Just a few more interesting points...

Here is Haley's first paper about PON1, pyridostigmine and sarin (from 1999): https://pubmed.ncbi.nlm.nih.gov/10373407/
in which the abstract says: "A history of advanced acute toxicity after taking pyridostigmine was also correlated with low PON1 type Q arylesterase activity."

Pyridostigmine is used in advance of chemical nerve agent attack because it blocks the pathways that the nerve agents use. However, if it is used too late, once a person has already been exposed to sublethal amounts of nerve agent, it can exacerbate the effects of the agent.

I'm wondering whether the reason it [Mestinon] doesn't work for some as a treatment for POTS is because of their particular PON1 subtype and/or activity?
Maybe there's also an interaction with pesticides too (pet flea treatments)?

Not sure if findings here overlap?
https://academic.oup.com/jid/article/197/8/1171/903299?login=true

Gene Expression Subtypes in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis
Jonathan R Kerr, Robert Petty, Beverley Burke, John Gough, David Fear, Lindsey I Sinclair, Derek L Mattey, Selwyn C. M Richards, Jane Montgomery, Don A Baldwin,
Paul Kellam, Tim J Harrison, George E Griffin, Janice Main, Derek Enlander, David J Nutt, Stephen T Holgate
The Journal of Infectious Diseases, Volume 197, Issue 8, 15 April 2008, Pages 1171–1184, https://doi.org/10.1086/533453
 
Nope, they didn't find any association between ME and PON1, but of course that study was tiny.
https://www.ncbi.nlm.nih.gov/gene/5444
PON1 paraoxonase 1 [ Homo sapiens (human) ]
Gene ID: 5444, updated on 8-May-2022



Summary

This gene encodes a member of the paraoxonase family of enzymes and exhibits lactonase and ester hydrolase activity. Following synthesis in the kidney and liver, the enzyme is secreted into the circulation, where it binds to high density lipoprotein (HDL) particles and hydrolyzes thiolactones and xenobiotics, including paraoxon, a metabolite of the insecticide parathion. Polymorphisms in this gene may be associated with coronary artery disease and diabetic retinopathy. The gene is found in a cluster of three related paraoxonase genes on chromosome 7. [provided by RefSeq, Aug 2017]
 
If Sarin is indeed the cause of GWI, then I guess we need to figure out how Sarin exposure leads to a permanent CFS-like state.
I have been wondering if ciguatera might be a clue - this is a very potent toxin in fish. The disease it causes in humans if ingested sometimes leads to long term symptoms that I think are essentially ME/CFS. Both ciguatera and sarin seem to have long term anti-cholinesterase activity. If I'm understanding things correctly, the pyridostigmine only has quite short-term activity - it binds to the acetylcholinesterase molecule, preventing the long acting binders latching on, but then detaches.

The action of the ciguatera poison is understood a bit - it seems to involve dysfunction of the volted gated channels.

I'll be interested to see what others think
Neurological Disturbances of Ciguatera Poisoning: Clinical Features and Pathophysiological Basis, 2020, L'Herondelle et al
 
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Nope, they didn't find any association between ME and PON1, but of course that study was tiny.

And of course, the mechanism here is that the PON1 variant reduces the rate at which sarin is metabolized (so presumably increases the exposure to low-level sarin in the blood because it is cleared significantly slower), which doesn't have anything to do with ME in general. So you wouldn't expect anything to be found for this variant in ME on the basis of this study. Whatever shared mechanisms between GWI and ME there might be would have to be downstream.
 
parathion
Parathion
Parathion, also called parathion-ethyl or diethyl parathion and locally known as "Folidol", is an organophosphate insecticide and acaricide. It was originally developed by IG Farben in the 1940s. It is highly toxic to non-target organisms, including humans, so its use has been banned or restricted in most countries. Wikipedia
Only banned early 2002 in say Switzerland......
Parathion is a cholinesterase inhibitor. It generally disrupts the nervous system by inhibiting acetylcholinesterase. It is absorbed via skin, mucous membranes, and orally. Absorbed parathion is rapidly metabolized to paraoxon, as described in Insecticidal activity. Paraoxon exposure can result in headaches, convulsions, poor vision, vomiting, abdominal pain, severe diarrhea, unconsciousness, tremor, dyspnea, and finally lung-edema as well as respiratory arrest. Symptoms of poisoning are known to last for extended periods, sometimes months. The most common and very specific antidote is atropine, in doses of up to 100 mg daily. Because atropine may also be toxic, it is recommended that small frequently repeated doses be used in treatment. If human poisoning is detected early and the treatment is prompt (atropine and artificial respiration), fatalities are infrequent. Insufficient oxygen will lead to cerebral hypoxia and permanent brain damage. Peripheral neuropathy including paralysis is noticed as late sequelae after recovery from acute intoxication. Parathion and related organophosphorus pesticides are used in hundreds of thousands of poisonings annually, especially suicides.[9] It is known as Schwiegermuttergift (mother-in-law poison) in Germany. For this reason, most formulations contain a blue dye providing warning.

Parathion was used as a chemical warfare agent, most notably by an element of the British South Africa Police (BSAP) attached to the Selous Scouts during the Rhodesian Bush War. They used it to poison clothing that was then supplied to anti-government guerrillas. When the enemy soldiers put on the clothes, they were poisoned by absorption through the skin.[10][11][12]

Based on animal studies, parathion is considered by the U.S. Environmental Protection Agency to be a possible human carcinogen.[13] Studies show that parathion is toxic to fetuses, but does not cause birth defects.[14]

It is classified by the United Nations Environment Programme (UNEP) as a persistent organic pollutant[citation needed] and by the World Health Organization (WHO) as Toxicity Class Ia (extremely hazardous).[citation needed]

Parathion is toxic to bees, fish, birds, and other forms of wildlife.[14]
 
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Sarin Gas as blamed for Gulf War Illness - BBC








I don't know whether this will hold up, but it makes sense. I wonder what Wesseley and his mates in the British defence forces think of this.

