. Practitioner 260, 17–20 (2016).O’Neil, C. K., Hanlon, J. T. & Marcum, Z. A. Adverse effects of analgesics commonly used by older adults with osteoarthritis: focus on non-opioid and opioid analgesics. Am. J. Geriatr. Pharmacother. 10, 331–342 (2012).Wang, Y., Teichtahl, A. J. & Cicuttini, F. M. Osteoarthritis year in review 2015: imaging. Osteoarthritis Cartilage 24, 49–57 (2016).Haringman, J. J., Smeets, T. J., Reinders-Blankert, P. & Tak, P. P. Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis. Ann. Rheum. Dis. 65, 294–300 (2006).de Lange-Brokaar, B. J. et al. Degree of synovitis on MRI by comprehensive whole knee semi-quantitative scoring method correlates with histologic and macroscopic features of synovial tissue inflammation in knee osteoarthritis. Osteoarthritis Cartilage 22, 1606–1613 (2014).Cook, A. D., Christensen, A. D., Tewari, D., McMahon, S. B. & Hamilton, J. A. Immune cytokines and their receptors in inflammatory pain. Trends Immunol. 39, 240–255 (2018).Malfait, A. M. & Schnitzer, T. J. Towards a mechanism-based approach to pain management in osteoarthritis. Nat. Rev. Rheumatol. 9, 654–664 (2013).Bellamy, N. et al. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst. Rev. 2, CD005328 (2006).McAlindon, T. E. et al. Effect of intra-articular triamcinolone versus saline on knee cartilage volume and pain in patients with knee osteoarthritis:a randomized clinical trial. JAMA 317, 1967–1975 (2017).Aitken, D. et al. A randomised double-blind placebo-controlled crossover trial of HUMira (adalimumab) for erosive hand OsteoaRthritis — the HUMOR trial. Osteoarthritis Cartilage 26, 880–887 (2018).Cohen, S. B. et al. A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee. Arthritis Res. Ther. 13, R125 (2011).Wang, S. X. et al. Safety, tolerability, and pharmacodynamics of an anti-interleukin-1alpha/beta dual variable domain immunoglobulin in patients with osteoarthritis of the knee: a randomized phase 1 study. Osteoarthritis Cartilage 25, 1952–1961 (2017).Eitner, A., Hofmann, G. O. & Schaible, H. G. Mechanisms of osteoarthritic pain. Studies in humans and experimental models. Front. Mol. Neurosci. 10, 349 (2017).Basbaum, A. I., Bautista, D. M., Scherrer, G. & Julius, D. Cellular and molecular mechanisms of pain. Cell 139, 267–284 (2009).Ji, R. R., Xu, Z. Z. & Gao, Y. J. Emerging targets in neuroinflammation-driven chronic pain. Nat. Rev. Drug Discov. 13, 533–548 (2014).McMahon, S. B., La Russa, F. & Bennett, D. L. Crosstalk between the nociceptive and immune systems in host defence and disease. Nat. Rev. Neurosci. 16, 389–402 (2015).Pinho-Ribeiro, F. A. et al. Blocking neuronal signaling to immune cells treats streptococcal invasive infection. Cell 173, 1083–1097 (2018).Shechter, R. et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLOS Med. 6, e1000113 (2009).Willemen, H. L. et al. Monocytes/macrophages control resolution of transient inflammatory pain. J. Pain 15, 496–506 (2014).Barthel, C. et al. Nerve growth factor and receptor expression in rheumatoid arthritis and spondyloarthritis. Arthritis Res. Ther. 11, R82 (2009).Skaper, S. D. Nerve growth factor: a neuroimmune crosstalk mediator for all seasons. Immunology 151, 1–15 (2017).Denk, F., Bennett, D. L. & McMahon, S. B. Nerve growth factor and pain mechanisms. Annu. Rev. Neurosci. 40, 307–325 (2017).Minnone, G., De Benedetti, F. & Bracci-Laudiero, L. NGF and its receptors in the regulation of inflammatory response. Int. J. Mol. Sci. 18, E1028 (2017).Bagal, S. K. et al. Discovery of potent, selective, and peripherally restricted Pan-Trk kinase inhibitors for the treatment of pain. J. Med. Chem. 61, 6779–6800 (2018).Pinho-Ribeiro, F. A., Verri, W. A. Jr & Chiu, I. M. Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol. 38, 5–19 (2017).Robinson, W. H. et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 580–592 (2016).de Lange-Brokaar, B. J. et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis Cartilage 20, 1484–1499 (2012).Rahmati, M., Mobasheri, A. & Mozafari, M. Inflammatory mediators in osteoarthritis: a critical review of the state-of-the-art, current prospects, and future challenges. Bone 85, 81–90 (2016).Urban, H. & Little, C. B. The role of fat and inflammation in the pathogenesis and management of osteoarthritis.Rheumatology 57, iv10–iv21 (2018).Dawes, J. M., Kiesewetter, H., Perkins, J. R.,Bennett, D. L. & McMahon, S. B. Chemokine expression in peripheral tissues from the monosodium iodoacetate model of chronic joint pain. Mol. Pain 9, 57 (2013).Driscoll, C. et al. Nociceptive sensitizers are regulated in damaged joint tissues, including articular cartilage, when osteoarthritic mice display pain behavior. Arthritis Rheumatol. 68, 857–867 (2016).Sweitzer, S. M., Hickey, W. F., Rutkowski, M. D., Pahl, J. L. & DeLeo, J. A. Focal peripheral nerve injury induces leukocyte trafficking into the central nervous system: potential relationship to neuropathic pain. Pain 100, 163–170 (2002).Hu, P., Bembrick, A. L., Keay, K. A. & McLachlan, E. M. Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transectionof the rat sciatic nerve. Brain Behav. Immun. 21, 599–616 (2007).Lems, W. F. Bisphosphonates: a therapeutic option for knee osteoarthritis? Ann. Rheum. Dis. 77, 1247–1248 (2018).Wenham, C. Y. et al. A randomized, double-blind, placebo-controlled trial of low-dose oral prednisolone for treating painful hand osteoarthritis. Rheumatology 51, 2286–2294 (2012).Dorleijn, D. M. J. et al. Intramuscular glucocorticoid injection versus placebo injection in hip osteoarthritis: a 12-week blinded randomised controlled trial. Ann. Rheum. Dis. 77, 875–882 (2018).McCabe, P. S. et al. Synovial fluid white blood cell count in knee osteoarthritis: association with structural findings and treatment response. Arthritis Rheumatol. 69, 103–107 (2017).Leung, Y. Y. et al. Colchicine lack of effectiveness in symptom and inflammation modification in knee osteoarthritis (COLKOA): a randomized controlled trial. Osteoarthritis Cartilage 26, 631–640 (2018).Kingsbury, S. R. et al. Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis: a randomized trial. Ann. Intern. Med. 168, 385–395 (2018).Lee, W. et al. Efficacy of hydroxychloroquine in hand osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res. 70, 1320–1325 (2018).Wenham, C. Y. et al. Methotrexate for pain relief in knee osteoarthritis: an open-label study. Rheumatology 52, 888–892 (2013).Kingsbury, S. R. et al. Significant pain reduction with oral methotrexate in knee osteoarthritis; results from a randomised controlled phase III trial of treatment effectiveness [abstract 428]. Arthritis Rheumatol. 70 (Suppl. 9), 454–455 (2018).Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).Kashyap, M. P., Roberts, C., Waseem, M. & Tyagi, P. Drug targets in neurotrophin signaling in the central and peripheral nervous system. Mol. Neurobiol. 55, 6939–6955 (2018).Bannwarth, B. & Kostine, M. Nerve growth factor antagonists: is the future of monoclonal antibodies becoming clearer? Drugs 77, 1377–1387 (2017).Baamonde, A., Lastra, A., Juarez, L., Hidalgo, A. & Menendez, L. TRPV1 desensitisation and endogenous vanilloid involvement in the enhanced analgesia induced by capsaicin in inflamed tissues. Brain Res. Bull. 67, 476–481 (2005).Hamilton, J. A., Cook, A. D. & Tak, P. P. Anti-colony- stimulating factor therapies for inflammatory and autoimmune diseases. Nat. Rev. Drug Discov. 16, 53–70 (2017).Schett, G. et al. A phase IIA study of anti-GM-CSF antibody GSK3196165 in subjects with inflammatory hand osteoarthritis [abstract 1365]. Arthritis Rheumatol. 70 (Suppl. 9), 1494 (2018).Achuthan, A. et al. Granulocyte macrophage colony-stimulating factor induces CCL17 production via IRF4 to mediate inflammation. J. Clin. Invest. 126, 3453–3466 (2016).Wylde, V., Hewlett, S., Learmonth, I. D. & Dieppe, P. Persistent pain after joint replacement: prevalence, sensory qualities, and postoperative determinants. Pain 152, 566–572 (2011).Beswick, A. D., Wylde, V., Gooberman-Hill, R., Blom, A. & Dieppe, P. What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients. BMJ Open 2, e000435 (2012).Li, H., Wang, R., Lu, Y., Xu, X. & Ni, J. Targeting G protein-coupled receptor for pain management. Brain Circ. 3, 109–113 (2017).

