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
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