Podcasts about concordant

Welcome back to the Stronger Bones Lifestyle Podcast. Today Debi welcomes back spinal surgeon Nick Birch to further discuss DEXA scans, REMS scans and overall bone health.In 2018 Nick founded OsteoscanUK with the intention of offering high quality bone health assessments locally, rather than in a hospital setting, using the Echolight REMS system and has carried out over 2200 REMS scans. Listen today as he discusses typical fractures he sees and some of the reasons behind them, the issues with DEXA scans and the importance of bone density and toughness.Join Nick and Debi as they talk about bone mineral density, comparing your DEXA scan numbers and the correlation between your body's build and your bone density. Key  Takeaways:[2:07] Maddie Young[4:16] What does your DEXA scan number mean[4:51] Correlation between bone density and your build[5:46] Concordant results[7:28] The subtle layer[10:00] What the DEXA scan scans[12:48] The genetic component to osteoporosis[14:28] The commonest error for spinal DEXA scan[17:35] What are my numbers?[18:23] Issues with DEXA[19:58] Comparing DEXAs[22:17] Who determines the osteoporosis diagnosis criteria[24:30] What inspired the creation of the REMS scan[25:22] Bone mineral density[28:00] An X-Ray analogy[28:57] Orthopedic surgeon frustration[30:20] Spine queries[34:16] Typical fractures[35:11] AdductorsWhere to Find Guest:WebsiteDensitometry DiscordancePrevalence of Major and Minor Discordance between Hip and Spine T Scores Using REMSMemorable Quotes:"REMS is taking at least one step towards what an MRI is going to offer for muscular skeletal imaging, rems is taking in the densitometry space." [29:39] - Nick "Again it comes back to toughness, if the hip is tough because its good strong thick bone then It has to be significantly weakened before it can fractured." [32:19] – Nick"And that's the thing about yoga that's so fantastic for osteoporosis is we place our limbs, our joints, in a different range of motion that we would normally and then we weight bear in it." [38:11] - DebiTo learn more about me and to stay connected, click on the links below:Instagram: @debirobinsonwellnessWebsite: DebiRobinson.comHealthy Gut Healthy Bones Program

The York Rite and the Scottish Rite Compared Our English Brethren and the York Rite Royal Order of Scotland Allied Masonic Degrees --- Send in a voice message: https://podcasters.spotify.com/pod/show/sslodge357/message Support this podcast: https://podcasters.spotify.com/pod/show/sslodge357/support

Mark DMs this Golden Vault Adventure for a bunch of clueless detectives! Featuring: Mark as the DM Joseph as the Dragonborn Cleric "Keldric" ShortStack as the Fawn Druid "Revi" Bun as the Herengon Bard "Lapin" Dustin as the Kenku Warlock "Eshok" Enjoy! YouTube: https://youtube.com/josephblanchette Twitter:  https://twitter.com/Joseph_LFrog Patreon:  https://www.patreon.com/legendaryfrog

The hosts of The DM's Book Club proudly bring you a new series, The DM's Travel Bookclub: A Guide to The Planes!In each episode, we'll explore the Planes of Existence as outlined in the Great Wheel cosmology in the roleplaying game, Dungeons & Dragons!In this special episode, we go into the area at the center of all the Planes, The Outlands; Also known as the Plane of Concordant Opposition, is the true neutral centre of the multiversal planes. However, this only means that good, evil, chaos & order are constantly in flux as the plane seeks to exert balance in all. This leads to it being one of the most complicated and conflicted realms of Planescape. With its centre it is also the border to all the other planes through their gate towns, all of which bring an essence of their being to the outlands, a sort of taster course, if you will, for adventurers to explore before the main meal of any plane. With all this, The Outlands is deceptively simple & safe, and in fact a perfect introduction for any adventuring party to the true wonder and dangers of the multiverse.Audio originally from 'The Outlands - The DM's Travel Bookclub: A Guide to The Planes Episode 17' on the Dragon YouTube channel.Book discussed: Planescape Campaign Setting, published by Wizards of the Coast (1994).Consider using our affiliate link when using DM's Guild!#SupportyourFLGSCredits The DM's Book Club is hosted, recorded, edited, and produced by Fiona Howat (@WAIR_Podcast) and Hamilton (@TheDragonDM). The DM's Book Club Logo was designed by Sam Robins (@Bobhatstand).The theme music is 'The Story Unfolds' by Jingle Punks.Get in touch!Email: TheDMsBookClub@gmail.comTwitter: @TheDMsBookClubLinktr.ee: DMBC#DMsBookClub

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.21.550042v1?rss=1 Authors: Rutkowski, D. M., Vincenzetti, V., Vavylonis, D., Martin, S. G. Abstract: Local Cdc42 GTPase activation promotes polarized exocytosis, resulting in membrane flows that deplete low-mobility membrane-associated proteins from the growth region. To investigate the self-organizing properties of the Cdc42 secretion-polarization system under membrane flow, we developed a reaction-diffusion particle model. The model includes positive feedback activation of Cdc42, hydrolysis by GTPase-activating proteins (GAPs), and flow-induced displacement by exo/endocytosis. Simulations show how polarization relies on flow-induced depletion of low mobility GAPs. To probe the role of Cdc42 mobility in the fission yeast Schizosaccharomyces pombe, we changed its membrane binding properties by replacing its prenylation site with 1, 2 or 3 repeats of the Rit1 C terminal membrane binding domain (ritC), yielding alleles with progressively lower unbinding and diffusion rates. Concordant modelling predictions and experimental observations show that lower Cdc42 mobility results in lower Cdc42 activation level and wider patches. Indeed, while Cdc42-1ritC cells are viable and polarized, Cdc42-2ritC polarize poorly and Cdc42-3ritC is inviable. The model further predicts that GAP depletion increases Cdc42 activity at the expense of loss of polarization. Experiments confirm this prediction, as deletion of Cdc42 GAPs restores viability to Cdc42-3ritC cells. Our combined experimental and modelling studies demonstrate how membrane flows are an integral part of Cdc42-driven pattern formation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Elijah and John the Baptist, Chapter 18 of Eternal Lives  Read along here and find the links to the video programs here: https://www.tumblr.com/fundamentallymormon/714228949273755648/elijah-and-john-the-baptist-chapter-18-of-eternal Apostle Matthew “...Jesus began to say unto the multitudes concerning John...A prophet? yea, I say unto you, and more than a prophet. For this is he of whom it is written, Behold I send my messenger before my face, which shall prepare thy way before thee. Verily I say unto you, Among them that are born of women there hath not risen a greater than John the Baptist: notwithstanding he that is least in the kingdom of heaven is greater than he... For all the prophets and the law prophesied until John. And if ye will receive it, this is Elias, which was for to come.” (Matthew 11:7,9-11,13-14) The Concordant version translates it as: “And if you are willing to receive him, he is Elijah...” (Matthew 11, Concordant Literal NT version.) “Why then do our teachers say that Elijah must come first? He replied, Yes Elijah will come and set everything right. But I tell you that Elijah has already come, and they failed to recognize him, and worked their will upon him; and in the same way the Son of Man is to suffer at their hands. Then the disciples understood that He meant John the Baptist.” (Matthew 17:10-13 New English version. Also see Matthew 17:10-13 KJV.)

