Podcasts about trpv1

Czy CBGA zmieni rynek konopny? te i inne kwestie podejmujemy w rozmowie z udziałem dr. Łukasza Kiragi, wiodącego eksperta w badaniach nad kannabinoidami. Zanurz się w świat CBGA, prekursora CBD i THC, i poznaj jego potencjał do rewolucjonizacji przemysłu konopnego. Dr Kiraga dzieli się wglądem w terapeutyczne korzyści CBGA, trendy rynkowe i wyzwania regulacyjne, co czyni ten odcinek must-listen dla entuzjastów cannabis i profesjonalistów z branży. Dr Łukasz Kiraga dzieli się wynikami przełomowych badań, wskazując, że CBGA działa przeciwdrgawkowo silniej niż CBD, a także efektywniej przenika do organizmu. Odcinek pełen jest naukowych faktów, które mogą zrewolucjonizować nie tylko rynek konopny, ale także podejście do terapii wielu ciężkich chorób.Więcej informacji i dodatkowe materiały edukacyjne znajdziesz na mojej stronie www.rozmowykonopne.pl oraz na moich profilach społecznościowych. Zapisz się na newsletter i otrzymuj cotygodniowe podsumowania odcinków oraz ekskluzywne treści!Czego się dowiesz z tego odcinka:✅ Dlaczego CBGA nazywane jest „ojcem” wszystkich kanabinoidów.✅ W jaki sposób CBGA przewyższa inne kanabinoidy w terapii padaczki lekoodpornej.✅ Potencjalne zastosowanie CBGA w leczeniu chorób autoimmunologicznych, jak choroba Crohna, IBD, padaczka lekooporna, neurodegeneracja (Alzheimer), a nawet rak sutka.✅ Jak wygląda wchłanianie CBGA w organizmie.✅ Przyszłe kierunki badań naukowych nad CBGA i ich znaczenie terapeutyczne.✅ W badaniach wchłania się 40x lepiej niż CBG i wykazuje silne działanie przeciwdrgawkowe.Kluczowe tematy z wywiadu:CBGA jako prekursor wszystkich fitokannabinoidów („ojciec wszystkich fitokannabinoidów”).Wyjątkowe właściwości CBGA (przeciwdrgawkowe, przeciwzapalne, przeciwwymiotne, przeciwlękowe, przeciwdepresyjne, przeciwzwłóknieniowe).Potencjalne zastosowanie CBGA w leczeniu chorób autoimmunologicznych (choroba Crohna, nieswoiste zapalenie jelit).Wysoka biodostępność CBGA w porównaniu do CBG.Możliwość synergii z innymi fitokannabinoidami.Nowatorskie metody podawania (mikrokapsułkowanie).Badania na zwierzętach, potencjalne przyszłe badania kliniczne.Rola receptorów (TRPM7, TRPV1, GPR55, 5HT3, 5HT1α).Potencjał terapeutyczny w padaczkach lekkoopornych.Unikalność badań prowadzonych w Polsce przez doktora Kiragę.Spotify: https://spoti.fi/3FXqgJ0YouTube: https://bit.ly/4ji1xgX

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.

In der heutigen Folge des Podcasts "Der Schmerzcode" tauchen Jan-Peer und Marco tief in das Mysterium des Schmerzes ein. Sie beginnen mit der Überarbeitung der Definition von Schmerz durch die International Association for the Study of Pain aus dem Jahr 2020 und diskutieren seine Komplexität als unangenehmes Sinnes- und Gefühlserlebnis. Die Einteilung des Schmerzes in akute und chronische Formen sowie deren individualisierte Therapieansätze stehen im Fokus ihrer Betrachtung. Die Hosts unterstreichen die psychosozialen und emotionalen Faktoren, die zu chronischen Schmerzen führen können und betonen die Notwendigkeit eines ganzheitlichen Behandlungsansatzes. In der fortgesetzten Diskussion konzentrieren sich Jan-Peer und Marco auf die verschiedenen Arten von Schmerz, darunter akuter Schmerz, nozizeptiver Schmerz und neuropathischer Schmerz. Sie erläutern die Entstehung und Wahrnehmung dieser Schmerztypen sowie die Unterschiede zwischen somatischem und viszeralem Schmerz. Die Reaktionen des Körpers auf Schmerz, wie Blutdruckveränderungen und die Interaktion zwischen dem sympathischen und parasympathischen Nervensystem, werden thematisiert. Die Vertiefung der Diskussion führt zu einem Verständnis der Schmerzweiterleitung über das Rückenmark und der übertragenen Schmerzen bei Organoperationen. Der Einfluss von Rezeptoren wie TRP-Rezeptoren auf die Schmerzwahrnehmung und -weiterleitung wird beleuchtet. Die Aktivierung und Sensibilisierung dieser Rezeptoren durch physische und chemische Reize sowie deren Auswirkungen auf die Schmerzsignale werden detailliert erläutert. Die Rolle von Calcium und Magnesium bei der Schmerzübertragung wird ebenfalls hervorgehoben. Weiterführend diskutieren Jan-Peer und Marco die Bedeutung von TRP-Rezeptoren, insbesondere TRPV1 und TRPV4, für die Schmerzwahrnehmung, genetische Mutationen in Natriumkanälen und mögliche Therapieansätze für Schmerzen. Sie geben Einblicke in die Schmerzweiterleitung über myelinisierte und unmyelinisierte Nervenfasern und vergleichen die Geschwindigkeiten mit Laufgeschwindigkeiten von Usain Bolt. Die Zukunftsaussichten des Podcasts beinhalten eine vertiefte Betrachtung der Schmerzweiterleitung auf zellulärer Ebene und der Schmerzverschaltung, in der Hoffnung, ein tieferes Verständnis der Schmerzmechanismen zu vermitteln.

La consommation d'un chili ou d'un tajine un peu relevé s'accompagne, chez de nombreuses personnes, d'une sensation marquée de chaleur. La hausse de la température corporelle, bien réelle, se traduit par une transpiration plus abondante. Explorons la physiologie consécutive à la consommation de nourriture épicée pour comprendre ce ressenti soudain de chaleur.Les composés présents dans les épicesLes épices connues pour conférer une hausse de température corporelle contiennent des composés chimiques bien précis. Le piment, par exemple, est riche en capsaïcine. Le poivre noir, lui, contient de la pipérine. Ces molécules interagissent de façon spécifique avec des récepteurs présents dans la bouche et l'estomac.Nommés récepteurs TRPV1, ces derniers enclenchent une série de réponses physiologiques. Lorsqu'un composé d'une épice se lie au récepteur, celui-ci informe le cerveau d'une sensation de brûlure similaire à celle provoquée par la chaleur. Bien qu'il n'y ait pas de source réelle de chaleur externe, le corps réagit comme si c'était le cas. Il active son système nerveux et libère des substances chimiques dans l'organisme pour lutter contre l'agression présumée.Les conséquences de l'activation des récepteurs TRPV1À la suite de l'interaction des molécules des épices avec les récepteurs TRPV1, une cascade de réactions se produit. Le corps libère des neuropeptides, activateurs du système nerveux, qui provoquent une légère inflammation. L'un des symptômes de l'inflammation est justement la hausse de la chaleur, qui aide à dilater les vaisseaux. Le sang circule mieux et plus vite pour propager les globules blancs vers le lieu de l'inflammation.La température corporelle augmente donc sous l'effet cumulé de la réponse inflammatoire et de l'activation du système nerveux. Pour se refroidir, l'organisme libère de la transpiration.La hausse du métabolismeEn plus de l'inflammation, le corps subit parfois une hausse de son métabolisme. La capsaïcine du piment, la pipérine du poivre, les ginsénosides du ginseng amplifient la thermogénèse. Ce processus de régulation de la température interne conduit à une consommation plus élevée de calories, avec une libération plus importante de chaleur dans le corps. Cet effet de courte durée est néanmoins mis en avant par les fabricants de compléments alimentaires destinés à accompagner la perte de poids.Une sensibilité variableDes facteurs génétiques et environnementaux jouent dans la perception plus ou moins marquée de chaleur lors de la consommation d'épices. Les populations habituées dès le plus jeune âge à consommer des plats épicés sont généralement plus tolérantes à leurs effets sur la température corporelle. À l'inverse, les peuplades qui consomment peut d'épices les tolèrent souvent moins bien. Hébergé par Acast. Visitez acast.com/privacy pour plus d'informations.

La consommation d'un chili ou d'un tajine un peu relevé s'accompagne, chez de nombreuses personnes, d'une sensation marquée de chaleur. La hausse de la température corporelle, bien réelle, se traduit par une transpiration plus abondante. Explorons la physiologie consécutive à la consommation de nourriture épicée pour comprendre ce ressenti soudain de chaleur. Les composés présents dans les épices Les épices connues pour conférer une hausse de température corporelle contiennent des composés chimiques bien précis. Le piment, par exemple, est riche en capsaïcine. Le poivre noir, lui, contient de la pipérine. Ces molécules interagissent de façon spécifique avec des récepteurs présents dans la bouche et l'estomac. Nommés récepteurs TRPV1, ces derniers enclenchent une série de réponses physiologiques. Lorsqu'un composé d'une épice se lie au récepteur, celui-ci informe le cerveau d'une sensation de brûlure similaire à celle provoquée par la chaleur. Bien qu'il n'y ait pas de source réelle de chaleur externe, le corps réagit comme si c'était le cas. Il active son système nerveux et libère des substances chimiques dans l'organisme pour lutter contre l'agression présumée. Les conséquences de l'activation des récepteurs TRPV1 À la suite de l'interaction des molécules des épices avec les récepteurs TRPV1, une cascade de réactions se produit. Le corps libère des neuropeptides, activateurs du système nerveux, qui provoquent une légère inflammation. L'un des symptômes de l'inflammation est justement la hausse de la chaleur, qui aide à dilater les vaisseaux. Le sang circule mieux et plus vite pour propager les globules blancs vers le lieu de l'inflammation. La température corporelle augmente donc sous l'effet cumulé de la réponse inflammatoire et de l'activation du système nerveux. Pour se refroidir, l'organisme libère de la transpiration. La hausse du métabolisme En plus de l'inflammation, le corps subit parfois une hausse de son métabolisme. La capsaïcine du piment, la pipérine du poivre, les ginsénosides du ginseng amplifient la thermogénèse. Ce processus de régulation de la température interne conduit à une consommation plus élevée de calories, avec une libération plus importante de chaleur dans le corps. Cet effet de courte durée est néanmoins mis en avant par les fabricants de compléments alimentaires destinés à accompagner la perte de poids. Une sensibilité variable Des facteurs génétiques et environnementaux jouent dans la perception plus ou moins marquée de chaleur lors de la consommation d'épices. Les populations habituées dès le plus jeune âge à consommer des plats épicés sont généralement plus tolérantes à leurs effets sur la température corporelle. À l'inverse, les peuplades qui consomment peut d'épices les tolèrent souvent moins bien. Learn more about your ad choices. Visit megaphone.fm/adchoices

Exposing the truth behind Burn Evolved 2.0 and its ingredients! Discover why TRPV1 claims are baseless, and what TRPV1 receptors actually do. For more information about this topic: https://brianyeungnd.com/2023/09/07/doctor-reviews-burn-evolved-2-0/ Get EXCLUSIVE content and SUPPORT us: https://ko-fi.com/brianyeungnd

We thought we had endometriosis all figured out. After all, we know it's a chronic pain syndrome that's hormone responsive. But there's more to it than that. Within the last few years, including this year 2023, we have grown even more in our understanding of this pelvic pain condition. We now have new data explaining the link between endometriosis and migraine attacks. Are you familiar with CGRP? While most attention has focused on this biochemical messenger's role in migraines, CGRP is also related to endometrial implants. In this episode, we will do a deep dive into the shared pathophysiology of endometriosis and migraine headaches. We will look at the role that CGRP and TRPV1 play in both of these pain conditions.

"TRPV1 Modulation: A “Spicy” Approach to Pain Relief" by Neel Atawala, Vats T. Ambai, MD, and Arun Kalava, MD. From ASRA Pain Medicine News, November 2023. See original article at www.asra.com/november23news for figures and references. This material is copyrighted. Support the show

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.13.548699v1?rss=1 Authors: Unda, S. R., Marongiu, R., Pomeranz, L. E., Dyke, J. P., Fung, E. K., Grosenick, L., Zirkel, R., Antoniazzi, A. M., Norman, S., Liston, C. M., Schaffer, C. B., Nishimura, N., Stanley, S. A., Friedman, J. M., Kaplitt, M. G. Abstract: Regulating the activity of discrete neuronal populations in living mammals after delivery of modified ion channels can be used to map functional circuits and potentially treat neurological diseases. Here we report a novel suite of magnetogenetic tools, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity in motor circuits when exposed to magnetic fields. AAV-mediated delivery of a cre-dependent nanobody-TRPV1 calcium channel into the striatum of adenosine 2a (A2a) receptor-cre driver mice led to restricted expression within D2 neurons, resulting in motor freezing when placed in a 3T MRI or adjacent to a transcranial magnetic stimulation (TMS) device. Functional imaging and fiber photometry both confirmed focal activation of the target region in response to the magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing cre into the globus pallidus led to similar circuit specificity and motor responses. Finally, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in subthalamic nucleus (STN) projection neurons in PitX2-cre parkinsonian mice resulted in reduced local c-fos expression and a corresponding improvement in motor rotational behavior during magnetic field exposure. These data demonstrate that AAV delivery of magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits non-invasively in vivo using clinically available devices for both preclinical analysis of circuit effects on behavior and potential human clinical translation. 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/2023.07.09.548214v1?rss=1 Authors: Crowther, A., Kashem, S., Jewell, M. E., Chang, H. L., Casillas, M. R., Midavaine, E., Rodriguez, S., Braz, J., Kania, A., Basbaum, A. Abstract: Mouse models that combine tetracycline-controlled gene expression systems and conditional genetic activation can tightly regulate transgene expression in discrete cell types and tissues. However, the commonly used Tet-Off variant, tetracycline transactivator (tTA), when overexpressed and fully active, can lead to developmental lethality, disease, or more subtle behavioral phenotypes. Here we describe a profound itch phenotype in mice expressing a genetically encoded tTA that is conditionally activated within the Phox2a lineage. Phox2a; tTA mice develop intense, localized scratching and regional skin lesions that can be controlled by the tTA inhibitor, doxycycline. As gabapentin, but not morphine, completely relieved the scratching, we consider this phenotype to result from chronic neuropathic itch, not pain. In contrast to the Phox2a lineage, mice with tTA activated within the Phox2b lineage, which has many similar areas of recombination within the nervous system, did not recapitulate the scratching phenotype. In Phox2a-Cre mice, but not Phox2b-Cre, intense Cre-dependent reporter expression was found in skin keratinocytes localized to the area of scratching-induced skin lesions. Most interestingly, topical application of the DREADD agonist, CNO, administered repeatedly over two months, which chronically induced Gi signaling in keratinocytes, completely reversed the localized scratching and skin lesions. Furthermore, ablation of TRPV1-expressing, primary afferent neurons reduced the scratching with a time course comparable to that produced by Gi-DREADD inhibition. These temporal properties suggest that the neuropathic itch condition arises not only from localized keratinocyte activation of peripheral nerves but also from a persistent, gabapentin-sensitive state of central sensitization. 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/2023.06.30.547260v1?rss=1 Authors: Tian, J., Bavencoffe, A. G., Zhu, M. X., Walters, E. T. Abstract: Nociceptor cell bodies generate spontaneous discharge that can promote ongoing pain in persistent pain conditions. Little is known about the underlying mechanisms. Recordings from nociceptor cell bodies (somata) dissociated from rodent and human dorsal root ganglia (DRGs) have shown that prior pain in vivo is associated with low-frequency discharge controlled by irregular depolarizing spontaneous fluctuations of membrane potential (DSFs), likely produced by transient inward currents across the somal input resistance. Here we show that DSFs are associated with high somal input resistance over a wide range of membrane potentials, including depolarized levels where DSFs approach action potential (AP) threshold. Input resistance and both the amplitude and frequency of DSFs were increased in neurons exhibiting spontaneous activity. Ion substitution experiments indicated that the depolarizing phase of DSFs is generated by spontaneous opening of channels permeable to Na+ and/or Ca2+, and that Ca2+-permeable channels are especially important for larger DSFs. Partial reduction of the amplitude and/or frequency of DSFs by perfusion of pharmacological inhibitors indicated small but significant contributions from Nav1.7, Nav1.8, TRPV1, TRPA1, TRPM4, and N-type Ca2+ channels. Less specific blockers suggested a contribution from NALCN channels, and global knockout suggested a role for Nav1.9. The combination of high somal input resistance plus background activity of diverse ion channels permeable to Na+ and/or Ca2+ produces DSFs that are poised to reach AP threshold if resting membrane potential (RMP) depolarizes, AP threshold decreases, and/or DSFs become enhanced -- all of which have been reported under painful neuropathic and inflammatory conditions. 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/2023.06.27.546676v1?rss=1 Authors: Mazor, Y., Engelmayer, N., Nashashibi, H., Rottenfusser, L., Lev, S., Binshtok, A. M. Abstract: Background and Aims: Abdominal pain in patients with inflammatory bowel disease (IBD) is common and debilitating. In our study, we aim to utilize transient receptor potential vanilloid 1 (TRPV1) channels, large-pore cation channels expressed on nociceptors, as a drug delivery system to selectively inhibit visceral nociceptors and thus visceral pain in a rodent model of IBD. Methods: We induced colitis in rats using intrarectal dinitrobenzene sulfonic acid. Visceral hypersensitivity, spontaneous pain, and responsiveness of the hind paws to noxious heat stimuli were examined before and after the intrarectal application of sodium channel blocker QX-314 alone or together with TRPV1 channel activators or blockers. Results: Intrarectal co-application of QX-314 with TRPV1 channel activator capsaicin significantly inhibited colitis-induced gut hypersensitivity. Furthermore, in the model of colitis, but not in naive rats, QX-314 alone was sufficient to reverse gut hypersensitivity. The blockade of TRPV1 channels prevented this effect of QX-314. Finally, applying QX-314 alone to the inflamed gut inhibited colitis-induced ongoing pain. Conclusions: Selective silencing of nociceptors by QX-314 entering via exogenously or endogenously activated TRPV1 channels diminish IBD-induced gut hypersensitivity. These results yet again confirm the central role of TRPV1-expressing nociceptive neurons in IBD pain. The lack of QX-314 effect on naive rats suggests its selective analgesic effect in IBD pain. Moreover, our results demonstrating the effect of QX-314 alone imply the role of a tonically active TRPV1 channel in the pathophysiology of IBD pain. This approach provides proof-of-concept for using charged activity blockers for selective and effective blockade of visceral pain. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Kanazawa University NanoLSI Podcast:Experiments reveal chilli-sensitive molecular structure fluctuation changes in TRPV1Transcript of this podcast Hello and welcome to the NanoLSI podcast. Thank you for joining us today. In this episode we feature the latest research by Ayumi Sumino at the Kanazawa University NanoLSI alongside Motoyuki Hattori at Fudan University in China, and their colleagues. The research described in this podcast was published in the journal Proceedings of the National Academy of Science in May 2023 Kanazawa University NanoLSI websitehttps://nanolsi.kanazawa-u.ac.jp/en/Experiments reveal chilli-sensitive molecular structure fluctuation changes in TRPV1Researchers at Kanazawa University report high-speed atomic force microscopy experiments that show how ligands associated with stimulating and suppressing activation of the TRPV1 protein increase and decrease the molecule's structural variations. The observations provide insights into how these heat- and chilli-sensing proteins function.The skin senses heat – both from increased temperature and molecules like capsaicin in chillies – through the activation of protein receptors called Transient receptor potential vanilloid member 1 or TRPV1. However, the mechanisms behind the function of TRPV1 have not been clear. Now Ayumi Sumino at Kanazawa University in Japan and Motoyuki Hattori at the Fudan University in China and their colleagues provide important insights into this mechanism. Using high-speed atomic force microscopy to compare the protein with and without stimulating or suppressing molecules – ligands – bound to it, they obtain what they describe as “the first experimental evidence showing the correlation between molecular fluctuation and the gating state (ligand binding)”.So what was already known about this mechanism?Well once activated, the TRPV1 channel opens, allowing ions to permeate and signalling to the nervous system that a noxious stimulant is present. And in 2011 researchers at the Howard Hughes Medical Institute in the US put forward a theoretical basis for the activation of the receptor derived from thermodynamics, a theoretical framework that has since been corroborated by experiment. The idea was that the molecule would respond to heat with a change in heat capacity, which is related to the fluctuations in the molecule's conformation. Structures for the TRPV1 protein were known from previous cryo electron microscopy studies but these did not clarify how the fluctuations in protein conformation might change with stimulating or suppressing molecules, or even whether temperature and chilli sensing shared the same molecular mechanism.Here's where the high-speed atomic force microscopy comes inAtomic force microscopy (AFM) senses the topology of surfaces through the effect of distance on the forces on a nanosized tip positioned directly above the surface. The microscope was first invented in 1986 but gained a new lease of life through work at Kanazawa University that enabled it to capture topologies at high speed thereby providing a window into the dynamics of structures.Sumino, Hattori and colleagues used high-speed AFM to image the TRPV1 receptor both in its unbound state and when bound to ligand molecules that either stimulate, that is agonist molecules, or suppress - antagonist molecules - the protein's activity. They used the molecule resiniferatoxin, which is 1000 times hotter than capsaicin, as the agonist and for the antagonist they used capsazepine, which blocks the pain of capsaicin.From the structures captured the researchers were able to observe fluctuations in the conformation of both the bound and unbound states of TRPV1. They found that resiniferaNanoLSI Podcast website

