Cytokine storm

If you do the "mouseover" thingy on this strip, you get a possible way to avoid the cytokine storm..

http://xkcd.com/574/

IIRC cytokine storm is also the mechanism implicated in Sin Nombre hantavirus fatalities.

There is an interesting flu cluster on central CA;
a Youth Academy (residential) near San Lois Obispo.

They reported two probable cases a few days ago, followed by two more cases - health workers who visited the camp.
None confirmed yet. Sick students were isolated.

They are now reporting 50 possible cases.
I'm inferring 300-400 students total given their graduation rate.

Steinn: I think we will be seeing more examples of transmission as the state labs are able to do the testing. California just got their PCR up with the new primers, so this is probably the leading edge of an accelerating phase. Maybe not, of course. This virus is unpredictable.

So Revere, I can find no main cause of death among those that passed. I know 1 or 2 in the briefing went from extreme temperatures-104F. One was dehydration. But those seem to be the exception rather than the rule. I didnt see pneumonias, in fact there was a complete lack of them if I read the reports right. Organ failure? But is that really like main organs when they say that or does that include the lung?

Is there a main cause of death?

I havenât seen a specific cause of death mentioned, but my guess would be that it is multiple organ failure secondary to mitochondria shut-down.

My hypothesis is that is the âgenericâ cause of death during extreme immune system activation, mitochondrial failure. Which organ fails first is a detail of that individualâs idiosyncratic physiology.

I talk about the mechanism in my blog of about a year ago (in a lot more detail and with links to the literature). What happens is the very high levels of NO from all the iNOS increase the ATP level via sGC. This has been demonstrated by muscle biopsy of people in sepsis. They had higher skeletal muscle ATP levels than did controls who were not in sepsis. This is good, and a generic need during an infection, it cranks up autophagy which is necessary to clear out everything that is in cells that doesnât belong, like bacteria. High ATP is necessary to clear intracellular infections like TB and Lyme.

The high ATP comes from glycolysis, and the high ATP level mostly shuts down the mitochondria (which is good because they canât operate in a high NO environment). To support enough glycolysis, the body needs gigantic amounts of glucose, more than can be supplied via normal liver metabolism. What the body does is turn the muscles to alanine, then turn the alanine into glucose. Once the glucose is turned into lactate, there isnât enough mitochondrial capacity to recycle it back into glucose via the Cori cycle, so the body disposes of it by turning it into fat. During sepsis you lose muscle and gain fat. You can lose tens of pounds of muscle in a few days. That is because making ATP from glucose is so inefficient.

If there is enough glucose to support enough glycolysis, then the ATP level remains high and the mitochondria remain off. If there isnât enough glucose, then the ATP level falls and the mitochondria turn on. This presents a problem. In the high NO environment from iNOS, cytochrome c oxidase is blocked by NO and doesnât reduce O2 to H2O. The mitochondria need to remove this NO to unblock cytochrome c oxidase. To do that they generate superoxide. Superoxide reacts with NO at near diffusion limited kinetics. Mitochondria have unlimited capacity to produce superoxide. They produce superoxide whenever they are called on to produce power, and the respiration chain is reduced. The respiration chain only gets reduced when the electrons canât flow off it and onto cytochrome c oxidase. When it is blocked with NO, then superoxide is produced, the superoxide pulls down the NO level, the respiration chain becomes unblocked and ATP generation can occur at a high rate.

The superoxide is generated on the inside of the mitochondria matrix where there is the mitochondrial superoxide dismutase, MnSOD. This reacts with superoxide at near diffusion limited kinetics too. There is a delicate balance between the superoxide reacting with NO and forming peroxynitrite and the superoxide being dismutated by MnSOD. Peroxynitrite can nitrate proteins, and in human MnSOD the nitration of a single tyrosine causes inhibition. In bacterial FeSOD (which is highly homologous to hMnSOD), there is no inhibition when 8 out of 9 tyrosines are nitrated. Since both enzymes are highly homologous, they evolved from a common ancestor. Since FeSOD is not inhibited by nitration, inhibition by nitration is not an inherent property of SOD. If bacteria could evolve resistance to inhibition by nitration, so could hMnSOD. It didnât, implying that the inhibition by nitration isnât a bug, it is a feature. I think that feature is to provide a shut-off mechanism when mitochondria start to produce too much superoxide.

Organisms can tolerate the loss of a few percent of their mitochondria; they cannot tolerate a few percent of their mitochondria making superoxide at their maximum rate.

