Nela and the Magic Flute

Nela is Monty’s excellent assistant at school, but today, because he is a bit sick, she came to Monty’s house instead.  Nela also has her own theatre school, which she runs in the afternoons.  Monty loves the theatre, and the curtains in particular.

Shortly after Nela arrived at our house, she said “Monty is going to see the Magic Flute”.

So how did Nela know that Monty is going to the opera (albeit the children’s version)?  Well, Monty told her, of course.  Now this might not sound much to you, but for me that is worthy of a big WOW.  Autistic kids are not big conversationalists at the best of times.   Even stranger, said Nela, was that he was really talkative all morning.

Now when his brother Ted is sick, it is about the only time he ever stops talking.

Then I said to Nela, actually it’s not strange at all; it is a proven fact that when autistic kids have a temperature they behave more “normal”.  I said that I would write about in my blog, so now I have to. I was actually saving this for a later post, when I set out the “Peter hypothesis of TRH induced homeostasis in autism”.

 

The post I originally intended to write

But, first a quick detour.  For those serious scientists among you, there is an excellent blog that you should take a look at.  It is written by a professional autism researcher, Paul Whitely.  The blog is called Questioning-Answers.

Now, late last night I was looking at Paul’s blog and reading all about something called tetrahydrobiopterin (also known as BH_{4 ,}THB, trade name Kuvan, or even sapropterin) and how it might be a useful drug to treat autism.  Then I looked at his links to the research papers and then I looked at the citations listed in those papers; it looked like another long session on Google might lie ahead.  Then, I concluded that since people have been talking about BH₄ and autism for 24 years; somebody should have done a serious controlled study by now.  So I will wait until they do, before getting out my textbooks.  Actually, by reading the label (the citations at the bottom of the study) I saw the following at number 53:-

 

53.  Klaiman C, Huffman L, Elliott GR. Sapropterin as a treatment for Autism Spectrum Disorders: a double-blind, placebo-controlled trial. J Child Adol Psychop 2013 (in press).

So after 24 years, it looks like someone has finally done a serious study.  I expect in a month or so it will appear on Paul’s blog, then I will take a good look.

Back to the Opera

So as not to disappoint Nela, let’s get back to business.  When I started this blog I was going to match my observations of Monty’s quirky behaviours to some solid science.  One observation was that whenever he stayed home sick, he was always great at his piano lesson, and with me on Whizz.com, the maths program, or doing literacy/numeracy with his assistant.

So applying some ANA, I found that the American Academy of Pediatrics (Americans spell it like that) had published a study called:-

“BehaviorsAssociated with Fever in Children with Autism Spectrum Disorders”

They concluded that it is indeed true; a fever makes you less autistic; but why ?

They put forward five possible reasons:- 

(1)  neurobiological effects of selected pro-inflammatory and/or anti-inflammatory cytokines, which have been found to be increased in cerebrospinal fluid (in the absence of fever) and postmortem brain tissue of individuals with autism and may be generated during different phases of responses to fever,  

(2)  modification of neuronal and synaptic function secondary to variations in body temperature that influence neural conduction velocities or synaptic transmission,  

(3)  modification of dynamic neural networks as a result of changes in cellular signal transduction and gene transcription that regulate synapse formation and function, 

(4)  increased production of other stress-related proteins, such as heat-shock proteins, during fever that might modify energy consumption and mitochondrial activity  

(5)  stimulation of the hypothalamic-pituitary-adrenal axis leading to modifications of neurotransmitter production and interaction.

 

And noted:- 

Should any of these mechanisms be proved to effect behavior changes in individuals with ASDs, this would stimulate research on potential treatments focused on these pathways.

Well this was another of my Eureka moments, since reason (5) fits very neatly with my TRH hypothesis, which was again based on other observations of Monty’s behavior.

For now, at least Paul and Nela will be intrigued; the rest of you may be bemused.  All will be revealed shortly, when my I finish my TRH project.

Now, as Monty would say,  “curtains close”.

 

 

 

Great Minds Don't Always Think Alike

Today’s post may appear to be just ramblings, but rest assured it is another necessary piece of our jigsaw puzzle.

What do you think I have in common with the President of the United States?

