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Showing posts with label Broccoli. Show all posts
Showing posts with label Broccoli. Show all posts

Friday 13 February 2015

Broccoli soup at school – washed down with a little grapefruit juice

A growing number of readers have discovered the remarkable effects of a specific preparation of broccoli sprout powder.  It was my suggested method to match the Sulforaphane, made in the lab at Johns Hopkins, and recently trialed with great results in young adults with autism.

I did mention to therapists working with Monty, aged 11 with ASD, what a surprise there would be at the local special school if they served up some extra-potent broccoli soup for lunch one day.  There would be some very bemused teachers and parents.  It would also be the world's cheapest randomized trial on 100 people and the fastest. (you would just have to note down who actually ate the soup, but I think it would be obvious later)

Since another reader stumbled upon the anti-oxidant capability of grapefruit juice the other day, I would add some of that to the school lunch.  Preferably pink grapefruit, since they also would have a dose of lycopene, another potent antioxidant.

As fate would have it, a trial is underway with a jar of the aforementioned broccoli powder.  It is not at the local special school, but at a private center for speech & behavioral therapy.  

A reader of this blog has told someone else, who then tried it on their child and now someone else has bought a jar to try on the children at the center.

Of course, in a litigious country, nobody would dream of doing this; but in some countries, common sense still prevails.

I do hope the center keeps a note of who tried it and what the effects were, so we can have some statistics.  The good thing is that because it is so fast-acting, the therapist will observe the effects unfolding within the very same session.

Since the main effects are on mood and speech, a speech therapist is probably the best person to observe and quantify the effect.

In the kind of children who attend such centers, where autism is a disability rather than a difference, I think the response rate with be really high.  I would guess 70+%.  If they want to write up a report, I will be delighted to post it on this blog.

Anyway, I give them 10 out of 10 for initiative.









Thursday 4 December 2014

PolyPill Reformulated

One reader of this blog, who found that 2.5ml of the Australian broccoli sprout powder, I suggested in an earlier post, works wonders for her son (40 minutes after the first dose), asked if I was going to include it in my Polypill.

Then yesterday Monty’s assistant at school asked to take some powder to try on another small child with ASD.  Today she tells me that the same positive result was repeated, in half an hour.

So I decided it is time to update the PolyPill.

I did tell the researcher, I was in touch with at John’s Hopkins, that it appears you can reliably make Sulforaphane at home, without your own laboratory and a deep freezer.  I think they somehow prefer things to be complicated and hard to access.

It does amaze me how people are not adopting, even super-safe, ideas that might help their child.  Many tens of thousands of parents affected by ASD must have read the stories in their newspapers about Broccoli (Sulforaphane) and autism.  How come almost nobody has made it work at home? Or at least, that is what it seems like if you look on Google.  People write about having read about it.  They usually then say, “ah well, Johns Hopkins say it does not work at home and you need a standardized dose”.

Sometimes you need to think for yourself.

Behind all this is the belief that “doctor” always knows best.  Most people are terrified of “experimenting” on their child.  Those that actually do this, are nearly exclusively in the US, with their DAN doctors.  They seem to give up after a year or two and accept whatever is left of the autism.

By the time the child is older and the parents are less worried about them trying drugs, they have given up and accepted the “inevitable”.


Reader feedback

When I started this blog, I rather optimistically expected to join forces with many other motivated, scientifically knowledgeable, parents.

This blog is visited 10,000 times a month, but I can count on two hands the number of people that have acted on it and shared their experience on/off line.  There have been some really great outcomes, which is wonderful for those concerned. (great outcomes = big improvements)

Without wanting to be biblical, but having recently sat through the film, Pulp Fiction, with Monty’s older brother, this does sum things up nicely:-

"Ask and it will be given to you; seek and you will find; knock and the door will be opened to you”

It just might take you a lot more work than you expected.


PolyPill

Regular readers will have noticed that the Polypill is my formulation for treating classic early-onset autism.  It is a combination of the clever ideas of others, some developed a little further, and some ideas of my own, based on the literature.

Many drugs and supplements have some impact on autism.  Some make it better, some make it worse, but most have no effect whatsoever.

Drugs and supplements can have side effects and they can react with each other.  So it is wise to use only those with a major impact.


