Podcasts about Glucocorticoid

Lower back pain is something most of us have experienced at some point. Whether it's from sitting too long, lifting something heavy, or just the wear and tear of daily life, it's a common issue. But with so many treatments available, which ones actually work? A team of researchers set out to answer this question in a massive study published in BMJ Evidence-Based Medicine. Gathering data from hundreds of previous studies, the researchers analysed 301 randomized controlled trials, covering 56 different treatments for low back pain. These treatments ranged from exercise and spinal manipulations to medications like NSAIDs (non-steroidal anti-inflammatory drugs) and antidepressants. To make the study even more precise, they divided the results into two categories: Acute low back pain (pain lasting less than 12 weeks). Chronic low back pain (pain lasting 12 weeks or more). Then, they compared each treatment to a placebo to see if it actually provided pain relief. The good news is that some non-surgical treatments do work, though not as dramatically as you might hope. For acute low back pain, NSAIDs (like ibuprofen) were the only treatment found to be effective, with a small but measurable pain reduction. For chronic low back pain, five treatments stood out: Exercise: Physical movement tailored to strengthen the back and improve flexibility. Spinal manipulative therapy: Techniques often used by chiropractors to adjust the spine. Taping: Using supportive tape to stabilize muscles and joints. Antidepressants: Certain medications that seem to reduce pain perception. TRPV1 agonists: A class of treatments that target pain receptors. Each of these treatments provided modest pain relief, meaning they worked better than a placebo, but not by much. What Doesn't Work? Some common treatments, surprisingly, did not provide significant pain relief. For acute low back pain, these treatments were found not to be effective: Exercise (which works better for chronic pain but not short-term pain). Glucocorticoid injections (steroid shots that are sometimes used for inflammation). Paracetamol (acetaminophen) (commonly recommended but found to be ineffective in this study). For chronic low back pain, these treatments failed to provide significant benefits: Antibiotics (sometimes prescribed for infections that might cause pain, but no clear benefit). Anaesthetics (numbing agents that didn't prove effective for long-term relief). Many treatments had inconclusive results, meaning there wasn't enough strong evidence to say whether they truly help. These included: Acupuncture Massage Heat therapy Laser therapy Electromagnetic therapy This doesn't necessarily mean they don't work, just that more high-quality research is needed. So, if you have low back pain and are looking for non-surgical options, the research suggests: If your pain is short-term, NSAIDs may help. If your pain is chronic, consider exercise, spinal manipulative therapy, taping, antidepressants, or TRPV1 agonists. Some treatments commonly recommended (like paracetamol and steroids) might not be as effective as previously thought. Many alternative treatments show promise but need better studies to confirm their benefits. See omnystudio.com/listener for privacy information.

Feel like you're working hard but not seeing the progress you want? It's NOT YOU or your PERFECTIONISM – it's your Person Account™ . Discover my proprietary framework that's changing the game for Perfectionist Solution's clients, and will do the same for you.  In this Episode You'll Learn:How ruminating + running a 10k impact you the exact same wayWhy perfectionist brains work overtime + cost more to operateHow to tell if you're operating in a constant state of depletion without realizing itWhat Cortisol actually is (it's NOT a STRESS HORMONE)The hidden reason therapy + personal development don't work On paper, you've got it together— isn't it time you felt like it? Whether it's stop playing out worst case scenarios in your head or JOYFULLY PRESENT AMBITIOUS again, Perfectionism Optimized, private 1-1 coaching gives you the life-long skills to *finally feel* as amazing on the inside as your life looks on the outside. Get your stress-free start today at https://courtneylovegavin.com/rewire Resources Mentioned In Episode 252:Perfect Start SessionMagic Skill for Control of Emotions [Neuroscience Series #1] Perfectionism Rewired Ep. 248How Perfectionist Brain *Actually* Works [Neuroscience Series #2] Perfectionism Rewired Ep. 249Can't Stop Ruminating? Here's Why [Neuroscience Series #3] Perfectionism Rewired Ep. 250  TIMESTAMPS:0:53-Why You're Not Making Progress Despite Trying Harder02:15-Allostasis: How Your Brain Allocates05:07-The Hidden Reason Therapy Isn't Working06:30-Why Perfectionist Brains Cost More to Operate07:25-Living in a Depleted State Without Realizing It09:31-Stressed out: Eustress vs. Distress10:29-Truth about Cortisol + Stress Response12:35-The Slow Drip of Perfectionist Burnout15:17-How to Tell if You're Running on Empty  Citations/Sources:Barrett, L. F. (2017). How emotions are made: The secret life of the brain. Houghton Mifflin Harcourt.Bobba-Alves, N., Juster, R.-P., & Picard, M. (2022). The energetic cost of allostasis and allostatic load. Psychoneuroendocrinology, 146, 105951. https://doi.org/10.1016/j.psyneuen.2022.105951Dwyer, P. (2022). The Neurodiversity Approach(es): What Are They and What Do They Mean for Researchers? Human Development, 66(2), 73–92. https://doi.org/10.1159/000523723Ganzel, B. L., & Morris, P. A. (2011). Allostasis and the developing human brain: Explicit consideration of implicit models. Development and Psychopathology, 23(4), 955–974. https://doi.org/10.1017/s0954579411000447‌Guidi, J., Lucente, M., Sonino, N., & Fava, Giovanni A. (2020). Allostatic Load and Its Impact on Health: A Systematic Review. Psychotherapy and Psychosomatics, 90(1), 11–27. https://doi.org/10.1159/000510696Kleckner, I. R., Zhang, J., Touroutoglou, A., Chanes, L., Xia, C., Simmons, W. K., Quigley, K. S., Dickerson, B. C., & Feldman Barrett, L. (2017). Evidence for a large-scale brain system supporting allostasis and interoception in humans. Nature Human Behaviour, 1(5). https://doi.org/10.1038/s41562-017-0069Knezevic, E., Katarina Nenic, Milanovic, V., & Knezevic, N. N. (2023). The Role of Cortisol in Chronic Stress, Neurodegenerative Diseases, and Psychological Disorders. Cells, 12(23), 2726–2726. https://doi.org/10.3390/cells12232726‌McEwen, B. S., & Gianaros, P. J. (2011). Stress- and Allostasis-Induced Brain Plasticity. Annual Review of Medicine, 62(1), 431–445. https://doi.org/10.1146/annurev-med-052209-100430 Perfectionism Rewired is committed to truth and accuracy through a perfectionist affirming lens, offering cutting-edge research on perfectionism, interoception + neuroscience, for the practical perfectionist who wants to enjoy the life they've worked so hard to create.

In this episode, Jonathan is joined by John H. Stone, Professor of Medicine at Harvard Medical School and The Edward A. Fox Chair in Medicine at Massachusetts General Hospital.  Stone discusses his groundbreaking work in systemic vasculitis, including granulomatosis with polyangiitis and ANCA-associated vasculitis. He also shares insights into the emerging field of IgG4-related disease and the exciting possibility of the first approved therapy for this condition. Alongside, he delves into his efforts to minimise glucocorticoid toxicity and his work through the IgG4ward! Foundation.   Timestamps: (00:30) – Introduction (04:00) – Stone's journey into rheumatology (07:28) – WEGET trial (10:30) – Developments in IgG4-related disease and the path to therapy approval (15:52) – Key advancements in the treatment of granulomatosis with polyangiitis (18:04) – Glucocorticoid toxicity and the Glucocorticoid Toxicity Index (GTI) (20:34) – The IgG4ward! Foundation (23:48) – Two Pearls and a Myth (26:45) – Stone's three wishes for rheumatology

Host: Charles Turck, PharmD, BCPS, BCCCP Guest: John Stone, MD, MPH Glucocorticoids are often successfully used as the mainstay of treatment for many inflammatory conditions, but adverse events associated with glucocorticoids use are common. Fortunately, there are steps we can take to reduce the risk of glucocorticoid toxicity, like monitoring patients, educating them on the possible side effects, and considering alternative treatments where available. Tune in to learn more about the side effects, risk factors, and prevention strategies with Dr. Charles Turck and Dr. John Stone. © 2024 Sanofi and Regeneron Pharmaceuticals, Inc. All rights reserved. MAT-US-2310647 v1.0 - PExpiration Date 04/16/2025

Host: Charles Turck, PharmD, BCPS, BCCCP Guest: John Stone, MD, MPH Glucocorticoids are often successfully used as the mainstay of treatment for many inflammatory conditions, but adverse events associated with glucocorticoids use are common. Fortunately, there are steps we can take to reduce the risk of glucocorticoid toxicity, like monitoring patients, educating them on the possible side effects, and considering alternative treatments where available. Tune in to learn more about the side effects, risk factors, and prevention strategies with Dr. Charles Turck and Dr. John Stone. © 2024 Sanofi and Regeneron Pharmaceuticals, Inc. All rights reserved. MAT-US-2310647 v1.0 - PExpiration Date 04/16/2025

Contributor: Ricky Dhaliwal MD Educational Pearls: Primary adrenal insufficiency (most common risk factor for adrenal crises) An autoimmune condition commonly known as Addison's Disease Defects in the cells of the adrenal glomerulosa and fasciculata result in deficient glucocorticoids and mineralocorticoids Mineralocorticoid deficiency leads to hyponatremia and hypovolemia Lack of aldosterone downregulates Endothelial Sodium Channels (ENaCs) at the renal tubules Water follows sodium and generates a hypovolemic state Glucocorticoid deficiency contributes further to hypotension and hyponatremia Decreased vascular responsiveness to angiotensin II Increased secretion of vasopressin (ADH) from the posterior pituitary An adrenal crisis is defined as a sudden worsening of adrenal insufficiency Presents with non-specific symptoms including nausea, vomiting, fatigue, confusion, and fevers Fevers may be the result of underlying infection Work-up in the ED includes labs looking for infection and adding cortisol + ACTH levels Emergent treatment is required 100 mg hydrocortisone bolus followed by 50 mg every 6 hours Immediate IV fluid repletion with 1L normal saline The most common cause of an adrenal crisis is an acute infection in patients with baseline adrenal insufficiency Often due to a gastrointestinal infection References 1. Bancos I, Hahner S, Tomlinson J, Arlt W. Diagnosis and management of adrenal insufficiency. Lancet Diabetes Endocrinol. 2015;3(3):216-226. doi:10.1016/S2213-8587(14)70142-1 2. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101(2):364-389. doi:10.1210/jc.2015-1710 3. Cronin CC, Callaghan N, Kearney PJ, Murnaghan DJ, Shanahan F. Addison disease in patients treated with glucocorticoid therapy. Arch Intern Med. 1997;157(4):456-458. 4. Feldman RD, Gros R. Vascular effects of aldosterone: sorting out the receptors and the ligands. Clin Exp Pharmacol Physiol. 2013;40(12):916-921. doi:10.1111/1440-1681.12157 5. Hahner S, Loeffler M, Bleicken B, et al. Epidemiology of adrenal crisis in chronic adrenal insufficiency: the need for new prevention strategies. Eur J Endocrinol. 2010;162(3):597-602. doi:10.1530/EJE-09-0884  Summarized by Jorge Chalit, OMSII | Edited by Meg Joyce & Jorge Chalit  

Sponsored by Antech. Head to dvm360 Flex and login or create a free CE account and claim your credit after listening to this episode. Program Description:  In this case-based session, we will discuss the hematologic analysis of Mac, a critically ill Greyhound mix, as we dissect the details of his CBC and blood film review that decode an interesting twist to a cool case with a suspenseful ending.  Program Agenda:  o   Introduce Mac's case o   Signalment o   History o   Presenting complaints o   PE findings o   Discuss hematology basics o   Sample quality o   Sample collection tips o   Proper sampling handling o   In-depth review of Mac's CBC results o   Anemia of inflammatory disease o   Inflammatory leukogram o   Bands as the hallmark of inflammation o   Glucocorticoid/stress leukogram o   Contrast with epinephrine leukogram pattern o   Discuss blood film basics o   Importance of fresh blood film   o   Technical tips o   Basics of blood film review o   Discuss findings from Mac's blood film review o   Toxic change in neutrophils to signify systemic inflammatory process o   Mastocythemia o   Review ACVIM retrospective study on mastocythemia in dogs and cats Learning Objectives:  1. Understand importance of sample quality and handling to accurate hematology results  2. Analyze each individual component of the CBC  3. Review leukogram patterns 4. Correlate CBC data with key microscopic findings from the blood film review  5. Evaluate morphologic changes of neutrophils consistent with toxicity 6. Learn clinical significance of mastocythemia 7. Discuss ancillary diagnostics performed in response to key CBC changes 

