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  1. Like
    Construct got a reaction from dr. frankenstein in Ketamine Works through mTORC1–4E-BP signaling   
    Surprisingly, Rapamycin pretreatment extend's ketamine's antidepressant effects: https://www.nature.com/articles/s41386-020-0644-9 However, it seems to have more to do with the fact that peripherally administered Rapamycin has limited penetration into the central nervous system.
     
    I'm glad they're also studying the (2R,6R)-hydroxynorketamine metabolite. Supposedly it doesn't have the same dissociative effects or abuse potential as ketamine, yet retains the antidepressant effects. 
  2. Haha
    Construct got a reaction from KCASANJO594 in Activity Levels   
    Had to move my office to the frigid, uninsulated basement and I keep the thermostat turned down. I grab the kettlebell whenever I start feeling too cold.
  3. Like
    Construct got a reaction from KCASANJO594 in Effectiveness of Face Masks   
    Same here. Too many of the anti-mask arguments revolve around moving the goalposts, or otherwise showing that masks aren't 100% effective.
     
    We know they aren't 100% effective. We know that wearing a mask won't make you immune from contracting or spreading infection. We know that mask mandates alone aren't sufficient to stop the virus at this point. However, those seem to be the same few strawman arguments that the anti-mask crowd continues to use to prop up their argument.
     
    The reality is that this whole pandemic thing is a game of managing R0. If R0 > 1, infection grows. If R0 < 0, infection shrinks. If R0 is sitting at something like 1.1 and masks (hypothetically, this is a random number for example purposes) reduce that value by 15%, we're back under an R0 of 1.0.
     
    Anecdotally, it's not hard to see that masks at least do something to capture droplets when people breathe out or talk (this is why masks end up slightly damp) and that they direct air upward rather than outward (this is why glasses get fogged up when people wear masks). If you're in a closed environment without any circulation, that probably doesn't matter. But if you're passing by someone in a supermarket aisle, I have a hard time believing that a mask wouldn't at least reduce the exposure to airborne droplets from other people. I'll take it.
  4. Like
    Construct reacted to dr. frankenstein in Ketamine Works through mTORC1–4E-BP signaling   
    .
    rodent studies
     
    Ketamine as antidepressant
     
    https://www.genengnews.com/news/how-ketamine-works-as-an-antidepressant-in-the-brain/
     
    “The antidepressant effects of ketamine and (2R,6R)-HNK in rodents require activation of the mTORC1 kinase. mTORC1 controls various neuronal functions, particularly through cap-dependent initiation of mRNA translation via the phosphorylation and inactivation of eukaryotic initiation factor 4E-binding proteins (4E-BPs).”
     
     
    -------
     Antidepressant actions of ketamine engage cell-specific translation via eIF4E
     
     
    .
  5. Like
    Construct got a reaction from dr. frankenstein in Psilocybin on treatment-resistant depression   
    It's too bad they didn't bother to include a placebo group. Placebo response in depression studies is surprisingly high, and placebo response rates are actually increasing in recent depression studies for whatever reason.
     
    It's not hard to imagine that the psychedelic experience could enhance the placebo effect significantly, given the propensity for psychedelics to increase suggestibility and generate an artificial sense of revelation.
     
    But then again, maybe it doesn't matter if it's placebo effect or not if the end result is a happier patient. The limitation here is duration of the remission and repeatability. The study only followed patients for 3 months, but depression scores were slowly creeping back up after the first month. Even a temporary remission would be valuable for treatment-resistant patients, but extrapolating to longer periods of illness might be difficult. If there really is something here, I would guess that it's more useful as an adjunct to psychotherapy and for kick-starting healthy life changes and elimination of negative thought patterns rather than as a chronic-type treatment like SSRIs.
     
    It's interesting that almost half of the small sample size in the study had previous experience with psilocybin, although only one of them within any recent timeframe. If the study recruiting mentioned the specifics of the study (psychedelic treatment for depression) it's very likely that the patients were self-selected "true believers" from the start.
     