Broccoli Sprout Powder

The most surprising ingredient I have tested is freeze dried broccoli powder from Australia.  Who would have thought that 2.5ml of this green powder would have an effect on autism.  But it does, and without any of the extra myrosinase, that I had expected to need. Johns Hopkin’s version is a deep frozen product, made after reacting broccoli sprouts with daikon radish sprouts in the laboratory.

All of people working with Monty, aged 11 with ASD, have noticed the difference, so it really is not a placebo effect


Incremental changes

·        Much more unprompted speech (> 50% increase)

·    He started to talk to animals and continues to do
·     He opened the car window to say hello and good bye to someone he recognized passing by – totally unheard of behavior

·        Increased awareness and presence of his surroundings

·        Now, while the TV news is on, Monty is reading aloud the news ticker at the bottom of the screen.  Before, the TV news was just “wallpaper”, unless there were some explosions  or other excitement.

·        Improved mood and mild euphoria

·        The broccoli powder still produces euphoria
·        In other people it may just improve mood

The good news is that Broccoli really is more of a food than a drug and so should not be harmful; although all kinds of things can interact in strange ways.  For example, vitamin C with cinnamon is not a good idea.


Method of action

As usual, I do like to know how and why things work.

The broccoli sprouts contain many substances, at least two of which might be involved:-

1.     Indole-3-carbinol (I3C).  I3C has some extremely interesting properties for both cancer and autism.  I3C up-regulates a protein called PTEN, encoded by the PTEN gene.  PTEN is an “autism gene”.

2.     Sulforaphane (SFN) is the chemical that John’s Hopkins think is the “active” ingredient of broccoli.

SFN is an activator of Nrf2, a “redox switch”.  This release of Nrf2 has a known on/off effect on about 300 genes involved in the response to oxidative stress.

SFN is also an HDI, or an inhibitor of HDAC (Histone Deacetylase)

HDIs have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics.

Interestingly, we learn from Wikipedia:- 

“To carry out gene expression, a cell must control the coiling and uncoiling of DNA around histones. This is accomplished with the assistance of histone acetyl transferases (HAT), which acetylate the lysine residues in core histones leading to a less compact and more transcriptionally active chromatin, and, on the converse, the actions of histone deacetylases (HDAC), which remove the acetyl groups from the lysine residues leading to the formation of a condensed and transcriptionally silenced chromatin. Reversible modification of the terminal tails of core histones constitutes the major epigenetic mechanism for remodeling higher-order chromatin structure and controlling gene expression. HDAC inhibitors (HDI) block this action and can result in hyperacetylation of histones, thereby affecting gene expression.

So it looks like those little broccoli sprouts might be initiating some very clever science, perhaps even some primitive gene therapy.













Conclusion

There are still plenty more ideas waiting to test, so there will no doubt be more updated versions of the PolyPill in future.

It does look like there may be more food ingredients and not just drugs, which is not what I expected.










Sunday 9 November 2014

Dr Dolittle, Autism and the Broccoli Sprouts


In the Dr Dolittle books and subsequent films, a man develops the power to communicate with animals.  It seems that one effect of broccoli sprout powder (and we assume Sulforaphane), in autism,  is an urge to talk, not only to humans, but also to animals.

Monty, aged 11 with ASD, took his first dose of 2.5ml of broccoli powder (Supersprouts brand from Australia) and after about half an hour developed euphoria.  The laughter later subsided and throughout the day he was very talkative.  This was relevant speech and not repeating things he had heard previously.  Other than the euphoria, which is the word chosen by elder brother Ted, a nice development was the desire to communicate with the animal world.


After a visit to his favourite ice cream shop, he looked up and saw the big railway bridge. “Bye bye railway station” commented Monty.  Walking up the hill we first passed a kitten, playing by the verge, “Hello baby kitten! Bye bye baby kitten!”  Then a big dog appeared “Hello big white dog and a woman! Bye bye big white dog and woman!”.  This was all rather unexpected.

The next day, another 2.5ml of broccoli powder and the same result.  Euphoria and lots of talking.

Then I decided to start experimenting with the dose.  I gave 1.25ml three times a day.

