35 Matching Annotations
  1. Jun 2021
    1. Time returned from a database can differ in precision from time objects in Ruby, so we need flexible tolerances when comparing in specs. We can use be_like_time to compare that times are within one second of each other.
    1. Firmina will be the longest cable in the world capable of running entirely from a single power source at one end of the cable if its other power source(s) become temporarily unavailable—a resilience boost at a time when reliable connectivity is more important than ever. 

      i was going to ask what good it is having a cable that has power, but not the data center behind it.

      i guess the situation is that the fiber optic cable also has power cables running along it too, powering the repeaters, and it's the power cables that might break. in this case, having single ended power would be very useful.

      i'm most curious to know how power is sent. is this 48V dc? higher? how much? kV?

  2. May 2021
    1. In contrast to its acute administration, repeated salvinorin A administration did not modify dialysate DA levels. Similarly, neither basal extracellular DA levels nor DA uptake was altered. Unlike synthetic KOPr agonists, prior repeated administration of salvinorin A did not attenuate the locomotor activating effects of an acute cocaine (20 mg/kg, i.p.) challenge. However, cocaine-evoked DA overflow was enhanced.

      Fascinating and useful stuff. This is close to what I was expecting. Though, I was expecting chronic exposure to upregulate dopamine beyond baseline. If I'm understanding this correctly, it was upregulated in the sense that it enhanced the dopaminergic effects of cocaine. I've not yet read the full study.

    1. Systemic administration of ultra-low doses of naltrexone (16.7, 20.0, and 25.0 ng/kg) with morphine (1.0 mg/kg) extended the duration of the morphine-induced conditioned place preference.

      This is important because it suggests mood-brightening. Contrast this with combining L-type calcium channel blockers with opioids, which appears to limit tolerance to opioid analgesia that does not correspond to mood brightening.

  3. Apr 2021
    1. However, coadministration of nefiracetam (5 or 10 mg/kg, p.o.), enprofylline (30 mg/kg, p.o.) and rolipram (0.3 or 1 mg/kg, i.p.) with morphine during the pretreatment period, significantly reduced the withdrawal signs, moreover, the tolerance was significantly attenuated.

      Looks promising. It's odd that theophylline had a lesser effect.

    1. Conclusion: Our data suggest that the combination of VLF with morphine may be a relevant therapeutic implication to manage pain even when tolerance to morphine exists. Moreover, our data demonstrates the involvement of L-Arg/NO/cGMP pathway in the prevention of morphine tolerance and dependence by venlafaxine.

      It's not clear if this has relevance to the subjective effects. I'm starting to think that I won't get an answer anytime soon.

    1. Results: Tadalafil showed anti-nociceptive effect when given alone at different doses (p<0.05). However, tadalafil significantly decreased the analgesic effect of morphine (p<0.05). In addition, tadalafil significantly increased the tolerance to morphine (p<0.05). Conclusions: The phosphodiesterase type 5 inhibitor tadalafil have anti-nociceptive properties and it decreases analgesic effect of morphine, in addition improves tolerance development. These effects probably may occur via NO/cGMP pathway.

      This is analgesia, so is not necessarily relevant for my purposes. Nonetheless, there implies some relevance of cGMP, but the direction isn't yet clear.

    1. Repeated KOR agonist exposure, on the other hand, can result in opposing effects on the dopamine system [27], and desensitization of the KOR [28]

      If they mean what I think they mean, then this implies that chronic KOR is useful. I'll need to check citation 27.

    1. These data suggested that PAT, an indirect-acting KOR agonist, share the common pharmacological property of KOR agonists on morphine tolerance

      PAT is apparently an herbal medicine I should look into. They also imply that KOR agonists act as I expect they do, but I'll need to read the full study to be sure.

      Edit: yup, it appears that chronic KOR agonism is probably a good idea.

      from full text "Utility of KOR agonists is a promising pharmacological tool for attenuating morphine tolerance (Pan, 1998), however, it is difficult to find effective KOR agonists that are devoid of dysphoric and psychotomimetic adverse effects in humans"

      This is the cited study.

