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
Saturday, January 31, 2009
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
Saturday, November 29, 2008
Eggs are here (well, one is anyway)
Some semblance of posting on Hyperlipid will probably resume late next week but, in the mean time, Penelope (Squiggs' favourite chicken, the one who lets herself be caught, cuddled and carried around) has laid an egg, our first ever home produced egg. A decent size for a first egg from a young chicken!
Not only that but it was a double yolker...
Guess who ate it!
Back when life gets in to more of a normal routine and I can get to answer some of the off blog emails and do some blogging too.
Peter
Not only that but it was a double yolker...
Guess who ate it!
Back when life gets in to more of a normal routine and I can get to answer some of the off blog emails and do some blogging too.
Peter
Tuesday, November 11, 2008
Cholesterol JUPITER link
For an absolute, all singing, all dancing excellent review of the JUPITER trial go read Sandy Szwarc over at Junkfood Science.
Don't expect to be done in 2 minutes!
Peter
Don't expect to be done in 2 minutes!
Peter
Monday, November 10, 2008
Pellagra and SMON
Back in the early 1900s it was patently obvious that pellagra (vitamin B3 deficiency) was a contageous disease.
You have to ask exactly how a disease caused by a vitamin deficiency could remotely have been classed as contagious, and exactly why this idea should have been so vigorously defended by the medical profession. To get the whole story you really need something like Alan Kraut's biography of Goldberger. I found it an interesting read, particularly the lengths Goldberger (and his family) went to in order to demonstrate on themselves that pellagra was not contagious, and quite how his wife put up with coming such a distant second place to his work is quite beyond me. Anyway, it turned out that the "Scourge of the South" could be cured by decent food, eventually replaceable by a teaspoonful of brewers yeast a day.
Just imagine heart disease being cured by a pint of cream a day...
How did the medical profession take this to phenomenal and meticulously tested hypothesis? If you think the AHA hated Dr Atkins, that has nothing of the violence of the reaction against Goldberger. To say they were not best pleased might be a slight understatement. They hated him. The reasons were essentially financial and political, a bit like heart disease today. Being correct does not always make for popularity.
Now let's have a look at subacute myelo-optico-neuropathy (SMON). OK, hands up if you have never heard of SMON.
The disease was pretty well limited to Japan between 1958 and 1972, so you may be excused. Identification of the cause was severely hampered by the obvious explanation that it was contagious and was caused by a gut virus. The fact that it ultimately turned out to be caused by a known neurotoxin marketed by Ciba Geigy as a drug for the treatment of diarrhoea was vigorously denied by the virus hunters, even after what had really happened became fully accepted by the Japanese government.
To get some idea of how much fun SMON was for the victims, over 1000 of them were still alive in 2004 (of the approximately 10,000 affected). These are the types of problem the survivors are still left with.
Here's a nice summary of the whole episode, it makes interesting reading. Duesberg is probably the world's leading AIDS denialist.
For those of us who were stacking straw bales in the university vacation during the blistering summer of 1976, SMON doesn't seem that long ago.
This poses the very interesting question: When did we stop making mistakes?
and the closely related question: Statins in the drinking water?
Peter
Hmmm, you could ask things about BSE and vCJD too....
You have to ask exactly how a disease caused by a vitamin deficiency could remotely have been classed as contagious, and exactly why this idea should have been so vigorously defended by the medical profession. To get the whole story you really need something like Alan Kraut's biography of Goldberger. I found it an interesting read, particularly the lengths Goldberger (and his family) went to in order to demonstrate on themselves that pellagra was not contagious, and quite how his wife put up with coming such a distant second place to his work is quite beyond me. Anyway, it turned out that the "Scourge of the South" could be cured by decent food, eventually replaceable by a teaspoonful of brewers yeast a day.
Just imagine heart disease being cured by a pint of cream a day...
How did the medical profession take this to phenomenal and meticulously tested hypothesis? If you think the AHA hated Dr Atkins, that has nothing of the violence of the reaction against Goldberger. To say they were not best pleased might be a slight understatement. They hated him. The reasons were essentially financial and political, a bit like heart disease today. Being correct does not always make for popularity.
Now let's have a look at subacute myelo-optico-neuropathy (SMON). OK, hands up if you have never heard of SMON.
