Just a quick post about moving, I was reminded by Tom Naughton's current post on his move.
We used a national company for the move, the driver plus three local helpers loaded the truck in Berkshire, he drove it up and two guys helped him unload at the Glasgow end.
All were thin as rakes. Obviously exercise makes you thin. Duh. These guys were exercising alright. Getting as many books as we own up the stairs, for storage in the bedroom cupboard, was no minor feat. This was almost certainly done on a diet of carbs and alcohol (not on the job of course, but one chap's comment was that he wouldn't want to attempt our Glasgow stairs on a Saturday night, crashing on the couch would be needed!).
At least that was how it seems on the surface. But in reality there is another factor involved. It brought home to me Gary Taubes' comment about nicotine releasing free fatty acids from adipocytes to allow humans access to the energy stored in their fat cells. Nicotine is an archetypal slimming drug.
Every 60 minutes there was an obligatory "fag break" as it was described. My impression was that they were automatically maintaining a fixed level of nicotine in their blood. Whether this was a fluke and we just happened to have six nicotine addicts in our crew, or whether people in hard manual labour accidentally discover that smoking makes the job a darn sight easier is open to speculation. But a few free fatty acids, irrespective of your insulin levels, might come in useful when you have to shift heavy stuff for hours at a time.
I doubt I'd have noticed anything without Gary Taubes giving the pointer.
Peter
Tuesday, August 11, 2009
Monday, August 10, 2009
Heart failure and insulin resistance
While I was off line for several weeks I had a browse through some of the random texts lying around my hard drive. This one in particular caught my eye and has started of a train of thought which seems interesting. This is the basics of the paper:
The healthy heart likes non esterified fatty acids:
"NEFA are the preferred metabolic substrate because of the high yield of ATP when NEFA are fully oxidized"
NEFA burn primarily in the mitochondria. But without oxygen there is no possibility of doing this, you cannot oxidise fats without oxygen. Glucose to lactate, an anaerobic process, yes:
"However, under circumstances of increased myocardial work or limited oxygen availability, the heart turns to glucose as the more efficient fuel for ATP generation"
Glycolysis, with its poor ATP yield, is better than no ATP at all and quite logical when there is insufficient oxygen to keep the mitochondria working. But when the heart is going in to failure it comes to prefer glucose, ultimately even at tickover:
"When the heart is injured and left ventricular (LV) function is depressed on a chronic basis, there is a shift to glucose as the preferred substrate under basal circumstances"
Why should this be? Why not stick with fat. NEFA are the devil you know and a very benign devil they are too... The problem is that the whole system for burning NEFA, from the cell surface receptor to the mitochondrial transport system has, by this stage, already been deliberately shut down:
"this shift in substrate preference is a highly regulated transcriptional event. Importantly, the changes in gene transcription involve down-regulation of transport mechanisms and enzymes involved in fatty acid oxidation. This includes decreases in the NEFA receptor—peroxisome proliferator activated receptor- alpha (PPAR alpha)—and its co-factor, the retinoic acid receptor RXR, as well as a series of enzymes, including carnitine palmitoyltransferase-1 (CPT-1), which is rate limiting in the transport of fatty acid coenzyme A (CoA) to the inner mitochondrial membrane".
You have to wonder why this is. It's not some accidental failure. The heart is sitting in a sea of both NEFA and glucose, and it carefully shuts down it's NEFA processsing equipment to rely on glucose, then shuts off glucose uptake and dies. This is not an adaptive process!
The shut down of glucose usage probably comes back to good old fatty acids causing insulin resistance. The body has sensors for detecting a decreased cardiac output. On an evolutionary basis the assumption is that a serious fall in cardiac output is due to a serious loss of blood volume. Fluid retention and increased sympathetic nervous system activity are standard adaptive responses to blood loss. Increased sympathetic nervous system activity not only boosts cardiac work (hence increases cardiac output to compensate for low blood volume, mimicked by the failing myocardium) at the cost of increased oxygen demand, but also releases free fatty acids from adipocytes to supply the evolutionarily preferred heart fuel. Actually, the NEFA will supply a large proportion of the whole body needs because if you been mauled by a tiger you're not going to go grubbing for tubers to run your metabolism on glucose. Free fatty acids are taken up by the heart down a concentration gradient. If they accumulate in the cytoplasm because the heart has shut down its fat burning system it's easy to see why triglycerides accumulate in the cell. This signals insulin resistance. There is enough fat, no need for glucose. This makes the heart say no to glucose, that's understandable.
Unfortunately, if the fatty acid burning system has been carefully and inappropriately shut down, saying no to glucose becomes catastrophic. Which it is.
The whole drive of the paper is to develop techniques to get the heart back running on glucose in the face of myocardial insulin resistance, for which we can read due to a failure to burn NEFA. Obviously a supra physiological infusion of insulin would overcome this, but it's a big volume to give to a heart failure patient and causes issues with sodium retention anyway, another post there. So insulin sensitisers are high on the priority list. Pity Actos and Avandia cause heart failure! Interestingly among the several postulated mechanism of action suggested for metformin, one is increasing fatty acid oxidation. In my simplistic view this would decrease intracellular triglycerides and allow a reduction in insulin resistance. Thiazolidinediones and other insulin sensitisers are the drugs the paper is thinking about:
"At present, concerns about peripheral edema have limited the use of TZDs (Thiazolidinediones [Actos and Avandia]) in patients with heart failure, although the mechanisms of this phenomenon have not been elucidated. An attractive alternative might involve the derivatives of the proglucagon family, the glucagonlike peptides, which possess insulinotropic, insulinomimetic, and glucagonostatic properties. Importantly, these naturally occurring incretins are largely devoid of hypoglycemic risks, as their insulinotropic properties are attenuated when plasma glucose falls below 70 mg/dL. The short duration of action requires continuous subcutaneous infusion, which constitutes a potential drawback to chronic treatment"
OK, hands up who has spotted the missing idea? Yes, right in one, ketone bodies. Straight to the mitochondria without insulin, CD38 or CPT-1. Increased cardiac work/output without increased oxygen demand. They completely by pass insulin resistance. So they're a nice sticking plaster on a much more interesting problem.
The interesting problem is: Why did the myocardium decide to shut down its fat burning system?
I think you can argue that it is because glucose is so toxic when it is present in high levels in the blood stream that it has to be burned first. While it is still within the power of the pancreas to force glucose in to muscles cells, those cells burn it rather than having it lying around glycating every protein in sight. A little can be stored as glycogen, but if you are on the SAD (including the 3.00am refrigerator raids, and that's not roast beef in the fridge...) and chronically hyperglycaemic/hyperinsulinaemic, glycogen stores are going to be more than full. No, chronic excess glucose oversupply needs burning as fast as possible, you can pack away the far burning system if blood glucose concentration is always being pushed upwards. Maintain this for long enough and it becomes a way of life, and eventually a way of death. Burning glucose in the face of increasing insulin resistance due to the sympathetic nervous system freeing up NEFA, being unaware of the catastrophic loss of fat burning ability, is a non starter.
Ketosis and normolgycaemia would allow the unpackaging of that stored fat burning system. It's not gone for ever, the genes are still there.... Given a few tools NEFA no longer need be the enemy, rather the preferred fuel once again. As the primary fuel the fact that they are present in the cytoplasm signalling the rejection of glucose by signalling insulin resistance is no problem. With efficient fat burning, as soon as the NEFA supply drops cytoplasm trigycerides will drop and insulin can get back to work to allow glucose to be used.
Things can get back to the way they were meant to be with NEFA as the primary fuel with the additional facility to use glucose in dire circumstances.
More on the shutting down of fat burning next.
Peter
The healthy heart likes non esterified fatty acids:
"NEFA are the preferred metabolic substrate because of the high yield of ATP when NEFA are fully oxidized"
NEFA burn primarily in the mitochondria. But without oxygen there is no possibility of doing this, you cannot oxidise fats without oxygen. Glucose to lactate, an anaerobic process, yes:
"However, under circumstances of increased myocardial work or limited oxygen availability, the heart turns to glucose as the more efficient fuel for ATP generation"
Glycolysis, with its poor ATP yield, is better than no ATP at all and quite logical when there is insufficient oxygen to keep the mitochondria working. But when the heart is going in to failure it comes to prefer glucose, ultimately even at tickover:
"When the heart is injured and left ventricular (LV) function is depressed on a chronic basis, there is a shift to glucose as the preferred substrate under basal circumstances"
Why should this be? Why not stick with fat. NEFA are the devil you know and a very benign devil they are too... The problem is that the whole system for burning NEFA, from the cell surface receptor to the mitochondrial transport system has, by this stage, already been deliberately shut down:
"this shift in substrate preference is a highly regulated transcriptional event. Importantly, the changes in gene transcription involve down-regulation of transport mechanisms and enzymes involved in fatty acid oxidation. This includes decreases in the NEFA receptor—peroxisome proliferator activated receptor- alpha (PPAR alpha)—and its co-factor, the retinoic acid receptor RXR, as well as a series of enzymes, including carnitine palmitoyltransferase-1 (CPT-1), which is rate limiting in the transport of fatty acid coenzyme A (CoA) to the inner mitochondrial membrane".
