I just thought I'd have a quick look (after viewing the PPT trawls) at the data trawls from WHEL in case they'd looked at the effect of a diet high in fruit 'n' fibre and low in fat on CVD. Of course they did. It gets kind of boring trotting out these bias confirming studies, but here's the punchline anyway:
"Over a mean of 8.1 years, a dietary intervention that reduced total fat intake and increased intakes of vegetables, fruits, and grains did not significantly reduce the risk of CHD, stroke, or CVD in postmenopausal women..."
Maybe they need more cream on the fruit? I'm just so grateful that they didn't get anything correct by accident. WHEL and PPT are such great sorces of hard data on crap diets.
Peter
Wednesday, July 28, 2010
Monday, July 26, 2010
Jimmy Moore on Dr Weil
Another one liner in case you don't follow Jimmy Moore, the post on Dr Weil is very interesting from the political point of view. Very interesting.
Peter
Peter
Sunday, July 25, 2010
Wheat and lactase
While I'm trying to clear my desk top a little, with limited access to the net during an oncall weekend, I thought I might post this link as I'm thinking wheat at the moment.
I think I've discussed the role of gluten in trashing the brush border cells, again without need for any sort of immune system involvement. The present study did involve immune-injured people but I see no reason why exactly the same principle shouldn't apply to antibody negative "coeliacs" (suffering from "imagination" or even, gasp, orthorexia nervosa, another from Elizabeth. Apologies for the picture of the bowl of rabbit food).
Another aspect of normalising the brush border is that far less food is going to be left in the small intestine to feed a bacterial overgrowth. On a LC, low fibre diet there are likely to be massive changes in gut flora. I have an anecdote from several years ago given to me by a lady and her mother who had gone LC plus gluten free and, after quite some time, both suddenly became lactose intolerant. This is the last thing I would have expected.
Now, I'm no great enthusiast for pre- or pro-biotics, but I do eat a fair amount of cheese, soured cream and high fat yogurt. The last of those occasionally in large amounts. So eating real-food dairy accidentally includes plenty of germs. Germs to which we are well adapted. Gut bacteria are normal to humans and lactobacilli are amongst the first bacteria to colonise the gut of a healthy infant, presumably because its mother provides lactose (and pre-biotics too, hmmmm). For humans who are not genetically adapted to adult lactose intake, are we borrowing the gene for lactose tolerance from the microbiome in our gut? Is it possible to lose lactose tolerance if we lose lactobacilli during the major bacterial starve-out that LC probably produces?
Alternatively, as coeliac disease appear to require certain bacteria, does lactose intolerance REQUIRE certain non-lactobacilli bacteria? This would fit better with two people developing lactose intolerance at the same time in the same household, if they simultaneously picked up the same bacterial opportunist.
Answers on a postcard to........
Peter
I think I've discussed the role of gluten in trashing the brush border cells, again without need for any sort of immune system involvement. The present study did involve immune-injured people but I see no reason why exactly the same principle shouldn't apply to antibody negative "coeliacs" (suffering from "imagination" or even, gasp, orthorexia nervosa, another from Elizabeth. Apologies for the picture of the bowl of rabbit food).
Another aspect of normalising the brush border is that far less food is going to be left in the small intestine to feed a bacterial overgrowth. On a LC, low fibre diet there are likely to be massive changes in gut flora. I have an anecdote from several years ago given to me by a lady and her mother who had gone LC plus gluten free and, after quite some time, both suddenly became lactose intolerant. This is the last thing I would have expected.
Now, I'm no great enthusiast for pre- or pro-biotics, but I do eat a fair amount of cheese, soured cream and high fat yogurt. The last of those occasionally in large amounts. So eating real-food dairy accidentally includes plenty of germs. Germs to which we are well adapted. Gut bacteria are normal to humans and lactobacilli are amongst the first bacteria to colonise the gut of a healthy infant, presumably because its mother provides lactose (and pre-biotics too, hmmmm). For humans who are not genetically adapted to adult lactose intake, are we borrowing the gene for lactose tolerance from the microbiome in our gut? Is it possible to lose lactose tolerance if we lose lactobacilli during the major bacterial starve-out that LC probably produces?
Alternatively, as coeliac disease appear to require certain bacteria, does lactose intolerance REQUIRE certain non-lactobacilli bacteria? This would fit better with two people developing lactose intolerance at the same time in the same household, if they simultaneously picked up the same bacterial opportunist.
Answers on a postcard to........
Peter
Wheat Germ Agglutinin; how little is enough?
Chignola's group have been at WGA again. Their basic interest is (was?) in using WGA as a drug carrier aimed at certain cell surface sugar groupings, hoping to target certain cancers, as far as I can see.
Their first paper in 2005 demonstrated direct intestinal cell toxicity at micro molar concentrations. However Glenn updated me on their more recent 2009 paper here:
"At nanomolar concentrations WGA stimulates the synthesis of pro-inflammatory cytokines and thus the biological activity of WGA should be reconsidered by taking into account the effects of WGA on the immune system at the gastrointestinal interface. These results shed new light onto the molecular mechanisms underlying the onset of gastrointestinal disorders observed in vivo upon dietary intake of wheat-based foods"
Notice there is no mention of coeliac disease, you do not need to be genetically predisposed by HLA type to have WGA toxicity. This looks to be yet more direct molecular toxicity.
Now we are talking nanomolar concentrations.
It's a bit difficult to get your head round a nanomole of WGA. One mole is the molecular weight expressed in grams. For WGA this is a BIG number of grams. A nanomole is not very much. So a nanomole is not very much of quite a lot of grams! Without struggling with the math I'd just suggest putting the bread in the bin and seeing if I could get out of my wheelchair as my gut integrity improved! An angry immune cell, looking at a soup of gut peptides, is not going to care what collateral damage it does.
Peter
BTW I heard that Sheffield vs Nottingham medics is generic and not limited to neurology... I can't remember who mentioned it, I'm pretty certain it was off blog at a supper party, from a physicist who had worked for Nottingham Queens Medical in some capacity.
Their first paper in 2005 demonstrated direct intestinal cell toxicity at micro molar concentrations. However Glenn updated me on their more recent 2009 paper here:
"At nanomolar concentrations WGA stimulates the synthesis of pro-inflammatory cytokines and thus the biological activity of WGA should be reconsidered by taking into account the effects of WGA on the immune system at the gastrointestinal interface. These results shed new light onto the molecular mechanisms underlying the onset of gastrointestinal disorders observed in vivo upon dietary intake of wheat-based foods"
Notice there is no mention of coeliac disease, you do not need to be genetically predisposed by HLA type to have WGA toxicity. This looks to be yet more direct molecular toxicity.
Now we are talking nanomolar concentrations.
It's a bit difficult to get your head round a nanomole of WGA. One mole is the molecular weight expressed in grams. For WGA this is a BIG number of grams. A nanomole is not very much. So a nanomole is not very much of quite a lot of grams! Without struggling with the math I'd just suggest putting the bread in the bin and seeing if I could get out of my wheelchair as my gut integrity improved! An angry immune cell, looking at a soup of gut peptides, is not going to care what collateral damage it does.
Peter
BTW I heard that Sheffield vs Nottingham medics is generic and not limited to neurology... I can't remember who mentioned it, I'm pretty certain it was off blog at a supper party, from a physicist who had worked for Nottingham Queens Medical in some capacity.
Thursday, July 22, 2010
Total Perspective Vortex and vegicide
For those who have failed to read the Hitchhiker's Guide to the Galaxy a little information about the Total Perspective Vortex is required. It's in context here.
The relevant quote is this one:
"To Trin Tragula’s horror, the shock completely annihilated her [his wife's] brain; but to his satisfaction he realized that he had proved conclusively that if life is going to exist in a Universe of this size, then the one thing it cannot have is a sense of proportion"
I hate to mention anyone with an annihilated brain after mentioning poor Dr Stanton, but here is the key quote from Dr T Colon Campbell (none of the rest is worth reading):
"In summary, Denise’s critique lacks a sense of proportionality."
Phew, just as well, we need Denise with a non annihilated brain to crunch numbers for us.
But the implication, unstated, is that Dr Colon has a sense of proportionality.
Explains a lot really.
Peter
BTW Zaphod eats the cake. There, ruined the series for you!
The relevant quote is this one:
"To Trin Tragula’s horror, the shock completely annihilated her [his wife's] brain; but to his satisfaction he realized that he had proved conclusively that if life is going to exist in a Universe of this size, then the one thing it cannot have is a sense of proportion"
I hate to mention anyone with an annihilated brain after mentioning poor Dr Stanton, but here is the key quote from Dr T Colon Campbell (none of the rest is worth reading):
"In summary, Denise’s critique lacks a sense of proportionality."
Phew, just as well, we need Denise with a non annihilated brain to crunch numbers for us.
But the implication, unstated, is that Dr Colon has a sense of proportionality.