This week, we talked about monocytes and what they do within the body! Thanks for listening and please share our podcast with fellow science-lovers in your life!

Ce serait facile si les résultats des expériences sur des souris de laboratoire s’appliquaient directement aux humains. La récente découverte de deux chercheuses québécoises nous donne de l’espoir! Avec Baptiste Zapirain et Charles Trahan

As an American researcher, Dr. Judy A. Mikovits is a vaccine and medical industry activist. As research director of the Whittemore Peterson Institute (WPI) in Reno, Nevada; on November 18, 2011 Mikovits was arrested for not handing over her research to her employer (WPI) regarding a controversial publication to the journal Science. Having been investigated for allegedly manipulating data, Mikovits had lead a research effort that reported in 2009 that a retrovirus known as xenotropic murine leukemia virus-related virus (XMRV) was associated with CFS and may have had a causal role. This research came under fire and lead the journal to make a retraction on December 22, 2011. Arrested in her Ventura, CA home, charges against her were later dismissed by the District Attorney's office - Reno, NV. Mikovits has a PhD in biochemistry and molecular biology from George Washington University (1992). Her doctorate thesis defense entitles "Negative Regulation of HIV Expression in Monocytes", changed the paradigm for therapeutic treatment of HIV. This won her the graduate student of the year award in 1991. Her studies are accredited to saving millions of lives infected with HIV/AIDS. In 2006 Dr Mikovits became attracted to the plight of families with neuroimmune diseases including ME/CFS and Autism and was primarily responsible for demonstrating the relationship between environmentally acquired immune dysfunction, chronic inflammation and these diseases. Apart from a 20 year career with the National Cancer Institute in Frederick, Maryland, and leading various pharmaceutical studies, in 2012 it was learned that XMRV was a contaminant of the Silverman lab and the XMRV's isolated were a new human exogenous and transmissible retrovirus family, which are strong associated with neuroimmune disease and cancer. Judy has co-authored more than 50 peer reviewed publications and book chapters. She is also co-author of the book Plague. --- This episode is sponsored by · Anchor: The easiest way to make a podcast. https://anchor.fm/app Support this podcast: https://anchor.fm/iantrottier/support

Cindy, Steph, and Vincent launch a new podcast, Immune, and reveal how warm temperature protects against atherosclerosis by regulating monocyte migration into the blood. Hosts: Vincent Racaniello, Stephanie Langel, and Cynthia Leifer Become a patron of Immune! Links for this episode Leifer Lab at Cornell Stephanie Langel Thermoneutrality suppresses monocyte egress from bone marrow (Circ Res) Fever regulates immunity (Nat Rev Immunol) Macrophage image by Blausen Medical Weekly Science Picks Cindy - FDA approves second CAR T cell therapy Steph - Gammaherpesvirus protects against asthma Vincent - Truth Wins by Jonathan Yewdell Intro music is by Steve Neal. Immune logo image by Blausen Medical. Send your immunology questions and comments to immune@microbe.tv

Simone Schuller is a pediatrician at the Boston's Children Hospital. She was awarded the Max Kade fellowship to conduct research into neonatal innate immune pathways to aid the development of vaccines for the very young. Previously, Simone was at the Medical University of Vienna, where she recently completed her residency and clinical training. In this episode, we hear how she has strengthened her laboratory experience over the years in a number of countries and has used some of these in vitro skills in a recent Pediatric Research paper about the effect of Pentoxyfylline on the preterm infant immune system in a model of sepsis. See acast.com/privacy for privacy and opt-out information.

