Podcasts about professional resources

As caregivers for our loved ones with Alzheimer's and other types of dementia, we often face the challenging question: "Is it time to change my care receiver's living situation?" We are Nancy Treaster and Sue Ryan, and through our experiences, we've developed five essential tips to help you navigate this complex decision-making process. Connect with us and share your tips: Website: https://www.thecaregiversjourney.comInstagram: https://www.instagram.com/thecaregiversjourney/Facebook: https://www.facebook.com/TheCaregiversJourneys/Linkedin: https://www.linkedin.com/in/suearmstrongryan/, https://www.linkedin.com/in/nancytreaster/Email: sue@thecaregiversjourney.com, nancy@thecaregiversjourney.com Full Show Notes https://thecaregiversjourney.com/time-for-a-change-home-and-community-living-options-five-essential-tips-alzheimers-and-other-dementias/ Takeaways 1. Understand Your Financial Resources This foundational step requires a thorough assessment of both current and future financial resources. Professional Resources to Consult: - Financial advisors (especially those specializing in senior care) - Elder care attorneys - Government program specialists Income Sources to Consider: - Care receiver's savings - Pensions - Long-term care insurance - Public health insurance (Medicaid in the US) - Social Security disability benefits - Family contributions Expenses to Evaluate: - Home modifications - Safety adjustments - In-home caregiving costs - Day program fees - Potential lost income if reducing work hours - Care community costs 2. Research Care Options There are three main categories of care options to evaluate: Non-Residential Options: - Respite programs - Memory cafes - Day programs In-Home Options: - Professional caregiving services - Government programs (VA benefits, Medicare services) - Family caregiver arrangements Care Communities: - Memory care specific facilities - Communities with memory care units - Different care models and staffing levels - Waiting list considerations 3. Assess Home Safety This evaluation should include multiple perspectives: Medical Assessment: - Get an updated medical evaluation - Discuss current and future safety risks - Request occupational therapy assessment Key Safety Considerations: - Wandering risk - Cabinet and door safety - Mobility challenges - Fall prevention - Depth perception issues - Stairs and accessibility - Emergency services access 4. Evaluate Medical Needs Current and Future Medical Considerations: - Impact of multiple diagnoses - Care complexity - Required medical procedures - Medication management - Physical care requirements 5. Prioritize Wellbeing for Both Care Receiver and Caregiver This final tip focuses on quality of life considerations for everyone involved. Socialization Needs: - Care receiver's social preferences - Community engagement opportunities - Caregiver isolation prevention - Balance of stimulation and comfort Safety and Emotional Considerations: - Physical safety for both parties - Emotional wellbeing - Caregiver burnout prevention - Managing aggressive behaviors - Personal boundaries Making the Final Decision: - Consider all evaluation points - Involve family members - Maintain awareness of available options - Stay connected with potential care communities - Be prepared to act when needed

In this episode of the Mob Mentality Show, we dive into our Software Professional Resources Board, a dynamic Trello-based hub designed for software professionals looking to enhance their learning and collaboration in the industry. Join us as we share the board's origin story and our journey in creating a comprehensive resource for everything from Extreme Programming (XP), mobbing, and leadership to cloud infrastructure, agile retrospectives, lean principles, and much more. ### What Makes Our Board Unique? We start by exploring why we chose **Trello** for our resource board and how it has become a cornerstone for organizing, sharing, and discovering knowledge. With its flexibility, Trello enables us to create an easily navigable environment, where resources are not only organized but can also be searched, linked, and explored across various software domains. Our conversation touches on other similar boards we've seen, like our popular "Retrospective Techniques for Coaches, Scrum Masters, and Facilitators" board, as well as spin-offs we've created for specific topics. ### A Variety of Topics Our board covers a broad spectrum of topics that are essential for modern software professionals, including **mobbing**, **refactoring**, **leadership**, **Infrastructure as Code (IaC)**, **agile** practices, and more. With resources curated for both technical and strategic learning, the board has become a go-to reference for articles, blog posts, videos, academic papers, book links, and quotes on various disciplines within software development. ### How We Use the Board for Continuous Learning Discover how we leverage the board not only to organize information but to foster continuous learning. We discuss Chris' “community-supported learning binges” and our process for capturing insightful book quotes and key takeaways, turning the board into a knowledge-sharing powerhouse for software teams and individual contributors alike. ### Refactoring the Mind: Evolving the Board to Stay Relevant Our discussion also delves into the concept of "refactoring my mind by refactoring the board"—an idea about how reorganizing knowledge can improve our mental clarity and adaptability in complex projects. This involves regularly revisiting, reshaping, and expanding board content to reflect the latest insights and trends in software development, keeping it a living, breathing resource for our community. ### The Impact of Public Knowledge Sharing One of the most inspiring aspects of this board is its role in **public knowledge sharing**. We highlight feedback from the community, stories of how others have used the board in their professional journeys, and our own experiences with learning in public. By sharing this resource openly, we invite others to benefit from it, create connections, and add to the body of knowledge that supports software development excellence. Whether you're a developer, coach, Scrum Master, or technical leader, this episode offers valuable insights into how to create and use a resources board to drive personal and team growth. Listen in for tips on organizing knowledge, capturing valuable insights, and using community feedback to make a resource board that truly enhances your software development journey. ### Topics Discussed: - The board's origin story and why we chose Trello - Organizing, searching, and sharing resources in Trello - Similar boards, including "Retrospective Techniques for Coaches, Scrum Masters, and Facilitators" - Variety of topics: mobbing, XP, leadership, IaC, agile, cloud, business, tech, retrospectives, and more - Types of media: articles, blogs, videos, book quotes, academic papers, and beyond - Spin-off boards and community learning sessions - Feedback from the community and lessons for public knowledge sharing **Subscribe on YouTube or your favorite podcast platform to catch this episode and more!** Video and Show Notes: https://youtu.be/GmfWWiIeaVY 

08-21-2024 Brian I. Gordon Learn more about the interview and get additional links here: https://usabusinessradio.com/what-professional-resources-should-seniors-their-families-know-about/ Subscribe to the best of our content here: https://priceofbusiness.substack.com/ Subscribe to our YouTube channel here: https://www.youtube.com/channel/UCywgbHv7dpiBG2Qswr_ceEQ

This episode of the Tactical Living Podcast, hosted by Coach Ashlie Walton and Sergeant Clint Walton, addresses a crucial aspect of first responder well-being: the importance of seeking and accepting help when dealing with mental health issues or stress. Titled Climbing Out Together: The Power of Support for First Responders, the discussion focuses on how leaning on colleagues, friends, and professional support can be the most effective way to overcome challenges and regain your footing. Understanding the Metaphor: The episode opens with an exploration of the metaphor that being stuck in a hole (Amazon affiliate) often requires a hand to get out, paralleling how first responders can feel overwhelmed or isolated by the pressures of their duties. The Stigma of Seeking Help: Discuss the common stigma associated with first responders seeking help for mental health issues, including the false perception that it shows weakness. The conversation highlights why this stigma is not only harmful but also untrue. Real-Life Challenges and Support: Share insights into the specific stressors and mental health challenges that first responders face, from the high-stakes nature of the job to the irregular hours that can strain personal life. Strategies for Reaching Out: Offer practical advice on how first responders can start conversations about their struggles, identify trustworthy support networks, and take the first steps toward seeking help. Role of Peers and Leadership: Discuss the crucial role that peers and leadership within the first responder community can play in supporting one another. Emphasize how creating an environment of openness and support can facilitate easier access to help. Professional Resources and Counseling: Highlight the availability of professional mental health resources specifically tailored to first responders, including counseling services, crisis hotlines, and wellness programs. Personal Stories of Recovery: Feature stories from first responders who have successfully sought help and found their way back to a healthier state, underscoring the message that asking for help is not only necessary but also effective. Recap the discussion on the importance of support systems for first responders facing mental health challenges. Reinforce the idea that asking for help is a sign of strength and an essential step in maintaining one's health and career longevity. Listeners are encouraged to reflect on their own experiences with seeking help and to consider strengthening their support networks. They are invited to share their stories and strategies for supporting mental health within the first responder community.   This episode is an essential listen for any first responder who might feel isolated by the unique pressures of their role. It provides vital perspectives on how asking for help can be the most effective way to address personal challenges, and how creating supportive environments can benefit the entire community. Tune in to gain insights and strategies for improving your mental health and supporting your colleagues in doing the same. All viewpoints discussed in this episode are for entertainment purposes only and are simply our opinions based off of our own experience, background and education. #policepodcast #policeofficer #leowarriors #thinbluelineusa #firstresponder #lawenforcementpodcast #LawEnforcement #LEOWarriors #traumarecovery #cptsd #ptsd #mentalhealth   ⩥ PLEASE SUBSCRIBE TO OUR YOUTUBE CHANNEL ⩤ https://geni.us/wAtlvPu     CLICK HERE for Amazon's Today's Deals on TACTICAL GEAR: https://geni.us/KmvaOVM (Affiliate Link) (Ad) Some product links are affiliate links which means if you buy something by clicking on one of our links, we'll receive a small commission.   CLICK HERE to join our free Police, Fire, Military and Families Facebook Group: https://geni.us/YM5tsB   Check out our website and learn more about how you can work with LEO Warriors by going to: https://www.leowarriors.com/   Like what you hear? We are honored. Drop a review and subscribe to our show.    The Tactical Living Podcast is owned by LEO Warriors, LLC. None of the content presented may be copied, repurposed or used without the owner's prior consent.   For PR, speaking requests and other networking opportunities, contact LEO Warriors: EMAIL: ashliewalton555@gmail.com. ADDRESS: P.O. Box 400115 Hesperia, Ca. 92340 ASHLIE'S FACEBOOK: https://www.facebook.com/police.fire.lawenforcement   ➤➤➤➤➤➤➤➤➤➤➤➤➤➤➤➤➤➤ This episode is NOT sponsored.   

