The Inflammation Highway: aka Autism

  By 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.

Comments

[Visitor]

In the last post the pdf on Th17 is not the full report, gives a skeletal view of the report which tells a good bit. If you happened to read some the sidebar linked reports there is a great deal of reallly good info. Curcummin for EAE is one of those. Another is the following and particularly the info on SIGIRR and also IL-1/
tuberous sclerosis complex/MTOR. The TH-17 is strongly tied to IL-1, IL-6,an TGF-b. Read if interested.

The Receptor SIGIRR Suppresses Th17 Cell Proliferation via Inhibition of the Interleukin-1 Receptor Pathway and mTOR Kinase Activation

http://www.sciencedirect.com/science/article/pii/S1074761309005445

THis may be more specefic to our case, but maybe not.

Common Polymorphisms in the PKP3-SIGIRR-TMEM16J Gene Region Are Associated With Susceptibility to Tuberculosis

http://jid.oxfordjournals.org/content/early/2012/01/02/infdis.jir785.abstract

SIGIRR apparently constrains epithiliel cell inflamation in the gut and inflmation in the airway. It also plays a role in tumors. It interacts with PRPK/TP53 and PRPK may have a role in Narcolepsy.

Gene Card - SIGIRR

http://www.genecards.org/cgi-bin/carddisp.pl?gene=SIGIRR&search=SIGIRR

More worth taking in.

Brain Transcriptional and Epigenetic Associations with Autism

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440365/

This one makes one wonder if enviromental factors are altering the second suppressive immune response in more women. The B^ mag came to mind, but many other pathogens could alter this too. The exhange amphasizes viral affects.
I have not read the report they cire in the discusssion, but c-met came to mind.

Why does mother's immune system not attack the embryo?

http://newsclick.in/international/why-does-mothers-immune-system-not-attack-embryo

[Visitor]

Since I can't get back into the things I was studying mentally, here are some interesting reports that bear on issues that appear to be involved and may be co-occurring. These are pathogens discussed in this thread and if they are involved in early development the affects would be expectedly more pronounced.

Increased mutations along with possible transgenerational affects of vaccines and non- Mendelian inheritance effects due to earlier effects in parents and grandparents combined with additional chemicals/endocrine disruptors/pesticides etc l and metals coupled with decreased detox abilities and dysfunctional innate and adaptive immune response may be allowing for the early and or easy infection from pathogenic microbes to invade immune cells and also alter brain cell function and development. This leaves cells vulnerable to more effects and infection.

Immune Problems May Leave Chronic Fatigue Syndrome Adolescents Open to Infections

http://www.prohealth.com/library/showarticle.cfm?libid=17238

The cytokines involved look familiar and the TH17 looks very familiar too. Here is a report on TH17 and genes.

A Validated Regulatory Network for Th17 Cell Specification

http://www.cell.com/retrieve/pii/S0092867412011233?cc=y

The PDF of the full report on TH17 is worth reading and found here:

http://download.cell.com/pdf/PIIS0092867412011233.pdf

In the "Gut Bug" thread ties to Alum and Nalp3, PTEN, PI3k, IGF-1, AKT and others were discussed and the possible relationship of these with Autism is put forward. Here is one report from the "Gut Bug" thread.

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

Abstract

“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."

http://www.ncbi.nlm.nih.gov/pubmed/21521652

This next report is on Mycoplasma in dogs. It speaks of immune down regulation and I am not sure yet if down regulation Natural Killer cells is a major part in this dog infection it is possible to see the earlier mentioned CF viruses up-regulation of certain immune factors mixed with already occurring down regulation of NK cells could be a major factor in the immune dysfunction in much Autism. The conditions they cause are not the same possibly contributing to Autism, but different Mycoplasma have varying immune effects most likely as mentioned related to varying immune suppression in the article. They even found the Mycoplasma somewhat common and hard to detect.
Here are parts of the article.

Analysis of bacterial genes may help ID cause of dog brain disease, researchers say

“The researchers found that the bacteria, known as Mycoplasma canis, invade dog's cells and suppress their immune system responses.

"This could explain how the bacteria are able to enter the brain in certain circumstances," said lead investigator Daniel Brown, an associate professor of infectious diseases at the UF College of Veterinary Medicine. "If our theory is correct, it is possible that antibiotic therapy aimed at the mycoplasma could be beneficial if the condition is diagnosed early enough."

The findings, which appear in the August issue of the Journal of Bacteriology, were also presented at the annual meeting of the International Organization for Mycoplasmology in France.

The researchers studied two common brain syndromes called granulomatous meningoencephalomyelitis, or GME, and necrotizing meningoencephalitis, or NME, which occur primarily in small toy-breed dogs such as pugs, Malteses, Yorkshire terriers, Chihuahuas and Pomeranians. The diseases affect the central nervous system, causing brain damage and symptoms such as seizures, decreased alertness and difficulty maintaining balance. There is no cure, but drugs can control the brain inflammation by suppressing the immune system.

No clear data exist on how widespread the disorders are.
"Although reliable information on new and existing cases is pretty scarce or nonexistent, inflammatory central nervous system disease is certainly one of the most common problems we deal with as veterinary neurologists," said Christopher Mariani, D.V.M., Ph.D., an assistant professor of neurology at North Carolina State University's College of Veterinary Medicine. Mariana was not involved in the UF study. “
The syndromes previously were thought to be caused by a virus or by an attack of the body's own immune system.

"This finding is tantalizing, because it may offer an explanation as to why scientists have never been able to specify a viral, autoimmune or other cause of GME and NME," Brown said. In addition, different strains of bacteria were not equally efficient at suppressing the dogs' immune responses. The researchers are continuing to analyze the effects of bacterial infection on immune system cells known as macrophages to determine how the bacteria could breach the blood-brain barrier. Later, they will extend their studies to examining how the bacteria interact with different types of brain cells.”

http://phys.org/news/2012-09-analysis-bacterial-genes-id-dog.html

It was of interest that while the Mycoplsama could suppress the immune response the treatment was to suppress the immune response causing brain inflammation.
This report is related in that it shows possible relationship to lung bacteria and more interrelated disease condition and immune function. I noted earlier reports on Mycoplasma P. and autism. This seems to show an emerging possible understanding of the microbiome {emerging for some}.

The concept sounds a lot like what many of think about the gut and its health and function, down to the part of same disease causing gene mutations, but different bacterial profiles and disease progression.
Of note it the quote saying; “Although decades of received scientific wisdom said healthy lungs lacked resident microbes, scientists had begun questioning that notion.” The medical field has other decades of received scientific wisdom that is under informed I think.

Identification of Microbes in Healthy Lungs Sheds Light On Cystic Fibrosis

"The lung is not a sterile organ," said David Cornfield, MD, an author of the new study, published Sept. 26 in Science Translational Medicine. Although decades of received scientific wisdom said healthy lungs lacked resident microbes, scientists had begun questioning that notion. "This research confirmed a long-held suspicion that a forest of microbes exists in both healthy and diseased lungs,"…

Healthy lungs' microbes have been overlooked in part because past research has focused heavily on lung diseases, Cornfield said. Another flaw in prior studies was a bias toward looking for micro-organisms that could be grown in labs. Many of the types of microbes that the Stanford researchers found in healthy lungs have never been cultured in a laboratory.

Different bacterial phyla predominated in the two groups: members of the Bacteroidetes and Fusobacteria phyla were much more prominent in healthy individuals, whereas CF patients had a larger percentage of Actinobacteria. Also, healthy people had a larger proportion of bacteria that had never been grown in a lab.

"I think the tendency toward decreased diversity can be metaphorically viewed as the same phenomenon that might happen in a rainforest," Cornfield said. "When the ecosystem of a rainforest is disturbed and one organism predominates, it undermines a carefully constructed balance and causes disturbances in overall ecosystem. I think it's reasonable to assume something similar could happen in the lung microbiome, where pathogenic bacteria may out-compete organisms that may play a salutary, health-affirming role."

The results open many questions for future research. No one has ever tested the idea that certain microbes benefit lung health, for instance. "We may need to consider strategies that allow favorable microbes to exist while eradicating disease-causing species," Cornfield said. "That paradigm, if it's true, would really turn the care of patients with pneumonia and other lower-airway diseases on its head." Future research might test whether CF or pneumonia patients could benefit from doses of probiotic bacteria to their lungs, he said.

In addition, no one is sure how the antibiotics often given to CF patients change the microbes in their lungs.

"The marked differences in composition and diversity of microbial communities from adults with cystic fibrosis and normal controls are intriguing," said Thomas Ferkol, MD, director of allergy, immunology and pulmonary medicine at the Washington University School of Medicine in St. Louis. "The question that remains to be answered is whether these differences are directly related to the underlying lung disease or simply a consequence of frequent antibiotic use, which has been shown to change microbiota of the upper airways." Ferkol was not involved in the research.

More questions arise from the fact that bacterial profiles varied within the group of CF patients. CF patients differ widely in their disease progression, even when they have the same disease-causing gene mutations. It is possible that patients' lung function may be linked to the bacteria present in their lungs. The research team now plans to study whether individual patients' bacterial profiles can be used to predict their clinical condition.”

http://www.sciencedaily.com/releases/2012/09/120928103804.htm

This last one speaks to possible problems of Benzodiazepines and dementia. I had already suspected strongly this is the case and not just for 65 and older or just dementia.

Over 65s at Increased Risk of Developing Dementia With Benzodiazepine, Study Suggests

http://www.sciencedaily.com/releases/2012/09/120927185916.htm

[Visitor]

Been going through a consolidation phase and realize have become to spread out trying to integrate more areas without developing enough process relationships in narrower ways to make more headway. Still, one odd idea has bubbled up in the attempt at the bigger picture. It may be false as usual. My wife does not have Down's syndrome and with all the other aspects of conditions she appears to have/had I never felt it would sound credible enough to state, but it really does not matter much what I write. On rare occassions when she has bee more notably physically ill she has taken on a Down syndromish look to her eyes that susbsided fairly quickly. Normally her eyses or face have absolutely no look of Down's to them,a nd it struck me as stange. With the epigentic and gene expression possibilities of this being produced as a result of immune and other subsequent actions taking place it seems plausble to consider if these were times when he was expressing more APP in he system that interacted in a way to give her eyes this look.

With the idea that those with Down's may over express APP and it mimics some Alzheimer at times it led back to the question of why and how could this take place if related. This idea that bubbled up is that in part APP, being anti-microbial in nature may be reacting to some antigen, and might be it is also a protein expressed to limit the processes that are the earliest ones in the genesis of cancer and since cell communication has a part in cancer spreading. This protein also blocks neuron communication, but may serve at least the two purposes of anibiotic and anti-tumor/cancer event.

Recently it has been promoted that EGFR increases Alzheimer and it is known that reduced PTEN expression promotes EGFR. Mycoplasma reuce PTEN. Te C-Met/Pten ratio might be a key in some aspects of Autism as perturbed Pten may be upsetting the C-Met values of people who before the last century had adapted to a C-Met or Pten function that was on the edges of functionally healthy and enviromental factors that effect thes tow genes at conception or anytime later develop suceptibilities to, or a condtion outright. Factors that bear on Pten esp. in early development might be more common in our day.

[Visitor]

I have read the idea of the woman who thought GMO's caused Autism, but given the timing of my wife's issues the GMO's did not figure in the process though it was reasoanable to think they could affect those fed them. Roundup on the other hand did figure in and there are pathways of effect that can be found to neuronal development immune function related to cancer type events and inflamation. Somne of those thoughts are in this thread and in the "Gut Bugs" thread some of you who may have followed this thread will be aware. This report even mentions tumors being a result. Female rats were more affected and ill in this study. This might reflect more systemic endocrine dysfucntion in females affected and co-occurring disease affects in females.

If this does show more ties to Autism it lends support to my belief and finding that the process of Autism is often begun at conception or in the womb and that the skewed system of many and this imbalances the interaction with mutations that otherwise would not have led to at least early conditions and maybe no conditions without triggers. For a lot this means that Vaccines would be a autoimmune/immune dysregulation trigger and other events and processes could be as well. The increase in vaccines and GMO/Roundup and other enviromental factors are increasing Autism and other immune related and infectious related conditions. The synergy cannot be ignored given that these combined effects appear to be altering many genetic functions and viewed one dimensionally make genes look like the main problem for many researchers. Gene fucntion is a major part, but the reasons for the gene fucntion changes is the key there.

France orders probe after rat study links GM corn, cancer

http://www.france24.com/en/20120919-france-orders-probe-after-rat-study-links-gm-corn-cancer

[Visitor]

I don't conclude at all that environmental factors don't work through these pathways or even not cause some of the issues in question, but the dysfunction discussed has much to recommend its involvement. I also, think in that the Nlgn3 aspect is a sign o many more issues and only part of the issue and expression of disturbance. In our case there are a number of additional disturbances occurring. It may be the list of system dysfunctions I have posted about are worsening, causing, or interacting with this problem. Some of what I have posted definitely is related as they are some of the same elements. The PTEN, Nlgn3, Retinoblastoma interaction is worthy of study. Nlgn3 has been considered as a candidate for a good while as the second report shows.

Rewiring the Autistic Brain

"Scheiffele and colleagues were studying a gene called neuroligin-3 (Nlgn3), involved in building the contact points, called synapses, between neurons. Many researchers believe that autism begins at the synapse, and mutations in Nlgn3 have appeared in some forms of the disorder. Sheiffele's team was focusing on synapses in the cerebellum, a part of the brain that controls movement, but, according to recent research, may also be involved in social behavior. Abnormalities in this region may contribute to both the unusual movements and the social problems seen in autistic patients.

To get a better handle on the role of Nlgn3, the scientists studied mice whose Nlgn3 genes were engineered with an on-off switch, called a promoter region, that is controlled by the antibiotic doxycycline. The animals were raised with the drug in their drinking water, which kept the switch in the off position. With the Nlgn3 gene disabled in the mice, neurons in their cerebellum made the abnormal connections seen in the autistic brain.

Specifically, and much to the researchers' surprise, the lack of Nlgn3 led to the overactivation of a receptor abbreviated as mGluR1α. This receptor is a component of a pathway that is also disrupted in fragile X syndrome, though it results from mutations in an entirely different gene. In the mice, the overabundance of these receptors led the neurons to make synaptic connections in the wrong places.

To see if turning Nlgn3 gene back on would correct these problems, the researchers withdrew the doxycycline. It worked: With Nlgn3 functioning once more, levels of the extraneous receptor receded back to normal, and the misplaced synapses began to disappear.

"Our finding demonstrates that there is still flexibility after the 'critical window' of brain development," Scheiffele says. "It raises the question: To what extent can a miswired brain be corrected?" The next step, he says, is to see whether motor abnormalities, such as ladder-climbing difficulties, and social interactions can be corrected with similar treatment in the engineered mice. His team is also studying whether drugs that block the mGluR1α receptor can have the same effect as genetically controlling the Nlgn3 gene, which isn't a treatment option for humans."

http://news.sciencemag.org/sciencenow/2012/09/rewiring-the-autistic-brain.html?ref=hp

A synaptic trek to autism.

Abstract
"Autism spectrum disorders (ASD) are diagnosed on the basis of three behavioral features namely deficits in social communication, absence or delay in language, and stereotypy. The susceptibility genes to ASD remain largely unknown, but two major pathways are emerging. Mutations in TSC1/TSC2, NF1, or PTEN activate the mTOR/PI3K pathway and lead to syndromic ASD with tuberous sclerosis, neurofibromatosis, or macrocephaly. Mutations in NLGN3/4, SHANK3, or NRXN1 alter synaptic function and lead to mental retardation, typical autism, or Asperger syndrome. The mTOR/PI3K pathway is associated with abnormal cellular/synaptic growth rate, whereas the NRXN-NLGN-SHANK pathway is associated with synaptogenesis and imbalance between excitatory and inhibitory currents. Taken together, these data strongly suggest that abnormal synaptic homeostasis represent a risk factor to ASD."

http://www.ncbi.nlm.nih.gov/pubmed?term=pten%20Nlgn3

As some Autism may possibly involve a diffuse cancer like aspect akin to Giloblastoma or Asrtocytoma the therapeutic action of Curcumin in Autism makes this report of interest in considering Cancer processes in Autism and brain cell growth and migration. This certainly looks like a connection to cancer.

The anti-cancer efficacy of curcumin scrutinized through core signaling pathways in glioblastoma.

Abstract

"Curcumin has been verified as an anti-cancer compound via multiple molecular targets. Its effective mechanisms include cell cycle arrest, inducing apoptosis, suppressing oncogenes, and enhancing tumor suppressor genes. The resistance of cells to chemotherapy, however, derives from the variable genetic aberration of cancer cells. Consequently, the core signaling pathways of glioblastoma have been explored to evaluate the efficacy of curcumin in proceeding through mutated genes in those pathways. In this study, the efficacy of curcumin was investigated in DBTRG cells. The cytotoxic ability was detected with MTT assay, and the influence of the cell cycle was checked with flow cytometry. The influence of the core signaling pathways was evaluated by Western blotting through the predominantly mutated proteins which included p53, p21, and cdc2 in the p53 pathway, CDKN2A/p16 and RB in the RB pathway, and EGFR, mTOR, Ras, PTEN, and Akt in the RTK-Ras-PI3K pathway. In addition, the apoptotic effect was determined by apoptosis-associated proteins Bcl-2, Bax, and caspase 3. Curcumin exhibits superior cytotoxicity on glioblastoma in a dose- and time-dependent manner in the MTT assay. In the core signaling pathways of glioblastoma, curcumin either significantly influences the p53 pathway by enhancing p53 and p21 and suppressing cdc2 or significantly inhibits the RB pathway by enhancing CDKN2A/p16 and suppressing phosphorylated RB. In the apoptotic pathway, the Bax and caspase 3 are significantly suppressed by curcumin and the Giemsa stain elucidates apoptotic features of DBTRG cells as well. In conclusion, curcumin appears to be an effective anti-glioblastoma drug through inhibition of the two core signaling pathways and promotion of the apoptotic pathway."

http://www.ncbi.nlm.nih.gov/pubmed/20596601

PTEN tumour suppressor is linked to the cell cycle control through the retinoblastoma protein.

Abstract

“The tumour suppressor PTEN, also named MMAC1 or TEP1, is associated with a number of malignancies in human populations. This protein has a dual protein phosphatase activity, being also capable to dephosphorylate phosphatidylinositol 3,4,5 triphosphate. We have studied the mechanism of growth suppression attributable to PTEN. We observed that PTEN overexpression inhibits cell growth in a variety of normal and transformed, human and murine cells. Bromodeoxyuridine (BrdU) incorporation and TUNEL labelling experiments in transiently transfected cells demonstrate that this inhibition is due to a cell cycle arrest rather than induction of apoptosis. Given that PTEN is unable to cause cell growth arrest in retinoblastoma (Rb)-deficient cell lines, we have explored the possible requirement for pRb in the PTEN-induced inhibition of cell proliferation. We found that the co-expression of SV40 antigen, but not a mutant form (which binds exclusively to p53), and cyclin D1/cdk4 are able to overcome the PTEN-mediated growth suppression. In addition, the reintroduction of a functional pRb, but not its relatives p107 or p130, in Rb-deficient cells restores the sensitivity to PTEN-induced arrest. Finally, the hyperphosphorylation of transfected pRb is inhibited by PTEN co-expression and restored by PI-3K co-expression. Accordingly, PTEN gene is mostly expressed, in parallel to Akt, in mid-late G1 phase during cell cycle progression prior to pRb hyperphosphorylation. Finally, we have studied the signal transduction pathways modulated by PTEN expression. We found that PTEN-induced growth arrest can be rescued by the co-expression of active PI-3K and downstream effectors such as Akt or PDK1, and also certain small GTPases such as Rac1 and Cdc42, but not by active Ha-ras, raf or RhoA. Collectively, our data link the tumour suppressor activities of PTEN to the machinery controlling cell cycle through the modulation of signalling molecules whose final target is the functional inactivation of the retinoblastoma gene product.”

http://www.ncbi.nlm.nih.gov/pubmed/10602505

Glioblastoma multiforme – Wiki

“For unknown reasons, GBM occurs more commonly in males.[4] Most glioblastoma tumors appear to be sporadic, without any genetic predisposition. No links have been found between glioblastoma and smoking,[5] consumption of cured meat,[6] or electromagnetic fields.[7][8][9][10] Alcohol consumption may be a possible risk factor.[11] Recently, evidence for a viral cause has been discovered, possibly SV40[12] or cytomegalovirus.[13] There also appears to be a small link between ionizing radiation and glioblastoma.[14] Some also believe that there may be a link between polyvinyl chloride (which is commonly used in construction) and glioblastoma.[15] A 2006 analysis links brain cancer to lead exposure in the work-place.[16] There is an association of brain tumor incidence and malaria, suggesting that the anopheles mosquito, the carrier of malaria, might transmit a virus or other agent that could cause glioblastoma.[17]”

Having one of the following genetic disorders is associated with an increased incidence of gliomas:

Neurofibromatosis
Tuberous sclerosis {This one stands out-my note}
Von Hippel-Lindau disease
Li-Fraumeni syndrome
Turcot syndrome

http://en.wikipedia.org/wiki/Glioblastoma_multiforme

With regard to CMV orSV40 mention in the Wiki entry here are a couple of articles that at least give some thoughts on how they could possibly relate.

Researchers Discover How Cytomegalovirus Damages Immune System: Plan to Stop It

http://www.prohealth.com/library/showarticle.cfm?libid=17131

Not much to go on here, but does agree with the wiki info.

The true story of SV40, the cancer-causing virus hidden in polio vaccines

http://www.naturalnews.com/032854_SV40_polio_vaccines.html

[Visitor]

When it is figured fully how many of the genes in the link below are systemically disturbed a lot of Autism answers will come. Apparently biomedical approaches are reversing or reducing the negative interaction. It may be in a lot of different combinations of ways.

ARGDB: Androgen Responsive Gene Database

http://argdb.fudan.edu.cn/goargshow.php?argnum=process_0032501

[Visitor]

This report attests to ACE involvement in immunity in even more ways and also in the testes and fertility. The alteration in ACE/Angiotensin was already starting to look difficult to untangle and this report, while strengthening the picture of involvement, presents points that are not easily fall into place with what I have already found related to ACE/Angiotensin 2 and the immune deregulation and autoimmunity. High red blood cell counts are found in Diabetes and are a risk factor for stroke though red blood cell "health" is not good in many with Autism. This may take a lot of work. Yet, it solidifies the broad connection.

Surprising New Roles for a Key Regulatory Enzyme of Blood Pressure

"ScienceDaily (Sep. 7, 2012) — Many patients with hypertension are treated with ACE inhibitors. These drugs block the angiotensin converting enzyme (ACE) that regulates the salt and water balance of the body and raises blood pressure. Recent studies by a research team led by Professor Ken Bernstein (Cedars-Sinai Medical Center, Los Angeles, California, USA) have, however, significantly broadened the enzyme's known task spectrum: The enzyme also plays a key role in blood formation, renal development and male fertility. In addition, the researchers showed that ACE has a hitherto unexpected influence on the immune response.

At the 1st ECRC "Franz-Volhard" Symposium on Sept. 7, 2012 at the Max Delbrück Center for Molecular Medicine (MDC) in Berlin-Buch, Professor Ken Bernstein reported that in mice an excess of ACE led to a much stronger immune response than usual. In animal experiments, not only could bacterial infections be combated more effectively, but also the growth of aggressive skin cancer (melanoma) in mice could be contained by a stronger response of the immune system. In contrast, if the mice lacked ACE, the immune cells worked less effectively.

In addition, ACE apparently has an influence on blood formation. It has been known for many years that, in humans, ACE inhibitors induce a small reduction of red blood cell levels. To elucidate the exact roles of ACE, the Bernstein's research team deactivated the genes in mice that normally provide the blueprint for the enzyme. As a consequence, these so-called "knock out" mice could no longer produce the enzyme. The examination of these mice revealed that they in fact had significantly fewer red blood cells. Also, the white blood cells in these animals were less functional. According to the researchers' studies, ACE evidently plays a role in the development of the different blood cells.

Bernstein's team also showed that ACE apparently plays an important role in the development of the kidneys. In mice that could not produce the enzyme, the small arteries and the tissue of the kidneys revealed pathological changes, and the urine flow was impaired.

According to these findings, male fertility is also associated with ACE. Male mice lacking ACE continued to produce sperm, but they were no longer able to reproduce. However, if in the mice not the enzyme itself, but rather a product of ACE -- namely the hormone angiotensin II -- was suppressed, they could continue to reproduce. Until now it was thought that ACE mainly exerts its effect through the production of angiotensin II. These results show, however, that ACE is enzymatically active and produces other active products apart from angiotensin II, for example in the testes."

http://www.sciencedaily.com/releases/2012/09/120908081615.htm

This is also of note.

Skin and Immune System Influence Salt Storage and Regulate Blood Pressure

http://www.sciencedaily.com/releases/2012/09/120908081613.htm

[Visitor]

I meant to add this report to the previous post.

Maternal thimerosal exposure results in aberrant cerebellar oxidative stress, thyroid hormone metabolism, and motor behavior in rat pups; sex- and strain-dependent effects.

http://www.ncbi.nlm.nih.gov/pubmed/22015705

[Benedetta]

Good GOSH NICK!!!!
What a find!
Thanks.
My daughter with Kawasakis went on to have bipolar - Insitol is the vitamin they recommend that she should take.

[Visitor]

It is my belief that there are many factors and can satisfie myself of the contribution of a host of these fators it remains that mercury does have its part. Yet, it may not be a necessary one in many cases. It may be involved in the more severe cases most often.

Administration of thimerosal to infant rats increases overflow of glutamate and aspartate in the prefrontal cortex: protective role of dehydroepiandrosterone sulfate.

http://www.ncbi.nlm.nih.gov/pubmed/22015977

Sex-dependent changes in cerebellar thyroid hormone-dependent gene expression following perinatal exposure to thimerosal in rats.

http://www.ncbi.nlm.nih.gov/pubmed/22791642

Thimerosal-Derived Ethylmercury Is a Mitochondrial Toxin in Human Astrocytes: Possible Role of Fenton Chemistry in the Oxidation and Breakage of mtDNA.

http://www.ncbi.nlm.nih.gov/pubmed/22811707

Prenatal exposure to organomercury, thimerosal, persistently impairs the serotonergic and dopaminergic systems in the rat brain: Implications for association with developmental disorders.

http://www.ncbi.nlm.nih.gov/pubmed/22658806

Cytoprotective effect of hyaluronic acid and hydroxypropyl methylcellulose against DNA damage induced by thimerosal in Chang conjunctival cells.

http://www.ncbi.nlm.nih.gov/pubmed/22729468

ITPKC susceptibility in Kawasaki syndrome as a sensitizing factor for autoimmunity and coronary arterial wall relaxation induced by thimerosal's effects on calcium signaling via IP3.

Abstract

"Recently, a single nucleotide polymorphism (SNP) of the inositol 1,4,5-triphosphate kinase C (ITPKC), rs28493229, was found to passively confer susceptibility for Kawasaki syndrome (KS) and subsequent coronary arterial lesions. This association is believed to be the result of defective phosphorylation of inositol 1,4,5-triphosphate (IP3), which releases calcium from intracellular stores, resulting from reduced genetic expression of ITPKC in carriers of the SNP. Reduced ITPKC activity would increase IP3 levels, and thus, increase calcium release. We hypothesized that an environmental agent which influences IP3-mediated calcium release is potentiated by the ITPKC SNP. This led us to an attractive candidate, thimerosal, an organomercurial medical preservative still used in several pediatric vaccines. Thimerosal is well-known to sensitize IP3 receptors via its induction of oxidative stress, resulting in enhanced release of intracellular calcium with distinctive consequences for various cell types. Dysregulated calcium signaling in T cells and other immune cells can result in autoimmunity, while hyperpolarization of vascular smooth muscle cells secondary to the stimulation of calcium-activated potassium channels can result in increased vascular permeability and arterial relaxation. We propose that ITPKC susceptibility in KS is related to its synergy with environmental triggers, such as thimerosal, which alter calcium homeostasis and promote oxidative stress. Therefore, carriers of the ITPKC SNP are more susceptible to thimerosal-induced autoimmunity and coronary arterial lesions observed in KS. This would explain why only a susceptible subset of children develops KS although pediatric thimerosal exposure is nearly universal due to vaccination. As was experienced with the infantile acrodynia epidemic, only 1 in 500 children developed the disease although pediatric mercury exposure was nearly ubiquitous due to the use calomel teething powders. This hypothesis also mirrors the current leading theory for KS in which a widespread infection only induces the disease in susceptible children. We conclude that KS may be the acute febrile form of acrodynia."

http://www.ncbi.nlm.nih.gov/pubmed/22498790

[Visitor]

Pieces..not proof

Epidemiology of infantile autism in southern Ibaraki, Japan: differences in prevalence in birth cohorts.

