Monday, December 22, 2008

Cholesterol and Son of J-LIT

The 10 year follow on to the J-LIT study is out. My view and update of the original J-LIT study was that it was one of the better statin studies and provided more information on the effects of pharmacologically lowered cholesterol levels, on a background of the known pleiotropic effects of the statin drugs, than most other studies. At a fixed dose of simvastatin (mostly 5mg per person per day) there is a relative beneficial effect if your statin induced hypocholesterolaemia is mild, with a significant increase in cardiovascular, cancer and all cause mortality if your TC drops below 160mg/dl and/or your LDL-C drops below 80mg/dl.

Well now the 10 year follow up is published.

What happens at the 10 year mark? Well, you are as welcome to try and find out as me, but I've failed.

There is a tabulated display of cardiac "events" vs on-study cholesterol levels in the results section. That's it. They have mortality data, including cardiac deaths and cancer deaths, for each cholesterol grouping, but these are not mentioned (they were there in J-LIT). Perhaps they have decided that we will be so preoccupied with the reduction in cardiac "events" that the risk of dying becomes so unimportant that we won't want to know about it.

Well I'd like to know.

This is the total of the information about all cause mortality by cholesterol level:

"The relative risk of all-cause mortality was also analyzed in relation to the average serum lipid levels during the 10-year treatment period in the primary prevention cohort study (data not shown comment: You bet it's not shown!). The results were the same as those in the previous report.2"

Now of course all studious cardiologists will naturally want to know exactly how lethal low cholesterol levels are, so will look up reference 2. You think not? Well, just to help out, here are the all cause mortality data from the 6 year report cited as ref 2 and plotted by TC intervals. The LDL-C vs all cause mortality curve is the same shape but a bit flatter. Look at the left hand end.

The left hand end is where these cardiologists want you to be. There is no difference between the data at 6 years vs those at 10 years is what they say. Seriously low TC or LDL-C will significantly increase you risk of being dead. Obviously, if you are a cardiologist, that is far better than having a cardiac "event"!

This 10 year report MUST also have the relative risk data for cardiac death in the low cholesterol group but they have forgotten to even mention it. I'd just remind you that in the original J-LIT study cardiac mortality was 6.23 time higher in the group with TC below 160mg/dl vs the reference group with TC of 200-219mg/dl. Again, perhaps having someone dead is less tiresome than having to manage a pesky survival heart attack. I dunno. BTW the LDL-C concentration in the group with TC <160mg/dl and 6.23 times relative risk of cardiac death was <80mg/dl, ie cardiological Nirvana.

Is that it? Not quite.

All cause mortality (irrespective of lipid levels) did get a brief mention:

"However, the overall mortality rate of the primary prevention cohort was higher during the 10-year period (4.47 deaths per 1,000 patient-years) than for the 6-year J-LIT period (3.69 deaths per 1,000 patient-years). The main factor contributing to the increase of mortality in the present study was probably aging, because the mean age had increased by 6 years for this extension study compared with that for the original J-LIT study"

Reading carefully here it seems they were comparing death rate in the first 6 years with death rate in the total 10 years, which included the first 6 years. That is, the all cause mortality in the last 4 years of the study must have been quite a bit higher per year than the overall quoted 10 year value as it is diluted down by the inclusion of the first six year value. Reverse engineering the numbers ties my brain in a knot. But that's how it has to be. What was to stop them adjusting the figures for age? Maybe the result!

They scared themselves with their honesty about mortality in the original J-LIT study and so they have been a lot more cautious with data release this time around.

So how do you sum up Son of J-LIT?

Dead bodies are less worrisome than cardiac "events".


PS I think I have commented that the original J-LIT study could be repeated on any cohort of people on a fixed dose of a given statin and that this has never been done, for obvious reasons. I think we can add that the exercise is so scary to a statinator that even the original J-LIT investigators have refused to repeat the exercise, even though they are the developers of the methodology and have the same cohort available. Wow.

Tuesday, December 16, 2008

Dodgy D'Anci

Just a few comments after reading through Stan's latest dodgy paper, the one by D'Anci et al in Appetite.

Here are some of my favorite quotes:

"The present study examined how the initial stages of two weight-reducing diets, a low-carbohydrate diet similar to the AtkinsTM diet, and another with macronutrients proportions typically recommended by the American Dietetic Association (ADA), affect cognitive performance"

Okaaaay. A week of zero carbs, a week of under 8g/d and a week of under 16g/day. If anyone has a spare copy of Dr Atkins New Diet Revolution, perhaps they could send it to D'Anci. She might even read it before her next "similar to the AtkinsTM" study. Or maybe not. After all, quoting the AtkinsTM diet is hard for a main stream nutritionist who thinks high fibre, brightly coloured, mostly leaf based vegetables are actually healthy. Especially the number of servings Atkins suggested of this mainstream approved garbage. You don't get many of the AtkinsTM induction veggies on zero carbs per day!

"To mimic this pattern of restriction and reintroduction of dietary carbohydrate, participants followed a 3-week dietary regimen that included a 1-week period that eliminated carbohydrates. We proposed that dietary carbohydrate restriction would impair cognitive performance in the early phases of the diet, and that this impairment would be ameliorated by the reintroduction of carbohydrate"

This is exactly what they found, that the cognitive impairment of zero carbing can be reversed by as little as 8g/d of carbohydrate. Perhaps skipping the zero carb phase would have left the study with absolutely no anti LC data? After all, the ADA dieters had higher confusion scores than the LC group at all time points...

"...weight loss was not significantly different over the 3-week experimental period, weight loss was less than 2 kg in each group (LC diet M = 1.88 kg; ADA diet M = 1.76 kg; n.s.)"

This is impressive. I can't really see how they achieved this. On an intensely ketogenic, carbohydrate restricted diet there was only slightly more weight loss in the LC group than could be achieved by simply following the ADA advice for weight loss. You would have expected the water loss from metabolism of liver glycogen would have accounted for a significantly greater weight loss in the first week in the zero carb group compared to the ADA group. How can this be? Beats me. Maybe the LC group were told to eat enough protein to keep out of ketosis? How can you tell? Nothing in the methods.

And this one, the absolute crowning achievement:

"Hunger ratings did not vary between the two diet conditions"

Sooooo, the AtkinsTM diet is a NON CALORIE RESTRICTED diet which, if actually followed, produces progressive weight loss. The ADA (low calorie macronutrient balanced) dieter's advice re calories is stated in the methods section as:

"Individuals who selected the ADA diet calculated their recommended caloric intake per day based on their current weight"

The closest I could find to what this really means on the ADA website was:

"An individualized reduced calorie diet is the basis of the dietary component of a comprehensive weight management program. Reducing dietary fat and/or carbohydrates is a practical way to create a caloric deficit of 500 – 1000 kcals below estimated energy needs and should result in a weight loss of 1 – 2 lbs per week."

It doesn't actually say anywhere in the paper how much of anything the participants ate! But what ever they ate, they were either HUNGRY on the AtkinsTM like diet or not hungry at all on a caloric deficit of up to 1000kcal on the ADA diet. Smell of fish here?

Another gem from the homilies in the discussion:

"Participants most likely selected into a diet best fit their eating habits, although this was not assessed. If so, the diet conditions may not have been sufficiently different from normal to produce much dysphoria or food preoccupation"

Zero carb is close to the diet of exactly how many Americans?

And finally (got to stop some time!)

"Another common phrase may be an important reminder to these prospective dieters—You Are What you Eat"

Humans are fat and protein, with a little carbohydrate thrown in. Maybe that's what we should eat!


Sunday, December 14, 2008

Cholesterol and innate immunity

You would be forgiven for thinking that the apoB100 protein (which defines the LDL or VLDL particle) has been evolved over the past 4.5 billion years to cause cardiovascular disease and the less of it you have the longer you will live. Listening to a cardiologist that is (or a BBC reporter on the Today Program grovelling before a cardiologist). The lower the better. It's impossible to have too low an LDL concentration. Statins in the drinking water. You know the patter.

Until you go in to hospital that is. Do you want an MRSA infection?

The apoB100 protein and its LDL particle are part of the innate immune system. OK, financial declaration time: Our household is 50% funded by the tail end of a PhD grant for a thesis on the innate immune system. If the post doc grant does not come through we're in big trouble. So the innate immune system REALLY matters. To us anyway.

Once upon a time you died in the ICU of overwhelming pseudomonas infection. Nowadays it's MRSA. Methycillin resistant staphylococcus aureus is an ubiquitous and mostly pretty harmless bug, unless you get ill. Then you can get in to serious trouble with it. Or maybe not... so what decides whether you live or die?

MRSA has a switch in its DNA which controls 4 genes that determine whether it sits on the skin surface as a virtual commensal or invades the tissues as a pathogen. One of these genes codes for a signalling peptide called AIP. In fact there is a choice of four different AIPs, AIP 1 being the one possessed by many particularly nasty clinical isolates of MRSA. AIP 1 is essential for the virulence of the bug and it is bound by the apoB100 protein. This binding is particularly effective when the protein is where it belongs, sitting on the surface of an LDL or VLDL particle. What seems to happen is that the AIP 1, which is lipid soluble, ends up in the lipid centre of the lipoprotein. In the mele of an acute infection the LDL particle becomes oxidised and so gets eaten, along with its AIP 1 burden, by a macrophage. Thus endeth the virulence factor of the MRSA, unless you have particularly low LDL or VLDL lipoprotein levels. In which case you are in big trouble.