Explains a lot really.
Peter
BTW Zaphod eats the cake. There, ruined the series for you!
Tuesday, July 20, 2010
Where is the brain of Rosemary Stanton?
I've posted on Dr Peter Clifton in the past. He's in the news again. Here's the link to the Telegraph article from Blogblog plus the text is also over on the trialblog archive for when the link goes down. Obviously there is a limit to the functionality of his brain implant (inability to perceive that obesity is a symptom not a disease for example, still pro vegetables because they are low in calories, no idea of the role of insulin in obesity etc) but he does seem to be able to conceive that five a day of fruit 'n' veg are a waste of money. That is utterly amazing.
Hmmmmm. On re reading the article, apart from finding fruit and veg useless, he still seems utterly lost as far as meaningful comprehension goes.
Still, Clifton's brain implant has some residual functionality. But where did the brain come from???? Could it have been stolen from Dr Rosemary Stanton? The Dr as in the last sentence in the Telegraph article:
"Nutritionist Dr Rosemary Stanton cast doubt on the findings and suggested the study [Clifton's] could be flawed."
Her brain could easily have been taken as the source of whatever residual central processing power is available to Dr Clifton. Replacing Dr Stanton's brain with a low IQ parrot would leave her fully functional as a nutritionist... It all fits together.
Peter
Hmmmmm. On re reading the article, apart from finding fruit and veg useless, he still seems utterly lost as far as meaningful comprehension goes.
Still, Clifton's brain implant has some residual functionality. But where did the brain come from???? Could it have been stolen from Dr Rosemary Stanton? The Dr as in the last sentence in the Telegraph article:
"Nutritionist Dr Rosemary Stanton cast doubt on the findings and suggested the study [Clifton's] could be flawed."
Her brain could easily have been taken as the source of whatever residual central processing power is available to Dr Clifton. Replacing Dr Stanton's brain with a low IQ parrot would leave her fully functional as a nutritionist... It all fits together.
Peter
Friday, July 16, 2010
Thursday, July 15, 2010
Polyp Prevention Trial and homocysteine
I don't know where to start with this. Let's begin with one of my all time favourite studies, the Polyp Prevention Trial, PPT. For those of us who have forgotten, this quote from the abstract sums up PPT:
"This study failed to show any effect of a low-fat, high-fiber, high-fruit and -vegetable eating pattern on adenoma recurrence even with 8 years of follow-up"
Now, would anyone like to guess how much the PPT cost? I've no idea, but I guess it cost enough that you are not going to accept a result like that after spending all of those tax dollars (thank goodness it wasn't pounds sterling, it's bad enough funding the FSA on this side of the Pond). So there is now an on-going avalanche of subgroup analysis papers flooding out from PPT, many of which are utterly hysterical. Some actually show, by accident, the injury done to many of the people in the intervention arm of the study. From these new papers you would NEVER guess the main trial primary end point was an utter destruction of the hypothesis that flatulence is good for you.
Let's start with that lovely sub group who ate all the dry beans. Upping your beans by 370% appeared to drop your risk for adenoma recurrence to an OR of 0.35 in the intervention arm. This is music to the fibre-ophile ear. The effect is massive. It really should show in observational studies if it is real. It doesn't.
Sub group analysis of the control group, observational only, suggests that contributing to global warming is NOT justified for colorectal cancer prevention. There is no excuse for flatulence. I dunno. Maybe the intervention trial is correct. But don't hold your breath, just your nose.
That last sub group analysis is particularly interesting once you get hold of the full text (many thanks Anna). It only looks at the control arm, so it's observational in nature. They blood sampled folks at the start of the study then counted polyps after four years on whatever shade of the SAD happened to be chosen by people who have had a polyp removed but no diet advice given (ie the lucky ones).
What is topical to me at the moment is that homocysteine (HCy) correlation with polyp recurrence. HCy at enrolment is a very good predictor of polyp recurrence in this group of untutored polyp formers over the next 4 years.
The suggestion, by the authors, is that reducing HCy will reduce adenoma recurrence. Really, someone should test this hypothesis. Maybe a trial increasing fruit, vegetables and fibre should be done to see if these miracle foods will reduce adenoma formation over a four or even eight year period?
Oh, it's been done has it? Ah yes, that's where this data trawl has come from! I remember, yes, that's it, eight years of fruit and fibre does bugger all to prevent polyp recurrence. Silly of me to forget. There was an intervention arm to PPT!
Remember that and re read the very carefully worded abstract... Would you have guessed?
Before I get on to a dietary intervention which might lower HCy (if you care, all this is observational), let's have a look at another subgroup analysis of the PPT data.
I now want to look at what happened in the intervention arm. We can tease out a sub group, the folks who really complied with the intervention, and compare them with the people in the intervention arm who complied poorly.
That's this subgroup analysis.
A total of 210 "super compliers" were noted and compared to controls. I can't really tell if the controls were on the SAD or were those less compliant members of the intervention arm, probably the latter. The odds ratio for adenoma recurrence of supercompliance was 0.65 and statistically significant.
So 210 people out of the 1,905 in the intervention arm benefited. That means that 1,695 people didn't benefit from four years of advice.
But hold on a minute. When the initial study compared intervention with non intervention there was no benefit from intervention compared to the SAD. So if 210 people did better than average, then 1,695 people MUST HAVE DONE WORSE than average. That is, they did worse than those on the SAD. You would have expected a 50:50 split, obviously half should do better and half should do worse than average!
EDIT: Of course if they compared 210 super compliers to the 1,695 injured people they possibly got p < 0.05 because these 1,695 did particularly badly. I wonder if p would have been < 0.05 if they had compared the 210 to the whole SAD group? Probably not would be my guess. Or they would have done it! Me, cynical? Surely not... END EDIT
We can summarise: 1,695 people were injured by being in the intervention arm of the PPT.
I would also point out that "super compliers" are super compliers. These are the sort of people who meticulously take their placebo tablets in clinical trials and consistently do better than those who are lackadaisical with consuming their placebo tablets. Mike Eades has blogged about it nicely here.
So did the 210 super compliers benefit from the diet or were they just the sort of people who comply with authority and automatically do well despite their doctor's best efforts? There was no scope for an adherer effect in the SAD non-intervention arm because they were left alone with no religious group therapy support. Oops, I mean dietary advice...
So was everyone injured in the intervention group but a few had their injury offset by the warm glow of study compliance?
Don't hold your breath waiting to see THAT get discussed in an NIH funded paper. We're looking to justify the cash spent on a superb study which has made no friends among people with control over the purse strings...
Anyhow, back to HCy. We all know from nauseous observational stuff that PPT intervention should have dropped HCy (I've not seen this analysis anywhere yet but I guess it did) but it still didn't drop adenoma recurrence and it probably worsened it in that vast majority of the participants who weren't super compliers.
What sort of HCy levels are present in the SAD arm of PPT and how do they stratify against adenoma recurrence risk? This is from the sub analysis of the control arm I wrote about earlier:
To summarise the right hand column, folks with no relapse had median HCy around 12.5micromol/l. Those groups with the worst recurrences generally had median HCy over 14micromol/l. Low HCy is "associated", observationally, with lower adenoma relapses.
Of course those who ate the most plants, fibre and general pre-poop had the lowest HCy... Really begs why the trial totally flopped. Something to do with the difference between observational studies and intervention studies I think! There may be no funding for basic science (ask my wife!) but there seems to be plenty for this sort of dogma support BS!
However, within the dogma that HCy is controlled by eating leaves, how bad must it get if you eat almost no plants, with the emphasis on peeled potatoes when you do indulge in vegi-cide, as little fibre as possible and as much animal fat as practical, say >70% of calories?
Well the HCy comes out, when eating to the Optimal Diet, with a median of about 10.7micromol/l. And relatively few plants were murdered (blame Elizabeth) in the process.
No leaves, no fibre, lots of saturated fat. The occasional spud. Please remember that the data from the OD is observational in nature too. You have to guess what the HCy level was pre OD.
Counter intuitive isn't it? But science does that sometimes. Just look at the money spent on supporting the long dead hypothesis that eating leaves is in some way beneficial for humans. There's a powerful need for self justification of the pig's-ear that PPT turned out to be. Depending on your point of view of course!
Peter
"This study failed to show any effect of a low-fat, high-fiber, high-fruit and -vegetable eating pattern on adenoma recurrence even with 8 years of follow-up"
Now, would anyone like to guess how much the PPT cost? I've no idea, but I guess it cost enough that you are not going to accept a result like that after spending all of those tax dollars (thank goodness it wasn't pounds sterling, it's bad enough funding the FSA on this side of the Pond). So there is now an on-going avalanche of subgroup analysis papers flooding out from PPT, many of which are utterly hysterical. Some actually show, by accident, the injury done to many of the people in the intervention arm of the study. From these new papers you would NEVER guess the main trial primary end point was an utter destruction of the hypothesis that flatulence is good for you.
