Dr. Wakefield Sues Brian Deer and BMJ's Fiona Godlee
That’s My Boy!

The Inflammation Highway: aka Autism

  Tummy-ache-abdominal-pain-t13513By Lisa Goes

"The one thing about my husband and I...we laugh...A lot. We find a way. We really do. Poop filled sleepless nights, injuries, missed appointments, clutter everywhere, missing paperwork...sometimes all you can do is laugh. But today, looking at the dark circles we've seen so many times under our children's eyes, seeing the suffering, the real genuine human suffering that we have worked for three years to alleviate...to see it reach these depths...there is no laughing today. There is sadness. Even the fight is gone. I should be sleeping, but I have to read up on one of our new remedies. Maybe this will be the one that touches his immune damage and regulates him? Maybe. Maybe, it will work for him like it has for THOUSANDS of other children. Maybe. I can't sleep when this could be it and I could be calling the next doctor tomorrow and we could have one less day of this. Plus, I already have an appointment to see a doctor tomorrow and I will need him to know that I know what I'm talking about. If there is one thing you learn as an autism parent it is that YOU MUST KNOW WHAT YOU ARE TALKING ABOUT WITH DOCTORS. You must learn to speak their language. If you don't you will get dismissed. Must read, now.

But, before I go, just need to let everyone know the women who work for us are angels from God. They were hurt today. Two of them. In their sweetest voices they kept repeating, "nice hands." And "time to get down monkey" when he climbed on the counter for the 27th time on their shift. He is 50 lbs now. Very fast and very strong. They get him. They see the real Noah in there, fighting like hell. He is mad. In fact, that's what he said in therapy today, "I'm MAD!" His therapists were thrilled. They were so excited to see him emote appropriately. I agree with them, it's encouraging. It's just that, he's mad he's sick. He's mad his head hurts all the time. He's mad his three year old brother can use the toliet and he cannot. He's mad that his body is rebelling against him and everything hurts. He's mad that in addition to not getting to go where everyone else goes and doing all the fun things other 5 year olds do, he also cannot EAT anything they do. It seems cruel doesn't it? It is.

Autism is the cruelest most malicious, devious, conniving, heinous disease. If you fear the chicken pox or diarrhea more you are in big, big trouble. Because I guarantee with the new schedule autism will come a knocking at your door. And it will get in. It finds a way. Sometimes it looks like OCD, sometimes it looks like ADHD, even arthritis. "That's nuts!", you say. Not really. It should all just be called autism. Because any time pharma causes inflammation they don't want you to find out about, they just make up a word for it. Autism. Asthma. ADD. Just made up words for inflammation. Off to read ABOUT AUTISM . It's a good one, you might want to check it out yourself... Much hope for all our beautiful children. xo lj "

Lisa Goes is Contributing Editor to Age of Autism.



Hi Benedetta, good to hear from you.

There are a number of things happening and contributing to the whole of the system dysfunction. I have mentioned aldehydes and alcohol/ethanol related genes in the past and Candida's contribution with aldehydes. This next report is long , but very good and it speaks of endogenous and exogenous aldehydes as they may pertain to autism. Getting the yeast under control was very helpful in our case.

The Pivotal Role of Aldehyde Toxicity in Autism Spectrum Disorder: The Therapeutic Potential of Micronutrient Supplementation

Aldehydes generated by gut microbiota
"Gastrointestinal abnormalities are common among those suffering from neurodevelopmental disorders, including ASD. In addition to malabsorption problems in unhealthy intestines, abnormal microbiota of the gut appear to be contributing factors in ASD mouse models28 as well as in humans.29 One suggested explanation is that yeast and bacterial gut flora generate toxins, including alcohols and aldehydes, such as methylg-lyoxal,30 during the metabolism of various carbohydrates. Methylglyoxal is a potent aldehyde implicated in numerous disorders.3 Certainly, Candida infections common in ASD31 have long been suspected of converting carbohydrates into ethanol,32 which is subsequently metabolized to the potent neurotoxin, acetaldehyde. Alterations in the normal gut microflora of mice have also been linked to oxidative stress.33 Research into the microbiota–gut–brain axis in neurodevelopmental disorders is in its earliest stages, but aldehydes may play an important role."...

"Taken together, aldehyde toxicity induces micronutrient deficiencies in sulfur-containing antioxidants, Zn2+, B6, B1, Mg2+, and folate, creating oxidative stress and disruptions in a cascade of metabolic reactions."



You have hit on a lot of great things - almost information overload since I got behind. Sorry.

Vasculitiis of the peripheral small capillaries was a good one article.

You hit upon Parkinson disease along those same lines. I am worried about just that for my son. I am worried about early on set Parkinson. My Father has it, and my son tends toward constipation.

I am making Kimchi right now. I raised the prettiest Nappa cabbage this spring. They have a curly leaf and look like a big green flower. I need to watch his diet a lot more. He is gluten free and casein free, but I am not getting those probiotics and fiber down him like I should. Or vitamins.

In spite of the article that said too many vitamins might be the problem - I would dare say it is the opposite - the gut is not absorbing . But as Jenny says - is that the right kind of vitamin - Folic or folate.

Toxins - metals has an extra electron on the out ring and wants to travel in pairs - was a great article. That is why everything like aluminum and antimony comes out first before mercury. That kind of ties it all together when it comes to the gold salts. Does gold bind with these heavy metals -- the answer is yes. Once attached to gold does it make it easier for the body to get rid of both gold and the heavy metal. I bet it does.

Raynards -- right on-- my neighbor's grand daughter in middle school has Raynards . She is thinking on things - I have pointed out to her that Raynards is a form of vasculiitis just like Kawaskis is.

Lots and lots of great stuff.

Thank You Nick.


Oh, I have missed a lot!

Let me catch up on it all this reading.

You are my friend too Nick and Thus, I love you too.


Where is love. I started this journey based on pure love. I implore those of you supremely educated in love to think in kind.

nick63 @twc.com

Benedetta. I ,love you and wonder at your insight at once. God bless you.


You are wrong. It is a form of autism I am describing. Cord clamping causes, or contributes, to very little autism.


Hope to develop this.

Measles and Nectins...so far Nectin 4 in epithelial cells. This would relate to lower cancer rates in Autism and the microvascular/capillary issues with the angiogenesis recently reported on in some with Autism. Possible Polio virus and flu vaccine ties. It is interesting certain measles virus vaccines are being worked on for certain cancers.


I still don't know if boosted Vitamin D could kink in GC-MAF, though I lean against the idea. What is somewhat convincing is the relationship of the GC protein with other elements perturbed in immune/cell/clock circadian ryhtm function with Autism.


I don't know why the GC protein is not available yet, but Dr. Bradstreet was correct. Is it just Nagalase levels hindering DBP? Whether that is the main issue in D3 not being transported to the receptor what I have used< Olmesartan, accomplishes the task it appears by also being able to activate the VDR. Therefore GC-Maf and Olmesartan would accomplish the same thing.


In the GC Gene card info one of the drugs for the GC gene is acetaminophen..hmmm. The GC gene biological processes also effected are:

female pregnancy IEA
lactation IEA
steroid metabolic process TAS
response to nutrient levels IEA
response to estradiol




Association of polymorphisms in the vitamin D receptor gene and serum 25-hydroxyvitamin D levels in children with autism spectrum disorder.


"Vitamin D is implicated in several aspects of human physiology, and polymorphisms in the vitamin D receptor gene (VDR) are associated with a variety of neuropsychiatric disorders. The aims of this study are to determine whether VDR polymorphisms are associated with autism spectrum disorder (ASD), to examine serum 25-hydroxyvitamin D (25(OH)D) levels in ASD, and to explore whether VDR polymorphisms influence serum 25(OH)D levels. We investigated 480 subjects (237 children with ASD and 243 healthy controls) for the following VDR polymorphisms: TaqI, BsmI, FokI, ApaI, and Cdx2.Within the same samples, 25(OH)D levels were available only for 85 patients and 82 controls. The Cdx-2 variation was shown to deviate from Hardy-Weinberg equilibrium in the controls and was therefore excluded from the study. We found that the frequency of rare FokI TT, TaqI CC, and BsmI AA genotypes differed significantly between children with ASD and the controls (p=0.042, p=0.016, p=0.038, respectively). After correction for multiple testing, only the TaqI CC genotype remained significant. Further analysis using a recessive model showed that rare genotypes of these polymorphisms were significantly higher in patients compared to controls (p=0.045, p=0.005 and p=0.031, respectively). However, no significant association was found between ApaI and ASD. We found serum 25(OH)D levels to be significantly higher in children with ASD (p<0.001) and that the FokI polymorphism had an effect on serum 25(OH)D levels in children with ASD (p=0.041). Additionally, we found the haplotype GTTT (BsmI/TaqI/FokI/ApaI) conferred an increased risk for developing ASD (p=0.022; odds ratio [95% confidence interval]=2.322 [1.105-4.879]). This is the first clinical study evaluating the association between serum 25(OH)D levels and VDR polymorphisms in children with ASD. Our results demonstrated a significant association between TaqI, BsmI, and FokI polymorphisms and ASD and showed for the first time that FokI polymorphisms and haplotype GTTT (BsmI/TaqI/FokI/ApaI) are associated with an increased risk of ASD. Our findings support the hypothesis that 25(OH)D is involved in the pathophysiology of autism and that serum 25(OH)D levels may be affected by FokI polymorphisms in children with ASD. Our results should be considered as preliminary and needs confirmation by future studies."




If I am wrong in the case of other groups with Autism it also may be the gene expression of the VDR is reduced and Vitamin D may levels rise, but not active the VDR. In such a scenario it might be possible that very high D levels could activate the fewer vitamin D receptors.


I had taken a break from all of this and have not considered the possible effect of very high D3 as resolving some of the problem, at least in some cases. In general I have found I am not in the main on Vitamin D supplementation and we do not use it. My wife tested very high in D3 and low in D2 and that was without supplementation. The sulfated vitamin D being required as well as LDL levels might be part of the problem. It also seems pathogen associated inflammation and sterile inflammation aspect may be occurring for many at the same time and this complicates the matter. The blood irradiation might reduce pathogens that provoke inflammation. But, the bigger problem is how the immune system is working and blood irradiation in Autism would likely produce mild benefits for a very brief time.

I don't think the issue is very simple though. Where there is immune dysfunction ate multiple levels, or individuals with additional biological variants, those effecting the gut vs those effecting the vascular or other area D levels and interaction may be more or less pathological and could benefit some areas while hindering others.

This report reflects my feelings about Vitamin D and feel it is probably more often how Vitamin D relates to Autism then viewing it as a long term treatment.

Infant Exposure to Excessive Vitamin D: A Risk Factor for Autism


A variant in some could complicate the issue of whether Vitamin D could be somewhat helpful.

Low Vitamin-D Levels Combined with PKP3-SIGIRR-TMEM16J Host Variants Is Associated with Tuberculosis and Death in HIV-Infected and -Exposed Infants



Interesting posts recently, Visitor!

It's my understanding that gluten has been used in labs to induce vitamin D deficiency. I can see that tying in in certain ways. Is vitamin D's situation in autism similar to what's been found out about thyroid stuff of late, that just because there are circulating blood levels doesn't necessarily mean its being used, or used correctly, taken up by cells/tissues, etc. Because there are other case reports of spontaneous correction of autistic symptoms upon use of clinically higher vitamin D3 levels - whether by accident or on purpose. Might it kick in GcMaf at a certain threshold, or mitigate mis? Am I interpreting this correctly?

How about this? Can any of this be tied together?


Since the angiogenesis in brain vessels in Autism is not verified, though I currently think it is involved in some or many, this association is speculative. I don't know if a lack of GCMAF is a factor in possible angiogenesis in the brain, yet this report seems noteworthy. There is not a lot to go on in this area so far. How GCMAF and MIF interact is of interest.

Effects of vitamin D(3)-binding protein-derived macrophage activating factor (GcMAF) on angiogenesis.


"BACKGROUND: The vitamin D(3)-binding protein (Gc protein)-derived macrophage activating factor (GcMAF) activates tumoricidal macrophages against a variety of cancers indiscriminately. We investigated whether GcMAF also acts as an antiangiogenic factor on endothelial cells.


The effects of GcMAF on angiogenic growth factor-induced cell proliferation, chemotaxis, and tube formation were examined in vitro by using cultured endothelial cells (murine IBE cells, porcine PAE cells, and human umbilical vein endothelial cells [HUVECs]) and in vivo by using a mouse cornea micropocket assay. Blocking monoclonal antibodies to CD36, a receptor for the antiangiogenic factor thrombospondin-1, which is also a possible receptor for GcMAF, were used to investigate the mechanism of GcMAF action.


GcMAF inhibited the endothelial cell proliferation, chemotaxis, and tube formation that were all stimulated by fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor-A, or angiopoietin 2. FGF-2-induced neovascularization in murine cornea was also inhibited by GcMAF. Monoclonal antibodies against murine and human CD36 receptor blocked the antiangiogenic action of GcMAF on the angiogenic factor stimulation of endothelial cell chemotaxis.


In addition to its ability to activate tumoricidal macrophages, GcMAF has direct antiangiogenic effects on endothelial cells independent of tissue origin. The antiangiogenic effects of GcMAF may be mediated through the CD36 receptor."


As far as taking Vitamin d{at least D3} this may be good to note.

"Children with autism often have very high levels of vitamin D3, occasionally toxic levels (and low levels of D2) which may be produced by gut bacteria. We do not recommend administering vitamin D3, which may result in severe hyperactivity, unless the child has had a vitamin D level test."


Macrophage migration inhibitory factor (MIF or MMIF)

"A cytokine recently linked to autism is macrophage migration inhibitory factor (MIF). MIF is a pro-inflammatory immune regulator that is constitutively expressed in brain tissues, and has important influences on neural and endocrine systems. This macrophage migration inhibitory factor cytokine is produced by neuroendocrine and immune tissues. Macrophage migration inhibitory factor possesses glucocorticoid-antagonist properties within the immune system and participates in the regulation of several endocrine circuits.
•Plasma levels of macrophage migration inhibitory factor (MIF) were higher in individuals with autism.
•Individuals with autism with the highest levels of plasma MIF were found to have the most severe behavioral symptoms.
•Macrophage migration inhibitory factor is of critical importance for the host response to microbial infections and in several autoimmune diseases.
•Macrophage migration inhibitory factor expression is usually constitutive at low levels."



While one may or may not have Kawasaki's there is an aspect that can be autoimmune based and as put forward earlier in this thread and may be related to mercury though other pathogens can be the trigger. This, again, associates HMGB1 with a vascular condition though MIF levels in Kawasaki's and those with only Autism show differing values. I can not speculate what the presence of both conditions together would give in MIF levels, but their is a partially shared pathology it appears.

New understanding of autoimmune diseases

"Thanks to a recent Yale study, physicians may soon adopt a new method to combat rheumatoid arthritis and other autoimmune diseases."

"Researchers at the Yale School of Medicine have discovered a transcription factor, ICBP90, that has been shown to regulate the expression levels of MIF — a gene that has been implicated in a number of diseases, primarily autoimmune diseases and cancer. The transcription factor, a protein responsible for facilitating the production of RNA from DNA, binds to MIF’s promoter region, which helps to regulate and initiate transcription. According to the study authors, by identifying the connection between ICBP90 and MIF, researchers can develop new methods of drug treatment for diseases including rheumatoid arthritis and cancer by targeting the gene in a more precise and personalized way."...

"Low expression of MIF has been shown to have benefits against certain diseases. Bucala noted that low expression of MIF confers resistance to death from malaria. Low expression also decreases susceptibility to autoimmune diseases and lessens their severity."...

"There are two potential therapeutic implications of the study, according to Maor Sauler, study co-author and medical school professor. The first will allow researchers to better understand how MIF is involved in disease, particularly in differentiating what is caused by environmental stimuli, and what is caused by the gene. The second implication is that scientists will be able to identify the MIF polymorphism in individual patients. This will help to indicate patients’ susceptibility to autoimmune diseases as well as signal which patients will respond best to anti-MIF or anti-ICBP90 therapy, Sauler added."


High mobility group box 1 (HMGB1) and macrophage migration inhibitory factor (MIF) in Kawasaki disease.



"To investigate whether two proinflammatory cytokines, high mobility group box 1 (HMGB1) and macrophage migration inhibitory factor (MIF) are involved in the development of Kawasaki disease (KD).


Twenty-seven patients with KD were included in this study. Eleven patients with sepsis and 28 healthy children served as controls. Serum levels of HMGB1 and MIF were measured by corresponding enzyme-linked immunosorbent assay (ELISA) kits, respectively. Real-time polymerase chain reaction (PCR) was used to quantify the expression levels of genes encoding receptor for advanced glycation end-products (RAGE), an HMGB1 receptor, and CD74, an MIF receptor in peripheral blood mononuclear cells (PBMCs).


Serum levels of HMGB1 and MIF in KD patients were the highest in the early acute phase and gradually decreased after defervescence. Serum HMGB1 and MIF levels in KD patients were significantly higher than those in controls (HMGB1, p<0.001; MIF, p<0.01). The expression levels of the RAGE gene and CD74 gene in KD patients were significantly higher than those in controls (RAGE, p<0.001; CD74, p<0.01).


These data suggest that HMGB1 and MIF play an important role in immune responses in KD patients."


Macrophage migration inhibitory factor and autism spectrum disorders.



"Autistic spectrum disorders are childhood neurodevelopmental disorders characterized by social and communicative impairment and repetitive and stereotypical behavior. Macrophage migration inhibitory factor (MIF) is an upstream regulator of innate immunity that promotes monocyte/macrophage-activation responses by increasing the expression of Toll-like receptors and inhibiting activation-induced apoptosis. On the basis of results of previous genetic linkage studies and reported altered innate immune response in autism spectrum disorder, we hypothesized that MIF could represent a candidate gene for autism spectrum disorder or its diagnostic components.


Genetic association between autism spectrum disorder and MIF was investigated in 2 independent sets of families of probands with autism spectrum disorder, from the United States (527 participants from 152 families) and Holland (532 participants from 183 families). Probands and their siblings, when available, were evaluated with clinical instruments used for autism spectrum disorder diagnoses. Genotyping was performed for 2 polymorphisms in the promoter region of the MIF gene in both samples sequentially. In addition, MIF plasma analyses were conducted in a subset of Dutch patients from whom plasma was available.


There were genetic associations between known functional polymorphisms in the promoter for MIF and autism spectrum disorder-related behaviors. Also, probands with autism spectrum disorder exhibited higher circulating MIF levels than did their unaffected siblings, and plasma MIF concentrations correlated with the severity of multiple autism spectrum disorder symptoms.


These results identify MIF as a possible susceptibility gene for autism spectrum disorder. Additional research is warranted on the precise relationship between MIF and the behavioral components of autism spectrum disorder, the mechanism by which MIF contributes to autism spectrum disorder pathogenesis, and the clinical use of MIF genotyping."


Serum levels of macrophage migration inhibitory factor in children and adolescents with autistic disorders


"Background: There is growing awareness of an immunological involvement in children with autistic disorder (AD). Studies suggest that innate rather than adaptive neuroimmune responses are associated with autism. Macrophage migration inhibitory factor (MIF), being an upstream regulator of innate and adaptive immunity, could play a role in this disorder. Objective: We aimed to study serum levels of MIF in a subset of children with autism and its relation to disease severity and important clinical manifestations of the disease. Methods: The study included 21 children and adolescents diagnosed with AD with a mean age of 6.9± 2.9 years. Patients were neurologically evaluated and categorized into those with mild to moderate autism and those with severe disorder. In addition to assessment of cognitive abilities and electroencephalogram performance, MIF levels were measured in the sera of included patients and were compared to those of a matched control group. Results: Levels of MIF were not significantly different in the patients and the control group. However, serum MIF was significantly reduced in patients with severe AD (z=2.197, P=0.029) compared to those with milder disease. Furthermore, there was a significant negative correlation between MIF levels and the degree of severity of the non-verbal communicative skills (r= -0.49, P=0.042). MIF levels were not different in patients with mental retardation, or abnormal electroencephalogram when compared to the rest of the patients. Conclusion: Our study suggests the presence of immune dysfunction in the form of derangement in serum MIF levels in children with AD. Its levels were specifically decreased in a subset of patients with severe disorder compared to those with mild to moderate disease. Decreased serum levels of MIF in patients with AD seem to be associated with worsening of the nonverbal communicative skills which is one of the disturbed behavioral parameters of AD. Further research is warranted to study the precise relationship of immune derangement and both the etiopathogenesis and the behavioral components of AD and its therapeutic implications."



Microglial activation state seems to be more important than microglial numbers, but reducing the amount of inflammatory microglia would be effective. Endotoxins{LPS], peripheral inflammation {esp gut}, mitochondrial dysfunction, and other factors driving the microglial damage being dealt with would be a more complete{enduring} and health giving solution.

Schizophrenia and Alzheimer’s disease risk linked to brain inflammation



Pivotal advance: inhibition of HMGB1 nuclear translocation as a mechanism for the anti-rheumatic effects of gold sodium thiomalate.