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.08.527219v1?rss=1 Authors: Revsine, C., Gonzalez-Castillo, J., Merriam, E., Bandettini, P. A., Ramirez, F. M. Abstract: Our ability to recognize faces regardless of viewpoint is a key property of the primate visual system. Traditional theories hold that facial viewpoint is represented by view-selective mechanisms at early visual processing stages and that representations become increasingly tolerant to viewpoint changes in higher-level visual areas. Newer theories, based on single-neuron monkey electrophysiological recordings, suggest an additional intermediate processing stage invariant to mirror-symmetric face views. Consistent with traditional theories, human studies combining neuroimaging and multivariate pattern analysis (MVPA) methods have provided evidence of view-selectivity in early visual cortex. However, contradictory results have been reported in higher-level visual areas concerning the existence in humans of mirror-symmetrically tuned representations. We believe these results reflect low-level stimulus confounds and data analysis choices. To probe for low-level confounds, we analyzed images from two popular face databases. Analyses of mean image luminance and contrast revealed biases across face views described by even polynomials--i.e., mirror-symmetric. To explain major trends across human neuroimaging studies of viewpoint selectivity, we constructed a network model that incorporates three biological constraints: cortical magnification, convergent feedforward projections, and interhemispheric connections. Given the identified low-level biases, we show that a gradual increase of interhemispheric connections across network layers is sufficient to replicate findings of mirror-symmetry in high-level processing stages, as well as view-tuning in early processing stages. Data analysis decisions--pattern dissimilarity measure and data recentering--accounted for the variable observation of mirror-symmetry in late processing stages. The model provides a unifying explanation of MVPA studies of viewpoint selectivity. We also show how common analysis choices can lead to erroneous conclusions. 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/2022.11.08.515720v1?rss=1 Authors: Barron, T., Yalcin, B., Mochizuki, A., Cantor, E., Shamardani, K., Tlais, D., Franson, A., Lyons, S., Mehta, V., Maleki Jahan, S., Taylor, K. R., Keough, M. B., Xu, H., Su, M., Quezada, M. A., Woo, P. J., Fisher, P. G., Campen, C. J., Partap, S., Koschmann, C., Monje, M. Abstract: Pediatric high-grade gliomas are the leading cause of brain cancer-related death in children. High-grade gliomas include clinically and molecularly distinct subtypes that stratify by anatomical location into diffuse midline gliomas (DMG) such as diffuse intrinsic pontine glioma (DIPG) and hemispheric high-grade gliomas. Neuronal activity drives high-grade glioma progression both through paracrine signaling(1,2) and direct neuron-to-glioma synapses(3-5). Glutamatergic, AMPA receptor-dependent synapses between neurons and malignant glioma cells have been demonstrated in both pediatric(3) and adult high-grade gliomas(4), but neuron-to-glioma synapses mediated by other neurotransmitters remain largely unexplored. Using whole-cell patch clamp electrophysiology, in vivo optogenetics and patient-derived glioma xenograft models, we have now identified functional, tumor-promoting GABAergic neuron-to-glioma synapses mediated by GABAA receptors in DMGs. GABAergic input has a depolarizing effect on DMG cells due to NKCC1 expression and consequently elevated intracellular chloride concentration in DMG tumor cells. As membrane depolarization increases glioma proliferation(3), we find that the activity of GABAergic interneurons promotes DMG proliferation in vivo. Increasing GABA signaling with the benzodiazepine lorazepam, a positive allosteric modulator of GABAA receptors commonly administered to children with DMG for nausea or anxiety, increases GABAA receptor conductance and increases glioma proliferation in orthotopic xenograft models of DMG. Conversely, levetiracetam, an anti-epileptic drug that attenuates GABAergic neuron-to-glioma synaptic currents, reduces glioma proliferation in patient-derived DMG xenografts and extends survival of mice bearing DMG xenografts. Concordant with gene expression patterns of GABAA receptor subunit genes across subtypes of glioma, depolarizing GABAergic currents were not found in hemispheric high-grade gliomas. Accordingly, neither lorazepam nor levetiracetam influenced the growth rate of hemispheric high-grade glioma patient-derived xenograft models. Retrospective real-world clinical data are consistent with these conclusions and should be replicated in future prospective clinical studies. Taken together, these findings uncover GABAergic synaptic communication between GABAergic interneurons and diffuse midline glioma cells, underscoring a tumor subtype-specific mechanism of brain cancer neurophysiology with important potential implications for commonly used drugs in this disease context. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Do a Gritty, Flourishing Hero Good!   In our last +1, we talked about how I read a book.   More specifically, we focused on how I choose the books I read—which, I believe, is ALWAYS the most important first step in how to read a book.   In short, I said that I follow Joseph Campbell's wisdom to “read the right books by the right people.”   Campbell tells us: “When you find an author who really grabs you, read everything he has done. Don't say, ‘Oh, I want to know what So-and-so did'—and don't bother at all with the best-seller list. Just read what this one author has to give you. And then you can go read what he had read. And the world opens up in a way that is consistent with a certain point of view. But when you go from one author to another, you may be able to tell us the date when each wrote such and such a poem—but he hasn't said anything to you.”   Scientists would agree with this approach of trusting yourself and doing what really grabs you—with books and with other things in life.    In fact, Tal Ben-Shahar connects the academic research on what's called “self-concordant goals” to Joseph Campbell to make the point.   Here's how Tal puts it in his great book Happier: “As research on self-concordant goals illustrates, Campbell's belief is much more than a superstition. When we follow our bliss, we not only enjoy the journey, we are also more successful.”   In the book, Tal walks us through the importance of goals in general and the importance of what psychologists call “self-concordant” goals in particular.   “Self-concordant goals” are “the goals we pursue out of deep personal conviction and/or a strong interest.”   As it turns out, Angela Duckworth echoes this wisdom in HER great book, Grit.   We talk about the four practices to build grit in this +1 on The Science of Grit.   Here they are: Interest + Practice + Purpose + Hope.   The first, MOST IMPORTANT aspect of Grit?   Interest.   If we want to cultivate the sustainable passion required to cultivate grit (whether that's for important, long-term goals or simply getting through a book!), we need to be intrinsically drawn to what we do. It needs to be, as we just discussed, SELF-CONCORDANT.   All of which leads us to Today's +1.   How are your goals?   Are they clear? Are they self-concordant?    Do they fire you up?   Let's not read books or do other such things because we think we “should.”    As Tony Robbins would say: Let's not “should on ourselves.” And, As Rory Vaden puts it, let's not be “should-heads.”     Let's do the things that grab us.   With gritty joy.   TODAY.

