Cesarian Delivery and Autism – another inconvenient truth?

Brasil is the C-section capital of the world, with rates in the public sector of 35–45%, and 80–90% in the private sector.

A recent study from the Karolinska Institute in Sweden, analysing 61 previous studies, has again shown a connection between birth by Cesarian Section and an increased risk of autism or indeed ADHD. 

C-sections account for just 16% of births in Sweden, but 32% in North America.

This of course prompted a reaction to reassure future mothers that they have nothing to fear, from experts in obstetrics who of course know nothing about the etiology of autism.  Mothers should be reassured, but trashing the study helps nobody.  Instead of a 1% risk of non-trivial autism, it rises to 1.3%. You still have more than a 98% chance of having a neurotypical child, all other factors being equal.  Without a medically necessary C-section, death is a real possibility.

It was a couple of years ago that the Karolinska Institute highlighted the fact that those with severe autism currently have a life expectancy of under 40 years.  Another inconvenient truth.

Association of Cesarean Delivery With Risk of Neurodevelopmental and Psychiatric Disorders in the Offspring 

Question  Is birth by cesarean delivery associated with an increased risk of neurodevelopmental and psychiatric disorders in the offspring compared with birth by vaginal delivery?

Findings  In this systematic review and meta-analysis of 61 studies comprising more than 20 million deliveries, birth by cesarean delivery was significantly associated with autism spectrum disorder and attention-deficit/hyperactivity disorder.

Meaning  The findings suggest that understanding the potential mechanisms behind these associations is important, especially given the increase in cesarean delivery rates for nonmedical reasons.

Abstract

Importance  Birth by cesarean delivery is increasing globally, particularly cesarean deliveries without medical indication. Children born via cesarean delivery may have an increased risk of negative health outcomes, but the evidence for psychiatric disorders is incomplete. 

Conclusions and Relevance  The findings suggest that cesarean delivery births are associated with an increased risk of autism spectrum disorder and attention-deficit/hyperactivity disorder, irrespective of cesarean delivery modality, compared with vaginal delivery. Future studies on the mechanisms behind these associations appear to be warranted. 

Very many things are known to slightly increase the odds of a person having autism and the more risk factors you have the more severely autistic you may be.  This ranges from maternal stress (anything from experiencing a hurricane, work stress, life trauma) to maternal/paternal age, obesity, gestational diabetes, alcohol/drug abuse, illness during pregnancy etc. This combines with whatever is in the parents’ DNA and random mutations that are bound to occur.    

A more rational reaction might be to investigate further why there might be a link and how you could counter any risk to children born by cesarian section.  You only have to read the existing research, or this blog.

There are 2 very good reasons why there should be a link between autism and C section, both have been covered in this blog.

1.     The microbiome comes from the mother. Science is only recently starting to understand the role of bacteria in health, but we know that it plays a key role in conditioning/calibrating the immune system of babies.  Once the immune system has been calibrated it is set for life.  Early exposure to bacteria is necessary and humans evolved to expect it.  If your immune system is over/under sensitive there will be consequences. Birth via C-section avoids exposure to bacteria in the birth canal, unless the newly arrived baby is “seeded” with bacteria from the mother. Mother’s milk is another key source of transferring the mother’s microbiome to the baby. 

2.     We saw that the birthing hormone Oxytocin plays a key role in triggering the “GABA switch” in new-borns. This is the process which transforms immature neurons with high chloride to mature neurons with low chloride shortly after birth.  During natural birth there is a surge in the hormone Oxytocin that is transferred to the baby, this causes the chloride transporter KCC2 to be further expressed and the “opposing” transporter NKCC1 to fade away.  In many people with severe autism their neurons remain in the immature state their entire life.  Just as you can replace the bacteria transfer lost in birth via C-section, there would be absolutely no reason why you could not replicate the surge in Oxytocin to "flip the GABA switch".

The recent study showed that elective C-sections (where the baby is in perfect health and not distressed) are associated with the elevated risk of both Autism and ASD.

Regular readers of this blog would probably be surprised if C-section did not increase autism prevalence.

The important thing is to acknowledge this likely connection and mitigate it, rather than try and fault the numerous studies that have shown the same effect.

The same of course applies to reducing the very small risk from vaccines, rather than construct new studies in a contrived way to show there is zero risk.   If you can safely and cheaply reduce the risk of a negative reaction to vaccines, why wouldn’t you?  Just follow Johns Hopkins example and give Ibuprofen or Montelukast (Singular) for a few days before and after and remember to never give Paracetamol/Acetaminophen (Tylenol) in response to fever after a vaccine. Paracetamol/ Acetaminophen reduces the body’s key antioxidant GSH just when the baby/child may need its neuroprotection most.