The disease was pretty well limited to Japan between 1958 and 1972, so you may be excused. Identification of the cause was severely hampered by the obvious explanation that it was contagious and was caused by a gut virus. The fact that it ultimately turned out to be caused by a known neurotoxin marketed by Ciba Geigy as a drug for the treatment of diarrhoea was vigorously denied by the virus hunters, even after what had really happened became fully accepted by the Japanese government.
To get some idea of how much fun SMON was for the victims, over 1000 of them were still alive in 2004 (of the approximately 10,000 affected). These are the types of problem the survivors are still left with.
Here's a nice summary of the whole episode, it makes interesting reading. Duesberg is probably the world's leading AIDS denialist.
For those of us who were stacking straw bales in the university vacation during the blistering summer of 1976, SMON doesn't seem that long ago.
This poses the very interesting question: When did we stop making mistakes?
and the closely related question: Statins in the drinking water?
Peter
Hmmm, you could ask things about BSE and vCJD too....
Cholesterol, heart attacks and JUPITER
There was a snippet on Radio 4 about the JUPTER study this morning. It was basically an ad for statins for everyone in the UK. Well, 75% of the adult population.
What the JUPITER study found was that in people with low cholesterol levels but elevated hsCRP levels, taking a statin dropped the overall mortality from low to a bit lower.
Bodycounts were 198/8901 in the statin group and 247/8901 in the placebo group. Clearly treating 8901 people for a year and a half will prevent 49 deaths. According to the lipid hypothesis, all of these lives saved should be as a result of less cardiovascular disease, such as fatal heart attacks.
Well Table 3 from the study gives you the total numbers of deaths from heart attacks, but not directly. You have to look at the line "Any myocardial infarction" and subtract the previous line, "non fatal myocardial infarction". Simple arithmetic, which didn't get done in the write up, then gives you the number of fatal heart attacks... Here are the missing numbers:
Heart attack deaths on statin: 9
Heart attack deaths on placebo: 6
Hmmm, 50% increase of being dead from a heart attack on Crestor, with an LDL half the level of the people on the placebo.......... Good job the study was not powered to detect this!
So what did the people die of in the placebo group? Well, it certainly wasn't heart attacks.
hsCRP is a protein produced by your liver as a message to your neutrophils to get out there and do whatever they should be doing, but more so. It probably does lots of other things too. The list of diseases that come with elevated hsCRP is huge. It looks like taking Crestor does blunt this message. Whether that is why the death rate dropped on the statin is anyone's guess. Statins have lots of effects and, believe it or not, not all are acutely bad!
As an aside: Why were there so many cardiac procedures in the placebo group? Perhaps this is what saved their lives? Unlikely. The explanation could be as simple as statins preventing chest pain, which they do by facilitating nitric oxide's vasodilating action (just Pubmed "statin nitric oxide"). Anyone in the USA with chest pain is very likely to get a "soft end point" procedure, as per the JUPITER study. Less chest pain, less Dr visits, less procedures. Dr Davis explains how Dr visits lead to procedures.
So, in summary, rosuvastatin has a minor effect on all cause mortality and no effect on heart attack deaths in people with elevated hsCRP.
What the news clips claimed was:
"The study [JUPITER] of 17,800 men and women with normal cholesterol levels found a new statin drug cut deaths from heart attacks and strokes"
Note the words "deaths", "heart attacks" and "strokes". There were 3 stroke deaths in the statin group, 6 in the placebo group. Exactly enough to reverse the heart attack effect. Phew!
I missed this snippet initially as I was off making tea and came back to find my wife grinding her teeth. Not so much at statinating the nation, we're pretty resigned to this. No, the problem was the deferential supplication of Sarah Montague (normally an infuriatingly aggressive interviewer) to the medic and statination. She would have torn a politician apart for such economy with the truth.
Peter
Thanks to the THINCS members for the full text and kicking these ideas around so thoroughly.
What the JUPITER study found was that in people with low cholesterol levels but elevated hsCRP levels, taking a statin dropped the overall mortality from low to a bit lower.
Bodycounts were 198/8901 in the statin group and 247/8901 in the placebo group. Clearly treating 8901 people for a year and a half will prevent 49 deaths. According to the lipid hypothesis, all of these lives saved should be as a result of less cardiovascular disease, such as fatal heart attacks.
Well Table 3 from the study gives you the total numbers of deaths from heart attacks, but not directly. You have to look at the line "Any myocardial infarction" and subtract the previous line, "non fatal myocardial infarction". Simple arithmetic, which didn't get done in the write up, then gives you the number of fatal heart attacks... Here are the missing numbers:
Heart attack deaths on statin: 9
Heart attack deaths on placebo: 6
Hmmm, 50% increase of being dead from a heart attack on Crestor, with an LDL half the level of the people on the placebo.......... Good job the study was not powered to detect this!