    It would be interesting to perform a study in which the patients were sedated first, then given either a 5-HT2A agonist psychedelic or placebo. The sedation would very obviously interfere with the trip aspect, but if there's any substance to the 5-HT2A downregulation theory then it might very well be revealed in such a study. I'm skeptical, though, because I'm not yet convinced that a single dose would have such long-lasting direct effects on the 5-HT2A system. If anything, I'd expect induction of some downstream changes similar to the way Ketamine seems to work in depression.
  6. Like
    Construct got a reaction from Mr.Kite in Effectiveness of Face Masks   
    Same here. Too many of the anti-mask arguments revolve around moving the goalposts, or otherwise showing that masks aren't 100% effective.
     
    We know they aren't 100% effective. We know that wearing a mask won't make you immune from contracting or spreading infection. We know that mask mandates alone aren't sufficient to stop the virus at this point. However, those seem to be the same few strawman arguments that the anti-mask crowd continues to use to prop up their argument.
     
    The reality is that this whole pandemic thing is a game of managing R0. If R0 > 1, infection grows. If R0 < 0, infection shrinks. If R0 is sitting at something like 1.1 and masks (hypothetically, this is a random number for example purposes) reduce that value by 15%, we're back under an R0 of 1.0.
     
    Anecdotally, it's not hard to see that masks at least do something to capture droplets when people breathe out or talk (this is why masks end up slightly damp) and that they direct air upward rather than outward (this is why glasses get fogged up when people wear masks). If you're in a closed environment without any circulation, that probably doesn't matter. But if you're passing by someone in a supermarket aisle, I have a hard time believing that a mask wouldn't at least reduce the exposure to airborne droplets from other people. I'll take it.
  7. Like
    Construct got a reaction from Something Anonymous in Effectiveness of Face Masks   
    Same here. Too many of the anti-mask arguments revolve around moving the goalposts, or otherwise showing that masks aren't 100% effective.
     
    We know they aren't 100% effective. We know that wearing a mask won't make you immune from contracting or spreading infection. We know that mask mandates alone aren't sufficient to stop the virus at this point. However, those seem to be the same few strawman arguments that the anti-mask crowd continues to use to prop up their argument.
     
    The reality is that this whole pandemic thing is a game of managing R0. If R0 > 1, infection grows. If R0 < 0, infection shrinks. If R0 is sitting at something like 1.1 and masks (hypothetically, this is a random number for example purposes) reduce that value by 15%, we're back under an R0 of 1.0.
     
    Anecdotally, it's not hard to see that masks at least do something to capture droplets when people breathe out or talk (this is why masks end up slightly damp) and that they direct air upward rather than outward (this is why glasses get fogged up when people wear masks). If you're in a closed environment without any circulation, that probably doesn't matter. But if you're passing by someone in a supermarket aisle, I have a hard time believing that a mask wouldn't at least reduce the exposure to airborne droplets from other people. I'll take it.
  8. Like
    Construct got a reaction from KCASANJO594 in Activity Levels   
    Losing access to gyms put a dent in my physical activity, but at least I could get outside. Now that the snow is falling, I'm struggling a bit.
     
    I've started doing pushups and kettlebell swings near my desk throughout the day. The downside is that I don't get any continuous exercise to break a sweat.
  9. Like
    Construct reacted to STENDEC in Vitamin D & ASD   
    Vitamin D Could Explain Why Autism Is Three Times More Common in Boys
     
    A deficiency in vitamin D on the mother’s side could explain why autism spectrum disorder is three times more common in boys, say Queensland Brain Institute researchers.
     
    In their latest study, Professor Darryl Eyles and Dr. Asad Ali found vitamin D deficiency during pregnancy caused an increase in testosterone in the developing brain of male rats.

    “The biological cause of autism spectrum disorder (ASD) is unknown but we have shown that one of the many risk factors—low vitamin D in mothers—causes an increase in testosterone in the brain of the male fetuses, as well as the maternal blood and amniotic fluid,” Professor Eyles said. “In addition to its role in calcium absorption, vitamin D is crucial to many developmental processes. Our research also showed that in vitamin D-deficient male fetuses, an enzyme which breaks down testosterone was silenced and could be contributing to the presence of high testosterone levels.”