Sometimes turtles can get caught up in nets and other sticky situations. Rehabilitation can help out these injured or exhausted turtles… but how do they fare when they are released back into the big wide ocean? Become a Patreon: https://www.patreon.com/herphighlights Full reference list available here: http://www.herphighlights.podbean.com Main Paper References: Robinson DP, Hyland K, Beukes G, Vettan A, Mabadikate A, Jabado RW, Rohner CA, Pierce SJ, Baverstock W. 2021. Satellite tracking of rehabilitated sea turtles suggests a high rate of short-term survival following release. PLOS ONE 16:e0246241. DOI: 10.1371/journal.pone.0246241. Other Mentioned Papers/Studies: BM Marshall, CT Strine, CS Fukushima, P Cardoso, MC Orr, AC Hughes. 2022. Searching the web builds fuller picture of arachnid trade. Communication Biology. DOI: 10.1038/s42003-022-03374-0 Szymura, J. M., Spolsky, C., & Uzzoll, T. (1985). Concordant change in mitochondrial and nuclear genes in a hybrid zone between two frog species (genus Bombina). Experientia, 41(11), 1469-1470. Other Links/Mentions: Bombina call from Explore Croatia - https://www.youtube.com/watch?v=wvMYU8drjg0 Music: Intro/outro – Treehouse by Ed Nelson Species Bi-week theme – Mike Mooney Other Music – The Passion HiFi, www.thepassionhifi.com

Interview with Kenneth L. Kehl, MD, MPH, author of Rates of Guideline-Concordant Surgery and Adjuvant Chemotherapy Among Patients With Early-Stage Lung Cancer in the US ALCHEMIST Study (Alliance A151216). Hosted by Jack West, MD.

Interview with Kenneth L. Kehl, MD, MPH, author of Rates of Guideline-Concordant Surgery and Adjuvant Chemotherapy Among Patients With Early-Stage Lung Cancer in the US ALCHEMIST Study (Alliance A151216). Hosted by Jack West, MD.

Go online to PeerView.com/NWD860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in oncology discuss the diagnosis of cancer-associated VTE, review the latest data and guidelines on currently available treatment options, and suggest strategies for including interprofessional collaboration in routine clinical practice. Upon completion of this accredited CE activity, participants should be better able to: Assess the global disease burden, etiopathogenesis, risk factors, and stratification scores for cancer-associated VTE using established diagnostic tools, Review safety & efficacy evidence, clinical trial data, and practice guidelines for currently available treatment options for managing cancer-associated VTE, Employ guideline-concordant, evidence-based care and shared decision-making strategies including multidisciplinary and interprofessional collaboration for prevention and treatment of cancer-associated VTE in routine clinical practice.

Go online to PeerView.com/NWD860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in oncology discuss the diagnosis of cancer-associated VTE, review the latest data and guidelines on currently available treatment options, and suggest strategies for including interprofessional collaboration in routine clinical practice. Upon completion of this accredited CE activity, participants should be better able to: Assess the global disease burden, etiopathogenesis, risk factors, and stratification scores for cancer-associated VTE using established diagnostic tools, Review safety & efficacy evidence, clinical trial data, and practice guidelines for currently available treatment options for managing cancer-associated VTE, Employ guideline-concordant, evidence-based care and shared decision-making strategies including multidisciplinary and interprofessional collaboration for prevention and treatment of cancer-associated VTE in routine clinical practice.

Go online to PeerView.com/NWD860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in oncology discuss the diagnosis of cancer-associated VTE, review the latest data and guidelines on currently available treatment options, and suggest strategies for including interprofessional collaboration in routine clinical practice. Upon completion of this accredited CE activity, participants should be better able to: Assess the global disease burden, etiopathogenesis, risk factors, and stratification scores for cancer-associated VTE using established diagnostic tools, Review safety & efficacy evidence, clinical trial data, and practice guidelines for currently available treatment options for managing cancer-associated VTE, Employ guideline-concordant, evidence-based care and shared decision-making strategies including multidisciplinary and interprofessional collaboration for prevention and treatment of cancer-associated VTE in routine clinical practice.

Go online to PeerView.com/NWD860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in oncology discuss the diagnosis of cancer-associated VTE, review the latest data and guidelines on currently available treatment options, and suggest strategies for including interprofessional collaboration in routine clinical practice. Upon completion of this accredited CE activity, participants should be better able to: Assess the global disease burden, etiopathogenesis, risk factors, and stratification scores for cancer-associated VTE using established diagnostic tools, Review safety & efficacy evidence, clinical trial data, and practice guidelines for currently available treatment options for managing cancer-associated VTE, Employ guideline-concordant, evidence-based care and shared decision-making strategies including multidisciplinary and interprofessional collaboration for prevention and treatment of cancer-associated VTE in routine clinical practice.

Go online to PeerView.com/NWD860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in oncology discuss the diagnosis of cancer-associated VTE, review the latest data and guidelines on currently available treatment options, and suggest strategies for including interprofessional collaboration in routine clinical practice. Upon completion of this accredited CE activity, participants should be better able to: Assess the global disease burden, etiopathogenesis, risk factors, and stratification scores for cancer-associated VTE using established diagnostic tools, Review safety & efficacy evidence, clinical trial data, and practice guidelines for currently available treatment options for managing cancer-associated VTE, Employ guideline-concordant, evidence-based care and shared decision-making strategies including multidisciplinary and interprofessional collaboration for prevention and treatment of cancer-associated VTE in routine clinical practice.

