Category Archives: Vitamins

Vitamins once more – mainly B vitamins and homocysteine – with a special mention for magnesium

6th December 2021

Here I am on vitamins again. I don’t wish to give the impression that all I care about is vitamins. However, I have been thinking about them recently for various reasons.

The first thing to say is that I do find it slightly strange that we have substances which are absolutely essential for life, that we must eat, because our bodies cannot make them. It seems a design flaw. I want my money back.

Added to this absolute reliance on them, we do not get any hint that we are running out. If we become dehydrated, we feel thirsty, and we drink. If our energy supplies are running down, we feel hungry and we eat.

On the other hand, if our Vitamin B₁₂ supplies are becoming perilously low – we might end up feeling bloody awful. In the final stages we could end up paralyzed, then dead, without knowing why. Vitamin B₁₂ is essential for the health of neurones (amongst other things). But there is nothing that triggers our desire to forage around for foodstuffs rich in vitamin B₁₂. Supposing we knew what they were anyway.

I presume this means that whilst we were evolving from the primeval soup, there were plenty of vitamins (and minerals) about. We had no need to seek them out specifically, because they were always present in the things we ate. In ample supply? Always …? Of course, it is not just vitamins, there are minerals we need too.

Magnesium

Most people are probably blissfully unaware they need magnesium. If you don’t have enough, how would you know? The first recognisable symptom may be … suddenly dropping dead.

Israel gives us a stark warning of what happens when magnesium goes missing, with no-one noticing. For many years, most of the water supply in Israel has been provided by desalination. This process does not just get rid of salt (NaCl), it also removes the other salts, and minerals, at the same time.

In normal circumstances people get most of the magnesium they need from drinking water. Which means there was clearly a potential for a major deficiency problem building up in Israel. As most of their water contained nothing but pure H₂0.

Did anyone notice? As in, did anyone say, ‘golly I feel low in magnesium today, I must go and eat a substance high in magnesium…’ Nope. Did anyone die. Yup, they did. As outlined in the paper ‘Association between exposure to desalinated sea water and ischemic heart disease, diabetes mellitus and colorectal cancer; A population-based study in Israel.’¹

There were possibly as many as 4,000 deaths a year:

‘An estimated 4,000 Israelis die in an average year due to an inadequate amount of magnesium in their bodies – and the amount they get from natural potable water sources is increasingly declining due to the growing desalination of sea water. The figure is 10-fold the death toll from road accidents.’²

The population of Israel is just over nine million. The equivalent death rate in the UK would be 30,000 deaths a year, or 180,000 in the US. A silent killer indeed.

Anyway, yes, magnesium is critical stuff. It is extremely important for health, especially heart health. It is required for the correct functioning of the electrical system in your heart, and a low level increases the risk of atrial fibrillation. Here from the paper ‘Low serum magnesium and the development of atrial fibrillation in the community: the Framingham Heart Study.’

‘…individuals in the lowest quartile of serum magnesium were ~50% more likely to develop AF…compared with those in the upper quartiles.’ ³

Unfortunately, despite its importance, we don’t feel magnesium depleted. We do not crave magnesium rich foods – as if we would have any idea what they might be … I certainly don’t. The symptoms of severe deficiency are also non-specific. The first symptom might be that your heart decides to stop beating.

It’s not just Israel. Here from the paper: ‘Subclinical magnesium deficiency: a principal driver of cardiovascular disease and a public health crisis.’

‘Furthermore, because of chronic diseases, medications, decreases in food crop magnesium contents, and the availability of refined and processed foods, the vast majority of people in modern societies are at risk for magnesium deficiency.’ ⁴

Have you ever heard of any of this? Did you even know you had magnesium in your body – or that it did anything important? I suspect not. However, from the same paper:

‘…magnesium deficiency can lead to serious morbidity and mortality and has been implicated in multiple cardiovascular diseases such as hypertension, cardiomyopathy, cardiac arrhythmia, atherosclerosis, dyslipidaemia and diabetes. Unfortunately, the western diet is often low in magnesium due to the refining and processing of foods, and hypomagnesaemia is often underdiagnosed in hospitalised patients.’⁴

My advice, take a supplement. Especially if you live in an area with ‘soft’ water – which generally means not many minerals. Doubly especially if you have atrial fibrillation. It might just go away. How much do you need to take? Around 400mg a day is fine.

