This paper came my way via Eddie Vos, through a discussion in the THINCS group.
OK, what's going on in the paper? It's the metabolic ward study to end all metabolic ward studies. Routine criminals who volunteered to live in a "food proof" prison and to eat a diet based on pure chemicals. This is a prison within a prison:
"The described study was conducted in an especially isolated wing of the California Medical Facility (CMF), a state institution for adult male felons. The isolated area included large indoor recreation, lounge, and shower areas, and 24 individual cells, and was so located as to prevent completely the passage of any food through or near the area."
And what yummy food did the inmates receive?
"These diets were unique in that a) their essential and nonessential nitrogen source was provided exclusively in the form of optically pure L-amino acids and b) they were administered as single, crystal clear aqueous solutions that were nutritionally complete in themselves. In essence, the diets were composed of balanced (but varying) proportions of L-amino acids, the required water-soluble and fat soluble vitamins, the pertinent mineral salts, glucose or other simple sugars as the source of carbohydrate, and ethyl linoleate as the source of essential fat."
Apparently the various versions of the diet all tasted disgusting, for want of a better word.
Apart from the interest of human experiments along these lines, there were a few other tweaks they applied. First we have to note that these diets were essentially ultra low fat diets, the same family as the diets used by McDougal and co. There is not a grain of white rice which does not end up as blood glucose. If you eat brown rice there is a split between the fibre and the minerals it is depriving you of (you know where they get flushed) and the starch, which ends up as blood glucose. So these are seriously low fat, high carbohydrate diets.
What happens when you feed an elemental diet based on glucose alone as its calorie source? Blood cholesterol drops, from a normal value found in a non statinated male of 227mg/dl (while eating 1970s style prison food), to a cardiologic near Nirvana of 160mg/dl. Replacing 25% of the glucose with sucrose produces a rise in cholesterol to 208mg/dl. Removing the sucrose and going back to pure glucose drops the cholesterol level back down to 151mg/dl.
Is that good or bad? You need to remember the old adage that the best cholesterol level is one that has not been measured. But what is happening probably goes back to that short section of the ApoB100 protein which glycates particularly easily, discussed here. I think it is worth pointing out again that fructose should never penetrate in to the systemic circulation, so its whole body damage should be indirect. It probably does this through the induction of hepatic insulin resistance. Fructose has to be metabolised immediately and the end result is raised intracellular hepatic triglycerides. We've seen before that a decent supply of intra cellular lipid makes a cell say no to glucose and that it does this by exhibiting insulin resistance. The liver normally stores glucose in response to insulin. Rendering it insulin resistant would logically stop it storing glucose and pour the stuff out in to the systemic circulation...
That's the basis of this post and it needs bearing in mind when we look at cholesterol variation and heart disease with a given population. But there's an aside first that really creased me up...
A quick pubmed looking for a reference to fructose and insulin resistance (there are hundreds) produced this gem, hot out of cyberpublishing a few days ago.
The group used an antisense oligonucleotide, which is a short section of DNA, RNA or a similar synthetic drug which specifically blocks the activity of a corresponding section of messenger RNA, which means the the relevant gene no longer gets successfully transcribed. By doing this they turned off lipid synthesis in the liver in response to fructose. No hepatic insulin resistance despite fructose intake: Wow!!!!!!!!!! Take this drug and you too can drink Pepsi Max without turning your liver in to foie gras. What else does it do? Oh, it lowers insulin resistance, whole body! Superb, give me some.
Oh oh, it's your butt which soaks up the plasma glucose... As they say of their own technique, it resulted in:
"increased insulin-stimulated whole-body glucose disposal due to a threefold increase in glucose uptake in white adipose tissue"
Translation: "our wonder drug makes you fat".
It is also described as a potential "treatment of NAFLD, hypertriglyceridemia, and insulin resistance associated with increased de novo lipogenesis", I would add "by making you fat". I'd also add that this de novo lipogenesis can easily be avoided by avoiding the fructose in the first place.
What is not remotely obvious from the abstract is: Where does the fructose go to, if it's not used to converted your liver to foie gras?
I guess it's either going to glycosylate your liver (sounds great for longevity) or spill in to your systemic circulation, where it can glycosylate whatever it come in to contact with.... Or it might just overload each liver cell with more pyruvate than it knows what to do with. Now there's grist for the mill of unintended consequences!
Back to the real world:
A fructose intake of 12% of your calories makes your metabolism unhappy enough that it has evolved a technique to increase cholesterol levels under these rather rare (until recent times) conditions. It probably has knock on effects through hepatic insulin resistance resulting in hyperglycaemia and all of the damage that this leads to.
While some fructose is perfectly OK (I too eat home grown fruit in season and a certain amount of sucrose) I suspect a large amount is not OK.
Under highly defined conditions, fructose raises your total cholesterol level.
Peter
EDIT: Sue has pointed out, off blog, that the other reason for a fall in cholesterol is due to minimal production of triglycerides. If glucose is being consumed within the ability of the liver to store it as glycogen there is no reason to convert it to fat and so there is no fat to export as triglycerides. Fructose immediately converts to fat and any fat produced in excess of the needs of the liver will be shipped out as LDL precursor particles, raising both LDL and TC.
Both mechanisms are fructose related but not fructose specific. The average trigs were 93mg/dl but the study did not split anything other than TC by the sucrose/fructose periods early in 19 weeks of the initial part of the diet. The volunteers remained pretty well weight stable throughout, as far as I can see.
So you have a choice of two mechanisms, there may be more, but the association still seems to hold that TC is a marker of fructose intake, with a number of confounders once you get off of chemical diets. BTW the TC went back to a normal >200mg/dl on return to normal food. Or uless you have a TC like mine (and a few other folks), which is a law unto itself.
Friday, March 06, 2009
Tuesday, March 03, 2009
That FSA apple
It seems that the FSA is suggesting that eating enough fructose will make a maggot eat your heart out! Some sense at last. Oh no! They think that apples are GOOD for you. But a maggot has certainly eaten a heart out of the apple... I suppose it's as accurate as suggesting that the temperature-drop induced phase change from liquid to solid of saturated fat, the one which blocks drains, will also block your arteries. Perhaps the FSA has a heart of ice!
My taxes are paying these idiots' wages!
To quote JohnN:
"What the apple hates anthropomorphically is the relentless human selection that gives rise to the grotesque size and fructose content of its fruit"
I love the concept of apples as grotesque!
Peter
My taxes are paying these idiots' wages!
To quote JohnN:
"What the apple hates anthropomorphically is the relentless human selection that gives rise to the grotesque size and fructose content of its fruit"
I love the concept of apples as grotesque!
Peter
Tuesday, February 24, 2009
Cholesterol presentation: Between countries
OK, this is the graph of heart deaths plotted against fat intake, produced by Ancel Keys in 1953. It's a beautiful curve, utterly convincing to any Congressperson looking to find fame by funding a cure for heart disease:
Unfortunately Excel doesn't do nice sweeping curves, so I've mangled it by eye to a straight line thus:
Which is still very convincing. Slightly less convincing is when the choice of different countries from the same data bases suggests that dietary fat has nothing to do with heart disease and that heart disease is very rare anyway:
Of course choosing a few other countries might have given a negative correlation:
And, with a little effort, we can see that if only we could just get everyone's fat intake above 40% of calories heart disease would be a thing of the past, just so long as we chose the correct countries to look at:
So let's stop playing and look at the whole database from which Keys carefully selected his six countries:
OK, there IS a correlation. It's pathetic, especially compared to the original line swept in by Keys. Of course things get worse if you add in the Masai, the Inuit, the Rendile, the Tokelau and a few others, shown as red dots:
At this point you would have thought that the name Keys would have become a joke and people would simply have ignored him as a self publicising evangelist with scant respect for the truth. But Keys was nothing if not determined. In 1958, the year after Yerushalmy and Hillebo had shown him to be a charlatan, out came this paper explaining the mechanism by which the high fat diet apparently caused heart disease, even if it didn't. Serum total cholesterol!!!!!! Picture credited to Dr Ravnskov (couldn't get the original).
Of course adding a few data points, which Keys had conveniently forgotten, gives this plot, again credited to Dr Ravnskov:
Anyone for a straight line? These studies are the core of the lipid hypothesis. They are where it all came from and the "science" is total junk.
As a final comment on between nation studies this figure, credited to Dr Kendrick, shows the rates of death from CHD plotted against the percent of a given population who are frankly hypercholesterolaemic. He extracted the data from the little discussed MONICA study:
Obviously living in Russia, Northern Ireland, the Czech Republic or Lithuania is bad news for CHD. Forget cholesterol.
That's as much as there was time for on between nations studies. Essentially they provide absolutely no support for dietary fat or serum total cholesterol as causes of coronary heart disease. It seems impossible that they should have spawned the current climate of cholesterol psychosis, but they did.
Within nations studies comes next.
Peter
OK, time to knuckle down to five very long days at work...
Unfortunately Excel doesn't do nice sweeping curves, so I've mangled it by eye to a straight line thus:
Which is still very convincing. Slightly less convincing is when the choice of different countries from the same data bases suggests that dietary fat has nothing to do with heart disease and that heart disease is very rare anyway:
Of course choosing a few other countries might have given a negative correlation:
And, with a little effort, we can see that if only we could just get everyone's fat intake above 40% of calories heart disease would be a thing of the past, just so long as we chose the correct countries to look at:
So let's stop playing and look at the whole database from which Keys carefully selected his six countries:
OK, there IS a correlation. It's pathetic, especially compared to the original line swept in by Keys. Of course things get worse if you add in the Masai, the Inuit, the Rendile, the Tokelau and a few others, shown as red dots:
At this point you would have thought that the name Keys would have become a joke and people would simply have ignored him as a self publicising evangelist with scant respect for the truth. But Keys was nothing if not determined. In 1958, the year after Yerushalmy and Hillebo had shown him to be a charlatan, out came this paper explaining the mechanism by which the high fat diet apparently caused heart disease, even if it didn't. Serum total cholesterol!!!!!! Picture credited to Dr Ravnskov (couldn't get the original).
Of course adding a few data points, which Keys had conveniently forgotten, gives this plot, again credited to Dr Ravnskov:
Anyone for a straight line? These studies are the core of the lipid hypothesis. They are where it all came from and the "science" is total junk.
As a final comment on between nation studies this figure, credited to Dr Kendrick, shows the rates of death from CHD plotted against the percent of a given population who are frankly hypercholesterolaemic. He extracted the data from the little discussed MONICA study:
Obviously living in Russia, Northern Ireland, the Czech Republic or Lithuania is bad news for CHD. Forget cholesterol.
That's as much as there was time for on between nations studies. Essentially they provide absolutely no support for dietary fat or serum total cholesterol as causes of coronary heart disease. It seems impossible that they should have spawned the current climate of cholesterol psychosis, but they did.
Within nations studies comes next.
Peter
OK, time to knuckle down to five very long days at work...
Fructose and heart attacks
Food: African Beef Stew
Just realised I never posted this recipe, the peanuts are distinctly neolithic but the flavour is yummie. Occasionally... It's on the top of the cooker now!