Go online to PeerView.com/NWD860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in oncology discuss the diagnosis of cancer-associated VTE, review the latest data and guidelines on currently available treatment options, and suggest strategies for including interprofessional collaboration in routine clinical practice. Upon completion of this accredited CE activity, participants should be better able to: Assess the global disease burden, etiopathogenesis, risk factors, and stratification scores for cancer-associated VTE using established diagnostic tools, Review safety & efficacy evidence, clinical trial data, and practice guidelines for currently available treatment options for managing cancer-associated VTE, Employ guideline-concordant, evidence-based care and shared decision-making strategies including multidisciplinary and interprofessional collaboration for prevention and treatment of cancer-associated VTE in routine clinical practice.

Go online to PeerView.com/NWD860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in oncology discuss the diagnosis of cancer-associated VTE, review the latest data and guidelines on currently available treatment options, and suggest strategies for including interprofessional collaboration in routine clinical practice. Upon completion of this accredited CE activity, participants should be better able to: Assess the global disease burden, etiopathogenesis, risk factors, and stratification scores for cancer-associated VTE using established diagnostic tools, Review safety & efficacy evidence, clinical trial data, and practice guidelines for currently available treatment options for managing cancer-associated VTE, Employ guideline-concordant, evidence-based care and shared decision-making strategies including multidisciplinary and interprofessional collaboration for prevention and treatment of cancer-associated VTE in routine clinical practice.

Go online to PeerView.com/NWD860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in oncology discuss the diagnosis of cancer-associated VTE, review the latest data and guidelines on currently available treatment options, and suggest strategies for including interprofessional collaboration in routine clinical practice. Upon completion of this accredited CE activity, participants should be better able to: Assess the global disease burden, etiopathogenesis, risk factors, and stratification scores for cancer-associated VTE using established diagnostic tools, Review safety & efficacy evidence, clinical trial data, and practice guidelines for currently available treatment options for managing cancer-associated VTE, Employ guideline-concordant, evidence-based care and shared decision-making strategies including multidisciplinary and interprofessional collaboration for prevention and treatment of cancer-associated VTE in routine clinical practice.

Go online to PeerView.com/NWD860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in oncology discuss the diagnosis of cancer-associated VTE, review the latest data and guidelines on currently available treatment options, and suggest strategies for including interprofessional collaboration in routine clinical practice. Upon completion of this accredited CE activity, participants should be better able to: Assess the global disease burden, etiopathogenesis, risk factors, and stratification scores for cancer-associated VTE using established diagnostic tools, Review safety & efficacy evidence, clinical trial data, and practice guidelines for currently available treatment options for managing cancer-associated VTE, Employ guideline-concordant, evidence-based care and shared decision-making strategies including multidisciplinary and interprofessional collaboration for prevention and treatment of cancer-associated VTE in routine clinical practice.

Go online to PeerView.com/NWD860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in oncology discuss the diagnosis of cancer-associated VTE, review the latest data and guidelines on currently available treatment options, and suggest strategies for including interprofessional collaboration in routine clinical practice. Upon completion of this accredited CE activity, participants should be better able to: Assess the global disease burden, etiopathogenesis, risk factors, and stratification scores for cancer-associated VTE using established diagnostic tools, Review safety & efficacy evidence, clinical trial data, and practice guidelines for currently available treatment options for managing cancer-associated VTE, Employ guideline-concordant, evidence-based care and shared decision-making strategies including multidisciplinary and interprofessional collaboration for prevention and treatment of cancer-associated VTE in routine clinical practice.

Annette Bieniusa, Co-founder of Concordant, Joins Adi Polak to discuss how Concordant leverage CRDTs for enabling multiple Edges/IoT devices to share consistent data more efficiently without relying on network connections. How to use it and what is the exciting open-source solution, AntidotDB that they developed, helped the community, Follow @CH9 http://www.twitter.com/ch9 Follow @TechExceptions https://twitter.com/TechExceptions Follow @Anne_biene https://twitter.com/anne_biene Follow @AdiPolak https://twitter.com/AdiPolak

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What does it mean to be CONCORDANT? Dr Gibson discusses if.

Do you know your strengths, talents and weaknesses or are you letting others tell you who you are?

Lets Talk About Some Concordant Bodies of Masonry!

The turn of the 12th century saw a revolution in the Catholic Church and a struggle for dominance between Pope and Emperor. The Investiture dispute would produce the Concordant at Worms that would have a profound impact on the future of the Church within the Empire.Website: conflictspodcast.comContact: conflictspodcast@gmail.comGiving a ratings in Itunes really helps the show get noticed, or better yet just tell someone about it.SHOWNOTES:Pope Gregory VIIEmperor Henry 4 at CanossaWorms Cathedral