"Gold compounds such as gold sodium thiomalate (GST) can reduce the symptoms of rheumatoid arthritis (RA), although their mechanism of action is not well defined. As the proinflammatory mediator high mobility group box chromosomal protein 1 (HMGB1) may play a role in the pathogenesis of RA, we have performed in vitro studies to investigate whether GST inhibits HMGB1 release as the basis of its mode of action. Murine RAW 264.7 or human THP-1 macrophage cells were stimulated in culture with agents causing extracellular HMGB1 release, including LPS, IFN-gamma, polyinosinic:polycytidylic acid, IFN-beta, or NO in the presence of GST, ranging from 0 microM to 250 microM. Secretion and intracellular location of HMGB1 were assessed by Western blotting, HMGB1-specific ELISPOT assay, and immunofluorescent staining. In parallel, TNF and IFN-beta levels were analyzed by ELISPOT and/or ELISA. Supernatant NO production was analyzed by the Griess method. At pharmacologically relevant doses, GST inhibited the extracellular release of HMGB1 from activated macrophages and caused the nuclear retention of this protein; in contrast, no effects were observed on the secretion or production of TNF. Release of the key endogenous mediators of HMGB1 translocation, IFN-beta and NO, was inhibited by GST. This inhibition required gold, as sodium thiomalate did not affect the responses measured. Furthermore, gold chloride also inhibited release of HMGB1. Together, these results suggest a new mechanism for the anti-rheumatic effects of gold salts in RA and the potential of drugs, which interfere with intracellular HMGB1 transport mechanisms, as novel agents to treat RA."



Pivotal advance: inhibition of HMGB1 nuclear translocation as a mechanism for the anti-rheumatic effects of gold sodium thiomalate.



Gold Salts - one type is gold sodium thiomalate, which is mentioned later in this quote, may be effecting angiogenesis in brain blood vessels.

Oxidative stress in angiogenesis and vascular disease

"Angiogenesis, either physiological or pathological, requires initiation by proangiogenic factors, exemplified by vascular endothelial growth factor (VEGF), placental growth factor, platelet-derived growth factor-B, transforming growth factor β, and angiopoietin-1 (ANG-1).2 In most situations, if not all, angiogenesis is closely interwoven with the mobilization of inflammatory cells.5 During physiological or repair processes, such as wound healing, the inflammation process is transient; most pathological conditions, exemplified by cancer, involve a continuous recruitment of inflammatory cells, which, in turn, serve as a substantial source of ROS.6 This functional connection between the inflammation-dependent generation of ROS and angiogenesis plays an important role during various stages of tumor progression, from its initiation stage to vascularization and metastasis. Moreover, in most pathologies, oxidative stress operates as part of a positive feedback mechanism, which gives it even more signification in the process.7

Oxidative stress, which is defined as an imbalance between prooxidant and antioxidant systems,7 can be both a cause and consequence of many vascular complications and serve as one of the biomarkers for these conditions. At the same time, well-controlled oxidative stress may be beneficial for angiogenesis during tissue repair. In this review, we summarize the history and recent findings on the relationship between oxidative stress and angiogenesis, and discuss the implications of oxidative stress on pathological conditions and therapeutic strategies"...

"By 1 electron at a time, oxygen can be sequentially reduced to 4 components: superoxide anion, hydrogen peroxide, hydroxyl radical, and a water molecule.8 During this reduction-oxidation (redox) reaction, ROS are produced as intermediates in vivo. Superoxide anion is known to be a main contributor to the generation of most ROS and a crucial mediator of electron transport chain reactions in mitochondria. Usually, superoxide anion is rapidly removed through dismutation to hydrogen peroxide, either spontaneously or by superoxide dismutases (SOD).8,9 Neutrophil-secreted myeloperoxidase further converts hydrogen peroxide and chloride into highly reactive hypochlorite. For vascular cells, superoxide anion and hydrogen peroxide appear to be particularly important because they are able to activate diverse pathways to induce either new vascular growth, or vascular dysfunction and destruction.10

ROS can be generated by all vascular cell types, including endothelial cells, smooth muscle cells, adventitial fibroblasts, and perivascular adipocytes.11 There are 2 main endogenous sources in the vasculature: mitochondrial electron transport chain reactions and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.11-13 In mitochondria, more than 95% of oxygen consumed by cells is used to yield water molecules through redox reactions.14 Particularly, at complex I and III in the transport chain, premature electron leakage to oxygen occurs, which causes less than 4% of oxygen to be reduced to superoxide anion, but not to water, generating oxidative stress.8,10 NADPH oxidase, an enzyme that generates superoxide anion by transferring electrons from NADPH to oxygen, is recognized as a major source of ROS in many cell types, including endothelial and smooth muscle cells.10,13-17 It is important to note that in many conditions, the respiratory (oxidative) burst of inflammatory cells, such as neutrophils and monocytes, is the main contributing factor to ROS levels in a number of vascular pathologies."...

"ROS act as a double-edged sword in the vasculature because chronically produced or highly concentrated ROS are detrimental for most tissues, whereas transient or low levels of ROS are able to activate signaling pathways that eventually promote regeneration and growth.21,22 Thus, ROS are implicated, either directly or indirectly, in the process of physiological, pathological, and excessive angiogenesis.

One of the early implications of ROS in angiogenesis resulted from the studies using thiol-containing compounds, which were shown to inhibit macrophage-derived proangiogenic activity, as the conditioned medium from gold sodium thiomalate-treated macrophages potently reduced angiogenesis in rat corneas.23,24 Although an effect was somewhat indirect, the follow-up studies from the same group demonstrated that thiol-containing compounds acting as ROS scavengers may inhibit production of angiogenic factors by macrophages."


Evaluation of oxidative stress in autism: defective antioxidant enzymes and increased lipid peroxidation.


"Autism is a neurodevelopmental disorder of childhood with poorly understood etiology and pathology. This pilot study aims to evaluate the levels of antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and levels of malondialdehyde (MDA), a marker of lipid peroxidation, in Egyptian autistic children. Autism is a neurodevelopmental disorder of childhood with poorly understood etiology and pathology. The present study included 20 children with autism diagnosed by DSM-IV-TR criteria and Childhood Autism Rating Scale. Controls included 25 age-matched healthy children. Cases were referred to Outpatient Clinic of Children with Special Needs Department, National Research Center, Cairo, Egypt. We compared levels of SOD, GSH-Px, and MDA in children with autism and controls. In children less than 6 years of age, levels of SOD, and GSH-Px were significantly lower in autistic children compared with their controls, while MDA was significantly higher among patients than controls. In children older than 6 years, there was no significant difference in any of these values between cases and controls. We concluded that children with autism are more vulnerable to oxidative stress in the form of increased lipid peroxidation and deficient antioxidant defense mechanism especially at younger children. We highlight that autistic children might benefit from antioxidants supplementation coupled with polyunsaturated fatty acids. Moreover, early assessment of antioxidant status would have better prognosis as it may decrease the oxidative stress before inducing more irreversible brain damage."


Olmesartan may raise superoxide dismutase levels and bear on ros related angiogenesis.


Synergistic Destruction: How Vaccines and GMOs Converge to Fuel Autism and Neurodegenerative Conditions


There is something going on with Superoxide dismutase, microglia, and angiogenesis, still looking at this.


Shinedown - Crow and the Butterfly


Evanescence - Bring Me To Life


The Doobie Brothers - What A Fool Believes



Pregnant Mother’s Gut Microbiome Sets The Stage For Baby’s Future Health

"One finding was particularly noteworthy.

“One of the reviews, by Koleva et al, discusses the studies that reveal that the womb is not sterile and that the microbiota of the child are already developing in utero,” said Dr. Sharon Meropol, associate director for research and evaluation at University Hospitals Rainbow Babies & Children’s Hospital’s Center for Child Health and Policy, in a press release. “This means that not only do we have to consider the microbiome of the child but also that of the mother, and the irony is that some of our modern medical practices, through their effect on these early microbiota, could have unintended consequences, interfering with normal development of children’s immune, metabolic, and neurologic systems.”

According to Meropol, the importance of protecting key steps in the transmission and maintenance of healthy microbiota in pregnant mothers and fetuses is supported by increasing evidence. “Disturbed microbiota could potentially contribute to a wide range of childhood diseases, including allergies, asthma, obesity, and autism-like neurodevelopmental conditions,” said Meropol, who is also assistant professor of pediatrics at Case Western Reserve University School of Medicine."



It is worth considering that given that many vaccines require a healthy gut microbiome to work effectively, or at all, that the reason gut issues are occurring in some autism and other gut related problems is that it is the bodies attempt to prevent heightened immune response to vaccines, or dietary antigens, or simply a result of an already stimulated immune response, acquired from the mother, to disease pathogens reflecting a deregulated immune system or one hypersensitive.


It may be that vaccines are the main catalyst for the increase in many immune related conditions{fibro, CFS, and others}, but the cumulative vaccine effects are leading to a plethora of effected mothers who are now giving birth to children already headed into autism or more children more susceptible to vaccines themselves leading into autism. So, it is not that vaccines are not an issue in most cases, but that it is getting to where immune changes in mothers response to infection additional vaccines{flu shots} and conditioned immune status effecting infants prenatally too is more often than before enough to bring about autism even before an infant receives their vaccines.

If this is the case, it blurs the line in seeing where the insults take place and ignoring immune effects in mothers by vaccines misses the tie to increased autoimmune and inflammatory diseases in the population at large. Because of these effects a child can now be born with autism beyond the limited "gene only" causes.


I have continuously expressed that vaccines are trigger only for some or, so I am clarifying my statement "vaccines lead to autism" in the last post. I realized after reading it again that I always wish to make this distinction.


Pecam1 is not a growth factor, but involved. I did not mean to call it a growth factor.


Vaccines lead to autism and other problems as many at AoA have known. It was no surprise when, after my wife fell, the examining physician noted her slightly blue fingers and nails and proclaimed she had Raynaud's a couple of years ago. My wife's mother also has the condition, but none known in other relatives before. My wife has had this condition since I have known her. I imagine in both women vaccines and other environmental factors led to the condition. Dr. Moulden has stated that Raynaud's is related to some Autism and I believe he was the first to associate it with Autism.

The sometimes comorbid conditions with neuroimmune function disturbance like arthritis, and Raynaud's both have relation to the vascular system and likely certain vascular wall growth factors such as pecam1 end egf and its receptor. If I remember correctly Dr Moulden proposed that the leukocytes become part of the occlusion in micro vessels and lekocyute transmigration and angiogenesis are part of the picture along with red blood cell clumping.

I have tried to use more conventional sources, but this first article is relevant.

Casualties in the War: New Research Confirms Vaccines Do Have a Dark Side

"One chapter calls adjuvants as “the ‘dirty little secret’ of immunologists” because, just like the natural infections they are used to deter, they carry a risk of triggering chronic disease. Scientists knew this at least as far back as 1956 when they induced arthritis in Wistar rats – known as “adjuvant’s disease” in the industry. It’s incredibly ironic that rather than removing them from vaccines immediately, they tailored this “right nuisance” and for six decades now have widely injected adjuvants into animals to create lab models of arthritis, allergies, asthma, lupus and more — so they can test drugs for the diseases that are increasingly plaguing humans injected with adjuvants.

ASIA Syndrome

Autoimmune/Inflammatory Syndrome Induced by Adjuvants (ASIA) was first described in the medical literature in 2011 but in reality it just identifies the old phenomenon of vague post-vaccine symptoms including muscle and joint pain, numbness and tingling, weakness and chronic fatigue, which vaccine researchers and physicians have dismissed and ignored, but which actually signify progressive and insidious immune system damage that can take years to manifest into full blown autoimmune disease.

It is probably adjuvants in the heavily vaccinated farmed salmon, say scientists from the University of Padua Italy, reviewing their effects in animals, that frequently cause them to “develop mild to severe pathological changes” including impaired growth, decreased carcass quality, spinal deformities, eye disease and gut inflammation. Who knows what else they would develop if we didn’t eat them first."


In the response to a post at AoA one said:

"Stress will cause aggregation in preparation for clotting in case of injury. Think "fight or flight" - when you are preparing for battle or to run away, there is a significant change you may get hurt. When the the balance of stress hormones is disrupted (shifted) due to high anxiety or panic, the body doesn't differentiate between real or perceived danger and prepares to clot. So thats ONE factor at work.

Heavy metals like lead and mercury (and aluminum which is not technically a "heavy" metal) also damage the circulatory system and lead to problems like Raynaud's Syndrome, atherosclerosis, hypertension, stroke, and aneurysm.

Metals and other toxins have something else in common - a single valence electron in their outermost ring. This makes them very attractive to each other - they don't like to be alone but like to travel in pairs so they will "hook up" with other toxins. This is one reason (along with impaired detoxificatio due to depletion of metallothionein) why our kids, once shot up (pun intended) with aluminum or thimerosal (flu vaccine, rhogam, etc.) become like magnets for other toxins. It's also why when chelating, mercury does not come out until after aluminum, antimony, and lead. The magnets (our children) hold onto the metals because their electrical charges have been altered.

The comment about babesia (a bacteria associated with Lyme disease) is also correct, which is why adults with chronic Lyme exhibit many of the same behavioral and neurological issues as do children with "autism."

Infections in the blood (from systemic yeast, viruses, strep, staph, etc) will also cause clumping, as what is left of the immune system tries to kick in and fight off the infection. Remember that one of the first things the immune system does is to send extra blood (and oxygen) to the sight of injury or infection. This is part of the healing process and is why we get the swelling, heat, and itching when we get a minor cut or scrape. That's the body's attempt to heal.

The problem is, in our children there are so many different things to fight that their bodies become confused and shift over into autoimmunity. The analogy I use is like the old Space Invaders game where you start of shooting at one bad guy and it's relatively easy, but as things speed up, there are too many bad guys to shoot at accurately and you end up crashing and burning."

Marcella Piper-Terry, M.S.


Mechanisms of aluminum adjuvant toxicity and autoimmunity in pediatric populations.


"Immune challenges during early development, including those vaccine-induced, can lead to permanent detrimental alterations of the brain and immune function. Experimental evidence also shows that simultaneous administration of as little as two to three immune adjuvants can overcome genetic resistance to autoimmunity. In some developed countries, by the time children are 4 to 6 years old, they will have received a total of 126 antigenic compounds along with high amounts of aluminum (Al) adjuvants through routine vaccinations. According to the US Food and Drug Administration, safety assessments for vaccines have often not included appropriate toxicity studies because vaccines have not been viewed as inherently toxic. Taken together, these observations raise plausible concerns about the overall safety of current childhood vaccination programs. When assessing adjuvant toxicity in children, several key points ought to be considered: (i) infants and children should not be viewed as "small adults" with regard to toxicological risk as their unique physiology makes them much more vulnerable to toxic insults; (ii) in adult humans Al vaccine adjuvants have been linked to a variety of serious autoimmune and inflammatory conditions (i.e., "ASIA"), yet children are regularly exposed to much higher amounts of Al from vaccines than adults; (iii) it is often assumed that peripheral immune responses do not affect brain function. However, it is now clearly established that there is a bidirectional neuro-immune cross-talk that plays crucial roles in immunoregulation as well as brain function. In turn, perturbations of the neuro-immune axis have been demonstrated in many autoimmune diseases encompassed in "ASIA" and are thought to be driven by a hyperactive immune response; and (iv) the same components of the neuro-immune axis that play key roles in brain development and immune function are heavily targeted by Al adjuvants. In summary, research evidence shows that increasing concerns about current vaccination practices may indeed be warranted. Because children may be most at risk of vaccine-induced complications, a rigorous evaluation of the vaccine-related adverse health impacts in the pediatric population is urgently needed."



Unless you have followed much of this thread individual reports may mean little, keep in my microglial activastion and cytokine function like TNF and this biphasic action related to angiogenesis, and its dysregulation, can be tied to autism and other neuroimmune conditions and maybe relate to the swings in bipolar and the persiods or contsant psychosis especially when increeased blood flow is occurring and be part of psychosis occurring with autism at times. I am posting a good bit of the report, but the whole is very enlightening.

Microglial activation state exerts a biphasic influence on brain endothelial cell proliferation by regulating the balance of TNF and TGF-β1



"Studies of cerebral ischemia and other neuroinflammatory states have demonstrated a strong association between new vessel formation and microglial recruitment and activation, raising the possibility that microglia may be involved in promoting angiogenesis. As endothelial cell proliferation is a fundamental early step in angiogenesis, the aim of this study was to test this hypothesis by examining the influence of microglial secreted factors on brain endothelial cell (BEC) proliferation using BrdU incorporation.


Primary cultures of mouse BEC, microglia and astrocytes were used in this study. Proliferation of BEC was examined by BrdU incorporation. ELISA was used to quantify TNF and TGF-β1 levels within cell culture supernatants.


Microglia regulated BEC proliferation in a biphasic manner; microglia conditioned medium (MG-CM) from resting microglia inhibited, while that from activated microglia promoted BEC proliferation. A screen of microglial cytokines revealed that BEC proliferation was inhibited by TGF-β1, but promoted by TNF. ELISA showed that TNF and TGF-β1 were both present in MG-CM, and that while TGF-β1 dominated in resting MG-CM, TNF levels were massively increased in activated MG-CM, shifting the balance in favor of TNF. Antibody-blocking studies revealed that the influence of MG-CM to inhibit or promote BEC proliferation was largely attributable to the cytokines TGF-β1 and TNF, respectively.


This data suggests that microglial activation state might be an important determinant of cerebral angiogenesis; inhibiting BEC proliferation and neovascularization in the normal central nervous system (CNS), but stimulating the growth of new capillaries under neuroinflammatory conditions.


Angiogenesis occurs in the central nervous system (CNS) not just during development [1], but also in pathological conditions, including cerebral ischemia [2], neoplasia [3], and neuroinflammation [4,5]. An improved understanding of the factors that control cerebral angiogenesis would be a big step forward in our attempts to regulate angiogenesis for therapeutic means, either to increase blood vessel growth during cerebral ischemia, or to inhibit vessel growth during neoplasia. Angiogenesis is regulated by a plethora of factors, including growth factors [6], cytokines [7], and extracellular matrix (ECM) molecules [8]. Within the CNS, it has been established that hypoxia promotes angiogenesis by at least two separate pathways. One involves hypoxia inducible factor-1α (HIF-1α)-dependent vascular endothelial growth factor (VEGF) release [9], and the other, that involves a HIF-1α-independent COX-2-dependent stimulation of PGE2, leading to angiopoietin-2 release [10]. In addition to soluble factors, ECM proteins also provide important instructional cues in angiogenesis [11], and recent work from our laboratory showing that fibronectin is strongly induced on angiogenic capillaries in the hypoxic CNS [12], as well as on angiogenic vessels in the developing CNS [13], suggests that this protein may also be important for cerebral angiogenesis.

In the normal adult CNS, brain endothelial cells (BEC) occupy an angiostatic state, and have the impermeable, tight-barrier characteristics of mature cerebral endothelium [14]. During cerebral ischemia and other neuroinflammatory conditions, vessels in the adult CNS mount an angiogenic response in which BEC proliferate to form new capillary sprouts [15,16]. Interestingly, studies of cerebral ischemic tissue have demonstrated a strong association between new vessel formation and microglial recruitment and activation [17,18], raising the possibility that microglia, the principal immune effector cells in the CNS, may actively promote angiogenesis. As endothelial cell proliferation is a fundamental early step in the angiogenic response, the aim of this study was to test this hypothesis by examining the influence of microglial secreted factors on BEC proliferation."


Heightened blood flow in the brain linked to development of psychosis

"Using a Magnetic Resonance Imaging (MRI) technique they found that 52 young people deemed to be at ultra high risk of psychosis had increased or 'hyperactive'levels of blood flow compared to 27 healthy controls in the hippocampus, striatum and midbrain - all brain regions that are particularly implicated in the onset of psychotic disorders like schizophrenia.

This study is one of the first in humans to confirm results from animal research, which has already shown that increased activity in these brain regions drives the development of psychosis.

In the study, published today in the American Journal of Psychiatry and funded by the Medical Research Council, the researchers also repeated the MRI scans after 18 months to examine how blood flow levels had changed. In participants whose presenting symptoms had resolved, the researchers found that resting blood flow levels in the hippocampus had decreased to the levels seen in healthy participants. This suggests that normalisation of blood flow in the hippocampus may underlie clinical improvement in these participants.

Professor Paul Allen from the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) at King's College London and the University of Roehampton said: 'Our research identified significant differences in brain blood flow between healthy people and those at ultra high risk of psychosis. These differences help us understand the neurobiological mechanisms that underlie the development of psychosis.'"



The angiogenesis relating to Autism is only preliminary in the study, so how this may have similar origins and effects in different conditions regarding angiogenesis is not clear.

It is reasonable to think the processes is similar in angiogenesis in RA, Parkinson's, and Autism and maybe in general.

Targeting angiogenesis in Parkinson’s disease

"Movement and balance disorders are a well-known consequence of Parkinson’s disease (PD). Hypothesizing that these features could be related to the formation of new blood vessels, a study published in Neurology assessed the presence of biomarkers of new blood vessel formation (angiogenesis) in the cerebrospinal fluid of patients with PD, and compared it with blood-brain barrier permeability, white matter lesions, and cerebral microbleeds. This study initially used samples from 100 PD patients and was followed by two additional validation groups of 87 patients with PD with dementia 93 patients with PD with and without dementia.