You have to wonder why this is. It's not some accidental failure. The heart is sitting in a sea of both NEFA and glucose, and it carefully shuts down it's NEFA processsing equipment to rely on glucose, then shuts off glucose uptake and dies. This is not an adaptive process!
The shut down of glucose usage probably comes back to good old fatty acids causing insulin resistance. The body has sensors for detecting a decreased cardiac output. On an evolutionary basis the assumption is that a serious fall in cardiac output is due to a serious loss of blood volume. Fluid retention and increased sympathetic nervous system activity are standard adaptive responses to blood loss. Increased sympathetic nervous system activity not only boosts cardiac work (hence increases cardiac output to compensate for low blood volume, mimicked by the failing myocardium) at the cost of increased oxygen demand, but also releases free fatty acids from adipocytes to supply the evolutionarily preferred heart fuel. Actually, the NEFA will supply a large proportion of the whole body needs because if you been mauled by a tiger you're not going to go grubbing for tubers to run your metabolism on glucose. Free fatty acids are taken up by the heart down a concentration gradient. If they accumulate in the cytoplasm because the heart has shut down its fat burning system it's easy to see why triglycerides accumulate in the cell. This signals insulin resistance. There is enough fat, no need for glucose. This makes the heart say no to glucose, that's understandable.
Unfortunately, if the fatty acid burning system has been carefully and inappropriately shut down, saying no to glucose becomes catastrophic. Which it is.
The whole drive of the paper is to develop techniques to get the heart back running on glucose in the face of myocardial insulin resistance, for which we can read due to a failure to burn NEFA. Obviously a supra physiological infusion of insulin would overcome this, but it's a big volume to give to a heart failure patient and causes issues with sodium retention anyway, another post there. So insulin sensitisers are high on the priority list. Pity Actos and Avandia cause heart failure! Interestingly among the several postulated mechanism of action suggested for metformin, one is increasing fatty acid oxidation. In my simplistic view this would decrease intracellular triglycerides and allow a reduction in insulin resistance. Thiazolidinediones and other insulin sensitisers are the drugs the paper is thinking about:
"At present, concerns about peripheral edema have limited the use of TZDs (Thiazolidinediones [Actos and Avandia]) in patients with heart failure, although the mechanisms of this phenomenon have not been elucidated. An attractive alternative might involve the derivatives of the proglucagon family, the glucagonlike peptides, which possess insulinotropic, insulinomimetic, and glucagonostatic properties. Importantly, these naturally occurring incretins are largely devoid of hypoglycemic risks, as their insulinotropic properties are attenuated when plasma glucose falls below 70 mg/dL. The short duration of action requires continuous subcutaneous infusion, which constitutes a potential drawback to chronic treatment"
OK, hands up who has spotted the missing idea? Yes, right in one, ketone bodies. Straight to the mitochondria without insulin, CD38 or CPT-1. Increased cardiac work/output without increased oxygen demand. They completely by pass insulin resistance. So they're a nice sticking plaster on a much more interesting problem.
The interesting problem is: Why did the myocardium decide to shut down its fat burning system?
I think you can argue that it is because glucose is so toxic when it is present in high levels in the blood stream that it has to be burned first. While it is still within the power of the pancreas to force glucose in to muscles cells, those cells burn it rather than having it lying around glycating every protein in sight. A little can be stored as glycogen, but if you are on the SAD (including the 3.00am refrigerator raids, and that's not roast beef in the fridge...) and chronically hyperglycaemic/hyperinsulinaemic, glycogen stores are going to be more than full. No, chronic excess glucose oversupply needs burning as fast as possible, you can pack away the far burning system if blood glucose concentration is always being pushed upwards. Maintain this for long enough and it becomes a way of life, and eventually a way of death. Burning glucose in the face of increasing insulin resistance due to the sympathetic nervous system freeing up NEFA, being unaware of the catastrophic loss of fat burning ability, is a non starter.
Ketosis and normolgycaemia would allow the unpackaging of that stored fat burning system. It's not gone for ever, the genes are still there.... Given a few tools NEFA no longer need be the enemy, rather the preferred fuel once again. As the primary fuel the fact that they are present in the cytoplasm signalling the rejection of glucose by signalling insulin resistance is no problem. With efficient fat burning, as soon as the NEFA supply drops cytoplasm trigycerides will drop and insulin can get back to work to allow glucose to be used.
Things can get back to the way they were meant to be with NEFA as the primary fuel with the additional facility to use glucose in dire circumstances.
More on the shutting down of fat burning next.
Peter
Thursday, August 06, 2009
Cholesterol: statins and oxLDL
I would just like to recap the lipid hypothesis for a moment. The basic idea is that an elevated level of LDL cholesterol, estimated by the Friedewald equation, makes these lipoprotein particles stick to your arterial walls, causes plaque to develop and eventually rupture. Saturated fat is the main dietary cause of heart disease because it is purported to elevate LDL cholesterol.
The key to treating heart disease is to lower LDL to below some arbitrary figure, mostly determined by the need for profit of Astra Zeneca or their ilk.
The most effective drugs to do this are the statins, which inhibit the synthesis of a basic metabolic precursor of many substances, one of which happens to be cholesterol. All tissues, particularly the liver, are then so desperate for cholesterol that they up-regulate the expression of genes coding for the LDL receptor and so pull in as much cholesterol as they can get by ingesting circulating LDL particles.
This lowering of LDL lipoproteins by statins is what is supposed to protect against, and even reverse, arteriosclerosis. Although some cardiologists accept that statins do have other effects, the lipid hypothesis says that dropping LDL is the core effect.
So, while taking a statin drug, we have cholesterol depleted cells sporting every LDL receptor they can muster to make up their deficit and this leads to a fall in plasma LDL level. Instead of there being 100 LDL particles per unit volume of blood there are now only 60 LDL particles, and hey presto, atheromatous plaque suddenly starts throwing its rancid lipids back in to those few LDL particles which still remain in the circulation!
Summary: At an LDL of 100mg/dl cholesterol packs in to arterial walls, at an LDL of 60mg/dl this very same lipoprotein becomes a magical hoover, sucking oxidised lipids out of the arterial wall.
You can even measure how good the statin is by how much oxidised phospholipid there is in your LDL lipoproteins!
If this seems to be a little far fetched, you are obviously not a cardiologist! Just check out here and here.
It is simply a fact that statinating people routinely increases the degree of oxidation of their few remaining LDL particles. Because statins are good, this change must be good too. It must be a marker of atheroma regression!
If the concept of an LDL particle sucking oxidised phospholipids out of atheroma sounds implausible, what is happening in statinated people to elevate their oxLDL? Is it good or bad?
Unadulterated LDL is non artherogenic and is taken up readily by cells which need cholesterol via their LDL receptors. Oxidised LDL is atherogenic but is NOT taken up by the LDL receptor because the glycation of the apoB100 protein, which also leads to LDL oxidation, stops it interacting with the LDL receptor.
So oxLDL tends to be left in the circulation while native LDL is taken up by cells affected by statins. There may be less oxLDL, but what is left is very sticky.
Perhaps this is good? Personally, while I think there are all sorts of considerations here, the overall answer seems to be that oxLDL is a Bad Thing. If you take a person who is exquisitely sensitive to simvastatin you can drop their TC from > 260mg/dl to < 160mg/dl. This will probably give an LDL of around 80mg/dl. And a six times greater risk of cardiovascular death than if their TC only dropped to 210mg/dl. Much of that residual LDL with be highly oxidised
An LDL of 60-80mg/dl, produced by removing ONLY the non-atherogenic component of LDL from the plasma, is going to be bad news. This is what statins do.
Never mind Nissen and his 500 victims, look at J-LIT and the 50,000. This gives a much better idea of what having a circulation with no LDL other than oxLDL does for you.
Does it seem incomprehensible that we could have made such a mistake with statins?
Yes, I think so.
Peter
The key to treating heart disease is to lower LDL to below some arbitrary figure, mostly determined by the need for profit of Astra Zeneca or their ilk.
The most effective drugs to do this are the statins, which inhibit the synthesis of a basic metabolic precursor of many substances, one of which happens to be cholesterol. All tissues, particularly the liver, are then so desperate for cholesterol that they up-regulate the expression of genes coding for the LDL receptor and so pull in as much cholesterol as they can get by ingesting circulating LDL particles.
This lowering of LDL lipoproteins by statins is what is supposed to protect against, and even reverse, arteriosclerosis. Although some cardiologists accept that statins do have other effects, the lipid hypothesis says that dropping LDL is the core effect.
So, while taking a statin drug, we have cholesterol depleted cells sporting every LDL receptor they can muster to make up their deficit and this leads to a fall in plasma LDL level. Instead of there being 100 LDL particles per unit volume of blood there are now only 60 LDL particles, and hey presto, atheromatous plaque suddenly starts throwing its rancid lipids back in to those few LDL particles which still remain in the circulation!
Summary: At an LDL of 100mg/dl cholesterol packs in to arterial walls, at an LDL of 60mg/dl this very same lipoprotein becomes a magical hoover, sucking oxidised lipids out of the arterial wall.
