Here we go again

There might not be a lot of posts over the next few months. I'll get Axen and Axen (2) posted when I can!

Axen and Axen (1)

Okay, the one without the chocolate all over their face is Ratty. He, Ratty, is 20 weeks old and weighs 360g. He is slim, active, well muscled (for a rat) and, of course, eats a very high fat diet. In fact he eats exactly the same food as we do with extra fried belly pork and cheese to snack on between meals of scrambled egg yolks (in butter), Bolognaise sauce, chilli mix or beef stew, should he ever get hungry between those main meals. My wife gave him a grape once. I removed it from his cage when it went mouldy.

I don't think he has metabolic syndrome. He eats an ad lib diet which provides about 70% of his calories from fat.

Now, I was looking through Axen and Axen's 2010 paper on managing metabolic syndrome in rats. First you have to make them obese. Hmmmm, now how might you do that? Ah ha! A high fat diet. In fact just 60% of calories will do the trick. Wow. Lets look at Table 1, column 2, HF diet used to induce obesity in rats. There it is: 60% fat, 25% protein and a mystery 15% carbohydrate.



Plus this line in the methods:

"The contents of saturated: monounsaturated: polyunsaturated fats were 25.3%:43.3%:31.3% in the HF diet and 31.7%:42.7%:25.5% in the VLC and HC diets (ω-3 fatty acids comprised ~2% of total fat)."

OK, are you thinking the carbohydrate was sucrose? Me too. Wrong! But the fat was supplied by Proctor and Gamble.

If you work through the paper to find out how this obesogenic diet was developed you get to ref 9, which is Axen and Axen again, this time in 2006. Once again, Table 1 for diet composition:



This tells us nothing more about the obesity diet (it's not really what the paper is about) but the fat was supplied by Proctor and Gamble. The paper does have another reference about the obesogenic diet, number 13 this time, which leads us to a gem from another Axen paper, just Kathleen and friends this time:

This is the sort of paper I love. Here is the abstract from 2003.

I think I have to put it here in full as it is really too important to summarise. They have a diet which develops metabolic syndrome in rats which CANNOT be prevented by restricting calories to normal body weight. Has any one heard of the "slim but metabolically obese" concept? The skinny type 2 diabetic? Kathleen Axen knows EXACTLY how to produce a skinny type 2 diabetic rat! And this is the paper. And here is the abstract:

"High fat, low carbohydrate diets are popularly advocated for weight loss and improvement in metabolic Syndrome X, a constellation of risk factors for type 2 diabetes mellitus and cardiovascular disease. The effects of an energy-restricted (to prevent weight gain in excess of normal growth) high fat (60% of energy), low carbohydrate (15%) diet were assessed in both lean rats and in rats previously rendered obese through ad libitum consumption of the same high fat diet. In obese rats, restriction of intake failed to improve impaired glucose tolerance, hyperinsulinemia, and hypertriglyceridemia, although it lowered visceral fat mass, liver lipid content and in vitro insulin hypersecretion compared with rats continuing to consume the high fat diet ad libitum. In lean rats, restricted intake of the high fat diet impaired glucose tolerance and increased visceral fat mass and liver lipid content. These findings support the conclusion that, in the absence of weight loss, a high fat, low carbohydrate diet not only may be ineffective in decreasing risk factors for cardiovascular disease and type 2 diabetes but may promote the development of disease in previously lower risk, nonobese individuals."

I think that that's pretty conclusive. A diet of 60% fat makes a rat glucose intolerant even if you starve it (and rats in the starved group will be HUNGRY, unlike Ratty) to a normal bodyweight. And no sucrose in sight. High fat and restricted carbohydrate diets might PROMOTE type two diabetes in rats (and people?) and give them heart attacks (do rats have heart attacks?) even if they were slim to begin with and stay slim on the diet. That's me and Ratty all right.

Ratty and I are doomed to diabetes it appears.

BTW, did I mention that Proctor and Gamble provided the fat?

Which fat? Well, here's the section which never made it in to the abstract:

"the other group was fed a high fat (HF;347 g fat/kg diet) low carbohydrate diet (22.6 kJ/g, 5.4 kcal/g). The HF diet was comprised of powdered Purina 5001 and hydrogenated vegetable fat (Proctor & Gamble, Cincinnati OH), with casein, L-methionine, AIN vitamin mix, and AIN mineral mix (Bio-serv, Frenchtown, NJ) (17) added to provide equivalent protein concentrations (LF, 234 g/kg diet; HF, 331 g/kg diet) and equivalent vitamin and mineral contents for the two diets. The hydrogenated vegetable fat contained 25% long-chain saturated, 44% monounsaturated and 28% PUFA, with 17% of total fat as trans fatty acids (manufacturer’s communication). This high fat, low carbohydrate diet was used because of the more pronounced obesity it has produced in rats in our laboratory than have several commercial high fat diets."