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.12.536625v1?rss=1 Authors: Huckleberry, K. A., Calitri, R., Li, A. J., Mejdell, M., Singh, A., Bhutani, V., Laine, M. A., Nastase, A. S., Morena, M., Hill, M., Shansky, R. M. Abstract: Increasing evidence suggests that the neurobiological processes that govern learning and memory can be different in males and females, and here we asked specifically whether the endocannabinoid (eCB) system could modulate Pavlovian fear conditioning in a sex-dependent manner. Systemic (i.p.) injection of CB1R antagonist AM251 in adult male and female Sprague Dawley rats prior to auditory cued fear conditioning produced a female-specific increase in freezing that persisted across extinction and extinction retrieval tests but was prevented by co-administration of TRPV1R antagonist Capsazepine. Notably, AM251 also produced robust freezing in a novel context prior to auditory cue presentation the day following drug administration, but not the day of, suggesting that CB1R blockade elicited contextual fear generalization in females. To identify a potential synaptic mechanism for these sex differences, we next used liquid chromatography/tandem mass spectrometry, Western Blot, and confocal-assisted immunofluorescence techniques to quantify anandamide (AEA), TRPV1R, and perisomatic CB1R expression, respectively, focusing on the ventral hippocampus (vHip). Fear conditioning elicited increased vHip AEA levels in females only, and in both sexes, CB1R expression around vHip efferents targeting the basolateral amygdala (BLA) was twice that at neighboring vHip neurons. Finally, quantification of the vHip-BLA projections themselves revealed that females have over twice the number of neurons in this pathway that males do. Together, our data support a model in which sexual dimorphism in vHip-BLA circuitry promotes a female-specific dependence on CB1Rs for context processing that is sensitive to TRPV1-mediated disruption when CB1Rs are blocked. 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/2023.03.13.532477v1?rss=1 Authors: Genovese, F., Xu, J., Tizzano, M., Reisert, J. Abstract: In the mammalian nose, two chemosensory systems, the trigeminal and the olfactory mediate the detection of volatile chemicals. Most odorants in fact are able to activate the trigeminal system, and vice versa, most trigeminal agonists activate the olfactory system as well. Although these two systems constitute two separate sensory modalities, trigeminal activation modulates the neural representation of an odor. The mechanisms behind the modulation of olfactory response by trigeminal activation are still poorly understood. In this study, we addressed this question by looking at the olfactory epithelium, where olfactory sensory neurons and trigeminal sensory fibers co-localize and where the olfactory signal is generated. We characterize the trigeminal activation in response to five different odorants by measuring intracellular Ca2+ changes from primary cultures of trigeminal neurons (TGNs). We also measured responses from mice lacking TRPA1 and TRPV1 channels known to mediate some trigeminal responses. Next, we tested how trigeminal activation affects the olfactory response in the olfactory epithelium using electro-olfactogram (EOG) recordings from WT and TRPA1/V1-KO mice. The trigeminal modulation of the olfactory response was determined by measuring responses to the odorant, 2-phenylethanol (PEA), an odorant with little trigeminal potency after stimulation with a trigeminal agonist. Trigeminal agonists induced a decrease in the EOG response to PEA, which depended on the level of TRPA1 and TRPV1 activation induced by the trigeminal agonist. This suggests that trigeminal activation can alter odorant responses even at the earliest stage of the olfactory sensory transduction. 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/2023.02.10.528062v1?rss=1 Authors: Akopian, A., Ruparel, S., Hovhannisyan, A. H., Lindquist, K., Tram, M., Perez, D., Mecklenburg, J., Salmon, A., Merlo, J., Corey, T. Abstract: Myogenous temporomandibular disorders (TMD-M) are the most prevalent group of painful orofacial conditions, and the second most frequent among musculoskeletal pain conditions. TMD-M is associated with an increased responsiveness of nerves innervating the masseter (MM), temporal (TM), medial pterygoid closing (MPM) and lateral pterygoid gliding muscles (LPM). Treatment of this disorder remains difficult and is further complicated by each muscle having diverse and functionally distinct nerve innervation. This study examined expression of sensory markers in MM, TM and LPM of adult male common marmosets, a type of non-human primate. Using immunohistochemistry, we found that masticatory muscles were predominantly innervated with A-fibers (NFH+). All C-fibers (pgp9.5+/NFH-) observed in masticatory muscles were peptidergic (CGRP+) and lacked antibody labeling for mrgprD, trpV1 and the silent nociceptive marker, CHRNA3. The proportion of C- to A-fibers was highest in LPM, while MM had a minimal percentage (6-8%) of C-fibers. Interestingly, C-fibers in masticatory muscle may have myelin sheath, since many NFH- nerves were labeled with GFAP+. A-fiber types were also dissimilar among these muscles. Thus, there are substantially more peptidergic A-fibers (CGRP+/NFH+) in TM and LPM compared to MM. Almost all A-fibers in MM expressed trkC, with some of them having trkB and parvalbumin (PV). In contrast, a lesser number of TM and LPM nerves expressed trkC, lacked trkB and had fewer PV+ fibers in LPM. Along with sensory fibers, the masticatory muscles contain sympathetic fibers (tyrosine hydroxylase; TH+), which are located around blood vessels. This TH expression was absent in trigeminal neurons. Overall, the masticatory muscles of male marmosets have distinct expression patterns when compared to each muscle of the jaw and cutaneous fibers innervated by DRG neurons. 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/2023.02.11.528146v1?rss=1 Authors: Chalmers, K. J., Hutchinson, M. R., Dodds, K. N., Kwok, Y. H., Evans, S. F., Moseley, G. L. Abstract: Problem: The neuroimmune interface has been characterised in few areas of the body. The objective of this study was to investigate the neuroimmune interface in the mouse vagina through a novel ex vivo model, to determine whether LPS could directly activate and produce TRPV1-mediated neuronal activation. Method of Study: Concentrations of IL-1{beta} and IL-6 release into the supernatant at different times post ex vivo stimulation with LPS, capsaicin, or a combination of the two were assessed using enzyme-linked immunosorbent assay. Results: There were no differences in the supernatant concentration of IL-6 with different stimulation type nor stimulation time. Supernatant concentrations of IL-1{beta} were greater at the 20 hour time point than the 4 hour time point, and were greater for stimulations involving LPS. Conclusion: There is a clear pattern of pro-inflammatory neuroimmune responses following ex vivo stimulation of mouse vaginal tissues with capsaicin and LPS, evident as an increased IL-1{beta} output. This output is greatest at 20 hours post-stimulation, indicating this neuroimmune response is time-dependent. 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/2023.01.23.525238v1?rss=1 Authors: Yang, C., Yamaki, S., Jung, T., Kim, B., Huynh, R., McKemy, D. D. Abstract: The detection of environmental temperatures is critical for survival, yet inappropriate responses to thermal stimuli can have a negative impact on overall health. The physiological effect of cold is distinct among somatosensory modalities in that it is soothing and analgesic, but also agonizing in the context of tissue damage. Inflammatory mediators produced during injury activate nociceptors to release neuropeptides, such as CGRP and substance P, inducing neurogenic inflammation which further exasperates pain. Many inflammatory mediators induce sensitization to heat and mechanical stimuli but, conversely, inhibit cold responsiveness, and the identity of molecules inducing cold pain peripherally is enigmatic, as are the cellular and molecular mechanisms altering cold sensitivity. Here, we asked if inflammatory mediators that induce neurogenic inflammation via the nociceptive ion channels TRPV1 and TRPA1 lead to cold pain in mice. Specifically, we tested cold sensitivity in mice after intraplantar injection of lysophosphatidic acid (LPA) or 4-hydroxy-2-nonenal (4HNE), finding each induces cold pain that is dependent on the cold-gated channel TRPM8. Inhibition of either CGRP, substance P, or toll-like receptor 4 (TLR4) signaling attenuates this phenotype, and each neuropeptide produces TRPM8-dependent cold pain directly. Further, the inhibition of CGRP or TLR4 signaling alleviates cold allodynia differentially by sex. Lastly, we find that cold pain induced by inflammatory mediators and neuropeptides requires the neurotrophin artemin and its receptor GFRalpha3. These results demonstrate that tissue damage alters cold sensitivity via neurogenic inflammation, likely leading to localized artemin release that induces cold pain via GFRalpha3 and TRPM8. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Understanding how our body senses and interacts with the world. Scientists are only now beginning to understand how our body senses the world, hence the '21 Nobel Prizes. This Nobel prize wining research helped others find a connection between the gut and our sense of touch. Internal organ pain can be crippling and require side effect laden treatments. How do organs like the gut detect and transmit pain signals? The same mechanism to detect soft touch is used by your organs to send pain signals. How does our body precisely control temperature? What region of the brain measures and control what temperature to set itself to? Zili Xie, Jing Feng, Timothy J. Hibberd, Bao Nan Chen, Yonghui Zhao, Kaikai Zang, Xueming Hu, Xingliang Yang, Lvyi Chen, Simon J. Brookes, Nick J. Spencer, Hongzhen Hu. Piezo2 channels expressed by colon-innervating TRPV1-lineage neurons mediate visceral mechanical hypersensitivity. Neuron, 2022; DOI: 10.1016/j.neuron.2022.11.015 Yoshiko Nakamura, Takaki Yahiro, Akihiro Fukushima, Naoya Kataoka, Hiroyuki Hioki, Kazuhiro Nakamura. Prostaglandin EP3 receptor–expressing preoptic neurons bidirectionally control body temperature via tonic GABAergic signaling. Science Advances, 2022; 8 (51) DOI: 10.1126/sciadv.add5463

Study links nutrients in blood to better brain connectivity, cognition in older adults University of Illinois, December 20, 2022 A new study links higher levels of several key nutrients in the blood with more efficient brain connectivity and performance on cognitive tests in older adults. The study, reported in the journal NeuroImage, looked at 32 key nutrients in the Mediterranean diet, which previous research has shown is associated with better brain function in aging. It included 116 healthy adults 65-75 years of age. "We wanted to investigate whether diet and nutrition predict cognitive performance in healthy older adults," said University of Illinois postdoctoral researcher Christopher Zwilling, who led the study with U. of I. psychology professor Aron Barbey in the Beckman Institute for Advanced Science and Technology. The analysis linked specific patterns of a handful of nutrient biomarkers in the blood to better brain health and cognition. The nutrient patterns included omega-3 fatty acids, which are abundant in fish, walnuts and Brussels sprouts; omega-6 fatty acids, found in flaxseed, pumpkin seeds, pine nuts and pistachios; lycopene, a vivid red pigment in tomatoes, watermelon and a few other fruits and vegetables; alpha- and beta-carotenoids, which give sweet potatoes and carrots their characteristic orange color; and vitamins B and D. The researchers relied on some of the most rigorous methods available for examining nutrient intake and brain health, Barbey said. Rather than asking participants to answer food-intake surveys, which require the accurate recall of what and how much participants ate, the team looked for patterns of nutrient "biomarkers" in the blood. The team also used functional magnetic resonance imaging to carefully evaluate the efficiency with which various brain networks performed. The analysis found a robust link between higher levels of several nutrient biomarkers in the blood and enhanced performance on specific cognitive tests. These nutrients, which appeared to work synergistically, included omega-3 and omega-6 fatty acids, carotenoids, lycopene, riboflavin, folate, vitamin B12 and vitamin D. The analysis also revealed that a pattern of omega-3s, omega-6s and carotene was linked to better functional brain network efficiency. Different nutrient patterns appeared to moderate the efficiency in different brain networks. For example, higher levels of omega-3 fatty acids paralleled the positive relationship between a healthy frontoparietal network and general intelligence. The frontoparietal network supports the ability to focus attention and engage in goal-directed behavior. "Our study suggests that diet and nutrition moderate the association between network efficiency and cognitive performance," Barbey said. "This means that the strength of the association between functional brain network efficiency and cognitive performance is associated with the level of the nutrients." (NEXT) Sunlight offers surprise benefit -- it energizes infection fighting T cells Georgetown University Medical Center, December 20, 2022 Sunlight allows us to make vitamin D, credited with healthier living, but a surprise research finding could reveal another powerful benefit of getting some sun. Georgetown University Medical Center researchers have found that sunlight, through a mechanism separate than vitamin D production, energizes T cells that play a central role in human immunity. Their findings, published in Scientific Reports, suggest how the skin, the body's largest organ, stays alert to the many microbes that can nest there. "We all know sunlight provides vitamin D, which is suggested to have an impact on immunity, among other things. But what we found is a completely separate role of sunlight on immunity," says the study's senior investigator, Gerard Ahern, PhD, associate professor in the Georgetown's Department of Pharmacology and Physiology. "Some of the roles attributed to vitamin D on immunity may be due to this new mechanism." They specifically found that low levels of blue light, found in sun rays, makes T cells move faster -- marking the first reported human cell responding to sunlight by speeding its pace. "T cells, whether they are helper or killer, need to move to do their work, which is to get to the site of an infection and orchestrate a response," Ahern says. "This study shows that sunlight directly activates key immune cells by increasing their movement." Ahern also added that while production of vitamin D required UV light, which can promote skin cancer and melanoma, blue light from the sun, as well as from special lamps, is safer. And while the human and T cells they studied in the laboratory were not specifically skin T cells -- they were isolated from mouse cell culture and from human blood -- the skin has a large share of T cells in humans, he says, approximately twice the number circulating in the blood. What drove the motility response in T cells was synthesis of hydrogen peroxide, which then activated a signaling pathway that increases T cell movement. Hydrogen peroxide is a compound that white blood cells release when they sense an infection in order to kill bacteria and to "call" T cells and other immune cells to mount an immune response. "We found that sunlight makes hydrogen peroxide in T cells, which makes the cells move. And we know that an immune response also uses hydrogen peroxide to make T cells move to the damage," Ahern says. "This all fits together." (NEXT)  Capsaicin molecule inhibits growth of breast cancer cells Centre of Genomics, Ruhr-Universität Bochum (Germany), December 22, 2022  Capsaicin, an active ingredient of pungent substances such as chilli or pepper, inhibits the growth of breast cancer cells. This was reported by a team headed by the Bochum-based scent researcher Prof Dr Dr Dr habil Hanns Hatt and Dr Lea Weber, following experiments in cultivated tumour cells. The experiments were carried out with the SUM149PT cell culture, a model system for a particularly aggressive type of breast cancer, i.e. the triple-negative type. Chemotherapy is currently the only available treatment for this type of cancer. In the cultivated cells, the team detected a number of typical olfactory receptors. One receptor occurred very frequently; it is usually found in the fifth cranial nerve, i.e. the trigeminal nerve. It belongs to the so-called Transient Receptor Potential Channels and is named TRPV1. That receptor is activated by the spicy molecule capsaicin as well as by helional – a scent of fresh sea breeze. In collaboration with Dr Gabriele Bonatz from the Augusta clinics in Bochum (Brustzentrum), Hatt's team confirmed the existence of TRPV1 in tumour cells in nine different samples from patients suffering from breast cancer. The researchers activated the TRPV1 receptor in the cell culture with capsaicin or helional, by adding the substances to the culture for a period of several hours or days. As a result, the cancer cells divide more slowly. Moreover, the treatment caused tumour cells to die in larger numbers. The surviving cells were no longer able to move as quickly as heretofore; this implies that their ability to form metastases in the body was impeded. Earlier studies had demonstrated that the chemical arvanil – with a chemical make-up similar to that of the spicy molecule capsaicin – was effective against brain tumours in mice; it reduces tumour growth in the animals. Due to its side effects, however, this substance is not approved for humans. In addition to capsaicin and helional, the endovanilloids, produced naturally in the body, also activate the TRPV1 receptor. (NEXT)  Losing body fat could be facilitated by light evening exercise and fasting Baylor College of Medicine, December 20, 2022 Making muscles burn more fat and less glucose can increase exercise endurance, but could simultaneously cause diabetes, says a team of scientists from Baylor College of Medicine and other institutions. Mouse muscles use glucose (carbohydrate) as fuel when the animals are awake and active and switch to fat (lipid) when they are asleep. The team discovered that disrupting this natural cycle may lead to diabetes but, surprisingly, can also enhance exercise endurance. The switch is controlled by a molecule called histone deacetylase 3, or HDAC3. This finding opens the possibility of selecting the right time to exercise for losing body fat but also raises the concern of using HDAC inhibitors as doping drugs for endurance exercise. The study appears in Nature Medicine. Skeletal muscles, the voluntary muscles, are important in the control of blood glucose in the body. They consume most of the glucose, and if they develop insulin resistance and consequently are not able to use glucose, then diabetes likely will develop. To study the role of HDAC3 in mouse skeletal muscle, Sun and colleagues genetically engineered laboratory mice to deplete HDAC3 only in the skeletal muscles. Then they compared these knocked out mice with normal mice regarding how their muscles burn fuel. When normal mice eat, their blood sugar increases and insulin is released, which stimulates muscles to take in and use glucose as fuel. "When the knocked out mice ate, their blood sugar increased and insulin was released just fine, but their muscles refused to take in and use glucose," said Sun. "Lacking HDAC3 made the mice insulin resistant and more prone to develop diabetes." Yet, when the HDAC3-knocked out mice ran on a treadmill, they showed superior endurance, "which was intriguing because diabetes is usually associated with poor muscle performance," said Sun. "Glucose is the main fuel of muscle, so if a condition limits the use of glucose, the expectation is low performance in endurance exercises. That's the surprise." The researchers then studied what fueled the HDAC3-knocked out mice's stellar performance using metabolomics approaches and found that their muscles break down more amino acids. This changed the muscles' preference from glucose to lipids and allowed them to burn lipid very efficiently. This explains the high endurance, because the body carries a much larger energy reservoir in the form of lipid than carbohydrate. The team performed a number of functional genomics studies that established the link between HDAC3 and the circadian clock. "In normal mice, when the mouse is awake, the clock in the muscle anticipates a feeding cycle and uses HDAC3 to turn off many metabolic genes. This leads the muscles to use more carbohydrate," said Sun. "When the animal is about to go to sleep and anticipates a fasting cycle, the clock removes HDAC3. This leads the muscles to use more lipid." Although these studies were done in mice, the researchers speculate that human muscles most likely will follow the same cycle. The study opens the possibility of promoting body fat burning by increasing exercise activity during the periods in which muscles use lipid, which is at night for people. "Losing body fat would be easier by exercising lightly and fasting at night," said Sun. "It's not a bad idea to take a walk after dinner." (NEXT)  Employees who are open about religion are happier, study suggests Kansas State University, December 17, 2022 It may be beneficial for employers to not only encourage office Christmas parties but also celebrate holidays and festivals from a variety of religions, according to a Kansas State University researcher. Sooyeol Kim was involved in a collaborative study that found that employees who openly discuss their religious beliefs at work are often happier and have higher job satisfaction than those employees who do not. "For many people, religion is the core of their lives," Kim said. "Being able to express important aspects of one's life can influence work-related issues, such as job satisfaction, work performance or engagement. It can be beneficial for organizations to have a climate that is welcoming to every religion and culture." Kim said employers might even want to consider a religion-friendly policy or find ways to encourage religious expression. For example, organizations could have an office Christmas party, but also could celebrate and recognize other religious holidays and dates, such as Hanukkah, Ramadan or Buddhist holidays. For the cross-cultural study, the researchers surveyed nearly 600 working adults from a variety of industries -- including education and finance -- in the U.S. and South Korea. The surveyed employees were all Christian, but identified with a variety of denominations, including Presbyterian, Baptist and Methodist, among others. Results showed that employees who valued religion as a core part of their lives were more likely to disclose their religion in the workplace. Employees who felt pressure to assimilate in the workplace were less likely to disclose their religious identity, Kim said. But most significantly, the researchers found that the employees who disclosed their religion in the workplace had several positive outcomes, including higher job satisfaction and higher perceived well-being. "Disclosing your religion can be beneficial for employees and individual well-being," Kim said. "When you try to hide your identity, you have to pretend or you have to lie to others, which can be stressful and negatively impact how you build relationships with co-workers." Kim said the research on religion in the workplace plays a part into work-life balance. Research continues to show that individual characteristics -- such as family and religion -- can influence work-related issues. (NEXT) New Cannabis Capsule Is So Powerful It's Going To Completely Replace All Pain Killers University of Pennsylvania, December 19, 2022    In places where medical marijuana is legal, opioid abuse and addiction has fallen by 25%, but the government maintain they are stumped as to why Opioid abuse and addiction is a massive problem all over the US, hence why people are eager to find natural alternatives. The health benefits of cannabis are become more and more accepted in mainstream society, as more studies which support cannaboid use are published. This doesn't sit well with big pharma, who are desperate to hold on to the monopoly they control. In the U.S. states where medical marijuana is legal to use, deaths from opioid overdoses have decreased by almost 25 percent, according to a new data. The study was done by Bachhuber, of the Philadelphia Veterans Affairs Medical Center and the University of Pennsylvania, and his colleagues who used state-level death certificate data for all 50 states. According to JAMA Medicine, in states with a medical marijuana law, overdose deaths from opioids like morphine, oxycodone and heroin decreased by an average of 20 percent after just one year. After two years, they continued to decrease to 25 percent. In the mean time, opioid overdose deaths across the country skyrocketed. The cannabis capsules are made from the extract of cannabis flower. The active ingredients are processed without microbials and then packaged with a specific mix of 60 mg of THC (tetrahydrocannabinol) and 10 mg of CBD (cannabidiol). The combination together creates the perfect effect to relieve pain. The THC helps send happy feelings to the brain, while the CBD helps promote relaxation of the muscles. This helps reduce muscle spasms as well as inflammation.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.03.510587v1?rss=1 Authors: Ramgoolam, K. H., Dolphin, A. C. Abstract: The N-type calcium channel, CaV2.2 is key to neurotransmission from the primary afferent terminals of dorsal root ganglion (DRG) neurons to their post-synaptic targets in the spinal cord. In this study we have utilized CaV2.2_HA knock-in mice, because the exofacial epitope tag in CaV2.2_HA enables accurate detection and localization of endogenous CaV2.2. CaV2.2_HA knock-in mice were used as a source of DRGs to exclusively study the presynaptic expression of N-type calcium channels in co-cultures between DRG neurons and wild-type spinal cord neurons. CaV2.2_HA is strongly expressed on the cell surface, particularly in TRPV1-positive small and medium DRG neurons. Super-resolution images of the presynaptic terminals revealed an increase in CaV2.2_HA expression and increased association with the post-synaptic marker Homer over time in vitro. Brief application of the TRPV1 agonist, capsaicin, resulted in a significant down-regulation of cell surface CaV2.2_HA expression in DRG neuron somata. At their presynaptic terminals, capsaicin caused a reduction in CaV2.2_HA proximity to and co-localization with the active zone marker RIM 1/2, as well as a lower contribution of N-type channels to single action potential-mediated Ca2+ influx. The mechanism of this down-regulation of CaV2.2_HA involves a Rab 11a-dependent trafficking process, since dominant-negative Rab11a(S25N) occludes the effect of capsaicin on presynaptic CaV2.2_HA expression, and also prevents the effect of capsaicin on action potential induced Ca2+ influx. Taken together, these data suggest that capsaicin causes a decrease in cell surface CaV2.2_HA expression in DRG terminals via a Rab11a-dependent endosomal trafficking pathway. 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/2022.09.15.508178v1?rss=1 Authors: Mitchell, M., Cook, L. F., Shiers, S., Tavares-Ferreira, D., Akopian, A. N., Dussor, G., Price, T. J. Abstract: Fragile X Mental Retardation Protein (FMRP) regulates activity-dependent RNA localization and local translation to modulate synaptic plasticity throughout the CNS. Mutations in the FMR1 gene that hinder or ablate FMRP function cause Fragile X Syndrome (FXS), a disorder associated with sensory processing dysfunction. FXS pre-mutations are associated with increased FMRP expression and neurological impairments including sex dimorphic presentations of chronic pain. In mice, FMRP ablation causes dysregulated DRG neuron excitability and synaptic vesicle exocytosis, spinal circuit activity, and decreased translation-dependent nociceptive sensitization. Activity-dependent, local translation is a key mechanism for enhancing primary nociceptor excitability which promotes pain in animals and humans. These works indicate that FMRP likely regulates nociception and pain at the level of the primary nociceptor or spinal cord. Therefore, we sought to better understand FMRP expression in the human dorsal root ganglion (DRG) and spinal cord using immunostaining in organ donor tissues. We find that FMRP is highly expressed in DRG and spinal neuron subsets with substantia gelatinosa exhibiting the most abundant immunoreactivity in spinal synaptic fields. Here, it is expressed in nociceptor axons. FMRP puncta colocalized with Nav1.7 and TRPV1 receptor signals suggesting a pool of axoplasmic FMRP localizes to plasma membrane-associated loci in these branches. Interestingly, FMRP puncta exhibited notable colocalization with calcitonin gene-related peptide (CGRP) immunoreactivity selectively in female spinal cord. Our results support a regulatory role for FMRP in human nociceptor axons of the dorsal horn and implicate it in the sex dimorphic actions of CGRP signaling in nociceptive sensitization and chronic pain. 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/2022.09.06.506411v1?rss=1 Authors: Inyang, K. E., Evans, C. M., Heussner, M., Petroff, M., Reimers, M., Vermer, P. D., Tykocki, N., Folger, J. K., Laumet, G. Abstract: Severe pain is often experienced by patients with head and neck cancer and is associated with a poor prognosis. Despite its frequency and severity, current treatments fail to adequately control cancer-associated pain, because of our lack of mechanistic understanding. Cancer-derived small extracellular vesicles (Cancer-sEVs) are well-positioned to function as mediators of communication between cancer cells and neurons. Inhibition of Cancer-sEV release attenuated pain in tumor-bearing mice. Injection of purified Cancer-sEVs is sufficient to induce pain hypersensitivity in naive mice. Cancer-sEVs triggered calcium influx in nociceptors and inhibition or ablation of nociceptors protect against cancer pain. Interrogation of published sequencing data of human sensory neurons exposed to human Cancer-sEVs suggested a stimulation of protein translation in neurons. Induction of translation by Cancer-sEVs was validated in our mouse model and its inhibition alleviated cancer pain in mice. These findings define a role of Cancer-sEVs in cancer pain and identify several druggable targets. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

This 13th episode of The Pain Beat is the first of a three-part series discussing the 2021 Nobel Prize in Physiology or Medicine – awarded to David Julius, University of California, San Francisco, USA and Ardem Patapoutian, Scripps Research, California, USA – for their work on molecules important for somatosensation (see PRF related interview here, and PRF related news story here). In this episode, The Pain Beat spoke with Nobel Prize laureate David Julius and Michael Caterina, Johns Hopkins University School of Medicine, Maryland, USA, to discuss their discovery of TRPV1. The conversation provides insight regarding their thought processes and problem solving, the enduring challenges of scientific discoveries, and the fun they had along the way. Podcast participants include: David Julius, PhD, University of California, San Francisco, USA Michael Caterina, MD, PhD, Johns Hopkins School of Medicine, Maryland, USA Tayler Sheahan, PhD, University of Pittsburgh, USA (Host)

This 13th episode of The Pain Beat is the first of a three-part series discussing the 2021 Nobel Prize in Physiology or Medicine – awarded to David Julius, University of California, San Francisco, USA and Ardem Patapoutian, Scripps Research, California, USA – for their work on molecules important for somatosensation (see PRF related interview here, and PRF related news story here). In this episode, The Pain Beat spoke with Nobel Prize laureate David Julius and Michael Caterina, Johns Hopkins University School of Medicine, Maryland, USA, to discuss their discovery of TRPV1. The conversation provides insight regarding their thought processes and problem solving, the enduring challenges of scientific discoveries, and the fun they had along the way. Podcast participants include: David Julius, PhD, University of California, San Francisco, USA Michael Caterina, MD, PhD, Johns Hopkins School of Medicine, Maryland, USA Tayler Sheahan, PhD, University of Pittsburgh, USA (Host)

Moderna Clinical Trials Terribly Flawed — and FDA Knew It, Former Pharma Executive Tells RFK, Jr. South African FM: ‘Patronizing bullying' not acceptable Prescription Playground: Why so many children are now taking ADHD drugs | 60 Minutes Australia   HEALTH NEWS Chili peppers for a healthy gut: Spicy chemical may inhibit gut tumors How Tart Cherries Reduce Inflammation and Oxidative Stress Uncovering the links between diet, gut health and immunity Southern-style diet ‘increases death risk' in kidney disease patients Could Hibiscus Tea be Better than High Blood Pressure Drugs? Can breast milk feed a love of vegetables? Chili peppers for a healthy gut: Spicy chemical may inhibit gut tumors University of California, San Diego   August 1, 2022 Researchers at the University of California, San Diego School of Medicine report that dietary capsaicin — the active ingredient in chili peppers — produces chronic activation of a receptor on cells lining the intestines of mice, triggering a reaction that ultimately reduces the risk of colorectal tumors. The receptor or ion channel, called TRPV1, was originally discovered in sensory neurons, where it acts as a sentinel for heat, acidity and spicy chemicals in the environment. TRPV1 was quickly described as a molecular ‘pain receptor.'  But Raz and colleagues have found that TPRV1 is also expressed by epithelial cells of the intestines, where it is activated by epidermal growth factor receptor or EGFR. EGFR is an important driver of cell proliferation in the intestines, whose epithelial lining is replaced approximately every four to six days. “These results showed us that epithelial TRPV1 normally works as a tumor suppressor in the intestines,” said de Jong. In addition, molecular studies of human colorectal cancer samples recently uncovered multiple mutations in the TRPV1 gene, though Raz noted that currently there is no direct evidence that TRPV1 deficiency is a risk factor for colorectal cancer in humans. The current study suggests one potential remedy might be spicy capsaicin, which acts as an irritant in mammals, generating a burning sensation in contact with tissue.  The researchers fed capsaicin to mice genetically prone to developing multiple tumors in the gastrointestinal tract. The treatment resulted in a reduced tumor burden and extended the lifespans of the mice by more than 30 percent. The treatment was even more effective when combined with celecoxib, a COX-2 non-steroidal anti-inflammatory drug already approved for treating some forms of arthritis and pain. “Our data suggest that individuals at high risk of developing recurrent intestinal tumors may benefit from chronic TRPV1 activation,” said Raz. “We have provided proof-of-principle.” How Tart Cherries Reduce Inflammation and Oxidative StressNorthumbria University (UK),  August 4, 2022Michigan researchers had previously shown that a cherry-enriched diet not only reduced overall body inflammation, but also reduced inflammation at key sites (belly fat, heart) known to affect heart disease risk in the obese.This study offers further promise that foods rich in antioxidants, such as cherries, could potentially reduce inflammation and have the potential to lower disease risk.”

