Taurine – a cheap Autism intervention worth a trial

 

I did recently write a post all about Taurine and the many effects it has on the body, some of which really should affect autism. 

Taurine for subgroups of Autism? Plus, vitamin B5 and L Carnitine for KAT6A syndrome?

 

Having read the literature, it looked to me that anyone over 50 years old is likely to benefit from a little extra Taurine, but it certainly was not clear whether it would make my 21 year old’s autism better or worse. I went ahead and ordered some to investigate.

In theory one of the many effects of Taurine is negative. Taurine does affect the KCC2 transporter that takes chloride out of neurons the “wrong” way. The other effects include on calcium homeostasis, which we know is disturbed in most autism.

 

N = 2 Trial

Subject #1 (Peter)

I took 2g a day for a month and noticed no effect at all, other than some mild GI irritation.

In adults the long-term effects are numerous and varied throughout the body. Even the cells that remodel your bones (osteoblasts and osteoclasts) have special taurine transporters, whose sole role is to let taurine inside – taurine makes the osteoblasts work harder, while encouraging osteoclasts to take a break. The net effect should be stronger bones.  As you get older your natural levels of taurine fall substantially. There are taurine-rich foods you can eat and if you engage in strenuous exercise your liver starts making more taurine.

 

Subject #2 (Monty)

There is a clear contradiction when it comes to Taurine and sleep. Many energy drinks contain Taurine to keep you alert, but in theory Taurine should be calming and many people take it add bedtime to improve sleep.

Monty, aged 21 with ASD, likes getting up early and going to bed early.

Adding 2g a day of Taurine at breakfast shifted his circadian rhythms, so that he now goes to bed at a time typical for a 21 year old, but still wants to get up at 7am. Monty even fell asleep on the sofa watching TV late one night, something big brother often does. Indeed, Monty received a nod of approval when big brother discovered him in the early hours. 

The most beneficial change has been on his spring and summertime aggression. This has been controlled for years using an L-type calcium channel blocker. This does not resolve the allergy at all, but it “switches off” the consequential anxiety/aggression. With the addition of allergy therapies and the immunomodulation of Pioglitazone (in peak allergy season) the problem behaviors are controlled.

It appears that Taurine has a similar anti-anxiety/aggression effect. Maybe its effect on calcium channels and broader calcium homeostasis is the reason why. Anyway, it works – simple, cheap, OTC and effective.  It has no effect on allergy, in case you are wondering.

  

Conclusion

Taurine can be bought as a bulk powder for very little money. It is not like those numerous expensive supplements that would cost you several hundred dollars/euros/pounds a year.

If you have your own “healthspan polytherapy”, to ward off high blood pressure, high cholesterol, type 2 diabetes, dementia, arthritis, osteoporosis etc, consider spending a few pennies more and add a scoop of taurine.

The people who write to me and tell me how Verapamil has transformed life at home, by banishing aggression and self-injurious behaviors, should seriously consider a trial of Taurine.

 

Glass Syndrome / SATB2-associated syndrome – Osteoporosis and ERβ

The world’s longest glass bridge is in China.

Today’s post is about Glass Syndrome / SATB2-associated syndrome, it occurs when something goes wrong with a gene called SATB2; there are several variants because different mutations in this gene are possible.

Glass Syndrome / SATB2-associated syndrome is another of those single gene types of autism, so you can think of SATB2 as another autism gene.  As we will see in today’s post SATB2 is involved in much more than autism and is very relevant to osteoporosis and some types of cancer.

While autism caused by SATB2 is very rare, diseases in old age quite often involve the SATB2 gene being either over expressed or under expressed. As a result there is much more research on SATB2 than I expected.

The current research into Glass Syndrome / SATB2-associated syndrome is mainly collecting data on those affected, rather than investigating therapies. There are some links later in this post, for those who are interested.

The research into SATB2, unrelated to childhood developmental disorders, is much more science heavy and already contains some interesting findings.   

I have only made a shallow study, but it seems that you can reduce SATB2 expression with a drug called Phenytoin and potentially increase expression via an estrogen receptor beta agonist. We saw in earlier posts that an estrogen receptor beta agonist might well be helpful in broader autism.

As with other single gene types of autism, it will be important to look at all the downstream effects caused by a lack of SATB2, some of which will very likely overlap with what occurs in some idiopathic autism or with other single gene autisms.

In Johns Hopkins’ simplification of autism into either hyper-active pro growth signaling, or hypo-active, SATB2 fits into the latter. It is associated with small heads and a small corpus callosum; that is the part that joins the left side of the brain to right side.

I think it is fair to say that SATB2 is associated with partial agenesis of the corpus callosum (ACC), a subject that has been covered in earlier posts.

