Wednesday, November 14, 2018

A brief aside in to statins and FH and all cause mortality

I must admit that I have not read this paper, just the abstract. My excuse is, once again, that I have no access to any ondansetron.

Statins in Familial Hypercholesterolemia: Consequences for Coronary Artery Disease and All-Cause Mortality

As always the results of statin therapy are, to say the least, dramatic.

"In patients with heterozygous FH, moderate- to high-intensity statin therapy lowered the risk for CAD and mortality by 44%".

Wow. But why the need for a composite end point?

If we leave aside soft end points which include coronary re-vascularisation (never influenced by serum lipid levels. No laughing at the back there!) and concentrate on the hard end point of all cause mortality we end up with, for non statinated people:

9 deaths per 4,892 person-years, which I make 1.8 deaths per 1000 person-years.

On a statin we have 17 deaths per 11,674 person-years, 1.5 per 1000 person-years.

That looks like a reduction in mortality of 0.3 people per 1000 person-years.

Or, being more whole numberish, 1 person saved by treating for 3,300 person-years on a statin.

Does that convert to treating 100 people for 33 years to avoid one premature fatality? We're all going to die one day so no one avoids death permanently, even by taking a statin. Unbelievable as that sounds.

If you have heterozygous FH your chances of dying tomorrow are rather low but not quite zero. If you take a statin it will reduce this chance by a vanishingly small amount.

Taking the difference between "rather-low-but-not-quite-zero" and "a-vanishingly-small-amount less than rather-low-but-not-quite-zero", dividing this difference by "rather-low-but-not-quite-zero" and multiplying by 100 we get a massive 17% reduction in all cause mortality. Which means diddly squat, but sounds good if you are a statinator. Admittedly not as good as 44% for the composite end point but hey... Neither means anything.

The main benefit of a statin appears to be that the number it gives you on a lab report might just influence a cardiologist to leave your coronary arteries alone.

Peter

Listeriosis is no fun

Just doing my bit

Vegetables, nine dead of listeriosis

Quick edit for when the link dies:

"9 people dead following Listeria outbreak – Tesco, Aldi, Waitrose, Iceland, Lidl, Aldi – Issue Product recall. Please please check on old people and loved ones who may not be in the loop, listeria can be more serious for people who have weakened immune systems.

Full 43 product list for recall is shown as follows issued by the FSA".

All vegetables.

Peter

Wednesday, November 07, 2018

Green Tea Extract; superb antioxidant?

Here is a little more from this paper:

High selenium impairs hepatic insulin sensitivity through opposite regulation of ROS

This is insulin signalling under massively supra-physiological insulin exposure in cell culture:


















This is, obviously, their best gel, that's the one you publish. The insulin resistance (fainter P-Akt band) when insulin and Se are both used compared to insulin w/o Se exposure does appear to be there. At physiological levels of insulin this differential seems likely to be maintained.

This implies blunting of insulin signalling, which allows more FFA oxidation, which generates greater levels of ROS than would occur under continued insulin action. These ROS would be physiological on a ketogenic diet or under extended fasting but are not so in cells under culture using 11mmol glucose (which is what I think is in the medium they used, they don't actually say) plus whatever insulin is present in 10% FBS. So we have this:










Control is from cells under RPMI 1640 alone, traditionally 11mmol/l glucose. Excess selenium blunts insulin signalling so allows FFA release from intracellular triglyceride stores, so increases ROS (in the same way as metformin does but w/o the suppression of gluconeogenesis intrinsic to metformin's action). Adding rotenone, as you would expect, blocks RET so blocks ROS generation. CCCP uncouples respiration, drops delta psi so blocks RET/ROS. Etomoxir blocks access of FFAs to mitochondria so blocks input at mtETFdh, so blocks RET/ROS. MitoQ powerfully targets all mitochondrial ROS so over-rides the FFA oxidation ROS generation effect. Chromium picolinate restores insulin signalling by repleting the Cr depletion induced by Se. MSA is an inhibitor of glutathione peroxidase, so it eliminates the effects of excess GPX. And SS, sodium salicylate, appears to block intracellular lipolysis in hepatocytes, so suppresses fatty acid supply to mitochondria, much as insulin or etomoxir would.

All a very plausible narrative.

Except for oligomycin. What does anyone expect the blockade of ATP synthase to do to ROS generation, throughout the electron transport chain? It is going to increase delta psi, reduce all of the redox complexes and generate a ton of RET and ROS through complex I and probably at ton at complex III too. It is specifically used to generate ROS in many other studies, example here:

The specificity of neuroprotection by antioxidants

I'm not very comfortable with oligomycin as a suppressor of FFA oxidation induced ROS. It is another, rather serious, blight on the paper. It certainly should have been discussed.

I would usually ignore the whole paper except Tom Naughton gave us all the heads up on a recent report of a chap taking what might have been a hefty dose of green tea extract who went in to liver failure. Obviously most folks just excrete antioxidants like GTE with little harm done. I just wonder if he got unlucky or took a huge dose while walking round with the sort of liver full of lipid so beloved of Public Health England. Losing the protection of insulin's inhibition of lipolysis simply dumped a ton of unregulated intra-hepatocyte FFAs from lipid droplets on to his mitochondria, which then popped their clogs.

Who knows? It's another nice narrative. I just wish I wasn't so suspicious of the selenium paper...

Both reports also play rather too well to my biases against antioxidants, but that's how it is...

Peter

Friday, November 02, 2018

Stone Agers in the Fast Lane?

A destruction of Paleo Diet as a management tool for metabolic syndrome in modern humans surfaced recently in a tweet from Miki Ben-Dor, along with his comment that he views meat as the default paleo food.

Plants used as "food" come and go and are nowadays developed in to reduced toxicity versions which are what we call vegetables. Meat is meat and even the invention of factory farming does not seem to be able to convert it in to anything as toxic as a courgette. Remember this?

Courgette stew kills pensioner in Heidelberg

Anyway, back to the Pacific Islanders. This is the book chapter we're interested in and it's entertaining.

Stone Agers in the Fast Lane? How Bioarchaeologists Can Address the Paleo Diet Myth

These people appear to have read (and cite) essentially every paper on gout in archeological record of the paleo Pacific Islander population. They are using gout as a skeletally preserved marker for metabolic syndrome, a fairly reasonable approach to my mind. The assumption that meat causes gout (lots of purines don'tchano) which is threaded throughout the chapter is less acceptable.

So we end up with this as a core summing up close to the end, for anyone who doesn't want to slog through the various straw men they set up to knock down:

"We have also used a case study of Pacific Islanders’ experiences with MetS and paleopathology evidence of gout to reexamine the very basis for the “necessity” of a return to a Paleo Diet. As discussed, the ancestral diet (based on tuberous root crops, not cereals) and population history of Pacific islanders are completely different to the Old and New Worlds where the Paleo Diet debate is entrenched. Yet the burden of MetS is extremely high in the Pacific. While the adoption of westernized diets has exacerbated the expression of MetS conditions in modern Polynesians, the paleopathological evidence (especially gout) suggests the origins of these conditions stems from their Lapita ancestors, who in turn trace their roots back to Island Southeast Asia".

Gout was widespread in the pre-Westernisation Pacific Islanders, despite their paleo diet. The core quote re this paleo diet is that it is "based on tuberous root crops, not cereals".

Translation: A Paleo Diet diet based on paleo tuberous root crops gives you paleo gout.

Eat some meat and get your calories from fat. Vegetables can be viewed as a recreational indulgence if you so wish. But maybe don't over do them unless you want Paleo Diet gout.

Peter