Abstract

"Infantile autism was diagnosed by DSM-III criteria in 132 children (26 girls) who were outpatients of the Tsuchiura Child Guidance Center during the years 1977-1985. The children, all Japanese except for one Laotian boy born in Laos, were classified according to year and month of birth. The prevalence rate of infantile autism in southern Ibaraki, Japan, within the birth cohort born between 1972 and 1978 was 13.9/10,000 children. The month of birth for infantile autism increased in the second quarter of the year. The prevalence rate of infantile autism in each 1-year birth cohort fluctuated in a 4-year cycle, which was closely correlated (r = .92) with the number of children admitted with pneumonia and bronchiolitis in that area. These findings led us to postulate that infectious factors of children's pneumonia and bronchiolitis may have some role in the cause of infantile autism."

http://www.ncbi.nlm.nih.gov/pubmed/3410807

I don't know if it means a thing, but Temple Grandin commented that gelatin was something she ate a lot. It was interseting that she would be minded to even mention it.

Dietary induction of angiotensin-converting enzyme in proximal and distal rat small intestine

Abstract

"Induction of angiotensin-converting enzyme was examined in proximal and distal intestinal segments of rats fed a low-protein (4%) diet and then switched to a high-protein (gelatin) diet. Animals were killed at varying time points, and brush-border membranes and total RNA were prepared from the segments. In the proximal intestine, there was a fivefold increase in angiotensin-converting enzyme levels after 14 days but only a twofold change in mRNA. In the distal intestine, there was no increase in enzyme activity but mRNA increased 2.4-fold. Organ culture was used to measure changes in enzyme biosynthesis. There was a 5- to 6-fold increase in the biosynthesis of angiotensin-converting enzyme in the proximal intestine 24 h after the switch to the gelatin diet and a 1.6-fold increase in mRNA levels...

previous studies from our laboratory (16, 18) have indicated that the amount and type of protein in the diet can have a profound effect on levels of small intestinal brush-border membrane peptidases. Two enzymes, namely angiotensin-converting enzyme (ACE; EC 3.415.1) and dipeptidyl peptidase IV (DPPIV; EC 3.4.14.5), are unusually responsive to dietary modulation, their levels being induced by diets containing high amounts of proline (24). These two enzymes are important in that they play a critical role in the terminal digestion of prolyl peptides, which are generally resistant to hydrolysis by the peptide-hydrolyzing enzymes of the stomach and pancreas. Proteins high in proline are important dietary constituents as evidenced by commonly ingested proteins such as collagen, casein, and gliadin. Thus the mammalian small intestine is particularly well suited to complete the digestion of these types of proteins because of the presence of the two aforementioned enzymes in addition to carboxypeptidase P and aminopeptidase P (5)."

http://ajpgi.physiology.org/content/281/5/G1221.full

Ther next report points to protection against infection by ACE inhibitor, but not by Angiotensin 2 receptor blockers. As regard to Olmesartan the dose of such a Ang 2 receptor blocker would have been a low, short term, does comapared to the Marshall Protocol and so the result of its use in this report not mattering is uninformative as regarding the Protocol outcomes in such pathogenic infection and relationship.

Angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers and pneumonia risk among stroke patients.

Abstract

OBJECTIVE:

"To investigate the effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on pneumonia hospitalization in patients with stroke history in Taiwan.

METHODS:

We conducted a case-crossover study using the National Health Insurance Research Database in Taiwan during the period from 1998 to 2007. Patients who had stroke history and were subsequently admitted for pneumonia were enrolled for analysis. The status of exposure to angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers 1-30 days prior to admission (case period) was compared to that during 91-120 days and 181-210 days before admission (control periods) for each patient. Conditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (95% CI) for the association between pneumonia and use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers.

RESULTS:

In this study, 13 832 patients with incident pneumonia from the stroke patient population were enrolled. After adjustment for time-varying confounding factors, angiotensin-converting enzyme inhibitor use was associated with a decreased pneumonia risk (OR 0.70; 95% CI 0.68-0.87) and a significant dose-response relationship (P http://www.ncbi.nlm.nih.gov/pubmed/22929610

The "addictive' aspect of certain foods in some with Autism may be due to the fact that the petides may actually lower somestress effects while affecting neurocogintion through the same mans and by other opiate/immune effects. Chrontorpic heart effects and hypotension might co-exist in those in these conditions. Yet, wat is happening in the gut with in these individuals to certain foods is likely atypical in that digestion itself is distrubed and current studies generally reflect the process in normal digestion.

Effects of Milk Casein Derived Tripeptides on Endothelial Enzymes In Vitro; a Study with Synthetic Tripeptides.

Abstract

"In the fermentation of milk by certain lactic acid bacteria, casein is degraded into bioactive tripeptides shown to lower blood pressure in experimental animal models and in mildly hypertensive humans. This effect is suggested to result mainly in inhibition of angiotensin converting enzyme 1 (ACE-1).Due to the complexity of renin-angiotensin system (RAS), several other enzymes than ACE-1 can participate in the production of vasoactive components. Therefore, in the present study we investigated effects of tripeptides isoleucine-proline-proline (IPP), valine-proline-proline (VPP) and leucine-proline-proline (LPP) on some endothelial enzymes that are important in RAS or otherwise have a role in the endothelial function. The enzymes investigated were renin, chymase, neutral endopeptidase (NEP), prolyl oligopeptidase (POP), cathepsin G, endothelin converting enzyme 1 (ECE-1), and cyclooxygenase 1 and 2 (COX -1 and COX-2).The tripeptides inhibited prolyl oligopeptidase (POP) dose-dependently. IPP was the most potent inhibitor (IC50 486±95 µM). Contrary, cathepsin G was activated by IPP, VPP and LPP as well as the amino acids proline and isoleucine. The other investigated enzymes were not affected. Inhibition of POP and activation of cathepsin G do not explain the blood pressure lowering effects of the tripeptides. Thus the inhibition of ACE-1 remains the most plausible mechanism of the antihypertensive effects of the tripeptides."

http://www.ncbi.nlm.nih.gov/pubmed/22918858

Here is a site I just found an have only watched the into videos. There many other factors not mentioned in the videos and the details of etiology seem only scantly touched upon, though the more detailed info there may give more. One section says "Autism is permanent" and I am not uite sure if I fully agree. I tend to agree that continuous measures of biomedical/diet treament institution are necessary in many, many cases. If caught and treated early enough it may look like recovery without need for applying the measures of treatemnt forever. I found that multiple and simultaneous treatment and reversal was necessary quickly and noted the metabolic aspect from the start. In fact, except for the new terms they apply, it is roughly the same as I encoutered and understood.

Autism Cascade

http://dshedu.com/protocols/Autism/

[Visitor]

Here is some good info on Mycoplasma. It is a little long, butwoth reading. If you don't want to read it all here are some snippets.

Interaction of Mycoplasmas With Host Cells

VII. MODULATING THE IMMUNE SYSTEM

A.  Modulatory Effects on Monocytes and Macrophages

"It is increasingly recognized that for many bacteria induction of cytokines is a major virulence mechanism (41,112). The induced cytokines have a wide range of effects on the eukaryotic host cell and are recognized as important mediators of tissue pathology in infectious diseases. It appears that although mycoplasmas circumvent phagocytosis, they interact with mononuclear and polymorphonuclear phagocytes stimulating the synthesis of cytokines with proinflammatory action (88, 92). These immunomodulatory influences depend on both the immune cells and theMycoplasma spp. involved. Macrophage-mediated cytolysis of fibrosarcoma A9HT induced by whole cells of M. orale was first described by Lowenstein et al. (58). Cytolysis of the neoplastic cells was obtained even with macrophages from the lipopolysaccharide (LPS)-unresponsive C3H/HeJ mice, suggesting that the mechanism of activation is different from that of LPS (53). Since then over 20Mycoplasma spp. have been shown to activate monocytes, macrophages, and brain astrocytes and induce secretion of the proinflammatory cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6, chemokines, such as IL-8, monocyte chemoattractant protein 1 (MCP-1), macrophage inflamatory protein 1 (MIP-1α), granulocyte-monocyte colony stimulating factors (GM-CSFs), as well as prostaglandins and nitric oxide (82,92). More recent observations suggest that the mechanisms underlying macrophage activation by whole cells are in many cases identical to those employed by their purified membrane lipoproteins, supporting the notion that lipoproteins are the principle component of intact mycoplasmas activating monocytes/macrophages and playing an important role in the inflammatory response during infection (13, 41).

The potent molecules and mediators released by cells responding to mycoplasmas and mycoplasma-derived cell components enhance expression of major histocompatibility complex (MHC) class I and class II antigens and of costimulatory end cell adhesion molecules in leukocytes and endothelial cells, induce recruitment and extravasation of leukocytes to the site of infection and cause local tissue damage (41, 82, 90). It is interesting to note that mycoplasmal infections are not necessarily associated with a strong inflammatory response, and some mycoplasmas colonize the respiratory and urogenital tracts with no apparent clinical symptoms. It is therefore tempting to speculate that in addition to triggering the production of proinflammatory cytokines, certain organisms have the capacity to downregulate NFκB or to induce anti-inflammatory cytokines such as IL-4, IL-10, IL-13, or transforming growth factor-β, contributing to the complex network of synergistic and antagonistic influences induced by mycoplasmas on cells of the immune system...

C.  Lipoproteins

Lipoproteins are found in the cytoplasmic membrane and in the outer membrane of many Gram-positive and Gram-negative bacteria. All membrane-anchored bacterial lipoproteins contain a lipoylated amino-terminal cysteinyl residue which, in some cases, is N-acylated (Fig. 5). Lipoproteins are extremely abundant in the cell membrane of mycoplasmas. In M. pneumoniae, for example, of an estimated number of 150 membrane proteins, 46 open reading frames encoding putative lipoprotein genes have been identified (46). Chemical analyses of mycoplasmal lipoproteins have revealed that their lipoylation mechanism is similar to that of Gram-negative and Gram-positive bacteria (13). However, in many mycoplasmas, the lipoproteins are not N-acylated (Fig. 3), nor has an N-acyltransferase gene been found in the genome (34, 45, 46). The first reports on the cytokine-inducing ability of mycoplasmal lipoproteins showed that a lipoprotein from M. fermentans (49,70) or M. arginini (44) is capable of stimulating the release of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α from human peripheral blood monocytes in a dose-dependent manner..."

http://physrev.physiology.org/content/83/2/417.full

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Correction: Last post said - "You may have noticed an odd appearance of BGG in this thread and in one report above.."

Meant:
You may have noticed an odd appearance of BGG in this thread and in one report in the last post.

Also it is Quorum Sensing. When you have 90 pages open sometimes a key stroke does not register.

[Visitor]

Dr. Marshall has the next report linked at his site.
You may have noticed an odd appearance of BGG in this thread and in one report above. The microbiome does not operate from one or two organisms, but from communities and free organisms in the body and appears to espescially use uorum Sensing among other mechanisms. That is a terribly simplistic portrayal, but makes the point.

Filterable forms and L-forms of Mycobacterium bovis BCG: Impact for live vaccine features.

Abstract

Bacterial L-form conversion, or existence without cell walls, is assumed a universal phenomenon in nature. An interesting aspect of this phenomenon is occurrence of L-forms in vaccine strains. Since BCG is currently a widely used and extensively studied live vaccine for tuberculosis, understanding L-form conversion of M. bovis BCG bacilli can provide new insight into behavior of BCG vaccine. In this respect, specific features, concerning the ability of BCG vaccine to produce viable filterable forms and L-forms, were studied by filtration and starvation stress experiments in vitro. The filterable forms obtained after filtration of BCG suspension, grew on Middlebrook 7H9 semisolid agar and formed typical "fried eggs" L-form colonies. Electron microscopy clearly demonstrated presence of L-form elements with size smaller than the size of bacterial filter pores of 0.2 µm in M. bovis BCG strains. Development of L-form subpopulation with typical morphological appearance of self-replicating cell wall-defective forms was observed after filtration, as well as after starvation stress. Specific DNA detection of pncA gene in derived L-form cultures from filterable and stressed BCG strains verified their identity as M. bovis BCG. In conclusion, the results confirm existence of filterable forms in commercial BCG vaccine, which are able to develop L-form population under appropriate conditions. L-form transformation of BCG bacilli displays a new intriguing aspect concerning exhibition of unusual features and atypical behavior of live BCG vaccine. Further research is requested to explore the influence of L-form phenomenon on BCG vaccine effects in vivo."

http://www.ncbi.nlm.nih.gov/pubmed/22495116

There are other openings that might intoduce the pathology.

Mycoplasma contamination and viral immunomodulatory activity: Dendritic cells open Pandora's box

http://www.sciencedirect.com/science/article/pii/S016524780700079X

To what degree the problem and progress of the disorder in Autism is debated. I think it has risk from the start and prgression may at varying degrees in the womb though it is clear the condition is latent and needs a trigger or set of treiggers for many for it to become a condition that alters function strongly. Whether or not the pathogens could or do effect sperm is an open question, but even if it is just causing problems after conception there is evidence of pathogens causing fetal brain inflamation.

The mycoplasma mentioned in the next report does not affect PTEN, but that does not measn others may not. Even then PTEN distrurbance can come later or by other means.

Effect of experimental genital mycoplasmosis on gene expression in the fetal brain.

Abstract

"Neurodevelopmental disorders may have their origins during intrauterine development. We used a well-defined animal model to test whether hematogenous infection with genital mycoplasma would alter the expression of genes associated with autism spectrum disorders (ASD). In a preliminary experiment, rats were exposed at 14 days gestation (GD14) to Mycoplasma pulmonis or sterile broth and sacrificed at GD18. Infection and inflammation status of the pups was ascertained by culture and cytokine ELISA. Intra-cardiac injection of 10(6)CFU M. pulmonis resulted in amniotic infection of 100% of the pups and was accompanied by higher levels of IL-1β in amniotic fluids. In a second experiment, animals were infected in a similar manner but dams and their litters were sacrificed at GD18, GD21 or postpartum day 3 (PPD3). Expression of proinflammatory cytokines and neurodevelopmental genes in the fetal brains was evaluated. M. pulmonis infection significantly increased the expression of IL-1β, TNF-α and COX-2 in fetal and neonatal brains. Expression of GFAP and CD11b, markers for activation on astrocytes and microglial cells, respectively, was also increased for infected animals. M. pulmonis significantly increased SHANK-3 gene expression at GD21 and PPD3 and PCP-2 expression at GD21. No effect of M. pulmonis infection on Reelin, PTEN, BDNF or HGF was detected. These data suggest that M. pulmonis infection at GD14 increases the expression of proinflammatory genes in the perinatal brain. Further studies with earlier time-points of infection and ones that use behavioral outcomes are needed to better understand the potential role of genital mycoplasmosis on pychopathology."

http://www.ncbi.nlm.nih.gov/pubmed/22244476

Purkinje cell protein-2 (Pcp2) stimulates differentiation in PC12 cells by Gbetagamma-mediated activation of Ras and p38 MAPK.

Abstract

"Purkinje cell protein-2 (Pcp2 or L7) is highly expressed in cerebellar Purkinje cells and retinal bipolar neurons and interacts with the Galpha(i/o) family of G-proteins. Although the expression pattern of Pcp2 in the developing central nervous system suggests a role in differentiation, its function remains unknown. We established Tet-off inducible expression of Pcp2 in PC12 cells (rat pheochromocytoma cells) to determine whether Pcp2 regulates neuronal differentiation. Utilizing a polyclonal antibody, Pcp2 was localized in the cell body and throughout neurites of differentiated PC12 cells, similar to its localization in cerebellar Purkinje cells. Pcp2 expression in PC12 cells stimulated process formation (5-fold) and NGF (nerve growth factor)-stimulated neurite length (2-fold). Under basal conditions, Pcp2-PC12 cells demonstrated a 5-fold increase in Ras activation relative to non-induced PC12 cells and there was no change in extracellular-signal-regulated kinase 1/2 activity with Pcp2 expression. However, Pcp2 induction led to a >3-fold increase in basal p38 MAPK (mitogen-activated protein kinase) activity and the addition of NGF significantly stimulated both Ras and p38 MAPK in Pcp2-PC12 cells relative to the controls. Pretreatment of Pcp2-PC12 cells with the p38-specific inhibitor SB203580 blocked both the increased neurite formation and NGF-stimulated neurite growth. Pertussis toxin treatment had no effect on neurite growth in control cells, but completely blocked Pcp2-mediated increased neurite growth. Transient transfection of the beta-adrenergic receptor kinase C-terminus to prevent signalling through Gbetagamma in Pcp2-PC12 cells also inhibited the Pcp2-induced phenotype and reduced the Pcp2-stimulated Ras activation. Taken together, these findings demonstrate that Pcp2 induces differentiation in PC12 cells, in part through Gbetagamma-mediated Ras and p38 MAPK activation and suggest the potential for similar signalling mechanisms in Purkinje cells."

http://www.ncbi.nlm.nih.gov/pubmed/15948714

Related reading

Kent Holtorf, M.D., on Effective Treatment of Chronic Fatigue Syndrome and Fibromyalgia

http://www.prohealth.com/library/showarticle.cfm?libid=9179

[Visitor]

Clinical Implication of the C Allele of the ITPKC Gene SNP rs28493229 in Kawasaki Disease: Association With Disease Susceptibility and BCG Scar Reactivation.

Abstract

BACKGROUND:

"a functional single nucleotide polymorphism (SNP) (rs28493229) in the inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) gene has been linked to the susceptibility to Kawasaki disease (KD). The implication remains unclear.

SUBJECTS AND METHODS:

genotyping for the ITPKC polymorphism was conducted on 280 unrelated Taiwanese children with KD and 492 healthy ethnically and gender-matched controls. The clinical manifestations and laboratory data were systemically collected.

RESULTS:

the GC and CC genotypes of ITPKC gene SNP rs28493229 were overrepresented in KD patients (GG:GC:CC was 236:43:1, C allele frequency: 8.04%) than those in the controls (GG:GC:CC was 454:37:1, C allele frequency: 3.96%; OR: 2.23, P = 0.001). In KD patients, those with GC or CC genotypes of SNP rs28493229 (19/44) were more likely to have reactivation at the Bacille Calmette-Guérin (BCG) inoculation site than those with GG genotypes (66/236; OR: 1.96, P = 0.044). Such association was particularly strong in patients aged http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed&cmd=search&term=20805785&dopt=b

Kawasaki Disease: Novel Insights into Etiology and Genetic Susceptibility

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021097/?tool=pubmed

Given the seeming involvement of PTEN notice the relationship of PTEN and ITPKC in the network display in the next link.

PTEN & ITPKC

http://string-db.org/version_9_0/newstring_cgi/show_network_section.pl?limit=0&targetmode=proteins&caller_identity=gene_cards&network_flavor=evidence&identifiers=9606.ENSP00000263370%0D9606.ENSP00000254712%0D9606.ENSP00000361064%0D9606.ENSP00000322234%0D9606.ENSP00000347792%0D9606.ENSP00000384534%0D9606.ENSP00000362115%0D9606.ENSP00000361021%0D9606.ENSP00000352575%0D9606.ENSP00000360154%0D9606.ENSP00000298229%0D9606.ENSP00000357583

Pathogenesis of extrapulmonary manifestations of Mycoplasma pneumoniae infection with special reference to pneumonia.

http://www.ncbi.nlm.nih.gov/pubmed/20186455

Prevalence of superantigen-secreting bacteria in patients with Kawasaki disease.

http://www.ncbi.nlm.nih.gov/pubmed/12072880/

Kawasaki syndrome associated with group A streptococcal and Epstein-Barr virus co-infections.

Abstract

"We present a case of Kawasaki syndrome complicated by coronary aneurysm in a 6-year-old boy with laboratory evidence of group A streptococcal infection and infectious mononucleosis. The case demonstrates that evidence of acute infection in a patient with features suggestive of Kawasaki syndrome should not exclude a diagnosis of the latter. Immunoglobulin therapy should be considered seriously in highly suggestive cases, even if diagnostic criteria are not fulfilled."

http://www.ncbi.nlm.nih.gov/pubmed/12369491/

[Visitor]

A little side association and additional Mycoplasma info connected to Kawasakis. P. Mycoplasma has been strongly related to cases of Pancreatitis too.

Mycoplasma pneumoniae infection in patients with Kawasaki disease.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120998/

Mycoplasma pneumoniae: a possible trigger of kawasaki disease or a mere coincidental association? Report of the first four Italian cases.

http://www.ncbi.nlm.nih.gov/pubmed/21042274

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Without focusing on the possible {likely} role of Mycoplasma in the gestation in various conditions , I suggest this article does express much of the cause of the complaints stated by those with CFS, parents relaying problems of many with Autism, sufferers of those with some autoimmune diseases. I have believed it was a major part for a long time, but there is never confirmation in the mainstream of medicine. How it may be involved in gene effects and/or developing neuropsychiatric and medical conditions does have quite a few proponents giving the rationale for it may or does. Yet, waiting only works in mild problems and if I had waited I imagine my wife may well have died by the early 2000's or been in bedridden state. The silver and other antimicrobials helped a lot, but the Olmesartan has done so much to control harmful inflammation and improve her immune function and that has been a major key to improvement.

I do not endorse or deny the charges about goverenment and pharma in this article as I don't know if they are true. It is possible and they apparently feel it's true. I do attest to the other statements about the Mycoplasma and disease. I am very hesitant to make bold firm declarations, but there is a ton of suffering going on due to this I think.

Molecular Terrorism
By Mycoplasm

{snippet from article}

“This has led medical science to perpetuate trash can labels to terms for symptoms of Mycoplasma to hide their ignorance.

Syndrome X, Graves disease, Systemic Lupus, Sjogren-Larsson syndrome, Huntington's chorea, Guillain-BarrÈ syndrome, myasthenia gravis, Creutzfeldt-Jakob disease, Rift Valley fever, Hashimoto, Parkinson's disease, Alzheimer's disease, post traumatic stress syndrome, ADDH, even the recent West Nile virus, are all virulent Mycoplasma invasions in disguise. The names of the mysterious diseases are simply the location of the Mycoplasma invasion/destruction, not a new disease. Almost every neurodegenerative and autoimmune disease has a pathogenic Mycoplasma species responsible for the initiation of the disease process.“

http://rense.com/general62/molecularterrorism.htm

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Again, there is much missing to know where the association of these changes in the child’s genetics meets the father's gene profile. But, the bridge of sperm condition appears to be the X factor and that is open to other effects than the father’s genetics. I can't tell from what I have read from the reports if therey are reporting gentics sequenced from the father or simply age related assertions based on the childs genetics.

Father’s Age Linked to Autism, Schizophrenia Risk

"However, when it comes to certain complex developmental and psychiatric problems, the highest genetic risk begins in the sperm, not the egg, the researchers found.

Prior studies have strongly suggested this as well, including an analysis published in April that showed that this risk was higher at age 35 than 25 and slowly escalated with age. For the first time, this new study calculates how much it accumulates each year.

The scientists discovered that the average child of a 20-year-old father had 25 random mutations that could be traced to the father’s genetics. That number rose steadily by two mutations a year, reaching 65 mutations for offspring of 40-year-old men.

From the mother’s side, the average number of mutations was 15, regardless of age, the study found.

“This study provides some of the first solid scientific evidence for a true increase in the condition (of autism),” said Dr. Fred R. Volkmar, director of the Child Study Center at the Yale School of Medicine, who was not involved in the research. “It is extremely well done and the sample meticulously characterized.”

The study, led by the Icelandic firm Decode Genetics, analyzed genetic material taken from blood samples of 78 parent-child trios.

It focused on families in which parents, who had no mental disorders, had a child who developed autism or schizophrenia. This method allowed researchers to isolate brand-new mutations (de novo mutations) in the genes of the child that were not found in the parents.

Most people have these de novo mutations, which appear spontaneously at or near conception, and most are harmless. But studies suggest that there are several such changes that can dramatically increase the risk for autism and possibly schizophrenia — and the more a child has, the more likely he or she is to develop a severe disorder."

http://psychcentral.com/news/2012/08/24/fathers-age-linked-to-autism-schizophrenia-risk/43626.html

Reactive oxygen species and sperm cells {good read}

Free radicals

"Free radicals are short-lived reactive chemical intermediates, which contain one or more electrons with unpaired spin (Table 1). They are highly reactive and oxidize lipids, amino acids and carbohydrates as well as causing DNA mutations. Reactive oxygen species therefore may have been implicated as an etiological factor of a very wide range of diseases [2-15]. Enhanced, pathological ROS generation in living organisms may be caused by several mechanisms like: ionizing radiation [16,17], bioactivation of xenobiotics [18], inflammatory cells [19], increased cellular metabolism [20], decompartmentalisation of transition metal ions [21], activation of oxidases and oxygenases [22] and loss of antioxidant capacity [23,24]."

http://www.rbej.com/content/2/1/12

The previous study linked on EPHB2 may have seemed unrelated as it focused on the pain/spine link {which I find relevant...somites}, but here is another that tells of one relation to brain function if interested.

Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1435730/

Another extreme thought since this is in chicks tied to cadmium, but tells of effects that may relate to autism.

EphB2/B3 gene expression is down-regulated during early embryogenesis in the cadmium-induced omphalocele chick model.

http://www.ncbi.nlm.nih.gov/pubmed/22595573

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I gave the wrong address to a report in the last post. Here is the correct one.

Seroepidemiology of Mycoplasma pneumoniae infections in Iceland 1987-96.

http://www.ncbi.nlm.nih.gov/pubmed/9730307

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There are a lot of questions for new proposals like the Father's age contribution to risk. There is likely a degree of truth in the results as relating to risk, but the reaction in the media reports isw typical. They headline it as nearly the whole cause. Some groups sre being responsible in this regard. While some may not respect Autism Speaks I would urge that we look at all information and assess it for what it is, or may be worth. in addition the report they give on it is rational.

The fact genes are involved in Autism is a given even from the simple standpoint that they can be enviromentally effected by disease and chemcail/biological materials and processes. The real question is how much does inheiritance figure in, and also what are the real contribution and causes of mutations. Since I don't find the researchers have a firm grasp on the reasons for mutations, even though they may explain much of the process of it occuring. The report itself seems to be based on a cohort only from Iceland. Do other studies from cohorts from other countries match the mutation profile of aging fathers? Even if they do the possible contributuin is a minority of involvement from the proposal even though a small risk of any disease or condtion would likely accrue from these errors in dna from aging and I doubt anyone much questioned this idea.

They may or may not have any knowledge on "de novo mutations" in 40 year old Icelandic men from 1980 so are they sure that mutation rates have not been increasing since then due to enviromental factors that cause mutation increase in the process of aging? I doubt they have previous data or this would not be so "novel" in it's perceived importance.

The Autism Speaks report cites a gene that does fit in the scenario of effect I have developed, but that does not necessarily mean it came from the mutation of the father's sperm due to age old event happening in aging fathers. It may be more mutations in fathers as they age is occuring as of late.

Father’s Age Linked to Increased Genetic Mutations in Children

"The study provided another important finding. The researchers identified specific genes that were impacted by these mutations. “A striking finding is that two genes previously associated with autism, known as CUL3, and EPHB2, were also linked to autism in this study,” says Daniel Smith, Ph.D., Autism Speaks senior director of discovery neuroscience. This is an important step in confirming the association between these genes and autism. “We can use this finding to understand what happens in the brains of individuals with ASD, and in turn advance our ability to diagnose and treat autism,” says Dr. Smith.

“This is a large and very well controlled study that furthers the association of paternal age as a risk factor for autism,” says Dr. Smith. “But the findings suggest risk, not cause, and would-be parents should consult their healthcare providers for further guidance.”

"While the average age of parents has increased, parental age alone cannot account for the dramatic rise in autism prevalence that we’ve seen over time,” adds Rosanoff. Other factors contribute to the risk of autism, including environmental exposures and their interaction with genetics."

http://www.autismspeaks.org/science/science-news/father%E2%80%99s-age-linked-increased-genetic-mutations-children

As for the gene I referenced form thewir report. Here is one aspect of it's function in the machinery of Autism.

PI3K Contributed to Modulation of Spinal Nociceptive Information Related to ephrinBs/EphBs.

