Autism Blog - Features of autism « Left Brain/Right Brain

29 Mar 2009

Author: Sullivan
Comments: 65

Features of autism

I was planning on writing something about this for the 1 year anniversary of when the Department of Justice concession to Hannah Poling was leaked.

Why wait until now? Because it was basically impossible to discuss this last year. Immediately after the leak, the phrase “features of autism” was made into a running joke. The vaccines-cause-autism people all made great fun of how the government coined the phrase, presumably to avoid using the simple word, autism.

Anyone want to go back and look at the document now? Search for the word “features”.

First hit:

Dr. Zimmerman observed that [Hannah Poling] watched the fluorescent lights repeatedly during the examination and would not make eye contact. Id. He diagnosed [Hannah Poling] with “regressive encephalopathy with features consistent with an autistic spectrum disorder, following normal development.”

Note that that’s in quotes: “features consistent with an autistic spectrum disorder”. That’s right, Andrew Zimmerman, Hannah Poling’s own neurologist used the phrase “features of autism” about her, long before the Department of Justice ever did.

This is the same Andrew Zimmerman who submitted an expert report on Hannah Poling. This is the same Andrew Zimmerman who wrote an expert report, for the government side, in the Autism Omnibus Proceeding.

Not the only place “features” is mentioned in the Rule 4© report, either:

Second Hit:

[Hannah Poling] was evaluated by Alice Kau and Kelley Duff, on May 16, 2001, at CARDS. Pet. Ex. 25 at 17. The clinicians concluded that [Hannah Poling] was developmentally delayed and demonstrated features of autistic disorder.

So, why is it surprising that the Department of Justice would write:

In sum, DVIC has concluded that the facts of this case meet the statutory criteria for demonstrating that the vaccinations [Hannah Poling] received on July 19, 2000, significantly aggravated an underlying mitochondrial disorder, which predisposed her to deficits in cellular energy metabolism, and manifested as a regressive encephalopathy with features of autism spectrum disorder.

That’s the third place that “features” is used in the concession document. But, hey, it isn’t funny to talk about Hannah Poling’s own specialists describing her as having “features” of an autistic spectrum disorder.

It is very easy to make more out of this than is warranted by the scant information we have available. We don’t know what is in the rest of the documents that were provided as part of the case. What we do know is that the U.S. government did not create the phrase “features of autism” to describe Hannah Poling.

Link to this post?

If you want to reference this post in your site, use the code below to link to me from your website.

<a href="http://leftbrainrightbrain.co.uk/2009/03/features-of-autism/">Features of autism</a>

Comments

65 Responses to “Features of autism”

Kev
March 29th, 2009
10:48:53

The thing that annoyed me at the time was people treating the phrase ‘features of autism’ as if it was interchangeable with ‘autism’. If it was, people would simply have said ‘autism’.
Bunny
March 29th, 2009
13:28:09

Yes, Kev, it seems to me that “features of autism” is referring to sub-clinical autism, i.e., behaviors associated with autism, but not enough to qualify for an autism diagnosis.

If doctors started diagnosing everyone who had “features of autism” with autism proper, half the world would have “autism.” And if they started diagnosing every forgetful person with Alzheimer’s and giving an OCD diagnosis to every person who checks twice to make sure the coffee pot is unplugged, there would be nobody left on earth without some kind of psychiatric diagnosis.

It’s absurd for these people to claim that features of a disorder are the same as having that disorder.
passionlessDrone
March 29th, 2009
14:04:47

LOL! LOL! Keep the jokes coming!

Not eight weeks ago, Kev admitted that Hannah Poling has a diagnosis of autism. Here, on his own blog!

Are you really still denying that Hannah Polling has as diagnosis of autism?

Uh, no. I never have done. What I’m saying is that its obvious based on the science presented that her vaccines didn’t cause her autism. Further more, no one outside the autism antivax community says they did.

Yet simultaneously, you don’t understand why this kind of semantic acrobatics is seen as funny by some folks. You aren’t doing yourself any favors.

– pD
RobinHausmanMorris
March 29th, 2009
15:12:24

I agree with Bunny. I call the rogue diagnosis of “on the spectrum” or “features of autism” a “garbage can of terms”. It is horrifying to recognize the interpretation, both legally, educationally, and even medically.
Sadly, we cannot take a biopsy of autism and stick it under a microscope. Given that reality the best we, as parents can do, is be educated consumers, as well as educators to the outside world.
Thank you Kevin for your diligent support.
xRobin
MJ
March 29th, 2009
15:18:30

You are referring to the same document three times so of course it is going to be consistent with the usage of “features” vs the diagnosis of autism.

The authors of the document could have very easily cherry picked the phrases out of the medical reports that they wanted.

@ Kev –
According to her parents Hannah Poling has a diagnosis of autism – they have stated numerous times publicly. Your continuing insistence that she doesn’t and just has “features” is absurd.
Kev
March 29th, 2009
15:45:42

MJ I’m going to go through this with you once more in the hopes you can one day understand.

I am not saying she is not autistic. I am saying that the ‘features of autism’ listed on her medical reports as being the result of vaccines are quite obviously not enough for anyone to say they are enoughto give a diagnosis of autism. What is so difficult for you to get here? A cold can give ‘features of pneumonia’ but the cold isn’t interchangeable with pneumonia.
Sullivan
March 29th, 2009
16:07:07

MJ,

my guess is that we on this site have referred to the Rule 4© report more than three times. Are you somehow mixing this document with the Pardo letter on neuroinflamation and the Zimmerman expert report on the Cedillo case?

I have to say I found it somewhat amusing for someone to suggest that referring to this document 3 time might be overplaying it. David Kirby can’t seem to mention autism without referring to this document. And as to cherry picking…well, David Kirby comes to mind again…and again….and again…
Sullivan
March 29th, 2009
19:19:09

pD,

perhaps you would like to read this post for content. It is not a post claiming that Hannah Poling is not autistic, nor is it a post about whether she has a diagnosis of autism.

Seriously, your comment demonstrates the exact lack of attention to detail that I was complaining about.

I guess I could respond in the childish manner you posted. Instead, I’ll ask you to read this post and other comments I’ve made on the subject—for content.

In this post, I am making a point that the “semantic acrobatics” that have been ongoing for over a year. It wasn’t the Department of Justice who first used the phrase “features of autism” in relation to Hannah Poling, it was her own neurologist. How can it be a joke when the government used the phrase, when they were quoting her neurologist?

The thing is, this is all obvious to anyone who actually read the rule 4© report. Anyone who made the jokes about the government’s use of the phrase “features of autism” was demonstrating a singular ignorance—a lack of willingness to read the very document they were poking fun at.

Since it hasn’t sunk in about what my opinion is about Miss Poling’s diagnosis, let me make it clear once again. She was a test case in the Omnibus proceeding. I don’t think the petitioner’s lawyers were so bad as to put a test case forward who didn’t have an autism diagnosis. Also, her father is a neurologist. Her parents appear to have been able to justify ABA from her school system (or considered it worthwhile enough to private pay).

It is quite obvious that Hannah Poling has a diagnosis of autism.

Her case does bring up some very important questions about what autism is. It would be good to discuss this without people acting as you just did.
Anne
March 30th, 2009
00:20:00

Probably Dr. Zimmerman distinguishes secondary autism, which is what Hannah Poling has, from idiopathic autism. There are those, like Bailey Banks’ neurologist Dr. Lopez, who don’t consider secondary autism (that is, autism secondary to another condition such as Fragile X, Congenital Rubella Syndrome, mitochondrial disorders, Joubert Syndrome, Tuberous Sclerosis, and so on) to be genuine autism.
passionlessDrone
March 30th, 2009
01:38:38

Hi Sullivan –

perhaps you would like to read this post for content. It is not a post claiming that Hannah Poling is not autistic, nor is it a post about whether she has a diagnosis of autism.

Seriously, your comment demonstrates the exact lack of attention to detail that I was complaining about.

I guess I could respond in the childish manner you posted. Instead, I’ll ask you to read this post and other comments I’ve made on the subject—for content.

Hehe.

But the content of your post is what is so funny! The fact that you think this is a meaningful subject; dueling wordsmithing and document mining to see who used the term ‘features of autism’ first. The notion that paying attention to this kind of “detail” in the world of autism is a worthwhile endeavor is funny. It is completely without utility, but is being taken seriously. Being utility free isn’t necessarily a crime, but simultaneously proclaiming that attention to detail is important smacks of hyprocrisy.

By way of example, when I pointed out to you in the Neuroinflammation thread that we have accumulated much more information regarding an active immune response in the brain of children with autism, you were genuinely unconcerned that you missed those details. The fact that these findings are indicative of an injurious component to immune activation in the brain wasn’t worth any more of your time; especially considering how important is was to address that there were people using the word features of autism inappropriately a year ago.

That is funny, and the joke is on you. Keep it up.