I have mentioned two therapies recently that seem to help in certain variants of  ACC. The reason SATB2 causes partial agenesis of the corpus callosum (ACC) is well understood.  SATB2 needs to be expressed in the neurons that extend axons across the corpus callosum, in effect you need to build a bridge across from one side of the brain to the other and all the connections across that bridge need to match up and not be jumbled up. In some people with SATB2 they have an apparently normal corpus callosum (the bridge) but it does not work properly (the connections do not function).

SATB2 is also associated with a cleft palette, this occurs because the roof of the mouth (another bridge) does not join correctly left to right. You end up with an unwanted opening into the nose.

Building bridges is never an easy business. The Chinese have found this with their recent glass bridges, as in this post’s photo above. It looks like SATB2 is the “bridging” protein for humans, if the SATB2 gene is mutated you do not make enough of the SATB2 protein. The less SATB2 expression the more consequences there will be.

The other extreme also exists, too much SATB2 expression. That will lead to too much growth which makes it another cancer gene. In cases of aggressive prostate cancer SATB2 is over-expressed. So a therapy to slow this cancer would be to reduce SATB2 expression. For Glass Syndrome we would want the opposite. 

There is SATB2 associated syndrome research, but it is still at the stage of collecting data on people who are affected and investigating what particular mutation is present.

The logical next stage is to see more precisely the role SATB2 plays in different parts of the brain. By seeing how SATB2 interacts with the world around it, it may be possible to correct for the lack of it.  For example there is an interaction with Ctip2, a transcription factor that is necessary and sufficient for the extension of subcortical projections by cortical neurons. This look very relevant to building bridges.

Confusingly, Ctip2 is also called B-cell lymphoma/leukemia 11B encoded by the BCL11B gene. 

A dual function of Bcl11b/Ctip2 in hippocampal neurogenesis.

BCL11B/CTIP2 is highly expressed in GABAergic interneurons of the mouse somatosensory cortex

The research relating your bones looks the most advanced and already suggests possible therapies to both increase and reduce SATB2 expression.

The role of SATB2 in skeletogenesis and human disease

The above paper (the full version is not public)  is very detailed and shows how important SATB2 may be in bone diseases and therefore be of wide clinical relevance.  It also suggests that it could be treated by gene therapy.

Molecular Regulation of SATB2 by Cytokines and Growth Factors

It appears that the anti-epileptic drug (AED) Phenytoin reduces SATB2 expression, which is the opposite of what we want, but shows that modification is possible.

Osteoporosis,  SATB2, Estrogen and ERβ

There already is much in this blog about estrogen/estradiol and estrogen receptor beta. There are was a phase in this blog when there were many comments about disturbed calcium metabolism in family members.

It appears they may be connected via SATB2.

Older people lack estrogen, particularly females, and this is associated with osteoporosis.

Very recent research shows that there is an ERβ-SATB2 pathway (ERβ = estrogen receptor beta, which is activated by estrogen). So a reduction in estrogen during aging reduces signaling along the ERβ-SATB2 pathway (making less SATB2).

We know from earlier posts that people with autism tend to have a reduced number of ERβ receptors and also a lower level of estrogen/estradiol. This might explain some of the problems readers reported with bones in their family members.

This raises the question of what happens to SATB2 expression when you add a little extra estrogen/estradiol. The implication from the Chinese study highlighted later is that this may well be one way to make more SATB2 from the non-mutated copy that you have (you likely have one mutated copy and one clean copy of this gene). This is something that should be investigated.

How to treat Glass Syndrome/SATB2?

Ideally you would use gene therapy to treat Glass Syndrome/SATB2; this will in future decades very likely be possible.  In the meantime the more old-fashioned options must be relied upon.

We know that people with partial agenesis of the corpus callosum (ACC) face challenges, some of which match those faced  with Glass Syndrome/SATB2. We know certain types of ACC do respond to treatment, based on research, so it would seem highly likely that treatment for  Glass Syndrome/SATB2 should be possible.

Very likely some of the myriad of treatments researched for autism may be helpful. But which ones?

The treatment proposed by Knut Wittkowski for very early intervention in idiopathic autism to alter the trajectory from severe autism towards Asperger’s looks interesting and particularly because our reader Ling finds it helpful for her daughter with SATB2. Knut’s research identified Ponstan (mefenamic acid) as a target drug to minimize the cascade of damaging events that occurs as autism progresses in early childhood.

Here you would hope that some researcher would create a mouse model of Glass Syndrome/SATB2 and then see if Ponstan (mefenamic acid) has any effect, not to mention estradiol.