Peter
African beef stew, serves 2, maybe 3...
ingredients:
1 lb diced beef
Tin tomatoes.
Medium carrot, sliced.
Medium onion, chopped.
50-75g butter, depends on how fatty the meat is.
50g peanut butter.
Bayleaf.
About 200ml water, to just cover meat.
Salt and pepper to taste.
Fresh root ginger, however much you like.
3 cloves garlic, crushed
Pinch Cayenne pepper
Pinch ground cloves
Tablespoon vinegar or lemon juice.
Place all ingredients in a casserole, bring to boil, stir well, cover, place in oven at gas mark four for 2-3 hours until meat melts in the mouth. Stir every half hour.
Can be cooked very slowly on top of the cooker.
Peter
African beef stew, serves 2, maybe 3...
ingredients:
1 lb diced beef
Tin tomatoes.
Medium carrot, sliced.
Medium onion, chopped.
50-75g butter, depends on how fatty the meat is.
50g peanut butter.
Bayleaf.
About 200ml water, to just cover meat.
Salt and pepper to taste.
Fresh root ginger, however much you like.
3 cloves garlic, crushed
Pinch Cayenne pepper
Pinch ground cloves
Tablespoon vinegar or lemon juice.
Place all ingredients in a casserole, bring to boil, stir well, cover, place in oven at gas mark four for 2-3 hours until meat melts in the mouth. Stir every half hour.
Can be cooked very slowly on top of the cooker.
Monday, February 23, 2009
Fats and absorbing endotoxin
Chris sent me a very interesting link a while ago and it just brought home to me how difficult it is to interpret a study in isolation. In fact, how random the world is in terms of what anyone does or doesn't know.
Bacterial endotoxin is a breakdown product of the cell wall of gram negative bacteria. It's a lipopolysaccharide and even quite small amounts of it are extremely unpleasant. In overwhelming gram negative infections killing the bacteria releases endotoxin which can itself be fatal to the patient. Not killing the bacteria can have the same effect on mortality, so the best advice I can give is to avoid overwhelming infection.
Now the scary thing is that eating a high fat meal, probably based on any fat which generates chylomicrons, markedly increases you uptake of endotoxin from your gut, which is obviously full of gram negative bacteria. Eating short chain fatty acids or carbohydrate does not have this effect.
OK, so the prediction from this research is that eating a diet which generates chylomicrons will produce all sorts of nasty changes in your body. Hmmmmm, well maybe, but I've not noticed.
Then came a fascinating random paper through my wife's journal club meetings, which are a routine part of her PhD. It's about superinfection with resistant bacteria when broad spectrum antibiotics are used. This is a routine problem for anyone in medicine, especially patients. The concept is very simple, you kill off the susceptible commensal bacteria in the gut and resistant pathogens have no competition, so they have a field day and superinfection causes severe problems for the unlucky patient.
Simple, straightforward and wrong.
It turns out that the immune system, that is the innate immune system (of course), continuously monitors the contents of the gut by looking at endotoxin production. Lots of bacteria mean lots of endotoxin and an active, on-guard innate immune system. Kill off 99% of your gut bacteria and exdotoxin production drops. The innate immune system goes on vacation and clostridium difficile gets in and wipes out your granny.
Simple administration of oral endotoxin to the experimental mice stopped this effect completely.
So yes, it looks like chylomicrons carry endotoxin. Phew. That's better than a clostridium difficile infection!
Reminds me of Uffe Ravnskov's paper on the benefits of LDL cholesterol in gram negative septicaemia. Must dig it out for an airing.
Peter
Bacterial endotoxin is a breakdown product of the cell wall of gram negative bacteria. It's a lipopolysaccharide and even quite small amounts of it are extremely unpleasant. In overwhelming gram negative infections killing the bacteria releases endotoxin which can itself be fatal to the patient. Not killing the bacteria can have the same effect on mortality, so the best advice I can give is to avoid overwhelming infection.
Now the scary thing is that eating a high fat meal, probably based on any fat which generates chylomicrons, markedly increases you uptake of endotoxin from your gut, which is obviously full of gram negative bacteria. Eating short chain fatty acids or carbohydrate does not have this effect.
OK, so the prediction from this research is that eating a diet which generates chylomicrons will produce all sorts of nasty changes in your body. Hmmmmm, well maybe, but I've not noticed.
Then came a fascinating random paper through my wife's journal club meetings, which are a routine part of her PhD. It's about superinfection with resistant bacteria when broad spectrum antibiotics are used. This is a routine problem for anyone in medicine, especially patients. The concept is very simple, you kill off the susceptible commensal bacteria in the gut and resistant pathogens have no competition, so they have a field day and superinfection causes severe problems for the unlucky patient.
Simple, straightforward and wrong.
It turns out that the immune system, that is the innate immune system (of course), continuously monitors the contents of the gut by looking at endotoxin production. Lots of bacteria mean lots of endotoxin and an active, on-guard innate immune system. Kill off 99% of your gut bacteria and exdotoxin production drops. The innate immune system goes on vacation and clostridium difficile gets in and wipes out your granny.
Simple administration of oral endotoxin to the experimental mice stopped this effect completely.
So yes, it looks like chylomicrons carry endotoxin. Phew. That's better than a clostridium difficile infection!
Reminds me of Uffe Ravnskov's paper on the benefits of LDL cholesterol in gram negative septicaemia. Must dig it out for an airing.
Peter
Fructose and triglycerides
Here's another interesting anti fructose snippet.
Slowly, slowly a tiny step at a time. The strange thing is that these people probably think it's the triglycerides that kill you. Probably their next step is to theorise that if they just had a drug to stop apples raising triglyceride levels you could eat that apple without raising your risk of a heart attack. But what if it's the fructose per se that is the problem and the trigs are just a marker of how much fructose you have eaten? The apple hates you for eating it and it will have its revenge.
Peter
Slowly, slowly a tiny step at a time. The strange thing is that these people probably think it's the triglycerides that kill you. Probably their next step is to theorise that if they just had a drug to stop apples raising triglyceride levels you could eat that apple without raising your risk of a heart attack. But what if it's the fructose per se that is the problem and the trigs are just a marker of how much fructose you have eaten? The apple hates you for eating it and it will have its revenge.
Peter
The cholesterol fed rabbit
This video clip reminded me to put up the first few slides from the cholesterol skeptic presentation late last year. Squiggs is cooking scrambled eggs to feed to his toy rabbits, and to himself of course. It's Leonard Cohen in the background.
I began the talk with a quick overview of cholesterol. How it was originally Bad, then it was subdivided in to Good and Bad. Then the Good became good Good and bad Good. And the bad became bad Bad (small dense LDL) and good Bad (large fluffy LDL). Of course not forgetting IDL which can be good or bad depending on when it occurs! And triglycerides were Bad (big trigs) unless, of course, they were Good (small trigs).
But the initial studies simply used total cholesterol to start the ball rolling, a measurement which is now generally considered irrelevant. The ball should have stayed still.
Next was a brief overview of the metabolism of the rabbit
the fact that it is a fibre-vore which runs its metabolism on free fatty acids derived from cellulose fermentation in its hind gut, usually eating Timothy Grass as its sole food.
Timothy grass is 0.6% fat fresh weight and contains no cholesterol. The lipid hypothesis was derived from feeding rabbits up to 5% of their food as chemical cholesterol dissolved in Wessen oil, which is mostly linoleic acid. This even shocked Ancel Keys!
Ultimately the stupidity of transferring this model to the cause of atherosclerosis in humans has to be summed up by Ancel Keys in one of his few moments of lucidity
The final slide in this section was looking at the cholesterol fed rabbit in human terms, including the chap who ate 25 eggs per day for 13 years plus.
Next was the Six Nations Study
Peter
I began the talk with a quick overview of cholesterol. How it was originally Bad, then it was subdivided in to Good and Bad. Then the Good became good Good and bad Good. And the bad became bad Bad (small dense LDL) and good Bad (large fluffy LDL). Of course not forgetting IDL which can be good or bad depending on when it occurs! And triglycerides were Bad (big trigs) unless, of course, they were Good (small trigs).
But the initial studies simply used total cholesterol to start the ball rolling, a measurement which is now generally considered irrelevant. The ball should have stayed still.
Next was a brief overview of the metabolism of the rabbit
the fact that it is a fibre-vore which runs its metabolism on free fatty acids derived from cellulose fermentation in its hind gut, usually eating Timothy Grass as its sole food.
Timothy grass is 0.6% fat fresh weight and contains no cholesterol. The lipid hypothesis was derived from feeding rabbits up to 5% of their food as chemical cholesterol dissolved in Wessen oil, which is mostly linoleic acid. This even shocked Ancel Keys!
Ultimately the stupidity of transferring this model to the cause of atherosclerosis in humans has to be summed up by Ancel Keys in one of his few moments of lucidity
The final slide in this section was looking at the cholesterol fed rabbit in human terms, including the chap who ate 25 eggs per day for 13 years plus.
Next was the Six Nations Study
Peter
Wednesday, February 18, 2009
Vitamin D3 again
For UK people looking to measure 25(OH)D3 (and a few other parameters thrown in it seems) Sue sent this address
http://www.biolab.co.uk/vitamins.html
Very reasonable cost but you will need guarenteed next day delivery or a courier, and time the sample appropriately too.
Peter
http://www.biolab.co.uk/vitamins.html
Very reasonable cost but you will need guarenteed next day delivery or a courier, and time the sample appropriately too.
Peter
Monday, February 16, 2009
Vitamin D3 supplements
Just got my 25(OH)D3 result back, 124ng/ml. Bit on the high side so I'll back off from 12,000 iu a day to 9,600 iu for the rest of the winter and maybe do 7,200 iu/d if I get some sun this summer... Roll on
Peter
EDIT: Ionised calcium 1.16mmol/l, normal range 1.12-1.37. No suggestion of hypercalcaemia.
Peter
EDIT: Ionised calcium 1.16mmol/l, normal range 1.12-1.37. No suggestion of hypercalcaemia.
Sunday, February 15, 2009
Multiple Sclerosis and Optic Neuritis
This post, like the first on MS, started with the conversation I had over lunch with Prof Ebringer and has been kicked around in my head for a few months afterwards. Here's the next phase.
The immune system is quite complex. Apart from defending us against microbes it appears to be quite important in healing. The formation of antibodies against damaged tissues seems to be quite routine and is probably part of the normal healing process. When those auto antibodies are made against proteins which are not limited to the damaged tissues you can get auto immune diseases in the aftermath of injury. Best documented is pemphigus, where the initial antibodies to skin proteins can be produced in response to damage by anything from UV radiation or thermal burns to surgery or drug adverse reactions. Sometimes the problem goes away with removal of the trigger or after healing of the injury, other times it's there for ever as a self perpetuating, on going, catastrophic problem with auto immune attack on the skin.
Let's talk optic neuritis and multiple sclerosis. Optic neuritis is an inflammatory injury to the optic nerve. Usually it has no obvious cause (think gluten!) but occasionally it comes directly associated with sinusitis. The sinusitis does not have to be caused by acinetobacter, any infection will do, it can even be subclinical.