The findings showed that there is indeed a connection between the presence of markers of angiogenesis in the brain and the motor and balance impairments of PD patients. Increased angiogenesis was also linked to an increased permeability of the blood-brain barrier, to white matter lesions, and to cerebral microbleeds. These results indicate that medication for angiogenesis may be an additional and promising therapy for PD patients in the future."


The role of High-mobility group box protein 1 in collagen antibody-induced arthritis is dependent on Vascular endothelial growth factor.



"High-mobility group box 1 (HMGB1) has been implicated in angiogenesis and rheumatoid arthritis (RA). The aim of this study was to better define the role of HMGB1 in the synovial angiogenesis and pathogenesis of an immune model of arthritis.


Balb/c mice were injected with monoclonal anti-collagen antibody cocktail followed by lipopolysaccharide to induce arthritis.


HMGB1 and VEGF were over-expressed in the areas of the synovium where more inflammation and neoangiogenesis were present. The selective blockade of HMGB1 or of VEGF alternatively resulted in a lower severity of arthritis evaluated by the arthritis index. Furthermore, exogenous HMGB1 administration caused a worsening of arthritis, associated with VEGF up-regulation and increased synovial angiogenesis. The selective inhibition of VEGF resulted in no induction of arthritis also in mice receiving exogenous HMGB1. Cytokine ELISA analyses performed on peripheral blood and synovial fluid demonstrated a significant reduction of IL-1β , IL-6 and TNF-α in mice where HMGB1 and VEGF pathways were blocked. Interestingly, the selective blockade of HMGB1 and VEGF resulted in an increase of the peripheral IL-17A concentration.


The development of arthritis mediated by HMGB1 and the synovial angiogenesis can be blocked by inhibiting the VEGF activity. The pro-inflammatory and pro-angiogenic cytokine IL-17A is increased when HMGB1 is inhibited, but the synovial angiogenesis is nevertheless reduced in this model of arthritis. Taken together, these findings shed new light on the role of this nuclear protein in the pathogenesis of arthritis in an RA-like model."




Fasting has been suggested to have some bearing on certain conditions like epilepsy, tumors, and stroke and possibly Alzheimer's and maybe Parkinson's and seizures. There is very little explicit literature I have found about fasting and these conditions. The relation to diet or fasting and angiogenesis may be found in relation to carbohydrates relating to advanced glycation end products. These interact with HMGB1 and HMGB1 does bear on inflammation and angiogenesis. This is an area I am working on presently. I am looking at leptin, glucose, and insulin in this area as well and fasting has some relation here too.


Have you looked at all into connections on the effects of fasting on angiogenesis and effects on the brain?


My wife had developed arthritis and Olmesartan, in combination with the dietary changes effecting the gut microbiome has arrested and even reversed the condition to a degree. Angiogenesis is implicated in some arthritis, so it all fits. It explains the inflamed and notable capillaries in her ears too I believe. It is has to to have been happening in her brain as well.

The codependence of angiogenesis and chronic inflammation.


"Angiogenesis is the growth of new blood vessels from existing ones. It is an important aspect of new tissue development, growth, and tissue repair. It is also a component of many diseases including cancer, blindness, and chronic inflammation such as rheumatoid arthritis (RA) and psoriasis. There is considerable evidence to suggest that angiogenesis and chronic inflammation are codependent; recent studies have begun to reveal the nature of this link, which involves both augmentation of cellular infiltration and proliferation and overlapping roles of regulatory growth factors and cytokines. Through these studies, we have begun to understand the codependence of chronic inflammation and angiogenesis, the potential benefits of targeting angiogenesis in the treatment of chronic inflammation, and of targeting chronic inflammation to affect angiogenesis."


Relationship between angiogenesis and inflammation in experimental arthritis.


Background. Angiogenesis is involved in rheumatoid arthritis (RA) leading to leucocyte recruitment and inflammation in the synovium. Furthermore, synovial inflammation itself further potentiates endothelial proliferation and angiogenesis. In this study, we aimed at evaluating the reciprocical relationship between synovial inflammation and angiogenesis in a RA model, namely collagen-induced arthritis (CIA). Methods. CIA was induced by immunization of DBA/1 mice with collagen type II in adjuvant. Endothelial cells were detected using a GSL-1 lectin-specific immunohistochemical staining on knee joint sections. Angiogenesis, clinical scores and histological signs of arthritis were evaluated from the induction of CIA until the end of the experiment. Angiogenesis was quantified by counting both the isolated endothelial cells and vessels stained on each section. To evaluate the effect of increased angiogenesis on CIA, VEGF gene transfer was performed using an adeno-associated virus encoding VEGF (AAV-VEGF), by intra-muscular or intra-articular injection in mice with CIA. Results. We showed an increase in synovial angiogenesis from day 6 to day 55 after CIA induction, and, moreover, joint vascularization and clinical scores of arthritis were correlated (p < 0.0001, r = 0.61). Vascularization and histological scores were also correlated (p = 0.0006, r = 0.51). Systemic VEGF overexpression in mice with CIA was followed by an aggravation of arthritis as compared to AAV-lacZ control group (p < 0.0001). In contrast, there was no difference in clinical scores between control mice and mice injected within the knee with AAV-VEGF, even if joint vascularization was higher in this group than in all other groups (p = 0,05 versus non-injected group). Intra-articular AAV-VEGF injections induced more severe signs of histological inflammation and bone destruction than AAV-Lac Z or no injection. Conclusion. Angiogenesis and joint inflammation evolve in parallel during collagen-induced arthritis. Furthermore, this work shows that exogenous VEGF can aggravate CIA. It is direct evidence that the increase in joint vascularization leads to an exacerbation of arthritis. Taken together, these results emphasize the role of angiogenesis in inflammatory arthritis. It also suggests an early involvement of angiogenesis in joint inflammation.


Angiotensin Receptor Blockade Modulates NFκB and STAT3 Signaling and Inhibits Glial Activation and Neuroinflammation Better than Angiotensin-Converting Enzyme Inhibition.


"Neuroinflammation, sustained by astroglial and microglial activation, is the preceding event in neurodegeneration. Various clinical reports showed better neuroprotection by AT1 receptor blockade (ARB) than angiotensin-converting enzyme inhibition (ACEi), but experimental evidences and associated mechanism for this observation are lacking. Therefore, we investigated the effect of ARB, using Candesartan, and ACEi, using Perindopril, in equimolar concentrations in astroglial (C6) and microglial (BV2) cells employing lipopolysaccharide (LPS) to induce neuroinflammation. Further, Candesartan (0.1 mg/kg) and Perindopril (0.1 mg/kg) were orally administered in male SD rats for five consecutive days, and on the fifth day, rats were challenged with LPS (i.p.; 250 μg/kg) and sacrificed after 24 h. LPS-induced neuroinflammation (increased astroglial and microglial activation, IκBα degradation, NFкB nuclear translocation, STAT3 activation, and TNF-α release) was more efficiently prevented by Candesartan (even at lower concentration of 1 nM) than by Perindopril (1 μM) in both the cell types and in rat model of neuroinflammation. In addition, increased AT1 receptor (AT1R) and decreased AT2 receptor (AT2R) expression was observed in LPS-induced neuroinflammation in both in vitro and in vivo studies. Candesartan, as compared to Perindopril, increased the expression of AT2R in both the experimental conditions. Interestingly, concomitant blockade of AT2R by PD123319 significantly reversed the beneficial effects of Candesartan in both the cell types and in rat model of neuroinflammation. Finally, our data emphasize that superiority of Candesartan as compared to Perindopril is due to better activation of AT2R which results in PP2A activation, IκBα stabilization, and suppression of NFкB and STAT3 inflammatory signaling."




The RAS system is involved in all sorts of development including ovarian and placental. It is also involved in retinal issues. I think I remember you saying your husband had some sort of eye condition. Am I remembering correctly? It is starting to look like the RAS may be a substantial part of the picture. The Aldosterone component is implicated too so I would include it as well. RAAS = renin-angiotensin-aldosterone system.


My uncle had a blocked blood vessel to his heart and so he grew another one all on his own.

Sounds like the same thing going on here too.


The continued angiogenesis mentioned two posts back seems to indicate that it is persistent though no reasons for this condition are stated. If Olmesartan down blocks AT1 receptors it may reduce angiogenesis and it may also increase activation of angiotensin AT2 and AT4 receptors that "trigger brain anti-ischemic mechanisms by favouring cerebral blood flow (angiogenesis and recruitment of pre-existing collateral circulation, specifically in the ischemic brain where AT2 receptors are overexpressed) or by directly increasing neuronal resistance to anoxia."

Angiotensin AT1-receptor blockers and cerebrovascular protection: do they actually have a cutting edge over angiotensin-converting enzyme inhibitors?


"First, an update of the vascular systemic and tissue renin-angiotensin-aldosterone system is provided to explain how it is regulated at the systemic and tissue levels, and how many angiotensin peptides and receptors can be modulated by the various antihypertensive drugs. Second, experimental data is presented to support the hypothesis that antihypertensive drugs that increase angiotensin II formation, such as diuretics, AT1-receptor blockers and dihydropyridines, may have greater brain anti-ischemic effects than antihypertensive drugs that decrease angiotensin II formation, such as beta-blockers and angiotensin-converting enzyme inhibitors, because they increase activation of angiotensin AT2 and AT4 receptors. Indeed, these trigger brain anti-ischemic mechanisms by favouring cerebral blood flow (angiogenesis and recruitment of pre-existing collateral circulation, specifically in the ischemic brain where AT2 receptors are overexpressed) or by directly increasing neuronal resistance to anoxia."

Reduced angiogenesis and delay in wound healing in angiotensin II type 1a receptor-deficient mice


"Angiotensin II (Ang II) is a bioactive peptide that plays important roles in blood pressure regulation and salt–water homeostasis. Recently, Ang II was reported to function in the promotion of angiogenesis. Since the wound healing process is highly dependent upon angiogenesis, we employed Ang II receptor knockout mice (AT1a−/−) to investigate whether or not Ang II facilitates angiogenesis and wound healing via AT1a receptor signaling. In comparison to wild-type (WT) mice, wound healing and wound-induced angiogenesis were significantly suppressed in AT1a−/− mice, and these mice exhibited reduced expression of CD31 in wound granulation tissues. In comparison to vehicle-treated mice, wound healing was delayed significantly in mice treated with an AT1-R antagonist and this delay was accompanied by the reduced expression of vascular endothelial growth factor in wound granulation tissues. These findings suggest that Ang II–AT1a signaling plays a crucial role in wound healing and wound-induced angiogenesis."


There are some disconnects in how reducing angiogenesis may be therapeutic at the same time reducing wound healing, but this remains to be understood.


I o9mmitted a link when I said this:

Please read beyond the abstact and click on "look inside" in the top blue bar"
It is here.

Regulation of Angiogenesis by Angiotensin II



If you have followed this thread you will have seen how I have emphasized the Angiotensin system. The relation of hypoxic. inflammatory, and ischemic events effecting the brain and its vasculature is beginning to be grasped as it relates to Autism and it appears Schizophrenia. Vaccines upregulating or causing these effects, particularly in what seems to be increasing amounts of infants with preexisting or hypersensitive inflammatory profiles would point to greater amounts of vaccine effects in these pathologies of the vasculature. This is a report I for which I have been hoping. Olmesartan...?

Please read beyond the abstact and click on "look inside" in the top blue bar. Neovascularization is a mechanism of wound response and attempt at healing, increasing blood supply, and oxygen supply. B6 levels increase after surgical wounds and b6 levels are often related to Autism. Wounded children.

Scientists find new vessel for detecting autism

"Evidence of autism may be found in the composition and malfunction of the brain's blood vessels, a team of scientists has found. Their research sheds new light on the causes of autism, which previously had pointed to neurological make-up rather than to the vascular system, and identifies a new target for potential therapeutic intervention.

"Our findings show that those afflicted with autism have unstable blood vessels, disrupting proper delivery of blood to the brain," explains Efrain Azmitia, a professor in NYU's Department of Biology and the study's senior author.

The study, "Persistent Angiogenesis in the Autism Brain: An Immunocytochemical Study of Postmortem Cortex, Brainstem and Cerebellum," appears in the Journal of Autism and Developmental Disorders. Its other co-authors were: Zachary Saccomano, an NYU graduate student; Mohammed Alzoobaee, an NYU undergraduate at the time of the study; Maura Boldrini, a research scientist in the Department of Psychiatry at Columbia University; and Patricia Whitaker-Azmitia, a professor in the Department of Psychology and director of the Graduate Program in Integrative Neurosciences at Stony Brook University.

"In a typical brain, blood vessels are stable, thereby ensuring a stable distribution of blood," adds Azmitia, also an adjunct professor at NYU School of Medicine's Department of Psychiatry. "Whereas in the autism brain, the cellular structure of blood vessels continually fluctuates, which results in circulation that is fluctuating and, ultimately, neurologically limiting."

In their study, the researchers examined human postmortem brain tissue—some from normal brains and others from those with an autism diagnosis. In the microscopic analysis, the scientists were blind to the nature of the tissue, not knowing if it came from an autistic brain or a typical one.

Their cellular studies uncovered angiogenesis—the creation of new blood vessels—in the autistic brain tissue, but not in that of typical brains. The distinction is a significant one—evidence of angiogenesis indicates that these vessels are repeatedly being formed and in constant flux, underscoring an instability in the blood's delivery mechanism. Specifically, in autistic brains, they found increased levels of the proteins nestin and CD34—molecular markers of angiogenesis—compared to typical brains.

"We found that angiogenesis is correlated with more neurogenesis in other brain diseases, therefore there is the possibility that a change in brain vasculature in autism means a change in cell proliferation or maturation, or survival, and brain plasticity in general. These changes could potentially affect brain networks," Boldrini noted.

"It's clear that there are changes in brain vascularization in autistic individuals from two to 20 years that are not seen in normally developing individuals past the age of two years," observes Azmitia. "Now that we know this, we have new ways of looking at this disorder and, hopefully with this new knowledge, novel and more effective ways to address it."


Angiotensin converting enzyme activity is positively associated with IL-17a levels in patients with schizophrenia.


"Previous studies of our group showed increased plasmatic Angiotensin-I Converting Enzyme (ACE) activity in schizophrenia (SCZ) patients compared to healthy controls, which was also associated to poor cognitive functioning. The ACE main product angiotensin II (Ang-II) has pro-inflammatory properties. Activated immune-inflammatory responses in SCZ and their association with disease progression and cognitive impairments are also well-described. Therefore, we examined here the association of plasma ACE activity and inflammatory mediators in 33 SCZ patients and 92 healthy controls. Non-parametric correlations were used to investigate the association of the enzyme activity and the peripheral levels of immune inflammatory markers as interleukins, tumor necrosis factor (TNF-α), and interferon (IFN-γ). Although no significant correlations could be observed for ACE activity and measured cytokines levels in healthy controls, a significant positive correlation for ACE enzymatic activity and IL-17a levels was observed in SCZ patients. Correcting for gender did not change these results. Moreover, a significant association for ACE activity and IFN-γ levels was also observed. To our knowledge, this is the first study to show a significant association between higher ACE activity and the levels of cytokines, namely IL-17a and IFN-γ, in patients with SCZ."


Increased serum Osteopontin levels in autistic children: Relation to the disease severity.


“Autoimmunity to brain may play an etiopathogenic role in autism. Osteopontin is a pro-inflammatory cytokine that has been shown to play an important role in various autoimmune neuroinflammatory diseases. Osteopontin induces IL-17 production by T-helper 17 lymphocytes, the key players in the pathogenesis of autoimmune disorders. Anti-osteopontin treatment reduces the clinical severity of some autoimmune neuroinflammatory diseases by reducing IL-17 production. We are the first to measure serum osteopontin levels, by ELISA, in 42 autistic children in comparison to 42 healthy-matched children. The relationship between serum osteopontin levels and the severity of autism, which was assessed by using the Childhood Autism Rating Scale (CARS), was also studied. Autistic children had significantly higher serum osteopontin levels than healthy controls."


Osteopontin - Wiki

"Stimulation of OPN expression also occurs upon exposure of cells to pro-inflammatory cytokines,[31] classical mediators of acute inflammation (e.g. tumour necrosis factor α [TNFα], infterleukin-1β [IL-1β]), angiotensin II, transforming growth factor β (TGFβ) and parathyroid hormone (PTH),[32][33] although a detailed mechanistic understanding of these regulatory pathways are not yet known. Hyperglycemia and hypoxia are also known to increase OPN expression."



As an addition to the last post here is another related article addressing causes of Ovarian issues including Polycystic Ovarian Disease. I had posted in this thread in 2012. It adds a larger perspective that the you tube in the last post.

Environmental toxicants causing ovarian disease across generations

"WSU reproductive biologist Michael Skinner and his laboratory colleagues, including Eric Nilsson and Carlos Guerrero-Bosagna, looked at how fungicide, pesticide, plastic, dioxin and hydrocarbon mixtures affected a gestating rat's progeny for multiple generations. They saw subsequent generations inherit ovarian disease by "epigenetic transgenerational inheritance."

Epigenetics regulates how genes are turned on and off in tissues and cells. Three generations were affected, showing fewer ovarian follicles -- the source of eggs -- and increased polycystic ovarian disease.

The findings suggest ancestral environmental exposures and epigenetics may be a significant added factor in the development of ovarian disease, Skinner said.

"What your great grandmother was exposed to when she was pregnant may promote ovarian disease in you, and you're going to pass it on to your grandchildren," he said. "Ovarian disease has been increasing over the past few decades to affect more than 10 percent of the human female population, and environmental epigenetics may provide a reason for this increase....

The new study, Skinner said, provides a proof of concept that ancestral environmental exposures and environmental epigenetics promote ovarian disease and can be used to further diagnose exposure to toxicants and their subsequent health impacts. It also opens the door to using epigenetic molecular markers to diagnose ovarian disease before it occurs so new therapies could be developed.

In a broader sense, the study shows how epigenetics can have a significant role in disease development and life itself."


All the increased risks for autism from modern inventions, but no real increase in autism?


Glyphosate makes the list.

The 3 Causes of Polycystic Ovarian Syndrome (PCOS) and High Androgens


A New Autism Risk Factor: Moms with Polycystic Ovaries



A couple of weeks back I posted this: "There is a lot unknown about the mitochondrial relation with NLRP3. I theorize a relation between NLRP3, NEk7,and microtubule formation and that this bears on neuronal plasticity and function. I have not gotten very far yet."

Today I found what is supposed to be a new finding about Nek7 and its relation to NLRP3. I had already believed this was the case, but I can't test what I find. I am encouraged and will pursue a relationship to microtubules.

Enzyme involved in cell division also plays a role in inflammation

"DALLAS - Dec. 7, 2015 - UT Southwestern Medical Center and California researchers today provide the first report that an enzyme previously known solely for its role in cell division also acts as an on-off switch in the innate immune system -- the body's first defense against infection.

The identification of the NEK7 enzyme's switch-like activity in immunity could lead to new treatments for a variety of medical conditions linked to inflammation via the NRLP3 inflammasome pathway, including certain metabolic disorders, influenza A, gout, atherosclerosis, and possibly some forms of cancer. The current study investigated mouse models of inflammatory bowel disease and multiple sclerosis.

"NRLP3 is one of several inflammasomes - multiprotein structures in disease-fighting white blood cells - the first of which was identified less than 15 years ago. The NRLP3 complex responds to microbes and other danger signals by activating molecules called cytokines, such as interleukin-1 beta, which trigger inflammation to fight infection," said Nobel Laureate Dr. Bruce Beutler, Director of the Center for the Genetics of Host Defense at UT Southwestern and senior author of the study published online in Nature Immunology"...

The researchers genetically screened thousands of mice and conducted exhaustive interdisciplinary experiments: identifying a defect in inflammasome function, ascribing that defect to a mutation in the gene for the NEK7 enzyme, and fully characterizing NEK7 function in innate immunity.

The enzyme was previously known only for its involvement in cell division, or mitosis, a process that involves the creation of two daughter cells from one parental cell. Specifically, mitosis is the phase of cell division in which the nucleus, which holds all of the cell's genetic material, divides to form two new cells, each with a full complement of genes.

"Our work has shown that the inflammasome cannot become activated during mitosis. This is possibly a protective mechanism that prevents damage to DNA during this part of the cell cycle," said Dr. Beutler, who shared the 2011 Nobel Prize in Physiology or Medicine for his groundbreaking work on innate immunity. Dr. Beutler, a Texas Regental Professor, also holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr."


My odds and ends posts might be delayed.


A couple of weeks back I posted this: "There is a lot unknown about the mitochondrial relation with NLRP3. I theorize a relation between NLRP3, NEk7,and microtubule formation and that this bears on neuronal plasticity and function. I have not gotten very far yet."

Today I found what is supposed to be news about Nek7 and NLRP3. I am encouraged and will see if the there is a relationship to microtubules.

Enzyme involved in cell division also plays a role in inflammation

"DALLAS - Dec. 7, 2015 - UT Southwestern Medical Center and California researchers today provide the first report that an enzyme previously known solely for its role in cell division also acts as an on-off switch in the innate immune system -- the body's first defense against infection.