The TWiP Titans solve the case of the Man from Queens with a Blister Burster, and explain the role of inflammatory monocytes during Leishmania infection of the skin. Hosts: Vincent Racaniello, Dickson Despommier, and Daniel Griffin Become a patron of TWiP. Links for this episode: Inflammatory monocytes and skin Leishmania (PLoS Path) Dracunculiasis (TWiP 37) Photo: Daniel using a LifeStraw Letters read on TWiP 136 This episode is brought to you by Blue Apron. Blue Apron is the #1 fresh ingredient and recipe delivery service in the country. See what’s on the menu this week and get your first 3 meals free with your first purchase – WITH FREE SHIPPING – by going to blueapron.com/twip. Case Study for TWiP 136 Patient seen by Daniel in India, 18 yo Islamic college student, left home, living in dorms in south, Hindu couple prepare meals, called dorm parents. He is being seen because developed lump in left side of neck, 1-2 cm mass. Previously completely healthy, no med/surg, no allergies. Prays multiple times a day, observes dietary restrictions. Afebrile, normal, but has 2 cm firm nontender lump inside interior portion of sternocleido mastoid muscle. Not tender. End of November, rainy season. No screens on dorm windows. No animal contact. Ultrasound done, and was helpful. Noticed in his neck over several weeks. Send your case diagnosis, questions and comments to twip@microbe.tv Music by Ronald Jenkees

Ivan Bogeski explains how redox-insensitive ORAI calcium channels enable monocytes to sustain calcium signaling while still producing bactericidal reactive oxygen species.

MDS presents the latest research and findings from the field of Movement Disorders. Abstracts of articles from the Society Journal, Movement Disorders, are taken from the March 2013 (Vol. 28, Issue 3) issue.

Hypersensitivity reactions to titanium (Ti) are very rare. Thus, we assessed the proinflammatory response and also potential tolerance favoring in vitro reactivity of human blood lymphocytes and monocytes (PBMC) to Ti in healthy individuals (14 without, 6 with complication-free dental Ti implants). The proliferation index (SI) in lymphocyte transformation test (LTT) and production of cytokines linked to innate immune response (IL-1 beta, IL-6, and TNF alpha) or immune regulation (IL-10) were assessed in response to TiO2 particles or Ti discs. In both groups, the Ti-LTT reactivity was not enhanced (e.g., SI < 3). The control antigen tetanus toxoid (TT) gave adequate reactivity (median SI individuals without/with implant: 20.6 +/- 5.97/19.58 +/- 2.99). Individuals without implant showed higher cytokine response to Ti materials than individuals with symptom-free implants; for example, TiO2 rutile particle induced increase of IL-1 beta 70.27-fold/8.49-fold versus control medium culture. PBMC of 5 of the 6 individuals with complication-free Ti implants showed an ex vivo ongoing production of IL-10 (mean 4.18 +/- 2.98 pg/mL)-but none of the 14 controls showed such IL-10 production. Thus in vitro IL-1 beta-, IL-6-, and TNF-alpha production reflects ``normal'' unspecific immune response to Ti. This might be reduced by production of tolerogenic IL-10 in individuals with symptom-free Ti dental implants.

Background: Udder infections with environmental pathogens like Escherichia coli are a serious problem for the dairy industry. Reduction of incidence and severity of mastitis is desirable and mild priming of the immune system either through vaccination or with low doses of immune stimulants such as lipopolysaccharide LPS was previously found to dampen detrimental effects of a subsequent infection. Monocytes/macrophages are known to develop tolerance towards the endotoxin LPS (endotoxin tolerance, ET) as adaptation strategy to prevent exuberant inflammation. We have recently observed that infusion of 1 mu g of LPS into the quarter of an udder effectively protected for several days against an experimentally elicited mastitis. We have modelled this process in primary cultures of mammary epithelial cells (MEC) from the cow. MEC are by far the most abundant cells in the healthy udder coming into contact with invading pathogens and little is known about their role in establishing ET. Results: We primed primary MEC cultures for 12 h with LPS (100 ng/ml) and stimulated three cultures either 12 h or 42 h later with 10(7)/ml particles of heat inactivated E. coli bacteria for six hours. Priming-related alterations in the global transcriptome of those cells were quantified with Affymetrix microarrays. LPS priming alone caused differential expression of 40 genes and mediated significantly different response to a subsequent E. coli challenge of 226 genes. Expression of 38 genes was enhanced while that of 188 was decreased. Higher expressed were antimicrobial factors (beta-defensin LAP, SLPI), cell and tissue protecting factors (DAF, MUC1, TGM1, TGM3) as well as mediators of the sentinel function of MEC (CCL5, CXCL8). Dampened was the expression of potentially harmful pro-inflammatory master cytokines (IL1B, IL6, TNF-alpha) and immune effectors (NOS2, matrix metalloproteases). Functional network analysis highlighted the reduced expression of IL1B and of IRF7 as key to this modulation. Conclusion: LPS-primed MEC are fitter to repel pathogens and better protected against misguided attacks of the immune response. Attenuated is the exuberant expression of factors potentially promoting immunopathological processes. MEC therefore recapitulate many aspects of ET known so far from professional immune cells.