So what did the people die of in the placebo group? Well, it certainly wasn't heart attacks.
hsCRP is a protein produced by your liver as a message to your neutrophils to get out there and do whatever they should be doing, but more so. It probably does lots of other things too. The list of diseases that come with elevated hsCRP is huge. It looks like taking Crestor does blunt this message. Whether that is why the death rate dropped on the statin is anyone's guess. Statins have lots of effects and, believe it or not, not all are acutely bad!
As an aside: Why were there so many cardiac procedures in the placebo group? Perhaps this is what saved their lives? Unlikely. The explanation could be as simple as statins preventing chest pain, which they do by facilitating nitric oxide's vasodilating action (just Pubmed "statin nitric oxide"). Anyone in the USA with chest pain is very likely to get a "soft end point" procedure, as per the JUPITER study. Less chest pain, less Dr visits, less procedures. Dr Davis explains how Dr visits lead to procedures.
So, in summary, rosuvastatin has a minor effect on all cause mortality and no effect on heart attack deaths in people with elevated hsCRP.
What the news clips claimed was:
"The study [JUPITER] of 17,800 men and women with normal cholesterol levels found a new statin drug cut deaths from heart attacks and strokes"
Note the words "deaths", "heart attacks" and "strokes". There were 3 stroke deaths in the statin group, 6 in the placebo group. Exactly enough to reverse the heart attack effect. Phew!
I missed this snippet initially as I was off making tea and came back to find my wife grinding her teeth. Not so much at statinating the nation, we're pretty resigned to this. No, the problem was the deferential supplication of Sarah Montague (normally an infuriatingly aggressive interviewer) to the medic and statination. She would have torn a politician apart for such economy with the truth.
Peter
Thanks to the THINCS members for the full text and kicking these ideas around so thoroughly.
Thursday, November 06, 2008
HLA-B27 some more
Well, there have been a few interesting developments in the last few days. The most interesting was being invited to lunch by Prof Ebringer. That was a very long conversation and has produced a stack of papers to read and a whole lot of ideas, plus a Drs appointment for myself to see if I can get HLA-B27 tested on the NHS. At £209 per test privately, I'm rather hoping to get my GP to fund this even if I have to offer a decent bottle of wine to cover the £20 odd it costs the practice!
The HLA-B27 discussion was very interesting. Apparently the allele is very common among the Eskimo and their descendants and very rare in people from equatorial regions. This fits nicely with the carnivorous HG in temperate or extreme climates vs more starch based gathering in the tropics. By a quirk of migration the gene is also very rare in Japan, but even there the link with ankylosing spondylitis is strong.
A medic, Dr Tani, working in Japan, was looking to publish a paper on AS and approached the Kings College group to get the Klebsiella antibody titres done. Prof Ebringer suggested sending the samples coded, plus some controls and some RA samples thrown in. This is the paper which came out of the collaboration.
The Kings College group did the same with a set of coded Dutch samples, written up here. Interestingly, two other labs failed to get the same result, using the same samples. But if Ebringer can get consistent results on both the Japanes and Dutch samples, I tend to think his group is quite good at immunology.
Obviously the AS hypothesis generates the starch avoidance protocol which seems to be in fairly widespread use in places like the KickAS site. The proof of the pudding is in the eating ie, do patients get better on a behaviour based on a hypothesis. If so that seems to support the hypothesis to me...
I think it is worth noting that AS primarily involves an IgA antibody, which suggests exposure to the trigger across a mucosal surface, typically the gut. Rheumatoid disease involves an IgG response and suggests a non surface immune response, in this case classically through a low grade chronic urinary infection. This gives a simple explanation for the response seen to minocycline and doxycycline in RA patients. Of course without antibiotics (or with them) you might approach starving the proteus which triggers RA by using a dilute urine approach (the proteus bug derives energy by splitting urea in the urinary tract) and possibly eating a low protein diet might well help too. It's worth noting that the true Optimal Diet is actually rather low in protein at around 40-50g/d, once you are well established on the diet. By eating the minimum amount necessary of the highest quality protein you produce the least quantity of waste, ie urea, which is better known as proteus fodder. I'm not down at this level of protein intake but it's another option for fighting RA. I guess getting your immune system back by dumping sugar would potentially get rid of the proteus bugs completely... There's an interesting study.