Of course your death in the ICU from an MRSA infection is of no concern to your cardiologist, after all, it wasn't due to a heart attack... The lower the better etc etc etc

The abstract of the AIP paper is here if you fancy a read.

Statin premed anyone?


Tuesday, December 09, 2008

Alzheimers and ketones

I was interested in the post Stan put up about medium chain triglycerides and Alzheimers Disease. I particularly like the pictorial record of the clock faces, showing memory improving quite markedly within 37 days.

One of the first posts I ever put up on Hyperlipid was the use of the full blown ketogenic diet for the partial reversal of Parkinsons Disease. As far as I can see AD, PD and ALS are all essentially the same disease, but the genetics of your glutamate receptor subtypes or quirks of your glutamate processing enzymes determine which you get. They're excitotoxin diseases, and Russell Blaylock has the most self consistent hypothesis of their generation that I've come across.

According to Blaylock the glutamate neurotransmitter receptor sporting cells can be driven to a catastrophic energy failure under certain conditions. Adding ketones as an alternative to glucose appears to supply energy to allow both survival and improved function of neurones which are doing very badly on glucose.

Having read Vanitallie's abstract and Marilyn Deaton's account of eating an extreme ketogenic diet, I'd imagined that we would be needing ketones ++++++, ie. off the top of the scale, as for the rather problematic ketogenic epilepsy diet (especially if designed by a cholesterophobic nutritionist).

But Dr Mary Newport got a detectable effect within 24 hours from 40ml, or 350kcal, of coconut oil. Without carbohydrate restriction. That's pretty impressive. BTW, if anyone else has already read this account, are you as puzzled as me as to how Mr Newport could stay in a drugs trial while confounding the outcome, admirably so, with MCT derived ketones? I think this is what the article says, correct me if I am wrong.

So the neuroprotection appears to kick in at very low levels of ketones. It might not even be necessary to go to Atkins induction. Something as mildly ketogenic as the Optimal Diet might just do the job. Although 0.8g/kg/d of carbs will keep you out of ketosis, you certainly have elevated ketones compared to the average person on a modern industrial diet... Plus once you start eating real food without excitotoxins the rate of progress might just slow too. I like to have a few ketones on tap.

And now here comes a complete tangent (that's just how stuff goes sometimes):

While I was googling to find out how ketogenic eating about 10% of calories from MCTs is, when added to a standard diet, I came across this gem from 1984. They fed their rats 5%, 15% or 25% of calories from MCT or long chain fats and measured all sorts of things including weight gain and calorie intake. Look at the calorie intake of the diabetic rats!

For normal rats diet composition made no difference to food intake. For diabetic rats (streptozotocin induced) see how appetite skyrocketed on low fat but virtually normalised with increasing fat content (any fat) by the time fat got up to 25% of calories. The lower the fat content, the more hyperphagic (read HUNGRY) the rats became, the fatter they became too. It just reminded me of the cruelty of telling human diabetics to eat a low fat, high carbohydrate diet and then berating them for their gross gluttony.

People keep inventing the wheel but it keeps getting lost!

BTW 15% of calories from MCTs produces about 0.3mmol/l of ketones in the plasma of a rat. My Ketostix would show 0.3mmol/l in urine as a faint trace. Seems quite modest compared to a ketogenic diet, but certainly delivers something.


Monday, December 08, 2008


Hi everyone,

Hyperlipid is now getting back to a reasonable semblance of normality. I'll try to answer the comments as soon as I can. What happened? Well, about six weeks ago I was invited to join THINCS. Within two weeks of my email address going up on the THINCS website I was invited by the Skeptics Society of St Paul's School in London to present a 40 minute overview of why I was unconvinced by the lipid hypothesis of CHD. After some initial teething problems due to lack of software ownership (resulting in a crash course of teach yourself Powerpoint on my wife's PC), I got a presentation together. It was two and a half hours long. Major butchery got it down to an hour and a half. Has anyone ever tried to demolish the lipid hypothesis in just over 30 minutes?

The presentation was last Tuesday and it was a really enjoyable day for all of us. Staff and sixthformers were very interested and the discussion carried on over lunch. I had pitched the talk as neutral as possible, just draw the graphs, discuss the studies and let the science speak for itself. Never mind statin bashing or the weird data from the 4S study.

Interestingly, most of the audience were perfectly willing to draw their own conclusions about data manipulation if you show them Yerushalmy and Hilleboe's paper analysing Keys' Six Countries Study (many thanks Alex). I never did mention the 4S study data.

A number of people commented, positively, on this fairly dead pan approach. You don't need to be aggressive or sarcastic to make your point when the facts speak for themselves so clearly.

It all took a great deal of preparation. In addition to this my wife is in the last two weeks of the lab work of her PhD (she has ligands, that's good! Woohoo, happy dance) and will start writing up over Christmas... Anyone who has played the PhD game will know exactly what this has meant for the last few months and what it will mean for the next few months. PhDs are not intended to be recreational!

So posting when I can and I'll answer the off blog outstanding emails soon. When I get to comments about a discussion forum, I agree, it would be a great idea but I think it would be impossible to do at the present time from my commitment perspective. I'm about 350 emails behind (just reading) on the THINCS discussion board at the moment.


Saturday, November 29, 2008

Eggs are here (well, one is anyway)

Some semblance of posting on Hyperlipid will probably resume late next week but, in the mean time, Penelope (Squiggs' favourite chicken, the one who lets herself be caught, cuddled and carried around) has laid an egg, our first ever home produced egg. A decent size for a first egg from a young chicken!

Not only that but it was a double yolker...

Guess who ate it!

Back when life gets in to more of a normal routine and I can get to answer some of the off blog emails and do some blogging too.


Tuesday, November 11, 2008

Cholesterol JUPITER link

For an absolute, all singing, all dancing excellent review of the JUPITER trial go read Sandy Szwarc over at Junkfood Science.

Don't expect to be done in 2 minutes!


Monday, November 10, 2008

Pellagra and SMON

Back in the early 1900s it was patently obvious that pellagra (vitamin B3 deficiency) was a contageous disease.

You have to ask exactly how a disease caused by a vitamin deficiency could remotely have been classed as contagious, and exactly why this idea should have been so vigorously defended by the medical profession. To get the whole story you really need something like Alan Kraut's biography of Goldberger. I found it an interesting read, particularly the lengths Goldberger (and his family) went to in order to demonstrate on themselves that pellagra was not contagious, and quite how his wife put up with coming such a distant second place to his work is quite beyond me. Anyway, it turned out that the "Scourge of the South" could be cured by decent food, eventually replaceable by a teaspoonful of brewers yeast a day.

Just imagine heart disease being cured by a pint of cream a day...

How did the medical profession take this to phenomenal and meticulously tested hypothesis? If you think the AHA hated Dr Atkins, that has nothing of the violence of the reaction against Goldberger. To say they were not best pleased might be a slight understatement. They hated him. The reasons were essentially financial and political, a bit like heart disease today. Being correct does not always make for popularity.

Now let's have a look at subacute myelo-optico-neuropathy (SMON). OK, hands up if you have never heard of SMON.

The disease was pretty well limited to Japan between 1958 and 1972, so you may be excused. Identification of the cause was severely hampered by the obvious explanation that it was contagious and was caused by a gut virus. The fact that it ultimately turned out to be caused by a known neurotoxin marketed by Ciba Geigy as a drug for the treatment of diarrhoea was vigorously denied by the virus hunters, even after what had really happened became fully accepted by the Japanese government.

To get some idea of how much fun SMON was for the victims, over 1000 of them were still alive in 2004 (of the approximately 10,000 affected). These are the types of problem the survivors are still left with.

Here's a nice summary of the whole episode, it makes interesting reading. Duesberg is probably the world's leading AIDS denialist.

For those of us who were stacking straw bales in the university vacation during the blistering summer of 1976, SMON doesn't seem that long ago.

This poses the very interesting question: When did we stop making mistakes?

and the closely related question: Statins in the drinking water?


Hmmm, you could ask things about BSE and vCJD too....

Cholesterol, heart attacks and JUPITER

There was a snippet on Radio 4 about the JUPTER study this morning. It was basically an ad for statins for everyone in the UK. Well, 75% of the adult population.

What the JUPITER study found was that in people with low cholesterol levels but elevated hsCRP levels, taking a statin dropped the overall mortality from low to a bit lower.

Bodycounts were 198/8901 in the statin group and 247/8901 in the placebo group. Clearly treating 8901 people for a year and a half will prevent 49 deaths. According to the lipid hypothesis, all of these lives saved should be as a result of less cardiovascular disease, such as fatal heart attacks.

Well Table 3 from the study gives you the total numbers of deaths from heart attacks, but not directly. You have to look at the line "Any myocardial infarction" and subtract the previous line, "non fatal myocardial infarction". Simple arithmetic, which didn't get done in the write up, then gives you the number of fatal heart attacks... Here are the missing numbers:

Heart attack deaths on statin: 9
Heart attack deaths on placebo: 6

Hmmm, 50% increase of being dead from a heart attack on Crestor, with an LDL half the level of the people on the placebo.......... Good job the study was not powered to detect this!