Some conditions are associated with preterm births, a good example is Cerebral Palsy (CP), which is twice as common in babies born very early. CP is rarely genetic and is usually considered to be caused by a complication during pregnancy, birth or shortly thereafter. I think you would find a correlation between C-sections and CP, but in this case I doubt you would find it in elective C-sections.   In other words C-sections do not “cause” CP, but they may be associated with it. The ID/MR often found in CP might be elevated by C-section and, if so, would be treatable.

Conclusion

In order to halt the rise in incidence of the disabling kinds of autism there should be steps taken to reduce some of the very many factors that are driving the increase, albeit each one sometimes by a tiny amount.

This would be a good application of all those thousands of autism research papers, many of which have shown what factors contribute to increased risk, that now sit gathering dust.

We are not at the stage of wide scale gene editing, but many simple steps can be taken today to improve future health.  This does not mean do not vaccinate, or avoid medically necessary C-sections; vaccinations and C-sections have saved millions of lives. But, why would you not want to take a good thing and make it even better?  That is what we humans tend to be good at, like the Swedes and their Volvos.

Perhaps take your C-section with a generous smear of Mum's bacteria and a shot of synthetic oxytocin?  

There will be more on Cerebral Palsy in a later post on D-NAC (Dendrimer N-Acetyl Cysteine). 

                                                               

Eosinophilic Esophagitis – another Granulocyte Disorder Associated with Autism

There are many comorbidities associated with autism.  I have long held the view that these comorbidities hold the key to understanding each particular case of autism.  In many cases this may be far more useful than genetic testing, which only seems to help in a minority of cases.

“Ringed esophagus” aka “Corrugated esophagus”


This then allows you to put people into sub-groups that may well respond to the same therapy.  This may all sound like common sense, but apparently is not.

Eosinophilic esophagitis (EoE) is a relatively new diagnosis and it is applies to a certain type of reflux/GERD/GORD that might be associated with a difficulty in swallowing and may not respond well to the standard stomach acid lowering therapies.

It is likely that most people with Eosinophilic esophagitis have never been correctly diagnosed. Many people have taken several years to get the correct diagnosis.

It is known that Eosinophilic esophagitis is much more common in autism than the general population. One study showed that EoE is four time more likely to be diagnosed in someone with autism. I suspect many people with autism never have their GI problems fully diagnosed.

We now have to add some new science to this blog

Granulocytes

There is a great deal already in this blog about mast cells.  Many readers have children who have allergies, mast cell activation, or even mastocytosis.  Mast cells are the ones (but not the only ones) that release histamine.

Mast cells are just one type of a class of cells called Granulocytes, that are produced in your bone marrow.

Granulocytes are a category of white blood cells characterized by the presence of granules, which release their contents when they degranulate.

The four types of granulocytes are:- 

·        mast cells

These have been well covered in the past. These are what cause problems for people with pollen allergy.

·        eosinophils

Eosinophils play a crucial part in the killing of parasites because their granules contain a unique, toxic basic protein and cationic protein. Eosinophils regulate other immune cell functions (e.g., CD4+ T cells, dendritic cells, B cells, mast cells, neutrophils, and basophils), they are involved in the destruction of tumor cells, and they promote the repair of damaged tissue. Interleukin-5 interacts with eosinophils and causes them to grow and differentiate; IL-5 is produced by basophils.

Note that some people with autism find that the TSO helminth parasites modify their immune system and improve their autism. This may relate to what is contained in the granules of eosinophils.  

·        basophils 

Basophils are similar to mast cells, in that they contain prestored histamine within their granules. Unlike mast cells they circulate in your blood . Basophils are the least common of the granulocytes, representing about 0.5 to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They can produce histamine and serotonin that induce inflammation, and heparin that prevents blood clotting.

There is research underway to try to develop basophil stabilizers.

·        neutrophils

Neutrophils are normally found in the bloodstream. During the beginning phase of inflammation, particularly as a result of bacterial infection, environmental exposure, and some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate towards the site of inflammation.

Neutrophils are recruited to the site of injury within minutes following trauma, and are the hallmark of acute inflammation; however, due to some pathogens being indigestible, they can be unable to resolve certain infections without the assistance of other types of immune cells.

Neutrophils also release an assortment of proteins in three types of granules by a process called degranulation. The contents of these granules have antimicrobial properties, and help combat infection.

An obvious question would be, if you know you have a problem with mast cells are you likely to have an issue with the other types of granulocytes?

One role of eosinophils is to regulate other immune cell functions (e.g., CD4+ T cells, dendritic cells, B cells, mast cells, neutrophils, and basophils).