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.19.545545v1?rss=1 Authors: Kandasamy, K., Fan, X., Haribalaganesh, R., Bharanidharan, D., Sharmila, R., Krishnadas, R., Muthukkaruppan, V., Willoughby, C. E., Srinivasan, S. Abstract: The present study aimed to understand the role of miRNAs in differential glucocorticoid (GC) responsiveness in human trabecular meshwork (HTM) cells using small RNA sequencing. For this, total RNA was extracted from cultured HTM cells with known GC responsiveness using Human organ-cultured anterior segment (HOCAS) (GC-responder GC-R; n=4) and GC-non-responder (GC-NR; n=4) after treatment with either 100nM dexamethasone (DEX) or ethanol (ETH) for 7 days. Differentially expressed miRNAs (DEMIRs) were compared among 5 groups and validated by RT-PCR. There were 13 and 21 DEMIRs identified in Group #1 (ETH vs DEX-treated GC-R) and Group #2 (ETH vs DEX-treated GC-NR) respectively. Seven miRNAs were found as common miRNAs dysregulated in both GC-R and GC-NR (Group #3). There were 6 and 14 unique DEMIRs were identified in GC-R (Gropu#4) and GC-NR (Group#5) HTM cells respectively. Ingenuity Pathway Analysis identified enriched pathways and biological processes associated with differential GC responsiveness in HTM cells. Integrative analysis of miRNA-mRNA of the same set of HTM cells revealed several molecular regulators for GC non-responsiveness. This is the first study revealed a unique miRNA signature between GC-R and GC-NR HTM cells which raises the possibility of developing new molecular targets for the management of steroid-OHT/glaucoma. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.14.536872v1?rss=1 Authors: Magalhes, R., Goncalves, N., Sousa, R., Coelho, A., Soares-Cunha, C., Moreira, P., Marques, P., Tuulari, J. J., Scheinin, N. M., Karlsson, L., Karlsson, H., Sousa, N., Rodrigues, A. J. Abstract: Synthetic Glucocorticoids (sGC) are commonly prescribed in preterm risk pregnancies in order to improve fetal organ maturation. This administration greatly reduces perinatal and neonatal mortality and respiratory distress syndrome associated with prematurity, but preclinical evidence warns for an adverse effect of sGC in the developing brain. In this work we evaluated the long-term effects of prenatal exposure to sGC in the brain of 17 years-old adolescents using multimodal MRI. From 4607 birth registrations from Hospital de Braga - Portugal, we selected participants that were born with similar gestational age, but that were either exposed during pregnancy to sGC (n=21) or non-exposed (n=24). After obtaining a detailed clinical history, participants were subjected to an extensive neuropsychological evaluation, followed by structural and functional MRI. No differences were found in the performance on neuropsychological tests between sGC-exposed and non-exposed participants. Moreover, no differences were found in regional brain volumes. However, the sGC-exposed group presented reduced functional connectivity at rest in a network involving primarily sub-cortical, cerebellar and frontal nodes in comparison to the non-exposed group, even after controlling for confounding factors such as gestational age at birth, birth weight, and sex. Our results suggest that prenatal sGC-exposed adolescents present no significant deviations in neuropsychological performance in the dimensions that we evaluated, although they presented altered functional connectivity, highlighting the need for additional studies to understand the impact of these changes in brain functioning and in behavior. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

MedLink Neurology Podcast is delighted to feature selected episodes from BrainWaves, courtesy of James E Siegler MD, its originator and host. BrainWaves is an academic audio podcast whose mission is to educate medical providers through clinical cases and topical reviews in neurology, medicine, and the humanities, and episodes originally aired from 2016 to 2021. Originally released: July 25, 2019 A 50-year-old gentleman presents with severe headaches and speech disturbance. The MRI shows acute strokes and multifocal vascular irregularities. Is it reversible cerebral vasoconstriction syndrome or primary angiitis of the central nervous system? Or is it something else entirely? RCVS and PACNS almost always pose a challenge--even to the most astute neurologist. But, because they are treated entirely differently and their clinical trajectories depend on these treatments, it is worth knowing how experts distinguish the two. This week on the BrainWaves podcast, Dr. Jesse Thon joins Jim Siegler in a discussion about the clinical and radiographic features of these two conditions and shares his experience in managing these patients. Produced by James E Siegler and Jesse Thon. Music courtesy of Nuno Adelaida, Peter Rudenko on the piano, Squire Tuck on the guitar, Swelling, and Uncanny. Sound effects by Mike Koenig and Daniel Simion. BrainWaves' podcasts and online content are intended for medical education only and should not be used for clinical decision-making. Be sure to follow us on Twitter @brainwavesaudio for the latest updates to the podcast. REFERENCES Birnbaum J, Hellmann DB. Primary angiitis of the central nervous system. Arch Neurol 2009;66(6):704-9. PMID 19506130 Miller TR, Shivashankar R, Mossa-Basha M, Gandhi D. Reversible cerebral vasoconstriction syndrome, part 1: epidemiology, pathogenesis, and clinical course. AJNR Am J Neuroradiol 2015;36(8):1392-9. PMID 25593203 Miller TR, Shivashankar R, Mossa-Basha M, Gandhi D. reversible cerebral vasoconstriction syndrome, part 2: Diagnostic work-up, imaging evaluation, and differential diagnosis. AJNR Am J Neuroradiol 2015;36(9):1580-8. PMID 25614476 Rocha EA, Topcuoglu MA, Silva GS, Singhal AB. RCVS2 score and diagnostic approach for reversible cerebral vasoconstriction syndrome. Neurology 2019;92(7):e639-47. PMID 30635475 Singhal AB. Diagnostic challenges in RCVS, PACNS, and other cerebral arteriopathies. Cephalalgia 2011;31(10):1067-70. PMID 21673004 Singhal AB, Topcuoglu MA. Glucocorticoid-associated worsening in reversible cerebral vasoconstriction syndrome. Neurology 2017;88(3):228-36. PMID 27940651 Singhal AB, Topcuoglu MA, Fok JW, et al. Reversible cerebral vasoconstriction syndromes and primary angiitis of the central nervous system: clinical, imaging, and angiographic comparison. Ann Neurol 2016;79(6):882-94. PMID 27043703  We believe that the principles expressed or implied in the podcast remain valid, but certain details may be superseded by evolving knowledge since the episode's original release date. 

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.13.528363v1?rss=1 Authors: Choi, M.-K., Cook, A., Eachus, H., Tochwin, A., Kuntz, S., Kim, S., Ryu, S. Abstract: Chronic or severe stress exposure during development primes an individual for altered stress sensitivity in adulthood and increases psychiatric disease susceptibility. However, the identity and function of genes affected by developmental stress exposure are poorly understood. Here, we used an optogenetic zebrafish model to identify brain-wide molecular alterations caused by chronic Glucocorticoid (GC) exposure during development and following subsequent exposure to an acute stressor in adulthood. We show that developmental GC-exposed fish display wide-ranging behavioral changes affecting social behavior, food consumption, and associative learning. The brain transcriptome of GC-exposed fish showed alteration of genes associated with DNA metabolism, axon development, and social behavior-related genes such as oxytocin across the life course. Strikingly, when GC-exposed fish were subjected to a stress challenge in adulthood, they showed exaggerated endocrine responses and a great number of brain-wide transcriptional changes, including gene sets associated with axon development, neuronal signaling, and epigenetic modulators. These altered gene sets showed an overrepresentation of genes linked to human psychiatric disorders. In short, our study provides a unique resource of long-term, time-dependent gene expression changes induced by developmental GC-exposure and identifies novel GC-primed genes which may shape adult responses of early life stress-exposed individuals. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.07.526836v1?rss=1 Authors: Hill, A., Johnston, C., Agranoff, I., Gavade, S., Spencer-Segal, J. Abstract: Survivors of critical illness are at high risk of developing post-traumatic stress disorder (PTSD) but administration of glucocorticoids during the illness can lower that risk. The mechanism is not known but may involve glucocorticoid modulation of hippocampal- and amygdalar-dependent memory formation. In this study, we sought to determine whether glucocorticoids given during an acute illness influence the formation and persistence of fear and non-fear memories from the time of the illness. We performed cecal ligation and puncture in male and female mice to induce an acute infectious illness. During the illness, mice were introduced to a neutral object in their home cage and separately underwent contextual fear conditioning. We then tested the persistence of object and fear memories after recovery. Glucocorticoid treatment enhanced object discrimination but did not alter the expression of contextual fear memory. During context re-exposure, neural activity was elevated in the dentate gyrus irrespective of fear conditioning. Our results suggest that glucocorticoids given during illness enhance hippocampal-dependent non-fear memory processes. This indicates that PTSD outcomes in critically ill patients may be improved by enhancing non-fear memories from the time of their illness. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.27.525966v1?rss=1 Authors: Eachus, H., Choi, M. K., Tochwin, A., Kaspareit, J., Ho, M., Ryu, S. Abstract: Exposure to excess glucocorticoid (GC) during early development is implicated in disease risk in later life. GC-induced acceleration of growth-rate leading to adverse phenotypes later is widely observed at the organism level, but cellular and molecular understanding of this process is currently lacking. Using an optogenetic zebrafish model, here we analysed the effects of GC exposure on neurogenesis during development in the whole brain. We identify that the hypothalamus is a highly GC-sensitive region where elevated GC causes precocious development followed by failed maturation and early decline accompanied by impaired feeding, growth, and longevity. In GC-exposed animals, the developmental trajectory of hypothalamic progenitor cells is strikingly altered, potentially mediated by direct regulation of transcription factors such as rx3 by GC. Our data provide cellular and molecular level insight to GC-induced adaptive plasticity leading to allostatic overload in a developing brain, a process crucial for health across the life-course. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.29.520757v1?rss=1 Authors: Basarrate, S., Monzel, A. S., Smith, J., Marsland, A. L., Trumpff, C., Picard, M. Abstract: Objective: Psychosocial stress is transduced into disease risk through energy-dependent release of hormones that affect target organs, tissues, and cells. The magnitude of the physiological stress responses reflects both systemic levels of these hormones and the sensitivity of target tissues to their effects. Thus, differential expression of receptors across organs likely contributes to stress transduction. Here we provide a quantitative whole-body map of glucocorticoid and adrenergic receptor expression. Methods: We systematically examined gene expression levels for the glucocorticoid receptor (GR), - and {beta}-adrenergic receptors (AR-1B, AR-2B AR-{beta}2, and AR-{beta}3), across 55 different organs using the Human Protein Atlas dataset. We also leveraged the Human Proteome Map and MitoCarta3.0 data to examine receptor protein levels and, given the energy-dependence of the stress response, the link between stress hormone receptor density and mitochondrial pathways. Finally, we tested the functional interplay between GR activation and AR expression in living human cells. Results: The GR was expressed ubiquitously across all investigated organ systems. Immune tissues and cells expressed the highest GR RNA and protein levels. In contrast, AR subtypes showed lower and more localized expression patterns. Co-regulation was found between GR and AR-1B, as well as between AR-1B and AR-2B. In human fibroblasts, activating the GR selectively increased AR-{beta}2 (3.6-fold) and AR-1B (2.2-fold) expression, confirming their interaction. Consistent with the energetic cost of stress responses, GR and AR expression were positively associated with the expression of key mitochondrial pathways. Conclusion: Our results provide a cartography of GR and AR expression across the human body. Tissue-specific stress hormone receptor expression patterns could make specific organ systems more responsive to the sustained, energetically expensive, neuroendocrine signaling pathways triggered by chronic psychosocial stress. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.11.519598v1?rss=1 Authors: Adedipe, I. I., Depaauw-Holt, L. R., Latraverse-Arquilla, J., Vaugeois, J., Duquenne, M., Rogers, B., Peyrard, S., Bosson, A., Murphy-Royal, C. Abstract: Early-life stress can have lifelong consequences, enhancing stress susceptibility and resulting in behavioural and cognitive deficits. While the effects of early-life stress (ELS) on neuronal function have been well-described, we still know very little about the contribution of non-neuronal brain cells to the cellular and behavioural adaptations following ELS. Here, using a rodent model of ELS, we report that astrocytes play a key role in mediating the impact of stress on amygdala-dependent behaviour and synaptic plasticity during adolescence. We report that ELS induces generalisation of fear, associated with increased levels of circulating corticosterone and activation of glucocorticoid receptors in astrocytes. In addition, we identify astrocyte glucocorticoid receptors as targets, mediating ELS-induced cognitive and synaptic impairments. This work establishes astrocytes as key elements in amygdala-dependent memory, and as central mediators of the effects of stress on cognitive function via stress hormone signalling pathways. 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/2022.09.19.508565v1?rss=1 Authors: Novaes, L. S., Bueno-de-Camargo, L. M., Shigeo-de-Almeida, A., Juliano, V. A. L., Dos Santos, N. B., Goosens, K., Munhoz, C. D. Abstract: Anxiety, a state related to anticipatory fear, can be adaptive in the face of environmental threats or stressors. However, anxiety can also become persistent and manifest as anxiety- and stress-related disorders, such as generalized anxiety or post-traumatic stress disorder (PTSD). In rodents, systemic administration of glucocorticoids (GCs) or short-term restraint stress induces anxiety-like behaviors and dendritic branching within the basolateral complex of the amygdala (BLA) ten days later. Additionally, increased arousal-related memory retention mediated by elevated GCs requires concomitant noradrenaline (NE) signaling, both acting in the BLA. It is unknown whether GCs and NE play a role in the delayed acute stress effects on BLA dendritic plasticity and behavior. Here, we show that inhibiting corticosterone (CORT) elevation during the two-hour restraint stress prevents stress-induced increases in delayed anxiety-like behaviors and BLA dendritic spine density in rats. Also, we show that acute stress's behavioral and morphological delayed effects are critically dependent on glucocorticoid receptor (GR) genomic actions in the BLA. Unlike CORT, the pharmacological enhancement of NE signaling in the BLA was insufficient to drive delayed anxiety-related behavior. Nonetheless, the delayed anxiety-like behavior 10 days after acute stress requires NE signaling in the BLA at the time it is expressed. Therefore, we define essential roles for two stress-related hormones acting at two different times, for the late stress consequences: CORT, via GR, immediately at stress; NE, via beta-adrenoceptors, during the expression of delayed behavior. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.09.507267v1?rss=1 Authors: Nagpal, J., Eachus, H., Lityagina, O., Ryu, S. Abstract: Organisms respond to stressors through a coordinated set of physiological and behavioural responses. Zebrafish provides an opportunity to study conserved mechanisms underlying the stress-response that is regulated largely by the neuroendocrine Hypothalamus-Pituitary-Adrenal/Interrenal (HPA) axis, with glucocorticoids (GC) as the final effector. In this study, we evaluated the effect of chronically active GC signalling in early life on the baseline and stress evoked GC(cortisol) levels in larval zebrafish. To this end, we employed an optogenetic actuator, Beggiatoa photoactivated adenylyl cyclase, expressed in the interrenal cells of zebrafish and demonstrate that its chronic activation leads to hypercortisolaemia and dampens the acute-stress evoked cortisol levels, across a variety of stressor modalities during early life. This blunting of stress-response, a phenotype reported by many studies to be observed in human subjects exposed to early-life trauma, was conserved in ontogeny at a later developmental stage. Furthermore, we observe a strong reduction of proopiomelanocortin (POMC)-expressing cells in the pituitary as well as global upregulation of FKBP5 gene expression, impinging on the negative feedback regulation elicited by elevated cortisol levels. Going forward, we propose that this model can be leveraged to tease apart the mechanisms underlying developmental programming of HPA axis by early-life stress and its implications for vulnerability and resilience to stress in adulthood. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