Two daily doses of the tart cherry concentrate was associated with significantly lower levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP), compared to placebo, according to findings published in Nutrients.

”This is the first study to investigate the impact of cherries on systemic inflammatory and oxidative stress induced by a series of metabolically challenging cycling bouts. Despite both groups demonstrating a similar drop off in performance and no differences in time trial performance, the results show that both oxidative stress and inflammatory responses were attenuated with Montmorency cherry concentrate supplementation versus placebo.” 

”With millions of Americans looking for ways to naturally manage pain, it's promising that tart cherries can help, without the possible side effects often associated with arthritis medications,” said Kerry Kuehl, M.D, Dr.PH., M.S., Oregon Health & Science University, principal study investigator. “I'm intrigued by the potential for a real food to offer such a powerful anti-inflammatory benefit — especially for active adults.”

Darren E. Huxley, MD says that a natural alternatives to pain medications are proving effective without unwanted side effects. “In this case we have cherries, another potent, natural antioxidant proving to be as, if not more effective than pain medications because of the ability for sustained long-term use without side effects in common anti-inflammatory drugs.Tart cherries have also been shown to contain naturally high levels of melatonin, a key compound in the human sleep-and-wake cycle, and new research in the European Journal of Nutrition confirms that melatonin from tart cherries is absorbed by humans.

In 2001, Burkhardt et al. even observed that the Montmorency variety, in particular, contains about six times more melatonin than the Balaton variety.  Uncovering the links between diet, gut health and immunity University of Sydney, August 5, 2022 A preclinical study from the University of Sydney has found a high-protein diet can change the microbiota of the gut, triggering an immune response. Researchers say the study takes us a step closer to understanding the way diet impacts gut health and immunity. “The focus of our work is on how the gut microbiota—the trillions of bacteria that inhabit the gut—affects the immune system,” said Associate Professor Laurence Macia from the University's Charles Perkins Center and Faculty of Medicine and Health. Traditionally, however, scientists have focused on the role of dietary fiber in maintaining a healthy gut. In this first-of-its-kind study, published in Nature Communications, the team from the Charles Perkins Center used sophisticated modeling to explore the impact of 10 diets with a different makeup of macronutrients—protein, fats and carbohydrate in mice. Mice fed a high protein diet increased their production of bacterial extracellular vesicles, complex cargo containing bacterial information such as DNA and protein. The body subsequently viewed this activity as a threat and triggered a sequence of events where immune cells traveled into the gut wall. “Here we found protein had a huge impact on the gut microbiota and it was not so much about the type of bacteria that were there, but the type of activity. In essence, we discovered a new way of communication between the gut bacteria and the host which was mediated by protein,” said Associate Professor Macia. While it is too early to say if this research might translate in humans, the researchers say activation of the immune system can prove either good or bad news. “By increasing antibodies in the gut you may see strong protection against potential pathogens, for example salmonella, but on the downside, an activated immune system could mean you are at increased risk of colitis, an inflammatory bowel disease, or autoimmune conditions like Crohn's,” said lead author and post-doctoral researcher Jian Tan. The results appear consistent with the population impacts of modern-day diets, with the Western world seeing lower rates of gastrointestinal infection but higher rates of chronic disease.  Southern-style diet ‘increases death risk' in kidney disease patients University of Alabama  1 August 2022 New research published in the National Kidney Foundation's American Journal of Kidney Diseases suggests that eating a “Southern-style diet” is linked with higher death rates in kidney disease patients. Investigating the influence of diet on kidney disease patients, the researchers studied  3,972 participants with stage 3-5 chronic kidney disease who had not started dialysis. Analyzing the dietary habits of the participants, the researchers found that those who regularly consumed foods familiar to Southern diets had a 50% increase in risk of death across the 6.5-year follow-up period. Foods that the authors identify as being part of a Southern diet include processed and fried foods, organ meats and sweetened beverages. Could Hibiscus Tea be Better than High Blood Pressure Drugs? Tufts University,  August 4th, 2022 Naturally healing foods, including hibiscus, don't carry the side effects of pharmaceuticals and can often offer similar (or better) benefits, without padding the pockets of Big Pharma companies. This is one example of a natural solution for high blood pressure. When it comes to high blood pressure, a completely preventable condition, there are many natural solutions. Things like cayenne pepper, apple cider vinegar, and celery are just a few alternatives, along with broad dietary and lifestyle changes. But many people aren't aware of the blood pressure lowering benefits of hibiscus. Dr. Diane McKay presented her own research on hibiscus Dr. McKay, of Tufts University, conducted a study on 65 people between the ages of 30 and 70 who had been diagnosed with prehypertension or mild hypertension. After receiving hibiscus tea daily for six weeks, participants experienced reduced diastolic, systolic, and mean arterial pressures when compared with those who received a placebo. The effects were most pronounced in those with the highest beginning baseline blood pressures. In another study, scientists received a surprise when looking at the effects of hibiscus tea on blood sugar. The study compared the effects of hibiscus and black teas and found that both impacted cholesterol levels. While the black tea positively influenced HDL levels, hibiscus tea helped keep LDL, HDL, and overall cholesterol at healthy levels. Can breast milk feed a love of vegetables?  Monell Chemical Senses Center, August 4, 2022  Want your preschooler to eat veggies without a fuss? Try eating veggies while you're breast-feeding. That's the message from a new study of lactating mothers and their breast-fed babies. The study found that those infants who took in veggie-flavored breast-milk were less likely to turn away from similar-tasting cereal when they graduated to more solid food. “Every baby's sensory experience is unique, but the flavor of their first food, beginning in utero, is dependent on what mom is eating,” said Julie Mennella. She is a biopsychologist at the Monell Chemical Senses Center in Philadelphia, and led the study. “The way I see it is: Mother's milk is the ultimate in precision medicine,” Mennella said. When an expectant mother eats vegetables, they flavor her amniotic fluid—and later, her breast-milk—and those flavors get passed along to her baby. As a result, the researchers said, if the baby learns early how veggies taste, he or she will be less apt to squawk when offered that first spoonful. For her study, Mennella randomly assigned 97 breast-feeding mothers to one of five groups. For a month, three groups drank a half-cup of carrot, celery, beet or vegetable juice before nursing. One group began when babies were two weeks old, another at 1-1/2 months of age and the third at 2-1/2 months. A fourth group of moms drank juice for three months, starting when their babies were two weeks old. A fifth group—the “control” group—did not use juice. The takeaway: Babies who'd been exposed to vegetable flavors in breast-milk preferred carrot-flavored cereal over plain cereal or cereal with the unfamiliar taste of broccoli. Only 8 percent rejected all of the foods, the findings showed.

Chili peppers for a healthy gut: Spicy chemical may inhibit gut tumors University of California, San Diego   April 14, 2022 Researchers at the University of California, San Diego School of Medicine report that dietary capsaicin -- the active ingredient in chili peppers -- produces chronic activation of a receptor on cells lining the intestines of mice, triggering a reaction that ultimately reduces the risk of colorectal tumors. The receptor or ion channel, called TRPV1, was originally discovered in sensory neurons, where it acts as a sentinel for heat, acidity and spicy chemicals in the environment. "These are all potentially harmful stimuli to cells," said Eyal Raz, MD, senior author of the study. "Thus, TRPV1 was quickly described as a molecular 'pain receptor.' But Raz and colleagues have found that TPRV1 is also expressed by epithelial cells of the intestines, where it is activated by epidermal growth factor receptor or EGFR. EGFR is an important driver of cell proliferation in the intestines, whose epithelial lining is replaced approximately every four to six days. The scientists discovered that TRPV1, once activated by the EGFR, initiates a direct negative feedback on the EGFR, dampening the latter to reduce the risk of unwanted growth and intestinal tumor development. They found that mice genetically modified to be TRPV1-deficient suffered higher-than-normal rates of intestinal tumor growths. The researchers fed capsaicin to mice genetically prone to developing multiple tumors in the gastrointestinal tract. The treatment resulted in a reduced tumor burden and extended the lifespans of the mice by more than 30 percent.   (NEXT)   How Tart Cherries Reduce Inflammation and Oxidative Stress University of Michigan,  April 15, 2022 Michigan researchers had previously shown that a cherry-enriched diet not only reduced overall body inflammation, but also reduced inflammation at key sites (belly fat, heart) known to affect heart disease risk in the obese. This study offers further promise that foods rich in antioxidants, such as cherries, could potentially reduce inflammation and have the potential to lower disease risk. Two daily doses of the tart cherry concentrate was associated with significantly lower levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP), compared to placebo, according to findings published in Nutrients. "This is the first study to investigate the impact of Montmorency cherries on systemic inflammatory and oxidative stress induced by a series of metabolically challenging cycling bouts.   (NEXT)   Water outperforms sports drinks for young athletes Penn State University, April 14, 2022 Most youngsters don't exert themselves at an intensity or duration that requires the extra sugar and salt contained in sports drinks. Sports drinks can replenish some of what you lost during exercise, but you really need to be exercising for more than 45 minutes to an hour before you would consider that. Many of our kids are not doing enough to warrant it. Energy drinks that contain caffeine or other stimulants are also ill-advised for children, the physicians said. These beverages can boost blood pressure, cause heart palpitations and heart rhythm disorders, headaches and upset stomach. Coaches and parents should provide water to make sure children are properly hydrated during exercise, the doctors said.   (NEXT)   Ginger Found to Reduce Premenstrual Pain and Mood Symptoms Tehran University of Medical Sciences, April 17, 2022 New research has confirmed other findings that ginger root (Zingiber officinale) can relieve premenstrual pain and associated symptoms, without some of the side effects associated with NSAIDs. Medical doctors from the Tehran University of Medical Sciences in Iran studied 70 female students between 18 and 35 years old in a three-month long double-blind, placebo-controlled trial. The women had regular menstruation cycles and were not taking medications, but they each had at least five symptoms of PMS during their normal cycles. Both groups' PMS symptom severity scores were calculated before and after each of the three months. The researchers found that while both groups averaged between 106 and 110 points on the PMS severity testing at the beginning of the study, the ginger group scored significantly lower on all PMS symptoms at the end of each month. After one month, the ginger group's scores averaged 51, while the placebo group averaged 105.7. After three months, the ginger group's scores averaged 49 while the placebo group averaged 107. After the third month, the ginger group's scores average 47 while the placebo group averaged 106.   (SUPERFOODS)   Oranges: The orange is a vitamin and mineral-packed treasure chest of a fruit, rich in vitamins A, B and C, potassium, and calcium, as well as being an excellent source of fiber. One phytonutrient in oranges that boosts it into the super food category is the flavonoid hesperidin. This biochemical works to support healthy blood vessels and reduces cholesterol. What has been established so far overlooks what the public considers the orange's defining health trait, it being stocked with vitamin C, an important antioxidant that limits free radicals while also building the immune system. Vitamin C's healing properties are well known and have been repeatedly scientifically validated. These include the lessening of arterial plaque as well as protecting from Alzheimer's, Parkinson's, and Crohn's diseases, arthritis, and diabetes.

Study estimates lower risk of cardiovascular disease associated with improved vitamin D level University of South Australia, December 10 2021. Research reported on December 5, 2021 in the European Heart Journal estimated that improvement of vitamin D levels to 20 ng/mL could eliminate 4.4% of all cases of cardiovascular disease. “Our results are exciting as they suggest that if we can raise levels of vitamin D within norms, we should also affect rates of cardiovascular disease,” she stated. “By increasing vitamin D-deficient individuals to levels of at least 50 nmol/L [20 ng/mL], we estimate that 4.4 percent of all cardiovascular disease cases could have been prevented.” (NEXT) Capsaicin molecule inhibits growth of breast cancer cells Centre of Genomics (Germany) December 18, 2021 Capsaicin, an active ingredient of pungent substances such as chilli or pepper, inhibits the growth of breast cancer cells. This was reported by a team following experiments in cultivated tumour cells. In the cultivated cells, the team detected a number of typical olfactory receptors. One receptor occurred very frequently; it is usually found in the fifth cranial nerve, i.e. the trigeminal nerve. It belongs to the so-called Transient Receptor Potential Channels and is named TRPV1. That receptor is activated by the spicy molecule capsaicin as well as by helional – a scent of fresh sea breeze. (NEXT) Running down the exercise 'sweet spot' to reverse cognitive decline University of Queensland (Australia), December 14 2021 University of Queensland researchers have discovered an exercise 'sweet spot' that reverses the cognitive decline in aging mice, paving the way for human studies. After more than a decade of research, led by Queensland Brain Institute, the team found 35 days of voluntary physical exercise improved learning and memory. "We tested the cognitive ability of elderly mice following defined periods of exercise and found an optimal period or 'sweet spot' that greatly improved their spatial learning," Dr. Blackmore said. The researchers also discovered how exercise improved learning. (NEXT) Reducing copper in the body alters cancer metabolism to reduce risk of aggressive breast cancer Weill Cornell Medicine, December 15, 2021 Depleting copper levels may reduce the production of energy that cancer cells need to travel and establish themselves in other parts of the body by a process referred to as metastasis, according to a new study by investigators from Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center (MSK). The discovery of the underlying mechanisms of how copper depletion may help reduce metastasis in breast cancer will help inform the design of future clinical trials. In a series of research papers from 2013 to 2021, Weill Cornell Medicine researchers showed that in a phase II clinical trial when patients who had high-risk triple-negative breast cancer (TNBC) were treated with a drug that lowers the levels of copper in their bodies, it prolonged the period of time before their cancer recurred and spread or metastasized. (NEXT) Yerba mate decreases your risk of metabolic disorders Kyungpook National University (Korea), December 4, 2021 Yerba mate is a herbal dietary supplement taken for weight loss. A study published in the Journal of Medicinal Food examined its ability to treat obesity and metabolic disorders. Rats were divided into two groups: a control group given a high-fat diet and a control group with a high-fat diet but supplemented with yerba mate. Upon analysis of the animals, the researchers found that yerba mate increased energy expenditure and thermogenic gene mRNA expression in white adipose tissue (WAT) and decreased fatty acid synthase (FAS) mRNA expression in WAT. These changes were associated with decreases in body weight, WAT weight, epididymal adipocyte size, and plasma leptin level. (OTHER NEWS NEXT) High-ORAC Foods May Slow Aging USDA. Foods that score high in an antioxidant analysis called ORAC may protect cells and their components from oxidative damage, according to studies of animals and human blood at the Agricultural Research Service's Human Nutrition Research Center on Aging at Tufts in Boston. ARS is the chief scientific agency of the U.S. Department of Agriculture ORAC, short for Oxygen Radical Absorbance Capacity, is a test tube analysis that measures the total antioxidant power of foods and other chemical substances. Early findings suggest that eating plenty of high-ORAC fruits and vegetables--such as spinach and blueberries--may help slow the processes associated with aging in both body and brain. In the studies, eating plenty of high-ORAC foods: Raised the antioxidant power of human blood 10 to 25 percent Prevented some loss of long-term memory and learning ability in middle-aged rats Maintained the ability of brain cells in middle-aged rats to respond to a chemical stimulus--a function that normally decreases with age Protected rats' tiny blood vessels--capillaries--against oxygen damage "It may be that combinations of nutrients found in foods have greater protective effects than each nutrient taken alone," said Guohua (Howard) Cao, a physician and chemist who developed the ORAC assay. Examples Women gave blood after separately ingesting spinach, strawberries and red wine--all high-ORAC foods--or taking 1,250 milligrams of vitamin C. A large serving of fresh spinach produced the biggest rise in the women's blood antioxidant scores--up to 25 percent--followed by vitamin C, strawberries and lastly, red wine Men and women had a 13- to 15-percent increase in the antioxidant power of their blood after doubling their daily fruit and vegetable intake compared to what they consumed before the study. Just doubling intake, without regard to ORAC scores of the fruits and vegetables, more than doubled the number of ORAC units the volunteers consumed, said Prior. Rats fed daily doses of blueberry extract for six weeks before being subjected to two days of pure oxygen apparently suffered much less damage to the capillaries in and around their lungs, Prior said. Middle-aged rats that had eaten diets fortified with spinach or strawberry extract or vitamin E for nine months. A daily dose of spinach extract "prevented some loss of long-term memory and learning ability normally experienced by the 15-month-old rats," said Shukitt-Hale. Spinach was also the most potent in protecting different types of nerve cells in two separate parts of the brain against the effects of aging, said Joseph. (NEXT) Paul Kingsnorth Interview Video  Paul Kingsnorth is an English environmental writer, novelist and the former deputy-editor of The Ecologist and a co-founder of the Dark Mountain Project. Kingsnorth's nonfiction writing addresses macro themes like environmentalism, globalization, and the challenges posed to humanity by civilization-level trends. He is a graduate of Oxford University and later joined the environmental campaign group EarthAction. He has subsequently worked as commissioning editor for openDemocracy, as a publications editor for Greenpeace and, between 1999 and 2001, as deputy editor of The Ecologist. He was named one of Britain's "top ten troublemakers" by the New Statesman magazine in 2001.  In 2020, he was called "England's greatest living writer" by Aris Roussinos. In 2004, he was one of the founders of the Free West Papua Campaign, which campaigns for the secession of the provinces of Papua and West Papua from Indonesia, where Kingsnorth was made an honorary member of the Lani tribe in 200.  His most notable book is Confessions of a Recovering Environmentalist (NEXT) Video - James Giordano Lecture James  Giordano, PhD, MPhil, is Chief of the Neuroethics Studies Program, Scholar-in-Residence, leads the Sub-Program in Military Medical Ethics, and Co-director of the O'Neill-Pellegrino Program in Brain Science and Global Health Law and Policy in the Pellegrino Center for Clinical Bioethics; and is Professor in the Departments of Neurology and Biochemistry at Georgetown University Medical Center, Washington, DC, USA.  He is also Distinguished Visiting Professor of Brain Science, Health Promotions and Ethics at the Coburg University of Applied Sciences, Coburg, Germany, and was formerly 2011-2012 JW Fulbright Foundation Visiting Professor of Neurosciences and Neuroethics at the Ludwig-Maximilians University, Munich, Germany. Prof. Giordano currently serves as Chair of the Neuroethics Program of the IEEE Brain Project, and an appointed member of the Neuroethics, Legal and Social Issues (NELSI) Advisory Panel of the Defense Advanced Research Projects' Agency (DARPA). He has previously served as Research Fellow and Task Leader of the EU Human Brain Project Sub-Project on Dual-Use Brain Science; an appointed member of United States Department of Health and Human Services Secretary's Advisory Council on Human Research Protections (SACHRP); and as Senior Science Advisory Fellow of the Strategic Multilayer Assessment Branch of the Joint Staff of the Pentagon.

The Nobel Prize for Physiology 2021 goes to two scientists who have helped us identify which receptors in our bodies sense heat, touch, temperature and pressure.In this podcast, we explain what these 4 receptors (TRPV1, TRPM8, PIEZO1, PIEZO2) mean, in simple terms for kids to understand. We also answer questions raised by our young listeners -a) We always knew that we had sensors for touch and heat that sent information to our brain. What does this research tell us additionally ?b) Why are these receptors important for us ? What would happen to us, if we did not have these receptors ?c) All this information sounds interesting to be printed on encyclopedias and science textbooks. But where would we really be using this?If you have any thoughts or questions, please email us at hello@wsnt.in

Autor: Winkelheide, Martin Sendung: Forschung aktuell Hören bis: 19.01.2038 04:14

El dolor es una sensación intuitiva que todos conocemos por experiencia propia, pero ¿qué es el dolor? ¿Qué es lo que está ocurriendo en nuestro cuerpo cuando sentimos dolor? Esas preguntas, en apariencia sencillas, resultan tener muchas posibles respuestas. El dolor no es una sola cosa, sino cualquier sensación que nuestro organismo interpreta como dañina, y las sentimos como dolorosas para que tengamos claro que debemos evitarlas. Así pues, el dolor puede venir de varios lugares diferentes, y en cada uno de esos lugares se detecta y se da la voz de alarma de formas ligeramente distintas, aunque nosotros llamemos genéricamente "dolor" a todas esas cosas. Hoy hablamos con David Julius, ganador del Premio Fronteras del Conocimiento de la Fundación BBVA en la categoría de Biología y Biomedicina y profesor en la Universidad de California en San Francisco. El profesor Julius ha dedicado su carrera a estudiar algunos de esos tipos de dolor: cómo se detecta, cómo reaccionan las células y cómo afecta el ambiente a la percepción del dolor. Os contamos el caso de TRPV1, la proteína responsable de detectar altas temperaturas, y por lo tanto de iniciar la cadena del dolor cuando nos quemamos. Si os interesa cómo se genera el dolor, pero no en las células sino en el cerebro, repasad el episodio s08e19. Si queréis refrescar cómo es una célula por dentro y cuál es el papel de las proteínas en la célula buscad el capítulo s10e04. Y para aprender sobre otros mecanismos celulares que son esencialmente "detectores", escuchad los episodios s07e47 y s09e06. Este programa se emitió originalmente el 17 de septiembre de 2021. Podéis escuchar el resto de audios de La Brújula en la app de Onda Cero y en su web, ondacero.es

