Vitamin P may be good for you!

Now if the tittle makes sense to you, either you are a Prozac fan, or you were around in the 1940s and 50s when there actually was a vitamin P.

This blog is about autism, and in the US lots of such kids are prescribed the powerful antidepressant Prozac. We are more interested in the other vitamin P; these days they are called flavonoids.  This post will meander into other health problems but will return to ASD later on.

Flavonoids are found in plants and there are 5,000 of them.  In plants they have various functions, one of which is to provide colour (usually yellow, red and blue); in humans it is proposed that certain flavonoids may account for the beneficial properties of certain foods, ranging from chocolate to red wine.

There are many food supplements sold that contain flavonoids, three of the popular ones seem to be:-
 

·         Rutin

·         Quercetin

·         Luteolin

There is even a special mix made for autistic people called NeuroProtek.

 

In Vitro or in Vivo?

Some things work well in the test tube but not so well in us humans.  In vitro means in the glass and in vivo means in us living creatures.

Well, flavonoids have wonderful antioxidant properties, but it seems that is in only true in the test tube.  In vivo they are rather a flop.  Yet, if you read all the advertising for these flavonoid supplements, they rave about the antioxidant properties.

 

A great discussion of flavonoids is presented by the Linus Pauling Institute at Oregon State University. I have summarized much of it here and added the autism part.

 

Some flavonoids are good for you, but not as antioxidants

If flavonoids are not good antioxidants, why are they supposed to be good for you?  It seems that they have an entirely different role as signalling molecules.

Concentrations of flavonoids required to affect cell-signaling pathways are considerably lower than those required to affect cellular antioxidant capacity. Flavonoid metabolites may retain their ability to interact with cell-signaling proteins even if their antioxidant activity is diminished. Effective signal transduction requires proteins known as kinases that catalyse the phosphorylation (transferring a phosphate group (-PO₄)) of target proteins at specific sites.

The results of numerous studies in cell culture suggest that flavonoids may affect chronic disease by selectively inhibiting kinases.

Cell growth and proliferation are also regulated by growth factors that initiate cell-signaling cascades by binding to specific receptors in cell membranes. Flavonoids may alter growth factor signaling by inhibiting receptor phosphorylation or blocking receptor binding by growth factors.

All this leads naturally to think that modulation of cell-signaling pathways by flavonoids could help prevent cancer.  Mechanisms proposed include:-

Stimulating phase II detoxification enzyme activity: Phase II detoxification enzymes catalyse that promote the excretion of potentially toxic or carcinogenic chemicals.

Preserving normal cell cycle regulation: Once a cell divides, it passes through a sequence of stages collectively known as the cell cycle before it divides again. Following DNA damage, the cell cycle can be transiently arrested at damage checkpoints, which allows for DNA repair or activation of pathways leading to cell death if the damage is irreparable. Defective cell cycle regulation may result in the propagation of mutations that contribute to the development of cancer.

Inhibiting proliferation and inducing apoptosis (cell death): Unlike normal cells, cancer cells proliferate rapidly and lose the ability to respond to cell death signals that initiate apoptosis.

Inhibiting tumor invasion and angiogenesis: Cancerous cells invade normal tissue aided by enzymes called matrix-metalloproteinases. To fuel their rapid growth, invasive tumors must develop new blood vessels by a process known as angiogenesis.

Decreasing inflammation: Inflammation can result in locally increased production of free radicals by inflammatory enzymes, as well as the release of inflammatory mediators that promote cell proliferation and angiogenesis (creation of new blood vessels) and inhibit apoptosis (beneficial cell death).

Modulation of cell-signaling pathways by flavonoids could help prevent cardiovascular disease by:

Decreasing inflammation: Atherosclerosis is now recognized as an inflammatory disease, and several measures of inflammation are associated with increased risk of heart attack.

Decreasing vascular cell adhesion molecule expression: One of the earliest events in the development of atherosclerosis is the recruitment of inflammatory white blood cells from the blood to the arterial wall.

Increasing endothelial nitric oxide synthase (eNOS) activity: eNOS is the enzyme that catalyzes the formation of nitric oxide by vascular endothelial cells. Nitric oxide is needed to maintain arterial relaxation. Impaired nitric oxide-dependent vasodilation is associated with increased risk of  cardiovascular disease.

Decreasing platelet aggregation: Platelet aggregation is one of the first steps in the formation of a blood clot that can occlude a coronary or cerebral artery, resulting in myocardial infarction or stroke, respectively. Inhibiting platelet aggregation is considered an important strategy in the primary and secondary prevention of cardiovascular disease.

 

Green tea and even red wine were supposed to have wonderful antioxidant properties; apparently this is not true after all.  They do seem to be good for you, but for completely different reasons.