– pD
Sullivan
March 30th, 2009
02:39:01

pD-

OK, you are one of those who put style over substance. Got it.
Sullivan
March 30th, 2009
02:52:09

Probably Dr. Zimmerman distinguishes secondary autism, which is what Hannah Poling has, from idiopathic autism. There are those, like Bailey Banks’ neurologist Dr. Lopez, who don’t consider secondary autism (that is, autism secondary to another condition such as Fragile X, Congenital Rubella Syndrome, mitochondrial disorders, Joubert Syndrome, Tuberous Sclerosis, and so on) to be genuine autism.

Given the comments he makes in his Cedillo reprt, I would say that he includes non-idiopathic autism as autism. Here’s what Dr. Zimmerman had to say:

About 10% of affected children can have
any of a large number of “known,” diagnosable conditions by examination and using currently available laboratory tests—conditions such as fragile X syndrome, Rett syndrome and tuberous sclerosis.
MC
March 30th, 2009
03:30:35

Passionless Drone must be stinging from the release of the Pardo letter and the Zimmerman report. The Pardo letter is directed at people just like pD—people who have been misusing the Zimmerman results to promote the idea that neuroinflamation is a sign of vaccine injury.

pD is particularly bad at this—he tends to post the results of, say, the Vargas study as though it is obvious to all that it supports the passionless drone position.
Here’s a good example (where he does pull in other studies as well, but same sort of mistakes).

However, what we are learning about children with autism is that they have a unique immunological profile consistent with problems regulating inflammatory immune responses; the heart and soul of how all vaccinations actually work, with or without thimerosal.

By way of example, did you know that we now have three studies showing greatly increased levels of pro-inflammatory cytokines in the brain and/or csf of children with autism compared to their non diagnosed peers?

He kinda leaves out the all important result that the immune responses observed could be beneficial.

Another pD from that same link:

“For example, in 2005, Vargas reported chronically activated microglia and immune activation in the brains of people with autism in “Neuroglial activation and neuroinflammation in the brain of patients with autism” Fancy that, evidence of exactly what the IOM defines as “a common feature in immune-mediated encephalitis ” in autism!”

Direct attempt to use Vargas/Zimmerman as though it is evidence of autism as vaccine injury.

He was just plain wrong in his interpretation of Vargas. Pardo and Zimmerman have made that clear. But, instead of owning his mistakes, he choses to come out gunning with sarcasm.
MJ
March 30th, 2009
03:44:16

Kev you said –
“What is so difficult for you to get here?”

The point of what you are trying to say.

On one hand you say that you don’t deny the diagnosis only to turn around and say that there isn’t enough evidence for it?

Or are you saying that only some of the “features” of autism were caused by the mito/vaccine issues therefore the autism wasn’t a result of the mito/vaccine issue?

Maybe I am just not smart enough to understand linguistic dance you are doing.

Sullivan you said –
“my guess is that we on this site have referred to the Rule 4© report more than three times. ”

Actually I was pointing out that your three “hits” that you list are all from the same document therefore it really isn’t surprising that they all say the same thing. Yet you are acting like it is a big discovery.

And as been pointed out ad nauseum many other places the phrase is nothing but an attempt to avoid a direct link between a vaccine and autism. The same thing was done in the case of Bailey Banks (the non-autism form of PDD-NOS).

There are some very small number of documented cases of autism being caused by vaccines, this is one of them. That doesn’t mean every case is or even that it fits into the top ten list of causes.

The world isn’t flat anymore. So accept it and move on already, you are just starting to look silly.
Do'C
March 30th, 2009
04:07:15

There are some very small number of documented cases of autism being caused by vaccines, this is one of them.

MJ, with regard to specific causation, you might do well to read this article and the referenced cases.

A Not-So-Hidden History
http://neurodiversity.com/weblog/article/148
MJ
March 30th, 2009
04:30:23

DoC – I read it a while back, but thanks for the link.
Do'C
March 30th, 2009
04:41:48

Then you are already aware that

cases of autism being caused by vaccines

is an inaccurate statement. Oh well.
Kev
March 30th, 2009
07:35:14

I give up MJ so far you are the only person who doesn’t get it. I guess you never will. Just take it as read that I am not saying Hannah didnt have autism.
century
March 30th, 2009
12:28:16

Kevin said

“..I am not saying Hannah didnt have autism”

For clarity, do you mean “didn’t” or “doesn’t”?
Kev
March 30th, 2009
18:17:13

I was trying to be absolutely sure MJ knew I was referring to the time of the medical exam so I did mean ‘didn’t’.

I have heard people close to the Polings claim Hannah no longer carries a diagnosis but I don’t know that for sure so I’m not saying either way if she still carries that diagnosis.
Roger
March 30th, 2009
20:19:58

# Kev on March 29th, 2009 10:48:53

The thing that annoyed me at the time was people treating the phrase ‘features of autism’ as if it was interchangeable with ‘autism’. If it was, people would simply have said ‘autism’.

RobinHausmanMorris on March 29th, 2009 15:12:24

I agree with Bunny. I call the rogue diagnosis of “on the spectrum” or “features of autism” a “garbage can of terms”. It is horrifying to recognize the interpretation, both legally, educationally, and even medically.

I think language,and terminology is a big problem here.Dr.Poling has been nothing but inconsistent in referring to his daughter’s condition,sometimes using the term mitochondrial disease.and sometimes autism. While those of us who have studied mitochondrial disease,know autism.or “features of autism” as it were can be a big part of mitochondrial disease.The trouble is,a sizable per centage the of the public at large,who do not read either the medical literature,or a certain segment of the autism blogosphere do not.As has been stated on this site before,the average American/Canadian/Brit etc,have only heard a sound bite news story saying that vaccines caused Hannah Poling’s “autism”,which is just the way the anti-vaxer fear mongers like it.

John Poling’s kowtowing to the pressure of the anti- vaxers aside,it would be very interesting to see what kind of medical problems Hannah develops in the next few years.

I have heard people close to the Polings claim Hannah no longer carries a diagnosis but I don’t know that for sure so I’m not saying either way if she still carries that diagnosis.

I have mitochondrial autism,and not only did I develop about 60% of my medical problems by age eleven,but last year as I am approaching middle age,I had to get my autism reevaluated.I now fall somewhere in that squishy grey area between Asperger’s, and Kanner autism.If Hannah Poling has mitochondrial autism,it would be very unlikely that she would lose her diagnosis.

The trouble is,of course this whole notion of the “autism spectrum” in the first place. And this gets us back to language,and terminology.Perhaps it is time to stop classifying autism,that occurs in conditions like mitochondrial disease,or fragile x autism.Call it something else entirely.This would make everybody happy.It would shut up the dangerous nuts with their whacked out theories,and it would give the neurodiversity movement some validity,since “their” condition was no longer associated with those of us with multiple disabilities.Everybody would win !
MJ
March 30th, 2009
22:45:05

DoC – I said I read it, I didn’t say that I agreed with and accepted every statement.

Kev – The way to clarity isn’t a double negative. Since I am so being so dense, can we do a simple fill in the blanks with an agree or disagree? No need to elaborate, just agree or disagree with the following and then I will drop the matter.

Hannah is born and does not have autism.

Hannah receives X number of shots in one day.

The shots trigger a mito condition that was either preexisting or induced by the shots

As a result of the mito issues Hannah develops/regresses into autism.

Hannah receives a diagnosis of autism.

Thanks
passionlessDrone
March 30th, 2009
23:25:22

Hi MC -

Passionless Drone must be stinging from the release of the Pardo letter and the Zimmerman report. The Pardo letter is directed at people just like pD—people who have been misusing the Zimmerman results to promote the idea that neuroinflamation is a sign of vaccine injury.

Hehe. What really drives me crazy about these letters is the fact that other people were using the term ‘features of autism’ first. Man does that drive me up the wall.

The post I was writing in the link was to detail that Mr. Offit is at least four years behind the times in autism science when he rather spectacularly claimed that we had no signs of immune activation in the CNS of people with autism. Furthermore, considering the IOM’s own admission that this had been studied only very sparsely, one might be given cause to wonder if Mr. Offit was interested in providing a detailed view of the available information.

He kinda leaves out the all important result that the immune responses observed could be beneficial.

First off, it isn’t an ‘all important result’, but rather, an increasingly remote possibility. From what I can tell, short term inflammatory responses in response to injury can have benificial effects, but long term, chronic inflammation is associated with a vareity of neurodegenrative diseases.

My understanding may be incorrect, if you (or anyone) have some evidence that chronic, long term neuroinflammation is benificial, I’d love to see some links.

If, on the other hand, you don’t have any such evidence, we have to contend with the fact that since 2005 we have loads of applied science telling us exactly the opposite of the possibility you’d like to use as such a large crutch; that an increased inflammatory profile and chronically activated microglia are hallmarks of pathology in a variety of neurological disorders.

The literature is so voluminous on this issue, I’ll stop after a while to see if you have anything other than a glorified letter to the editor as evidence that chronic neuroinflammation might be a good thing.