The identification of the NEK7 enzyme's switch-like activity in immunity could lead to new treatments for a variety of medical conditions linked to inflammation via the NRLP3 inflammasome pathway, including certain metabolic disorders, influenza A, gout, atherosclerosis, and possibly some forms of cancer. The current study investigated mouse models of inflammatory bowel disease and multiple sclerosis.

"NRLP3 is one of several inflammasomes - multiprotein structures in disease-fighting white blood cells - the first of which was identified less than 15 years ago. The NRLP3 complex responds to microbes and other danger signals by activating molecules called cytokines, such as interleukin-1 beta, which trigger inflammation to fight infection," said Nobel Laureate Dr. Bruce Beutler, Director of the Center for the Genetics of Host Defense at UT Southwestern and senior author of the study published online in Nature Immunology"...

The researchers genetically screened thousands of mice and conducted exhaustive interdisciplinary experiments: identifying a defect in inflammasome function, ascribing that defect to a mutation in the gene for the NEK7 enzyme, and fully characterizing NEK7 function in innate immunity.

The enzyme was previously known only for its involvement in cell division, or mitosis, a process that involves the creation of two daughter cells from one parental cell. Specifically, mitosis is the phase of cell division in which the nucleus, which holds all of the cell's genetic material, divides to form two new cells, each with a full complement of genes.

"Our work has shown that the inflammasome cannot become activated during mitosis. This is possibly a protective mechanism that prevents damage to DNA during this part of the cell cycle," said Dr. Beutler, who shared the 2011 Nobel Prize in Physiology or Medicine for his groundbreaking work on innate immunity. Dr. Beutler, a Texas Regental Professor, also holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr."


My odds and ends posts might be delayed.


A few old odds and ends with this post and a couple of the next to follow. A credentialed source by the way.

IgG dynamics of dietary antigens point to cerebrospinal fluid barrier or flow dysfunction in first-episode schizophrenia.


"Schizophrenia is a complex brain disorder that may be accompanied by idiopathic inflammation. Classic central nervous system (CNS) inflammatory disorders such as viral encephalitis or multiple sclerosis can be characterized by incongruent serum and cerebrospinal fluid (CSF) IgG due in part to localized intrathecal synthesis of antibodies. The dietary antigens, wheat gluten and bovine milk casein, can induce a humoral immune response in susceptible individuals with schizophrenia, but the correlation between the food-derived serological and intrathecal IgG response is not known. Here, we measured IgG to wheat gluten and bovine milk casein in matched serum and CSF samples from 105 individuals with first-episode schizophrenia (n=75 antipsychotic-naïve), and 61 controls. We found striking correlations in the levels of IgG response to dietary proteins between serum and CSF of schizophrenia patients, but not controls (schizophrenia, R(2)=0.34-0.55, p⩽0.0001; controls R(2)=0.05-0.06, p>0.33). A gauge of blood-CSF barrier permeability and CSF flow rate, the CSF-to-serum albumin ratio, was significantly elevated in cases compared to controls (p⩽0.001-0.003). Indicators of intrathecal IgG production, the CSF IgG index and the specific Antibody Index, were not significantly altered in schizophrenia compared to controls. Thus, the selective diffusion of bovine milk casein and wheat gluten antibodies between serum and CSF in schizophrenia may be the function of a low-level anatomical barrier dysfunction or altered CSF flow rate, which may be transient in nature."

Copyright © 2014 Elsevier Inc. All rights reserved.

KEYWORDS: Arachnoid membrane; Autism; Bipolar disorder; Blood–brain barrier; Choroid plexus; Endothelial; Epithelial; Gastrointestinal; Psychoses




What you said makes sense and some things we are encountering with good intent are a problem for many. The same way ramping up the immune system in little ones can change the microbiota in the gut and then further effect the immune system and gut/brain axis, though it is hard to know this is the sequence or if it is reciprocal process all along with the gut immunity and the immune system peripheral to it being disturbed together.

It seems in the regressive Autism the effect of the vaccine, whnen involved, acts fairly quickly and tends to support the idea that the immune stimulation/inflammatory response leads to the gut microbiota changes being made. It also seems some increased products from certain bacteria like propionic acid, while causing other problems, are the attempt to prevent even worse colonization and even keep fungal numbers in check. So while dysbiosis creates problems it seems even this represent some helpful elements.


Hi Visitor: was looking back at some of your recent posts - I can see you mentioned folic acid early in November. I do think the synthetic version folic acid is not a good thing, that brains would need folate in the natural plant form and that the synthetic version might displace what little there is of the real stuff in a pregnant mum and I don't think manmade vitamins can ever do exactly the same thing that human development evolved with over the course of history.
There is a group called Vitamin Angels, a non profit pushing vitamins over in undeveloped countries to "help" them. I sent them information several months ago re: the potential issue with folic acid, since most of their "partners" use folic acid in their vitamins, hoping to get their attention. No response. Those poor people in those countries who think they are recipients of only good charity are destined to be victims of the same tragedy American children and pregnant women have gone through, a combination of synthetic folic acid and forced vaccines. So sad.


About three post back I mentioned microtubule formation, as in stability. The following link speaks about a theory, concerning microtubules, I have followed for a long time and thought it had merit. This is a jump ahead, maybe in a primary way, in terms of process about what I have posted, but for those who wonder about the biomedical disruptions in the "soft machine" relating to consciousness this may be intriguing, and for now is a bit of a frontier marker for me.

Discovery of quantum vibrations in 'microtubules' inside brain neurons supports controversial theory of consciousness

"A review and update of a controversial 20-year-old theory of consciousness published in Physics of Life Reviews claims that consciousness derives from deeper level, finer scale activities inside brain neurons. The recent discovery of quantum vibrations in "microtubules" inside brain neurons corroborates this theory, according to review authors Stuart Hameroff and Sir Roger Penrose. They suggest that EEG rhythms (brain waves) also derive from deeper level microtubule vibrations, and that from a practical standpoint, treating brain microtubule vibrations could benefit a host of mental, neurological, and cognitive conditions.

The theory, called "orchestrated objective reduction" ('Orch OR'), was first put forward in the mid-1990s by eminent mathematical physicist Sir Roger Penrose, FRS, Mathematical Institute and Wadham College, University of Oxford, and prominent anesthesiologist Stuart Hameroff, MD, Anesthesiology, Psychology and Center for Consciousness Studies, The University of Arizona, Tucson. They suggested that quantum vibrational computations in microtubules were "orchestrated" ("Orch") by synaptic inputs and memory stored in microtubules, and terminated by Penrose "objective reduction" ('OR'), hence "Orch OR." Microtubules are major components of the cell structural skeleton.

Orch OR was harshly criticized from its inception, as the brain was considered too "warm, wet, and noisy" for seemingly delicate quantum processes.. However, evidence has now shown warm quantum coherence in plant photosynthesis, bird brain navigation, our sense of smell, and brain microtubules. The recent discovery of warm temperature quantum vibrations in microtubules inside brain neurons by the research group led by Anirban Bandyopadhyay, PhD, at the National Institute of Material Sciences in Tsukuba, Japan (and now at MIT), corroborates the pair's theory and suggests that EEG rhythms also derive from deeper level microtubule vibrations. In addition, work from the laboratory of Roderick G. Eckenhoff, MD, at the University of Pennsylvania, suggests that anesthesia, which selectively erases consciousness while sparing non-conscious brain activities, acts via microtubules in brain neurons.

"The origin of consciousness reflects our place in the universe, the nature of our existence. Did consciousness evolve from complex computations among brain neurons, as most scientists assert? Or has consciousness, in some sense, been here all along, as spiritual approaches maintain?" ask Hameroff and Penrose in the current review. "This opens a potential Pandora's Box, but our theory accommodates both these views, suggesting consciousness derives from quantum vibrations in microtubules, protein polymers inside brain neurons, which both govern neuronal and synaptic function, and connect brain processes to self-organizing processes in the fine scale, 'proto-conscious' quantum structure of reality."

After 20 years of skeptical criticism, "the evidence now clearly supports Orch OR," continue Hameroff and Penrose. "Our new paper updates the evidence, clarifies Orch OR quantum bits, or "qubits," as helical pathways in microtubule lattices, rebuts critics, and reviews 20 testable predictions of Orch OR published in 1998 -- of these, six are confirmed and none refuted..."



The first report does not mention effects on other neurons, but you have to think...

Aluminum Activates PERK-EIF2α Signaling and Inflammatory Proteins in Human Neuroblastoma SH-SY5Y Cells.


"Aluminum is the third most abundant element present in the earth's crust and human exposure to it is possible due to industrialization, utensils, medicines, antiperspirants, etc. Evidences suggest involvement of aluminum in a variety of neurodegenerative disorders including Alzheimer's disease. Endoplasmic reticulum (ER) stress has been implicated in various neurological disorders. ER stress may be a result of impaired calcium homeostasis due to perturbed redox balance and is known to elicit inflammation through the activation of unfolded protein response (UPR). In the present study, we aimed to investigate the role of aluminum in ER stress-mediated activation of inflammatory responses in neuroblastoma cells. Lactate dehydrogenase (LDH) release assay revealed that aluminum compromised the membrane integrity of neuroblastoma cells, probably due to membrane damage, as indicated by enhanced levels of lipid peroxidation (LPO). Besides this, our results clearly demonstrated elevated reactive oxygen species (ROS) levels and a weakened antioxidant defence system manifested by decrease in catalase (CAT) activity and cellular glutathione (GSH). Moreover, we studied the expression of key apoptosis-related proteins, ER stress-mediated activation of UPR, and its downstream inflammatory pathway. It was observed that aluminum potentially enhanced protein levels of PERK, EIF2α, caspase 9, caspase 3, and inflammatory markers like NF-κB, NLRP3, HMGB1, and nitric oxide (NO). Furthermore, aluminum altered TNFα, IL1β, IL6, and IL10 mRNA levels as well. The overall findings indicated that aluminum mediates UPR activation through ER stress, which results in induction of inflammatory pathway and apoptotic proteins in neuronal cells."


HMGB1 levels may be already be higher in those susceptible to vaccine injury and this would tie increased autoimmune and inflammatory conditions in the population to the increase in Autism as reports have found HMGB1 levels elevated in those with Autism. HMGB1 acts as an adjuvant itself and the trigger of the vaccine{esp. aluminum} may moderately to precipitously raise inflammation and include effects on neuronal migration and plasticity involving NLRP3 as previously addressed. Severe reactions could kill and show as a child with a severely inflamed body and brain.
Mothers and grandmothers may be having increased epigenetic and immune effects that are predisposing their offspring.

Hep B below


Microglia Control Synapse Number in Multiple Disease States


HMGB1 and Cord Blood: Its Role as Immuno-Adjuvant Factor in Innate Immunity



Likely part of Dr. Bradstreet's venue and related to NLRP3.

NLRP3 inflammasome and its inhibitors: a review

"Cannabinoid receptor 2 (CB2R) is an already demonstrated therapeutic target in inflammation-related diseases (Smoum et al., 2015). Work from our own laboratory (Shao et al., 2014) has shown that autophagy induction may help explain why activation of the anti-inflammatory CB2R leads to inhibition of NLRP3 inflammasome priming and activation in mouse BV2 microglia stimulated with LPS and ATP as well as in a mouse model of EAE. Such CB2R activation reduces the severity of EAE in mice. Thus CB2R agonists similar to the HU-308 used in our work may become an effective therapy for treating NLRP3 inflammasome-related diseases by inducing autophagy."


There is a lot of interrelated function with NLRP3 and various autoimmune and auotinflammatory conditions.


"Nothing happens in a vacuum in life: every action has a series of consequences, and sometimes it takes a long time to fully understand the consequences of our actions."

Khaled Hosseini

The Adaptor MAVS Promotes NLRP3 Mitochondrial Localization and Inflammasome Activation


NLRP3 is involved in inflammatory conditions highlighted in RA studies and effect. The mitochondrial issues in Autism likely relate to this function and immune stimulation due to various causes including vaccines. Still not sure if TNFAIP3 expression in some with inflammatory conditions related to Autism bears on the increase of NF-kappa B found in groups with Autism.

Vaccine Adjuvants - Review Good To Read

Mechanisms of adjuvants

"Adjuvants may exert their effects through different mechanisms. Some adjuvants, such as alum and emulsions (e.g. MF59®), function as delivery systems by generating depots that trap antigens at the injection site, providing slow release in order to continue the stimulation of the immune system. These adjuvants enhance the antigen persistence at the injection site and increase recruitment and activation of antigen presenting cells (APCs). Particulate adjuvants (e.g. alum) have the capability to bind antigens to form multi-molecular aggregates which will encourage uptake by APCs [1].
Some adjuvants are also capable of directing antigen presentation by the major histocompatibility complexes (MHC) [1].
Other adjuvants, essentially ligands for pattern recognition receptors (PRR), act by inducing the innate immunity, predominantly targeting the APCs and consequently influencing the adaptative immune response. Members of nearly all of the PRR families are potential targets for adjuvants. These include Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs) and C-type lectin receptors (CLRs). They signal through pathways that involve distinct adaptor molecules leading to the activation of different transcription factors. These transcription factors (NF-κB, IRF3) induce the production of cytokines and chemokines that play a key role in the priming, expansion and polarization of the immune responses. Activation of some members of the NLR family, such as NLRP3 and NLRC4, triggers the formation of a protein complex, called inflammasome, implicated in the induction of the pro-inflammatory cytokines IL-1β [2] and IL-18. The NLRP3 and NLRC4 inflammasomes have been involved in the innate immunity induced by certain adjuvants but their mechanism of action remains unclear.

Alum & emulsions

Alum is the most commonly used adjuvant in human vaccination. It is found in numerous vaccines, including diphtheria-tetanus-pertussis, human papillomavirus and hepatitis vaccines [3]. Alum provokes a strong Th2 response, but is rather ineffective against pathogens that require Th1–cell-mediated immunity. Alum induces the immune response by a depot effect and activation of APCs. Recently, the NLRP3 inflammasome has been linked to the immunostimulatory properties of alum [2] although its role in adjuvant-induced antibody responses remains controversial."


There is a lot unknown about the mitochondrial relation with NLRP3. I theorize a relation between NLRP3, NEk7,and microtubule formation and that this bears on neuronal plasticity and function. I have not gotten very far yet.
TNFAIP3 - Wiki

"This gene was identified as a gene whose expression is rapidly induced by the tumor necrosis factor (TNF). The protein encoded by this gene is a zinc finger protein, and has been shown to inhibit NF-kappa B activation as well as TNF-mediated apoptosis. Knockout studies of a similar gene in mice suggested that this gene is critical for limiting inflammation by terminating TNF-induced NF-kappa B responses.[2]"




Measurement in saliva from neurotypical adults of biomarkers pertinent to autism spectrum disorders



To be clear, after the pathology in the gut than nutrient and vitamin status would change and supplementation of some vitamins would then become therapeutic.


Definitely two reports, after the Wiki blurb, that are extremely woth reading below. It seems that while an immune stressor or trigger like vaccines may start or elevate a condition, the table has often been set in the womb as autism occurs without vaccine being implicated and maybe more so as the years go by. If autism was exceedingly rare before 194o then it would appear that a lack of vitamin supplementation was not a reason for autism. It may be that the increase in processed foods had a bearing on a mother and, by extension, child's neurodevelopment, but the total picture does not lend credence to the idea that lack of vitamin's was a big factor in the increase in autism. The increased ingestion of some vitamins along with all the environmental factors{negative contributors, toxins, chemicals, metals, v etc...} could have made the need for other vitamins greater and a cycle of supplementation of some vitamins at certain states, esp. in pregnancy became more crucial. For example the rise of spina bifida causing more folic acid to curb. Anyway, the altered gene expression in those with autism and other conditions may be a reaction to the taxing of some nutrients and the excess of others. Morning sickness may be in part result of these imbalances and for the disturbance in the methyl groups sulfation and other systems needed catecholamine cycles and processing xenobiotics and detoxification. It may be why only certain vitamins are found helpful for some autism as well as the imbalance creates greater need.

Wiki - Vitamin

"Until the mid-1930s, when the first commercial yeast-extract vitamin B complex and semi-synthetic vitamin C supplement tablets were sold, vitamins were obtained solely through food intake, and changes in diet (which, for example, could occur during a particular growing season) usually greatly altered the types and amounts of vitamins ingested. However, vitamins have been produced as commodity chemicals and made widely available as inexpensive semisynthetic and synthetic-source multivitamin dietary and food supplements and additives, since the middle of the 20th century."


Microarray Analysis Reveals Higher Gestational Folic Acid Alters Expression of Genes in the Cerebellum of Mice Offspring—A Pilot Study


"Folate is a water-soluble vitamin that is critical for nucleotide synthesis and can modulate methylation of DNA by altering one-carbon metabolism. Previous studies have shown that folate status during pregnancy is associated with various congenital defects including the risk of aberrant neural tube closure. Maternal exposure to a methyl supplemented diet also can alter DNA methylation and gene expression, which may influence the phenotype of offspring. We investigated if higher gestational folic acid (FA) in the diet dysregulates the expression of genes in the cerebellum of offspring in C57BL/6 J mice. One week before gestation and throughout the pregnancy, groups of dams were supplemented with FA either at 2 mg/kg or 20 mg/kg of diet. Microarray analysis was used to investigate the genome wide gene expression profile in the cerebellum from day old pups. Our results revealed that exposure to the higher dose FA diet during gestation dysregulated expression of several genes in the cerebellum of both male and female pups. Several transcription factors, imprinted genes, neuro-developmental genes and genes associated with autism spectrum disorder exhibited altered expression levels. These findings suggest that higher gestational FA potentially dysregulates gene expression in the offspring brain and such changes may adversely alter fetal programming and overall brain development."


Early Infant Exposure to Excess Multivitamin: A Risk Factor for Autism?


"Autism, a neurodevelopmental disorder that affects boys more than girls, is often associated with altered levels of monoamines (serotonin and catecholamines), especially elevated serotonin levels. The monoamines act as both neurotransmitters and signaling molecules in the gastrointestinal and immune systems. The evidence related to monoamine metabolism may be summarized as follows: (i) monoamine neurotransmitters are enzymatically degraded/inactivated by three mechanisms: oxidative deamination, methylation, and sulfation. The latter two are limited by the supply of methyl groups and sulfate, respectively. (ii) A decrease in methylation- and sulfation-mediated monoamine inactivation can be compensated by an increase in the oxidative deamination catalyzed by monoamine oxidase, an X-linked enzyme exhibiting higher activity in females than in males. (iii) Vitamins can, on one hand, facilitate the synthesis of monoamine neurotransmitters and, on the other hand, inhibit their inactivation by competing for methylation and sulfation. Therefore, we postulate that excess multivitamin feeding in early infancy, which has become very popular over the past few decades, may be a potential risk factor for disturbed monoamine metabolism. In this paper, we will focus on the relationship between excess multivitamin exposure and the inactivation/degradation of monoamine neurotransmitters and its possible role in the development of autism...."

"It has been known for over a century that the dose-response curve for many micronutrients is nonmonotonic, having an initial stage of increasing benefits with increased intake, followed by increasing costs as excesses become toxic [39]. Both vitamin deficiency and vitamin excess are known to cause toxicity, including neurotoxicity [15, 40]. A meta-analysis of randomized trials of antioxidant supplements for primary and secondary prevention suggests that supplementation of vitamin A and E may increase mortality [41]. Supplemental folic acid (the synthetic form of folate) was also found to be associated with increased mortality [42, 43]. Davis and colleagues [44] found an association between high serum thiamine levels and sudden infant death syndrome (SIDS, a sudden and unexplained infant death most likely to occur between 2 and 4 months of age), and they further demonstrated that high doses of thiamine could cause death in rabbits and mice due to respiratory failure."



Speaking of Dr. Wakefield, he, with others released a report a number of years back about theses matters related to the second article in last post. It is linked below. The report mentions esophageal reflux, gastritis, and constipation related to autism and the gut matters discussed. I had noted and dealt with these in my wife in 96' forward and found it very confirming that these conditions{with others} originally present in that overall assessment were later associated as conditions found in much higher amounts in many with autism.

Review article: The concept of enterocolonic encephalopathy, autism and opioid recepter ligands


In some, maybe a large part, the vaccines may disturb the gut, and brain neuroplasticity along with the glial effects. Then the gut function being altered makes this an ongoing pathology with neuroinflammation and mild or more encephalopathy.

Perinatal brain damage in children: neuroplasticity, early intervention, and molecular mechanisms of recovery.


"During the perinatal period, the nervous system is very vulnerable to insult. At this time, the brain undergoes fast and complex maturational processes such as synaptogenesis, arborization, and apoptosis, and the response to the insult is highly dependent on its exact timing. There is evidence that some of the neuroplastic mechanisms adopted by the young brain after damage are unavailable at a later stage of maturation. This applies, for example, to the reorganization of language, the sensorimotor system, or the visual system. Expanding our knowledge on these mechanisms could help the development of early therapeutic interventions aimed at supporting and enhancing functional reorganization at a time of greatest potential brain plasticity."