This US article gives a few more details along with background information
"Researchers think they've found the cause of Gulf War Illness"
https://www.military.com/daily-news...k-theyve-found-cause-of-gulf-war-illness.html

A Twitter thread with a few extracts from the two articles above
 
The Gulf War Illness and the Iraqi population, 2023

A brief note highlighting that the Iraqi population was also exposed to sarin when coalition forces bombed storage depots and Iraqi Kurds were also deliberately exposed by their government. The Swedish author notes that these people report similar symptoms to the coalition forces, and calls for investigations and support.

It's an important observation from an humanitarian perspective, but also because these exposures could narrow down the possible causes of GWI.
 
There have been a few instances of mass sarin exposure. Here's the event list from the history section of the Sarin Wikipedia page, with bolding added for the events where a large number of people may have been exposed, comparable to the exposure seen during the Gulf War in 1991:
  • 1950s (early): NATO adopted sarin as a standard chemical weapon. The USSR and the United States produced sarin for military purposes.
  • 1953: 20-year-old Ronald Maddison, a Royal Air Force engineer from Consett, County Durham, died in human testing of sarin at the Porton Down chemical warfare testing facility in Wiltshire, England. Ten days after his death an inquest was held in secret which returned a verdict of misadventure. In 2004, the inquest was reopened and, after a 64-day inquest hearing, the jury ruled that Maddison had been unlawfully killed by the "application of a nerve agent in a non-therapeutic experiment".[48]
  • 1957: Regular production of sarin chemical weapons ceased in the United States, though existing stocks of bulk sarin were re-distilled until 1970.[30]
  • 1970: During Operation Tailwind, America may have deployed Sarin gas against the Communist Pathet Lao, alongside American defectors to the Laotian Communists.[49]
  • 1976: Chile's intelligence service, DINA, assigned biochemist Eugenio Berríos to develop Sarin gas within its program Proyecto Andrea, to be used as a weapon against its opponents.[50] One of DINA's goals was to package it in spray cans for easy use, which, according to testimony by former DINA agent Michael Townley, was one of the planned procedures in the 1976 assassination of Orlando Letelier.[50] Berríos later testified that it was used in a number of assassinations and it was planned to be used to kill inhabitants, through poisoning the water supply of Argentine capital Buenos Aires, in case Operation Soberanía took place.[51][52]
  • March 1988: Halabja chemical attack; Over two days in March, the ethnic Kurdish city of Halabja in northern Iraq (population 70,000) was bombarded by Saddam Hussein's Iraqi Air Force jets with chemical bombs including sarin. An estimated 5,000 people died, almost all civilians.[53]
  • April 1988: Iraq used Sarin four times against Iranian soldiers at the end of the Iran–Iraq War, helping Iraqi forces to retake control of the al-Faw Peninsula during the Second Battle of al-Faw.
  • 1993: The United Nations Chemical Weapons Convention was signed by 162 member countries, banning the production and stockpiling of many chemical weapons, including sarin. It went into effect on April 29, 1997, and called for the complete destruction of all specified stockpiles of chemical weapons by April 2007.[54] When the convention entered force, the parties declared worldwide stockpiles of 15,047 tonnes of sarin. As of November 28, 2019, 98% of the stockpiles have been destroyed.[55]
  • 1994: Matsumoto incident; the Japanese religious sect Aum Shinrikyo released an impure form of sarin in Matsumoto, Nagano, killing eight people and harming over 500. The Australian sheep station Banjawarn was a testing ground.
  • 1995: Tokyo subway sarin attack; the Aum Shinrikyo sect released an impure form of sarin in the Tokyo Metro. Thirteen people died, and over 6,200 people received injuries.[56][57]
  • 2002: Pro-Chechen militant Ibn al-Khattab may have been assassinated with sarin by the Russian government.[58][59]
  • May 2004: Iraqi insurgents detonated a 155 mm shell containing binary precursors for sarin near a U.S. convoy in Iraq. The shell was designed to mix the chemicals as it spun during flight. The detonated shell released only a small amount of sarin gas, either because the explosion failed to mix the binary agents properly or because the chemicals inside the shell had degraded with age. Two United States soldiers were treated after displaying the early symptoms of exposure to sarin.[60]
  • March 2013: Khan al-Assal chemical attack; Sarin was used in an attack on a town west of Aleppo city in Syria, killing 28 and wounding 124.[61]
  • August 2013: Ghouta chemical attack; Sarin was used in multiple simultaneous attacks in the Ghouta region of the Rif Dimashq Governorate of Syria during the Syrian Civil War.[62] Varying[63] sources gave a death toll of 322[64] to 1,729.[65]
  • April 2017: Khan Shaykhun chemical attack: The Syrian Air Force released sarin gas in rebel-held Idlib Province in Syria during an airstrike.[66][67]
  • April 2018: Victims of the Douma chemical attack in Syria reported to have symptoms consistent with exposure to sarin and other agents. On July 6, 2018, the Fact-Finding Mission (FFM) of the OPCW published their interim report. The report stated that, "The results show that no organophosphorous [sarin] nerve agents or their degradation products were detected in the environmental samples or in the plasma samples taken from alleged casualties". The chemical agent used in the attack was later identified as elemental chlorine.[68]
  • July 2023: The U.S. destroyed the last of its declared chemical weapons, a sarin nerve agent-filled M55 rocket, on July 7, 2023.[69]
 
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