Websites with Information on Glass Syndrome/ SATB2 associated syndrome 

http://satb2gene.com/

http://onlinelibrary.wiley.com/doi/10.1002/ajmg.a.38022/pdf

https://ghr.nlm.nih.gov/condition/satb2-associated-syndrome#synonyms

Some Research Relating to SATB2

Satb2 Regulates Callosal Projection Neuron Identity in the Developing Cerebral Cortex

Satb2 is a DNA-binding protein that regulates chromatin organization and gene expression. In the developing brain, Satb2 is expressed in cortical neurons that extend axons across the corpus callosum. To assess the role of Satb2 in neurons, we analyzed mice in which the Satb2 locus was disrupted by insertion of a LacZ gene. In mutant mice, β-galactosidase-labeled axons are absent from the corpus callosum and instead descend along the corticospinal tract. Satb2 mutant neurons acquire expression of Ctip2, a transcription factor that is necessary and sufficient for the extension of subcortical projections by cortical neurons. Conversely, ectopic expression of Satb2 in neural stem cells markedly decreases Ctip2 expression. Finally, we find that Satb2 binds directly to regulatory regions of Ctip2 and induces changes in chromatin structure. These data suggest that Satb2 functions as a repressor of Ctip2 and regulatory determinant of corticocortical connections in the developing cerebral cortex.

Ctip2 Controls the Differentiation of Medium Spiny Neurons and the Establishment of the Cellular Architecture of the Striatum

Striatal medium spiny neurons (MSN) are critically involved in motor control, and their degeneration is a principal component of Huntington's disease. We find that the transcription factor Ctip2 (also known as Bcl11b) is central to MSN differentiation and striatal development. Within the striatum, it is expressed by all MSN, although it is excluded from essentially all striatal interneurons. In the absence of Ctip2, MSN do not fully differentiate, as demonstrated by dramatically reduced expression of a large number of MSN markers, including DARPP-32, FOXP1, Chrm4, Reelin, MOR1 (μ-opioid receptor 1), glutamate receptor 1, and Plexin-D1. Furthermore, MSN fail to aggregate into patches, resulting in severely disrupted patch-matrix organization within the striatum. Finally, heterotopic cellular aggregates invade the Ctip2^−/− striatum, suggesting a failure by MSN to repel these cells in the absence of Ctip2. This is associated with abnormal dopaminergic innervation of the mutant striatum and dramatic changes in gene expression, including dysregulation of molecules involved in cellular repulsion. Together, these data indicate that Ctip2 is a critical regulator of MSN differentiation, striatal patch development, and the establishment of the cellular architecture of the striatum.

Upregulation of SATB1 Is Associated with Prostate Cancer Aggressiveness and Disease Progression

Genotype and Phenotype in 12 additional individuals withSATB2-Associated Syndrome

SATB2-Associated Syndrome

Neuroimaging. Brain abnormalities, documented in half of affected individuals who underwent head MRI, include nonspecific findings such as enlarged ventricles (12%), agenesis of the corpus callosum (5%), and prominent perivascular spaces (5%). Of interest, abnormal myelination for age and/or non-progressive white matter abnormalities appear to be particularly common (26%) in those with pathogenic nonsense, frameshift, and missense variants [Zarate & Fish 2017, Zarate et al 2017a]. Note that these findings are not sufficiently distinct to specifically suggest the diagnosis of SAS.

Other neurologic manifestations

·         Hypotonia, particularly during infancy (42%)

·         Clinical seizures (14%)

·         EEG abnormalities without clinically recognizable seizures [Zarate et al 2017a]

·         Less common neurologic issues include gait abnormalities/ataxia (17%), hypertonicity and/or spasticity (4%), and hyperreflexia (3%).

Growth restriction. Pre- and postnatal growth restriction, sometimes with associated microcephaly, can be found in individuals with SAS, particularly in those with large deletions involving SATB2 and adjacent genes (71%).

This is likely to be the most relevant paper, even though the tittle might not suggest it:-

Estrogen regulates stemness and senescence of bone marrow stromal cells to prevent osteoporosis via ERβ-SATB2 pathway

Decline of pluripotency in bone marrow stromal cells (BMSCs) associated with estrogen deficiency leads to a bone formation defect in osteoporosis. Special AT-rich sequence binding protein 2 (SATB2) is crucial for maintaining stemness and osteogenic differentiation of BMSCs. However, whether SATB2 is involved in estrogen-deficiency associated-osteoporosis is largely unknown. In this study, we found that estrogen mediated pluripotency and senescence of BMSCs, primarily through estrogen receptor beta (ERβ). BMSCs from the OVX rats displayed increased senescence and weaker SATB2 expression, stemness, and osteogenic differentiation, while estrogen could rescue these phenotypes. Inhibition of ERβ or ERα confirmed that SATB2 was associated with ERβ in estrogen-mediated pluripotency and senescence of BMSCs. Furthermore, estrogen mediated the upregulation of SATB2 through the induction of ERβ binding to estrogen response elements (ERE) located at -488 of the SATB2 gene. SATB2 overexpression alleviated senescence and enhanced stemness and osteogenic differentiation of OVX-BMSCs. SATB2-modified BMSCs transplantation could prevent trabecular bone loss in an ovariectomized rat model. Collectively, our study revealed the role of SATB2 in stemness, senescence and osteogenesis of OVX-BMSCs. Collectively, these results indicate that estrogen prevents osteoporosis by promoting stemness and osteogenesis and inhibiting senescence of BMSCs through an ERβ-SATB2 pathway.