After the breakfast dose, no euphoria but still plenty of speech.  After lunch, the second dose and the return of mild euphoria.  After the evening dose, more euphoria.  The half-life of Sulforaphane in people is claimed to be about two hours.

Based on this limited experience, I think 2.5ml is about right.  There is no need for more.
  

Cost

I paid AU$ 110 (US$ 95 or GBP 60) for 300g of broccoli powder including shipping.

2.5ml of powder weighs 1.1g.  So using that daily dose of 2.5ml the cost would be 35 US cents (22 UK pence).

My earlier assumption was that a dose of about 18 g of fresh sprouts would produce the required level of Sulforaphane.  In theory, this would be 3 ml of broccoli powder, if it had 100% of the right enzymes in it and none of the bad stuff (called ESP, from the last post).  I was quite surprised at the effect of 2.5ml.  Johns Hopkins told me that most broccoli powders are no good; that is why I looked around before choosing the Australian product.

As a dosage comparison, this supplement is sold in Australia with a suggested daily dose of 5g, which equates to about 11 ml. 

So my “autism dose" looks quite conservative.  I think even half the suggested adult dose would make Monty completely hyper.

Note that the dose of the anti-oxidant NAC used in autism trials is 4X the usual adult dose of NAC and 2X the adult dose for adults with COPD (severe asthma).


The effect on an adult

I tried a scaled up dose myself, but sadly no euphoria followed.

  
Note
Monty is already taking a potent anti-oxidant called NAC, which has been investigated in an autism trial at Stanford.
The broccoli sprouts produce a substance called Sulforaphane (SFN).  This substance activates Nrf2 which upregulates “phase II enzymes”; they increase the body’s antioxidant response.  SFN is also an inhibitor of HDAC (Histone Deacetylase) and this may give SFN the ability to target aberrant epigenetic patterns.
SFN is therefore a secondary anti-oxidant.  It has been shown to improve the body’s response to cancer and environmental toxins.  The chemoprotective properties may result from SFN’s epigenetic properties or the anti-oxidant properties.
SFN was shown in a recent study at Johns Hopkins to improve autism in young adults.  It is not known definitively why it was effective.

Conclusion
My experiment indicates that, in classic autism, Sulforaphane (SFN) does provide a marked and immediate benefit over NAC alone, which is what I set out to determine.

Australian broccoli sprout powder appears to be a relatively cheap and effective way to make SFN at home. 



Thursday 6 November 2014

Sulforaphane, Epithiospecifier Proteins (ESP) or just Sulforadex for Autism




  
One reader of the last post on Sulforaphane raised the issue of whether she should cook her broccoli sprouts, to optimize her autism therapy.

This seemed a bit strange, since even the researchers at Johns Hopkins are eating their sprouts raw.  She does have a valid point.  It seems that while sprouts have large amounts of glucoraphanin and the required enzyme myrosinase, they also have something called Epithiospecifier Protein (ESP).  If there is much ESP present, instead of Sulforaphane you get a very similar compound called Sulforaphane Nitrile.  You can see that the “S” has been replaced by an “N”.




All is not lost, for those of you with sprouts growing in the kitchen.
Further research showed that the concentration of ESP in the sprouts peaks on the second day and that by day 5 has dropped dramatically.





It was also showed that raising the temperature of the sprouts to 60 degrees Celsius deactivated the ESP.  Heating Broccoli florets much beyond this then reduced the Sulforaphane produced, but not heating the sprouts.