In this Pod Club and Bi Lingual episode, we cull the gems from last week's full length episode with Yaqueline Martinez, author, chef and Founder of Yaqueline Y Su Sabor Cubano catering business. Yaqueline shares the not so secret advice for starting your own business and the step by step on where to start. The best part is the encouragement to increase your monetary goals with 2 invaluable assets so be sure to listen for the free guidance on setting your mindset towards big goals and how to cash in on them. Highlights:

The RSB Show 4-18-23 - Krissy Chin, Health professional resources, Immune system support, Cashless England, Scott Schara, GraceSchara.com, Death by protocol, St. Elizabeth's Hospital lawsuit

In this episode, we get to know Hannah, a multi-faceted and multi-talented educator and mental health professional. Hannah explains how she is a “third culture kid” as well as a product of a military family upbringing. She tells us how these experiences helped her to become highly sensitive and tune

This episode we sit down with Parveen Sehra, the Director of Professional Resources at Singleton Urquhart Reynolds LLP. She leads the student program for summer and articling students, including recruitment, engagement, and professional development. She is skilled in helping young professionals develop and further their skills and has a broad range of experience within the legal industry. Parveen was most recently one of our speakers on September 14, 2021, for the panel titled “Navigating the Recruitment Process as an Asian-Canadian Law Student: Putting Your Best Foot Forward”. This episode is a recap of that event with OCI guidance, and provides further background on Parveen's path to legal recruitment.

Jessica Watkins – the National Director of Professional Resources at Miller Thomson LLP – shares invaluable insights and advice about what it takes to succeed as a law firm associate in today's competitive legal market. Topics discussed include: the importance of taking ownership of your career, your work, and your mistakes; reasons associates leave private... The post Succeeding as a Law Firm Associate with Jessica Watkins appeared first on Exellegal.

Hope you enjoy this episode all about professional resources available to our veterans! CareerProPlus: https://www.careerproplus.com/resume-services/military-resumes/veteran-ex-military-resumes/ Save A Suit: https://www.saveasuit.org/ TopStackResume: https://www.topstackresume.com/

In this episode, Don interviews Barry Vince! Barry is the co-founder and partner of Two Roads Professional Resources. He is on a mission to empower technical professionals to find meaningful careers, and for companies to find talent through innovative technical staffing solutions. Barry has over 22 years of experience in this business. He talks about […]

Lindsay Aagard practices in the area of Government Relations and Strategy at Fasken.Mary Jackson is the Chief Officer, Professional Resources at Blakes, Cassels, & Graydon LLP.Get more examples of what lawyers, law firms and other professions are doing to advance gender equality and obtain 5 h 45 m of EDI hours by watching the full and recorded program from the OBA’s Momentum Summit.Document your CPD Hours --> HEREHave feedback? Email us at pod@oba.org with your thoughts and comments.CREDITSPaula Todd, Interviewer and Professor, School of Media, Seneca CollegeLindsay Aagard, FaskenMary Jackson, Blake Cassels, & Graydon LLPLynne Vicars, Host and OBA Immediate Past PresidentRoy Bornmann, Policy and Programming LawyerRachel Winer, ProducerAndrea Miller, Audio Technician

May is Mental Health Awareness Month. This episode discusses professional resources for those seeking assistance as well as provides self-help tips for those just wanting to maintain a balance. I am not a medical professional and this is not medical advice. This information comes from research, personal experiences, and the experience of others. If you are in need of professional help, please seek it out immediately.This is my first listener recommended episode and I am truly thankful. 

Read, Lead and Succeed - Imperative Family NotesDr. Danny Brassell - Affectionately known as “Jim Carrey with a Ph.D.,” Dr. Danny Brassell (www.DannyBrassell.com) has held numerous titles and worked with leaders from a variety of fields and disciplines, but he has always considered himself first and foremost a teacher. He is a best-selling author of 15 books, including The Reading Makeover, based on his popular TEDx talk. Thousands, from school districts to businesses to association conferences, have enjoyed his energetic, interactive and informative presentations on how to read and lead. He Loves To Teach How To Read & LeadHe has spoken to over 2,000 different audiences worldwide and is the co-founder of the world's top reading engagement system for struggling and reluctant readers, http://www.ReadBetterin67Steps.com/ (www.ReadBetterin67Steps.com.) Ed Note: This is a replay, published earlier and republished here because it was so well received previously. Danny is making a big difference, and he tells you how you can learn more about the lifetime value of his outstanding reading protocols. For CoreBrain Journal Listeners: Read & LeadCheck This Out! - "As a thank you for letting me appear as your guest, and as an add-on for your listeners, I'd like to supply everyone with a complimentary e-copy of my book Read, Lead & Succeed, available at http://readleadandsucceed.com (www.ReadLeadandSucceed.com.) - I'm on a mission to help people succeed by building their love of reading. - Let me know how I can further serve your audience." Own This InterviewI'll tell you straight up - I love this guy. Read and lead is for your home, your family, and you - must listen. Dr. Brassell provides remarkably useful reading development tips and presents details in such an interesting way. Now I'm trying to read to my grandchildren long distance! Take Dr. Brassell up on this offer, his insights are researched, useful and exceedingly interesting. Then forward this link to everyone you know http://corebrainjournal.com/253 (http://corebrainjournal.com/253) Photo by https://unsplash.com/photos/cwGk-u9PHOo?utm_source=unsplash&utm_medium=referral&utm_content=creditCopyText (Josh Applegate) on https://unsplash.com/search/photos/reading?utm_source=unsplash&utm_medium=referral&utm_content=creditCopyText (Unsplash) ------------ Linkshttp://geni.us/brassell (The Reading Makeover )- Brassell, Professional Resources - Global Amazon Link http://www.DannyBrassell.com (http://www.DannyBrassell.com/) http://ReadLeadandSucceed.com/ (http://ReadLeadandSucceed.com/ ) http://www.readbetterin67steps.com/ (http://www.readbetterin67steps.com/) ------------Dr. Brassell On TEDx --------------Multiple Additional CBJ Experts on Life MasteryThese Mindset Experts: http://corebrainjournal.com/mindset (http://corebrainjournal.com/mindset) Family & Teen Experts: http://corebrainjournal.com/teen (http://corebrainjournal.com/teen) Relationship Experts: http://corebrainjournal.com/relationships (http://corebrainjournal.com/relationships) Life Mapping for Improved Travels - Pahuta:http://corebrainjournal.com/239 ( http://corebrainjournal.com/239) What Your ADHD Child Wishes You Knew: http://corebrainjournal.com/261 (http://corebrainjournal.com/261) Twitter: @DannyBrassell ------------ Forward This Audio Message Link To a Friendhttp://corebrainjournal.com/285 (http://corebrainjournal.com/285) -----------ThanksThanks, Dr. Brassell, for joining us here at CBJ to review your personal observations and research about the absolute importance of starting reading in a systematic way - early! Have some feedback you'd like to share? Leave a note in the comment section below. If you enjoyed this episode, please share it using the social media buttons you see at the bottom of the post....