Back to vitamins – in this case, Vitamin(s) B

The reason for the detour is that I really wanted to make it clear that it is certainly not a given that we routinely get all the essential micro-nutrients we need from our diet.

Modern living, modern food production and farming, modern food processing … have all have a significant impact on what our food, and water, contains.

The lazy mainstream assumption that micronutrient deficiencies simply do not exist is, therefore, wrong. Try looking at Iodine deficiency in Switzerland sometime. In addition, I am extremely dubious that we truly know what the optimal intake of micronutrients may be. The research in this area is sketchy, to say the least.

This, eventually, takes us onto vitamins, more specifically, the B vitamins. There are many of them – eight, in fact.

B1 (thiamine)
B2 (riboflavin)
B3 (niacin)
B5 (pantothenic acid)
B6 (pyridoxine)
B7 (biotin)
B9 (folate ak.a. folic acid)
B12 (cobalamin)

The first question that springs to mind is the following. Where are numbers four, eight, ten and eleven? What happened to them? It’s a bit like clotting factors. We have VII, VIII, IX etc. But there is no factor one, or two. Who gets to name things in medicine anyway?

Moving on. My main interest in the B vitamins is that, if you are low in three of them, maybe four of them: three, six, nine and twelve, this can lead to an increased level of a protein in the blood called homocysteine. [I think B6 is more important than B3, but we shall let this go for now].

The reason why this is important is if you have a high level of homocysteine then this is strongly associated with an increased risk of cardiovascular disease. The mechanism of action appears to be that homocysteine is toxic to endothelial cells.

‘Elevated homocysteine (Hc) levels have a well-established and clear causal relationship to epithelial damage leading to coronary artery disease.’⁵

On the other hand, low levels of homocysteine are associated with a lower risk:

‘In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels.’[i]

As you may have gathered from that short quote, if you have a high homocysteine level, and you take B vitamins, your homocysteine levels will fall. As confirmed in a study in the American Journal of Clinical Nutrition:

‘Elevated levels of homocysteine is an indication of inadequate folate and vitamin B-12 in the diet, writes lead author Giovanni Ravaglia, a researcher with University Hospital S. Orsola-Malpighi in Bologna, Italy. His paper appears in the March American Journal of Clinical Nutrition….High homocysteine levels can be treated very easily with vitamins, including folate, niacin, and B-12.’ ⁶

I think the connection between B vitamins, and homocysteine, were first noted by Kilmer McCully. He studied the area in detail at Harvard University. At least he did so for a while, before he was unceremoniously booted out for carrying out research that threatened to undermine the almighty cholesterol hypothesis. A sorry tale, as reported in the New York Times:

‘Thomas N. James, a cardiologist and president of the University of Texas Medical Branch who was also the president of the American Heart Association in 1979 and ’80, is even harsher [regarding the treatment of McCully]. ”It was worse than that you couldn’t get ideas funded that went in other directions than cholesterol,” he says. ”You were intentionally discouraged from pursuing alternative questions. I’ve never dealt with a subject in my life that elicited such an immediate hostile response.”

It took two years for McCully to find a new research job. His children were reaching college age; he and his wife refinanced their house and borrowed from her parents. McCully says that his job search developed a pattern: he would hear of an opening, go for interviews and then the process would grind to a stop. Finally, he heard rumors of what he calls ”poison phone calls” from Harvard. ”It smelled to high heaven,” he says.’

McCully says that when he was interviewed on Canadian television after he left Harvard, he received a call from the public-affairs director of Mass. General. ”He told me to shut up,” McCully recalls. ”He said he didn’t want the names of Harvard and Mass. General associated with my theories.’ ⁷

And you wonder why researchers are wary of questioning the cholesterol hypothesis? Yes, crushing scientific debate has a long and inglorious history, starting long before COVID19 first appeared over the horizon. In the world of cholesterol, it has been going on for well over sixty years.

Homocysteine, B vitamins and dementia

Now, dear reader, having just focussed on B vitamins, homocysteine and cardiovascular disease, I am going to abruptly change tack. I shall now move away from heart disease to Alzheimer’s disease. The reason for this is straightforward.

As I began to research this area in more detail, it become increasingly clear that there was a worrying association between raised homocysteine, brain damage, and dementia. This certainly attracted my attention. Because I like my brain, and I want to keep it healthy for a long as possible.

