The over-activated immune system, Kv1.3, ASD-IE, Acacetin and sloppy science

One of the people I have met during my investigation into autism, recently pointed out to me that much scientific research cannot be trusted.  He forwarded a study to me showing just how many researchers admit is omitting data that did not suit what they were trying to prove.  I replied that I made a point of checking the credentials of the lead author.  He then replied that it is not the lead researcher who collects the data, he has a little army of PhD students doing this and nobody is checking them.

The study showed it was the younger researchers, eager to prove themselves that were the most likely to “fiddle” the results.  The problem is that by the time you become an “older researcher” you are not the one collecting the data.

Doubts about Sprouts 

One of the people who I keep forgetting to add to my Dean’s list is John Gargus; he is a professor at University of California at Irvine and Director of the Center for Autism Research and Treatment at UCI.  He is also a specialist in the complex field of ion channels and channelopathies.

He was asked to comment about the Johns Hopkins broccoli/Sulforaphane autism trial.

Trial sprouts doubts about broccoli extract for autism

Cruciferous caution: 

Some independent researchers have similar reservations, noting that the control group showed an unusually small placebo response.“You always see a 20 to 25 percent improvement in placebo,” says John Jay Gargus, director of the Center for Autism Research and Translation at the University of California, Irvine. For example, the placebo effect plagued trials of the gut hormone secretin and antidepressants for autism.
“It’s stunning that they’ve managed to have found a placebo that doesn’t give the placebo effect that we see in every other neuropsychiatric drug trial,” Gargus says.

Now as regular readers will know, at least in Monty, aged 11 with ASD, broccoli sprout powder and we assume the Sulforaphane produced by it, does have a near immediate effect.

But as Gargus says, you will always have some people with the placebo appearing to improve.  In an old post I looked at the placebo effect in autism.  It seems that the more involved the trial and hence the more 1:1 attention the child gets, the more the placebo appears to make things better.  In fact it was not the placebo, it was the 1:1 attention that improved the autism.

So, just as we have to be cautious of the placebo effect, we have to be cautious of sloppy science/scientists.  When financial interests are involved you need to be even more cautious.

The other thing I have learnt to be cautious of, is scientists who have spent many years in one very narrow field, often trying to prove their initial hypothesis to be correct.  Their eyes are then closed to everything else.

Autism Flare-ups, Summertime raging and GI issues

We have investigated in depth the fact that in some people with autism their immune system appears to be over-activated, as the result of an allergic response.  What then happens is that their autism “flares-up” and therapies that previously worked, seem to stop doing so.

The conclusion was that the allergy had caused mast cell activation and this triggered the release of pro-inflammatory chemicals (IL-6, histamine etc).  The solution was:-

·        Avoid the allergen (a type of food, or even airborne pollen)
·        Use mast cell stabilizers to minimize degranulation; even common H1 anti-histamines are partially effective
·        Inhibit the potassium ion channel Kv1.3, which seems to mediate the resulting “over-activation” of the immune response.

The good news is that it really does work and not just in Monty.  The bad news is that the optimal therapy uses a prescription drug (Verapamil).

While trawling through the research on novel anti-oxidants, I stumbled upon something that may help those people who cannot access Verapamil.

There is a flavonoid called Acacetin, which is found in asplenioid ferns.  This flavonoid has long been has used for its anti-inflammatory and immunomodulatory effects.  Now it has been shown to block Kv1.3 channels and inhibits human T cell activation.  This is one of the effects of Verapamil (there are others).  Acacetin has also been shown to have anti-cancer properties in prostate cancer cells.

Acacetin Blocks Kv1.3 Channels and Inhibits Human T Cell Activation

Acacetin (5,7-dihydroxy-4'-methoxyflavone)exhibits in vitro and in vivo anticancer activity through the suppression of NF-κB/Akt signaling in prostate cancer cells

Remember the odd therapy used to block Kv1.3, those TSO parasites, I mentioned in previous posts.  My favorite is this one:-

Immunomodulatory Therapy in Autism - Potassium ChannelKv1.3, Parasitic Worms, and their ShK–related peptides

Acacetin is available as a supplement.  So if you think blocking Kv1.3 might help and cannot access Verapamil or TSO, there are other options.