You can even measure how good the statin is by how much oxidised phospholipid there is in your LDL lipoproteins!
If this seems to be a little far fetched, you are obviously not a cardiologist! Just check out here and here.
It is simply a fact that statinating people routinely increases the degree of oxidation of their few remaining LDL particles. Because statins are good, this change must be good too. It must be a marker of atheroma regression!
If the concept of an LDL particle sucking oxidised phospholipids out of atheroma sounds implausible, what is happening in statinated people to elevate their oxLDL? Is it good or bad?
Unadulterated LDL is non artherogenic and is taken up readily by cells which need cholesterol via their LDL receptors. Oxidised LDL is atherogenic but is NOT taken up by the LDL receptor because the glycation of the apoB100 protein, which also leads to LDL oxidation, stops it interacting with the LDL receptor.
So oxLDL tends to be left in the circulation while native LDL is taken up by cells affected by statins. There may be less oxLDL, but what is left is very sticky.
Perhaps this is good? Personally, while I think there are all sorts of considerations here, the overall answer seems to be that oxLDL is a Bad Thing. If you take a person who is exquisitely sensitive to simvastatin you can drop their TC from > 260mg/dl to < 160mg/dl. This will probably give an LDL of around 80mg/dl. And a six times greater risk of cardiovascular death than if their TC only dropped to 210mg/dl. Much of that residual LDL with be highly oxidised
An LDL of 60-80mg/dl, produced by removing ONLY the non-atherogenic component of LDL from the plasma, is going to be bad news. This is what statins do.
Never mind Nissen and his 500 victims, look at J-LIT and the 50,000. This gives a much better idea of what having a circulation with no LDL other than oxLDL does for you.
Does it seem incomprehensible that we could have made such a mistake with statins?
Yes, I think so.
Peter
Wednesday, August 05, 2009
Back on line
BT have finally strung the necessary two tin cans and piece of string to our rental house in Bearsden and we are back on line. A bit of reading to do and then I'll get to a few replies and posts.
Glasgow is excellent. There are really weird things like not having to pay at railway station car parks or for parking anywhere else outside the city centre, a train service to town where you don't look at the time table, just pole up and wait for a train, there are hills pushing in to the suburbs, it's light much longer than down south (until the equinox) but the really strange thing is how polite everyone is. A minor near collision with a supermarket trolley is grounds for profuse apologies on both sides. It's not like the M4 corridor! Just weird. But nice.
Peter
Glasgow is excellent. There are really weird things like not having to pay at railway station car parks or for parking anywhere else outside the city centre, a train service to town where you don't look at the time table, just pole up and wait for a train, there are hills pushing in to the suburbs, it's light much longer than down south (until the equinox) but the really strange thing is how polite everyone is. A minor near collision with a supermarket trolley is grounds for profuse apologies on both sides. It's not like the M4 corridor! Just weird. But nice.
Peter
Monday, July 20, 2009
Here we go
OK, the move begins tomorrow. Apologies for the several non answered emails, I'll get to them when we're a bit unpacked and have got net access up and running in Bearsden!
Peter
Peter
Tuesday, July 07, 2009
May 2009: ASTEROID destroys lipid hypothesis!
Here's a nice quote from this paper:
"Atheroma regression occurred in most patients and was not linked to the LDL cholesterol achieved"
Read that line very carefully. Now read it again. That's it, the rest of the post is just rambling on my part.
But is the lipid hypothesis dead? To quote Malcolm Kendrick from 2005 on a different study:
"The great ship Cholesterol-Lowering has ripped its guts out on the harsh rocks of evidence, but still it does not sink"
ASTEROID was a mini version of the J-LIT study (see below) with three modifications. First it was only 501 patients, so there was never any possibility of looking at clinical outcomes, good or bad. Second was it was only run for two years, which repeats point one but with underlining. Third is that they used a crippling dose of statin, sufficient to drop the mean LDL cholesterol level to 60mg/dl.
Luckily there were minimal adverse reactions to this, if you believe Nissen, which I don't:
"Adverse events were infrequent and similar to other statin trials"
Anyway, they went looking for adverse reactions by level of LDL cholesterol, much as did J-LIT. As might be expected there was no graduation of adverse reactions by cholesterol level because, as Nissen might say, there weren't any!
"Adverse events occurred infrequently during the trial, and no pattern appeared relating the frequency of any adverse event to the achieved LDL cholesterol"
Dying of cancer is difficult in 2 years in the USA. Try five years in Japan, or 10 years in Japan, and use over a 40,000 rather than 500 patients. The excess deaths in the lowest LDL groups will be there, just don't expect them to show in 500 patients.
Final quote:
"Similarly, the on-treatment atheroma volume, change in atheroma volume, and high percentage of subjects with atheroma regression did not differ by the achieved LDL cholesterol"
This is a classic. If the lowering of LDL does not correlate with atheroma volume decrease, why do people believe that lowering LDL is what shrinks atheroma? And if the statin per se is causing atheroma shrinkage, which it certainly is, how come long term large studies of the same design show an increasing body count from cardiac causes when statinating to very low levels of LDL? That's what happened in J-LIT and it's what will happen in ASTEROID if they keep going, except 500 people is far to small to separate the occasional death from chance. Is statin induced atheroma shrinkage beneficial? J-LIT suggests not and ASTEROID is too miniscule to look at clinical outcomes. They will be bad.
Executive summary: lower LDL cholesterol has no linkage to shrinkage of plaque.
Peter
"Atheroma regression occurred in most patients and was not linked to the LDL cholesterol achieved"
Read that line very carefully. Now read it again. That's it, the rest of the post is just rambling on my part.
But is the lipid hypothesis dead? To quote Malcolm Kendrick from 2005 on a different study:
"The great ship Cholesterol-Lowering has ripped its guts out on the harsh rocks of evidence, but still it does not sink"
ASTEROID was a mini version of the J-LIT study (see below) with three modifications. First it was only 501 patients, so there was never any possibility of looking at clinical outcomes, good or bad. Second was it was only run for two years, which repeats point one but with underlining. Third is that they used a crippling dose of statin, sufficient to drop the mean LDL cholesterol level to 60mg/dl.
Luckily there were minimal adverse reactions to this, if you believe Nissen, which I don't:
"Adverse events were infrequent and similar to other statin trials"
Anyway, they went looking for adverse reactions by level of LDL cholesterol, much as did J-LIT. As might be expected there was no graduation of adverse reactions by cholesterol level because, as Nissen might say, there weren't any!
"Adverse events occurred infrequently during the trial, and no pattern appeared relating the frequency of any adverse event to the achieved LDL cholesterol"
Dying of cancer is difficult in 2 years in the USA. Try five years in Japan, or 10 years in Japan, and use over a 40,000 rather than 500 patients. The excess deaths in the lowest LDL groups will be there, just don't expect them to show in 500 patients.
Final quote:
"Similarly, the on-treatment atheroma volume, change in atheroma volume, and high percentage of subjects with atheroma regression did not differ by the achieved LDL cholesterol"
This is a classic. If the lowering of LDL does not correlate with atheroma volume decrease, why do people believe that lowering LDL is what shrinks atheroma? And if the statin per se is causing atheroma shrinkage, which it certainly is, how come long term large studies of the same design show an increasing body count from cardiac causes when statinating to very low levels of LDL? That's what happened in J-LIT and it's what will happen in ASTEROID if they keep going, except 500 people is far to small to separate the occasional death from chance. Is statin induced atheroma shrinkage beneficial? J-LIT suggests not and ASTEROID is too miniscule to look at clinical outcomes. They will be bad.
Executive summary: lower LDL cholesterol has no linkage to shrinkage of plaque.
Peter
Tuesday, June 30, 2009
Gluten and schizophrenia SPECT scan
I've been meaning to post about the gluten schizophrenia paper in Nutrition and Metabolism, prompted by the paper itself, a forward from Bloggeier and now a reminder on the THINCS formum by Bogdan. But it turned in to an epic with lots of threads to interweave so, while I get it sorted, here's a quick one liner on the joys of a gluten based diet that I can fit in over a coffee break now I've run out of filler and floor board timber.
Take one adult established schizophrenic with recent onset diarrhoea and weight loss. For some reason do a SPECT scan to look at the blood flow within their brain and note that it is abnormal in the left frontal lobe.
Place on gluten free diet.
Re-scan a little while later and re-biopsy the gut.
All cured, including the "schizophrenic" disorder.
You don't have to be mad to eat bread, but you might end up that way!
Peter
BTW it's possible to speculate whether the blood flow is a vascular phenomenon due to the gluten affecting the arteries in the brain or a hypoperfusion due to abnormal brain metabolism, ie a direct neural effect. I'd never really considered that the gluten effects on the brain might be vascular...
Take one adult established schizophrenic with recent onset diarrhoea and weight loss. For some reason do a SPECT scan to look at the blood flow within their brain and note that it is abnormal in the left frontal lobe.
Place on gluten free diet.
Re-scan a little while later and re-biopsy the gut.
All cured, including the "schizophrenic" disorder.
You don't have to be mad to eat bread, but you might end up that way!