Abstract
Sulforaphane, an isothiocyanate from broccoli, is one of the most potent food-derived anticarcinogens. This compound is not present in the intact vegetable, rather it is formed from its glucosinolate precursor, glucoraphanin, by the action of myrosinase, a thioglucosidase enzyme, when broccoli tissue is crushed or chewed. However, a number of studies have demonstrated that sulforaphane yield from glucoraphanin is low, and that a non-bioactive nitrile analog, sulforaphane nitrile, is the primary hydrolysis product when plant tissue is crushed at room temperature. Recent evidence suggests that in Arabidopsis, nitrile formation from glucosinolates is controlled by a heat-sensitive protein, epithiospecifier protein (ESP), a non-catalytic cofactor of myrosinase. Our objectives were to examine the effects of heating broccoli florets and sprouts on sulforaphane and sulforaphane nitrile formation, to determine if broccoli contains ESP activity, then to correlate heat-dependent changes in ESP activity, sulforaphane content and bioactivity, as measured by induction of the phase II detoxification enzyme quinone reductase (QR) in cell culture. Heating fresh broccoli florets or broccoli sprouts to 60 degrees C prior to homogenization simultaneously increased sulforaphane formation and decreased sulforaphane nitrile formation. A significant loss of ESP activity paralleled the decrease in sulforaphane nitrile formation. Heating to 70 degrees C and above decreased the formation of both products in broccoli florets, but not in broccoli sprouts. The induction of QR in cultured mouse hepatoma Hepa lclc7 cells paralleled increases in sulforaphane formation.



So it would seem that if you want to eat the sprouts raw, you need to wait for five days before consuming them.  Not good to eat them when two days old.

If you cook them, you do risk affecting the myrosinase and then you might need to add back some more from another source, just as Nicole mentioned in her comment.  But some research implies the sprouts are heat stable.

This all starts to get rather complicated.

Personally I decided to buy freeze dried broccoli sprout powder from Australia.  They claim to measure for ESP, and there is very little.  Their myrosinase has not been deactivated in processing.

If true, their product is near ideal.  Is say near ideal, because one spoonful also has the taste of a plateful of broccoli.

Mine has now arrived and so I will serve one level teaspoonful a day.

Other research actually suggested that Daikon radish may be event better than broccoli.  Johns Hopkins chose to patent the broccoli.  In their research compound, they reacted broccoli sprouts with daikon radish sprouts to make a standardized Sulforaphane which is then freeze dried and kept frozen.

RADISH SPROUTS VERSUS BROCCOLI SPROUTS: A COMPARISON OF ANTI-CANCER POTENTIAL BASED ON GLUCOSINOLATE BREAKDOWN PRODUCTS





Daikon powder is readily available and is a potent source of heat stable myrosinase.

So I will seek to get the optimal output from my Australian sprout powder by adding a dash of Daikon powder.


A better way?  Sulforadex

This kitchen chemistry may all seem rather haphazard and indeed it is.

Rather than try and make 8 mg of Sulforaphane in your kitchen, would it not be better to buy 8 mg of standardized heat stable Sulforaphane in the pharmacy?

Sulforadex is potentially exactly that; it is an analog of Sulforaphane.  Trials have started in humans and at very much higher doses to check for toxicity and side effects.

Here is a link to the Phase 1 trial:-


The only questions I have are:- is anyone 100% certain that Sulforaphane is the only beneficial compound produced by eating broccoli?  Is Sulforaphane the only compound present in Johns Hopkin’s frozen capsules?  When they react their broccoli sprouts with daikon sprouts in the lab, there are other compounds produced.

Monty, aged 11 with ASD, is by now remarkably accommodating when it comes to downing unappetizing potions.  NAC tastes pretty bad, unless you use the more expensive effervescent variety.  But this pales in comparison to what a spoonful of broccoli sprout powder tastes like (and looks like).

They also make this powder in capsule form, for those who can swallow them. 

The more appetising anti-oxidant would be a bar of high flavanol dark chocolate, as we discovered in the previous post.  As well as tasting better, it may quite possibly be just as effective.







Tuesday 4 November 2014

Why not Cocoa Flavanols for Autism?







  
Judging by my blog statistics, lots of people are interested in broccoli (Sulforaphane) to treat autism.  Thanks to the patents held by Johns Hopkins, you can expect to hear much more about Sulforaphane in the coming years.

Meanwhile, Columbia University and Mars, the chocolate people, have released a study showing that “flavanoids” in cocoa can do wonders for memory loss in older people.  In effect, they can restore memory in 60 years olds to where it was 20 or 30 years earlier.

If you take a step back and look at what is known by science about oxidative stress and antioxidants, all will become much clearer.


Oxidative Stress Pioneers

In an earlier post we met Paul Talalay, a German-American, who worked at Johns Hopkins.  He specializes in foods that protect you from cancer.  He is Mr Broccoli. 