Treatment, by aggressive surgical and medical management can produce prompt resolution of both the neuritis and sinusitis if a correct diagnosis is made (difficult if the sinus problem is subclinical and an MRI is not available!). The theory linking the two problems seems to be a localised inflammation, plus venous spread of a frightening soup of inflammatory mediators from the sinus past the optic nerve.
The nerve is clearly injured, as reflected by the chunks of lost vision. The injury is not permanent if the sinusitis is successfully treated. The question to me is whether there is enough damage to the optic nerve for the myelin sheathes to be recognised by the immune system as needing antibody production, aka skin burns and auto antibodies to skin. If the damaged nerve does trigger antibody production you are set up with anti-myelin antibodies, which just might have you set up with an on going anti myelin syndrome, call it MS.
About half to three quarters of the people who get idiopathic optic neuritis go on to develop MS. The question to me is whether these are the half or more who had acinetobacter in their sinuses or those who developed auto antibodies to their myelin as a direct result of inflammatory mediator damage. I don't think there is information available which allows us to come to any conclusion about this. It is even possible that the initial priming of the immune system by direct nerve damage from sinusitis can be maintained and promoted by chronic acinetobacter respiratory infection or vice versa... A number of MS patients may be straight gluten toxicity mediated by the innate immune system in the absence of antibodies to anything.
The idea (somewhat abstract) of antibodies to damaged nerves is interesting as it has similarities to immune mediated damage to nerves seen in the various experimental autoimmune encephalomyelitis models used to study MS. These are interesting in their own right and being injected with nerve tissue, especially from other species, appears to be a particularly potent way of generating "MS like" syndromes. They can be another post.
Peter
The immune system is quite complex. Apart from defending us against microbes it appears to be quite important in healing. The formation of antibodies against damaged tissues seems to be quite routine and is probably part of the normal healing process. When those auto antibodies are made against proteins which are not limited to the damaged tissues you can get auto immune diseases in the aftermath of injury. Best documented is pemphigus, where the initial antibodies to skin proteins can be produced in response to damage by anything from UV radiation or thermal burns to surgery or drug adverse reactions. Sometimes the problem goes away with removal of the trigger or after healing of the injury, other times it's there for ever as a self perpetuating, on going, catastrophic problem with auto immune attack on the skin.
Let's talk optic neuritis and multiple sclerosis. Optic neuritis is an inflammatory injury to the optic nerve. Usually it has no obvious cause (think gluten!) but occasionally it comes directly associated with sinusitis. The sinusitis does not have to be caused by acinetobacter, any infection will do, it can even be subclinical.
Treatment, by aggressive surgical and medical management can produce prompt resolution of both the neuritis and sinusitis if a correct diagnosis is made (difficult if the sinus problem is subclinical and an MRI is not available!). The theory linking the two problems seems to be a localised inflammation, plus venous spread of a frightening soup of inflammatory mediators from the sinus past the optic nerve.
The nerve is clearly injured, as reflected by the chunks of lost vision. The injury is not permanent if the sinusitis is successfully treated. The question to me is whether there is enough damage to the optic nerve for the myelin sheathes to be recognised by the immune system as needing antibody production, aka skin burns and auto antibodies to skin. If the damaged nerve does trigger antibody production you are set up with anti-myelin antibodies, which just might have you set up with an on going anti myelin syndrome, call it MS.
About half to three quarters of the people who get idiopathic optic neuritis go on to develop MS. The question to me is whether these are the half or more who had acinetobacter in their sinuses or those who developed auto antibodies to their myelin as a direct result of inflammatory mediator damage. I don't think there is information available which allows us to come to any conclusion about this. It is even possible that the initial priming of the immune system by direct nerve damage from sinusitis can be maintained and promoted by chronic acinetobacter respiratory infection or vice versa... A number of MS patients may be straight gluten toxicity mediated by the innate immune system in the absence of antibodies to anything.
The idea (somewhat abstract) of antibodies to damaged nerves is interesting as it has similarities to immune mediated damage to nerves seen in the various experimental autoimmune encephalomyelitis models used to study MS. These are interesting in their own right and being injected with nerve tissue, especially from other species, appears to be a particularly potent way of generating "MS like" syndromes. They can be another post.
Peter
Monday, February 09, 2009
Multiple Sclerosis and Hydrogen
Thanks to Stephan for getting me re started on this post. Hydrogen matters.
I've been interested in diet and MS for some time. JK has apparently treated a small number of patients and Barry Groves has an interesting section on Second Opinions, mostly discussing a small series of 15 patients treated by Dr Lutz, plus a lady who put her MS in to remission by following the dietary advice in Eat Fat Get Thin.
Lutz is very interesting and cautions against aggressive, sudden onset LC nutrition in this disease as there can be a severe flare. He also mentions this phenomenon in a number of (non MS) sections of Life Without Bread. Being a medic he has the facility to use corticosteroids under these circumstances and did so as needed. There is probably a whole post related to this idea, but I think it holds water.
Anyway, MS appears to be manageable using diet. I'm going to try and look at some of the aspects as to why, though there seem to be several related ways of developing MS, which complicates matters. Intestinal dysbiosis and hydrogen production are probably crucial to development and offer some plausible mechanism for achieveing remission.
As we all know, helicobacter gastritis is facilitated by hydrogen gas produced from carbohydrate fermentation in the colon (or the small intestine if you have adequate dysbiosis). Interestingly helicobacter appears quite happy to colonise both your respiratory system and the calculus on your teeth, presumably given enough hydrogen. The authors of the paper which looked at the role of hydrogen speculated that other infections, particularly of the respiratory tract, might also be facilitated by access to hydrogen.
One other bacterium which appears to be extremely fond of hydrogen is acinetobacter. In its free living guise, just look where you can find it. All you have to do is to give some legumes the equivalent of intestinal dysbiosis by modifying their nitrogen fixing bacteria to "excrete" hydrogen, plant them in a field and there are the acinetobacter, eating it up.
Acinetobacter bacteria are ubiquitous in soil, as commensals on skin/ mucous membranes and as pathogens. The pathogenic species love the respiratory system of critically ill patients and have an initial preference for the sinuses before generalising in to the lungs, blood stream and mortuary.
Respiratory infection, especially sinusitis, has a very long and respectable association with MS. This paper gives the picture:
"MS and chronic sinus infection were also significantly associated in the timing of attacks, in the age at which patients suffered their attacks, and in the seasonal pattern of attacks"
The p value for the association was p<0.0001, quite impressive provided you remember it's an association in a retrospective observational study, not an intervention trial.
I am interested in Prof Ebringer's work on MS and acinetobacter. Prof Ebringer has a systematic technique for seeking out peptides in bacterial proteins which might reasonably be associated with auto immune diseases in humans. Obviously, for MS, you are looking for amino acid sequences in bacterial proteins which resemble a protein in myelin, the one which is targeted for attack by the immune system to give MS. Plus a few other neurological protein targets.
Acinetobacter has such peptide sequences in several rather obscure sounding enzymes. The next question is whether patients with MS have elevated antibodies to acinetobacter bacteria. Yes, they do and they also have elevated antibody counts against synthetic peptides identical to those putative trigger sequences too.
So where does that leave diet? I'm not a great enthusiast for using antibiotics for treating chronic recurrent sinusitis. Drugs are great for acute life threatening problems, or even for acute onset severe sinusitis. Guessing the correct one is part of my job. But bacteria like acinetobacter and its close relative pseudomonas (which shares similar myelin resembling peptides) simply laugh at the pharmaceutical industry's offerings. No, reducing the pathogenicity of these bacteria requires manipulation of their environment.
As an aside on pseudomonas, I was a student in Camden Town just after the IRA bombed the Tower of London in 1974. The many burns patients from this particular episode (which made you quite uncomfortable walking past litter bins in central London) were successfully treated for potentially lethal pseudomonas infections using the vinegar and hair drier technique mentioned above, when all of the antibiotics available at the time were useless. This was cutting edge for our pharmacology lecturers and it certainly taught me something about bacteria.
Back to acinetobacter and respiratory infection. I still get colds. So do my wife and son. LC friends do too. But the chronic persistent gunky nasal discharge, chronic sinusitis or persistent cough (for weeks or even months for some) that used to be a routine sequel to colds are a thing of the past. Respiratory bacteria live in an oxygen rich environment. Hydrogen, as noted by Stephan, Kwasniewski and NASA, is a very high energy molecule in the presence of oxygen. It can power a respiratory infection just as well as it can power an Apollo rocket. No hydrogen means no fuel.
Acinetobacter live everywhere. Having them in your nose is common. We've probably always had them. Converting that balance to a chronic purulent sinus infection is arriving in the modern world.
Getting rid of sinusitis strikes me as one route to removing the most likely trigger factors for MS. Marked reduction of hydrogen production from gut dysbiosis is probably essential to this. That means minimal fibre, minimal fructose, minimal gluten, minimal flatulence. Anything else we can do to normalise our immune function after that will probably help too.
But for someone with MS and a weakness for baked beans, hmmmmmm......
Peter
I've been interested in diet and MS for some time. JK has apparently treated a small number of patients and Barry Groves has an interesting section on Second Opinions, mostly discussing a small series of 15 patients treated by Dr Lutz, plus a lady who put her MS in to remission by following the dietary advice in Eat Fat Get Thin.
Lutz is very interesting and cautions against aggressive, sudden onset LC nutrition in this disease as there can be a severe flare. He also mentions this phenomenon in a number of (non MS) sections of Life Without Bread. Being a medic he has the facility to use corticosteroids under these circumstances and did so as needed. There is probably a whole post related to this idea, but I think it holds water.
Anyway, MS appears to be manageable using diet. I'm going to try and look at some of the aspects as to why, though there seem to be several related ways of developing MS, which complicates matters. Intestinal dysbiosis and hydrogen production are probably crucial to development and offer some plausible mechanism for achieveing remission.
As we all know, helicobacter gastritis is facilitated by hydrogen gas produced from carbohydrate fermentation in the colon (or the small intestine if you have adequate dysbiosis). Interestingly helicobacter appears quite happy to colonise both your respiratory system and the calculus on your teeth, presumably given enough hydrogen. The authors of the paper which looked at the role of hydrogen speculated that other infections, particularly of the respiratory tract, might also be facilitated by access to hydrogen.
One other bacterium which appears to be extremely fond of hydrogen is acinetobacter. In its free living guise, just look where you can find it. All you have to do is to give some legumes the equivalent of intestinal dysbiosis by modifying their nitrogen fixing bacteria to "excrete" hydrogen, plant them in a field and there are the acinetobacter, eating it up.
Acinetobacter bacteria are ubiquitous in soil, as commensals on skin/ mucous membranes and as pathogens. The pathogenic species love the respiratory system of critically ill patients and have an initial preference for the sinuses before generalising in to the lungs, blood stream and mortuary.
Respiratory infection, especially sinusitis, has a very long and respectable association with MS. This paper gives the picture:
"MS and chronic sinus infection were also significantly associated in the timing of attacks, in the age at which patients suffered their attacks, and in the seasonal pattern of attacks"
The p value for the association was p<0.0001, quite impressive provided you remember it's an association in a retrospective observational study, not an intervention trial.