Therefore, SATB2 is a novel anti-osteoporosis target gene.

3.2 Estrogen enhanced SATB2 levels, pluripotency and alleviated senescence of OVX-BMSCs.

Estrogen has been shown to promote bone formation and proliferation both in vivo and in vitro (Wang, J. et al., 2014; Du, Z. et al., 2015; Kim, R. Y. et al., 2015), so we asked whether estrogen affected SATB2 expression, stemness and osteogenic differentiation of BMSCs. We found that both Sham-BMSCs and OVX-BMSCs treated with 10-8M estrogen (Matsumoto, Y. et al., 2013) regained the colony forming capacity as compared to the control (Fig. 2A). Higher expression levels of SATB2, Nanog, Sox2 and Oct4, were observed in BMSCs treated with estrogen relative to the control group (Fig. 2B, C). These results were further confirmed by human BMSCs (Fig. 2D). The role of estrogen on anti-senescence was verified by the decreased SA-β-gal positive cells and alleviated expression of senescence markers (Fig. 2E, F). After osteogenic induction, the expression of osteogenic markers, Runx2 and OCN, significantly increased (Fig. 2G and H). Consistently, estrogen significantly enhanced the mineralized node formation (Fig. 2I). Interestingly, the expression of osteoclast-related activator, RANKL, and inhibitor, OPG, significantly changed in OVX-BMSCs treated with estrogen (Fig. 2J).

Together, these results suggest that estrogen rescued pluripotency and alleviated senescence of OVX-BMSCs accompanied by a higher expression of SATB2.

3.4 SATB2 is a confirmed target of ERβ.  

Estrogen is known to regulate gene expression by binding to ERs, which subsequently binds to EREs present in promoters (Klinge, C. M. 2001). Analysis of 2 kb upstream and 50bp downstream of SATB2, using Promo 3.0 software, showed the presence of three putative EREs that had (achieved through site-directed mutagenesis at the ERβ binding site in the SATB2 promoter). As anticipated, ERβ overexpression induced by estrogen increased luciferase activity in wild-type but not mutant promoter region A (Fig. 4C, D). 

 Further, to check dynamic recruitment of ERβ to the EREs following estrogen treatment, we used chromatin immunoprecipitation (CHIP). CHIP analysis was conducted in OVX-BMSCs with or without estrogen treatment using antibodies specific to ERβ or IgG control. This revealed that following estrogen treatment, various putative EREs facilitated dynamic recruitment of ERβ. Furthermore, the binding of ERβ was considerably more robust in region A than other regions (Fig. 4E). Thus, the induction of SATB2 by estrogen is mediated by the binding of ERβ to various EREs present in the SATB2 promoter.

Discussion

Although it is well-known that osteoporosis due to estrogen deficiency is associated with bone loss, the detailed mechanisms underlying this are not fully understood (Liao, L. et al., 2013; Villa, A. et al., 2015; Wang, J. et al., 2016). We recently found that the expression of SATB2 was associated with ERs, especially ERβ, after estrogen treatment of BMSCs (Fig. 3A). In this study, we successfully established an ovariectomized rat model of postmenopausal osteoporosis and showed that STAB2 was associated with estrogen-ERβ complex in OVX-BMSCs. Moreover, our data demonstrated that SATB2 was a downstream effector of ERβ. The induction of SATB2 by estrogen was mediated by binding of ERβ to various EREs present upstream of SATB2. Our study suggested the central role of SATB2 in the etiology of postmenopausal osteoporosis, suggesting it as a candidate target of osteoporosis prevention and treatment.

                                                                                                                                 

Conclusion

Our reader Ling is busy researching this syndrome and this is a good place to post comments with her findings, so others can find them later.

Combatting Brain Calcification in Some Autism (and Bipolar and Schizophrenia) and Osteoprotegerin (OPG) as a potential biomarker, implicating Cav1.2

In today’s post there is more supposition than normal, but plenty of anecdotal evidence.  It follows on from the previous post that suggested calcification might be an issue in some types of autism.  As we know, many unrelated biological dysfunctions can lead to autism, but there do seem to be some commonly affected pathways.