References Genes Immun. 2020 May; 21(3): 150–168 BMC Rheumatology 2020. volume 4, Article number: 4 Nature Immunology.2002. August. volume 3 no 8 Cell Tissue Res. 2019 Jan; 375(1): 143–172. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message

Reliever Inhaled Glucocorticoid TreatmentBlack and Latinx patients are disproportionately impacted by asthma. In fact, asthma mortality rates are twice as high in Black patients compared to White patients. Are there different treatment options to help improve mortality in these populations? Join host Geoff Wall with guest Dr. Matt Trump as they discuss the PREPARE trial.The GameChangerEmerging data suggests that using a bronchodilator with an inhaled corticosteroid (ICS) may improve asthma exacerbation symptoms in diverse patient populations. This is contrary to current standards of care that encourage the use of a short-acting bronchodilator alone.  Show Segments00:00 – Introduction02:05 – Asthma in Diverse Populations04:25 – Inhaled Corticosteroids in Asthma Management 06:50 – PREPARE Trial                                                                                   18:33 – The GameChanger28:11 – Closing Remarks HostGeoff Wall, PharmD., BCPS, FCCP, CGP Professor of Pharmacy Practice, Drake University Internal Medicine/Critical Care, UnityPoint Health GuestDr. Matt Trump, DO, FACP, FCCPPulmonary & Critical Care SpecialistThe Iowa Clinic Dr. Trump is a consultant for Fishter and Paykel Healthcare and an investigator for Astra Zeneca. All relevant financial relationships have been mitigated.References and ResourcesReliever-Triggered Inhaled Glucocorticoid in Black and Latinx Adults with Asthma Redeem your CPE or CME here!Pharmacist Members CME Need a membership?Join for CPE CreditJoin for CME Credit CE InformationLearning ObjectivesUpon successful completion of this knowledge-based activity, participants should be able to:1.     Describe the disparity of outcomes in asthma between different demographics2.     Discuss the role of reliever inhaled glucocorticoids for persons with asthma 0.05 CEU/0.5 HrUAN: 0107-0000-22-176-H01-PInitial release date: 03/24/2022         Expiration date: 03/24/2023Additional CPE and CME details can be found here. 

CommonSpirit Health Physician Enterprise 5-Minute Check In with Dr. Thomas McGinn features:- Omicron update- New booster recommendations: https://docs.google.com/presentation/d/1qJ9t-eVVZZ3Nm1Ox0imAViukqwsb3ZM79o9DjnxbpNQ/edit?usp=sharing - Black and Latinx patients bear a disproportionate burden of asthma and existing guideline recommendations have not been based on clinical trials in these populations. We will discuss a new open-label trial that looks at reliever-triggered inhaled glucocorticoid in Black and Latinx adults and what it means for patient care.https://www.nejm.org/doi/pdf/10.1056/NEJMoa2118813 - RSVP Summit- Finally, we're inspired by John Legend's tribute to Ukraine at the Grammys. Catch the performance here:  https://twitter.com/i/status/1510834007587504136

Glucocorticoids can do a lot of harm over time. In this episode, John Stone, MD, MPH, walks us through the Glucocorticoid Toxicity Index (GTI), a validated tool to measure steroid toxicity over time that we'll be seeing more of in the future. Intro :11 Stone introduction :26 About the GTI 1:13 Professional development opportunities for rheumatologists 2:32 The interview 4:27 What is the GTI, how did it come about and how do you think rheumatologists now and in the future will be utilizing it? 5:28 What are the difficulties in measuring steroid toxicities in trials? 10:58 How did you go about putting this instrument together? 13:04 What makes up the GTI? 19:11 Can you explain the Cumulative Worsening Score and the Aggregate Improvement Score? 20:53 Walk us through a patient coming in and being evaluated for the GTI 25:49 What's the future of the GTI in your opinion? 30:32 Do you think the GTI is going to be something that can eventually be used in day-to-day clinical practice? 33:42 Thank you, Dr. John Stone 34:43 John Stone, MD, MPH, is director of clinical rheumatology at Massachusetts General Hospital. Disclosures: Brown reports no relevant financial disclosures. Stone is one of the experts who developed the Glucocorticoid Toxicity Index.  We'd love to hear from you! Send your comments/questions to Dr. Brown at rheuminationspodcast@healio.com. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum

Intergenerational effects of early adversity on survival in wild baboons, Social bonds, social status and survival in wild baboons: a tale of two sexes, Better baboon break-ups: collective decision theory of complex social network fissions, Maternal death and offspring fitness in multiple wild primates, Better baboon break-ups: collective decision theory of complex social network fissions, and Glucocorticoid exposure predicts survival in female baboons Scientific Sense ® by Gill Eapen: Prof. Susan Alberts is Professor of Biology and chair of the Evolutionary Anthropology department at Duke University. She studies the behavior, ecology, physiology, and genetics of wild populations of large mammals. Join this channel to get access to perks: https://www.youtube.com/channel/UCo2wiIHPM35xPawotek2IDA/join --- Send in a voice message: https://anchor.fm/scientificsense/message Support this podcast: https://anchor.fm/scientificsense/support