The subject is highly complex and again not fully understood, but it is clear that granulocytes are all interrelated and so a problem with one may well be associated with a problem with others.

In the case of Eosinophilic esophagitis (EoE), both eosinophils and mast cell are directly involved.

Basophils, like mast cells, release histamine among other things when they degranulate.

Mast cells usually do not circulate in the blood stream, but instead are located in connective tissue.  Circulating granulocytes, like basophils can be recruited out of the blood into a tissue when needed.

So in addition to mast cell stabilizers perhaps, we might benefit from basophil and eosinophil stabilizers.

Surprisingly, the antihistamine cetirizine has Eosinophil-stabilizing properties, as does the asthma drug Montelukast. Both drugs are widely used in children.

Another substance, curine, also inhibits eosinophil influx and activation and is seen as a potential new treatment for asthma.  Interestingly the drug curine, is an alkaloid, that blocks L-type Ca²⁺ channels.

Regular readers may recall that I proposed the L-type calcium channel blocker Verapamil to control my son’s mast cell degranulation. Mast cells degranulate in a very complex fashion that involves the flow of Ca²⁺.

This may or may not be a coincidence. 

Fullerene nanomaterials are being developed as both mast cell and peripheral blood basophil stabilizers.

L-type calcium channels and GI disorders in Autism

There are many types of GI disorder in autism, however I suggest that a large group can be categorized as being broadly Granulocyte Disorders, which may well all respond to L-type calcium channel blockers, to some extent.

Indeed this may be a better solution than the widely used cromolyn sodium.

Perhaps people with autism, and their family members have certain calcium channels that are either overexpressed, or do not close fast enough, leading to a higher level of intracellular calcium.  This of course ties back in with Professor Gargus and his theories about IP3R and the calcium store inside the “endoplasmic reticulum”.

This all gets extremely complex.

My rather simple suggestion would be that if you have autism and any GI problem from the esophagus downwards, a three day trial of verapamil just might change your life.  As is almost always the case, there are some people who do not tolerate verapamil.

Interleukin 5

Interleukin 5 (IL-5) is an inflammatory cytokine produced by type-2 T helper cells  (Th2), mast cells, basophils and eosinophils.

IL-5 interacts with eosinophils and causes them to grow and differentiate.

IL-5 has long been associated with the cause of several allergic diseases including allergic rhinitis and asthma, where a large increase in the number of circulating, airway tissue, and induced sputum eosinophils have been observed.

You might expect high levels of IL-5 in people with Eosinophilic esophagitis (EoE)

Anti–IL-5 (mepolizumab) therapy for eosinophilic esophagitis 

Anti–IL-5 therapy is associated with marked decreases in peripheral blood and esophageal eosinophilia (including the number of CCR3⁺ blood cells) in patients with EE and improved clinical outcomes.

Not surprisingly the same anti-IL-5 therapy has been approved to treat severe asthma.

NICE recommends first-of-its kind asthma treatment mepolizumab  

Patients are given mepolizumab by injection every four weeks. It costs £840 per dose.

Mepolizumab for autism?

It is very expensive, so I doubt many people will think of Mepolizumab for autism.  If you have EoE, or severe asthma, you may be able to access this IL-5 therapy, my guess is that it would also reduce the severity of any comorbid autism.

Back to Eosinophilic Esophagitis

I was writing a while ago about food allergy in my book and came across the opinion that food allergy is no more common in autism than in typical people, but what is more common is Eosinophilic Esophagitis.

Eosinophilic esophagitis is a chronic immune system disease. It has been identified only in the past two decades, but is now considered a major cause of digestive system (gastrointestinal) illness.  In many cases it likely remains undiagnosed. If it continues, after a few years swallowing becomes difficult, in part because a “ringed esophagus” develops that impedes the passage of food.

As seems to be often the case there are plenty of contradictions in the diagnosis and treatment, as you will find as you read on.

The symptoms are broadly what would normally be diagnosed as reflux/GERD/GORD. This is very often found in people with autism and I expect in their relatives.

It is relevant to autism because it will be yet another comorbidity that when treated should improve autism, but it is also another marker of a particular sub-group of autism.

There are numerous other GI conditions comorbid with autism - colitis, IBD, IBS etc.  In the end I imagine that the molecular basis of some of these diagnoses is actually the same, so you will find the same therapies may be effective.

It looks like that one common factor is the mast cell and, just as in pollen allergy and asthma, stabilizing mast cells yields great benefit. Stabilizing mast cells is complex but involves the flow of calcium ions, Ca²⁺.  By modifying the flow of Ca²⁺ you can prevent mast cells degranulating.  This was one of my earlier discoveries, but there is now research showing the L type calcium channels “open” mast cells.  Keeping these channels closed is actually quite simple.