The elements of immune response to HBV and related synaptic plasticity mentioned in the last post overlaps with those elements of inflammatory microglial activation associated with intestinal and peripheral inflammation. The nest report details a number related things such as colitis that covers and may include the similar gut issue defined by Dr. Wakefield. The whole article should be read to see the full idea. It also makes a reassessment of minocycline in some with autism seem desirable.

Microglia-Dependent Alteration of Glutamatergic Synaptic Transmission and Plasticity in the Hippocampus during Peripheral Inflammation


"Peripheral inflammatory diseases are often associated with behavioral comorbidities including anxiety, depression, and cognitive dysfunction, but the mechanism for these is not well understood. Changes in the neuronal and synaptic functions associated with neuroinflammation may underlie these behavioral abnormalities. We have used a model of colonic inflammation induced by 2,4,6-trinitrobenzenesulfonic acid in Sprague Dawley rats to identify inflammation-induced changes in hippocampal synaptic transmission. Hippocampal slices obtained 4 d after the induction of inflammation revealed enhanced Schaffer collateral-induced excitatory field potentials in CA1 stratum radiatum. This was associated with larger-amplitude mEPSCs, but unchanged mEPSC frequencies and paired-pulse ratios, suggesting altered postsynaptic effects. Both AMPA- and NMDA-mediated synaptic currents were enhanced, and analysis of AMPA-mediated currents revealed increased contributions of GluR2-lacking receptors. In keeping with this, both transcripts and protein levels of the GluR2 subunit were reduced in hippocampus. Both long-term potentiation (LTP) and depression (LTD) were significantly reduced in hippocampal slices taken from inflamed animals. Chronic administration of the microglial/macrophage activation inhibitor minocycline to the inflamed animals both lowered the level of the cytokine tumor necrosis factor α in the hippocampus and completely abolished the effect of peripheral inflammation on the field potentials and synaptic plasticity (LTP and LTD). Our results reveal profound synaptic changes caused by a mirror microglia-mediated inflammatory response in hippocampus during peripheral organ inflammation. These synaptic changes may underlie the behavioral comorbidities seen in patients.


Peripheral inflammation is a feature of many diseases, including inflammatory bowel disease (Häuser et al., 2011), rheumatoid arthritis (Maini et al., 2004; Mayoux-Benhamou, 2006), and inflammatory liver disease (Gralnek et al., 2000; Butterworth, 2013; D'Mello and Swain, 2014), and is often associated with marked behavioral changes, including mood disorders, fatigue, cognitive and memory dysfunction, and sleep disturbances. Moreover, the inflammation is capable of aggravating other neurological and neuropsychiatric conditions, including seizure disorders (Vezzani et al., 2013), major depression (Raison et al., 2006), Alzheimer's disease (Ferrari and Tarelli, 2011), multiple sclerosis (Benson and Kerr, 2014), Parkinson's disease (Collins et al., 2012), and stroke (Ferrari and Tarelli, 2011). These comorbid effects can have considerable impact on both health and the quality of life of the patients.

The behavioral manifestations associated with peripheral inflammation clearly indicate CNS involvement; thus, a number of mechanisms have been suggested to underlie the communication between these peripheral inflammatory conditions and the brain (Walker et al., 2014). Peripheral tissue inflammation results in the production of proinflammatory cytokines that signal to the brain via cytokine receptors at the blood–brain barrier, within circumventricular organs or on sensory afferents. There is now compelling evidence that the cytokines generated during peripheral inflammation activate a secondary, mirror inflammatory response in the brain that is characterized by activation of microglia and production of proinflammatory cytokines, most importantly, tumor necrosis factor α (TNFα), interleukin (IL)-1β, and IL-6 (Quan et al., 1998; D'Mello et al., 2013; Thomson et al., 2014). These cytokines have profound effects on synaptic transmission and synaptic plasticity (for review, see Pickering and O'Connor, 2007), effects that most likely underlie the cognitive dysfunction, altered behavior, and other interactions with preexisting pathologies seen in peripheral inflammatory disease (Raison et al., 2006; Galic et al., 2012; Santello and Volterra, 2012; Nisticò et al., 2013; Camara et al., 2015). There is accumulating evidence that alterations in glutamatergic transmission underlie some of these behaviors (for review, see Walker et al., 2014).

In a rat model of inflammatory colitis, we previously reported reduced thresholds to chemically induced seizures in vivo and increased excitability of the hippocampus in vitro (Riazi et al., 2008). The increased excitability is mediated by activated microglia and production of TNFα in the hippocampus. However, the neuronal and synaptic changes that correlate with such increased excitability are unknown. Previous work indicates that TNFα alters expression of glutamate (Stellwagen and Malenka, 2006) and GABA (Pribiag and Stellwagen, 2013) receptors in vitro. In addition, direct application of proinflammatory cytokines to hippocampal slices in vitro alters the ability of excitatory synapses to display long-term potentiation (LTP; Pickering and O'Connor, 2007), a type of plasticity associated with learning and memory. Following up on our previous studies revealing an elevation of inflammatory cytokines in the brain (Riazi et al., 2008), we hypothesize that glutamatergic synaptic transmission and plasticity are altered during inflammatory colitis due to microglial activation. In a rat model of inflammatory colitis, we now report changes in hippocampal synaptic transmission associated with a profound reduction in synaptic plasticity."


Autistic enterocolitis: Fact or fiction?


"Autism spectrum disorder refers to syndromes of varying severity, typified by impaired social interactions, communicative delays and restricted, repetitive behaviours and interests. The prevalence of autism spectrum disorders has been on the rise, while the etiology remains unclear and most likely multifactorial. There have been several reports of a link between autism and chronic gastrointestinal symptoms. Endoscopy trials have demonstrated a higher prevalence of nonspecific colitis, lymphoid hyperplasia and focally enhanced gastritis compared with controls. Postulated mechanisms include aberrant immune responses to some dietary proteins, abnormal intestinal permeability and unfavourable gut microflora. Two autism spectrum disorder patients with chronic intestinal symptoms and abnormal endoscopic findings are described, followed by a review of this controversial topic."...

There have been several reports, mainly anecdotal, of a link between ASD and chronic gastrointestinal (GI) symptoms; however, scientific data are scarce and often criticized. Frequent complaints have included chronic diarrhea, bloating, abdominal pain, distension and abnormal stool consistency. In a recent cross-sectional study, comparing autistic children with matched neurotypical controls as well as children with other developmental disabilities (ODD), 70% of children with ASD reported a history of GI complaints, compared with 28% of neurotypical controls (P<0.001) and 42% with ODD (P=0.03) (5). GI problems have more commonly been linked to a ‘regressive’ form of autism, characterized by loss of previously acquired skills and late onset of behavioural anomalies, not observed in the first year of life.

One of the earliest studies investigating GI anomalies in autistic children was reported by Wakefield et al (6) in 1998. In this study, 12 children with regressive developmental disorders (nine of whom were autistic) were all reported to have abnormal colonoscopies. The most consistent finding was lymphoid nodular hyperplasia (LNH), present in nine of the 12 children. Eight had mucosal abnormalities including granularity, loss of vascular pattern, patchy erythema, aphthoid ulcerations and ‘red halo’ signs in the cecal base. Histologically, the lamina propria was infiltrated by mononuclear cells in a focal or diffuse pattern, in the absence of intraepithelial lymphocytes, granulomata or crypt abscesses (6). This mild to moderate colitis was deemed nonspecific on the basis of not fulfilling criteria for either Crohn’s disease or ulcerative colitis.

Criticism regarding the ‘normalcy’ of LNH in children prompted Wakefield et al (7) to perform ileocolonoscopy in 60 children with regressive developmental disorders and compare them with 37 developmentally normal controls. In this trial, ileal LNH was present in 93% of affected children versus 14.3% of controls (P<0.001), with chronic colitis in 88% of affected children versus 4.5% of controls (7).

With respect to the upper GI tract, Horvath et al (8) investigated 36 autistic children complaining of abdominal pain, bloating or chronic diarrhea by gastroscopy. The most common histological finding was reflux esophagitis (69.4%), while 41.7% had chronic gastritis and 66.7% had chronic duodenitis in the absence of H pylori infection...."

ASD patients and their caregivers often report improvement on elimination diets, not only in the GI symptoms, but also in behavioural and cognitive problems such as hyper-activity, communication skills and attentiveness. Interestingly, 36% of children with ASD have a history of cow’s milk and/or soy protein intolerance in infancy (8). Also, while studies have not proven an increased incidence of celiac disease in these individuals, parents have often reported an improvement in their child’s behavioural disturbances on a gluten-free diet. These benefits have not consistently been seen in randomized trials (10), however a Cochrane review (11) did report a significant reduction in autistic traits on a gluten-free casein-free diet.

One hypothesis is that ASD may be accompanied by aberrant innate immune responses to dietary proteins, leading to GI inflammation and aggravation of behavioural problems. One study (12) measuring proinflammatory cytokines in response to common dietary proteins showed a greater than two SD excess in tumour necrosis factor-alpha and interferon-gamma production in response to gluten and cow’s milk protein among ASD children compared with controls. A subsequent study confirmed a higher prevalence of elevated tumour necrosis factor-alpha and interleukin-12 production with beta-lactoglobin and alpha-lactoglobin, but not casein, in autistic children as well as children with nonallergic food hypersensitivity, compared with normal controls (13).

Another theory suggests that abnormal intestinal permeability in children with ASD causes them to absorb fragments of incompletely broken-down peptides such as gluten or casein, which cross the blood-brain barrier and act as endogenous opioids. D’Eufemia et al (14) demonstrated a higher mean lactulose recovery in 43% of autistic subjects versus none of the controls.

The gut microflora has also been targeted as a potential player. There have been anecdotal reports of the onset of autism following broad-spectrum antibiotics, suggesting that disruption of the indigenous flora may lead to colonization by neurotoxin-producing bacteria. Autistic children have been shown to have higher counts and more species of clostridia than age- and sex-matched controls (15–17). A small prospective trial (18) demonstrated a significant but transient improvement in autistic features following a course of vancomycin therapy, with relapses presumed to occur because of persistent spores that proliferate on antibiotic discontinuation."



The last two posts were quite speculative, but even so I mentioned possible effects of neurogenesis in the pre-frontal cortex and apparently those neurons numbers are static at birth except in those born pre-mature so a vaccine would seem not to be causing neurogenesis there. The reports are speaking of neurogenesis in the hippocampus though synaptic effects might be more broad.


This report by the same authors answers whether there could be conflicting effects from other vaccines. I should have read a bit further in the kinks on the original page. They say Hepatitis B vaccine gives an opposite effect.

Neonatal vaccination with bacillus Calmette-Guérin and hepatitis B vaccines modulates hippocampal synaptic plasticity in rats.


"Immune activation can exert multiple effects on synaptic transmission. Our study demonstrates the influence of neonatal vaccination on hippocampal synaptic plasticity in rats under normal physiological conditions. The results revealed that neonatal BCG vaccination enhanced synaptic plasticity. In contrast, HBV hampered it. Furthermore, we found that the cytokine balance shifted in favour of the T helper type 1/T helper type 2 immune response in BCG/HBV-vaccinated rats in the periphery. The peripheral IFN-γ:IL-4 ratio was positively correlated with BDNF and IGF-1 in the hippocampus. BCG raised IFN-γ, IL-4, BDNF and IGF-1 and reduced IL-1β, IL-6, and TNF-α in the hippocampus, whereas, HBV triggered the opposite effects."



I put the wrong title for the abstract in the last post it is:
Neonatal BCG Vaccination of Mice Improves Neurogenesis and Behavior in Early Life.



This is more of an anecdotal report, but it is funny how they so easily tie the BCG vaccine to neurogenesis and report what appears to be a positive effect inducing ostensibly neuroprotection in mice. For kicks, and giving the theory and results some credence, think of the notion of the proposition that a somewhat common vaccine can effect the brain. Also, if this one does would other vaccines quite possibly, or even likely have effects in the brain as well? If this theory is translated to humans then tampering with microglial activation in an infant who does not need intervention for brain conditions is rolling the dice and you have to ask what is the unintended consequence of increasing neurogenesis in subject. Given that many with autism have increased neuronal synapses and an excess of neurons in the pre-frontal cortex it makes you wonder in vaccines are triggering these outcomes. Not to mention possible compound effects from multiple vaccines and/or conflicting effects on microglia from various vaccines.
The opening line of the abstract says;
"Bacillus Calmette-Guérin (BCG) is administered to neonates worldwide, but it is still unknown whether this neonatal vaccination affects brain development during early postnatal life, despite the close association of the immune system with the brain."

This implies that it is reasonable to wonder what immune system stimulation/alteration might do in the brain and I would add the gut and maybe additional organs.

Differential Roles of M1 and M2 Microglia in Neurodegenerative Diseases.


"Bacillus Calmette-Guérin (BCG) is administered to neonates worldwide, but it is still unknown whether this neonatal vaccination affects brain development during early postnatal life, despite the close association of the immune system with the brain. Newborn C57BL/6 mice were injected subcutaneously with BCG or phosphate-buffered saline (PBS) and their mood status and spatial cognition were observed at four and eight weeks (w) old. The mice were also subjected to tests at 2 and 6 w to examine BCG's effects on neurogenesis, the hippocampal microglia phenotype and number, and the expression of hippocampal neuroimmune molecules and peripheral cytokines. The BCG-injected mice showed better behavioral performances at 4 w. We observed elevated neurogenesis, M2 microglial activation and a neurotrophic profile of neuroimmune molecules [more interferon (IFN)-γ, interleukin (IL)-4, transforming growth factor (TGF)-β, brain-derived neurotrophic factor (BDNF) and insulin-like growth factor (IGF)-1 and less tumor necrosis factor (TNF)-α and IL-1β] in the hippocampus of the 2-w-old BCG-mice. In the periphery, BCG induced a T helper (Th)-1 serum response. At the individual level, there were positive correlations between the serum IFN-γ/IL-4 ratio and the levels of neurotrophins and neurogenesis in the hippocampus. These findings suggest that neonatal BCG vaccination improved neurogenesis and mouse behavior in early life by affecting the neuroimmune milieu in the brain, which may be associated with a systemic Th1 bias."


The development of brain trajectory in autism suggests the growth and microglial status is later skewed negatively and boosting or skewing in infancy would be a good idea to consider for later maladaptive function.


More inflammation, yet this report suggests less able to fight off infection in autism.

Study confirms mitochondrial deficits in children with autism

"Children with autism experience deficits in a type of immune cell that protects the body from infection. Called granulocytes, the cells exhibit one-third the capacity to fight infection and protect the body from invasion compared with the same cells in children who are developing normally.

The cells, which circulate in the bloodstream, are less able to deliver crucial infection-fighting oxidative responses to combat invading pathogens because of dysfunction in their tiny energy-generating organelles, the mitochondria....

In an earlier study the research team found decreased mitochondrial fortitude in another type of immune cell, the lymphocytes. Together, the findings suggest that deficiencies in the cells’ ability to fuel brain neurons might lead to some of the cognitive impairments associated with autism. Higher levels of free radicals also might contribute to autism severity.

“The response found among granulocytes mirrors earlier results obtained with lymphocytes from children with severe autism, underscoring the cross-talk between energy metabolism and response to oxidative damage,” said Cecilia Giulivi, professor in the Department of Molecular Biosciences in the UC Davis School of Veterinary Medicine and the study’s senior author.

“It also suggests that the immune response seems to be modulated by a nuclear factor named NRF2,” that controls antioxidant response to environmental factors and may hold clues to the gene-environment interaction in autism, Giulivi said."



Increased plasma levels of the high mobility group box 1 protein (HMGB1) are associated with a higher score of gastrointestinal dysfunction in individuals with autism.


"Autism is a disorder of neural development characterized by impairments in communication, social interaction, restricted interests and repetitive behavior. The etiology of autism is poorly understood, the evidence indicates that inflammation may play a key role. In autism a high prevalence of gastrointestinal disturbances is reported, that are linked to a low-grade chronic inflammation of the intestinal mucosa. High mobility group box 1 protein (HMGB1) is an intranuclear protein that can be passively released from necrotic cells or actively secreted under inflammatory conditions as alarmin or late proinflammatory cytokine. The objective of this study was to measure plasma levels of HMGB1 in individuals with autism and to analyze their association with gastrointestinal symptoms. The study involved 31 subjects with low-functioning autistic disorder aged 2-22 years and 16 healthy controls. Plasma HMGB1 levels were significantly higher in individuals with autism than in controls (13.8+/-11.7 ng/ml vs. 7.90+/-4.0 ng/ml, p<0.02). In subjects with plasma HMGB1 levels higher than 11 ng/ml severe forms of GI disorders were more prevalent (83.3 %) than in subjects with lower levels (38.9 %, p<0.04). Results of the study support the involvement of the systemic low-grade inflammation in the pathomechanisms of autism and its possible association with GI symptoms."


Increased serum levels of high mobility group box 1 protein in patients with autistic disorder.


"High mobility group box 1 (HMGB1) is a highly conserved, ubiquitous protein that functions as an activator for inducing the immune response and can be released from neurons after glutamate excitotoxicity. The objective of the present study was to measure serum levels of HMGB1 in patients with autistic disorder and to study their relationship with clinical characteristics.

We enrolled 22 adult patients with autistic disorder (mean age: 28.1+/-7.7 years) and 28 age- and gender-matched healthy controls (mean age: 28.7+/-8.1 years). Serum levels of HMGB1 were measured by enzyme-linked immunosorbent assay (ELISA).

Compared with healthy subjects, serum levels of HMGB1 were significantly higher in patients with autistic disorder (10.8+/-2.6 ng/mL versus 5.6+/-2.5 ng/mL, respectively, P<0.001). After adjustment for potential confounders, serum HMGB1 levels were independently associated with their domain A scores in the Autism Diagnostic Interview-Revised, which reflects their impairments in social interaction.

These results suggest that HMGB1 levels may be affected in autistic disorder. Increased HMGB1 may be a biological correlate of the impaired reciprocal social interactions in this neurodevelopmental disorder."



Thanks, Visitor


Serotonin, tryptophan metabolism and the brain-gut-microbiome axis

"Tryptophan and its metabolite serotonin have an expansive physiological repertoire, making them fundamental to health and there are numerous associations between alterations in this system and disease [1], [2] and [3]. A growing body of data is also pointing to the influence of this system far beyond the traditional focus on its signalling pathways in the central nervous system (CNS) (see Reviews in this Special Issue). Moreover, emerging data implicates the gut microbiome in the regulation of brain and behaviour in general with a specific emphasis on its impact on tryptophan metabolism and the serotonergic system.

Research in this area builds on the principles of the brain-gut axis concept (see Fig. 1), a bidirectional communication network between the brain and the gut with serotonin functioning as a key signalling molecule in both the enteric nervous system (ENS) and the CNS [4], [5] and [6]. Recently, it has become clear that the gut microbiome is a critical component of this axis and one which exerts control at multiple levels, not just locally in the gastrointestinal tract [7], [8], [9] and [10]. Using a variety of preclinical strategies, it has been established that manipulating the composition of the gut microbiota across the lifespan or altering the trajectory of microbial colonisation of the gastrointestinal tract early in life influences the availability of tryptophan. In tandem and possibly related to this capacity, this research has also illuminated a role for the gut microbiota in serotonergic signalling at the level of the CNS. There is also a substantial overlap between many of the behaviours underpinned by serotonergic signalling and those which are influenced by alterations in the composition, diversity or stability of the microbiota. Taken together, it seems plausible that the gut microbiota can either directly or indirectly recruit tryptophan metabolism and serotonergic signalling within the framework of the brain-gut axis to modulate host behaviour."



There is more delved into than just depression in the article. Here is a snippet.

Could Depression Be Caused By An Infection?

"Dr. Roger McIntyre, a professor of psychiatry and pharmacology at the University of Toronto, tells Shots that he believes an upset in the "immune-inflammatory system" is at the core of mental illness and that psychiatric disorders might be an unfortunate cost of our powerful immune defenses. "Throughout evolution our enemy up until vaccines and antibiotics were developed was infection," he says. "Our immune system evolved to fight infections so we could survive and pass our genes to the next generation. However, our immune-inflammatory system doesn't distinguish between what's provoking it." McIntyre explains how stressors of any kind — physical or sexual abuse, sleep deprivation, grief — can activate our immune alarms. "For reasons other than fighting infection, our immune-inflammatory response can stay activated for weeks, months or years and result in collateral damage," he says."


Stress sounds the alarmin: The role of the danger-associated molecular pattern HMGB1 in stress-induced neuroinflammatory priming.




As inositol is made in the body it is often thought that you need not supplement it. I don't think it is in most multi vitamins, but as you know, it can be purchased. Benedetta may have more thoughts on it as she said she used it for one of her children and seemed to think lithium actually facilitated it's availability though I have found literature still stating that lithium interferes with its metabolism. There are those who say it helps with mood, ocd, and anxiety, but I have found little about how much it might be of use in Autism. While we never used it in additional amounts wo what was in the Vitamin complex we used it seems reasonable that in some cases it would be helpful with some symptoms.








Very interesting about thiamin, and leptin, too. Info on leptin and grehlin is very interesting to me right now, in regard to their effect on mood.