The NF-kappa B/REL-family of transcription factors plays a central role in coordinating the expression of a wide variety of genes controlling immune responses including autoimmunity of the central nervous system (CNS). The inactive form of NF-kappa B consists of a heterodimer which is complexed with its inhibitor, I kappa B. Conditional knockout-mice for I kappa B alpha in myeloid cells (IysMCreI kappa B alpha(fl/fl)) have been generated and are characterized by a constitutive activation of NF-kappa B proteins allowing the study of this transcription factor in myelin-oligodendrocyte-glycoprotein induced experimental autoimmune encephalomyelitis (MOG-EAE), a well established experimental model for autoimmune demyelination of the CNS. In comparison to controls, IysMCreI kappa B alpha(fl/fl) mice developed a more severe clinical course of EAE. Upon histological analysis on day 15 p.i., there was an over two fold increased infiltration of T-cells and macrophages/microglia. In addition, IysMCreI kappa B alpha(fl/fl) mice displayed an increased expression of the NF-kappa B dependent factor inducible nitric oxide synthase in inflamed lesions. These changes in the CNS are associated with increased numbers of CD11b positive splenocytes and a higher expression of Ly6c on monocytes in the periphery. Well in accordance with these changes in the myeloid cell compartment, there was an increased production of the monocyte cytokines interleukin(IL)-12 p70, IL-6 and IL-1beta in splenocytes. In contrast, production of the T-cell associated cytokines interferon gamma (IFN-gamma) and IL-17 was not influenced. In summary, myeloid cell derived NF-kappa B plays a crucial role in autoimmune inflammation of the CNS and drives a pathogenic role of monocytes and macrophages independently from T-cells.

Background: MUC16 is a cell surface mucin expressed at high levels by epithelial ovarian tumors. Following proteolytic cleavage, cell surface MUC16 (csMUC16) is shed in the extracellular milieu and is detected in the serum of cancer patients as the tumor marker CA125. csMUC16 acts as an adhesion molecule and facilitates peritoneal metastasis of ovarian tumors. Both sMUC16 and csMUC16 also protect cancer cells from cytotoxic responses of natural killer (NK) cells. In a previous study we demonstrated that sMUC16 binds to specific subset of NK cells. Here, we identify the csMUC16/sMUC16 binding partner expressed on immune cells. Results: Analysis of immune cells from the peripheral blood and peritoneal fluid of ovarian cancer patients indicates that in addition to NK cells, sMUC16 also binds to B cells and monocytes isolated from the peripheral blood and peritoneal fluid. I-type lectin, Siglec-9, is identified as the sMUC16 receptor on these immune cells. Siglec-9 is expressed on approximately 30-40% of CD16(pos)/CD56(dim) NK cells, 20-30% of B cells and > 95% of monocytes. sMUC16 binds to the majority of the Siglec-9(pos) NK cells, B cells and monocytes. sMUC16 is released from the immune cells following neuraminidase treatment. Siglec-9 transfected Jurkat cells and monocytes isolated from healthy donors bind to ovarian tumor cells via Siglec-9-csMUC16 interaction. Conclusions: Recent studies indicate that csMUC16 can act as an anti-adhesive agent that blocks tumor-immune cell interactions. Our results demonstrate that similar to other mucins, csMUC16 can also facilitate cell adhesion by interacting with a suitable binding partner such as mesothelin or Siglec-9. Siglec-9 is an inhibitory receptor that attenuates T cell and NK cell function. sMUC16/csMUC16-Siglec-9 binding likely mediates inhibition of anti-tumor immune responses.

Introduction Severe tissue trauma results in a general inflammatory immune response (SIRS) representing an overall inflammatory reaction of the immune system. However, there is little known about the functional alterations of monocytes in the early posttraumatic phase, characterized by the battle of the individual with the initial trauma. Methods Thirteen patients with severe multiple injury; injury severity score (ISS) >16 points (17 to 57) were included. The cytokine synthesis profiles of monocytes were characterized on admission, and followed up 6, 12, 24, 48, and 72 hours after severe multiple injury using flow cytometry. Whole blood was challenged with lipopolysaccharide (LPS) and subsequently analyzed for intracellular monocyte-related TNF-alpha, IL-1 beta, IL-6, and IL-8. The degree of organ dysfunction was assessed using the multiple organ dysfunction syndrome (MODS)-score of Marshall on admission, 24 hours and 72 hours after injury. Results Our data clearly show that the capacity of circulating monocytes to produce these mediators de novo was significantly diminished very early reaching a nadir 24 hours after severe injury followed by a rapid and nearly complete recovery another 48 hours later compared with admission and controls, respectively. In contrast to the initial injury severity, there was a significant correlation detectable between the clinical signs of multiple organ dysfunction and the ex vivo cytokine response. Conclusions As our data derived from very narrow intervals of measurements, they might contribute to a more detailed understanding of the early immune alterations recognized after severe trauma. It can be concluded that indeed as previously postulated an immediate hyperactivation of circulating monocytes is rapidly followed by a substantial paralysis of cell function. Moreover, our findings clearly demonstrate that the restricted capacity of monocytes to produce proinflammatory cytokines after severe injury is not only an in vitro phenomenon but also undistinguishable associated with the onset of organ dysfunction in the clinical scenario.