I am interested in Prof Ebringer's work on MS and acinetobacter. Prof Ebringer has a systematic technique for seeking out peptides in bacterial proteins which might reasonably be associated with auto immune diseases in humans. Obviously, for MS, you are looking for amino acid sequences in bacterial proteins which resemble a protein in myelin, the one which is targeted for attack by the immune system to give MS. Plus a few other neurological protein targets.
Acinetobacter has such peptide sequences in several rather obscure sounding enzymes. The next question is whether patients with MS have elevated antibodies to acinetobacter bacteria. Yes, they do and they also have elevated antibody counts against synthetic peptides identical to those putative trigger sequences too.
So where does that leave diet? I'm not a great enthusiast for using antibiotics for treating chronic recurrent sinusitis. Drugs are great for acute life threatening problems, or even for acute onset severe sinusitis. Guessing the correct one is part of my job. But bacteria like acinetobacter and its close relative pseudomonas (which shares similar myelin resembling peptides) simply laugh at the pharmaceutical industry's offerings. No, reducing the pathogenicity of these bacteria requires manipulation of their environment.
As an aside on pseudomonas, I was a student in Camden Town just after the IRA bombed the Tower of London in 1974. The many burns patients from this particular episode (which made you quite uncomfortable walking past litter bins in central London) were successfully treated for potentially lethal pseudomonas infections using the vinegar and hair drier technique mentioned above, when all of the antibiotics available at the time were useless. This was cutting edge for our pharmacology lecturers and it certainly taught me something about bacteria.
Back to acinetobacter and respiratory infection. I still get colds. So do my wife and son. LC friends do too. But the chronic persistent gunky nasal discharge, chronic sinusitis or persistent cough (for weeks or even months for some) that used to be a routine sequel to colds are a thing of the past. Respiratory bacteria live in an oxygen rich environment. Hydrogen, as noted by Stephan, Kwasniewski and NASA, is a very high energy molecule in the presence of oxygen. It can power a respiratory infection just as well as it can power an Apollo rocket. No hydrogen means no fuel.
Acinetobacter live everywhere. Having them in your nose is common. We've probably always had them. Converting that balance to a chronic purulent sinus infection is arriving in the modern world.
Getting rid of sinusitis strikes me as one route to removing the most likely trigger factors for MS. Marked reduction of hydrogen production from gut dysbiosis is probably essential to this. That means minimal fibre, minimal fructose, minimal gluten, minimal flatulence. Anything else we can do to normalise our immune function after that will probably help too.
But for someone with MS and a weakness for baked beans, hmmmmmm......
Peter
Thursday, February 05, 2009
Saturated fat and the FSA
Well it looks like the doner kebab defamation is just a tiny part of a more concerted attack on saturated fat by the UK Food Standards Agency. After Chris ruined my morning by forwarding this link (thanks Chris! No, seriously, we need to know that stuff like this is happening...) I spent some time browsing the FSA web site. Ugh.
A brief snippet looks like this, on colorectal cancer
"There are thought to be a substantial number of dietary factors, and factors related to the diet, which may modify the risk of colorectal cancer, e.g. diets rich in plant foods are thought to be protective. The mechanisms by which dietary factors can alter the risk, and a clear causal link between diet and the risk of colorectal cancer, are yet to be fully established"
Especially the way they say that there is no "fully established" mechanism or "clear causal link" between such practices as eating plants and colorectal health, there is an assumption being expressed here. Maybe I should email them some of the papers from the WHEL study. Or maybe emigrate. Unfortunately the FSA seems to rule Scotland too, so not much benefit from heading north of the border...
The main up side is that even in the USA it looks to be possible, as Richard shows, to buy good quality food, though it might not be available in every location. I can see us going the same route. Food elitism for the educated. The rest eating what JK describes as slave food.
Peter
A brief snippet looks like this, on colorectal cancer
"There are thought to be a substantial number of dietary factors, and factors related to the diet, which may modify the risk of colorectal cancer, e.g. diets rich in plant foods are thought to be protective. The mechanisms by which dietary factors can alter the risk, and a clear causal link between diet and the risk of colorectal cancer, are yet to be fully established"
Especially the way they say that there is no "fully established" mechanism or "clear causal link" between such practices as eating plants and colorectal health, there is an assumption being expressed here. Maybe I should email them some of the papers from the WHEL study. Or maybe emigrate. Unfortunately the FSA seems to rule Scotland too, so not much benefit from heading north of the border...
The main up side is that even in the USA it looks to be possible, as Richard shows, to buy good quality food, though it might not be available in every location. I can see us going the same route. Food elitism for the educated. The rest eating what JK describes as slave food.
Peter
Sunday, February 01, 2009
Hunting, gathering and starving
I like Ray Mears, or to be more accurate, I enjoyed the TV series he and prof Gordon Hillman made for the Beeb back in 2007. This is probably the one set of programs, other than the Simpsons, that I've watched in the last five years.
Their struggle to find, and then render edible, any sort of bulk carbohydrate in a temperate climate was amusing, especially when they offered the camera crew a taste of one of the less edible concoctions they had produced! The fish and the venison looked good.
The camera crew are very important. Whenever I see advertising for a jungle survival documentary I always think first of the poor camera crews in deepest Borneo or wherever, lugging all their food around as well as their film gear. It must be hard filming someone living off the land while subsisting on baked beans, but then television is a hard calling. Happily Survivorman is self filmed, which limits the suffering of film crews.
The post by Dr Davis had me thinking about evolution and survival, especially these lines:
"The Survivorman show documents the (self-filmed) 7-day adventures of Les Stroud, who is dropped into various remote corners of the world to survive on little but ingenuity and will to live. Starting without food or water, the Survivorman scrapes and scrambles in the wilderness for essentials to survive in habitats as far ranging as the Ecuadorian rainforest to sub-arctic Labrador"
Looking at this sort of TV entertainment (which is probably very good TV, I'd probably enjoy it) as a lead to how humans ate before civilisation strikes me as a bit flawed. There are actually a few places on Earth which are fundamentally uninhabitable, but then no one lives in them. If there is food and an even remotely hospitable environment, we seem to have moved in there long ago, before eventually being wiped out by the forefathers of TV crews.
But we weren't hungry, at least not for most of the time. Population size is controlled by food supply, humans live in tribes of between about 20 and 80 individuals and a tribe will have a territory of a size appropriate to support itself. The members of the tribe will be highly adept at obtaining adequate food supplies from that area. If this is impossible then the tribe would either be smaller or it would be somewhere else. Or dead.
Everyone alive today comes from a very, very long line of successful hunter gatherers. The only reason we are here is because what our distant ancestors did was highly successful. Anyone who's great great great great (X100)th's grandmother died of starvation before having any children is not here today. We are the product of success.
That is tribalism as it has always been. All tribal humans are fully equipped with absolutely everything they need in terms of utensils and knowledge to survive in reasonable comfort where they live. If the comfort is too great, humans will breed to use up the extra food supply. Tight times may be intermittent, but they function to reduce the population slightly and maintain the balance. Tribalism got us here and the phenomenon of a solitary struggle to survive in extreme conditions is a product of Civilisation. The struggle often comes from the ignorance of tribal survival knowledge. Even a group of 100 individuals do not make a tribe. Look what happens when you put over a hundred Royal Navy explorers on to the Arctic ice in 1845 without tribal knowledge or behaviour. Probably with complete disdain for the natives.
This is the unsuccessful Arctic expedition of Sir John Franklin, when all 120+ men perished. The accounts are quite depressing but what is most interesting is that in this extreme, lethal environment where explorers (at the then cutting edge of British naval ability) were starving to death, over 100 native Eskimo were living. Living as they always had, men and women, making babies and looking after toddlers, routine tribal stuff. To the Inuit, fully educated in tribal life of the area, Franklin's expedition died of starvation in a food aisle of Sainsburys. A good speculative account, such as could be made out in the 1930s, comes from Stefansson's "Unsolved Mysteries of the Arctic", cheap on Amazon and far more detailed than anything on Wikepedia, though it lacks some of the modern forensic evidence.
The follow-on from this is the complete lack of respect for the early explorers amongst the Inuit.
The Inuit were there in the Arctic, which was an extreme environment to the Victorians, because there was enough food, shelter and warmth for them to live family lives there. It may not always have been comfortable, but it was successful. They certainly were not struggling to survive. A man alone with a camera is not where they were ever at.
Peter
My favourite source of thought on human evolution is, as always, Daniel Quinn.
Their struggle to find, and then render edible, any sort of bulk carbohydrate in a temperate climate was amusing, especially when they offered the camera crew a taste of one of the less edible concoctions they had produced! The fish and the venison looked good.
The camera crew are very important. Whenever I see advertising for a jungle survival documentary I always think first of the poor camera crews in deepest Borneo or wherever, lugging all their food around as well as their film gear. It must be hard filming someone living off the land while subsisting on baked beans, but then television is a hard calling. Happily Survivorman is self filmed, which limits the suffering of film crews.
The post by Dr Davis had me thinking about evolution and survival, especially these lines:
"The Survivorman show documents the (self-filmed) 7-day adventures of Les Stroud, who is dropped into various remote corners of the world to survive on little but ingenuity and will to live. Starting without food or water, the Survivorman scrapes and scrambles in the wilderness for essentials to survive in habitats as far ranging as the Ecuadorian rainforest to sub-arctic Labrador"
Looking at this sort of TV entertainment (which is probably very good TV, I'd probably enjoy it) as a lead to how humans ate before civilisation strikes me as a bit flawed. There are actually a few places on Earth which are fundamentally uninhabitable, but then no one lives in them. If there is food and an even remotely hospitable environment, we seem to have moved in there long ago, before eventually being wiped out by the forefathers of TV crews.
But we weren't hungry, at least not for most of the time. Population size is controlled by food supply, humans live in tribes of between about 20 and 80 individuals and a tribe will have a territory of a size appropriate to support itself. The members of the tribe will be highly adept at obtaining adequate food supplies from that area. If this is impossible then the tribe would either be smaller or it would be somewhere else. Or dead.
Everyone alive today comes from a very, very long line of successful hunter gatherers. The only reason we are here is because what our distant ancestors did was highly successful. Anyone who's great great great great (X100)th's grandmother died of starvation before having any children is not here today. We are the product of success.
That is tribalism as it has always been. All tribal humans are fully equipped with absolutely everything they need in terms of utensils and knowledge to survive in reasonable comfort where they live. If the comfort is too great, humans will breed to use up the extra food supply. Tight times may be intermittent, but they function to reduce the population slightly and maintain the balance. Tribalism got us here and the phenomenon of a solitary struggle to survive in extreme conditions is a product of Civilisation. The struggle often comes from the ignorance of tribal survival knowledge. Even a group of 100 individuals do not make a tribe. Look what happens when you put over a hundred Royal Navy explorers on to the Arctic ice in 1845 without tribal knowledge or behaviour. Probably with complete disdain for the natives.