Let's start with that lovely sub group who ate all the dry beans. Upping your beans by 370% appeared to drop your risk for adenoma recurrence to an OR of 0.35 in the intervention arm. This is music to the fibre-ophile ear. The effect is massive. It really should show in observational studies if it is real. It doesn't.
Sub group analysis of the control group, observational only, suggests that contributing to global warming is NOT justified for colorectal cancer prevention. There is no excuse for flatulence. I dunno. Maybe the intervention trial is correct. But don't hold your breath, just your nose.
That last sub group analysis is particularly interesting once you get hold of the full text (many thanks Anna). It only looks at the control arm, so it's observational in nature. They blood sampled folks at the start of the study then counted polyps after four years on whatever shade of the SAD happened to be chosen by people who have had a polyp removed but no diet advice given (ie the lucky ones).
What is topical to me at the moment is that homocysteine (HCy) correlation with polyp recurrence. HCy at enrolment is a very good predictor of polyp recurrence in this group of untutored polyp formers over the next 4 years.
The suggestion, by the authors, is that reducing HCy will reduce adenoma recurrence. Really, someone should test this hypothesis. Maybe a trial increasing fruit, vegetables and fibre should be done to see if these miracle foods will reduce adenoma formation over a four or even eight year period?
Oh, it's been done has it? Ah yes, that's where this data trawl has come from! I remember, yes, that's it, eight years of fruit and fibre does bugger all to prevent polyp recurrence. Silly of me to forget. There was an intervention arm to PPT!
Remember that and re read the very carefully worded abstract... Would you have guessed?
Before I get on to a dietary intervention which might lower HCy (if you care, all this is observational), let's have a look at another subgroup analysis of the PPT data.
I now want to look at what happened in the intervention arm. We can tease out a sub group, the folks who really complied with the intervention, and compare them with the people in the intervention arm who complied poorly.
That's this subgroup analysis.
A total of 210 "super compliers" were noted and compared to controls. I can't really tell if the controls were on the SAD or were those less compliant members of the intervention arm, probably the latter. The odds ratio for adenoma recurrence of supercompliance was 0.65 and statistically significant.
So 210 people out of the 1,905 in the intervention arm benefited. That means that 1,695 people didn't benefit from four years of advice.
But hold on a minute. When the initial study compared intervention with non intervention there was no benefit from intervention compared to the SAD. So if 210 people did better than average, then 1,695 people MUST HAVE DONE WORSE than average. That is, they did worse than those on the SAD. You would have expected a 50:50 split, obviously half should do better and half should do worse than average!
EDIT: Of course if they compared 210 super compliers to the 1,695 injured people they possibly got p < 0.05 because these 1,695 did particularly badly. I wonder if p would have been < 0.05 if they had compared the 210 to the whole SAD group? Probably not would be my guess. Or they would have done it! Me, cynical? Surely not... END EDIT
We can summarise: 1,695 people were injured by being in the intervention arm of the PPT.
I would also point out that "super compliers" are super compliers. These are the sort of people who meticulously take their placebo tablets in clinical trials and consistently do better than those who are lackadaisical with consuming their placebo tablets. Mike Eades has blogged about it nicely here.
So did the 210 super compliers benefit from the diet or were they just the sort of people who comply with authority and automatically do well despite their doctor's best efforts? There was no scope for an adherer effect in the SAD non-intervention arm because they were left alone with no religious group therapy support. Oops, I mean dietary advice...
So was everyone injured in the intervention group but a few had their injury offset by the warm glow of study compliance?
Don't hold your breath waiting to see THAT get discussed in an NIH funded paper. We're looking to justify the cash spent on a superb study which has made no friends among people with control over the purse strings...
Anyhow, back to HCy. We all know from nauseous observational stuff that PPT intervention should have dropped HCy (I've not seen this analysis anywhere yet but I guess it did) but it still didn't drop adenoma recurrence and it probably worsened it in that vast majority of the participants who weren't super compliers.
What sort of HCy levels are present in the SAD arm of PPT and how do they stratify against adenoma recurrence risk? This is from the sub analysis of the control arm I wrote about earlier:
To summarise the right hand column, folks with no relapse had median HCy around 12.5micromol/l. Those groups with the worst recurrences generally had median HCy over 14micromol/l. Low HCy is "associated", observationally, with lower adenoma relapses.
Of course those who ate the most plants, fibre and general pre-poop had the lowest HCy... Really begs why the trial totally flopped. Something to do with the difference between observational studies and intervention studies I think! There may be no funding for basic science (ask my wife!) but there seems to be plenty for this sort of dogma support BS!
However, within the dogma that HCy is controlled by eating leaves, how bad must it get if you eat almost no plants, with the emphasis on peeled potatoes when you do indulge in vegi-cide, as little fibre as possible and as much animal fat as practical, say >70% of calories?
Well the HCy comes out, when eating to the Optimal Diet, with a median of about 10.7micromol/l. And relatively few plants were murdered (blame Elizabeth) in the process.
No leaves, no fibre, lots of saturated fat. The occasional spud. Please remember that the data from the OD is observational in nature too. You have to guess what the HCy level was pre OD.
Counter intuitive isn't it? But science does that sometimes. Just look at the money spent on supporting the long dead hypothesis that eating leaves is in some way beneficial for humans. There's a powerful need for self justification of the pig's-ear that PPT turned out to be. Depending on your point of view of course!
Peter
More fighting talk
Very briefly because there's nothing here we don't know inside out, this is fighting talk. More along the lines of de Lorgeril but in a very public forum.
Does anyone remember how permanent the Berlin Wall seemed for decades and how quickly it fell when it went....
Peter
Does anyone remember how permanent the Berlin Wall seemed for decades and how quickly it fell when it went....
Peter
Sunday, July 11, 2010
Rimonabant and hemopressin
"All right Mr Bender, before we enrol you in this clinical trial I need to be certain that you do not now, or ever have in the past, partake of any recreational drug, specifically those targeting the CB1 receptors in your brain?"
"Well yeah man, like sure, err, I mean, like no, like what was the question?"
"I'll take that as a no"
"Well sure doc, whatever, like, that's cool. You got something new for me to try?"
"We've developed hemopressin, a totally natural appetite modifying peptide. We don't know where it works in the brain, which neuronal circuits it influences or whether it is safe in humans. We think it's a good idea to give it to you at industrial dose rates which will flood your whole body to boost the micromolar concentrations naturally present in your brain. We think it's harmless and won't produce the depression or suicidal ideation which had Rimonabant withdrawn from the market a few years back. There's a big cheque involved."
"Ok doc, whatever. Like, ok, err, how much did you err like err, um, pay me?"
"My secretary will assist you with completing the deposit slip for your bank account. You do have a bank account?"
"Yeah, well, yeah, well, I can't remember really, did you say bank errr account...?"
"That door there, Mr Bender, the one you came in through."
"Ok, yeah, right"
Two weeks later
"Ah, good morning Mr Bender, a lovely day."
"What's the point? I think I'll just kill myself"
"How is you preoccupation with food?"
"What's the point? I think I'll just kill myself."
"Have you noticed any change in post coital satisfaction?"
"What's the point? I think I'll just kill myself."
"How is your satisfaction rating for visual appreciation?"
"What's the point, I think I'll just kill myself."
"Heard any good bands in the last two weeks?"
"What's the point, I think I'll just kill myself."
"Hmmmmmm. But interest in food is really down, yes?"
"What's the point, I think I'll just kill myself. Oh, Doc, before I go do it, those obese babies in nappies, are they on dope to get that obese? And the fat bankers too, they pot heads too? Never mind. What's the point, I think I'll just kill myself."
"Hmmmmm, partial success with that one I think..."
This post might be less perplexing if you've read this press release about this paper. Hemopressin will bomb like Rimonabant. It's based on the "toxic food environment" hypothesis, which says that the only reason I weigh under 65kg is my diet is too non-hedonistic for me to over indulge in. Conversely a toke of dope should make you obese by rendering the contents of the food aisle of a late night garage in to an hedonistic experience....
BTW, being a good member of law abiding citizenry I have no idea who does or doesn't do dope. But obesity is not a feature of any of the people whom I don't know don't do dope. I've heard about the munchies. I guess dope heads must eat less next day or exercise more, the skinny ones that is....
Peter
OK back to the OD and homocysteine as soon as I can get the next post written. Loads of great links have been emailed to me too, if I could just remember where I left them...
"Well yeah man, like sure, err, I mean, like no, like what was the question?"
"I'll take that as a no"
"Well sure doc, whatever, like, that's cool. You got something new for me to try?"
"We've developed hemopressin, a totally natural appetite modifying peptide. We don't know where it works in the brain, which neuronal circuits it influences or whether it is safe in humans. We think it's a good idea to give it to you at industrial dose rates which will flood your whole body to boost the micromolar concentrations naturally present in your brain. We think it's harmless and won't produce the depression or suicidal ideation which had Rimonabant withdrawn from the market a few years back. There's a big cheque involved."