Peter
BTW it's possible to speculate whether the blood flow is a vascular phenomenon due to the gluten affecting the arteries in the brain or a hypoperfusion due to abnormal brain metabolism, ie a direct neural effect. I'd never really considered that the gluten effects on the brain might be vascular...
Saturday, June 27, 2009
Alzheimers and BSE: Prions are not Tau
While sniffing around BSE research in the aftermath of the Tau protein paper find I came upon this quite interesting review. A quick pubmed of the author suggests that BSE is, in her book, a viral infection by a currently uncharacterised virus about 25nm across. I'm not experienced enough at looking at electron micrographs to tell how convincing her pictures are, but they certainly look OK to me.
If she is correct then Prof Ebringer is wrong on this one, as he feels that the TSEs are auto immune attacks comparable to MS.
The biggest problem with the virus hypothesis is the effect of converting the virus to ash and still having it retain its infectivity. I'm a bit puzzled as to how formalin fixation might enhance the virulence of a virus too. This is not typical behaviour of virus particles. Where as sticking ash or formalin fixed gunk in to a brain may do enough of the right sort of damage to trigger an auto immune attack.
On top of this there is the fact that SCID (severe combined immunodeficient) mice are extremely resistant to BSE. How many viral problems are blunted by having a crippled immune system?
The problem here for the auto immune hypothesis is that while SCID mice are very resistant to BSE, they are not completely so. This is less of a problem to me as even SCID mice have some residual functional immune tissue and auto immune attack does not seem to be wholly dependent on antibodies, it probably uses all sorts of cells.
But ultimately it is becoming clearer that the prion hypothesis is probably wrong because the better the purification of putative infectious prion proteins, the lower the infectivity. I would guess that synthetic prion proteins will prove to be fully harmless unless their injection in to a mouse's brain does as much damage as injecting ash.
Add to this the limited ability of the brain to produce disease specific pathologies (ie most end stage diseases look similar!). CJD looks VERY like MS to a histopathologist and simply injecting TNFalpha in to the eye produces lesions indistinguishable from CJD in the optic nerve!
I think the jury is definitely out on this one but it will be interesting to watch the progress of the prion hypothesis and whether prions turn out to be neurotoxic at all.
Peter
If she is correct then Prof Ebringer is wrong on this one, as he feels that the TSEs are auto immune attacks comparable to MS.
The biggest problem with the virus hypothesis is the effect of converting the virus to ash and still having it retain its infectivity. I'm a bit puzzled as to how formalin fixation might enhance the virulence of a virus too. This is not typical behaviour of virus particles. Where as sticking ash or formalin fixed gunk in to a brain may do enough of the right sort of damage to trigger an auto immune attack.
On top of this there is the fact that SCID (severe combined immunodeficient) mice are extremely resistant to BSE. How many viral problems are blunted by having a crippled immune system?
The problem here for the auto immune hypothesis is that while SCID mice are very resistant to BSE, they are not completely so. This is less of a problem to me as even SCID mice have some residual functional immune tissue and auto immune attack does not seem to be wholly dependent on antibodies, it probably uses all sorts of cells.
But ultimately it is becoming clearer that the prion hypothesis is probably wrong because the better the purification of putative infectious prion proteins, the lower the infectivity. I would guess that synthetic prion proteins will prove to be fully harmless unless their injection in to a mouse's brain does as much damage as injecting ash.
Add to this the limited ability of the brain to produce disease specific pathologies (ie most end stage diseases look similar!). CJD looks VERY like MS to a histopathologist and simply injecting TNFalpha in to the eye produces lesions indistinguishable from CJD in the optic nerve!
I think the jury is definitely out on this one but it will be interesting to watch the progress of the prion hypothesis and whether prions turn out to be neurotoxic at all.
Peter
Thursday, June 25, 2009
Alzheimers and Tau proteins
This report on the "spreadable" nature of Alzheimers within the brain is in New Scientist and came to me via Glyn Wainwright on the THINCS forum. It's interesting in it's own right but I rather liked the related paper it linked to about the "contagious" nature of misfolded Tau proteins.
I think it would be reasonable to summarise the abstract as claiming that Tau proteins are non pathogenic structural proteins present inside, and essential to, normal nerve cells. Tau protein aggregates, which are abnormal products, "are observed" outside cells. My assumption is that, as healthy Tau are normally intracellular proteins, they have to be either excreted or exocytosed. Or the cell has to die to released them, before they can be found outside cells. The latter seems the more believable option.
Placing healthy monomer Tau proteins outside neuronal cells in culture does nothing. Placing Tau aggregates outside cells promotes endocytosis of those aggregates and, once endocytosed, the aggregates are directly toxic ("induce fibrillization") to the normal intracellular structural Tau. When this cell then dies it too will release it's abnormal Tau aggregates, which will go on to kill further recipient cells.
OMG its a locally contagious protein! Except it's not, it's a toxic substance which triggers the production of the same toxic substance from healthy tissue on contact.
Where do the original Tau aggregates come from? I suspect that Blaylock would argue they are shrapnel from the death of a neurone killed by catastrophic energy failure, induced by excitotoxins hitting glutamate-receptor sporting cells. This will no doubt involve hyperphosphorylation of Tau and all of the other exciting co factors for Alzheimers. Oh, and might be avoidable by supplying alternative energy molecules such as ketones. The shrapnel is itself neurotoxic and the product of its damage is more of the same neurotoxic shrapnel. This is a chain reaction and Alzheimers then becomes the neurological equivalent of Hiroshima. At this point Blaylock must be feeling quite justified in his views.
The obvious comparison, which is made in the abstract, is to prion proteins as featured in BSE.
If misfolded prion proteins are endocytosed, as Tau proteins are, and are themselves toxic to normal prion proteins, you then have the mirage of a contagious protein.
BSE can be induced in the brain of almost any recipient species by injecting a slurrry from the brain of a BSE case, which contains misfolded prion protein. But what is the trigger for the initial misfolding?
If I was prof Ebringer I might strongly suggest that the original trigger for prion misfolding is an autoimmune attack on myelin basic protein, or a similar structural protein, in the brain. We're not thinking neat and tidy apoptosis here, more like sudden death and spill your contents. Once the misfolding chain reaction is started the progression to BSE via more misfolding and cell death might then follow on, exactly as the Tau aggregates spread.
There is then no need for a contagious protein. In fact, it is easy to "spread" BSE by injecting the ash from incinerated BSE brain (600 deg C in the presence of oxygen. This means incinerated!!!). All you need is for the ash to damage the recipient brain enough to trigger protein misfolding and you have "transmitted" BSE using ash. Thoroughly formalin fixed brain tissue does the job rather better than fresh brain tissue too!
You really have to wonder what is going on here and the Tau "transmission" abstract makes Prof Ebringer and Russell Blaylock look pretty good as proposers of the correct triggers for the respective diseases to me.
Fascinating stuff.
Peter
I think it would be reasonable to summarise the abstract as claiming that Tau proteins are non pathogenic structural proteins present inside, and essential to, normal nerve cells. Tau protein aggregates, which are abnormal products, "are observed" outside cells. My assumption is that, as healthy Tau are normally intracellular proteins, they have to be either excreted or exocytosed. Or the cell has to die to released them, before they can be found outside cells. The latter seems the more believable option.
Placing healthy monomer Tau proteins outside neuronal cells in culture does nothing. Placing Tau aggregates outside cells promotes endocytosis of those aggregates and, once endocytosed, the aggregates are directly toxic ("induce fibrillization") to the normal intracellular structural Tau. When this cell then dies it too will release it's abnormal Tau aggregates, which will go on to kill further recipient cells.
OMG its a locally contagious protein! Except it's not, it's a toxic substance which triggers the production of the same toxic substance from healthy tissue on contact.
Where do the original Tau aggregates come from? I suspect that Blaylock would argue they are shrapnel from the death of a neurone killed by catastrophic energy failure, induced by excitotoxins hitting glutamate-receptor sporting cells. This will no doubt involve hyperphosphorylation of Tau and all of the other exciting co factors for Alzheimers. Oh, and might be avoidable by supplying alternative energy molecules such as ketones. The shrapnel is itself neurotoxic and the product of its damage is more of the same neurotoxic shrapnel. This is a chain reaction and Alzheimers then becomes the neurological equivalent of Hiroshima. At this point Blaylock must be feeling quite justified in his views.
The obvious comparison, which is made in the abstract, is to prion proteins as featured in BSE.
If misfolded prion proteins are endocytosed, as Tau proteins are, and are themselves toxic to normal prion proteins, you then have the mirage of a contagious protein.
BSE can be induced in the brain of almost any recipient species by injecting a slurrry from the brain of a BSE case, which contains misfolded prion protein. But what is the trigger for the initial misfolding?
If I was prof Ebringer I might strongly suggest that the original trigger for prion misfolding is an autoimmune attack on myelin basic protein, or a similar structural protein, in the brain. We're not thinking neat and tidy apoptosis here, more like sudden death and spill your contents. Once the misfolding chain reaction is started the progression to BSE via more misfolding and cell death might then follow on, exactly as the Tau aggregates spread.