This is the unsuccessful Arctic expedition of Sir John Franklin, when all 120+ men perished. The accounts are quite depressing but what is most interesting is that in this extreme, lethal environment where explorers (at the then cutting edge of British naval ability) were starving to death, over 100 native Eskimo were living. Living as they always had, men and women, making babies and looking after toddlers, routine tribal stuff. To the Inuit, fully educated in tribal life of the area, Franklin's expedition died of starvation in a food aisle of Sainsburys. A good speculative account, such as could be made out in the 1930s, comes from Stefansson's "Unsolved Mysteries of the Arctic", cheap on Amazon and far more detailed than anything on Wikepedia, though it lacks some of the modern forensic evidence.
The follow-on from this is the complete lack of respect for the early explorers amongst the Inuit.
The Inuit were there in the Arctic, which was an extreme environment to the Victorians, because there was enough food, shelter and warmth for them to live family lives there. It may not always have been comfortable, but it was successful. They certainly were not struggling to survive. A man alone with a camera is not where they were ever at.
Peter
My favourite source of thought on human evolution is, as always, Daniel Quinn.
Saturday, January 31, 2009
Kebab update
Slightly mixed news on the kebab front for UK fans of saturated fat. While a single average doner can give you, if you're a woman, a cracking 346% of you nanny state saturated fat allowance, the down side is that some kebabs contain trans fats. While I'm probably not as phobic about trans fats as some (since reading this table here, where 2.2% of calories from trans fats was associated with significantly less progression of CAD than 1.0%! Discussed here), I'd still prefer not to eat them at all. Of course, with the level of disingenuity in this and similar reports, they could be refering to vaccenic acid and conjugated linoleic acid from ruminal bacteria. Who knows?
A wine glass and a half, nearly two, of fairly saturated animal fat seems to be an excellent base for a meal, although the article describes this as drinking, pardon my quick retch in the corner, that much "cooking oil"!!!!!
Main stream nutrition seems to have it in for kebabs at the moment. There must be something seriously good about that much fat to draw such fire...
This evening's kebab was very good.
Peter
A wine glass and a half, nearly two, of fairly saturated animal fat seems to be an excellent base for a meal, although the article describes this as drinking, pardon my quick retch in the corner, that much "cooking oil"!!!!!
Main stream nutrition seems to have it in for kebabs at the moment. There must be something seriously good about that much fat to draw such fire...
This evening's kebab was very good.
Peter
Monday, January 26, 2009
Recipe group
I run a Mac and everything on Facebook seems to take forever, when it doesn't freeze, so I don't use it as much as a lot of people seem to. But it does have some uses. My wife has set up an open group for posting gluten free recipes. It mostly came out of family members asking for recipes for food we have served, coupled with the growing realisation by many people that you don't have to feel rubbish all of the time and that eliminating gluten is a big step to feeling better. Family are all on Facebook so that's where the recipes ended up.
It's not particularly LC but of course most recipes can be adapted by simple moves such as not serving with rice or potatoes...
Anyway the group is here if anyone who is on facebook feels like adding recipes. All welcome. I've stuck most of those from the "Food" posts over there.
Peter
It's not particularly LC but of course most recipes can be adapted by simple moves such as not serving with rice or potatoes...
Anyway the group is here if anyone who is on facebook feels like adding recipes. All welcome. I've stuck most of those from the "Food" posts over there.
Peter
Monday, January 19, 2009
Kwasniewski paper
A friend has emailed me the full text of Pawel Grieb's paper documenting a number of physiological parameters of medium to long term Optimal Diet (OD) eaters in Poland, as pointed out by Flo and Stan. There are a few points worth making. The biggest mistake, BTW, is that the authors claim (correctly) that the OD diet aims for >70% fat with (incorrectly) "no restriction on the type of fat (saturated or unsaturated) or cholesterol level". I think they meant that the OD does not ban saturated fats. This is of course true but the impression given is that the OD allows "healthy" fats, which are, of course, inedible. So the heavy emphasis on saturated fats is missed by the paper. A pity, anyone might be left thinking corn oil is a human food...
The first positive aspect is that this is a multi author study, eleven authors from several medical centres/unversities. So it's not a one man band case report. I like that.
The second is that it is remarkably positive about the findings throughout. Even the elevated LDL cholesterol levels are not taken as extreme and are not trumpeted from the rooftops as the portent of imminent cardiovascular doom. So refreshing!
There aren't really any things in the paper which don't come through in the abstract. The one patient with a marginally elevated HOMA score had both glucose and insulin within lab reference ranges, just both were high enough to get the HOMA score out of the accepted physiological range. I don't think this is a big deal because there is one rather major point which the paper never addressed.
If you read JK about the OD he will point out that it is very rare for an individual to adopt and stick with the OD for the long term unless they have a serious medical problem which forces this. Of the 31 people studied, 22 had actually been on the OD for at least 3 years. So although the researchers express their wish for a comparable group of normal diet eating people, I would personally be much more interested in the lab data of 31 non OD patients, but with a variety of medical problems of sufficient seriousness that they SHOULD be on the Optimal Diet. Then we'd probably see some metabolic syndrome results and statin deficiencies!
Still, anyone seriously considering the OD could do worse than to read through this paper or to present it to their GP if they were getting grief about the risks involved in eating all of that (saturated) fat...
Peter
The first positive aspect is that this is a multi author study, eleven authors from several medical centres/unversities. So it's not a one man band case report. I like that.
The second is that it is remarkably positive about the findings throughout. Even the elevated LDL cholesterol levels are not taken as extreme and are not trumpeted from the rooftops as the portent of imminent cardiovascular doom. So refreshing!
There aren't really any things in the paper which don't come through in the abstract. The one patient with a marginally elevated HOMA score had both glucose and insulin within lab reference ranges, just both were high enough to get the HOMA score out of the accepted physiological range. I don't think this is a big deal because there is one rather major point which the paper never addressed.
If you read JK about the OD he will point out that it is very rare for an individual to adopt and stick with the OD for the long term unless they have a serious medical problem which forces this. Of the 31 people studied, 22 had actually been on the OD for at least 3 years. So although the researchers express their wish for a comparable group of normal diet eating people, I would personally be much more interested in the lab data of 31 non OD patients, but with a variety of medical problems of sufficient seriousness that they SHOULD be on the Optimal Diet. Then we'd probably see some metabolic syndrome results and statin deficiencies!
Still, anyone seriously considering the OD could do worse than to read through this paper or to present it to their GP if they were getting grief about the risks involved in eating all of that (saturated) fat...
Peter
Sunday, January 18, 2009
Rheumatoid arthritis and kidney stones
I just wanted to tidy up some loose ends I have in my head about rheumatoid arthritis, diet, kidney infections and kidney stones before I can get on to other ideas. Squiggs is over chickenpox and multiple on-call shifts are over for a while, so I just might get some blogging done...
My understanding of RA is based around Prof Ebringer's work, summarised here, linking urinary proteus infection to antibody production against its urease enzyme. The antibody against this bacterial protein cross reacts with the collagen in small joints and the end result is RA.
Why is RA so intractable? Why doesn't a short course of antibiotics clear up both the urinary proteus and the RA? There are several reasons.
As you well know, RA patients have a high incidence of kidney stones.
This is probably important and here's why:
Ammonia is pretty toxic to mammals, sufficiently toxic that we expend energy in joining two molecules of ammonia to one of carbon dioxide to give a relatively non toxic compound, urea. We can then excrete this with ease. Of course to a bacterium, with no concerns about the toxicity of ammonia to mammals, urea is just a food source. Splitting urea with a urease releases both the energy invested by the mammal and, unfortunately, the rather unpleasant ammonia.
What happens to the ammonmia? OK, it gets urinated out. But it also does two things on the way. First it renders the urine alkaline and second it provides NH4+ ions. So what? Both things are bad, but can be made worse.
There is also an association between RA and metabolic syndrome. Two of the hallmarks of metabolic syndrome are hyperglycaemia and hyperinsulinaemia. Importantly it is also associated with magnesium deficiency.
Because modern diets tend to be grossly magnesium deficient, you would expect the body to hang on to its magnesium as tightly as possible. But that doesn't seem to happen. Both hyperinsulinaemia and hyperglycaemia cause urinary magnesium loss.
So magnesuria in the face of magnesium deficiency is a feature of metabolic syndrome. What about a link between phosphate loss and insulin resistance? Metabolic syndrome is associated with phosphate loss in the urine too.
BTW: Coupled with the urinary calcium loss which also occurs, this is how you urinate your bones down the loo to get osteoporosis if you follow mainstream nutritional advice.
What do you get when you mix ammonium ions, magnesium ions and phosphate ions at an alkaline pH? Answer: Struvite urinary stones. Magnesium ammonium phosphate.
Struvite is a common form of urinary tract stone. It forms with ease when a person with metabolic syndrome (magnesium and phosphate in the urine) gets a low grade urinary infection with a urease producing bacterium (providing ammonium ions and an alkaline pH in the urine). Struvite is porous and harbours those very same urea splitting bacteria in a location where it is remarkably difficult to get antibiotics to penetrate... These stones can become enormous. They don't go away unless you sort out the metabolic syndrome as well as the urinary infection, which is often sub clinical and the person carrying it doesn't even know they have it. In fact the first warning sign many people with a kidney stone get is the sudden agony when the stone enters and stretches a ureter...
Proteus is one of the best struvite generating bacteria available. It's a normal commensal in the gut where it does well in the anaerobic conditions of the colon. It is highly motile and gets from the gut to the urinary tract with some ease. Ascending infection would be expected to be commoner in females than in males, owing to anatomical considerations. So RA should be commoner in females than males. It is.
So to summarise: A combination of metabolic syndrome with Proteus mirabilis infection is a generator of struvite stones. The bacterial enzyme used to extract energy from urea while generating ammonium ions has a peptide sequence remarkably similar to the collagen in small joints and is the best candidate to trigger rheumatoid arthritis. The process of urea splitting to release energy is an anaerobic reaction, the bacterium is just extracting the energy previously used to make the ammonia safe... Urea splitting is obviously well suited to the urinary tract, which is as anaerobic as the colon.
So antibiotic therapy tends to be limited in effect as it is difficult to clear the urinary infection in the presence of struvite stone(s) and difficult to dissolve the stones in the presence of metabolic syndrome. It is also essentially impossible to eliminate all proteus from the gut using antibiotics, provided the gut environment is convivial to the microbe. How does all of this fit in with diet?
I want to flick through the diet trials which have been used and those which haven't but perhaps should be. First thing to note is that, as detailed by Kjeldsen-Kragh, these trials are appallingly difficult to conduct.
Skoldstam's group started it all off back in the 1970s and looked at both fasting and vegetarianism. The fasting had some effect but there was always that niggly problem of only being able to use it for short periods and the vegetarian diet immediately re established the problem. They seem to have gone the vegetarian route as there was huge popular confidence in this approach at the time. It didn't work.
Another swedish group did that vegan diet diet study which was initially gluten free and found some effect, but only in the subgroup who adhered well to the diet (lapsing from the diet shows as the production of anti gliadin antibodies, only those who stayed anti gliadin antibody negative improved). You can't say from this study if it was the successful gluten avoidance which worked or the vegan aspect. But I can guess! They didn't look at proteus.