"Ok doc, whatever. Like, ok, err, how much did you err like err, um, pay me?"
"My secretary will assist you with completing the deposit slip for your bank account. You do have a bank account?"
"Yeah, well, yeah, well, I can't remember really, did you say bank errr account...?"
"That door there, Mr Bender, the one you came in through."
"Ok, yeah, right"
Two weeks later
"Ah, good morning Mr Bender, a lovely day."
"What's the point? I think I'll just kill myself"
"How is you preoccupation with food?"
"What's the point? I think I'll just kill myself."
"Have you noticed any change in post coital satisfaction?"
"What's the point? I think I'll just kill myself."
"How is your satisfaction rating for visual appreciation?"
"What's the point, I think I'll just kill myself."
"Heard any good bands in the last two weeks?"
"What's the point, I think I'll just kill myself."
"Hmmmmmm. But interest in food is really down, yes?"
"What's the point, I think I'll just kill myself. Oh, Doc, before I go do it, those obese babies in nappies, are they on dope to get that obese? And the fat bankers too, they pot heads too? Never mind. What's the point, I think I'll just kill myself."
"Hmmmmm, partial success with that one I think..."
This post might be less perplexing if you've read this press release about this paper. Hemopressin will bomb like Rimonabant. It's based on the "toxic food environment" hypothesis, which says that the only reason I weigh under 65kg is my diet is too non-hedonistic for me to over indulge in. Conversely a toke of dope should make you obese by rendering the contents of the food aisle of a late night garage in to an hedonistic experience....
BTW, being a good member of law abiding citizenry I have no idea who does or doesn't do dope. But obesity is not a feature of any of the people whom I don't know don't do dope. I've heard about the munchies. I guess dope heads must eat less next day or exercise more, the skinny ones that is....
Peter
OK back to the OD and homocysteine as soon as I can get the next post written. Loads of great links have been emailed to me too, if I could just remember where I left them...
Sunday, July 04, 2010
Cholesterol hypothesis in 2010 part 2
Brief news update, keep reading the discussion (pdf). Ridker vs de Lorgeril goes on. Jupiter is looking like a gift to truth. Has to happen at some stage! Another great link from O'Primitivo.
EDIT: Here and here are two copies of the original article, just pulled up from comments. One has some problem with a Japanese character set (probably the first).
Peter
BTW comment moderation is in place (sorry Ricardo) on older posts to keep the viagra spam under control. I'll get to genuine comments asap, which is not always that soon at the moment!
EDIT: Here and here are two copies of the original article, just pulled up from comments. One has some problem with a Japanese character set (probably the first).
Peter
BTW comment moderation is in place (sorry Ricardo) on older posts to keep the viagra spam under control. I'll get to genuine comments asap, which is not always that soon at the moment!
Saturday, July 03, 2010
David Blaine and refeeding syndrome
I was looking around pubmed for the effects of fasting on homocysteine concentration. I'd seen a reference which claimed that HCy rose progressively with extended fasting beyond 12h, making a 12h fast the ideal time to measure. For some reason (probably to do with having 10 windows open in two web browsers) I lost it. While pubmeding to relocate it (and failing) I tripped over this rather nice paper on starvation.
It looks very like the second author is the chap in the box and this news report gives an idea of how the first and second authors interacted. It also explains why there were no "pre box" blood values for Blaine!
The paper has a number of gem lines in it. First was that, whatever homocysteine levels do in acute starvation, by 44 days of water fasting they are normal. Normal does not appear to be zero.
Next was the acute hypophosphataemia induced by re feeding. This kicked in by the end of day one. By this time Blaine had been given three cartons of a commercial liquid "food" including a total of just under 40 grams of sucrose. I wouldn't like to mention fructose as a trigger for hypophosphataemia, but it does get an honourable mention here and we've all listened to Lustig discuss fructose the net. Glucose also requires its place in the syndrome too. Dr Powel-Tuck seems to feel that this hypophosphataemia is to do with the energy intake. I suppose this is true if you are stuck in the time warp that energy=glucose, before anyone realised that free fatty acids could be used for energy. As far as I am aware no one has ever precipitated acute hypophosphataemia with an Intralipid infusion, disgusting though the thought of soya bean oil intravenously might be.
You just have to wonder what a supply of calories as fat and protein might have done by perhaps using, gasp, cheese. High in phosphate anyway.... Then add that essential nutrient, sucrose, later. In fact on day five Blaine took himself to the hospital canteen and had fish and chips against doctors orders. Marked fluid retention was the end result but nothing worse.
The fluid retention is very interesting. This is what they noted:
"A raised haematocrit on admission (reflecting haemoconcentration) changed to progressively lower values, despite cautious refeeding, and total avoidance of saline or additional salt during the hospital stay (Table 3). Albumin concentration on admission to hospital was slightly raised and declined gradually over 5 days probably due to plasma expansion. By day 10, 5 days after he left hospital on a free diet, he demonstrated mild pitting oedema."
and here is my favourite
"As refeeding raises plasma insulin, [then] potassium, phosphate and magnesium are driven intracellularly, and sodium extracellularly, expanding circulating volume and causing haemodilution, as indicated in D B by changes in his haematocrit and albumin levels."
It doesn't mention that insulin also causes renal sodium retention, but it does. I rather like this paper, I've not worked through the free full text but I note from the abstract that an insulin infusion with normoglycaemia causes sodium retention even in control rats, never mind spontaneously hypertensive rats. You learn so much from the control groups, even if thay are only rats. And we all thought that folks with hypertension while hyperinsulinaemic on a high carbohydrate diet were born with an in-built frusemide deficiency! Sounds more like Fanta poisoning to me. So, for Blaine, you have to ask whether the immediate return to a "balanced" diet, rich in nourishing sucrose and insulin spiking starch, is what precipitated the fluid retention and whether a more lipid based diet with gradual transition at real food for a few days before diving in to the "sugar as the main course with spuds for dessert" regime might have been less problematic.
I can't imagine anyone testing this idea, so perhaps it's a good job we have phosphate infusions available in UK teaching hospitals to pull post-starvation patients back from the brink of iatrogenic sugar poisoning during refeeding!
Peter
It looks very like the second author is the chap in the box and this news report gives an idea of how the first and second authors interacted. It also explains why there were no "pre box" blood values for Blaine!
The paper has a number of gem lines in it. First was that, whatever homocysteine levels do in acute starvation, by 44 days of water fasting they are normal. Normal does not appear to be zero.
Next was the acute hypophosphataemia induced by re feeding. This kicked in by the end of day one. By this time Blaine had been given three cartons of a commercial liquid "food" including a total of just under 40 grams of sucrose. I wouldn't like to mention fructose as a trigger for hypophosphataemia, but it does get an honourable mention here and we've all listened to Lustig discuss fructose the net. Glucose also requires its place in the syndrome too. Dr Powel-Tuck seems to feel that this hypophosphataemia is to do with the energy intake. I suppose this is true if you are stuck in the time warp that energy=glucose, before anyone realised that free fatty acids could be used for energy. As far as I am aware no one has ever precipitated acute hypophosphataemia with an Intralipid infusion, disgusting though the thought of soya bean oil intravenously might be.
You just have to wonder what a supply of calories as fat and protein might have done by perhaps using, gasp, cheese. High in phosphate anyway.... Then add that essential nutrient, sucrose, later. In fact on day five Blaine took himself to the hospital canteen and had fish and chips against doctors orders. Marked fluid retention was the end result but nothing worse.
The fluid retention is very interesting. This is what they noted:
"A raised haematocrit on admission (reflecting haemoconcentration) changed to progressively lower values, despite cautious refeeding, and total avoidance of saline or additional salt during the hospital stay (Table 3). Albumin concentration on admission to hospital was slightly raised and declined gradually over 5 days probably due to plasma expansion. By day 10, 5 days after he left hospital on a free diet, he demonstrated mild pitting oedema."
and here is my favourite
"As refeeding raises plasma insulin, [then] potassium, phosphate and magnesium are driven intracellularly, and sodium extracellularly, expanding circulating volume and causing haemodilution, as indicated in D B by changes in his haematocrit and albumin levels."
It doesn't mention that insulin also causes renal sodium retention, but it does. I rather like this paper, I've not worked through the free full text but I note from the abstract that an insulin infusion with normoglycaemia causes sodium retention even in control rats, never mind spontaneously hypertensive rats. You learn so much from the control groups, even if thay are only rats. And we all thought that folks with hypertension while hyperinsulinaemic on a high carbohydrate diet were born with an in-built frusemide deficiency! Sounds more like Fanta poisoning to me. So, for Blaine, you have to ask whether the immediate return to a "balanced" diet, rich in nourishing sucrose and insulin spiking starch, is what precipitated the fluid retention and whether a more lipid based diet with gradual transition at real food for a few days before diving in to the "sugar as the main course with spuds for dessert" regime might have been less problematic.