Abstract

"There is accumulating evidence to implicate the importance of EphBs receptors and ephrinBs ligands were involved in modulation of spinal nociceptive information. However, the downstream mechanisms that control this process are not well understood. In the present study, we investigated whether phosphatidylinositol 3-kinase (PI3K), as the downstream effectors, participates in modulation of spinal nociceptive information related to ephrinBs/EphBs. Intrathecal injection of ephrinB1-Fc produced a dose- and time-dependent thermal and mechanical hyperalgesia, accompanied by the increase of spinal PI3K-p110γ, phosphorylation of AKT (p-AKT) and c-Fos expression. Pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented activation of spinal AKT induced by ephrinB1-Fc. Inhibition of spinal PI3K signaling dose-dependently prevented and reversed pain behaviors and spinal c-Fos protein expression induced by intrathecal injection of ephrinB1-Fc. Inhibition of EphBs receptors by intrathecal injection of EphB1-Fc reduced formalin-induced inflammation and chronic constrictive injury-induced neuropathic pain behaviors accompanied by decreased expression of spinal PI3K,p-AKT and c-Fos protein. Furthermore, pre-treatment with PI3K inhibitor wortmannin or LY294002 prevented ephrinB1-Fc-induced ERK activation in spinal. These data demonstrated that PI3K and PI3K crosstalk to ERK signaling contributed to modulation of spinal nociceptive information related to ephrinBs/EphBs."

http://www.ncbi.nlm.nih.gov/pubmed/22879882

Also, there are other things that could be messing with the genes and as I have been focusing on Mycoplasma I would simply suggest you never know until you research something if it could be involved in an issue like mutations as I alludded to a few posts ago.

Mycoplasma pneumoniae infections.

http://www.ncbi.nlm.nih.gov/pubmed/11979130

Seroepidemiology of Mycoplasma pneumoniae infections in Iceland 1987-96.

http://www.ncbi.nlm.nih.gov/pubmed/11979130

Relationship between mycoplasma infection and germ cell sulfogalactosylglycerolipid.

http://www.ncbi.nlm.nih.gov/pubmed/15080072

The phospholipid profile of mycoplasmas.

http://www.ncbi.nlm.nih.gov/pubmed/22848839

General - Infections with Chlamydia & Mycoplasma damage sperm DNA!

http://www.southwestvasectomyreversal.com/news/detail/general-infections-with-chlamydia-mycoplasma-damage-sperm-dna/

Someones Thoughts on Mycoplasma...

MYCOPLASMA INFECTIONS

http://goulburn.net.au/~shackel/mycoplasma.htm

Related via oxidation, bronchitis, and mercury{used NAC to deal with likely metals}

A Powerful Antioxidant That Treats Autism, Diabetes, Bronchitis and Removes Heavy Metals

http://preventdisease.com/news/12/060712_A-Powerful-Antioxidant-That-Treats-Autism-Diabetes-Bronchitis-and-Removes-Heavy-Metals.shtml

[Visitor]

This is not specific to addressing the INF-G or particular immune syndrome, but it does provide a concept about how a vaccine approach or profile can alter immunity and precipitate susceptibility to infection and/or dysfunction if you think out possible consequnces of the result described in this report.

Risk of immunodeficiency virus infection may increase with vaccine-induced immune response.

Abstract

"To explore the efficacy of novel complementary prime-boost immunization regimens in a non-human primate model for HIV infection, rhesus monkeys primed by different DNA vaccines were boosted with virus-like particles (VLP) and then challenged by repeated low-dose rectal exposure to simian immunodeficiency virus (SIV). Characteristic for the cellular immune response after the VLP booster immunization were high numbers of SIV-specific, interferon-γ secreting cells after stimulation with inactivated SIV particles, but not SIV peptides, and the absence of detectable levels of CD8+ T cell responses. Antibodies specific to SIV Gag and SIV Env could be induced in all animals, but consistent with a poor neutralizing activity at the time of challenge, vaccinated monkeys were not protected from acquisition of infection and did not control viremia. Surprisingly, vaccinees with high numbers of SIV-specific, interferon-γ secreting cells were infected fastest during the repeated low-dose exposures and the numbers of these immune cells in vaccinated macaques correlated with susceptibility to infection. Thus, in the absence of protective antibodies or cytotoxic T cell responses, vaccine-induced immune responses may increase the susceptibility to acquisition of immunodeficiency virus infection. The results are consistent with the hypothesis that virus-specific T-helper cells mediate this detrimental effect and contribute to the inefficacy of past HIV vaccination attempts (e.g. STEP study)."

http://www.ncbi.nlm.nih.gov/pubmed/22811518

[Visitor]

It is not that my memory is bad, but there is too much to keep in mind over time concerning the many aspects of this condition. I went back to my old literature and was reminded this is stuff I already had read and researched, but the new things I have found clarify the relationship and importance of sulphation , IFN-G and many other related factors. This site brings together some of these things and though I had read these facts in previous articles previous to finding this site it is concise at explaining some relevant points. I focused more on teaching and working with my wife after a while and some the things that had been very important early on slipped into the shadows.

From the site:

"Autism: An Overview"

Written and Maintained by Lewis Mehl-Madrona, M.D., Ph.D.

"Gamma Interferon Theory

Dr. Vijendra Singh has found elevated levels of interleukin-12 and gamma interferon in autistic patients. Opioids can increase levels of gamma interferon.

[More information on this topic coming soon!]

[Return to "Quick-Index" of Theories of Autism]
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Free Sulphate Theory

Dr. Rosemary Waring has demonstrated low levels of free sulfate in the plasma of autistic people. Free sulfate homeostasis is regulated by reabsorption in renal tubules primarily. Opioids change sodium, bicarbonate, and chloride reabsorption in the kidney, but no work has been done on sulfate reabsorption.

Waring (1993) has demonstrated deficiencies in the sulphur-transferase capabilities of people with autism. This inadequacy is not the consequence of a missing enzyme (sulphur transferase) but of insufficient sulphate ions for the sulphation to be accomplished.

Sulphur transferase activity is important for many biological reactions in the body, some of which may be relevant to autism. These reactions include the breakdown of bilirubin and biliverdin, which are the breakdown products of haemoglobin; as well as the breakdown and removal of phenolic compounds. The tests used to estimate sulphur-transferase activity rely upon the conversion of paracetamol to its sulphate.

An inadequately functioning sulphur-transferase system will also affect the metabolism of some neurotransmitters. Serotonin (5-HT) metabolism will be affected, and the appearance of unusual metabolites (such as the hallucinogen bufotenin) could be predicted. Himwich (1972) has reported this, but the significance is uncertain.

Foods with high phenolic content should exacerbate symptoms since the overtax the available sulphur resources of the body. Anecdotal reports abound about the adverse effects of apples, oranges and other citrus fruits, chocolate (possibly on account of the phenol flavoring vanillin) and other phenolic foods on behavior in children with autism. Interestingly, two parents (who must remain anonymous). Cranberry juice has been anecdotally reported to reduce or even eliminate these effects. Whether this due to the sulphur content of the juice or some other mechanism including placebo remains to be determined.

Sulphate ions are not absorbed from the gut so this route is not a possibility for replenishment. The main source of free sulphate in the body is the amino acid "cysteine" which is obtained from the breakdown of protein. Some parents have attempted to combat this by feeding their children large doses of cysteine in tablet or powder form with mixed results reported. Other parents have introduced other sulphur containing amino-acids and claim this therapy beneficial. One of the sulphur containing amino-acids used for this purpose is "taurine," which is reported to have an anti-opioid effect (Braverman 1987).

Parents have also been experimenting with alternative routes of administration. One popular route is percutaneous, in which magnesium sulphate (Epsom Salts) are placed in the bath water in the hope that the sulphate will enter the body through the skin. Anecdotal benefits are claimed from this therapy, though increased irritability has also been reported.

Similar sulphate deficiencies have been reported in people with migraine, rheumatoid arthritis, jaundice and other allergic conditions all of which are anecdotally reported as common in the families of people with autism.

More information on Rosemary Waring’s work is available at the Autism, Intolerance & Allergy Network (AIA).

Dr. Robert Sinaiko has also written an interesting paper, The Biochemistry of Attentional/Behavioral Problems, in this area.

Also, see Paul Shattock's discussion of Waring's work, Back to The Future: An assessment of some of the unorthodox forms of biomedical intervention currently being applied to autism, at The Autism Research Unit's Website.

Sulfated glycosoaminoglycans are critical to the formation of the neuromuscular junction and the development of appropriate motor control and function.

[Return to "Quick-Index" of Theories of Autism]
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Other Sulfation Problems in Autism

®Sulfation problems have been described by Rosemary Waring at the University of Birmingham in autism which could lead to an inability to handle virus infections, with a disruption of cell-mediated immunity® as well as an impairment of natural killer cell function.® Unlike the situation with type I interferons, which are released by infected cells, interferon gamma (a type II interferon) is released by T lymphocytes and natural killer cells, but that happens not when they themselves have been activated, but rather, when they are alerted to the presence of infection by other immune cells or by a superantigen or a chemical mitogen.

Sulfate also plays an important role in initiating interferon gamma's signal.® [ Reference:® Benito A. Yard, Christian P. Lorentz, Dieter Herr, Fokko Van Der Woude.® Sulfation-dependent Down-Regulation of Interferon-gamma-induced Major Histocompatibility Complex I and II Intercellular Adhesion Molecule-1 Expression on Tubular and Endothelial Cells by Glycosaminoglycans.® Transplantation Vol.66(9), November 15, 1998, pp. 1244-1250]. Glycosaminoglycans (GAG) are sulfated sugars, involved with great deal of the action on the cell surface.® They also have activity in their "shed" form, where they act in the extracellular matrix, external to the cell.® All cells make GAGs, and shed GAGs continuously, but to properly assemble these sulfated GAGs, each cell has to be supplied with adequate sulfate, which is low in autism.® When these sugars are not sufficiently populated with sulfate, they will not behave normally, and their interaction with other chemistry can be hampered.® If sulfated GAGs are required for the proper action of interferon gamma, then a problem with sulfation may indeed be able to explain why so many autistic children have a hampered cell-mediated immunity and poor natural killer cell function.

Sulfated GAGs on the cell surface appear necessary for interferon gamma to generate a signal through its receptors on the cell surface.® More highly sulfated GAGs do indeed bind interferon and prevent it from binding to its receptors and generating its signal into the cell.® This varies in a dose-dependent manner.

Sulfated cell surface GAGs are required to dimerize, or assemble, two different components of receptors. Also, in the extracellular matrix around the cell, sulfated GAGs have been found to provide an escort for the GAG-binding chemical to get to the cell surface, actually protecting it from degradation as it wends its way to its cell-bound GAG/receptor complex.® Another example of this process is seen in chylomicron metabolism, where sulfated GAGs in most pathways are necessary for helping the cells in the liver to "eat" and process cholesterol-laden fatty particles.

There is another article from the May 1994 Scientific American: "How Interferons Fight Disease", by Howard M. Johnson et al., that gives a particularly valuable review of what a problem with the interferon gamma signal would be expected to produce.® Even though this article does not even mention GAGs, it does say that in order to activate its receptor, some part of the interferon gamma molecule which is coming from the outside of the cell has to associate with a part of its receptor that is actually underneath the cell membrane and in the cytosol, so the authors speculate that the whole complex has to at least be partially endocytosed (taken inside the cell) before this could happen.® That may be where these GAGs are functioning, as they are recognized in the liver also as being involved with the endocytosis of ligand/receptor complexes.

But, if this process were inhibited by poor sulfation what would be the consequences?

[Exerpts from the article in Scientific American]:
"Interferons activate pathways that cause cells to transcribe, or copy, certain genes into molecules of messenger RNA.® The RNA transcripts, in turn are translated into proteins that interfere with viral replication or produce other effects...

Interference with viral protein translation:

For example, one of the best-studied proteins (the eIF-2-alpha protein kinase) interferes with the cellular machinery that viruses exploit in order to reproduce themselves.® Viruses trick the protein-making machinery of host cells into translating viral messenger RNA into the proteins needed to make new infectious particles.® Messenger RNA, viral or otherwise, is translated by ribosomes.® These structures travel down the length of the RNA strand, linking one specified amino after another to a growing protein chain. First, however, each ribosome has to be built.® Several molecules join together to form the smaller of two ribosomal subunits, and then the larger subunit comes on board.

All three interferons can precipitate the production of the eIF-2-alpha protein kinase, the active form of which phosphorylates one component required for forming the smaller ribosomal unit.® Such phosphorylation blocks further construction of the subunit and thus stalls protein synthesis.® The newly made kinase becomes active only when it encounters double-stranded RNA.® Such RNA appears in a cell only when a virus replicates its genetic material.® Consequently, the enzyme blocks protein synthesis in infected cells but not in healthy ones.

Destruction of viral RNA:

Among other groups of proteins induced by both type I and type II interferons is the family consisting of the 2',5'-oligo (A) synthetases. These enzymes, too, interfere with the production of viral proteins, but they do so by activating enzymes that break down RNA before it can be translated into protein. ...

Enhancement of macrophage function:

Interferon gamma can induce macrophages to kill tumor cells and cells infected by parasites, bacteria or viruses.® It can also prod macrophages ot destroy pathogens that have colonized the scavengers themselves.® And interferon gamma stimulates macrophages to produce what are called class II MHC (major histocompatibility complex) molecules.® After macrophages ingest pathogens, they break up several of the microbes and fit the fragments into grooves on the MHC molecules, which are then transported to the cell surface.® There they display the antigenic fragments to what are called CD4 T cells.® (These lymphocytes can "see" antigens only if the foreign fragments are complexed with a class II MHC molecule.)® Having recognized particular antigens, the CD4 cells proliferate and release chemicals that help other immune system cells to fight off infection..

Interferon gamma...serves as a kind of immunologic switch.® The protein helps to turn on the cell-mediated arm of the immune system, consisting of macrophages, various kinds of T cells and other cells that respond to microbes inside the cells of other tissues.® At the same time, interferon gamma may dampen the production of antibodies.® Antibodies are better suited to eradicating pathogens that establish colonies outside of cells."

The article does not really talk about natural killer cells, but it would make sense if they are the other cell type besides macrophages that release interferon gamma, that their effectiveness would be greatly reduced if their signal from interferon was lost because of poor reception by the recipient cell.

All in all, these two articles go far in explaining the possible cause of the particular weaknesses we've found in some children's immune system with both poor cell-mediated immunity and impaired function of natural killer cells that go along with their sulfation problems."

http://www.healing-arts.org/children/autism-overview.htm

[Visitor]

I'll try to figure this out as it pertains to Mycoplasma and Autism related to NK cells and IFN-Gamma that I recently wrote about. Mercury may fit into this in an unusal way.

New Immune-Deficiency Illness Emerging in East Asia

"Investigators say they've identified an emerging immune-deficiency syndrome that is killing or sickening people in East Asia.

Although human immunodeficiency virus (HIV) is not linked to the illness, the illnesses appear similar to what people with HIV often get, say the team from the U.S. National Institutes of Health.

The new syndrome, which does not seem to pass from person to person, involves an immune-system antibody that blocks a molecule critical to fighting off infections and auto-immune diseases.

The antibody works against a common protective molecule called interferon-gamma (IFN-gamma), triggering immunodeficiency in some adults, the research team said.

People with the syndrome seem especially susceptible to infections caused by what are called opportunistic microbes, which can lie dormant in the body for years but are activated and multiply when the body's immune system is weakened. They're more likely to get diseases such as nontuberculous mycobacteria (NTM), a rare cousin to tuberculosis that can cause severe lung disease.

NTM and other opportunistic diseases often are seen in people with immune deficiency, but are rare in those with healthy immune systems. Researchers in countries such as Taiwan and Thailand have recently reported several cases of NTM in people with no history of immune-system problems.

"It's too soon to know the cause," said Dr. Sarah Browne, lead author of the study, which was published Aug. 23 in the New England Journal of Medicine. "The problem could be related to something genetic in people of Asian descent or it could be tied to environmental factors, but it's too early to know."

Browne, who is assistant clinical investigator at the U.S. National Institute of Allergy and Infectious Disease in Bethesda, Md., said although some people with the problem become extremely ill and may die, others experience a long-term, chronic disease that waxes and wanes. And although some are susceptible to infectious illnesses, others develop auto-immune diseases such as rheumatoid arthritis or lupus.

"This is a big, big finding," said Dr. Marc Siegel, associate professor of medicine at New York University Langone Medical Center in New York City.

"There's a sub-group of Asians that probably have a genetic abnormality that's making them susceptible to an auto-immune problem making antibodies to interferon," he explained. "This reemphasizes how important interferon is [to the immune system]. Basically, it stabilizes cells so viruses can't transmit from cell to cell, which obviously cuts down on viral infections."

Siegel boils it down to this: "When interferon is in trouble -- basically in this case because there are antibodies working against it -- opportunistic infections can spread."

Siegel explained how the threat posed by the IFN-gamma antibodies is different from that seen with HIV.

"In this case, the body is making antibodies against itself, and in HIV it's an actual viral infection," he said.

The study involved 203 participants from Thailand and Taiwan between the ages of 18 and 78; 52 had NTM infections, 45 had other opportunistic infections (some also with NTM co-infection), 58 had tuberculosis and 48 were healthy. All were HIV-negative. The researchers checked blood samples for antibodies and found 88 percent of the people with NTM or other opportunistic infections had antibodies that blocked their IFN-gamma.

The researchers noted that people with NTM or other opportunistic infections tended to be 50 years of age or older, suggesting that the syndrome might develop over time.

Browne pointed out that more patients with the antibody blockers may fall under the radar of local health officials because they respond positively to antibiotics and get better. "We're only seeing the ones who don't respond to antibiotics," she noted.

The challenge, Browne said, is to get a handle on what's causing the disease."

http://health.usnews.com/health-news/news/articles/2012/08/22/new-immune-deficiency-illness-emerging-in-east-asia

Löwenstein–Jensen medium {growth medium for Mycoplasma}

The usual composition[2] as applicable to Mycobacterium tuberculosis is:

Malachite green

Glycerol

Asparagine

Potato starch
Coagulated eggs
Mineral salt solution

Potassium dihydrogen phosphate

Magnesium sulfate

Sodium citrate

"Presence of glycerol enhances the growth of Mycobacterium tuberculosis...

For cultivation of M.bovis, glycerol is omitted and sodium pyruvate is added."

http://en.wikipedia.org/wiki/L%C3%B6wenstein-Jensen_medium

Pyruvic acid {pyruvate}

http://en.wikipedia.org/wiki/Pyruvate
Initial thoughts:
Mycoplasma like sulphate and Clostridia byproducts use sulphate. Mag is likely lowered or depleted by these. B6 inhibits PST and needs Mag as cofactor.
PST problems arise from depleted sulphate. Clostridia makes propionic acid{not news}. More on this hopefully.

[Visitor]

This is a good descritpion of what I have generally found to be happening in our case, and Mycoplasma and various triggers and enviromental factors conspire to cause or elevate the dysfunction. I had posted part of this concept last year.

Insulin signaling and autism

http://www.frontiersin.org/Cellular_Endocrinology/10.3389/fendo.2011.00054/full

Aslo effecting Pten via upregulation is apperntly able to help. Regulating immune function by gut and vascular/immune/brain and bringing about homeostasis is the goal as I have tried to put forth in this thread.

The Angiotensin aspect is important.

Angiotensin (1-7) Attenuates the Chronotropic Response to Angiotensin II via Stimulation of PTEN in the Spontaneously Hypertensive Rat Neurons

http://ajpheart.physiology.org/content/early/2011/12/20/ajpheart.00832.2011.abstract

[Visitor]

The metabolic issues are more primary and intrinsic in early Autism related to PTen. Insulin resistance may be brought about by diet, but it is predisposed or cuased early in many cases by no "lifestyle factors. The "dissosiative" disorders as well are not normally psychogenic they are neuronal effects prducing altered perception and cognitive proceses imo.

PTEN, a widely known negative regulator of insulin/PI3K signaling, positively regulates neuronal insulin resistance

Abstract

"Lipid and protein tyrosine phosphatase, PTEN, is a widely known negative regulator of insulin/PI3K signaling. Down regulation of PTEN is thus widely documented to ameliorate insulin resistance in peripheral tissues like skeletal muscle and adipose. However, not much is known about its exact role in neuronal insulin signaling and insulin resistance. Moreover, alterations of PTEN in neuronal systems has led to discovery of several unexpected outcomes including in neurodegenerative disorder, Alzheimer's disease (AD), which is increasingly being recognised as a brain-specific form of diabetes. Also, contrary to expectations its neuron-specific deletion in mice resulted in development of diet-sensitve obesity. Our present study reports that PTEN, paradoxically, positively regulates neuronal insulin signaling and glucose uptake. Its down-regulation exacerbates neuronal insulin resistance. The positive role of PTEN in neuronal insulin signaling is likely due to its protein phosphatase actions, which prevents the activation of FAK and ERK, the kinases critically involved in neuronal energy impairment and neurodegeneration. Results suggest that PTEN acting through FAK, the direct protein-substrate of PTEN, prevents ERK activation. Our findings provide explanation for unexpected outcomes earlier reported with PTEN alterations in neuronal systems and also propose a novel molecular pathway linking neuronal insulin resistance and AD, the two pathophysiological states that are being demonstrated to be closely interlinked."

http://www.molbiolcell.org/content/early/2012/08/06/mbc.E12-05-0337.abstract

[Visitor]

Regulation of T cell homeostasis and responses by pten.

Abstract

"The generation of lipid products catalyzed by PI3K is critical for normal T cell homeostasis and a productive immune response. PI3K can be activated in response to antigen receptor, co-stimulatory, cytokine, and chemokine signals. Moreover, dysregulation of this pathway frequently occurs in T cell lymphomas and is implicated in lymphoproliferative autoimmune disease. Akt acts as a central mediator of PI3K signals, downstream of which is the mTOR pathway, controlling cell growth and metabolism. Members of the Foxo family of transcription factors are also regulated by Akt, thus linking control over homing and migration of T cells, as well cell cycle entry, apoptosis, and DNA damage and oxidative stress responses, to PI3K signaling. PTEN, first identified as a tumor suppressor gene, encodes a lipid phosphatase that, by catalyzing the reverse of the PI3K "reaction," directly opposes PI3K signaling. However, PTEN may have other functions as well, and recent reports have suggested roles for PTEN as a tumor suppressor independent of its effects on PI3K signaling. Through the use of models in which Pten is deleted specifically in T cells, it is becoming increasingly clear that control over autoimmunity and lymphomagenesis by PTEN involves multi-faceted functions of this molecule at multiple stages within the T cell compartment."

http://www.ncbi.nlm.nih.gov/pubmed/22715338

[Visitor]

Well...

Inhibition of Mycobacterial Infection by the Tumor Suppressor PTEN.

Abstract

"The tumor suppressor PTEN is a lipid phosphatase that is frequently mutated in various human cancers. PTEN suppresses tumor cell proliferation, survival, and growth mainly by inhibiting the PI3K-Akt signaling pathway through dephosphorylation of phosphatidylinositol 3,4,5-triphosphate. In addition to it role in tumor suppression, the PTEN-PI3K pathway controls many cellular functions, some of which may be important for cellular resistance to infection. Currently, the intersection between tumorigenic signaling pathways and cellular susceptibility to infection is not well defined. In this study we report that PTEN signaling regulates infection of both noncancerous and cancerous cells by multiple intracellular mycobacterial pathogens and that pharmacological modulation of PTEN signaling can affect mycobacterial infection. We found that PTEN deficiency renders multiple types of cells hyper-susceptible to infection by Mycoplasma and Mycobacterium bovis Bacillus Calmette-Guérin (BCG). The lipid phosphatase activity of PTEN is required for attenuating infection. Furthermore, we found mycobacterial infection activates host cell Akt phosphorylation, and pharmacological inhibition of Akt or PI3K activity reduced levels of intracellular infection. Intriguingly, inhibition of mTOR, one of the downstream components of the Akt signaling and a promising cancer therapeutic target, also lowered intracellular Bacillus Calmette-Guérin levels in mammary epithelial cancer MCF-7 cells. These findings demonstrate a critical role of PTEN-regulated pathways in pathogen infection. The relationship of PTEN-PI3K-Akt mTOR status and susceptibility to mycobacterial infection suggests that the interaction of mycobacterial pathogens with cancer cells may be influenced by genetic alterations in the tumor cells."

http://www.ncbi.nlm.nih.gov/pubmed/22613768

[Visitor]

Using optogenetics to translate the "inflammatory dialogue" between heart and brain in the context of stress.

Abstract

"Inflammatory processes are an integral part of the stress response and are likely to result from a programmed adaptation that is vital to the organism's survival and well-being. The whole inflammatory response is mediated by largely overlapping circuits in the limbic forebrain, hypothalamus and brainstem, but is also under the control of the neuroendocrine and autonomic nervous systems. Genetically predisposed individuals who fail to tune the respective contributions of the two systems in accordance with stressor modality and intensity after adverse experiences can be at risk for stress-related psychiatric disorders and cardiovascular diseases. Altered glucocorticoid (GC) homeostasis due to GC resistance leads to the failure of neural and negative feedback regulation of the hypothalamic-pituitary-adrenal axis during chronic inflammation, and this might be the mechanism underlying the ensuing brain and heart diseases and the high prevalence of co-morbidity between the two systems. By the combined use of light and genetically-encoded light-sensitive proteins, optogenetics allows cell-type-specific, fast (millisecond-scale) control of precisely defined events in biological systems. This method is an important breakthrough to explore the causality between neural activity patterns and behavioral profiles relevant to anxiety, depression, autism and schizophrenia. Optogenetics also helps to understand the "inflammatory dialogue", the inflammatory processes in psychiatric disorders and cardiovascular diseases, shared by heart and brain in the context of stress."

http://www.ncbi.nlm.nih.gov/pubmed/22833041

In regard to the former how about hypoxia in the womb or an autoimmune attack or other enviromental assault/trigger as "adverse experiences"? Everyone will have an adverse event, so it will be axiomatic if psychological stress is going to cause it.

Antiinflammatory Treatment Ameliorates HPA Stress Axis Dysfunction in a Mouse Model of Stress Sensitivity.

Abstract

"Dysregulated stress responsivity is a hallmark of neuropsychiatric disease. The regulation of stress activation and recovery involves tight coordination between neuronal and glial networks. At a certain threshold of sensitivity, stress exposure can evoke a neuroimmune response. Astrocytes are potential mediators of these effects because they are able to respond to neuroimmune effector molecules and regulate neuronal activity. Mice deficient in corticotropin-releasing factor receptor-2 display increased stress sensitivity and are therefore a useful model in which to examine the intersection of neuroimmune activation and stress pathway dysregulation. We hypothesized that a component of elevated stress reactivity may involve an engagement of neuroimmune effectors, including astrocytes. Therefore, we hypothesized that this phenotype may be rescued by concomitant nonsteroidal antiinflammatory drug (NSAID) treatment. To examine this, mice exposed to chronic stress were treated with NSAID in their drinking water, and changes in hypothalamic-pituitary-adrenal stress axis function were examined. As a correlate of altered astrocyte function, levels of glial fibrillary acidic protein were measured. Supportive of our hypothesis, NSAID treatment rescued the hypothalamic-pituitary-adrenal stress axis dysfunction in stress-sensitive corticotropin-releasing factor receptor-2(-/-) mice and also reversed the stress-induced increase in glial fibrillary acidic protein in stress-regulating brain regions including the paraventricular nucleus of the hypothalamus, ventral hippocampus, and prefrontal cortex. These findings support the local involvement of astrocytes in the exacerbation of stress pathway dysregulation. The specificity of these effects in a stress-sensitive genotype highlights the importance of utilizing a model of stress dysregulation in the examination of factors that may translate to neuropsychiatric disease."

http://www.ncbi.nlm.nih.gov/pubmed/22893724

[Visitor]

IGF-1 suspected involvement is not new, but the last post and new info shows more of how it is involved. Also, it may be too much or too little of IGF-1 causing the problems. Here are a few more things.

Wiki - IGF-1

"In rat experiments the amount of IGF-1 mRNA in the liver was positively associated with dietary casein and negatively associated with a protein-free diet..."

Insulin-like growth factor 1 receptor (IGF-1R) and other tyrosine kinase growth factor receptors signal through multiple pathways. A key pathway is regulated by phosphatidylinositol-3 kinase (PI3K) and its downstream partner, the mammalian target of rapamycin (mTOR). Rapamycins complex with FKBPP12 to inhibit the mTORC1 complex. mTORC2 remains unaffected and responds by upregulating Akt, driving signals through the inhibited mTORC1. Phosphorylation of eukaryotic initiation factor 4e (eif-4E) [4EBP] by mTOR inhibits the capacity of 4EBP to inhibit eif-4E and slow metabolism....