Here is one that just came out:

Inhibition of soluble TNF signaling in a mouse model of Alzheimer’s disease prevents pre-plaque amyloid-associated neuropathology

Here authors acknowledge that microglial activation and overproduction of inflammatory cytokines is associated with Alzheimers, but the relationship is unclear. Using inhibitors of tnf alpha, however, the researchers were able to prevent accumulation of proteins that led them to conclude targeted inhibition of tnf alpha may be of use in preventing cognitive decline. Do you think they’ve seen the Pardo letter?

Here is another relatively recent one, this one linking early life seizures to chronically activated microglia and ‘long term neurological dysfunction’.

Glial activation links early-life seizures and long-term neurologic dysfunction: evidence using a small molecule inhibitor of proinflammatory cytokine upregulation.

Snipped for length:

Early-life seizures increase vulnerability to subsequent neurologic insult. We tested the hypothesis that early-life seizures increase susceptibility to later neurologic injury by causing chronic glial activation. . . . Treatment with Minozac, a small molecule inhibitor of proinflammatory cytokine upregulation, following early-life seizures prevented both the long-term increase in activated glia and the associated behavioral impairment.

Here we can see that the only course of action necessary to prevent behavioral abnormalities was inhibition of the immune response. If you didn’t, you got chronically activated microglia and increased succeptibility to seizures into adulthood. If the immune response is benificial, what is it protecting against?.

We know that having more tnf-alpha means having more seizures.

Microglial activation and TNFalpha production mediate altered CNS excitability following peripheral inflammation

This one is particularly interesting:

The TNBS-treated rats exhibited a marked, reversible inflammatory response within the hippocampus, characterized by microglial activation and increases in tumor necrosis factor alpha (TNFalpha) levels. Central antagonism of TNFalpha using a monoclonal antibody or inhibition of microglial activation by i.c.v. injection of minocycline prevented the increase in seizure susceptibility. Moreover, i.c.v. infusion of TNFalpha in untreated rats for 4 days also increased seizure susceptibility and thus mimicked the changes in seizure threshold observed with intestinal inflammation. Our finding of a microglia-dependent TNFalpha-mediated increase in CNS excitability provides insight into potential mechanisms underlying the disparate neurological and behavioral changes associated with chronic inflammation.

Great stuff. Induce peripheral inflammation and you wind up with activated microglia and more seizures. If you inhibit tnf alpha, these effects dissapear. Likewise, if you skip the peripheral inflammation and just give tnf alpha, you get the same results. Please paint for me a scenario where we can believe that the immune response is benificial.

I’ve only scratched the surface, but this is already a long post. If you’ve got some good reasons, as to why in the case of autism chronically activated microglia might be a good thing, lets discuss them.

– pD
Joseph
March 31st, 2009
00:14:59

The shots trigger a mito condition that was either preexisting or induced by the shots

Did any of the experts (besides Dr. Poling) claim the mito condition was or could’ve been induced by the shots? That seems made up, without foundation.
Joseph
March 31st, 2009
00:39:56

BTW, there’s simply no convincing scientific evidence that shots can cause developmental regression. If there is, show me. The Hannah Poling concession and a case report are not enough to call them convincing scientific evidence. The concession occurred because there was plausibility – nothing more.

The stuff about Hannah Poling being autistic, very autistic or not autistic enough, is beside the point, and I’ve said that before. It would be sufficient to show that vaccines can cause developmental regression. Autism is fairly common among the developmentally disabled, just like it’s common in Down Syndrome, for example.
MJ Silva
March 31st, 2009
15:53:34

In Sept 2001 Terry Poling made the following comments in a post to the Recovered Kids list.

“I can tell you that i have had more
than my share of tetanus shots and immunoglobulin, extra measles from my
days as an ICU nurse. makes you wonder…..
I am just saying that i would be very careful, it is not an easy answer. I
probably will not immunize my children again. In fact, our geneticist at
Johns Hopkins said he did not think that i should…In his view it was the
pertussus on the DPT that hurt hannah. ”

So, if there was medical evidence or expert testimony that it was the pertussis, that is the reason the case was pulled from the Hg test cases in the Omnibus – not the previously believed reason that it was the unique situation of the child’s underlying mitochondria disease.
Robert Rampson
March 31st, 2009
15:56:15

I am so grateful to all of you for helping to debunk the vaccinnes-causes-autism loonies. You have no idea the problems that they have caused us in the pharmaceutical industry. A major part of our profits are generated by vaccine sales and any sales drop affects shareholders. Our shareholders are often pension funds and this means that ordinary people suffer a drop in their pensions. The fact that 1 in 38 boys in the UK are now on the sutistic spectrum is irrelevant. For every autistic child there are 37 perfectly healthy ones – where’s the problem?

of course it’s not just our profits that are hit. Can you imagine what the NHS would have to pay out if it were shown there was a connection? It’d probably put a couple of pence on income tax. Believe me, we can’t let this thing get legs…. keep up the good work, guys!
Sullivan
March 31st, 2009
17:56:36

Nice troll, Robert Rampson. Pretending to be in the pharmaceutical industry doesn’t help your message.
HCN
March 31st, 2009
21:06:09

So, Rampson, do you have any data that shows there is a bigger prophet margin in preventing disease through vaccine versus treating diseases? Because this paper says that Big Pharma gets LESS when kids don’t get sick:
http://archpedi.ama-assn.org/c.....59/12/1136

Surely, when a kid get pertussis or measles and ends up in the hospital (which happens often with vaccine preventable diseases) you get to sell IV drugs, respiratory support equipment and all sorts of stuff like that.

Only an idiot plays the Big Pharma card when it comes to vaccines.
Kev
March 31st, 2009
22:25:07

MJ, you’re not being dense you’re being obtuse.

We don’t need your yes/no answers as there are no shades of grey in it. Theres nothing but shades of grey in autism.

Look its straightforward. Poling, Zimmerman, Shoffner and Frye wrote a case study on Hannah Poling. This was the medical evidence used by HHS to form their report.

In that report they stated that some medical symptoms were caused by a vaccine(s).

Also in that report were listed the ‘features of autism’ that the co-authors felt were caused by these vaccines.

When we take a look at these particular symptoms we can see by simple comparison that only three are represented on the DSM (IV).

MJ, you have that case study. I’m sure you have the DSM somewhere to hand. Check for yourself.

Now. Does this mean that Hannah Poling is not autistic at the time? No – it simply means that these co authors could only find three symptoms which they could both attribute to her vaccines and which also appeared on the DSM.

How it happens I don’t know. But my guess is that Hannah Poling was already beginning to exhibit signs of autism prior to her vaccines and that the maturation of her autism simply carried on through the vaccination period. She was also injured by her vaccines as some kids are.
Dedj
March 31st, 2009
22:32:20

Sorry, but why did Zimmerman order genetic screening if he believed it was vaccine induced autism?

That seems much more like the work of someone who believes there was a pre-existing genetic disorder at play.
MJ
March 31st, 2009
23:13:55

Ah, so you are saying that the vaccines gave her some of her autism (say 35%) but the rest came from somewhere else. I hadn’t realized that was possible, but there you go, being obtuse and all it isn’t surprising that I didn’t know that.
Chris
April 1st, 2009
03:35:36

MJ, the rest came from her mother. Mitochondrial disorders are maternally inherited.
Kev
April 1st, 2009
06:07:41

No MJ I’m not. I’m saying I think she already had autism. I also think her vaccines gave her some things that had ‘features of’ (or to put it another way, resembled) autism.
MJ
April 1st, 2009
17:22:44

“I think she already had autism”

How wouldn’t that be classified as “somewhere else”?
Prometheus
April 4th, 2009
16:26:23

Once again, pD ventures into deep waters:

From what I can tell, short term inflammatory responses in response to injury can have benificial effects, but long term, chronic inflammation is associated with a vareity [sic] of neurodegenrative [sic] diseases.

The key phrase here being “...from what I can tell…”

This is certainly the “man on the street” understanding of inflammation – maybe even a bit further on than that, since he realizes that there is a function for acute inflammation. However, there are a couple of points that should ponder before trying to “enlighten” us further:

[1] Is neuroinflammation the cause of the neurodegenerative diseases pD is referring to? Sometimes it is and sometimes it isn’t and sometimes it isn’t at all clear.

[2] Neurodegenerative diseases which have inflammation as a significant feature tend to be progressive (e.g. sub-acute sclerosing pan-encephalitis, multiple sclerosis). Autism, on the other hand, is not progressive.

All people with autism show show developmental delay (that’s a part of the diagnosis), but they do develop. A static or progressive disability is more typical of chronic inflammation, but autism is neither of those (by definition).

[3] Is the neuroinflammation reported in autism a real and consistent feature of autism or is it spurious or rare? We don’t have that information yet, although pD seems to think we do.