I can't imagine anyone testing this idea, so perhaps it's a good job we have phosphate infusions available in UK teaching hospitals to pull post-starvation patients back from the brink of iatrogenic sugar poisoning during refeeding!
Peter
Folate and homocysteine
Anna (many thanks) supplied me with a copy of the paper with a title which suggested that homocysteine was a stimulator of sulphate incorporation in to cartilage comparable to ILGF-1 (somatomedin/sulphation factor in those days). They were looking at concentrations of homocysteine comparable to those seen in children with the genetic lack of the enzyme cystathione synthetase, around 10mg/dl. That's VERY high, about 10 times the level in the blood of a normal person.
At this concentration there are undoubtedly marked skeletal deformities in children with homocysteinuria, presumably due to elevated homocysteine mimicing ILGF1 in their growing bones. As normal children appear to develop GAG containing arteriosclerosis at an early age then the ability of markedly elevated homocysteine to produces excessive GAG incorporation in to cartilage might very well be expected to increase the incorporation of GAG in to arterial plaque from physiological amounts to pathological amounts. That doesn't seem controversial to me.
The question is then whether homocysteine, at the concentrations seen in the plasma of the genetically more normal general population, drives arteriosclerosis. And, much more interesting, whether lowering homocysteine prevents cardiovascular disease in this population.
The vast majority of the work on homocysteine was done by Kilmer McCully and is covered by his book The Homocysteine Revolution. I think it's reasonable to summarise his approach to diet and cardiovascular health as to "eat Food". Food, with a capital F, denotes sources of B6, B12 and folate, three of the main factors for the metabolism of homocysteine. Needless to say there is a marked de-emphasis of sucrose and white flour consumption. But there is also a de-emephasis on white fat. Obviously there is not a whole lot of B6, B12 or folate in lard or beef dripping. When you take this line of thought to its logical conclusion you end up with a diet containing lots of fruit, vegetables, fresh whole grains and good quality lean meat. It's not exactly the Optimal Diet, in fact the term that comes to mind is "Ornish" plus meat. Would this work? Who knows? As far as I am aware Ornish has never tested his diet ideas. But the concept of whole food, freshly prepared, makes a lot of sense provided you don't mind the auto immune diseases from gluten and have not already broken you liver with decades of the SAD to allow blood glucose of spike to 200mg/dl after a bowl of whole meal pasta.
For folks too lazy to cook or juice some leaves, how about a B12/folate/B6 pill? Well the Norwegians have checked it and the initial problem is that it doesn't work for CVD, though it drops homocysteine nicely. The paper is from 2009. You can read the full text if you would like the to know their proposed mechanisms for the failure of vitamin induced reductions of homocysteine to prevent CVD events, but here's the executive summary:
"All the above mechanisms partly explain why clinical trials on Hcy lowering, such as the VISP, NORVIT, or HOPE-2 and possibly others to be conducted, failed to report any improvement in CVD risk and clinical outcome. Maybe more efficient ways to target Hcy metabolism, other than vitamin supplementation, should be examined. Focusing on increasing Hcy renal clearance or reducing asymmetric dimethylarginine levels would be potentially useful. In addition, other strategies able to increase intracellular 5-MTHF should be developed, to achieve the maximum regulation of intracellular Hcy metabolism."
The problems with vitamin treatment for elevated homocysteine in CVD have continued to in 2010. There has also been a follow on report on cancer and all cause mortality, a 2010 paper from the Norway studies, which does not make the lowering of homocysteine by using B vitamins look too helpful.
The increase in all cause mortality is a very interesting finding. You could argue that, in people without genetic homocysteinuria, that there might be some benefit from homocysteine at around 13micromol/l which is lost by lowering it to 9micromol/l, assuming you are eating a diet which has already established your heart disease. Or, equally, you could argue that taking vitamin B12 and folate, in the form of a vitamin supplement, is bad for you. Perhaps 0.8mg of synthetic drug grade folic acid is not quite the same as eating a few leaves. Quite a lot of leaves in fact.
The later idea is interesting as the WHEL intervention study, with it's significantly increased vegetable (and so probably folate) intake, didn't actually kill anyone beyond the death rate in the control group. Mind you, it didn't help anyone either but then eating leaves for health is a bit of a weird idea to me.....
So there's the choice. Is B12/folate supplementation bad for you? Or is homocystene helpful in small amounts and damaging in large amounts? A bit like oxygen.
Peter
EDIT there has been a similar report from Oxford with similar trends but with no statistical significance. The Oxford study used 0.4mg folic acid and the placebo group will have been eating UK breakfast cereals which are folate supplemented. Norway does not supplement it's food supply with folate so compared 0.8mg folate with zero supplementary folate level for the placebo group. There looks to be a dose response rate to folic acid toxiciy, if that's what the driver is for the problems. Heartwire produced a nice summary slide.
I realise that none of the changes are statistically significant but every parameter was worse in the folic acid/B12 group. The Norway study is in a better position to find significant effects and p does drop below 0.05. The Norway study is also much less likely to be drug money influenced. Tends to be convincing.
At this concentration there are undoubtedly marked skeletal deformities in children with homocysteinuria, presumably due to elevated homocysteine mimicing ILGF1 in their growing bones. As normal children appear to develop GAG containing arteriosclerosis at an early age then the ability of markedly elevated homocysteine to produces excessive GAG incorporation in to cartilage might very well be expected to increase the incorporation of GAG in to arterial plaque from physiological amounts to pathological amounts. That doesn't seem controversial to me.
The question is then whether homocysteine, at the concentrations seen in the plasma of the genetically more normal general population, drives arteriosclerosis. And, much more interesting, whether lowering homocysteine prevents cardiovascular disease in this population.
The vast majority of the work on homocysteine was done by Kilmer McCully and is covered by his book The Homocysteine Revolution. I think it's reasonable to summarise his approach to diet and cardiovascular health as to "eat Food". Food, with a capital F, denotes sources of B6, B12 and folate, three of the main factors for the metabolism of homocysteine. Needless to say there is a marked de-emphasis of sucrose and white flour consumption. But there is also a de-emephasis on white fat. Obviously there is not a whole lot of B6, B12 or folate in lard or beef dripping. When you take this line of thought to its logical conclusion you end up with a diet containing lots of fruit, vegetables, fresh whole grains and good quality lean meat. It's not exactly the Optimal Diet, in fact the term that comes to mind is "Ornish" plus meat. Would this work? Who knows? As far as I am aware Ornish has never tested his diet ideas. But the concept of whole food, freshly prepared, makes a lot of sense provided you don't mind the auto immune diseases from gluten and have not already broken you liver with decades of the SAD to allow blood glucose of spike to 200mg/dl after a bowl of whole meal pasta.
For folks too lazy to cook or juice some leaves, how about a B12/folate/B6 pill? Well the Norwegians have checked it and the initial problem is that it doesn't work for CVD, though it drops homocysteine nicely. The paper is from 2009. You can read the full text if you would like the to know their proposed mechanisms for the failure of vitamin induced reductions of homocysteine to prevent CVD events, but here's the executive summary:
"All the above mechanisms partly explain why clinical trials on Hcy lowering, such as the VISP, NORVIT, or HOPE-2 and possibly others to be conducted, failed to report any improvement in CVD risk and clinical outcome. Maybe more efficient ways to target Hcy metabolism, other than vitamin supplementation, should be examined. Focusing on increasing Hcy renal clearance or reducing asymmetric dimethylarginine levels would be potentially useful. In addition, other strategies able to increase intracellular 5-MTHF should be developed, to achieve the maximum regulation of intracellular Hcy metabolism."
The problems with vitamin treatment for elevated homocysteine in CVD have continued to in 2010. There has also been a follow on report on cancer and all cause mortality, a 2010 paper from the Norway studies, which does not make the lowering of homocysteine by using B vitamins look too helpful.
The increase in all cause mortality is a very interesting finding. You could argue that, in people without genetic homocysteinuria, that there might be some benefit from homocysteine at around 13micromol/l which is lost by lowering it to 9micromol/l, assuming you are eating a diet which has already established your heart disease. Or, equally, you could argue that taking vitamin B12 and folate, in the form of a vitamin supplement, is bad for you. Perhaps 0.8mg of synthetic drug grade folic acid is not quite the same as eating a few leaves. Quite a lot of leaves in fact.
The later idea is interesting as the WHEL intervention study, with it's significantly increased vegetable (and so probably folate) intake, didn't actually kill anyone beyond the death rate in the control group. Mind you, it didn't help anyone either but then eating leaves for health is a bit of a weird idea to me.....
So there's the choice. Is B12/folate supplementation bad for you? Or is homocystene helpful in small amounts and damaging in large amounts? A bit like oxygen.