In a new Legal Executive Institute podcast, we feature a discussion about career trajectories that occurred at the 2017 Women's Transformative Leadership Forum, which was held in Toronto in late-June. The podcast features Charlotte Rushton, the Managing Director for U.S. large law firms at Thomson Reuters, speaking to Shanin Lott, Managing Director for Talent and Professional Resources at the law firm of Stikeman Elliott, and a co-chair of the Women's Transformative Leadership Forum.

[intro music]Host – Dan Keller Hello, and welcome to Episode Fifty-Two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.This week’s podcast features Dr. David Tabby, who discusses the incidence of headache in MS. But first, here are some new items in the MS Discovery Forum.According to our curated list of the latest scientific articles related to MS, 53 such articles were published between August 14 and 21. To see these publications and the articles we selected as Editors Picks, go to msdiscovery.org and click on Papers. We’ve made some recent updates to our Funding Opportunities and our Meetings and Events listings, both of which can be found under our Professional Resources tab. Be sure to take a look at a newly-posted funding announcement entitled, “National MS Society: Health Care Delivery and Policy Research Contracts.” If you know of any meetings, events, or funding opportunities that are missing from our lists, please email us at editor@msdiscovery.org so that we can include them. Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This past week, we’ve added one new trial and 15 other pieces of information. The drugs with important additions are dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, and ofatumumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline. [transition music]And now to the interview. Dr. David Tabby is an adult general practice neurologist, with a subspecialty in multiple sclerosis, in Bala Cynwyd, Pennsylvania. He was formerly associated with Drexel University College of Medicine in Philadelphia where he carried out the study on headache and MS that we discussed.Interviewer – Dan Keller Could you just tell me what the aim was? I think you were looking the variables affecting headache occurrence in MS patients.Interviewee – David Tabby Well, to be perfectly frank about that, my business manager had noted that many of my MS patients also had migraine, and she asked what’s going on with that. So we did a cursory review and found that close to 50% of my MS patients also had migraine. So that prompted the survey in a more formal fashion.MSDFWhom did you look at, and what were some of the variables you looked at?Dr. TabbyWell, we looked at everyone who was willing to answer a survey. And we wanted to include some typical migraine variables like frequency and intensity and triggers and age of onset and duration at that time and which came first, MS or migraine.MSDFAnd what were some of the major findings?Dr. TabbyI think our biggest contribution was that it seemed that we could correlate exacerbations with increase in headache, which I don’t think was known before that. Sometimes headache a little bit before the exacerbation, and sometimes exacerbation first, then with headache. But that raised the question about the role of inflammation in both headache and MS exacerbations. You know, I don’t think one is the cause of the other, but they’re clearly related.MSDFWhat about migraine with aura or without? Are there differences in the MS presentations or symptoms or relations in time?Dr. TabbyWe didn’t have a lot of migraine with aura patients. That’s only about 20% of the migraine population anyway. We didn’t have a big enough number to make any kind of association that would be distinguishing migraine with or the migraine without aura.MSDFDo you have a proposed mechanism in mind how these two may be linked – mechanism of migraine, mechanism of MS?Dr. TabbyI don’t think there’s a lot of work about what the immune system’s role is in migraine, but stress affects the immune system. My patients tell me that a particularly stressful event can seem to precipitate an exacerbation, and, no big secret, that stress can precipitate a migraine.MSDFFatigue can be a trigger, and obviously, that’s a large proportion of MS patients have it. So do you think there may be a link there, one triggering the other?Dr. Tabby90% of MS patients will complain of fatigue at some point, and I think that’s clearly got something to do with it. So anyone with migraine will tell you that when they overdo it and get overtired, they get a migraine.Interviewer – Dan KellerI think I saw something in the paper was talking about metalloproteinases in the CNS and leakiness of vessels and allowing either antigens out or T cells in. Does that have any legs or where does that idea come from?Dr. TabbyThat idea came from a paper that we found in our literature review of the basic pathophysiology of an MS exacerbation that matrix metalloproteinases have to be activated first, to increase vascular permeability of the CNS. Migraine was thought, at one time, to be a primarily vascular issue. It’s not. It’s primarily a neurochemical issue that affects the vasculature, but results in dramatic changes in blood vessel permeability. There’s a kind of leakage of fluid around blood vessels, which helps make them more sensitive.MSDFThere’s also a component of calcium flux in migraine. Would that have any effect on the immune system? There’s calcineurin inhibitors that are immunosuppressants, so I’m wondering if calcium in itself – could be an imbalance be a stimulant?Dr. TabbyThe role of calcium in modulating neural function can’t be overstated. I’m not ready to give you an exact mechanism of how that might function.MSDFPatients with migraine supposedly have more symptomatic clinical course of MS. Do you have any numbers there? What did you find?Dr. TabbyWe weren’t a longitudinal study. We’re really just a snapshot kind of picture to determine, you know, a relationship now. That was another one of our hypotheses that the worse headache you had the worse MS you were going to have. Our take-home message from the paper was MS doctors should be very aggressive about addressing migraine symptoms in their patients, because we think that it could have an effect in long-term prognosis in MS. And it’s not just the patient complaining about, oh, I have a really bad headache. There is a relationship. It’s been known for many years. I mean, you might have seen in our bibliography that some of the papers went back to the 1960s about the relationship with headache and MS. So, just to reiterate, migraine prophylactic therapy, migraine abortive therapy is important in the context of treating MS.MSDFCan pre-existing migraine before the MS diagnosis give you any clue as to being a risk factor in itself?Dr. TabbyThat’s an excellent point. We didn’t have a big enough group to come to that conclusion, but 12% of Americans have migraine – 18% of women, 6% of men. Less than 1% of the population has MS. Something else has to be happening.MSDFAlso, I guess you found that people with stabbing pain had more acute MS exacerbations than if they had other more throbbing kinds of pain.Dr. TabbyWell, we were just using that as an indicator of severity of the headache. Stabbing’s not a typical word used to describe migraine. We gave choices. We just didn’t leave it open-ended. We gave some example words for their responses to the survey to tick off. Yes, stabbing was one of them, and there was a correlation between the ones who said stabbing and worse exacerbation.MSDFSome of the patients you surveyed did not have pre-existing migraine, only after their MS diagnosis. Do you think that migraine is something that one should investigate whether they actually may be in a prodrome of MS, if they present late - develop migraine late in life – later in life?Dr. TabbyIn our world, pretty much everyone with a bad headache who sees a doctor about it, at some point is going to get some sort of imaging study of the brain. It might be a CAT scan, in which case there might not be enough information. But if it’s an MRI, there’s a good chance of seeing high-signal lesions scattered through the white matter. They may be real small and not particularly typical of MS. But not uncommonly, they’ll see a pattern that looks really quite like MS. And you examine the patient, and you don’t find anything that’s consistent with MS. You do a history, and you don’t find any symptoms that are consistent with MS. So this is the sort of thing you just file away and see what happens. I don’t think anyone would suggest that treatment for MS should be started at that point. There’s an entity that’s finally gotten a name, called radiologically isolated syndrome, which people get MRIs of their brain for some reason – head trauma, headache, anything really – and the pattern looks really quite like MS, but there’s no clinical support of MS. So same thing; we don’t forget about these people. You recheck their MRIs at some point in the future. You look for new lesions or enhancing lesions. I think the latest statistic is somewhere around 50% of them are eventually going to present as having multiple sclerosis.MSDFWould each entity be treated or each condition be treated as if it existed in isolation? Or do they complicate the management of the other?Dr. TabbyMy approach has been to treat them independently. Just follow the basic principles of headache treatment for the headache and the basic principles for MS treatment and adjustments of therapy and symptomatic therapy for MS. I would not suggest some interlinked therapy system.MSDFBut something like interferon and possibly other drugs may cause exacerbation of headache. Would that lead to noncompliance of the MS treatment or would you switch drugs or how do you handle that?Dr. TabbyThat doesn’t necessarily involve the headache issue. I think someone who has bad headaches on interferon who’s not taking their medicine, you know, you might try to fix it – fix the headache that is. But you’re probably fighting an uphill battle when that patient has negative associations with taking their medicine. I still tend to think of these two things as related but separate.MSDFSo what’s the big take-home message for a physician?Dr. TabbyReally just about treating migraine aggressively in their MS patients, and keeping in mind that we work very hard to preserve function to reduce the accumulation of disability, with drugs and other sorts of interventions. But intervening for migraine may be just one other way to reduce the burden of disability in the future, for your patients.[transition music]MSDFThank you for listening to Episode Fifty-Two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org. [outro music]