Factors that are known to cause variation in the levels of growth hormone (GH) and IGF-1 in the circulation include: genetic make-up, the time of day, age, sex, exercise status, stress levels, nutrition level and body mass index (BMI), disease state, race, estrogen status and xenobiotic intake.[18] The later inclusion of xenobiotic intake as a factor influencing GH-IGF status highlights the fact that the GH-IGF axis is a potential target for certain endocrine disrupting chemicals - see also endocrine disruptor."

http://en.wikipedia.org/wiki/IGF-1

Effects of Mercury on Methionine Synthase: Implications for Disordered Methylation in Autism

http://legacy.autism.com/medical/research/deth.htm

Possible Treatment For Neurological Disorder Rett Syndrome -- Most Common Basis Of Autism In Girls

http://www.sciencedaily.com/releases/2009/02/090209205047.htm

Milk and Other Dairy Products

Should we be concerned about recombinant bovine growth hormone?

"Known as rBGH, this is a genetically engineered hormone that some dairy farmers inject into cows to increase milk production. It causes udder infections in cows (known as mastitis), which necessitate increased use of antibiotics, and there is also evidence that rBGH promotes tumor growth in laboratory animals. In addition, rBGH significantly stimulates a cow's production of another hormone that's secreted in milk, insulin growth factor-1 (IGF-1), which has been linked with breast cancer. Our bodies already manufacture IGF-1; when we consume dairy products that contain IGF-1, it appears that we're overdosing ourselves with a hormone that prompts cells in our body to multiply-possibly even including cancer cells.

Last May, Susan Hankinson, Sc.D., published a sobering report in the Lancet about the relationship between IGF-1 levels and breast cancer. Dr. Hankinson had blood samples from thousands of woman enrolled in the Nurses' Health Study in 1989-90. Tests showed that those women with high IGF-1 levels in their blood had up to five times the risk of developing breast cancer than those with low IGF-levels."

http://www.autismndi.com/news/display.asp?content=Resources&shownews=20040802120405

[Visitor]

Olmesartan downregulates TGF-B
TGF-B Downregulates PTEN
Inhibin is a member of TGF-B family

Theory on autism challenged

"Otago anatomy department researchers have discovered variations within normal-range levels of anti-Mullerian hormone (AMH) and inhibin B (InhB) are linked with the severity of symptoms in boys with autism spectrum disorders (ASDs).

However, among boys with an ASD, those with high InhB levels tended to have worse symptoms than those with low levels.

ASD boys with high AMH levels tended to have fewer symptoms."

http://www.odt.co.nz/news/dunedin/221648/theory-autism-challenged

Wiki - Activin and inhibin

"Activin and inhibin are two closely related protein complexes that have almost directly opposite biological effects. Activin enhances FSH biosynthesis and secretion, and participates in the regulation of the menstrual cycle. Many other functions have been found to be exerted by activin, including roles in cell proliferation, differentiation, apoptosis,[1] metabolism, homeostasis, immune response, wound repair,[2] and endocrine function. Conversely inhibin down regulates FSH synthesis and inhibits FSH secretion.[3]

Activin is a dimer composed of two identical or very similar beta subunits. Inhibin is also a dimer wherein the first component is a beta subunit similar or identical to the beta subunit in activin. However, in contrast to activin, the second component of the inhibin dimer is a more distantly-related alpha subunit.[4][5] Activin, inhibin and a number of other structurally related proteins such as anti-Müllerian hormone, bone morphogenetic protein, and growth differentiation factor belong to the TGF-β protein superfamily.[6]"

Lack of activin during development results in neural developmental defects.

[edit] Inhibin

In both females and males, inhibin inhibits FSH production and GnRH release[citation needed] from the hypothalamus. However, the overall mechanism differs between the sexes:

[edit] In females

Inhibin is produced in the gonads, pituitary gland, placenta, corpus luteum and other organs.

FSH stimulates the secretion of inhibin from the granulosa cells of the ovarian follicles in the ovaries. In turn, inhibin suppresses FSH.
Inhibin B reaches a peak in the early- to mid-follicular phase, and a second peak at ovulation.
Inhibin A reaches its peak in the mid-luteal phase.

Inhibin secretion is diminished by GnRH, and enhanced by insulin-like growth factor-1 (IGF-1)."

http://en.wikipedia.org/wiki/Activin_and_inhibin

Factors Involved Via Inhibin

Follicle-stimulating hormone

"The gene for the FSH beta subunit is located on chromosome 11p13, and is expressed in gonadotropes of the pituitary cells, controlled by GnRH, inhibited by inhibin, and enhanced by activin."

http://en.wikipedia.org/wiki/Follicle-stimulating_hormone

Gonadotropin-releasing hormone

"The GnRH neurons are regulated by many different afferent neurons, using several different transmitters (including norepinephrine, GABA, glutamate). For instance, dopamine appears to stimulate LH release (through GnRH) in estrogen-progesterone-primed females; dopamine may inhibit LH release in ovariectomized females.[2] Kisspeptin appears to be an important regulator of GnRH release.[3] GnRH release can also be regulated by estrogen. It has been reported that there are kisspeptin-producing neurons that also express estrogen receptor alpha.

http://en.wikipedia.org/wiki/GnRH

[Visitor]

A hodgepodge of thoughts.

When and how the gene expression/mutation/epigenetic changes occur and which of these mechanisms of disruption might be involved is crucial to understanding causation and ways to reverse the effects fully. Narrowing down the most likely central genes involved is a challenge and being confident in what is happening in the genes or to the genes is still an unknown to me. The most difficult factor to discern is the role and reality of mutations, at least in the majority of cases. If the researchers are correct mutations are clearly causing the problems in a small percentage of cases.

Some mutations appear to be a part of some susceptibility overall. Yet, we all have some mutations that may never cause any functional problems, but may be problematic under certain environmental conditions.

Some may infer my citing this PTEN gene factor as laying the cause of autism mainly or solely on genetic inheritance. That is not the case though the jury is out on exactly what is happening. The process of dysfunction could come through multiple routes and/or in synergy.

Dr. Trevor Marshall suggests that the testing of genes described as mutations is actually the result of pathogens messing with gene assembly.

He just wrote:

"The final few slides in my St Petersburg presentation explain how the Genetic testing being done these days is subject to very significant errors. I stated that many, perhaps most, of these "mutations" or "haplotypes" or whatever are just artifacts of microbes affecting the assembly of the human genome."

http://www.marshallprotocol.com/forum39/14033-4.html

I have tried to discover the mutation angle as a large increase in mutations would require a mutagen it seems or distrubance in oxygen and nutrients leading to mutations. If he is correct the pathogens {bacteria mainly} are involved from the start and the parents could even be affected at some level with these pathogens at the time of the conception of their children or in the gestation period of the offspring at least. The Mycoplasma
could therefore plausibly be a major reason for the increase in many diseases. But they might also be a later contributor depending on each case. This puts the Pten gene function and other genes in question as put forward as related to Autism as environmentally disturbed and not inheritance defects. Other factors can effect gene expression and this further complicates the matter.

The UC Davis Mind release mentions that a PTEN gene defect has been found in Autism and explains how "abnormal action" of this gene causes behavior found in Autism. It is fair to conclude a gene defect can and will do this, but the jump should not be made out of hand that because a gene defect like this has been shown to produce Autism and one can explain the effect of this abnormal action that it is inherited or that that it is a "mutation" as currently defined. The intentional knockout of a gene in mice does not necessarily reflect how the same gene involved in a human problem is disrupted.

The function of the PTEN gene, or others, being faulty, may reflect environmental damage through trophoblast death leading indeed to a mutation. It might be as Dr. Marshall suggests, an effect of certain bacteria Or it it could be abnormally functioning due to ATF2 transgenerational effects, other epigenetic effects, or a combination of any of these mechanisms.

The effect of Mycoplasma in altering the gene function deserves a look as well as the effects of metals and drugs that may affect gene function. This would include SSR's, Carbmazepine, and Isoniazid. Pesticides and endocrine disruptors make the list too.

So, seeing the involvement of a gene does not diminish environmental factors and vaccines, it just makes it hard to determine what role each alone or together may be playing.

I mentioned B6 for mooring sickness and the possible role of too much or too little B6 might be playing inutero. I would add that my wife's mother took the B6/antihistamine compound when carrying her due to nausea, my wife did not with our two children and they are not affected. That is just an anecdotal point I wished to make and I can't conclude much from it. Still it does match a tentative association of action.

More about PTEN and other things mentioned in this thread as they relate to PTEN

Pancreas-specific Pten deficiency causes partial resistance to diabetes and elevated hepatic AKT signaling

"eIF3, an important factor recruited to ER-bound ribosome for translation initiation 38, showed decreased levels in the liver of PPKO mice. The second group consists of three mitochondrial proteins: carbamoyl phosphate synthase (CPS), dehydrogenase/reductase SDR (short-chain dehydrogenases/reductases) family member 1 (DHRS1), and mitochondrial fission 1 protein (FIS1). CPS and DHRS1, both important in the urea cycle 39, showed increased levels in the liver of PPKO mice, while FIS1, functional in mitochondrial fission and apoptosis 40, displayed a modestly decreased level in PPKO mice.

Serum amylase, which is secreted by acinar cells, increased dramatically in the PPKO mice. We also examined amino metabolism-related indexes, and found blood urea nitrogen (BUN) increased markedly in PPKO mice,...

On the other hand, our results demonstrated that PPKO mice had altered amino metabolism. Dramatic increased level of CPS (Figure 4C), a critical enzyme in the urea cycle, in the liver was consistent with increased blood urea levels in PPKO mice (Table 1). This increased BUN could be partly due to increased serum amylase in PPKO mice, since increased serum amylase was reported to be associated with increased nitrogen loss 48.

Altogether, we have found novel responses of the liver to pancreatic PPKO: elevated AKT signaling, decreased GRP78, and increased CPS."

http://www.nature.com/cr/journal/v19/n6/full/cr200942a.html

You may have read in this thread about increased Amylase and also about altered Nitrogen metabolism in Autism.

The last report mentioned increased CPS in PTEN knockout.

Wiki - Carbamoyl phosphate synthetase

http://en.wikipedia.org/wiki/Carbamoyl_phosphate_synthetase
My wife was found to be insulin resistant, but never went on to Diabetes. I imagine she has been insulin resistant all of her life.

Valuable Further Reading

PTEN phosphatase and tensin homolog

http://www.genecards.org/cgi-bin/carddisp.pl?gene=PTEN&search=pten

New insights into PTEN

http://jcs.biologists.org/content/120/23/4071.full

[Visitor]

Olmesartan downregulates TGF-B.

Suppressed immune systems make infants fall sick too often

"Blocking of key cell signals could prevent infants from falling sick too often, researchers claim.

University of Michigan Health System researchers have found that by blocking the transforming growth factor-Beta (TGF-B) cells, which prevents the growth of essential immune cells, can make infants less prone to viral infections.

"What happens at early age is that natural killer cells, like many other immune cells, do not complete their functional maturation until adulthood," senior author Yasmina Laouar said.

"During this time we are left with an immature immune system that cannot protect us against infections, the reason why newborns and infants are more prone to infection," she added.

There is a large gap in understanding infant immunity, specifically why the natural killer cell responses are deficient.

"Our overall goal was to determine the factors that constraint the production and maturation of natural killer cells early in life," says Laouar.

The study showed the production of natural killer cells is controlled by TGF-Beta, which is produced in the bone marrow.

In infant mice, the maturation of natural killer cells progressed faster in the absence of TGF-Beta signalling. By adulthood, mice had 10 times more mature natural killer cells if TGF-Beta signalling was blocked.

"Our overall goal was to determine the factors that constraint the production and maturation of natural killer cells early in life," says Laouar, adding "To our surprise, we discovered that natural killer cells can complete maturation as early as 10 days of age if TGF-Beta signalling is blocked."

Authors say it's tempting to propose the functional inactivation TGF-Beta signalling as a strategy to reverse the deficit of natural killer cells early in life."

http://www.moneycontrol.com/news/health/suppressed-immune-systems-make-infants-fall-sick-too-often_743914.html

NK cells also deal with more than viruses though, also the Mycoplasma.

[Visitor]

Protein proves to be vital in immune response to bacteria

"ISG15 is a protein involved in a cascade of protein-cell interactions that help drive the immune system to eliminate a pathogen from the body. In studies spanning two and a half years, Bogunovic and colleagues worked out the protein’s function. They found it was secreted by granulocytes, a type of white blood cell, and that it prompted another white blood cell, called a natural killer cell, to release interferon-gamma, a protein crucial to fighting mycobacterial infections."

http://newswire.rockefeller.edu/2012/08/10/protein-found-to-be-vital-in-immune-response-to-bacteria/

Immunoregulatory properties of ISG15, an interferon-induced cytokine.

Abstract

"ISG15 is a 15-kDa protein of unique primary amino acid sequence, which is transcriptionally regulated by interferon (IFN) alpha and IFN-beta. Because it is synthesized in many cell types and secreted from human monocytes and lymphocytes, we postulated that ISG15 might act to modulate immune cell function. ISG15 stimulated B-depleted lymphocyte proliferation in a dose-dependent manner with significant proliferation induced by amounts of ISG15 as low as 1 ng/ml (58 pM). Maximal stimulation of [3H]thymidine incorporation by B-depleted lymphocytes occurred at 6-7 days. Immunophenotyping of ISG15-treated B-depleted lymphocyte cultures indicated a 26-fold expansion of natural killer (NK) cells (CD56+). In cytotoxicity assays, ISG15 was a potent inducer of cytolytic activity directed against both K562 (100 lytic units per 10(6) cells) and Daudi (80 lytic units per 10(6) cells) tumor cell targets, indicating that ISG15 enhanced lymphokine-activated killer-like activity. ISG15-induced NK cell proliferation required coculturing of T and NK cells, suggesting that soluble factor(s) were required. Measurement of ISG15-treated cell culture supernatants for cytokines indicated production of IFN-gamma (> 700 units/ml). No interleukin 2 or interleukin 12 was detected. IFN-gamma itself failed to stimulate lymphocyte proliferation and lymphokine-activated killer cell activation. Further, induced expression of IFN-gamma mRNA was detected by reverse transcription-PCR in T lymphocytes after ISG15 treatment but not in NK cells. Enhancement of NK cell proliferation, augmentation of non-major histocompatibility complex-restricted cytotoxicity, and induction of IFN-gamma from T cells identify ISG15 as a member of the cytokine cascade and suggest that it may be responsible for amplifying and directing some of the immunomodulatory effects of IFN-alpha or IFN-beta."

http://www.ncbi.nlm.nih.gov/pubmed/8552607

[Visitor]

This is in agreement with what I have found in our case. Pten

Research shows gene defect's role in autism-like behavior

"Scientists affiliated with the UC Davis MIND Institute have discovered how a defective gene causes brain changes that lead to the atypical social behavior characteristic of autism. The research offers a potential target for drugs to treat the condition.

Earlier research already has shown that the gene is defective in children with autism, but its effect on neurons in the brain was not known. The new studies in mice show that abnormal action of just this one gene disrupted energy use in neurons. The harmful changes were coupled with antisocial and prolonged repetitive behavior -- traits found in autism.

The research is published online today in the scientific journal PLoS ONE.

"A number of genes and environmental factors have been shown to be involved in autism, but this study points to a mechanism -- how one gene defect may trigger this type of neurological behavior," said study senior author Cecilia Giulivi, professor of molecular biosciences in the UC Davis School of Veterinary Medicine and a researcher affiliated with the UC Davis MIND Institute.

"Once you understand the mechanism, that opens the way for developing drugs to treat the condition," she said.

The defective gene appears to disrupt neurons' use of energy, Giulivi said, the critical process that relies on the cell's molecular energy factories called mitochondria.

In the research, a gene called pten was tweaked in the mice so that neurons lacked the normal amount of pten's protein. The scientists detected malfunctioning mitochondria in the mice as early as 4 to 6 weeks after birth.

By 20 to 29 weeks, DNA damage in the mitochondria and disruption of their function had increased dramatically. At this time the mice began to avoid contact with their litter mates and engage in repetitive grooming behavior. Mice without the single gene change exhibited neither the mitochondria malfunctions nor the behavioral problems.

The antisocial behavior was most pronounced in the mice at an age comparable in humans to the early teenage years, when schizophrenia and other behavioral disorders become most apparent, Giulivi said.

The research showed that, when defective, pten's protein interacts with the protein of a second gene known as p53 to dampen energy production in neurons. This severe stress leads to a spike in harmful mitochondrial DNA changes and abnormal levels of energy production in the cerebellum and hippocampus -- brain regions critical for social behavior and cognition.

Pten mutations previously have been linked to Alzheimer's disease as well as a spectrum of autism disorders. The new research shows that when pten protein was insufficient, its interaction with p53 triggered deficiencies and defects in other proteins that also have been found in patients with learning disabilities including autism."

http://www.sciencecodex.com/research_shows_gene_defects_role_in_autismlike_behavior-96402

[Visitor]

In the last "further reading" article you will find this:

“In addition to steroids, other therapies, including plasmapheresis, plasma exchange and intravenous IgG, have been used to treat patients with severe CNS complications. None of these strategies has been tested in randomised double-blind clinical trials, and their benefit therefore remains unclear. Plasmapheresis was reported to be effective in cases of transverse myelitis or polyradiculitis [60]. Despite the absence of evidence, it seems reasonable to consider the use of immunomodulatory therapies, together with antibiotics, in severe cases."

http://onlinelibrary.wiley.com/doi/10.1111/j.1469-0691.2007.01834.x/full

The antibiotics in those less affected might reverse the problem enough in early stages to allow the immune system to get on track, but gut alterations are of concern and the long term outcome is unsure. It may stall the problem for a bit and return as the bacterial issues return. The steroids may halt inflammation, but facilitate bacterial PERSISTANCE.

Olmesartan taken long term per the Marshall Protocol is conceived to deal with the infestation of these bacteria in the cells by unblocking and activating the VDR to help in the clearance of this type of bacteria. We made great progress with the biomed approach, but it appears were never able to get this type bacteria under good control as mental effects and bodily problems like tonsil inflammation, arthritis, fatigue, and strong allergies persisted to some degree. Her bone spur pain remitted as well as a major reduction in her Arthritis have occurred and seem to continue fade. I would guess that at least 20-30 percent of her mental function ability has come because of the Olmesartan, yet without the biomed/diet I don't think the Olmesartan would have been that effective as the bacteria are not the only problem in these conditions. Olmesartan does reduce inflammation and bacterial loads overtime, but restoring gut health is a must in those with gut issues. The gut/brain restoration is reciprocal.

[Visitor]

For any interested this pertains to a matter in another new thread at AoA. I don't wish to insert myself, but have been down that road and broadly reducing autoimmune/dysregulated immunity is a more beneficial approach. Just in case it may help here are some thoughts.

I posted this last year in another thread at AoA.

"My wife had chronic bronchitis and this could have been related to an l-form reversion to Mycoplasma Pneumoniae also finding expression due to her immune suppression/deregulation."

WHAT IS MYCOPLASMA?

"Mycoplasmas are the smallest and simplest organism known. They are not new. They were discovered over 100 years ago and evolved from bacteria. The "garden variety" mycoplasma is not usually associated with severe diseases. (13) However, sometime over the past 30 years, the organism has been altered to become more lethal. The Mycoplasmas found by the Nicolson’s, in their lab, contain unusual gene sequences that were probably inserted into the Mycoplasma by a specific laboratory procedure. This discovery has led them to conclude that the new forms of mycoplasma were specifically engineered for germ warfare. (9) In it’s laboratory evolution, the Mycoplasmas have became more invasive, more difficult to find, and capable of causing severe diseases in humans. Diseases, like Gulf War Illness, CFS, FMS, MCS, Rheumatoid Arthritis, and AIDS, for instance.

The earlier form of Mycoplasma was studied by Dr. Shyh Lo, formerly of Tanox Biosystems, a spin-off biotechnology company from the Baylor College of Medicine, but now affiliated with the Armed Forces Institute of Pathology in Washington D.C. Dr. Lo has been credited with discovering the new pathogenic form of Mycoplasmas, and he currently holds several patents on methods for special handling of the organisms for study and development. (10) In one of his patents (in 1991), Dr. Lo lists the following diseases that are caused by Mycoplasma: HIV infection, AIDS, Aids Related Complex (ARC), Chronic Fatigue Syndrome, Wegener’s Disease, Sarcoidosis, Respiratory Distress Syndrome, Kibuchi’s Disease, Alzheimer’s Disease, and Lupus. (10) In addition, Baseman and Tully have reviewed the literature on the role of Mycoplasmal infections in human disease and have concluded that they are important factors or co-factors in a variety of chronic illnesses. (11)

Unlike bacteria, the Mycoplasma has no cell wall. This enables it to invade tissue cells, incorporating the cell's nutrients, and using the cell to replicate itself (much like a retrovirus). (13) When the Mycoplasma breaks out of the cell, it takes a piece of the host cell membrane with it. When the immune system attacks the Mycoplasma, it also gets "turned on" to attacking the host cell. In this way, an autoimmune condition can begin. Autoimmune conditions associated with Mycoplasmas include arthritis, Fibromyalgia, myositis, thyroid dysfunction (Hashimoto’s or Grave’s Diseases), and adrenal dysfunction, signs and symptoms of Lupus, Multiple Sclerosis, and Lou Gehrig’s Disease. (12)

The Mycoplasma organism has the capacity to invade cells, tissues and blood, producing systemic infections in numerous organ systems. According to Dr. Nicholson, it can penetrate the central and peripheral nervous system. Because it has the ability to damage the immune system by invading the natural killer cells (NK cells) of the lymphocytes, it weakens them, reduces their numbers, and renders them susceptible to viral infections, such as Human Herpes Virus 6 (HHV6), HHV7 or HHV8. (14) (15) (16) It may also explain some of the environmentally sensitive responses that are seen with CFIDS and MCS.

Mycoplasma infection can trigger inflammatory cytokine over-production that is commonly seen in CFS/FMS. With the induction of CD-4+ helper cells of the immune system, an over production of cytokines such as Interleukin-1, Interleukin-6 and Tumor Necrosis Factor-alpha occurs. (15)(16)(17) These elevated cytokines have been implicated in the development of many of the CFS/FMS symptoms, including neurological involvement. (19)(20) They can have specific or nonspecific stimulatory or suppressive effects on lymphocytes, as measured by B and T cell activation. (18) In addition, the Mycoplasma infection has immunomodulating effects, activating the hypothalmic-pituitary-adrenal axis. This can cause a cascade of limbic system symptoms characteristic of CFS/FMS. (19)"

http://www.chelationtherapyonline.com/anatomy/p111.htm

IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis.

http://www.ncbi.nlm.nih.gov/pubmed/20944000

MP Pathology in Detail
Pathology is complex for M. pneumonia, other Mycoplasmas (M. hominis, fermentans, et al), and other persistent, obligate microbes. The first order symptomology of MP is pneumonia, bronchitis and COPD. Since MP is persistent, COPD is episodic. Since the human herd is near 100% infected by Chlamydia pneumoniae, and RSV (respiratory syncytial virus) the other persistent microbes can all work together to infiltrate immune cells, to suppress immune system functions and to infect/invade blood and epithelial cells in various other parts of the body.
A wide spectrum of rheumatic conditions are linked to MP as a co-factor,

Alzheimer’s disease, Amyotrophic Lateral Sclerosis (ALS), Arthritis Asthma, Arterial sclerosis, Atypical pneumonia, Bronchitis, Cardiovascular diseases, CFS/CFIDS, Crohn’s diseases, COPD, fibromyalgia syndrome (FMS), Interstitial cystitis, Leukemia, Lymphoma, Lupus (SLE), Multiple sclerosis (MS), Pelvic inflammatory disease (PID), Psoriasis, Scleroderma, Solid (&lung) cancers, Sjogren’s syndrome,.

Mycoplasmas can change in nerve conduction, demyelation (a degenerative process that erodes away the myelin sheath that normally protects nerve fibers) and sensitivity.

Mycoplasmas can also disrupt the host’s immune system. They can stimulate lymphocytes to secrete inflammatory cytokines, which lead to inflammation and both stimulation and/or suppression of the immune system.

Mycoplasmas leaving an infected cell incorporate host’s cell surface material into their own surface structure, they can instigate an autoimmune response. Meanwhile the emerging mycoplasmas can evade the immune system by hiding inside host cells or fusing with the host cellular membranes.

Pathogenic mycoplasmas can also invade lymphocytes and disrupt their functioning, provoking defective immune responses. Using molecular mimicry, mycoplasmas can even closely replicate host cells’ surface structures to resemble normal host cells.

After invading host cells, mycoplasmas can trigger the release of reactive oxygen free-radicals (ROS) that modify the RNA and DNA of the cells, leading to malignant cellular transformations without apoptosis. Benign (non-cancerous) cells infected by mycoplasmas became irreversibly malignant (cancerous) after 18 cell divisions.

Drs. Nicolson, See and Akbarpour, of the Immune Institute in Huntington Beach found ~90% of certain late stage cancer patients have mycoplasma infections. Mycoplasmas increase the progression growth rate of cancer cells.

Mycoplasmas can also invade the epithelial lining of blood vessels, where they appear to facilitate the release of molecules that can cause vasculitis (inflammation) and the formation of plaque inside blood vessel wall surfaces. In the absence/shortage of protecting vitamin C and Lysine See Pauling Case History.

Mycoplasmas Shape Change to multiple forms:

Mycoplasmas and other persistent microbes are equipped to change shapes and form, appearing then disappearing, changing shape, shuffling their surface elements, invade host cells, then hang out as normal flora coated with molecules taken from the cells they invaded. They even have protective forms to defeat antibiotics and some can shift to this form in a few short minutes as seen in vitro under a microscope. Pulsing the antibiotic can multiply-attrite the shape-changing microbes, but this pulsing protocol is not widely followed. It should be.

MP are pleomorphic (structurally changing). In place of rigid cell walls, they have flexible lipid (water insoluble fat) outer surfaces. Like amoebas they bend and move, squeezing into tight spaces. They are so small they slide through laboratory and hospital filters used to produce or maintain bacterial sterility -- making them one of the most common contaminants in diagnostic laboratories and vaccine manufacturing.

Mycoplasmas Contaminate other Vaccines:

They grow in the same live cell media used to grow virus vaccines. In one recent study of vaccines, mycoplasmas were found to contaminate about six percent of commercial vaccines. As contaminants of both live and killed vaccines, their presence can generate an unintended immune response.

Past trials of experimental M. pneumonia vaccines were reported as dangerous failures. The tested MP vaccines both did not protect, but they also generated a significant fraction of life-threatening, very strong immune/inflammation reactions to the wild mycoplasma test challenge forms. So mycoplasma vaccine contamination makes the vaccines dangerous for a significant (~5%) fraction of those inoculated. Total risk factor is .05*.06= .003 or .3% or 3 in 1000 cases. Live MMP vaccines contaminated with mycoplasmas, can infect the vaccinated. Cases of infected live virus vaccines documented in the literature include contamination with HIV, SIV, parvovirus, measles, smallpox and polio strains that lead to

Mycoplasmas infect everything including animals, plants, and possibly other microbes. Generally, strains have adapted to specific host species, with some exceptions. Garth Nicolson the pets of GWI or CFS patients exhibited similar symptoms as their owners, and then tested positive for the same mycoplasmas. They are highly contagious, but not all infected show noticeable symptoms. Transmission occur among people in close proximity (families, classmates, etc).

HOW MYCOPLASMAS INTERACT IN THE BODY
Mycoplasmas invade the cells of the host (patient) and oror to attach-to or imbed-into the outside of host cells.

They depend on host cells for nutrients such as cholesterol, certain amino acids, etc. They compete with the host cells for these nutrients and energy which can interfere with host cell functions. Fatigue is one symptom.

A mycoplasma has very little DNA of its own, but is capable of using/controlling DNA from an invaded cell causing that cell to malfunction in many significant ways (mitochondrial dysfunction) and/or die, or invasion can cause inflammation and DNA/RNA mutation and damage of the host cells.

Mycoplasmas attach to host cells with a tiny arm coated in protein which attaches to the protein coating of host cells. For this reason, antibiotics like tetracycline, which are classified as "protein synthesis inhibitors" are often used against mycoplasma infections. While these antibiotics may block this protein attachment and very slowly starve it from the nutrients it needs from host cells to thrive and replicate, it still takes a healthy immune system to actually kill the mycoplasma for good. Better nutrition, especially vitamin C in high consistent levels, can stimulate invaded cell apoptosis (death).