Peter
EDIT there has been a similar report from Oxford with similar trends but with no statistical significance. The Oxford study used 0.4mg folic acid and the placebo group will have been eating UK breakfast cereals which are folate supplemented. Norway does not supplement it's food supply with folate so compared 0.8mg folate with zero supplementary folate level for the placebo group. There looks to be a dose response rate to folic acid toxiciy, if that's what the driver is for the problems. Heartwire produced a nice summary slide.
I realise that none of the changes are statistically significant but every parameter was worse in the folic acid/B12 group. The Norway study is in a better position to find significant effects and p does drop below 0.05. The Norway study is also much less likely to be drug money influenced. Tends to be convincing.
Saturday, June 26, 2010
Gwyneth Paltrow has osteopaenia
Just a brief mention. Poor girl. Wrecking your health on macrobiotics and fish. The things people do! Interestingly it reminds me of the vegetarianism and hypovitaminosis D in Glasgow. Meat seems to be more effective than D supplements, though D will do the job in big enough doses...
Peter
Still not a lot of net or thinking time but a post is cooking.
Peter
Still not a lot of net or thinking time but a post is cooking.
Wednesday, June 02, 2010
Arteriosclerosis (5) GAG and sudden death part two; the pictures
Many thanks to everyone who sent me various pdfs after the sudden cardiac death without arteriosclerosis post. Anna got me the pictures of the arterial supply to a "normal" person's atrioventricular node and that to the AV node of a sudden death person from Burke et al's paper.
Here is the "normal". Moon would describe this, correctly, as moderately arteriosclerotic. Lots of intimal hyperplasia and you can't tell much about the degree of damage to the elastic layer from this picture. I'm loathe to believe the authors' suggestion that the elastic layer is completely normal:
Next is the "non arteriosclerotic but dysplastic" artery from a sudden death victim. Burke et al ignore 100 years of pathology by describing it as non arteriosclerotic. You might forgive them as the lesions contain no cholesterol and they are lost in the idea that LDL cholesterol is the primary driver of arteriosclerosis which means, obviously, that they are not in a position to understand what they see. Or to investigate causes. They might want to start with copper status, ascorbate status, insulin levels at the time of death and familial problems with elastin structure; these might do for a start. Maybe clotting factors too. Also, given a retrospectoscope, the post prandial sympathetic response to a PowerBar would be very interesting. But LDL cholesterol? What can that have to do with the formative lesions of arteriosclerosis which contain no cholesterol?
Notice that the intimal thickening is present but there is also marked hypertrophy of the medial muscle cells. This is a classic resonse to severe elastosis, there's another post there; elastin as a regulator of vascular smooth muscle phenotype...
Peter
Afterthought: I wonder whether location of the artery matters. The left anterior descending coronary artery, where I have my seven point calcium score, is the least supported by cardiac muscle, so experiences the greatest trans-mural pressure gradient during systole. LAD is the classic site for calcification in non smokers. It would be interesting to see if sudden death victims have more superficial arteries supplying their AV node than non sudden death people........ Haven't checked the anatomy for this, hmmmmm.
Here is the "normal". Moon would describe this, correctly, as moderately arteriosclerotic. Lots of intimal hyperplasia and you can't tell much about the degree of damage to the elastic layer from this picture. I'm loathe to believe the authors' suggestion that the elastic layer is completely normal:
Next is the "non arteriosclerotic but dysplastic" artery from a sudden death victim. Burke et al ignore 100 years of pathology by describing it as non arteriosclerotic. You might forgive them as the lesions contain no cholesterol and they are lost in the idea that LDL cholesterol is the primary driver of arteriosclerosis which means, obviously, that they are not in a position to understand what they see. Or to investigate causes. They might want to start with copper status, ascorbate status, insulin levels at the time of death and familial problems with elastin structure; these might do for a start. Maybe clotting factors too. Also, given a retrospectoscope, the post prandial sympathetic response to a PowerBar would be very interesting. But LDL cholesterol? What can that have to do with the formative lesions of arteriosclerosis which contain no cholesterol?
Notice that the intimal thickening is present but there is also marked hypertrophy of the medial muscle cells. This is a classic resonse to severe elastosis, there's another post there; elastin as a regulator of vascular smooth muscle phenotype...
Peter
Afterthought: I wonder whether location of the artery matters. The left anterior descending coronary artery, where I have my seven point calcium score, is the least supported by cardiac muscle, so experiences the greatest trans-mural pressure gradient during systole. LAD is the classic site for calcification in non smokers. It would be interesting to see if sudden death victims have more superficial arteries supplying their AV node than non sudden death people........ Haven't checked the anatomy for this, hmmmmm.
Tuesday, June 01, 2010
Costa del Glasgow
It's official (according to me), Dean Ornish is the cause of the current reversal of the recent fall in global temperature cause by us eating all of the mammoths. That's one hell of an achievement for one person's flatulence.
Peter
You have Elizabeth to blame for this post!
Peter
You have Elizabeth to blame for this post!
Cholesterol hypothesis in 2010
FSA in Glasgow
I thought I might just take a little time for a brief post , just some lightweight stuff from up here in Glasgow.
Glasgow is generally considered to be one of the less healthy cities in the UK, in terms of chronic disease. That makes it an excellent test-bed for ideas which might improve the health status of the population here and for the rest of the UK. You would have thought that we Glaswegians had nothing to lose from a dose of healthy eating. Siobhan Higgins and her group decided to test whether the current healthy eating advice from the Food Standard Agency (as of 2007) and the advice from the Department of Health, not updated since 1991, was good for Glasgow's post menopausal women. Or not.
The results of the Higgins study were published in 2009, so "nae rush" about checking the 1991 advice from the Department of Health.
The FSA-DoH advice is to reduce fat, especially saturated fat, to reduce sugar only if it is >10% of calories, plus to eat lots of stuff which is going to go down the loo 12 hours later (fibre).
The conclusion is that following UK Government advice, as epitomised by the FSA, damages every measured parameter reported in the study and probably damages a number more which were measured but didn't get reported. There is one exception, more on that later.
The change in HDL (downwards, of course) was not only statistically significant but biologically and probably clinically significant too (to a lipid hypothesis believer like Higgins). Of course this is rationalised by claiming that a subnormal HDL level is GOOD thing if you have a low HDL due to eating to FSA advice. The same low HDL is lethal if you self-select your diet. Hmmmmmmmmmm. What's the science behind this strange variation in the significance of a low HDL level?
Garbage trucks. My son loves garbage trucks. The blokes doing the wheelie bins always give him a wave and a grin. Back in Berkshire it was one of the highlights of his week! Aparently HDL is a garbage truck. Eat to FSA advice and your need for garbage trucks goes down. Woooooow! FSA + low HDL = Good Thing.
How true is this? Well Higgins has a reference! This is what she says:
"Lower fat intake is known to reduce the requirement for HDL-mediated cholesterol removal [27]"
Reference [27] says that a high carbohydrate diet lowers your HDL by decreasing production of ApoAs. The implication is that this is Good. I think that's bollocks. If you believe low HDL is bad, it's bad. Otherwise why measure the stuff, why try and raise it with torcetrapib?
FSA-DoH advice dropped these women's HDL to an unacceptable level. This is unacceptable. The women were injured. Full stop.
So what else happened? Despite weight loss triglycerides increased, fasting glucose rose, fasting insulin rose, HOMA rose, LDL dropped (probably smaller and denser LDL, obviously this was not checked but it will have been the case) and CRP rose.
NOTHING improved.
Luckily very few changes reached statistical significance within 4 weeks, but then it is hard to take a normal post menopausal woman in Glasgow and make her frankly diabetic in 4 weeks. But you can sure as hell get her started! Just employ a mainstream dietitian spouting FSA advice. I wonder if they did power calculations to make sure the p value for changes in glucose and insulin would fail to reach statistical significance by limiting the study size to just 12 victims? Bit of a cock-up on the HDL calculation then...
I was also wondering about the weight loss. It would have been interesting to measure waist:hip ratio and absolute change in waist circumference on a disaster diet. I was disappointed they didn't report these. Until I read the methods carefully and found that they actually did measure them. They just didn't report the changes in those measurements. I read the results very carefully, not reported. So I think we can safely assume the waist expanded, the hip measurement didn't change and the victims lost muscle. Non of these changes need to have been statistically significant but because fasting insulin rose it seems reasonable the assume the changes were toward that pot bellied, sarcopaenic physique so beloved of a modern dietician.
Final words of Higgins et al:
"In conclusion, the results of this study showed that whilst following the UK dietary guidelines to increase carbohydrate and reduce fat intake did appear to have adverse effects on HDL cholesterol concentration, these same dietary changes were also associated with some positive health effects on the antioxidant potential of the plasma and a reduction in BMI."
No no no no no. The HDL didn't "appear" to drop. It dropped. It dropped right out of the clinically acceptable range. These women were injured in the study, directly by the dietitians and indirectly by the FSA. I wonder if they were told to go back to their previous self selected diet to get their HDL back in to the clinically acceptable range and their triglycerides down? Ha ha ha.