Dr Carolyn Lam:                Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr. Carolyn Lam, associate editor from the National Heart Centre and Duke National University of Singapore. Our featured paper this week is an in-depth paper on the cardiovascular and metabolic heterogeneity of obesity, and we will have a discussion with the authors on the clinical challenges, implications for management, and much more coming right up after these summaries.                                                 How does MRI quantification compare with standard Doppler echo approach to identify organic mitral regurgitation and predict adverse outcomes? Well, our first paper this week addresses this question, led by first and corresponding author, Dr. Penicka from the Cardiovascular Center OLV Clinic in Belgium. These authors studied 258 asymptomatic patients with preserved left ventricular ejection fraction and chronic moderate and severe organic mitral regurgitation by echo. All patients underwent MRI to quantify regurgitant volume of this organic mitral regurgitation by subtracting aortic flow volume from the total left ventricular stroke volume. Severe organic mitral regurgitation was defined as a regurgitant volume of greater or equal to 60 milliliters.                                                 The authors found that mean echo-derived regurgitant volume was an average 17 milliliters larger than the MRI-derived regurgitant volume. Concordant grading of organic mitral regurgitation severity with both techniques was observed in 76% of individuals. In the remaining 24% of individuals with discordant findings between the two techniques, this was mainly observed in patients with late systolic, eccentric, or multiple jets.                                                 The MRI-derived regurgitant volume showed the highest discriminative power among all the imaging parameters to predict all cause mortality or its combination with development of indication for mitral valve surgery. Thus, this study demonstrates that MRI-derived assessments of organic mitral regurgitation are clinically accurate to identify asymptomatic patients with severe organic mitral regurgitation and at first outcomes. This may be particularly so when the mitral regurgitation is late systolic, eccentric, or multiple in jets where misclassification may occur with echo-derived approach.                                                 The next study is the first large population-based study to analyze the association between low-dose ionizing radiation from cardiac procedures and incident cancer in adults with congenital heart disease. First author Dr. Cohen, corresponding author Dr. Marelli from McGill University, studied the population from the Quebec Congenital Heart Disease Database and performed a nested case control study comparing cancer cases with controls matched on sex, congenital heart disease severity, birth year, and age. They found that the cumulative incidence of cancer in adults with congenital heart disease between the ages of 18 and 64 years was 15%. The cumulative low-dose ionizing radiation exposure from cardiac procedures was independently associated with incident cancer after adjusting for age, sex, year of birth, congenital heart disease severity and comorbidities.                                                 Results were similar using either the number of procedures or estimates of the effective doses with a possible dose-related response relationship between the low-dose ionizing radiation exposure level and cancer risk. Thus, increasing exposure to low-dose ionizing radiation from cardiac imaging in adults with congenital heart disease raises concerns about life-long risk of malignancy.  Confirmation of these findings by prospective studies is needed to reinforce policy recommendations for radiation surveillance in patients with congenital heart disease.                                                 The next study characterizes the long-term dynamics of potassium in heart failure and its associated risk of mortality. First and corresponding author, Dr. Nunez from Hospital Clinic University of Valencia in Spain, evaluated the prognostic implications of long-term longitudinal monitoring and dynamics of serum potassium in a prospective and consecutive cohort of patients following a hospitalization for acute heart failure. In these patients, serum potassium was measured at every physician-patient encounter, including hospital admissions and ambulatory settings.                                                 The authors found that on a continuous scale, the followup trajectory of serum potassium levels independently predicted mortality through a U-shaped association with higher risk at both ends of the distribution, and the same was true using potassium categories. Furthermore, dynamic changes in potassium were independently associated with substantial differences in mortality risk. Persistence of normal potassium levels was linked to a higher risk of death compared to patients who maintained or returned to normal values. Conversely, potassium normalization was independently associated with a lower mortality risk.                                                 These findings support the need for close monitoring of serum potassium after an episode of acute decompensated heart failure and suggest that maintaining serum potassium levels within normal range may be considered a therapeutic target.                                                 The next study gives us an example of how functional metabolomics can translate into metabolomics derived biomarkers of disease mechanisms. Co-first authors, Dr. Zhang, Wei, and Li; co-corresponding authors, Dr. Zhu, Li, and Qi from Nanjing, China, studied a cohort of 2324 patients who underwent coronary angiography from four independent centers. They used a combination of ultra-performance liquid chromatography and quadrupole time-of-flight mass spectrometry in the negative ion mode for untargeted analysis of metabolites in the plasma.                                                 The authors identified a total of 36 differential metabolites related to coronary artery disease progression. In particular, N-Acetyl-neuraminic acid, a metabolic marker highly elevated during coronary artery disease progression, acted as a signaling molecule to trigger RhoA and Cdc42 dependent myocardial injury via activation of the Rho-RACK signaling pathway.                                                 Silencing neuraminidase-1, which is the enzyme that regulates N-Acetyl-neuraminic acid generation, ameliorated myocardial injury in vitro and in vivo. Pharmacologic inhibition of neuraminidase by anti-influenza drugs protected cardiomyocytes and the heart from myocardial injury.                                                 Thus, in summary, functional metabolomics identified a key role for N-Acetyl-neuraminic acid in acute myocardial injury, and targeting neuraminidase-1 may represent an unrecognized therapeutic intervention for coronary artery disease.                                                 The final study addresses the controversy of whether high density lipoprotein, or HDL cholesterol, plays a causal role in cardioprotection. First and corresponding author, Dr. Jensen from Harvard T.H. Chan School of Public Health and colleagues, hypothesized that subspecies of HDL defined by apolipoprotein C3, a key regulator of lipoprotein metabolism, may contribute new information to prediction of cardiovascular risk.                                                 They used immunoaffinity chromatography to measure the apo A1 concentrations of HDL that contained or lacked apolipoprotein C3, or apo C3, in two prospective studies of adults free of coronary heart disease, the Multiethnic Study of Atherosclerosis and the Danish Diet, Cancer and Health Study. They then conducted a meta-analysis that combined these results with the previously published findings from two cohort studies that used similar laboratory methodology to measure lipoproteins.                                                 The authors identified a subspecies of HDL that contained apo C3. HDL that contained apo C3 comprised 5 to 6% of apo A1 or 10 to 15% of HDL cholesterol. In the four prospective studies, HDL containing apo C3 was associated with a greater risk of coronary heart disease, whereas HDL that lacked apo C3 was inversely associated with risk more strongly than the total HDL.                                                 These findings support the hypothesis that apo C3 may mark a subfraction of HDL cholesterol that is associated with higher risk of coronary heart disease. These findings therefore provide novel insights for cardiovascular risk that extend beyond traditional plasma HDL cholesterol concentrations. And that brings us to a close for the summaries. Now for our feature discussion.                                                 For today's featured discussion, we are talking about obesity, a universal issue, or is it? And when we talk about obesity, are we talking about one thing or many things? Today's in-depth review is just such a great paper. I highly recommend it to everyone. So pleased to be discussing it with Dr. Ian Neeland today from UT Southwestern Medical Center.                                                 Ian, first of all, congratulations. A beautiful paper. I learned so much reading it, and I've got so many questions. You started off pointing out that we talk about obesity. We've always defined it by body mass index, but that may not be the ideal biomarker. I love the way you said that. So, tell us a bit more about the reason for this review. Dr Ian Neeland:                Obesity, like you said, we define it by body mass index, but body mass index is such a crude marker. It's great to use for the clinic. It's easy to implement, but it doesn't really tell us a lot of information about the person. And so you can just look at a third of the population in the US right now is thought to be obese. And if you take a third of the population, clearly not everyone has diabetes and heart disease.                                                 So, obesity in and of itself, defined by the body mass index really is very heterogeneous, and it's not possible to use that alone to tell an individual if they're really at risk for disease. And so this review is really about getting deeper under the skin, no pun intended, to really get a sense of what it means to be obese, how the body fat plays a role in disease, and really getting to the different aspects of obesity and how we can understand it a little bit better. Dr Carolyn Lam:                Yeah. You know, Ian, you had me at hello if I could say when I read your paper because I'm from Asia, and here, the World Health Organization actually even suggests that we use lower body mass index cutoffs to define obesity, simply because there's a different relationship as well with cardiometabolic disease. So, so true, but before we get there, to maybe ethnic differences, I want to ask you something. I heard the term, obesity paradox, thrown around a lot, and sometimes I think we don't really know what we're talking about when we say obesity paradox.                                                 I love the way, in your paper, you broke it down into four types. There are four paradoxes. Do you want to just clarify this for the audience? I think it's important. Dr Ian Neeland:                So, the obesity paradox, what we mean by that is we think that obesity causes disease and gives someone an increased risk for disease and mortality and death, but the obesity paradox means that some people who are obese we see actually have better outcomes than those who are not obese. And how to describe that paradox and why that exists is really the subject of lots and lots of research and discussion.                                                 And so when we talk about the obesity paradox, really it's important to understand that most of the time we're talking about people who already have established disease. Let's say, for example, heart disease. So people with heart disease who are obese tend to have better outcomes than those who are not, and there are a few ways to understand that.                                                 