I'm interested, too, in the mention of inositol 1,4,5 in relation to relevant neurological pathways, though I don't see mention of tics on the chart, though anxiety and OCD are there and I think of tics being in that same behavior class.
Would supplementing with inositol alone be worthwhile? Isn't it a b vitamin? I'm not sure it's included in regular B vitamin complexes or not, though. It's necessary for the growth of yeast, I read, so I could see how one might think twice about using it, yet other b vitamins are critical, it appears, so why not b8?


Some of the inflammatory mediators have been connected to Autism others have not, though they seem to all be involved in my wife's case. {NLRP3 = NALP3}

The redox state of the alarmin HMGB1 is a pivotal factor in neuroinflammatory and microglial priming: a role for the NLRP3 inflammasome.


"The alarmin high mobility group box-1 (HMGB1) has been implicated as a key factor mediating neuroinflammatory processes. Recent findings suggest that the redox state of HMGB1 is a critical molecular feature of HMGB1 such that the reduced form (fr-HMGB1) is chemotactic, while the disulfide form (ds-HMGB1) is pro-inflammatory. The present study examined the neuroinflammatory effects of these molecular forms as well as the ability of these forms to prime the neuroinflammatory and microglial response to an immune challenge. To examine the neuroinflammatory effects of these molecular forms in vivo, animals were administered intra-cisterna magna (ICM) a single dose of fr-HMGB1 (10 μg), ds-HMGB1 (10 μg) or vehicle and basal pro-inflammatory effects were measured 2 and 24h post-injection in hippocampus. Results of this initial experiment demonstrated that ds-HMGB1 increased hippocampal pro-inflammatory mediators at 2h (NF-κBIα mRNA, NLRP3 mRNA and IL-1β protein) and 24h (NF-κBIα mRNA, TNFα mRNA, and NLRP3 protein) after injection. fr-HMGB1 had no effect on these mediators. These neuroinflammatory effects of ds-HMGB1 suggested that ds-HMGB1 may function to prime the neuroinflammatory response to a subsequent immune challenge. To assess the neuroinflammatory priming effects of these molecular forms, animals were administered ICM a single dose of fr-HMGB1 (10 μg), ds-HMGB1 (10 μg) or vehicle and 24h after injection, animals were challenged with LPS (10 μg/kg IP) or vehicle. Neuroinflammatory mediators and the sickness response (3, 8 and 24h after injection) were measured 2h after immune challenge. We found that ds-HMGB1 potentiated the neuroinflammatory (NF-κBIα mRNA, TNFα mRNA, IL-1β mRNA, IL-6 mRNA, NLRP3 mRNA and IL-1β protein) and sickness response (reduced social exploration) to LPS challenge. fr-HMGB1 failed to potentiate the neuroinflammatory response to LPS. To examine whether these molecular forms of HMGB1 directly induce neuroinflammatory effects in isolated microglia, whole brain microglia were isolated and treated with fr-HMGB1 (0, 1, 10, 100, or 1000 ng/ml) or ds-HMGB1 (0, 1, 10, 100, or 1000 ng/ml) for 4h and pro-inflammatory mediators measured. To assess the effects of these molecular forms on microglia priming, whole brain microglia were pre-exposed to these forms of HMGB1 (0, 1, 10, 100, or 1000 ng/ml) and subsequently challenged with LPS (10 ng/ml). We found that ds-HMGB1 increased expression of NF-κBIα mRNA and NLRP3 mRNA in isolated microglia, and potentiated the microglial pro-inflammatory response (TNFα mRNA, IL-1β mRNA and IL-1β protein) to LPS. fr-HMGB1 failed to potentiate the microglial pro-inflammatory response to LPS. Consistent with prior reports, the present findings demonstrate that the disulfide form of HMGB1 not only potentiates the neuroinflammatory response to a subsequent immune challenge in vivo, but also potentiates the sickness response to that challenge. Moreover, the present findings demonstrate for the first time that ds-HMGB1 directly potentiates the microglia pro-inflammatory response to an immune challenge, a finding that parallels the effects of ds-HMGB1 in vivo. In addition, ds-HMGB1 induced expression of NLRP3 and NF-κBIα in vivo and in vitro suggesting that the NLRP3 inflammasome may play role in the priming effects of ds-HMGB1. Taken together, the present results suggest that the redox state of HMGB1 is a critical determinant of the priming properties of HMGB1 such that the disulfide form of HMGB1 induces a primed immunophenotype in the CNS, which may result in an exacerbated neuroinflammatory response upon exposure to a subsequent pro-inflammatory stimulus."


Innate Immunity and Neuroinflammation



The relation between things like Fibro and Chronic Fatigue show a relation to microglia as has been known. They are related to Autism and lately to Schizophrenia it appears. While not quoted below the article mentions Naltrexone and Curcumin related to calming neuroinflammation. This article ties Leptin to CFS as seems true and addressed in the following.

Solving the mysteries of fibromyalgia could help patients break free

"Younger, an associate professor recruited to the UAB College of Arts and Sciences Department of Psychology in 2014, became interested in fibromyalgia and chronic fatigue syndrome as a postdoctoral fellow at Stanford University's medical school. He had been studying pain more broadly when he realized how poorly understood these disorders were.

"Patients are wholly affected," Younger says. "Some used to be athletes, some used to be business owners, and then their lives are taken over." Often, he points out, patients visit doctor after doctor, only to be told repeatedly that they're healthy—and that the pain or fatigue is all in their heads.

Younger, along with many other researchers and clinicians, believed otherwise. "I made it my mission to figure out what is wrong with these patients and how to treat them," he says.

As a Stanford postdoctoral fellow and faculty member, Younger spearheaded studies that surveyed immune molecules in the blood. He homed in on one particular protein called leptin, released by fat tissue, which appears in greater amounts in the blood of chronic fatigue patients. In fact, Younger could even gauge the day-to-day severity of a patient's symptoms just by tracking his or her leptin levels. These initial findings spurred him to continue investigating inflammatory immune molecules—and to start looking at the brain's role in the diseases.

Leptin has the ability to cross the blood-brain barrier and affect neural cells, causing pain and fatigue. But exactly how that happens remains a mystery. Younger thinks it has something to do with microglia, a type of immune cell found in the brain that normally helps to protect neurons.

"Microglia defend our brain against everything," Younger explains. "When we get the flu, for instance, microglia are activated. These cells make us want to crawl into bed and do nothing—so our body can devote its resources to fighting off the flu."

In both fibromyalgia and chronic fatigue patients, Younger hypothesizes, the microglia are turned on when they're not supposed to be, causing fatigue or pain, a depressed mood, and cognitive dysfunction. At UAB, he is planning follow-up studies to help find evidence supporting this idea. He faces a crucial challenge, however: Currently, no methods are available to look directly at the activation or inflammation of microglia in living humans. But Younger and his colleagues are working on solutions, including specialized brain scans that measure the temperature of the brain or the presence of certain chemicals.

"It's only very recently that people are starting to explore what sensitizes microglia," Younger says. "The cells can be in a quiet, helpful state, or an active, warlike state." His findings, he hopes, will help reveal the difference."


The next report emphasizes maternal infection and immune response as effecting neurodevelopment, but the immune response is goes beyond what may happen in the womb for most and may happen in the individual post utero in most imo. Both pre and post utero or a combination of effect may be the case from person to person.

Infections and Brain Development.


"Several different bodies of evidence support a link between infection and altered brain development. Maternal infections, such as influenza and human immunodeficiency virus, have been linked to the development of autism spectrum disorders, differences in cognitive test scores, and bipolar disorder; an association that has been shown in both epidemiologic and retrospective studies. Several viral, bacterial, and parasitic illnesses are associated with alterations in fetal brain structural anomalies including brain calcifications and hydrocephalus. The process of infection can activate inflammatory pathways causing the release of various proinflammatory biomarkers and histological changes consistent with an infectious intrauterine environment (chorioamnionitis) or umbilical cord (funisitis). Elevations in inflammatory cytokines are correlated with cerebral palsy, schizophrenias, and autism. Animal studies indicate that the balance of proinflammatory and anti-inflammatory cytokines is critical to the effect prenatal inflammation plays in neurodevelopment. Finally, chorioamnionitis is associated with cerebral palsy and other abnormal neurodevelopmental outcomes. In conclusion, a plethora of evidence supports, albeit with various degrees of certainty, the theory that maternal infection and inflammation that occur during critical periods of fetal development could theoretically alter brain structure and function in a time-sensitive manner."



Just a note.

I read and post all studies and articles posted with the notion others will follow the overall understanding of the complete picture by comprehending the information in it's full by reading and seeing the full picture and by following up by researching elements contained within. For Benedetta I add this link.

Activation of ligand-responsive sigma-1 receptor by agonists is likely to have beneficial effects in the cells.

Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication
Accumulating evidence suggests that sigma-1 receptor regulates a variety of cellular functions, such as inositol 1,4,5-triphosphate (IP3) receptor-mediated Ca2+ signaling, ion channel firing, protein kinase location/activation, cellular redox, neurotransmitter release, inflammation, cellular differentiation, neuronal survival and synaptogenesis (3), (4) and (5). Furthermore, sigma-1 receptor plays an important role in neuronal plasticity, a process implicated in the pathophysiology of neuropsychiatric diseases (5), (6), (7), (8) and (9).



I have stalled and taken a good break on the recent area of study in the last several posts and hope to re-engage the subjects, but the theme of microglia, Angiotensin, and inflammatory aspects are something I like to note. The gut immune relation, and the bacterial toxins figure as agents priming the inflammation as many like ,myself hold. Gene expression is theorized to be effected in this scenario of dysfunction.

Chronic Brain Inflammation: The Neurochemical Basis for Drugs to Reduce Inflammation.


"It is now recognized that the brain and the peripheral immune system have bidirectional communication in both health and neuronal diseases. Brain inflammation results after both acute injury and also with the appearance of mutated proteins or endogenous neurotoxic metabolites associated with slow neurodegenerative diseases such as Alzheimer's and Parkinson's diseases and some psychiatric disorders. Microglia play a key role in brain inflammation by the release of pro-inflammatory cytokines and with ageing, microglia exhibit 'priming' leading to increased basal release of the pro-inflammatory cytokines. Neurochemical targets to reduce or slow chronic brain inflammation include cyclooxygenase enzymes, Nrf2 transcription factor, angiotensin AT1 receptors and sigma-1 receptors. Development of more selective drugs to act at these targets is occurring but large scale clinical trials to validate the drugs will take significant time."



This is a quote I meant to place from this report:

Rats fed a thiamin-deficient diet had higher concentra-
tions of P450, cytochrome b5, and NADPH:cytochrome c
reductase activity in liver microsomes than those fed a diet
sufficient in thiamin. The deficient rats also had increased
rates in the metabolism of acetaminophen, NDMA, amino-
pyrine, ethylmorphine, zoxazolamine, heptachlor, aniline,
N-methylaniline, acetanilide, and BP, but not in the metabo-
lism of hexobarbital (8). Recent studies from our laboratory
indicated that thiamin deficiency increased the hepatic micro-somal P450 2E1 level (two- to fivefold) but not the P450 2Cll level (44). This observation provides an enzymatic basis for the enhanced rate of in vivo metabolism of aniline, NDMA, and acetaminophen, all of which are substrates for P450 2El. Thiamin deficiency was shown to increase cytosolic glutathi-one S-transferase activity moderately but not steroid isomer-ase activity (44). The mechanisms of these effects on drug-metabolizing enzymes remain to be elucidated.



edit last post..I meant:

"How this relates to pregnancy issues like morning sickness and p450 function"


Thiamine relation to autism is not obscure as many have reported on, and discussed the matter as it pertains to autism and possible PON 1 function and other areas. This report discusses a lot of factors that those of us finding diet and yeast being involved in ASD. It discusses thiamine deficiency and totally syncs with many accounts I have read of others dealing with such factors. It also briefly mentions vaccination. How this relates to pregnancy issues like morning sickness and p400 function is what I am looking at related to some heavy metals and toxins like glyphosate. The their is apparently something going on in pregnancy that is perturbed in these areas and morning sickness and some areas of detoxification in the mother may be because of nutrient metabolism or deficiency or even some levels of nutrient levels like thiamine may be lowered in early pregnancy to balance certain detox function. Still studying. The whole report is very good and I suggest you read it. I am just posting a small snippet.

Dysautonomia in Autism Spectrum Disorder: Case Reports of a Family with Review of the Literature

"Pregnancy toxemia has been linked to thiamine deficiency..."


Not much of a credential with this, but I thought I would post it for thought.


"As all these hormonal changes are occurring there are also some symptoms the mother experiences, such as morning sickness. Pregnancy sickness is an adaptation or solution to the problem of teratogen ingestion during fetal organogenesis. Teratogens are drugs and other agents that can cause fetal malformation. During pregnancy sickness the mother experiences nausea, with or without vomiting, during the first trimester. It has been shown that women that experience morning sickness are less likely to miscarry during the first trimester than are asymptomatic women.


Effects of thiamine deficiency on hepatic cytochromes P450 and drug-metabolizing enzyme activities.


Dietary effects on cytochromes P450, xenobiotic metabolism, and toxicity.


"The levels and activities of cytochrome P450 enzymes are influenced by a variety of factors, including the diet. In this article, the effects of selected non-nutritive dietary chemicals, macronutrients, micronutrients, and ethanol on cytochromes P450 and xenobiotic metabolism are reviewed in the light of our current understanding of the multiplicity and substrate specificity of cytochrome P450 enzymes. Although the mechanisms of action of several dietary chemicals on specific cytochrome P450 isozymes have been established, those for macro- and micronutrients are largely unknown. It is known, however, that specific nutrients may have varied effects on different cytochrome P450 forms and thus may affect the metabolism of various drugs differently. Nutritional deficiencies generally cause lowered rates of xenobiotic metabolism. In certain cases, such as thiamin deficiency and mild riboflavin deficiency, however, enhanced rates of metabolism of xenobiotics were observed. The effects of dietary modulation of xenobiotic metabolism on chemical toxicity and carcinogenicity are discussed...."

"During fasting, microsomal aminopyrine N-demethylase
and hexobarbital hydroxylase activities were decreased, but
aniline p-hydroxylase and p-nitroanisole O-demethylase ac-
tivities were increased in male rats (32). The induction of
P450 2E1 by fasting (17) can account for the increased ani-
line hydroxylase and NDMA demethylase activities. Fasting
for 2 or 3 days caused a 50% decrease in the level of the
male-specific P450 2C11 (33), and this may account for the
previously observed decrease in aminopyrine demethylase
activity. During fasting, the mRNA for P450 2E1 was sig-
nificantly elevated, a situation similar to diabetes (34), but such elevation was not observed during the induction of
P450 2E1 by acetone pretreatment (19). The results Suggest
that there are differences in the mechanisms of P450 2E1 in-
duction under these conditions."


Sex steroid hormones regulate constitutive expression of Cyp2e1 in female mouse liver.


"CYP2E1 is of paramount toxicological significance because it metabolically activates a large number of low-molecular-weight toxicants and carcinogens. In this context, factors that interfere with Cyp2e1 regulation may critically affect xenobiotic toxicity and carcinogenicity. The aim of this study was to investigate the role of female steroid hormones in the regulation of CYP2E1, as estrogens and progesterone are the bases of contraceptives and hormonal replacement therapy in menopausal women. Interestingly, a fluctuation in the hepatic expression pattern of Cyp2e1 was revealed in the different phases of the estrous cycle of female mice, with higher Cyp2e1 expression at estrus (E) and lower at methestrus (ME), highly correlated with that in plasma gonadal hormone levels. Depletion of sex steroids by ovariectomy repressed Cyp2e1 expression to levels similar to those detected in males and cyclic females at ME. Hormonal supplementation brought Cyp2e1 expression back to levels detected at E. The role of progesterone appeared to be more prominent than that of 17β-estradiol. Progesterone-induced Cyp2e1 upregulation could be attributed to inactivation of the insulin/PI3K/Akt/FOXO1 signaling pathway. Tamoxifen, an anti-estrogen, repressed Cyp2e1 expression potentially via activation of the PI3K/Akt/FOXO1 and GH/STAT5b-linked pathways. The sex steroid hormone-related changes in hepatic Cyp2e1 expression were highly correlated with those observed in Hnf-1α, β-catenin, and Srebp-1c. In conclusion, female steroid hormones are clearly involved in the regulation of CYP2E1, thus affecting the metabolism of a plethora of toxicants and carcinogenic agents, conditions that may trigger several pathologies or exacerbate the outcomes of various pathophysiological states."


Hypoxia-inducible factor 1 transactivates the human leptin gene promoter.


"Increased placental leptin has been demonstrated in preeclampsia, a pregnancy disorder associated with placental hypoxia. This suggests that leptin gene expression is enhanced in response to oxygen deficiency in this organ. In support of this hypothesis, we have previously shown that hypoxia activates the leptin promoter in trophoblast-derived BeWo cells. Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric HIF-1alpha/HIF-1beta complex that regulates the transcription of hypoxia-responsive genes. To test whether this factor is involved in hypoxia-induced leptin promoter activation, BeWo cells were transiently transfected with a HIF-1alpha expression vector. Exogenous HIF-1alpha markedly increased luciferase reporter activity driven by the leptin promoter when HIF-1beta was co-expressed in the same cells. This effect was similar to that elicited by CoCl2, an agent known to stabilize endogenous HIF-1alpha. These data suggest that HIF-1alpha/HIF-1beta dimers are involved in the effect of CoCl2 to activate the leptin promoter. To confirm the implication of HIF-1, the cells were transfected with a dominant negative form of HIF-1alpha producing transcriptionally inactive HIF-1beta/HIF-1alpha dimers. This mutant HIF-1alpha protein abolished CoCl2 activation of the leptin promoter, providing direct evidence that the effect of CoCl2 is mediated by endogenous HIF-1alpha. Deletion analysis and site-specific mutagenesis demonstrated that a HIF-1 consensus binding site (HRE) spanning -120 to -116 bp relative to the start site was required for CoCl2 and exogenous HIF-1alpha induction of leptin promoter activity. Electrophoretic mobility shift assays performed with in vitro-translated HIF-1alpha and HIF-1beta proteins demonstrated binding to this HRE and not to mutated sequences only when both subunits were used together. These data demonstrate that leptin is a new hypoxia-inducible gene, which is stimulated in a placental cell line through HIF-1 interaction with a consensus HRE site located at -116 in the proximal promoter."


Hypoxia-ischemia and thiamine deficiency.


"In order to test the hypothesis that Wernicke's encephalopathy is of topographic rather than of pathogenetic specificity we examined the brains of 49 patients without any evidence of chronic alcoholism. They had died at least four days after an event of severe hypoxia-ischemia. They all showed extensive lesions in the cortex, in the thalamus and in other regions. In 19 of them there was additional necrosis in the mamillary bodies which apparently was of the same age as the associated cortical and thalamic lesions and which could not be distinguished from Wernicke's encephalopathy. In three of the 19 cases there was a total necrosis within the mamillary bodies. By re-examining the mamillary bodies of 12 known alcoholics without any evidence for an ischemic impact we could affirm that total necrosis may fit into the spectrum of Wernicke's encephalopathy. Our findings demonstrate that the morphological changes in the mamillary bodies due to thiamine deficiency and those due to hypoxia-ischemia may be identical."


One more with added overview ideas.

The Role of Thiamin in High Calorie Malnutrition



The fact fat is a toxin repository is also of note. Some this relates a good bit with a lot Dr. Seneff mentions in one of her reports. The proposed effect of Glyphoste effecting gut bacterial composition and subsequent sulfate and phenol levels and function do ties together a great deal of the things That I had believed and documented.

Glyphosate’s Suppression of Cytochrome P450 Enzymes and Amino Acid Biosynthesis by the Gut Microbiome: Pathways to Modern




The tremendous amount of system interaction in physiology does make this whole process so daunting that attempting to find key areas that point to the etiology of ASD's a vast challenge. How each person's system handles toxicity from chemicals, and in relation metals, along with degrees and type of exposure along with how the fetus's genetics may respond to the mother's status at least raises the question about how morning sickness and things like leptin and ghrelin levels may be involved. Adipose tissue, esp. visceral fat, relates to neuroendocrine and lymphoid function and bear on energy production and metabolism and involve the hypothalmus. Fatty acid metabolism and peroxisomal function and disorders and perturbed function in these systems would certainly present as areas related to the hormonal, immune and energy production and nutrition all intricately related to the changes in, and processes in pregnancy. How morning sickness severity or lack thereof relates to possible abilities of dealing with toxins or a sensitivity to them and how this bears on the development of the fetus is compelling in my view. It may be that severe morning sickness in some cases helps in fetal development in ways or in some may be a sign of a pathology or even some of both. Yet, there appears to be a relationship. The fact the brain uses so much energy and is mainly fat also buttress the ides of studying the finding of altered leptin and ghrelin levels in autism and their changes in pregnancy. How this relates to fatty acid metabolism, an area that many of us already believe to be a factor, is also somewhat researched and seems to tie into all of this.

Solving the Autism Puzzle – The Fatty Acid Question and “Big, Fat Neurons”!