A.    Peter and Barack are fans of the Discovery Channel show, Myth Busters

or

B.    Peter and Barack had a drink with both  Michael Bloomberg and Vladimir Putin

It was a trick question.  The answer is (A) and (B).

For those of you who do not have Discovery Channel at home, Myth Busters is a hit TV show filmed in San Francisco, where Adam Savage and Jamie Hyneman set out to test popular myths, to see if they are plausible, confirmed or busted.  Adam and Jamie worked in the Hollywood special effects industry, but they have very unusual backgrounds.  They have a great approach to testing myths/hypotheses and always start with an open mind.

If Adam and Jamie were to join us on our quest – they would probably call it a crusade – we would have valuable support indeed.

Cold calling and networking in Business, but not in Medical Science

Now I could write a book about cold calling and networking in the business world.  If you have a bright idea, you can use it to open doors in most parts of the world.  Like most things, it works best in America, but it even worked well in some former communist countries, just a few years after the Berlin Wall came tumbling down. Romania is a good example, still in my 20s, I managed to get one to one meetings with important people, including with two of the five richest people in the country.  From my flat in Kensington, I got summoned to meet Lord Rothermere, the last of the great English press barons, to discuss an idea.  The list goes on.

But either I have lost my magic, or it just does not work on doctors and medical researchers.  They are not interested to talk to me, I find this quite perplexing.   Maybe I need a white coat?

They seem to be very closed-minded, or just not interested in autism.  Even American researchers are not interested!  Even when they are working in the field of neuroscience.

I think the medical world needs some kind of shock from the real world.  It seems, at least in case of polio and malaria, they are getting just that.

 

Bill Gates, Paul Allen and Peter (me)

Next cryptic puzzle; what do Bill, Paul and Peter have in common?

Well, you surely know that Bill Gates is the man behind Microsoft.  You may not know that Paul Allen is the co-founder of Microsoft.   Paul also set up the Allen Institute for Brain Science, which he and his sister endowed with $100 million.

Now Bill Gates is applying his business acumen (and not inconsiderable fortune) to eradicating polio.  If you want some inspiration just listen to Bill talk about how he is going about eradicating polio.  He is applying business common sense, rather than any medical knowledge.  He is making great progress.  If you live in the UK you can watch the full 60 minute lecture on the BBC iplayer just search:-   Bill Gates: The Impatient Optimist - The Richard Dimbleby Lecture. If you do not live in the UK you can only watch access the short preview on YouTube.

There is so far only a very weak link between Peter and Paul.  Before starting this blog, but after watching Bill talk about polio, I wrote to Paul.  In essence, I said go talk to those French research guys about Bumetanide and put your millions to good use.  Well at least I got a polite reply from the Institute.

I have not met Bill;  maybe one day I will.  It turns out that Mike (Bloomberg) and Bill are now joining forces to eradicate Polio.

By the way, in case you did not know, Mike is Mayor of New York and founder of Bloomberg LP a leading global provider of financial data, analysis and news.  He is also a great guy (and my former client).

Conclusion

Well, does all this really fit together?  I think it does.  We need a little something from the Myth Busters (Adam and Jamie) and some more from the philanthropists (Bill, Paul and Mike).  I think it’s called inspiration !

As for Vladimir, well Barack might not agree, but I think he is doing a pretty good job over there in the Kremlin.

до свидания

 

The Holy Grail - and where to find it

If you were are a 12 year old boy, like Ted, who loves watching the History Channel, you would know all about the Holy Grail.  Depending on your religion, you may know it as a sacred cup linked to certain important Christian events; but there are also Celtic myths about a cauldron with magical powers.  Throughout history, people have been searching for the Grail, from King Arthur to Indiana Jones.

This blog is itself a search for the Holy Grail.

Monty is a big fan of a well-known picture book series called Meg & Mog.  It is about a nice witch called Meg and her black cat called Mog.  Featured prominently is a magic cauldron, which Meg uses to cast her magic spells.  Just click on the above link and all will become clear.

So, we are looking for the Grail

Well, if you have struggled through all of this blog from the begining, you already know where to start looking.  California looks pretty hot, but then again there are some rumours about somewhere in France.  All will be explained, as we proceed further.

Homeostasis

First we need to learn a new word, Homeostasis, if you already know what it means, you are much brighter than me.