People who consume larger amounts of flavonoids do seem to be healthier; but sadly that does not prove that eating flavonoids makes you healthy.  It might just be that a healthy diet just happens to be flavonoid-rich.

There is on-going research and multiple clinical trials into the possible benefits of flavonoids in these areas:-

Cardiovascular Disease

The results of some controlled clinical trials suggest that relatively high intakes of some flavonoid-rich foods and beverages, including black tea, purple grape juice, and cocoa (dark chocolate) has health benefits.

Cancer

The research is ongoing, it seems to show that those people with a diet rich in flavonoids have a lower risk of certain cancers; but it seems that tea consumption has no benefit here.

Neurodegenerative Disease

It is not clear to what extent flavonoids can cross into the brain thought the BBB (blood brain barrier).  Research is ongoing to see whether Parkinson’s disease, Alzheimer’s and dementia are correlated to flavonoids in the diet.  With 5,000 flavonoids this will take some time!

 

Flavonoid Content in Food

 

There are 5 principal types of flavonoids

1.    ANTHOCYANIDINS

Examples:- Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin

Supplements available include: Bilberry, elderberry, black currant, blueberry, red grape, and mixed berry extracts.  Don’t forget the red wine.

 

2.    FLAVONOLS

Examples:- Quercetin, Kaempferol, Myricetin, Isorhamnetin

The flavonol aglycone, quercetin, and its glycoside rutin are available as dietary supplements without a prescription in the U.S. Other names for rutin include rutinoside, quercetin-3-rutinoside, and sophorin. Citrus bioflavonoid supplements may also contain quercetin or rutin.

Flavonols are found in yellow onions, scallions, kale, broccoli, apples, berries and teas.

3.    FLAVONES

Examples:-  Luteolin, Apigenin

The peels of citrus fruits are rich in polymethoxylated flavones: tangeretin, nobiletin, and sinensetin. Although dietary intakes of these naturally occurring flavones are generally low, they are often present in citrus bioflavonoid supplements.

Flavones are found in parsley, thyme, celery, hot peppers, and chamomile

4.     LAVANONES

Examples:- Hesperetin, Naringenin, Eriodictyol

Citrus bioflavonoid supplements may contain glycosides of hesperetin (hesperidin), naringenin (naringin), and eriodictyol (eriocitrin). Hesperidin is also available in hesperidin-complex supplements

Lavanones are found in citrus fruits and juices, e.g., oranges, grapefruits, lemons

5.    FLAVANOLS 

A.    Monomers (Catechins)

examples:- Catechin, Epicatechin, Epigallocatechin Epicatechin gallate, Epigallocatechin gallate

B.    Dimers and Polymers:
examples:-  Theaflavins,  Thearubigins, Proanthocyanidins

Here is where to find them:-

Catechins: Teas (particularly green and white), chocolate, grapes, berries, apples
Theaflavins, Thearubigins: Teas (particularly black and oolong)
Proanthocyanidins: Chocolate, apples, berries, red grapes, red wine

 

USDA Database for the Flavonoid Content of Selected Foods

If you want to know which food contains how much of each flavonoid, just click on the link to go to a large database held by the US Department of Agriculture.

 

USDA Database for the Flavonoid Content of Selected Foods

 

Another flurry of Patents

Not for the first time, I have noted that a flurry of patents have been filed in connection with autism.  This time it’s a couple of guys from the University of South Florida who see promise in the flavonoids :-  luteolin, diosmin, and diosmin's aglycone form, diosmetin.

 

The more prolific publisher is Theoharis Theoharides.  Here is an excerpt, from his patent:-

  

 

Theoharides is a big believer the benefit of luteolin.  Here is his main hypothesis Neuro-inflammation, blood-brain barrier, seizures and autism.

A more recent paper, again about luteolin is:- Corticotropin-releasing hormone and extracellular mitochondria augment IgE-stimulated human mast-cell vascular endothelial growth factor release,which is inhibited by luteolin

I like the fact that he is questioning the permeability of the BBB (blood brain barrier) in autism.  It seems entirely plausible and would account for many things.

  

Conclusion

 

Well I was already convinced that red wine was good for me.  Now I just have add the right vitamin P.

Time for a cup of tea, better make it chamomile (for the luteolin) and some dark chocolate.

Monty is still rather young for the red wine.  If he was French, though ….


 

Oxytocin - Not to be sniffed at?

Things seem to move slowly in the world of autism research.

Since the 1970s it has been discussed that oxytocin might be a wonder hormone that could make you feel better.  The problem was that it cannot cross the BBB (blood brain barrier).  Oxytocin secreted from the pituitary gland cannot re-enter the brain because of the BBB. Instead, the behavioral effects of oxytocin are thought to reflect release from centrally projecting oxytocin neurons, different from those that project to the pituitary gland.