[intro music]   Host – Dan Keller Hello, and welcome to Episode Forty-nine of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features Dr. Hugh Rosen of the Scripps Research Institute. But first here are some new items in the MS Discovery Forum.   If you’re an MS researcher, you may want to keep an eye on our Bulletin Board section, where we post a variety of news items that may be of interest. One of the items we posted this week is directly related to Dr. Rosen’s work. It’s a notice that a phase 3 trial of a sphingosine 1-phosphate receptor modulator called RPC1063 has started recruiting twelve hundred patients with relapsing remitting MS in the US. RPC1063 had its origins in Dr. Rosen’s lab.   We also recently added a notice of another clinical trial to the Bulletin Board. That one’s a phase 2 trial of oral laquinimod in primary progressive MS. And a third new Bulletin Board announcement is a request for information from the Patient Centered Outcomes Research Institute to identify patient registries and research groups with established cohorts of patients for potential collaborative research opportunities on comparative effectiveness research in MS treatment.   To read any of these announcements, go to msdiscovery.org and click first on Professional Resources and then on Bulletin Board. And if you have an announcement you think may be of interest to MS researchers, please send it to editor@msdiscovery.org. We won’t post purely promotional press releases, but if we judge the notice to be of general interest, we’ll be happy to post it at no charge.   In other news, it was a relatively slow week in published MS research. According to our curated list of the latest scientific articles related to MS, only 22 such articles were published last week. Typically at least 40 MS-related peer-reviewed articles are published weekly, and we’ve seen some weeks with more than a hundred. To see the weekly lists going back to March 2012, go to msdiscovery.org and click on Papers.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. This past week we added 2 new trials and 7 other pieces of information. The drugs with important additions are dalfampridine, fingolimod, masitinib, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline   [transition music]   Now to the interview. Dr. Hugh Rosen studies chemical and biological approaches to the molecular mechanisms regulating lymphocyte trafficking. I met with him in his office at the Scripps Research Institute in La Jolla, California.   Interviewer – Dan Keller We're talking about mostly new compounds, S1P1 receptor compounds; the prototype now I suppose is fingolimod. What's in development and do they appear to offer advantages?   Interviewee – Hugh Rosen So, firstly, let me disclose that I am a cofounder of a biotechnology company called Receptos that has licensed an S1PR1 agonist from the Scripps Research Institute, so I have and my institution have a significant interest in this particular field.   Sphingosine 1-phosphate receptors act in a number of ways to modulate immune tissue damages in both autoimmune diseases and in viral infections. They've proven to be particularly efficacious in multiple sclerosis. Gilenya, of course discovered by Yoshitomi in Japan and developed by Novartis, has proven to be a clinically useful compound in the treatment of relapsing-remitting multiple sclerosis. And it appears to do so, at least in part, by altering the ability of lymphocytes to recirculate, and thus lymphocytes to reach the target tissues where they, in fact, produce demyelinating damage to the white matter of the central nervous system, and then the signs and symptoms of multiple sclerosis. So clearly these are useful compounds.   Gilenya, of course, is not a selective small molecule, it is an agonist of four of the five high affinity receptors for sphingosine 1-phosphate – S1P1, 3, 4, and 5 – and some of the associated side effects may be attributable in part to activity of Gilenya on other receptors like the S1P3 receptor that are not required for modulation in the treatment of multiple sclerosis.   MSDF I see that it's referred to as an immunomodulator, not necessarily referred to as a receptor agonist. Does it not have pure agonist effect? Does it have any effects either because of the other receptors or at that same S1P1 receptor?   Dr. Rosen No. In fact, Gilenya when phosphorylated is a full agonist of the sphingosine 1-phosphate receptors, and the newer compounds that are much more selective are also agonists of the sphingosine 1-phosphate 1 receptor. And some of the effects on them for cyto-mediated by downmodulation of the receptor, but I don't use the term modulators or immunomodulators because of the activity on the sphingolipid receptors per se, I use the term immunomodulator because of some of the unique advantages that we've demonstrated in model systems and in man about altering the activity of the sphingosine 1 receptor, because one of the beauties of immunomodulation is to blunt the immune response that causes collateral damage to the tissues whilst leaving sufficient of the immune response intact to allow protection from opportunistic pathogens – bacteria, viruses, and yeasts.   So one of the most striking features that we found – and these have been in some experiments done as a collaboration between my laboratory and the laboratory of Professor Michael Oldstone here at Scripps – has been in the area of influenza; pandemic influenza causes significant collateral tissue damage by having an overactive immune response. What we show is that the sphingosine 1-phosphate 1 receptor blunts that immune response and blunts the amplification of cytokines and chemokines so that you protect from the collateral tissue damage, but you leave intact the ability to mount protective, sterilizing T cell and B cell immunity to the virus. So you can eradicate the virus, sterilize it, you can provide a long-term memory both on the T-lymphocyte side as well as on the antibody side; there's class switching, there's affinity maturation, there are good protective immunity that is produced, and all this while blunting the immune response.   This is the Holy Grail as we think about treating patients, because the window for patients with autoimmune diseases like multiple sclerosis is that window between effective blunting of the immune response and the prevention of deleterious opportunistic infections that can have life-threatening consequences. So one of the advantages that I suspect we will see over time is that the sphingosine 1-phosphate agonists will prove to be particularly well-tolerated and have a wide window between the ability to limit tissue damage and progression of RRMS, and the need to protect patients from intercurrent infections or subclinical infections that become expressed later.   MSDF Do the other sphingosine 1-phosphate receptors interfere with lymphocyte trafficking also, or do they have other effects which nonselective ligands would then induce these adverse effects through them, or do they also have some effect in terms of trafficking?   Dr. Rosen They don't have significant effects on lymphocyte trafficking the way that S1PR1 does, both from the chemical approaches and the genetic evidence. S1P1 is clearly a toggle switch for lymphocyte trafficking. S1P2 is involved in the maintenance of hearing and in the function of vascular smooth muscle, so it regulates blood pressure. S1P3 is involved in cardiac contractility and also in the control of coronary artery caliber and the control of the airways, so S1P3 agonism is not a useful thing, it's actually quite deleterious. S1P4 and 5 have really no rate-limiting functions, at least of which I am aware, so there may be some redundancy and may not play a critical role in the modulation of health and disease.   MSDF Do you see compounds coming along which will be more selective and therefore not lead to the adverse effects so much? And if so, are these compounds chemically similar or do they have different structures to attach to the receptor, the S1P1?   Dr. Rosen These are clearly different structures, they're structurally very distinct from Gilenya and from each other. Novartis have a backup called siponimod. Actelion had a compound but it's only being used in psoriasis called ponesimod. Receptos has a compound now known as ozanimod – formerly known as RPC1063 – that is in two phase 3 studies for relapsing-remitting multiple sclerosis, a two-year study called RADIANCE and a one-year study called SUNBEAM, both of which are enrolling twelve hundred patients each.   MSDF And the RADIANCE trial results looked pretty good; I mean, you had 85, 90% effects at 12 to 24 weeks or even at a year in terms of relapse rate. Does this look like the next compound to emerge?   Dr. Rosen I think it's likely that ozanimod will be the next compound to be submitted for the regulatory process here in the United States and probably in Europe as well. The pleasing thing about the phase 2 data for ozanimod was, in fact, both the strong efficacy signal and a very well-tolerated safety profile; in fact the adverse effect profile of ozanimod and placebo were, in fact, indistinguishable and overlapping in the phase 2 studies. In addition, this very well-tolerated, favorable safety profile has been replicated in a highly successful phase 2 study in ulcerative colitis called TOUCHSTONE that was released recently. So clearly this is a mechanism of immunomodulation that could well prove to be useful for relapsing-remitting multiple sclerosis, but also in a range of other autoimmune diseases where treatments are hard to come by.   MSDF Even with Gilenya, I think there have been reports of a couple of cases of progressive multifocal leukoencephalopathy, so it gives a nice balance between immune surveillance and inhibiting T cell trafficking, but it seems like not a perfect balance. Does it look like that margin will be narrowed in the future with other compounds?   Dr. Rosen It's possible that it will be. I think the critical point to bear in mind is that real-world experience in tens of thousands of patients with hundreds of thousands of patient-years is really ultimately what is required to define these very rare events that on occasions do occur, and preexisting treatments with other immune-modifying agents such as Tysabri, for instance, may predispose to issues being seen later with PML. And I think that we always have to say that long-term patient experience and physician comfort are ultimately the best guides to the risk-benefit ratio.   MSDF I think you've identified something like four compounds in development, those are some that I had seen. Are there others, or these are really the ones to focus on at this point for people to keep an eye on?   Dr. Rosen There may well be others that are further behind. There have been a number of others that have had safety signals, particularly liver enzyme elevations, and significant first-dose cardiac effects. Arena have a compound that has recently completed a phase 1 multiple-dosing study and will go on to phase 2. So, you know, there are additional compounds and there will be additional compounds. Ultimately, patients do best when the best compounds appear, and the only way one knows that is to test them in man over the long-haul and define that risk-benefits for patients. And, you know, these multiple efforts really reflect the fact that a field has advanced, and that advancing field really does improve through intelligent intervention our ability to offer patients a better set of choices and a better set of long-term outcomes, which is what we're all about.   MSDF We're still focusing here on RRMS, none of this applies to the progressive phase. Is there anything coming along there?   Dr. Rosen You know, there's been one trial in primary-progressive; this was the Gilenya trial which didn't meet its endpoints. It may be that the mechanisms in rapidly progressive MS are a little different and that we don't yet, I think, understand the pathogenesis of that rather different presentation. So I'm not aware of a good alternate approaches to that, but that doesn't mean that the understanding isn't there for that to happen over time, it simply means that I'm not yet aware of it.   MSDF Finally, in secondary-progressive MS, we can understand what's going on, what led to it; if you limit relapses, that's good. But does it look like primary and secondary really may be overlapping but not the same disease?   Dr. Rosen I think there may be balances of pathogenesis where you can intervene more easily in some than in others. Clearly the sphingosine 1-phosphate agonists work particularly well by inhibiting the movement of lymphocytes into the brain. The movement of lymphocytes from the perivascular cuff into the parenchyma, into the white matter, where the demyelination proceeds. However, in parallel in multiple sclerosis, there are also events where there is collateral damage to neurons; we see axonal severing, we see elements of neuronal loss. Certainly with the sphingosine 1-phosphate agonists, there is some evidence that there is a diminution of cortical thinning over time with treatment, and that may be a really good thing.   I think that the neurodegenerative components is one that is hard to get a handle on right now, and that I think that these differences will become more obvious with early treatments of the immunopathology of multiple sclerosis. And that may well separate the autoimmune inflammatory damage and its sequelae from neurodegenerative mechanisms that may be entrained, and I think we will learn a lot from looking at those subsets of patients over time, particularly as more, better, and earlier treatment modalities allow the avoidance of significant damage in most patients.   MSDF Is there anything important we've missed or you'd like to add?   Dr. Rosen You know, I think for all of us who try to work at this interface of therapeutics, we do so because disease is, in fact, personal. We all know patients, we've all seen the multigenerational impact and depredations of multiple sclerosis on friends and family. And I think this is the very strong underlying motivator that drives us as scientists and as physician scientists to really try and bear in mind that the basic mechanisms and the basic therapeutic approaches that we pursue ultimately need a safe and effective human face to change the lives of patients in a positive way.   MSDF Very good. Thank you.   [transition music]   Thank you for listening to Episode Forty-nine of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.    [outro music]