There is then no need for a contagious protein. In fact, it is easy to "spread" BSE by injecting the ash from incinerated BSE brain (600 deg C in the presence of oxygen. This means incinerated!!!). All you need is for the ash to damage the recipient brain enough to trigger protein misfolding and you have "transmitted" BSE using ash. Thoroughly formalin fixed brain tissue does the job rather better than fresh brain tissue too!
You really have to wonder what is going on here and the Tau "transmission" abstract makes Prof Ebringer and Russell Blaylock look pretty good as proposers of the correct triggers for the respective diseases to me.
Fascinating stuff.
Peter
Sunday, June 14, 2009
Bob Michell on meta-analysis
Quote of the century, from Bob Michell (taught me applied physiology many moons ago at the RVC and is a seriously bright guy).
"Meta-analysis of dross remains dross"
Ahhhhh that's good.
Peter
Edit: It's possibly as good as Malcolm Kendrick's definition of meta-analysis: one, two, skip a few, 99, one hundred.
"Meta-analysis of dross remains dross"
Ahhhhh that's good.
Peter
Edit: It's possibly as good as Malcolm Kendrick's definition of meta-analysis: one, two, skip a few, 99, one hundred.
Tuesday, June 02, 2009
Gluten: The NICE guidelines for UK diagnosis
For UK readers who want to go the mainstream route here are the NICE guidelines as supplied by Ali in the comments after the Gluten and MS post.
This is part of her comment:
"I am sure you will be pleased to note that the care pathway now includes the referral to a gastroenterologist of those with negative tests but persisting coeliac symptoms."
Yes, too right. I'd personally still go LC as part of my gluten free approach but not everyone wants to go that way. I suppose I went gluten free without anything other than reading the literature! But being armed with the information you are positively coeliac is an opportunity to avoid so many auto immune diseases. If you need a positive test to make the change, these guidelines will help you.
Thanks Ali.
Peter
This is part of her comment:
"I am sure you will be pleased to note that the care pathway now includes the referral to a gastroenterologist of those with negative tests but persisting coeliac symptoms."
Yes, too right. I'd personally still go LC as part of my gluten free approach but not everyone wants to go that way. I suppose I went gluten free without anything other than reading the literature! But being armed with the information you are positively coeliac is an opportunity to avoid so many auto immune diseases. If you need a positive test to make the change, these guidelines will help you.
Thanks Ali.
Peter
Monday, June 01, 2009
Gluten, coeliac and multiple sclerosis
These are a set of MRI images taken from a paper in Spanish entitled "Sustained clinical remission in a patient with remittent-recurrent multiple sclerosis and celiac disease gluten-free diet for 6 years". Something seems to have gotten lost in translation, but you get the gist. Pictures A are before gluten free eating and B after six years gluten free, I think.
Even on the relatively poor reproduction here you can see the white plaques typical of MS lesions on the left and their absence on the right is equally notable. Click to enlarge. That's as far as my Spanish (which is non existent) will take me with the paper.
Of course this may just be a complete fluke, MS does do remission. But I doubt it and anyone with MS or related problems can take note and realise that it is not necessarily a one way ticket, remission is possible, six years is a good start and eating gluten is probably your key to progression of the disease. It becomes debatable whether eating low carbohydrate is needed but, if nothing else, going low carb makes the avoidance of gluten about a million times easier than deciding whether to trust the labelling for complete freedom from gluten. No gluten in a home cooked steak.
For those who do have MS but don't have coeliac disease, I stumbled on this paper as a link related to the Spanish paper. It is almost impossible to describe how utterly, totally and completely cr*p the antibody tests for coelaic disease are. In the UK you will not get an intestinal biopsy unless you are antibody positive. You can have flat intestinal villi with a negative antibody titre. You can also have flat villi in large areas of your gut and the guy driving the endoscope might just biopsy the last six minute patches of normal mucosa you had left. Leaving you with no normal gut lining, a negative diagnosis and a label of over vivid imagination about gut pain. Conclusion: A deficiency of Prozac. The hydrogen breath test seems a lot better than serology, if you can get one done.
There is no need to believe you are coeliac negative. If you have MS it seems very unlikely you would be coeliac negative. Risking MS progression for toast is a pretty amazing trade off! There are no adverse reactions to a gluten free diet. Oh, once you are through the withdrawal syndrome that is, about 4-6 weeks.
Peter
Even on the relatively poor reproduction here you can see the white plaques typical of MS lesions on the left and their absence on the right is equally notable. Click to enlarge. That's as far as my Spanish (which is non existent) will take me with the paper.
Of course this may just be a complete fluke, MS does do remission. But I doubt it and anyone with MS or related problems can take note and realise that it is not necessarily a one way ticket, remission is possible, six years is a good start and eating gluten is probably your key to progression of the disease. It becomes debatable whether eating low carbohydrate is needed but, if nothing else, going low carb makes the avoidance of gluten about a million times easier than deciding whether to trust the labelling for complete freedom from gluten. No gluten in a home cooked steak.
For those who do have MS but don't have coeliac disease, I stumbled on this paper as a link related to the Spanish paper. It is almost impossible to describe how utterly, totally and completely cr*p the antibody tests for coelaic disease are. In the UK you will not get an intestinal biopsy unless you are antibody positive. You can have flat intestinal villi with a negative antibody titre. You can also have flat villi in large areas of your gut and the guy driving the endoscope might just biopsy the last six minute patches of normal mucosa you had left. Leaving you with no normal gut lining, a negative diagnosis and a label of over vivid imagination about gut pain. Conclusion: A deficiency of Prozac. The hydrogen breath test seems a lot better than serology, if you can get one done.
There is no need to believe you are coeliac negative. If you have MS it seems very unlikely you would be coeliac negative. Risking MS progression for toast is a pretty amazing trade off! There are no adverse reactions to a gluten free diet. Oh, once you are through the withdrawal syndrome that is, about 4-6 weeks.
Peter
Friday, May 15, 2009
Cholesterol and heart attack survival
OK, I have to share this one.
Take 517 sequential NSTEMI*(see edit) heart attack victims and measure their LDL cholesterol on admission to hospital. You know, that artery clogging lipoprotein of which you cannot have too little, the lower the better, take this statin blah blah. Divide those patients up in to cardiological Nirvana (those with a value below 105mg/dl, mean value 79mg/dl) or those with astronomically high LDL, ie > 105mg/dl, mean 144mg/dl. Gasp at the hypercholesterolaemia and be afraid.
BTW the MEAN LDL in the low group was 79mg/dl, some must have been well below this because the upper end of the range was 105mg/dl. What is someone with an LDL of below 60mg/dl doing having a heart attack, if the lipid hypothesis is correct? Oh, that means that....
Anyway. Wait three years and then do a body count. The heap is twice the size in the low cholesterol group than the high cholesterol group. This is statistically significant, p= 0.005, I checked the number of zeros. There may be some biological significance too, especially for those who died. I have mentioned previously the possibility of falling LDL being accompanied by a black cloak and scythe.
The paper doesn't mention CV mortality at 3 years, so I'll assume it is as bad in the low LDL group as the higher LDL group. Virtually all listed CV outcomes were non (statistically) significantly worse in the low LDL group.
So the lower the better, if you want to be dead that is!
My take home message is that having a low LDL cholesterol, as guesstimated by your cardiologist using the Friedwald equation, is very bad news if you have just had a heart attack.
So what does matter for survival?
In the low LDL group there were 38% with diabetes, in the higher LDL group 27% were diabetic, p=0.013. Mmmmmmm sugar.....
Does hyperglycaemia matter if you want to survive? Or perhaps HbA1c?
Certainly having a low LDL on admission is associated with an increased risk of being dead three years later.
Peter
Oh! Perhaps a continuous infusion of LDL might improve all cause mortality!!!!!! Now, where can I get a grant to test this hypothesis?
EDIT: NSTEMI added to increase accuracy, NSTEMI "only" represents more than half of all heart attack victims, see comments.
Take 517 sequential NSTEMI*(see edit) heart attack victims and measure their LDL cholesterol on admission to hospital. You know, that artery clogging lipoprotein of which you cannot have too little, the lower the better, take this statin blah blah. Divide those patients up in to cardiological Nirvana (those with a value below 105mg/dl, mean value 79mg/dl) or those with astronomically high LDL, ie > 105mg/dl, mean 144mg/dl. Gasp at the hypercholesterolaemia and be afraid.
BTW the MEAN LDL in the low group was 79mg/dl, some must have been well below this because the upper end of the range was 105mg/dl. What is someone with an LDL of below 60mg/dl doing having a heart attack, if the lipid hypothesis is correct? Oh, that means that....
Anyway. Wait three years and then do a body count. The heap is twice the size in the low cholesterol group than the high cholesterol group. This is statistically significant, p= 0.005, I checked the number of zeros. There may be some biological significance too, especially for those who died. I have mentioned previously the possibility of falling LDL being accompanied by a black cloak and scythe.
The paper doesn't mention CV mortality at 3 years, so I'll assume it is as bad in the low LDL group as the higher LDL group. Virtually all listed CV outcomes were non (statistically) significantly worse in the low LDL group.
So the lower the better, if you want to be dead that is!
My take home message is that having a low LDL cholesterol, as guesstimated by your cardiologist using the Friedwald equation, is very bad news if you have just had a heart attack.