Kjeldsen-Kragh's group in Norway used a similar vegan gluten free diet followed by a vegetarian diet with some success. They were associated with Ebringer's proteus group from King's College. Here it was the subgroup which lowered both faecal proteus count and blood anti proteus IgG count which improved. They didn't look at anti gliadin antibodies but the initial diet was gluten free.
Skoldstam's group has more recently tried applying the Mediterranean Diet, at least as Mediterranian as envisaged in the Lyon heart study diet, based around canola oil gloop. Again they got some improvement, possibly due to improved lipid composition of the diet (more omega threes) rather than changing the disease process itself. I doesn't look like remission to me.
So how do you integrate all of this in to one concept? My feeling is that people will have to have a genetic predisposition. This will relate to those human leucocyte antigens known to be associated with RA (there are several). No one can change these and they simply set limits on what you can "get away with" in terms of your internal environment. These leucocyte antigens determine what you see as self or non-self. I don't see them as the "cause" per se. In general I feel genetics is phenomenally important in determining how we "break" under adverse conditions. Your genetics don't do the breaking. Mostly your diet does the breaking. Another post there to clarify that.
They have to have metabolic syndrome. This is side step-able.
They have to have intestinal dysbiosis with a predominance of proteus in their colonic bacteria. The best way to get this is probably to eat gluten but clearly gluten is not the be all and end all of the problem.
They have to have recurrent or continuous low grade urinary tract proteus infection, probably without signs and probably derived from their colonic bacterial population.
There may well be background maintenance of the immune response to proteus due to its ability to cross in to the blood stream directly from the gut and so be seen by the immune system, without necessarily invading the urinary tract. I think it is unlikely to be around and expressing urease for very long in the systemic circulation.
So that sums up the diets and the problems to me. It looks like you need to side step the metabolic syndrome while damping down proteus levels.
So which diet is out there in the mainstream and just crying out to be tried in RA?
Let's go back to Ray Audette and Neanderthin (bit of a collector's item by the current used prices!). This little book was not in my early reading but I've had a copy for some time. It's an interesting read, especially the early sections. Here Audette describes the miseries of his life with RA, which were later compounded by the additional miseries of type two diabetes. He did the paleo thing for his diabetes and virtually immediately ate his way to normoglycaemia. The RA went the same way as the diabetes.
Anyone reading Stephan's blog on diabetes trials will remember Lindeberg's paleo diet trial for human type two diabetes. Essentially, Lindeberg replicated Audette's approach in a bigger group than n=1. It was certainly quite effective for type two diabetes, despite not being a particularly LC approach. I suspect that reducing fruit consumption would improve Lindeberg's diet a lot, but it's pretty good as it is.
So what I would love to see is Lindeberg's diet applied to RA.
Okay, I'd really rather see the Optimal Diet applied to RA, but I'm not waiting around for that one...
Peter
My understanding of RA is based around Prof Ebringer's work, summarised here, linking urinary proteus infection to antibody production against its urease enzyme. The antibody against this bacterial protein cross reacts with the collagen in small joints and the end result is RA.
Why is RA so intractable? Why doesn't a short course of antibiotics clear up both the urinary proteus and the RA? There are several reasons.
As you well know, RA patients have a high incidence of kidney stones.
This is probably important and here's why:
Ammonia is pretty toxic to mammals, sufficiently toxic that we expend energy in joining two molecules of ammonia to one of carbon dioxide to give a relatively non toxic compound, urea. We can then excrete this with ease. Of course to a bacterium, with no concerns about the toxicity of ammonia to mammals, urea is just a food source. Splitting urea with a urease releases both the energy invested by the mammal and, unfortunately, the rather unpleasant ammonia.
What happens to the ammonmia? OK, it gets urinated out. But it also does two things on the way. First it renders the urine alkaline and second it provides NH4+ ions. So what? Both things are bad, but can be made worse.
There is also an association between RA and metabolic syndrome. Two of the hallmarks of metabolic syndrome are hyperglycaemia and hyperinsulinaemia. Importantly it is also associated with magnesium deficiency.
Because modern diets tend to be grossly magnesium deficient, you would expect the body to hang on to its magnesium as tightly as possible. But that doesn't seem to happen. Both hyperinsulinaemia and hyperglycaemia cause urinary magnesium loss.
So magnesuria in the face of magnesium deficiency is a feature of metabolic syndrome. What about a link between phosphate loss and insulin resistance? Metabolic syndrome is associated with phosphate loss in the urine too.
BTW: Coupled with the urinary calcium loss which also occurs, this is how you urinate your bones down the loo to get osteoporosis if you follow mainstream nutritional advice.
What do you get when you mix ammonium ions, magnesium ions and phosphate ions at an alkaline pH? Answer: Struvite urinary stones. Magnesium ammonium phosphate.
Struvite is a common form of urinary tract stone. It forms with ease when a person with metabolic syndrome (magnesium and phosphate in the urine) gets a low grade urinary infection with a urease producing bacterium (providing ammonium ions and an alkaline pH in the urine). Struvite is porous and harbours those very same urea splitting bacteria in a location where it is remarkably difficult to get antibiotics to penetrate... These stones can become enormous. They don't go away unless you sort out the metabolic syndrome as well as the urinary infection, which is often sub clinical and the person carrying it doesn't even know they have it. In fact the first warning sign many people with a kidney stone get is the sudden agony when the stone enters and stretches a ureter...
Proteus is one of the best struvite generating bacteria available. It's a normal commensal in the gut where it does well in the anaerobic conditions of the colon. It is highly motile and gets from the gut to the urinary tract with some ease. Ascending infection would be expected to be commoner in females than in males, owing to anatomical considerations. So RA should be commoner in females than males. It is.
So to summarise: A combination of metabolic syndrome with Proteus mirabilis infection is a generator of struvite stones. The bacterial enzyme used to extract energy from urea while generating ammonium ions has a peptide sequence remarkably similar to the collagen in small joints and is the best candidate to trigger rheumatoid arthritis. The process of urea splitting to release energy is an anaerobic reaction, the bacterium is just extracting the energy previously used to make the ammonia safe... Urea splitting is obviously well suited to the urinary tract, which is as anaerobic as the colon.
So antibiotic therapy tends to be limited in effect as it is difficult to clear the urinary infection in the presence of struvite stone(s) and difficult to dissolve the stones in the presence of metabolic syndrome. It is also essentially impossible to eliminate all proteus from the gut using antibiotics, provided the gut environment is convivial to the microbe. How does all of this fit in with diet?
I want to flick through the diet trials which have been used and those which haven't but perhaps should be. First thing to note is that, as detailed by Kjeldsen-Kragh, these trials are appallingly difficult to conduct.
Skoldstam's group started it all off back in the 1970s and looked at both fasting and vegetarianism. The fasting had some effect but there was always that niggly problem of only being able to use it for short periods and the vegetarian diet immediately re established the problem. They seem to have gone the vegetarian route as there was huge popular confidence in this approach at the time. It didn't work.
Another swedish group did that vegan diet diet study which was initially gluten free and found some effect, but only in the subgroup who adhered well to the diet (lapsing from the diet shows as the production of anti gliadin antibodies, only those who stayed anti gliadin antibody negative improved). You can't say from this study if it was the successful gluten avoidance which worked or the vegan aspect. But I can guess! They didn't look at proteus.
Kjeldsen-Kragh's group in Norway used a similar vegan gluten free diet followed by a vegetarian diet with some success. They were associated with Ebringer's proteus group from King's College. Here it was the subgroup which lowered both faecal proteus count and blood anti proteus IgG count which improved. They didn't look at anti gliadin antibodies but the initial diet was gluten free.
Skoldstam's group has more recently tried applying the Mediterranean Diet, at least as Mediterranian as envisaged in the Lyon heart study diet, based around canola oil gloop. Again they got some improvement, possibly due to improved lipid composition of the diet (more omega threes) rather than changing the disease process itself. I doesn't look like remission to me.
So how do you integrate all of this in to one concept? My feeling is that people will have to have a genetic predisposition. This will relate to those human leucocyte antigens known to be associated with RA (there are several). No one can change these and they simply set limits on what you can "get away with" in terms of your internal environment. These leucocyte antigens determine what you see as self or non-self. I don't see them as the "cause" per se. In general I feel genetics is phenomenally important in determining how we "break" under adverse conditions. Your genetics don't do the breaking. Mostly your diet does the breaking. Another post there to clarify that.
They have to have metabolic syndrome. This is side step-able.
They have to have intestinal dysbiosis with a predominance of proteus in their colonic bacteria. The best way to get this is probably to eat gluten but clearly gluten is not the be all and end all of the problem.
They have to have recurrent or continuous low grade urinary tract proteus infection, probably without signs and probably derived from their colonic bacterial population.
There may well be background maintenance of the immune response to proteus due to its ability to cross in to the blood stream directly from the gut and so be seen by the immune system, without necessarily invading the urinary tract. I think it is unlikely to be around and expressing urease for very long in the systemic circulation.
So that sums up the diets and the problems to me. It looks like you need to side step the metabolic syndrome while damping down proteus levels.
So which diet is out there in the mainstream and just crying out to be tried in RA?
Let's go back to Ray Audette and Neanderthin (bit of a collector's item by the current used prices!). This little book was not in my early reading but I've had a copy for some time. It's an interesting read, especially the early sections. Here Audette describes the miseries of his life with RA, which were later compounded by the additional miseries of type two diabetes. He did the paleo thing for his diabetes and virtually immediately ate his way to normoglycaemia. The RA went the same way as the diabetes.
Anyone reading Stephan's blog on diabetes trials will remember Lindeberg's paleo diet trial for human type two diabetes. Essentially, Lindeberg replicated Audette's approach in a bigger group than n=1. It was certainly quite effective for type two diabetes, despite not being a particularly LC approach. I suspect that reducing fruit consumption would improve Lindeberg's diet a lot, but it's pretty good as it is.
So what I would love to see is Lindeberg's diet applied to RA.
Okay, I'd really rather see the Optimal Diet applied to RA, but I'm not waiting around for that one...
Peter
Sunday, January 04, 2009
Maternal Diet Affects Offspring Preferences
OMG it's true!
I should have snapped an up to date pic of him demolishing either my egg yolks or my cream today, but the camera was out of reach and I was trying to keep the bulk of the cream off of the carpet in the sitting room! Had other concerns about no lunch left for me too. Anyway...
I've been trying to make head or tail of this study, sent to me by a couple of people off blog.
It's not easy. There is no information about what was done, physiologically, to the mothers of the metabolically damaged rat pups. If you don't know that, you can't work back to what the intrauterine environment was likely to have been for the rat pups. The logical conclusion seems to be that you should not eat, when pregnant, a 50% fat diet if the rest of your non protein calories are a sucrose, maltodextrin and corn starch mix. Probably you shouldn't eat huge amounts of it either. That's a reasonable approach to life in general. If sucrose derived fructose causes hepatic insulin resistance, with hyperglycaemia from the readily available glucose, you are not going to burn fat very well. But I can't get at the data from the earlier studies by this group to see what the physiology of the dams was like.