    1. The results also showed that diltiazem was able to selectively potentiate the analgesic effect of morphine but not of fentanyl (the reason was not known).

      Fascinating. However, this provides no insight into the subjective effects. However, it does reduce my certainty that any given combination of drugs (sharing these mechanism) will work. There doesn't seem to be consistent results with these L-CCBs plus opioid studies.

    1. The results suggest the euphorigenic and analgesic effects of opioids may be differentiated by using Ca++ channel blockers.

      Yes. That also means that most of the rat studies I've been reading are useless for my purposes.

    1. Results:Nimodipine when administered as a single bolus dose before naloxone administration in morphine-dependant rats reduced the features of withdrawal reactions more effectively than continuous administration of nimodipine along with morphine throughout the experimental period.

      Weird and surprising.This plausibly implies that L-type calcium channel blockers may not be as effective as it first appears.

    1. Nimodipine controlled the escalation of the morphine dose in 9 patients (65%), and placebo in 4 (28%), the difference being statistically significant (P=0.03).

      Consistent with rat data. This is from 1998. I'm sure there's more evidence by now. It's been a while since i researched this, but I think I've previously seen at least one other study.

    1. These results suggest that the elevation of the cyclic AMP levels is involved in the development of morphine withdrawal syndrome and that blockade of the morphine-induced reduction of cyclic AMP levels by chronic rolipram inhibits the development of dependence and the behavioural and biochemical changes induced by naloxone. Furthermore, rolipram may be a useful drug for attenuating the development of morphine dependence.

      Excellent. This implies that theobromine may help prevent opioid tolerance.

  4. Dec 2020
  5. Nov 2020
    1. Big corporations have been doing this for a while. In 1027, after Trump implemented the travel ban on people coming from countries that sponsor terrorism, Airbnb responded with an ad during the Super Bowl called “We Accept.” It featured people of different nationalities and declared, “We believe no matter who you are, where you’re from, who you love or who you worship, we all belong. The world is more beautiful the more you accept.”

      AirBnB ostensibly failed to realize that if you accept unacceptance, you're shooting yourself in the foot.

  6. Oct 2020
    1. Cessation of nitrous oxide resulted in characteristic convulsions similar to those seen in alcohol withdrawal in all mice.

      This demonstrates that tolerance is possible. However, exposure in humans lasts only several minutes at a time. Let's assume 3 exposures per day lasting 10 minutes each (i.e. 30 minutes total). It would take 68 days to reach 34 hours of exposure. Alternatively, that's a ratio of 1 to 47 exposure to non-exposure. It's unclear whether that would be sufficient for tolerance.

      In the 50% exposure group, convulsion score was effectively zero by hour 6 (from full text). This does not mean that withdrawal symptoms were gone. However, it does imply that recovery is rapid. It seems plausible that 20 hours between doses is sufficient to reach baseline, rendering tolerance in humans extremely unlikely. I will need to compare to alcohol withdrawal to confirm.

      Edit: Alcohol withdrawal in mice can be induced with 72 hours of alcohol exposure. That implies it is similar to NO. In humans, "the shakes" appear to last 1 or two weeks. In mice, convulsions appear to be half gone in 25 hours, suggesting that they last a few days. Thus, it appears that NO withdrawal is possibly an order of magnitude shorter than alcohol withdrawal.

      In conclusion, NO used in a normal fashion is unlikely to be harmful (except for risk of inducing B12 deficiency). Even if it is harmful, the short half life means that it will be apparent very quickly. I'm aware of several reports of B12 deficiency from NO abuse, but I haven't seen any reports of withdrawal symptoms.

  7. Sep 2020
  8. Aug 2020
  9. May 2020
    1. While somewhat modest in size, the literature on chronic tolerance to nicotine in humans is reasonably consistent in showing clear evidence of tolerance to subjective mood effects but little or no tolerance to cardiovascular, performance or other nicotine effects

      This is what I'd expect for tobacco, but it tells me little about nicotine. Most of the subjective effects are not from tobacco, so It's still plausible that nicotine does not develop tolerance. Indeed, the effects that don't go away are the effects expected from nicotine.