Do not confuse it with Homeopathy.  There may be another coincidence here as well.  Those generous people at Wikipedia give us this definition:-

Homeopathy  /ˌhoʊmiˈɒpəθi/ (also spelled homoeopathy or homœopathy; from the Greek hómoios- ὅμοιος- "like-" + páthos πάθος "suffering") is a system of alternative medicine originated in 1796 by Samuel Hahnemann, based on his doctrine of similia similibus curentur ("like cures like"), according to which a substance that causes the symptoms of a disease in healthy people will cure similar symptoms in sick people.  Scientific research has found homeopathic remedies ineffective and their postulated mechanisms of action implausible. The scientific community regards homeopathy as a sham;  the American Medical Association considers homeopathy to be quackery,^]and homeopathic remedies have been criticized as unethical.

Now let’s get back to Homeostatis and to help us really understand it, I decided to give a detailed example using the medical condition diabetes.

Homeostatis is a process through which the body's internal environment is kept stable.  For example, when the level of sugar in your blood is too high, your body detects this, an alarm goes off and the body acts to reduce it; conversely when blood sugar is too low, again the body detects this and sends a signal to raise it.  All this happens 24/7 and you do not even need to think about it.  That is, unless you are diabetic.

So we have:-

·         A  receptor, like a tiny sensor that is constantly measuring blood sugar.

·         Positive feedback, when the receptor detects a low level and then tells the body to raise the level of sugar 

·        Negative feedback is when another receptor alarm goes off, and the body needs to lower the level of sugar in the blood. 

·        Homeostatic imbalance occurs when the body is overwhelmed and can no longer regulate itself and regain stability.  Many diseases are indeed the result of such an imbalance; diabetes is but one.

Insulin is the principal hormone that regulates uptake of glucose (sugar) from your blood.  Insulin is released into the blood after eating.  Insulin is also the principal control signal for conversion of glucose to glycogen, for storage in your liver (and muscle cells).

Lowered glucose levels result both in the reduced release of insulin and in the conversion of glycogen to glucose. This is mainly controlled by the hormone glucagon, which acts in the opposite manner to insulin. Glucose is forcibly produced from the liver (where it had been stored as glycogen) and enters the bloodstream.

Both insulin and, its opposite, glucagon are produced in the pancreas.

Summary

So we have a receptor constantly measuring your blood sugar.  You eat a chocolate bar, blood sugar rises fast, an alarm goes off.  Release the insulin !  Insulin is released from the pancreas.  Remove excess glucose and store it (as glycogen) in the liver !  Blood sugar level is falling. Homeostatis restored; panic over.

Then you go for jog in the park.  Receptor detects falling blood sugar.  Release glucagon !  Glucagon is released from the pancreas.  Go to the liver and tell it to start converting glycogen back to glucose !  Blood sugar level is now rising.  Homeostatis restored, panic over.

Back to Ted and the quest for the grail

Ted sometimes finds it hard to explain what Dad’s job really is;   he is not the first to ponder this.  Now, Ted has decided that his Dad can officially be described as a wizard.  This helps me a great deal with this blog. 

We will now opt for the pagan Celtic myth about a cauldron with magical powers, this will be our Holy Grail.  We just need a cauldron, a wizard, some ingredients and a magic spell.  We are nearly there.

We even know part of the spell:- “ homeostatis and channelopathy  .........”

A final few words

In our first two weeks of this blog, we have been busy travelling.  We started in France, went all the way to the Punjab to meet a clever chap called Baldeep in  Chandigarh.  Then we headed over to Palo Alto in California.

The good news is that back at Monty's house, the cauldron is bubbling and the magic already seems to be working.  We just lack a few more ingredients and that elusive spell.

Eat Fish! - all about Omega-3

I did put one very well-known therapy on my list to investigate; that of omega-3 fish oil supplementation.  This is the territory of Complementary and Alternative Medicine (CAM) and maybe not surprisingly there is a lack of high quality research.  This is a pity, because there are some very good scientific reasons why it just might work.

There is only one study that was carried out like a serious clinical drug trial and seemed to show a serious positive result.  It was carried out at the Medical University of Vienna and involved 1.5 g per day of EPA/DHA (0.84g EPA and 0.7g DHA).