Stop, rewind, slow frame:

"with 17% of total fat as trans fatty acids"


That's a very special fat. Magic fat. Unless I am very much mistaken Proctor and Gamble make commercial bootpolish marketed as fit for human consumption. I think it's called Crisco. They have been poisoning America with it for decades.

DO NOT, UNDER ANY CIRCUMSTANCES, BASE YOUR DIET ON 60% OF CALORIES FROM FAT WHICH INCLUDES 17% TRANS FATTY ACIDS.

DO NOT DO IT.

Just say no.

But oh, oh, oh, Kathleen, why did you leave this out of the abstract????????????

People will think that eating fat makes you fat......

It certainly will if Proctor and Gamble supplied it.

Peter

OK, the 2006 and 2010 studies need looking at next in some detail. They are really quite funny in combination. Also, to give K Axen her due she does discuss trans fat toxicity extensively in the discussion of the paper. But not the abstract. There it's "fat" all the way. A pinguid diet (for Gary; ok do I win at Scrabble now?).

Actually, re reading the last sentence of the abstract: This is a very unpleasant piece of writing. Would people go as far as the full text to read what the paper is actually about?

Thoughts on problems with high fat diets

Back comments section of the uric acid post _Flo passed on the news of the death, due to stomach cancer, of a prominent long term Optimal Diet follower. This is not the sort of in formation that should be ignored although, from an individual case, I doubt whether there is anything we will every actually find out about causation. The main thing it brings home forcefully is that none of us is immortal and a good diet will not allow us to automatically reach an advanced age. The OD and similar approaches brings marked improvement in many of the diseases of civilisation but clearly not all. For someone who has achieved remission from multiple sclerosis or ankylosing spondylitis it is depressing to accept that those same diet changes might not be cancer protective, or not completely so.

_Flo has made her own modifications to her diet which are sensible in their own right and represent her choices. As regards the type of cancer it quite interesting to note that Poland has one of the highest rates of stomach cancer in the world. This snippet was passed along by another friend on the net and is corroborated by pubmed. It does suggest that speculation based on the location/type of the tumour may not be representative a specific diet related factor, rather the result of living in Poland. Of course it might be diet related.

I have my own personal tweaks to the OD and do not see any clear way of improving what I have already achieved.


So let be set here in print. No one has all of the answers.


I thought I would take this chance to discuss the possibility that there are people for whom low carbohydrate eating might be genuinely problematic. I have picked up a couple of hints along these lines over the years, so here we go with some thoughts.

I discussed a secondary prevention trial for heart disease here. All of these people had glucose regulation problems (that's part of my definition of having a heart attack). Adding 500-600kcal of either corn or olive oil to a very low fat diet precipitated diabetes in two of these individuals. Why? That's a good question. Type two diabetes is intrinsically linked to insulin resistance. Normally people eating a bolus of fat will reduce the rest of their calorie intake to compensate. Anyone who didn't would have placed a significant carbohydrate load on top of fat induced insulin resistance (even vegetable oils induce this, although palmitic acid does a rather better job) and failed to deal with their relatively high carbohydrate intake. Pure speculation but a low fat diet, with 80ml of added vegetable oil, undoubtedly triggered 2 cases of type two diabetes. I found that interesting.

Second hint was Jenny Ruhl's comment that she had come across very, very occasional individuals with diabetes who responded to low carbohydrate eating by deterioration of glycaemic control. Again, I have no details what so ever but anyone's ears should prick up when they hear things like this. Denial is not where it's at.

Then Carb Sane introduced me to the Otsuka Long-Evans Tokushima Fatty strain (OLETF) of rats. These rats are a diabetologists dream. Under fixed isocaloric conditions they gain weight and fat mass in direct proportion to the percentage of fat in an exactly measured 28.7 joule daily ration. Like, wow. Fat really does make you fat!

Of course the OLETF rat is described as a Good Model for human type two diabetes. It explains exactly why all diabetics put on to a LC, high fat diet become obese and hyperglycaemiac. What do you mean, they don't? Oh, not enough testosterone! The OLETF rats only become diabetic if they are male. That's why all type two diabetics are blokes. What do you mean, women get type two diabetes? But out model says only blokes should. And it's a Good Model...

OK facetiousness aside, what is happening in the OLETF rats? Is it possible that there are some humans out there with OLEFT rat style type two diabetes. Well, why not?

Let's have a look at what is happening from the point of view that insulin is the primary hormone in the development of obesity. If you think about someone eating just once a day, essentially all of their calories are going to get stored. Glycogen in the liver and fat in the fat. What determines weight gain is how much of that stored energy fails to be extracted from storage before the next meal arrives.