Eat Cool: Good Food for Hot DaysBy Vanessa Seder Intro: Welcome to the number one cookbook podcast, Cookery by the Book with Suzy Chase. She's just a home cook in New York City, sitting at her dining room table, talking to cookbook authors.Vanessa Seder: This is Vanessa Seder, and I'm here to chat about my new cookbook, Eat Cool: Good Food for Hot Days.Suzy Chase: You are a chef, food stylist, recipe developer, teacher, author, and founding member of Relish & Co. a Portland based culinary design collaborative and I'm excited to chat about Eat Cool. Your second cookbook, 100 plus recipes, tips, ideas, and support to help you eat and cook your way through hot weather. So Eat Cool is another one of these cookbooks that will pull us out of the pandemic rut. It's a fun versatile guidebook. What's the objective behind Eat Cool.Vanessa Seder: It just came from this organic place where I just started cooking in a new kind of a way and I found that I was getting good results. My body wasn't feeling tired or overly heated from the way we were eating. We were eating really delicious food. We didn't feel depleted. So it kind of encompasses a number of things, it's to cook in ways that reduce oven, stove top use, or making food items that require no cooking whatsoever. It's also cutting things in ways that kind of cut down on the cooking time. Eating foods that are naturally cooling, fruits, vegetables, grains, plant-based proteins and proteins that are lower in fat and less meat focused. And I'm not saying omitting all these things, but the food items that are heavier, alcohol-based, fattier to eat those more sparingly when it's really, really hot.Suzy Chase: What are some of the different cuisines that you include in this cookbook?Vanessa Seder: I'm really inspired by cuisines from around the world. In my first cookbook Secret Sauces, it also kind of has an international angle. So in this book, there are recipes that are inspired by, I would say Japanese Thai, Korean, Mediterranean, Indian, Mexican, middle Eastern, and maybe farm local source centric recipes. I grew up in Los Angeles. That's where I’m originally from, my grandmother was actually born there so I'm a true Los Angeleno and if you look at the history there, there's a lot of Mexican, South American, Central American and a lot of Asian culture. So I grew up eating a lot of that kind of food. Plus going up North, I have an aunt lives up North a bit. And so, you know, going into olive oil tastings and eating artichokes and all that kind of stuff, that was part of, of my childhood. So that kind of inspires a lot of my cooking style.Suzy Chase: So this is something that you don't often get in cookbooks. You have a list of five criteria for this cookbook. What are they?Vanessa Seder: Is it delicious and enjoyable to eat? Well, obviously that's very important. You know, I don't want anybody to go to the supermarket or the farmer's market and spend all this time and effort cooking food and having it not taste and look delicious. Number two, will it keep you relatively cool? So that's really important here when you're eating cool. I had all these recipes tested by friends and neighbors, and I asked them how they felt after cooking the different things or not cooking the different things. Cause there's a lot of recipes in this book for you don't even cook. And then I was in the kitchen on stop during the summer and I was developing into the fall winter, but it really did start. I did a majority when it was very, very hot, just seeing how I felt after eating these dishes that I was developing. So that was really important. The third one is, does it avoid the need for lots of labor and cooking? You know, you want to kind of cut down as much as possible, the cooking and chopping and cleaning when you're just so worn out at the end of the day. I tried to keep things simple so that it's not too time consuming. The fourth is can the home chef make it successfully? So yes, of course I also work as a teacher every month. I teach cooking at the Stonewall Kitchen headquarters here in Maine and I absolutely love teaching because I think that cooking is a life skill that everyone should have. And so the teacher, part of me comes out when writing a book too, and I want to make sure that everything is really clear and really well explained in the recipes so that people cooking the food, know exactly what to do when making the recipes. And then number five are its ingredients easy to find or can viable substitutions be provided. And for that definitely in a lot of the recipes I include in the head notes suggestions for where to put purchase hard to find items. There's always the internet these days as we've probably all use a lot of within the last year because of the pandemic. And if there's anything that's a little bit exotic, I offer suggestions for where to find those itemsSuzy Chase: Does eating something hot, actually cool, a person down.Vanessa Seder: I did a bunch of research on this. I am not a scientist, but I really explored this concept of why do people eat this way in hot climate. And what it is, is there a special protein structures called receptors in our mouth. And the one that kind of detects hot spicy food and drinks is called the TRPV1 receptor. And so when we eat or drink something that's hot or spicy, it triggers the TRPV1 receptor. And that cues, the nervous system to transmit a signal to the hypothalamus, which is kind of like our brains thermostat. So when you eat the spicy food or drink something hot, it triggers it. And what happens next is our body starts sweating and that's what cools down our body. So that's eating hot to cool, in a sense. So on the flip side of that, when you eat really cold rich foods, such as ice cream, or like an alcoholic slushie, which I actually have some of those in the book, but I say in the headnote to eat them sparingly, if it's really, really hot, it cools the body down a lot quicker, but it's more temporary because it has to work harder to digest it, which heats up your body.Suzy Chase: Now moving from hot to cold, let's talk about your soup chapter. What is the key to good gazpacho? Because I feel like you either get out-of-this-world gazpacho or you get like, so- so good gazpacho.Vanessa Seder: I, 100% agree with you there. Well, I was kind of on the fence actually, if I should include a good gazpacho recipe, just because there are so many out there in the world, but I think what it comes down to is that because everything is raw and in a gazpacho the end result really depends on the quality and ripeness of the individual ingredients of the soup. So if you're using tomatoes, cucumbers, peppers, chilies, herbs that are peak ripeness during the summer and are from a farmer's market or a garden, obviously it's going to taste so much better than off season tomatoes, peppers, cucumbers, right? And then you have the olive oil. So I think that really matters here. I'm lucky enough. I mentioned it before, but I have an aunt who lives in Atascadero California. That's near lots of vineyards and olive groves and she sends us bottles of really good olive oil, Pasolivo and Kitehawk farm, are some of my favorite that come out of that area. And so when I am making a gazpacho, I saved my really good olive oil for my gazpacho because it comes through. And then I would say the last part would be to bread or not to add bread. And I like adding bread in my gazpacho because I find that it absorbs some of the acid from the tomatoes and the vinegar, and also adding bread to gazpacho is a great to use an extra bread or bread becoming stale.Suzy Chase: How did it feel getting written up by Florence Fabricant in the New York Times, she is notoriously hard to impress, take it from me. She has never wanted to write anything about this podcast. Oh wow. She has written, I pitched her and she, she wrote try again. And then I pitched her more. Try again. She wrote that like four times to me, I just kept saying, I'm the only cookbook podcast Florence.Vanessa Seder: Wow, honestly it was a thrill and a highlight I have to say and I got an email out of the blue and when I saw who it was from, I got a little teary because I've been doing this for so long and to get Eat Cool, noticed by someone I respect and admire meant so much to me. And she said that she liked the book and thought it was a very timely subject and had some questions about some of the recipes in the book and it made me a little nervous, but I held my breath and I just did my best to answer them straightforwardly and accurately as best I could. It was just a really great honor that the book caught her notice, the notice of the great Flo Fab. What a great name, huh?Suzy Chase: Oh my gosh. I mean, you have to frame that.Vanessa Seder: Oh, I don't know if I'll frame it, but I'll definitely keep it.Suzy Chase: Definitely. Yeah.Vanessa Seder: It's definitely kept in a safe placeSuzy Chase: In the cookbook. You said the cold seafood spread is akin to the charcuterie, meze or cheese platter. Can you tell us about that?Vanessa Seder: I find that when it's really, really hot out, I love a good tinned seafood. There's a whole variety, you know, you can buy really inexpensive tins of seafood and they're fine for the most part. Or you can move up the ladder and purchase really expensive tins that come from Spain, all sorts of things like razor clams, kippers, herring, oysters, sardines. They're really all pretty good, I think. And so it's kind of a play on the charcuterie cheese board where you assemble a beautiful board, but with your tin seafood, but then you balance it with peppery greens, different sauces, crackers, chips, crudité all sorts of things like that. It just makes for a really easy meal when it's hot, as blazes outside.Suzy Chase: So normally when I start doing research for a cookbook, I look at every single one of the cookbook authors, Instagram posts, it kind of gives me a feel of their personality. And immediately when I looked at Instagram, I thought we need to be friends. She's my new friend. Yay. You have such a knack with photography. Your little family is darling. And I got so sad when I saw your beloved cat Birdie passed away, but then you rescued two kittens. So one particular Instagram post that caught my eye was the beautiful cookbook collection at the Lincolnville Motel in Lincolnville Maine.Vanessa Seder: He stayed there in 2019 feels like a world ago and we were up that way cause I was teaching a class at The Saltwater Farm Cooking School run by Annemarie Ahearn and it's this cute modern yet classic Maine inn and shout out to Alice who runs it. She's great. It's a little bit North of Camden, Maine. There's a lot of great restaurants up there, like Long Grain. So yeah, if you're ever in the area, you should make a trip, go up there, kind of a fun place to stay.Suzy Chase: For desserts on a hot day I have such a hard time thinking outside the fruit box. What sorts of ideas do you have for cooling desserts?Vanessa Seder: For the non fruit variety, I would suggest either the Chocolate Panna Cotta with salty Praline Peanut Crumble, Summer Corn Ice Cream, White Almond Sorbet, Ginger Cardamom Saffron Ice Cream, The Tropical Crispy Bars or the Malted Chocolate Icebox Cake. When I was creating this book, I purposely stayed away from shortcakes, tarts, pies, layer cakes, things like that because they take longer in the oven to bake and also when you're making something like a pate brisee which is a butter class of laminated dough, biscuit dough, the butter needs to remain very cold and that's really difficult to achieve when it's hot as blazes.Suzy Chase: Tell me about the Summer Corn Ice Cream. I've never heard of corn ice cream.Vanessa Seder: I think it's good, but you have to like corn, of course.Suzy Chase: I'm from Kansas. I love corn.Vanessa Seder: Well I didn't grow up with the best corn. When I started dating my husband, we met in college, he's from Massachusets. We went to go to his dad's house for kind of a grill outside and he served corn I just kind of blown away by the sweetness and quality of the corn we had, as simple as it was, and so that was my real introduction to New England corn and I have a huge respect for it and I wait all year to eat corn. I don't want to just have any corn and want that corn. So what I do every summer is I absolutely love making ice cream and so I used that corn and I soaked the cobs in the cream and the milk to get as much flavor out of the corn cob. And then I add the fresh corn to it and then I create a custard base and then run it through the machine. And it has a really intense corn flavor and it's just really delicious. I love it.Suzy Chase: That sweet corn is like heaven on earth.Vanessa Seder: I think so too. I mean, that's the thing. I don't think everyone loves corn. I don't know why, but we all love corn here that sweet summer corn. And if you like things like, like a corn custard or a cream corn, then you'll love the ice cream.Suzy Chase: Okay. Here's a super random question. I would love to hear about your dining room table.Vanessa Seder: Well we love antiques when we were first in Maine we went in search of a table and we ended up finding the table that it was in Buxton, Maine, and it was in a barn and it was just sitting there. It barely cost us anything and it had been in the same family for over 50 years and the why they were getting rid of it, but we just absolutely love it. And it's where we gather. And it served our family really well and we just love it and we try to take as best care of it as we can. I love old things. I like new things too, but I think it's also better for the environment. You know, you're just repurposing and you're loving something again and you're bringing new life into it. So I'm all for that. I.Suzy Chase: I know you're endlessly curious about food. So what is some sort of culinary thing you learned this past?Vanessa Seder: Okay, well this is gonna probably sound boring and a bit cliche at this point.Suzy Chase: Sourdough?Vanessa Seder: Wow. How did you guess? I mean, there's not much to get, I mean, we just really upped our sourdough starter making game and it got to this point where we were making bagels and bread and it became part of our weekly cooking rotation. But between working and remote school this year, our daughter's been in remote school all year. It just was hard to keep it going. And also it was just getting to this point where we were just eating way too much bread. So I would say that ultimately this year was about figuring out ways to avoid shopping as much as possible and getting really creative with leftovers in our fridge.Suzy Chase: You have a section called Fun with Rotisserie chicken. There's six options to make rotisserie chicken more interesting. When it's a hot hot day to pick up a rotisserie chicken is such a lifesaver. So I made your Quicker Shawarma recipe over the weekend. Can you tell us about this recipe?Vanessa Seder: Well, what did you think? First of all.Suzy Chase: I loved it And it was so easy and fun for my family and easy for me to make because it's a rotisserie chicken. It's great for moms everywhere, but that sauce was so darned good.Vanessa Seder: Which sauce did you use?Suzy Chase: It was the chili sauce. The toasted garlic and chili sauce. And I didn't have chili's so I used jalapenos.Vanessa Seder: Perfect. I love that. You're improvising. So my point with this page, which is kind of a sidebar was that if you're so hot and so tired and so burned out, go get a rotisserie chicken. There's nothing bad about it. And you don't have to just think of it as chicken leg. You can transform it into so many dishes shawarma is cooked on a vertical spit for hours. And so this is a huge shortcut. And why heat up your kitchen? When you can just go to the store and get her history chicken, season it up, put it in a slightly warmed pita, add a sauce of your choice. I offer a couple suggestions, top it with some lettuce and tomato, yogurt, but you can improvise too, you could add some avocado. It's a loose interpretation, obviously, you could add hummus anything you'd like, but I'm glad you enjoyed it.Suzy Chase: It's a full dinner. You don't have to make a side or anything. You just shove everything into the warm pita. And by the way, what's better than a warm pita?Vanessa Seder: I don't think anything. Nothing, right? Yeah. It's great. A warm pita is just delicious.Suzy Chase: Over the weekend. I sort of combined pages 111 and 113 to make grilled shrimp with herb butter, tomatoes and micro greens on sourdough toast. I really, really love the toast idea.Vanessa Seder: Why have two pieces of bread when you can just have one and still feel like you're getting a full meal. And I'm glad you combine the recipes actually. I mean, I tell students this, when I'm teaching that you can look at a lot of recipes as just kind of a loose blueprint or a jumping off point to improvise, but I'm really glad that you're having fun with the book and you're improvising from it. If you don't have all the ingredients that I hope people are doing that.Suzy Chase: Now for my segment called Last Night's Dinner, where I ask you what you had last night for dinner.Vanessa Seder: So I started off with some really good olive oil, and then I toasted leftover pasta. I think we had rigatoni so I toasted that up in the pan until it got kind of like crisp chewy tender and it had some more texture to it. And then I added some nice asparagus and fresh garlic to that and just kind of tossed it through and just heated it so that the asparagus was kind of crisp, tender, a little bit of salt and pepper. And then I added eggs to it and I kind of scrambled it all together and then a little bit of spicy chili and a shaving of parm. And then we had it with Cortaterre. It's an Oregon Pinot Noir. It's just fabulous. We really are into good Oregon Pinot Noir.Suzy Chase: I want to give a shout out to your editor, Jono Jarrett.Vanessa Seder: I think you should. He's incredible. I can't say enough good things about him. I love Jono.Suzy Chase: You know, we are from the same hometown.Vanessa Seder: Stop. It really?Suzy Chase: Yes. We're from Prairie, Kansas. We're Instagram friends. And I'm like, wait, how did I, how did I not know you? My mom has to know your mom!Vanessa Seder: What a small world. It is a small world. He was just so great and involved in so much of this book and he would ship props over, you know, cause I did all the propping styling with Stacy and Jennifer, the three of us did the book together and everybody contributed so much to this book. It's really a huge process to write a cookbook. Yeah. He was just such a wonderful editor to have.Suzy Chase: So where can we find you on the web and social media?Vanessa Seder: VanessaSeder.com or RelishandCo.com and then I'm @VSeder on Instagram.Suzy Chase: Eat Cool is going to be my go-to at the beach house this summer. Thanks Vanessa for coming on Cookery by the Book podcast.Vanessa Seder: Thanks for having me. It's been a pleasure.Outro: Follow Cookery by the Book on Instagram. And thanks for listening to the number one cookbook podcast, Cookery by the Book.

The Cannabis Professor has Crossed 50 Episodes, and we are on the road to 100!In celebration of this milestone - we are going to perform a human experiment with Cannabis.  Cannabis Professional and Amateur wrestler Rich Steve joins us to take on the hottest chip in the world - the famous ONE CHIP CHALLENGE - a Carolina Reaper coated tortilla chip that will make you feel the burn.You see, there is a receptor in the human body called the Capsaicin Receptor (TRPV1) and this receptor is what makes you feel the pain of hot foods.  Well, it looks like THC and other cannabis molecules can change that response - time for an experiment!We eat the chip and see if any medical marijuana products can fight the reaction.  Tune in if you want to find out if the hypothesis works! (P.S. the results are amazing!)@thecannabis.professor

CBD you can trust. Feel and perform your best every day. Physician Developed Step-by-Step Usage Guide CBDA and CBD share many properties, including activity at the 5-HT1A serotonin and TRPV1 capsaicin receptors. CBDA and CBD also have some differences: CBDA does not impact the CB1 receptor, and CBDA does inhibit the COX-2 enzyme. CBDA has much higher oral bioavailability than CBD, and seems to be much more potent in certain models. Low doses of CBDA, like those found in tea made from hemp flowers or type 3 cannabis varieties, are likely ideal.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.04.368597v1?rss=1 Authors: Klein, A., Solinski, H. J., Malewicz, N., Ieong, H. F.-h., Shimada, S., Hartke, T. V., Wooten, M., Wu, G., Hoon, M. A., LaMotte, R. H., Ringkamp, M. Abstract: In human, intradermal administration of {beta}-alanine (ALA) and bovine adrenal medulla peptide 8-22 (BAM8-22) evokes the sensation of itch. Currently, it is unknown which human dorsal root ganglion (DRG) neurons express the receptors of these pruritogens, MRGPRD and MRGPRX1 respectively, and which cutaneous afferents these pruritogens activate in primate. In situ hybridization studies revealed that MRGPRD and MRGPRX1 are co-expressed in a subpopulation of TRPV1+ human DRG neurons. In electrophysiological recordings in nonhuman primates (Macaca nemestrina), subtypes of polymodal C-fiber nociceptors are preferentially activated by ALA and BAM8-22, with significant overlap. When pruritogens ALA, BAM8-22 and histamine, that activate different subclasses of C-fiber afferents, are administered in combination, human volunteers report itch and nociceptive sensations similar to those induced by a single pruritogen. Our results provide evidence for differences in pruriceptive processing between primates and rodents, and do not support the spatial contrast theory of coding of itch and pain. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.21.348037v1?rss=1 Authors: Wu, X., Jiang, Y., Rommelfanger, N. J., Yin, R., Liu, J., Cai, S., Ren, W., Shin, A., Ong, K. S., Pu, K., Hong, G. Abstract: Neural modulation techniques with electricity, light and other forms of energy have enabled the deconstruction of neural circuitry. One major challenge of existing neural modulation techniques is the invasive brain implants and the permanent skull attachment of an optical fiber for modulating neural activity in the deep brain. Here we report an implant-free and tether-free optical neuromodulation technique in deep-brain regions through the intact scalp with brain-penetrant second near-infrared (NIR-II) illumination. Macromolecular infrared nanotransducers for deep-brain stimulation (MINDS) demonstrate exceptional photothermal conversion efficiency of 71% at 1064 nm, the wavelength that minimizes light attenuation by the brain in the entire 400-1700 nm spectrum. Upon widefield 1064-nm illumination >50 cm above the mouse head at a low incident power density of 10 mW/mm2, deep-brain neurons are activated by MINDS-sensitized TRPV1 channels with minimal thermal damage. Our approach could open opportunities for simultaneous neuromodulation of multiple socially interacting animals by remotely irradiating NIR-II light to stimulate each subject individually. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.14.339382v1?rss=1 Authors: Shiers, S., Sankaranarayanan, I., Jeevakumar, V., Cervantes, A., Reese, J. C., Price, T. J. Abstract: Peripheral sensory neurons are characterized by their size, molecular profiles, and physiological responses to specific stimuli. In mouse, the peptidergic and non-peptidergic subsets of nociceptors are distinct and innervate different lamina of the spinal dorsal horn. The unique molecular signature and neuroanatomical organization of these neurons supports a labeled line theory for certain types of nociceptive stimuli. However, long standing evidence supports the polymodal nature of nociceptors in many species. We have recently shown that the peptidergic marker, CGRP, and the non-peptidergic marker, P2X3R, show largely overlapping expression at the mRNA level in human dorsal root ganglion (DRG). Herein, our aim was to assess the protein distribution of nociceptor markers, including their central projections, in the human DRG and spinal cord. Using DRGs obtained from organ donors, we observed that CGRP and P2X3R were co-expressed by approximately 33% of human DRG neurons and TrpV1 was expressed in ~60% of human DRG neurons. In the dorsal spinal cord, CGRP, P2X3R, TrpV1 and Nav1.7 protein stained the entirety of lamina II, with only P2XR3 showing a gradient of expression. This was confirmed by measuring the size of the substantia gelatinosa using Hematoxylin and Eosin staining of adjacent sections. Our findings are consistent with the known polymodal nature of most primate nociceptors and indicate that the central projection patterns of nociceptors are different between mice and humans. Elucidating how human nociceptors connect to subsets of dorsal horn neurons will be important for understanding the physiological consequences of these species differences. Copy rights belong to original authors. Visit the link for more info

In this episode, we discuss the mechanisms of burning with propofol infusion and explore the evidence behind strategies like mixing lidocaine with propofol.  Our guest today is Dr. Stu Forman, Professor of Anesthesiology at Massachusetts General Hospital. He is an investigator on several NIH-sponsored basic research grants and co-director of the Harvard Anesthesia Research Training Fellowship. Connect with us @DepthAnesthesia on Twitter or email us at depthofanesthesia@gmail.com. Thanks for listening! Please rate us on iTunes and share with your colleagues.  Music by Stephen Campbell, MD.  -- References Bengalorkar GM, Bhuvana K, Sarala N, Kumar T. Fospropofol: clinical pharmacology. J Anaesthesiol Clin Pharmacol. 2011 Jan;27(1):79-83. PMID: 21804712; PMCID: PMC3146164. Dajun Song, Mohamed A. Hamza, Paul F. White, Stephanie I. Byerly, Stephanie B. Jones, Amy D. Macaluso; Comparison of a Lower-lipid Propofol Emulsion with the Standard Emulsion for Sedation during Monitored Anesthesia Care. Anesthesiology 2004; 100:1072–1075 doi: https://doi.org/10.1097/00000542-200405000-00007 Euasobhon P, Dej-Arkom S, Siriussawakul A, Muangman S, Sriraj W, Pattanittum P, Lumbiganon P. Lidocaine for reducing propofol-induced pain on induction of anaesthesia in adults. Cochrane Database Syst Rev. 2016 Feb 18;2(2):CD007874. doi: 10.1002/14651858.CD007874.pub2. PMID: 26888026; PMCID: PMC6463799. Fischer MJ, Leffler A, Niedermirtl F, Kistner K, Eberhardt M, Reeh PW, Nau C. The general anesthetic propofol excites nociceptors by activating TRPV1 and TRPA1 rather than GABAA receptors. J Biol Chem. 2010 Nov 5;285(45):34781-92. doi: 10.1074/jbc.M110.143958. Epub 2010 Sep 7. PMID: 20826794; PMCID: PMC2966094. Jalota L, Kalira V, George E, Shi YY, Hornuss C, Radke O, Pace NL, Apfel CC; Perioperative Clinical Research Core. Prevention of pain on injection of propofol: systematic review and meta-analysis. BMJ. 2011 Mar 15;342:d1110. doi: 10.1136/bmj.d1110. PMID: 21406529. Klement W, Arndt JO. Pain on i.v. injection of some anaesthetic agents is evoked by the unphysiological osmolality or pH of their formulations. Br J Anaesth. 1991 Feb;66(2):189-95. doi: 10.1093/bja/66.2.189. PMID: 1817619. Sahinovic MM, Struys MMRF, Absalom AR. Clinical Pharmacokinetics and Pharmacodynamics of Propofol. Clin Pharmacokinet. 2018;57(12):1539-1558. doi:10.1007/s40262-018-0672-3 Scott RP, Saunders DA, Norman J. Propofol: clinical strategies for preventing the pain of injection. Anaesthesia. 1988 Jun;43(6):492-4. doi: 10.1111/j.1365-2044.1988.tb06641.x. PMID: 3261547.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.25.312108v1?rss=1 Authors: Li, J., Zain, M., Bonin, R. P. Abstract: Common approaches to studying chronic pain in pre-clinical animal models paradoxically involve measuring reflexive withdrawal responses that are more indicative of acute nociceptive pain. These methods typically do not capture the ongoing nature of chronic pain nor report on behavioral changes associated with pain. In addition, data collection and analysis protocols are often labour-intensive and require direct investigator interactions, potentially introducing bias. In this study, we develop and characterize a low-cost, easily assembled behavioral assay that yields self-reported temperature preference from mice which is sensitive to peripheral sensitization protocols. This system uses a partially automated and freely available analysis pipeline to streamline the data collection process and enable objective analysis. We found that after intraplantar administration of the TrpV1 agonist, capsaicin, mice preferred to stay in cooler temperatures than control injected mice. We further observed that gabapentin, a non-opioid analgesic commonly prescribed to treat chronic pain, reversed this aversion to higher temperatures. We further observed that optogenetic activation of the central terminals of TrpV1+ primary afferents via in vivo spinal light delivery did not induce a similar change in thermal preference, indicating a role for peripheral nociceptor activity in the modulation of temperature preference. We conclude that this easily produced and robust sensory assay provides an alternative approach to investigate the contribution of central and peripheral mechanisms to pathological sensory processing that does not rely on reflexive responses evoked by noxious stimuli. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.05.267708v1?rss=1 Authors: Li, T., Wang, G., Hui, V. C. C., Saad, D., de Sousa Valente, J., La Montanara, P., Nagy, I. Abstract: Increased activity and excitability (sensitisation) of a series of molecules including the transient receptor potential ion channel, vanilloid subfamily, member 1 (TRPV1) in pain-sensing (nociceptive) primary sensory neurons are pivotal for developing pathological pain experiences in tissue injuries. TRPV1 sensitisation is induced and maintained by two major mechanisms; post-translational and transcriptional changes in TRPV1 induced by inflammatory mediators produced and accumulated in injured tissues, and TRPV1 activation-induced feed-forward signalling. The latter mechanism includes synthesis of TRPV1 agonists within minutes, and upregulation of various receptors functionally linked to TRPV1 within a few hours, in nociceptive primary sensory neurons. Here, we report that a novel mechanism, which contributes to TRPV1 activation-induced TRPV1-sensitisation within ~30 minutes in at least ~30% of TRPV1-expressing cultured murine primary sensory neurons, is mediated through upregulation in cyclooxygenase 2 (COX2) expression and increased synthesis of a series of COX2 products. These findings highlight the importance of feed-forward signalling in sensitisation, and the value of inhibiting COX2 activity to control pain, in nociceptive primary sensory neurons in tissue injuries. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.18.255109v1?rss=1 Authors: Fujimura, S., Mio, K., Kuramochi, M., Sekiguchi, H., Keigo, I., Mio, M., Hengphasatporn, K., Shigeta, Y., Kubo, T., Sasaki, Y. C. Abstract: Transient receptor potential vanilloid type 1 (TRPV1) channels are activated by heat, vanilloids, and extracellular protons. Cryo-EM has revealed various conformations of TRPV1, and these structures suggest an intramolecular twisting motion in response to ligand binding. However, limited experimental data support this observation. Here we analyzed the intramolecular motion of TRPV1 using diffracted X-ray tracking (DXT). DXT analyzes trajectories of Laue spots generated from attached gold nanocrystals, and provides picometer spatial and microsecond time scale information about intramolecular motion. We observed that both an agonist and a competitive antagonist evoked rotating bias in TRPV1, though these biases were in opposing directions. Furthermore, the rotational bias generated by capsaicin was reversed between the wild type and the capsaicin-insensitive Y511A mutant. Our findings bolster the understanding of the mechanisms used activation and modulation of TRP channels, and this knowledge can be exploited for pharmacological usage such as inhibitor design. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.11.245738v1?rss=1 Authors: Jeong, I., Yun, S., Shahapal, A., Cho, E. B., Hwang, S. W., Seong, J. Y., Park, H.-C. Abstract: Family with sequence similarity 19 (chemokine (C-C motif)-like), member A5 (FAM19A5) is a chemokine-like secretory protein recently identified to be involved in the regulation of osteoclast formation, post-injury neointima formation, and depression. Here, we identified FAM19A5l, an orthologous zebrafish gene that originated from a common ancestral FAM19A5 gene. FAM19A5l was expressed in trigeminal and dorsal root ganglion neurons as well as distinct neuronal subsets of the central nervous system of zebrafish. Interestingly, FAM19A5l+ trigeminal neurons were nociceptors that co-localized with TRPA1b and TRPV1, and responded to mustard-oil treatment. Behavioral analysis revealed that the nociceptive response to mustard oil decreased in FAM19A5l-knockout zebrafish larvae. In addition, TRPA1b and NGFa mRNA levels were down- and up-regulated in FAM19A5l-knockout and -overexpressing transgenic zebrafish, respectively. Together, our data suggested that FAM19A5l played a role in nociceptive responses to mustard oil by regulating TRPA1b and NGFa expression in zebrafish. Copy rights belong to original authors. Visit the link for more info