Once too many mitochondria get shut off, the ATP level in the cells irreversibly falls and the cell dies, if too many cells die, the organ dies, if too many organs die, the organism dies. Once that happens, death is irreversible. I think that is why you feel so weak during immune system stimulation, it is to prevent you from using ATP because the threshold for irreversible damage is much lower.

The only ways I can think of to reduce this is via prevention. Prevent the very high NO levels in the first place, increase pre-exposure mitochondria number to provide more of a reserve, reduce ATP consumption as much as possible (i.e. respirators reduce the metabolic load on the lung muscles and so reduce their ATP requirements), supply glucose intravenously (to hyperglycemic levels if possible), remove lactate by dialysis with urea containing fluids, give insulin to get the glucose into the cells at high enough rates for them to use it. You really want to prevent the ATP level from falling because once it does, it is too late and you are SOL.

So Deadie, what you are saying is that the Adenosine levels dropped straight through the floor, the cells mitochondria couldnt generate their normal functions and basically cell death occurs? Or do I have that in reverse?

ATP, not adenosine. ATP is adenosine tri phosphate. It is adenosine with 3 phosphates attached to it.

It is the mitochondria's "normal" function to turn off when they make too much superoxide for the NO environment they are in. All mitochondria eventually turn off. Either they turn off by making too much superoxide which nitrates things and inhibits them, or they make not enough superoxide in which case cytochrome c is released from the inter-membrane space which causes them to make more superoxide. The only way they canât make any superoxide is when the mitochondria potential falls so much that they canât make any ATP. Then they start consuming ATP to maintain the mitochondrial potential.

Mitochondria turning off is like a circuit breaker. There are multiple control mechanisms that do it, some are reversible, but reversing them depends on a supply of ATP. If there isnât any, either from other mitochondria or from glycolysis, then the cell is SOL. The final turn-off is like a fuse, a one time irreversible turn off. Mitochondria have a finite lifetime, the longest lived are in the CNS. In rats they last about a month.

That irreversible turn-off is what happens if you push them too hard for too long. I think that normal vigorous aerobic exercise does that to the fraction of mitochondria that are the most marginal. They get turned off and that is what causes the fatigue of very vigorous exercise. Some get turned back on, the few percent that donât get recycled that night when you are sleeping and replaced with fresh new mitochondria. It isnât the exercise per se that causes increased endurance, it is the replacement of the stressed out mitochondria (plus some extra) that does. Without enough rest for mitochondria replacement, that mitochondria increase canât happen and people end up with not enough mitochondria. I think that is the mechanism for chronic fatigue syndrome; immune system stimulation under high stress conditions. The high stress lowers the NO level, disinhibits NFkB, you get a mini cytokine storm, if you canât get your NO level high enough to replace the mitochondria that are damaged (it is NO that triggers mitochondria biogenesis) because of the chronic stress, you end up with not enough mitochondria and perpetual low NO and the low mitochondria number becomes perpetual.

I think that is the mechanism for gulf war syndrome, vaccinations with very harsh agents (i.e. anthrax) while in a war zone (a very high stress environment). Keep the stress and immune system stimulation up for a few weeks (via multiple vaccinations) and you end up with permanently depleted mitochondria. I also call that the âlow NO ratchetâ because with each instance of immune system stimulation the NO level can ratchet lower (due to feedback inhibition due to the high NO from the iNOS).

Well I cant speak to GW Syndrome, but I can tell you that it would explain a lot of the veterans and their "depression". I was in Central America during Ollies Trolley and for about 8 months I got about 4 hours of sleep and cat naps. I could sleep on a fence post if someone propped me up on it. But, some that had to get that "8 hours" were some of the worst performers I have ever seen. Chronically late, kind of in a fuzz and normally we would chalk it off to the crud but even that ended within a week or so.

It would also account for the pneumonias related to flu down there. High stress, lack of sleep, and keyed up even in your sleep. I could drop off that fence post into a firing position in under a second. Lasted for years after I got out. Noise that wasnt normal, I would flip out of the bed with a .45 ready to rock. I have seen those vaccinations get out of hand too. Hazing by drill instructors, just barely enough sleep, bed drills and midnight PT and then the next day vax. The used to use those air cannons until HIV came along, then it was back to the needles. Saw a lot of people end up in the hospital the next day and in there for weeks afterwards.

I knew the ATP was the A. Triphosphate. But I guess if you are right (can you prove it?) this might also explain how humans really die. It explains the situation for many things really. Old people get stressed, they dont eat right, they dont sleep but about 5 hours a day and then someone gives them a vax, stresses them out about paying for rent, electric. Bingo? Its like winning the death lottery.

Interesting shit Deadie.