It seems nobody else has been able to repeat this result with a similar randomized controlled trial.  What does that tell you?  Maybe those Austrians have a special kind of fish oil ?  Or maybe there is a chemical reaction going on with all that Apple Strudel they were eating?

Even this study did not convince the serious scientists at the University of California, San Francisco.  They did a review of all omega 3 trials from 1966 to September 2008, mentioning autism and omega-3.  It is very readable and their full report  Omega-3 Fatty Acids for Autistic Spectrum Disorder: A Systematic Review  is available free (just click it). A summary, in table form, is on page 1148.  But if you are in a hurry, their conclusion was:-

“there is currently insufficient scientific evidence to determine if omega-3 fatty acids are safe or effective for ASD”

I still have not finished my research, but I can already say with 90% certainly, I know what my final conclusion is likely to be;  Eat Fish ! and I have already implemented it.
 
Here are some undisputed facts:-

1.    Autistic children have lower levels of omega 3 relative to omega 6 and lower levels of the good cholesterol HDL, than typical children.  This implies a lipid metabolism disorder.  If you read my Glutathione (GSH) Part II you will know that such a  lipid disorder should be expected in people with a GSH Redox problem.  NADP/NADPH which is required for lipid and cholesterol synthesis is also required for the GSH Redox chemical reaction.  So if there is a GSH Redox problem (proved already by serious scientists),  NADP/NADPH are highly likely to be involved and if they are, then it is no surprise if omega 3 and cholesterol levels are way off where they should be.  We are already getting side-tracked into the details, just to tell you that NADP is Nicotinamide Adenine Dinucleotide Phosphate and NADPH is the reduced form of the same chemical.  For more info click here.

2.    Omega-3 is proven to be good for the heart, in just about everyone.  The main benefits are related to cholesterol (Hypertriglyceridemia to be precise), cardiovascular disease prevention and high blood pressure.  For a full list of conditions for which Omega-3 has a benefit, to those where it is proved to have no benefit, we have a ready-made solution from the US National Institutes of Health. (Just click and read on), if you are curious to know more.

3.    Always read the label.  There are only two omega-3 oils that seem to have any potential medical benefit; eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).  Nobody seems to know which is better than the other or what the optimal ratio is.  To do much good to your heart, the research shows you need something like 2g of EPA/DHA daily, note that 2g = 2000 mg. 

Now go look on the label of those expensive fish oil tablets you have in the bathroom cabinet.  For a start you can forget about Omega-6 oil, your diet already has way too much and also ALA, you do not need any more of that either.  It also looks like any Omega-9 is not going to do much either, your body can make that itself. Omega-3 and Omega-6 oils are considered “essential” fatty acids, since your body cannot make them, and it does need them.  Western diets have far too much Omega-6 and too little Omega-3. It seems that the ration is often 10:1, when it should be much closer to 1:1.  Processed junk food is full of omega-6.

 

 

one capsule contains  180 mg of EPA /DHA ( no data given is it mainly EPA or DHA)

one capsule contains 192 mg of EPA / DHA (24g EPA and 168g DHA)

 

Eye q liquid.  5ml contains 244mg of EPA / DHA (186g EPA and 58g DHA)

• Entire 200ml bottle has 9.8g EPA/DHA.
• 500g of farmed atlantic salmon contains 10.7g EPA/DHA

 

If you do want to give EPA/DHA to your child why not give them fish to eat?  It may be true that tuna and swordfish have high levels of mercury, this is because they are large fish.  Large fish eat small fish and then accumulate mercury.  Large sea fish tend to be very expensive and beyond your budget anyway.  There are smaller cheaper fish that are full of EPA/DHA.  The U.S. Department of Health and Human Services (go on, click it) produces a great list of hoe much EPA/DHA is in 80+ types of fish.  Note that tinned tuna has almost no EPA/DHA because it is cooked before it is canned.

 

• A cheap fish like farmed trout has 1.15g EPA/DHA per 100g
•  Herring has even more oil; it has 2g EPA/DHA per 100g

•  Farmed salmon has 1.2g EPA/DHA per 100g

•  Don’t forget sardines, anchovies, mackerel, whitebait etc.