So people who have obesity with established disease who may have better outcomes; that's the classic obesity paradox. Then there's a paradox really about fitness and being fat and fit, and that concept that you can be fat, but if you're fit, if you're able to do exercise and you have good cardiorespiratory fitness, that you actually may be protected from disease as well. And then there's also the obesity paradox of basically the pre-obesity paradox, so that overweight, right, where you haven't yet met the threshold for obesity can also be protective in people who don't have disease. And so being a little bit plump may be protective for different diseases down the road. And then the final one is that the metabolically health obesity. When we say that, it means that the person who is obese by body mass index but doesn't really have any hypertension or diabetes or lipid abnormalities. So, that's the metabolically healthy obese person.                                                 Those are the four types of individuals we see who may be obese but actually have better outcomes long term, and the question is why that exists. So there's a lot of thinking about it. Maybe it has to do with the fact that being normal weight nowadays, often we have older folks that are normal weight. Well, they tend to be more deconditioned. They may be frail. They may have undiagnosed disease like cancer. And that might be why those people are the worst. And there are the naysayers out there who think that it's all just about what we call confounding, so things we can't account for when we look at that. People who smoke tend to be lower weight, and obviously they have worse outcomes, and then also people who are older.  So it's kind of a conundrum, this obesity paradox, but there's lots and lots of data out there coming out all the time that we keep seeing it again and again and again.                                                 One of the areas in the paper that I wanted to address was this concept of obesity heterogeneity in the obesity paradox, meaning to say is it potentially where the body fat is that may be playing a role in which obese person gets disease, and which obese person may be protected from disease. So it could be that it's not how much fat you have but where that fat is that is really telling about what someone's risk is, and that might help to describe the obesity paradox and get us a little bit more understanding. Dr Carolyn Lam:                Yeah, now, I thought that bit was just so key and important. Not how much fat, not weight per se, but where that fat is. Do you want to elaborate on that a bit? Dr Ian Neeland:                Sure. For, I don't know, 50, 60 years we've had this concept of the apple and the pear. Right? Fat in the belly being the apple shape and fat in the pear being fat in the hips and buttocks and that being two different body types of body fat. So we have a lot of technology nowadays, and we can actually directly image body fat and where it is in the body. So we can do MRI, we can do CT, and we can actually see where the body fat is distributed and how much body fat in one area may be related to disease compared with another area.                                                 So we've gone away from the apple and pear and really getting down to what we call body fat depots or adipose tissue depots where we deposit fat. And the area that we deposit fat that has the most risk for cardiometabolic diseases is this visceral adipose tissue or VAT.  VAT is fat that's around the intra-abdominal organs, also near the kidneys, and you can't actually tell how much visceral fat someone has just by BMI or waist circumference or just looking at them. You really have to do this dedicated imaging to find out. And the reason for that is that in the belly there's two types of fat. There's the visceral fat, and there's the subcutaneous, which is the fat under the skin. Both those fat areas make up the belly fat, but they're very different. And part of the review is really going into depth about why these are different and how they're different.                                                 They have completely different metabolic profiles, so if you would take blood, lipids, inflammatory markers, they would look completely different even in a single individual. And then if you look at the genetics of where the fat is, they're different. If you look at what these fat areas secrete, they're completely different. So it's really important to know where the fat is, and that's why I think this concept of sick fat versus healthy fat comes into play.                                                 So, sick fat is fat that's usually in this visceral fat depot, and that is really the three central tenets we talk about are visceral fat or ectopic fat. Ectopic means fat where it doesn't belong. Then inflammation and cytokines, so secretion of abnormal factors in the blood from this fat, and then insulin resistance. So those are the three kind of tenets of this sick fat.  So that's why we think that the sick fat plays a role in disease, and then there's a concept of less sick fat or healthy fat, which is maybe a sink. It actually buffers some of these cytokines and inflammation from causing disease in the body. Dr Carolyn Lam:                Yeah. I found that concept so fascinating, and just to bring it back to the obesity paradox. So, some larger people may enjoy better outcomes because they actually have a predisposition to put the fat subcutaneously perhaps, rather than viscerally. Would that be correct? You worded it so eloquently in your paper. There are some ethnicities or some genetic predispositions that could make one lose that inability to put it peripherally, and therefore it all goes viscerally, is what I got from it. And that's the stuff that puts people at risk. Dr Ian Neeland:                Yeah. We find that fat in the lower body, the hips and the buttocks, is actually in epidemiology, protective against heart disease, protective against cancer. And the problem is we don't know why some people put fat in the belly and some people put it in the hips and buttocks. There's very interesting twin-twin studies that show if someone has a predisposition for obesity, so twins may be both obese, but there is some difference in where they actually put the fat. So I think genetics certainly plays a role, but environment also plays a role. And environments, things like appropriate nutrition and physical activity can really alter genetics and help someone to put fat where it should be and prevent disease.                                                 So this obesity paradox, this concept of putting fat where it should be, is really the next frontier for this type of research. How can we modulate it? How can we fix it? Dr Carolyn Lam:                Exactly, and I love the way you ended your review when you said, "Therefore, maybe in all our complaints and so on, saying that we want weight loss, we should actually be focusing on waist loss. You could redistribute the fat to healthy areas, not change your weight, and still become healthier."  That was the concept, right? Dr Ian Neeland:                That's right. Yeah. It really is amazing, and it's been shown again and again that people can stay the same weight, but their body fat really is very plastic. It can change, and it's modifiable. And that really makes a difference with health outcomes. So whether we can do that with lifestyle changes, so there's some data to support that. There's also some data to support pharmacology, so medications may be able to move fat from one area to another. And then certainly surgery, which is now getting a lot of popularity for people who are really high risk for cardiometabolic disease. Bariatric surgery has been shown to decrease visceral fat significantly, and that may be one of the reasons why it works so well. Dr Carolyn Lam:                Exactly, Ian. Fascinating, fascinating. I tell you what. Could I just ask you to give us some take-home messages? Dr Ian Neeland:                Sure. So one take-home message I think is that we can move beyond the BMI, beyond the body mass index. Obesity is no longer just a number. It's really about the entire individual, biologic systems, what's going on, and there's just remarkable heterogeneity in the structure of obesity, where body fat is, the activity of body fat, the physiology of it, and also how it relates to diseases, either causing disease and potentially being protective for harmful outcomes.                                                 I think it's also a key message to understand that there's sick fat and there is healthy fat and they're very different. And we can get to the bottom of those using specialized tools like imaging and special testing, but they're really very different, and not all body fat is created equal.                                                 And then lastly, I think it's important to consider, like you mentioned earlier, that really public health and lifestyle going forward is going to be so important, and focusing on those areas that will have the biggest impact for people such as trying to promote waist loss, like you said, as opposed to weight loss. Really focusing and using our knowledge of body fat and obesity and how it's so different across individuals and populations, that it's really important to use that knowledge for our future goals and to have that mind when we recommend weight-modifying therapies for our patients.                                                 It's really going to be a new frontier in weight. We're really moving beyond this concept of just check your weight and your height, and we can tell you what your risk is. No, it's really much more complex and complicated and much more interesting than that. Dr Carolyn Lam:                Oh, Ian, that's just so wonderful. I cannot help this last question. Who knows whether we'll put it in, but I just have to ask you. So how do you monitor your own status or your patients' status? Do you really get them DEXAs, all of them? Or PETs, FDGs? Or do you take your own weight? Dr Ian Neeland:                Yeah. I do. One thing I have noticed, I actually started an exercise and diet program for myself to improve my health about a year and a half ago. I took the research, and I said, "Okay, I'm really going to use this and apply this to my life." So, what's interesting is what I found and actually what other colleagues of mine in research are finding is that you can actually melt away visceral fat just with exercise alone, even if you don't actually go on a diet. And they've done studies like this where they do DEXA scans, and they give people high-intensity interval training. They don't give them a special diet. They just say maintain your current diet, and the visceral fat goes away.                                                 It's really remarkable how lifestyle can be so important and make such a change. And you can see people who have diabetes who can cure their diabetes with a lifestyle program by really decreasing the visceral fat. Even if their weight doesn't change or only changes by a small amount, but their weight may change by, I don't know, five, 10 pounds, but their visceral fat may go away by 50%. And that really makes the difference.                                                 It's obviously hard to monitor. We don't really have these tools clinically every day. Not everyone can do a DEXA and has the software to measure the visceral fat. Certainly could be coming in the future, but right now we should use the tools we do have and use the biomarkers we have and the clinical use, the waist circumference, triglycerides. These things are all surrogates for visceral fat but can be very useful to monitor for change. And it's not just about the scale. It's really about more than that with a person's metabolic status. Dr Carolyn Lam:                That is so helpful. Thank you so much, and I'm so glad you said that it was exercise, and you don't jump into a ice pool or something to try and convert the fat to brown fat or something. That's really, really encouraging to me. Thank you, Ian. This was so enjoyable. I'm sure all our listeners are thanking you as well.                                                 Listeners, you've been listening to Circulation on the Run. Please tune in again next week.  