Mild hyperhomocysteinemia is an independent risk factor for the development of coronary artery disease, cerebrovascular disease and peripheral arterial disease. The mechanisms by which hyperhomocysteinemia promotes vascular disease are not completely understood yet. An increasing body of evidence has implicated oxidative stress as being contributory to homocysteine’s deleterious effects on the vasculature. Elevated levels of homocysteine lead to increased generation of superoxide anion in endothelial cells by a biochemical mechanism involving nitric oxide synthase, and, to a lesser extent, by an increase in the chemical oxidation rate of homocysteine and other aminothiols in the circulation. Furthermore, homocysteine has been shown to inhibit the activity of important cellular antioxidant enzymes, like the cellular isoform of glutathione peroxidase or superoxide dismutase, which may contribute to homocysteine’s induced oxidant stress. The resulting increase in reactive oxygen species leads to decreased bioavailability of the endothelium-derived signaling molecule nitric oxide via oxidative inactivation and thereby induces endothelial dysfunction. This seems to play a central role in the molecular mechanisms underlying the effects of homocysteine on vascular function. Hyperhomocysteinemia not only leads to endothelial dysfunction but also promotes the development and propagation of atherosclerotic lesion in atherosclerosis-prone animal models. As the recruitment of circulating monocytes to the vessel wall plays a crucial role in the process of atherosclerosis, the purpose of this study was to examine the influence of homocysteine on the interaction of endothelial cells with monocytes. Exposure of endothelial monolayers to D,L- and L-homocysteine resulted in a time- and dose-dependent increase in adherent THP-1 cells by upregulating ICAM-1 expression on endothelial cells. L-cysteine and D-homocysteine had no effects. This indicates that the stimulatory effect is specific for the naturally occurring L-stereoisomer and rather a biochemical than a chemical effect. The increased endothelial expression of ICAM-1 seems to be mediated by increased activation of the nuclear transcription factor NF-kB, as shown by increased nuclear translocation of NF-kB in homocysteine-incubated endothelial cells. In accordance, inhibition of NF-kB translocation by a synthetic inhibitor Bay 11-7082 significantly diminished homocysteine-induced ICAM-1 expression and adhesion of monocytes to endothelial cells. In addition, incubation of monocytes with D,L- homocysteine and L-homocysteine resulted in significant increase in the number of adhering monocytes to unstimulated endothelial monolayer by upregulating the expression of beta-2 integrins. Furthermore, homocysteine-incubation of endothelial cells and monocytes resulted in a dose-dependent and significant increase in the intracellular generation of reactive oxygen species. In support of the role of increased oxidant stress for the above mentioned effects, treatment of endothelial cells with the superoxide scavengers MnTBAP or Tiron together with homocysteine abolished homocysteine-induced monocyte adhesion, ICAM-1 expression and the nuclear translocation of NF-kB. Incubation of THP-1 monocytes with Tiron abolished homocysteine-induced beta-2 integrin expression on these cells and adhesion to unstimulated endothelial cells. These findings suggest that superoxide anion radicals mediate homocysteine’s effects on endothelium-monocyte interactions. In addition to previous studies that indicated that a significant source of reactive oxygen species in homocysteine-treated endothelial cells might be endothelial nitric oxide synthase, experiments using inhibitors of nitric oxide synthase in THP-1 cells indicated that nitric oxide synthase-dependent generation of superoxide anion also occurs in homocysteine-incubated THP-1 cells. This mechanism may contribute to homocysteine-induced oxidant stress. The information generated from these studies may be helpful in designing intervention strategies aimed at inhibiting the generation of reactive oxygen species in the vasculature that is associated with signaling events of monocyte recruitment and infiltration involved in atherosclerosis.