As an aside, any time pD “laughs” in his comment (e.g. “LOL” or “hehe”), it’s usually a sign that he knows he’s on shaky ground. After all, he is “self-educated” in immunology (a very complex field), which means that he doesn’t know what he doesn’t know.

I’m all for educating people who are asking questions, but pD demands that people prove him wrong, an approach I find tiresome at best.

Prometheus
dr treg
April 4th, 2009
20:50:08

The neuro-inflammation in autism may be primary or secondary but it seems that the brain`s immunogenic response in autism is abnormal although perhaps not in the manner of encephalitis or meningitis.
http://www.brainbank.org/Zimmerman.pdf
Although Johns Hopkins do not believe that the usual immuno-suppressants are effective in autism clinical improvement with steroids and immunoglobulins has been described and there is a trial of steroids in autism either on-going or planned.
http://www.neuro.jhmi.edu/neur.....m_faqs.htm
http://www.aheadwithautism.com/research.html
Other drugs affecting TNF cytokine levels are also being studied in autism e.g. naltrexone clonidine rapamycin and pioglitazone.
The dendrite spines appear to be the main anatomical target in autism and other psychiatric diseases and the structural components of dendrite spines e.g.cypin snapin and shank are being studied.
Gene therapy in mice increased dendrite firing rates and reduced autistic features in fragile X syndrome.
Perhaps the immunogenic response is primary or secondary to infection, dietary constituents or other exposure and results in dendrite spine malfunction and the abnormal firing rates result in the clinical features. As the reference above confirms Johns Hopkins research is directed at reducing microglial activation
dr treg
April 5th, 2009
14:41:54

Autism is usually if not always associated with an abnormal immunogenic response in the brain according to Johns Hopkins.
http://www.neuro.jhmi.edu/neur.....m_faqs.htm
However it may related to endogenous substances or exogenous substances e.g. infection, dietary components.
The main anatomical abnormality in autism and other diseases affecting development affects the dendrite spines which change in number and shape.
Autism is also more common where there are abnormalities of dendrite enzymes/proteins e.g. cypin snapin shank and MEF2
The immunogenic response and dendrite spine changes are probably correlated.
Many treatments being used or being studied in autism affect the immunogenic response e.g. naltrexone clonidine pioglitazone rapamycin.
Johns Hopkins are probably incorrect when they describe the inflammation in autism as unique and not being affected by steroids or immunoglobulin treatment as both of these treatments have resulted in clinical improvement in the past.
Autism is progressive i.e. the loss of previously achieved developmental milestones.
Schwartz
April 5th, 2009
15:05:32

HCN,

“Because this paper says that Big Pharma gets LESS when kids don’t get sick:”

You use a scientific study clearly outlines it’s limited ability to test for sensitivity analysis, despite the hundreds of assumptions required for such an analysis?

You use a scientific study from 2001 that states: “although newer vaccines (eg, varicella and pneumococcal conjugate) have proved to be more expensive than older ones. However, future recommendations should not be limited to vaccines that demonstrate cost savings.”

You see, they specifically excluded the expensive vaccines from the study (they used the same basic vaccines which have low profit margins), while prepping you for a new age of expensive vaccines to get added to the mandated schedule that will not be cost effective. You can also note, that between 2001 and today, vaccines have figured more and more prominently on the quarterly reports of big Pharma.

I also can’t recall the last time I saw profits from IV products when I read through the quarterly report of any of the big pharma companies. I am certain however, that the guaranteed recurring revenue stream provided by new mandated vaccines made the press release. (Prevnar excluded, Gardasil excluded, Ceravix excluded, pnemococcal excluded, rotavirus excluded, ...)

Only an idiot would exclude the most expensive vaccines from consideration in a financial argument and assume that the financial profits from vaccines have remained anywhere near static for the past 7 years which has seen a resurgence of blockbuster vaccines that make big financial headlines.
Sullivan
April 5th, 2009
16:42:28

Vaccine profits—like profits from any product—will vary depending on patent protection. It will be a temporary boost.

The quote you use doesn’t say what yoare vlaiming. You do realize that, don’t you? Are you referring to a different part of the papoer or are you merely misrepresenting the study?

Also, only a supreme idiot would try to argue that it isn’t more profitable to treat disease than to prevent it. Seriously, the argument is obvious to anyone who has spent a few nights in the hospital with a kid.

Profit is not a bad word. Gee, big pharma may have made a few hubdred dollars keeping my kids safe from polio, measles, mumps….

Money well spent.

You haven’t gotten any better with your time off, Schwartz.
Schwartz
April 5th, 2009
17:44:47

Sullivan,

“Vaccine profits—like profits from any product—will vary depending on patent protection. It will be a temporary boost.”

That is incredibly naive. My company has always made money from products that have no patent protection. In case you didn’t realize patent protection on pharmaceuticals can be extended by patenting difficult manufacturing techniques—this is very practical in the domain of vaccines. Also, they can reformulate the older vaccines into different combinations to create new vaccines for the same diseases.

But you’re distracting from the point. Are you actually attempting to argue that mandated vaccines don’t provide a continuous predictable stream of revenue? If not, what exactly are you trying to disagree with?

“The quote you use doesn’t say what yoare vlaiming. You do realize that, don’t you?”

I suggest you re-read the post for comprehension.

I made the quote first, and explained it in the following paragraph. I stated that they didn’t account for more expensive vaccines in their analysis (which was a cost comparison analysis), and they imply that these more expensive upcoming vaccines should still be recommended for use even if they are not cost effective.

If you want the quote for the limited sensitivity analysis in the preceeding paragraph, here it is:
“Data on the probability distributions of variables are unavailable, which prevents us from conducting a Monte Carlo simulation for a multivariate probabilistic sensitivity analysis and estimating confidence intervals.”

Sullivan said:
“Also, only a supreme idiot would try to argue that it isn’t more profitable to treat disease than to prevent it. Seriously, the argument is obvious to anyone who has spent a few nights in the hospital with a kid.”

I think you need to re-read my post for comprehension again. Please point out where I made that argument?

“Profit is not a bad word. Gee, big pharma may have made a few hubdred dollars keeping my kids safe from polio, measles, mumps….”

Please point out where I stated profit was a bad word? You really seem to have a comprehension problem today.

You’ll note that I made no judgements about profit. I made no arguments about decisions drawing from any cost/benefit analysis—but I guarantee you, your government does all the time, perhaps, you should take it up with them?

Perhaps you should take up your profit problems with the previous poster.

My post clearly illustrated HCN’s hypothesis was fantasy and unsubstantiated by the study he/she provided. If you want to convince anyone that Big pharma makes more profit from the hospitalization of children from vaccine preventable diseases, stand up and say so and please provide some evidence to back it up.

Get with the program.
HCN
April 5th, 2009
20:12:30

To repeat Sullivan: “Also, only a supreme idiot would try to argue that it isn’t more profitable to treat disease than to prevent it. Seriously, the argument is obvious to anyone who has spent a few nights in the hospital with a kid.”

Schwartzy, you’ve never spent a night in the hospital with a small child who could not speak (even though he was three years old), have you? From what I know, all of your kids are perfectly healthy (as they are relying on the herd immunity to protect them from disease), and none are autistic. You are just an anti-vaccine zealot who just twists the literature in incomprehensible knots.

Anyway, you are completely clueless… and have yet to tell us what real studies show that the vaccines are worse than the diseases. Basically, I ignore you.
Brian Deer
April 5th, 2009
20:13:04

Gee, this is a difficult one. An unvaccinated ($$ lost to industry) person might become sick ($$ gained by industry). Thus, the argument goes, more money could be made selling expensive (three-times-daily)drugs than (a handful of times a lifetime) vaccines.

So far, so good.

But then the patient might die. And this would be bad news for industry (and possibly the deceased).

Since the bulk of drug sales are to (or at least for) old people, cheap children’s vaccines would be moneyspinners in the long run by keeping people egregiously alive. They could be really coining it. That dastardly Big Pharma!

I can see Dr Evil of Whitehouse Station NJ sweating over his pocket calculator, even now.
Schwartz
April 5th, 2009
20:47:57

HCN,

To repeat: You need to re-read the post for comprehension. You stated that it is more profitable for Big pharma to treat illness than to sell vaccines. The financial evidence suggests otherwise. The analysis you provided also infers otherwise. Your flawed assumption is that the total cost of treating illness goes to big pharma AND you assume that the hospital or treatment related services have a high profit margin for Big Pharma. But this isn’t a total cost discussion.

We’re talking about PROFITS to big pharma. Anyone who has ever run various businesses knows quite well that you have the opportunity to make far more margin on product sales than services and service margins (i.e. hospitals, doctors etc) are pretty much capped, let alone the fact they don’t go to big pharma.

So provide some credible evidence and save your personal anecdote for the proper debate. You should have taken the advice outlined in the study itself:

“Finally, as in most economic analyses, caution should be exercised in interpreting and generalizing these results.”

Until then, I suggest you take philosophical argument up with the person who is making that point. I strongly suggest however, that the financial evidence is pretty clear that big pharma makes far more profit selling expensive vaccine products than any services or hospital products.