When you consider detoxifying enzymes, esp. the cytochrome P450 enzymes as Stephanie Seneff has reported on related to Glyphoste the problems with toxicity in pregnancy you also wonder how morning sickness relates to these matters.

Adipose Tissue Immune Response: Novel Triggers and Consequences for Chronic Inflammatory Conditions

Aryl Hydrocarbon Receptor Agonists

"The rapid increase in the number of people with obesity and obesity-induced chronic inflammatory diseases is now attributed to intricate cross talk between genetic makeup and so termed environmental “obesogens” [96]. Among these, more than 20 chemicals have been shown to cause long-term weight gain based on exposures during critical periods of development. Smoking and nicotine, persistent organophosphate pesticides, flame retardants, plasticizers and plastics, and fungicides, for example, have all been linked to obesity in animals. These highly lipophilic toxicants have very long half-lives that allow them to accumulate in the food chain. Western style diet, based on high consumption of animal fat, increases human exposure to these ubiquitous toxicants. The dioxin and dioxin-like pollutants are among the most dangerous. Due to their long half-life and lipophilicity, they accumulate in adipocytes and participate in the pathophysiology of obesity and obesity-associated chronic inflammatory diseases [97, 98] through activation of the aryl hydrocarbon receptor (AhR) [99, 100]. AhR is a ligand-activated transcription factor with important roles not only in the xenobiotic metabolism but in developmental and normal physiology as well. This particular receptor is ubiquitously present in adipocytes and, most importantly, in all the cells that participate in the immune system responses [101, 102]. Moreover, the preadipocytes that differentiate into mature adipocytes in the presence of even low levels of these toxic AhR ligands produce significantly more inflammatory cytokines such as TNF-α, IL-6, and chemokine MCP-1 [103]. Long-term exposure of mice to dioxin-like AhR agonists led to increased visceral adipose tissue mass, ectopic fat deposition in the liver (hepatic steatosis) and peritoneal cavity, and abnormal serum lipid profile similar with the metabolic syndrome [98]. Importantly, under the same treatment, AhR KO mice appear resistant to obesity and its metabolic consequences. Consistent with these observations, ApoE−/−mice that received dioxin-like PCBs (AhR agonists) developed atherosclerosis, as early event in the pathogenesis of abdominal aortic aneurysms (AAAs) [98]."


The things I have mentioned are only the broadest associations and often I just post these broad matters as to allow others to simply see the concept. If I post something too intricate or lengthy I doubt any would delve into reading these posts. I have looked at the systems in depth and there is a lot of reasonableness to connect toxins, enzyme function and attendant metabolic and immune effects in gestation and even morning sickness to these functions.


I appreciate it, too, Visitor. I'm just not as fast at absorbing and processing it all as you are. I'm still intrigued about the intersection of some stuff you've found and the information both Teresa Conrick and Eileen Nicole Simon post, combined with vitamin (prehormone D3) and their combined roles, and the new lymph findings take it all to another level.

Re: lymph around the head/brain area, brings to mind discussions I've read on sites about cranialsacral therapy and people that find it helpful. Obviously oxygen is critical in the body for certain chemical reactions to occur properly so any challenges to that need to be remedied, and then there has to be an ONGOING way to remove the toxic byproducts of that. I read periodic stuff about advance glycation endpoints, etc, and see interesting info in the Anti-Aging medicine movement/organizations and their work on telomeres. I haven't checked to see if there have been any studies done on autistic children on what their telomeres look like comparatively. And I also want to look into the Heritage Study about VO2max non-responders, which have found that going beyond a certain level of exercise actually causes health problems, ie, their stuff may have clues as to the existance of a subgroup of people epigenetically at a loss to properly process oxygen based reactions in the body and/or manage its byproducts, which to me would be them at a higher risk for ANY other environmental challenges, including vaccine adverse reactions(thrombocytopenia, for example)that might normally cause only minimal or transient damage in people that are NOT VO2max non-responders.

I think the morning sickness leptin/ghrelin stuff is intriguing but haven't read through the science - my primary question there is do any of those studies look at the diets of the women who do or do not have morning sickness. It goes against my intuition to think that those with morning sickness miscarry less than those without. Personally, I interpret most and maybe all physical discomforts as symptoms of reaction against an existing problem/imbalance not some mysterious preventive mechanism. For instance, if HCG is present in higher levels early on in a pregnancy and morning sickness got its name from brief mild nausea in the am, HCG may be cyclical not just from a trimester standpoint, but from a daily cyclical standpoint, just like cortisone in the body and melatonin, for example (both known to be affected by diet, and of course various stressors). What would cause HCG & leptin & ghrelin to NOT to maintain their natural cycles? Is there some molecular mimicry going on there or something? What effect does a healthy/unhealthy microbiome have on hormone cycles? We know the gut microbiome creates seratonin - what does it do for these other hormones?

There are many questions and not enough time in the day - and all of it needs to be conveyed somehow to the public and politicians, but at $35 per article in general, the big corporations have it shut down tight.


I appreciate that Donna K. Glad to know someone is maybe getting something from this.

Donna K

Always interested in seeing what new info or insights you have come across to contribute. Thank you.


This quote is related the 2nd post back on leptin and related matters. I have been looking at ghrelin for a long time and had missed this report until recently. Then whole report is well worth reading.

Altered ghrelin levels in boys with autism: a novel finding associated with hormonal dysregulation

"Numerous hormone studies have been undertaken in children with autism; however, to our knowledge, this study is the first in which ghrelin was measured. Plasma levels of both AG and DG were significantly reduced in the autism group compared with healthy controls. This result can be attributed to local factors affecting ghrelin-secreting cells and to hormonal influences. Gastrointestinal (GIT) problems are frequent in autism, including dysbiosis, chronic GIT inflammation and chronic fungal, viral and bacterial infections19. These disorders could affect the gastric mucosa and interfere with the normal function of ghrelin-secreting cells. Furthermore, ghrelin deficiency by itself can affect the gastric mucosa, as ghrelin is known for its role in maintaining mucosal health and integrity20. Thus, a loss of mucosal health and integrity could result in a further decrease in plasma ghrelin levels.

Alterations in plasma ghrelin levels may also be part of the extensive, well-studied hormonal dysregulation that characterizes autism, particularly the dysregulation of TT, FT, leptin and GH. In agreement with the findings of the current study, previous studies have shown that androgen levels are significantly higher in autism patients11. At the same time, it is well established that ghrelin plasma levels are negatively correlated with high plasma testosterone levels12. The current study confirms the negative correlation between FT and DG. This correlation may indicate that the reduced plasma level of ghrelin in autistic children is in part a consequence of suppression by elevated androgens.

Another hormone that has been studied in autism is leptin. Its relevance to ghrelin function comes from the observation that elevated plasma leptin levels are associated with reduced plasma ghrelin levels14, 15. This finding is in agreement with the results of the current study, which revealed a significant elevation of leptin and a reduction of ghrelin levels in the autism group. In support of this notion, Komori et al. provided a novel molecular link between leptin and ghrelin signaling, namely, the leptin-induced negative regulatory element-binding protein (NREBP), which suppresses ghrelin signalling21. The high serum leptin levels in the current study is consistent with other studies that reported a significant elevation of leptin levels in autistic children14, 22. The elevation of leptin levels can be explained in part by the observed significant elevation of androgen levels in autistic children. Both animal and human studies have shown that adipocytes have androgen receptors (ARs), and androgens are known to modulate the plasma leptin level23, 24. Consistent with these reports, the current study revealed a significant positive correlation between leptin and FT. The significant elevation of leptin levels in autism may also be a consequence of the significant decrease in GH levels in autistic children, as will be discussed later.

Alterations in the levels of both ghrelin and leptin are known to be associated with adiposity25, 26. As can be noted from the anthropometric data in the current study, the only significant difference between the autism and control groups was in body weight, which was significantly higher in the autism group. To exclude the effect of weight on the levels of these hormones, we excluded four children with high body weight from the autism group to create a group that was age-, sex- and weight-matched with the controls, as shown in Table 3. As presented in Table 3, there were significant reductions in both AG and DG plasma levels, with a significant increase in the plasma leptin level in the autism group compared with weight-matched controls."



They are showing the pieces, but haven't much of a clue about the triggers or causes. A very good overview though.

The Many Roads To Mitochondrial Dysfunction In Neroimmune And Neuropsychiatric Disorders



This addresses autism with a specific idea about metals/toxicity and enzyme function. Since my wife had such severe morning sickness{hyperemesis gravidarum} I am also proposing a relationship in the chemistry and functions believed to be involved with it and a relationship with autism that may exist in her as well as possibly mothers of children who have autism.

1,25-Dihydroxyvitamin D regulates expression of the tryptophan hydroxylase 2 and leptin genes: implication for behavioral influences of vitamin D.


"To investigate vitamin D-related control of brain-expressed genes, candidate vitamin D responsive elements (VDREs) at -7/-10 kb in human tryptophan hydroxylase (TPH)2 were probed. Both VDREs bound the vitamin D receptor (VDR)-retinoid X receptor (RXR) complex and drove reporter gene transcription in response to 1,25-dihydroxyvitamin D3 (1,25D). Brain TPH2 mRNA, encoding the rate-limiting enzyme in serotonin synthesis, was induced 2.2-fold by 10 nM 1,25D in human U87 glioblastoma cells and 47.8-fold in rat serotonergic RN46A-B14 cells. 1,25D regulation of leptin (Lep), encoding a serotoninlike satiety factor, was also examined. In mouse adipocytes, 1,25D repressed leptin mRNA levels by at least 84%, whereas 1,25D induced leptin mRNA 15.1-fold in human glioblastoma cells. Chromatin immunoprecipitation sequencing analysis of the mouse Lep gene in response to 1,25D revealed a cluster of regulatory sites (cis-regulatory module; CRM) at -28 kb that 1,25D-dependently docked VDR, RXR, C/EBPβ, and RUNX2. This CRM harbored 3 VDREs and single C/EBPβ and RUNX2 sites. Therefore, the expression of human TPH2 and mouse Lep are governed by 1,25D, potentially via respective VDREs located at -7/-10 kb and -28 kb. These results imply that vitamin D affects brain serotonin concentrations, which may be relevant to psychiatric disorders, such as autism, and may control leptin levels and affect eating behavior."


Leptin and leptin receptor levels in pregnant women with hyperemesis gravidarum


"Objective:  To investigate the association between the leptin, leptin receptor and hormone levels and hyperemesis gravidarum, and to determine whether these two parameters may be early markers for hyperemesis gravidarum.

Methods:  The study group consisted of 18 pregnant women with hyperemesis gravidarum and the control group consisted of 18 healthy pregnant women. Demographic characteristics were recorded and body mass index (BMI) values were calculated for all the pregnant women. Serum leptin, leptin receptor, insulin, cortisol, thyroid hormone and human chorionic gonadotrophin (hCG) levels were measured.

Results:  When the two groups were compared with respect to leptin levels, the group with hyperemesis gravidarum was found to have significantly higher leptin levels (P = 0.037). No intergroup differences were observed in serum cortisol, insulin, hCG, thyroid hormone levels or BMI values. In the group with hyperemesis gravidarum, an inverse correlation was detected between cortisol and leptin (r = –0.762, P < 0.01), and hCG and thyroid-stimulating hormone (r = –0.503, P < 0.05), whereas a significant correlation was detected between insulin and leptin (r = 0.538, P < 0.05), leptin and BMI (r = 0.711, P < 0.01), and between TT3 and hCG (r = 0.605, P < 0.01).

Conclusion:  It was concluded that leptin could play a role in, and be defined as, a marker of hyperemesis gravidarum."


Hyperemesis gravidarum - Wiki

"Intravenous fluids[edit]

IV hydration often includes supplementation of electrolytes as persistent vomiting frequently leads to a deficiency. Likewise, supplementation for lost thiamine (Vitamin B1) must be considered to reduce the risk of Wernicke's encephalopathy.[20] A and B vitamins are depleted within two weeks, so extended malnutrition indicates a need for evaluation and supplementation. In addition, electrolyte levels should be monitored and supplemented; of particular concern are sodium and potassium."

"Signs and symptoms[edit]

When hyperemesis gravidarum is severe or inadequately treated, it may result in the following:[1]
##Loss of 5% or more of pre-pregnancy body weight
##Dehydration, causing ketosis,[3] and constipation
##Nutritional disorders such as vitamin B1 (thiamine) deficiency, vitamin B6 deficiency or vitamin B12 deficiency
##Metabolic imbalances such as metabolic ketoacidosis[1] or thyrotoxicosis[4]"...


There are numerous theories regarding the cause of HG, but the cause remains controversial. It is thought that HG is due to a combination of factors which may vary between women and include: genetics,[1] body chemistry, and overall health.[8]

One factor is an adverse reaction to the hormonal changes of pregnancy, in particular, elevated levels of beta human chorionic gonadotropin (hCG).[9][10] This theory would also explain why hyperemesis gravidarum is most frequently encountered in the first trimester (often around 8–12 weeks of gestation), as hCG levels are highest at that time and decline afterward. Another postulated cause of HG is an increase in maternal levels of estrogens (decreasing intestinal motility and gastric emptying leading to nausea/vomiting).[1]

Morning sickness
Although the pathophysiology of HG is poorly understood, the most commonly accepted theory suggests that levels of hCG are associated with it.[11] Leptin may also play a role."


Wernicke–Korsakoff syndrome

"One as-yet-unreplicated study has associated susceptibility to this syndrome with a hereditary deficiency of transketolase, an enzyme that requires thiamine as a coenzyme.[17]"


Wernicke's encephalopathy _ Wiki


Thiamine deficiency and errors of thiamine metabolism are believed to be the primary cause of Wernicke encephalopathy. Thiamine, also called B1, helps to break down glucose. Specifically, it acts as an essential coenzyme to the TCA cycle and the pentose phosphate shunt. Thiamine is first metabolised to its more active form, thiamine diphosphate (TDP), before it is used. The body only has 2–3 weeks of thiamine reserves, which are readily exhausted without intake, or if depletion occurs rapidly, such as in chronic inflammatory states or in diabetes.[6][34] Thiamine is involved in:[34][42]
1.Metabolism of carbohydrates, creating energy.
2.Production of neurotransmitters including glutamic acid and GABA.
3.Lipid metabolism, necessary for myelin production.
4.Amino acid modification. Probably linked to the production of taurine, of great cardiac importance.[43][44]


The primary neurological-related injury caused by thiamine deficiency in WE is three-fold: oxidative damage, mitochondrial injury leading to apoptosis, and directly stimulating a pro-apoptotic pathway.[45] Thiamine deficiency affects both neurons and astrocytes, glial cells of the brain. Thiamine deficiency alters the glutamate uptake of astrocytes, through changes in the expression of astrocytic glutamate transporters EAAT1 and EAAT2, leading to excitotoxicity. Other changes include those to the GABA transporter subtype GAT-3, GFAP, glutamine synthetase, and the Aquaporin 4 channel.[46"...

"Other nutritional abnormalities should also be looked for, as they may be exacerbating the disease.[28][58] In particular, magnesium, a cofactor of transketolase which may induce or aggravate the disease.[34]

Other supplements may also be needed, including: cobalamin, ascorbic acid, folic acid, nicotinamide, zinc,[59][60] phosphorus (dicalcium phosphate)[61] and in some cases taurine, especially suitable when there cardiocirculatory impairment.[62][63] Patient-guided nutrition is suggested. In patients with Wernicke-Korsakoff syndrome, even higher doses of parenteral thiamine are recommended."


Morning sickness - Wiki

Morning sickness as a defense mechanism[edit]

"Morning sickness is understood as an evolved trait that protects the fetus against toxins ingested by the mother.[6] [7] Many plants contain chemical toxins that serve as a deterrent to being eaten. Adult humans, like other animals, have defenses against plant toxins, including extensive arrays of detoxification enzymes manufactured by the liver and the surface tissues of various other organs. In the fetus, these defenses are not yet fully developed, and even small doses of plant toxins that have negligible effects on the adult can be harmful or lethal to the embryo.[8] Pregnancy sickness causes women to experience nausea when exposed to the smell or taste of foods that are likely to contain toxins injurious to the fetus, even though they may be harmless to her.

There is considerable evidence in support of this theory, including:[9][10]
##Morning sickness is very common among pregnant women, which argues in favor of its being a functional adaptation and against the idea that it is a pathology.
##Fetal vulnerability to toxins peaks at around 3 months, which is also the time of peak susceptibility to morning sickness.
##There is a good correlation between toxin concentrations in foods, and the tastes and odors that cause revulsion.

Women who have no morning sickness are more likely to miscarry.[11] This may be because such women are more likely to ingest substances that are harmful to the fetus.[12]"


The role of trace elements, thiamin (e) and transketolase in autism and autistic spectrum disorder.


"Although there has been much research into autism or autistic spectrum disorder (ASD), there is room for considerable conjecture regarding the etiology of these developmental brain disorders. ASD is marked by a complex interaction between environmental factors and genetic predisposition, including epistasis. This manuscript argues that changes in oxidative metabolism, thiamine homeostasis, heavy metal deposition and cellular immunity have a role in the etiopathogenesis of autism and ASD. Recent findings from our group and others provide evidence for abnormal thiol metabolism, marked by significant alteration in the deposition of several trace heavy metal species. Together with these, we find differences in thiamine homeostasis in ASD patients, which can be corrected by supplementation. We hypothesize that altered thiol metabolism from heavy metal toxicity, one of the key mechanisms for oxidative stress production, may be responsible for the biochemical alterations in transketolase, dysautonomia and abnormal thiamine homeostasis. Although it is unknown why these particular metals accumulate, we suspect that children with ASD and forms of autism may have particular trouble excreting thiol-toxic heavy metal species, many of which exist as divalent cations. We maintain mercury accumulation is evidence of altered clearance. Together with concomitant oxidative stress, these findings may offer an intriguing component or possible mechanism for oxidative stress-mediated neurodegeneration in ASD patients. Regardless of the exact cause, these factors may be more important to the etiology of this symptomatically diverse disease spectrum. Here, we offer insight into new avenues of exploration as well as the development of novel treatment approaches for these growing and devastating diseases."


Altered Heavy Metals and Transketolase Found in Autistic
Spectrum Disorder



Well, on a simpler note -- maybe by parental instinct there are so many trampolines in back yards.

Of all the toys to have, I have often wondered how those became so popular.

I will be the first to admit that my parental instincts really stink as I kept allowing vaccinations after tons of reactions.

But an up note; They did have a bouncing horse or two.


I am also wondering whether heavy metals, mercury and aluminum of course being of interest, would be present in lymph fluid longer than in blood, possibly leading to a new lab test that could indicate heavy metal overload, different from or supporting provoked urine tests. Could be a better indicator of how efficiently or not a body rids itself of toxins, and therefore offer insight about whether a person could be severely damaged by vaccines or not.



Have you been up on some of the ideas on oxygen that you mentioned or were you just surmising that it was a logical idea. On one sight I linked in another article the author indeed mentions the idea of oxygen related to lymphatic circulation. I am aware that some have called these quack ideas, but they also did not know about these new lymph vessels. Some quacks are looking better all the time. Even though the author here also did not know of these new found vessels the association was not excluded as apparently other evidence indicated the importance.

Activating Lymphatics Improves Detoxification In The Brain

"The brain depends on proper circulation to detox acidic cellular waste from its tissues. Even though the brain has no lymph vessels the membranes that surround the spinal cord and brain has lymph vessels. By manually activating the lymphatics in the neck and face you dramatically improve circulation and reabsorption of cerebrospinal fluid and cellular waste into the lymphatic system. This improved circulation delivers oxygen and nutrition to the cells while improving cellular detoxification throughout the body."

"My point, if you have a young child with autism like behavior, you need to see that acid is a contributing factor in their cognitive problems, digestive issues, skin irritations, aggression, hyperactivity or lethargy. The first step should be to balance their pH and activate the lymphatic system. Start with Epsom salt and baking soda baths, alkalizing supplements, systemic enzymes, probiotics, and some type of lymph drainage therapy to open the lymph-brain connection."




The mechanical assistance that could move the lymphatic system along is reasonable as a therapeutic idea. The fact that the immune system and brain function have been so compelling in study and observation to some has had some element of problem due to how this is/was occurring. The blood brain barrier has seemed a possible route, and still may be, for some of the interplay, but this news of these lymphatic vessels gives a new route to consider strongly. There is still some element of uncertainty about the extent these vessels could impact the brain as there is little known about them at this point. Yet, the plausible effects are hard not to be very interested about. I don't know about oxygen availability, but I will be looking more into this. As for now this seems to be interesting to a good number who are also of the mind that the immune system is related to Autism. That is good to me. This is also an area that has already be in view by some studying Autism, though the vessels found is a new thing. Please share what you find here as I will do the same.

Discovery of brain-immune link could advance understanding of autism


Activating the Lymphatic System Can Help Autism Spectrum Disorders


Helping autism spectrum disorders by opening the lymph/brain connection


Lymphatic Therapy



Visitor re: lymph propulsion cessation: I had started pondering last year that in certain cancer therapies, trampolining or vibration is deemed important - to force the lymph fluid to move when it otherwise might. I thought that the movement would be very similar to children with autism responding well to horse riding therapy and could explain the nature of those benefits. If so, once again, the solution points to the problem. I also wonder if / what lymph propulsion cessation might do re: oxygen availability in the body, if anything.