[intro music]   Host – Dan Keller Hello, and welcome to Episode Twenty-one of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. Paul Matthews about imaging in multiple sclerosis. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   We recently reported on a draft of a review released by the Agency for Healthcare and Research Quality about discontinuing disease-modifying therapies in patients with MS. Though the report’s main conclusion was that little evidence is available to assess the risks and benefits of discontinuing therapies, several MS groups came together to criticize the report during the open comment period. Groups like the National MS Society and Medical Partners 4 MS raised concerns that the review was not conducted properly and that insurance providers may use it as justification to reduce coverage of DMTs for MS. The AHRQ told Multiple Sclerosis Discovery Forum that they would consider the comments carefully and make any necessary revisions.   MSDF’s parent organization, the Accelerated Cure Project, is launching a new research resource called iConquer MS. Hollie Schmidt, Vice President of Scientific Operations at the Accelerated Cure Project, recently wrote a blog post explaining that the new initiative aims to take data and biosamples from 20,000 people with MS and make them open-access to researchers. We want your input about what you may want to do with such a resource. If you’re interested, go to the blogs section of MS Discovery Forum under the “News and Future Directions” tab and click on the blog post titled, “Invitation to Share Your Thoughts on a New MS Research Resource.”   Our list of meetings and events is ever-growing. We’ve posted multiple meetings of all shapes and sizes sprinkled throughout 2015 and even into 2016. And if you know of a meeting that’s not yet listed, please do submit what information you have. We’ll take care of the rest. Just go to “Meetings and Events” under the “Professional Resources” tab on our website and click on the “submit new item” button to tell us about your event. We’re even willing to list local departmental seminars and journal clubs.   [transition music]   Now to the interview. Professor Paul Matthews is at Imperial College London in brain sciences. He met with MSDF to talk shop about imaging in MS.   Interviewer – Dan Keller Welcome, Professor Matthews. What do you see now as new modalities or new ways of doing imaging, and what’s coming along?   Interviewee - Paul Matthews Thanks, Dan. Imaging continues to reinvent itself in areas particularly like MS. Magnetic resonance is becoming more and more powerful with use of particularly multiband techniques, allowing multiple coils to be used to accelerate the imaging process, and because of that being able to collect much more data to enhance particularly diffusion images. So, for example, within the Human Connectome Project, development of new multiband techniques has accelerated imaging to the point where very high resolution diffusion tensor images can be acquired in spaces of 15-20 minutes. The implications of this for MS are that we can begin to develop powerful approaches to expression of the diffusion tensor information in terms of diffusion parallel to the fibers, perpendicular to the fibers, and free diffusion that is anisotropic. This means that potentially we’re going to be able to separate out free-water contributions from those contributions arising from myelin and axonal loss, providing a very powerful complement to magnetization transfer images.   A second area of major development in magnetic resonance is the increased use of ultra-high field systems at 7T, and potentially higher, for applications in MS. The first advantage this has brought is for increased spatial resolution that can be used to begin to image cortical lesions with a really impressively enhanced sensitivity. The second area has been new kinds of contrast. The high magnetic fields allow new susceptibility-weighted contrast to be generated which provides a powerful way of visualizing vessels. It’s very clearly defining the vessels at the center of most of the inflammatory lesions, helping a little bit with differential diagnosis, but even more importantly helping us understand what the microvascular architecture is in and around lesions.   A second potential advantage of the ultra-high field is simply increasing the sensitivity of MR for applications in magnetic resonance spectroscopy. We’ve known for a long time that signals from myo-inositol can help us understand glial components of inflammatory lesions, but there’s increasing interest in applying this kind of tool to measurements of glutathione, to provide indices related to reactive oxygen species generation, and potentially also to measuring excitotoxic neurotransmitters such as glutamate.   In a completely different space, positron emission tomography (PET) has begun to play a renewed kind of role in MS. I’ve always been a little bit disappointed that more wasn’t done with it over the last decade or so since pioneering studies that demonstrated that assessments of energy metabolism based on simply the fluorodeoxyglucose signal not only discriminated people with MS from healthy volunteers, but, more importantly, began to show discrimination between different stages of the disease and a relationship to cognitive impairment, with potentially reversible components with treatment. Now, that still is an area of potential work.   But more recently focus has shifted particularly to use of ligands that bind to the 18 kilodalton translocator protein which provides a marker of microglial inflammation in the brain. While it’s not entirely specific and with the caveat that we have little understanding of the relationship between the TSPO expression and the microglial phenotype, it clearly is highlighting some very interesting things. First, we found that the TSPO binding by ligands is increased multifocally in brains of people with MS; it’s increased multifocally in the white matter and in the grey matter. Moreover, increases in binding in both regions are related to degrees of disability; patients with higher disability show increased binding particularly in the cortex.   There’s emerging evidence, driven first by elegant preclinical studies done by the Finnish group and some human studies yet to be fully reported, that there are also strong treatment effects with powerful amino modulators. So because this provided us a window that is clearly giving us information distinct from that provided by T2 hyperintense lesions on MRI or by gadolinium enhancement on MRI, it promises a powerful adjunct.   And, finally, just to kind of round that idea out, it’s clear that it will be the combination of MR and PET that’s powerful rather than PET replacing MR in some way in our diagnostic or monitoring armamentarium for treatment. One manufacturer has already started supplying commercially integrated MRI-PET systems. Another manufacturer is expected to do so very soon, and potentially a third. This may become a platform for brain imaging that is very powerful for disorders like MS that have multifocal manifestations where the registration – the precise registration – between the MRI and the PET becomes important. Moreover, the potential to use dynamic MRI acquisitions where we’re just imaging very, very rapidly throughout the entire PET scanning period to follow the position of the head within the PET scanner may allow a new kind of precision of special resolution in the PET scan that allows MS studies where we rely on this very much to be done with far greater precision than it’s been possible in the past. So with these developments in MR, with the new radioligands in PET, and with this new technology for integrated MRI-PET, I think the brain imaging is off in incredibly new spaces.   Now I can’t close the discussion of imaging without at least making a mention of the revolution in applications of optical coherence tomography that have been conducted over the last five years in particular for MS. This is really exciting, too. It’s an inexpensive examination that can be performed very rapidly in any clinic that provides very high-resolution measures of optic nerve fiber layers, of multifocal edematous regions within the nerve fiber layer, all of which can provide measures to stage MS and its associated neurodegeneration, and potentially to usefully monitor it in assessing the progress of patients on treatments. It’s an exciting time for imaging.   Interviewer - MSDF Now just to clarify, this is optical coherence tomography of the retina and its surrounding structures.   Interviewee - Dr. Matthews Yeah, Dan, thanks for clarifying that. Absolutely. So it’s an eye examination, but it’s an adjunct because the retina is just an extension of what we study in the brain.   Interviewer - MSDF Either using metabolic markers or following metabolism with PET or something else, or using other ligands and markers, can you discern or image where remyelination is occurring?   Interviewee - Dr. Matthews So, of course, the world of PET is a big one because what we can observe changes with the type of radiotracer that we use. Recently, Yanming Wang, who I had the privilege of collaborating with at Case Western, published, I think, a really groundbreaking paper. Although it was a preclinical study, I think it shows the way we could be moving in this space. Using a novel radiotracer that he developed called MeDAS – MeDAS for short – this carbon positron-emitting isotope-incorporated tracer allows specific myelin proteins to be imaged, and thus provides a marker of myelin integrity in life. Yanming has shown how it can selectively image myelin, it can image both established myelin and new myelin being formed, and he demonstrated in a proof of concept study in rodents that the dynamics of demyelination and remyelination following therapeutic intervention can be followed, and moreover, that the therapeutic effect can be quantified relative to an untreated control group.   Really exciting and a potentially important adjunct to MTR or diffusion measurements in human studies. The trick of moving a tracer from preclinical studies into humans is not without some need for care, but because only microdoses of these tracers are used for the human imaging experiment, Yanming, myself, and colleagues believe we can make this transition rapidly. We’re watching closely to see what happens next.   Interviewer - MSDF Pretty good. I appreciate it.   Interviewee - Dr. Matthews Thanks, Dan.   [transition music]   Thank you for listening to Episode Twenty-one of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.    [outro music]