This subject is definitely worthy of much more detailed study than my post, which is based on an initial review of the science.  Some leading researchers, like Persico and Courchesne are fully aware of the issue.  I am not sure who would undertake such a study.  There is no physician specialty dedicated solely to osteoporosis, so we are lacking experts.  The bone-vascular axis is worthy of more study, as much for heart disease as autism.

A variety of medical specialists treat people with osteoporosis, including internists, gynecologists, family physicians, endocrinologists, rheumatologists, physiatrists, orthopaedists, and geriatricians.  If you do not know what a physiatrist is, I also had to look it up.  Physical Medicine and Rehabilitation (PM&R) physicians, also known as physiatrists, treat a wide variety of medical conditions affecting the brain, spinal cord, nerves, bones, joints, ligaments, muscles, and tendons.

 

Overview

There is more support for the potential use of calcium channel blockers that affect Cav1.2, via its effect on calcification by modulating Osteoprotegerin (OPG).  OPG is known to be elevated in autism and its two older brothers schizophrenia and bipolar.

It appears that in some people with severe brain calcification, that shows up on CT scans, biphosphanate drugs can be helpful, but do not actually shrink the calcification, perhaps they stop it growing.

Biphosphanate drugs used to treat osteoporosis are not without side effects in some people.

Some people have disturbed calcium homeostasis as a result of drugs they are taking, for example antiepileptic drugs.

So-called “chelation” using powerful intravenous antioxidants has been shown in the TACT clinical trial to reduce future heart problems, but only in people with diabetes. Diabetics are known to have disturbed calcium homeostasis leading to calcification, heart disease and osteoporosis.

In some counties intravenous antioxidants have long been given to people with diabetes to treat its main side effects but not to clear calcification.  In those countries this is seen as perfectly safe and routine. Preventative care for diabetics is actually rather poor in the UK and US.

Vitamin K plays a key role in calcium homeostasis and in some people just giving large amounts of this vitamin has the required therapeutic effect.  Unless given alongside blood thinning drugs, it is claimed that high dose Vitamin K does not have side effects.

Perhaps the most common osteoporosis therapy, calcium plus vitamin D is shown in some trials to be of no value whatsoever.  This therapy would most likely be ill advised in autism.

Osteoprotegerin (OPG)

Osteoprotegerin (OPG) is a cytokine involved in calcification and inflammation.

Osteoprotegerin has been used experimentally to decrease bone resorption in women with postmenopausal osteoporosis.

 It has been particularly related to the increase in cardiovascular risk in patients suffering from diabetes

Interestingly it has been shown that the L type calcium channel Cav1.2 regulates Osteoprotegerin (OPG) expression and secretion.

A NASA space shuttle flight in 2001 tested the effects of osteoprotegerin on mice in microgravity, finding that it did prevent increase in resorption and maintained bone mineralization.  Space flight is not good for your bones.

Osteoprotegerin levels are elevated in people with bipolar and schizophrenia.

Osteoprotegerin levels in patients with severe mental disorders

Severe mental disorders are associated with elevated levels of inflammatory markers. In the present study, we investigated whether osteoprotegerin (OPG), a member of the tumour necrosis factor receptor family involved in calcification and inflammation, is elevated in patients with severe mental disorders.

Methods

We measured the plasma levels of OPG in patients with severe mental disorders (n = 312; 125 with bipolar disorder and 187 with schizophrenia) and healthy volunteers (n = 239).

The mean plasma levels of OPG were significantly higher in patients than in controls (t₅₃₁ = 2.6, p = 0.01), with the same pattern in bipolar disorder and schizophrenia. The increase was significant after adjustment for possible confounding variables, including age, sex, ethnic background, alcohol consumption, liver and kidney function, diabetes, cardiovascular disease, autoimmune diseases and levels of cholesterol, glucose and C-reactive protein.

Conclusion

Our results indicate that elevated OPG levels are associated with severe mental disorders and suggest that mechanisms related to calcification and inflammation may play a role in disease development.

As shown in the study below, many inflammatory cytokines are elevated in autism, just look at those insulin-like growth factor binding proteins.  Osteoprotegerin is a modest 500% of what it might be expected to be in non autism.

Neuroglial Activation and Neuroinflammation in the Brain of Patients with Autism

Chelation

Because of the continuing non-debate in scientific terms about vaccines and autism, it is unlikely that there will ever be any study about calcium chelation and autism.  Rather than admit that in a small number of cases vaccination may trigger mitochondrial disease and result in autism, there is complete denial, at least in public. In private it is an open secret.

The planned chelation trial in autism was banned, on “safety grounds”.

It looks to me that the enemy is not mercury or other heavy metals, the problem is much less exotic. 