Indeed, for completeness, there at least two other Kv1.3 blockers that are available.  One is progesterone, the hormone and the other is Curcumin.

  

A nongenomic mechanism for progesterone-mediated immunosuppression: inhibition of K+ channels, Ca2+ signaling, and gene expression in T lymphocytes.  Curcumin serves as a human kv1.3 blocker to inhibit effector memory T lymphocyte activities.

  

You may recall that Progesterone was found to be highly neuro-protective and for this reason was trialed for use in the ER, immediately after a traumatic brain injury.  It was shown to save lives.  In autism, we previously found that some people, at the high functioning end, find they feel better when they apply progesterone cream, i.e. transdermal route.

Curcumin has been used for centuries as a drug.

I have not tried them, but I will continue to use Verapamil.  Acacetin, Progesterone and Curcumin share some, but not all of each other’s effects.

Progesterone, in common with Verapamil, affects both potassium and calcium channels.

There are many different potassium and calcium channels and you would hope to find a selective channel blocker and hence affect only the ones you need to.

ASD-IS  (Inflammatory Subtype)

I came across a promising study on Paul Whiteley’s blog.  It is a study of a sub-type of autism characterized by fluctuating behavioral symptoms following immune insults.  In the trial group the children all had GI problems, some had enterocolitis or esophagitis.  The entire group had been noticed by teachers/therapists to lose cognitive skills following immune insults.

Cytokine profilesby peripheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an inflammatory subtype?

Regular readers of this blog will see lots of familiar points.  This appears to be exactly the same thing as my “over-activated immune response”.

Now this study comprised children who had Non-IgE mediated allergies.  This does matter because classic allergies are called IgE-mediated and they result in little cells called mast cells getting activated and then releasing IL-6 and histamine in the blood supply.

From Wikipedia we have a summary:-

Conditions caused by food allergies are classified into 3 groups according to the mechanism of the allergic response:

1.     IgE-mediated (classic) – the most common type, occurs shortly after eating and may involve anaphalaxis.

2.     Non-IgE mediated – characterized by an immune response not involving immunoglobulin E; may occur some hours after eating, complicating diagnosis.

3.     IgE and/or non-IgE-mediated – a hybrid of the above two types.

Treating allergy is a “fuzzy” area and, depending on which country you live in, some aspects are seen as science and others pseudo-science. 

Perhaps we should see it as an important, but emerging field of science.

I am not an allergist/immunologist, so I have to look things up.

Since in the trial the children had Non-IgE mediated allergies, we can then look to see whether mast cell activation is relevant.

NON-IgE MEDIATED FOOD ALLERGY 

Mast cell and eosinophil activation is an important component of the non-IgE-mediated response

The authors of the autism study believe that the research subjects with allergy did not have mast cell activation, because they had NON-IgE mediated allergies.

Since I am not an allergist, all I can say is the author of the above paper from the Royal Free & University College School of Medicine in London thinks that mast cell activation is an important component of the non-IgE-mediated response.

Anyway, make your own mind up and continue to see what the study found.

The study looked at children with autism and allergy, whose autism flares up and affects (impairs) their cognitive function.  This group is ASD-IS (Inflammatory Subtype)

ASD-IS children: ASD-IS children are defined as those with a history of fluctuating behavioral symptoms following immune insults (mainly microbial infection). Symptoms must have been documented by individuals other than parents, such as teachers/therapists, a minimum of three times. In addition, a history of persistent GI symptoms, often diagnosed as non-IgE mediated food allergy (NFA - see next section for diagnostic criteria), is required. Among the ASD-IS subjects, 14/24 subjects were diagnosed with food protein induced enterocolitis syndrome (FPIES), a severe form of NFA, prior to enrollment in this study, and two ASD-IS subjects were diagnosed with eosinophilic esophagitis (EoE) on the basis of biopsy results. These ASD-IS subjects reported to have had loss of once-acquired cognitive skills based on the reports of teachers, therapists and/or previous records of developmental assessment.