It would seem logical that the same approach could be therapeutic to other conditions that are, at least in part, mediated by mast cells.

According to the Mayo Clinic these are symptoms of eosinophilic-esophagitis

Adults:

·         Difficulty swallowing (dysphagia)

·         Food impaction

·         Chest pain that is often centrally located and does not respond to antacids

·         Persistent heartburn

·         Upper abdominal pain

·         No response to gastroesophageal reflux disease (GERD) medication

·         Backflow of undigested food (regurgitation)

Children:

·         Difficulty feeding

·         Vomiting

·         Abdominal pain

·         Difficulty swallowing (dysphagia)

·         Food impaction

·         No response to GERD medication

·         Failure to thrive (poor growth, malnutrition and weight loss)

The diagnosis of EoE is typically made on the combination of symptoms and findings of diagnostic testing.


Prior to the development of the EE Diagnostic Panel, EoE could only be diagnosed if gastroesophageal reflux did not respond to a six-week trial of twice-a-day high-dose proton-pump inhibitors (PPIs) or if a negative ambulatory pH study ruled out gastroesophageal reflux disease (GERD).

Treatment strategies include dietary modification to exclude food allergens, medical therapy, and mechanical dilatation of the esophagus.

The current recommendation for first line treatment is PPI in lieu of diet as a significant portion of EOE cases respond to this, and it is a low risk, low cost treatment.

The second and third line therapies are an elimination diet of either the 6 or 4 most common triggers, or topical corticosteroids, including both fluticasone, and topical viscous budesonide.

Elimination diets would be followed by re-introduction of foods under supervision if the first diet is successful. Allergy evaluation has not been found to be an effective means to determine what foods to eliminate.

  

Eosinophilic esophagitis in adults: An update

MAST CELL STABILIZERS

In a small case series, Cromolyn sodium failed to show any clinical or histologic improvement in EoE patients

LEUKOTRIENE INHIBITORS

Montelukast is an eosinophil stabilizing agent. It improved clinical symptoms in EoE but there was no histological improvement

PROGNOSIS

As mentioned earlier, EoE is a chronic inflammatory disease of the esophagus. The inflammation leads to remodeling, fibrosis and stricture. Fortunately, no case of esophageal malignancy has been reported in EoE. Patients are generally diagnosed after several years of their symptoms. Although symptomatic improvement occurs after treatment, recurrence is common after discontinuation of treatment. So maintenance therapy is needed to prevent recurrences. At the present time there is no head to head study to suggest the best maintenance treatment. Continuation of swallowed corticosteroid and/or dietary therapy should be done in all EoE patients particularly in those with history of food impaction, dysphagia, esophageal stricture, and in those with rapid symptomatic and histologic relapse following initial treatment

Eosinophilic esophagitis and Mast Cells

Eosinophilic esophagitis is called Eosinophilic because it is mediated by Eosinophils, however it has been established that mast cells also play a role. 

Involvement of mast cells in eosinophilic esophagitis

Whereas prior studies have primarily focused on the role of eosinophils in disease diagnosis and pathogenesis, this study investigates the involvement of mast cells.

Herein we have identified local mastocytosis and mast cell degranulation in the esophagus of EE patients; identified an esophageal mast cell associated transcriptome that is significantly divergent from the eosinophil-associated transcriptome with CPA3 mRNA levels serving as the best mast cell surrogate marker; and provide evidence for the involvement of KIT ligand in the pathogenesis of EE.

One possible explanation for eosinophilic esophagitis:

Expanding the paradigm of eosinophilic esophagitis: mast cells and IL-9

A potential immunological mechanism involved in the pathogenesis of EoE. An uncontrolled TH2 immune response initiated by an allergic insult results in the transition of the esophagus from a normal (NL) to EoE phenotype through enhanced IL-13 production that induces highly elevated CCL26 (eotaxin-3) expression by esophageal epithelium. Dysregulated TH2 immune response and enhanced CCL26 secretion together promote the infiltration of CD4⁺TH2 cells, eosinophils, and mast cells, and potentially, type-2 innate lymphoid cells (ILC2) and CD4⁺TH9 cells; into the esophagus. TGF-β and IL-4 produced by the activated mast cells and CD4⁺TH2 cells may induce eosinophils, ILC2, and/or CD4⁺TH9 cells to produce IL-9, which in turn, promotes esophageal mastocytosis that contributes to the development of EoE pathophysiology.