So what does matter for survival?
In the low LDL group there were 38% with diabetes, in the higher LDL group 27% were diabetic, p=0.013. Mmmmmmm sugar.....
Does hyperglycaemia matter if you want to survive? Or perhaps HbA1c?
Certainly having a low LDL on admission is associated with an increased risk of being dead three years later.
Peter
Oh! Perhaps a continuous infusion of LDL might improve all cause mortality!!!!!! Now, where can I get a grant to test this hypothesis?
EDIT: NSTEMI added to increase accuracy, NSTEMI "only" represents more than half of all heart attack victims, see comments.
Thursday, April 30, 2009
Update
Well, we're moving to Glasgow, the coolest, cloudiest and probably most UVB deprived city in the UK. But it does have some advantages. Despite there being no surf within easy access, there are rivers which are quite impressive.
This is the Orchy, the picture is of me in a miss spent youth (circa 1977ish) and it had been raining for a solid month, so a normal August in the hills north of Glasgow... I still remember vividly the feeling of paddling round the first bend below Bridge of Orchy, in the middle of a river as big as the Trent in full flood, and realising that it went down hill in front of me, rather steeply, and there was nowhere to go except down... Thank goodness for brown underwear.
So life is a mix of building work, chasing nurseries, chasing rental accommodation, organising a trip to start house hunting, chasing a plumber, builder, plasterer, finding the shower unit won't fit the bathroom, starting to ebay the shower and my motorcycle, rehoming the chickens (tragic this aspect, what will Squiggs do with no Penelope chicken to cuddle, the cats are worried). You know the stuff... There seems to be an inordinate amount of cutting and stitching to do at work too.
By hook or by crook my wife's pathology residency starts 3rd of August in Bearsden and I've handed notice my notice in for 17th July. It's a little tight! But very exciting.
Peter
This is the Orchy, the picture is of me in a miss spent youth (circa 1977ish) and it had been raining for a solid month, so a normal August in the hills north of Glasgow... I still remember vividly the feeling of paddling round the first bend below Bridge of Orchy, in the middle of a river as big as the Trent in full flood, and realising that it went down hill in front of me, rather steeply, and there was nowhere to go except down... Thank goodness for brown underwear.
So life is a mix of building work, chasing nurseries, chasing rental accommodation, organising a trip to start house hunting, chasing a plumber, builder, plasterer, finding the shower unit won't fit the bathroom, starting to ebay the shower and my motorcycle, rehoming the chickens (tragic this aspect, what will Squiggs do with no Penelope chicken to cuddle, the cats are worried). You know the stuff... There seems to be an inordinate amount of cutting and stitching to do at work too.
By hook or by crook my wife's pathology residency starts 3rd of August in Bearsden and I've handed notice my notice in for 17th July. It's a little tight! But very exciting.
Peter
Monday, March 16, 2009
Sabbatical
I was looking for Mary Enig's "Know Your Fats" on the bookshelves a couple of days ago and came across my unopened copy of Edward Tenner's "Why Things Bite Back" next to a 2/3 read copy of "Mistakes Were Made", an unopened copy of Desolate Landscapes and a recently arrived copy of Prothero's Evolution. John Peel's biography is part read (fascinating and sad to watch the progress of metabolic syndrome through the illustrations!). I have two novels from my daughter, unopened since Christmas and there's my wife's copy of Neverwhere that I'd love to read. I also keep getting emails from Lovefilm to ask why it takes me a month to watch "Iris".
This is trying to tell me something.
I've also finally accepted to an invitation to speak to a group on diet and health in the near future, which will be a fair undertaking. Plus we have to have the house sold by the end of July which is not a minor objective.
So I think I may be going to have to take a bit of a sabbatical from blogging in the next few months, until we are settled in to wherever the post PhD job market takes us and I have found work too.
Sorry for this, but stuff creeps up on you and you need to think, read and live, as well as blog!
As Richard commented off blog, there will always be papers I can't resist a two liner on (like the last one on AMI) but there is just too much to get done...
Back in the Summer, all things being equal
Peter
EDIT: The comments thread on this post has been used by a proponent of a particular view of life which is labelled, by them self, as the HED, the High Everything Diet. I'm leaving the comments in place as they are fascinating in their own right. A reasonable but slightly overgeneral idea of what I personally feel is going is available here.
Please bear in mind that it looks like, while the proponent is mentally unwell, he is also very intelligent and it's YOUR health that YOU are playing with. Play safe on the net.
This is trying to tell me something.
I've also finally accepted to an invitation to speak to a group on diet and health in the near future, which will be a fair undertaking. Plus we have to have the house sold by the end of July which is not a minor objective.
So I think I may be going to have to take a bit of a sabbatical from blogging in the next few months, until we are settled in to wherever the post PhD job market takes us and I have found work too.
Sorry for this, but stuff creeps up on you and you need to think, read and live, as well as blog!
As Richard commented off blog, there will always be papers I can't resist a two liner on (like the last one on AMI) but there is just too much to get done...
Back in the Summer, all things being equal
Peter
EDIT: The comments thread on this post has been used by a proponent of a particular view of life which is labelled, by them self, as the HED, the High Everything Diet. I'm leaving the comments in place as they are fascinating in their own right. A reasonable but slightly overgeneral idea of what I personally feel is going is available here.
Please bear in mind that it looks like, while the proponent is mentally unwell, he is also very intelligent and it's YOUR health that YOU are playing with. Play safe on the net.
It's never too late to normalise your glucose (so long as you are still alive)
I've just plotted the risk of being dead in the near future vs post admission glucose for coronary patients in this study. Haven't seen the full text so I've no idea whether there was an acute drop in LDL cholesterol in the survival patients, to keep cardiologists happy, but I guess not or they would have mentioned it. In fact, if you had to guess, you could do worse than to guess that an acute drop in LDL would come accompanied by a black cloak and scythe.
Anyway here are data from the abstract in graph form. Enjoy.
Although it is possible the hyperglycaemia is the problem per se, it is equally possible that it simply reflects underlying insulin resistance. But I doubt anyone is going to ask for an IV glucose infusion plus some diazoxide post MI to find out!
Peter
Anyway here are data from the abstract in graph form. Enjoy.
Although it is possible the hyperglycaemia is the problem per se, it is equally possible that it simply reflects underlying insulin resistance. But I doubt anyone is going to ask for an IV glucose infusion plus some diazoxide post MI to find out!
Peter
Tuesday, March 10, 2009
Cholesterol within nations studies
These are the slides from the within-countries discussion on cholesterol and heart disease. I've allowed the sarcasm back in, which was strictly limited when the slides were originally presented. OK, there is a correlation. In fact, if you are a bloke, having a cholesterol above that certain magic number on the graph is clearly catastrophic and boy, are you in trouble. No statins to save your life in those days!
But what is the mystery number which sentences you to cardiac death? Obviously the original Framingham study did not use a random scale. But the scale used in the study was highly non linear. Here is the same graph with the real numbers added.
Once you have realised quite how unlinear the scale is I would just like to draw your attention to that number on the bottom right written in RED. No, it's not a typo. That really is 1124mg/dl. Okaaaaaaaaay. Hands up if you think a TC of 1124mg/dl is part of a normal distribution of cholesterol values in a "normal" population. Are there any conditions which elevate cholesterol and increase the risk of heart disease? Answers on a postcard to any endocrinology department you happen to know the address of.
Anyway, next thing to do is to linearise the scale. I've been kind and left the upper data point in the middle, not placed it at the upper end, of the range quoted:
Now here is my main cheat, and I admit it's a cheat. There must be a population towards the upper end of that last data point who have medical problems to give them an increased risk of heart disease. Cushings Syndrome and hypothyroidism are two for starters. So I would argue that it is only fair to the representatives of this subpopluation that the risk scale is extended up for their benefit. 100 "events" per 1000 in this group seems possible, hence the extended scale:
So let's go back and look at the initial random points and leave the top cholesterol data point where it belongs, about a yard to the right of your screen:
Ah, that's better. Some semblance of honesty now. But again, not quite as convincing as the first graph. BTW did anyone notice that the left hand scale was events, not deaths?
Did the Framingham investiators look at deaths? Hahahahahahahahahahahaha bonk. Sorry, that's me laughing my head off. Of course they did. There is no association between elevated cholesterol and increased cardiac deaths, but the trend is that high cholesterol is protective. Luckily for the Framingham researchers they were underpowered to detect this. A whiff of the low powered studies we see nowadays.
Now let's just look at the MRFIT screenees. These are the many, many people who were looked through before cherry picking the victims for the MRFIT intervention trial which, incidentally, killed more people in the intervention group than died in the the usual care group. Luckily (again) this did not reach statistical significance, though it may have been of some biological significance to those extra people who ended up dead in the intervention group.
The original study had non linear group sizes (like Framingham) to specifically, oh, I mean accidentally, obscure the effects on all cause mortality in the low cholesterol individuals. The graphs above are taken from a later sub-analysis by a rather more honest and objective lead researcher. Such people do exist in cardiology.
The other hysterical aspect of these graphs is that the original data presented from the MRFIT screenees wasn't, wait for it......