Compound found in some vegetables may reduce diabetes-related kidney damage Phenethyl isothiocyanate, derived from watercress and other cruciferous vegetables, shows benefits Al-Maarefa University (Saudi Arabia), April 27, 2021 New research conducted in rats suggests a compound that gives some cruciferous vegetables their pungent taste could help to reverse kidney problems associated with diabetes.  It is estimated that about one-quarter of people with diabetes will eventually develop diabetic nephropathy, a gradual loss of kidney function eventually requiring dialysis. The condition is a leading cause of chronic kidney disease in the U.S. and is also associated with a high risk of heart disease. There is currently no cure.  For the new study, researchers assessed the effects of phenethyl isothiocyanate (PEITC) in rats with diabetic nephropathy. PEITC is found in several types of vegetables but is most concentrated in watercress.  "Our study provides, for the first time, evidence that PEITC might be effective as a naturally occurring agent to reverse serious kidney damage in people with diabetes," said lead study author Mohamed El-Sherbiny, PhD, a postdoctoral fellow at AlMaarefa University in Riyadh, Saudi Arabia. "Our study introduces mechanistic evidence of how PEITC might manage kidney injury associated with diabetes by targeting multiple interconnected pathways involved in diabetic nephropathy, including inflammation, glycation and oxidative status." El-Sherbiny will present the research at the American Association for Anatomy annual meeting during the Experimental Biology (EB) 2021 meeting, held virtually April 27-30.  Previous studies have suggested sulforaphane, a related compound in cruciferous vegetables, also helps reduce diabetes-associated kidney damage. The new study bolsters the evidence that eating more vegetables containing these compounds could help people with diabetes to stave off kidney problems.  "PEITC seems to manage one of the most serious and painful diabetic complications. Luckily, PEITC is naturally present in many dietary sources, importantly watercress, broccoli, turnips and radish," said El-Sherbiny.  Since the research was conducted in animal models, further studies will be needed to confirm the findings and understand how the results could translate to new treatments or dietary recommendations for people with diabetes.   Eating probiotic foods helps improve bone health in women Kyung Hee University (South Korea), April 23, 2021 A recent study by researchers at Kyung Hee University (KHU) in South Korea presents a good example of how powerful probiotics are and how they can be used for medicinal purposes. The researchers examined the effects of probiotics on vaginosis caused by the bacterium, Gardnerella vaginalis, and osteoporosis induced by ovariectomy. They reported that probiotics, specifically, anti-inflammatory bacteria isolated from kimchi, caused significant improvements in female mice with the above-mentioned conditions. The researchers discussed their findings in an in an article published in the Journal of Medicinal Food. Probiotics from fermented food offer substantial benefits for women Bacterial vaginosis (BV) is a type of inflammation caused by the overgrowth of bacterialike G. vaginalis, which naturally reside in the vagina. Normally, good bacteria outnumber bad bacteria and keep them in check; but certain activities, such as frequent douching or unprotected sex, can disrupt the microbial balance in the vagina and promote the growth of bad bacteria. Osteoporosis, also called “porous bone,” is a disease characterized by either the loss of too much bone in the body, a decreased formation of bone, or both. These events cause the bones to become weak and more likely to break from a fall, a minor bump or even from sneezing. According to statistics, osteoporosis is more common in women, with one in three over the age of 50 experiencing bone fractures because of it, while only one in five men experience the same. Genetics and age can play a part in osteoporosis development, along with low calcium intake, thyroid problems, inflammatory conditions and the use of corticosteroid medications. In their study, the team from KHU noted that the excessive expression of tumor necrosis factor-a (TNF-a), a signaling protein (cytokine) secreted by inflammatory cells, is known to aggravate BV and osteoporosis. To determine if probiotics can influence the expression of TNF-a and alleviate these conditions, they isolated anti-inflammatory Lactobacillus plantarum NK3 and Bifidobacterium longum NK49 from kimchi as well as from human fecal samples. They then tested the effects of these good bacteria in female mice with BV and osteoporosis. The researchers reported that oral gavage of NK3 alone or in combination with NK49 significantly alleviated GV-induced vaginosis and decreased GV population in the vagina. The probiotics also inhibited the activation of NF-kB, a transcription factor that increases the production of inflammatory cytokines, and TNF-a expression in the vagina and uterus of the female mice. The researchers also found that treatment with NK3 alone or in combination with NK49 alleviated ovariectomy-induced osteoporosis and obesity. Moreover, it increased blood calcium, phosphorus and osteocalcin levels, as well as suppressed weight gain. NK3 and/or NK49 treatment also reduced TNF-a expression and NF-kB activation in the colon and restored optimal gut microbiota composition. Based on these findings, the researchers concluded that the probiotics present in fermented foods like kimchi can alleviate BV and osteoporosis by reducing inflammation and regulating gut microbial composition.     Chronic stress may reduce lifespan in wild baboons, according to new multi-decadal study Duke University, April 21, 2021 Female baboons may not have bills to pay or deadlines to meet, but their lives are extremely challenging. They face food and water scarcity and must be constantly attuned to predators, illnesses and parasites, all while raising infants and maintaining their social status. A new study appearing April 21 in Science Advances shows that female baboons with high life-long levels of glucocorticoids, the hormones involved in the 'fight or flight' response, have a greater risk of dying than those with lower levels. Glucocorticoids are a group of hormones that help prepare the body for a challenge. While these hormones have many functions in the body, persistently high levels of glucocorticoids in the bloodstream can be a marker of stress. To understand the relationship between stress responses and survival, scientists studied 242 female baboons in Amboseli National Park, in Kenya. For more than 20 years, they measured glucocorticoid levels in the baboons' feces, a task that drew upon one of the world's largest collections of data from a wild primate population. Females with higher levels of glucocorticoids in their feces, either due to more frequent exposure to different types of challenges, or more intense stress responses, tended to die younger. The researchers then used these real values of hormone levels and risk of death to simulate a comparison between females that lived at opposite ends of the stress spectrum. The model showed that a hypothetical female whose glucocorticoid levels were kept very elevated would die 5.4 years sooner than a female whose glucocorticoid levels were kept very low. If they reach adulthood, female baboons have an expected lifespan of about 19 years, so 5.4-years represents a 25% shorter life. Five years more life can also represent enough time to raise one or two more infants. The team's simulations represent extreme values that are unlikely to be maintained throughout the females' lives, said Fernando Campos, an assistant professor at the University of Texas San Antonio and lead author of the study. Nonetheless, the link between exposure to stress-associated hormones and survival is clear. "Whether it's due to your environment or your genes or something that we are not measuring, having more glucocorticoids shortens your life," said Susan Alberts, a professor of biology and chair of evolutionary anthropology at Duke and senior author on the paper. The variation in glucocorticoid levels observed by Campos, Alberts, and their team shows that some females have it worse than others. Glucocorticoid levels may vary due to environmental factors, such as growing up in very hot and dry years, social factors, such as living in an unusually small or large group, and individual differences, such as being pregnant more often. "Those are the things we know about," said Alberts, "there's a whole bunch of horrible things that happen to animals that we just can't measure." "Whatever is exposing you to the glucocorticoids is going to shorten your life," Alberts said. "The more hits you get, the worse your outcome." Glucocorticoids play all sorts of vital roles in our bodies. They regulate our immunity, help our bodies access energy from sugars and fats, and modulate metabolic reactions to prepare the body for a challenge. But being constantly prepared for a challenge has high costs: maintenance processes get shut down, and fight or flight processes stay active for longer. Over time, these effects accumulate. "This chronic activation of the stress response leads to a caustic downstream physiological environment of not enough immune system, and not enough attention to maintenance," said Alberts. Associations between stress and survival are extremely difficult to test in a natural scenario. They require very frequent data collection for a very long period of time, in this case through the Amboseli Baboon Research Project, which was launched in 1971. Amboseli females are followed daily from birth to death, their activity is monitored, big events in their lives are recorded, and their feces are periodically collected. "In my lab we have one of the largest collections of primate behavioral data in the world," said Alberts, "and also one of the biggest primate poop collections." More than 14,000 fecal samples were used in this study. Poop is a very valuable, if slightly smelly, repository of information. By measuring hormone levels in feces rather than in blood or saliva, researchers avoid handling and stressing the animals, which could influence hormone levels. "People have long hypothesized that glucocorticoids play a role in how long you live," said Campos, "but to our knowledge this is the first direct evidence that chronic exposure to glucocorticoids strongly predicts survival in wild primates."   Smoking cannabis significantly impairs vision, study finds Smoking cannabis significantly impairs vision but many users are unaware of it University of Granada (Spain), April 15, 2021 A study carried out by the University of Granada indicates that smoking cannabis significantly alters key visual functions, such as visual acuity, contrast sensitivity, three-dimensional vision (stereopsis), the ability to focus, and glare sensitivity Yet, more than 90% of users believe that using cannabis has no effect on their vision, or only a slight effect A group of researchers from the Department of Optics of the University of Granada (UGR) has studied the effects of smoking cannabis on various visual parameters compared to the effect that the users themselves perceive the drug to have on their vision. This study, led by Carolina Ortiz Herrera and Rosario González Anera, has been published in the journal Scientific Reports. Its main author, Sonia Ortiz Peregrina, explains that cannabis use is on the rise despite being an illegal drug. According to the national Survey on Alcohol, Drugs and Other Addictions in Spain 2019-2020, cannabis use nationally has increased since 2011, with 37% of Spanish adults having used this drug at some time. Approximately 10% consumed it in the last year.  In this study, which had the approval of the Human Research Ethics Committee of the UGR (ref. 921/CCEIH/2019), an exhaustive visual trial was conducted on 31 cannabis users, both when they had not consumed any substance in advance and also when they were under the effect of the drug. The researchers also studied the participants' perception of the visual effects of having consumed this drug. The results showed that, following consumption, visual aspects such as visual acuity, contrast sensitivity, three-dimensional vision (stereopsis), the ability to focus, and glare sensitivity significantly worsened. Despite this, not all subjects reported a worsening of their vision after smoking cannabis. Indeed, 30% reported that their vision had not suffered at all, while 65% responded that it had worsened only slightly. The authors note that the visual parameter that could be most strongly linked to users' perception of the visual effect is contrast sensitivity. The study found a negative effect on all of the visual parameters evaluated, with the effect of cannabis on some of the parameters being analysed for the first time in this research. These results, together with the lack of awareness that the participants presented about the visual impairment caused by smoking cannabis, indicate the need to carry out awareness-raising campaigns, as this visual deterioration can pose a danger when performing everyday tasks.   Poor iodine levels in pregnancy poses risks to fetal intellectual development   University of South Australia, April 23, 2021 A growing number of young Australian women are at increased risk of having children born with impaired neurological conditions, due to poor iodine intake. Dietary changes, including a growing trend towards the avoidance of bread and iodised salt, as well as a reduced intake of animal products containing iodine can contribute to low iodine levels. A small pilot study undertaken by the University of South Australia (UniSA) comparing iodine levels between 31 vegan/plant-based participants and 26 omnivores has flagged the potential health risk. Urine samples showed iodine readings of 44 ug/L in the plant-based group, compared to the meat eaters' 64 ug/L level. Neither group came close to the World Health Organization's recommended 100 grams per liter. Participants from both groups who chose pink or Himalayan salt instead of iodised salt had severely deficient iodine levels, averaging 23 ug/L. The findings have been published in the International Journal of Environmental Research and Public Health. While the study was undertaken in South Australia, it builds evidence on a 2017 US study (1) that found nearly two billion people worldwide were iodine deficient, resulting in 50 million experiencing clinical side effects. UniSA research dietitian Jane Whitbread says adequate iodine is essential for fetal intellectual development. "Mild to moderate iodine deficiency has been shown to affect language development, memory and mental processing speeds," Ms Whitbread says. "During pregnancy, the need for iodine is increased and a 150mcg supplement is recommended prior to conception and throughout pregnancy. Unfortunately, most women do not take iodine supplements before conceiving. It is important to consume adequate iodine, especially during the reproductive years." Dietary sources of iodine include fortified bread, iodized salt, seafoods including seaweeds, eggs, and dairy foods. Concerns about the link between poor iodine status and impaired neurological conditions in newborns prompted the mandatory fortification of non-organic bread with iodised salt in 2009 in Australia. It has since been reported that women who consume 100g of iodine-fortified bread every day (approximately three pieces) have five times greater chance of meeting their iodine intake compared to women who don't consume that much. The average amount of bread consumed by women in this study was one piece of bread. The growing preference of Himalayan salt over iodized table salt may also be problematic, Ms Whitbread says. A quarter of women in the study reported using the pink salt which contains an insignificant level of iodine. Another issue is that plant-based milks have low levels of iodine and are not currently fortified with this nutrient. Neither group met the estimated average requirement (EAR) for calcium. The vegan/plant-based group also did not reach the recommended levels for selenium and B12 without supplementation, but their dietary intake of iron, magnesium, vitamin C, folate and fibre was higher than the meat eaters. This reflects the inclusion of iron-rich soy products, wholemeal foods, legumes, and green leafy vegetables in their diet. The researchers recommended that both new salts and plant milks be fortified with iodine as well as a campaign to raise awareness about the importance of iodine in the diet, especially for women in their reproductive years. They also called for a larger study sample to determine iodine status of Australian women.   Taking vitamin D could lower heart disease risk for people with dark skin Racial disparities in heart disease may be linked to vitamin D deficiency Penn State University, April 26, 2021 New research suggests a simple step could help millions of people reduce their risk of heart disease: make sure to get enough vitamin D. Elucidating linkages between skin pigmentation, vitamin D and indicators of cardiovascular health, the new study, combined with evidence from previous research, suggests vitamin D deficiency could contribute to the high rate of heart disease among African Americans.  "More darkly-pigmented individuals may be at greater risk of vitamin D deficiency, particularly in areas of relatively low sun exposure or high seasonality of sun exposure," said S. Tony Wolf, PhD, a postdoctoral fellow at the Pennsylvania State University and the study's lead author. "These findings may help to explain some of the differences that we see in the risk for developing blood vessel dysfunction, hypertension and overt cardiovascular disease between ethnic groups in the United States. Although there are many factors that contribute to the development of hypertension and cardiovascular disease, vitamin D supplementation may provide a simple and cost-effective strategy to reduce those disparities." Wolf noted that the need for vitamin D supplementation depends on a variety of factors, including where you live, how much time you spend in the sun, your skin pigmentation and your age.  Wolf will present the research at the American Physiological Society annual meeting during the Experimental Biology (EB) 2021 meeting, held virtually April 27-30.  Melanin, which is more concentrated in darker skin, is known to inhibit the process our bodies use to make vitamin D in the presence of sunlight. As a result, darkly pigmented people may make less vitamin D, potentially leading to vitamin D deficiency. For the study, Wolf and colleagues measured skin pigmentation, vitamin D and the activity of nitric oxide in the small blood vessels beneath the skin in 18 heathy adults of varying skin tones. Nitric oxide is important for blood vessel function, and reduced nitric oxide availability is thought to predispose an individual to the development of hypertension or cardiovascular disease. Previous studies suggest vitamin D helps to promote nitric oxide availability.  Study participants with darker skin had lower levels of vitamin D and lower nitric oxide availability. In addition, the researchers found that lower levels of vitamin D were related to reduced nitric oxide-mediated blood vessel function. The results align with those of a separate study by the same research group, which found that vitamin D supplementation improved blood vitamin D levels and nitric oxide-mediated blood vessel function in otherwise healthy, young African American adults. "Vitamin D supplementation is a simple and safe strategy to ensure vitamin D sufficiency," said Wolf. "Our findings suggest that promoting adequate vitamin D status in young, otherwise healthy adults may improve nitric oxide availability and blood vessel function, and thereby serve as a prophylactic to reduce risk of future development of hypertension or cardiovascular disease."   Men's loneliness linked to an increased risk of cancer University of Eastern Finland, April 27, 2021 A recent study by the University of Eastern Finland shows that loneliness among middle-aged men is associated with an increased risk of cancer. According to the researchers, taking account of loneliness and social relationships should thus be an important part of comprehensive health care and disease prevention. The findings were published in Psychiatry Research. "It has been estimated, on the basis of studies carried out in recent years, that loneliness could be as significant a health risk as smoking or overweight. Our findings support the idea that attention should be paid to this issue," Project Researcher Siiri-Liisi Kraav from the University of Eastern Finland says.  The study was launched in the 1980s with 2,570 middle-aged men from eastern Finland participating. Their health and mortality have been monitored on the basis of register data up until present days. During the follow-up, 649 men, i.e. 25% of the participants, developed cancer, and 283 men (11%) died of cancer. Loneliness increased the risk of cancer by about ten per cent. This association with the risk of cancer was observed regardless of age, socio-economic status, lifestyle, sleep quality, depression symptoms, body mass index, heart disease and their risk factors. In addition, cancer mortality was higher in cancer patients who were unmarried, widowed or divorced at baseline.  "Awareness of the health effects of loneliness is constantly increasing. Therefore, it is important to examine, in more detail, the mechanisms by which loneliness causes adverse health effects. This information would enable us to better alleviate loneliness and the harm caused by it, as well as to find optimal ways to target preventive measures."     How exercise and the simple act of moving your body can improve mental health   University of Toronto, April 26, 2021 Whether running around a track or simply stretching in your living room, physical activity can go a long way toward making you happier. Catherine Sabiston, a professor in the University of Toronto's Faculty of Kinesiology & Physical Education, says the positive impact of exercise on mental health is well-documented. "There is uncontested evidence that physical activity is conducive to mental health," she says. For example, Sabiston co-authored a study in the Journal of Sport and Exercise Psychology that adolescents who consistently participated in team sports during high school reported lower depression levels in early adulthood. A Canada Research Chair in physical activity and mental health, Sabiston directs a lab that studies the connections between physical activity and mental health, developing and evaluating interventions to promote physical activity and mental wellness among people who are at risk of inactivity and mental health problems. The lab also runs a six-week program called MoveU.HappyU that provides customized coaching and training aimed at reducing the stress and anxiety of students in the lab through physical movement. She recently spoke with U of T News about why it's important to stay active during the pandemic—and how to feel good doing it. How closely connected are physical activity and mental health? Symptoms of mental illness such as anxiety and depression can impede physical activity and vice versa. When you are experiencing symptoms, you may also encounter feelings of low self-worth and an inability to be motivated. It's very hard to find a type of physical activity that you can engage in when you lack interest in most things. Many of the symptoms tied to mental illness are also barriers to physical activity. On the flip side, there is uncontested evidence that physical activity is conducive to mental health. Physical activity prevents some forms of mental illness, and, for individuals who have been diagnosed with mental illness, physical activity can help reduce those symptoms and improve their quality of life. It holds its own weight in comparison to all other forms of treatment for mental illness, including psychotherapy and even medication. Physical activity is a potential adjunct to any other form of preventative or treatment-focused therapy. How exactly does exercise lift our mood? There are a number of mechanisms at play, including physical activity effects that are tied to our brain activity and brain chemistry. Physical activity increases our body temperature. When we are warmer, we are given the sense that we are comfortable and cared for. Also, from a historical perspective, we know that humans were naturally much more active in the past than we are now. So, physical activity brings us closer to that core level of movement that human bodies are meant to be. Moreover, physical activity can mimic mental health symptoms such as anxiety. When you exercise, you may sweat or feel your heart racing. That mimics the feeling of panic, so by engaging in exercise, you are producing a similar physical effect that can make you more accustomed to those symptoms. Exercise also provides you with an opportunity, whether for two minutes or 20, to break away from your usual routines or worries. This escape can help people better cope with their symptoms while experiencing a sense of purpose or accomplishment. In fact, feelings of mastery and accomplishment are also specific ways that physical activity impacts mental health. Small goals and activities inherent to physical activity offer plenty of opportunities for positive feedback, feeling successful and achieving, which helps stave off symptoms of mental illness. Finally, physical activity is something you can partake in outdoors, which has a potentiating effect on mental health. That allows you to see other people, even if you are not interacting with them, and feel a sense of connectedness. What are some ways people can stay active and motivated during the pandemic? We want to dispel the myth that physical activity is just running, biking and lifting weights. Physical activity can be any movement where your heart is increasing its work capacity and your body is moving. In "MoveU.HappyU," we coach students on day-to-day strategies for how to maintain a level of physical activity. Because the program is virtual now, we have trained students who are currently all over the world. Some students who had never spoken to their families about their mental health struggles are now actually having their whole families join in on the physical activities. The physical activity you are doing should be something that you enjoy. If you don't enjoy it, you're not going to continue to do it. We also want people to engage in physical activity to improve function rather than appearance. It's important to uncouple the relationship between physical activity for weight and body-size reasons and move towards physical activity for enjoyment and fun reasons. If it's fun, you are more likely to do it, and more likely to do it leads to more benefits. Do you have any tips for people looking to boost physical activity at home? There are many ways you can innovate physical activity to make it more varied, even when you are stuck in the same place. The best part of physical activity is thinking about the endless possibilities of ways your body can move. If you are purposeful about it, physical activity can be integrated into your everyday routines: Set aside time as you would if you were going to the gym or commuting. Mark it in your calendar or set an alarm to give you an actual reminder. Use your phone or a pedometer to measure your step count. Having something that measures how many steps you're taking gives you a baseline: If you know you walked a certain number of steps on day one, you can add five additional steps on day two. That way you'll have a tangible goal for increasing movement. Consciously link items or places in your home to short bouts of movement. For example, if you use the toaster oven every morning, make a habit of doing squats while you're waiting for your bread. Or when you are wheeling from one room to another, add some extra distance. When you're outside, use aspects of your environment to change up your physical activity. You can change the intensity of your walking or wheeling, for instance, each time that you pass a lamppost or see a blue car. Make it fun to change up the intensity, type, and timing of your activities. Create movement challenges for yourself and your friends, family, colleagues, or students. Set goals for taking a certain number of steps or finishing a certain number of arm raises each day. Making physical activity more like a game is a proven strategy for increasing movement—and enjoying it.    