    Professor Eyles’ previous research has shown that vitamin D plays a critical role in brain development and that giving vitamin D supplements to mice during pregnancy completely prevented autism-like traits in their offspring. Co-author Dr. Ali said that excessive exposure of the developing brain to sex hormones like testosterone was thought to be an underlying cause of ASD, but the reasons remained unclear.
    “Vitamin D is involved in pathways controlling many sex hormones,” Dr. Ali said.
     
    “When the rat mothers were fed a low vitamin D diet, it caused male fetal brains to have high levels of exposure to testosterone.”
    Time to study more risk factors for ASD Professor Eyles said the study was the first to show that a known risk factor for ASD alters testosterone in both the fetal brain and the mother’s blood — one possible contributor to why ASD is more prevalent in males.
     
    “We have only studied one risk factor for ASD — vitamin D deficiency during development — our next step is to look at other possible risk factors, such as maternal stress and hypoxia – lack of oxygen – and see if they have the same effect,” he said.
     
    Reference: “Developmental vitamin D deficiency increases foetal exposure to testosterone” by Asad Amanat Ali, Xiaoying Cui, Renata Aparecida Nedel Pertile, Xiang Li, Gregory Medley, Suzanne Adele Alexander, Andrew J. O. Whitehouse, John Joseph McGrath and Darryl Walter Eyles, 10 December 2020, Molecular Autism.
     
    https://scitechdaily.com/vitamin-d-could-explain-why-autism-is-three-times-more-common-in-boys/
  10. Like
    Construct reacted to STENDEC in Fountain of Youth?   
    Blocking protein restores strength, endurance in old mice
    Science News
    December 10, 2020

    Blocking the activity of a single protein in old mice for one month restores mass and strength to the animals' withered muscles and helps them run longer on a treadmill, according to a study by researchers at the Stanford University School of Medicine. Conversely, increasing the expression of the protein in young mice causes their muscles to atrophy and weaken.
     
    "The improvement is really quite dramatic" said Helen Blau, PhD, professor of microbiology and immunology. "The old mice are about 15% to 20% stronger after one month of treatment, and their muscle fibers look like young muscle. Considering that humans lose about 10% of muscle strength per decade after about age 50, this is quite remarkable."
     
    The protein hasn't previously been implicated in aging. The researchers show that the amount of the protein, called 15-PGDH, is elevated in old muscle and is widely expressed in other old tissues. Experiments they conducted in human tissue raise hopes for a future treatment for the muscle weakness that occurs as people age.
     
    Blau, the Donald E. and Delia B. Baxter Foundation Professor and director of the Baxter Laboratory for Stem Cell Biology, is the senior author of the study, which will be published online Dec. 10 in Science. Senior scientist Adelaida Palla, PhD, is the lead author.
     
    Muscle loss during aging is known as sarcopenia, and it accounts for billions of dollars of health care expenditures in the United States each year as people lose the ability to care for themselves, experience more falls and become increasingly less mobile. It is due to changes in muscle structure and function: The muscle fibers shrink and the number and function of the cellular powerhouses known as mitochondria dwindle.
     
    Blau and her colleagues have long been interested in understanding muscle function after muscle injury and in diseases like Duchenne muscular dystrophy. Previously, they found that a molecule called prostaglandin E2 can activate muscle stem cells that spring into action to repair damaged muscle fibers.
     
    "We wondered whether this same pathway might also be important in aging," Blau said. "We were surprised to find that PGE2 not only augments the function of stem cells in regeneration, but also acts on mature muscle fibers. It has a potent dual role. Prostaglandin E2 levels are regulated by 15-PGDH, which breaks down prostaglandin E2. The researchers used a highly sensitive version of mass spectrometry, a method for differentiating closely related molecules, to determine that compared with young mice, the 15-PGDH levels are elevated in the muscles of older animals, and the levels of prostaglandin E2 are lower.
     