But one of the references they did cite, which does have full text access, was this one with a beautiful summing up in the conclusion (I just love the beacon carried by the word "inappropriate" and the phrase "looked as thin as"). Talk about nailing your colours to the mast:
"In summary, this study in Wistar rats gives evidence of a metabolic imprinting of the progeny born to dams fed an inappropriate high-fat diet since 6 wk before mating, which did not became overtly obese before gestation and even lost more body weight than control dams at the end of lactation. The long-term metabolic consequence of this maternal imprinting was an altered hypothalamic leptin signaling in male and female offspring which, however, looked as thin as controls in adulthood, even when weaned onto the HF diet"
That's pretty awful. Deranged leptin signalling. And that's just on 40% fat. Imagine the awful effects of our 70-80% fat diet on our son.... Arghhhhhhh. Oh, but despite deranged leptin signaling neither the mothers nor their offspring became obese, even following the offspring through to adulthood on a high fat diet.... Hmmmmmm
So let's just skip the biased discussion and have a look in the RESULTS section. If we ignore the really clever stuff about STAT-3 signaling and gene expression, what are the end results in terms that we might observe in my son?
Table 3 of the results section is here.
First it's males at the top and females at the bottom. We want the left hand column throughout for the rats fed mostly on sugar (maternally in pregnancy and as their post weaning diet) and the extreme right hand column for the rats fed fat throughout the study. You can browse the middle columns if you want to see what crossovers do, but let's keep it simple. Many of the changes do not reach statistical significance. Just look at the trends in these small groups.
Males: High fat diet produces:
An extra 7g of body weight out of 350ish grams. Bad? Biologically significant? I weighed 120lb as a teenager. Obesity angst at 123lb? I think not.
LOWER triglycerides, probably Good.
LOWER cholesterol (who cares? But these researchers should have considered this Good)
HIGHER glucose, probably Bad, but remember physiological insulin resistance in HF feeding.
LOWER insulin. Very Good.
HIGHER leptin, hence the conclusions. Bad, but not very much higher and well within physiological limits
LOWER HOMA score. This is Very Good.
In the females the high fat feeding results are pretty much the same as or better than the chow fed rats. Especially the HOMA estimate of insulin sensitivity.
So in this study offspring of the 40% fat fed dams, fed a 40% fat diet themselves, did pretty well compared to those fed 4% fat.
How does this lead the the conclusions reached by the researchers? I dunno.
More importantly, how did the New York group (Chang et al) manage to successfully mangle the metabolism of a group of pups fed 50% fat vs those fed 25% fat? How can 40% be as good or better than 4%, but 50% be worse than 25%?
Well, I don't know. One of life's mysteries.
But I'm impressed at the skill of the Chang et al in managing to develop a model which holds up their preconceptions.
Presumably, if the study of Chang et al is correct, it explains why the Masai, Inuit and Tokelau islanders all died out of obesity when they started eating more than 40% of their calories from fat on a real food diet.
Oh, they didn't?
Back to drawing board then.
But I still wonder how she did it (Chang, that is).
Oh, and the other seriously important conclusion is that a high fat diet perinatally produces what looks to be a neurotransmitter pattern for fat preference. This is considered to be a Bad Thing. But not by me. A fat preference is a GOOD THING.
Remember Sweden! "Healthy 4 year-olds who eat lots of fat weigh less" and "More fat linked to less weight in kids study". Are you still fat phobic?
Now a sucrose preference... That would be bad, but non exposure just might lead to non preference. I hope so, but I'm not expecting Chang to find out for me.
Peter
I should have snapped an up to date pic of him demolishing either my egg yolks or my cream today, but the camera was out of reach and I was trying to keep the bulk of the cream off of the carpet in the sitting room! Had other concerns about no lunch left for me too. Anyway...
I've been trying to make head or tail of this study, sent to me by a couple of people off blog.
It's not easy. There is no information about what was done, physiologically, to the mothers of the metabolically damaged rat pups. If you don't know that, you can't work back to what the intrauterine environment was likely to have been for the rat pups. The logical conclusion seems to be that you should not eat, when pregnant, a 50% fat diet if the rest of your non protein calories are a sucrose, maltodextrin and corn starch mix. Probably you shouldn't eat huge amounts of it either. That's a reasonable approach to life in general. If sucrose derived fructose causes hepatic insulin resistance, with hyperglycaemia from the readily available glucose, you are not going to burn fat very well. But I can't get at the data from the earlier studies by this group to see what the physiology of the dams was like.
But one of the references they did cite, which does have full text access, was this one with a beautiful summing up in the conclusion (I just love the beacon carried by the word "inappropriate" and the phrase "looked as thin as"). Talk about nailing your colours to the mast:
"In summary, this study in Wistar rats gives evidence of a metabolic imprinting of the progeny born to dams fed an inappropriate high-fat diet since 6 wk before mating, which did not became overtly obese before gestation and even lost more body weight than control dams at the end of lactation. The long-term metabolic consequence of this maternal imprinting was an altered hypothalamic leptin signaling in male and female offspring which, however, looked as thin as controls in adulthood, even when weaned onto the HF diet"
That's pretty awful. Deranged leptin signalling. And that's just on 40% fat. Imagine the awful effects of our 70-80% fat diet on our son.... Arghhhhhhh. Oh, but despite deranged leptin signaling neither the mothers nor their offspring became obese, even following the offspring through to adulthood on a high fat diet.... Hmmmmmm
So let's just skip the biased discussion and have a look in the RESULTS section. If we ignore the really clever stuff about STAT-3 signaling and gene expression, what are the end results in terms that we might observe in my son?
Table 3 of the results section is here.
First it's males at the top and females at the bottom. We want the left hand column throughout for the rats fed mostly on sugar (maternally in pregnancy and as their post weaning diet) and the extreme right hand column for the rats fed fat throughout the study. You can browse the middle columns if you want to see what crossovers do, but let's keep it simple. Many of the changes do not reach statistical significance. Just look at the trends in these small groups.
Males: High fat diet produces:
An extra 7g of body weight out of 350ish grams. Bad? Biologically significant? I weighed 120lb as a teenager. Obesity angst at 123lb? I think not.
LOWER triglycerides, probably Good.
LOWER cholesterol (who cares? But these researchers should have considered this Good)
HIGHER glucose, probably Bad, but remember physiological insulin resistance in HF feeding.
LOWER insulin. Very Good.
HIGHER leptin, hence the conclusions. Bad, but not very much higher and well within physiological limits
LOWER HOMA score. This is Very Good.
In the females the high fat feeding results are pretty much the same as or better than the chow fed rats. Especially the HOMA estimate of insulin sensitivity.
So in this study offspring of the 40% fat fed dams, fed a 40% fat diet themselves, did pretty well compared to those fed 4% fat.
How does this lead the the conclusions reached by the researchers? I dunno.
More importantly, how did the New York group (Chang et al) manage to successfully mangle the metabolism of a group of pups fed 50% fat vs those fed 25% fat? How can 40% be as good or better than 4%, but 50% be worse than 25%?
Well, I don't know. One of life's mysteries.
But I'm impressed at the skill of the Chang et al in managing to develop a model which holds up their preconceptions.
Presumably, if the study of Chang et al is correct, it explains why the Masai, Inuit and Tokelau islanders all died out of obesity when they started eating more than 40% of their calories from fat on a real food diet.
Oh, they didn't?
Back to drawing board then.
But I still wonder how she did it (Chang, that is).
Oh, and the other seriously important conclusion is that a high fat diet perinatally produces what looks to be a neurotransmitter pattern for fat preference. This is considered to be a Bad Thing. But not by me. A fat preference is a GOOD THING.
Remember Sweden! "Healthy 4 year-olds who eat lots of fat weigh less" and "More fat linked to less weight in kids study". Are you still fat phobic?
Now a sucrose preference... That would be bad, but non exposure just might lead to non preference. I hope so, but I'm not expecting Chang to find out for me.
Peter
Thursday, January 01, 2009
DHA in rats
I had a slog through this paper and this paper, trying to tease out a little more on DHA and free radical damage.
DHA enriched brains are substantially protected against the free radical damage which occurs in response to reperfusion after exposure to an hypoxic state. This is unexpected in view of the host of oxidisable double bonds in the DHA molecule. Oxidative damage is what happens if you throw DHA on to cell cultures and challenge them with free radicals. It also happens in your bloodstream when you drink 30ml of fish oil unless you dose up on vitamin E at the same time. So we can say that the DHA per se, in triglycerides and in cells, generates and propagates free radicals. This is probably Bad.
But if you supply DHA (as the ethyl ester injected in to the amniotic fluid) to an intact rat foetus it concentrates it in the brain and you get neuroprotection... How come?
Hydroxyl radicals are one of the nastier oxygen derived free radicals and there is a 70% reduction of their generation in DHA enriched brain tissue from these rat pups.
Supplying oleate enrichment does nothing for hydroxyl reduction and EPA enrichment is not as good as using DHA, despite the conversion of EPA in to DHA... That is, it's not the DHA per se that matters, because the amount of DHA was increased equally by EPA as by DHA but the DHA supplemented rats were better protected than those given EPA.
The explanation is in the phospholipids.
A triglyceride is, quite obviously, a glycerol molecule with three fatty acids attached. DHA here is unstable without vitamin E. A phospholipid is what cell membranes are made up of and consist of that same glycerol molecule with two fatty acids attached but with a very interesting and highly water soluble moiety in the place of the third fatty acid. This is a phosphate group plus a small organic molecule of various types. They make up the lipid bilayer, the phosphate grouping lying either inside or outside the cell in the aqueous phase and the lipids snuggled up in the hydrophobic structure of the cell membrane itself. With beloved cholesterol to regulate fluidity and perform about a million other functions.
The small organic molecules matter. We are interested in ethanolamine and serine, two amino groupings attached to the phosphate to give phosphatidylethanolamine (PE) and phopshatidylserine (PS).
Both PE and PS are the preferred phospholipids to which DHA is attached, and DHA pre treatement (but neither oleate nor EPA) increases the percentage of these phospholipids in the brain cell membranes.
Summary: DHA pretreatment increases DHA, PE and PS and they all live together quite happily.
PS is an iron chelator. Iron is superb for free radical propagation. It can't do this when it's been grabbed by PS.
PE containing phospholipid is an effective antioxidant, it grabs free radicals and there the free radical propagation ends. PE also commonly contains a strange lipid called a vinyl alcohol, making it a substance called plasmalogen. The extra double bond in the vinyl group makes it an effective antioxidant. Not all double bonds are bad.
What conclusions can you draw from this type of experiment, very artificial though it is? The impression I get is that DHA is useful to brain tissue, yet it is clearly unstable on an oxidative damage basis. The obvious answer is that the brain looks after DHA by sticking a set of peroxidation protectors on to the molecule. It can then use DHA for whatever it needs to, without worrying about all of those lipid peroxides which we might see were we to drink 30ml of unprotected fish oil...