Mycoplasmas are highly adaptable to changing environments and can move anywhere in the body, attaching to or invading virtually any type of cell in the body that has a shape that matches the form of its protein hooks.

The mycoplasma adhesion proteins are very similar to human proteins. Once adhered to the host cell, the mycoplasma can completely mimic or copy the protein cell of the host cell. This can cause the immune system to begin attacking the body's own cells, diagnosed as an autoimmune disease.

Certain Mycoplasma species can either activate or suppress host immune systems, and they may use these activities to evade host immune responses. Mycoplasmas can turn on the chain reaction immune responses. This includes the generation of pro-inflammatory cytokine molecules which are found in inflammatory disorders, called autoimmune diseases.

Mycoplasma can signal and attract immune system phagocytes (natural killer NK cells) that are supposed to eat them. Inside these phagocytes, they can make copies of themselves and be carried to new locations of inflammation.

When a mycoplasma attaches to a host cell, it generates and releases hydrogen peroxide and superoxide Nitrogen and Reactive Oxygen Species, AKA free-radicals, (NOS and ROS) and these (hy)peroxides damage cells organs, tissues, mitochondria, and DNA/RNA, aging the host. Vitamin C is the antidote.

http://www.ra-infection-connection.com/Mpneumoniae.htm

My two cents is that fairly moderate additional Vitamin C is better.

Low natural killer cell cytotoxic activity in autism: the role of glutathione, IL-2 and IL-15.

Abstract

Although many articles have reported immune abnormalities in autism, NK cell activity has only been examined in one study of 31 patients, of whom 12 were found to have reduced NK activity. The mechanism behind this low NK cell activity was not explored. For this reason, we explored the measurement of NK cell activity in 1027 blood samples from autistic children obtained from ten clinics and compared the results to 113 healthy controls. This counting of NK cells and the measurement of their lytic activity enabled us to express the NK cell activity/100 cells. At the cutoff of 15-50 LU we found that NK cell activity was low in 41-81% of the patients from the different clinics. This NK cell activity below 15 LU was found in only 8% of healthy subjects (phttp://www.ncbi.nlm.nih.gov/pubmed/18929414

Taking the last two articles together suggest low glutathione is part of of a detox/metal problem and the mycoplasma may come before or after the pathology begins, but worsen the problem by hindering NK function. Some appear to not ahow the Mycoplasm P strain, but another strain might be involved or the Mycoplasma P may possibly undetected though present. The first report suggests the mycoplasma could even come via a vaccine.

The potential role of the antioxidant and detoxification properties of glutathione in autism spectrum disorders: a systematic review and meta-analysis.

ABSTRACT:

BACKGROUND:

"Glutathione has a wide range of functions; it is an endogenous anti-oxidant and plays a key role in the maintenance of intracellular redox balance and detoxification of xenobiotics. Several studies have indicated that children with autism spectrum disorders may have altered glutathione metabolism which could play a key role in the condition.

METHODS:

A systematic literature review and meta-analysis was conducted of studies examining metabolites, interventions and/or genes of the glutathione metabolism pathways i.e. the γ-glutamyl cycle and trans-sulphuration pathway in autism spectrum disorders.

RESULTS:

Thirty nine studies were included in the review comprising an in vitro study, thirty two metabolite and/or co-factor studies, six intervention studies and six studies with genetic data as well as eight studies examining enzyme activity.

CONCLUSIONS:

The review found evidence for the involvement of the γ-glutamyl cycle and trans-sulphuration pathway in autistic disorder is sufficiently consistent, particularly with respect to the glutathione redox ratio, to warrant further investigation to determine the significance in relation to clinical outcomes. Large, well designed intervention studies that link metabolites, cofactors and genes of the γ-glutamyl cycle and trans-sulphuration pathway with objective behavioural outcomes in children with autism spectrum disorders are required. Future risk factor analysis should include consideration of multiple nutritional status and metabolite biomarkers of pathways linked with the γ-glutamyl cycle and the interaction of genotype in relation to these factors."

http://www.ncbi.nlm.nih.gov/pubmed/22524510

It is debatable whether the Mycoplasma is present due to an initial low immune function or if the Mycoplasma come in and do more of the damage after enough insults and disruptions occur. It may be different for each person and it may be they are not involved in many cases as the percentages of infection suggest, but they are able to hide in tissues and cells, so they may be there all along. Low levels of some Cytokines and high levels of other Cytokines have been documented in groups with Autism. Those with active and strong Mycoplasma involvement are the ones who are likely to have other disease conditions or symptoms.

Further reading

Mycoplasma pneumoniae—an emerging extra-pulmonary pathogen

http://onlinelibrary.wiley.com/doi/10.1111/j.1469-0691.2007.01834.x/full

[Benedetta]

Nick;
Ketogenic diet has a lot of cream in the diet plan.
Atkins diet has a lot of soy protein and whey protein in it.
Maybe that is one reason they work so well for some forms of - well the majority of epilepsy.

We take N-acetyl cysteine
I read somewhere that sweet corn is very good too???
You read, and read, and read and you don't know if you should believe half of what you read.

Coconut oil is dangerous; as is avocado oil - it gets solid at a cooler room temp and that is how you know it is bad
will give you all heart attacks - so all the studies showed way back in the 80- 90s

Now, now, now - studies show that coconut oil is good for alzeiheimers and such.

Last time I checked the heart was in the same body as the brain and what is good for one has to be good for the other.
That is just the way it works don't you think?

[Visitor]

Another good that they are looking, but we have been saying this for years study.

N-acetylcysteine may hold potential for treating autism

"Autism may have several causes, and some of them include increased levels of the neurotransmitter glutamate, which is excitatory, and high oxidative stress. Researchers of the above study highlight one of the causes of the disease is disequilibrium between antioxidants and oxidants. This causes an increase in reactive oxygen species (ROS), and this causes damage to several cells and organs. Synthesis of glutathione, the body’s main antioxidant, is also perturbed.

NAC may work because it increases glutathione and beneficially modulates the release of glutamate. Whey protein can also raise glutathione levels, and other researchers have also previously found that NAC can raise glutathione."

http://www.digitaljournal.com/article/330225

They say: "Autism may have several causes,..."

No, it does have many causes and it takes multifaceted approaches over time to reverse in those that are amenable to these approaches.

The glutamate issue is a given in these types.

[Visitor]

The temptation to doubt the desire to truly treat these conditions is strong, but instead I will be mainly thankful that they are looking more at the immune factors. This report speaks of Schizophrenia and IL-6 relationship. The involvement of IL-6 and others related to Autism has been thrown out there for years, yet the "conventional" medicine groups don't seem all that interested, well until now possibly. The first link is one example from 2002 about immune factors, including IL-6 and others, in Autism and the second is the one on Schizophrenia and IL-6.

Activation of the inflammatory response system in autism.

http://www.ncbi.nlm.nih.gov/pubmed/11803234

Researchers pursue red flag for schizophrenia relapse

http://medicalxpress.com/news/2012-08-pursue-red-flag-schizophrenia-relapse.html

Also, for those who have openness to this the following about MET are a part, at least in some, as I see it.
Association of a MET genetic variant with autism-associated maternal autoantibodies to fetal brain proteins and cytokine expression.

http://www.ncbi.nlm.nih.gov/pubmed/22833194

If you think Enhansa helps you should try Olmesartan. I have done both and the Olmesartan is much, much better but costs more. It addresses more of the factors. There are many things it does. Mast cell derived Renin would also have it's effects blocked by Olmesartan, to name an unusual one it deals with.

[Visitor]

To clarify when I recently wrote: "The cry protein..", I mean the cry 1,2 gene function as explained here.

Gene Expression Profiling Differentiates Autism Case–Controls and Phenotypic Variants of Autism Spectrum Disorders: Evidence for Circadian Rhythm Dysfunction in Severe Autism

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2737477/

If interested.

Circadian clocks: regulators of endocrine and metabolic rhythms

http://joe.endocrinology-journals.org/content/195/2/187.full

[Visitor]

The inclusion of Glyphosate as a possible contributor to the rise in Autism in the last 25-35 years is all I am suggeseting. It was first prodced in the early 1970's. I don't know if it has efected Ribokinase in people, but Pyridoxal 5'-phosphate problems exist it in some it seems.

[Visitor]

If I had kept this this info in mind it would have been easier. The b6 burdens PST without adequate magnesium. This may be happening inutero.

B6 and Sulfation

"A journal article, “Inhibition of phenol sulfotransferase by pyridoxal phosphate,” By R. Bartzatt and J. D. Beckmann (Biochemical Pharmacoloy, 1994) has raised some concern among parents who use vitamin B6 to help their autistic children. The study is of questionable revelance, since it involved an in vitro (test tube) experiment rather than living subjects, and used cells of bovine rather than human origin. Nevertheless, ARI decided to investigate this matter, and provided a grant to Dr. Rosemary Waring, of the university of Birmingham School of Medicine in England, a preeminent researcher on sulphation problems in autism.

Dr. Waring’s results confirm what ARI had first reported in 1973: whenever extra vitamin B6 is given, it must be accompanied by extra magnesium, or adverse effects may be seen. In our first study of vitamin B6 in autistic children, conducted in the late 1960s, a small number of the autistic children in the experiment showed increased sound sensitivity, irritability and enuresis when the B6 was started. When magnesium was added, these side effects immediately disappeared and the beneficial effects of the B6 were enhanced. Several studies by the research team led by Dr. Gilbert LeLord of Tours University Medical School, in France, confirmed our report that the combination of vitamin B6 and magnesium was markedly more effective than either vitamin B6 or magnesium alone."

—Bernard Rimland, Ph.D.

Sulfotransferase enzymes use PAPS (3’-phospho-adenosive-5’-phosphosulfate) to transfer sulfate residues onto a wide variety of substrates. TPST substrates require sulfation for efficient function while sulfation by SULT 1A1 greatly alters substrate properties, usually decreasing their activity.

a) Tyrosylprotein sulfotransferase (TPST)
Substrates - tyrosine residues on gastrin, cholecystokinin, mucin proteins"

http://legacy.autism.com/medical/research/drwaringstudy.htm

So, if a lot of B6 is taken in pregnancy it could be negative for the baby it seems. The reason the mother is helped by it, or at least has reduced nausea, may be a seaprate issue for her system. If stores are low in a mother it will sequestered from tissues and this may present it's won issues for the baby without adequate amouns. I appears mag should be given to mothers with B6 if taken for morning sickness.

Inhibition of phenol sulfotransferase by pyridoxal phosphate.

http://www.ncbi.nlm.nih.gov/pubmed/8010994

low biotin in Autism and SAM

Biosynthesis of biotin and lipoic acid.

http://www.ncbi.nlm.nih.gov/pubmed/11153271

[Visitor]

Biomedical aspects of pyridoxal 5'-phosphate availability.

Abstract

“The biologically active form of vitamin B6, pyridoxal 5'-phosphate (PLP), is a cofactor in over 160 enzyme activities involved in a number of metabolic pathways, including neurotransmitter synthesis and degradation. In humans, PLP is recycled from food and from degraded PLP-dependent enzymes in a salvage pathway requiring the action of pyridoxal kinase, pyridoxine 5'-phosphate oxidase and phosphatases. Once pyridoxal 5'-phosphate is made, it is targeted to the dozens different apoenzymes that need it as a cofactor. The regulation of the salvage pathway and the mechanism of addition of PLP to the apoenzymes are poorly understood and represent a very challenging research field. Severe neurological disorders, such as convulsions and epileptic encephalopathy, result from a reduced availability of pyridoxal 5'-phosphate in the cell, due to inborn errors in the enzymes of the salvage pathway or other metabolisms and to interactions of drugs with PLP or pyridoxal kinase. Multifactorial neurological pathologies, such as autism, schizophrenia, Alzheimer's disease, Parkinson's disease and epilepsy have also been correlated to inadequate intracellular levels of PLP.”

http://www.ncbi.nlm.nih.gov/pubmed/22201923

The following muddies the picture a bit, but illustrates an association.

Type 1 Diabetes and Autism Association Seems to Be Linked to the Incidence of Diabetes

http://care.diabetesjournals.org/content/29/8/1985.1.full

[Visitor]

Type 1 diabetes is considered an autoimmune related condition. Pyridoxal Kinase is a Ribokinase.

Gene Card - Ribokinase

Enzyme regulation: Competitively inhibited by...

N-(phosphonomethyl)glycine...

4 Novoseek chemical compound relationships for RBKS gene
Compound -log (P-Val) Hits PubMed IDs for Articles with Shared Sentences (# sentences)
ribose 75.3 3 9843365 (1), 11563694 (1), 18560757 (1)
pyridoxal 69.4 4 12235162 (3), 16600635 (1)
vitamin b6 50.4 1 16600635 (1)
atp 48.8 1 9843365 (1)

http://www.genecards.org/cgi-bin/carddisp.pl?gene=RBKS&search=ribokinase

Glyphosate Toxic & Roundup Worse

"Broad-spectrum herbicide

glyphosate =

N-(phosphonomethyl)glycine),...

http://www.i-sis.org.uk/GTARW.php

Wiki - Pyridoxal kinase

"In enzymology, a pyridoxal kinase (EC 2.7.1.35) is an enzyme that catalyzes the chemical reaction
ATP + pyridoxal ADP + pyridoxal 5'-phosphate
Thus, the two substrates of this enzyme are ATP and pyridoxal, whereas its two products are ADP and pyridoxal 5'-phosphate.

This enzyme belongs to the family of transferases, specifically those transferring phosphorus-containing groups (phosphotransferases) with an alcohol group as acceptor. The systematic name of this enzyme class is ATP:pyridoxal 5'-phosphotransferase. Other names in common use include pyridoxal kinase (phosphorylating), pyridoxal 5-phosphate-kinase, pyridoxal phosphokinase, and pyridoxine kinase. This enzyme participates in vitamin B6 metabolism."

http://en.wikipedia.org/wiki/Pyridoxal_kinase

Pyridoxal 5'-phosphate (PLP) deficiency might contribute to the onset of type I diabetes.

Abstract

"The incidence of type I diabetes is rising worldwide, particularly in young children. Type I diabetes is considered a multifactorial disease with genetic predisposition and environmental factors participating. Currently, despite years of research, there is no consensus regarding the factors that initiate the autoimmune response. Type I diabetes is preceded by autoimmunity to islet antigens, among them the protein glutamic acid decarboxylase, GAD-65. Pyridoxal 5'-phosphate (PLP) is formed from vitamin B6 by the action of pyridoxal kinase. Interaction of GAD65 with PLP is necessary for GAD65-mediated synthesis of the neurotransmitter γ-aminobutyric acid (GABA). PLP is also a required cofactor for dopamine synthesis by L-aromatic decarboxylase (L-AADC). Both GAD65 and L-AADC are expressed in pancreatic islets. Here it is proposed that lack of the vitamin B6 derivative pyridoxal 5'-phosphate might contribute to the appearance of pancreatic islet autoimmunity and type I diabetes onset."

http://www.ncbi.nlm.nih.gov/pubmed/22088923

The cry protein and NF-kb relate this to diabetes and other immune related conditions. Also, Glyphoste may only increase the susceptibility or problem and numerous other factors are involved of course. I am still working on this and the conncetion possibly to phenylic sensitivity. B^ given for morning sickness seems to help nausea. I am also studying whether the additional B6 is totally helpfucl of has a negative and positive effect.

[Visitor]

Having just come across link to a release on the following subject from this author I went to it, but it was a pay piece. I searched to see if it was available elsewhere and found this book apparently detailing this research. It appears it is being viewed as novel in connecting the brain and immune function. These folks seem to have missed or ignored the biomedical community completely, or do not wish to acknowledge that the fringe had already thought this was a major part of the problem and has been told they were not scientific. I am going to get and read this book as I imagine it will be the first to look at this from a traditionally clinical background. This should provide a good value in integrating valuable neuropsychological methods with is the real catalyst for dysfunction as some of us have known. The example chapter linked at another site mentions a factor that can mediate some of this effect. I am wondering if it is Angiotensin 2.

Infectious Behavior: Brain-Immune Connections in Autism, Schizophrenia, and Depression

http://www.amazon.com/Infectious-Behavior-Brain-Immune-Connections-Schizophrenia/dp/0262016451

[Visitor]

They are very willing to cite biomed problems for causing other conditions, but won't attempt to understand what happens in infancy when these same problems occur in stronger ways to help cause much more drastic effects in the brain as in some or much Autism.

The same problems first, which were much earlier suggested to be involved with Autism, were said to either not occur or would not impact the brain if they did. Those suggesting they did were ridiculed.

Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior.

Abstract

"The potential contribution of chronic inflammation to the development of neuropsychiatric disorders such as major depression has received increasing attention. Elevated biomarkers of inflammation, including inflammatory cytokines and acute-phase proteins, have been found in depressed patients, and administration of inflammatory stimuli has been associated with the development of depressive symptoms. Data also have demonstrated that inflammatory cytokines can interact with multiple pathways known to be involved in the development of depression, including monoamine metabolism, neuroendocrine function, synaptic plasticity, and neurocircuits relevant to mood regulation. Further understanding of mechanisms by which cytokines alter behavior have revealed a host of pharmacologic targets that may be unique to the impact of inflammation on behavior and may be especially relevant to the treatment and prevention of depression in patients with evidence of increased inflammation. Such targets include the inflammatory signaling pathways cyclooxygenase, p38 mitogen-activated protein kinase, and nuclear factor-κB, as well as the metabolic enzyme, indoleamine-2,3-dioxygenase, which breaks down tryptophan into kynurenine. Other targets include the cytokines themselves in addition to chemokines, which attract inflammatory cells from the periphery to the brain. Psychosocial stress, diet, obesity, a leaky gut, and an imbalance between regulatory and pro-inflammatory T cells also contribute to inflammation and may serve as a focus for preventative strategies relevant to both the development of depression and its recurrence. Taken together, identification of mechanisms by which cytokines influence behavior may reveal a panoply of personalized treatment options that target the unique contributions of the immune system to depression."

http://www.ncbi.nlm.nih.gov/pubmed/21918508

[Visitor]

Inflammation in anxiety.

"However, considering a big socioeconomic impact due to an alarming increase in anxiety disorder patients, there is an urgent research need for a better understanding of the role of cytokines in anxiety."

http://www.ncbi.nlm.nih.gov/pubmed/22814704

Let me be the first to point out that there is no real increase in "anxiety disorder patients", only better diagnosing. These things labeled "anxiety disorders" are just different ways of thinking and should be celebrated.
Self harm is a from of creativity and self expression.

Immune system to brain signaling: neuropsychopharmacological implications.

http://www.ncbi.nlm.nih.gov/pubmed/21334376

The previous links were found at the following links and there are other reports linked there worth reading.

Cognitive Impairment and Diabetes and Autism

http://asdresearchinitiative.wordpress.com/2012/07/27/cognitive-impairment-and-diabetes-and-autism/

Psychiatric comorbidities and Asperger’s – Immune System Relationship ?

http://asdresearchinitiative.wordpress.com/2012/07/27/psychiatric-comorbidities-and-aspergers-immune-system-relationship/

There is also this one that alludes to the same type chemical that Dr. Shaw found elevated lon ago related to Clostridia.

More Rats, Propionic Acid and Autism – IMFAR 2012

http://asdresearchinitiative.wordpress.com/2012/05/24/more-rats-propionic-acid-and-autism-imfar-2012/

[Visitor]

It appears that the basic idea of microglial activation by Angiotensin 2 via the Angiotensin 1 receptor has been proposed already. It is therefore, it seems, fairly theoreticallly sound. The lack of ACE2 function in the gut and vascular/renal/heart/brain system may represent a ordered dysregulation or an imbalanced dysregulation. I do not know yet. All of these reports are ones I just found, but are welcome finds.

Autonomic-immune-vascular interaction: an emerging concept for neurogenic hypertension.

http://www.ncbi.nlm.nih.gov/pubmed/21536990

Figure 1 from that report

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105900/figure/F1/

Signalling across the blood brain barrier by angiotensin II: novel implications for neurogenic hypertension.

http://www.ncbi.nlm.nih.gov/pubmed/18443753

Angiotensin II inhibits neuronal nitric oxide synthase activation through the ERK1/2-RSK signaling pathway to modulate central control of blood pressure.

http://www.ncbi.nlm.nih.gov/pubmed/20056918

Shift to an involvement of phosphatidylinositol 3-kinase in angiotensin II actions on nucleus tractus solitarii neurons of the spontaneously hypertensive rat.

http://www.ncbi.nlm.nih.gov/pubmed/19850939

[Visitor]

The cut off in the last post was not my doing. I double checked before I posted. Here is the the last part of the last report that was cut off.

"RESULTS:

The vitamin/mineral supplement was generally well-tolerated, and individually titrated to optimum benefit. Levels of many vitamins, minerals, and biomarkers improved/increased showing good compliance and absorption. Statistically significant improvements in metabolic status were many including: total sulfate (+17%, p = 0.001), S-adenosylmethionine (SAM; +6%, p = 0.003), reduced glutathione (+17%, p = 0.0008), ratio of oxidized glutathione to reduced glutathione (GSSG:GSH; -27%, p = 0.002), nitrotyrosine (-29%, p = 0.004), ATP (+25%, p = 0.000001), NADH (+28%, p = 0.0002), and NADPH (+30%, p = 0.001). Most of these metabolic biomarkers improved to normal or near-normal levels.The supplement group had significantly greater improvements than the placebo group on the Parental Global Impressions-Revised (PGI-R, Average Change, p = 0.008), and on the subscores for Hyperactivity (p = 0.003), Tantrumming (p = 0.009), Overall (p = 0.02), and Receptive Language (p = 0.03). For the other three assessment tools the difference between treatment group and placebo group was not statistically significant.Regression analysis revealed that the degree of improvement on the Average Change of the PGI-R was strongly associated with several biomarkers (adj. R2 = 0.61, p http://www.ncbi.nlm.nih.gov/pubmed/22151477

[Visitor]

The last post was messed up. Here it is fully.

This first report I noticed on the Marshall forum. The group that did the study first I think first tested ofr NADH/NADPH and that seemed to have helped direct their testing. Anyway the report is confirmation. Also, notice the low plasma Tryptophan levels found and consider the ACE 2/low Tryptophan in the last post report on malnutrition and inflamed instestines.

ACE 2 function may be a main mediator for gut function and helps precipitate ption and dysbiosis effecting those with biomed Autism.{most} ACE2 has a lot of impact elsewhere as well as I see it.

Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity.

Abstract

BACKGROUND:

"The relationship between relative metabolic disturbances and developmental disorders is an emerging research focus. This study compares the nutritional and metabolic status of children with autism with that of neurotypical children and investigates the possible association of autism severity with biomarkers.

METHOD:

Participants were children ages 5-16 years in Arizona with Autistic Spectrum Disorder (n = 55) compared with non-sibling, neurotypical controls (n = 44) of similar age, gender and geographical distribution. Neither group had taken any vitamin/mineral supplements in the two months prior to sample collection. Autism severity was assessed using the Pervasive Development Disorder Behavior Inventory (PDD-BI), Autism Treatment Evaluation Checklist (ATEC), and Severity of Autism Scale (SAS). Study measurements included: vitamins, biomarkers of vitamin status, minerals, plasma amino acids, plasma glutathione, and biomarkers of oxidative stress, methylation, sulfation and energy production.

RESULTS:

Biomarkers of children with autism compared to those of controls using a t-test or Wilcoxon test found the following statistically significant differences (p http://www.ncbi.nlm.nih.gov/pubmed/21651783

The next report is further confirmation of these problems.

Effect of a vitamin/mineral supplement on children and adults with autism.

Abstract

BACKGROUND:

"Vitamin/mineral supplements are among the most commonly used treatments for autism, but the research on their use for treating autism has been limited.

METHOD:

This study is a randomized, double-blind, placebo-controlled three month vitamin/mineral treatment study. The study involved 141 children and adults with autism, and pre and post symptoms of autism were assessed. None of the participants had taken a vitamin/mineral supplement in the two months prior to the start of the study. For a subset of the participants (53 children ages 5-16) pre and post measurements of nutritional and metabolic status were also conducted.

RESULTS:

The vitamin/mineral supplement was generally well-tolerated, and individually titrated to optimum benefit. Levels of many vitamins, minerals, and biomarkers improved/increased showing good compliance and absorption. Statistically significant improvements in metabolic status were many including: total sulfate (+17%, p = 0.001), S-adenosylmethionine (SAM; +6%, p = 0.003), reduced glutathione (+17%, p = 0.0008), ratio of oxidized glutathione to reduced glutathione (GSSG:GSH; -27%, p = 0.002), nitrotyrosine (-29%, p = 0.004), ATP (+25%, p = 0.000001), NADH (+28%, p = 0.0002), and NADPH (+30%, p = 0.001). Most of these metabolic biomarkers improved to normal or near-normal levels.The supplement group had significantly greater improvements than the placebo group on the Parental Global Impressions-Revised (PGI-R, Average Change, p = 0.008), and on the subscores for Hyperactivity (p = 0.003), Tantrumming (p = 0.009), Overall (p = 0.02), and Receptive Language (p = 0.03). For the other three assessment tools the difference between treatment group and placebo group was not statistically significant.Regression analysis revealed that the degree of improvement on the Average Change of the PGI-R was strongly associated with several biomarkers (adj. R2 = 0.61, p http://www.ncbi.nlm.nih.gov/pubmed/22151477

Not news, but maybe accpetance of biomed will soon follow.

[Visitor]

This first report I noticed on the Marshall forum. The group that did the study first I think first tested ofr NADH/NADPH and that seemed to have helped direct their testing. Anyway the report is confirmation. Also, notice the low plasma Tryptophan levels found and consider the ACE 2/low Tryptophan in the last post report on malnutrition.
ACE 2 function may be a main mediator for gut and function effecting those with biomed Autism.{most} ACE2 has a lot of impact elsewhere as well as I see it.

Nutritional and metabolic status of children with autism vs. neurotypical children, and the association with autism severity.

Abstract

BACKGROUND:

"The relationship between relative metabolic disturbances and developmental disorders is an emerging research focus. This study compares the nutritional and metabolic status of children with autism with that of neurotypical children and investigates the possible association of autism severity with biomarkers.

METHOD:

Participants were children ages 5-16 years in Arizona with Autistic Spectrum Disorder (n = 55) compared with non-sibling, neurotypical controls (n = 44) of similar age, gender and geographical distribution. Neither group had taken any vitamin/mineral supplements in the two months prior to sample collection. Autism severity was assessed using the Pervasive Development Disorder Behavior Inventory (PDD-BI), Autism Treatment Evaluation Checklist (ATEC), and Severity of Autism Scale (SAS). Study measurements included: vitamins, biomarkers of vitamin status, minerals, plasma amino acids, plasma glutathione, and biomarkers of oxidative stress, methylation, sulfation and energy production.

RESULTS:

Biomarkers of children with autism compared to those of controls using a t-test or Wilcoxon test found the following statistically significant differences (p http://www.ncbi.nlm.nih.gov/pubmed/22151477

Not news, but maybe accpetance of biomed will soon follow.

[Visitor]

How Malnutrition Leads to Inflamed Intestines

"More than one billion people in poor countries are starving, and malnutrition remains a major problem even in rich countries, making it a leading cause of death in the world. For over a hundred years, doctors have known that a lack of protein in the diet or low levels of amino acids, the building blocks of proteins, can lead to symptoms like diarrhoea, inflamed intestines and other immune system disorders, which weaken the body and can be fatal. However, the molecular mechanism which explains how malnutrition causes such severe symptoms has been largely unexplored.

Now a research group led by Josef Penninger, the director of the Institute of Molecular Biotechnology (IMBA) in Vienna, Austria, in cooperation with Philip Rosenstiel, University of Kiel, Germany, has found a molecular explanation for the increased susceptibility to intestinal inflammation in malnutrition. The researchers were studying an enzyme which helps to control blood pressure, kidney failure in diabetes, heart failure and lung injury, called the Angiotensin Converting Enzyme 2, or ACE2. This enzyme was identified as the key receptor for SARS virus infections, but the researchers also discovered an entirely new function. ACE2 controls the way our intestines take in amino acids from our food, via amino acid transporters, and in particular the uptake of the essential amino acid tryptophan.

Too little tryptophan alters our natural immune system, which changes the types of bacteria which can live in our bowels and guts, leading to higher sensitivity and eventually diarrhoea and inflamed intestines. Increasing the intake of tryptophan in their diet provided relief for mice suffering from intestinal inflammation. The mixture of bacteria returned to normal, the inflammation died down, and the mice also became less susceptible to new attacks.