Last two comments are about those positive effects, those on FRAP and BMI.
The group never mentioned uric acid. That's the mammalian antioxidant which normally goes up in response to fructose intake and gives the superficial impression that the sucrose in fruit is somehow healthy. I can't see the extra sucrose in any of the diet tables (obviously it went up as a % of calories, I was looking for an absolute increase) but I'm suspicious it's there somewhere. What was the uric acid level? Not measured. Duh.
The BMI dropped. Whoopee. Talk about treating a number! BMI decrease, especially in older people, is bad news anyway (for all cause mortality). Imagining that weight loss which is accompanied by a deterioration of every measured parameter is "a positive health benefit" just insults the intelligence. If it were "weight" per se which mattered then carrying a backpack or gaining muscle would be risk factors for heart disease.
So, can you make a resident of the least healthy city in the UK less healthy by altering their diet? Absolutely. Just follow FSA advice.
Peter
Glasgow is generally considered to be one of the less healthy cities in the UK, in terms of chronic disease. That makes it an excellent test-bed for ideas which might improve the health status of the population here and for the rest of the UK. You would have thought that we Glaswegians had nothing to lose from a dose of healthy eating. Siobhan Higgins and her group decided to test whether the current healthy eating advice from the Food Standard Agency (as of 2007) and the advice from the Department of Health, not updated since 1991, was good for Glasgow's post menopausal women. Or not.
The results of the Higgins study were published in 2009, so "nae rush" about checking the 1991 advice from the Department of Health.
The FSA-DoH advice is to reduce fat, especially saturated fat, to reduce sugar only if it is >10% of calories, plus to eat lots of stuff which is going to go down the loo 12 hours later (fibre).
The conclusion is that following UK Government advice, as epitomised by the FSA, damages every measured parameter reported in the study and probably damages a number more which were measured but didn't get reported. There is one exception, more on that later.
The change in HDL (downwards, of course) was not only statistically significant but biologically and probably clinically significant too (to a lipid hypothesis believer like Higgins). Of course this is rationalised by claiming that a subnormal HDL level is GOOD thing if you have a low HDL due to eating to FSA advice. The same low HDL is lethal if you self-select your diet. Hmmmmmmmmmm. What's the science behind this strange variation in the significance of a low HDL level?
Garbage trucks. My son loves garbage trucks. The blokes doing the wheelie bins always give him a wave and a grin. Back in Berkshire it was one of the highlights of his week! Aparently HDL is a garbage truck. Eat to FSA advice and your need for garbage trucks goes down. Woooooow! FSA + low HDL = Good Thing.
How true is this? Well Higgins has a reference! This is what she says:
"Lower fat intake is known to reduce the requirement for HDL-mediated cholesterol removal [27]"
Reference [27] says that a high carbohydrate diet lowers your HDL by decreasing production of ApoAs. The implication is that this is Good. I think that's bollocks. If you believe low HDL is bad, it's bad. Otherwise why measure the stuff, why try and raise it with torcetrapib?
FSA-DoH advice dropped these women's HDL to an unacceptable level. This is unacceptable. The women were injured. Full stop.
So what else happened? Despite weight loss triglycerides increased, fasting glucose rose, fasting insulin rose, HOMA rose, LDL dropped (probably smaller and denser LDL, obviously this was not checked but it will have been the case) and CRP rose.
NOTHING improved.
Luckily very few changes reached statistical significance within 4 weeks, but then it is hard to take a normal post menopausal woman in Glasgow and make her frankly diabetic in 4 weeks. But you can sure as hell get her started! Just employ a mainstream dietitian spouting FSA advice. I wonder if they did power calculations to make sure the p value for changes in glucose and insulin would fail to reach statistical significance by limiting the study size to just 12 victims? Bit of a cock-up on the HDL calculation then...
I was also wondering about the weight loss. It would have been interesting to measure waist:hip ratio and absolute change in waist circumference on a disaster diet. I was disappointed they didn't report these. Until I read the methods carefully and found that they actually did measure them. They just didn't report the changes in those measurements. I read the results very carefully, not reported. So I think we can safely assume the waist expanded, the hip measurement didn't change and the victims lost muscle. Non of these changes need to have been statistically significant but because fasting insulin rose it seems reasonable the assume the changes were toward that pot bellied, sarcopaenic physique so beloved of a modern dietician.
Final words of Higgins et al:
"In conclusion, the results of this study showed that whilst following the UK dietary guidelines to increase carbohydrate and reduce fat intake did appear to have adverse effects on HDL cholesterol concentration, these same dietary changes were also associated with some positive health effects on the antioxidant potential of the plasma and a reduction in BMI."
No no no no no. The HDL didn't "appear" to drop. It dropped. It dropped right out of the clinically acceptable range. These women were injured in the study, directly by the dietitians and indirectly by the FSA. I wonder if they were told to go back to their previous self selected diet to get their HDL back in to the clinically acceptable range and their triglycerides down? Ha ha ha.
Last two comments are about those positive effects, those on FRAP and BMI.
The group never mentioned uric acid. That's the mammalian antioxidant which normally goes up in response to fructose intake and gives the superficial impression that the sucrose in fruit is somehow healthy. I can't see the extra sucrose in any of the diet tables (obviously it went up as a % of calories, I was looking for an absolute increase) but I'm suspicious it's there somewhere. What was the uric acid level? Not measured. Duh.
The BMI dropped. Whoopee. Talk about treating a number! BMI decrease, especially in older people, is bad news anyway (for all cause mortality). Imagining that weight loss which is accompanied by a deterioration of every measured parameter is "a positive health benefit" just insults the intelligence. If it were "weight" per se which mattered then carrying a backpack or gaining muscle would be risk factors for heart disease.
So, can you make a resident of the least healthy city in the UK less healthy by altering their diet? Absolutely. Just follow FSA advice.
Peter
Wednesday, May 12, 2010
Arteriosclerosis (2) and sulphation factor
The alpha granules of platelets contain many substances which are useful for repairing damaged tissue, especially damaged blood vessels. That's no surprise.
The addition of sulphate to sugar and sugar derived molecules is essential for the production of many glycosaminoglycans. Most of the work with sulphation has centred on cartilage development but an equally interesting location of sulphated GAG production is the arterial wall which leads to the formation of fibrous plaques, via proteoglycans, in stressed areas.
In ancient days of old Salmon and Daughaday (1957 from the look of this title) wanted to assay Growth Hormone. They developed GH deficient rats (better not ask how) then took cartilage samples and added GH to see if they could get sulphate uptake as a method of assaying GH levels in serum, a bioassay. The idea failed and they eventually found out that "Sulphation Factor" was needed for sulphate uptake and SF was produced in response to GH by the liver, GH per se was not active on isolated chondrocytes. To confuse matters further, at some stage SF was re named Somatomedin. To make matters even more confusing somatomedin was even later discovered to be ILGF-1. There is a nice summary of the story here.
Even today we still use ILGF-1 as a surrogate for measuring GH in cats with GH secreting tumours.
So the sulphation of proteoglycans is mediated through ILGF-1. A brief scan (Wiki) of the contents of alpha granules in platelets lists ILGF-1 as the first ingredient. Platelets deliver ILGF-1 to damaged areas. It's not exactly surprising that ILGF-1 promotes proteoglycan sulphation as well as, or as part of, tissue repair.
Human beings are not designed to have fasting insulin levels over 200pmol with a rise of up to 1000pmol (in extreme cases) post prandially. If we do things to ourselves which produce this effect we can expect to have insulin interacting of ILGF-1 receptors which were never designed to see such astronomical insulin levels. Even if their true ligand is at minimal concentration, arterial wall cells will behave as if platelets are delivering ILGF-1 in "damage repairing" amounts. Even in the absence of damage.
It does not take a great leap of faith to suggest that the normal physiological response to normal vascular injury might be driven beyond an appropriate level by chronic hyperinsulinaemia acting on ILGF-1 receptors.
Perhaps type two diabetics should be at increased risk of heart disease? I wonder if anyone has checked this...
Peter
BTW anyone who has followed the homocystine hypothesis of CVD will find the title (all I can get) of this paper of some interest.
The addition of sulphate to sugar and sugar derived molecules is essential for the production of many glycosaminoglycans. Most of the work with sulphation has centred on cartilage development but an equally interesting location of sulphated GAG production is the arterial wall which leads to the formation of fibrous plaques, via proteoglycans, in stressed areas.
In ancient days of old Salmon and Daughaday (1957 from the look of this title) wanted to assay Growth Hormone. They developed GH deficient rats (better not ask how) then took cartilage samples and added GH to see if they could get sulphate uptake as a method of assaying GH levels in serum, a bioassay. The idea failed and they eventually found out that "Sulphation Factor" was needed for sulphate uptake and SF was produced in response to GH by the liver, GH per se was not active on isolated chondrocytes. To confuse matters further, at some stage SF was re named Somatomedin. To make matters even more confusing somatomedin was even later discovered to be ILGF-1. There is a nice summary of the story here.