Disclaimer: The sole purpose of these articles and podcasts is to provide information and education about health, nutrition, fitness, and wellness. This information is not intended for use in the diagnosis, treatment, cure or prevention of any disease. If you have any serious acute or chronic health concern, please consult your personal health professional who can fully assess your needs and address them effectively within a medical/clinical setting. Check with your doctor before practicing any nutritional/fitness strategies, especially, before taking any supplements, herbs or using essential oils, especially, when pregnant or nursing. Please do not use the information provided in these podcasts to make any changes to your medication, diet, or lifestyle. If you do so, be sure to do it at your own discretion.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.14.150755v1?rss=1 Authors: Honeywell, K. M., Freels, T. G., McWain, M. A., Chaffin, A. S., Nolen, H. G., Sable, H. J., Lester, D. B. Abstract: A major problem with current anxiolytic medications is abuse liability; thus, new pharmaceutical targets are being explored. The cannabinoid system is one potential target. The current paper examined behavioral and neurochemical changes related to abuse liability following chronic administration of the indirect cannabinoid agonist arachidonoyl serotonin (AA-5-HT) and the direct cannabinoid type 1 receptor (CB1R) agonist arachidonyl-2-chloro-ethylamide (ACEA). AA-5-HT indirectly agonizes the cannabinoid system via inhibition of the dual fatty acid amide hydrolase (FAAH) while also inhibiting transient vanilloid type 1 (TRPV1) channels. Neither AA-5-HT nor ACEA induced conditioned place preference (CPP) or altered behaviors during open field (OF) or saccharin preference testing. AA-5-HT did not alter phasic dopamine release in the nucleus accumbens, as measured with in vivo fixed potential amperometry; however, ACEA decreased dopamine release and enhanced the dopaminergic effect of cocaine. Overall, neither AA-5-HT nor ACEA induced behavioral or neurochemical changes associated with abuse liability; however, indirect mechanisms of agonizing the cannabinoid system may be a better alternative than direct mechanisms if concerned with disrupting dopamine function. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.11.146829v1?rss=1 Authors: Ishida, K., Mbanefo, E., Le, L., Lamanna, O., Pennington, L., Finkel, J., Jardetzky, T., Falcone, F., Hsieh, M. Abstract: The transient receptor potential cation channel subfamily V member 1 (TRPV1) receptor is an important mediator of nociception and its expression is enriched in nociceptive neurons. TRPV1 signaling has been implicated in bladder pain and is a potential analgesic target. Resiniferatoxin is the most potent known agonist of TRPV1. Acute exposure of the rat bladder to resiniferatoxin has been demonstrated to result in pain-related freezing and licking behaviors that are alleviated by virally encoded IL-4. The interleukin-4-inducing principle of Schistosoma mansoni eggs (IPSE) is a powerful inducer of IL-4 secretion, and is also known to alter host cell transcription through a nuclear localization sequence-dependent mechanism. We previously reported that IPSE ameliorates ifosfamide-induced bladder pain in an IL-4- and nuclear localization sequence-dependent manner. We hypothesized that pre-administration of IPSE to resiniferatoxin-challenged mice would dampen pain-related behaviors. IPSE indeed lessened resiniferatoxin-triggered freezing behaviors in mice. This was a nuclear localization sequence-dependent phenomenon, since administration of a nuclear localization sequence mutant version of IPSE abrogated IPSEs analgesic effect. In contrast, IPSEs analgesic effect did not seem IL-4-dependent, since use of anti-IL-4 antibody in mice given both IPSE and resiniferatoxin did not dramatically affect freezing behaviors. RNA-Seq analysis of resiniferatoxin- and IPSE-exposed bladders revealed differential expression of TNF/NF-Kb-related signaling pathway genes. In vitro testing of IPSE uptake by urothelial cells and TRPV1-expressing neuronal cells showed uptake by both cell types. Thus, IPSEs nuclear localization sequence-dependent therapeutic effects on TRPV1-mediated bladder pain may act on TRPV1-expressing neurons and/or may rely upon urothelial mechanisms. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.31.126805v1?rss=1 Authors: Wang, Z., Jiang, C., Yao, H., Chen, O., Rahman, S., Gu, Y., Huh, Y., Ji, R.-R. Abstract: Opioids, such as morphine are mainstay treatments for clinical pain conditions. Itch is a common side effect of opioids, particularly as a result of epidural or intrathecal (i.t.) administration. Recent progress has advanced our understanding of itch circuits in the spinal cord. However, the mechanisms underlying opioid-induced itch are not fully understood, although an interaction between mu opioid receptor (MOR) and gastrin-releasing peptide receptor (GRPR) in spinal GRPR-expressing neurons has been implicated. In this study we investigated the cellular mechanisms of intrathecal (i.t.) opioid-induced itch by conditional deletion of MOR-encoding Oprm1 in distinct populations of interneurons and sensory neurons. We found that i.t. injection of the MOR agonists morphine or DAMGO elicited dose-dependent scratching, but this pruritus was totally abolished in mice with a specific Oprm1 deletion in Vgat+ neurons (Oprm1-Vgat). Loss of MOR in somatostatin+ interneurons and TRPV1+ sensory neurons did not affect morphine-induced itch but impaired morphine-induced antinociception. In situ hybridization revealed Oprm1 expression in 30% of inhibitory and 20% of excitatory interneurons in the spinal dorsal horn. Whole-cell recordings from spinal cord slices showed that DAMGO induced outward currents in 9 out of 19 Vgat+ interneurons examined. Morphine also inhibited action potentials in Vgat+ interneurons and suppressed evoked IPSCs in postsynaptic Vgat- excitatory neurons, suggesting a mechanism of disinhibition by MOR agonists. Notably, morphine-elicited itch was suppressed by i.t. administration of NPY and abolished by spinal ablation of GRPR+ neurons, whereas i.t. GRP-induced itch response remained intact in mice lacking Oprm1-Vgat. Additionally, chronic itch from DNFB-induced allergic contact dermatitis was decreased by Oprm1-Vgat deletion. Finally, naloxone, but not peripherally restricted naloxone methiodide, inhibited chronic itch in the DNFB model and the cutaneous T-cell lymphoma (CTCL) model, indicating a contribution of central MOR signaling to chronic itch. Our findings demonstrate that i.t. morphine elicits itch via acting on MOR on spinal inhibitory interneurons, leading to disinhibition of the spinal itch circuit. Our data also suggest that chronic itch could be effectively treated with CNS-targeted naloxone. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.30.069849v1?rss=1 Authors: Mulier, M., Van Ranst, N., Corthout, N., Munck, S., Vanden Berghe, P., Vriens, J., Voets, T., Moilanen, L. Abstract: Genetic ablation or pharmacological inhibition of the heat-activated cation channel TRPM3 alleviates heat hyperhyperalgesia in animal models of inflammation, but the mechanisms whereby the channel contributes to inflammatory pain are unknown. Here, we induced unilateral inflammation of the hind paw in mice, and directly compared expression and function of TRPM3 and two other heat-activated TRP channels (TRPV1 and TRPA1) in sensory neurons innervating the ipsilateral and contralateral paw. We detected increased Trpm3 mRNA levels in dorsal root ganglion neurons innervating the inflamed paw, as well as augmented TRP channel-mediated calcium responses, both in the cell bodies and the intact peripheral endings of nociceptors. Notably, inflammation provoked a pronounced increase in nociceptors co-expressing functional TRPM3 with TRPV1 and TRPA1, and pharmacological inhibition of TRPM3 caused normalization of TRPV1- and TRPA1-mediated responses. These new insights into the mechanisms underlying inflammatory heat hypersensitivity provide a rationale for developing TRPM3 antagonists to treat pathological pain. Copy rights belong to original authors. Visit the link for more info

Dr. Sexton is the Endocannabinoid System Doctor (ecsdoctor.com). She is Assistant Adjunct Professor at UCSD in the Department of Anesthesiology. She graduated from Bastyr University in 2008. She completed a postdoctoral fellowship at the University of Washington where she formally studied the endocannabinoid system for 6 years. Her NIH-funded pre-doctoral and postdoctoral research on the topic of cannabinoids and their roles in neuroinflammation and neurodegeneration investigated cannabis use and impact on inflammatory markers. She has continued her research into health effects of cannabis at UCSD. Prior to medical school, she was a midwife and herbalist for 15 years. Dr. Sexton has presented he research internationally and published in peer-reviewed journals. Dr. Sexton's clinical practice, research and teaching focus on the endocannabinoid system and roles for integrative medicine, including cannabis to treat a range of conditions across the lifespan. She is a member of the International Cannabinoid Research Society, the International Association of Cannabinoid Medicine The Society of Cannabis Clinicians and the American Association of Naturopathic Doctors. She is a Board Member on the California Association of Naturopathic Doctors. She maintains a medical practice in the Pacific Beach neighborhood of San Diego, CA.When not caring for patients or pursuing research activities, you can find her in the garden, paying music, playing with grandchildren, swimming or riding her bike to the beach for a surf session! Part 1 1:40 - Michelle's background 5:00 - Immunity, inflammation and the CB2 receptor 6:22 - The endocannabinoid & immune systems 7:00 - CB2 receptors on white blood cells 10:00 - Cross-talk between systems, TNF-alpha 10:40 - What is immune suppression? Is it good? 12:30 - CBD and inflammation. Measuring the CB2 receptor 14:35 - CBD and other receptors 14:50 - TRPV1 receptor 15:50 - Cannabis modulating the immune system 18:20 - Cannabinoids and COVID-19 20:00 - Dosing of THC 21:05 - The role of TNF-alpha 23:35 - Sepsis 25:00 - Smoking & risks of complications 27:12 - Cannabinoids won't protect you from COVID-19 Michelle Sexton's clinical practice: http://www.msextonnd.com Online course: Women's Health and Cannabis Across the LIfespan and Endocannabinoid System 101 https://ecsdoctor.teachable.com

On this weeks episode of Off The Strength, the guys catch up with Co-Founder and CEO at RCVR Dan Hunt and discuss his origins and pivotal early realizations in the cannabis industry, life lesson learned from wrestling and jujitsu, how recovery and sleep became a early priority, how start up success came with start up stress, how philosophy plays a role in being able to stay calm in chaos, and role flow plays on his path to success.For Dan and RCVR, catch up with him at:IG: @tryrcvr , @danhuntWeb: https://www.rcvr.com/Be sure to like listen and subscribe! Follow the OTS Squad on IG at:Show - @offthestrength_Tony - @atrainercalledtonyCorey -@yourtrainercoreyKyle - @krjones_Troy - @troy_brooks The Effects Of CBD On Anxiety & StressStudies in humans, including many of those cited below, have demonstrated that CBD reduces anxiety. This is due to the action of CBD on 5HT1A and TRPV1 receptors, both of which are involved in mitigating the anxiolytic, panic and fear responses to stress.Here are the studies that have specifically investigated CBD’s role as an anxiolytic: Cannabidiol, a Cannabis sativa constituent, as an anxiolytic drug (PubMed)Antidepressant-Like and Anxiolytic-Like Effects of Cannabidiol: A Chemical Compound of Cannabis Sativa (PubMed)Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients(PubMed)When it comes to stress, which is of course significantly related to anxiety, the host of studies are just as impressive: Endogenous cannabinoid signaling is essential for stress adaptation (PubMed)Regulation of endocannabinoid signaling by stress: Implications for stress-related affective disorders (PubMed)Functional interactions between stress and the endocannabinoid system: from synaptic signaling to behavioral output(PubMed)This is just a small sample of the research showing the role that CBD plays in reducing stress and reducing anxiety. Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress (PubMed)The endocannabinoid system: an emerging key player in inflammation (PubMed)The Effects Of CBD On InflammationCannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress (PubMed)The endocannabinoid system: an emerging key player in inflammation (PubMed)Anti-inflammatory role of cannabidiol and O-1602 in cerulein-induced acute pancreatitis in mice(PubMed)The Effects Of CBD On SleepPatients with sleep issues report that ingesting a CBD-rich tincture or extract a few hours before bedtime has a balancing effect that facilitates a good night’s sleep.Here are the studies on CBD and sleep.Cannabis, pain, and sleep: Lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine (PubMed)Effects of acute systemic administration of cannabidiol on sleep-wake cycle in rats (PubMed)Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults(PubMed)Cannabidiol, a constituent of Cannabis sativa, modulates sleep in rats See acast.com/privacy for privacy and opt-out information.

Capsaicin, found in chili peppers, is a compound that stimulates your Transient Receptor Potential Vanilloid-1 (TRPV1), which leads to increase calcium release, which allows you to contract your muscle for a longer period of time while you are fatigued.

¡Gracias por escuchar! En este episodio hablaré del papel que juega la inflamación en la generación de dolor en pacientes con osteoartritis. La OA tiene una morbilidad asociada sustancial y constituye un creciente problema de salud pública derivado en gran medida del envejecimiento poblacional. Los síntomas de la OA pueden ser funcionales pero se manifiestan principalmente como dolor y el manejo de la enfermedad se centra principalmente en su control.Agradezco que escuchen este podcast y les recuerdo que se encuentra disponible en el catálogo de iTunes, en Google Play (siendo accesible a través del gestor de podcasts de su dispositivo móvil), así como en Spotify. Agradezco también su retroalimentación en estas plataformas y les pido amablemente que califiquen el podcast ya que esto es importante para su continuado desarrollo.A continuación se enlistan las referencias mencionadas en este episodio: Grace, P. M., Hutchinson, M. R., Maier, S. F. & Watkins, L. R. 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Degree of synovitis on MRI by comprehensive whole knee semi-quantitative scoring method correlates with histologic and macroscopic features of synovial tissue inflammation in knee osteoarthritis. Osteoarthritis Cartilage 22, 1606–1613 (2014).Cook, A. D., Christensen, A. D., Tewari, D., McMahon, S. B. & Hamilton, J. A. Immune cytokines and their receptors in inflammatory pain. Trends Immunol. 39, 240–255 (2018).Malfait, A. M. & Schnitzer, T. J. Towards a mechanism-based approach to pain management in osteoarthritis. Nat. Rev. Rheumatol. 9, 654–664 (2013).Bellamy, N. et al. Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane Database Syst. Rev. 2, CD005328 (2006).McAlindon, T. E. et al. Effect of intra-articular triamcinolone versus saline on knee cartilage volume and pain in patients with knee osteoarthritis:a randomized clinical trial. JAMA 317, 1967–1975 (2017).Aitken, D. et al. 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Emerging targets in neuroinflammation-driven chronic pain. Nat. Rev. Drug Discov. 13, 533–548 (2014).McMahon, S. B., La Russa, F. & Bennett, D. L. Crosstalk between the nociceptive and immune systems in host defence and disease. Nat. Rev. Neurosci. 16, 389–402 (2015).Pinho-Ribeiro, F. A. et al. Blocking neuronal signaling to immune cells treats streptococcal invasive infection. Cell 173, 1083–1097 (2018).Shechter, R. et al. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLOS Med. 6, e1000113 (2009).Willemen, H. L. et al. Monocytes/macrophages control resolution of transient inflammatory pain. J. Pain 15, 496–506 (2014).Barthel, C. et al. Nerve growth factor and receptor expression in rheumatoid arthritis and spondyloarthritis. Arthritis Res. Ther. 11, R82 (2009).Skaper, S. D. Nerve growth factor: a neuroimmune crosstalk mediator for all seasons. Immunology 151, 1–15 (2017).Denk, F., Bennett, D. L. & McMahon, S. B. Nerve growth factor and pain mechanisms. Annu. Rev. Neurosci. 40, 307–325 (2017).Minnone, G., De Benedetti, F. & Bracci-Laudiero, L. NGF and its receptors in the regulation of inflammatory response. Int. J. Mol. Sci. 18, E1028 (2017).Bagal, S. K. et al. Discovery of potent, selective, and peripherally restricted Pan-Trk kinase inhibitors for the treatment of pain. J. Med. Chem. 61, 6779–6800 (2018).Pinho-Ribeiro, F. A., Verri, W. A. Jr & Chiu, I. M. Nociceptor sensory neuron-immune interactions in pain and inflammation. Trends Immunol. 38, 5–19 (2017).Robinson, W. H. et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 580–592 (2016).de Lange-Brokaar, B. J. et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis Cartilage 20, 1484–1499 (2012).Rahmati, M., Mobasheri, A. & Mozafari, M. Inflammatory mediators in osteoarthritis: a critical review of the state-of-the-art, current prospects, and future challenges. Bone 85, 81–90 (2016).Urban, H. & Little, C. B. The role of fat and inflammation in the pathogenesis and management of osteoarthritis.Rheumatology 57, iv10–iv21 (2018).Dawes, J. M., Kiesewetter, H., Perkins, J. R.,Bennett, D. L. & McMahon, S. B. Chemokine expression in peripheral tissues from the monosodium iodoacetate model of chronic joint pain. Mol. Pain 9, 57 (2013).Driscoll, C. et al. Nociceptive sensitizers are regulated in damaged joint tissues, including articular cartilage, when osteoarthritic mice display pain behavior. Arthritis Rheumatol. 68, 857–867 (2016).Sweitzer, S. M., Hickey, W. F., Rutkowski, M. D., Pahl, J. L. & DeLeo, J. A. Focal peripheral nerve injury induces leukocyte trafficking into the central nervous system: potential relationship to neuropathic pain. Pain 100, 163–170 (2002).Hu, P., Bembrick, A. L., Keay, K. A. & McLachlan, E. M. Immune cell involvement in dorsal root ganglia and spinal cord after chronic constriction or transectionof the rat sciatic nerve. Brain Behav. Immun. 21, 599–616 (2007).Lems, W. F. Bisphosphonates: a therapeutic option for knee osteoarthritis? Ann. Rheum. Dis. 77, 1247–1248 (2018).Wenham, C. Y. et al. A randomized, double-blind, placebo-controlled trial of low-dose oral prednisolone for treating painful hand osteoarthritis. Rheumatology 51, 2286–2294 (2012).Dorleijn, D. M. J. et al. Intramuscular glucocorticoid injection versus placebo injection in hip osteoarthritis: a 12-week blinded randomised controlled trial. Ann. Rheum. Dis. 77, 875–882 (2018).McCabe, P. S. et al. Synovial fluid white blood cell count in knee osteoarthritis: association with structural findings and treatment response. Arthritis Rheumatol. 69, 103–107 (2017).Leung, Y. Y. et al. Colchicine lack of effectiveness in symptom and inflammation modification in knee osteoarthritis (COLKOA): a randomized controlled trial. Osteoarthritis Cartilage 26, 631–640 (2018).Kingsbury, S. R. et al. Hydroxychloroquine effectiveness in reducing symptoms of hand osteoarthritis: a randomized trial. Ann. Intern. Med. 168, 385–395 (2018).Lee, W. et al. Efficacy of hydroxychloroquine in hand osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Care Res. 70, 1320–1325 (2018).Wenham, C. Y. et al. Methotrexate for pain relief in knee osteoarthritis: an open-label study. Rheumatology 52, 888–892 (2013).Kingsbury, S. R. et al. Significant pain reduction with oral methotrexate in knee osteoarthritis; results from a randomised controlled phase III trial of treatment effectiveness [abstract 428]. Arthritis Rheumatol. 70 (Suppl. 9), 454–455 (2018).Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).Kashyap, M. P., Roberts, C., Waseem, M. & Tyagi, P. 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Cheng shows how his laboratory has used Cryo-EM to study the atomic resolution of membrane proteins. It is challenging to use conventional methods to study membrane protein structure, given that the 3D structure of most membrane proteins is dependent on their interaction with the phospholipid bilayer. Cheng describes how his laboratory has overcome these challenges to successfully solve the protein structure of the TRPV1 ion channel in different conformations at atomic resolution. He describes the benefits of using of amphipols, lipid nanodiscs, and Fab-assisted approaches to facilitate structural studies.

Today we go Xtreme. We swim through pools of saliva to eat hot worms, capsules and torpedoes. We learn some Spice Girls trivia, all about TRPV1, and the beginning of Molly's fear of dental emergencies.

Naked Jane owner Kadri Gedelec has a lot to say about CBD and the unique process his company Naked Jane uses to distinguish themselves above and beyond the plethora of competitors who have jumped on the CBD oil trend bandwagon. Kadri recognizes not all CBD is created equal and uses a seven step process to create only the worlds highest quality of CBD oil. Make sure you check out why Naked Jane's process is unique and why their benefits outweigh their competition, even if that competition now offers their CBD in hamburger form. Naked Jane CBD oilEverything You Wanted to Know About CBD Oilby Jim GoetzColts Neck, NJAllow me to clarify that we are not poteads, stoners or what you could consider, "druggies". We never were.I (Jim Goetz), personally grew up a "normal" kid, playing with my blocks, He-Man and Teenage Mutant Ninja Turtles and ran around outside until my mom had to come find me and drag me in for dinner.When I met Chantea in college, I was a clean cut college baseball player with a huge substance abuse problem. I ate copious amounts of pecan pie, took large amounts of creatine (until I burped poweder), and drank large amounts of protein shake and water. I guess other than the pecan pie (something I had never been exposed to living in the Northeast all my life up until that point), these so called "problems" were typical of any jock and most likely still are. Until recently, the closest thing I have come to what would be considered a "substance" is utilizing nootropics for school, work and training such as nicotine and adrafinil along with melatonin and L-theanine. My mushrooms come in the form of chaga and lions mane. Of course the nootropics made by Alexander and Stefan of Nooflux are awesome! If you have not heard this podcast check out the show notes and take a gander after you are done here. You may already know or have done it yourself but many now are experimenting with edible tetrahydrocannabinol (THC) for exercise performance, and also experimenting with vaporizing indica-rich strains of marijuana for creativity, relaxation and sleep. In these show notes and podcast, we delve into a derivative of the cannabis plant family that is now being used as an infusion into a fast food burger. It has some pretty massive payoffs for balancing your endocrine system, relieving anxiety, modulating chronic stress, shutting down inflammation and chronic pain, decreasing blood sugar, decreasing appetite and lowering abdominal obesity.Sit back, grab your favorite nootropic and learn about a form of cannabis with zero psychoactive effects of weed but gives you all of the good stuff you want. Cannabis 101When you hear someone discuss the topic of marijuana, typically they are referring to THC. This is the part of the plant (known as a hemp plant), that induces a state of euphoria. Some may enjoy this state while others find it annoying. Some however, believe it makes certain movies and cartoons, such as the entire Adult Swim, more than simply mildly palpable.The THC content is what the majority of recreational marijuana users desire. Back in the 1960's, bontanists were able to increase the amount of THC in marijuana (weed) from 3% to 5% to a whopping 28%, which is the amount typically found in the plant today. Back in the 60's, individuals would find a mild euphoric state as compared to today, which that same individual would find themselves inebriated on their ass.THC is a chemical compound that fits into a receptor already found in your body from birth called, CB1. This CB1 receptor is located in the cerebral cortex (brain).  Fill too many receptors (intake a crapton of THC) and you will find yourself on your couch all day.There are currently 85 active cannabinoids identified in cannabis. One of which is called, Cannabidiol (CBD). This accounts for 40% of a plants total cannabinoid content.Whether you have seen the South Park episode where everyone becomes weed farmers or not; in these hemp fields, cannabis plants grow in a manner that the male plants are able to fertilize the female plants. When the male plants are quarantined from the female plants, they are no longer able to fertilize them. When females cannot be pollinated, they produce copious amounts of THC. When a female is happily fertilized, she only produces less than 1% THC. I am sure there is some joke that can be associated with this but I will let it go for now and leave it up to you the reader to come up with something good.Production of CBD (international standards require less than 1% THC), is dependent on good relations between the male and female cannabis plants. Chemistry, Biochemistry, Organic Chemistry and Inoragnic Chemistry???I have been asked why would you want to take CBD without the fun of THC? other than being concerned about progress of your day and appearing as a coherent professional, there are a crapton of reasons why.But first, let us get into the text book stuff so you can understand the physiology of your body and what CBD’e effects truly are.As previously discussed, THC attaches primarily to CB1 receptors. CBD however, has a low affinity for both CB1 and CB2 receptors and acts as an indirect antagonist of the agonist. This means that what activates CB1 or CB2 are turned off by CBD.An example of this is CBD can increasing CB1 receptor density so that there’s too many CB1 receptors for THC to bind to, thus taking the edge off the potential psychoactivity of weed, while still retaining all the opioid-like painkilling effects.This means you have to increase the consumption of THC if you are using CBD separately. It also means that CBD will prolong the duration of effects of THC in your system as it inhibits cytochrome P-450. This enzyme causes the rapid metabolism of THC. As it is inhibited, the THC lasts longer and therefore you feel the effects longer.In using CBD, plasma concentrations of THC increase, causing increased amounts of THC to be available to CB1 receptors. With the increase, CBD acts as an antagonist at a cannabinoid receptor named GPR55, located in the caudate nucleus of the putamen (brain). This reduces the effects of THC. What this boils down to is by using CBD on it’s own, THC lasts longer but reduces any psychoactive effects. An actual receptor CBD effects is called 5-HT1A. This is why CBD has anti-depressant and anti-anxiety effects and is neuroprotective. It is also an “allosteric modulator” of opioid receptors, which is why it reduces pain and chronic inflammation.CBD was found to eliminate memory loss problems from marijuana (agonist/ antagonist relationship). CBD has really strong anti-oxidant and anti-inflammatory properties, due primarily to its effects on your adenosine receptors and cytochrome P-450 and 2C enzymes.Research has shown as with weed that includes THC, it is not possible to overdose on CBD. CBD has an unusually low level of toxicity. In over 6,000 years, not one individual has overdosed on pure CBD.Did you know:-NSAIDS (ibuprofen, Advil, Tylenol, and aspirin) kill over 1,000 people per year?-Alcohol kills over 110,000 people each year?-marijuana kills 0 people each year.  Nada. Not one.CBD and AddictionThe reason CBD is not addictive is because CBD does not act on any receptors in your brain that produce an addiction. We discussed this previously...remember?Former national administrator of the US governments marijuana research programs, Dr. Tod Mikriya stated, “no other single drug or substance has as many therapeutic benefits as cannabis”. Dr. Mikriya never found or discussed any evidence of addiction to cannabis. I hear all the time though individuals state that cannabis is addictive. I hear all the time cannabis is a gateway drug and the federal government even locks people away for decades because of canabis. The Boggs Act of 1951 established mandatory sentences for drug users and stated that cannabis was addictive and has held it’s effect despite what other government officials and researchers such as Dr. Mikriya have discovered. Even Dr. Harris Isbell the Director of Research at the Public Health Service Hospital located in Lexington, Kentucky have villified the idea that cannabidols are not physically addictive. Oriental medicine has been used for over 6,000 years and used cannabis as a popular remedy. There have been no reported cases of addiction. The research study, Ganja in Jamaica: A Medical Anthropological Study of Chronic Marijuana Use, which was published in the Journal of the American Medical Association in 1975, disclosed zero concerns with addiction, even after patients who had used cannabis for decades had stopped. The 1980 study Cannabis in Costa Rica: A Study in Chronic Marijuana Use backed this up. Most interestingly, studies like this are not finding any addictive potential with CBD even in the presence of THC.Cannabis Safety​For over 40 years, Dr. Lester Grinspoon, Professor Emeritus at Harvard Medical School, spent the majority of his professional life studying cannabis. The result was “Marijuana: The Forbidden Medicine“. As you can see, Dr. Grinspoon didn’t find one single case of death, stating, “There are no deaths from cannabis use. Anywhere. You can’t find one.”Francis Young, an administrative DEA judge, took medical testimony for over two weeks, and at the end of it, he said, “Marijuana, in its natural form, is one of the safest therapeutically active substances known to man.”In proper doses, CBD may produce the same pain reduction compared to opioid prescription drugs, such as morphine, hydrocodone, and oxycodone, and when combined with these drugs, allows you to use far less of the actual prescription, thus reducing the toxic load on your liver and kidneys.CBD and Your HormonesYour choice at this point is to stop reading, read a bunch of journal articles and do your own peer reviews, read a bunch of opinions online and at your local grocery store, or keep reading…...good...glad you are still here.Your endocrine system consists of glands throughout your body which regulates literally every function in your body from metabolism to sex and so forth. One function of your hormones is that in response to the fight or flight response. When your sympathetic system is activated, you produce excess cortisol levels. However, when cortisol levels continue to rise, you feel exhausted at all times and your performance decreases. CBD decreases plasma cortisol levels and as a result, can increase your performance and quality of life. But CBD has other effects on your endocrine system, particularly your appetite. You may simply think that marijuana produces the munchies and therefore makes you fat, and although this makes logical sense, science has shown that it’s not the case that marijuana makes you fat, especially when CBD is present.The idea behind smoking weed is that you get the munchies afterwards and as a result- gain weight. The opposite is true though. CBD stabilizes insulin, regulates your appetite and decreases cortisol. These are all aspects of weight gain/ loss. But it is actually the THC that increases your appetite. On the flip side, CBD can suppress your appetite. Hmmm….Physiologically speaking, your pancreas secretes the hormones glucagon and insulin to regulate blood sugar by signaling your liver to break down fat into sugar (glucagon) or to store sugar as fat (insulin). These hormones work as a pair to maintain homeostasis, and they stimulate the release of each other through a complex feedback mechanism. While THC primarily increases glucagon and blood sugar, CBD lowers insulin levels, and it is this CBD action that helps to explain why marijuana users tend to eat more calories but do not gain any extra weight, have less obesity and have lower rates of type II diabetes than non-users, and is also why some diabetics find that marijuana makes it easier to manage their blood sugar.Type II diabetics (whose pancreas still functions) tend to have very high levels of insulin, but the liver is unable to use that insulin, so blood sugar stays high, and the pancreas eventually damages itself by trying to continually produce more and more insulin, eventually leading to organ failure if the diabetes is unmanaged. By lowering pancreatic insulin release, CBD may alleviate or prevent the progression of type II diabetes and blood sugar disorders. Cannabinoid antagonists such as CBD have been shown to reduce obesity, and not only do rodents given these antagonists eat less, but they also lose more weight than their reduced feeding can account for.So the summary of the biggest effects of CBD on the endocrine system? Lower cortisol and better blood sugar control. Yep...Your Anxiety and Stress and CBDWe discussed the effects of CBD and cortisol. When it comes to the full plant, it is THC that causes stress and anxiety unless there is enough CBD present in order to negate the effects. (recall the agonist/ antagonist relationship). This is due to CBD’s direct action on your 5HT1A and TRPV1 receptors (responsible for anxiolytic response to stress).Effective dosing appears  to fall within the ranges from 10 mg to 100 mg, depending on the individual and the situation and even time of day. This is far healthier than the alternatives of addictive drugs such as Valium or Xanax. CBD and Your SleepIt is believed that in the United States, approximately 70 million people suffer from insomnia, insufficient sleep or another sleep disorder. It’s ironic that Cannabidiol actually activates the adenosine receptors as does caffeine, a stimulant. It has been found though that CBD has a calming effect that research shows allows people to sleep.You can use larger amounts of CBD to help drift blissfully to sleep (ex. 100 mg) or use smaller amounts and combine it with melatonin, lemon balm, valerian root, magnesium, chamomile or your favorite bedtime relaxation herb.CBD and InflammationInflammation is all the rage now-a-days, isn’t it? The answer to pre-mature aging and chronic disease is inflammation. It’s not really a rage or the trend but the truth. Low level inflammation is the enemy and easily caused by our faced paced, high stress lives with great amounts of pollution in our environment and pro-inflammatory foods that are consumed.Let’s nerd out for a moment. Signaling proteins called, cytokines are synthesized and secreted by your immune cells (macrophages, T-lymphocytes, B-lymphocytes, mast cells, endothelial cells, fibroblasts and stromal cells) when stimulated by a pathogen. CBD inhibits cytokine and IL-6 (pro-inflammatory) production.In one interesting study, researchers decided to test the effect of CBD on four cell signaling or mediating molecules associated with intestinal inflammation and oxidative damage to the gut. Their findings were as follows:Inducible nitric oxide synthase (iNOS) – CBD reduced the overexpression of iNOS in response to colitis. iNOS overexpression is well correlated with disease activity with colitis, and inhibitors of iNOS lead to improvement in experimental models of IBD. iNOS results in high-output production of NO, which results in oxidative damage to the intestine via reactive oxygen species (ROS).Interleukin-1β – levels significantly increased with experimental colitis. CBD was shown to decrease levels. IL-1β is shown to have potent pro-inflammatory activity and thus heightens the inflammatory response that leads to intestinal injury. IL-1β amplifies the production of inflammatory leukocytes (immune system cells), resulting in an increase of inflammation.Interleukin-10 – levels significantly decreased with experimental colitis. CBD was shown to restore levels. IL-10 has anti-inflammatory activity by inhibiting the release of pro-inflammatory cytokines. Restoration of IL-10 activity is critical to intestinal health.The reduction of iNOS and reactive oxygen species by CBD, along with the reduction of lipid peroxidation, shows the important therapeutic action of CBD in reduction of colonic inflammation by indirect reduction of oxidative damage. In addition, the dysregulation of the interleukins IL-1B and IL-10 is a well-known disruption caused by irritable bowel disease (IBD). The restoration of these interleukins to normal behavior by CBD, although the specific pathway is unknown, is another important therapeutic action that CBD has on reduction of colonic inflammation.It is the CBD in marijuana that is being researched to treat mTBI and other head traumas. Athletes in the US have been using marijuana for decades, often to relax them but without (or with) factual knowledge been using it to recover their bodies from inflammation and the pain they undergo in order to perform at their peak right away.DosageRegarding dosage, most clinical trials show CBD dosing ranging from 10-800 mg of CBD per day (although to treat schizophrenia, doses may be as high as 1,300mg). But everyone is different and you’ll likely need to experiment with a dosage range that works for you. A lot of this also depends on absorption. Not all CBD supplements are created equal. AbsorptionWhat is the purpose of consuming something beneficial if your body cannot absorb it? Most hemp CBD carries a particle size of 150 nm to 5,000 nm. This makes it nearly impossible to fully absorb and even to cross the blood/ brain barrier. CBD Oils such as Naked Jane use a nano-emulsion system that bring the particle size down to 25 nm-60 nm making this in of itself better bioavailable.  This means that a hybrid-nanoengineered CBD is over 10x more bioavailable in the body than any other oil based CBD and that just 10mg of a nanoparticle CBD is comparable to 100 mg of standard CBD.Combining a nano-emulsion system in cannabinoids and terpenoids in CBD with the isolated curcuminoids of a high-curcumin containing turmeric plant, the bioavailability of the CBD increases even greater!!! As curcumin in of itself is poorly absorbed, combining it with piperine will create the mack daddy of all absorption. Read the Full Show Notes  