"The research shows how the food we eat can directly change the good bacteria in our intestines to bad bacteria and so influence our health”, says Thomas Perlot, the first author of the study. “Our results might also explain nutritional effects that have been known for centuries and provide a molecular link between malnutrition and the bacteria living in our intestines. This discovery could be used in the future to treat patients with a simple regulated diet or by taking tryptophan as a food supplement. And there is hardly any risk of side effects from artificially increasing an amino acid found in the normal diet.”

Josef Penninger, the lead author, says “I have studied ACE2 for more than 10 years and was completely stunned by this novel link between ACE2 and amino acid balance in the gut. Biology continues to surprise me. Up to a billion people in the world are malnourished, especially the poor and disadvantaged. In Austria alone, around 80,000 people suffer from a chronic inflammatory bowel disease like ulcerative colitis or Crohn's disease. I hope that our findings have opened a door to a better molecular understanding how malnutrition affects human health. Whether simple tryptophan diets can indeed cure the effects of malnutrition in humans now needs to be carefully tested in clinical trials.”

http://www.sciencedaily.com/releases/2012/07/120725132133.htm

[Visitor]

Correction:

I wrote: "is that in the state of constantly not having the brain cells in regions for goal-directed behavior from her earliest development.." I meant not having those cells active in those brain regions. This would have been due to a constantly upregulated norephinephrine{noradrenaline} level. Then the complement system may have marked them for destruction via lysis if inactive cells may be marked for destruction by complement if not active. I also meant Lupus, not Luus.

This is not a report on Autism and Complement, but may have a similar activity in this cell loss scenario.

Decay-Accelerating Factor (CD55) Is Expressed by Neurons in Response to Chronic but Not Acute Autoimmune Central Nervous System Inflammation Associated with Complement Activation1

http://www.jimmunol.org/content/174/4/2353.full

If there is a non-functioning neuron/inflamation/neuronloss/neurogensis cycle it may not be discerned yet and it will be interesting to see what the inflamation in brain samples actually reveal. It may also expalin why their is not notable brain matter loss in Autism as far as I know.

[Visitor]

The value to understanding the patterns of behavior in Autism from the main concept explained in this report maybe subjective to each person and the degree of it's involvement. Yet, it seems this was in full swing effecting my wife. I suspect one part of this process is that in the state of constantly not having the brain cells in regions for goal-directed behavior from her earliest development she not only operated from habitually trained patterns, but may have also lost cells in thoses regions.

The complement factor C3 protein {note c3 in this thread}, which has been found circulating in curious amounts in systems of some with Autism, has reportedly been related to the the marking of removal of unused brain cells. It is also involved in pathogen control, inflamation/tissue destruction, and neurogenesis. This may be an apect of cycling destruction and attempted repair in some with Autism. Some have half jokingly refferred to bimod autism as "baby alzheimer's, and there may be an overlap of process in inflamation and neuron dysfucntion. Luus also shows some of the same complement expression as do other conditions.

In some with Autism, if this is involved, this may be a large part of the reason for the repetitive and sterotyped behavior.

Force of Habit: Stress Hormones Switch Off Areas of the Brain for Goal-Directed Behaviour

"The researchers have now reported in the Journal of Neuroscience that the interaction of the stress hormones hydrocortisone and noradrenaline shut down the activity of brain regions for goal-directed behaviour. The brain regions responsible for habitual behaviour remained unaffected.

In order to test the different stress hormones, the cognition psychologists used three substances -- a placebo, the stress hormone hydrocortisone and yohimbine, which ensures that the stress hormone noradrenaline stays active longer.

The brain data revealed: The combination of yohimbine and hydrocortisone reduced the activity in the forebrain -- in the so-called orbitofrontal and medial prefrontal cortex. These areas have been already previously associated with goal-directed behaviour. The brain regions which are important for habitual learning, on the other hand, were similarly active for all volunteers."

http://www.sciencedaily.com/releases/2012/07/120725090042.htm

[Visitor]

I maybe should have not called it TBI, but an ongoing process in Autism that has similar effects overall.

[Visitor]

Some of you may recognize the benefit of the drug mentioned in the following report for Autism Ctokine control as TBI quick or slow is involved in the biomed Autism pathology. We have used Olmesartan for Cytokine control, but this may prove to be an option for some not open to that drug. If you read through this thread you will see the mix of diseases mentioned in the piece and some details of what is damaged and how. Also, there is explanation as to how Olmesartan stops some of these effects.

Part of my recent thoughts on BBB and inflamation are things I have known since the first year I looked into these matters, but the myraid of connections did not start to completely come together until the last year. For those with the Cytokine involvement, like my wife, this may begin in her earliest time. It was likely upregulated in her first few years of life and she learned certain facts and patterns, but could not generate a social contruct. She was "programmed" and mimicked/reflected processes, including social interactive responses as part of her due to her global network being disrupted. Some portion, maybe the majority, of Autism has some common biological causes, but each individual is unique.

New Drug Could Treat Alzheimer's, Multiple Sclerosis and Brain Injury

"When too many of the cytokines are produced, the synapses of the brain begin to misfire. Eventually the entire organization of the brain falls into disarray, like a computer failing. The neurons lose their connections with each other and can eventually die. The resulting damage in the cortex and hippocampus can compromise memory and decision-making."

http://www.sciencedaily.com/releases/2012/07/120724171302.htm

[Visitor]

http://blogs.psychcentral.com/creative-mind/2012/07/creative-introverted-then-youre-probably-not-seen-as-a-leader/

[Visitor]

The link to the last paper in the last post was dead, so here is a working one.

Research Demonstrates Immune System Connection to Low-Cholesterol Syndrome

http://www.niams.nih.gov/News_and_Events/Spotlight_on_Research/2006/low_cholesterol_syndrome.asp

Here is one on Mercury and mast cells that may be well know here.

Mercury induces inflammatory mediator release from human mast cells

"The results of the present study support the biological plausibility of how mercury could contribute to ASD pathogenesis by inducing VEGF and IL-6 release from mast cells, and as a result disrupt the BBB and thus permit brain inflammation. Further studies should investigate the effect of mercury and thimerosal alone or together with allergic and non-immune triggers."

http://www.jneuroinflammation.com/content/7/1/20

[Visitor]

In the side bar of the paper link in the last post there are other helpful papers linked. Here are a couple of them.

Perinatal stress, brain inflammation and risk of autism-Review and proposal.

http://www.ncbi.nlm.nih.gov/pubmed/22747567

Mast cell activation and autism.

http://www.ncbi.nlm.nih.gov/pubmed/21193035

Some other related info I have posted previously elswhere.

New study shows low cholesterol levels could have negative effect on autism

"Today Rose is reading, smiling, and interacting like never before. And a packet of cholesterol could have helped make the difference.
As part of a clinical trial, the Barkers added a packet of cholesterol to Rose's diet twice a day and that simple act may have had a profound effect.
Dr. Eugene Arnold with Ohio State University Medical Center says, "It's possible that too low cholesterol could be one of several causes of autism, affecting a sub-group of children with autism."
Dr. Arnold launched an initial study with a simple premise. Knowing that proper levels of cholesterol are essential for brain development and function, he wanted to see if increasing cholesterol could reduce symptoms in autism."

If her cholesterol level is relevant to her autism, I wonder why her levels were low?

http://www.abc2news.com/dpp/news/health/childrens_health/new-study-shows-low-cholesterol-levels-could-have-negative-effect-on-autism

The next article is about genetic defect in cholesterol metabolism, but it may inform what altered cholesterol levels may affect.

Research Demonstrates Immune System Connection to Low-Cholesterol Syndrome

"Juan Rivera, Ph.D., director of the NIAMS Office of Science and Technology and chief of the Molecular Inflammation Section, became interested in SLOS because his lab had been studying a type of inflammatory cell called a mast cell, the principal cell in triggering allergies, including food intolerances. In previous studies, his group had found that cholesterol is a key component in mast cells' ability to initiate signals that tell other inflammatory cells to either rev up or slow down. "We made the hypothesis that one of the issues related to the food intolerance is that these mast cells are somewhat more hyper-responsive in these individuals and that led them to being easily triggered," he says."

http://www.niams.nih.gov/News_and_Events/Spotlight_on_Research/2006/low_cholesterol_syndrome

[Visitor]

The disturbance that may start in the womb or postnatally with other triggers along with gut dysfunction and immune reaction is part of the pathology for altered brain function. If this begins inutero the effect would be nearly intrinsic to all development. Thishttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3293070/

Low cholesterol would worsen the nerve/mast cell problem in a subset of Autism I think

[Visitor]

Benedetta,

I don't doubt your take on your daughter. I stand by what I have said.

[Visitor]

Dr. Amy Yasko that is...I meant no slight it is just Dr. Wakefield, Dr. Rosemary Waring, and Dr. Shaw and other doctors I have referenced were ones more involved in my thinking as I was dealing with recovery. From what I read Dr. Yasko is very astute in many matters.

[Benedetta]

Nick
We do not know what goes on inside the minds of those afflicked.
I have to admit my daughter kept me confused.
My gosh Nick my daughter has very deep feelings and smart enoughto know she was in trouble with her health and scared.

Later she was lucky to be able to communicate with me what was going on at that time -- it is a whole different level of Consciousness, but they are darn well in there.
If you thought at first you shared something special with your wife - then you did, you really did - don't let her gradual descent play games with your memory on those special times. .

[Visitor]

Benedetta,

If I was convinced that Activated Liquid Zeolite could not elicit any immune response it would be my first choice to start with. I hope someone with greater knowledge of it's interaction/safety might read this and chime in with their perspective. I had read that it cannot get "stuck" in the body but it's immune potential remians unknown to me. I assume that some promoters of its use for autism chelation/detox think it is safe, but they may not have considered any possible immune effects.

[Visitor]

Benedetta,

Thank You for the compliment, I have clung to the notion I am not deluded through all of the "mind messing" this imparted. Even here until now I have communicated that she "may have an atypical Autism" though I had concluded she has/had this aspectfor a long time. My story is not usual and the fact as a woman theis presentaion does not accord with the accounts of kids not speaking or hitting their heads and I wished to have some community. I felt if I declared it so with the stroy we have those here did not understand would feel I was intruding with another condition in an Autism forum.

You are the first to think what I have portrayed is is meaningful and not madness. If this is ever validated at large I think it will represnet a fundemental shift in thinking, though my wife may be an extreme exception in certain regards. Yet, there may be a number out there with this form.

I did not plan to go through where this took me and all that I came to understand. But, In fact, while I found her lack of resentment toward anyone amazing and so admired that trait in her {a little bit of Angelman?}, as I was troubled at the way many people think and behave and she never registered any offense in a way I had ever seen, I also experienced confusion over her seeming insensitivity at times when she was “acting” so without any goal or "payoff". I would end up telling myself that I must still just have problems and let it go without being able to understand her and that somehow I needed to get past caring about others unkindness or inconsiderate social behavior and thinking. Tons of these types of interactions happened with her and I resigned myself to the fact that somehow they were quirks with no malice involved. When it finally began dawning on me what all of this meant it hit me like an atomic blast and I started to realize every moment we shared was only real in my mind. It would take a large volume to begin to chronicle the journey. One strange part is that she good in school {grades}. She could do Algebra, but not add 28 and 14 in her head.

I never was minded to try Zeolite with its alumina aspect. In fact since it seems to come from the volcanic type material that looks like what may be related to those with the skin disease reaction to alumina in the rock. I am glad I never tried it when I first came across it. It may not have that effect in these conditions, but I was not willing to try it when I first learned of it due to her high Aluminum hair levels and gladder since reading of the skin-aluminum connection I just referenced and the seeming effect it can have in autoimmunity. The other drug is amine in nature and that too put me off, let alone its possible effect on HO {Heme Oxygenase}. The chelating agent that many parents use may be the best bet.

Activated Liquid Zeolite

http://www.liquidzeolite.org/

[Benedetta]

Nick:
You are a genius for figuring it out, really.
I had three sitting in front of me, and actually saw vaccine reaction 9 times (that I recognized)
My mother even told me she had reacted to a flu shot when she was young

and I just listen to "modern Medicine" instead.

zeolite?? I am going to look that up right now.

Oh, I keep hearing malic acid -- apple juice.

And you know it may work because I actually gave my kids a lot of apple juice as kis. My son doesn't have classical autism - and believe me he did when little.

[Visitor]

On the edge seems like a good description and in some a "short circuit" produces worse symptoms. While I said Dr. Shaw's testing was "narrow" in 96 that in no way diiminishes his contribution in the areas he was looking into he was well ahead of the curve. A very insightful man from my take. I emailed him a couple of times back then and appreciated his feedback. I even sent him the "notebook" foreward" I think in July of 97. He is one of the pioneers in my view.

I never responded to your question on aluminum removal. I have never used any removal drugs/supplemets specifically made for that prupose. It may have been wise to have done so, and still might be apporopiate now. My hope was with getting her on track by diet, nutrients, immune therapy, pathogen removal, gut therapy, and other supplements her system would be able to excrete these agin properly. I think it has wroked, but may have been a slow route. I mentioned in the notebook forward that the aluminum levels in her hair were very high, but I did not not understand what the connection was in 96, though I began searching and you know the rest to some degree. Two ways I have read about are by using activated liquid zeolite and also using the drug Desferrioxamine. I don't think Zeolite was promoted for these pruposes at that time and don't know if the drug was then. I was trying to be as natural as possible in recovery and only used Diflucan because of the severity of yeast problems and intractibility of that issue. It conctians other elemnts that her sytem had some trouble metabolizing I think, so that was touchy as well {phenolic). We were heavy on the epsom salt baths to try to keep those issues in check.

Also, when I said, "it took me a good while to think that I was dealing with a degree of atypical Autism.." I meant it took me a while to be completly convinced that it was atypical auitsm. When you are determining something on your own that you have almost no precedent for there is a lot of uncertainty.

[Benedetta]

oh, I am glad you do not feel bad - because you just did not know.
I think all this is a new thing for us all.

And don't get me wrong, I am very into diet. I feel if I could lock them in a basement and just feed them what I want them to have they would get better.

But inspite of them cheating - Just had a birthday and they had to have a cake - so my son is sick with body aches and a sinus problem. He thinks it is an infection but I was reading somewhere that cortisol is released enough in the sinuses that for Cushings they actually take samples from that area if -- well I would have to look again because I do not remember. But anyway when they hurt too much they buckle down and watch the carbs more and get better. It is that simple.

I have lots of supplements - I don't know if they work as good as the diet - I think vitamin D keeps the yeast away though.

Girls present different from boys.

I have looked at my daughter and consider this.
She did have a tiny bit of a speech problem which suprised me - for language she has really a gift for it.

She won young author award for the whole state from the Kentucky education department-- when she was a Senior. Her language problem was she stuck her tongue out to far when she said the ch sound when she was small.

My son suffered a stroke - or something like a stroke and it actually caused ischemia - white spots show up on his brain so it is autism, at first very bad but he improved a lot. But he does have an actually brain injury.

Where as my daughter I believe is more endocrine dysfunction that drives or mood.

So no she does not have autism.

That is inflammation though isn't it. We are just ont the razor's edge. A endocrine/ immune problem that could get bad enough to close off the blood vessels and we have stroke like episodes, ischemia to organs including the brain.

and all that may be standing in the way is diet - and oh yeah I give asprin every day and pour turmeric on food and in pills - raise the cherries, blueberries, blackberries because they are listed as anti - inflammatory food - and and and they are low carb sweet.

[Visitor]

Since my thinking is that at the core the issues we deal with are biomedical Autism issues we could have found a doctor by 2000 or shortly thereafter that tests and treats more specifically in these ways. Amy Yasko, who I discovered a couple of years ago does much testing. There was/is Dr. Shaw of Great Plains, but his approach was very narrow in 96. I think he has broadened his coverage a lot since then. I know there are more these days, but names escape me at the moment. Granted, there are no "mainstream" caregivers that deal with these issues as a system. If you don't think your children's issues are like those in biomed Autism treatment, then I would agre, there are no whlistic help available. You can find a a connection to Ghrelin in studies on Schizophrenia,Autism, Bioplar and others along with metabolic connection, so knowing the mind is more impotant in some circumstances than knowing a group of bodily symptoms in determing what one is dealing with. I, also can't feel to bad since it took me a good while to think that I was dealing with a degree of atypical Autism plus a good bit more.

This report tells of a mother who apparently would not be believed either and even says what she noticed about her mimicking things. My wife's mimicry was virtually undetectable and it took me 13 years of being with her to understand it as her's was not repeated scripts per se, but computer language type if/then reflections. Her daughter is said to at least get some extreme emotions, my wife didn't.

Not just a boy thing: how doctors are letting down girls with autism

"What angers me is that for years I was dismissed by doctors purely because Rachel was a girl. Ryan was spotted very quickly because the autism symptoms that doctors look for are so male-orientated," said Lewns. "But Rachel's autism was hidden unless you knew where to look for it.

"Rachel could express herself, she had a couple of friends and understood emotions if someone was at an extreme: really upset or really happy. But you didn't really have to look too hard to see she didn't genuinely understand emotions or relationships: she was just mimicking scripts and scenarios from TV."

"The doctors failed time and time again to see through her coping strategies. I fought for years but I was confronted with a wall of disbelief and scepticism. They were simply unable to understand that a girl might present differently to a boy."

While Ryan's condition was acknowledged by their local authority, and he is now at a specialist school, Rachel continues to struggle at a mainstream school. "Ryan is being taught all sorts of tools and techniques to cope with his condition but Rachel is not," said Lewns.

Estimates of the ratio of females to males diagnosed with Asperger's syndrome or high-functioning autism varies from 1:4 to 1:10. No one understands this gender disparity: whether women really are less likely to be on the spectrum than men – or whether doctors are failing to spot the disorder in women."

http://www.guardian.co.uk/society/2012/jul/13/girls-autism-sex-bias-children?newsfeed=true

[Benedetta]

Nick;
There were no treatments back then.
There are no treatments now.
We are on our own -

[Visitor]

Benedetta,

As I mentioned in the past, I did note that Kawasaki's could present without some of the classical markers. So, I can't completely rule it out. I also can't know if it was involved. I re-read one of your latest posts and I am just now getting how much your daughter and husband is still dealing with. You are really giving wonderful support to them both. It sounds like your daughter is still undergoing strong biological dysfunction and your husband has apparently been physically damaged by the process.

I guess we may had been better off finding a doc or group earlier on with knowledge of biomedical testing and treatment. But, since I was not sure what I was dealing with and there wasn't much in the way of these overall caregivers in these areas back then I don't know if I could have gotten her any more "professional" help besides her quite capable allergist. H At least he did delve into some things and treat for problems most allergist would not have, at least back then. Additionally, when I first took her to the psych in 96 I tried to explain what I thought about the biological/biomedical problems I had noted at that point. I tried to get them to test her for biological/biochemical organic causes as I already felt they had to be causative. No dice, I think I just seemed a distraught misguided and likely deluded husband. I underwent sessions then too though I never probably would have outside of the circumstances we were dealing with. I needed help, but got pills and hand holding. I found myself thanking my psyche for his help when in reality I felt the only help we had gotten was a confirmation that her problems were not psychological.

I have read a lot about stress and the proposals that stress and abuse can produce a lot of disorders. They may in some cases, but with all the increase in metabolic syndrome and autoimmune/endocrine conditions there must be a lot more stress and sexual abuse in the world {ha}. In some cases psychological stress may lead to or help lead to syndromes and disorders, but probably more often organic assault and effects form environmental{non-psyche} in causing these problems and more in those more susceptible to these biological pathogens/elements. The history of association of biomedical problems as mediators/causative factors of much Autism goes back before the time when such problems were proposed to explains PTSD or stress induced conditions and while other preceding biological changes seemed to have taken place the concept that a particular biological trigger can send this into "overdrive" or set the whole cycle in motion is never mentioned outside our community as plausible.

The two following reports are the same work in essence, and they do layout some of the aspects that are central to some, or layered over or intertwined with much Autism and seeming apart of a gamut of medical/mind issues. It will look like some of what I detailed before they laid out this "stress" based view. I think the stress as the earliest cause and catalyst is the model in a minority of these cases and stress response problems are more often a reflection of an organic problem caused other things and that those children who have a vaccine and go through acute inflammation reaction are having their stress system elevated greatly and their immune systems are part of this "overdrive". The process may vary in speed for others.
In the end if mainly strss caused or materially caused the the effects on the mind are present. In stess in you get overly anxious and pass out you can deal with the mind and often prevent the outcome , if you ake a drug that causes the same biological effect and you pass out thre is a difference and taking the drug again will often produce the same outcome.

Pediatric Stress: Hormonal Mediators and Human Development

http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowFulltext&ArtikelNr=69325&ProduktNr=229036

Stress and obesity/metabolic syndrome in childhood and adolescence

http://onlinelibrary.wiley.com/doi/10.3109/17477166.2011.615996/full

[Benedetta]

Nick;
Yes, I read that a couple of years back - well not this article but- anyway even my husband's heart doctor says he needs to see her. She refueses - she is tired of going to doctors.

But I will copy this off and try to get her to go.
The thing is my son has had it too only not classical.
I think every last one of these kids that have had a vaccine reaction and developed into autism -- had atypical Kawasakis.

[Visitor]

Immune abnormalities and autism spectrum disorder

"The immune system—particularly maternal infection—is thought to factor critically in the development of autism spectrum disorder (ASD), but it remains unclear whether immune system abnormalities contribute to the pathogenesis of ASD or stem from primary neural dysfunctions of the disease. Elaine Hsiao et al. explored links between prenatal programming and long-term immune alterations in ASD by examining immune function in the offspring of immune-activated mothers using the maternal immune activation (MIA) mouse model that reproduces many features of autism. Consistent with a proinflammatory phenotype, the authors report, MIA offspring exhibit systemic deficits in T regulatory cells, known suppressors of innate and adaptive immunity. In addition, the authors found that CD4+ T helper cells from MIA offspring produce elevated levels of IL-6 and IL-17—two cytokines that play key proinflammatory roles in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Transplanted immunologically normal bone marrow reduced two core diagnostic features of ASD in MIA offspring, suggesting that immune abnormalities may contribute to ASD-related behaviors. The findings, the authors propose, support causal links between cellular-level immune dysregulation and ASD behavioral deficits in a mouse model of autism."

http://www.pnas.org/site/misc/highlights.shtml#autism

In a lengthier release on this same report there is this including gut function and interest in looking at the gut bacteria in relation to this overall "dysfunction"/damage.

Researchers find evidence of link between immune irregularities and autism

"What has remained unanswered, however, is whether the immune changes play a causative role in the development of the disease or are merely a side effect. Now a new Caltech study suggests that specific changes in an overactive immune system can indeed contribute to autism-like behaviors in mice, and that in some cases, this activation can be related to what a developing fetus experiences in the womb....

Next, the researchers characterized the immune system of the offspring of mothers that had been infected and found that the offspring display a number of immune changes. Some of those changes parallel those seen in people with autism, including decreased levels of regulatory T cells, which play a key role in suppressing the immune response. Taken together, the observed immune alterations add up to an immune system in overdrive—one that promotes inflammation.

"Remarkably, we saw these immune abnormalities in both young and adult offspring of immune-activated mothers," Hsiao says. "This tells us that a prenatal challenge can result in long-term consequences for health and development."

With the mouse model established, the group was then able to test whether the offspring's immune problems contribute to their autism-related behaviors. In a revealing test of this hypothesis, the researchers were able to correct many of the autism-like behaviors in the offspring of immune-activated mothers by giving the offspring a bone-marrow transplant from typical mice. The normal stem cells in the transplanted bone marrow not only replenished the immune system of the host animals but altered their autism-like behavioral impairments.

However, Patterson says, the results do suggest that immune irregularities in children could be an important target for innovative immune manipulations in addressing the behaviors associated with autism spectrum disorder. By correcting these immune problems, he says, it might be possible to ameliorate some of the classic developmental delays seen in autism. In future studies, the researchers plan to examine the effects of highly targeted anti-inflammatory treatments on mice that display autism-related behaviors and immune changes. They are also interested in considering the gastrointestinal (GI) bacteria, or microbiota, of such mice. Coauthor Sarkis Mazmanian, a professor of biology at Caltech, has shown that gut bacteria are intimately tied to the function of the immune system. He and Patterson are investigating whether changes to the microbiota of these mice might also influence their autism-related behaviors."

http://medicalxpress.com/news/2012-07-evidence-link-immune-irregularities-autism.html

Could it be the immune system and gut/bacteria are related to Autism?

[Visitor]

Benedetta,

Just for you. Quotes from the release.

Kawasaki Disease in Childhood Linked to Increased Risk of Adult Heart Disease

"ScienceDaily (July 17, 2012) — Cedars-Sinai researchers have linked Kawasaki Disease, a serious childhood illness that causes inflammation of blood vessels throughout the body, with early-onset and accelerated atherosclerosis, a leading cause of heart disease in adults.

In a study published in the August 2012 print edition of Arteriosclerosis, Thrombosis, and Vascular Biology, an American Heart Association peer-reviewed medical journal, a team of researchers showed how Kawasaki Disease in young mice predisposed them to develop accelerated atherosclerosis, often called hardening of the arteries, in young adulthood. The study also suggests that aggressive early treatment of the blood vessel inflammation caused by Kawasaki Disease may reduce the future risk of developing accelerated atherosclerosis. Up to 25 percent of children with Kawasaki Disease will develop inflammation of the coronary arteries, making it the leading cause of acquired heart disease among children in developed countries..

"By recognizing the connection between this vascular inflammatory disease and hardening of the arteries in young adults, physicians will be better prepared to provide preventive care to these vulnerable patients."

http://www.sciencedaily.com/releases/2012/07/120717182957.htm

[Benedetta]

Nick;
When sometimes we dispair, there is no need to explain it as a pity party.
I doubt that is the case at all. - we are not worried for ourselves, but for our love ones.
Hardly makes it a pity party when we have pity/concern for those we love, now does it.

[Benedetta]

Messing with your mind.
Well that is easy enough done!

What messes the most with my mind.
Is the professors (many) at the univerities saying vaccines are safe, get them, get them now.

Fast forward 20 years or more and they are telling my daughter (damaged by vaccines/with a brother and father damaged with vaccine) they are safe, get them. As she sits beside another girl who is a mother to a little boy that she knows has been vaccine damaged.

What also messes with my mind is - our local newspaper, last week said our area, is number one in the entire state for drug abuse. And I have good reason to suspect that these drug abusers/ stealers/ thieves are suffering from mannia highs of bipolar as they climb electric lines to strip copper from live wires. Meth??? why are they taking a drug that is an upper to begin with? and how are they smart enough to make it --- and they are --- sure they are burning down all the old, eye sore farm houses - probably again while in some mood that they are invincible and can do anything!

I want to write the newspaper, put an article in the editorial - but I would just sound like a nut. Which maybe I just might be???? Not near as scary a thought though - that I am right and I and I alone know it!

[Visitor]

Benedetta,

I need to correct a phrase from the last post.
I wrote:

"she has no memory of any of our life before very end of 1996 until now.."

I meant:

she had/has no memory of our life from the very end of 1996 back.

She has no autobiograpical memory for anything before the end of 96, just the a lot of facts and awareness of how to do things she did before. The one thing that stands out is she will remember faces only if if she saw a photograph of them before 96 and seeing it more than once usually I think was needed. People may label such event sdissociation in many cases, but whatever she regurgitated was what was said by others bout an event and she would create a mental playout of the event afterwards based on what was said about the event, not from a personal experience of the event.

Oh well.

[Visitor]

Benedetta,

I do view my rabbit hole comments as speculative, that is why I called it a rabbit hole. There is a logic that may pertain though.