Episode 42: Baker’s Cyst.What is a Baker’s cyst and how to treat it? Alzheimer’s disease may be linked to sleeping pills, polyarthalgia question. Today is March 1, 2021.Arreaza: Spring season is here! A renewal of life and a renewal of hope in the future, and for some, a renewal of allergies. But we will not talk about allergies in our intro today, we will talk about dementia.Civelli: Research is increasingly showing that poor sleep correlates to dementia[1]. In 2019, an article was published by the Alzheimer’s Association International Conference (AAIC) which highlighted several links between sleep medication, sleep disorders and dementia, while also showing us what we still don’t know.  Arreaza: Investigators at Utah State University (go Aggies! – my wife told me to say that) found interesting sex-related differences: For Men who reported using sleep medication for sleep issues, there was a 3-fold risk of developing Alzheimer’s disease than men who did not use sleep medications. Women however had different results. For Women who did NOT report having any sleep disturbance but still used sleep meds, the risk of Alzheimer’s disease was nearly 4x’s greater. However, in Women who DID self-report sleep disturbances at baseline, but also took sleeping pills, there was actually a 33% reduction in risk for Alzheimer’s disease. Civelli: Another study by investigators at University of California, San Francisco (UCSF) did not echo these findings. They found no sex-related differences, and they adjusted for a variety of genetic and lifestyle confounders. In this UCSF research, frequent sleep meds and later dementia were strongly correlated – but only in Caucasian adults. The specific sleep medications were not identified however, some meds such as benzos, antihistamines, antidepressants, or others were included. Arreaza: At the University of East Anglia in Norwich, England, in 2018 it was found that long-term exposure to anticholinergic drugs, some antidepressants and antihistamines were specifically associated with a higher risk of dementia, while use of benzodiazepines were not.Civelli: Meanwhile in pursuit of physical proof: 337 brains from the U.K. brain bank were examined. 17% and 21% had known benzodiazepines and anticholinergic chronic exposures. Slight signals in neuronal loss in the nucleus basalis of Meynert were identified. Whether benzodiazepine exposure relates to dementia remains controversial.Arreaza: Suvorexant (Belsomra), the only orexin receptor antagonist that regulates wakefulness, is being tested in Alzheimer’s disease. This targeted therapy decreases sleep fragmentation and increases total sleep time. It may be the future. We will see.Civelli: Lastly, although not a magic bullet, trazodone, has been shown to increase total sleep time in patients with Alzheimer’s disease without affecting next-day cognitive performance, and even slowing down cognitive decline in patients who complained of sleep disturbance. According to Dr. Karageorgiou of UCSF “You’re not going to see long-term cognitive benefits if it’s not improving your sleep, So, whether trazodone improves sleep or not in a patient after a few months can be an early indicator for the clinician to continue using it or suspend it”. More prospective research is needed. Arreaza: The bottom line is: Dementias are associated with serious circadian rhythm disturbances. Physicians are encouraged to focus on improving sleep to help patients with, or at risk for, dementia by consolidating their sleep rhythms. So, what will you do to help your patients sleep better today? This is Rio Bravo qWeek, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California. Our program is affiliated with UCLA, and it’s sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home.________________________Question of the Month: Polyarthralgiaby Ikenna Nwosu A 49-year-old female comes to clinic reporting bilateral wrist and ankle pain for 1 month. The pain is worse with movement and responds well to ibuprofen. She denies joint swelling, warmth, or morning stiffness. She reports feeling more fatigued than usual this past month. You note on her chart that she was diagnosed with COVID-19 approximately 6 weeks ago for which she did not need to be hospitalized.  She denies history of diabetes, thyroid disease, lupus, rheumatoid arthritis, trauma, or anemia. She denies fecal, urinary, or vaginal bleeding, no headaches, no chest pain, no SOB or dizziness. Exam is remarkable for a “tired look” and tenderness to palpation at bilateral wrist and ankles. No signs of inflammation on joints are noted. What do you think is the etiology of this patient’s symptoms and what workup would you order (if any)? Let’s repeat the question: What do you think is the etiology of the symptoms in a 49-year-old female who complains of symmetrical POLYARTHRALGIA and fatigue for 1 month, and what workup would you order (if any)? Clue: Listen carefully to the history of the patient. Send us your answer to rbresidency@clinicasierravista.org before March 22, 2021. The winner will be announced and will receive a prize.Quote: “Coming together is a beginning; keeping together is progress; working together is success.”—Edward Everett Hale __________________________Popliteal (Baker’s) CystIntroduction: Baker’s cyst is named for William Morrant Baker, a 19th-century surgeon who first described the condition. It presents as swelling in popliteal fossa due to enlargement of gastrocnemius-semimembranosus bursa. It is often due to degenerative inflammatory joint disease or injury. It usually communicates with the adjacent knee joint space. The Prevalence increases with age. It is often Accompanied by OA.Clinical Features: Posterior knee pain, stiffness, swelling, and other symptoms related to OA.Complications: Enlarging, dissection and/or rupture, leading to compressing of adjacent structures and signs resembling thrombophlebitis.Diagnosis: Clinically, there is a medial popliteal mass most prominent with standing and knee fully extended. Swelling softens or disappears with flexion to 45 degrees (Foucher’s sign). Imaging, usually plain radiography and US, performed if diagnosis is uncertain or another condition suspected. Differentials include DVT, other cystic masses, tumors, or popliteal aneurysms.Management:Treat underlying joint disorder: Such OA, RA, or meniscal injury which may be causing increased synovial fluid. Initial therapy: Arthrocentesis of knee and intraarticular injection with glucocorticoids (40mg triamcinolone). Decrease in size of cyst and/or discomfort observed in approx. 2/3 of patients within 2 days to 1 week from time of injection.Glucocorticoid injections into joint space can also be effective in patients with cysts but without joint effusion. In refractory cases: initial diagnosis of a Baker's cyst should be re-evaluated. In patients who do not respond to intraarticular injection, ultrasound-guided direct aspiration of popliteal cysts, followed by injection of glucocorticoids, can be performed by clinicians experienced in this procedure. Generally, surgical excision should be reserved only for those cases where more conservative interventions have failed and where there is significant functional impairment that can be ascribed to the cysts.Overall good prognosis:   Most popliteal cysts do not cause symptoms or complications. Some cysts resolve without any intervention, and most respond to treatment of associated disorders of the knee joint.Arreaza:After we turned off the mics, we always come up with good topics of conversation. So, after I turned off the mics, Dr McGill reminded me of an important principle in medicine. What’s true today, may be not true tomorrow. We remembered when enlarged tonsils were treated successfully with Nasopharyngeal Radium Irradiation[2] for more than 20 years, until the late 1960s. Those practices were discontinued because of improved treatments were created and because of concerns with carcinogenesis. During this COVID-19 pandemic I feel we have woken up every day with a new recommendation in favor or against multiple clinical practices, too many to count. One of them is the use of face masks. At the beginning, it was not recommended, later it was recommended, most recently double masking is showing some evidence of effectiveness. My message is, make sure you stay on top of the updates, especially during this era of “information”, which some may later be called “the era of misinformation” or “the era of fake news”.  ____________________________For your Sanity: ***by “AJ” Arash Farzan, MS3A patient goes to the doctor and after a full discussion on diets the doctor says: “I guess you need to cut carbs”. The patient got very excited and asked: “Should I cut the with a fork or a knife?”Now we conclude our episode number 42 “Baker’s Cyst”, a common complaint in patients who have any kind of joint effusion such as ACL tears, meniscal tears, rheumatoid arthritis, but especially osteoarthritis. Remember our question for this month. What is the etiology of polyarthralgia in a 49-year-old female with increased fatigue for 1 month? What workup would you order (if any)? Clue: Listen carefully to the history of the patient. Send us your answer by email before March 22, 2021. Remember, even without trying, every night you go to bed being a little wiser.Thanks for listening to Rio Bravo qWeek. If you have any feedback about this podcast, contact us by email RBresidency@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. This podcast was created with educational purposes only. Visit your primary care physician for additional medical advice. This week we thank Hector Arreaza, Valerie Civelli, Terrance McGill, Ikenna Nwosu, and “AJ” Arash Farzan. Audio edition: Suraj Amrutia. See you next week!_____________________References:Smith Jennies, Sleep aids and dementia: Studies find both risks and benefits, MDedge News, August 7, 2019, https://www.mdedge.com/chestphysician/article/206002/alzheimers-cognition/sleep-aids-and-dementia-studies-find-both-risks?sso=true.NRI: General Information, Centers for Disease Control and Prevention, https://www.cdc.gov/nceh/radiation/nri/default.htm