Of course, if you prefer to stick to name calling or personal insults, go ahead. Whatever satisfies you.
Schwartz
April 5th, 2009
21:56:29

Brian Deer,

You seem to have the same reading comprehension problems as everyone else here today.

Let’s review the quote from HCN:

“Because this paper says that Big Pharma gets LESS when kids don’t get sick:”

Now please point out in the study where it states that Big Pharma makes more money from sick kids?

“($$ lost to industry)”

Hmm, except industry is not equal to big pharma in this example is it?

“Thus, the argument goes, more money could be made selling expensive (three-times-daily)drugs than (a handful of times a lifetime) vaccines.”

Except high volume on bulk generic drugs for seniors aren’t overly profitable. Remember, we’re talking profit, not sales.
passionlessDrone
April 7th, 2009
01:53:52

Hi Prometheus –

Is neuroinflammation the cause of the neurodegenerative diseases pD is referring to? Sometimes it is and sometimes it isn’t and sometimes it isn’t at all clear.

Again, while it may not be causative, the overwhelming consensus is that neuroinflammation is a bad thing to have. That it results in more dead neurons than a state of less neuroinflammation does not seem to be in dispute. There may be some situations where an inflammatory response might be better than the alternative, but I have yet to find anything referencing chronic neuroinflammation where a beneficial effect has been posited.

Likewise, I’ve seen arguments that some components of an immune response might be benificial towards repair, but even in these cases, the point seemed to be that if you are going to have neuroinflammation in the first place, there are parts that aren’t all together bad.

You may not believe it, but I am genuinely curious about all things autism, and eager to learn. If you could point me in the direction of some relevent papers for me to read concerning the upside of chronic neuroinflammation, I will try to get copies and read them. It just so happens, that when I goto pubmed and type ‘chronic neuroinflammation’, there aren’t too many hits that come back about the benifits. There are a couple of speculative ones, but they ones I’ve gotten my hands on have the very large caveats outlined above, at least as I understood them.

Furhtermore, I’ve read (and posted above) several animal studies where there was nothing except an immune response that wound up causing behavioral abnormalities and physiological abnormalities into adulthood that resembled some characteristics of autism. In these instances, administration of inflammatory inhibitors was sufficient to make the treatment group undiscernable from the placebo group. Cause seems pretty straightforward in these instances; there was nothing else.

Is the neuroinflammation reported in autism a real and consistent feature of autism or is it spurious or rare? We don’t have that information yet, although pD seems to think we do.

Well, our available evidence right now tells us there is a link. While we must face the possibility that some groups have looked for neuroinflammation, failed to find it, and failed to publish those results, our existing data ponts to a relationship. On what else should we form an opinion?

I understand (I think) that you are coming from a viewpoint of extreme caution, likely resulting from knowledge of other situations where something that looked correct based on some preliminary studies was later found to be incorrect with more sublte evaluations.

However, what I’m having a difficult time with in this case is that for an abnormal immune response not to be playing a part in autism, we have to throw out much more than just three studies that have found inflammation in the CNS.

We also have at least four studies showing increased pro inflammatory cytokine production to a variety of stimulants.

Further, we have evidence that regulating inflammation is impaired in both directions; both by increases in MIF, as well as decreases in TGF-Beta and IL-10.

If there is something capable of driving both autism and abberant immune responses, it seems to be capable of acting across a wide range of immune system components, and always in the same general direction; towards a pro inflammatory state. What we do not find, in any reference I’ve seen with appropriate measurements, is a heightened ability regulate inflammation, or indications of a reduced inflammatory state compared to people without autism; it is always the other way around. Maybe there are some studies I’m not reading?

So, to my mind, it isn’t just that we have three studies showing increased neuroinflammation, but rather, a whole suite of studies showing by several lines of evidence that we are observing a population with a propensity towards a proinflammatory state. Based on the background sections of the papers I have been reading, this type of finding seems to be consistent with what people getting funding to perform research believe to be the case as well.

I’m open to the possibility that all of those studies are wrong; but I’d like to see some evidence that this might be the case. In most cases around here, having evidence is a good thing. I make no demands.

As an aside, any time pD “laughs” in his comment (e.g. “LOL” or “hehe”), it’s usually a sign that he knows he’s on shaky ground. After all, he is “self-educated” in immunology (a very complex field), which means that he doesn’t know what he doesn’t know.

Well, with AutismDiva’s departure, I suppose someone had to take up the position of dime store psychoanalyst. Six years ago, previous to my introduction to autism, I suppose that someone continously mistaking my social state would probably have been quite funny.

I would prefer to describe myself as self learning. While I may not know what I don’t know, I will know more tomorrow than I know today.

– pD
Sullivan
April 7th, 2009
04:37:23

pD asserts:

Again, while it may not be causative, the overwhelming consensus is that neuroinflammation is a bad thing to have.

I guess you didn’t read the Vargas letter we recently discussed? Perhaps this section could help you:

Another issue that is important to clarify is the notion that neuroinflammatory responses mediated by innate responses and neuroglial activation are directly associated with injury. At present, we are not able to conclude that these neuroglial reactions are deleterious for the central nervous system. These reactions may invoke anti-inflammatory and repairing processes as demonstrated in our study in which one potent anti-inflammatory cytokine, the transforming growth factor ?-1 (TGF?1) was significantly present in all areas of the brain.

emphasis added.

You could also read the Zimmerman report, which again was blogged here. Again, I’ll quote from it:

There is no evidence in brain tissue or CSF of infection, and the immune activation we observed contained pro-inflammatory as well as anti-inflammatory elements. Further research is needed to determine if the immune
activation in the brain in autism is harmful or beneficial to the brain (it may be either or both), is a residual immature pattern of development from an earlier age, or results from abnormal regulation of brain cells (neurons or astroglia) or a genetic abnormality affecting the immune system, among other possibilities.

So, I guess the concensus is “overwhelming” except for the top experts in the field?

I’m open to the possibility that all of those studies are wrong…

That isn’t the situation here. It isn’t that the studies are wrong—it’s that you are incorrect in your interpretation. You are making assertions that are not supported by the studies, nor the researchers who performed them.
dr treg
April 7th, 2009
19:58:00

Neuro-inflammation doesnt have to result in “dead neurons” – an old-fashioned concept, but increasingly it is noted that neuro-inflammation affects the structure of neurons particularly the dendrite spines which are abnormal in many psychiatric diseases. Such changes can be reversible because of the plasticity of the dendrites and their spines.
The immune system isnt “off or on” it is usually in a state of balance between pro and anti inflammatory activity probably related to regulatory T cell and neuroglial activity. Disease occurs when the balance is abnormal. Perhaps the presence of pro-inflammatory (MCP-1) and anti inflammatory ( TGF beta-1) cytokines in the brain/CSF in autism reflects ongoing inflammation combined with attempts to heal inflamed areas.
http://www.neuro.jhmi.edu/neur.....ndings.htm
Any unifying theory of autism must include the immunological or neuro-inflammation, genetic and neuron anatomy findings and their relation to the clinical features.
passionlessDrone
April 7th, 2009
21:46:01

Hi Dr. Treg –

Disease occurs when the balance is abnormal.

We don’t seem to observe tramautic brain damage, signs of persistent infection, demylination, or lesions commonly linked with many degenerative diseases; but we do see the associated inflammation.

Because of this, my thoughts are that what we are witnessing in autism is a state where the homeostasis has been knocked off kilter somehow, and doesn’t get back on track.

Perhaps the presence of pro-inflammatory (MCP-1) and anti inflammatory ( TGF beta-1) cytokines in the brain/CSF in autism reflects ongoing inflammation combined with attempts to heal inflamed areas.

This was very much along the lines of my thought processes after doing more reading on the multiple facets of the broad term, activated microglia. However, I’m still bothered by the amount of stretching necessary to turn chronic neuroinflammation into a good thing, finding it roughly equivalent to noting that because the firemen are present at the sites of fires, fires are good.

Can you post some links in regards to dendrite spines in autism and/or immunological interactions?

– pD
passionlessDrone
April 7th, 2009
22:41:07

Hi Sullivan –

I guess you didn’t read the Vargas letter we recently discussed?

But the larger point is, there are a great number of studies on having an activated immune system in the brain outside of what Pardo and Zimmerman have authored. All of them are associated with conditions you’d rather not have, as opposed to have. Further, the consensus seems to be that while activated microglia are capable of having benificial effects; by decreasing inflammation, chronically activated microglia either initiate, or aggravate a range of disorders. There doesn’t seem to be evidence of just a good side, only a bad side, and sometimes, maybe a good side. Just because firemen put out fires doesn’t mean you want to see them in front of your house.

All abstracts below are snipped for space purposes. Any emphasis is my own.