Peter
DHA enriched brains are substantially protected against the free radical damage which occurs in response to reperfusion after exposure to an hypoxic state. This is unexpected in view of the host of oxidisable double bonds in the DHA molecule. Oxidative damage is what happens if you throw DHA on to cell cultures and challenge them with free radicals. It also happens in your bloodstream when you drink 30ml of fish oil unless you dose up on vitamin E at the same time. So we can say that the DHA per se, in triglycerides and in cells, generates and propagates free radicals. This is probably Bad.
But if you supply DHA (as the ethyl ester injected in to the amniotic fluid) to an intact rat foetus it concentrates it in the brain and you get neuroprotection... How come?
Hydroxyl radicals are one of the nastier oxygen derived free radicals and there is a 70% reduction of their generation in DHA enriched brain tissue from these rat pups.
Supplying oleate enrichment does nothing for hydroxyl reduction and EPA enrichment is not as good as using DHA, despite the conversion of EPA in to DHA... That is, it's not the DHA per se that matters, because the amount of DHA was increased equally by EPA as by DHA but the DHA supplemented rats were better protected than those given EPA.
The explanation is in the phospholipids.
A triglyceride is, quite obviously, a glycerol molecule with three fatty acids attached. DHA here is unstable without vitamin E. A phospholipid is what cell membranes are made up of and consist of that same glycerol molecule with two fatty acids attached but with a very interesting and highly water soluble moiety in the place of the third fatty acid. This is a phosphate group plus a small organic molecule of various types. They make up the lipid bilayer, the phosphate grouping lying either inside or outside the cell in the aqueous phase and the lipids snuggled up in the hydrophobic structure of the cell membrane itself. With beloved cholesterol to regulate fluidity and perform about a million other functions.
The small organic molecules matter. We are interested in ethanolamine and serine, two amino groupings attached to the phosphate to give phosphatidylethanolamine (PE) and phopshatidylserine (PS).
Both PE and PS are the preferred phospholipids to which DHA is attached, and DHA pre treatement (but neither oleate nor EPA) increases the percentage of these phospholipids in the brain cell membranes.
Summary: DHA pretreatment increases DHA, PE and PS and they all live together quite happily.
PS is an iron chelator. Iron is superb for free radical propagation. It can't do this when it's been grabbed by PS.
PE containing phospholipid is an effective antioxidant, it grabs free radicals and there the free radical propagation ends. PE also commonly contains a strange lipid called a vinyl alcohol, making it a substance called plasmalogen. The extra double bond in the vinyl group makes it an effective antioxidant. Not all double bonds are bad.
What conclusions can you draw from this type of experiment, very artificial though it is? The impression I get is that DHA is useful to brain tissue, yet it is clearly unstable on an oxidative damage basis. The obvious answer is that the brain looks after DHA by sticking a set of peroxidation protectors on to the molecule. It can then use DHA for whatever it needs to, without worrying about all of those lipid peroxides which we might see were we to drink 30ml of unprotected fish oil...
Peter
Cholesterol: LDL in Oslo
There is a group of doctors in Oslo who run a coronary care unit and, as part of their day to day work, they do quite a bit of coronary arteriography. They put in the dye and look at the arteries. It's part of their job. I assume they are quite good at it.
They did something very, very strange and then wrote a letter to the editor of the JACC about it, presumably because they couldn't get it published in any other way.
This is what they did.
They simply selected sequential patients with LDL cholesterol scores below 2.7mmol/l. In the old terms that so much cardiac work is published in I think this means an LDL of below 100mg/dl. Quite why anyone with an LDL this low would need a coronary arteriogram is a good question to ask anyone who believes in the lipid hypothesis.
They ignored all people with LDL concentrations from 2.7 to 4.5mmol/l but did enroll all people with an LDL >4.5mmol/l, that is above about 180mg/dl.
So they then had two groups of people, those at catastrophic risk of LDL-blocked-arteries and those with so little LDL they couldn't stick a tail to a donkey, or absorb a bacterial toxin, with it.
They did the scheduled angiography and checked how many patients had >70% blockage of at least two coronary arteries in each group.
Guess what: LDL cholesterol doesn't matter. They recruited 47 patients with low LDL-C, of whom 21 had significant CAD. They got 46 high LDL-C patients, of whom 24 turned out to have CAD.
I know that this is a calculated LDL value, not a particle number etc etc etc but this calculated guestimate is the basis of the lipid hypothesis in its current persona, until it gets its next adhoc makeover.
To a cholesterol sceptic that's pretty much what you would expect, serious heart disease affects people pretty well independently of LDL value and no one should be surprised at this. There is nothing strange in the study so far.
The really weird thing that the Oslo group did was this, wait for it:
They went looking for what might really cause heart disease!
Where do you start looking in a wide open field like this? It's almost like having virgin soil to plough...
It turns out that it's pretty easy to differentiate the groups with heart disease from those without. Here is a list of things which are significantly different between the patient groups with heart disease and those without it, in no particular order:
Ability of arterioles to vasodilate in response to applied acetylcholine
Level of von Willebrand factor (a platelet adhesion factor)
Level of hsCRP
BTW: Remember the JUPITER fiasco? Elevated hsCRP in the Oslo study marked out the groups with at least two severely stenosed coronary arteries, irrespective of LDL level. JUPITER subjects with elevated hsCRP would fit in to the low LDL-C with severe CHD grouping in this study. That is; they quite probably had CHD. Back to Oslo:
Level of TNF alpha
There is an inverse effect of interleukin 10 (it's anti inflammatory)
Enhanced platelet activation as assessed by soluble CD40 ligand
Levels of endothelial and platelet activation as assessed by soluble P selectin
Blood flow response to sodium nitroprusside couldn't distinguish CHD groups from non CHD groups any more than LDL-C could.
Exactly what all of these things mean at the molecular level is not too important, though I'd bet a fair few of them are controlled by NFkappaB (hence by hyperglycaemia and hyperinsulinaemia). What matters to me is that (a) LDL cholesterol doesn't matter and (b) there are at least eight researchers in the cardiology community who are looking for the cause of CHD.
Thank goodness someone is. Good luck to them.
Peter
They did something very, very strange and then wrote a letter to the editor of the JACC about it, presumably because they couldn't get it published in any other way.
This is what they did.
They simply selected sequential patients with LDL cholesterol scores below 2.7mmol/l. In the old terms that so much cardiac work is published in I think this means an LDL of below 100mg/dl. Quite why anyone with an LDL this low would need a coronary arteriogram is a good question to ask anyone who believes in the lipid hypothesis.
They ignored all people with LDL concentrations from 2.7 to 4.5mmol/l but did enroll all people with an LDL >4.5mmol/l, that is above about 180mg/dl.
So they then had two groups of people, those at catastrophic risk of LDL-blocked-arteries and those with so little LDL they couldn't stick a tail to a donkey, or absorb a bacterial toxin, with it.
They did the scheduled angiography and checked how many patients had >70% blockage of at least two coronary arteries in each group.
Guess what: LDL cholesterol doesn't matter. They recruited 47 patients with low LDL-C, of whom 21 had significant CAD. They got 46 high LDL-C patients, of whom 24 turned out to have CAD.
I know that this is a calculated LDL value, not a particle number etc etc etc but this calculated guestimate is the basis of the lipid hypothesis in its current persona, until it gets its next adhoc makeover.
To a cholesterol sceptic that's pretty much what you would expect, serious heart disease affects people pretty well independently of LDL value and no one should be surprised at this. There is nothing strange in the study so far.
The really weird thing that the Oslo group did was this, wait for it:
They went looking for what might really cause heart disease!
Where do you start looking in a wide open field like this? It's almost like having virgin soil to plough...
It turns out that it's pretty easy to differentiate the groups with heart disease from those without. Here is a list of things which are significantly different between the patient groups with heart disease and those without it, in no particular order:
Ability of arterioles to vasodilate in response to applied acetylcholine
Level of von Willebrand factor (a platelet adhesion factor)
Level of hsCRP
BTW: Remember the JUPITER fiasco? Elevated hsCRP in the Oslo study marked out the groups with at least two severely stenosed coronary arteries, irrespective of LDL level. JUPITER subjects with elevated hsCRP would fit in to the low LDL-C with severe CHD grouping in this study. That is; they quite probably had CHD. Back to Oslo:
Level of TNF alpha
There is an inverse effect of interleukin 10 (it's anti inflammatory)
Enhanced platelet activation as assessed by soluble CD40 ligand
Levels of endothelial and platelet activation as assessed by soluble P selectin
Blood flow response to sodium nitroprusside couldn't distinguish CHD groups from non CHD groups any more than LDL-C could.
Exactly what all of these things mean at the molecular level is not too important, though I'd bet a fair few of them are controlled by NFkappaB (hence by hyperglycaemia and hyperinsulinaemia). What matters to me is that (a) LDL cholesterol doesn't matter and (b) there are at least eight researchers in the cardiology community who are looking for the cause of CHD.
Thank goodness someone is. Good luck to them.
Peter
Back on line
Happy Christmas and New Year all,
The Winter Solstice turned out to be on call tending to a dog with an acute abdomen, so no bonfires for me... Christmas was far more successful and we had a great time. Hee hee, 7 days without net access and now back at work and in the middle of a 5 day stint.
As we were going to be on the coast I took the 'yak. Almost didn't bother as the forecast was pretty awful for surf.
Wind went hard Easterly on Christmas day and by Monday there was an usable swell with faces of about 3-4 feet. Not epic but fun.
This is First Bay
There is a beacon post (you can see its shadow on the water) on the northern end of the right hand reef which, with the tide a foot or two lower than in this Multimap image, is the place to hang out to pick up a wave. You can almost always get a left hand run in to the shelter of the reef and a then a rip current carries you back out to the post... Cool place. Me, three board surfers and a seal. Clear blue sky, bright sunshine and the frost was just about gone at mid day. Magic, even if the colour of the North Sea is always that deep brown in Winter...
Couple of post I wrote off line to put up soon and then I'll try for the comments...
Happy New Year
Peter
The Winter Solstice turned out to be on call tending to a dog with an acute abdomen, so no bonfires for me... Christmas was far more successful and we had a great time. Hee hee, 7 days without net access and now back at work and in the middle of a 5 day stint.
As we were going to be on the coast I took the 'yak. Almost didn't bother as the forecast was pretty awful for surf.
Wind went hard Easterly on Christmas day and by Monday there was an usable swell with faces of about 3-4 feet. Not epic but fun.
This is First Bay
There is a beacon post (you can see its shadow on the water) on the northern end of the right hand reef which, with the tide a foot or two lower than in this Multimap image, is the place to hang out to pick up a wave. You can almost always get a left hand run in to the shelter of the reef and a then a rip current carries you back out to the post... Cool place. Me, three board surfers and a seal. Clear blue sky, bright sunshine and the frost was just about gone at mid day. Magic, even if the colour of the North Sea is always that deep brown in Winter...
Couple of post I wrote off line to put up soon and then I'll try for the comments...
Happy New Year
Peter
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".
Peter
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.
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".
Peter
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!
Peter
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!
Peter
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?
Peter
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?
Peter
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.
Peter
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.
Peter
Monday, December 08, 2008
Update
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.
Peter
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.
Peter
Subscribe to:
Posts (Atom)