 

Depending on where on the planet you live, the price of both supplements and fish varies greatly; but by my calculations it is much cheaper to eat the fish.  Fortunately for me, Monty just loves to eat all kinds of fish, not just fish fingers.

 

Conclusion

 

There is currently no proven scientific case to give expensive omega 3 supplements as a treatment in autism.  It would be pretty straightforward to conduct such research; the fact that it has not been done, must tell you something.
 

There is a single interesting study that has not been replicated.  Even that study used dosage  levels of EPA/DHA that are 6 times higher than the supplement makers are recommending.  So a EUR 20 bottle of Eye Q would last you just 6 days.

 

There is plenty of evidence that fish is good for you and your son.  So just eat fish, and plenty of it. Maybe it will help with his autism, maybe not; it is certainly much healthier than red meat, processed meat and even his favourite chicken nuggets.

 

 

 

 

Glutathione (GSH) Part II - N-Acetylcysteine (NAC)

Please take a look at Part I before reading this post.  Remember this is a blog, not medical research or medical advice.  Always read the full clinical study and then go talk to your paediatrician.
 

Here is the final part of my current research into GSH which, you will be pleased to learn, leads to where it should; a successful clinical trial.  This time it is not in France, the trial will be in Palo Alto, California, home of Stanford University.

You will recall, that while researching one evening in February, I had rather stumbled upon the subject of GSH.  In Part I you learned all about GSH, Redox and came across a funny type of stinky chemical called a thiol.  I asked you to make a note of one particular thiol called Cysteine.

 

1.     Brain region-specific glutathione redox imbalance in autism

 We now go inside the autistic brain.  Last year some very smart Americans did some research measuring GSH and GSH Redox  (the ratio of GSH/GSSG) in different regions of the brain of autistic subjects.  You will probably prefer not to know how they managed to do this.

 They were able to prove that in certain parts of the brain, GSH Redox was decreased by more than half in the autistic subjects, compared to typical subjects of the same age.  That means GSH was low and GSSG was high.  By consequence, the autistic brains had a much higher level of oxidative stress (always a bad thing) than the other subjects.

They suggested that this might leads directly to the neurodevelopmental abnormalities in autism.

To read the abstract click here.

 

2.    Regulation of cellular glutathione

So now I was on a roll, I had found a serious biological abnormality in autism, but would it lead me to another Epiphany? Highly unlikely I thought, but onwards I went.

The next step was to find out a bit more about GSH

This part is both interesting and rather complicated, so I am going to give you just the highlights.

• Glutathione synthesis and metabolism

The way GSH is synthesized in the body seems well understood in the literature.  While hoping to simplify this text I do need to point out I just noticed another odd coincidence that I have to follow up on later (NADP/NADPH the actual chemical required for the GSH Redox chemical reaction to take place also has other known functions in human biology NADPH is used for processes such as lipid synthesis, cholesterol synthesis and fatty acid elongation.  I have another parallel investigation into omega 3 and autism, where I have learnt that in autistic children  there is a proven lipid metabolism disorder that causes high cholesterol and low omega3/omega6 ratio.  So have to add NADP/NADPH to my list of things to investigate).

GSH is all over your body - brain, lungs, liver, kidneys and in all these places some of it gets converted to GSSH.  But on balance, if your body is in good shape GSH should be greater than 99% and GSSH less than 1%.  If not, bad stuff will happen.

There are five known ways to increase the level of GSH (a good thing to do):-

1.    Enhancement of uptake of cystine

2.    Reduction of cystine to cysteine  (add a reducing agent such as NAC)

3.    Provision of alternative sources of cyst(e)ine

4.    Provide a GSH precursor (γ-Glutamylcysteine) directly

5.    Add GSH directly (intravenously, not by eating it)

 

3.    Clinical trial of glutathione supplementation in autism spectrum disorders

I came across a study from 2011 when some well-meaning folk wanted to test GSH supplementation in autism.  Now the problem is that they neglected to spend 4 hours on Google Scholar before they started.  Now, if you think I am beginning to sound smug, well you are entirely correct.  It seems Peter, doing research in the spare room, knows more about something than some white coated researchers.