    They found a similar pattern of 15-PGDH expression in human muscle tissues, as those from people in their 70s and early 80s expressed higher levels than those from people in their mid-20s. "We knew from our previous work that prostaglandin E2 was beneficial for regeneration of young muscles," Palla said. "But its short half-life makes it difficult to translate into a therapy. When we inhibited 15-PGDH, we observed a systemic elevation of prostaglandin E2 levels leading to a bodywide muscle improvement in aged mice."
     
    The researchers administered a small molecule that blocks the activity of 15-PGDH to the mice daily for one month and assessed the effect of the treatment on the old and young animals. "We found that, in old mice, even just partially inhibiting 15-PGDH restored prostaglandin E2 to physiological levels found in younger mice," Blau said. "The muscle fibers in these mice grew larger, and were stronger, than before the treatment. The mitochondria were more numerous, and looked and functioned like mitochondria in young muscle."
     
    When Palla and her colleagues performed the reverse experiment -- overexpressing 15-PGDH in young mice -- the opposite occurred. The animals lost muscle tone and strength, and their muscle fibers shrank and became weaker, like those of old animals.
     
    Finally, the researchers observed the effect of prostaglandin E2 on human myotubes -- immature muscle fibers -- growing in a lab dish. They found that treating the myotubes with prostaglandin E2 caused them to increase in diameter, and protein synthesis in the myotubes was increased -- evidence that prostaglandin E2 worked directly on the muscle cells, not on other cells in the tissue microenvironment.
     
    "It's clear that this one regulator, 15-PGDH, has a profound effect on muscle function," Blau said. "We're hopeful that these findings may lead to new ways to improve human health and impact the quality of life for many people. That's one of my main goals." Blau and Palla are studying more about what controls the levels and activity of 15-PGDH during normal aging, and how it might affect the function of other tissues in the body.
     
    "The mice perform better on a treadmill, but that requires more than just an increase in muscle strength," Blau said. "Other organ systems are involved -- the heart and lungs, for example. It suggests an overall improvement in the function of the whole animal."
     
    Journal Reference:
    A. R. Palla, M. Ravichandran, Y. X. Wang, L. Alexandrova, A. V. Yang, P. Kraft, C. A. Holbrook, C. M. Schürch, A. T. V. Ho, H. M. Blau. Inhibition of prostaglandin-degrading enzyme 15-PGDH rejuvenates aged muscle mass and strength. Science, 2020; eabc8059 DOI: 10.1126/science.abc8059
  11. Like
    Construct got a reaction from KCASANJO594 in Low dose Colchicine for prevention of atherosclerosis   
    Colchicine is typically used in doses of 0.6mg to 1.2mg to prevent gout flare-ups. It's not entirely without side effects, but it's generally well tolerated.
     
    More recently, Colchicine has been observed to have some value in prevention of heart disease:
     
     
    More info in the full paper here: https://www.clinicaltherapeutics.com/article/S0149-2918(18)30596-4/pdf . The authors suggest that 0.5mg/day of Colchicine could have significant value in preventing heart disease, albeit as a second-line treatment.
     
    To date, most Colchicine trials have used 1mg/day doses. Results have been largely positive for all-cause mortality and several other cardiac markers: https://pubmed.ncbi.nlm.nih.gov/26318871/
     
     
     
  12. Like
    Construct got a reaction from STENDEC in Low dose Colchicine for prevention of atherosclerosis   
    Colchicine is typically used in doses of 0.6mg to 1.2mg to prevent gout flare-ups. It's not entirely without side effects, but it's generally well tolerated.
     
    More recently, Colchicine has been observed to have some value in prevention of heart disease:
     
     
    More info in the full paper here: https://www.clinicaltherapeutics.com/article/S0149-2918(18)30596-4/pdf . The authors suggest that 0.5mg/day of Colchicine could have significant value in preventing heart disease, albeit as a second-line treatment.
     