We defined ‘flares’ as worsening behavioral symptoms following immune insults, despite the resolution of acute conditions such as viral syndrome (that is, the resolution of other infectious symptoms if associated with a microbial infection, lack of fever, and no other acute physical symptoms associated with immune insults). Most of the immune insults in this study were clinically judged to be microbial infection (mainly viral syndrome). In ASD-IS children, we obtained samples at least once in the ‘flare’ and ‘non-flare’ states. Changes in behavioral symptoms by parental reports were confirmed by reports from

teachers and other caregivers.

The authors have an entirely different hypothesis to mine.

But I find their data remarkably similar to what I see being caused by a pollen allergy in my son - summertime autism flare-up and regression.  This is why there were so many posts about the inflammatory cytokine IL-6 and how to minimize it.

Have the authors stumbled upon exactly the same phenomenon as I did?  I very much think so.

I have shared my therapy with the authors, but they think that Non-IgE mediated allergies have nothing to do with mast cell activation.   That sounds odd to me.

How to avoid Autism (and also treat TBI)

It appears that in classic autism, most of the damage is done before birth, but a gradual second decline does often seem to occur between 24 and 54 months, even in a child who you would not think of as suffering from regressive autism.

When people think back about their child with regressive autism, they often recall examples of odd behaviours occurring long before the big regression occurred.

So my "extrapolation" from this, is that there are actually two waves of neurological damage in these two common types of autism. It is just that in one case there is a tidal wave before birth and a smaller change as a toddler.  In regressive autism, the first wave usually passes unnoticed, and the main, unmistakable damage occurs in the second wave.

Perhaps we can avoid this first wave of damage done before birth, in both classic early onset autism and regressive autism.

In an earlier post, I made my case for why girls do not get mild autism and why mothers, who are alpha-females, are more prone to have kids with ASD.

Why Girls don’t get Mild Autism and Why Alpha Females may have Kids with Autism.

This was based on reading that the female hormone progesterone is extremely neuro-protective and that oxidative stress, now seen as a cause of autism, has many causes and is extremely damaging to the brain.  A good example of progesterone use, is its experimental use immediately after a traumatic brain injury.  All I did was extend this to autism.  Now it appears I am not the only one.

Here is a paper I spotted in a corner on Paul Whiteley’s ASD blog.

Low maternal progesterone may contribute to both obstetrical complications and autism

Abstract

Studies show increased autism risk among children born to mothers experiencing obstetrical complications. Although this is usually interpreted as suggesting that the obstetrical complications could be causing autism, it is possible that a single factor could be responsible for both complications and autism. We hypothesized that low levels of the hormone progesterone is responsible since it is supplied to the fetus maternally and does not only support pregnancy but also promotes brain development. Following a review of the literature, we report findings from a survey of mothers of autistic children (n=86) compared to mothers of typically-developing children (n=88) regarding obstetrical histories, including five obstetrical risk factors indicative of low progesterone Using this analysis, the ASD group had significantly more risk factors than controls (1.21 ± 0.09 vs. 0.76 ± 0.08, p< .0001), suggesting low progesterone. Thus, results suggest that low progesterone may be responsible for both obstetrical complications and brain changes associated with autism and that progesterone levels should be routinely monitored in at-risk pregnancies. Our hypothesis also suggests that ensuring adequate levels of progesterone may decrease the likelihood of autism.

The authors’ hypothesis suggests that ensuring adequate levels of progesterone may decrease the likelihood of autism.  Well, I for one, find this interesting.