Part 3 of how NUTRITION has a HUGE impact on your BRAIN! Everything in your brain is something you ate, something you made from something you ate, or, in a few cases, something your mother ate. Nutrition impacts your mental and emotional health, the function of your five senses, and your conscious and unconscious control over your body movements. Join me as I lead you in a safari through the textbook, “Neuroscience,” pointing out along the way all the interesting connections to nutrition. Listen in for part 2 on the THE FIVE SENSES! This episode is brought to you by Ample. Ample is a meal-in-a-bottle that takes a total of two minutes to prepare, consume, and clean up. It provides the right balance of nutrients needed for a single meal, all from a blend of natural ingredients. Ample is available in original, vegan, and keto versions, portioned as either 400 or 600 calories per meal. I'm an advisor to Ample, and I use it to save time when I'm working on major projects on a tight schedule. Head to https://amplemeal.com and enter the promo code “CHRIS15” at checkout for a 15% discount off your first order.” This episode is brought to you by Ancestral Supplements' "Living" Collagen. Our Native American ancestors believed that eating the organs from a healthy animal would support the health of the corresponding organ of the individual. Ancestral Supplements has a nose-to-tail product line of grass-fed liver, organs, "living" collagen, bone marrow and more... in the convenience of a capsule. For more information or to buy any of their products, go to https://chrismasterjohnphd.com/ancestral To get these episodes free of ads, with transcripts, and weeks or sometimes even months before they are released to the public, along with access to monthly live Q&A sessions, sign up for the CMJ Masterpass at https://chrismasterjohnphd.com/masterpass. Use the code LITE10 to get 10% off. To make it easier to get the discount, use this link, which has the coupon already activated: https://masterpass.chrismasterjohnphd.com/cmj-masterpass/2200/buy?coupon=LITE10 In this episode, you will find all of the following and more: 00:35 Cliff Notes 08:50 Exteroception and proprioception are mediated by mechanoreceptors. 11:32 Pain is mediated by nociceptors, which are unspecialized, low-sensitivity neurons. 13:10 Capsaicin activates the TRPV1 receptor, which is also activated by hot temperatures. 15:12 The use of topical capsaicin to relieve chronic pain 18:25 Interoception is our sense of the physiological state within the body. 20:20 Why anorexics crave spicy foods 22:17 Managing pain in the peripheral nervous system; acidity sensitizes pain receptors. 24:12 Managing the fatty acids that help resolve inflammation, particularly arachidonic acid and DHA, to help with peripheral sensitization to pain 25:59 Combining aspirin with fish oil, glycine, and bicarbonate to help with peripheral sensitization to pain 30:50 Central sensitization to pain occurs through an LTP-like process, which is mediated by NMDA receptors. 32:47 Overview of vision and the importance of vitamin A 38:21 The role of vitamin A in preventing night blindness and its very closely related role in setting your circadian rhythm 41:54 Overview of hearing 44:20 Nutrients important for hearing 45:44 Overview of smell 47:41 Overview of taste  

Show Notes Disclaimer: This is the unedited transcript of the podcast. Please excuse any typos. Jeff:  Welcome back to Emplify, the podcast corollary to EB Medicine’s Emergency Medicine Practice. I’m Jeff Nusbaum, and I’m back with my co-host, Nachi Gupta and we’ll be taking you through the August 2018 issue of Emergency Medicine Practice. Nachi: This month’s topic is one that Jeff has significant personal experience with from his college days. We’re reviewing Cannabinoids -- and emerging evidence in their use and abuse. Jeff: Um… that is definitely not true. I was actually a varsity rower in college... Are we still reviewing talking points together before we start recording these episodes? Nachi: Sometimes… Jeff: This month’s issue was authored by Mollie Williams, who is the EM residency program director at the Brooklyn Hospital Center. It was peer-reviewed by Joseph Habboushe, assistant professor at NYU and Nadia Maria Shaukat, director of the emergency and critical care ultrasound at Coney Island Hospital in Brooklyn, New York. Nachi: We’re going to be talking about the pathophysiology of cannabinoids, clinical findings in abuse, best practice management, differences between natural and synthetic cannabinoids, and treatment for cannabinoid hyperemesis syndrome. So buckle up and get ready. Jeff: As you’re listening through this episode, remember that the means that we are about to answer one of the CME questions from the end of the print issue. If you’re not driving while listening, be sure to jot down these answers and get your CME credit when we’re going through this issue.. Nachi: As of June 2018, there are 31 states, the District of Columbia, and 2 US territories that possess state and local-level laws allowing the use of cannabis medicinally or in recreational formulations. Marijuana actually maintains the highest lifetime use of an illicit drug used within the US. Jeff: There are a shocking 22 million past-month users of marijuana in the US, followed by pain relievers at 3.8 million, and cocaine at 1.9 million. Clearly, an important topic worth discussion, especially as synthetic products have become more widely available. Nachi: And worth noting -- Colorado, where medicinal and recreational marijuana use has been decriminalized and later legalized, has shown a nearly 2-fold increase in the prevalence of ED visits, which may be related to marijuana exposure. Jeff: Medicinally, cannabinoids are currently used in the treatment of chronic pain syndromes, complications of multiple sclerosis and paraplegia, weight loss due to appetite suppression in HIV/aids, chemotherapy-induced nausea and vomiting, seizures, and many other neuropsychiatric disorders. In fact, cannabis use has been documented for medical use dating as far back as 600 BC in West and Central Asia. Nachi: All of that being said though, there is an absence of high-quality reviews and evidence to support the use of cannabinoids for any of the indications you just mentioned. And the US DEA maintains cannabis as a Schedule I substance. Jeff: This DEA designation limits the ability to do research and obtain federal funding for such research. General lack of federal regulations on chemical content also leads to product variation, which may be a cause of increased incidences of accidental overdoses. Nachi: To attain the most up to date information for this article, Dr. Williams searched the PubMed and Cochrane Databases from 1950 to 2018. This produced predominantly case reports and retrospective studies. There were just a few randomized prospective studies -- not surprising. Jeff: Let’s get started with the pathophysiology. There are 3 cannabis species to be aware of: Cannabis sativa, cannabis indica, and cannabis ruderalis. Within these species, over 545 active cannabis-derived components have been described. Nachi: There are ten main constituents of cannabis sativa. Of these, 9-tetrahydrocannabinol (delta-9-THC) and cannabidiol (CBD) are found in the greatest quantities. The neuropsychiatric and addictive properties of cannabis are due primarily to the delta-9-THC. Jeff: THC and other cannabis derivatives work through the endocannabinoid system and other neuroregulators. The endogenous cannabinoid system has 4 components: (1) endogenous endocannabinoids, (2) receptors, (3) degradation enzymes, and (4) transport mechanisms. Nachi: There are two endogenous endocannabinoids to know about: anandamide (AEA) and 2-arachidonoyl-glycerol. Jeff: Cannabinoid receptors are broadly dispersed through the central nervous system, and to a lesser degree, also to other organ systems. Nachi: Because CB receptors are concentrated within the central nervous system, they exert the majority of their effects on the neuropsychiatric systems. And   -- yes that’s a double ding -- the cannabinoid 1 (or CB1) receptor is most responsible for cannabis-induced neuropsychiatric effects. Jeff: Interestingly, the anti-emetic effects and possible palliative properties of cannabis derivatives are thought to be secondary to the inhibitory effects on serotonin receptors and the excitatory effects on the transient receptor potential vanilloid 1 (or TRPV1).  More on TRPV1 later... Nachi: So far we have been talking about cannabinoids from the cannabis plant, but with cannabis being illegal in many states, there has been a growing emergence of synthetic cannabinoids. Synthetics were initially developed in the 1980s largely for research purposes. Jeff: Because the current DEA controlled substances schedule designations are based on original chemical names, synthetics have gained popularity as manufacturers are able to produce newer compounds and circumvent DEA designation as well as routine urine drug screening tests. Nachi: You may be familiar with some of the street names for synthetics -- like spice, K2, scooby snacks, black mamba, kush, and kronic. These can often be purchased over the internet or through specialty smoke shops. Jeff: Scooby Snacks, what a fantastic name, mooovingggg on… Synthetic cannabinoids often have greater affinity for the CB1 receptor than naturally occurring cannabinoids -- and synthetics can produce 100 times the effect. As a result, the presenting symptoms with synthetic intoxication can be difficult to differentiate from crystal meth or bath salt abuse. Nachi: Manufacturers sometimes use solvents and other contaminants. Clusters of toxic ingestions and deaths have occurred. Emergency clinicians need to be aware of this and should report suspicious events immediately. Jeff: For more on synthetic intoxications in the ED, be sure to take a look at the recent May 2018 issue of Pediatric Emergency Medicine Practice on Synthetic Drug Intoxication in Children if you haven’t already read it. Also, just a quick FYI - If you’re not a current subscriber to Pediatric Emergency Medicine Practice, we’re giving away a free copy of the issue specifically for our listeners. Just head over to ebmedicine.net/drugs for the PDF of the issue. Nachi: A free issue for our listeners, that’s nice! Let’s move on to a discussion about current indications for cannabinoids. So, there is no clear consensus on these indications, but there is some research of varying quality that supports the treatment of some chronically debilitating diseases with cannabinoids. Jeff: A systematic review and meta-analysis from 2015 found low-quality evidence to support cannabis therapy for appetite suppression in HIV and aids patients; moderate-quality evidence for treatment of chronic pain and spasticity; and also moderate quality evidence for some chronic debilitating diseases. Nachi: While talking about evidence-based medicine here, another review by the National Academies of Science, Engineering, and Medicine on possible associations between cannabis and cancers arising in the lungs, head, and neck, or testicles -- showed no statistically significant associations exist. Jeff: So in case that wasn’t clear - the overall evidence to support cannabis therapy, in general, is weak. Also, be aware that there are various formulations of cannabis that allow for different routes of administration. We’re talking oils, tinctures, teas, extracts, edibles like candies and baked goods, parenteral formulations, eye solutions, intranasal, sublingual, transmucosal, tablets, sprays, skin patches, topical creams, rectal suppositories, and capsules -- just to name, a few. Nachi: A few! That seems pretty complete to me. Basically, any way you can imagine, it seems like a route of administration has been explored. But of importance, these formulations have different absorption times -- as you might expect. The shortest duration to peak plasma levels of delta-9-THC is through the inhalation route, which can produce effects within 3 minutes. On the longer end, rectal cannabis administration can take up to 8 hours to reach peak plasma concentrations. Jeff: Let’s talk about some of the clinical findings and systemic effects associated with cannabis use. First up is the link between cannabis use and stroke or TIA. Cannabis users who smoked at least once weekly had a 3.3 times higher risk of stroke or TIA. Nachi: And there is moderate quality evidence that this link may be dose-dependent. Larger amounts of cannabis use lead to cerebral vasospasm and a reduction in cerebral blood flow. Jeff: In terms of psychiatric effects, several low-to-moderate quality studies have shown statistically significant associations between psychosis and self-reported cannabis use. Some association between high potency cannabis or synthetic cannabinoid use with new-onset psychosis or relapse in previous psychiatric disorders has also been found. Lastly, there is weak data supporting a correlation between cannabis use and depression. Nachi: From a cardiovascular standpoint, cannabis use is associated with increased resting heart rate, hypertension, and decreases in the anginal threshold for patients with chronic stable angina. A 2001 study described an augmented risk of myocardial infarction within the first hour of cannabis use and found an almost 5-fold increase in those who reported smoking cannabis at least weekly when compared to those who smoked monthly or less. Jeff: Dysrhythmias, qt prolongation, av blocks, myocarditis, and sudden death have all been reported with cannabinoids. Nachi: In terms of pulmonary effects, these are not really related to cannabis use directly, but rather the smoke inhalation and combustion materials of synthetic cannabinoids. Effects from chronic use can be seen. Jeff: Renally speaking, acute kidney injury and rhabdomyolysis are associated with synthetic cannabinoids and have been observed in several case reports. The rhabdo is believed to be due, in part, to associated seizures, muscle tremors, and agitation. Nachi: Among metabolic abnormalities, patients can present with hyperthermia, hypoglycemia, hypokalemia, hyponatremia, and metabolic acidosis. Jeff: Orally and dentally, dry mouth is the most common finding in acute cannabis toxicity. Chronic use has also been linked to severe periodontitis. Nachi: And ophthalmologically, there is, of course, the commonly seen conjunctival injection. Cannabis has also been found to decrease intraocular pressure when used topically -- and of note, there have also been rare reports of acute angle closure glaucoma and central retinal vein occlusion. Jeff: While talking about clinical findings and systemic effects of cannabis use, we certainly need to go over cannabinoid hyperemesis syndrome (or CHS), which is -- quite simply put -- associated with frequent visits to the ED in chronic users. It presents with nausea, vomiting, and abdominal pain. Nachi: CHS is commonly misdiagnosed as cyclical vomiting syndrome. After the legalization of marijuana in Colorado, it was reported that nearly twice as many patients had presented for what was thought to be cyclical vomiting syndrome. And ironically, though cannabis has been used as an anti-emetic, chronic use can cause the opposite reaction, leading to CHS, which is typically refractory to traditional anti-emetics. Jeff: And the etiology of CHS is not well understood. Similarly, the exact criteria for CHS are poorly defined. It presents as a recurrent and relapsing disorder that can be divided into 3 phases: prodromal, hyperemetic, and recovery. Nachi: In the prodromal phase, patients complain of early morning nausea without vomiting, and they can have mild abdominal discomfort. This can last from months to years. In the hyperemetic phase, patients complain of severe, unremitting abdominal pain with repeated episodes of vomiting and retching. This is often associated with an inability to tolerate po. Jeff: The hyperemetic phase lasts 24-48 hours and can lead to dehydration, electrolyte abnormalities, and weight loss. Patients may learn to relieve symptoms by compulsively bathing in hot water. Nachi: Resolution of symptoms is seen when the patient stops using cannabis. This is during the recovery phase, which can last from days to months. But this can be short-lived if the patients begin using cannabis again. Jeff: On that note, we should also touch on cannabis withdrawal. Termination of heavy and habitual use can lead to withdrawal syndromes within 48 hours. Symptoms here include irritability, anxiety, restlessness, sleep difficulty, seizures, and aggression. Medications that can be helpful include benzodiazepines, neuroleptic agents, and quetiapine in refractory cases. Nachi: Moving on to the next sections in the article, let’s talk about differential diagnosis and prehospital care. The differential for acute cannabinoid intoxication, as you might suspect, is broad, and it includes some life-threatening processes. We won’t list them here, but be sure to think broadly before deciding on cannabis as the cause of your patient’s symptoms. Jeff: For the prehospital providers -- care here is mainly supportive. Provide airway protection as needed - gather information from the patient’s environment, looking for empty pill bottles or another empty packaging. Nachi: Let’s move on to care once in the ED. All patients who are in distress and suspected of drug ingestion should be disrobed completely and placed on a cardiac monitor. Fully assess for trauma and place an IV in the patient. Search the patient’s clothing for drugs and paraphernalia, which may help in making the diagnosis. Jeff: When getting a complete history from the patient, it may also be worthwhile to talk with any persons accompanying the patient to the ER for more information. In your history, be sure to ask about a pattern of use and possible co-ingestions. Nachi: When considering cannabis hyperemesis syndrome, a detailed history and physical exam are crucial for making the diagnosis. To differentiate between other etiologies of abdominal pain and vomiting, be sure to ask about the use of hot baths for relief, resolution of symptoms after stopping cannabis use, and the predominance of symptoms in the morning hours. Jeff: On physical exam, for cannabis intoxication, there isn’t a particular toxidrome to look for. Monitor vital signs closely, looking out for alterations in blood pressure and heart rate. A complete neurologic and mental status examination will be the key here. Nachi: Decisions for lab testing should be dependent on the patient’s presentation. Possible tests include CBC, BMP, LFT’s, lipase, cpk, ckmb, troponin, urinalysis, urine drug screening, serum tox screens (for alcohol, aspirin, and acetaminophen), and any other drug levels for medications that the patient is taking for medicinal purposes, like phenytoin or lithium levels. Jeff: One study supported point of care urine drug testing in the ED. However, know that acute cannabis intoxication can be difficult in the chronic user, as delta-9-THC will be present in urine for up to 24 days. Testing for synthetically derived cannabinoids is difficult due to changes in synthetic compounds. Nachi: Interestingly, there are a number of medications that are associated with false positive cannabinoid screenings. These include ibuprofen, pantoprazole, efavirenz, and lamotrigine. Jeff: For any patient arriving with suspected cannabis or synthetic abuse, consider checking an EKG. You’re looking for signs of ischemia, arrhythmia, and interval abnormalities. Serum and urine tox tests are not particularly helpful in the acute chest pain patient who is using synthetic marijuana. Nachi: Not surprisingly, there are no specific diagnostic imaging modalities to help diagnose cannabis or synthetic cannabinoid intoxication. But imaging may help with assessing other disease states on a patient’s differential, so stay mindful of that. Jeff: Now that we’ve talked about history, physical exam, and useful testing modalities, let’s talk about treatment for cannabis and synthetic cannabinoid toxicity… therapy is primarily focused on supportive care. Most ED visits only require a short stay. Nachi: That’s right, there are no antidotes to give for treatment here. Be sure to look for and treat dehydration, acute renal failure, and rhabdo though. In severe cases of neuropsychotropic effect, give benzodiazepines, like lorazepam, to help with control. Jeff: For GI effects, first-line treatment is traditional anti-emetics like ondansetron or metoclopramide. Recent literature and case reports have shown significant improvement with butyrophenones like haloperidol as a second-line treatment. Nachi: While talking about treating the gastrointestinal effects of cannabis toxicity, let’s also discuss methods to control cannabinoid hyperemesis syndrome. The mainstays for treatment here are actually supportive therapy and cessation of cannabis use. Jeff: And can you tell us more about why these patients crave hot showers and improve after? Is there a pathophysiology or mechanism to know about there? Nachi: There is a well-studied theory here and it relates to the TRPV1 receptor that we talked about earlier. Temperatures in excess of 109 degrees Fahrenheit, acidic conditions, and compounds found in certain foods and plants (like cannabis) activate this receptor. It’s believed that intermittent and repetitive exposure to agonists of the TRPV1 receptor leads to a persistent state of nausea and vomiting. Desensitization of the receptor happens after repeated stimulation, and repetitive topical capsaicin or hot water is believed to function as an exogenous agonist. Jeff: In any case of repetitive emesis, be sure to consider electrolyte replacement if needed. In many cases, hydration or repletion will need to happen through an IV. Proton pump inhibitors can also help in some cases where GI symptoms are a dominating complaint of the patient. Nachi: Recent literature supporting the use of haloperidol for nausea and vomiting has found that symptoms improve approx 1hr after administration. This can decrease the need for observation or admission. Jeff: Haloperidol works via dopamine 2 receptor antagonism. D2 receptors are found in high concentrations throughout the nervous system and bind with high affinity to haloperidol. The suggested starting dose is 2.5mg IV with a repeat dose of 5mg IV if needed. An RCT is underway in Canada on the use of ondansetron versus haloperidol with an estimated completion of July 2019. Nachi: Capsaicin has similarly shown promise in cannabis hyperemesis syndrome through the TRPV1 receptor as we discussed already. Currently, there are no dosing recommendations or application instructions for capsaicin. There is some evidence supporting relief within 30 to 45 minutes, and capsaicin can be applied topically to any nonmucosal surface like the abdomen, chest, or back. Jeff: So to recap -for cannabis hyperemesis syndrome, treat with anti-emetics, PPI’s, electrolyte repletion, and IV hydration as needed. As a second line treatment, consider haloperidol and topical capsaicin applied to the chest, abdomen, or back. Nachi: Let’s talk about some special populations next -- starting with Pediatrics. According to data from 2012, of the 130 million people reporting illicit drug use within their lifetime, 25% were children between 12 and 17 years of age. Jeff: And according to the national poison data system, states with marijuana use laws have seen a 30% increase in calls related to marijuana use by children. From 2010 to 2011, the number of ED visits by children aged 12 to 17 years old due to synthetic cannabinoid use also has doubled. Nachi: Many children and adults believe that synthetic cannabinoids don’t pose serious health risks, as these are not illegal to purchase. And this class of drugs is particularly attractive to adolescents since it will not readily test positive on urine drug tests. All of this is very concerning for emergency clinicians. Jeff: There have been several recent reports of myocarditis in association with marijuana use. One case resulted in death due to myocyte necrosis after an unknown amount of edible marijuana was consumed by a toddler. Nachi: Horrific! Jeff: And the exact mechanism through which the myocardial necrosis happens isn’t known. Nachi: For all children and adolescents who present to the ED with alteration in mental status, psychosis, or chest pain -- be sure to screen for cannabis or synthetic cannabinoid use.  There are case reports in the pediatric literature of STEMIs seen in patients without pre-existing cardiac disease or risk factors. Jeff: Keep in mind that urine drug screens can be falsely positive from certain proton pump inhibitors, so if possible, assess a urine drug screen prior to starting a PPI in these patients. Nachi: Moving on to our next special population… pregnant women. Know that it can be difficult to the differential between hyperemesis gravidarum and cannabis hyperemesis syndrome in pregnant patients. Ask specific questions regarding marijuana use before and during the pregnancy. Jeff: It’s also worth noting that cannabis is known to cause adverse outcomes on babies such as low birth weight and more frequent perinatal ICU placement. Nachi: Let’s move on to the final major section of the article, which is on the legal status of cannabis and cannabinoids. Much of the controversy surrounding cannabis for medicinal use relates to the absence of quality evidence. More research is needed to evaluate potential public health risks posed by variations in quality and potency, potential impact to our healthcare system, and ability to legislate for synthetic cannabinoids. Jeff: Though marijuana and all whole-plant derivatives are schedules I controlled substances, there are a few cannabinoid-based drugs approved by the FDA for medicinal purposes -- with lower schedule designations. Dronabinol is a schedule III drug derived synthetically from delta-9-THC. It’s used in chemotherapy-induced nausea/vomiting, as well as anorexia and weight loss from AIDS/cancer. Nachi: Nabilone, a schedule II synthetic variant of THC, has been approved in the treatment of aids-related anorexia and chemotherapy-induced nausea also. Jeff: Nabiximols, a plant-derived cannabinoid, has been approved in Europe and Canada for multiple sclerosis induced spasticity and cancer-related pain. Nabiximols are not yet approved in the US. Nachi: And lastly, we should mention cannabidiol, which is a schedule I controlled substance approved for treatment of seizures with 2 rare diseases -- Lennox-gastaut syndrome and dravet syndrome. Compared with placebo alone cannabidiol and other medications have shown efficacy in lowering the rate of seizures for these diseases. Jeff:  Lots of interesting stuff to look out for there in cannabinoid-related medications. Alright, on to disposition - Nachi: Most patients who present with uncomplicated acute cannabis or synthetic cannabinoid intoxication can be observed until clinically sober. Discharge home should be in the care of a sober family member or friend. Make sure that the patient knows not to operate vehicles or heavy machinery under the influence of drugs. Counsel them on drug abuse also. Jeff:   In more rare situations, patients will require admission. Consider this particularly for patients who have end-organ damage, rhabdomyolysis, acute renal failure -- evidence of cardiovascular, cerebrovascular, or ophthalmologic insults -- intractable vomiting, or acute psychosis. Nachi: And for cannabinoid hyperemesis syndrome, patients may require admission for IV hydration and electrolyte correction. Once the patient is tolerating PO and lab derangements have been corrected, they can be discharged. Jeff: Let’s wrap up the episode with key points and clinical pearls… N: Marijuana is the most commonly used illicit substance in the US. States that have legalized marijuana for medical and recreational purposes are showing increased rates of marijuana abuse and dependence. J: When concerned with drug intoxication, search your patient’s clothing for drugs and paraphernalia on arrival. N: The neuropsychiatric and addictive properties of cannabis are due primarily to delta-9-THC. J: Synthetic cannabinoids have gained popularity as manufacturers are able to produce newer compounds and circumvent DEA designations as well as routine urine drug screening tests. N: Manufacturers of synthetic cannabinoids sometimes use solvents and other contaminants, which have caused clusters of toxic ingestions and death. J: The shortest duration to peak plasma levels of delta-9-THC is through the inhalational route. Effects can be seen within 3 minutes. N: Cannabis users who smoke at least once weekly can have a 3.3 times higher risk of stroke or TIA. J: The risk of myocardial infarction is increased within the first hour of use, and there is an almost 5-fold increase for individuals who smoke at least once per week. N: Acute kidney injury and rhabdomyolysis have been noted with synthetic cannabinoid use in several case reports. J: Cannabis intoxication is associated with many metabolic abnormalities like hyperthermia, hypoglycemia, hypokalemia, hyponatremia, and metabolic acidosis. N: Cannabis hyperemesis syndrome, which presents with abdominal pain and vomiting, is associated with frequent visits to the ED in chronic users. J: The mainstay for treatment of cannabis hyperemesis syndrome is supportive therapies and cessation of cannabis use. N: Patients with cannabis hyperemesis syndrome crave hot showers because of activation of the TRPV1 receptor. J: Topical capsaicin may also help in the treatment of cannabis hyperemesis syndrome through activation of the TRPV1 receptors. N: Haloperidol at 2.5mg IV may help in refractory vomiting associated with cannabis hyperemesis syndrome. J: Many children and adults do not believe synthetic cannabinoids pose serious health issues as the they are not illegal to purchase. This is incorrect. N: Most patients with acute uncomplicated cannabis intoxication can be observed and discharged. Admit if there are any signs of end organ damage, intractable vomiting, or acute psychosis. Jeff: So that wraps up the August 2018 episode of Emplify. Nachi: For those of you looking for CME - the address for this months credit is ebmedicine.net/E0818, so head over there right away to get the credit you deserve.  Remember that the you heard throughout the episode corresponds to the answers to the CME questions. Jeff: And don’t forget to grab your free issue of Synthetic Drug Intoxication in Children at ebmedicine.net/drugs specifically for emplify listeners. Feel free to share the link with your colleagues or through social media too. See you next time! Most Important References 5. * Kim HS, Monte AA. Colorado cannabis legalization and its effect on emergency care. Ann Emerg Med. 2016;68(1):71-75. (Literature review; 21 studies)7. * Baron EP. Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: What a long strange trip it’s been …. Headache. 2015;55(6):885-916. (Review)9. * Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313(24):2456-2473. (Retrospective chart review; 4 cases)64. * Tournebize J, Gibaja V, Kahn JP. Acute effects of synthetic cannabinoids: update 2015. Subst Abus. 2016:1-23. (Systematic review; 46 articles, 114 patients)83. * Wallace EA, Andrews SE, Garmany CL, et al. Cannabinoid hyperemesis syndrome: literature review and proposed diagnosis and treatment algorithm. South Med J. 2011;104(9):659-664. (Review)