Even today we still use ILGF-1 as a surrogate for measuring GH in cats with GH secreting tumours.
So the sulphation of proteoglycans is mediated through ILGF-1. A brief scan (Wiki) of the contents of alpha granules in platelets lists ILGF-1 as the first ingredient. Platelets deliver ILGF-1 to damaged areas. It's not exactly surprising that ILGF-1 promotes proteoglycan sulphation as well as, or as part of, tissue repair.
Human beings are not designed to have fasting insulin levels over 200pmol with a rise of up to 1000pmol (in extreme cases) post prandially. If we do things to ourselves which produce this effect we can expect to have insulin interacting of ILGF-1 receptors which were never designed to see such astronomical insulin levels. Even if their true ligand is at minimal concentration, arterial wall cells will behave as if platelets are delivering ILGF-1 in "damage repairing" amounts. Even in the absence of damage.
It does not take a great leap of faith to suggest that the normal physiological response to normal vascular injury might be driven beyond an appropriate level by chronic hyperinsulinaemia acting on ILGF-1 receptors.
Perhaps type two diabetics should be at increased risk of heart disease? I wonder if anyone has checked this...
Peter
BTW anyone who has followed the homocystine hypothesis of CVD will find the title (all I can get) of this paper of some interest.
Monday, May 10, 2010
Arteriosclerosis (3) and von Willebrand Disease
As soon as you start to think about arteriosclerosis as a thrombotic, platelet driven process you immediately think about von Willebrand disease (vWD) of course. vWD is a real laugh for a surgeon who makes the diagnosis 10 minutes in to an operation on a young Doberman which won't stop bleeding wherever he cuts it. Giving that NSAID at premed time suddenly seems to have morphed in to a very dumb idea. And the desmopressin seemed too expensive to have on the shelf before today. But I digress.
vWD means your platelets won't stick. Generally this is a Bad Thing.
OK, more pictures. Fuster's group produced this nice early paper "Resistance to arteriosclerosis in pigs with von Willebrand's disease. Spontaneous and high cholesterol diet-induced arteriosclerosis" from which the micrographs are taken.
Similar data were generated by Griggs et al but interpreted somewhat differently. Personally Fuster comes over as by far the more convincing. At least he doesn't inflate a balloon in a coronary artery, then pull on the catheter to induce "arteriosclerosis"!
Happily there is some convergence of opinion, as should happen when both sides are fairly correct and a lot of ifs, buts and maybes are still present in our knowledge base of arteriosclerosis.
So lets look at the micrographs from Fuster. Here's the first set:
These are all taken from normal pigs eating normal crap in a bag. Image A is stained for elastin and was taken from a non damaged area of aorta. Look at the elastin layer. Nice and continuous. Intima is one cell thick.
Image B is from a similar pig but the section is taken through a fibrous plaque. Obviously there's a plaque, which is what Fuster is interested in. But to me there is duplication and fraying of the elastin layer, especially on the left of the picture, but also to the right. Both images A and B are taken at X160 magnification, just eyeball-compare the quality of the elastin in the two areas.
Image C is Sudan IV stained for lipid, so elastin doesn't show. The arrow shows a cell with lipid. There are a few more scattered around but this is certainly not a lipid lesion. It's worth pointing out that platelets are 17% lipid, so some will be floating around from this source.
These next two pictures are from a pig with severe homozygous vWD:
The macroscopic picture is of the fatty areas (Griggs, the rival paper, describes these as "sudanophilia" and implies that they are arteriosclerotic. They're not). The micrograph below in image B is also stained with Sudan IV and shows exactly how shallow this lipid layer is. There is no intimal thickening, no fibrosis and there is absolutely no change in the media below the lesion. At some time I'll have a think about what is going on here, but for the moment let's leave it as non-arteriosclerostic fatty accumulation which does not form an epithelium and does not stop Evans Blue dye from penetrating in to the wall of the aorta.
Finally some fantastic electron micrographs, all from pigs with severe vWD:
First look at the scanning EM image C. This is a non stressed area of aorta. Nice epithelialised surface. Image A is from a stressed area of aorta which would have developed a fibrous plaque, given a few platelets to cover it, but in vWD this is not going to happen. Rough is not the word. Images B and D are the comparable transmission EMs.
Having vWD is no fun. Endothelial injury is normal. vWD patients bruise all over the place, all the time. These injuries also occur in normal people and are repaired without problem in normal people. Duguid considered atherosclerosis to be pathological and Moon came to the same conclusion. I'm not sure it is that simple. The process which causes arteriosclerosis also keeps us alive. Life saving pathology?
Addendum: Eddie Vos, through THINCS, quoted from this book while I was typing the above post.
From a section describing 49 aortas from monkeys SHOT in the wild,(page 248):
"The small elevated plaques are composed predominantly of smooth muscle cells and elastic tissue and are practically devoid of fats. Thus, the resemblance to human fibrous plaques noted grossly is not borne out microscopically."
My own opinion is that this would be true if all human lesions were lipid based. As many humans develop many small non lipid plaques which sound to be of similar nature to those described in chimps I'm tempted to believe these lesions are normal and physiological. Converting these non lipid plaques to unstable plaques full of linoleic acid and cholesterol crystals is the trick needed to keep cardiologists in business.
Peter
vWD means your platelets won't stick. Generally this is a Bad Thing.
OK, more pictures. Fuster's group produced this nice early paper "Resistance to arteriosclerosis in pigs with von Willebrand's disease. Spontaneous and high cholesterol diet-induced arteriosclerosis" from which the micrographs are taken.
Similar data were generated by Griggs et al but interpreted somewhat differently. Personally Fuster comes over as by far the more convincing. At least he doesn't inflate a balloon in a coronary artery, then pull on the catheter to induce "arteriosclerosis"!
Happily there is some convergence of opinion, as should happen when both sides are fairly correct and a lot of ifs, buts and maybes are still present in our knowledge base of arteriosclerosis.
So lets look at the micrographs from Fuster. Here's the first set:
These are all taken from normal pigs eating normal crap in a bag. Image A is stained for elastin and was taken from a non damaged area of aorta. Look at the elastin layer. Nice and continuous. Intima is one cell thick.
Image B is from a similar pig but the section is taken through a fibrous plaque. Obviously there's a plaque, which is what Fuster is interested in. But to me there is duplication and fraying of the elastin layer, especially on the left of the picture, but also to the right. Both images A and B are taken at X160 magnification, just eyeball-compare the quality of the elastin in the two areas.
Image C is Sudan IV stained for lipid, so elastin doesn't show. The arrow shows a cell with lipid. There are a few more scattered around but this is certainly not a lipid lesion. It's worth pointing out that platelets are 17% lipid, so some will be floating around from this source.
These next two pictures are from a pig with severe homozygous vWD:
The macroscopic picture is of the fatty areas (Griggs, the rival paper, describes these as "sudanophilia" and implies that they are arteriosclerotic. They're not). The micrograph below in image B is also stained with Sudan IV and shows exactly how shallow this lipid layer is. There is no intimal thickening, no fibrosis and there is absolutely no change in the media below the lesion. At some time I'll have a think about what is going on here, but for the moment let's leave it as non-arteriosclerostic fatty accumulation which does not form an epithelium and does not stop Evans Blue dye from penetrating in to the wall of the aorta.
Finally some fantastic electron micrographs, all from pigs with severe vWD:
First look at the scanning EM image C. This is a non stressed area of aorta. Nice epithelialised surface. Image A is from a stressed area of aorta which would have developed a fibrous plaque, given a few platelets to cover it, but in vWD this is not going to happen. Rough is not the word. Images B and D are the comparable transmission EMs.
Having vWD is no fun. Endothelial injury is normal. vWD patients bruise all over the place, all the time. These injuries also occur in normal people and are repaired without problem in normal people. Duguid considered atherosclerosis to be pathological and Moon came to the same conclusion. I'm not sure it is that simple. The process which causes arteriosclerosis also keeps us alive. Life saving pathology?
Addendum: Eddie Vos, through THINCS, quoted from this book while I was typing the above post.
From a section describing 49 aortas from monkeys SHOT in the wild,(page 248):
"The small elevated plaques are composed predominantly of smooth muscle cells and elastic tissue and are practically devoid of fats. Thus, the resemblance to human fibrous plaques noted grossly is not borne out microscopically."
My own opinion is that this would be true if all human lesions were lipid based. As many humans develop many small non lipid plaques which sound to be of similar nature to those described in chimps I'm tempted to believe these lesions are normal and physiological. Converting these non lipid plaques to unstable plaques full of linoleic acid and cholesterol crystals is the trick needed to keep cardiologists in business.
Peter
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