Of course we spent a lot of time talking about BSE, scrapie, CJD, vCJD and MS. There is probably a book could be written here so I'll stop until I think I understand it a bit better and have had chance to tease out a few of the more problematic features of both the prion hypothesis and the auto immune hypothesis...
Peter
The HLA-B27 discussion was very interesting. Apparently the allele is very common among the Eskimo and their descendants and very rare in people from equatorial regions. This fits nicely with the carnivorous HG in temperate or extreme climates vs more starch based gathering in the tropics. By a quirk of migration the gene is also very rare in Japan, but even there the link with ankylosing spondylitis is strong.
A medic, Dr Tani, working in Japan, was looking to publish a paper on AS and approached the Kings College group to get the Klebsiella antibody titres done. Prof Ebringer suggested sending the samples coded, plus some controls and some RA samples thrown in. This is the paper which came out of the collaboration.
The Kings College group did the same with a set of coded Dutch samples, written up here. Interestingly, two other labs failed to get the same result, using the same samples. But if Ebringer can get consistent results on both the Japanes and Dutch samples, I tend to think his group is quite good at immunology.
Obviously the AS hypothesis generates the starch avoidance protocol which seems to be in fairly widespread use in places like the KickAS site. The proof of the pudding is in the eating ie, do patients get better on a behaviour based on a hypothesis. If so that seems to support the hypothesis to me...
I think it is worth noting that AS primarily involves an IgA antibody, which suggests exposure to the trigger across a mucosal surface, typically the gut. Rheumatoid disease involves an IgG response and suggests a non surface immune response, in this case classically through a low grade chronic urinary infection. This gives a simple explanation for the response seen to minocycline and doxycycline in RA patients. Of course without antibiotics (or with them) you might approach starving the proteus which triggers RA by using a dilute urine approach (the proteus bug derives energy by splitting urea in the urinary tract) and possibly eating a low protein diet might well help too. It's worth noting that the true Optimal Diet is actually rather low in protein at around 40-50g/d, once you are well established on the diet. By eating the minimum amount necessary of the highest quality protein you produce the least quantity of waste, ie urea, which is better known as proteus fodder. I'm not down at this level of protein intake but it's another option for fighting RA. I guess getting your immune system back by dumping sugar would potentially get rid of the proteus bugs completely... There's an interesting study.
Of course we spent a lot of time talking about BSE, scrapie, CJD, vCJD and MS. There is probably a book could be written here so I'll stop until I think I understand it a bit better and have had chance to tease out a few of the more problematic features of both the prion hypothesis and the auto immune hypothesis...
Peter
Monday, October 27, 2008
Cholesterol, it's not a competition
Barry Groves has a new book out which might be worth a look. There is an interesting review in the Telegraph here which gives a little back ground to the author of "Eat Fat Get Thin!", one of my early core LC books.
For those of us worrying about a TC just outside of cardiological nirvana, Barry Groves seems to be doing okay at 8.2mmol/l. Of course that's not quite as cool as 8.6mmol/l, but hey, I've a few years to go before I get in to my seventies...
Peter
For those of us worrying about a TC just outside of cardiological nirvana, Barry Groves seems to be doing okay at 8.2mmol/l. Of course that's not quite as cool as 8.6mmol/l, but hey, I've a few years to go before I get in to my seventies...
Peter
Monday, October 20, 2008
Familial Hypercholesterolaemia; Brown and Goldstein
Brown and Glodstein won the 1985 Nobel Prize for medicine.
You can download their acceptance address as a pdf here.
Their work was primarily based around familial hypercholesterolaemia.
The world is full of genetic problems where the heterozygote, with one copy of an affected gene, has an advantage over people in whom neither copies of the gene is affected. Being a carrier (heterozygote) for sickle cell anaemia protects you from malaria without any disadvantage. Being the far rarer homozygote (both genes affected) is bad news because your haemoglobin polymerises under hypoxic conditions and your red blood cells become dysfunctional. Not nice. Hurts like hell, apparently.
There are lots of types of familial hypercholesterolaemia but I'll stick to the type where the receptor for LDL particles is fully dysfunctional. Get one copy of the gene and you have elevated cholesterol levels but are at no excess risk for CVD, unless you come from a family which has a history of premature CVD. Get two copies of the FH gene and, as for sickle cell disease, you are potentially in trouble. Why is part of a future AGE, RAGE and ALE post, so I'll leave it there for the time being.