Microglia in normal condition and pathology

Since 1970s there has been wide recognition that microglial cells are immune effectors in the CNS that respond to pathological conditions and participate in initiation and progression of neurological disorders including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and acquired immune deficiency syndrome dementia complex by releasing potentially cytotoxic molecules such as proinflammatory cytokine, reactive oxygen intermediates, proteinases and complement proteins. There is also evidence to suggest that microglia is capable of secreting neurotrophic or neuron survival factors upon activation during inflammation or injury.

Inflammation in Parkinson’s diseases and other neurodegenerative diseases: cause and therapeutic implications

... While different mechanisms including environmental toxins and genetic factors initiate neuronal damage in the substantia nigra and striatum in PD, there is unequivocal evidence that activation of neuroinflammatory cells aggravates this neurodegenerative process. . . The addition of human NM to microglial cell cultures induced positive chemotactic effects, activated the pro-inflammatory transcription factor nuclear factor kappa B (NF-kappaB) via phosphorylation and degradation of the inhibitor protein kappaB (IkappaB), and led to an upregulation of TNF-alpha, IL-6 and NO. These findings demonstrate a crucial role of NM in the pathogenesis of Parkinson’s disease by augmentation of microglial activation, leading to a vicious cycle of neuronal death, exposure of additional neuromelanin and chronification of inflammation. Antiinflammatory drugs may be one of the new approaches in the treatment of PD.

Excitatory amino acid transporter expression by astrocytes is neuroprotective against microglial excitotoxicity

Glutamate-induced excitotoxicity is considered as a major cause of neurodegenerative disease . . . Conversely, activated microglia released an excess of glutamate that induced excitotoxic neuronal death. Astrocytes rescued neurons from microglial glutamate-induced death in a ratio-dependent manner

Are aware of highly increased rates of glutamate have been observed in autism? Genetic components in glutamate processing are also highly implicated, which would seem to indicate that having microglia generate lots of extra glutamate would be a bad thing, as opposed to a good one.

All of these studies post date the Pardo paper by several years. There are many others. In particular, there are many, many efforts underway to combat neurological diseases by investigating methods of inhibiting the immune response. Why do you suppose that is? Is everyone misreading Pardo? When the NIH funded a study on minocycline in autism based on observed anti inflammatory effects, do you think they made a mistake?

In a technical sense, you could argue that autism may be fundamentally different than all of the other neurological disorders which present with activated microglia, and in autism, and autism only, this is a good thing and there are no deleterious effects. You could argue that in autism, highly increased levels of tnf alpha and IL-6 are a good thing, as opposed to a bad thing in these other conditions. You might argue that excess generation of ROS is a bad thing to have in any situation but autism. But ideally, we’d have some evidence that this might be the case. The letters from Pardo and Zimmerman do not constitue such evidence, but rather, the acknowledgement of the incremental nature of understanding a “new” disorder. Proving that in the case of autism, the observations impart only benificial effects requires nearly transcendental findings that seem to only operate in one particular disorder.

One view put forth by Prometheus, that our existing studies may not be large enough to prove that an active immune process in the CNS is actually common to autism has more earth under its feet; but still relies on all of our existing studies being wrong in exactly the same way, and a grand total of zero studies showing a lack of an active immune response in the CNS.

– pD
Sullivan
April 8th, 2009
05:03:18

But the larger point is, there are a great number of studies on having an activated immune system in the brain outside of what Pardo and Zimmerman have authored.

1) I understood your point

but

2) You act as though Pardo and Zimmerman are unaware of the information you are providing. Sounds like a bad assumption.

All of these studies post date the Pardo paper by several years.

Not a good measure, is it? Why not compare to the date that the Pardo letter was written? May 13, 2008.

Let’s see—you cite what appears to be a review paper by someone in Ukraine from 2008. Likely not new information that Pardo wouldn’t have known.

You cite a paper from 2007. Obviously, Pardo had access to this.

Then you cite a paper from 2008, which doesn’t really make a clear case that the neuroinflamation observed by Pardo and Zimmerman is damaging or causative in autism.

What you are doing is demonstrating the exact thought process that leads to much harm in the autism community. You are connecting dots with very qualitative reasoning, but not admitting that your conclusions are merely hypotheses (at best). Hypotheses are OK—right up to the point that people start treating people based on the hypotheses. Also, when people go beyond hypotheses into the realm of being just plain wrong in order to support the idea that vaccines cause autism, the pseudo-logic is quite damaging.

Pardo made a couple of very clear statements which are very damaging to the idea that vaccines cause autism—the neuroinflamation is not caused by toxicity nor is it caused by an infectious agent.
Joseph
April 8th, 2009
19:55:12

Out of curiosity, in these studies of pro-inflammatory cytokines, has psychological stress been controlled for? It looks like psychological stress tends to increase levels of TNF-?, IL-6, etc. See, for example, this.
passionlessDrone
April 8th, 2009
20:15:19

Hi Joseph –
As far as I know, pyschological stress was not controlled for in any of these. It would seem to be relatively straightforward to concurrently measure cortisol, atch, or crh. It seems possible that the lack of such controls is the result of what Prometheus says, the first step is figuring out how common is actually is; then trying to descrambe the cause(s).

Indeed, it wouldn’t suprize me to find that increased levels of stress could be a component in many cases. If LoftMatt were around, I’m sure that he could give us a voluminous source of references regarding the effect of psychological stress and it’s capacities to generate a wide range of physiological findings in autism.

Here is a great one he pointed out to me on another site:

Glutathione Depletion, Lipid Peroxidation and Mitochondrial Dysfunction Are Induced by Chronic Stress in Rat Brain

I’d say that pretty much hits some sweet spots for autism!

There are bunches, bunches more, but it will take me a while to dig them up.

– pD
dr treg
April 8th, 2009
21:27:51

As well as affecting cytokine levels stress also affects the structure of dendrite spines i.e. the length and density of dendrite spines.
http://www.sciencedaily.com/re.....182434.htm
Loftmatt
April 9th, 2009
04:23:26

pD, I am out here. Just time deprived. Below is some text I have consolidated from a good article named Stress, Inflammation, and Hypertension on the acute phase response. I will add cites tomorrow on my favorite topic.

Not surprisingly, most of the research on the effects of stress on blood pressure and cardiovascular disease has focused on the sympathetic nervous system, but there is another component of the stress response that may be relevant. This is the inflammatory or acute-phase response, which is switched on more gradually than the sympathetic nervous system and the HPA axis, but which is also partly under the control of the central nervous system. The function of this response may be to aid the healing of wounds inflicted during the fight and flight response by activating both the blood clotting cascade and the inflammatory response. It also serves as a defense against what the body regards as intruders, such as bacteria.

The acute-phase response is mediated by cytokines (chemical messengers of the immune system), which are proteins and peptides produced in cells throughout the body, including in the liver, endothelium, fat cells, and brain. The cytokine that has attracted the most interest in the study of cardiovascular disease is C-reactive protein (CRP). Produced in the liver, CRP is a major player in the acute-phase response. While CRP levels increase during acute inflammatory responses such as with infections, the finding of slightly high levels in patients with cardiovascular disease, and its predictive value for events, was the trigger for the surge of interest in this field. The main inducer of the response, however, is another important pro-inflammatory cytokine, interleukin 6 (IL-6). When subcutaneously administered to humans, IL-6 provokes an acute-phase response, which is associated with an increase in CRP level. Thus, the levels of CRP and IL-6 are closely correlated, whereas other cytokines are not. IL-6 largely comes from macrophages, which, when activated, not only release IL-6, but also other cytokines such as IL-1 and tumor necrosis factor ? (TNF-?), both of which also stimulate CRP release. Evidence for a causal role of IL-6 comes from the observation that IL-6 knockout mice are unable to generate a normal acute-phase response.

The acute-phase response is also an integral part of the response to external sources of stress that is mediated by the central nervous system. There is extensive evidence that during the acute stress response, cortisol, catecholamines, angiotensin, and other stress hormones, which are part of the central nervous system response, induce the liver and abdominal fat tissue to release cytokines and other inflammatory mediators, including IL-6. In general, the sympathetic nervous system increases cytokine secretion, while cortisol suppresses it. The relationship with cortisol is a 2-way street, however, since IL-6 acts on the hypothalamus to increase cortisol release. This sympathetically mediated secretion of IL-6 comes predominantly from adipocytes. Exercise is another potent activator of the sympathetic nervous system, and it also increases IL-6: in one study, a positive correlation was observed between peak plasma adrenaline or noradrenaline and IL-6 levels after 15 minutes of aerobic exercise.