Rick Gold joins host Kevin Cottrell today to discuss circadian based health & wellness.  Rick is a Functional Wellness practitioner from South Florida with a passion for helping educate, treat and heal patients. Rick is a certified FDN & Functional Wellness Practitioner and is well-versed in the concepts of functional medicine.  Working with clients locally in South Florida and around the world, Rick helps his clients identify and eliminate many of the underlying causes of their symptoms, with a specialization in gut health and circadian rhythms. Prior to his career in health & wellness, Rick worked for Wall Street firms as a financial adviser, institutional trader, and hedge fund recruiter.  So, how did someone working for Wall Street end up as a Functional Wellness Practitioner? For most of his adult life, Rick suffered from 24/7/365 allergies, frequent colds and sinus infections, indigestion, heartburn, GERD, stomach and joint pain.  He was able to find temporary relief using conventional medicine doctors, but the conventional medicine route never identified or fixed the underlying causes of his health issues.   Rick used functional lab testing and lifestyle changes to vastly improve his health.  Dietary and other lifestyle modifications essentially reversed most of his health challenges which are now a distant memory. Additional research, references, and recommended reading from Rick Gold Here are some more (in addition to what I’ve linked to in the text throughout this building block) circadian rhythm, blue light/ALAN studies, sunlight, and nnEMF research articles, and videos for you to learn more (mind you this is just a SMALL sampling of the THOUSANDS of studies out there on these topics.  The research is so definitive it makes one wonder why it isn’t more mainstream!): Blue light, ALAN, Sunlight, and Melatonin (Study) Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness – “These results demonstrate that evening exposure to an LE-eBook phase-delays the circadian clock, acutely suppresses melatonin, and has important implications for understanding the impact of such technologies on sleep, performance, health, and safety.” (Article) How light affects human melatonin levels – Florida Atlantic University.  “Researchers are finding that exposure to bright nocturnal light decreases the human body's production of melatonin. A decrease in melatonin production has been linked to higher rates of certain cancers, such as breast cancer in women and prostate cancer in men.” (Video) The end of night: potential impact on cancer incidence – Russel J. Reiter, PhD (Study) Light at night and breast cancer risk: results from a population-based case–control study in Connecticut, USA “The results from this study suggest a potential increased risk of breast cancer associated with domestic exposure to LAN (Light at Night).” (Video) – The impact of screens on sleep – Dr. Daniel Siegel (Study) Nocturnal light pollution and underexposure to daytime sunlight - Complementary mechanisms of circadian disruption and related diseases – “Nighttime use of personal computers, mobile phones, electronic tablets, televisions, and the like--now epidemic in adolescents and adults and highly prevalent in pre-school and school-aged children--is a new source of ALAN. However, ALAN exposure occurs concomitantly with almost complete absence of daytime sunlight, whose blue-violet (446-484 nm λ) spectrum synchronizes the CTS and whose UV-B (290-315 nm λ) spectrum stimulates vitamin D synthesis. ““The observed elevated incidence of medical conditions the two are alleged to influence through many complementary bioprocesses of cells, tissues, and organs led us to examine effects of the totality of the artificial light environment in which humans reside today. Never have chronobiologic or epidemiologic investigations comprehensively researched the potentially deleterious consequences of the combination of suppressed vitamin D plus melatonin synthesis due to life in today's man-made artificial light environment, which in our opinion is long overdue.” (Study) Avoidance of sun exposure is a risk factor for all-cause mortality – “The results of this study provide observational evidence that avoiding sun exposure is a risk factor for all-cause mortality. Following sun exposure advice that is very restrictive in countries with low solar intensity might in fact be harmful to women's health.” (Study) Blue light hazard – “Blue light can induce formation of toxic reactive oxygen species that cause photochemical damage, leading to the death by apoptosis first of critical retinal pigment epithelial (RPE) cells and then photoreceptors. This slow process, in which damage accumulates over a lifetime, has been implicated in the pathogenesis of retinal degenerative diseases such as age-related macular degeneration (AMD).” (Study) Blue Light Induces Mitochondrial DNA Damage and Free Radical Production in Epithelial Cells – “We conclude that visible light can cause cell dysfunction through the action of reactive oxygen species on DNA and that this may contribute to cellular aging, age-related pathologies, and tumorigenesis.” (Study) Bright light exposure reduces TH-positive dopamine neurons- Implications of light pollution in Parkinson's disease epidemiology – “Remarkably, in preliminary analysis that accounted for population density, the age and race adjusted Parkinson's disease prevalence significantly correlated with average satellite-observed sky light pollution.” (Study) Daily, seasonal, and latitudinal variations in solar ultraviolet A and B radiation in relation to vitamin D production and risk for skin cancer – “The best way to obtain a given dose of vitamin D with minimal carcinogenic risk is through a non-burning exposure in the middle of the day, rather than in the afternoon or morning.” (Study) Environmental Light Exposure Is Associated with Increased Body Mass in Children – “The findings identify that light exposure may be a contributor to the obesogenic environment during early childhood.” (Article) Study of fruit fly 'brain in a jar' reveals mechanics of jet lag – “He explained that a single light pulse cues the biological clock of the fruit fly brain to shift two hours ahead of its original schedule through a process the researchers call "phase retuning."    Circadian Rhythms (Video) The clock in our genes and in every cell of your body | Joseph Takahashi | TEDxSMU 2013 – Great Ted Talk that teaches you about circadian biology.  (Article) Circadian rhythm and human health – Joan E. Roberts, Fordham University “Humans evolved being exposed to different spectra of light in the morning, the late afternoon and evening. So it should not be surprising that human physiology is profoundly affected by the daily and seasonal changes in the visible light spectrum. Exposure to the appropriate spectrum of light during the day and evening enhances human health and wellbeing, immune response and productivity. However, exposure to light sources that do not match the natural solar spectrum to the time of day or evening, is hazardous to human health. The reason visible light has such a powerful effect on human health is that light exposure through the eye modifies circadian rhythm.” (Article) Around the Clock – “The circadian clock influences far more than daily habits, according to a few decades of research. Obesity, diabetes, cardiovascular disease, liver disease, cancer, and depression have all been linked to malfunctions of the internal timekeeping scheme. Almost every cell in a living organism, it turns out, sees daily fluctuations in levels of genes and proteins, and when these fluctuations are dampened or stopped, things can go awry.” (Study) Circadian stage-dependent inhibition of human breast cancer metabolism and growth by the nocturnal melatonin signal: consequences of its disruption by light at night in rats and women. “This biological mechanism (ALAN) may partially explain the higher risk of breast and other cancers in women working rotating night shifts and possibly others who also experience prolonged exposure to light at night.” (Article) From Fertility To Mood, Sunlight Found To Affect Human Biology – NYT article from 1981!  “Dr. Richard J. Wurtman - 'we are all unwitting subjects of a long-term experiment on the effects of artificial lighting on health. Until much more is known, we should design indoor lighting to resemble as closely as possible what the sun provides.'' (Study) A functional circadian clock is required for proper insulin secretion by human pancreatic islet cells – (Think diabetes!) (Study) Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. – “Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase the risk of obesity and diabetes.” (Study) Circadian Clock Control of Liver Metabolic Functions – “A wide variety of processes throughout the entire gastrointestinal tract and notably the liver appear to be under circadian control. These include various metabolic functions such as nutrient uptake, processing, and detoxification, which align organ function to cycle with nutrient supply and demand. Remarkably, genetic or environmental disruption of the circadian clock can cause metabolic diseases or exacerbate pathological states.” (Audio) BBC talk on circadian rhythms and their importance.   (Study) Circadian clocks, obesity and cardiometabolic function – “Disrupting this process through mutations in the core clock genes or by interfering with the environmental zeitgebers that entrain the clock appear to modulate the function of cells and tissues, leading to an increased risk for cardiometabolic disease.” (Study) Circadian rhythm-related genes - implication in autoimmunity and type 1 diabetes – “The hypothesis that circadian genes are involved in type 1 diabetes is reinforced by findings that the immune system undergoes circadian variation and that several autoimmune diseases are associated with circadian genes. Recent findings in the non-obese diabetic mouse model pinpoint to specific mechanisms controlling type 1 diabetes by the clock-related gene Arntl2 in the immune system.” (Study) Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans – “We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers” (Study) Gut Clock - Implication Of Circadian Rhythms In The Gastrointestinal Tract – “Motor and secretory activity, as well as the rhythm of cell proliferation in the GIT (Gastrointestinal Tract) and liver, are subject to many circadian rhythms, mediated by autonomic cells and some enterohormones (gastrin, ghrelin and somatostatin). Disruption of circadian physiology, due to sleep disturbance or shift work, may result in various gastrointestinal diseases, such as irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD) or peptic ulcer disease. In addition, circadian disruption accelerates aging, and promotes tumorigenesis in the liver and GIT.”  (Study) Keeping circadian time with hormones – “Circadian deregulation of hormonal rhythms may participate in internal desynchronization and associated increase in metabolic risks.” (Study) Thyroid hormone and seasonal regulation of reproduction – “In mammals, the eyes are the only photoreceptor involved in photoperiodic time perception and nocturnal melatonin secretion provides an endocrine signal of photoperiod to the PT to regulate TSH (Thyroid Stimulating Hormone).” (Study) Exposure to Room Light before Bedtime Suppresses Melatonin Onset and Shortens Melatonin Duration in Humans – “These findings indicate that room light exerts a profound suppressive effect on melatonin levels and shortens the body's internal representation of night duration. Hence, chronically exposing oneself to electrical lighting in the late evening disrupts melatonin signaling and could therefore potentially impact sleep, thermoregulation, blood pressure, and glucose homeostasis.” (Article) UCI study finds jet lag-like sleep disruptions spur Alzheimer’s memory, learning loss – “Chemical changes in brain cells caused by disturbances in the body’s day-night cycle may be a key underlying cause of the learning and memory loss associated with Alzheimer’s disease, according to a University of California, Irvine study.”   nnEMF (Non-Native Electromagnetic Fields) (Article) Stress from Current And Radiation – This is a transcript of a lecture given by journalist Wolfgang Maes in Los Angeles, California in 1990.  Wolfgang suffered from EHS and tells his story and how he fixed his surroundings and his health by lowering his night time exposure to nnEMF.  (Video) Electromagnetic Fields and DNA Damage: Dr. Jerry Phillips – In this video, Dr. Phillips discusses how nnEMFs damage your DNA, but he also tackles the topic of conflicting research between the independent science and the industry-funded science.  By the way this video is from 2012, before Dr. Martin Pall’s work in 2013 that actually FOUND the non-thermal mechanism by which nnEMF disrupts cellular function.  (Article)  Cell Phone Radiation Boosts Cancer Rates in Animals – “The cell phone cancer controversy will never be the same again.  The U.S. National Toxicology Program (NTP) is expected to issue a public announcement that cell phone radiation presents a cancer risk for humans. The move comes soon after its recently completed study showed statistically significant increases in cancer among rats that had been exposed to GSM or CDMA signals for two-years.” (Video) Dr. Martin Pall – How Wi-Fi & other EMFs Cause Biological Harm – Amazing talk by Dr. Pall where he goes in depth and breaks down the non-thermal biological effects of Wi-Fi.  (Documentary) – Resonance Beings of Frequency – An eye-opening documentary that will teach you a tremendous amount about the dangers of nnEMF.  (Study) – Genetic Analysis of Circadian Responses to Low Frequency Electromagnetic Fields in Drosophila melanogaster – “Our results are therefore not consistent with the classical Trp triad-mediated RPM and suggest that CRYs act as blue-light/EMF sensors depending on trans-acting factors that are present in particular cellular environments.” Translation – nnEMF is perceived as light by sensory proteins in your body and that can mess with your circadian biology.  (Study) - Is it Blue Light or Increased Electromagnetic Fields which Affects the Circadian Rhythm in People who Use Smartphones at Night – “Furthermore, previous reports have indicated a significant association between exposure to RF-EMFs of mobile or cordless phones and sleep problems (2, 3). The 2nd shortcoming of this paper comes from ignoring this point that electromagnetic fields may affect the level of plasma melatonin (4, 5).” (Study) Critical time delay of the pineal melatonin rhythm in humans due to weak electromagnetic exposure. –“The results show that significant melatonin interruption and changes to the circadian rhythm occur due to the perturbation of chemical reaction rates, as also reported in previous studies. The results also show the influence of the mRNA degradation rate on the circadian rhythm's critical time delay or maturation time. The results support the hypothesis that exposure to weak EMFs via melatonin disruption can adversely affect human health.” (Study) Why are living things sensitive to weak magnetic fields? – “This implies that weak magnetic field interactions may have a chronodisruptive basis, homologous to the more familiar effects on the biological clock arising from sleep deprivation, phase-shift employment and light at night. It is conceivable that the widespread sensitivity of biological systems to weak ELF magnetic fields is vestigially derived from this diurnal geomagnetic effect.” (Article) - 'Radiogenetics' seeks to remotely control cells and genes – “The new system, dubbed radiogenetics, uses a signal, in this case low-frequency radio waves or a magnetic field, to heat or move ferritin particles. They, in turn, prompt the opening of TRPV1, which is situated in the membrane surrounding the cell. Calcium ions then travel through the channel, switching on a synthetic piece of DNA the scientists developed to turn on the production of a downstream gene, which in this study was the insulin gene.”Translation – Scientists are actively using nnEMFs NON-THERMAL effects on cells to develop therapies for diabetes.  How can anyone read this and deny the non-thermal effects of nnEMF?? (Documentary) – Searching for a Golden Cage – A short and informative film that documents the plight of people who suffer from EHS.  (Documentary) – Take Back Your Power – A must-watch documentary that illuminates the dangers of electric company-installed smart meters on homes and in apartment buildings.  (Study) – Access to electricity is linked to reduced sleep – “New research comparing traditional hunter-gatherer living conditions to a more modern setting shows that access to artificial light and electricity has shortened the amount of sleep humans get each night.” (Study) Mitochondrial calcium overload is a key determinant in heart failure – This study in particular does not mention nnEMF as a cause of heart failure, but if you remember Dr. Martin Pall’s work that showed how nnEMF causes excess calcium in the cell, and you see how this study links excess calcium in the cell to heart failure, it’s easy to connect the dots!  Heart attacks kill a staggering number of Americans every year.  Might nnEMF be a hidden cause that no one is considering?  Food for thought.  (Study) Effects of the Effect of Ultra High Frequency Mobile Phone Radiation on Human Health – “The results of this study and International Commission of Non Ionization Radiation Protection (ICNIRP) reports showed the people who spend more than 50 minutes a day using a cell phone could have early dementia or other thermal damage due to the burning of glucose in the brain.” (Study) Cancer incidence vs. FM radio transmitter density – “The findings present strong support to the earlier presented hypothesis that body-resonant broadcasting radiation emitted by horizontally polarized main FM transmitters has an immune-disturbing effect. “ (Article) Diabetes and Electro sensitivity – This article raises the possibility that diabetes is caused by nnEMF.  (Article) Wireless technology – studies on health effects, lawsuits & court rulings. – This is a fantastic resource that links to a tremendous treasure trove of research and other evidence of the harm that nnEMF causes to human health.  (Article) New research links cell phones to health issues in children – “For years, we’ve heard of a possible link between cell phone use and cancer. Now, this week, researchers in Baltimore say the evidence is clear, and children are more at risk.”  This is crucial to watch and read if you have children.  (Study) Schumann resonance is found in the earth and in the human brain – Think about that.  Our brains resonate at the same frequency as the natural frequency emitted by the earth that gets charged by lightening.  With no nnEMFs this is how we are supposed to resonate.  nnEMFs disturb this natural resonance and we pay the price with our health. (Video) Magda Havas talks at NIEHS May 9, 2016 on electro smog and electro hypersensitivity – She shows what nnEMFs do to our blood under a microscope, and shows how reducing nnEMFs helped several MS patients.  (Article) The pulsed microwave radar tower and the cell – the role of calcium – This one is definitely more for the science geeks, but it goes into great detail about how nnEMF affects the calcium in and around our cells.  (Article) Mobile Phones are cooking men’s sperm – “Study finds sperm levels of men who kept their phones in their pocket during the day were quite seriously affected in 47 per cent of cases“ (Article) Wireless devices & wildlife – This is a fascinating and well-referenced article that depicts the effects of Wi-Fi on animals and plants.  It discusses key studies done on bees that show how Wi-Fi is causing colony collapse disorder.  (Article) nnEMF research collection – And finally, a massive collection of research on nnEMF that includes a link to 2300 studies done by the US Navy showing the biological impacts of nnEMF!  (Study) Prenatal Exposure to weak magnetic fields leads to childhood asthma – “Li's study is the first prospective epidemiological study ever carried out on any group exposed to any type of electromagnetic fields (EMFs). The mothers' magnetic field exposures were measured during the first or second trimester and the health of their children —a total of 626 boys and girls— was followed for the next 13 years. Li sees a clear dose-response: Every 1 mG increase in median magnetic field exposure during pregnancy led to a 15% increase in asthma in the offspring. The trend is highly significant.” Connect with Rick Gold Gold Functional Wellness Rate, Review, Connect, Inspire Stay updated on new episodes, guest interviews, and health, wellness, and fitness information and resources by subscribing to the HealthCastNow Podcast Show on iTunes. Every day we bring you actionable insight, demystified truth, and simple steps to help you navigate the complex, often confusing health, wellness, and fitness information and answer the questions you’ve been asking. Visit HealthCastNow.Com or subscribe on iTunes today!