Oxytocin is destroyed in the gastrointestinal tract, so must be administered by injection or as a nasal spray.  Because of the BBB any injected oxytocin should fail to enter the brain.  The nasal method of delivery uses the nasal membrane as a means of transferring the oxytocin.  But when it passes through that membrane it surely enters the blood and then will struggle to cross the BBB.  Note that most of oxytocin’s primary functions are outside of the brain; the ones relevant to autism however occur inside the brain.

For several years it was assumed that the nasal spray oxytocin could not possible affect behaviours, since it could not enter the brain.  This view now seems to be in question.  It seems fair to assume that either a small portion of the oxytocin manages to cross the BBB, or perhaps the BBB is indeed more permeable in some people.  There is a school of thought that believes that autism is caused by a BBB malfunction, and certain harmful substances that should have been kept out of the brain, were let in.  If this were indeed the case, perhaps that faulty BBB would also let the oxytocin in?

I had rather assumed that after 30-40 years, if there was some element of truth in the therapeutic value of oxytocin, it would have been proved by now.

The Good(ish) News

A five year study of the benefits of oxytocin nasal spray in autism will start this year in the US at some leading hospitals including Massachusetts General Hospital.  The study is managed by researcher Dr Linmarie Sikich, MD of the ASPIRE Research Program at the University of North Carolina-Chapel Hill.  The study will have 300 participants.

It is a follow-on study to one already completed by Dr Sikich and funded in part by Autism Speaks.  This initial study involved just 25 children, but seemed to have a positive outcome.

The Science Part

As I mentioned, there has been a great deal of research into Oxytocin.  Here is free paper called Social effects of oxytocinin humans: context and person matter.

A study was carried out in 2012 on adults with autism; the researchers did not seem to be that excited about the results, but suggested that the results warranted further studies.  The study is free to access:  Intranasal oxytocin versus placebo in the treatment of adults with autismspectrum disorders: a randomized controlled trial

A more typical study is this one:- Oxytocin, vasopressin and pair bonding: Implications for autism.  It sounds interesting, but in fact is more about the mating patterns of prairie voles vs. meadow voles.

In 2003 a study using an infusion of oxytocin vs. a placebo looked at the effects on repetitive behaviours:-  Oxytocin Infusion Reduces RepetitiveBehaviors in Adults with Autistic and Asperger’s Disorders

 
I wish these scientists would decide once and for all if oxytocin can cross the BBB.  If it cannot, then a huge amount of time and money is being wasted.

 

Conclusion

It seems that oxytocin spray does not appear to do harm.  It is already available over the counter (OTC) and indeed over the internet.  If you take too much oxytocin, some pretty strange things will start happening, since it is a hormone with many specific roles in the human body, other than making you feel good.

Some researchers and parents seem very impressed by its effects on autistic subjects.  Other scientists think it cannot possibly cross into the brain.

In five years’ time we should know conclusively whether it really does “work”.

 
I would put it in my plausible, but not proven, category. 

If you do try it at home, do let us all know the results.


 

Spinocerebellar Ataxia (SCA) and Autism

Reviewing the literature on autism, various terms are used to classify the various shades of autism.-

·         Autism

·         High Functioning autism

·         Asperger’s syndrome

·         Autistic Spectrum Disorder (ASD)

 

The trend coming from the US is to classify all the disorders as a single disorder, and then by widening the definition, draw in an even greater pool of subjects; hence the so-called autism epidemic.

This is extremely un-scientific and indeed unhelpful.  Autism is just a collection of observable and indeed measurable behaviors.  The extent to which a subject is affected by each type of behavior varies wildly.

When a patient goes to his doctor, an initial investigation might involve taking temperature, measuring pulse, examining ear, nose and throat.  The doctor does not simply conclude the patient is sick; he has to look for a specific combination of symptoms and measurable variables and make a specific diagnosis.

Now consider a rare brain disorder, Spinocerebellar Ataxia (SCA).

SCA affects about 0.025% of the population.  Moderate to severe autism affects about 0.3% of the population.  We can say that autism is 12 times more prevalent than SCA, or if we use the latest American definition and use CDC data we would say that autism is 40 times more prevalent than SCA.

Yet SCA seems far better understood and thoroughly researched than ASD.  You need go no further than Wikipedia, to see that 60 sub-types have been identified.  The disease itself is a progressive and degenerative but each sub-type has a unique cause and indeed a unique prognosis.  Usually the diagnosis comes after examination by a neurologist, which includes a physical exam, family history, and testing such as an MRI of the brain and spine and a spinal tap.

The prognosis is not good for any of the 60 types, but at least in Japan the pharmaceutical industry did develop a drug therapy.  Somewhat bizarrely, this therapy is unavailable outside Japan.  Equally bizarre is that a drug like Prozac, which is commonly prescribed to children in the US with ASD, is illegal in Japan.

The major sub-types of SCA are shown in the table.  