Oxidative Stress

Most people with autism have oxidative stress, which should be improved by any potent antioxidant.  Agents used to chelate metals have to be potent antioxidants.

Calcification

In some yet to be determined percentage of people they potentially have disturbed calcium homeostasis resulting in some calcium deposits in the brain.  Those chelating to remove, most likely non-existing, “toxins” may sometimes be reducing harmful calcification.

Fortunately there has been a very large study, called TACT, on de-calcification (calcium chelation) in Coronary Heart Disease.

One large group of people at risk from low bone density are those with diabetes.

Patients with diabetes, who made up approximately one third of the 1,708 TACT participants, had a 41 percent overall reduction in the risk of any cardiovascular event; a 40 percent reduction in the risk of death from heart disease, nonfatal stroke, or nonfatal heart attack; a 52 percent reduction in recurrent heart attacks; and a 43 percent reduction in death from any cause.

   

Chelation for Coronary Heart Disease

§  Patients with diabetes, who made up approximately one third of the 1,708 TACT participants, had a 41 percent overall reduction in the risk of any cardiovascular event; a 40 percent reduction in the risk of death from heart disease, nonfatal stroke, or nonfatal heart attack; a 52 percent reduction in recurrent heart attacks; and a 43 percent reduction in death from any cause. In contrast, there was no significant benefit of EDTA treatment in participants who didn't have diabetes.

Source:  https://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_446204.pdf

From the Mayo Clinic:-

          Results of trial to assess chelation therapy (TACT) study presented

 A further review from TACT just looking at patients with diabetes:- 

The Effect of an EDTA-based Chelation Regimen on Patients with Diabetes and Prior Myocardial Infarction in TACT

Patients with diabetes:-

Patients without diabetes (no benefit over placebo):-

Treatment

The 10 component 500 mL intravenous solution in TACT consisted of 3 g of disodium EDTA, adjusted downward based on estimated glomerular filtration rate; 7 g of ascorbic acid; 2 g of magnesium chloride; B-vitamins, and other components (eTable 4). The placebo solution consisted of 500 mL of normal saline and 1.2% dextrose (2.5 g total). The solution was infused over at least 3 hours through a peripheral intravenous line weekly for 30 weeks and then biweekly to bimonthly to complete 40 infusions.

Background

The Trial to Assess Chelation Therapy (TACT) showed clinical benefit of an ethylene diamine tetraacetic acid (EDTA-based) infusion regimen in patients 50 years or older with prior myocardial infarction (MI). Diabetes prior to enrollment was a pre-specified subgroup.

Methods and Results

Patients received 40 infusions of EDTA chelation or placebo. 633 (37%) had diabetes (322 EDTA, 311 placebo). EDTA reduced the primary endpoint (death, reinfarction, stroke, coronary revascularization, or hospitalization for angina) [25% vs 38%, hazard ratio (HR) 0.59, 95% confidence interval (CI) (0.44, 0.79), p<0.001] over 5 years. The result remained significant after Bonferroni adjustment for multiple subgroups (99.4% CI (0.39, 0.88), adjusted p=0.002). All-cause mortality was reduced by EDTA chelation [10% vs 16%, HR 0.57, 95% CI (0.36, 0.88) p=0.011], as was the secondary endpoint (cardiovascular death, reinfarction, or stroke) [11% vs 17% HR 0.60, 95% CI (0.39, 0.91), p=0.017]. After adjusting for multiple subgroups, however, those results were no longer significant. The number needed to treat to reduce one primary endpoint was 6.5 over 5 years (95% CI (4.4, 12.7). There was no reduction in events in non-diabetics (n=1075, p=0.877), resulting in a treatment by diabetes interaction (p=0.004).

Conclusions

Post-MI diabetic patients age 50 or older demonstrated a marked reduction in cardiovascular events with EDTA chelation. These findings support efforts to replicate these findings and define the mechanisms of benefit. They do not, however, constitute sufficient evidence to indicate the routine use of chelation therapy for all post-MI diabetic patients.

Effect of the Polypill on Calcification

Oral antioxidants like NAC and Alpha lipoic Acid given daily will have both a direct and indirect “chelating” effect.

Alpha-Lipoic Acid Promotes Osteoblastic Formation in H2O2 -Treated MC3T3-E1 Cells and Prevents Bone Lossin Ovariectomized Rats.