So what did the people die of in the placebo group? Well, it certainly wasn't heart attacks.

hsCRP is a protein produced by your liver as a message to your neutrophils to get out there and do whatever they should be doing, but more so. It probably does lots of other things too. The list of diseases that come with elevated hsCRP is huge. It looks like taking Crestor does blunt this message. Whether that is why the death rate dropped on the statin is anyone's guess. Statins have lots of effects and, believe it or not, not all are acutely bad!

As an aside: Why were there so many cardiac procedures in the placebo group? Perhaps this is what saved their lives? Unlikely. The explanation could be as simple as statins preventing chest pain, which they do by facilitating nitric oxide's vasodilating action (just Pubmed "statin nitric oxide"). Anyone in the USA with chest pain is very likely to get a "soft end point" procedure, as per the JUPITER study. Less chest pain, less Dr visits, less procedures. Dr Davis explains how Dr visits lead to procedures.

So, in summary, rosuvastatin has a minor effect on all cause mortality and no effect on heart attack deaths in people with elevated hsCRP.

What the news clips claimed was:

"The study [JUPITER] of 17,800 men and women with normal cholesterol levels found a new statin drug cut deaths from heart attacks and strokes"

Note the words "deaths", "heart attacks" and "strokes". There were 3 stroke deaths in the statin group, 6 in the placebo group. Exactly enough to reverse the heart attack effect. Phew!

I missed this snippet initially as I was off making tea and came back to find my wife grinding her teeth. Not so much at statinating the nation, we're pretty resigned to this. No, the problem was the deferential supplication of Sarah Montague (normally an infuriatingly aggressive interviewer) to the medic and statination. She would have torn a politician apart for such economy with the truth.


Thanks to the THINCS members for the full text and kicking these ideas around so thoroughly.

Thursday, November 06, 2008

HLA-B27 some more

Well, there have been a few interesting developments in the last few days. The most interesting was being invited to lunch by Prof Ebringer. That was a very long conversation and has produced a stack of papers to read and a whole lot of ideas, plus a Drs appointment for myself to see if I can get HLA-B27 tested on the NHS. At £209 per test privately, I'm rather hoping to get my GP to fund this even if I have to offer a decent bottle of wine to cover the £20 odd it costs the practice!

The HLA-B27 discussion was very interesting. Apparently the allele is very common among the Eskimo and their descendants and very rare in people from equatorial regions. This fits nicely with the carnivorous HG in temperate or extreme climates vs more starch based gathering in the tropics. By a quirk of migration the gene is also very rare in Japan, but even there the link with ankylosing spondylitis is strong.

A medic, Dr Tani, working in Japan, was looking to publish a paper on AS and approached the Kings College group to get the Klebsiella antibody titres done. Prof Ebringer suggested sending the samples coded, plus some controls and some RA samples thrown in. This is the paper which came out of the collaboration.

The Kings College group did the same with a set of coded Dutch samples, written up here. Interestingly, two other labs failed to get the same result, using the same samples. But if Ebringer can get consistent results on both the Japanes and Dutch samples, I tend to think his group is quite good at immunology.

Obviously the AS hypothesis generates the starch avoidance protocol which seems to be in fairly widespread use in places like the KickAS site. The proof of the pudding is in the eating ie, do patients get better on a behaviour based on a hypothesis. If so that seems to support the hypothesis to me...

I think it is worth noting that AS primarily involves an IgA antibody, which suggests exposure to the trigger across a mucosal surface, typically the gut. Rheumatoid disease involves an IgG response and suggests a non surface immune response, in this case classically through a low grade chronic urinary infection. This gives a simple explanation for the response seen to minocycline and doxycycline in RA patients. Of course without antibiotics (or with them) you might approach starving the proteus which triggers RA by using a dilute urine approach (the proteus bug derives energy by splitting urea in the urinary tract) and possibly eating a low protein diet might well help too. It's worth noting that the true Optimal Diet is actually rather low in protein at around 40-50g/d, once you are well established on the diet. By eating the minimum amount necessary of the highest quality protein you produce the least quantity of waste, ie urea, which is better known as proteus fodder. I'm not down at this level of protein intake but it's another option for fighting RA. I guess getting your immune system back by dumping sugar would potentially get rid of the proteus bugs completely... There's an interesting study.

Of course we spent a lot of time talking about BSE, scrapie, CJD, vCJD and MS. There is probably a book could be written here so I'll stop until I think I understand it a bit better and have had chance to tease out a few of the more problematic features of both the prion hypothesis and the auto immune hypothesis...


Monday, October 27, 2008

Cholesterol, it's not a competition

Barry Groves has a new book out which might be worth a look. There is an interesting review in the Telegraph here which gives a little back ground to the author of "Eat Fat Get Thin!", one of my early core LC books.

For those of us worrying about a TC just outside of cardiological nirvana, Barry Groves seems to be doing okay at 8.2mmol/l. Of course that's not quite as cool as 8.6mmol/l, but hey, I've a few years to go before I get in to my seventies...


Monday, October 20, 2008

Familial Hypercholesterolaemia; Brown and Goldstein

Brown and Glodstein won the 1985 Nobel Prize for medicine.
You can download their acceptance address as a pdf here.

Their work was primarily based around familial hypercholesterolaemia.

The world is full of genetic problems where the heterozygote, with one copy of an affected gene, has an advantage over people in whom neither copies of the gene is affected. Being a carrier (heterozygote) for sickle cell anaemia protects you from malaria without any disadvantage. Being the far rarer homozygote (both genes affected) is bad news because your haemoglobin polymerises under hypoxic conditions and your red blood cells become dysfunctional. Not nice. Hurts like hell, apparently.

There are lots of types of familial hypercholesterolaemia but I'll stick to the type where the receptor for LDL particles is fully dysfunctional. Get one copy of the gene and you have elevated cholesterol levels but are at no excess risk for CVD, unless you come from a family which has a history of premature CVD. Get two copies of the FH gene and, as for sickle cell disease, you are potentially in trouble. Why is part of a future AGE, RAGE and ALE post, so I'll leave it there for the time being.

Brown and Goldstein came up with a therapy for managing heterozygous familial hypercholesterolaemia.

Heterozygous FH (hFH) people make a lower number of functional LDL receptors because one of their genes for this protein is naff. The other gene is fine. B and G noted that the level of cholesterol within our cells controls the expression of the genes for the LDL receptor. Lower intracellular free cholesterol and you up regulate the LDL receptor gene, to grab extra cholesterol from passing LDL particles. Get enough functional receptors on to cell surface and you behave as if you are normal, LDL-wise.

So they put in place the concept of lowering plasma LDL by up regulating the LDL receptor expression by inhibiting cholesterol synthesis within the cell. You can particularly target the liver by, in addition, depriving it of bile acids. These cholesterol derivatives are fiendishly important and normally get very efficiently recycled. Treating with cholestyramine guarantees, along with gut ache, that most bile acids go down the loo. Now the liver REALLY needs cholesterol (partly to make more bile acids) but also because HMG CoA, the rate controlling enzyme cholesterol synthesis, can be blocked by a mould fungus (eventually to be marketed as lovastatin). So it sticks out lots of LDL receptors and normalises plasma LDL.

And all heart problems disappear. But B and G worked in the 1970s. At that time it had not occurred to anyone that it is only those hFH people with heart disease that get heart disease. The rest are fine. The heart disease cannot be from the elevated LDL, because the non CVD families have similar LDL yet stubbornly have no heart disease. Back in the 1970's no one thought to look for healthy hFH "victims", all of the hFH patients were found through cardiology clinics..........

So the basic principle which was used to usher in lovastatin was based on a mistake. Very clever science, but based on a mistake non the less. Who gave B and G the idea that elevated LDL cholesterol caused heart disease? Who do they cite as the source of elevated cholesterol being the cause of heart disease in their nobel acceptance address?

Well, you can bet it wasn't Yerushalmy and Hilleboe.

Oh, you've never heard of Yerushalmy and Hilleboe? Obviously neither had B and G.

B and G cited Ancel Keys and his seven countries study linking saturated fat to heart disease via elevated cholesterol:

"Extensive epidemiologic studies performed in many populations in many countries over the past three decades have pointed strongly to a general association of high blood cholesterol levels with heart attacks. Among the most striking examples is the seven-country study of coronary artery disease directed by Ansel Keys (116)"

ref 116 is to a text book published in 1980. The original publications were in the 1950s, this one comes from 1953. Unfortunately papers this old are not freely available so I'll personally have trust to Dr Ravnskov to have seen the actual paper based papers.

Yerushalmy and Hilleboe, in 1957, pointed out that Keys had selected his countries to fit his hypothesis and that inclusion of all of the data available at the time showed no association between saturated fat and blood cholesterol, let alone heart disease. Really, that should have been the end of the diet heart hypothesis.