The acute-phase response includes the release of other proteins besides CRP, including serum amyloid A and fibrinogen. These cytokines may contribute to the development of metabolic syndrome. Serum amyloid A lowers high-density lipoprotein cholesterol levels, and TNF-? and IL-6 both have effects that lead to insulin resistance. Furthermore, circulating IL-6 stimulates the HPA axis, activation of which is associated with central obesity, hypertension, and insulin resistance. Adipocytes are an important source of IL-6 and other cytokines, and the blood levels of IL-6, CRP, TNF-? and fibrinogen are all correlated with visceral obesity. About 25% of circulating IL-6 comes from fat cells, and visceral fat releases 2 to 3 times more IL-6 than other fat cells. The acute-phase response leads to increased fibrinogen levels; IL-1 and TNF-? increase platelet number and activity. These considerations have led Yudkin and colleagues to propose that IL-6 is a central mediator of the relationship between chronic stress, inflammation, obesity, and coronary heart disease.
dr treg
April 9th, 2009
14:14:50

Perhaps though in autism, CSF TNF-alpha might be a better measurement of neuro-inflammation than CRP as this quote from Medscape shows:
“Michael Chez, MD, a pediatric neurologist at Hawthorne Health Center, Libertyville, Illinois, and colleagues[4] measured the titers of TNF-alpha, a proinflammatory cytokine, in 8 boys who developed autistic regression between 15 and 24 months of age. At the time of the CSF measurement, their ages ranged from 2.1 to 9.5 years. All 8 patients had elevated TNF-alpha levels in CSF compared with in serum (P = .049). The 4 patients who had not been treated with immunosuppressants had the highest CSF:serum TNF-alpha ratios (33:1) compared with ratios for the 4 patients who had received immunosuppressant therapy (6:1). Values of other CSF components, such as cell count, glucose, protein, immunoglobulin production, myelin basic protein, oligoclonal bands, and lactic acid levels were unremarkable. Dr. Chez observed, “Larger studies with a control group are needed to examine predictive markers of autism that may also be useful as indicators of response to treatment. Early intervention against heightened TNF-alpha in the CSF may prove to be protective.”
passionlessDrone
April 9th, 2009
14:50:52

Hi Sullivan –

Not a good measure, is it? Why not compare to the date that the Pardo letter was written? May 13, 2008.

Sure. But the Pardo letter wasn’t meant to provide an overview of the science, just to refute what he felt were specific problems with interpretations of his particular paper. As far as thimerosal goes, I’d actually be inclined to agree with him.

Then you cite a paper from 2008, which doesn’t really make a clear case that the neuroinflamation observed by Pardo and Zimmerman is damaging or causative in autism.

Again, however, here we need a reason that excess glutamate release isn’t bad for autism, and is bad for every other condition. I’m not making the case that what Pardo or Zimmerman observed is damaging or causative in autism. Instead, I’m making the case that common byproducts of neuroinflammation are damaging for any condition. Excessive generation of ROS is bad for anyone; if you happen to have impairments in systems responsible for cleaning up this type of byproduct, then it is even worse. Excessive generation of glutamate is bad for anyone; if you happen to have genetic impairments in glutamate processing and/or compensatory calming neurotransmitters (i.e., GABA), then this is even worse. Likewise for tnf alpha; and if you’ve been shown to create more tnf alpha than ‘normal’ people to similar stimulating factors, then that’s even worse. If you are more likely to produce less anti inflammatory cytokines than others, the implications are again, worse. We have evidence for all of these things in the autism world.

What you are doing is demonstrating the exact thought process that leads to much harm in the autism community. You are connecting dots with very qualitative reasoning, but not admitting that your conclusions are merely hypotheses (at best). Hypotheses are OK—right up to the point that people start treating people based on the hypotheses.

Well, we’ve got several different things happening here, at least that what’s I’m getting from the above sentence.

1) It does not appear to be a hypothesis that the results of excessive immune activation in the brain are capable of generating a suite of chemicals that are deliterious in a vareity of ways. If this is common to autism, we’ve addressed, as a maybe, though our available evidence indicates it is. As if this is causative of autism is much more difficult to detangle; at this point I have no problem admitting a lack of evidence that such immune activation causes autism, but that does nothing to mitigate the body of knowledge that the by products of immune activation have been shown again and again to be injurious by a vareity of mechanisms.

2) A possible association to vaccines.

3) I’ll freely admit that I’m thinking out loud, hypothesizing, theorizing, and/or participating in ‘idle speculation’ in terms of whether or not neuroinflammation is causitive of autism.

I make no recommendations as to possible treatment options as a result of my thoughts. As towards whether or not my thought process leads to much harm in the autism community is based in very personal interpretations, and we are unlikely to resolve.

Also, when people go beyond hypotheses into the realm of being just plain wrong in order to support the idea that vaccines cause autism, the pseudo-logic is quite damaging.

I am saddened by how rapidly I have gone from qualitative reasoning to psuedo logic. :(

My position is not necessarily that vaccines can cause autism, but rather, they may be able to cause some of the physiological effects associated with autism, and in parallel, we haven’t really studied vaccines very efficiently; as vaccines are far more varied than just thimerosal and the MMR. I’m generally much more concerned about the potential effects our actions are having in children at ages far earlier than generally described in the existing court cases; where an unmistakable, drastic change in behavior occurred. Just because we don’t have parents reporting that their children’s behavior changed after their two month appointments doesn’t mean we might not be affecting a small subset of children; espeically those that have some particular qualities in terms of responding to, and resolving inflammatory immune responses that have been observed in autism. Please note that our picture gets lots fuzzier, and harder to descramble if instead of looking for a ‘cause’ of autism, we go looking for increasing risk factors for specific components consistent with autism physiology. From my perspective, it seems like the biological components of autism seem to include lots of little things going wrong, as opposed to one big thing, and as such, an approach evaluating how some of these little things might be caused seems warranted. You may feel otherwise.

I’ll freely acknowledge my concerns are speculatory; unfortunately, I’m not sure how we resolve our apparent differences as towards whether or not such out loud speculation is damaging or not. (?)

Pardo made a couple of very clear statements which are very damaging to the idea that vaccines cause autism—the neuroinflamation is not caused by toxicity nor is it caused by an infectious agent

I’d say that Pardo made a couple of clear statements that are damaging to the idea that thimerosal, or persistent infection via vaccination can cause autism. You have quietly substituted in that these two components are the only mechanisms by which vaccination could cause the observed immune activation. While these may be the only things put forth by claimants and some very vocal groups, this does not mean the list is necessarily comprehensive.

Of particular importance here, to my speculative mind, is what Pardo failed to find; signs of ongoing infection. And yet, we have this observed imbalance; so what is causing it? There are many possibilities, as mentioned by Pardo:

. . . immature pattern of development from an earlier age, or results from abnormal regulation of brain cells (neurons or astroglia) or a genetic abnormality affecting the immune system, among other possibilities.

(my emphasis)

I’d agree; there are probably lots of ways to get to this point. And, further, I’d bet that in any given individual, you could have many of these pathways involved; in lots of cases it might be immature patterns of development, genetic risk, and other things all working in concert.

But why did I emphasize immature pattern of development? Because we have animal models showing that an immune response, and an immune response only is capable of creating long term behavioral and physiological changes that mimic some of what is observed in autism. I have referenced several of those studies above. In other words, immune challenges and/or seizures during specific timeframes seem to have the ability to permenantly alter the neuroimmune system of animals; so that in essence, animals without any sign of ongoing infection none the less display an activated immune response in the brain, increased succeptibility to seizures, and behavioral changes into adulthood. In many instances, the driving factor seems to be an increase in tnf alpha, a proinflammatory cytokine that people with autism just happen to generate at highly exaggerated rates when compared to people without that diagnosis. Concurrent administration of inflammatory inhibitors is sufficient to make control and treatment groups undiscernable. Other groups are evaluating the for long term, subtle changes from a variety of bacterial exposures in neonates. Somehow along the way, thimerosal and MMR have become synonomous with vaccination in whole; you might be surprized to find that I honestly hope this has been a benign juxtaposition.

You can accuse me of stringing pearls, engaging in speculation, or psuedo logic all you want. I will openly acknowlege the problems of jumping from rodent models to humans. But when the rubber meets the road, you cannot show me a study wherein the fundamental function of vaccination; initiation of an immune response in infants, has been evaluated beyond MMR based studies. For all the bluster, this doesn’t seem to be an acknowledgement I ever read; and in fact, is usually ignored, as if this means the that their cannot be a problem. None of this would seem important to me if we haven’t established that children with autism have dramatically different immune systems than their non diagnosed peers.

– pD
passionlessDrone
April 9th, 2009
14:58:11

Hi Dr. Treg –

Perhaps though in autism, CSF TNF-alpha might be a better measurement of neuro-inflammation than CRP

Indeed it may. In the Chez paper, he went to describe extremely high CSF to serum ratios of tnf alpha when compared to a variety of other neurological conditions such as Alzheimers and Parkinsons.

The ratio of the cerebrospinal fluid levels to serum levels averaged 53.7:1. This ratio is significantly higher than the elevations reported for other pathological states for which cerebrospinal fluid and serum tumor necrosis factor-alpha levels have been simultaneously measured.

Elevation of tumor necrosis factor-alpha in cerebrospinal fluid of autistic children

– pD
Roger
April 9th, 2009
18:06:32

Can you post some links in regards to dendrite spines in autism and/or immunological interactions?
– pD

pD,it’s “dendritic,dear.