 

Alpha-lipoic acid (ALA), a naturally occurring compound and dietary supplement, has been established as a potent antioxidant that is a strong scavenger of free radicals. Recently, accumulating evidences has indicated the relationship between oxidative stress and osteoporosis (OP). Some studies have investigated the possible beneficial effects of ALA on OP both in vivo and in vitro; however, the precise mechanism(s) underlying the bone-protective action of ALA remains unclear. Considering this, we focused on the anti-oxidative capacity of ALA to exert bone-protective effects in vitro and in vivo. In the present study, the effects of ALA on osteoblastic formation in H(2)O(2) -treated MC3T3-E1 pre-osteoblasts and ovariectomy (OVX)-induced bone loss in rats were investigated. The results showed that ALA promoted osteoblast differentiation, mineralization and maturation and inhibited osteoblast apoptosis, thus increasing the OPG/receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) ratio and leading to enhanced bone formation in vitro and inhibited bone loss in vivo. Further study revealed that ALA exerted its bone-protective effects by inhibiting reactive oxygen species (ROS) generation by down-regulating Nox4 gene expression and protein synthesis and attenuating the transcriptional activation of NF-κB. In addition, ALA might exert its bone-protective effects by activating the Wnt/Lrp5/β-catenin signaling pathway. Taken together, the present study indicated that ALA promoted osteoblastic formation in H(2)O(2) -treated MC3T3-E1 cells and prevented OVX-induced bone loss in rats by regulating Nox4/ROS/NF-κB and Wnt/Lrp5/β-catenin signaling pathways, which provided possible mechanisms of bone-protective effects in regulating osteoblastic formation and preventing bone loss. Taken together, the results suggest that ALA may be a candidate for clinical OP treatment.

Statins are known to promote bone health.

Statins and osteoporosis:new role for old drugs.

Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to significant morbidity and high expenditure. Most of the current therapies available for its treatment are limited to the prevention or slowing down of bone loss rather than enhancing bone formation. Recent discovery of statins (HMG-CoA reductase inhibitors) as bone anabolic agents has spurred a great deal of interest among both basic and clinical bone researchers. In-vitro and some animal studies suggest that statins increase the bone mass by enhancing bone morphogenetic protein-2 (BMP-2)-mediated osteoblast expression. Although a limited number of case-control studies suggest that statins may have the potential to reduce the risk of fractures by increasing bone formation, other studies have failed to show a benefit in fracture reduction. Randomized, controlled clinical trials are needed to resolve this conflict. One possible reason for the discrepancy in the results of preclinical, as well as clinical, studies is the liver-specific nature of statins. Considering their high liver specificity and low oral bioavailability, distribution of statins to the bone microenvironment in optimum concentration is questionable. To unravel their exact mechanism and confirm beneficial action on bone, statins should reach the bone microenvironment in optimum concentration. Dose optimization and use of novel controlled drug delivery systems may help in increasing the bioavailability and distribution of statins to the bone microenvironment. Discovery of bone-specific statins or their bone-targeted delivery offers great potential in the treatment of osteoporosis. In this review, we have summarized various preclinical and clinical studies of statins and their action on bone. We have also discussed the possible mechanism of action of statins on bone. Finally, the role of drug delivery systems in confirming and assessing the actual potential of statins as anti-osteoporotic agents is highlighted.

Verapamil via the effect on OPG should have positive effect on bones and reduce vascular calcification.

Use of Biphosphanate Drugs to Treat Brain Calcification

Primary brain calcification in patients undergoing treatment with the biphosphanate alendronate

Brain calcification might be associated with various metabolic, infectious or vascular conditions. Clinically, brain calcification can include symptoms such as migraine, Parkinsonism, psychosis or dementia. The term Primary Brain Calcification was recently used for those patients without an obvious cause (formerly idiopathic) while Primary Familial Brain Calcifications was left for the cases with autosomal dominant inheritance. Recent studies found mutations in four genes (SLC20A2,PDGFRB, PDGFB and XPR1). However, these genes represent only 60% of all familial cases suggesting other genes remain to be elucidated. Studies evaluating treatments for such a devastating disease are scattered, usually appearing as single case reports. In the present study, we describe a case series of 7 patients treated with Alendronate, a widely prescribed biphosphanate. We observed good

tolerance and evidence of improvements and stability by some patients. No side effects were reported and no specific symptoms related to medication. Younger patients and one individual continuing a prescription (prior to study commencement) appeared to respond more positively with some referred improvements in symptoms. Biphosphanates may represent an excellent prospect for the treatment of brain calcifications due to their being well tolerated and easily available. Conversely, prospective and controlled studies should promptly address weaknesses found in the present analysis.

Patient 3. A 43-year-old man, one of seven children born to the same mother (described below as Patient 4), presented with rapid progression of parkinsonism. In the last 5 years, a progressive presentation of general bradykinesia, rigidity, and paresis in the right arm had developed. He had previously been an active individual with regular employment. Prior to recruitment, this patient had been on carbidopa/levodopa, which was continued throughout the duration of the present study. Genetic screening identified a SLC20A2 mutation (c.1483 G > A)3, and the patient was placed on alendronate therapy.