In another earlier post, I referred to my advice to Ted, the nom de guerre of my very neuro-typical elder son, on how to avoid autism in the next generation.  I think I can now extend that advice further:-

People like Ted, with a close relative with ASD, could do some of the following:-

·        Find a partner who is calm beta-type female

·        Ensure she avoids emotional stress and shocks during pregnancy (particularly early on)

·       Take maternity leave straight after pregnancy is noticed, rather than mainly after birth; or, best of all, have the partner quit work as soon as pregnancy is noted

·        Ensure high levels of neuro-protective agents throughout pregnancy

·        Progesterone

·        Glutathione GSH (i.e. take NAC)

 

You might be expecting me to have statins on my list, since they are also very neuro-protective, but I do not;  even though:-

Johns Hopkins – a new use for statins

Statins in traumatic brain injury

During pregnancy, statins are detrimental to human placental development.  So although people in high speed skiing accidents, who suffer traumatic brain injuries, would have a clear benefit, for a woman with a 10% chance of having a child with ASD, the risks would outweigh the possible benefit.  Most likely, the primary, cholesterol lowering effect of the statin, is doing the damage, since the baby’s brain does need cholesterol. 

Statin warning for pregnant women

Progesterone would also be a potential therapy for people with ASD.  It might though not be wise for boys around puberty.  There are reports of people with ADHD finding progesterone helpful.
 

Should I happen to have a TBI (traumatic brain injury), please put in my IV drip progesterone, atorvastatin/lovastatin and N-acetylcysteine.


P.S.  During pregnancy, ensuring the mother is not hypothyroid and does take folic acid will also shift the odds away from an outcome with ASD.

 

 

Why Girls don’t get Mild Autism and Why Alpha Females may have Kids with Autism.

You may or may not have seen the 2006 comedy film Borat; it was critically acclaimed in the US, but took a bit of time to become a commercial hit.  It brought to public attention its writer, producer and leading man, Sacha Baron Cohen.

Ted, aged 13 and very neurotypical, is a fan of Borat.

In the autism research community, Sacha’s brother Simon is equally well known.  He is the Director of the Cambridge University's Autism Research Centre and a Fellow of Trinity College.

All very interesting,  Ted’s Grandfather also went to Trinity College Cambridge.  Ted’s brother, Monty aged 10 with ASD, has yet to produce a movie, but he has helped to produce an autism blog.    

As you may have noted on this blog, I am rather disappointed with the autism research coming out of the United Kingdom.  90% of the good stuff is from the US.

The extreme male brain theory of autism

One of the well-known autism theories is from Simon Baron-Cohen, it is called:-

The extreme male brain theory of autism

Simon has been developing his theory that something called “assortative mating” may be at least partly to blame for the spectacular rise in autism diagnoses.

The theory states that when people with strongly “systemising” personalities – the sort of people who become engineers, doctors and computer experts – marry each other and produce children, the effects of this kind of “male brain” are genetically magnified, increasing the chances of producing an autistic child – a child with what Simon suspects is an “extreme male brain”.

Strong “systemisers” are often slightly obsessive, perfectionist and make great scientists and are often extremely talented at music. But they sometimes have difficulties socially interacting with other people – a combination of traits that can blend into the milder end of the autism spectrum.

Some of the sharpest increases in autism diagnoses have been found in Silicon Valley, home to perhaps the largest population of successful systemisers on Earth. Tens of thousands of technicians, engineers and programmers work in the computer industry;  inevitably, many of these people marry each other.

Until relatively recently, being exceptionally bright was not much use to you if you were female. The opportunities for a woman to earn her living through brainpower alone were extremely limited. You could be a teacher, or perhaps, if you were lucky, a doctor.

Going to university was difficult and expensive; most did not even allow girls to study. There were certainly few opportunities for careers in engineering or the sciences.

Brainy women were not even seen as particularly desirable partners. Clever or rich men chose brides on the grounds of looks, “breeding” or both. If she did have a job, many employers would automatically fire a woman the moment she turned up with an engagement ring. So many clever, “systemising” women simply did not marry, or married late and probably had fewer children when they did.

Now everything has changed. Not only have the legal and social barriers to women entering the workplace as equals been largely dismantled, we also have the phenomenon of the desirable “alpha female”.

Fifty years ago many men were scared of smart women. Now, increasingly, alpha males want someone their equal. Fifty years ago, male airline pilots typically married stewardesses; now they marry other pilots. Doctors used to marry nurses; now they marry other doctors.

But the phenomenon of like marrying like may be having completely unexpected consequences.  