There are a lot great homeopaths who have contributed greatly to our Materia Medica in a variety of ways, but when I realized that I wanted to start bringing more MM into the podcast- I thought about calling the person who wrote the book I reach for the most- Frans Vermeulen, the creator and author of Prisma….   Frans graciously agreed to talk with me, shortly after he and his wife Dr. Linda Johnston, moved to Texas.   Now, before I make some short remarks about our conversation, I want to make sure we’re all on the same page about who Frans Vermeulen is, and what he has contributed to our Materia Medica. I’ll save the biographical details for him, as he shares them in our conversation.   Publication wise, he has published   Prisma- as I mentioned- and the The Concordant Reference, first and expanded Second Edition   I’d like to share a review by Will Taylor, commenting on these two references:   Franz Vermeulen's Prisma is - first of all - a beautiful book. Care in creation is what we've all come to expect from a work of Vermeulen's, and this offering merely brings that expectation to a new level. While the author's Concordant Materia Medica has become the gold-standard of a luggable reference to our medicinary - fodder for the 'left brain' of our art - Prisma strikes off in a new direction, as a resource for the right-brained appreciation of our materia medica. It is often far too easy for us to regard our remedies as little white pellets with unpronounceable names and incomprehensible lists of symptoms. Vermeulen counters this loss with detailed descriptions of the substance in the natural world, folding in generous volumes of insight from anthroposophy, folklore, mythology, toxicology and eclectic use. While the Concordant is the hands-down winner for succinct comprehensiveness in describing the symptomatology of our remedies, Prisma turns to the task of bringing the most essential of these symptoms to life. In the Main Symptoms sections, carefully-selected narratives from the provings, cases or classical teachers expand the meaning of individual symptoms. One can begin to imagine that Ernest Farrington, Constantine Hering or Margaret Tyler were reading over your shoulder and expanding on each point. Vermeulen's Concordant is one of the few books of which I own 2 copies -one at the office, one at home so as never to be without it. Prisma, I am certain, will join that honor. Will Taylor, MD   The Synoptic Reference 1 published in 2012 covers 500 remedies including polycrest and rare, new and small remedies. Synoptic Reference 2, published in 2015 240 Plants 172 Animals 88 Minerals 49 Organic compounds, chemicals and drugs 30 Nosodes, sarcodes and biochemicals 16 Fungi 11 Imponderables   208 Traditional and 398 New Remedies   Materia Medica based on 732 Provings from 29 countries   Monera Kingdom- Bacteria and Viruses- Spectrum MM Vol. 1 History of bacteria, viruses & diseases · classification & relationships · Scientific data · Provings old, new & redone   Kingdom Fungi- Spectrum MM Vol. 2 write up: Vermeulen’s library of books about fungi expanded from one single book to 80 during the course of his research. As the homeopathic materia medica of fungi is far from complete, most of the information is synthesized from other sources. In the past, the fungi have been grouped into the Kingdom Plantae, and sometimes as ‘excrescences of the earth!’ Now, however, particularly with the means of DNA testing, it is important that these organisms, and also the fungus-like moulds and yeasts, take their place in their own Kingdom. We must desist from making any comparison between the plants and fungi.   Fungi, the second book in the Spectrum Materia Medica series, continues the fastidious research and production standards that we expect of Emryss Publishers. As well as being a valuable materia medica, it also makes fascinating reading.   Synoptic MM 2, of 348 small remedies   and - not last, and certainly not least-   PLANTS_ a 4 Volume set, co-authored with Linda Johnston This major work details over 2000 individual plant remedies classified in 150 botanic families. Drawing on a wealth of information from provings, clinical observations, herbal uses, folk lore, mythology, botany, personal accounts, toxicology and other sources, the authors weave an in-depth, coherent picture of each botanic family and its members. Each family’s themes and organ system affinities are discussed, supported by the plants’ chemical composition, physiological and pharmacological effects. In addition, for each plant remedy, Plants, lists the number of rubrics in modern repertories, as well as phytochemical composition, official and common names, botanical descriptions and distribution.   Combining the clarity and detail for which Frans' work is renowned with Linda's years of clinical experience promises to deliver a definitive text on plant remedies. ————-   plus articles, DVDs, and probably much more *not to mention* what sounds like a couple of his biggest projects to date that are still in the works, that he shared with me before we wrapped up.   And you’ll hear that we tried to wrap up the call at least 3 times, but it was hard to stop talking! I felt like I had *barely* scratched the surface of my curiosity and questions for an individual who has been immersed and dedicated to our MM for over 25 years on top of 20 years of clinical practice.   —— You also might note that we actually don’t talk that much about materia medica, in terms of remedies. Frans asked me to send him a list of questions or topics in advance, which I was happy to do, though in truth we did not stick to them past the standard first question- how did you find homeopathy? When I talk with guests for the podcast, I want to connect and understand the person and follow whatever interesting thread happens to come up.   Through this conversation with Frans, we get that glimpse of how rich the history of our MM is, both from a specimen standpoint, but also in terms of its lineage and the tentacles that reach out and connect to other disciplines. These are the tidbits of our heritage which I find to be so fascinating, and often only to be found by connecting with those who have dedicated years of their lives to the study. Frans has offered us the fruits of his labor through his incredible library, and I’m so grateful that he joined me to share what often cannot be found in books.   But enough of my rambling…   before I switch to the interview   I also want to give you a quick heads up that You will also hear some distracting back-ground noise on my end about 30 min. into the call…   I conduct these interviews in a small separate office we have at our home, and it dawned on me during our call that I had left the oven on before I headed out to take the call.   Frans and I were on the phone, rather than Skype, and so I continued the call while I took the short walk back into my home to turn off the oven, which was making a jolly little song, and I think my dog was barking.   So- I apologize for that distraction- otherwise the call was uninterrupted and the quality was great.   Enjoy!