Actually there’s quite a bit of findings out there about this.Here are a couple of the top results from Google:

Shelley Halpain, Ph.D., and Research Associate Barbara Calabrese, Ph.D., describe how a protein called MARCKS affects the shape of neurons, particularly the part of the neurons known as dendritic spines, which are essential for learning and memory.

Because dendritic spines are so central to mental functioning, it’s no surprise they are associated with neurological and psychiatric diseases. In mental retardation and autism, for instance, the shape of the dendritic spines are different. Under a microscope, the dendritic spines of many mentally retarded people are longer and appear more immature. In recent years, scientists have become increasingly aware of the possibility that a number of psychiatric and neurodegenerative diseases like Alzheimer’s are also affected by synaptic changes brought about by spine morphology. The brains of schizophrenic patients or people suffering from mood disorders also show a reduced number of dendritic spines i

Because dendritic spines are so central to mental functioning, it’s no surprise they are associated with neurological and psychiatric diseases. In mental retardation and autism, for instance, the shape of the dendritic spines are different. Under a microscope, the dendritic spines of many mentally retarded people are longer and appear more immature. In recent years, scientists have become increasingly aware of the possibility that a number of psychiatric and neurodegenerative diseases like Alzheimer’s are also affected by synaptic changes brought about by spine morphology.

http://www.scripps.edu/philanthropy/autism.html

Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1.
Hung AY, Futai K, Sala C, Valtschanoff JG, Ryu J, Woodworth MA, Kidd FL, Sung CC, Miyakawa T, Bear MF, Weinberg RJ, Sheng M.

The Institute of Physical and Chemical Research (RIKEN)-Massachusetts Institute of Technology Neuroscience Research Center, Cambridge, Massachusetts 02139, USA.

Experience-dependent changes in the structure of dendritic spines may contribute to learning and memory. Encoded by three genes, the Shank family of postsynaptic scaffold proteins are abundant and enriched in the postsynaptic density (PSD) of central excitatory synapses. When expressed in cultured hippocampal neurons, Shank promotes the maturation and enlargement of dendritic spines. Recently, Shank3 has been genetically implicated in human autism, suggesting an important role for Shank proteins in normal cognitive development. Here, we report the phenotype of Shank1 knock-out mice. Shank1 mutants showed altered PSD protein composition; reduced size of dendritic spines; smaller, thinner PSDs; and weaker basal synaptic transmission. Standard measures of synaptic plasticity were normal. Behaviorally, they had increased anxiety-related behavior and impaired contextual fear memory. Remarkably, Shank1-deficient mice displayed enhanced performance in a spatial learning task; however, their long-term memory retention in this task was impaired. These results affirm the importance of Shank1 for synapse structure and function in vivo, and they highlight a differential role for Shank1 in specific cognitive processes, a feature that may be relevant to human autism spectrum disorders.

PMID: 18272690 [PubMed – indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/18272690

Current genetic evidence links autism with defects in signaling between neurons, particularly at specialized regions of the cells known as synapses. Bernardo Sabatini and his colleagues at Harvard Medical School plan to study how neuron activity affects synapse formation, focusing on the role of three autism-associated proteins in this pathway.

To create a synapse, a cytoplasmic extension from one neuron, known as dendritic spine, makes contact with the axon of a nearby cell. Once the synapse is formed, electrical activation in the axon causes release of neurotransmitter from the axon, inducing an electrical and chemical pulse in the spine. Activity in both cells is necessary to stabilize the connection and strengthen the synapse. This process occurs both during normal development and during learning, but some evidence suggests it is impaired in autism. Dendritic spines are abnormal in mouse models of the disorder, as they are in models of the related disorders Fragile X Syndrome and Tuberous Sclerosis Complex. Three of the known autism-associated genes, including members of the Shank, neurexin and neuregulin families, also produce proteins that are found in the synapse and that probably form a complex. Preliminary data from the Sabatini team suggest that, after neurotransmitter is detected in the spine, one of these Shank proteins travels out the active dendritic spine. The protein’s role in the spine and why activity causes it to leave the spine remains unclear.

Sabatini and colleagues plan to study synapse formation in neurons deficient for these autism-associated genes, specifically looking for defects in the activity-dependent final steps. Using a combination of optics and chemistry, the researchers plan to carefully control the release of the neurotransmitter glutamate sensed by a dendritic spine. This technique will mimic the release of glutamate from the axon and trigger the electrochemical pulses that would normally be induced in the spine. The researchers then plan to look for changes in the number of synapses and in the morphology and composition of the dendritic spines. Based on their hypothesis that autism-related proteins assist in synapse formation, the researchers expect that loss of the proteins will cause consistent defects in these structures and in their signaling strength, which may underlie the learning and social impairments seen in people with autism.

http://sfari.org/grants/name/p.....-in-autism

Lots more,but this should get you started.
passionlessDrone
April 10th, 2009
00:39:59

Hi Roger –
Great stuff, and very much appreciated! Thank you!

– pD
me.yahoo.com/a/TuRz.joYnfzpKUWMPSYwTtN6HTLFunmLzPblUMkn
April 10th, 2009
18:18:51

Mental retardation is associated with the absence of short thick spines.

“Golgi studies reveal abnormally long, thin spines and the absence of short, thick spines on dendrites of cortical neurons in retarded children with normal karyotypes. The degree of dendritic spine loss and abnormality appears to be related to age and the severity of developmental retardation. Dendritic spine “dysgenesis” is a common feature of the microstructural pathology that occurs in profound mental retardation of unknown etiology”.
http://www.sciencemag.org/cgi/...../4169/1126

As the immune system is becoming more implicated in autism the term autistic dendritis i.e. inflammation of dendrites rather than dysgenesis may be a more useful model.
Dendrite structural changes are related to their function i.e. dendrite firing rates and the clinical features of autism. Increasing dendrite firing rates in fragile X syndrome with gene therapy improved the autistic features of frgile X syndrome.
http://www.pnas.org/content/10.....type=HWCIT

Here is some more food for thought:
http://www.associatedcontent.c.....tml?cat=70
http://www.associatedcontent.c.....tml?cat=72
me.yahoo.com/a/TuRz.joYnfzpKUWMPSYwTtN6HTLFunmLzPblUMkn
April 10th, 2009
23:06:07

The dendrite spines or dendritic spines whatever are short and thick in diseases ssociated with mental retardation.

“Golgi studies reveal abnormally long, thin spines and the absence of short, thick spines on dendrites of cortical neurons in retarded children with normal karyotypes. The degree of dendritic spine loss and abnormality appears to be related to age and the severity of developmental retardation. Dendritic spine “dysgenesis” is a common feature of the microstructural pathology that occurs in profound mental retardation of unknown etiology”.
http://www.sciencemag.org/cgi/...../4169/1126

As it appears that immunological abnormalities are increasingly associated with psychiatric diseases including autism the term “autistic dendritis” rather than dysgenesis may be a more appropriate description.
passionlessDrone
April 14th, 2009
14:12:11

Hi Roger and Dr. Treg –
A friend of mine forwarded me this link this morning:

http://www.webmd.com/brain/new.....-the-brain

Specific to this conversation, alterations to dendrite plasticity are mentioned as a result of PCB exposure.

Generalizing out to autism as a whole, these studies would tend to have some rather bleak implications regarding the question as to if we are observing a real increase in the number of children with developmental disabilities, as well as the oft repeated mantra that ‘the poison is in the dose’.

– pD
Matt
April 16th, 2009
01:57:57

pD, a new study came out today related to your question above. You can find it at the following site. Not sure how to drop in a hyperlink on this page. http://news.yahoo.com/s/nm/200.....cortisol_1

According to the article, it reports that children with Asperger’s Syndrome show a flat marginal cortisol response to the stress of transitioning from sleep to wakefulness and getting up in the morning. This is additive to the literature on cortisol abnormalities in autism.
passionlessDrone
April 20th, 2009
17:29:31

Hello friends –
Is anyone still following this thread? I doubt it. Anyways, here is a link to a paper that indicates that an inflammatory process initiated by lps administration is able to affect dendritic length and density, and significantly increase oxidative damage as measured by isoprostane measurements; even though the inflammation levels were not sufficient to produce the more tell tale signs of neurodegeneration. Unsurprizingly, a pre-treatment regiment of some types of anti inflammatories were sufficient to amerliorate these symptoms. This approach was taken after a vareity of knockout mice incapable of generating an innate immune response via TLR4 were found not to suffer effects from LPS injection.

As noted by the authors, a limitation here is that this was an acute state of neuroinflammation, as opposed to a chronic condition. None the less, if our broader question is whether or not we have evidence that inflammation is capable of affecting causing physiological changes consistent with autism without more obvious signs of pathology; the answer seems to be yes.

Neuronal oxidative damage and dendritic degeneration following activation of CD14-dependent innate immune response in vivo

– pD