Possible Eosinophil stabilizers

An Open Label Add-On Trial of Cetirizine for Neuromyelitis Optica (P4.003)

CONCLUSIONS Eosinophil-stabilizing properties and favorable safety profile make cetirizine an attractive add-on therapy for NMO. Thus far it has been well-tolerated in our patient population, with incoming data about efficacy expected over the coming months

Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma

·        Curine is a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum.

·        Curine inhibits eosinophil influx and activation and airway hyper-responsiveness.

·        Curine mechanisms involve inhibition of Ca²⁺ influx, and IL-13 and eotaxin secretion.

·        No significant toxicity was observed in mice orally treated with curine for 7 days.

·         Curine has the potential for the development of anti-asthmatic drugs.

  

Conclusion

Non conventional therapies for eosinophilic esophagitis might include:-

·        Cetirizine

·        Verapamil

·        Montelukast

·        Curine

The very expensive therapy is Mepolizumab.

If you have one type granulocyte causing a disorder, is seems almost inevitable that the other types of granulocyte are also involved.

Treating granulocyte disorders should improve autism and left untreated they may mask the effect of otherwise useful autism therapies. 

One reader did previously suggest a bone marrow transplant for autism. A rather radical solution, but if someone with autism was given donor bone marrow as part of another therapy, you might well see their autism improve.

2016 To-do List

I expect many readers of this blog have a list of things to trial in 2016; I certainly do.

Monty’s older brother, codenamed Ted, did say to me recently, “I thought you said you’d be all finished with this, in a couple of years”; that was indeed the intention.  

A medicine cabinet to be proud of, but not mine

It has now been three years.  I never really intended to go so deeply into the science, and I never expected there to be so many “obvious” things un/under-investigated by researchers.

Most people diagnosed these days with “autism” are fortunate to be relatively mildly affected.  Parents of those kids likely find this blog rather shocking; how can so many pills be needed and still you want more?

Some other people also diagnosed with autism, face really big challenges, not limited to:-

  

     ·        Unable to talk
·        Unable to walk
·        Unable to eat (must use G tube)
·        Unable to be toilet trained
·        Unable to read
·        Unable to write
·        Have seizures 

So when asked by a teacher at school, if Monty, now aged 12, has severe autism I responded in the negative.  He does not tick any of the above boxes.

If you have more than “mild autism” it seems that there are likely many dysfunctions and the more you treat, the better the result.  A quest without an end.

School

Ted hates his relatives discussing his school grades and I agree with him that they are entirely his business.  We all know that typical kids vary in how smart they are and how motivated they are.  NT kids tend to get the grades they deserve.

I do break these rules with Monty, but that is because I really want to show that when a person has numerous neurological dysfunctions, as those found in classic autism, if you treat them with science (not with bleach and other nonsense), you can end up in a different, better place. 99.99999% of the world do not know this; perhaps 500 people do know.

Improving IQ will improve the person’s ability to understand and compensate for the dysfunctions that have not been treated.  

Grading academic performance at school is something we all understand and along with its limitations.  We have all been there, so let's use it.

Kids with classic autism do not get the grades they potentially deserve.  Most can be made smarter and it is easy to measure.

Before coming to my to-do list, I did receive another question about what exactly is the effect of bumetanide. 

When I collected Monty from school the other day, his assistant was proudly holding up the latest “quick fire” math test, where speed is seemingly even more important than the right answer.

So Monty, the only one with autism, came first and by a long way. 3 minutes and 35 seconds, with the runner up taking 3:56.  He got 90% correct, but that is enough to keep first place.   The previous test before Christmas he got 100%, but finished 7^th out of 16 on speed.  It must be the turkey.

The questions are very simple, since you have to be very fast; but until the age of 9, and the introduction of Bumetanide, the class teacher would never have dreamt of having Monty compete at all.  Coming a distant last in everything would be disheartening, for the teacher. Monty would not have even noticed, let alone cared.

People with Classic Autism, or what Knut termed SDA (strict definition autism), are usually hopeless academically; but with Bumetanide, it does not have to be that way. 

Many people with classic autism leave school 18 years old, still at the level of single digit addition and subtraction, or perhaps up to 20.

If you reach the academic level of Grade 2 (Year 3 in the UK system), that of a typical 7 or 8 year old, by the time you “graduate” high school, you are doing above average.

So Ted is not alone in being able to get good grades.  The PolyPill is indeed worth all the bother.

To-do list

I did have to go through by supply cupboard to see what I had not got round to testing and that I still think has some potential merit.  Some things did get thrown out.

Some old ideas are worth revisiting.

·        Biotin (high dose)

This did seem to have a marginal positive effect and is both cheap and harmless. 