Brown and Goldstein came up with a therapy for managing heterozygous familial hypercholesterolaemia.
Heterozygous FH (hFH) people make a lower number of functional LDL receptors because one of their genes for this protein is naff. The other gene is fine. B and G noted that the level of cholesterol within our cells controls the expression of the genes for the LDL receptor. Lower intracellular free cholesterol and you up regulate the LDL receptor gene, to grab extra cholesterol from passing LDL particles. Get enough functional receptors on to cell surface and you behave as if you are normal, LDL-wise.
So they put in place the concept of lowering plasma LDL by up regulating the LDL receptor expression by inhibiting cholesterol synthesis within the cell. You can particularly target the liver by, in addition, depriving it of bile acids. These cholesterol derivatives are fiendishly important and normally get very efficiently recycled. Treating with cholestyramine guarantees, along with gut ache, that most bile acids go down the loo. Now the liver REALLY needs cholesterol (partly to make more bile acids) but also because HMG CoA, the rate controlling enzyme cholesterol synthesis, can be blocked by a mould fungus (eventually to be marketed as lovastatin). So it sticks out lots of LDL receptors and normalises plasma LDL.
And all heart problems disappear. But B and G worked in the 1970s. At that time it had not occurred to anyone that it is only those hFH people with heart disease that get heart disease. The rest are fine. The heart disease cannot be from the elevated LDL, because the non CVD families have similar LDL yet stubbornly have no heart disease. Back in the 1970's no one thought to look for healthy hFH "victims", all of the hFH patients were found through cardiology clinics..........
So the basic principle which was used to usher in lovastatin was based on a mistake. Very clever science, but based on a mistake non the less. Who gave B and G the idea that elevated LDL cholesterol caused heart disease? Who do they cite as the source of elevated cholesterol being the cause of heart disease in their nobel acceptance address?
Well, you can bet it wasn't Yerushalmy and Hilleboe.
Oh, you've never heard of Yerushalmy and Hilleboe? Obviously neither had B and G.
B and G cited Ancel Keys and his seven countries study linking saturated fat to heart disease via elevated cholesterol:
"Extensive epidemiologic studies performed in many populations in many countries over the past three decades have pointed strongly to a general association of high blood cholesterol levels with heart attacks. Among the most striking examples is the seven-country study of coronary artery disease directed by Ansel Keys (116)"
ref 116 is to a text book published in 1980. The original publications were in the 1950s, this one comes from 1953. Unfortunately papers this old are not freely available so I'll personally have trust to Dr Ravnskov to have seen the actual paper based papers.
Yerushalmy and Hilleboe, in 1957, pointed out that Keys had selected his countries to fit his hypothesis and that inclusion of all of the data available at the time showed no association between saturated fat and blood cholesterol, let alone heart disease. Really, that should have been the end of the diet heart hypothesis.
But what is MUCH more interesting (than their believing Ancel Keys) is B and G's opinion about homozygous FH. It was obvious to them that you CANNOT up regulate the effective LDL receptors of homozygous FH patients because they DO NOT HAVE ANY GENES FOR EFFECTIVE LDL RECEPTORS AT ALL. Quote from B and G:
"The principles applied to treatment of FH heterozygotes cannot, unfortunately, be applied to homozygotes, especially those who have totally defective LDL receptor genes. These individuals do not respond to the above-mentioned drugs because they cannot synthesize LDL receptors"
Oh.
So why give statins to homozygous FH patients? Remember, statins are used, in B and G's scenario, to upregulate LDL receptors.
Clearly there is no logic to this.
You could say medicine has been very lucky in the multitude of unsought after beneficial effects from the fungal toxin lovastatin, in addition to it's very unpleasant ability to inhibit HMG CoA reductase and along side a few other rather nasty effects which negate any overall mortality benefit.
Or maybe you could say science has been held back for 25 years by that fluke and that medicine is no closer today to the real causes of heart disease than it was in 1953. Thanks again to Dr Keys.
Peter
You can download their acceptance address as a pdf here.
Their work was primarily based around familial hypercholesterolaemia.
The world is full of genetic problems where the heterozygote, with one copy of an affected gene, has an advantage over people in whom neither copies of the gene is affected. Being a carrier (heterozygote) for sickle cell anaemia protects you from malaria without any disadvantage. Being the far rarer homozygote (both genes affected) is bad news because your haemoglobin polymerises under hypoxic conditions and your red blood cells become dysfunctional. Not nice. Hurts like hell, apparently.