But what is MUCH more interesting (than their believing Ancel Keys) is B and G's opinion about homozygous FH. It was obvious to them that you CANNOT up regulate the effective LDL receptors of homozygous FH patients because they DO NOT HAVE ANY GENES FOR EFFECTIVE LDL RECEPTORS AT ALL. Quote from B and G:

"The principles applied to treatment of FH heterozygotes cannot, unfortunately, be applied to homozygotes, especially those who have totally defective LDL receptor genes. These individuals do not respond to the above-mentioned drugs because they cannot synthesize LDL receptors"


So why give statins to homozygous FH patients? Remember, statins are used, in B and G's scenario, to upregulate LDL receptors.

Clearly there is no logic to this.

You could say medicine has been very lucky in the multitude of unsought after beneficial effects from the fungal toxin lovastatin, in addition to it's very unpleasant ability to inhibit HMG CoA reductase and along side a few other rather nasty effects which negate any overall mortality benefit.

Or maybe you could say science has been held back for 25 years by that fluke and that medicine is no closer today to the real causes of heart disease than it was in 1953. Thanks again to Dr Keys.


Alzheimers and omega 6s

My wife picked this up on the BBC news last night. Again, I think we are looking at the shrapnel of a neurological bomb (in a transgenic mouse!). Shrapnel is nasty stuff but not the cause of the explosion. Still, excellent to see that the medics can see that eating "healthy" "vegetables, fruits and nuts" can kill your brain. Excellent, even if the link is a bit tenuous.

Actually, I don't see a lot of omega sixes in fruit and veg, and even in nuts they're nowhere up near sunflower oil....... Bit of a booboo there. The BBC did manage to blame eggs as a source of omega sixes.

When will the link get made between a heart health diet, cardiologists and brain death? Soon, you can just hope.


Fructose and leptin

Just a quickie. This was forwarded to me by Gary. It just keeps bringing home to me that leptin is very interesting stuff and fructose is very nasty stuff.


Chickens are in

But somewhat difficult to photograph. They certainly move faster than the camera can meter!

Saturday, October 18, 2008

Familial Hypercholesterolaemia; heterozygous survival

When you sit here with an LDL cholesterol which makes a cardiologist's trigger finger itch for a reflex prescription of lovastatin, you get quite interested in the fate of others with high LDL cholesterol levels. I found this familial hypercholesterolaemia paper by accident while looking for a paper on blood insulin levels by some big noise in USA cardiology.

BTW: That hunt was triggered by Michael Eades' post (back on line here) on ITT (intention to treat) analysis and the murkier aspects of statistical techniques. The insulin paper was mind boggling. Their limit of detection for plasma insulin was 2.0microIU/ml. A big chunk of their patient base had insulin levels below this, SO THEY MADE UP A DATASET, based on an assumed distribution. Duh. Wish I could find it! Plus I remember them as obese USA citizens, non of whom were type 1 diabetics or were at the end stage of type 2 diabetes. No healthy person runs a fasting insulin below 2.0microIU/ml. So the assay was probably rubbish anyway!

Anyway, back to heterozygous FH. It's another paper by Sijbrands on the mortality of patients with untreated FH.

Here's the first paragraph of the discussion:

"In the present study, mortality was highest in families which were ascertained through cases with a premature onset of CAD. These families — in particular the male patients in middle age — had high excess mortality. This high excess mortality underscores that our results do not detract from the older finding of increased mortality in families in whom the disorder was clinically recognised. These old studies described a decreased life expectancy in families with familial hypercholesterolaemia that were investigated because the probands — or even multiple family members — had presented themselves with premature cardiovascular disease"

This translates as: In families with FH and premature heart disease there is premature heart disease. Yes, that's what it says.

"Presumably these families — and our families with a premature onset of CAD — were characterised by clustering of risk factors. In the present study, a lot of families were not ascertained by clinical outcome but by routine measurement of cholesterol and they had a life expectancy similar to the Dutch population, suggesting the presence of protecting factors or the absence of additional risk factors"

Translation: In families WITH heterozygous familial hypercholesterolaemia, but WITHOUT premature heart disease, life expectancy is NORMAL (rather, the phrase is "similar to the Dutch population"). There is no premature CVD. There are a lot of these families. I wonder if they are all on statins? If so, why?

"Others also observed normal survival of some familial hypercholesterolaemic patients [3 and 4]. The factors involved in this reduced risk of mortality from the disorder are yet unknown and their identification is needed to enable prediction of longevity"

What I feel is missing from the paper is the inclusion, taken from the normocholesterolaemic Dutch population, of a group of people with normal cholesterol receptor genetics but WITH premature heart disease. There are plenty of families with this predicament. Then do some comparisons with the various FH groups discussed by Sijbrands... That might put FH in to perspective.


HLA-B27 and Ebringer BSE text

This is a huge post, probably of very little interest to anyone, about the BSE/acinetobacter hypothesis. I'd just re iterate that, as pointed out by Johnn on the first Ebringer post comments, no one can say if the BSE was caused by the antibodies to acinetobacter or whether the antibodies were formed to the prion-damaged brain tissue and they happen to cross react with bacterial antigens as a coincidence. It's a long slog to read, go there if you wish but it's not really nutrition. It does gives a window in to how funding works. The work here was done for "small change" in terms of funding.


OK, here's the text:


This is a report on Government commissioned

research into the autoimmune theory of “bovine

spongiform encephalopathy” or BSE.

In 1997 (CSA 4302) and in 1999 (CSA 5115) the Government

through the Ministry of Agriculture, Fisheries and Food

(MAFF) (Now, Department of the Environment, Food and

Rural Affairs) (DEFRA) authorized and funded 2 studies into

the possibility that BSE could be an autoimmune disease.

The following report is the result of these studies which

were carried out at King’s College (University of London) in

the Department of Life Sciences, under the supervision of


(1) Costs of commissioned studies:

(1a) CSA 4302: £ 18,032

The first study commissioned in 1997 involved a pilot study to determine, whether BSE animals had antibodies to a soil bacterium,
Acinetobacter calcoaceticus, after it had been shown that this microbe possesses molecular sequences resembling bovine and human brain tissues (Ebringer et al., Environmental Health Perspectives 1997; 105: 1172-1174) (Paper 1 in Appendix)

The results of the pilot study were published in “Infection & Immunity”, a journal of the American Society of Microbiology.
(Tiwana et al., Infection & Immunity 1999; 67: 6591-6595).
(Paper 2 in Appendix)

(1b) CSA 5115: £ 216,228

The second study commissioned in 1999 involved an investigation of
128 BSE animals and 127 healthy controls, after the pilot study involving 29 BSE affected animals compared to 102 healthy ones showed elevated titres of antibodies to Acinetobacter but not to 2 other
control bacteria.

The combined results of these two studies, involving 157 BSE affected animals and 229 healthy ones, form the basis of this report.

Total costs of commissioned studies: £ 234,260.

(2) Background to BSE problem:

BSE is a neurological disease of cattle, that appeared in the U.K.,
following changes in the preparation of “meat-and-bone meal” (MBM) or “winter feed”, based on abattoir materials obtained from brain, spinal cord, pancreas and guts with their contents.

By 1988, some 60,000 cows had been identified as suffering from BSE and scientists from the “Ministry of Agriculture, Fisheries and Food” (MAFF)(Now DEFRA), suggested that “brains” in the “winter feed” could have been contaminated by “prions” or similar agents, from sheep having had scrapie and thereby probably caused BSE in cattle.

The use of these “winter feed” or MBM preparations was banned and since then the incidence of BSE in British herds has drastically fallen, although not to zero levels. (See figure, adapted from P. Brown
in Brit Med J, 2001;Vol.322;841-843)

(3) Theories of BSE:

Several theories have been proposed as the cause of BSE.

It has been suggested that BSE could be caused by viruses (1), organo-phosphates (2) or by “proteinaceous infectious particles” or “prions” (3).

“Normal prions” are cell membrane proteins, which are found in almost all organs, but in highest concentrations in brain tissues and are encoded by a gene found on chromosome 20 in humans.

Professor PRUSINER from San Francisco has suggested that “abnormal prions” convert “normal prions” into infectious particles which then probably cause various neurological diseases, such as scrapie in sheep, “kuru” in New Guinea natives from the Fore tribe,
BSE in cattle and Creutzfeldt-Jakob disease (CJD) in man.

How these diseases are transmitted is unknown, but it has been suggested that consumption of meat or brain tissues, containing such “abnormal prions” could start the conversion of “normal prions” into
infectious particles and thereby produce these neurological diseases, either in animals or man.

Although the “prion theory” has wide acceptance it also has some serious limitations:

(3.1) “Prions” as independent, infectious particles have not been demonstrated to be present in the environment.

(3.2) The absence of nucleic acids in the “abnormal prions” raises the
molecular biology issue of how diversity can occur without DNA, given that many “different strains” have been described.

(4) Spongiform changes in brain and BSE

The microscopical examination of brain tissues, from animals who had died from scrapie or BSE, showed characteristic “spongiform changes” and these diseases were therefore described as “spongiform

Similar changes were observed in patients who had died from CJD.

Injection of brain tissues from sheep affected by scrapie or cows suffering from BSE, into experimental animals led to the development
of a neurological disease characterized by tremors, ataxia or progressive loss of control of limb movements and eventually death.