It turns out that perhaps the real pioneer in this field is a 100% German, called Helmut Sies, who also studies foods that act as antioxidants and nutrients that provide protection from cancer.  We have his very detailed diagram below, that explains the relationship between many of the factors involved in oxidative stress.  I wish I had found it earlier.  I added the six outer boxes.

If you want to read clever studies about this subject, just include Helmut Sies in your search; for example “selenium Helmut Sies”.


Redox Pioneer: Professor Helmut Sies













On this graphic you will see GSH (Glutathione).  When you take NAC (N-acetylcysteine) you directly raise the level of GSH.  When eat broccoli you activate Nrf2, which is a Redox switch, just under the traffic light in the graphic.

When you eat certain flavonoids, like Cocoa, or carotenoids like lycopene (found in tomatoes), you again promote the anti-oxidative free radical scavenger effect.  Look in the blue boxes under diet.

Not on the diagram, we also have flavonolignans which are natural phenols composed of a part flavonoid and a part lignan. As pointed out in a comment in the last post by Seth Bittker, one interesting  flavonolignan is Silibinin, which has anti-oxidant and chemoprotective effects

Note the presence of (Coenzyme) Q10 in the yellow box.  This is part of the mitochondrial cocktail suggested by Dr Kelley from Johns Hopkins for regressive autism.  Q10 is depleted by statins.

Glutathione peroxidases, in the yellow box, are also very interesting.  These are selenium-containing enzymes.  GPx (x goes from 1 to 8)  catalyze the reduction of H2O2 and organic hydroperoxides to harmless products. This function helps to maintain membrane integrity and to reduce further oxidative damage to molecules such as lipids and lipoproteins with the associated increased risk of conditions such as atherosclerosis.  It appears GP1 may be defective in autism and this is contributes to increased oxidative stress.  This area has been well studied due to its impact on heart disease.  You appear to be able to counter the lack of GPx with yeast-bound selenium, other forms of selenium do not work, due to a lack of bioavailability. A post will appear just on Selenium.

There are several other potent (exogenous) antioxidants that we have come across:-

  • Alpha lipoic acid also known as ALA or Tioctic acid (found  in Dr Kelley’s cocktail)
  •   L-Carnosine (studied by Dr Chez )
  •  Vitamin C (suggested by many, including Dr Kelley)


Another day, another anti-oxidant

In human health, two well used anti-oxidant drugs are Alpha lipoic Acid (ALA,  also known as Tioctic acid) and N-acetyl cysteine (NAC).  They share many similar effects.

  •       Potent antioxidant
  •       Increase insulin sensitivity
  •       Improve memory in those with mild cognitive          impairment
  •       May lower blood pressure
  •       Improve behavior in autism

NAC is widely used to treat Chronic obstructive pulmonary disease (COPD) and ALA is used to treat diabetic neuropathy. Perhaps they could be interchanged

·        NAC has a chemoprotective effect
·        ALA has been shown to induce cell cycle arrest in  human breast cancers      cells

Back to Cocoa Flavanols and Mars

This flurry of activity was driven by a well publicized study done at Columbia University Medical Center (CUMC), using a high cocoa flavanol concentration drink provided by Mars.


   
In the CUMC study, 37 healthy volunteers, ages 50 to 69, were randomized to receive either a high-flavanol diet (900 mg of flavanols a day) or a low-flavanol diet (10 mg of flavanols a day) for three months. Brain imaging and memory tests were administered to each participant before and after the study. The brain imaging measured blood volume in the dentate gyrus, a measure of metabolism, and the memory test involved a 20-minute pattern-recognition exercise designed to evaluate a type of memory controlled by the dentate gyrus.
The high-flavanol group also performed significantly better on the memory test. “If a participant had the memory of a typical 60-year-old at the beginning of the study, after three months that person on average had the memory of a typical 30- or 40-year-old,” said Dr. Small. He cautioned, however, that the findings need to be replicated in a larger study—which he and his team plan to do.


This is very impressive.  But how do the other anti-oxidants compare?

Well, without funding from Mars, researchers only managed the money to test ALA and NAC on mice; but as you might expect, the result was similar.