Summary: No one stores lipids or glucose in their blood stream. It all goes in to short term storage. What comes out determines weight loss. Insulin determines what comes out.

OLETF rats, on high fat, fixed calorie diet of 28.7 joules per day put all of this energy in to storage but fail to extract as many of these calories/joules from storage as those OLETF rats on 28.7 joules of a high starch diet. What is going on?

If you accept the insulin hypothesis of weight gain, the answer is that dietary fat is being trapped in adipocytes by excessive blood insulin. There must be excess insulin.

Why is the insulin elevated when there is a reduced dietary stimulus for insulin production? These rats have peripheral, almost certainly muscle based, insulin resistance. But only on a high fat diet.

High fat diets put lipids in to muscles, muscles full of lipid don't accept glucose. If the system works correctly the muscles run on lipids until there is a balance between fat supply rejecting glucose and fat depletion allowing glucose acceptance. A few billion years is ample time to get this system working correctly to maintain normoglycaemia in the face of varied macronutrient intakes from day to day.

What might be broken in this system in the OLETF rat?

Well, if you can get lipids in to muscle cells but cannot then use that lipid for beta oxidation you would expect to develop muscle insulin resistance in proportion to the amount of fat you supply, ie if the fat enters the muscles but does not go any further those muscles will become insulin resistant and stay insulin resistant. If muscles are not accepting glucose because they are insulin resistant the glucose is going to have to be dealt with by increased levels of insulin. Hyperglycaemia is unacceptable.

The extra insulin needed to maintain normoglycaemia then traps stored dietary fat in adipocytes. The rats get fat because they cannot get fat out of adipocytes. They will also do less running around and will probably feel colder than normal rats because they have no access to their fatty tissue for energy supplies. If they had access to food they would eat more, but 28.7 joules per day was the limit in this experiment. If they had access to more calories they would clearly eat more because no one likes the hunger and shivering produced by sequestering a chunk of your caloric fat intake in your adipocytes and locking it in there with insulin.

Once your fat cells get full enough they will spill free fatty acids because they are now too full to listen to insulin any more. These FFAs join those intra cellular muscle tissue di and tri glycerides from the metabolic defect. Intra myocyte fatty acids still have no where to go, so muscle insulin resistance rockets, plasma glucose rockets and you have a superb model of fat induced obesity and peripheral insulin resistance.

Glucose enters mitochondria as pyruvate. Fatty acids enter mitochondria as acyl CoA moieties. The place to be looking for explanations for the syndrome seen in the OLETF rat is in fatty acid processing. My guess is that lipid molecules get in to myocytes but never get effectively passed to the mitochondria. Quite what testosterone has to do with this is beyond me, it's not me that is suggesting the OLETF rat is a good model for human type 2 diabetes!

You have to ask what would have happened on a ketogenic diet. Would ketosis have side stepped this problem? Ketone bodies enter mitochondria without any need for long chain fatty acid transporters. They use monocarboxylate transporters, just like pyruvate... You don't really think that Kaneko et al would so something as stupid as putting an OLETF rat on a ketogenic diet? But it would have been interesting. I'm not sure it would side step the problem but it might. I'm certainly not expecting a diabetologist to find out for me.

I really enjoyed the OLETF rat. Does it tell me something about type two diabetes? Only that there might be very, very special people who respond to dietary fat with hyperglycaemia.

I never did find any teeth in my chickens. I understand hen's teeth are rare. So are OLETF humans.

But they probably exist (not the hen's teeth!).

Peter

Urate, ascorbate, resveratrol and land mines

It only needs a brief glance through the literature to realise that uric acid is a prime mover in metabolic syndrome and might reasonably compete with cholesterol as the premier mammalian-synthesised molecule of self destruction.

Until of course you come across interesting papers like this one which suggests that uric acid is a signal of tissue injury, a mobiliser of repair systems and, in particular, a recruiter of endothelial progenitor cells.

In modern terms, stepping on a land-mine will produce a surge of uric acid to blunt the effects of the renal ischaemia which will occur as you bleed out through the remains of where your foot used to be. In evolutionary terms you can see how surviving acute trauma might be beneficial and it looks like uric acid is seriously useful in this context. Stepping on a land mine every day fairly rapidly becomes problematic in terms of all cause mortality and even uric acid is unlikely to maintain its efficacy with prolonged usage. Chronic drug induced hyper uricaemia appears to be a Bad Thing in that it blunts the benefits of acute elevations.



If you don't live in a heavily land-mined country you are (a) lucky and (b) more likely to be injured by a bottle of cola or a bowl of apples. Or maybe oranges, stawberries, kiwis etc. Whether it is simply the fructose in the cola or some other plant nasty in the fruit in addition to fructose isn't particularly clear. But your body produces a spike of uric acid in response. It's been injured.