These features of tremors, progressive loss of control of limb movements, especially hindquarters, are also characteristic of animals affected by BSE.

Microscopical examination of the brains of these experimental animals, showed “spongiform changes” and similar observations were made in the human diseases sporadic CJD and kuru.

Since the neurological and microscopical features of the condition had been transmitted to experimental animals, these diseases were grouped together under the name of “transmissible spongiform encephalopathies” or TSE’s.

Could TSE’s be autoimmune diseases?

What are autoimmune diseases?

(5) Autoimmune diseases and rheumatic fever

“Autoimmune diseases” are characterised by presence of antibodies, which bind to “self-tissues” and are therefore known as “autoantibodies”. In some diseases such autoantibodies can cause tissue damage. Many human diseases, such as multiple sclerosis, juvenile diabetes and rheumatoid arthritis are considered as examples of autoimmune diseases.
The origin of such autoantibodies is unknown, but two main theories have been proposed: either the immune system spontaneously
starts producing tissue damaging immune cells or infection occurs by a microbiological agent, which possesses structures, showing molecular similarity or “molecular mimicry” with some of the tissues of the host.
Following infection, antibodies will be produced against the invading microbe and a portion of these antibodies will bind to self tissues of the host, acting as autoantibodies. When present in high concentrations, such autoantibodies can cause tissue damage and eventually lead to a disease involving the organ possessing structures resembling the invading pathogen.
A classical example of such a disease is “rheumatic fever”.
The microbe Streptococcus possesses molecular sequences which resemble the human heart. Following a severe upper respiratory tract
infection or tonsillitis, anti-streptococcal antibodies bind to human heart tissues and cause tissue damage. The patient develops a cardiac murmur, fever and muscle pains and is then said to suffer from “rheumatic fever”.
Since autoantibodies cause tissue damage, this is an example of an autoimmune disease produced by an infection.
Rheumatic fever has more or less disappeared in the Western World, over the last forty years.
It has been suggested that the widespread use of penicillin and similar antibiotics to control early streptococcal infections, since 1960’s, has led to the virtual disappearance of rheumatic fever, although in the Third World, it is still a relatively common disease.
The question arises whether other autoimmune diseases could be
prevented by the early removal of the offending microbe.

(6) Autoimmune diseases at King’s College London

Over the last thirty years, scientific work at King’s College London, has been involved in trying to find microbes, like Streptococcus in rheumatic fever, which would explain other autoimmune diseases.

The microbe Klebsiella has been found to be involved in the disease “ankylosing spondylitis” (AS) which manifests itself as recurrent backache, especially in young people and affects some half million individuals in the U.K. (4).

The microbe Proteus, which causes upper urinary tract infections, especially in women, has been found to be involved in the disease “rheumatoid arthritis” (RA) which manifests itself as severe arthritis, predominantly of the small joints of hands and feet, and affects some one million individuals in the U.K. (5).

In both AS and RA, autoantibodies are found against the white cell
blood groups (Human Leucocyte Antigens - HLA) linked to these diseases (HLA-B27 in AS and HLA-DR4/1 in RA) (6) and also against various types of collagens (7).

During active phases of the disease, elevated levels of antibodies
against Klebsiella are found in AS and against Proteus in RA (8).

When patients are in inactive phases of the disease, the levels of anti-bacterial antibodies fall to normal levels.

Drugs which interfere with cell divisions and reduce antibody production such as methotrexate, have been shown to produce therapeutic improvements in controlled trials in both diseases.

Dietary control aimed at reducing Klebsiella in AS (9) and
Proteus in RA (10) have led to some therapeutic benefits.

(7) Autoimmune diseases and BSE

Since BSE was thought to have arisen in cattle by feeding them modified MBM preparations, containing a pathogenic neurological agent, the late Emeritus Professor of Microbiology at King’s College London, John PIRT, raised the possibility, that as we were treating the autoimmune diseases AS and RA by diet, BSE could also be an autoimmune disease.

Dr. Clyde WILSON, from our group, who had been working on AS and RA, pointed out that in 1980, the GAJDUSEK group from Washington demonstrated the presence of autoantibodies to brain tissues in patients with kuru and CJD (11) and in sheep affected by scrapie (12).

Furthermore mice with a deficient immune system (SCID – Severe Combined Immuno-Deficiency) would not develop a neurological disease when injected peripherally with brain tissues from animals affected by scrapie (13).

This was most unusual, since SCID animals readily die from viral and bacterial infections, yet in this case the opposite from the expected outcome was happening - the agent was unable to produce the disease.

The orthodox explanation was that “prions” require a normal immune system to proliferate, but to an immunologist, an alternative explanation immediately suggests itself:





(8) Experimental allergic encephalomyelitis and BSE

“Experimental allergic encephalomyelitis” (EAE) is an animal model of an autoimmune disease and is thought to resemble “multiple sclerosis”.

It was discovered by accident, over 120 years ago, in 1880 by the French immunologist, PASTEUR, when he first described anti-rabies immunisation.

PASTEUR and colleagues immunised humans who had been bitten
by rabid dogs or wolves, with brain homogenates from rabbits which had been infected with rabies.
Some patients developed anti-rabies immunity but a proportion, some one hundred individuals died of a disease which was labelled as
“allergic encephalomyelitis”.

The cause for this unexpected and lethal response was not explained till the 1930’s, when it was shown that injection of foreign brain homogenates will evoke an immune response in the immunised individual or animal by the production of anti-brain autoantibodies which will damage the brain tissues of the host (14).

In the 1950’s it became apparent that this was a general observation in immunology: immunisation with any organ homogenate would produce an autoimmune disease in the target organ.
The classical work of ROSE and WITEBSKY from Buffalo, demonstrated that peripheral injection of homogenates of thyroid tissue produced an experimental disease in animals which was similar to the human autoimmune disease “Hashimoto’s thyroiditis”.

Injection of brain homogenates from animals with BSE or scrapie led to a neurological disease and this was described as transmission of the disease: However the question arose whether this was not an example of “allergic encephalomyelitis”, the disease PASTEUR had observed one hundred years earlier.

(9) Spongiform changes in EAE, bovine myelin and Acinetobacter

In “acute EAE”, observed one to three weeks, following immunisation with brain homogenates, there is perivascular infiltration with inflammatory cells in brain vessels.

However in “chronic EAE”, observed three to six months, following immunisation, characteristic “spongiform changes” have been described, at least in rabbits in 1969 (15) and in guinea pigs in 1974 (16), by RAINE’s group from New York.
It would appear that “spongiform changes” also occur in EAE.

The factor in the central nervous system responsible for EAE is a basic protein present in myelin, the white matter of the brain.

In 1970, EYLAR’s group from San Diego, identified a highly active peptide from bovine myelin, which when injected in microgram quantities into guinea pigs, would produce hind leg paralysis, tremors, weight loss and death (17).

These features of hind quarters paralysis, tremors, weight loss and death, are also the features described in cattle affected by BSE.

Furthermore, the biological activity of this peptide was retained when it was heated to 100ºC for one hour or treated with 8 molar urea and these are properties also described for “prions”.

We proposed the hypothesis that there may be in the environment a microbe which could possess a protein resembling “brain tissues”, similar to the situation of Streptococcus in rheumatic fever.

Computer analysis of proteins in bacteria, using the EYLAR sequence from bovine myelin as a probe, revealed that the microbe Acinetobacter, which is present in soil, contaminated water and fecal materials had such a sequence. (Ebringer et al., Env. Health Perspect. 1997,105: 1172-1174) (Paper 1 in Appendix)

(10) Acinetobacter, molecular mimicry and BSE

The discovery that the common environmental microbe Acinetobacter, which is found in muddy soils and on the skin of animals and man, has a sequence resembling brain tissues, suggested a possible mechanism, as to how cattle could have developed BSE.

Offal material from abattoirs was used in the preparation of MBM
and could have inadvertently become contaminated by Acinetobacter.

Although heat treatment was still applied, the demonstration by EYLAR and co-workers, that these peptides were highly resistant to heat denaturation meant that if these bacterial fragments were present in MBM, then not only would the cows make antibodies against them but because of “molecular mimicry” or similarity between brain tissues and Acinetobacter (See figure), any antibodies produced would also attack the brain and cause a neurological disease.

The mechanism proposed is similar to the situation of Streptococcus in rheumatic fever and if such antibodies could be demonstrated in affected animals then this would make BSE an autoimmune disease.

Molecular mimicry between EYLAR peptide and Acinetobacter (Adapted from Env.Health Perspect. 1997;105: 1173 - Fig.1)

(11) BSE as an autoimmune disease

If BSE were to be an autoimmune disease, then two important immunological features would appear to be necessary:

(11.1) IgA antibodies

The mucosal immune system produces a characteristic antibody, the IgA isotype.
Over 90% of mucosal immunity is accounted for by the gastro-intestinal tract.
If Acinetobacter peptides had been present in the MBM feeds, then the highest relative levels of antibodies should be present in the IgA class.

(11.2) Autoantibodies

Since the EYLAR probe consisted of myelin peptides, following exposure to Acinetobacter peptides, autoantibodies should be present against myelin, the white matter of the brain.