·        Pregnenolone (very low dose)

This also appeared to have some positive effect and should affect GABA subunit expression. High doses have been used in a Stanford clinical trial. We saw in earlier posts that allopregnanolone possesses biphasic, U-shaped actions at the GABA_A receptor, meaning that a tiny dose can have the same effect as a large dose.

 I like low doses.  

Old ideas worth developing:-

·        Miyairi 588 bacteria, but at higher doses

This is the bacteria used as a probiotic in Japan for humans, since the 1940s.  It is also added to animal feed to avoid inflammatory disease and so produce healthier animals.

The science showed that it should be helpful to raise Butyrate levels.  It can be achieved directly via supplementation, with sodium butyrate, and indirectly by adding a butyrate-producing bacteria, such as Clostridium Butyricum or Miyari 588.

I have been using a tiny dose of Miyari 588 for months.  It achieves what it is sold for in Japan, in that it reduces gas, which is the only obvious negative side effect of Monty’s Polypill, other than diuresis.

The positive side effect of the Polypill is near perfect asthma control.  Asthma is an auto-immune/inflammatory disease, highly comorbid with autism. 

The effect of Miyari 588 is reversible because this bacteria cannot survive long in the intestines, which is why you have to take it every day.  It crowds out some of the other bacteria in the intestines, but they will soon grow back.

New ideas already in this blog:-

·        Diamox

I did suggest on several occasions that it might be possible to get a “Bumetanide plus” effect by adding Diamox.

Diamox (Acetazolamide) is another diuretic and it is a carbonic anhydrase inhibitor

Acetazolamide is a carbonic anhydrase inhibitor, hence causing the accumulation of carbonic acid Carbonic anhydrase is an enzyme found in red blood cells that catalyses the following reaction:

hence lowering blood pH, by means of the following reaction that carbonic acid undergoes:

The mechanism of diuresis involves the proximal tubule of the kidney. The enzyme carbonic anhydrase is found here, allowing the reabsorption of bicarbonate, sodium, and chloride. By inhibiting this enzyme, these ions are excreted, along with excess water, lowering blood pressure, intracranial pressure, and intraocular pressure. By excreting bicarbonate, the blood becomes acidic, causing compensatory hyperventilation, increasing levels of oxygen and decreasing levels of carbon dioxide in the blood

This change in bicarbonate will also affect the AE3 and NDAE exchangers.

As you will see in the figure below the regulation of bicarbonate HCO3- and pH is directly connected to chloride Cl- homeostasis.  This means that via AE3 and NDAE you can affect intracellular chloride levels by change the level of HCO3-

In turns this means that Diamox (Acetazolamide) really should have an effect on the level of intracellular chloride.

This in turn suggested to me that Diamox could augment the effect that bumetanide has on NKCC1.

 In the case that Bumetanide can lower intracellular chloride, but not to the optimal level to correct the GABA dysfunction, Diamox might be able to lower chloride levels a little further so further shifting GABA to inhibitory.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1317631/

Neuronal activity results in significant pH shifts in neurons, glia, and interstitial space. Several transport mechanisms are involved in the fine-tuning and regulation of extra- and intracellular pH. The sodium-independent electroneutral anion exchangers (AEs) exchange intracellular bicarbonate for extracellular chloride and thereby lower the intracellular pH. Recently, a significant association was found with the variant Ala867Asp of the anion exchanger AE3, which is predominantly expressed in brain and heart, in a large cohort of patients with idiopathic generalized epilepsy. To analyze a possible involvement of AE3 dysfunction in the pathogenesis of seizures, we generated an AE3-knockout mouse model by targeted disruption of Slc4a3. AE3-knockout mice were apparently healthy, and neither displayed gross histological and behavioral abnormalities nor spontaneous seizures or spike wave complexes in electrocorticograms. 

After only a couple of days of Diamox, it is pretty clear that there is indeed a “bumetanide plus” effect.  So the same changes that were noted when starting bumetanide appear again.

A promising start to 2016.

·        Ponstan

This is the NSAID that is also suggested to be useful to affect the ion channels expressed by the genes ANO 2/4/7 & KCNMA1.  We saw in this post

http://epiphanyasd.blogspot.com/2015/12/autism-treatments-proposed-by-clinical.html

where Knut highlighted that Fenamates act as CaCC inhibitors and also stimulate BKCa channel activity.  Ponstan is a Fenamate.

·        Vitamin A

This was Maja’s discovery, that in some people vitamin A will stimulate oxytocin, via upregulation of CD38.

·        Zinc

Zinc should affect GABA, particularly in immature neurons.  Zinc homeostasis is disturbed in some autism and perhaps, in some people, a small dose of zinc may actually have a positive effect.  Simple to check.