[intro music]   Hello, and welcome to Episode Twenty of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. Jeffery Cohen about two clinical trials. But to begin, here is a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org. Genome-wide association studies are raising more questions than they answer for multiple sclerosis, according to new research. As the number of risky genetic variants grew, researchers began to wonder if many of those variants would be found in the murky waters of “noncoding DNA,” which comprises about 98% of the human genome. Those fears were confirmed in a study published last month in the journal Nature. According to the report, almost 90% of the risk variants fell within the noncoding region and 60% were found in areas known as enhancers or switches. These areas manage gene activity, though researchers are far from fully understanding how they work. While genome-wide association studies have been helpful to researchers, this study highlights that they are just a first step towards a better understanding of MS and the human genome.   The International Progressive MS Alliance recently released a call for applications for their second round of grants. To go along with this announcement, Professor Alan Thompson, the head of the Alliance’s scientific steering committee, penned a post for our blog. In his post, he emphasizes the urgent need for more research into progressive MS. He notes that over one million people worldwide live with progressive MS, yet no specific treatments exist for this condition. You can read Professor Thompson’s post in the blog section of the News and Future directions tab at msdiscovery.org. To get more information about the grants from the Alliance, visit our “Funding Opportunities” section under the “Professional Resources” tab on our website.   In addition to the latest funding opportunity from the Progressive MS Alliance, we also recently posted a long list of funding opportunities from the National MS Society.   [transition music]   Now to the interview. Dr. Jeffrey Cohen is a neurologist and director of the Mellen Center for multiple sclerosis at the Cleveland Clinic. He spoke with MSDF about two clinical trials, one examining the clinical use of stem cells, the other about a generic version of glatiramer acetate, Copaxone.   Interviewer – Dan Keller First of all, what was the aim of the clinical stem cell trial and what phase was it done in?   Interviewee – Jeffrey Cohen So we now have 11 medications approved to treat multiple sclerosis. They are all effective in the early, relapsing remitting stage of the disease, but there is a major unmet need for treatments that repair damage and might be effective in progressive MS. Our main goal was to explore cell-based therapies to treat multiple sclerosis, specifically to test the feasibility and safety of administering so-called mesenchymal stem cells. This was a Phase I study of mesenchymal stem cells. These are stem cells that are present in many tissues of the body. We isolated them from bone marrow which is probably the version that is the best studied previously. We grew them in the laboratory to increase their numbers, and then readministered them intravenously. We were focusing primarily on safety, as I said. We had fairly intense monitoring for any complications. Thankfully, we saw none. We also looked in a very preliminary way for benefit using clinical measures, a variety of imaging approaches and immunologic measures.   MSDF What is the hypothesis here that they are doing? Do they actually get into the brain? You are infusing them IV. There is a blood-brain barrier, these are pretty big objects.   Dr. Cohen There are actually a large number of studies in the laboratory and in animals that suggest that these cells have a number of properties that we think would be of use in a disease like multiple sclerosis. First of all, they seem to modulate the immune response. They dampen down inflammation. But more importantly, they appear to be able to produce a wide range of soluble factors, growth factors and other substances that we think promote repair. We think of them as the delivery system for growth factors that promote repair. We don't think that they themselves develop into brain tissue but will become neuro-cells, but rather that they create a milieu that is conducive for the natural intrinsic repair processes to remyelinate or restore neurologic function. The other property that is potentially very advantageous is that they appear to be attracted to areas of tissue damage or inflammation. They appear to have the ability to migrate within tissues, and in fact to migrate from either the cerebral spinal fluid into the brain or from the blood into the nervous system. So we think we can take advantage of that by administering them intravenously.   MSDF Did you do dose-ranging here?   Dr. Cohen: We did not. One of the things we learned from this study is that there are a lot of unknowns about cell-based therapies. What the appropriate dose is? Whether multiple doses are needed? What is the best route of administration? Whether there are nuances as to how you grow the cells in culture? What characteristics you want to augment? Dose-ranging in particular is something that has been very difficult to do in the field, particularly for some of these cells that are grown in culture; you usually have the dose that you have. That has been an issue that we have struggled with as have others in the field.   MSDF How long did you follow these patients and what did you find?   Dr. Cohen We followed them for two months prior to infusion. That is the time during which their cells were being cultured, and then for six months after infusion. So very reassuringly there were no serious or severe adverse events. In fact, there were very little, if any, side effects. Patients were not immunosuppressed. They had no premedication. The only side effect was that the culture media contains a chemical called DSMO. Some patients got a garlic taste in their mouth. If they don't like Italian food, they didn't like that. We also looked in a preliminary way for evidence of benefit with the caveat that this study was not really designed to look for benefit. We used this as an opportunity to explore a variety of measures that might show tissue repair. We saw enticing improvement in some measures in some patients, but for patients as a group, there was no clear-cut evidence of benefit. We have to be very careful how we interpret these results.   MSDF Could you follow them in any way? Were they tagged or any other way that you know where they went?   Dr. Cohen No. That is another aspect of the cell therapy field that is getting a lot of attention. At the moment it is largely a black box. After we administer the cells, knowing whether they survive and where they go and how long they live there. That is another line of research besides pursuing further clinical trials of these cells is also to develop methods to track them within the body. There are some promising approaches that we are in the process of developing.   MSDF Now I take it these were not modified in any way, they were just cultured to multiply them?   Dr. Cohen There were some growth factors in the culture media, but they were from the regulatory point of view, not very manipulated. That is the terminology that is used. That is another area of debate is some of the specifics of the culture approach, whether we should add other factors that might change the properties of the cells. Whether it is okay for them to be frozen, which we do largely for convenience because then we can schedule the infusion. Or whether they should be taken fresh from the culture and administered. There are arguments for both approaches.   MSDF Many cells seem to hone right back to where they came from. Do these just go back to the bone marrow do you think, or do you think they actually went somewhere because that area needed repair?   Dr. Cohen There have been a few studies in some other conditions where these cells have been given. One of the interesting properties is that you can administer these cells from another person and they are not rejected. They become, I wouldn't say the standard, but a very common treatment for what is called graft-versus-host disease, which is a very severe complication of allogeneic bone marrow transplant where the transplanted immune system attacks the recipient's body. That is where the immunomodulatory effects of mesenchymal stem cells were first observed. There are, unfortunately, have been a couple of instances where MSCs that were from another person of a different gender, were administered to someone with graft-versus-host disease who unfortunately, subsequently died of GVH. In those cases, these cells were found in a range of tissues including bone marrow. Probably a more important obstacle is for after intravenous administration is the lung because that is where the blood goes from the veins. These cells probably collect in the lung initially and then percolate out into the tissues.   MSDF Do you have any concerns, any caveats about potential harms, limitations, from using this? Is it feasible on a large scale?   Dr. Cohen We took a very conservative approach with the idea that there are so many unknowns of cell-based therapies, including precedence in multiple sclerosis where therapies had a different effect than we anticipated. We thought it was appropriate to take a very careful systematic approach starting with a small safety study and then building from there. At least within the limitations of our study, meaning that it was relatively short, and relatively small, we saw no indications of any complications. Some of the hypothetical concerns would be cancer. Stem cells share some properties that are similar to cancer cells, or ectopic tissue formation. Stem cells have the natural ability to develop into almost any kind of tissue. At least, presumably they could go to one tissue and develop into another type of cell, so bone within the heart or something like that. We really saw no indication of that. There are really no examples of that in the literature, but because of those sorts of concerns, we took a very careful approach. We feel comfortable now moving on to a bigger program.    MSDF You had discussed some of the problems that arose using allogeneic cells. Just to clarify, this was using autologous cells?   Dr. Cohen Correct. These were cells from the patient themselves. There is still some debate in the field, which approach is better. Whether to take cells from the person themselves or whether to take cells from someone who does not have the disease that you are treating. That again is an issue that has not been settled. I think some of the cell tracking we were talking about earlier may help with that. Rather than answering all of these questions one trial at a time, we may be able to adjudicate some of these questions by seeing whether cells traffic more effectively.   MSDF Let’s shift to your other trial, the GATE trial using generic Copaxone. Is that available now and what was the point of the trial?   Dr. Cohen The purpose of this trial was potentially to have a generic version of one of the established multiple sclerosis drugs come available. The incentive would be that presumably because of the lower development costs, that the generic version would save money for payers and for patients. The trial we just completed was of a generic version of glatiramer acetate, Copaxone, one of the initial drugs approved to treat MS, a drug that we have a great deal of experience with. It has established efficacy and a known good safety profile. This study tested a generic version of that with the intent of showing that it had equivalent efficacy, in this case, as tested by MRI and had equivalent safety and tolerability.   MSDF These were all patients with relapsing, remitting MS? You had, what, about 735?   Dr. Cohen Correct. This was in a patient population with relapsing, remitting MS; the population for which Copaxone is approved.   MSDF What were the interventions, the test group?   Dr. Cohen There were three groups in this trial. One group was treated with generic glatiramer acetate. One group was treated with the brand Copaxone and then there was also a small placebo group to demonstrate what is called study assay sensitivity. The purpose of which was to show for the trial overall that the generic glatiramer acetate is equivalent to the brand-name, the reference drug as it is called, but also that within this trial with this population, that both drugs were effective.   MSDF Where was this done, and is that ethical?   Dr. Cohen One of the things we have encountered increasingly in developing multiple sclerosis drugs is that there are ethical and practical issues to including placebo groups. At this point it has become extremely difficult to include a placebo group in a large Phase III study that goes on for several years. In this case, this was a short trial, with the advantage of using MRI as the endpoint. It was conducted to some extent in North America, but primarily in Eastern Europe and other  countries where unfortunately, multiple sclerosis treatments are not as available.    MSDF What did you find?   Dr. Cohen The study was successful. It showed equivalent efficacy as measured by gadolinium-enhanced MRI, and also showed equivalent safety and tolerability as measured by adverse events and injection site tolerability.   MSDF What would this mean for patients if someone brought out a generic?   Dr. Cohen The hope would be, is that if this drug is approved, that it would be less expensive. Multiple sclerosis is an expensive disease to care for and a great part of that cost is medication costs. So the hope would be that this would be less expensive. The other caveat is that complicated molecules such as Copaxone are difficult to replicate. In addition to very extensive chemical and biophysical analyses, that is why a trial was conducted, because of the feeling that it would only be with clinical data that we could…we assure ourselves that this was in fact similar to Copaxone.   MSDF I would take it, that this would only apply to the generic you tested. I mean generics have a certain tolerance level margin compared to the approved brand, so not all generics are the same.   Dr. Cohen That is correct. It is actually quite tricky to develop a generic of a complicated molecule, either a complex mixture such as glatiramer acetate or a so-called biological like a monoclonal antibody. Each one has to be tested one at a time.   MSDF Anything important that we have missed, or to add?   Dr. Cohen This trial was designed with the assistance of, and discussions with EMA, the European Regulatory Agency. It has been somewhat more difficult in the United States. The FDA is still somewhat unclear on their policies and the procedures for testing complex generics and biosimilars. The status of this trial in the United States is still somewhat uncertain.   MSDF Very good. Thank you.   Dr. Cohen Thank you.   [transition music]   Thank you for listening to Episode Twenty of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.    Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.   [outro music]    