Aging and chronic stress can obtain activation of CNS-resident microglia and astrocytes, that produce type 1 interferons (T1 IFNs) which signal through the heterodimeric IFN-α/β receptor (IFNAR) where receptor binding of T1 IFNs activates the JAK/STAT thus inducing IFN-stimulated genes (ISGs) which mediate both pro- and anti-inflammatory functions depending upon the cellular micro-environment. Now consider how aging is linked to elevated & activated leukocyte counts and it becomes clear that this is a patho-biochemical phenocopy to T cell acute lymphoblastc leukaemia (T-ALL) where signaling through Notch, Jak/Stat, PI3K/Akt/mTOR, and MAPK are shared. IL7-induced glucocorticoid resistance is diagnostic of certain subtypes of T-ALL and this is also associated with the senescence associated secretory phenotype of aging-linked morbidity and mortality. Finally, consider that chronic CNS stress leads to increased glucocorticoid production leading to a suppression of cell adhesion protein thus corrupting synaptic plasticity, memory re-formation, and cognitive acuity while promoting sarcopenia by stimulating proteasomal removal of contractile proteins and inhibiting the PI3-kinase/Akt pathway. Glucocorticoids also prevent IL-2 synthesis and secretion thus causing immune suppression by blocking T cell activation. J Neuroinflammation. 2019; 16: 236. Cytokine & Growth Factor Reviews, 22 Apr 2017, 35:85-96 --- Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.10.376327v1?rss=1 Authors: Frank, F., Liu, X., Ortlund, E. A. Abstract: The glucocorticoid receptor (GR) is a ligand-regulated transcription factor (TF) that controls the tissue- and gene-specific transactivation and transrepression of thousands of target genes. Distinct GR DNA binding sequences with activating or repressive activities have been identified, but how they modulate transcription in opposite ways is not known. We show that GR forms phase-separated condensates that specifically concentrate known co-regulators via their intrinsically disordered regions (IDRs) in vitro. A combination of dynamic, multivalent (between IDRs) and specific, stable interactions (between LxxLL motifs and the GR ligand binding domain) control the degree of recruitment. Importantly, GR DNA-binding directs the selective partitioning of co-regulators within GR condensates such that activating DNAs cause enhanced recruitment of co-activators. Our work shows that condensation controls GR function by modulating co-regulator recruitment and provides a mechanism for the up- and down-regulation of GR target genes controlled by distinct DNA recognition elements. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.07.330282v1?rss=1 Authors: Obleser, J., Kreitewolf, J., Vielhauer, R., Lindner, F., David, C., Oster, H., Tune, S. Abstract: Perceptual abilities fluctuate on time scales of seconds or minutes. However, it is unclear how slower, circadian neurobiological rhythms such as the expression of glucocorticoid (GC) hormones modulate our perceptual abilities. Here, we show that phasic, moderate increases in GC availability prove beneficial to auditory discrimination. In an age-varying sample of N = 68 healthy human participants, we characterise the covariation of saliva cortisol with perceptual sensitivity in an auditory pitch-discrimination task at five time points across the sleep--wake cycle. First, momentary saliva cortisol levels were captured well by the time relative to the wake-up cycle and overall sleep duration. Second, within individuals, higher cortisol levels just prior to behavioural testing improved participant's pitch discrimination abilities, expressed as a steepened psychometric curve. This effect of glucocorticoids on perceptual sensitivity held under a set of statistical control models. Our results pave the way for more in-depth studies on neuroendo-crinological determinants of sensory encoding and perception. Copy rights belong to original authors. Visit the link for more info

Pedro, Iago e Rapha debatem sobre 4 clinicagens sobre uma classe de medicamentos extremamente comum na prática: os corticoides. 1. Comp desmamar corticoide 2. Quais seus efeitos adversos 3. Quais os impactos dos corticoides na imunidade e 4. Existe alergia a corticoide?  Minutagem: (5:25) Desmame do corticoide  (18:17) Efeitos adversos do paciente em uso de corticoide (32:42) Infecção associadas ao corticoide  (38:35) Existe alergia a corticoide? (44:00) Salves (47:20) Resposta desafio anterior (troponina) (48:22) Desafio dessa semana Gostou do episódio? Tem algum comentário para nós? Manda uma mensagem no @tadeclinicagem ou tadeclinicagem@gmail.com. 1.Glucocorticoid Withdrawl. Daniel E Furst. Kenneth G Saag. Uptodate Agosto 2020. 2. HOCHBERG, Ze’ev; PACAK, Karel; CHROUSOS, George P. Endocrine withdrawal syndromes. Endocrine reviews, v. 24, n. 4, p. 523-538, 2003. 3. TORNATORE, Kathleen M. et al. Pharmacokinetics of methylprednisolone in elderly and young healthy males. Journal of the American Geriatrics Society, v. 42, n. 10, p. 1118-1122, 1994. 4. BYYNY, Richard L. Withdrawal from glucocorticoid therapy. New England Journal of Medicine, v. 295, n. 1, p. 30-32, 1976. 5. DONALD, R. A. Dexamethasone suppression of the plasma corticosterone response to stress in the rat. The Journal of physiology, v. 182, n. 3, p. 603, 1966. 6. FRASER, Charles G.; PREUSS, Fred S.; BIGFORD, Walter D. Adrenal atrophy and irreversible shock associated with cortisone therapy. Journal of the American Medical Association, v. 149, n. 17, p. 1542-1543, 1952. 7. JOSEPH, Rebecca M. et al. Systemic glucocorticoid therapy and adrenal insufficiency in adults: a systematic review. In: Seminars in arthritis and rheumatism. WB Saunders, 2016. p. 133-141. 8. VOLKMANN, Elizabeth R. et al. We still don’t know how to taper glucocorticoids in rheumatoid arthritis, and we can do better. 2013. 9. RICHTER, Bernd; NEISES, Gudrun; CLAR, Christine. Glucocorticoid withdrawal schemes in chronic medical disorders: A systematic review. In: Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. Centre for Reviews and Dissemination (UK), 2002. 10. Liu, Dora, et al. "A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy." Allergy, Asthma & Clinical Immunology 9.1 (2013): 30. 11. Saag, Kenneth et al. Major side effects of systemic glucocorticoids. Uptodate.com acesso em 02/09/2020 12 Harold N Rosenet al. Prevention and treatment of glucocorticoid-induced osteoporosis. Uptodate.com acesso em 02/09/2020

Dr Guerra discusses the Glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR) and its role in stabilizing T Regulatory cell populations relative to T memory cells and T effector Cells in healthy and End-Stage Renal Disease patients of differing chronological age. This plank is laid down to form the final structural foundations that allow us to examine dialectically, the role(s) of the Immune system on aging and the chronic and auto-immune diseases of the elderly. Published 08 September 2020 by DJGPhD. Please subscribe to Authentic Biochemistry and give us a % star review and please donate directly to the podcast or join our Patreon page https://anchor.fm/dr-daniel-j-guerra --- Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

Dr. Gianfranco Umberto Meduri, Professor of Pulmonary and Critical Care Medicine at the University of Tennessee Health Science Center, presents on glucocorticoid therapy in ARDS.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.03.280834v1?rss=1 Authors: Herzog, D. P., Perumal, N., Manicam, C., Treccani, G., Nadig, J., Rossmanith, M., Engelmann, J., Jene, T., Hasch, A., van der Kooij, M. A., Lieb, K., Gassen, N. C., Grus, F. H., Mueller, M. B. Abstract: The delayed onset of antidepressant action is a major shortcoming in depression treatment. Ketamine, an N-methyl-D-aspartate (NMDA)-receptor antagonist and, more recently, its metabolite (2R,6R)-hydroxynorketamine (HNK) have emerged as promising rapid-acting antidepressants. Still, knowledge about their mechanism of action remains fragmentary. In the present study, we first confirmed the antidepressant-responsive mouse strain DBA/2J to be a suitable strain sensitive to the effects of both ketamine and HNK. To decode the molecular pathways mediating HNKs rapid antidepressant effects, we took advantage of an in vivo approach enabling longitudinal proteome profiling of acute and sustained antidepressant-like effects of (2R,6R)-hydroxynorketamine (HNK) in cerebrospinal fluid (CSF) of conscious DBA/2J mice. Serial CSF samples were investigated using an unbiased, hypothesis-free mass spectrometry-based approach. We identified a total of 387 proteins in murine CSF, among them were several protein targets involved in the glucocorticoid receptor signaling pathway; thus revealing an intriguing mechanistic link between HNKs antidepressant mechanism of action and regulation of the stress hormone system. In addition, mTOR and BDNF were predicted to be important upstream regulators of HNK treatment. Our data substantially contribute to a more precise understanding of the temporal dynamics and molecular targets underlying HNKs rapid antidepressant-like effects, and can be used as a proteomic database supporting the development of improved treatment strategies for depression in the future. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.01.278556v1?rss=1 Authors: Taylor, W. W., Imhoff, B. R., Sathi, Z. S., Garza, K. M., Dias, B. G. Abstract: Dysfunctions in memory recall lead to pathological fear; a hallmark of trauma-related disorders, like Post-Traumatic Stress Disorder (PTSD). Heightened recall of an association between a cue and trauma, as well as impoverished recall that a previously trauma-related cue is no longer a threat both result in a debilitating fear toward the cue. Glucocorticoid-mediated action via the glucocorticoid receptor (GR) influences memory recall. This literature has primarily focused on GRs expressed in neurons or ignored cell-type specific contributions. To ask how GR action in non-neuronal cells influences memory recall, we combined auditory fear conditioning in mice and the knockout of GRs in astrocytes in the prefrontal cortex (PFC), a brain region implicated in memory recall. We found that GRs in astrocytes in the PFC calibrate recall in female but not male mice. Specifically, we found that knocking out GRs in astrocytes in the PFC of female mice (AstroGRKO) after fear conditioning resulted in higher recall of fear to the CS+ tone when compared to controls (AstroGRintact). While we did not find any differences in extinction of fear toward the CS+ between these groups, AstroGRKO female mice showed impaired recall of extinction training. We did not observe any significant results in male mice. These results suggest a sex-specific calibration of memory recall by GRs in astrocytes in the PFC. These data demonstrate the need to examine GR action in cortical astrocytes to elucidate the basic neurobiology underlying memory recall and potential mechanisms that underlie female-specific biases in the incidence of PTSD. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.05.078386v1?rss=1 Authors: Moser, D. A., Mueller, S., Hummel, E. M., Limberg, A., Dieckmann, L., Frach, L., Pakusch, J., Flasbeck, V., Bruene, M., Beygo, J., Klein-Hitpass, L., Kumsta, R. Abstract: DNA methylation analysis is increasingly used in stress research. Available methods are expensive, laborious and often limited by either the analysis of short CpG stretches or low assay sensitivity. Here, we present a cost-efficient next generation sequencing-based strategy for the simultaneous investigation of multiple candidate genes in large cohorts. To illustrate the method, we present analysis of four candidate genes commonly assessed in psychoneuroendocrine research: Glucocorticoid receptor (NR3C1), Serotonin transporter (SLC6A4), FKBP Prolyl isomerase 5 (FKBP5), and the Oxytocin receptor (OXTR). DNA methylation standards and DNA of a female and male donor were bisulfite treated in three independent trials and were used to generate sequencing libraries for 42 CpGs from the NR3C1 1F promoter region, 83 CpGs of the SLC6A4 5' regulatory region, 5 CpGs located in FKBP5 intron 7, and additional 12 CpGs located in a potential enhancer element in intron 3 of the OXTR. In addition, DNA of 45 patients with borderline personality disorder (BPD) and 45 healthy controls was assayed. Multiplex libraries of all samples were sequenced on a MiSeq system and analyzed for mean methylation values of all CpG sites using amplikyzer2 software. Results indicated excellent accuracy of the assays when investigating replicates generated from the same bisulfite converted DNA, and very high linearity (R2 > 0.9) of the assays shown by the analysis of differentially methylated DNA standards. Comparing DNA methylation between BPD and healthy controls revealed no biologically relevant differences. The technical approach as described here facilitates targeted DNA methylation analysis and represents a highly sensitive, cost-efficient and high throughput tool to close the gap between coverage and precision in epigenetic research of stress-associated phenotypes. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.27.064725v1?rss=1 Authors: Rasiah, N., Rosenegger, D., Daviu Abant, N., Fuzesi, T., Muir, J., Sterley, T. L., Bains, J. S. Abstract: An increase in circulating glucocorticoids (CORT) is an essential part of the response to stress. Sustained elevations of CORT, however, have dramatic consequences on behavior, endocrine systems and peripheral organs. Critically, they dampen the endocrine response to acute challenges and decrease intrinsic excitability of corticotropin-releasing hormone neurons in the paraventricular nucleus (CRHPVN), suggesting key circuits may be less responsive to stress. Here, we make the surprising discovery that CRHPVN neurons harness a form of adaptive synaptic scaling to escape the persistent negative feedback pressure from CORT and maintain stable output in vivo. Specifically, there is an increase in glutamatergic drive to these cells that is mediated by a postsynaptic, multiplicative increase in synaptic strength. These findings suggest that dysfunctions associated with chronic stress may not be due to the primary actions of CORT, but instead reflect the emergence of synaptic adaptations as networks seek to re-establish intrinsic activity setpoints. Copy rights belong to original authors. Visit the link for more info