Patient 4. This 84-year-old woman presented with mild depression, late-stage parkinsonism, and large calcifications (10.85 cm3) in the basal ganglia and cerebellum. She is the mother of Patient 3 and carries the same SLC20A2 mutation. This patient had been taking alendronate for 10 years due to a diagnosis of osteoporosis. Intriguingly, she presented with fewer symptoms than her son, despite being 41 years old older.

We chose alendronate due to its availability, safety, and comfortable dosing schedule (oral administration, once a week). Etidronate probably works via a different mechanism (bulk action binding to hydroxyapatite) than

the newer amino bisphosphonate alendronate (inhibition of osteoclasts). This might explain why the effects seen in our series were less dramatic than those seen in patients treated with etidronate. Thus, while alendronate has a more convenient dosing schedule and, possibly, fewer side effects, a larger clinical trial should consider the choice of bisphosphonate carefully.

To date, there is no specific treatment for primary brain calcification; the main goal is symptom management.

Clinicians should make sure that the idiopathic/primary profile is accurately defined to rule out any underlying organic cause, e.g., in non-idiopathic basal ganglia calcification caused by abnormal calcium regulation, such as in primary endocrine disorders.

Bisphosphonates represent the only effective (although still anecdotal) treatment that could have wider applications in basal ganglia calcification. Prospective, controlled studies should be conducted to address the weaknesses of the present manuscript and establish a definitive analysis of bisphosphonate therapy for primary brain calcification. Furthermore, the excellent tolerability profile of alendronate in primary brain calcifications suggests that a trial in asymptomatic patients could help address the potential benefit of this strategy to control symptoms in younger patients.

Conclusion

Bisphosphonates may be applicable, safe and change the natural progression of primary brain calcifications, especially in younger patients and across prolonged periods. Nevertheless, future studies with adequate design should answer remaining questions.

Metabolic Bone Diseases

There are numerous things that can affect the bone-vascular axis including various  metabolic diseases.  This is rather beyond the scope of an autism blog, but if you are interested here is a link.

Imaging Findings and Evaluation of Metabolic Bone Disease

Conclusion

Unless you have evidence of osteoporosis, or a brain scan showing calcification, it might be rather extreme to take a biphosphanate drug like Fosamax.

If you already take oral NAC , ALA or L-carnitine you have a pretty potent therapy which would target any calcification, if indeed it existed.  Intravenous ALA, as used my Monty’s Grandad for years, should be even more effective as it is for diabetic neuropathy.

Those using verapamil appear to have another layer of protection against calcification. I did suggest to Agnieszka that elevated OMG might indeed be the biomarker needed for the use of verapamil in Autism. Remember to contact her to participate in her study.

Verapamil use in Autism – Request for Case Reports from Parents

Vitamin K2 is claimed to be extremely safe unless you are taking a blood thinning drug like Warfarin, that are Vitamin K antagonists.

Some studies claim great results from K2, while some others are more mixed.  It is likely that depending on what underlying dysfunction exists, high dose K2 may help or do nothing.  It is clear that low amounts of K2 are damaging.

So K2 would seem worthwhile trialing.  It is found in the not so pleasant tasting Natto.  Vitamin K (more K1 than K2) is found in broad-leafed vegetables.  The excellent Linus Pauling Institute reviewed all the vitamin K evidence and concluded people should:-

 “eat at least one cup of dark green leafy vegetables daily”

This brings me back to where I started the previous post with the Mediterranean diet, rich in dark green leafy vegetables.

Intravenous infusion of antioxidants looks like a very good idea for people with diabetes.  Where we live this has been standard practice for years, where Monty’s grandad goes twice a year for 10 days of ALA infusion, the rest of the year he is prescribed oral ALA.  This is given to control diabetic neuropathy, but clearly a side effect is that it will reduce the likelihood of a heart attack or stroke.

I have no doubt IV infusion of ALA would be beneficial for some with autism, but I think they might get sufficient benefit from oral ALA or indeed NAC.

I wish the FDA would permit the “chelation” autism trial in the US, I have no doubt it would show a positive effect, but not for the reasons put forward by DAN doctors and the chelation cults. 

The TACT chelation trial in older people showed that the therapy was very well tolerated.  IV ALA therapy is also well tolerated.

Public health officials should not fear the truth.  In the long run the truth is the best policy and when given all the facts the public are not stupid.  If vaccination is in the interest of their child, enough parents will happily cooperate. The Herd Immunity Threshold (HIT) is the percentage of people who need to be vaccinated.  HIT is 95% for measles.  Therapies used at Johns Hopkins exist to minimize the possible damaging effect on mitochondria and never give paracetamol/acetaminophen to children after a vaccination.