[intro music]   Host – Dan Keller  Hello, and welcome to Episode Five of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m your host, Dan Keller.    This week’s Podcast features an interview with Dr. Anne Cross, who reflects on the past year in MS research. But to begin, here’s a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.    Researchers have discovered that multiple sclerosis may have something in common with colon cancer; the Wnt pathway. It’s a genetic pathway important in development, stem cell maintenance, and cell differentiation. In colon cancer, the mutation of a mediator gene called APC causes the Wnt pathway to become overactive, leading to tumor formation. Now, researchers have discovered that a loss of function mutation of APC in the brain also leads to an overactive Wnt pathway, ultimately freezing oligodendrocyte progenitor cells in their undifferentiated state.    Next, what disease-modifying therapies should women start or stop before pregnancy? In our latest news synthesis, we discuss the difficulties many women with MS have in deciding when to stop DMT before trying to conceive. Since it can take months, and even years, for a woman to conceive, it’s important that she spend the least amount of time off medication as possible to reduce the chance of relapse. Some drugs may be worth taking during pregnancy anyway, but it’s up to the neurologist to do a risk-benefit analysis for each patient. Nevertheless, many women opt to go off of DMT altogether to reduce the risk of adverse effects on the fetus.   Finally, we would like to direct your attention to funding opportunities on the MSDF webpage. Under the Professional Resources tab at msdiscovery.org, you can find a listing of various organizations offering funding for research grants, fellowship grants, and more. Currently, there are several opportunities offered from ECTRIMS with deadlines this winter. There are also several deadlines for funding from the National MS Society coming up in August.    Now for the interview.   Interviewer – Bob Finn This is Bob Finn. I’m here with Dr. Anne Cross of the Washington University in St. Louis. Dr. Cross will later today be giving a talk at the American Academy of Neurology meeting on what the year has been like in MS research. And, so, let me ask you briefly, what has the year been like? Has it been a good year, a bad year, an exciting year, a boring year?   Interviewee – Anne Cross  I think it’s been a pretty good year. There have been some mainly good things, a couple of bad things, some rather interesting and unexpected things, too. I guess some of the good things involve genetics research papers that have come out identifying genes that are associated with risk of developing MS. That’s been kind of exciting. Actually, there were 48 new genes that were identified and published this year by the International MS Genetics Consortium, which is a very large group of international researchers that have amassed probably close to 30,000 genetic samples from MS patients over the years that they’ve been in existence, which is about 10 years, plus close to double that of controls. And all these MS patient samples are from patients who were well characterized and submitted by, generally, MS specialists.    And that group did a study using something called the Immunochip, which is a genotyping array that was actually developed by a group of investigators who work on autoimmune disorders, so that array is very much weighted towards beings with immunologic function. So not too unexpectedly, all 48 of the newest identified genes all relate in some way to the immune system or are very closely linked to genes of immune function. But prior to that, the same group – the International MS Genetics Consortium – had identified about 50, a little over 50 genes that are associated with MS risk, and most of them were also related to genes of immune function. So I think together, all of this data certainly implicates the immune system, which we already knew, but I think things are certainly solidifying around that with the newest data.   MSDF  Let me ask you, if they’re using techniques that are specific for immunological genes, are they missing other genes?   Dr. Cross  They very well could be. The original studies that this group did which were published, the biggest study was published in the summer of 2011, did not do it in that fashion, though, they just did a genome-wide association study, and most of the genes that they identified were related to the immune system directly or indirectly. So, yes, I’m sure that some are being missed that aren’t related to the genes that are on this Immunochip microarray, but they’re trying to hone down a bit.    And some of the other things that were discovered were that, well, they identified 5 allelic variants; the particular allelic variant was over 50% of the time associated with risk of MS. And they also identified in this latest search – well, the strongest association was with a gene that has immune function called Vcl-10 – they actually in this latest search rediscovered the same 50 or so that they had discovered before, so they were actually mostly in this Immunochip microarray.   MSDF  So, aside from the genome-wide association studies, what else has been interesting in MS research this year?   Dr. Cross  Well, I think some of the clinical trials that have been published in the past year, and also that are just ongoing and aren’t published yet, have been interesting. This past week, Dr. Rhonda Voskuhl, who’s from UCLA, spoke and presented for the first time ever recent data from a study of estriol, which is a pregnancy hormone that was added to glatiramer acetate in women with relapsing-remitting MS, and that was compared to placebo pills added to glatiramer acetate. And the results were pretty positive, especially in the first year when there was an almost 50% reduction in relapse rate in the group that received estriol plus glatiramer. And, you know, that’s, of course, based upon longstanding data that we’ve known, that women with MS who have relapsing disease have a much decreased relapse rate during pregnancy. And then Dr. Voskuhl had done a good bit of work with estriol, in particular, which is a fairly safe pregnancy estrogen hormone compared to some of the others, but it’s not available in the United States right now.    MSDF  You mentioned that there were some disappoints.   Dr. Cross  At least for me, and probably for a lot of MS patients, the biggest disappointment was the failure of the FDA to approve a drug called alemtuzumab, which is a humanized monoclonal antibody against an antigen that’s on pretty much all the mononuclear cells of the immune system. And the US FDA failed to approve it, although, I believe, 32 countries and counting have approved it at this point, including Canada and Mexico and all of the countries of Western Europe, Australia, Brazil.   MSDF  Have there been any interesting developments on the remyelination front?   Dr. Cross  Yes, yes, yes. In fact, I hope to speak about that today. There are studies in early-phase trials right now of anti-LINGO-1, which is a humanized monoclonal antibody against a molecule called LINGO-1, which is found only in the central nervous system – at least that’s what the data says so far – and it’s expressed by oligodendroglial cells, or the cells that make central nervous system myelin. And, for whatever reason, it’s involved in inhibiting remyelination in the central nervous system. So the monoclonal antibody that inhibits it then enhances remyelination. And in mouse models it looked very good, and it also led to less injury to axons, or nerve fibers, so it had more than just a remyelinating effect. And it’s now in phase II studies in relapsing-remitting MS and optic neuritis patients. At least the relapsing-remitting MS study is fully enrolled, and so we’ll be looking forward to those results.   