It wasn't corrected for smoking!
Yet another re-analysis shows a marked association between TC and cardiac deaths, but only in smokers. About what you would expect if LDL cholesterol was doing its best to repair smoking induced damage and failing.
The association is still present in non smokers and is statistically significant but so much weaker that the biological significance is highly debatable. It probably represents sucrose intake.
So in summary, the original MRFIT screenees study (presented as the clincher for cholesterol causing heart disease) obscured the scary aspects of low TC and, err, forgot to correct for smoking!
Don't you love the foundations of modern cardiology! Can't sum up MRFIT better than Dr Werko.
For a breath of fresh air it's worth going to Norfolk in the UK.
This innocent little graph is plotted from the EPIC Norfolk data. Now I'd hate to suggest that being hyperglycaemic has anything to do with heart disease, but you can read the graph as well as I can. Association not causation. And of course we know that eating fat causes hyperglycaemia, just ask any diabetologist. Shrug.
The weird thing about UK researchers is that they give you the raw data, it's not a matter of a little table of regression coefficients corrected for this, that and the other. You can read the results tables and plot the graphs. They even give you raw smoking data. And of course you get both TC and that evil killer, the LDL level. Let's plot them on the same graph as the HbA1c vs relative risk of cardiac events.
Personally I'd be looking to minimise my HbA1c rather than my LDL-C.
But then I would say that.
Peter
But what is the mystery number which sentences you to cardiac death? Obviously the original Framingham study did not use a random scale. But the scale used in the study was highly non linear. Here is the same graph with the real numbers added.
Once you have realised quite how unlinear the scale is I would just like to draw your attention to that number on the bottom right written in RED. No, it's not a typo. That really is 1124mg/dl. Okaaaaaaaaay. Hands up if you think a TC of 1124mg/dl is part of a normal distribution of cholesterol values in a "normal" population. Are there any conditions which elevate cholesterol and increase the risk of heart disease? Answers on a postcard to any endocrinology department you happen to know the address of.
Anyway, next thing to do is to linearise the scale. I've been kind and left the upper data point in the middle, not placed it at the upper end, of the range quoted:
Now here is my main cheat, and I admit it's a cheat. There must be a population towards the upper end of that last data point who have medical problems to give them an increased risk of heart disease. Cushings Syndrome and hypothyroidism are two for starters. So I would argue that it is only fair to the representatives of this subpopluation that the risk scale is extended up for their benefit. 100 "events" per 1000 in this group seems possible, hence the extended scale:
So let's go back and look at the initial random points and leave the top cholesterol data point where it belongs, about a yard to the right of your screen:
Ah, that's better. Some semblance of honesty now. But again, not quite as convincing as the first graph. BTW did anyone notice that the left hand scale was events, not deaths?
Did the Framingham investiators look at deaths? Hahahahahahahahahahahaha bonk. Sorry, that's me laughing my head off. Of course they did. There is no association between elevated cholesterol and increased cardiac deaths, but the trend is that high cholesterol is protective. Luckily for the Framingham researchers they were underpowered to detect this. A whiff of the low powered studies we see nowadays.
Now let's just look at the MRFIT screenees. These are the many, many people who were looked through before cherry picking the victims for the MRFIT intervention trial which, incidentally, killed more people in the intervention group than died in the the usual care group. Luckily (again) this did not reach statistical significance, though it may have been of some biological significance to those extra people who ended up dead in the intervention group.
The original study had non linear group sizes (like Framingham) to specifically, oh, I mean accidentally, obscure the effects on all cause mortality in the low cholesterol individuals. The graphs above are taken from a later sub-analysis by a rather more honest and objective lead researcher. Such people do exist in cardiology.
The other hysterical aspect of these graphs is that the original data presented from the MRFIT screenees wasn't, wait for it......
It wasn't corrected for smoking!
Yet another re-analysis shows a marked association between TC and cardiac deaths, but only in smokers. About what you would expect if LDL cholesterol was doing its best to repair smoking induced damage and failing.
The association is still present in non smokers and is statistically significant but so much weaker that the biological significance is highly debatable. It probably represents sucrose intake.
So in summary, the original MRFIT screenees study (presented as the clincher for cholesterol causing heart disease) obscured the scary aspects of low TC and, err, forgot to correct for smoking!
Don't you love the foundations of modern cardiology! Can't sum up MRFIT better than Dr Werko.
For a breath of fresh air it's worth going to Norfolk in the UK.
This innocent little graph is plotted from the EPIC Norfolk data. Now I'd hate to suggest that being hyperglycaemic has anything to do with heart disease, but you can read the graph as well as I can. Association not causation. And of course we know that eating fat causes hyperglycaemia, just ask any diabetologist. Shrug.
The weird thing about UK researchers is that they give you the raw data, it's not a matter of a little table of regression coefficients corrected for this, that and the other. You can read the results tables and plot the graphs. They even give you raw smoking data. And of course you get both TC and that evil killer, the LDL level. Let's plot them on the same graph as the HbA1c vs relative risk of cardiac events.
Personally I'd be looking to minimise my HbA1c rather than my LDL-C.
But then I would say that.
Peter
Monday, March 09, 2009
In the gym
We were discussing weight and BMI at work and the secretary who has named me Tigger was pretty adamant that that I was at least 2kg too skinny. I thought about it for a while and decided she was right so I'd set up a gym at home and see if I could put on a couple of kg of muscle, rather than fat. In general all of my exercise is opportunist at the moment. So here's the gym:
I can just lift one end of this railway sleeper and lever it to above my head. My workouts consist of moving moving it about. I spend about 30-60 seconds a day doing this. Been doing it for about a week and, despite muscle gain, I've dropped below 64.0kg for the first time in ages. I'll give it a month and see how I feel. So much for using exercise to gain weight!
Peter
I can just lift one end of this railway sleeper and lever it to above my head. My workouts consist of moving moving it about. I spend about 30-60 seconds a day doing this. Been doing it for about a week and, despite muscle gain, I've dropped below 64.0kg for the first time in ages. I'll give it a month and see how I feel. So much for using exercise to gain weight!
Peter
Friday, March 06, 2009
Fructose, Glucose and Cholesterol
This paper came my way via Eddie Vos, through a discussion in the THINCS group.
OK, what's going on in the paper? It's the metabolic ward study to end all metabolic ward studies. Routine criminals who volunteered to live in a "food proof" prison and to eat a diet based on pure chemicals. This is a prison within a prison:
"The described study was conducted in an especially isolated wing of the California Medical Facility (CMF), a state institution for adult male felons. The isolated area included large indoor recreation, lounge, and shower areas, and 24 individual cells, and was so located as to prevent completely the passage of any food through or near the area."
And what yummy food did the inmates receive?
"These diets were unique in that a) their essential and nonessential nitrogen source was provided exclusively in the form of optically pure L-amino acids and b) they were administered as single, crystal clear aqueous solutions that were nutritionally complete in themselves. In essence, the diets were composed of balanced (but varying) proportions of L-amino acids, the required water-soluble and fat soluble vitamins, the pertinent mineral salts, glucose or other simple sugars as the source of carbohydrate, and ethyl linoleate as the source of essential fat."
Apparently the various versions of the diet all tasted disgusting, for want of a better word.
Apart from the interest of human experiments along these lines, there were a few other tweaks they applied. First we have to note that these diets were essentially ultra low fat diets, the same family as the diets used by McDougal and co. There is not a grain of white rice which does not end up as blood glucose. If you eat brown rice there is a split between the fibre and the minerals it is depriving you of (you know where they get flushed) and the starch, which ends up as blood glucose. So these are seriously low fat, high carbohydrate diets.
What happens when you feed an elemental diet based on glucose alone as its calorie source? Blood cholesterol drops, from a normal value found in a non statinated male of 227mg/dl (while eating 1970s style prison food), to a cardiologic near Nirvana of 160mg/dl. Replacing 25% of the glucose with sucrose produces a rise in cholesterol to 208mg/dl. Removing the sucrose and going back to pure glucose drops the cholesterol level back down to 151mg/dl.
Is that good or bad? You need to remember the old adage that the best cholesterol level is one that has not been measured. But what is happening probably goes back to that short section of the ApoB100 protein which glycates particularly easily, discussed here. I think it is worth pointing out again that fructose should never penetrate in to the systemic circulation, so its whole body damage should be indirect. It probably does this through the induction of hepatic insulin resistance. Fructose has to be metabolised immediately and the end result is raised intracellular hepatic triglycerides. We've seen before that a decent supply of intra cellular lipid makes a cell say no to glucose and that it does this by exhibiting insulin resistance. The liver normally stores glucose in response to insulin. Rendering it insulin resistant would logically stop it storing glucose and pour the stuff out in to the systemic circulation...
That's the basis of this post and it needs bearing in mind when we look at cholesterol variation and heart disease with a given population. But there's an aside first that really creased me up...
A quick pubmed looking for a reference to fructose and insulin resistance (there are hundreds) produced this gem, hot out of cyberpublishing a few days ago.