Growth Hormone Belly Button and Oral Steroid Overdose - The Steroids Podcast Episode 25 https://steroidspodcast.com Daily Text Msg Coaching $99/month and 1 Hour Phone Call Consult $59 Send Email to inquire about Coaching to "Steroidspodcast@gmail.com" ULTIMATE GUIDE TO ROIDS #1 BOOK ON TRUTH IN THE HISTORY OF BODYBUILDING https://bodybuilderinthailand.com/ultimate-guide-to-roids/ 0:00 Why do so many bodybuilders have a hernia on their belly button 2:50 Growth hormone gut distension 3:45 My umbilical hernia story from growth hormone and heavy lifting and my subsequent HGH belly button hernia surgery 5:00 The steroids I used to make the jump to where i am obviously on steroids 6:15 HGH Dick 6:55 Heavy Weight Lifting has risks 7:55 Youtube comments by the official steroids podcast crew of listeners 9:00 what an umbilical hernia looks like in bodybuilders 10:35 Joesthetics Joe Linder on Instagram has an umbilical hernia 12:00 The belly button is an area very sensitive to HGH 12:45 Black guys are genetically predisposed to herniated belly button and on them is not a sign of HGH use 13:45 Results of my growth hormone belly button hernia surgery 17:15 Why Steroid Esters take time to Kick in - Why aren't the full effects of steroids felt immediately 18:45 How the Androgen Receptor works 21:50 Glucocorticoid receptors and anabolic steroids 23:35 Front Loading a steroid cycle in order to get the muscle gains and strength kicking in faster 25:40 My first ever steroid injection 27:00 What age to start HGH anti aging therapy 29:00 Skin Tightens up on growth hormone - Growth hormone effects on the skin and collagen 31:20 Jacked up IFBB Pro tells you he is not on a lot of steroids 33:14 Side effects from Running 500mg Testosterone Enanthate per Week Year Round 36:35 human and dog both experience Linear response of increased muscle in strength as testosterone dosage is increased 38:55 Superdrol toxicity 40:55 Oral Steroid Toxicity Explained 41:45 Long term risk of steroid use 44:00 Oral steroids danger is generally not 'acute' it is 'cumulative' 46:00 Dianabol overdose 48:30 Nutrient Partitioning Effects of Superdrol Methasteron 50:30 A few weeks on superdrol can completely change the appearance of a person 53:00 Superdrol Cycle Results 54:10 Supedrol dosages and toxicity This Podcast is for entertainment and conversational purposes only. This author does not support the use of illegal performance enhancing drugs. If any substances mentioned in this video are illegal in your country do not use them. Consult a doctor before beginning any exercise or supplement routine. Do not take anything mentioned in this video as advice. It is simply conversation, not advice.

A 50-year-old gentleman presents with severe headaches and speech disturbance. The MRI shows acute strokes and multifocal vascular irregularities. Is it reversible cerebral vasoconstriction syndrome or primary angiitis of the central nervous system? Or is it something else entirely? RCVS and PACNS almost always pose a challenge--even to the most astute neurologist. But, because they are treated entirely differently and their clinical trajectories depend on these treatments, it is worth knowing how experts distinguish the two. This week on the BrainWaves podcast, Dr. Jesse Thon joins Jim Siegler in a discussion about the clinical and radiographic features of these two conditions, and shares his experience in managing these patients. Produced by James E. Siegler and Jesse Thon. Music courtesy of Nuno Adelaida, Peter Rudenko on the piano, Squire Tuck on the guitar, Swelling, and Uncanny. Sound effects by Mike Koenig and Daniel Simion. BrainWaves' podcasts and online content are intended for medical education only and should not be used for clinical decision making. Be sure to follow us on Twitter @brainwavesaudio for the latest updates to the podcast. REFERENCES Singhal AB. Diagnostic challenges in RCVS, PACNS, and other cerebral arteriopathies. Cephalalgia. 2011;31:1067-70. Miller TR, Shivashankar R, Mossa-Basha M and Gandhi D. Reversible Cerebral Vasoconstriction Syndrome, Part 2: Diagnostic Work-Up, Imaging Evaluation, and Differential Diagnosis. AJNR American journal of neuroradiology. 2015;36:1580-8. Miller TR, Shivashankar R, Mossa-Basha M and Gandhi D. Reversible Cerebral Vasoconstriction Syndrome, Part 1: Epidemiology, Pathogenesis, and Clinical Course. AJNR American journal of neuroradiology. 2015;36:1392-9. Singhal AB, Topcuoglu MA, Fok JW, Kursun O, Nogueira RG, Frosch MP and Caviness VS, Jr. Reversible cerebral vasoconstriction syndromes and primary angiitis of the central nervous system: clinical, imaging, and angiographic comparison. Annals of neurology. 2016;79:882-94. Singhal AB and Topcuoglu MA. Glucocorticoid-associated worsening in reversible cerebral vasoconstriction syndrome. Neurology. 2017;88:228-236. Rocha EA, Topcuoglu MA, Silva GS and Singhal AB. RCVS2 score and diagnostic approach for reversible cerebral vasoconstriction syndrome. Neurology. 2019;92:e639-e647. Birnbaum J and Hellmann DB. Primary angiitis of the central nervous system. Archives of neurology. 2009;66:704-9.

What are your favourite sports medicine research articles from 2018? This week, we are excited to share an AMSSM Sport Medcast hosted by Drs Scott Young and Dr. Meghan Raleigh In this abbreviated episode, learn about the latest research regarding: · Treatment of Achilles tendinopathy · Effect of NSAIDs on bone healing rates · Management of lateral hip pain · Exercise as medicine for concussion · Physiotherapy vs surgery for meniscal tears To listen to the full episode and learn about all ten studies, please visit the AMSSM’s website: https://www.amssm.org/E-Learning.php Further reading: Johannsen F, Jensen S, Wetke E. 10-year follow-up after standardised treatment for Achilles tendinopathy. BMJ open sport & exercise medicine. 2018 Oct 1;4(1):e000415. Wheatley BM, Nappo KE, Christensen DL, Holman AM, Brooks DI, Potter BK. Effect of NSAIDs on Bone Healing Rates: A Meta-analysis. JAAOS-Journal of the American Academy of Orthopaedic Surgeons. 2019 Apr 1;27(7):e330-6. Nissen MJ, Brulhart L, Faundez A, Finckh A, Courvoisier DS, Genevay S. Glucocorticoid injections for greater trochanteric pain syndrome: a randomised double-blind placebo-controlled (GLUTEAL) trial. Clinical rheumatology. 2019 Mar 14;38(3):647-55. Leddy JJ, Haider MN, Ellis M, Willer BS. Exercise is medicine for concussion. Current sports medicine reports. 2018 Aug 1;17(8):262-70. van de Graaf VA, Noorduyn JC, Willigenburg NW, Butter IK, de Gast A, Mol BW, Saris DB, Twisk JW, Poolman RW. Effect of early surgery vs physical therapy on knee function among patients with nonobstructive meniscal tears: the ESCAPE randomized clinical trial. Jama. 2018 Oct 2;320(13):1328-37.

Less is More: A Journal Club on the Impact of Reducing Glucocorticoid Use in Patients With Severe Asthma

Less is More: A Journal Club on the Impact of Reducing Glucocorticoid Use in Patients With Severe Asthma

Less is More: A Journal Club on the Impact of Reducing Glucocorticoid Use in Patients With Severe Asthma

Dr Megan Holmes of the University of Edinburgh talks to NEN at ICN 2018 Toronto about early life stress and glucocorticoid signaling and the problems it has on longterm outcomes.   Interview by Dr. Julie Ann Lough

David Walker, a Ph.D. student at The University of St Andrews in Scotland discusses his research looking at the impact of early life stress and long-term outcomes in quails. He also explored the impact of the hormonal stress response later in life.  Interview by Dr. Julie Ann Lough Published in: David J. Walker, Cédric Zimmer, Maria Larriva, Susan D. Healy, Karen A. Spencer. Early-life adversity programs long-term cytokine and microglia expression within the HPA axis in female Japanese quail. Journal of Experimental Biology 2019 : jeb.187039 doi: 10.1242/jeb.187039 Walker DJ, Spencer KA. Glucocorticoid programming of neuroimmune function. Gen Comp Endocrinol. 2018;256:80-88.

In this podcast Dr Marcelo Paez-Pereda talks about his recent paper 'A C-terminal HSP90 inhibitor restores glucocorticoid sensitivity and relieves a mouse allograft model of Cushing disease.' published in Nature Medicine, February 2015.

1) Glucocorticoid-associated worsening in reversible cerebral vasoconstriction syndrome2) What's Trending: Upcoming changes regarding the Neurology® Resident & Fellow section 3) Topic of the Month: Neuromuscular topicsThis podcast begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the January 17, 2017 issue of Neurology. In the first segment, Dr. Andy Southerland talks with Dr. Aneesh Singhal about his paper on glucocorticoid-associated worsening of reversible cerebral vasoconstriction syndrome. Dr. Ted Burns talks with Dr. Roy Strowd about upcoming changes regarding the Neurology Resident & Fellow section for our “What's Trending” feature of the week. In the next part of the podcast, Dr. Ted Burns focuses his interview with Dr. Volker Straub on limb-girdle dystrophy. Disclosures can be found at Neurology.org.DISCLOSURES: Dr. Southerland serves as Podcast Deputy Editor for Neurology; receives research support from the American Heart Association-American Stroke Association National Clinical Research Program, American Academy of Neurology, American Board of Psychiatry and Neurology, Health Resources Services Administration and the NIH; has a provisional patent application titled: “Method, system and computer readable medium for improving treatment times for rapid evaluation of acute stroke via mobile telemedicine;” and gave legal expert review. Dr. Aneesh Singhal has served on the scientific advisory boards of Biogen and DSMB; has served on the editorial board of Medical Gas Research; has received publishing royalties for the book Reversible Cerebral Vasoconstriction Syndromes; has been a consultant to Biogen; has acted as an event adjudicator for the Thrombolysis in Myocardial Infarction (TIMI) Trial Group; has received research support from Boehringer Ingelheim, NIH-NINDS, the American Academy of Neurology, UpToDate, and Medlink; and has served as a medicolegal expert witness for individual cases concerning stroke. Dr. Burns serves as Podcast Editor for Neurology®; and has received research support for consulting activities with UCB, CSL Behring, Walgreens and Alexion Pharmaceuticals, Inc. Dr. Strowd serves on the editorial team for the Neurology® Resident and Fellow Section. Dr. Straub has served on the scientific advisory boards for Pfizer, Italfarmaco, Audentes Therapeutics, Bristol-Myer Squibb, Summit Therapeutics, Tivorsan, and the Nationwide Children's Hospital; has received travel funding and speaker honoraria from Sanofi Genzyme; has served on the editorial boards of Neuromuscular Disorders, the Journal of Neuromuscular Diseases, and PLoS Currents Muscular Dystrophy; has been a consultant for Sanofi Genzyme; and has received research support from Sanofi Genzyme, BioMarin, Ionis Pharmaceuticals, Sarepta Therapeutics, Ultragenyx, the European Commission, the UK Medical Research Council, Newcastle University, the Parent Project Muscular Dystrophy, the Association Fracaise Contre les Myopathies, the LGMD2I Research Fund, the Wellcome Trust, the Sylvia Aitken Charitable Trust, Muscular Dystrophy UK, and Action Medical Research.All other participants have no disclosures.