Implications of multiple types of autism

If autism also has many variants, it likely will also have many different causes and therefore likely have different pharmacological interventions.

This has a massive impact on clinical trials for possible therapies.

The fact that a subgroup of 20% might respond to a treatment but 80% do not, should perhaps be viewed as a success and not a failure.

Drug therapies must be related to a specific biological failure.

If, as seems likely, the same aberrant behaviour can be caused by more than one biological failure, then researchers have to be very much more wary how they conduct their clinical trials and more importantly how they interpret the results.

 

 

 

Do you call it Solfège or Solfeggio?

Unless you are a music teacher, you probably do not know what is solfège, or solfeggio.  I did not know what it was, but I am reliably informed that if you want to progress with your piano playing, you need to learn it.  The system has been in use as a pedagogical aid since it was developed by Guido D'Arrezzo in the eleventh century.

I have two piano playing sons; Ted, aged 12, and Monty, aged 9.  Monty, as you will know, has ASD.

Who do you think is going to be the first to learn solfège?   It’s going to be Monty.

Ted is not amused.

Garbage Can Model of Autism Research

Stanford University vs. Peter (INSEAD)

I only remember two things from my BIO (Behaviour in Industrial Organisations) class, many years ago at Imperial College in London.  Both were mildly amusing.

The first was that lecturer thought it was wonderful that the head of my engineering department would sometimes come to work with his things in a plastic shopping bag, rather than in a smart briefcase.  The rather lefty lecturer of this token, non-technical, course thought the highly paid Professor was truly “one of us” and he was demonstrating this with his choice of bag.  In reality, I think he just picked up what was nearest to his front door and he just did not care if somebody saw him walking down Exhibition Road with a Tesco bag.

The second thing was the wonderful sounding “Garbage Can Model of Decision Making”.  The more I read about autism on the web and in the literature, the more I think about garbage cans; so I decided to go back and see what that model was all about.

 

The Garbage Can Model of Decision Making

The model was dreamt up by three guys (Cohen, March & Olsen) at Stanford University in 1972, and I suppose that is a big part of why people got to hear about it.  It is frequently misunderstood; I think that my lecturer at Imperial College had decided it was really about situations when you have an answer and are desperately trying to find the question.  A good example of that is hyperbaric oxygen therapy.  We all know it exists, but other than for deep seas divers and fighter pilots, what is it for?  Well, the people who own these machines have been seeking new people to treat for decades.  They have the therapy and they just need to have a diagnosis, so they try autism.

The real garbage can model seems to be more about justifying bad decision making with a fancy name.

The Stanford three started by looking at how large organizations function.  They found that they operate on the basis of inconsistent and ill-defined preferences.  Technology is unclear and the participants in decision making come and go and they vary in how much time and commitment they have got. This results in organized anarchy.  Sound familiar?

The garbage can model is based on the assumption that decision making is sloppy and haphazard. Decisions result from an interaction between four independent streams of events: problems, solutions, participants, and choice opportunities.

From the horse’s mouth (James March) in the Harvard Business Review, October 2006:-

We were operating at two levels. On one level, we were saying that choice is fundamentally ambiguous. There is a lot of uncertainty and confusion that isn't well represented by standard theories of decision making. Opportunities for choice attract all sorts of unrelated but simultaneously available problems, solutions, goals, interests, and concerns. So a meeting called to discuss parking lots may become a discussion of research plans, sexual harassment, managerial compensation, and advertising policies. Time is scarce for decision makers, though, and what happens depends on how they allocate that time to choice opportunities.

On the second level, we tried to describe the way in which organizations deal with flows of problems, solutions, and decision makers in garbage can situations. The central ideas were that a link between a problem and a solution depends heavily on the simultaneity of their "arrivals," that choices depend on the ways in which decision makers allocate time and energy to choice opportunities, that choice situations can easily become overloaded with problems, and that choices often can be made only after problems (and their sponsors) have moved to other decision arenas and thus typically are not resolved.

In our minds, the garbage can process is a very orderly process. It looks a little peculiar from some points of view, but it isn't terribly complex, and it isn't terribly jumbled. The good thing, I think, is that our perspective has opened up the possibility for people to say, "That's a garbage can process" -- meaning it's an understandable process in which things are connected by their simultaneous presence more than by anything else, even though they look all mixed-up.

 

So what does this tell us?

Well I think on the one hand, it is a complete load of nonsense; but on the other hand, it seems an all too familiar unstructured, ill-defined approach that means problems do not get solved properly and so bad things do not get changed.

It also helps explain why most successful organisations are not democratic at all, they have much more in common with dictatorships; but at least they get things done.

  

Peter’s Garbage Can Model of Autism Research

Don’t get me wrong, there is some truly excellent research; but there could be a lot more and it could be far better coordinated and integrated.  Here is my garbage can model.