They just had to look on Wikipedia to learn that “Raising GSH levels through direct supplementation of glutathione is difficult.  Research suggests that glutathione taken orally is not well absorbed across the gastrointestinal tract”  They quote research from 1992, so it must be widely known by 2011.

The study used oral GSH and a commercial transdermal GSH preparation called KIRKMAN Reduced L-Glutathione Lotion (50 g will set you back  EUR 45)

 But at least the idea behind the trial was good.

 

4.     Glutathione precursors to raise GSH levels in plasma (N-acetylcysteine, whey protein)

Going back to hard science, you quickly find that there are already well established methods to successfully raise GSH levels, via the administration of certain supplements.

 ·         Whey protein, as used by body builders, but not so cheap

 ·         N-acetylcysteine, otherwise known as NAC and pretty cheap.

 

So I follow up both and later opted for NAC.

5.     N-acetylcysteine (NAC)  in the Emergency Room and  Psychiatry

NAC has been used as a precursor to GSH for more than 30 years.  It is the standard Emergency Room treatment in the case of paracetamol overdose.

It turns out that NAC is another little wonder.  It is already used in obsessive compulsive disorder, schizophrenia, trichotillomania (a new one to me) and bipolar disorder.  It is even used in HIV therapy.

But no mention of Autism.

NAC is available as a drug or as a supplement without prescription.

6.    A Randomized Controlled Pilot Trial of Oral N-Acetylcysteine in Children with Autism

Finally, the bit you have been waiting for.  When I found this clinical trial at the end of  my 4 hour Googling session, I would have fallen off my chair, had I not been lying down at the time.

A eureka moment perhaps;  I found a clinical trial testing just what I wanted to test -  a serious study of NAC on the behaviour of kids with autism.  This study was carried out by Antonio Hardan at Stanford University, California.

Enough said.

Here is the lightweight version.

  

Here is the study itself.

 

If you want the full version they expect you to pay $31.50.

Well that was a productive 4 hours, but it set me back another $31.50.

Sadly, finding all the references again and writing my two posts on GSH has taken another 4 hours.

That was of course a few weeks ago.  The rest is history.  I suggest that you turn on your speakers., and click the link below.

 

To all you Mums and Dads, or should I say Mammas &Pappas.

 

1965 was an important year.  One of them was that this song was produced and is apparently  #89 in  Rolling Stones list of the 500 greatest songs of all time.

 

Glutathione(GSH) Part I

Glutathione (GSH) Part III

Neurology – I think I like it

In the real world coincidences are quite rare;  in this blog they seem to happen alarmingly often.  Here is another one.

You will surely have noticed by now that an old diuretic called Bumetanide has found a new application in the treatment of autism.

Similarly less known, is a strange phenomenon called Hypokalemic Sensory Overstimulation (HypoSO). This is when the sufferer gets overwhelmed by their senses of sound, light etc, but reverts to normal, as if by magic, after drinking oral potassium.  The extreme case of this is Hypokalemic Periodic Paralysis (HypoPP), when you don’t just get sensory overload, you actually become paralyzed.

My ANA hypotheses number 2 was that maybe sensory overload in autism was a form of Hypokalemic Sensory Overstimulation (HypoSo).  It seemed a wild idea, but when we tested it, we found the hypothesis entirely plausible.  We made an experiment with Monty, Ted and Dule. (click the link).  In other words, we found that autistic children seem to suffer from HypoSO and maybe some also suffer from its scarier cousin HypoPP.

Well, having decided to give my blog a rest for a couple of days, I did a mere 5 minutes work on Saturday and look what I found.

 

Bumetanide prevents transient decreases in muscle force in murine Hypokalemic Periodic Paralysis

That link takes you to a very recent paper (last month, in fact), and look how the abstract ends:- 

Conclusions: The Na-K-2Cl inhibitor bumetanide was highly effective in preventing attacks of weakness in the NaV1.4-R669H mouse model of HypoPP and should be considered for management of patients with HypoPP due to sodium channel mutations.

What does this really mean?  Well I have my opinions, but I am not yet ready to share them.  I did write to the authors of the study, but my experience to date is that Neurologists are far too busy to reply to a poor speller like myself.
 
Anyway, it looks like another reason to favour Bumetanide. I like coincidences, so it seems that I have got to like Neurology.