I think I have left you with the wrong impression about my wife. There have been some very difficult periods during her long road, and even though she still has a temperamental immune system and feels worse more often than the average person, she is doing failry well a lot of the time. Sometimes she does have bouts with feeling quite poorly still though. The hardest part is she has no memory of any of our life before very end of 1996 until now, and a lot of the time since then has been a developmental period. It was slower and had reversals at times due to the fact her immune system was still in overdrive to some extent. The Olmesartan has helped a great deal. The "lonely" aspect you mentioned is that I could not convince anyone of this reality and when you are living with someone who shares an unusual history with you and the history you thought you had was not real it messes with your mind. I imagine I am not able to convey the effect this has, but until the last 2 or3 years she was still unaware of a number of important concepts about social interaction and given the distance that caused and the fact no one was in this world because they did not believe what I said it was quite isolating and if your family doesn't believe you most others won't either and don't care enough to wade into the matter. So, as of now and the last couple of years things are much better as she understands all of what these dynamics have created and in this I have company. I still can't keep the dichotomy of realities at bay at times and slip through the cracks like I did here a while back and posted my "pity party" event. This happens when I am trying too hard to put enough together in the "science" and findings to cause those I had tried to communicate all this to understand. While one of my family members may consider things differently and see some of the medical aspects the global aspect is too strange to embrace and I think I will not succeed. A lot of the time I no longer care what they belive, but sometimes I still do. After all this time the social interest in denying it is other than what they believed would be very uncomfortable. For all I know they can't understand because it would take having seen and been through with her for it to change fundamental attitudes that are not intuitively accepted. That is why I post here. People who understand the lack of some of the aspects of comprehension as some with Autism have are contemplated by those here and these become the caregiver’s reference of mind about things others do not want to accept. For instance it is not a biological condition it is just bad behavior and poor parenting.
I do appreciate your kind concern, but it is not my wife that is my problem. The first ten years were the very hard, but the first 2 were other worldly mind bending.
I hope your family can get improvement health wise too. As you can tell I think Angiotensin is fairly impactful in these immune related deregulations and if you have not given the articles and ideas in this thread good thought it might be profitable to do so as this type of process could be part of their issues too and cytokine control may be very helpful in your family as well.

I meant to add PTEN to the gene list in the last post.

[Benedetta]

I meant she wrote a book
not
work a book.
Sorry can't type.

[Benedetta]

Nick;
You have said some really deep stuff, and it is going to take me a while to ponder on it. Considering 30 years ago they were looking at aluminium - it sounds very reasonable. How to get it out though???

Have you found anything on that?

Rabbit holes, rabies, bipolar using energy while you have energy -- - I use to read Scientific America a lot and other science magazines. That kind of stuff makes for entertainment and deep thought but in the end - it is well - just spectulation.

Is your wife not doing mentally well at all?
I am sorry, Nick - that can be very lonely.

Mentally here --we are doing well.
Emotionally - are ups and downs- and I do mean that loops back to the mental part of it.
However; Real painful aches and painsis a reallllllllllll BIIIIGGGGGG Problems.

I spent an hour last night rubbing my daughters shoulders.
I have spent many of a night rubbing her legs.
My husband is on really powerful pain killers and if he exercises he must sleep all day long the next. That is lonely.

The only healthy one in the bunch is my son - who is delighted with his health in the last five years and brags.
He obssessess alot thought. Right now all he wants to talk about is the show "Eureka".
But he is helping me put up a fence for the cattle -- I do worry though that he is 26 - I would like him to have a life, mate, children - It looks like my two kids will have each other forever -- I did want more for them.

I am sorry your wife is so ill, my mother-in-law slowly descended into dementia after illness for a very long time. She too could be lead to think as the people around her did. She was also very intelligent and work a dietary book used by California Hospitals for a very long time. .

Good luck with it Nick, Know I will include you and your wife each day in my prayers.

[Visitor]

Benedetta,

I think in part it is a matter of timing and degree. My thoughts are that in some with Autism this begins in the womb and for others it is a suceptibility that will either begin as one interacts with the postnatal enviroment or will stay at a bay unless triggered by an assault alone or in combination of some nature such as vaccines, infections, chemicals/toxins, more metals, or antibiotics/drugs, and microbiome/intestinal bacterial profiles.

For those the degree of dysregulation may be lesser and they are likely to be affected at the time of hormone surges at adolescence/puberty and additionally for women more during pregnancy and interactive with the menstrual cycle.

The recent reports connceting Autism, Schizophrenia, and Bipolar in families has been apart of my thought since the 90's. I also suspect there is a non- Hodgkin lymphomas susceptibility among many of these type families.

But, even though Autism ans bioplar may share some common biological distrubances. They are worm holes at different times of dvelopment and the mental states in each are very distinct. My wife had totally dilated pupils from the time I met her and was noticed in her from her earliest years. If you have read the Mecp2/ angiotensin connections I asserted in this thread it could be thought that if this effect is happening very early you would have a drastic effect compared to much milder or adult onset of this effect and the person would have a more typical global interactive understanding of typical human concepts and relationships, those effected in the womb or in the first 3 years would see mcuh more drastic changes. This does not account fo the other neurochemica/mitochondrial/immune effects that effect the infant mind compared to later, even adult onset. Schizophrenia could be a more static alteration state mediated more by the immune system aspect usually later than Autism and maybe in those with lower Estrogen. Yet, genetic/epigentic profiles pre-condition each of these conditions as a susceptibility or as a strongly causitive factor in some cases it seems.

Hypothalmus and brain stem invovlemnt....yes. But, what is the vaccine conection? Nalp3 via alum is the most likley as it effects Angiotensin/Vasopressin and this works in the brain stem, vagal verve system, and these effects bear on the hypothalmus. The glycine may affect cellular membranes and cause a number of effects in susceptible kids and this forms a disruption in the cardio/vascular/neuroimmune/energy ATP, and immune system relationship. These relate to the norephinephrine and hypertension/pupil size and heart rate parts I mentioned in this thead. Her system was in overdrive and had been all of her life. After all the other biomed treatments approaches we used{and they were tremendously positive, there was still a progression of certain problems and menatal barriers remained or flucuated in severity. The Olmesartan has done a great deal to remedy or control these remaining issues and thes issues were not small. I considered every imaginable condition when first trying to understand her problems and read volumes on each. Nothing fit that well, but the core aspect of strong Autism with a twist was the most explanatory in our particular case She was simply a condtioned mind that had no concept of being and reflected the social patters around her and the strongest or most controlling personality directed her.
It was not biologically possible for her to do otherwise.

In the notebook I said she could not make sense of the confusion in her mind. it turns out there was no confusion until I was bringing her into reality, only facts and patterns. Nobody meant anything to her before.

Rabbit trail comment. In rabies the infection causes an animal to be more aggressive and more likly to bite. Why? Is it beacause the anmal subconciously at it's core is a viscous antio-social creature, or is it beacuase an infection that causes that behavior is most likely to be transmitted to others though aggressive biting and spread and survive. An infection that makes you more of a predator or a prey allows the infectious organism to spread, propagate, and survive. Bipolar may be the bodies way of showing a battle between these two effects of sickness behavior in certaion immune response scenarios with spreading behavior or motivated buying/gathering to prepare for a downtime of homeostasis and recovery in certain immune phaseses and depression and withdrawl in the other when the body is trying to reach homeostasis. In our day those bahaviors semm more strange as getting things is relatively easy and obtaining anything that conveys survial states is a reward. In the past in lean times killing an animal in the wild for food would have been such a reward.
Now t5hat reward may be a hunting gathering buying spree.

After saying all of this I can tell you my wife was/is not bipolar.

One thing I have been looking into is the relationship of phenlic sensitivfity and pyrxoidal kinase. I have not reached any firm thoughts, but it is hard to not think that if b6 can help relive moring sickness it may be of particular relevence to what is happening in some inutero as the shift to glycolysis is tied to this and both my wife and her mother had severe morning sickness. I have tied this to Isoniazid in her mother, but the whole interaction tied to the glutamate/Gaba system and this vitamin/kinase has a lot of ties so far.

With all the likely enviromental assaults there are susceptible genetic profiles and gene expression issues. I think Shank 2, Stat 3, IGF-1, PI3K and AKT are ones for our scenario to decue in relationship to, but as in the Aluminum problem in those with the skin condition we discussed in another thread. These condtions in those with susceptibily may never be a problem without enviroment causes making them so.

[Benedetta]

Visitor;
That is very true for mine.
Also with bipolar - when in a mannia state have very dilated pupils too. Another thing that I can attest to.

And when bipolar goes psychotic - dilated too.
Lower brain function like around the brian stem - up around the hypothalmus - do you think?

[Visitor]

Saliva and Pupil Size Differences in Autism Show System in Overdrive

"University of Kansas researchers have found larger resting pupil size and lower levels of a salivary enzyme associated with the neurotransmitter norepinephrine in children with autism spectrum disorder.

However, even though the levels of the enzyme, salivary alpha-amylase (sAA), were lower than those of typically-developing children in samples taken in the afternoon in the lab, samples taken at home throughout the day showed that sAA levels were higher in general across the day and much less variable for children with ASD.

"What this says is that the autonomic system of children with ASD is always on the same level," Christa Anderson, assistant research professor, said. "They are in overdrive."

The sAA levels of typically-developing children gradually rise and fall over the day, said Anderson, who co-directed the study with John Colombo, professor of psychology.

Norepinephrine (NE) has been found in the blood plasma levels of individuals with ASD but some researchers have questioned whether these levels were just related to the stress from blood draws.

The KU study addressed this by collecting salivary measures by simply placing a highly absorbent sponge swab under the child's tongue and confirmed that this method of collection did not stress the children by assessing their stress levels through cortisol, another hormone.

Collecting sAA levels has the potential for physicians to screen children for ASD much earlier, noninvasively and relatively inexpensively, said Anderson.

But Anderson and Colombo also see pupil size and sAA levels as biomarkers that could be the physiological signatures of a possible dysfunction in the autonomic nervous system.

"Many theories of autism propose that the disorder is due to deficits in higher-order brain areas," said Colombo. "Our findings, however, suggest that the core deficits may lie in areas of the brain typically associated with more fundamental, vital functions."

http://www.sciencedaily.com/releases/2012/07/120712131529.htm

[Benedetta]

Nick;
Thanks for the summary.
Vaccines are targeting the hypothalmus and cascades on down to pituitary, thyroid, pancreas, adrenal glands.
But how is it being targeted; uptake of aluminium, mercury or the immune system attacks it?

[Visitor]

Back in March of this year there was a post on children dying in Uganda. It is found here:

Uganda’s Children are Dying! Are Pharmaceutical Trials to Blame?

http://www.ageofautism.com/2012/03/ugandas-children-are-dying-are-pharmaceutical-trials-to-blame.html

At the time I tried to post some thoughts about it, but for whatever reason they did not show up. Since I am commenting on PI3K/AKT now the things I attempeted to post then are possibly helpful in the conected features of manifestations connected to predispositions and triggers due to releated factors effecting or involving PI3k/AKT.

Here is what I tried to post to that thread.

Increased GABA Levels in Medial Prefrontal Cortex of Young Adults with Narcolepsy

"Recently, narcolepsy has strongly been suggested to be caused by hypocretin deficiency,1 as narcoleptic patients have shown a markedly decreased hypocretin concentration in the cerebrospinal fluid (CSF).2,3However, hypocretin cannot solely regulate the sleep-wake or REM-NREM sleep state. A number of neurotransmitters work in concert with hypocretin for the modulation of the sleep-wake state.4 Among sleep-related neurotransmitters, gamma amino-butyric acid (GABA) and glutamate are major inhibitory and excitatory neurotransmitters, respectively.5,6 Hypocretin neurons have positive feedback mechanism with glutamate and negative feedback mechanism with GABA.4 Therefore, narcolepsy may accompany changes of GABA and/or glutamate."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2276749/

It was stated in the post that:

"In all cases the symptoms were characterized by unavoidable falling asleep during daytime, different sleep disturbances combined with changes in the appetite and metabolism. It seems that eating sets off attacks, which is why many of the children, at least in Uganda, have been reported as malnourished and underdeveloped."

If eating sets off attacks what could be affected to mediate the symptoms from eating.

Wiki - Orexin

"Orexins, also called hypocretins, are the common names given to a pair of excitatory neuropeptide hormones that were simultaneously discovered by two groups of researchers of rat brains...Although these peptides are produced by a very small population of cells in the lateral and posterior hypothalamus, they send projections throughout the brain...
The orexin/hypocretin system was initially suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of orexin A/hypocretin-1 increases food intake. In addition, it stimulates wakefulness and energy expenditure...
Orexin seems to promote wakefulness. Recent studies indicate that a major role of the orexin/hypocretin system is to integrate metabolic, circadian and sleep debt influences to determine whether an animal should be asleep or awake and active. Orexin/hypocretin neurons strongly excite various brain nuclei with important roles in wakefulness including the dopamine, norepinephrine, histamine and acetylcholine systems[5][6] and appear to play an important role in stabilizing wakefulness and sleep...

Food Intake

Orexin increases the craving for food, and correlates with the function of the substances that promote its production.
Leptin is a hormone produced by fat cells and acts as a long-term internal measure of energy state. Ghrelin is a short-term factor secreted by the stomach just before an expected meal, and strongly promotes food intake.
Hypocretin-producing cells have recently been shown to be inhibited by leptin (through the leptin receptor pathway), but are activated by ghrelin and hypoglycemia (glucose inhibits orexin production). Orexin/hypocretin, as of 2007, is claimed to be a very important link between metabolism and sleep regulation.[citation needed] Such a relationship has been long suspected, based on the observation that long-term sleep deprivation in rodents dramatically increases food intake and energy metabolism, i.e., catabolism, with lethal consequences on a long-term basis...

Lipid metabolism

Orexin-A (OXA) has been recently demonstrated to have direct effect on a part of the lipid metabolism. OXA stimulates glucose uptake in 3T3-L1 adipocytes and that increased energy uptake is stored as lipids (triacylglycerol). OXA thus increases lipogenesis. It also inhibits lipolysis and stimulates the secretion of adiponectin. These effects are thought to be mostly conferred via the PI3K pathway because this pathway inhibitor (LY294002) completely blocks OXA effects in adipocytes...

Interaction with other neurotransmitter systems
Orexinergic neurons have been shown to be sensitive to inputs from Group III metabotropic glutamate receptors,[23] adenosine A1 receptors,[24] muscarinic M3 receptors,[25] serotonin 5-HT1A receptors,[26] neuropeptide Y receptors,[27] cholecystokinin A receptors,[28] and catecholamines,[29][30] as well as to ghrelin, leptin, and glucose.[31] Orexinergic neurons themselves regulate release of acetylcholine,[32][33] serotonin and noradrenaline,[34] so despite the relatively small number of orexinergic neurons compared to other neurotransmitter systems in the brain, this system plays a key regulatory role and extensive research will be required to unravel the details. Orexins act on Gq-protein-coupled receptors signaling through phospholipase C (PLC) and calcium-dependent as well as calcium-independent transduction pathways. These include activation of electrogenic sodium-calcium exchangers (NCX) and a non-specific cationic conductance, likely channels of the transient receptor potential canonical-(TRPC) type activation of L-type voltage-dependent calcium channels, closure of G-protein-activated inward rectifier potassium channels (GIRK), and activation of protein kinases, including protein kinase C (PKC), protein kinase A (PKA), and mitogen-associated protein kinase, also called mitogen-activated protein kinase (MAPK). Postsynaptic actions of orexins on their numerous neuronal targets throughout the CNS are almost entirely excitatory.[35]"
http://en.wikipedia.org/wiki/Orexin

If a vaccine has caused or set in motion or promoted a process causing an "ischemic neuronal injury" then the orexin/leptin/ghrelin/circadian clock/metabolism interaction could be altered. This may be a protective mechanism to prevent damage, but may also be a condition being triggered that is needed due to injury but is not needed constantly in these children and is functioning relative to an autoimmune like condition. GH and other endocrine function and system wide effects would be produced. If the eating orexin/hypocretin reaction was effected in a certain way that a small amount of food may inhibit orexin and inbalanced gaba/glutamte responses may produce extreme lethargy or even narcolepsy.

Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3 beta and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical neuronal cells.

http://www.ncbi.nlm.nih.gov/pubmed/18541646

Ghrelin protects spinal cord motoneurons against chronic glutamate-induced excitotoxicity via ERK1/2 and phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3β pathways

http://www.sciencedirect.com/science/article/pii/S0014488611001178

[Visitor]

Also, my consideration of the gene issues mentioned, if true or not, in the last post does not take away from any of the chain of events, explanations, contributions from other noxious elements, metabolic/immune conditions, biological interactions, and treatments of them I have written about in this or any posting I have made at AoA. It does seemingly help explain part of what helped them come about though. I am not dismissing the vaccine role in up regulating and/or setting off the cascade in those who are thereby sensitized to this becoming a pathological deregulation that may be interacting in a few ways to do so. It may be as well that Trophblast death may lead to hypoxia and nutrional deficits that help bring about mutaitons, particularly the ones in question here. It could be I am allowing a finish line too as I realize other factors could lead to disruptions in theses gene pathways besides mutations, but there should be a lot to follow about these pathways if they are as definitively a factor in disease/disorder as they propose.

While I also think the immune response of the mother, epigenteic effects, toxins, metals, chemicals or bacteria aand viruses may play a role the idea remains that certain genotypes and phenotyps would be more likely to be affected by these.

In another thread at AoA on gut microbes I posted ideas and theories related to these new genes mentioned in this report. Here are the links and some comments I made then.

The last post contains a basic theory that certainly is basically a thought experiment. I felt I should not have posted it afterwards. But, with the connection I find compelling wiith TH17 and by relation TH1, I find this new relaease today makes the theory a little more plausible as it mentions a linkage beween TH17, PI-3K, and Akt . PTEN is often linked to prostate cancer. That at least has a slight tie to the idea that autism is much higher in boys.
Also, about PTEN Wiki says:

Cell Regeneration

"PTEN's strong link to cell growth inhibition is being studied as a possible therapeutic target in tissues that do not traditionally regenerate in mature animals, such as central neurons. PTEN deletion mutants have recently[8] been shown to allow nerve regeneration in mice.[9]"

A Novel Mechanism That Regulates Pro Inflammatory Cells Is Identified

"Cytokines such as IL-2 or IL-7, which share a common receptor component (called gamma-c) are released by other T cells or specialized non-lymphoid cells. This family of cytokines is critical in the development, survival, proliferation and differentiation of T cell subsets. Gamma-c cytokines activate several signaling pathways within the cells that lead to activation of transcription factors, which then turn on and off specific genes. The researchers found that gamma-c cytokines induced Th17 cell function by activating a specific pathway involving the kinases PI-3K and Akt. They further showed that two transcription factors called FOXO1 and KLF2, which are normally inhibited by PI-3K and Akt activity, suppress the production of Th17 cytokines when overexpressed, even if PI-3K and Akt are fully active. These lines of evidence highlight a novel anti-inflammatory mechanism of action for PI-3K and Akt inhibitors, some of which are in clinical development for cancer-related indications."

http://www.newswise.com/articles/a-novel-mechanism-that-regulates-pro-inflammatory-cells-is-identified

The Pten gene has been associated with some Autism and with some cancer. Here is a theory. It might be that there is a widespread effect on regions of brain cortical cells that is the earliest part of the cancer process. This might be thought of as a very limited diffuse cortical cancer process. The gene expression is primed to these processes with attendant cancer type reactions of inflamation and immune response. Inflamation and immune irregularities are cited by some research on brains of those with autism. This could be tied to dna release, aging,and apoptosis timing alteration. That could be relevant to why brain cells of those with autism grow more quickly and then, from what I have read, parts of the brain shrink more quickly with age.

PTen Gene - Wiki

http://en.wikipedia.org/wiki/PTEN_(gene)

PTEN and the PI3-Kinase Pathway in Cancer

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2710138/

Phosphatidylinositol-3-kinase/Akt/glycogensynthase kinase-3 b and ERK1/2 pathways mediate protective effects of acylated andunacylated ghrelinagainst oxygen-glucose deprivation-inducedapoptosis in primary rat cortical neuronal cells

http://www.google.com/url?sa=t&rct=j&q=phosphatidylinositol-3-kinase%2Fakt%2Fglycogen%20synthase%20kinase-3b%20and%20erk1%2F2%20pathways%20mediate%20protective%20effects%20of%20acylated%20and%20unacylated&source=web&cd=1&ved=0CEoQFjAA&url=http%3A%2F%2Fjoe.endocrinology-journals.org%2Fcontent%2F198%2F3%2F511.full.pdf&ei=QDruT8jeC5Ka8gSh1N2RAg&usg=AFQjCNGIIUfrnuEarpH3pwNO9hmiHHFRbA

Autism Glutathione Levels Low In Some Autistics-Why?
Abstract
We have examined the integrity of J774 cell nitric oxide (NO) production and glutathione maintenance, whilst NADPH supply was compromised by inhibition of the pentose pathway with 6-aminonicotinamide. In resting cells 6-phosphogluconate accumulation began after 4 h and glutathione depletion after 24 h of 6-aminonicotinamide treatment. Cellular activation by lipopolysaccharide/interferon-λ decreased glutathione by ∼50% and synchronous 6-aminonicotinamide treatment exacerbated this to 31.2% of control (Phttp://linkinghub.elsevier.com/retrieve/pii/S0014579398009594

http://endo.endojournals.org/cgi/content/abstract/141/7/2429

http://en.wikipedia.org/wiki/Phosphoinositide_3-kinase

http://www.ncbi.nlm.nih.gov/pubmed/16439036

Dealing with the Grehlin connection here are some articles and thoughts.

Trophoblast apoptosis is inhibited by hepatocyte growth factor through the Akt and beta-catenin mediated up-regulation of inducible nitric oxide synthase.

http://www.researchgate.net/publication/8048090_Trophoblast_apoptosis_is_inhibited_by_hepatocyte_growth_factor_through_the_Akt_and_beta-catenin_mediated_up-regulation_of_inducible_nitric_oxide_synthase

Having believed AGE's are a problem in my wife and may be in at some point in Autism and other conditions this shows Ghrelins anti-apoptotic effect.

Ghrelin inhibits AGEs-induced apoptosis in human endothelial cells involving ERK1/2 and PI3K/Akt pathways

http://scienceindex.com/stories/1505812/Ghrelin_inhibits_AGEsinduced_apoptosis_in_human_endothelial_cells_involving_ERK12_and_PI3KAkt_pathways.html

Wiki Ghrelin I would suggest reading the whole entry.

"Ghrelin is a potent stimulator of growth hormone from the anterior pituitary gland.[3] The ghrelin receptor is a G protein-coupled receptor, known as the growth hormone secretagogue receptor. Ghrelin binds to the GHSR1a splice-variant of this receptor which is present in high density in the hypothalamus, pituitary as well as vagal afferent cell bodies and vagal afferent endings throughout the gastro-intestinal tract [4][5]

Ghrelin plays a significant role in neurotrophy, particularly in the hippocampus, and is essential for cognitive adaptation to changing environments and the process of learning.[6][7] Recently, ghrelin has been shown to activate the endothelial isoform of nitric oxide synthase in a pathway that depends on various kinases including Akt.[8]...

Ghrelin has been proposed as a hormone which promotes intestinal cell proliferation and inhibits its apoptosis during inflammatory states and oxidative stress.[25][26] It also suppresses the pro-inflammatory mechanisms and augments anti-inflammatory mechanisms thus creating a possibility of its therapeutic use in various gastrointestinal inflammatory conditions including colitis, ischemia reperfusion injury and sepsis.[27][28] In fact, animal models of colitis, ischemia re-perfusion and sepsis related gut dysfunction have been shown to be benefited with therapeutic doses of ghrelin."

http://en.wikipedia.org/wiki/Ghrelin

[Visitor]

Many of you may feel this is not relevant and it is quite possible that your child doeas not have the gene issues this new finding describes, but just in case here are some thoughts and the new info.

I have consistently allowed a place for genes and epigentic involvement and find this new information of value and likely to apply to many. I have doubted that that genes alone cause the majority of Autism and that a genetic susceptibility does exist and more often than not is triggered by a later event or events.

Other genes may be involved in a particular person and other gene expression may be affected by these genes. Those who may have these issues may need a trigger after birth for the genetic influences to become pathological and biomedical approches to deal with the problems they predispose to, if not already strongly causing congenital disease, may reverse or keep in check the problem{s}. Enviromental factors could be causing more of these mutations or making their existance a problems for those who develop them. Those with the gene issues spoken of in the following report would reasonably vary in their effect on an individual with these issues, but given what I have found it makes abundant sense to think my wife has issues with these genes.

They say these mutations may occur after conception. What causes them is still in question from what I can tell from the report. These gene pathways are dead center in the scope of what I have found myself studying in tracing where my wife's problems relate. If it is part of her problem ther other metabolic immune problems I have found and understood would be a mediator precipitation the malfunction with or without triggers. I still believe it is clearly with triggers if involved in her case. It still could be that these are minor in their effect in some and enviorment factors cause the derailment of development.

As a side note I suspect the Angiotensin system was perturbed in her brain and vascular system in the womb in concert with the gene issuse here or subsequntly effected. This scenario of effect may lie at the heart of many disease that these genes are involved throughtout life with various triggers or lifestyle being the tipping point or just aging.

Here is the heart of the report.

Study Finds New Gene Mutations That Lead to Enlarged Brain Size, Cancer, Autism, Epilepsy

A research team led by Seattle Children’s Research Institute has discovered new gene mutations associated with markedly enlarged brain size, or megalencephaly. Mutations in three genes, AKT3, PIK3R2 and PIK3CA, were also found to be associated with a constellation of disorders including cancer, hydrocephalus, epilepsy, autism, vascular anomalies and skin growth disorders. The study, “De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes,” was published online June 24 in Nature Genetics.

The discovery offers several important lessons and hope for the future in medicine. First, the research team discovered additional proof that the genetic make-up of a person is not completely determined at the moment of conception. Researchers previously recognized that genetic changes may occur after conception, but this was believed to be quite rare. Second, discovery of the genetic causes of these human diseases, including developmental disorders, may also lead directly to new possibilities for treatment.

AKT3, PIK3R2 and PIK3CA are present in all humans, but mutations in the genes are what lead to conditions including megalencephaly, cancer and other disorders. PIK3CA is a known cancer-related gene, and appears able to make cancer more aggressive. Scientists at Boston Children’s Hospital recently published similar findings related to PIK3CA and a rare condition known as CLOVES syndrome in the American Journal of Human Genetics.

Physician researcher James Olson, MD, PhD, a pediatric cancer expert at Seattle Children’s and Fred Hutchinson Cancer Research Center who was not affiliated with the study, acknowledged the two decades-worth of work that led to the findings. “This study represents ideal integration of clinical medicine and cutting-edge genomics,” he said. “I hope and believe that the research will establish a foundation for successfully using drugs that were originally developed to treat cancer in a way that helps normalize intellectual and physical development of affected children. The team ‘knocked it out of the park’ by deep sequencing exceptionally rare familial cases and unrelated cases to identify the culprit pathway.” The genes— AKT3, PIK3R2 and PIK3CA—all encode core components of the phosphatidylinositol-3-kinase (P13K)/AKT pathway, the “culprit pathway” referenced by Olson.

The research provides a first, critical step in solving the mystery behind chronic childhood conditions and diseases. At the bedside, children with these conditions could see new treatments in the next decade. “This is a huge finding that provides not only new insight for certain brain malformations, but also, and more importantly, provides clues for what to look for in less severe cases and in conditions that affect many children,” said William Dobyns, MD, a geneticist at Seattle Children’s Research Institute. “Kids with cancer, for example, do not have a brain malformation, but they may have subtle growth features that haven’t yet been identified. Physicians and researchers can now take an additional look at these genes in the search for underlying causes and answers.”...

http://www.newswise.com/articles/study-finds-new-gene-mutations-that-lead-to-enlarged-brain-size-cancer-autism-epilepsy

[Visitor]

On second thought I stand by my original assessemnt about that report when I said, "That report barely acknowledges the down side though it does mention long term activation suppresses the immune system." I was inadverdently crediting them with the better assessemnt given in the report I quoted afterewards speaking of the real problems of long term stress activation.

The following is pretty much what I have thought to be true as well.
If you read the posts in this thread you will find a lot of the same overview. I am looking forward to reading the full report as it may contain information that will be additionally useful in Autism, it already explains some things.

A neuro-immune explanation for the remitting/relapsing nature of ME/CFS

http://www.prohealth.com/library/showarticle.cfm?libid=17058

[Benedetta]

Well, they did..
But they have been missing it for a very long time because that meeting we went to was in 2001 - I do believe.

I kind of reminds me of the time I saw a bunch of boys working on a car and it would only run while gas was in the carburator (I think that was it). They finally took of the hood, one sat upon the engine holding a cup full of gas and pouring gas into the carburator as it used it up; meanwhile the other drove --and down the road they went.

A button to press an electrical charge to the vagus nerve kind of reminds me of that. : )

[Visitor]

A few posts back about a report I said:

Much earlier in this thread someone spoke of "missing the forest{wood} for the trees". This report seems to miss the forest.

How Stress Can Boost Immune System

Correction: I said they missed the forest. I was wrong they do tell about long term problems of stress/immune activation.