    To date, most Colchicine trials have used 1mg/day doses. Results have been largely positive for all-cause mortality and several other cardiac markers: https://pubmed.ncbi.nlm.nih.gov/26318871/
     
     
     
  13. Like
    Construct reacted to STENDEC in Doxazosin: interesting metabolic effects   
    Alpha-1 adrenergic receptor antagonists to prevent hyperinflammation and death from
    lower respiratory tract infection
    Allison Koenecke1,†, Michael Powell2,†, Ruoxuan Xiong3, Zhu Shen4, Nicole Fischer5, Sakibul
    Huq6, Adham M. Khalafallah6, Marco Trevisan7, Pär Sparen7, Juan J Carrero7, Akihiko Nishimura8,
    Brian Caffo8, Elizabeth A. Stuart8, Renyuan Bai6, Verena Staedtke6, Nickolas Papadopoulos9,
    Kenneth W. Kinzler9, Bert Vogelstein9, Shibin Zhou9, Chetan Bettegowda5,9, Maximilian F.
    Konig10*, Brett Mensh11*, Joshua T. Vogelstein2,8,†,*, Susan Athey12*

    In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication
    phase is often followed by hyperinflammation, which can lead to acute respiratory distress
    syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic
    receptor (⍺1-AR) antagonists can prevent hyperinflammation (cytokine storm syndrome) in mice.
    Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory
    distress (ARD, n=18,547) and three cohorts with pneumonia (n=400,907). Federated across two
    ARD cohorts, we find that patients exposed to ⍺1-AR antagonists, as compared to unexposed
    patients, had a 34% relative risk reduction for mechanical ventilation and death (OR=0.70,
    p=0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on
    both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent
    need for prospective trials testing whether prophylactic use of ⍺1-AR antagonists ameliorates
    lower respiratory tract infection-associated cytokine storm syndrome, as observed in COVID-19.
  14. Like
    Construct reacted to STENDEC in Ashwagandha, more than an adaptogen   
    After a week or so on Ashwagandha, I can confirm this same effect....took me a while to figure it out but I was experiencing this low level of background anxiety that I couldn't connect to anything and discontinuing seems to have resolved it.
  15. Like
    Construct reacted to STENDEC in Normal Testosterone levels by age   
    Reference ranges are essential for partitioning testosterone levels into low or normal and making the diagnosis of androgen deficiency. We established reference ranges for total testosterone (TT) and free testosterone (FT) in a community-based sample of men.
     
    In a reference sample of 456 men, mean (SD), median (quartile), and 2.5th percentile values were 723.8 (221.1), 698.7 (296.5), and 348.3 ng/dl for TT and 141. 8 (45.0), 134.0 (60.0), and 70.0 pg/ml for FT, respectively. In all three samples, men with low TT and FT were more likely to have slow walking speed, difficulty climbing stairs, or frailty and diabetes than those with normal levels. In EMAS, men with low TT and FT were more likely to report sexual symptoms than men with normal levels. Men with low TT and FT were more likely to have at least one of the following: sexual symptoms (EMAS only), physical dysfunction, or diabetes.
     
    FT
  16. Like
    Construct reacted to KCASANJO594 in Monitoring CO2 levels in the home?   
    airnow.gov now includes purpleair sensors on their maps. I'm pushing Ambient to find a way in to the "inexpensive sensor program" with airnow, because we track the same things as purpleair, and more sensors seems to be a good thing to me.
  17. Like
    Construct got a reaction from STENDEC in Keto meal replacement shakes   
    1-2 tablespoons of MCT oil doesn't bother my stomach much when mixed with normal meals.
     
    The problem with the meal replacement shakes is that the powder doesn't have much volume. It's a very dense drink, so there isn't much to buffer the 60mL of oil in your stomach.
  18. Like
    Construct got a reaction from KCASANJO594 in Monitoring CO2 levels in the home?   
    In my experience, the days with bad PM2.5 pollution are visible to the naked eye as long as you can see some distant landmarks. The 100-400 PM2.5 days are visibly bad, especially with smoke particles in the air. You probably wouldn't be very excited to go outside on the really bad days anyway.
     