Chronic administration of either LA or NAC improved cognition of 12-month-old SAMP8 mice in both the T-maze footshock avoidance paradigm and the lever press appetitive task without inducing non-specific effects on motor activity, motivation to avoid shock, or body weight. These effects probably occurred directly within the brain, as NAC crossed the blood-brain barrier and accumulated in the brain. Furthermore, treatment of 12-month-old SAMP8 mice with LA reversed all three indexes of oxidative stress. These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants.



Cocoa Flavanols are good for your heart

This is also good news, but it does seem that antioxidants are generally very good for your heart.

First cocoa.

In this study blood pressure, glucose, insulin and cholesterol were all markedly affected for the better by the cocoa as was cognitive function.

This is great;  but it is what Helmut Sies has been telling the world for many years.


Abstract—Flavanol consumption is favorably associated with cognitive function. We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment. We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing _990 mg (high flavanols), _520 mg (intermediate flavanols), or _45 mg (low flavanols) of cocoa flavanols per day. Cognitive function was assessed by Mini Mental State Examination, Trail Making Test A and B, and verbal fluency test. At the end of the follow-up period, Mini Mental State Examination was similar in the 3 treatment groups (P_0.13). The time required to complete Trail Making Test A and Trail Making Test B was significantly (P_0.05) lower in subjects assigned to high flavanols (38.10_10.94 and 104.10_28.73 seconds, respectively) and intermediate flavanols (40.20_11.35 and 115.97_28.35 seconds, respectively) in comparison with those assigned to low flavanols (52.60_17.97 and 139.23_43.02 seconds, respectively). Similarly, verbal fluency test score was significantly (P_0.05) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols (27.50_6.75 versus 22.30_8.09 words per 60 seconds). Insulin resistance, blood pressure, and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups. Changes of insulin resistance explained _40% of composite z score variability through the study period (partial r2_0.4013; P_0.0001). To the best of our knowledge, this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment. This effect appears mediated in part by an improvement in insulin sensitivity.







There are more cocoa studies:-




Cocoa Flavanols as a therapy for Autism

Based on the work of Helmut Sies and the trials funded by Mars, it is pretty obvious that 1,000mg of cocoa flavanols a day would very likely have a marked effect on someone with autism, assuming that is they were not already taking NAC, ALA, Carnosine, Broccoli, Sulforaphane or Selenium.  500 mg should also have an effect.


Choice of antioxidant

The question is what is the ultimate treatment for oxidative stress in autism?

I guess this will depend on exactly what type of autism you have (regressive or not), to what extent you have a mitochondrial dysfunction and whether you have any genetic dysfunction related to oxidative stress.

What works best in Billy, may be suboptimal in Charlie, but still much better than nothing at all.

It looks to me that NAC and ALA will likely be the most potent antioxidants.

If you live in the US, you can buy cocoa flavanols in standardized doses from Mars.  One capsule = 125mg of cocoa flavanols.   I have to add that I am far more inclined to believe Mars, than those supplement companies out there.  You can buy tablets saying they contain 50 mcg of Selenium, but what do they really contain? 

You can also buy “high flavanol” raw (non-alkalized) cocoa powder in big bags.  This lighter brown cocoa has lost far less of the flavonoids in the processing process.  In theory, a 5g teaspoon of the very best one will contain (on a good day) 415 mg of flavavols.

Mars are only supplying their CocoaVia products in North America, so if you want to try cocoa flavanols you have a few options:-

·        8.5 teaspoons of standard raw cocoa  (content will vary widely)
                or
·        1.2 teaspoons of “Chococru” upmarket raw cocoa

                or
·        4 capsules of CocoaVia from Mars  

Each of the above should give you 500mg of cocoa flavanols, which would look like a good starting point.  As with NAC, the studies show that the benefit increases the more you take, but the extra benefit drops off.

If somebody in the US tries CocoaVia, do let us know the result.

Not surprising, Mars tell us on the label that the product is not intended for children.  I do not suppose they ever thought of it being an autism therapy either.

I do like the idea of the redox switch, Nrf2, which Sulforaphane is known to activate.  I also like the idea of the enzyme GP1 that acts as catalyst in the oxidation/reduction process.

The science is around 20 years old and nobody has yet figured it all out;  they probably will not conclusively do so in the next 20 years either.


Food for thought!