However GAJDUSEK’s studies had shown that autoantibodies in kuru, CJD and in animals with scrapie were present against neurofilaments, which are components of the gray matter of the brain.

Thus autoantibodies should be present against both white and gray
matter components of the brain.

MAFF was approached with our idea that BSE could be an autoimmune disease caused by Acinetobacter infection.

The Chief Scientist at MAFF, Dr. David SHANNON, agreed that a pilot study should be carried out and provided resources and access to BSE and control sera.

(12) Results of pilot study (CSA 4302) : Acinetobacter antibodies

(12.1) Sera from animals with and without BSE
MAFF provided sera from 29 animals which had been found at post-mortem to satisfy the criteria of BSE and 18 animals which did not have the disorder. The sera were supplied by the Central Veterinary Laboratory (CVL) at New Haw, Addlestone, Surrey.
The 18 animals which did not have BSE had been referred to CVL because of abnormal behaviour involving ataxia and suggesting a neurological disease. Post-mortem examinations were carried out to exclude BSE.
The majority of BSE positive animals came from dairy Friesian

(12.2) Sera from animals from an organic farm
In addition, sera were obtained from an additional 58 healthy animals to act as extra controls: 30 serum samples from animals aged less than 30 months (8 Friesians and 21 Hereford-Friesian and one Charolais-Friesian crossbreeds, the crossbreeds being raised for meat production) and 28 serum samples from animals aged more than 30 months, all of which were dairy Friesians.
The animals were raised on a farm where no cases of BSE had been
reported and were kept under organic farming conditions, with winter feeds consisting of hay and grains but no MBM supplements.
Serum samples were obtained during annual herd testing for brucellosis.

(12.3) Antibodies to Acinetobacter

Antibodies to Acinetobacter calcoaceticus were significantly elevated in the 29 BSE animals, when compared to the 18 CVL controls (p<0.001), 30 organically raised cows aged less than 30 months (p<0.001) and to 28 organically raised cows aged more than 30 months (p<0.001), but no such elevations were found against 2 control bacteria E.coli and Agrobacterium. (See Fig.2a in Tiwana et al., Inf & Immunity 1999;67: 6591-6595) ( Paper 2 in Appendix)

(13) Results of pilot study (CSA 4302): Autoantibodies.

High levels of autoantibodies were found against both, bovine neurofilaments (Fig.1a) which are components of gray matter of the brain and also against bovine myelin (Fig.1b) which are components of the white matter of the brain.

These autoantibodies could be absorbed out with Acinetobacter

The highest levels were found in the IgA isotype suggesting that these antibodies had been produced following exposure to Acinetobacter antigens across the gut mucosa and not as a result of brain damage produced by “prions”.

This is the first report of autoantibodies to brain components in BSE.

(14) Results of study (CSA 5115): Specific antibodies to Acinetobacter.

In view of the results of the pilot study, a grant was submitted to MAFF, to study whether injection of Acinetobacter bacteria into experimental animals would reproduce a “spongiform disease”, resembling BSE.

This grant was rejected but another one approved to determine, firstly whether a larger series of samples from BSE affected animals would confirm the original results of the pilot study and secondly to ascertain whether such antibodies could be used to obtain an ante-mortem test for BSE, so that cases of affected animals could be excluded from entry into slaughter houses and therefore the human food chain.

The results so far obtained confirm the data from the pilot study.

Antibody responses were measured to Acinetobacter, Pseudomonas,
Bacillus, E. coli, Serratia, Proteus and Klebsiella, in 128 BSE positive animals, 63 BSE negative animals and 64 healthy control animals.

Elevated levels of antibodies to Acinetobacter (p<0.0001) and against Pseudomonas (p<0.001) were found in the BSE affected animals when compared to BSE negative animals or to healthy controls.

There was a significant elevation against Pseudomonas in BSE affected animals, although not as high as against Acinetobacter .
These two microbes are related in that both have molecular sequences resembling the EYLAR peptide. (See paragraph 9)

In the pilot study no elevation in antibodies was found against Agrobacterium and therefore the results of these two combined studies indicate that specific elevation of antibodies to Acinetobacter is present in BSE affected animals but not against six other bacteria.

(15) Results of study (CSA 5115): IgA gut antibody responses

The simplest explanation for the presence of specific antibodies to Acinetobacter bacteria in BSE affected animals is that they have been exposed either to the whole bacteria or bacterial fragments which then produced specific brain autoantibodies and these may have been responsible for the disease.
There are two main competing theories in trying to explain the origin of BSE, the “prion” theory and the autoimmune theory.

These two theories have been compared over ten different biological and medical criteria, and in each case they predict different
experimental observations and veterinary or clinical outcomes which are relevant to policy decisions in the field of health, food safety and the cattle industry. (See Table overleaf) (Ebringer et al., J. of Nutrit. & Env. Medicine, 1998; 8: 265-276)(Paper 3 in Appendix)

If the autoantibodies are produced by exposure to Acinetobacter fragments in the MBM feeds, then the highest relative levels should be present in the mucosal IgA antibody class (Points 2 and 5 of comparison of theories) (See Table overleaf)

The levels of IgA, IgG and IgM autoantibodies to bovine neurofilaments and bovine myelin have been measured in 128 BSE affected animals and compared to 127 healthy ones (Controls = 100%)

The relative increases in the immunoglobulin classes in the BSE animals, for neurofilaments was as follows: IgA (191%), IgG (173%) and IgM (143%) and for bovine myelin it was: IgA (184%), IgG (147%) and IgM (109%).

These results have been submitted for publication.

If brain damage had been caused by “prions” and evoked the formation of autoantibodies, it is difficult to see why they should have predominantly stimulated gut immunity, but presence of Acinetobacter in MBM feeds readily explains IgA responses.

(16) Results of study (CSA 5115): Peptide studies and M.A.N. assay

Antibody levels have also been measured against synthetic peptides,
consisting of 16 amino acids in length and representing EYLAR peptide (bovine myelin), Acinetobacter peptide (in enzyme 4-carboxy-mucono-lactone decarboxylase) and neurofilament peptide.

These measurements were combined into an algorithm the Myelin-
Acinetobacter-Neurofilament (M.A.N.) assay and values calculated for
28 BSE affected animals compared to 18 healthy ones.

The results show that all 28 BSE animals could be separated from the healthy ones - in that the BSE animals exceeded the 99.9% confidence limit (p<0.001) of the 18 controls. (See figure)

These results were presented at the Cambridge Healthtech Institute 2nd Annual International Meeting on “Transmissible Spongiform Encephalopathies”, which was held in Alexandria, Virginia, U.S.A. in October 2000. (Paper 4 in Appendix)

Further peptide studies with larger numbers of BSE and control sera are in progress.

(17) Antibodies to Acinetobacter in multiple sclerosis

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the nervous system affecting some 80,000 individuals in the U.K.

Although there are many different clinical manifestations of MS, a lower limb ataxia, characterised by difficulty in walking, is a well recognised feature of the disease.

Since hind quarters paralysis is a characteristic feature of both EAE and BSE, and since EAE is considered an animal model of MS, the question arose whether antibodies to Acinetobacter, a ubiquitous environmental microbe possessing sequences resembling brain tissues, could also be detected in this disease.

Prof. Edward J. THOMPSON, of the Institute of Neurology, The National Hospital for Neurology & Neurosurgery, Queen Square, London was approached and he provided access to sera from 53 MS patients, 2 patients with sporadic CJD and 10 patients with viral encephalitis.

In an open study, the 2 sporadic CJD and 10 MS patients had elevated levels of antibodies to Acinetobacter when compared to 12 healthy blood donors. (See figure)

(18) Antibodies to Acinetobacter in MS and M.A.N. assay

In an endeavour to compare these observations, with other neurological diseases, Dr. John CROKER, from the Department of eriatric Medicine at University College Hospital (London) provided 20 sera from patients who had sustained in the preceding twelve months a cerebro-vascular accident or stroke.

A coded study involving 26 MS patients, 20 with strokes and 25 healthy blood donors, showed that only MS patients had elevated levels of antibodies to 5 different strains of Acinetobacter, as well as against Pseudomonas, but not against E.coli.

The results were reported at the XVIIth World Congress of Neurology, which was held in London in June 2001 (Hughes et al., Journal of the Neurological Sciences 2001; 187: PO764, S265).
(Paper 5 in Appendix)

A paper by Hughes et al, describing these results in detail, as well as the use of the M.A.N. index in the diagnosis of MS has appeared in the November 2001 issue of the journal “Clinical & Diagnostic Laboratory Immunology” (2001; Vol.8: 1181-1188) (Paper 6) which is a publication of the American Society of Microbiology.

How such patients acquired antibodies to Acinetobacter is at the moment unclear but MS patients frequently suffer from sinusitis (18) and upper respiratory tract infections (19) and since this saprophytic microbe is found on human skin, inadvertent exposure may have produced such immune responses.

However, the question whether Acinetobacter infections precede or follow onset of MS awaits further studies.

(19A) Conclusions from the MAFF sponsored studies:

(19.1) BSE affected animals have elevated levels of antibodies to Acinetobacter, a microbe which possesses molecular sequences resembling brain tissues and is found in the environment.