    Air pollution is becoming a popular research topic. There are an increasing number of studies with tentative links between air pollution exposure and various negative health effects. I went ahead and put HEPA air purifiers in my house and my office (back when that was a thing) so I could at least ensure most of my waking hours were spent in very low air pollution.
     
    If you're doing outdoor activities like hiking or skiing or otherwise getting away from town and into higher elevations, you're probably getting away from the air pollution anyway.
     
    I can't remember the full details, but from what I recall: Living near busy roads was a significant source of pollution. Not just the various gases from the cars, but from all of the particle emissions from tires and brake pads wearing down. We all replace our tires and brakes every few years, but where does that rubber and metal actually go? It's not building up on the road surfaces.
  19. Like
    Construct reacted to KCASANJO594 in Keto meal replacement shakes   
    It is benign from a taste perspective. but it often puts me in the shitter the first few times I use it until I get used to a tablespoon or so of it. 
     
    Why Does MCT Oil Cause Diarrhea?
    It is not explicitly known why MCT oil may cause diarrhea. The 1967 Journal of Gastroenterology offers this suggestion:
    To put this in simple terms, when MCT oil is consumed, it is broken down further with water (hydrolosis) so it can be readily absorbed by the body. MCT’s are then directed straight into the liver through the portal vein where they are converted to endogenous ketones.
    We weren’t able to find clinical studies specific to the association between MCT oil consumption and diarrhea. It seems that it is simply reported as a side effect and is usually related to dosage:
    On a personal level, I have never suffered diarrhea when taking MCT oil, however, I mix it in my coffee and drink it slowly. I have suffered abdominal cramping on one occasion when I used too much MCT oil in one dose. 
  20. Like
    Construct reacted to STENDEC in Forget The Fish Oil   
    A new study published in Mayo Clinic Proceedings provides the most comprehensive analysis of the role of omega-3 dosage on cardiovascular prevention to date. The meta-analysis, which is an in-depth review of 40 clinical trials, provides authoritative evidence for consuming more EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) omega-3 fats.
     
    The research concludes that EPA and DHA omega-3 intake is associated with reduced risk of coronary heart disease (CHD) events, the cause of 7.4 million deaths globally each year, and reduced risk of myocardial infarction (heart attack), including fatal heart attack.
     
    Full Article
  21. Like
    Construct got a reaction from KCASANJO594 in Ashwagandha, more than an adaptogen   
    Same here. For me, it's a strange mix of apathy and subtly heightened background anxiety.
     
    I've wondered if a lower dose might make more sense, but I haven't tried it.
  22. Like
    Construct reacted to KCASANJO594 in Starting Anew   
    301.6 yesterday after a walk.
     
    I've gotten in several 18h fasts after having a hard time managing even 12 for a few weeks. 
     
    I "ran" a mile in 14:26 today. I haven't run a mile that fast since high school.
     
    Feeling pretty good, overall. I have good and bad days like everyone else, but I'm not feeling consistently poor at the moment. 
  23. Like
    Construct got a reaction from STENDEC in GF's "CS Goes Pubic" Log   
    That's very interesting. Thanks for thinking of me.
     
    I'll investigate this line of thinking. Really, I'll investigate any possible leads at this point. Strangely enough, I can trigger my leg soreness by doing purely upper body work now. The soreness is bearable, but it's the general malaise and mental fog that really causes problems.
     
    I've been taking a convenient break from heavy lifting until the pandemic blows over. Really starting to miss it, though.
  24. Like
    Construct got a reaction from KCASANJO594 in Starting Anew   
    Health still moving in the right direction?
     
    Clomid and its active metabolites have extremely long half-lives. IIRC, the more estrogenic isomer sticks around longer than the anti-estrogenic isomer and some of the metabolites can stick around for over a month. 
  25. Like
    Construct got a reaction from STENDEC in Starting Anew   
    Health still moving in the right direction?
     
    Clomid and its active metabolites have extremely long half-lives. IIRC, the more estrogenic isomer sticks around longer than the anti-estrogenic isomer and some of the metabolites can stick around for over a month. 
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