N-iminoethyl-L-lysine mentioned in the abstract in the last post is in view here. This is focusing on Alzheimer, but may relate to inflammation in other neurological conditions like Autism.

N-iminoethyl-L-lysine improves memory and reduces amyloid pathology in a transgenic mouse model of amyloid deposition.


"A large body of evidence suggests the importance of inflammation and oxidative or nitrosative stress in Alzheimer's disease (AD) pathogenesis. Inflammatory stimuli upregulate transcription of inducible nitric oxide synthase (iNOS), which can lead to the production of nitric oxide and other reactive nitrogen species. We previously found that genetic deletion of iNOS in mice overexpressing the amyloid precursor protein (APP) and presenilin-1 (PS1) reduced mortality, nitrosative stress, amyloid plaque burden, microgliosis, astrocytosis, and peri-plaque tau phosphorylation. We therefore examined the effects of N6-(1-iminoethyl)-L-lysine (L-NIL), a pharmacological iNOS inhibitor, or d-NIL, its enantiomeric control, in a transgenic mouse model of amyloid deposition. Tg19959 mice carry human APP with two mutations and develop amyloid plaques and memory impairment starting at 3-4 months of age. Mice were given L-NIL or D-NIL in the drinking water from 1 month of age and assessed behaviorally and histopathologically at 8 months of age. We found that L-NIL administration reduced disinhibition in the elevated plus maze, improved spatial memory performance in the Morris water maze, and decreased cortical amyloid deposition as well as microglial activation in 8-month-old Tg19959 mice. These findings are consistent with previous reports demonstrating that iNOS inhibition ameliorates AD pathogenesis."


The following may be of relevance here.

Nitric Oxide Can Regulate Gene Expression



Ridiculous to speculate I guess, but concerning the last post here is an early Idea.

Cytokines are systemic effectors of lymphatic function in acute inflammation.


"The response of the lymphatic system to inflammatory insult and infection is not completely understood. Using a near-infrared fluorescence (NIRF) imaging system to noninvasively document propulsive function, we noted the short-term cessation of murine lymphatic propulsion as early as 4h following LPS injection. Notably, the effects were systemic, displaying bilateral lymphatic pumping cessation after a unilateral insult. Furthermore, IL-1β, TNF-α, and IL-6, cytokines that were found to be elevated in serum during lymphatic pumping cessation, were shown separately to acutely and systemically decrease lymphatic pulsing frequency and velocity following intradermal administration. Surprisingly, marked lymphatic vessel dilation and leakiness were noted in limbs contralateral to IL-1β intradermal administration, but not in ipsilateral limbs. The effects of IL-1β on lymphatic pumping were abated by pre-treatment with an inhibitor of inducible nitric oxide synthase, L-NIL (N-iminoethyl-L-lysine). The results suggest that lymphatic propulsion is systemically impaired within 4h of acute inflammatory insult, and that some cytokines are major effectors of lymphatic pumping cessation through nitric oxide-mediated mechanisms. These findings may help in understanding the actions of cytokines as mediators of lymphatic function in inflammatory and infectious states."



Curious as to what this may eventually show, but it is interesting.

Missing link found between brain, immune system



New hope for autism: Canadian researcher reports to Sweden's Nobel Forum

"Autism rates have skyrocketed from 1 in 10,000 a half a century ago to 1 in 68 persons today. Expert opinion and funding to date has mostly focused on genetic causes and have attempted to explain the increase as better reporting of autism cases. MacFabe's research points strongly in another direction: changes in our gut bacteria.

Dr. MacFabe and his colleagues have shown that compounds, known as short chain fatty acids, which are produced by bacteria found in our intestines affect brain function and behaviour. Collaborating with Dr. Richard Frye of the University of Arkansas, their research has shown that these compounds affect the efficiency of mitochondria, the energy storehouse of cells.

Work with Dr. Bistra Nankova of New York Medical College has revealed that these fatty acid products can also act as epigenetic modulators, in effect acting as "switches" for many autism associated genes known to affect neural development and transmission, but also those involved in inflammation and energy metabolism, also reported in autism.

MacFabe, whose work has been featured on CBC Television's The Nature of Things, says these associated autism genes need not only be irreversibly damaged but can actually be switched on and off by compounds produced by autism associated intestinal bacteria. This provides an important link between the gut and the brain in autism. It also lends credibility to reports from parents who often see a connection between digestive upsets and autism symptoms in their children, he says. Such symptoms include impaired language, repetitive behaviours, restricted interests, social impairment and self-injurious behaviour, but often of a variable course or severity.

Dr. Suzanne Lewis, Director of the Autism Spectrum Interdisciplinary Research (ASPIRE) Program, Department of Medical Genetics, University of British Columbia has worked collaboratively with Dr. MacFabe for the past six years. Dr. Lewis states: "Genetic changes alone cannot explain the rising rate of autism within one generation. We need to look at environmental factors that can impact autism behaviours, for which a growing evidence points to changes involving the gut microbiome."



Biochemical, Histopathological and Morphological Profiling of a Rat Model of Early Immune Stimulation: Relation to Psychopathology.


"Perinatal immune challenge leads to neurodevelopmental dysfunction, permanent immune dysregulation and abnormal behaviour, which have been shown to have translational validity to findings in human neuropsychiatric disorders (e.g. schizophrenia, mood and anxiety disorders, autism, Parkinson's disease and Alzheimer's disease). The aim of this animal study was to elucidate the influence of early immune stimulation triggered by systemic postnatal lipopolysaccharide administration on biochemical, histopathological and morphological measures, which may be relevant to the neurobiology of human psychopathology. In the present study of adult male Wistar rats we examined the brain and plasma levels of monoamines (dopamine, serotonin), their metabolites, the levels of the main excitatory and inhibitory neurotransmitters glutamate and γ-aminobutyric acid and the levels of tryptophan and its metabolites from the kynurenine catabolic pathway. Further, we focused on histopathological and morphological markers related to pathogenesis of brain diseases - glial cell activation, neurodegeneration, hippocampal volume reduction and dopaminergic synthesis in the substantia nigra. Our results show that early immune stimulation in adult animals alters the levels of neurotransmitters and their metabolites, activates the kynurenine pathway of tryptophan metabolism and leads to astrogliosis, hippocampal volume reduction and a decrease of tyrosine hydroxylase immunoreactivity in the substantia nigra. These findings support the crucial pathophysiological role of early immune stimulation in the above mentioned neuropsychiatric disorders."


I wonder if vaccines fit in their idea of "perinatal immune challenges"?


Treating the brain and the immune system in tandem

"For years, studies have shown that patients with a wide range of mental illnesses tend to have signs of inflammation, the body’s natural response against infection and injury. But lately, scientists have been zeroing in on an explanation. They’re accumulating evidence to suggest that infection, autoimmune diseases and environmental factors such as stress or diet can trigger the immune system to go awry, causing it to damage the brain instead of attacking foreign pathogens. The result: an array of psychiatric conditions, including schizophrenia, autism spectrum disorder, Alzheimer’s disease, depression and anorexia nervosa."

"This hypothesis does not suggest immune responses are at the root of all psychiatric cases. Rather, it points to the idea that common mental illnesses have multiple causes, a haywire immune system being just one. The immune hypothesis is nevertheless a paradigm shift that not only offers a tangible, biological basis for subsets of many previously inexplicable psychiatric conditions, it raises the possibility of successfully diagnosing, treating and perhaps even preventing them by homing in on the immune system and managing inflammation. Although the research is still in its early days, there’s a growing sense of excitement over the prospect that certain individuals may regain mental health with antibiotics, intravenous immunoglobulin (IVIG) treatments (infusions of antibodies) and possibly dietary changes, instead of traditional psychiatric drugs and brain stimulation treatments."

“I think we’re on the cusp of something that’s really huge and truly revolutionary in the way in which we ... both diagnose people, as well as to make them better,” says Mady Hornig, associate professor of epidemiology at the Columbia University Medical Center, whose research focuses on the role of microbes and immune factors in neuropsychiatric illness."

"Scientists are now recognizing that a host of external stimuli can disrupt the normal crosstalk between the brain and the immune system. Those stimuli can include stress, changes in the microbiome (the universe of microbes that live in our bodies), and certain viruses and bacteria."

"It’s believed this disruption can affect the brain, and thereby behaviour. In PANDAS, it is suggested that streptococcal bacteria may mimic brain proteins, prompting the body to produce antibodies that mistakenly target the brain."

"So why doesn’t everyone infected with strep throat come down with the same neurological and psychiatric symptoms that O’Donnell’s daughter experienced? The answer may lie in genetics. Hornig explains that some individuals may be more genetically susceptible to producing a faulty immune response."

"What is so remarkable and so exciting to researchers is that if certain neuropsychiatric disorders are triggered by external stimuli, it means they can be controlled, Hornig says. However, she adds, since genetics likely play a role, susceptible individuals could be vulnerable to falling ill again whenever they encounter such triggers."

"A month after her symptoms disappeared, O’Donnell’s daughter experienced a relapse of Tourette and OCD-like behaviour, and again tested positive for strep. Though she fully recovered a second time, O’Donnell notes that her child has since shown other signs of potential immune-related sensitivities. For example, she experienced a bout of anxiety after an unidentified viral infection. Meanwhile, recent dietary changes aimed at reducing inflammation, specifically eliminating gluten, seemed to alleviate her anxiety."

“Anything that your immune system sees as an invader, whether it’s gluten or a bee sting or whatever, or a virus or a bacteria, you now have to be careful and watching for almost a mental health symptom,” O’Donnell says."...

“It probably brings us closer to hammering in the idea that mental illness is a disease,” she says. “It’s a disease we don’t fully understand.”

"Each new finding, however, is tempered with caution.

"Using nationwide data from Denmark, Benros found a strong link between infection and autoimmune diseases and mood disorders. People who had visited the hospital for an infection at any time had a 62-per-cent higher risk of later being diagnosed with depression or bipolar disorder. Those who were hospitalized for autoimmune diseases had a 45-per-cent risk of subsequent depression or bipolar disorder."...

"This suggests the need for immunopsychiatry, a new approach that recognizes the immune system and the brain are inexorably linked and should be treated in tandem, he adds."

“I am one of the believers who thinks that the body is one big entity that shouldn’t be split into different disciplines,” Sakic says. “The problem is it’s way more complex than we like to think.”



Considering the role of the immune system and increasing evidence of microbiome effect in autism this may shed more light on heritability and environment in the demographics of autism.

Environment, not genes, plays starring role in human immune variation, study finds

The power of environment

"Examining differences in the levels and activity states of these components within pairs of monozygotic and dizygotic twins, the Stanford scientists found that in three-quarters of the measurements, nonheritable influences — such as previous microbial or toxic exposures, vaccinations, diet and dental hygiene — trumped heritable ones when it came to accounting for differences within a pair of twins. This environmental dominance was more pronounced in older identical twins (age 60 and up) than in younger twins (under age 20)"...

“Nonheritable influences, particularly microbes, seem to play a huge role in driving immune variation,” said Davis. “At least for the first 20 or so years of your life, when your immune system is maturing, this amazing system appears able to adapt to wildly different environmental conditions. A healthy human immune system continually adapts to its encounters with hostile pathogens, friendly gut microbes, nutritional components and more, overshadowing the influences of most heritable factors.”



A number of those with autism display psychotic traits according to studies. A lot of of effected brain areas are the same in both conditions.Some of the cause for both conditions may overlap. When and how much "damage" is occurring could be the difference with autism and psychotic disorders.

Gray matter loss and inflamed brain associated with development of psychosis

"Thirty-five individuals ultimately converted to psychosis and they showed a steeper rate of thinning in prefrontal cortex compared with those who did not convert and the healthy control group. Importantly, this tissue loss was not explained by exposure to antipsychotic drugs."

"Because this differential rate of tissue loss was observed among subjects who had never been exposed to psychiatric drugs, we can conclude that the brain changes are part of the natural course of the disorder rather than being a consequence of treatment," explained Cannon."

"Interestingly, the tissue loss observed in the converters was correlated with levels of proinflammatory cytokines in plasma, suggesting the presence of systemic neuroinflammation."

"The findings are also important in showing that markers of proinflammatory cytokines at the baseline assessment predicted the rate of gray matter loss among the individuals who converted to psychosis, suggesting that activation of microglia was involved in the tissue loss," he added. "This could mean that psychosis is associated with an abnormal acceleration in the processes underlying normal synaptic pruning during late adolescence/early adulthood, or that some kind of immune-related process is involved in psychosis onset, or both."

"Inflammation is increasingly recognized as a contributing factor to the emergence of progression of disease in every organ in the body," said Dr. John Krystal, Editor of Biological Psychiatry. "This report suggests that neuroinflammation may be a process that in some cases 'tips people over' from the at-risk state into psychosis."


Psychosis and autism: magnetic resonance imaging study of brain anatomy

Overlapping developmental brain abnormalities

"People with autism-spectrum disorder already have significant developmental abnormalities in brain regions typically affected in psychosis (e.g temporal and frontal lobes), therefore it may be more difficult to detect subtle additional differences associated with further neuropsychiatric disorder."


Toddlers' Autistic Behaviors Linked to Preteen Psychosis

"Autistic-like behaviors in toddlers might predict psychotic events in adolescence, a retrospective study has determined."

"Speech problems and ritualistic behaviors in 3- and 7-year-olds showed a particularly strong influence, increasing the risk of psychosis in preteens by up to 300%, Rhys Bevan Jones, Ph.D., and colleagues wrote in the March issue of Schizophrenia Research (Schizophr Res. 2012;135:164-9)."

"In the study, nearly 20% of children with these characteristics at age 7 went on to develop psychotic episodes by age 12."

"The findings of this study suggest that clinicians should ask about psychotic experiences in those with autistic traits," wrote Dr. Jones of Cardiff (Wales) University. "Clinicians should also assess for traits of autism in those who develop psychotic experiences (23% of those with psychotic experiences in adolescence had at least one autistic trait at the age of 3, and 10% had at least one psychotic trait at the age of 7). Clinical care is likely to be enhanced by careful consideration of premorbid and comorbid autistic traits that might be impacting on patient function."

"It is also possible that [autism spectrum disorders] and psychotic disorders represent part of the same disorder that is manifest differently at different stages of development."



Mounting Research Shows Gut-Brain Connection

"The work of these three researchers (some of the studies on mice) raises the possibility that brain disorders, including anxiety, depression, and autism, may be treated through the gut, which is a much easier target for drug delivery than the brain."

"The human body contains trillions of microbes, collectively called the microbiome. In just one person’s body, they are estimated to weigh two to six pounds — up to twice the weight of the average human brain."

"Most reside in the gut and intestines, where they can help us to digest food, synthesize vitamins, and fight off infection. But their influence seems to reach the brain in a powerful way."

“The big question right now is how the microbiome exerts its effects on the brain,” said Christopher Lowry, Associate Professor of Integrative Physiology at the University of Colorado, Boulder..."

"Dr. Sarkis Mazmanian, a Louis & Nelly Soux Professor of Microbiology at the California Institute of Technology, is investigating the connection between gut bacteria, gastrointestinal disease and autism, a neurodevelopmental disorder."

"He has found that the gut microbiome communicates with the brain through molecules that are produced by gut bacteria and then enter the bloodstream. These molecules are strong enough to change the behavior of mice."

“We’ve shown, for example, that a metabolite produced by gut bacteria is sufficient to cause behavioral abnormalities associated with autism and with anxiety when it is injected into otherwise healthy mice,” said Mazmanian."

"There is still much more work to be done to understand the gut-microbiome-brain connection, the researchers said. Mazmanian’s lab is also exploring whether the microbiome plays a role in neurodegenerative diseases such as Alzheimer’s and Parkinson’s."

“There are flash bulbs going off in the dark, suggesting that very complex neurodegenerative disorders may be linked to the microbiome. But once again this is very speculative. These seminal findings, the flash bulbs, are only just beginning to illuminate our vision of the gut-microbiome-brain connection,” said Mazmanian."



We are less crazy as the days go by. My wife was diagnosed with RA, but with diet mod and immune modulation we have reversed it to a very large degree. That was a few years ago. The effects in some autism will be more clear soon it seems.

Joint Pain, From the Gut

“It’s become more and more clear that these microbes can affect the immune system, even in diseases that are not in the gut,” says Veena Taneja, an immunologist at the Mayo Clinic in Rochester, Minnesota, who has found clear differences in the bacterial populations of mice bred to be genetically prone to rheumatoid arthritis. In those more susceptible to the disease, a species of bacteria from the Clostridium family dominates. In mice without arthritis, other strains flourish, and the Clostridium strains are scarce...."

“This is frontier stuff,” says Scher, the director of the NYU’s Microbiome Center for Rheumatology and Autoimmunity. “This is a shift in paradigm. By including the microbiome, we’ve added a new player to the game.”

"In fact, these bacteria have a powerful vested interest in controlling how our bodies respond to interlopers. Blaser and others say that it appears that many of the bugs that live inside us have thrived by modulating the immune system to avoid being recognized—and attacked—as invaders; in essence, these organisms train immune cells not to be trigger-happy. A microbiome with the wrong sorts of bugs, or the wrong ratio of bugs—a situation known as dysbiosis—may unbalance this immune system, causing immune cells to assault not only bacteria, but also the body itself."

"Microbes are especially influential in the gut, which houses two-thirds of the body’s immune cells. As the pathway for digestion, the gastrointestinal tract must deal with a constant stream of food-related foreign microbes, which must be monitored and, if they are harmful, destroyed. To do this, our intestines have developed an extensive immune system, whose effects reach far beyond the gut. Immune cells in the gut seem to be able to activate inflammatory cells throughout the body, including in joints."



Peripheral Blood Monocytes and innate immune dysregulation in ASD-IS or ASD-Inflammatory Subtype. So, peripheral blood cytokines and non IgE food allergy are proposed as possible bio markers that appear to effect behavior according to this study. This has to be effecting the brain too and suggests dealing with these elements in the periphery can be beneficial in this sub type. I am guessing this is a fairly large group in the ASD world.

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


"In summary, studies of purified PB Mo from ASD-IS children indicate that they have dysregulated innate immune responses. Specifically, these relate to the production of IL-1ß and IL-10, revealing significant changes in ‘flare’ versus ‘non-flare’ states. These responses, for the most part, were not observed in ASD/non-ASD controls. These results indicate that further analysis of the regulatory mechanisms of PB Mo in ASD-IS subjects may lead to the identification of biomarkers and even treatment options for ASD-IS subjects who typically do not respond well to the first-line therapeutic measures."



Understanding why some of the immune genes are constantly turned on will be key it appears, but they did say that mutations are not the reason as I suspected they were not. This is a good read and seems on track. Again, etiology is a ways off in their pursuit it seems.

Postmortem brains point to molecular signature of autism

"The new study suggests that autism-linked mutations tend to strike genes involved in neurons’ functions. By contrast, the activation of microglia-related genes appears to be unrelated to mutations."



Have read this in the past, but it should be pinned somewhere.

The Danger of Excessive Vaccination During Brain Development



This article may be controversial, but in my wife's case it is confirming information of her condition. It deals with autism and perception of self.

Autism markers found in CMU study of brain activity

"For example, thinking about the word “hug” evoked activity in the posterior midline region of the brain in “neurotypical” individuals — where activation is associated with the “self factor,” or thoughts of oneself. The study investigated this verb and other similar verbs because in autism social interactions are believed to be experienced in an altered way. The new results now identify what the alteration is: People with autism think about social interactions without including thoughts of themselves."

"The machine learning program was able to accurately classify people as having autism or not by assessing whether or not the self factor was activated during functional magnetic resonance imaging of their brains as they thought about the social-interaction verbs."


Years ago when first documenting my wife's condition I wrote this in a list of her physical and mental markers:

"11. Lack of self, only reacting to others in a patterned way, she had no motives or feelings of her own and was often just operating at the prompting of others."

"14. Avoidance of eye contact especially during serious conversation {this trait was something I noticed from the time we were married and probably not noticed by others in that it occurred in relation to my trying to get her to make decisions or give opinions concerning matters that revolved around self; i.e. why do you like or dislike this, that, or someone and why did you do this or that."

"Over time, with hundreds of hours of counseling and my constantly teaching her about social interaction and logical thinking, she has developed a self. But this counseling /therapy would have been useless without dealing with the maze of biological problems she had and changing her diet."

Many things were part of her recovery, but this self aspect is exactly in sync with what she was like.


There are other foods and a few drugs mentioned in literature that ameliorate microglial inflammation, but apparently some drugs are untested or produce bad long term effects. Apparently there are systemic ways of tempering microglial activation as many have seen their children recover without any of these substances being used, only diet and other supplements.


Dr. Datis Kharraaian; said that once the T Cells of the body get the immune cells of the brain going there is no shutting these brain immune cells -- glial cells off. Three was No known drug. He said though that certian types of foods would;

Reveratorol, turmeric and luteolin

I went to a concert a couple of years in a role when my kids were teenagers to see Michael Smith. He is wonderful.


My sister sent me this song and I would like to share.


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