(19.2) The origin of these antibodies is at the moment unclear, but it is not beyond the bounds of cautious speculation that Acinetobacter bacteria or antigens were incorporated in the winter feeds of cattle (Meat-and-Bone-Meal = MBM) and thereby evoked these antibodies.

(19.3) BSE affected animals have autoantibodies against both myelin (white matter) and neurofilament (gray matter) components of the brain.

(19.4) If these antibodies were evoked by antigens present in the food materials of cows, then such antibodies should be highest in the mucosal antibody isotype, namely IgA.
The highest levels of anti-Acinetobacter antibodies are present in the mucosal IgA isotype, thereby supporting the hypothesis that such antibodies were produced as a result of antigens present in the food chain and not as the result of brain damage produced by “prions”.

(19.5) This is a powerful argument against the proposition that BSE
damage occurs following exposure to “prions” and the resultant auto-antibodies are a consequence of such damage.
It is difficult to explain why the majority of anti-Acinetobacter antibodies are in the IgA mucosal isotype.

(19.6) It is not clear whether antibodies to Acinetobacter, appeared before or after the onset of BSE.
However one clear conclusion is that when brain homogenates from BSE affected animals are injected into experimental animals, and then they develop a neurological disease, it cannot be said that BSE has been transmitted, unless they also have antibodies to Acinetobacter.
If such anti-Acinetobacter antibodies are not present, then maybe only EAE has been transmitted.

(19B) Conclusions from the MAFF sponsored studies

(19.7) If it can be confirmed that BSE is an autoimmune disease caused by Acinetobacter then it cannot be transmitted by meat consumption, as long as it is hygienically prepared.
This conclusion would appear to be compatible with the extensive nutritional studies carried out by the “National CJD Surveillance Unit” in Edinburgh, who in their yearly reports state that “...the link between meat consumption and v-CJD is less than compelling”.

(19.8) Therefore the public’s fears about the safety of meat consumption could be allayed by publicising these new facts concerning BSE.

(19.9) The culling of healthy animals would appear to be unnecessary, thereby saving substantial amounts of taxpayers’ money.

(19.10) Finally the use of the M.A.N. (Myelin-Acinetobacter-Neurofilament) assay provides a simple ante-mortem test of BSE.
The test could determine whether a cow has BSE before it is sent to a slaughter house and thus prevent its entry into the human food chain.

(19.11) The M.A.N. test could also be used in the diagnosis of MS.

(20) Recommendations:

(20.1) Further studies are required to determine whether antibodies to Acinetobacter species precede or follow the development of clinical disease in BSE affected cattle.

(20.2) This question could be resolved if it could be shown in small experimental animals (mice, rats, guinea pigs or rabbits) that exposure or immunisation with Acinetobacter bacteria or antigens leads to a neurological disease, with development of autoantibodies to both white (myelin) and gray (neurofilaments) brain matter and post-mortem studies show spongiform changes similar to those seen in BSE affected animals.

(20.3) Irrespective of their origin, the measurement of anti-Acinetobacter antibodies, especially in the M.A.N. assay, could be used as an ante-mortem test of BSE, before an animal goes to a slaughter house and thereby prevent its entry into the human food chain.

(20.4) A “reference laboratory” should be set up where such measurements could be carried out and the specific microbiological and immunological tests developed so that veterinarians and other laboratory personnel could be trained in the use of such techniques.

(20.5) King’s College London has both space and research facilities available for such a “reference laboratory”.

(20.6) The costs of setting up such a facility together with staffing involving trained personnel would amount to £ 2 million.

(20.7) In view of the enormous costs so far involved in both BSE together with the human costs of “multiple sclerosis”, the setting up of a research facility which offers hope in tackling both BSE and MS, would appear to be a not too onerous step to take with public resources.

This report is dedicated to the memory of the late Professor John
PIRT, who passed away in the spring of 2000.

During the war he flew with Bomber Command, afterwards he worked for the government at Porton Down and then became Professor of Microbiology, initially at Queen Elizabeth College and later at King’s College.

He strongly supported the work of a microbiological link to autoimmune diseases and appeared before the Phillips Inquiry on

20th August 2001

Professor of Immunology, King’s College London.

Tel. 020-7848-4302
Fax 020-7848-4500

Circulation: Government (DEFRA)


Principal of King’s College


The following have contributed to the work described in this report and their efforts and help were invaluable.

King’s College London

Dr. Clyde WILSON (MAFF) The late Prof. John PIRT
Dr. Harmale TIWANA (MAFF) Dr. Camille ETTELAIE
Ms Lucy HUGHES Ph.D cand. Mr. Phil CUNNINGHAM
Mr Carlos THORPE Dr Sukvinder BANSAL

Wickham Laboratories, Wickham, Hampshire

Dr. William CARTMELL

University of Cambridge

Prof. D.Allen.L. DAVIES

Institute of Neurology, The National Hospital for Neurology and
Neurosurgery, Queen Square

Prof. Edward J. THOMPSON Dr. Viqar CHAMOUN
Dr. Allison GREEN

Department of Geriatric Medicine, University College Hospital



Dr. David SHANNON Dr. Mandy BAILEY
Dr. Hilary GATES

Central Veterinary Laboratory (Now Central Veterinary Agency)



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agent is prevalent in the human population. Proc Natl Acad Sci 1993; 90: 7724-28.

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J Rheumatol 1997; 24: 109-114.

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Paper 1

Paper 6

HLA-B27 and Ebringer speech text

This is just a quickie as the RSPH website reshuffle (pretty well on the day of the last post) deleted Ebringer's text. It doesn't seem to be anywhere official on the net nowadays, so I feel OK to put it up here. I would just add that while I feel his work is very interesting, the pathology of MS and the pathology of BSE appear to be quite different. I've got a pdf of the BSE/acinetobacter work pre publication too, I'll probably stick that up in a few minutes and people can pick it over if they wish...


Here's the text:

Prof. Alan EBRINGER,
King’s College London

Your Royal Highnesses, Mr. Chairman, Ladies and Gentlemen.

I would like to thank The Royal Society for the Promotion of Health for the great honour it has bestowed on me in awarding the Donaldson Gold Medal to me for the work from our group,on “Bovine Spongiform Encephalopathy or BSE or more commonly known as mad cow disease. This work is a credit to the outstanding group of research workers in our Unit, especially Dr. Clyde Wilson, who recently was elected a Member of the Royal College of Pathologists, rather than to anything I may have done personally.

I graduated in Medicine from the University of Melbourne way back in 1962, obtained a Travelling Scholarship from the “Royal Australasian College of Physicians” to come to the U.K. and I have been working in the University of London since 1970. Over the last thirty years, our group has been studying the autoimmune diseases, ankylosing spondylitis, a chronic condition characterized by backache and also another arthritic disease rheumatoid arthritis. We have found that ankylosing spondylitis is triggered by the bowel microbe klebsiella and rheumatoid arthritis is produced following a urinary tract infection by the microbe proteus.

Prof. Feltkamp from Amsterdam in the Netherlands, asked us to cooperate in a joint study, which showed that Dutch patients with ankylosing spondylitis have antibodies to klebsiella and Dutch patients with rheumatoid arthritis have antibodies to proteus, as do English patients. These results have been published.

In auto immune diseases patients have antibodies which attack their own organs and these are called autoantibodies. Our model for studying autoimmune diseases was rheumatic fever, which is caused by the microbe streptococcus, which infects the tonsils and has components which resemble the human heart.

Following a streptococcal tonsillitis antibodies are produced which attack not only the microbe itself but also the human heart and cause rheumatic fever. Thus molecular mimicry or similarity between a microbe and a target organ produces an autoimmune disease.

Rheumatic fever is no longer a problem in the Western world because streptococcal tonsillitis responds to antibiotics but in countries of the Third World where access to such drugs is financially prohibitive, the disease remains a serious problem.

We have used this concept of molecular mimicry to identify the trigger factors in rheumatoid arthritis and ankylosing spondylitis.

Over the last seven years, our group has been studying “bovine spongiform encephalopathy” (BSE), also known as mad cow disease. A computer analysis showed that the soil and skin microbe acinetobacter has components which resemble brain tissues.

We approached MAFF (Ministry of Agriculture, Fisheries and Food) with the idea that we had an alternative theory, an autoimmune theory, to the prion hypothesis, which could explain the origin of BSE. Despite a few objections from some quarters, some funds were made available and access given to BSE material.

A study of BSE affected cattle showed that they have elevated levels of antibodies to the soil bacterium acinetobacter, a microbe which has components resembling brain tissues and to a lesser extent to the related microbe pseudomonas.

So far we have studied 508 animals; 218 with BSE and compared them to 290 controls.

These results are specific since the BSE animals do not show antibody elevations to five other microbes: klebsiella, proteus, serratia, E. coli, bacillus and agrobacterium.

The elevated levels of antibodies to acinetobacter found in BSE cattle lends itself to the development for an ante-mortem test for BSE, It has been proposed that BSE is caused by exposure to acinetobacter fragments, found in the “meat-and-bonemeal” flour meal fed to cattle.

The hypothesis is that antibodies against acinetobacter, attack the brain and cause mad cow disease.