Jeremy Cohen took us on an Adrenal Function journey at SMACC Chicago with his talk Raging Hormones in Critical Care. Cohen explores the natural roll of cortisol in the human body, various schools of thought and recent research in the areas of sepsis and cortisol resistance.

The Glucocorticoid Receptor (starts at 5:30): We interview Dr. Miles Pufall who studies the glucocorticoid receptor, a protein in cell membranes that is the target of drugs used to treat a variety of conditions from asthma to cancer. Binding cortisol causes the receptor to be moved to the nucleus where it turns on (or off) numerous genes. One of the big questions is how does each cell type 'know' which genes should be targeted? Hosts: Beth Bennett, Joel Parker Producer: Beth Bennett Engineer: Beth Bennett Additional Contributions: Joel Parker, Susan Moran Executive Producer: Joel Parker Listen to the show:

Todd Rosen and Bingbing Wang report on an epigenetic mechanism by which glucocorticoids trigger placental expression of a stress hormone associated with labor.

SRJ Episode 05, Volume 1(1) by Sussman and Mautner

Epigenetic programming facilitates the adaptation of an organism to changes in the environment through lasting alterations in gene expression that underlie certain physical and behavioral phenotypes. Exposure to adverse events in early postnatal life is known to increase the risk for stress-related psychiatric disorders later on. Our previous studies showed that early-life stress (ELS) in mice caused by periodic infant-mother separation (MS) leads to increased hyperactivity of the HPA axis, reduced glucocorticoid feedback inhibition, and depressive-like behavior. Moreover, our work revealed ELS-induced hypomethylation of the arginine vasopressin (Avp) gene enhancer and pro-opiomelanocortin (Pomc) promoter. The aim of the study was to investigate whether ELS can also lead to epigenetic programming of the mouse glucocorticoid receptor (GR, Nr3c1). GR is a major feedback regulator of the hypothalamic-pituitary adrenal (HPA) stress axis and its expression is regulated by multiple promoters associated with its5’ untranslated first exons. Given the fact that the mouse GR promoter was only partly characterized, we aimed to determine its genomic structure. In addition, tissue distribution and absolute quantification of newly identified alternative first exon transcripts were analysed. Although most of the first exon transcripts were found to be widely expressed, some of them are shown to be differentially regulated by growth factor- and depolarization-induced signaling. In the present work we show also that mice with a history of maternal separation display up-regulated GR mRNA levels. This observation was confined to Crh-producing neurons in the hypothalamic paraventricular nucleus (PVN), which are principal effectors of the stress response. Moreover, elevated levels of GR are shown to be responsible for stronger induction of its downstream target genes (Fkbp5, Sgk1, and DUSP1), which suggests an enhanced transcriptional activity of the GR in ELS mice. This effect is supported by a higher occupancy of the GR at the glucocorticoid response elements (GREs), following corticosterone injection (i.p.). Finally, we report here that an enhanced level of GR expression in ELS mice is accompanied by an increased methylation of specific CpG residues at the CpG island shore region of the GR promoter. These ELS-responsive CpGs comprise a DNA binding site for the transcriptional repressor Yin Yang 1 (YY1). Given the high homology of the mouse and human GR promoter, and the conservation of the YY1 binding site, we conducted a methylation analysis of the hGR CpG island shore region in peripheral tissues and post mortem brain samples. Our findings might serve as a basis for comparing the methylation patterns in tissues from control subjects and patients with stress-related brain disorders.

The main function of glucocorticoids in corticotroph cells is to suppress proopiomelanocortin, the precursor of the stress hormone adrenocorticotropin (ACTH). Cushing’s disease is a rare but severe neuroendocrine condition caused by partially glucocorticoid resistant corticotroph adenomas, which consequently secrete excessive amounts of ACTH in an uncontrolled fashion. The patients suffer from chronic hypercortisolism due to excessive stimulation of the adrenal glands by ACTH to produce glucocorticoids. Impairing mutations of the glucocorticoid receptor (GR) only sporadically explain the reduced glucocorticoid sensitivity in the adenomas – the molecular mechanism behind the partial resistance is poorly understood. The function of GR depends on direct interactions with the molecular chaperone Hsp90. Both the reduction and overexpression of Hsp90 impedes GR activity in different experimental settings. Therefore, the expression of the inducible Hsp90α isoform was determined in biopsy specimens of corticotroph pituitary adenomas from patients with Cushing’s disease. Its strong overexpression compared to normal human pituitary cells paved the way to study its role in the function of corticotroph adenomas using small molecules which target Hsp90. The three distinct Hsp90 inhibitors 17–AAG, Novobiocin and Silibinin showed antiproliferative effects in AtT–20 cells through the degradation of the oncogenic client kinase Cdc2, a hallmark of pharmacologic inhibition of Hsp90. Surprisingly, only the N–terminal Hsp90 inhibitor 17–AAG caused the degradation of GR, as was reported also for other Geldanamycin–based Hsp90 inhibitors. Neither Silibinin nor the C–terminal Hsp90 inhibitor Novobiocin affected GR protein levels. These converging effects led to the assumption that both compounds bind to the same domain in Hsp90. It was shown here that Novobiocin displaces Silibinin from the C–terminal domain of Hsp90, and that these compounds dissociate mature GR from Hsp90 at the biochemical level. As a result, increased levels of mature receptor were present in the cell able to bind glucocorticoids with high affinity. This novel molecular mechanism proved to potentiate GR transcriptional activity in AtT–20 cells. The potentiation in GR activity also led to enhanced suppression of ACTH elicited by low concentrations of Dexamethasone in AtT–20 cells and in primary cultures of human corticotroph adenomas from patients with Cushing’s disease. In contrast, Silibinin did not show effects on rat normal pituitary cells. Finally, Silibinin reduced tumor growth, partially reverted hormonal alterations, and alleviated symptoms in a mouse allograft model for Cushing’s disease. These results suggest that the regulation of GR sensitivity by overexpressed Hsp90 may represent a pharmacologically reversible mechanism in the pathogenesis of this disease. Together, a proof of principle is provided that the clinically safe Hsp90 inhibitor Silibinin potentially restores glucocorticoid sensitivity in corticotroph adenomas in vitro and in vivo, and that it might be used to treat Cushing’s patients in the future.

Interview with Jonas Rutishauser, MD, author of Short-term vs Conventional Glucocorticoid Therapy in Acute Exacerbations of Chronic Obstructive Pulmonary Disease: The REDUCE Randomized Clinical Trial

Presented by Kristi Watterberg, MD

Presented by Kristi Watterberg, MD

Background: Endocannabinoids (ECs) are rapidly acting immune-modulatory lipid-signaling molecules that are important for adaptation to stressful and aversive situations. They are known to interact with glucocorticoids and other stress-responsive systems. Maladaptation to acute or chronic stress represents a major risk factor for the development of psychiatric disorders. In the present study, we administered stress doses of hydrocortisone in a prospective, randomized, placebo-controlled double-blind study in patients undergoing cardiac surgery (CS) to examine the relationship between the use of glucocorticoids, plasma EC levels, and the occurrence of early postoperative cognitive dysfunction (delirium) and of later development of depression. Methods: We determined plasma levels of the ECs anandamide and 2-arachidonoylglycerol (2-AG) in CS patients of the hydrocortisone (n=56) and the placebo group (n=55) preoperatively, at postoperative day (POD) 1, at intensive care unit discharge, and at 6 months after CS (n=68). Postoperative delirium was diagnosed according to Diagnostic and Statistical Manual of the American Psychiatric Association IVth Edition (DSM-IV) criteria, and depression was determined by validated questionnaires and a standardized psychological interview (Structured Clinical Interview for DSM-IV). Results: Stress doses of hydrocortisone did not affect plasma EC levels and the occurrence of delirium or depression. However, patients who developed delirium on POD 1 had significantly lower preoperative 2-AG levels of the neuroprotective EC 2-AG (median values, 3.8 vs. 11.3 ng/ml; p=0.03). Preoperative 2-AG concentrations were predictive of postoperative delirium (sensitivity=0.70; specificity=0.69; cutoff value=4.9 ng/ml; receiver operating characteristic curve area=0.70; 95% confidence interval=0.54-0.85). Patients with depression at 6 months after CS (n=16) had significantly lower anandamide and 2-AG levels during the perioperative period. Conclusions: A low perioperative EC response may indicate an increased risk for early cognitive dysfunction and long-term depression in patients after CS. Glucocorticoids do not seem to influence this relationship.

Patients with glucocorticoid-remediable aldosteronism (GRA) possess a chimeric gene resulting from fusion of the genes encoding steroid aldosterone synthase and 11 beta-hydroxylase. In the adrenal zona fasciculata, this may lead to ectopic expression under ACTH control of aldosterone synthase activity and increased formation of cortisol C18 oxidation products. We assessed mineralocorticoid and glucocorticoid pathways in three patients with GRA. Baseline plasma progesterone, 17 alpha-hydroxyprogesterone, corticosterone, and cortisol were normal in all patients, whereas 11-deoxycorticosterone, aldosterone, and 11-deoxycortisol were above normal. The ratios of both corticosterone/11-deoxycorticosterone and cortisol/11-deoxycortisol were abnormally low, and decreased further 60 min after administration of ACTH-(1-24) (250 micrograms) as an i.v. bolus. A low corticosterone/11-deoxycorticosterone ratio is consistent with an increased aldosterone synthase activity forming aldosterone by corticosterone. Similarly, a decreased cortisol/11-deoxycortisol ratio could reflect enhanced cortisol C18 oxidation. Our findings are in agreement with a hyperfunction of the 11 beta-hydroxylase/aldosterone synthase complex in the adrenal zona fasciculata of GRA induced by the new chimeric gene.

Glucocorticoid hormones suppress the secretion of ACTH evoked by secretagogues such as CRF and arginine vasopressin. In this study, we investigated the effects of glucocorticoids on ACTH release induced by oxytocin (OT) and on intracellular free calcium ion levels in corticotropes prepared from the adenohypophyses of female Wistar rats. Pulsatile additions of physiological concentration of OT (10 nM) to superfused anterior pituitary cells caused pulsatile ACTH release about 4-fold above basal secretion with similar peak amounts of ACTH during subsequent OT pulses. Exposure of the cells to corticosterone (100 nM) or to a selective glucocorticoid receptor agonist RU 28362 (100 nM) for 30 min suppressed OT-stimulated but not basal ACTH release by approximately 60%. Inhibition gradually disappeared during subsequent pulses of OT in the absence of corticosterone. Pretreatment with the selective antagonist RU 38486 (1 microM) completely blocked the inhibitory effect of corticosterone on OT-induced ACTH secretion. Changes in free cytosolic calcium levels in single cultured pituitary cells were measured using the calcium indicator Fura-2. OT caused calcium transients in corticotropes, which were identified by immunocytochemistry. They responded in a similar manner to a second OT stimulus when preincubated for 30 min with corticosterone (1 microM) or with RU 28362 (1 microM). Our data indicate that glucocorticoids, via glucocorticoid receptors, rapidly inhibit OT-stimulated ACTH secretion by corticotropes without affecting intracellular calcium transients due to OT. Therefore, we conclude that rapid inhibition of ACTH release by glucocorticoids interferes with cellular signal transduction beyond the step of calcium mobilization.

Sun, 1 Jan 1989 12:00:00 +0100 http://epub.ub.uni-muenchen.de/3208/ http://epub.ub.uni-muenchen.de/3208/1/005.pdf Strähle, Uwe; Boshart, Michael; Klock, G.; Stewart, A. F.; Schütz, Günther Strähle, Uwe; Boshart, Michael; Klock, G.; Stewart, A. F. und Schütz, Günther (1989): Glucocorticoid- and progesterone-specific effects are determined by differential expression of the respective hormone receptors. In: Nature, Vol. 339: pp. 6

Two glucocorticoid response elements (GREs) located 2.5 kb upstream of the transcription initiation site of the tyrosine aminotransferase gene were identified by gene transfer experiments and shown to bind to purified glucocorticoid receptor. Although the proximal GRE has no inherent capacity by itself to stimulate transcription, when present in conjunction with the distal GRE, this element synergistically enhances glucocorticoid induction of gene expression. Cooperativity of the two GREs is maintained when they are transposed upstream of a heterologous promoter. An oligonucleotide of 22 bp representing the distal GRE is sufficient to confer glucocorticoid inducibility. As evidenced by the mapping of DNAase I hypersensitive sites, local alterations in the structure of chromatin at the GREs take place as a consequence of hormonal treatment.

Wed, 1 Jan 1986 12:00:00 +0100 https://epub.ub.uni-muenchen.de/7666/1/in_vivo_protein-dna_interactions_7666.pdf Schütz, Günther; Strähle, Uwe; Schmid, Wolfgang; Gloss, Bernd; Becker, Peter B.