The group used an antisense oligonucleotide, which is a short section of DNA, RNA or a similar synthetic drug which specifically blocks the activity of a corresponding section of messenger RNA, which means the the relevant gene no longer gets successfully transcribed. By doing this they turned off lipid synthesis in the liver in response to fructose. No hepatic insulin resistance despite fructose intake: Wow!!!!!!!!!! Take this drug and you too can drink Pepsi Max without turning your liver in to foie gras. What else does it do? Oh, it lowers insulin resistance, whole body! Superb, give me some.
Oh oh, it's your butt which soaks up the plasma glucose... As they say of their own technique, it resulted in:
"increased insulin-stimulated whole-body glucose disposal due to a threefold increase in glucose uptake in white adipose tissue"
Translation: "our wonder drug makes you fat".
It is also described as a potential "treatment of NAFLD, hypertriglyceridemia, and insulin resistance associated with increased de novo lipogenesis", I would add "by making you fat". I'd also add that this de novo lipogenesis can easily be avoided by avoiding the fructose in the first place.
What is not remotely obvious from the abstract is: Where does the fructose go to, if it's not used to converted your liver to foie gras?
I guess it's either going to glycosylate your liver (sounds great for longevity) or spill in to your systemic circulation, where it can glycosylate whatever it come in to contact with.... Or it might just overload each liver cell with more pyruvate than it knows what to do with. Now there's grist for the mill of unintended consequences!
Back to the real world:
A fructose intake of 12% of your calories makes your metabolism unhappy enough that it has evolved a technique to increase cholesterol levels under these rather rare (until recent times) conditions. It probably has knock on effects through hepatic insulin resistance resulting in hyperglycaemia and all of the damage that this leads to.
While some fructose is perfectly OK (I too eat home grown fruit in season and a certain amount of sucrose) I suspect a large amount is not OK.
Under highly defined conditions, fructose raises your total cholesterol level.
Peter
EDIT: Sue has pointed out, off blog, that the other reason for a fall in cholesterol is due to minimal production of triglycerides. If glucose is being consumed within the ability of the liver to store it as glycogen there is no reason to convert it to fat and so there is no fat to export as triglycerides. Fructose immediately converts to fat and any fat produced in excess of the needs of the liver will be shipped out as LDL precursor particles, raising both LDL and TC.
Both mechanisms are fructose related but not fructose specific. The average trigs were 93mg/dl but the study did not split anything other than TC by the sucrose/fructose periods early in 19 weeks of the initial part of the diet. The volunteers remained pretty well weight stable throughout, as far as I can see.
So you have a choice of two mechanisms, there may be more, but the association still seems to hold that TC is a marker of fructose intake, with a number of confounders once you get off of chemical diets. BTW the TC went back to a normal >200mg/dl on return to normal food. Or uless you have a TC like mine (and a few other folks), which is a law unto itself.
OK, what's going on in the paper? It's the metabolic ward study to end all metabolic ward studies. Routine criminals who volunteered to live in a "food proof" prison and to eat a diet based on pure chemicals. This is a prison within a prison:
"The described study was conducted in an especially isolated wing of the California Medical Facility (CMF), a state institution for adult male felons. The isolated area included large indoor recreation, lounge, and shower areas, and 24 individual cells, and was so located as to prevent completely the passage of any food through or near the area."
And what yummy food did the inmates receive?
"These diets were unique in that a) their essential and nonessential nitrogen source was provided exclusively in the form of optically pure L-amino acids and b) they were administered as single, crystal clear aqueous solutions that were nutritionally complete in themselves. In essence, the diets were composed of balanced (but varying) proportions of L-amino acids, the required water-soluble and fat soluble vitamins, the pertinent mineral salts, glucose or other simple sugars as the source of carbohydrate, and ethyl linoleate as the source of essential fat."
Apparently the various versions of the diet all tasted disgusting, for want of a better word.
Apart from the interest of human experiments along these lines, there were a few other tweaks they applied. First we have to note that these diets were essentially ultra low fat diets, the same family as the diets used by McDougal and co. There is not a grain of white rice which does not end up as blood glucose. If you eat brown rice there is a split between the fibre and the minerals it is depriving you of (you know where they get flushed) and the starch, which ends up as blood glucose. So these are seriously low fat, high carbohydrate diets.
What happens when you feed an elemental diet based on glucose alone as its calorie source? Blood cholesterol drops, from a normal value found in a non statinated male of 227mg/dl (while eating 1970s style prison food), to a cardiologic near Nirvana of 160mg/dl. Replacing 25% of the glucose with sucrose produces a rise in cholesterol to 208mg/dl. Removing the sucrose and going back to pure glucose drops the cholesterol level back down to 151mg/dl.
Is that good or bad? You need to remember the old adage that the best cholesterol level is one that has not been measured. But what is happening probably goes back to that short section of the ApoB100 protein which glycates particularly easily, discussed here. I think it is worth pointing out again that fructose should never penetrate in to the systemic circulation, so its whole body damage should be indirect. It probably does this through the induction of hepatic insulin resistance. Fructose has to be metabolised immediately and the end result is raised intracellular hepatic triglycerides. We've seen before that a decent supply of intra cellular lipid makes a cell say no to glucose and that it does this by exhibiting insulin resistance. The liver normally stores glucose in response to insulin. Rendering it insulin resistant would logically stop it storing glucose and pour the stuff out in to the systemic circulation...
That's the basis of this post and it needs bearing in mind when we look at cholesterol variation and heart disease with a given population. But there's an aside first that really creased me up...
A quick pubmed looking for a reference to fructose and insulin resistance (there are hundreds) produced this gem, hot out of cyberpublishing a few days ago.
The group used an antisense oligonucleotide, which is a short section of DNA, RNA or a similar synthetic drug which specifically blocks the activity of a corresponding section of messenger RNA, which means the the relevant gene no longer gets successfully transcribed. By doing this they turned off lipid synthesis in the liver in response to fructose. No hepatic insulin resistance despite fructose intake: Wow!!!!!!!!!! Take this drug and you too can drink Pepsi Max without turning your liver in to foie gras. What else does it do? Oh, it lowers insulin resistance, whole body! Superb, give me some.
Oh oh, it's your butt which soaks up the plasma glucose... As they say of their own technique, it resulted in:
"increased insulin-stimulated whole-body glucose disposal due to a threefold increase in glucose uptake in white adipose tissue"
Translation: "our wonder drug makes you fat".
It is also described as a potential "treatment of NAFLD, hypertriglyceridemia, and insulin resistance associated with increased de novo lipogenesis", I would add "by making you fat". I'd also add that this de novo lipogenesis can easily be avoided by avoiding the fructose in the first place.
What is not remotely obvious from the abstract is: Where does the fructose go to, if it's not used to converted your liver to foie gras?
I guess it's either going to glycosylate your liver (sounds great for longevity) or spill in to your systemic circulation, where it can glycosylate whatever it come in to contact with.... Or it might just overload each liver cell with more pyruvate than it knows what to do with. Now there's grist for the mill of unintended consequences!
Back to the real world:
A fructose intake of 12% of your calories makes your metabolism unhappy enough that it has evolved a technique to increase cholesterol levels under these rather rare (until recent times) conditions. It probably has knock on effects through hepatic insulin resistance resulting in hyperglycaemia and all of the damage that this leads to.
While some fructose is perfectly OK (I too eat home grown fruit in season and a certain amount of sucrose) I suspect a large amount is not OK.
Under highly defined conditions, fructose raises your total cholesterol level.
Peter
EDIT: Sue has pointed out, off blog, that the other reason for a fall in cholesterol is due to minimal production of triglycerides. If glucose is being consumed within the ability of the liver to store it as glycogen there is no reason to convert it to fat and so there is no fat to export as triglycerides. Fructose immediately converts to fat and any fat produced in excess of the needs of the liver will be shipped out as LDL precursor particles, raising both LDL and TC.
Both mechanisms are fructose related but not fructose specific. The average trigs were 93mg/dl but the study did not split anything other than TC by the sucrose/fructose periods early in 19 weeks of the initial part of the diet. The volunteers remained pretty well weight stable throughout, as far as I can see.
So you have a choice of two mechanisms, there may be more, but the association still seems to hold that TC is a marker of fructose intake, with a number of confounders once you get off of chemical diets. BTW the TC went back to a normal >200mg/dl on return to normal food. Or uless you have a TC like mine (and a few other folks), which is a law unto itself.
Tuesday, March 03, 2009
That FSA apple
It seems that the FSA is suggesting that eating enough fructose will make a maggot eat your heart out! Some sense at last. Oh no! They think that apples are GOOD for you. But a maggot has certainly eaten a heart out of the apple... I suppose it's as accurate as suggesting that the temperature-drop induced phase change from liquid to solid of saturated fat, the one which blocks drains, will also block your arteries. Perhaps the FSA has a heart of ice!
My taxes are paying these idiots' wages!
To quote JohnN:
"What the apple hates anthropomorphically is the relentless human selection that gives rise to the grotesque size and fructose content of its fruit"
I love the concept of apples as grotesque!
Peter
My taxes are paying these idiots' wages!
To quote JohnN:
"What the apple hates anthropomorphically is the relentless human selection that gives rise to the grotesque size and fructose content of its fruit"
I love the concept of apples as grotesque!
Peter
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