Clioquinol, the drug that shifts zinc to the “right” place, is not without risks.

·        Picamilon

Once the GABA switch has been repaired, it may be time for a little extra GABA.  GABA should not be able to cross the blood brain barrier (BBB), but in the form of Picamilion, it does cross the BBB.

·        Inositol

This it naturally produced in the body from glucose and used to be known as vitamin B8.  In some people Inositol reduces OCD and stereotypy.  Simple to check.

·        Montelukast

This is an asthma drug, considered very safe in children, that Dr Kelley (formerly of Johns Hopkins and likely the cleverest autism clinician)  uses in children with AMD, as a short term therapy, when they are sick and, very interestingly, before immunizations.  This is to avoid further mitochondrial damage.  Montelukast is a leukotriene receptor antagonist (LTRA) used for the maintenance treatment of asthma and to relieve symptoms of seasonal allergies.

Dr Kelley also uses Ibuprofen as a short term therapy to counter the effects of increased cytokine production.  Montelukast is more potent and has different side effects, meaning it might be a better choice than ibuprofen for some people.

Ibuprofen may be OTC, but, more than very occasional use, can cause side effects in many people.  These side effects are caused by NSAIDs also being COX-2 inhibitors, which leads to stomach and intestinal adverse reactions.

Since I have determined that in the case of autism I deal with, the surge in cytokines like IL6 causes behavioral regression, Montelukast might be a good alternative to Ibuprofen to treat some types of autism flare.  

So a new addition to the autism flare-up toolkit, I hope.

  

Ideas not yet in this blog:-

·        Curcumin

Curcumin, and particularly some of the substances within it, have been shown to have very interesting autism-relevant effects, particularly in vitro (in test tubes).  Whether taking curcumin orally, in reasonable doses, produces any of these effects in humans is a big question.  Many such substances like luteolin and resveratrol fail to meet expectations in humans, due to poor bioavailability.

There are various ways to improve the bioavailability of curcumin, so it seems worth investigating.

·        5-loxin

Frankincense has been used for 5,000 years.  More recently, two thousand years ago, three wise men did bring gifts of gold, frankincense, and myrrh.

Frankincense is an aromatic resin obtained from trees of the genus Boswellia.  Boswellia is used for inflammatory conditions like arthritis in a similar way to curcumin.

There are six boswellic acids, one is most active. This fraction is called AKBA. 5-Loxin is a boswellia supplement claiming to deliver a high standardized level of AKBA.

5-Loxin does seem to help some people with arthritis, but does it have any benefit for the pro-inflammatory aspects found in some autism?  I am not expecting much, but you never know.

  

Ideas suggested to me by others, that look interesting:-

·        Mint/Menthol

This is Natasa’s discovery and there is evidence to show that Menthol does indeed affect GABA_A receptors.

Menthol enhances phasic and tonic GABAA receptor-mediated currents in midbrain periaqueductal grey neurons

These results suggest that menthol positively modulates both synaptic and extrasynaptic populations of GABA_A receptors in native PAG neurons. The development of agents that potentiate GABA_A-mediated tonic currents and phasic IPSCs in a manner similar to menthol could provide a basis for novel GABA_A-related pharmacotherapies.

  

·        NIAGEN / Nicotinamide Riboside

This was highlighted by Tyler and is another potential therapy for oxidative stress.  Not as cheap as peppermint, but definitely interesting, perhaps particularly for those with autism and mitochondrial dysfunction.

Also note that there are odd recurring links between some autism and obesity. This is not the first anti-obesity therapy that potentially has some benefit for autism.

The NAD+ Precursor Nicotinamide Riboside Enhances Oxidative Metabolism and Protects against High-Fat Diet-Induced Obesity

Summary

As NAD⁺ is a rate-limiting cosubstrate for the sirtuin enzymes, its modulation is emerging as a valuable tool to regulate sirtuin function and, consequently, oxidative metabolism. In line with this premise, decreased activity of PARP-1 or CD38—both NAD⁺ consumers—increases NAD⁺ bioavailability, resulting in SIRT1 activation and protection against metabolic disease. Here we evaluated whether similar effects could be achieved by increasing the supply of nicotinamide riboside (NR), a recently described natural NAD⁺ precursor with the ability to increase NAD⁺ levels, Sir2-dependent gene silencing, and replicative life span in yeast. We show that NR supplementation in mammalian cells and mouse tissues increases NAD⁺ levels and activates SIRT1 and SIRT3, culminating in enhanced oxidative metabolism and protection against high-fat diet-induced metabolic abnormalities. Consequently, our results indicate that the natural vitamin NR could be used as a nutritional supplement to ameliorate metabolic and age-related disorders characterized by defective mitochondrial function.