  10. Oct 2019
    1. “Under 'zero tolerance' — which is the reason they are separating families in the first place

      "Zero Tolerance" its main goal is to deter and punish at a very high cost the families that are seeking a safe place to live. to send a message to those who are contemplating to come to the US to stop or they will take their children.

  11. May 2019
  12. Mar 2019
    1. Das sei, sagt Schaal, nichts anderes, als mit den Emotionen anderer nüchtern und sachlich umgehen zu lernen. Dazu gehöre, die Weltbilder der anderen nicht pauschal als verrückt zu diffamieren, sondern sich in „Frustrationstoleranz zu üben“, wie er es nennt.
    1. CONCLUSION: Tolerance to famotidine occurs during continuous administration for 14 days, as previously shown in ranitidine studies.

      This is good for my purposes. It means high doses can be taken for brain effects without disturbing stomach acidity. The question remains, of course, whether coinciding CNS tolerance develops.

  13. Jan 2019
    1. inverse agonist activity was not required for mu-opioid receptor up-regulation and supersensitivity.

      The question, then, is whether the opioid receptors are involved at all in this upregulation. For example, it could be mediated by TLR4 or filamin A.

    1. . Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects

      I would not expect doses this small to impact the opioid receptors.

    1. Treatment effects were more pronounced at discharge

      Symptoms in the treatment group continually improved, whereas symptoms in the placebo group plateaued. Thus, I'm interested in seeing a longer treatment period. Projecting from symptom scores, elimination of symptoms would occur in about 10 days.

    1. Mitragynine/Corynantheidine Pseudoindoxyls As Opioid Analgesics with Mu Agonism and Delta Antagonism, Which Do Not Recruit β-Arrestin-2

      I've found elsewhere that mu agonism combined with delta antagonism provides analgesia while minimizing tolerance.

  14. Nov 2018
    1. Nimodipine controlled the escalation of the morphine dose in 9 patients (65%), and placebo in 4 (28%), the difference being statistically significant (P=0.03). The dose of morphine was reduced from 313±52 to 174±33 mg/day (P<0.001) in the nimodipine group, and from 254±26 to 218±19 mg/day (not significant) in the placebo group.

      Nimodipine reduced morphine dose in already tolerant patients.

  15. Sep 2017
    1. This book is not about religion, although I talk about religion. It's about religious tolerance and the fight for human rights; the first battlefront in public discourse about human rights.

      Freedom of religion was the first base upon which other understandings of freedom have been built upon.

    2. This is the story of 16th century Europe, and the political earthquake that was protestantism. The overarching historical narrative unfolds around the lives of fictional characters who might have lived in this historic period.

      Follett's literary reenactment explores the intricacies of the Protestant Reformation through a cast of strategically diverse characters, whose stories span across multiple continents, nations, and cities. Each character is an important harbinger of larger historical trends. Within the masterfully established geo-political reality, each of their decisions serve to gradually reveal their distinct personalities and temperaments, belief systems and ideologies, and cultural identities.

    3. The real enemies, then as now, are not the rival religions. The true battle pitches those who believe in tolerance and compromise against the tyrants who would impose their ideas on everyone else—no matter what the cost.

      Reminiscent of our current geo-political climate. The extended cycles of history.

  16. Nov 2016
  17. Jun 2015
    1. Most people reading this will already be fairly tolerant. But there is a step beyond thinking of yourself as x but tolerating y: not even to consider yourself an x. The more labels you have for yourself, the dumber they make you.

      The only counter-argument that comes to mind for me didn't form itself until I had read this last paragraph a few times.

      If your identity marker connotes tolerance then it hopefully has the opposite effect. Insofar as the experience of marginalization promotes empathy such identities might be good evidence for intelligence, and I do think individuals who feel oppressed or marginalized tend to empathize with others who suffer for different, marginalized identities.

      These identities will only breed stupidity if the individual feels a competition for scarce resources that overwhelms their empathy, whence the perniciousness of the belief in zero sum attention economics as a greater threat to activism than inaction, ignorance, and exhaustion.