The first time that a BSE cow was observed, it was found to be standing on its forelegs but falling down by its hindquarters and in this it resembles multiple sclerosis patients who have a greater incidence of lower limb paralysis.

Patients with multiple sclerosis were also found to have antibodies to acinetobacter and to the related microbe pseudomonas.

Over 50% of patients with multiple sclerosis suffer from sinusitis and thus could have become infected by the saprophytic microbe acinetobacter.

The general hypothesis is proposed that BSE is multiple sclerosis in cows and therefore it is an autoimmune disease which CANNOT BE TRANSMITTED BY THE CONSUMPTION OF “BSE” AFFECTED MEAT. If this theory can be confirmed then the following conclusions arise:

(1) Consumption of meat is safe and has always been safe.
(2) Culling of cattle was unnecessary.
(3) There will be no epidemic of CJD.
(4) An ante-mortem test for detecting BSE in live cattle is feasible.

Clearly the autoimmune theory of BSE requires further investigations but two months ago, DEFRA withdrew research funds for such studies.

We are currently cooperating with our Dutch colleagues in studying patients with multiple sclerosis. We hope that such Anglo-Dutch studies will continue in the future and serve not only international cooperation but also the aims and mission of the Royal Society for thePromotion of Health.

Thank you for your attention.

Sunday, October 12, 2008

HLA-B27 and Ebringer

This review [EDIT: the review has gone pay only and the abstract is yet to arrive on pubmed so I'll link to this when I can] was forwarded to me off blog and makes some very interesting reading. It's also a great excuse to post this picture:

Now, this might look like a plastic sausage in a plastic bun, forming a plastic hot dog, all from my son's toy cooking set, but to an immunologist (my wife) it's obviously an MHC molecule presenting a peptide. The sausage is the peptide, it's not to scale! The primary function of MHC class I molecules is to signal to the immune system that something is very wrong inside the cell, something represented by the peptide fragment, and the organism would be better off without that particular cell. Usually immune cells with a CD8 receptor get in and do the killing when MHC class I molecules present peptide.

The paper links a broad array of arthritic conditions to gut inflammation, much of which is subclinical (ie the person has arthritis and gut problems but considers their state of gut dysfunction to be "normal") and spends rather a lot of time discussing the role of HLA-B27 in this process. HLA-B27 is one of those buns, an MHC class I molecule. Your genetics determine whether you carry this particular MHC bun/molecule or not. The identity of the sausage is skirted around in the paper and never mentioned, except it is considered to be derived from the gut bacteria. The rat model used to prove this has to have the human HLA-B27 gene inserted. Err, but not just one or two copies the way HLA-B27 occurs in humans. More like 55 copies! You have to wonder about the cause of some of the problems these rats develop (clogged endoplasmic reticulum for a start) and how typical of the human condition they are!

To summarise the paper: there's something in common between gut and joint problems. We don't know what. But the answer will lie in tinkering with the immune system (an aside, does anybody remember Northwick Park? TGN1412 was looking to cure problems like ankylosing sponylitis, something of a high risk stratagem it seems).

I had a look through the references and the main citations, especially about HLA-B27, are by Mielants, who looks to be the group leader of Jacques and Elewaut (review authors). Nothing wrong with citing your boss. Mielants is also an author on the recent consensus report on evidence based management of ankylosing spondylitis, an Opinion Leader.

Jacques and Elewaut didn't mention Ebringer. Who is Ebringer? If you go to pubmed and search on "Ebringer" "HLA B27" you will get the idea of the size of the hole in the Nature paper. Ebringer's first HLA-B27/AS paper was published in 1980. Jacques and Elewaut must know this.

But Ebringer is a maverick, as far as I can see. He is the main proponent for the role of klebsiella pneumoniae, a gut bacterium, as the origin of the peptide in the HLA-B27 bun. There are a number of groups who have worked with him on this, but I suspect Mielants and his group represent the mainstream view. I've yet to see personal exchanges of the type seen between Nottingham neurologists and Sheffield neurologists, but Ebringer is not going to get a mention in a conventional review. He just doesn't get rated.

This is a pity.

Carol Sinclair wrote a book based on Ebringer's work. The book is not perfect but it will get remission of GI and arthritic problems for a lot of AS/IBS sufferers. In it she recounts the anecdote she heard from Ebringer, about how he found the dietary treatment for AS. The episode has a lot in common with my own experience.

Ebringer was managing a patient with AS using conventional drugs. The patient wanted to loose weight. Ebringer gave him advice derived from the low carbohydrate approach (shows how dodgy he is!), possibly influenced by Yudkin who was London based around the time that Ebringer would have been coming through medical school (I'm guessing the dates). The patient went LC and his AS went in to remission. The standard medical approach to this sort of phenomenon is to ignore it (prime example was my relative handing her beta blockers back to her cardiologist, he was uninterested). Ebringer didn't do this. He went on to fix more people using the LC diet approach, modified to a low starch approach.

Why low starch? The whole situation relating to HLA-B27, klebsiella and AS is horribly complex, but at the core is the enzyme pullulonase, which provides the peptide sausage which fits the HLA-B27 bun. I've been trying to find exactly which sugar triplet pullulonase degrades and it's not clear from Wiki. What is clear is that the triplet is present in starch and the enzyme pullulonase is produced whenever klebsiella meets starch. The enzyme is surface mounted on the bacterium and is in an ideal position to be seen by the immune system. If an HLA-B27 carrying white blood cell kills a klebsiella microbe it will easily produce the short peptide from pullulonase which fits the HLA-B27 molecule on its surface. That signals to both the innate and the adaptive immune systems to become active and (a) attack and (b) make antibodies against the peptide fragment. It's a bit unfortunate that the antibodies made against pullulanase, presented by HLA-B27, also fit the collagen around your spine, knees and often fingers. This labels the collagen as foreign, as well as doing a few other things. Result: ankylosing spondylitis, plus gut problems from the local damage.

I get the impression that neither Mielants, Jacques nor Elewaut believe a word of this. That's tough, as the Ebringer/Sinclair diet works pretty well. I used to have a moderate osteopath/chiropracter habit, just a few hundred pounds a year. When I went to Atkins induction I eliminated all starches, essentially by accident. My back pain simply disappeared. I had my first episode of neck pain at about 12 years of age and started with low back pain at about 20 years of age. It persisted through to Atkins induction at 46ish. It fluctuated quite a bit and the sciatica was thankfully very intermittent.

I have learned many of those tricks needed to get dressed without bending your spine. You know, sitting down to get you underpants around both ankles, then using one foot to pull them up to the knees, where you could just about reach them to pull them the rest of the way up. Easy really. You just do it.

Suddenly it all stopped with LC eating. I remember sitting in my car and turning around in the seat to reverse out of the drive, a few yards down the road and then in to a small side road, an "S" shaped reversing maneuver (a necessity of the road layout). Now I could do it, every day, easily, with no neck or lumbar pain. A joy! I used to sit there on the drive and grin at the thought I could turn around and look out of the back windscreen.

So, personally, I have a lot of time for Ebringer. How wacky is he, that the rest of rheumatology would rather not mention him?

This wacky: Does anybody remember Bovine Spongiform Encephalopathy, known as BSE or Mad Cow Disease? This paper shows how Ebringer views the disease. It does not make him popular. Frankly I'm amazed he got it published.

This is the Royal Society for the Promotion of Health. It looks quite respectable to me. The society makes various awards for outstanding work. Ebringer got the 2004 RSPH Gold Medal. From the [original] website:

"This medal is awarded for any major innovation or development which has significantly improved or promises to improve the quality and dignity of human life"

Ebringer got it for his work on BSE. This is the text of Ebringer's acceptance speech and these are the implications of his point of view as regards BSE, taken from that pdf:

[EDIT here's the full text as the RSPH website revamp deleted it]

(1) Consumption of meat is safe and has always been safe.
(2) Culling of cattle was unnecessary.
(3) There will be no epidemic of CJD.
(4) An ante-mortem test for detecting BSE in live cattle is feasible.

It is worth noting that cutting edge researchers in to the prion hypothesis of BSE (currently the mainstream paradigm) are very careful to maintain that their hypothesis is an hypothesis. This subtlety tends to get lost in political decision making. Of course Ebringer may be completely wrong about both BSE and AS and we should be grateful for the cattle cull and TNFA blocking antibodies.

If so I guess my spine problems just went in to spontaneous remission five years ago when I changed my diet, by coincidence. Phew, was I lucky. And so too was my daughter, a few months ago, when she did the same diet change with the same result! Strange, that...

Back to HLA-B27: On an evolutionary basis HLA-B27 would be no problem for a primarily carnivorous hunter gatherer. Probably some degree of intestinal wall damage is needed for the immune system to "see" klebsiella in the gut. So woe betide when grains arrived in the Nile valley, gluten and starch as a continuous combination!

Perhaps you need to build pyramids as your ticket to future happiness because life is currently so awful, there must be something better than the ancient Egyptian everyday arthritis grind. An afterlife would need to be blissful and pain free as a reward for the daily suffering which was life with ankylosing spondylitis.


PS there's a nice link to this paper about Egyptian arthritis in DrBG's post on "300". I think she likes the film.