There are lots of types of familial hypercholesterolaemia but I'll stick to the type where the receptor for LDL particles is fully dysfunctional. Get one copy of the gene and you have elevated cholesterol levels but are at no excess risk for CVD, unless you come from a family which has a history of premature CVD. Get two copies of the FH gene and, as for sickle cell disease, you are potentially in trouble. Why is part of a future AGE, RAGE and ALE post, so I'll leave it there for the time being.
Brown and Goldstein came up with a therapy for managing heterozygous familial hypercholesterolaemia.
Heterozygous FH (hFH) people make a lower number of functional LDL receptors because one of their genes for this protein is naff. The other gene is fine. B and G noted that the level of cholesterol within our cells controls the expression of the genes for the LDL receptor. Lower intracellular free cholesterol and you up regulate the LDL receptor gene, to grab extra cholesterol from passing LDL particles. Get enough functional receptors on to cell surface and you behave as if you are normal, LDL-wise.
So they put in place the concept of lowering plasma LDL by up regulating the LDL receptor expression by inhibiting cholesterol synthesis within the cell. You can particularly target the liver by, in addition, depriving it of bile acids. These cholesterol derivatives are fiendishly important and normally get very efficiently recycled. Treating with cholestyramine guarantees, along with gut ache, that most bile acids go down the loo. Now the liver REALLY needs cholesterol (partly to make more bile acids) but also because HMG CoA, the rate controlling enzyme cholesterol synthesis, can be blocked by a mould fungus (eventually to be marketed as lovastatin). So it sticks out lots of LDL receptors and normalises plasma LDL.
And all heart problems disappear. But B and G worked in the 1970s. At that time it had not occurred to anyone that it is only those hFH people with heart disease that get heart disease. The rest are fine. The heart disease cannot be from the elevated LDL, because the non CVD families have similar LDL yet stubbornly have no heart disease. Back in the 1970's no one thought to look for healthy hFH "victims", all of the hFH patients were found through cardiology clinics..........
So the basic principle which was used to usher in lovastatin was based on a mistake. Very clever science, but based on a mistake non the less. Who gave B and G the idea that elevated LDL cholesterol caused heart disease? Who do they cite as the source of elevated cholesterol being the cause of heart disease in their nobel acceptance address?
Well, you can bet it wasn't Yerushalmy and Hilleboe.
Oh, you've never heard of Yerushalmy and Hilleboe? Obviously neither had B and G.
B and G cited Ancel Keys and his seven countries study linking saturated fat to heart disease via elevated cholesterol:
"Extensive epidemiologic studies performed in many populations in many countries over the past three decades have pointed strongly to a general association of high blood cholesterol levels with heart attacks. Among the most striking examples is the seven-country study of coronary artery disease directed by Ansel Keys (116)"
ref 116 is to a text book published in 1980. The original publications were in the 1950s, this one comes from 1953. Unfortunately papers this old are not freely available so I'll personally have trust to Dr Ravnskov to have seen the actual paper based papers.
Yerushalmy and Hilleboe, in 1957, pointed out that Keys had selected his countries to fit his hypothesis and that inclusion of all of the data available at the time showed no association between saturated fat and blood cholesterol, let alone heart disease. Really, that should have been the end of the diet heart hypothesis.
But what is MUCH more interesting (than their believing Ancel Keys) is B and G's opinion about homozygous FH. It was obvious to them that you CANNOT up regulate the effective LDL receptors of homozygous FH patients because they DO NOT HAVE ANY GENES FOR EFFECTIVE LDL RECEPTORS AT ALL. Quote from B and G:
"The principles applied to treatment of FH heterozygotes cannot, unfortunately, be applied to homozygotes, especially those who have totally defective LDL receptor genes. These individuals do not respond to the above-mentioned drugs because they cannot synthesize LDL receptors"
Oh.
So why give statins to homozygous FH patients? Remember, statins are used, in B and G's scenario, to upregulate LDL receptors.
Clearly there is no logic to this.
You could say medicine has been very lucky in the multitude of unsought after beneficial effects from the fungal toxin lovastatin, in addition to it's very unpleasant ability to inhibit HMG CoA reductase and along side a few other rather nasty effects which negate any overall mortality benefit.
Or maybe you could say science has been held back for 25 years by that fluke and that medicine is no closer today to the real causes of heart disease than it was in 1953. Thanks again to Dr Keys.
Peter
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