Al talks about trees, pillars, and the plane at the center of the D&D multiverse: the Concordant Opposition.

Hello and welcome to episode 36 of Nerd Monster Radio, with me your host Jose Aparicio of www.nerdmonster.net. Without trying to I realize when i was making my notes for this episode that the list of songs were more or less paired into twins; either by region or style, or record labels. So here you have it some twins. Most of these are very new hot off the presses releases, some without albums to their names. A more subdude but still upbeat set a tracks for your ears. Enjoy.0. SONG - ARTIST - ALBUM1. Vestiges - Martin Courtney2. Another One - Mac Demarco - Another One3. XII - Island Science - XII4. Delusive - SASKATCHEWAN - Delusive5. Sharp Dressed Man - Grape St - Wallpaper6. Demons - Summer Twins - Limbo7. I Need A Woman - Hockey Dad - Dreamin'8. Limitless - Megan Washington - There There9. Te Vi - Julieta Venegas - Los Momentos10. Refractor - Painted Palms - Horizons11. Martin - Hey Elbow - Every Other

The goal of this study was to investigate the function of the heat shock protein 70 family members, expressed in tumors under physiological and stress conditions and to dissect their role in tumor immune recognition as a function of intra- versus extracellular location. Another goal was to investigate whether heat-treatment at clinically relevant thermal doses affects the immunophenotype of a given tumor, as defined by tumor cell sensitivity to immune effector cells. For these questions, the human melanoma system was selected because it is well characterized with regards to tumor-associated antigens, like tyrosinase and Melan-A/MART-1, their epitopes and restriction elements for MHC class I presentation. In the first part of the study the focus specifically was on the time-temperature dependent effects of heat exposure. Two different thermal doses (41,8°C/120 minutes and 45°C/22 minutes) were selected that mimic the heterogeneity of the achieved temperature distribution within the tumor and the time-temperature dependent changes were determined in: a) antigen expression (tyrosinase and Melan-A/MART-1) at the protein and mRNA level; b) expression of the inducible HSP70 and the constitutive HSC70; c) processing and presentation of tyrosinase and MART-1 via MHC class I; d) susceptibility of melanoma cell lines to cytotoxic T lymphocytes like CD8+ T cells, LAK and NK cells. It was demonstrated that HSP70 and antigen expression display distinct expression and kinetics that reflect the thermohistory of the cells, i.e. exposure to high or low thermal doses. Immunologically, a low thermal dose did not alter immune recognition of the cells despite the fact that intracellular HSP70 and tyrosinase protein were upregulated. High thermal dose induced a pleiotropy of effects, including stronger upregulation of HSP70 and tyrosinase protein but downregulation of tyrosinase at mRNA level. Concordant with reduced HLA-A2 surface expression and tyrosinase mRNA levels, immune recognition of the heat-treated cells was initially reduced, but pretreatment levels were restored after 72 hours of recovery. The observation that tumor cells treated with temperatures below the breakpoint temperature maintain an immunological homeostasis during the heat shock response is of critical importance for the clinical application of hyperthermia in the treatment of tumors. In the second part of the study, the ability of HSP70 to cross-present a naturally expressed human tumor antigen, tyrosinase, that is of low immunigenicity, a situation that more closely resembles the patient situation was investigated. It was demonstrated that HSP70-peptide complexes (HSP70-PC) purified from tyrosinase-positive (HSP70-PC/tyr+) but not from tyrosinase-negative (HSP70-PC/tyr-) melanoma cells deliver the tyrosinase antigen to immature DCs for MHC class I restricted T cell recognition. T cell stimulation by HSP70-PC/tyr+ incubated with immature DCs with was very efficient even without additional DC maturation signals (e.g. exogenous TNF-?) demonstrating the ability of tumor-derived HSP70-PC to act as a chaperone for peptides and a signal for DC maturation. HSP70-PC in exerting both functions on DCs, delivering antigens and maturing DCs, ensures that the peptides that are delivered to the DCs are presented in an immunogenic context optimal for T cell stimulation. In conlusion, induction of intracellular heat shock proteins (HSPs) by heat does not interfere with the tumor immune recognition and when HSPs are expressed extracellularly they acquire immunostimulatory properties. These observations open new perspectives for the application of hyperthermia in combination with HSP-based vaccine in the treatment of solid tumors.