Rick Gold joins host Kevin Cottrell today to discuss circadian based health & wellness.  Rick is a Functional Wellness practitioner from South Florida with a passion for helping educate, treat and heal patients. Rick is a certified FDN & Functional Wellness Practitioner and is well-versed in the concepts of functional medicine.  Working with clients locally in South Florida and around the world, Rick helps his clients identify and eliminate many of the underlying causes of their symptoms, with a specialization in gut health and circadian rhythms. Prior to his career in health & wellness, Rick worked for Wall Street firms as a financial adviser, institutional trader, and hedge fund recruiter.  So, how did someone working for Wall Street end up as a Functional Wellness Practitioner? For most of his adult life, Rick suffered from 24/7/365 allergies, frequent colds and sinus infections, indigestion, heartburn, GERD, stomach and joint pain.  He was able to find temporary relief using conventional medicine doctors, but the conventional medicine route never identified or fixed the underlying causes of his health issues.   Rick used functional lab testing and lifestyle changes to vastly improve his health.  Dietary and other lifestyle modifications essentially reversed most of his health challenges which are now a distant memory. Additional research, references, and recommended reading from Rick Gold Here are some more (in addition to what I’ve linked to in the text throughout this building block) circadian rhythm, blue light/ALAN studies, sunlight, and nnEMF research articles, and videos for you to learn more (mind you this is just a SMALL sampling of the THOUSANDS of studies out there on these topics.  The research is so definitive it makes one wonder why it isn’t more mainstream!): Blue light, ALAN, Sunlight, and Melatonin (Study) Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness – “These results demonstrate that evening exposure to an LE-eBook phase-delays the circadian clock, acutely suppresses melatonin, and has important implications for understanding the impact of such technologies on sleep, performance, health, and safety.” (Article) How light affects human melatonin levels – Florida Atlantic University.  “Researchers are finding that exposure to bright nocturnal light decreases the human body's production of melatonin. A decrease in melatonin production has been linked to higher rates of certain cancers, such as breast cancer in women and prostate cancer in men.” (Video) The end of night: potential impact on cancer incidence – Russel J. Reiter, PhD (Study) Light at night and breast cancer risk: results from a population-based case–control study in Connecticut, USA “The results from this study suggest a potential increased risk of breast cancer associated with domestic exposure to LAN (Light at Night).” (Video) – The impact of screens on sleep – Dr. Daniel Siegel (Study) Nocturnal light pollution and underexposure to daytime sunlight - Complementary mechanisms of circadian disruption and related diseases – “Nighttime use of personal computers, mobile phones, electronic tablets, televisions, and the like--now epidemic in adolescents and adults and highly prevalent in pre-school and school-aged children--is a new source of ALAN. However, ALAN exposure occurs concomitantly with almost complete absence of daytime sunlight, whose blue-violet (446-484 nm λ) spectrum synchronizes the CTS and whose UV-B (290-315 nm λ) spectrum stimulates vitamin D synthesis. ““The observed elevated incidence of medical conditions the two are alleged to influence through many complementary bioprocesses of cells, tissues, and organs led us to examine effects of the totality of the artificial light environment in which humans reside today. Never have chronobiologic or epidemiologic investigations comprehensively researched the potentially deleterious consequences of the combination of suppressed vitamin D plus melatonin synthesis due to life in today's man-made artificial light environment, which in our opinion is long overdue.” (Study) Avoidance of sun exposure is a risk factor for all-cause mortality – “The results of this study provide observational evidence that avoiding sun exposure is a risk factor for all-cause mortality. Following sun exposure advice that is very restrictive in countries with low solar intensity might in fact be harmful to women's health.” (Study) Blue light hazard – “Blue light can induce formation of toxic reactive oxygen species that cause photochemical damage, leading to the death by apoptosis first of critical retinal pigment epithelial (RPE) cells and then photoreceptors. This slow process, in which damage accumulates over a lifetime, has been implicated in the pathogenesis of retinal degenerative diseases such as age-related macular degeneration (AMD).” (Study) Blue Light Induces Mitochondrial DNA Damage and Free Radical Production in Epithelial Cells – “We conclude that visible light can cause cell dysfunction through the action of reactive oxygen species on DNA and that this may contribute to cellular aging, age-related pathologies, and tumorigenesis.” (Study) Bright light exposure reduces TH-positive dopamine neurons- Implications of light pollution in Parkinson's disease epidemiology – “Remarkably, in preliminary analysis that accounted for population density, the age and race adjusted Parkinson's disease prevalence significantly correlated with average satellite-observed sky light pollution.” (Study) Daily, seasonal, and latitudinal variations in solar ultraviolet A and B radiation in relation to vitamin D production and risk for skin cancer – “The best way to obtain a given dose of vitamin D with minimal carcinogenic risk is through a non-burning exposure in the middle of the day, rather than in the afternoon or morning.” (Study) Environmental Light Exposure Is Associated with Increased Body Mass in Children – “The findings identify that light exposure may be a contributor to the obesogenic environment during early childhood.” (Article) Study of fruit fly 'brain in a jar' reveals mechanics of jet lag – “He explained that a single light pulse cues the biological clock of the fruit fly brain to shift two hours ahead of its original schedule through a process the researchers call "phase retuning."    Circadian Rhythms (Video) The clock in our genes and in every cell of your body | Joseph Takahashi | TEDxSMU 2013 – Great Ted Talk that teaches you about circadian biology.  (Article) Circadian rhythm and human health – Joan E. Roberts, Fordham University “Humans evolved being exposed to different spectra of light in the morning, the late afternoon and evening. So it should not be surprising that human physiology is profoundly affected by the daily and seasonal changes in the visible light spectrum. Exposure to the appropriate spectrum of light during the day and evening enhances human health and wellbeing, immune response and productivity. However, exposure to light sources that do not match the natural solar spectrum to the time of day or evening, is hazardous to human health. The reason visible light has such a powerful effect on human health is that light exposure through the eye modifies circadian rhythm.” (Article) Around the Clock – “The circadian clock influences far more than daily habits, according to a few decades of research. Obesity, diabetes, cardiovascular disease, liver disease, cancer, and depression have all been linked to malfunctions of the internal timekeeping scheme. Almost every cell in a living organism, it turns out, sees daily fluctuations in levels of genes and proteins, and when these fluctuations are dampened or stopped, things can go awry.” (Study) Circadian stage-dependent inhibition of human breast cancer metabolism and growth by the nocturnal melatonin signal: consequences of its disruption by light at night in rats and women. “This biological mechanism (ALAN) may partially explain the higher risk of breast and other cancers in women working rotating night shifts and possibly others who also experience prolonged exposure to light at night.” (Article) From Fertility To Mood, Sunlight Found To Affect Human Biology – NYT article from 1981!  “Dr. Richard J. Wurtman - 'we are all unwitting subjects of a long-term experiment on the effects of artificial lighting on health. Until much more is known, we should design indoor lighting to resemble as closely as possible what the sun provides.'' (Study) A functional circadian clock is required for proper insulin secretion by human pancreatic islet cells – (Think diabetes!) (Study) Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption. – “Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase the risk of obesity and diabetes.” (Study) Circadian Clock Control of Liver Metabolic Functions – “A wide variety of processes throughout the entire gastrointestinal tract and notably the liver appear to be under circadian control. These include various metabolic functions such as nutrient uptake, processing, and detoxification, which align organ function to cycle with nutrient supply and demand. Remarkably, genetic or environmental disruption of the circadian clock can cause metabolic diseases or exacerbate pathological states.” (Audio) BBC talk on circadian rhythms and their importance.   (Study) Circadian clocks, obesity and cardiometabolic function – “Disrupting this process through mutations in the core clock genes or by interfering with the environmental zeitgebers that entrain the clock appear to modulate the function of cells and tissues, leading to an increased risk for cardiometabolic disease.” (Study) Circadian rhythm-related genes - implication in autoimmunity and type 1 diabetes – “The hypothesis that circadian genes are involved in type 1 diabetes is reinforced by findings that the immune system undergoes circadian variation and that several autoimmune diseases are associated with circadian genes. Recent findings in the non-obese diabetic mouse model pinpoint to specific mechanisms controlling type 1 diabetes by the clock-related gene Arntl2 in the immune system.” (Study) Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans – “We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers” (Study) Gut Clock - Implication Of Circadian Rhythms In The Gastrointestinal Tract – “Motor and secretory activity, as well as the rhythm of cell proliferation in the GIT (Gastrointestinal Tract) and liver, are subject to many circadian rhythms, mediated by autonomic cells and some enterohormones (gastrin, ghrelin and somatostatin). Disruption of circadian physiology, due to sleep disturbance or shift work, may result in various gastrointestinal diseases, such as irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD) or peptic ulcer disease. In addition, circadian disruption accelerates aging, and promotes tumorigenesis in the liver and GIT.”  (Study) Keeping circadian time with hormones – “Circadian deregulation of hormonal rhythms may participate in internal desynchronization and associated increase in metabolic risks.” (Study) Thyroid hormone and seasonal regulation of reproduction – “In mammals, the eyes are the only photoreceptor involved in photoperiodic time perception and nocturnal melatonin secretion provides an endocrine signal of photoperiod to the PT to regulate TSH (Thyroid Stimulating Hormone).” (Study) Exposure to Room Light before Bedtime Suppresses Melatonin Onset and Shortens Melatonin Duration in Humans – “These findings indicate that room light exerts a profound suppressive effect on melatonin levels and shortens the body's internal representation of night duration. Hence, chronically exposing oneself to electrical lighting in the late evening disrupts melatonin signaling and could therefore potentially impact sleep, thermoregulation, blood pressure, and glucose homeostasis.” (Article) UCI study finds jet lag-like sleep disruptions spur Alzheimer’s memory, learning loss – “Chemical changes in brain cells caused by disturbances in the body’s day-night cycle may be a key underlying cause of the learning and memory loss associated with Alzheimer’s disease, according to a University of California, Irvine study.”   nnEMF (Non-Native Electromagnetic Fields) (Article) Stress from Current And Radiation – This is a transcript of a lecture given by journalist Wolfgang Maes in Los Angeles, California in 1990.  Wolfgang suffered from EHS and tells his story and how he fixed his surroundings and his health by lowering his night time exposure to nnEMF.  (Video) Electromagnetic Fields and DNA Damage: Dr. Jerry Phillips – In this video, Dr. Phillips discusses how nnEMFs damage your DNA, but he also tackles the topic of conflicting research between the independent science and the industry-funded science.  By the way this video is from 2012, before Dr. Martin Pall’s work in 2013 that actually FOUND the non-thermal mechanism by which nnEMF disrupts cellular function.  (Article)  Cell Phone Radiation Boosts Cancer Rates in Animals – “The cell phone cancer controversy will never be the same again.  The U.S. National Toxicology Program (NTP) is expected to issue a public announcement that cell phone radiation presents a cancer risk for humans. The move comes soon after its recently completed study showed statistically significant increases in cancer among rats that had been exposed to GSM or CDMA signals for two-years.” (Video) Dr. Martin Pall – How Wi-Fi & other EMFs Cause Biological Harm – Amazing talk by Dr. Pall where he goes in depth and breaks down the non-thermal biological effects of Wi-Fi.  (Documentary) – Resonance Beings of Frequency – An eye-opening documentary that will teach you a tremendous amount about the dangers of nnEMF.  (Study) – Genetic Analysis of Circadian Responses to Low Frequency Electromagnetic Fields in Drosophila melanogaster – “Our results are therefore not consistent with the classical Trp triad-mediated RPM and suggest that CRYs act as blue-light/EMF sensors depending on trans-acting factors that are present in particular cellular environments.” Translation – nnEMF is perceived as light by sensory proteins in your body and that can mess with your circadian biology.  (Study) - Is it Blue Light or Increased Electromagnetic Fields which Affects the Circadian Rhythm in People who Use Smartphones at Night – “Furthermore, previous reports have indicated a significant association between exposure to RF-EMFs of mobile or cordless phones and sleep problems (2, 3). The 2nd shortcoming of this paper comes from ignoring this point that electromagnetic fields may affect the level of plasma melatonin (4, 5).” (Study) Critical time delay of the pineal melatonin rhythm in humans due to weak electromagnetic exposure. –“The results show that significant melatonin interruption and changes to the circadian rhythm occur due to the perturbation of chemical reaction rates, as also reported in previous studies. The results also show the influence of the mRNA degradation rate on the circadian rhythm's critical time delay or maturation time. The results support the hypothesis that exposure to weak EMFs via melatonin disruption can adversely affect human health.” (Study) Why are living things sensitive to weak magnetic fields? – “This implies that weak magnetic field interactions may have a chronodisruptive basis, homologous to the more familiar effects on the biological clock arising from sleep deprivation, phase-shift employment and light at night. It is conceivable that the widespread sensitivity of biological systems to weak ELF magnetic fields is vestigially derived from this diurnal geomagnetic effect.” (Article) - 'Radiogenetics' seeks to remotely control cells and genes – “The new system, dubbed radiogenetics, uses a signal, in this case low-frequency radio waves or a magnetic field, to heat or move ferritin particles. They, in turn, prompt the opening of TRPV1, which is situated in the membrane surrounding the cell. Calcium ions then travel through the channel, switching on a synthetic piece of DNA the scientists developed to turn on the production of a downstream gene, which in this study was the insulin gene.”Translation – Scientists are actively using nnEMFs NON-THERMAL effects on cells to develop therapies for diabetes.  How can anyone read this and deny the non-thermal effects of nnEMF?? (Documentary) – Searching for a Golden Cage – A short and informative film that documents the plight of people who suffer from EHS.  (Documentary) – Take Back Your Power – A must-watch documentary that illuminates the dangers of electric company-installed smart meters on homes and in apartment buildings.  (Study) – Access to electricity is linked to reduced sleep – “New research comparing traditional hunter-gatherer living conditions to a more modern setting shows that access to artificial light and electricity has shortened the amount of sleep humans get each night.” (Study) Mitochondrial calcium overload is a key determinant in heart failure – This study in particular does not mention nnEMF as a cause of heart failure, but if you remember Dr. Martin Pall’s work that showed how nnEMF causes excess calcium in the cell, and you see how this study links excess calcium in the cell to heart failure, it’s easy to connect the dots!  Heart attacks kill a staggering number of Americans every year.  Might nnEMF be a hidden cause that no one is considering?  Food for thought.  (Study) Effects of the Effect of Ultra High Frequency Mobile Phone Radiation on Human Health – “The results of this study and International Commission of Non Ionization Radiation Protection (ICNIRP) reports showed the people who spend more than 50 minutes a day using a cell phone could have early dementia or other thermal damage due to the burning of glucose in the brain.” (Study) Cancer incidence vs. FM radio transmitter density – “The findings present strong support to the earlier presented hypothesis that body-resonant broadcasting radiation emitted by horizontally polarized main FM transmitters has an immune-disturbing effect. “ (Article) Diabetes and Electro sensitivity – This article raises the possibility that diabetes is caused by nnEMF.  (Article) Wireless technology – studies on health effects, lawsuits & court rulings. – This is a fantastic resource that links to a tremendous treasure trove of research and other evidence of the harm that nnEMF causes to human health.  (Article) New research links cell phones to health issues in children – “For years, we’ve heard of a possible link between cell phone use and cancer. Now, this week, researchers in Baltimore say the evidence is clear, and children are more at risk.”  This is crucial to watch and read if you have children.  (Study) Schumann resonance is found in the earth and in the human brain – Think about that.  Our brains resonate at the same frequency as the natural frequency emitted by the earth that gets charged by lightening.  With no nnEMFs this is how we are supposed to resonate.  nnEMFs disturb this natural resonance and we pay the price with our health. (Video) Magda Havas talks at NIEHS May 9, 2016 on electro smog and electro hypersensitivity – She shows what nnEMFs do to our blood under a microscope, and shows how reducing nnEMFs helped several MS patients.  (Article) The pulsed microwave radar tower and the cell – the role of calcium – This one is definitely more for the science geeks, but it goes into great detail about how nnEMF affects the calcium in and around our cells.  (Article) Mobile Phones are cooking men’s sperm – “Study finds sperm levels of men who kept their phones in their pocket during the day were quite seriously affected in 47 per cent of cases“ (Article) Wireless devices & wildlife – This is a fascinating and well-referenced article that depicts the effects of Wi-Fi on animals and plants.  It discusses key studies done on bees that show how Wi-Fi is causing colony collapse disorder.  (Article) nnEMF research collection – And finally, a massive collection of research on nnEMF that includes a link to 2300 studies done by the US Navy showing the biological impacts of nnEMF!  (Study) Prenatal Exposure to weak magnetic fields leads to childhood asthma – “Li's study is the first prospective epidemiological study ever carried out on any group exposed to any type of electromagnetic fields (EMFs). The mothers' magnetic field exposures were measured during the first or second trimester and the health of their children —a total of 626 boys and girls— was followed for the next 13 years. Li sees a clear dose-response: Every 1 mG increase in median magnetic field exposure during pregnancy led to a 15% increase in asthma in the offspring. The trend is highly significant.” Connect with Rick Gold Gold Functional Wellness Rate, Review, Connect, Inspire Stay updated on new episodes, guest interviews, and health, wellness, and fitness information and resources by subscribing to the HealthCastNow Podcast Show on iTunes. Every day we bring you actionable insight, demystified truth, and simple steps to help you navigate the complex, often confusing health, wellness, and fitness information and answer the questions you’ve been asking. Visit HealthCastNow.Com or subscribe on iTunes today!

Der humane Mas-related gene X1 (hMrgX1)-Rezeptor ist ein G-Protein-gekoppelter Rezeptor, der selektiv in nozizeptiven Spinalganglienneuronen exprimiert wird. Eine spezifische Aktivierung des Rezeptors durch das Proenkephalin-Spaltprodukt BAM8-22 (bovine adrenal medulla 8-22) wird als schmerzhaft wahrgenommen. Damit stellt der hMrgX1-Rezeptor eine neue molekulare Zielstruktur für eine potentiell nebenwirkungsarme, analgetische Therapie dar. Trotz dieses Potentials sind die pro-algetischen Signalwege des hMrgX1-Rezeptors bislang nicht verstanden. Der MrgX1-Rezeptor entwickelte sich unter hohem positivem Selektionsdruck und kommt nur in Primaten vor. Trotzdem wurden die nicht-homologen MrgC-Rezeptoren der Nagetiere zur Analyse des hMrgX1-Rezeptors verwendet. Im Rahmen dieser Arbeit wurden daher zunächst vergleichende Ligandenprofile des hMrgX1- und der MrgC-Rezeptoren aus Maus und Ratte erstellt. Dabei wurden deutliche Unterschiede offensichtlich, da der hMrgX1-Rezeptor exklusiv von BAM8-22 aktiviert wurde, während die MrgC-Rezeptoren durch weitere Liganden, u. a. Spaltprodukte des Proopiomelanocortins, z. T. sogar effizienter aktiviert wurden. Zudem konnte gezeigt werden, dass die MrgC-vermittelte Ca2+-Mobilisation auf Grund einer β-Arrestin-abhängigen Rezeptorendozytose deutlich desensitisierte, während der hMrgX1-Rezeptor resistent gegenüber dieser Liganden-induzierten Regulation war. Daher können die MrgC-Rezeptoren der Nagetiere nicht als Modellsytem für den hMrgX1-Rezeptor verwendet werden, so dass in dieser Arbeit weiterführend Signalwege des hMrgX1-Rezeptors in Spinalganglienneuronen-ähnlichen F11-Zellen und primären Spinalganglienneuronen untersucht wurden. Dabei zeigte sich eine duale funktionelle Regulation des etablierten pro-algetischen TRPV1 (transient receptor potential cation channel vanilloid 1)-Ionenkanals. Zum einen sensitisierte der hMrgX1-Rezeptor den TRPV1 über einen etablierten, Proteinkinase C-abhängigen Signalweg. Zum anderen zeigte sich eine direkte hMrgX1-mediierte Aktivierung des TRPV1. Dieser Regulationsmechanismus wurde durch eine Phospholipase C (PLC)-β-induzierte Produktion des endogenen TRPV1-Liganden Diacylglycerol und durch die Degradation des tonisch TRPV1-inhibierenden PLC-β-Substrates Phosphatidylinositol-4,5-bisphosphat vermittelt. Neben der TRPV1-Modulation induzierte der hMrgX1-Rezeptor die Expression verschiedener Gene, deren zentrale Bedeutung bei der inflammatorischen und neuropathischen Schmerzchronifizierung etabliert ist. Einerseits wurde eine hMrgX1-induzierte Phosphorylierung der extracellular signal-regulated kinases 1/2 beobachtet, die in einer Aktivierung von serum response factor-abhängigen Reportergenkonstrukten und in der Induktion von c-Fos auf mRNA- und von early growth response protein 1 auf mRNA- und Proteinebene resultierte. Andererseits zeigte sich die transkriptionelle Ca2+/Calcineurin-abhängige Aktivierung des nuclear factor of activated t cells, die in der Induktion des CCR2 (chemokine receptor 2) auf mRNA- und Proteinebene resultierte. Somit konnte erstmalig ein physiologischer Induktor des CCR2 in Spinalganglienneuronen beschrieben werden. Weiterhin wurde nach der Etablierung der endogenen Proteinexpression des hMrgX1-Rezeptors in LAD2-Mastzellen eine BAM8-22-induzierte Freisetzung des CCR2-Agonisten chemokine ligand 2 ermittelt, so dass der hMrgX1-Rezeptor die parakrine Stimulation von nozizeptiven Spinalganglienneuronen durch Mastzellen fördern könnte. Diese Dissertation trägt somit zum besseren molekularen Verständnis akuter und chronischer pro-algetischer Funktionen des hMrgX1-Rezeptors bei und könnte damit die Entwicklung neuer analgetischer Wirkstoffe ermöglichen.

Biz söylemiştik Mayıs sayımızdaki “Apartman Çocuğu Olmak” başlıklı yazıda söylemiştik: Şehirlerde büyüyen ve yaşayan insanların şizofreni gibi ruhsal rahatsızlıklara yakalanma riskleri kırsal kesimdeki insanlara göre daha fazla. Beynin şiddet ve öfke içerikli davranışlarla ilişkilendirilen amigdala bölgesindeki etkinliğin kontrolü, şehir hayatına bağlı faktörlerden dolayı kayboluyor. Şehir planlamaları bu ayrıntı göz önüne alınarak yapılmalı. Daha fazla yeşil, daha çok doğa, daha sakin ortamlara ihtiyaç var şehirlerde. Biz bunları ay başında söylerken ay sonuna doğru dünyadaki diğer metropollerin parklarıyla karşılaştırılamayacak kadar küçük ama yine de İstanbullunun yeşile duyduğu hasreti biraz olsun gidermesine yardımcı olan Gezi Parkı’nın yıkım çalışmalarına başlanacağından haberimiz yoktu. Tesadüf oldu. Ağaçların kesilmesine direnenlerin ne kadar haklı olduğunu bilimsel çalışmaları göz önünde bulundurarak anlatmış olduk. Olaylar sırasında biber gazı bol bol kullanıldı. Peki nedir bu biber gazı ve çalışma mekanizması nasıldır? Biber gazı ne kadar acı? Biber türlerinin acılık ölçeği. Dolmalık biber acı değilken, biber gazının acılığı dayanılmaz boyutlarda (9). Biber gazının içindeki etken madde bibere de acı tat veren kapsaisindir. Kapsaisinin yoğunluğuna göre farklı biber türlerinin acılığı da değişir. Biberlerinin yakıcılığı Scoville Acılık Birimi (SHU) kullanılarak yandaki figürdeki gibi ölçeklendirilebiliyor. Bu ölçeğe göre dolmalık biber hiç acı değilken, yani 0 SHU iken, Türk sofralarında sıkça kullanılan acı biberler 100-500 SHU kadar acı olabiliyor. Biber gazının acılığı ise kapsaisin yoğunluğuna göre 2 milyon ile 5 milyon SHU arasında değişiyor. Yani ağzınızı yakan acı biberin onbinlerce kat daha acısını düşünün... Bir terleme hissettiniz mi? :-) Kapsaisin nasıl acı verir? Çağrı Yalgın’ın Şubat 2012 sayısında bahsettiği gibi kapsaisin, TRPV1 (VR1) isimli bir reseptör tarafından algılanıyor. Aynı zamanda sıcaklığa da duyarlı olan bu reseptörü üreten C-fibre ve Aδ denen sinir hücreleri deri, dil, omurilik, eklemler, iç organlar, solunum yolları ve mesaneden gelen bilgileri beyne iletiyor1,2. TRPV1, en basit tanımıyla, bir kalsiyum iyonu (Ca2+) kanalı. Yani, sinir hücreleri arasındaki sinyal iletimi sırasında gerekli olan Ca2+ iyonunun hücre içine girişini sağlayan bir geçit.  Sıcaklık ve kapsaisin varlığına bağlı olarak uyarıldığı zaman kanal açılıyor ve hücre dışındaki Ca2+ iyonlarının hücre içine girmesini sağlıyor. Örneğin, TRPV1, 42˚C sıcaklığa maruz kaldığı zaman çalışmaya başlıyor. TRPV1’e sahip olmayan farelerden elde edilen sinir hücreleri üzerinde yapılan deneylerde, hücrelerin 42˚C’ye tepki vermediğini, fakat 55˚C’den sonra TRPV2 denen başka bir reseptörün devreye girmesiyle hücrelerin sıcaklığı algılamaya başladığı gözleniyor3,4. Acı biber yediğimizde, yaptığımız yaramazlıktan sonra annemiz ağzımıza acı biber sürdüğünde veya direndiğimizde devlet babamız üstümüze biber gazı veya kapsaisinli su sıktığında sıcaklık-yanma hissetmemizin sebebi kapsaisinin ve sıcaklığın aynı mekanizma tarafından algılanıyor olması. Kapsaisin, madde-P ve astım şeytan üçgeni Kapsaisin sadece yanma hissine neden olmuyor. Aynı zamanda sinir hücrelerinden “madde-P” isimli bir “mesajcı”nın hücrelerden salgılanmasını sağlıyor. Madde-P’nin iltihap başlatma özelliğinin yanı sıra akciğerlere giden havayollarının daralmasına neden olduğu biliniyor5. Bu yüzden biber gazına maruz kalan insanlarda solunum zorluğu görülebiliyor. Astım hastalarının madde-P’ye karşı hassasiyetinin daha yüksek olduğu tespit edilmiş5. Buna bağlı olarak astım hastalarının biber gazına tepkileri çok daha kuvvetli olabiliyor ki ölüme kadar giden sonuçlar doğurabiliyor. Bu yüzden protestolar sırasında astım hastalarının da olabileceği göz önünde bulundurularak göstericilere müdahale edilmesi hayati önem taşıyor. Türkiye’de coğrafi konuma bağlı olarak astım görülme sıklığının %2-6 arasında değiştiğini düşünürsek; 1000 insanın olduğu ...