The Peter Theory of the Neuroprotective Effect of Female Hormones in Autism

Unlike Simon, I do not have a brother who is a movie star, with a Golden Globe; my brother designs car engines, but his engine did win the International Engine of the Year Award in 2013.

I always wondered why it was that kids with autism are mainly boys and when you do meet an autistic girl, she tends to be at the moderate to severely affected end of the spectrum.  Then there is Simon’s observation that alpha females produce disproportionately more kids with ASD.  Then there is the question as to why Anglo-Saxon countries (Australia, Canada, New Zealand, the United Kingdom, and the United States) but particularly the US, have a higher incidence of autism than the rest of the world; is it really just over-diagnosis?

The hormones Estrogen and Progesterone are known to be highly neuroprotective.  Testosterone may also have some neuroprotective properties, but they seem to be of a lesser extent.   While Estrogen and Progesterone are known as female hormones and Testosterone is the male hormone, both sexes have all three hormones, just in different amounts.  We learnt in an earlier post that the stress hormone Cortisol is neurotoxic.

Imagine an experiment:

On the left, you have a stressed alpha female
 (cortisol↑ testosterone↑ estrogen↓  progesterone↓)

with a male fetus (testosterone↑ estrogen↓ progesterone↓)

On the right, you have a calm beta female
 (cortisol↓ testosterone↓ estrogen↑  progesterone↑)

with a female fetus (testosterone↓  estrogen↑  progesterone↑)  

Then both subjects experience a sharp oxidative shock from the environment.

The beta female, with the female fetus, have a major neuroprotective advantage . They can generally weather the storm; only in severe cases is the neuroprotection overcome and the result is a severely autistic girl. 

The alpha female, with the male fetus, cannot weather even a moderate shock and the result is a mildly affected autistic boy.  The more rare severe shocks, produce severe autism.

The kind of insults that produce damaging oxidative shocks have been well documented by researchers like Abha Chauhan. 

Conclusion

This latest Peter Theory is hopefully flawed, after all, what do you learn about biology in Engineering School and Business School?  There should be much more talented people out there.  If it was correct, it would open up avenues in very simple preventative medicine.


P.S.   I am using a little dramatic license; Simon is actually Borat's cousin, not strictly his brother.

Hormonal Remedy for Brain Injuries

Autism is a non-traumatic type of brain injury; the kind you typically see in the Emergency Room is TBI (Traumatic Brain Injury), after a car crash or, in the US, a shooting.

TBIs are very common and frequently fatal; when not fatal they often produce grave ongoing physical and psychological consequences, some of which may be life-long.  As a result there is a great deal of research into understanding TBIs and how to best treat them.

In this blog we have already mentioned that statins are being used to successfully treat TBI.  As I discovered, they have an impact in autism as well.

My renewed interest in TBI is two fold:-

1. Does TBI cause ongoing hormonal changes in the brain? (as does ASD)
2. Are there hormone therapies for TBI? (there are experimental ones for ASD)

The answer is yes and yes.

After a TBI there frequently are hormonal changes and they have even been given a name.

Post TBI Hormonal Deficiency Syndrome

The most frequently affected hormones are reported to be growth hormone (GH) and insulin-like growth factor (IGF-1).  This is interesting because these same hormones appear to be affected in autism.

There is a hormone therapy for TBI and it is currently undergoing a third stage clinical trial at 67 hospitals across the US. 

Progesterone for the Treatment of Traumatic Brain Injury (ProTECT III)

You can read all about the study with the above link.  If you are curious as to how Progesterone can reduce neuroinflammation and be neuroprotective, here is another paper:-
Progesterone as a neuroprotective factor in traumatic and ischemic brain injury

Regular readers of this blog will know that I like charts.  Here is a neat summary of how progesterone helps in TBI.

Progesterone is indeed a female hormone, but it is also present in small amounts in the male brain.  It is a fringe therapy for ADD and ADHD with the hormone given transdermally.

In TBI, progesterone is being given intravenously in the ER, as soon as possible after the accident.

In autism we are working many years after the brain injury occurred, but that should not stop us looking further.  The same applies to statins.