  

Nicotinamide Riboside Ameliorates Hepatic Metaflammation by Modulating NLRP3 Inflammasome in a RodentModel of Type 2 Diabetes

Low-grade chronic inflammation (metaflammation) is a major contributing factor for the onset and development of metabolic diseases, such as type 2 diabetes, obesity, and cardiovascular disease. Nicotinamide riboside (NR), which is present in milk and beer, is a functional vitamin B₃ having advantageous effects on metabolic regulation. However, the anti-inflammatory capacity of NR is unknown. This study evaluated whether NR modulates hepatic nucleotide binding and oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome. Male, 8-week-old KK/HlJ mice were allocated to the control or NR group. NR (100 mg/kg/day) or vehicle (phosphate-buffered saline) was administrated by an osmotic pump for 7 days. Glucose control, lipid profiles, NLRP3 inflammasome, and inflammation markers were analyzed, and structural and histological analyses were conducted. NR treatment did not affect body weight gain, food intake, and liver function. Glucose control based on the oral glucose tolerance test and levels of serum insulin and adiponectin was improved by NR treatment. Among tested lipid profiles, NR lowered the total cholesterol concentration in the liver. Histological and structural analysis by hematoxylin and eosin staining and transmission electron microscopy, respectively, showed that NR rescued the disrupted cellular integrity of the mitochondria and nucleus in the livers of obese and diabetic KK mice. In addition, NR treatment significantly improved hepatic proinflammatory markers, including tumor necrosis factor-alpha, interleukin (IL)-6, and IL-1. These ameliorations were accompanied by significant shifts of NLRP3 inflammasome components (NLRP3, ASC, and caspase1). These results demonstrate that NR attenuates hepatic metaflammation by modulating the NLRP3 inflammasome

  

NLRP3 inflammasome and itsinhibitors: a review

  

Activation and regulation of the inflammasomes

  

An apparently crazy idea of my own, but actually serious:-

·        Propolis tincture, without the propolis

The BIO 30 Propolis from New Zealand is a (mild) PAK1 inhibitor.  One reader is convinced of its cognitive enhancing effects in autism .  I also think it had an effect, but in our case not as potent as that reader.  Now I am wondering what was it that produced this effect. 

Most propolis is made as a tincture with ethanol.  Propolis is not soluble in water.  They typically use 70% ethanol to make propolis tincture.  “Non-alcoholic” tinctures use glycol.

In the last post we saw ethanol has pronounced effects on several GABA_A receptor subunits, mainly delta but also alpha, including possibly down regulating alpha 5.

So was it the propolis, or the ethanol that has the effect?

Propolis tincture is either made with ethanol (grain alcohol) or if it is “alcohol free” they use propylene glycol.  Propylene glycol actually is a food ingredient but it is also used to de-ice aircraft in winter.  Ethylene glycol is the antifreeze in your car and you would not want to drink that.

Compared to ethanol, glycol can dissolve less propolis, 

A quick check of school chemistry reminds us that if it is an –ol , it’s an alcohol.

·        Alcohols have at least one hydroxyl group

·        Diols have two hydroxyl groups

Propylene glycol is  C₃H₈O₂  and as you can see below it has two hydroxyl groups (the – OH), so it is both a diol and an alcohol. 

So your Propolis tincture can be ethanol-free, but it cannot be alcohol-free.  Someone might point that out to the supplement makers.

It also should be noted that propylene glycol has known effects on GABA very similar to ethanol.

Propylene glycol elicits anxiolytic responses to the elevated plus-maze in male mice

  

This suggests that the users of ethanol-free BIO30 may also be seeing responses unrelated to propolis.

Propylene glycol even has an E-number, it is E1520.  It is cheap and they even sell it on Amazon.

Food grade ethanol is normally not sold to the public.

In lay terms, ethanol and alcohol are interchangeable, so one corner of the supermarket contains food grade ethanol, with some impurities.

Japanese research suggests that these impurities are much more potent than ethanol in modulating GABA receptors.  It is the fragrant compounds that accumulate over the years on wooden barrels that cause this effect.

The twenty drops of propolis suggested to me by the Japanese PAK1 researcher/doctor contained about 1ml of ethanol.  It seems that to get an effect on GABA similar to this amount of ethanol would require a much smaller amount to well-aged Japanese whiskey.

So if someone over 18 responds well to twenty drops of BIO 30 propolis, it would helpful if they could compare the effect with 1ml of Propylene glycol (E1520), 1ml of ethanol, if they find it, and with a few drops of well-aged whiskey.