It is perfectly possible to consume cola or fruit on a chronic basis without the immediately obvious effects of repeatedly treading on a land mine.

This leads me to whether there are direct benefits from minor damage of eating fruit via hormesis or whether it is just all bad. I suspect it depends on the dose and the chronicity. When you look at WHEL and PPT there may well be some sort of accommodation which leaves total mortality unchanged by eight years of eating extra fruit and veg. There seems to be little doubt that an acute rise in uric acid is beneficial and chronically elevated uric acid may be less so. This flies in the face of Kwasniewski's opinions about uric acid, the more the better. But he is talking about elevated uric acid in a LC high saturated fat situation, not after eating a bowl of apples a day for a few years.... Of course he never cites references but I'm keeping an eye out!

Ascorbate is interesting as it is a rather ubiquitous antioxidant and does appear to be used by humans for assorted essential functions, all be it in very small amounts, despite the fact we cannot synthesise it. Most mammals tightly regulate their ascorbate production to their needs as they can produce it on demand. Not so humans. We don't produce it and our intake is completely random, varying from 10mg per day or less on an all meat diet to a few 1000mgs if you fall face down in a clump of cranberries and keep eating all day.

The chances of you meeting the cranberries every day for six weeks are slim, so if you want to study the effect of relatively high doses of ascorbate on free radical mediated processes in humans you have to use supplements. Eating 1000mg represents an awful lot of berries but is a common supplement dose.

This group in Spain actually pre empted the group in Germany in demonstrating the adverse effects of ascorbate supplementation on the effects of exercise.

Exercise produces free radicals, free radicals signal for both muscle cell division and mitochondrial number increase (using the surrogate of cytochrome C for mitochondrial number).





If you dose with 1000mg ascorbate daily you will scavenge the free radicals and blunt the increase in both muscle mass and mitochondrial number which should have been generated by those free radicals. You might expect this and it's worth noting that the effect appears to clearly detectable but far from complete.

I have worked on the assumption that taking antioxidants should down regulate your own endogenous antioxidant production. The Spanish group used rats for this part of their research and did indeed find that gene expression for synthesis of both superoxide dismutase and glutathione peroxidase are markedly down regulated. A zero increase with ascorbate supplemented exercise compared to a 3.5 fold increase after three weeks of unsupplemented exercise.





Think of the implications. You exercise, exercise generates free radicals, free radicals build muscle and upregulate production of antioxidant enzymes. So exercise is, fundamentally, antioxidant (while ever it is kept within the limits which can be accommodated by synthesis of SOD and GPx). Obviously ultra-marathon runners must be willing to injure themselves for their sport.

Mega dosing with ascorbate markedly blunts the induction of the intrinsic antioxidant system of mammals, even of a rat which naturally produces ascorbate.

What about resveratrol? Feed it to a mouse in quantities equivalent to between 150 and 1,500 bottles of wine a day and you get some improvement in inflammatory markers. Do you simultaneously down regulate SOD and GPx synthesis? Now there is a question!

That will be a cracking study. The answer will be yes if resveratrol really scavenges significant numbers free radicals. Our own endogenous antioxidant systems are fine tuned to our needs. What does a blanket treatment with a highly potent antioxidant do to our ability to respond to the daily alterations in free radicals? Free radicals carry information. How do we replace the information lost if they are stuck to a resveratrol molecule?

Luckily our bodies try hard not to absorb the stuff and normally metabolise it to sulphated or glucuronated forms within minutes. It's unlikely that we ever have much free resveratrol (or dark chocolate favanoids either, phew) in our bloodstream until human ingenuity invented the resveratrol chewing gum.

Unintended consequences anyone?

Peter

BTW The Wiki article on resveratrol appears to be very contentious. Wiki becomes a battleground once you get on to sticky subjects like cholesterol and, apparently, resveratrol. I've kept the text for when it gets edited to "Resveratrol explains the French paradox and will make us live for ever"

What's the secret of time travel doing on Fry's ass?

I would just like to paraphrase that relevant line from Futurama:

What's the secret of Eternal Youth doing on a grapeskin? It was bound to be somewhere..........

Resveratrol. Gift of plants. Oh oh, wrong again!

Many thanks to Blogblog for the link to that hysterical abstract, I just love it. If anyone thinks that resveratrol is the answer to the French Paradox, or that there even is a French Paradox, or that plants will gift us eternal youth, then you're in the wrong place on the net I'm afraid, just hit the back button!

Peter

My penance for cribbing 7.9 seconds from the Futurama movie: "Buy it, buyyyyyyy it......."

Fruit and vegetables (12) WHEL and CVD

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

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

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

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.

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!

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

PPT and unreported side effects

Gifted by Gary!

Peter

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

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

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...

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!

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

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.

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.

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.