[Benedetta]

Vistor;
My son and I went to a eplipesy meeting in Mt. Pleasant, Michigan - I could not get use to March being the dead of winter and snow up to my thighs - from Kentucky and March is crocus and red buds.
But anyway;
The whole meeting was on vagus nerve stimualation. Many there were thinking about having an implant - for if they felt a seizure coming on they push a button that sent an electric shock to the vagus nerve.

They had no idea why it worked. I know because we all asked. So at last - this is the answer.
Thanks.

[Visitor]

The causation of the brain/immune/vascular/gut dysregulation clearly involves many factors that interact and different events in one are can effect the others, but where is the funemental nexus or mediator? Allowing many factors become involved and even that mainly stress{psychological} can cause dysfunction in some cases it is important to find if in many cases the main cause is due to a biological issue or enviromental effect occurring anywhere in life. Particularly for some Autism has an non-psychological factor dysregulated or even damaged a biolgic system that continually disorders the mind and body?

This report explains how a neurogenic factor may be key and while not addressing possible psycholgical elements bearing on it, it does make very reasonable if not likely that this factor in part causes dysregulation and is itself dysregulated by non-psychological factors.

Since I have quoted a great deal you may just want to go to the link at the end and read the whole thing keeping in mind the Vagus nerve, related to angeiotensin and the Solitary Nucleus{the possible neurogenic factor} discusssed in an earlier post.

Autonomic Neural Regulation of the Immune System

Implications for Hypertension and Cardiovascular Disease

"The autonomic and the immune systems play major roles in the pathogenesis of cardiovascular disease and hypertension. To date, those 2 systems have been studied extensively but independently by cardiovascular biologists and by immunologists. The notion that the autonomic system can modulate the immune system and thereby influence the pathogenesis of cardiovascular disease and hypertension and their clinical outcome is novel and critical.

In this brief review we focus on that interaction and an integrated understanding of the neuro-immune axis. We also highlight recent progress and future research directions.

The main theme is that dysregulation of the autonomic system enhances the inflammatory response of the innate and adaptive immune systems leading to the initiation or acceleration of pathological processes and worsening of cardiovascular risks. The therapeutic potential of restoring an optimal autonomic control of the immune system is very promising.

Both components of the neuro-immune axis may be involved in its disruption. One is the autonomic nervous system, which may be dysregulated or imbalanced with increased sympathetic and decreased parasympathetic activation. The other is the immune system itself, which may be abnormally sensitive to the modulatory influence of the autonomic system. These 2 components are briefly described below...

The complexity of cardiovascular mechanisms that contribute to hypertension has been challenging. The roles of vascular and renal abnormalities are undeniable. Changes in vasomotor tone, sodium retention, and renal renin release are all well established. For decades the contribution of the sympathetic nervous system to chronic hypertension was not fully appreciated. Its importance is now well recognized.1–5 In a 1982 review, we described the neural sites and mechanisms involved in exaggerated sympathetic nerve activity (SNA) in several animal models, as well as in human hypertension.1 Moreover, there has been a surge of data highlighting the damaging cardiovascular effects and the increased mortality and morbidity associated with exaggerated SNA in a variety of cardiovascular diseases.6–10 In the Cannon Lecture of 2009 titled, “In Search of Autonomic Balance: the Good, the Bad, and the Ugly,” the parasympathetic nerve activity was portrayed as good, the sympathetic activity as bad, and the generation of reactive oxygen species by the renin-angiotensin-aldosterone system as the ugly.11 Although an essential role of the kidney has been established in angiotensin II (Ang II) hypertension,12 the renin-angiotensin-aldosterone system can initiate and maintain a state of sympathetic overactivity through its action on central neurons in the subfornical organ of the forebrain.3,11,13...

A hallmark study demonstrated that vagal nerve stimulation protected mice from lipopolysaccharide-induced sepsis and was associated with a decrease in the secretion of tumor necrosis factor-α.17 In later studies, this effect was shown to be mediated by the α7-nicotinic acetylcholine (ACh) receptor.18 The suppression of the immune responses has been coined the “cholinergic inflammatory reflex,” drawing an analogy to the vago-vagal neural reflex.19 These studies set the stage for further exploration of the autonomic regulation of the immune system in cardiovascular disease. The enhanced inflammatory response in hypertension or other cardiovascular diseases may, thus, be attributed to the loss of the inhibitory parasympathetic influence or an increased sympathetic influence. It could also be because of abnormal sensitivities of excitatory or inhibitory receptors on the immune cells.

Uemura et al22 demonstrated in an ischemia-reperfusion model of myocardial injury that vagal stimulation enhances the activity of tissue inhibitors of metalloproteinase 1 and suppresses the active matrix metalloproteinase 9. Conversely, β-adrenergic stimulation induces apoptosis of ventricular myocytes, because propranolol but not prazosin abrogates the norepinephrine-induced apoptosis.23 The sustained lowering of blood pressure in dogs with chronic renal hypertension during carotid sinus nerve stimulation is a compelling demonstration of a renin-independent antihypertensive effect of prolonged reflex suppression of the sympathetic nervous system and activation of the parasympathetic system.24

Although, Ang II is known to induce hypertension in experimental models, it also induces upregulation of interleukin (IL) 1-β, tumor necrosis factor-α, monocyte chemoattractant protein 1, and intercellular adhesion molecule 1.38 Elevated levels of intercellular adhesion molecule 1 and IL-6 have also been documented in apparently healthy men.39 These findings are significant because IL-6 causes myocardial hypertrophy, fibrosis, and apoptosis in experimental models of hypertension and appears to be involved in the pathogenesis of hypertension.40 Moreover, IL-6 knockout mice are refractory to Ang II–induced hypertension.41

Although, Ang II is known to induce hypertension in experimental models, it also induces upregulation of interleukin (IL) 1-β, tumor necrosis factor-α, monocyte chemoattractant protein 1, and intercellular adhesion molecule 1.38 Elevated levels of intercellular adhesion molecule 1 and IL-6 have also been documented in apparently healthy men.39 These findings are significant because IL-6 causes myocardial hypertrophy, fibrosis, and apoptosis in experimental models of hypertension and appears to be involved in the pathogenesis of hypertension.40 Moreover, IL-6 knockout mice are refractory to Ang II–induced hypertension.41

Another model that confirms the dependence of Ang II–induced hypertension on the immune system is the immune-deficient RAG−/− mouse. In this model, the pressor response to Ang II infusion was blunted.42 It was restored to the high levels seen in the C57BL/6 control mouse by the adoptive transfer of T lymphocytes. The transfer of B lymphocytes did not restore the pressor response.42

The possibility that a latent activation of the innate immune system may exist in the prehypertensive state and initiate the development of hypertension is suggested by 2 observations. One is our early result in the young prehypertensive SHR that indicates a significant enhancement of cytokine release from splenocytes in response to activation of TLRs, which induce the transcription of cytokines.43 This prehypertensive enhancement of cytokine release may explain the increase in regional sympathetic activity reported in the prehypertensive phase of SHR by Cabassi et al.25

The other observation by Harrison et al44 proposes that, in the prehypertensive state, an initial stress that may be of neural origin causes some vascular damage and the release of endogenous “neoantigens.” These activate the innate immune system and the release of cytokines, which, in turn, activate the T lymphocytes and the adaptive immune system, resulting in inflammatory consequences and hypertension.

The neurogenic origin of hemodynamic changes in hypertension is well accepted.2,11,45 However, the concept that the autonomic nervous system exerts long-term effects on the cardiovascular system in pathological states through the regulation of the immune system is novel. It represents a major shift in our thinking about the mechanisms of cardiovascular actions of the autonomic nervous system. The shift is from accepting the primacy of the direct hemodynamic effects to the recognition that the more chronic functional and structural pathological processes are mediated through the interaction of the autonomic and the immune systems. There is strong evidence to support the direct sympathetic innervation of immune organs.46 Immunomodulation by cholinergic and adrenergic agonists has also been shown, strengthening the functional significance of this anatomic association.47...

Second is the evidence that vagus nerve activity restrains the inflammatory system. A compelling indication of a suppressive influence of resting vagal tone is the demonstration of a marked increase in nuclear factor κB–activation in the colon by photon emission tomography 4 weeks after subdiaphragmatic vagotomy (Figure 4A).49 The colon is densely populated with lymphoid tissue. A significant increase in nuclear factor κB, most likely in the innate immune cells, is the ultimate product of cellular inflammation and a major determinant of gene expression of cytokines.49 In a parallel experiment, vagotomy increased significantly the cytokine production including interferon-γ, tumor necrosis factor, and IL-6 in CD3/CD28 (CD4+) T lymphocytes from the murine spleen (Figure 4B).50 In addition, activation of nicotinic cholinergic receptors has also been shown to play a role in B-lymphocyte maturation.51 Recently, studies have shown that T lymphocytes can synthesize and release ACh, thus serving as effectors of the vagal nerve circuit.52

Third is the evidence that vagal nerve stimulation exerts a protective anti-inflammatory effect and abrogates the detrimental responses in heart failure and endotoxic shock. In a canine model of pacing-induced heart failure, vagus nerve stimulation improved left ventricular ejection fraction, decreased cardiac size, and increased baroreflex sensitivity, when compared with the sham unstimulated animals.53 This functional improvement was associated with a significant reduction of the clinically used biomarker of inflammation, C-reactive protein, at 4 weeks and its nearly total suppression at 8 weeks.53

Vagus nerve stimulation was also protective in a murine model of sepsis.17 It attenuated the hypotension or shock induced in mice by endotoxin. It also suppressed serum, as well as hepatic tumor necrosis factor-α.17 These anti-inflammatory effects were later determined to be mediated by the activation of α7 nicotinic ACh receptors on macrophages.

Some of the most recent work and ideas for future directions in the area of inflammation/immunity relevant to hypertension cover the communications between the nervous system and the immune system. These occur at both a central and peripheral level.54

At the level of the central nervous system, circulating cytokines, or cytokines released from astrocytes and microglia, may activate specific nuclei in the hypothalamus or brain stem and induce an increase in SNA and hypertension. Alternatively, the migration of innate immune cells, such as macrophages and monocytes or T regulatory or cytotoxic lymphocytes, from the circulation to the central nervous system may induce an inflammatory response and a similar neuronal activation.

An intriguing hypothesis, proposed by Zubcevic et al,45 is that hypoperfusion of the brain stem may evoke hypertension. The hypothesis is based on the analogy that hypertension in the giraffe is an essential adjustment to maintain the cerebral circulation. The link between brain hypoperfusion and hypertension may be an inflammation of the brain microvasculature triggered by increased expression of adhesion molecules on the endothelium, which attracts leukocytes and lymphocytes.45,55 Inflammation of the brain microvasculature causes localized ischemia. The transduction mechanisms that evoke sympathoexcitation and hypertension might include vascular-glial-neuronal signaling pathways that require further exploration.56 The proposition is that long-term control of blood pressure may need to be viewed in the context of maintenance of cerebral blood flow by a process that involves central inflammatory/immune mechanisms.

A second important concept is the realization that the immune system, which is a major determinant of most cardiovascular pathological processes, can be modulated extensively by the autonomic system. This means that our notion of autonomic control of the circulation needs to be expanded beyond its hemodynamic influence and extended into its influence on cellular and structural pathological processes. These are accentuated by the proinflammatory activation of the innate and adaptive immune systems.

http://hyper.ahajournals.org/content/59/4/755.full

[Visitor]

Another that appears related and may be key at the time of infection or vaccination is some.

Mechanism Behind Mind-Body Connection Discovered

"UCLA scientists found that the stress hormone cortisol suppresses immune cells' ability to activate their telomerase. This may explain why the cells of persons under chronic stress have shorter telomeres.

The study reveals how stress makes people more susceptible to illness. The findings also suggest a potential drug target for preventing damage to the immune systems of persons who are under long-term stress, such as caregivers to chronically ill family members, as well as astronauts, soldiers, air traffic controllers and people who drive long daily commutes."

{my note - and some with Autism or other conditions}

"When the body is under stress, it boosts production of cortisol to support a "fight or flight" response," explains Effros. "If the hormone remains elevated in the bloodstream for long periods of time, though, it wears down the immune system. We are testing therapeutic ways of enhancing telomerase levels to help the immune system ward off cortisol's effect. If we're successful, one day a pill may exist to strengthen the immune system's ability to weather chronic emotional stress."

http://www.sciencedaily.com/releases/2008/07/080715152325.htm

[Visitor]

On the Science Daily page for the last article I cited you might have noticed the following link:

Stress Affects the Balance of Bacteria in the Gut and Immune Response

"Stress can change the balance of bacteria that naturally live in the gut, according to research published this month in the journal Brain, Behavior, and Immunity.

"These bacteria affect immune function, and may help explain why stress dysregulates the immune response," said lead researcher Michael Bailey.

Exposure to stress led to changes in composition, diversity and number of gut microorganisms, according to scientists from The Ohio State University. The bacterial communities in the intestine became less diverse, and had greater numbers of potentially harmful bacteria, such as Clostridium.

"These changes can have profound implications for physiological function," explained Dr Bailey. "When we reduced the number of bacteria in the intestines using antibiotics, we found that some of the effects of stress on the immune system were prevented," he added. "This suggests that not only does stress change the bacteria levels in the gut, but that these alterations can, in turn, impact our immunity."

"This is the first evidence that the gut microorganisms may play a role in innate immunological stress responses," said Monika Fleshner, Professor of Integrative Physiology at the University of Colorado, Boulder. "The study reveals the dynamic interactions between multiple physiological systems including the intestinal microbiota and the immune system."

http://www.sciencedaily.com/releases/2011/03/110321094231.htm

While I due think many with Autism are sensitized by effects before later particular triggers like vaccines it is fair to say that once the stress prone biology is set in motion the things that bring on stress are atypical and often produce a stress cycle in some Autism and other conditions. Often just existing becomes stress in the proccess.

Earlier I framed this stress factor this way.

The built in "stress" due to biological assault or condition may be seen in some children in the dilated pupils caused by the altered norepinephrine levels in such children and some adults.

[Visitor]

Much earlier in this thread someone spoke of "missing the forest{wood} for the trees". This report seems to miss the forest.

How Stress Can Boost Immune System

"The study's findings provide a thorough overview of how a triad of stress hormones affects the main cell subpopulations of the immune system. They also offer the prospect of, someday, being able to manipulate stress-hormone levels to improve patients' recovery from surgery or wounds or their responses to vaccines...

The immune system is crucial for wound healing and preventing or fighting infection, and both wounds and infections are common risks during chases, escapes and combat.

The experiments in this study were performed on rats, which Dhabhar subjected to mild stress by confining them (gently, and with full ventilation) in transparent Plexiglas enclosures to induce stress. He drew blood several times over a two-hour period and, for each time point, measured levels of three major hormones -- norepinephrine, epinephrine and corticosterone (the rat analog of cortisol in humans) -- as well as of several distinct immune-cell types in the blood.

To show that specific hormones were responsible for movements of specific cell types, Dhabhar administered the three hormones, separately or in various combinations, to rats whose adrenal glands had been removed so they couldn't generate their own stress hormones. When the researchers mimicked the pattern of stress-hormone release previously observed in the confined rats, the same immune-cell migration patterns emerged in the rats without adrenal glands. Placebo treatment produced no such effect.

The general pattern, Dhabhar said, was that norepinephrine is released early and is primarily involved in mobilizing all major immune-cell types -- monocytes, neutrophils and lymphocytes -- into the blood. Epinephrine, also released early, mobilized monocytes and neutrophils into the blood, while nudging lymphocytes out into "battlefield" destinations such as skin. And corticosterone, released somewhat later, caused virtually all immune cell types to head out of circulation to the "battlefields."

http://www.sciencedaily.com/releases/2012/06/120621223525.htm

That report barely acknowledges the down side though it does mention long term activation suppresses the immune system. What about who are being enviromentally effected from toxins, gemicals/drugs, vaccines who have this proccess kicked into overdrive long term? This ties to the hypertension and vascular/immune brain function throughout this thread. I posted this from a report earlier in the thread"

Study Shows How Stress Triggers Immune System

"It's well-known that stress causes several reactions in the body. "Stress activates the immune system in preparation for fighting infection and healing wounds," explained Dr. Andrew Miller, a professor of psychiatry and behavioral sciences at Emory University School of Medicine, in Atlanta. "This is not a bad thing, especially in the context of a situation where a fight and wounding may ensue. However, if the immune system is constantly activated, this can contribute to a multitude of chronic health problems, including cardiovascular disease, diabetes, cancer and neuropsychiatric disorders."

In the new study, researchers sought to determine whether the stress of personal conflicts and competitive sports would trigger the release of molecules known as cytokines, which are linked to inflammation."

Why does it matter if stress triggers molecules linked to inflammation? "If you aren't wounded, there's no place for them to go, and they're circulating," Taylor said. "It's not like they've gone to the site of a wound and engaged in anti-infection activity."

With this altered system the immune responses are further changed in many and the Il-l7 involvement is further heightened.

REG3A molecule may lead to new treatments for psoriasis, wound-healing

An international team of scientists led by principal investigator Richard L. Gallo, MD, PhD, professor of medicine and chief of UC San Diego's Division of Dermatology, analyzed skin biopsies of patients with and without psoriasis, as well as the skin of mice with psoriasis and with wounds on their backs. They discovered that a molecule called regenerating islet-derived protein 3-alpha (REG3A) is highly expressed in skin cells during psoriasis and wound-healing, but not under normal skin conditions.

In tests on mice, researchers found that inhibiting REG3A slowed wound-healing but cleared up psoriasis, which is commonly characterized by patches of inflammation and white, scaly skin.

The scientists also noted that REG3A acts in concert with interleukin-17 (IL-17), an immune system protein involved in the signaling cascade which prompts skin cells to multiply in excess numbers. "IL-17 binds to receptors on skin cells and causes REG3A to be expressed, which then binds to another protein inside the cells that promotes cell growth," said first author Yuping Lai, PhD, professor of microbiology and immunity at East China Normal University in Shanghai.

Gallo said the discovery of REG3A's dual roles provides a new target for different therapies.

"A drug that inhibits the expression of REG3A could represent a more targeted way to treat psoriasis without the systemic immunosuppression problems of current treatments. Conversely, a drug that stimulates or mimics REG3A could boost cell growth and improve wound healing."

http://www.news-medical.net/news/20120622/REG3A-molecule-may-lead-to-new-treatments-for-psoriasis-wound-healing.aspx

[Visitor]

New Anti-Inflammatory Drugs Pinch Off Reactive Oxygen Species at the Source

"Nox2 inhibitors could be valuable with many conditions where inflammation plays a role," says senior author David Lambeth, MD, PhD, professor of pathology and laboratory medicine at Emory University School of Medicine.

ROS and the Nox enzymes play vital roles in the immune and cardiovascular systems, but too much ROS leads to oxidative stress, linked with tissue damage and conditions such as stroke, heart failure and neurodegenerative diseases...

Antioxidants are supposed to absorb ROS, but many clinical studies examining antioxidants' benefits have been disappointing. Compounds that inhibit the Nox enzymes would stop ROS production at the source, rather than mop them up like antioxidants do.

A side effect of Nox2 inhibition could be impairment of immune responses to bacteria and fungi, Lambeth says. One of Nox2's main functions in immune cells is to produce a toxic burst of ROS for killing bacteria and fungi.

People with an inherited deficiency in Nox2 develop chronic granulomatous disease (CGD), and are unable to fight off common infections. However, short-term or incomplete inhibition could have therapeutic effects without disabling antibacterial activity. CGD carriers who have reduced but residual Nox2 activity do not display symptoms."

http://www.sciencedaily.com/releases/2012/06/120621130712.htm

An earlier post in this thread speaks of the fact Olmesartan downregulates the protein P91-PHOX{NOX2} among others. Another earlier posted abstract was:

"Olmesartan, an AT1 Antagonist, Attenuates Oxidative Stress, Endoplasmic Reticulum Stress and Cardiac Inflammatory Mediators in Rats with Heart Failure Induced by Experimental Autoimmune Myocarditis"

This next report speaks of NOX2 expression related to myocardial infarction {hear attack}, but the same damaging process can and does occur in Autoimmune Myocarditis and though the heart itself may or may not be suffering this process in the conditons related to an Autism or other condition in the scope of the conditions I have been mentioning some dysfunction appears to be occuring mediated within the Solitary nucleus in the brainstem.

Increased Nox2 expression in human cardiomyocytes after acute myocardial infarction

"Cardiomyocytes produce reactive oxygen species (ROS) under different pathological conditions.1 From studies in non-cardiomyocytes it is known that ROS do not only induce cell damage, but also play a role in processes such as cell proliferation, apoptosis, gene expression, and aging.2–6 Furthermore, recent studies also point to a new, more or less cell specific source of ROS, namely homologues of the NADPH oxidase of phagocytes.7

The catalytic core of the phagocytic NADPH oxidase is a membrane integrated flavocytochrome b558, comprising the p22phox and the enzymatic gp91phox (Nox2) subunits. Recently, several Nox2 homologues have been identified in various human cell types. For instance, in blood vessels Nox2 has been reported in endothelial cells,8 whereas the Nox2 homologues, Nox1 and Nox4, were found in vascular smooth muscle cells.9 In addition, in thyroid, ThOX1 and ThOX2 were identified,10 and in the kidney Nox4.11 In heart homogenates from guinea pigs suffering from experimental hypertension, Nox2 was also found to be expressed, although it was not specified whether the enzyme was located in cardiomyocytes, fibroblasts, or endothelial cells.12

“Reactive oxygen species do not only induce cell damage, but also play a role in processes such as cell proliferation, apoptosis, gene expression, and aging”

To date, there are no data available regarding the expression of Nox2 or its homologues in human cardiomyocytes. Therefore, we have analysed the expression of Nox2 by human cardiomyocytes at the cellular level. Furthermore, we have studied the putative expression of Nox2 in the hearts of 62 patients who died as a result of acute myocardial infarction (AMI), to obtain some insight into the expression of the enzyme in pathological conditions."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1769897/

Oxidative Stress

Nox2, Ca2+, and Protein Kinase C Play a Role in Angiotensin II-Induced Free Radical Production in Nucleus Tractus Solitarius

"The dorsomedial portion of the nucleus tractus solitarius (dmNTS) is the site of termination of baroreceptor and cardiorespiratory vagal afferents and plays a critical role in cardiovascular regulation. Angiotensin II (Ang II) is a powerful signaling molecule in dmNTS neurons and exerts some of its biological effects by modulating Ca2+ currents via reactive oxygen species (ROS) derived from reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase. We investigated whether a Nox2-containing NADPH oxidase is the source of the Ang II—induced ROS production and whether the signaling mechanisms of its activation require intracellular Ca2+ or protein kinase C (PKC). Second-order dmNTS neurons were anterogradely labeled with 4-(4-[didecylamino]styryl)-N-methylpyridinium iodide transported from the vagus and isolated from the brain stem. ROS production was assessed in 4-(4-[didecylamino]styryl)-N-methylpyridinium iodide-positive dmNTS neurons using the fluorescent dye 6-carboxy-2′,7′-dichlorodihydro-fluorescein di(acetoxymethyl ester). Ang II (3 to 2000 nmol/L) increased ROS production in dmNTS neurons (EC50=38.3 nmol/L). The effect was abolished by the ROS scavenger Mn (III) porphyrin 5,10,20-tetrakis (benzoic acid) porphyrin manganese (III), the Ang II type 1 receptor antagonist losartan, or the NADPH oxidase inhibitors apocynin or gp91ds-tat. Ang II failed to increase ROS production or to potentiate L-type Ca2+ currents in dmNTS neurons of mice lacking Nox2. The PKC inhibitor GF109203X or depletion of intracellular Ca2+ attenuated Ang II-elicited ROS production. We conclude that the powerful effects of Ang II on Ca2+ currents in dmNTS neurons are mediated by PKC activation leading to ROS production via Nox2. Thus, a Nox2-containing NADPH oxidase is the critical link between Ang II and the enhancement of Ca2+ currents that underlie the actions of Ang II on central autonomic regulation...

The dmNTS is a critical central relay for cardiopulmonary afferents regulating cardiovascular homeostasis. We have demonstrated that Nox2 and AT1 receptors are present in second-order dmNTS neurons in which exposure to Ang II induces ROS production and activation of Ca2+ currents. The Ang II-induced ROS production and Ca2+ currents were not observed in mice lacking Nox2. Furthermore, we have shown that Ang II-dependent ROS production requires intracellular Ca2+ and PKC. The data indicate that Ang II induces ROS production in second-order dmNTS neurons through a Nox2-containing NADPH oxidase. The NADPH oxidase-derived ROS, in turn, activate L-type Ca2+ channels. These findings provide the mechanistic basis for the powerful actions of Ang II in dmNTS and support the concept that ROS derived from Nox2 are critical signaling molecules in central autonomic neurons. They also support the growing evidence that ROS derived from Nox2 play a vital role in both central and peripheral mechanisms of hypertension."

http://hyper.ahajournals.org/content/48/3/482.full

Solitary nucleus {nucleus tractus solitarius} Wiki
{notice the nerves associated with this nucleus in the Wiki entry}

http://en.wikipedia.org/wiki/Nucleus_tractus_solitarius

CYBB [NOX2} Wiki

Cytochrome b-245, beta polypeptide (chronic granulomatous disease)-- also known as CYBB, P91-PHOX, and NOX2-- is a human gene encoding a glycoprotein.

"Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes. CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole.[1]"

http://en.wikipedia.org/wiki/CYBB

NADPH oxidase Wiki

Under normal circumstances, the complex is latent in neutrophils and is activated to assemble in the membranes during respiratory burst.

NADPH oxidase generates superoxide by transferring electrons from NADPH inside the cell across the membrane and coupling these to molecular oxygen to produce superoxide anion, a reactive free-radical. Superoxide can be produced in phagosomes, which contain ingested bacteria and fungi, or it can be produced outside of the cell. In a phagosome, superoxide can spontaneously form hydrogen peroxide that will undergo further reactions to generate reactive oxygen species (ROS).

"Superoxide kills bacteria and fungi by mechanisms that are not yet fully understood (see article on superoxide), but may inactivate critical metabolic enzymes, initiate lipid peroxidation, and liberate redox-active iron, which allows the generation of indiscriminate oxidants such as the hydroxyl radical. It is presumed that superoxide kills bacteria directly, as the virulence of many pathogens is dramatically attenuated when their superoxide dismutase (SOD) genes are deleted. However, downstream products of superoxide also include hydrogen peroxide and hypochlorous acid, the reactive agent in bleach."

http://en.wikipedia.org/wiki/NADPH_oxidase

[Benedetta]

Yes, I remember Nick.
It is an interesting article. Anything that mentions lymphpenia I am interested in.

[Visitor]

Also, if the BBB is only mildy permeable the vascular permeability could cause these issues as well

[Visitor]

Given where the evidence and information leads it seems part of the problem may involve low grade and longterm or chronically some degree of either Hypertensive Encephalopathy or Hepatatic Encephalopathy in some groups or some degree of both types in an individual at times as in our case I think. The description paints Hypertensive Encephalopathy as severe epsiodes, but it may be sub acute long term occurrence of thes conditions could be part of the developmental effects from infancy. The blood brain barrier is not impermeable in the womb for much of the time and any events or problems may have a genesis there or leave achild suscepible to ongoing issues that are later made pathological by a number of events and/or biologicall developmental factors inteacting with the BBB, inflamatory events especially. My nurse practitioner sister described the Hepatatic Encephalopathy as a strong and major problem seemingly making it too obvious a marker to not be seen and not really subtle, but there are grades of this and I don't rule out a low grade aspect. Considering the stories of some parents describing the reaction of their infant/toddler after vaccinations with seizures and severe pain and afterwards what appears as brain effects descending into a regressive Autism this is a tenable explanation. This still includes all othe other previously mentioned factors like epigentic effects, genetic predisposition, gut/bacteria, and others. There appear to be a number of factors able to increas the permeability of the BBB withe some more capable than others of doing so. A combination of these factors also does this. Depending on what combination or, if one factor in high concentration is doing this it may be part of the reason why there are differing effects of diseases in the brain. It may be that depending on how it is opened it is still partially discriminatory of what passes. But, it seems it must be that if it isopened enough by any factor alone or in combination it may lose it's discriminatory ability.

Benedetta,
If you remember our conversation the the Gut Bug thread about colic the following may be of interest to you.

Sphingosine 1-phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrier

http://7thspace.com/headlines/415171/sphingosine_1_phosphate_receptor_5_mediates_the_immune_quiescence_of_the_human_brain_endothelial_barrier.html

[Visitor]

Dan,

It seems it was 1994 that Deer reported on Septra/Bactrim. GSK made Septra.