So another potential remyelinating agent is a little bit behind anti-LINGO-1. It’s called recombinant human IgM22, and it was developed from a natural IgM antibody that was discovered at Mayo Clinic that binds to a surface antigen on oligodendrocytes – the cells that make central nervous system myelin – and it enhances myelination in mouse models of demyelination, and, in fact, in some studies, just a single dose of that led to longstanding remyelination in the mouse model. So that’s in dose-finding studies in human beings at the present time, and hopefully will move forward from there.   Other exciting things, at least to me, are studies of stem cells that can be differentiated into different types of cells. And, at this point, you can actually take human skin cells or human fibroblasts and revert them back to stem cells; they’re called induced pluripotent stem cells. So you can actually take a person’s skin and do that, and then you can differentiate it forward into whatever cell type you want, really, these days; I mean, you can differentiate them into neurons. And in MS, we’re very interested in differentiating them into oligodendrocyte precursor cells – cells that form the cells that make central nervous system myelin.    And a study that I plan to talk about this afternoon took such cells and made them into human oligodendrocyte precursor cells and put them into the central nervous systems of mice who had a genetic mutation in myelin basic proteins, so they are essentially unmyelinated. And these mice die very soon after being born, much earlier than normal, and they put these human cells in. They had to immunosuppress the mice so that they’d accept the human cells. But these cells actually made myelin, and it was functional myelin at least from the standpoint of wrapping around fairly normal-looking nerve fibers, axons, from the mice, and forming compact, normal-appearing myelin. So that particular group, they’re from New York State and they’re affiliated with several other medical centers, and they plan to get this into humans pretty soon. Their first project, however, is going to involve fetal stem cells first, because that was easier to get approved and moved forward on, and so I believe they’re already funded to do a three-center – all in New York State – stem cell study injecting such cells into the central nervous system of people with secondary progressive MS.    MSDF  Now some patients aren’t waiting for the studies, I understand, but what is your point-of-view about that?   Dr. Cross  It depends on where they’re going and what they’re doing. I personally think there’s some shoddy research, some charlatans you might call them, out there who are taking the money and presenting false hopes to patients that I certainly disagree with. And I have one particular patient I know who went to another country and had stem cell therapy done in what she described as a very dirty environment. And luckily nothing bad happened to her from this experience, but nothing good happened either. I’m hoping that she’ll be able to get into some of these well-done, scientifically valid, protocol-driven studies that seem to have some promise.    MSDF  Any other interesting areas of MS research in the past year?   Dr. Cross  I think the unexpected finding that I plan to talk about is an association of salt – sodium in particular, the sodium component of sodium chloride – in the development of a particular type of pathogenic T-cell that at least is related to the mouse model of MS called experimental autoimmune encephalomyelitis. These are Th17 cells and they’ve been shown to, at least in some models, cause the EAE model for MS. And it was found that if you increase the salt intake of mice that had been induced to develop this model and compared them to mice who weren’t getting extra salt in their diet, that the mice who got extra salt got disease earlier; they had a more severe course, they didn’t recover as well, and they had histologically when you looked at their central nervous systems, more cells infiltrating and just more damaging. So that was kind of interesting and quite unexpected, I would say.    Two different groups of investigators sort of came up with that at the same time; I’m sure they were speaking to each other about it, that the studies came out right together. It certainly would be a modifiable environmental thing if it proves to be true, and perhaps even a little bit simple. And there is actually a scientific reason behind why this might occur. Well, there’s a response in the body by something called p38 MAP kinase in response to, like, many different stresses, but including among them osmotic stress which increased salt could cause. And that pathway that p38 MAP kinase is involved in eventually can lead to the induction of a particular kinase that is key to the development of Th17 cells. So it sort of all, you know, fits together.    There are certainly some things that don’t fit with that. I think that certain areas of the world, for example, have very high salt intake and yet have low MS rates, but it may be that there’s this environmental factor. There probably are many different environmental factors that’s going together with a genetic predisposition, and those together are probably leading, perhaps, to MS. In any event, this will have to be proven by other groups, but if the association is true, it would certainly be modifiable.     MSDF  So looking ahead into the next year of MS research, what are you particularly looking forward to seeing?   Dr. Cross  I’d like to see more data come out on some of the other oral agents; there are a couple that are in the pipeline that are being looked at that perhaps have other mechanisms of actions from what we have now. I’d like to see other studies funded for estriol so that perhaps it could come to the United States and be an adjunctive therapy probably for women with MS and probably pretty safe. I’m really hopeful – I’m not sure if it’ll be in the next year – that we’ll see some good data coming out from these scientifically valid stem cells projects to help people with progressive MS, and help people who have longstanding disability to recover some function; those are the people that really, really need help in the MS world right now.   MSDF  Well, Dr. Cross, thank you very much.   Dr. Cross  Thank you.   [transition music]   Thank you for listening to Episode Five of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.    Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.   [outro music]   

Join host Curt Peyton as he talks live with customers who bought vehicles from Dealerships. Sharing experiences both good and bad. Sales Managers and Sales Professionals should all tune in to hear this show. This will be a great training and information for sales staff.Listen as Curt talks to the Customers and gives ideas to your sales staff.Hear customers frustrations and positives alike.

Join host Curt Peyton as he talks live with customers who bought vehicles from Dealerships. Sharing experiences both good and bad. Sales Managers and Sales Professionals should all tune in to hear this show. This will be a great training and information for sales staff.Listen as Curt talks to the Customers and gives ideas to your sales staff.Hear customers frustrations and positives alike.