I came across papers such as this: ‘Plasma Homocysteine as a Risk Factor for Dementia and Alzheimer’s Disease.’

‘An increased plasma homocysteine level is a strong, independent risk factor for the development of dementia and Alzheimer’s disease.’ ⁸

There were many more such papers, but you probably get the general idea. Raised homocysteine … Bad.

At this point I already knew that the B vitamins can lower the homocysteine level – if it is high. In addition, B vitamins are well known to have vital functions in the central and peripheral nervous system.

Here, from the paper: ‘B Vitamins in the nervous system: Current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin.’

Neurotropic B vitamins play crucial roles as coenzymes and beyond in the nervous system. Particularly vitamin B1 (thiamine), B6 (pyridoxine), and B12 (cobalamin) contribute essentially to the maintenance of a healthy nervous system. Their importance is highlighted by many neurological diseases related to deficiencies in one or more of these vitamins, but they can improve certain neurological conditions even without a (proven) deficiency.’ ⁹

So, not only do certain B vitamins lower homocysteine levels. A number of them play a critical role in the growth and support of nerve cells, and suchlike.

None of this is exactly news. It has been known for centuries that excess alcohol consumption – which blocks Vitamin B1 absorption from the gut – can cause a specific form of dementia called Korsakoff’s dementia. Because of this, people with alcohol problems are often prescribed high dose vitamin B1 (Thiamine).

Which means that it was never a stretch to suggest that giving people B vitamins might be an extremely good thing if you want to prevent, or delay, the progression of Alzheimer’s/brain shrinkage. Either through the benefits on lowering raised homocysteine, or via the critical functions of B vitamins on the structure and function of the brain.

That, anyway, was the underlying science. But does giving B vitamins actually work? Well researchers at Cambridge University certainly believed it was a splendid idea:

‘In an initial, randomized controlled study on elderly subjects with increased dementia risk, we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 years.’¹⁰

In a follow-up study, this group of researchers then found that, in people with raised homocysteine levels, who already had signs of dementia, B-vitamins reduced brain destruction and slowed, even halted, the progression of Alzheimer’s. In their own words, from the paper ‘Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment’:

‘….we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 years. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven-fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD (Alzheimer’s Disease) process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine.’ ¹¹

Yes, it was all looking quite good. By the way, this study came out in 2013.

But then we need to factor in the knowledge that B vitamins are very cheap. Very cheap indeed. In addition, they cannot be patented. Which makes it extremely difficult for any pharmaceutical company to make money from them. You can, of course sell them for a small profit, but pharmaceutical companies need billions to feed the machine. They require unique, patentable, blockbuster drugs. Drugs my precious.

Had any drug shown such a significant effect on brain shrinkage, I am one hundred per cent certain that the finding would have been shouted from the rooftops. We would be looking at a massive blockbuster. Probably the biggest selling drug in the world – ever.

As it was, the research from Cambridge was passed over in virtual silence … I suspect you never heard anything about it. Then, with a certain inevitability, the findings were, effectively squashed.

How was this done?

It was done through the power of the meta-analysis. A meta-analysis is a fancy term describing an attempt to bring together all the relevant trials that have been done in a therapeutic area. In order to construct a ‘meta’ study, or meta-analysis.

They can be a very useful way to bring together all of the relevant research, where there have been a large number of different studies done. In an attempt to establish the definitive answer to a medical question. Does drug x, or intervention y, actually work. If so, what are the true benefits? Assuming that the trials have all showed subtle, or not so subtle, differences in their effects.

Meta-analyses are often treated as though they are the very pinnacle of medical research. Tablets of stone handed down by Gods. In realty, they need to be treated with a very large pinch of salt, and a healthy dose of scepticism.

This is because meta-analyses often ram together studies with very different populations, using different doses of drugs, or vitamins. Or completely different drugs or vitamins, for different lengths of time.

Just to add to the potential messiness, studies can be included that have completely unrelated outcomes. You end up comparing apples and bananas, in order to decide if pomegranates actually work. In computing it would be called garbage in, garbage out – GIGO.

Moving on, in 2014, the year after the Cambridge study, a whole number of different studies on B-vitamins were brought together in a ‘meta-analysis.’ I use the term meta-analysis very loosely here. It was called: ‘Effects of homocysteine lowering with B vitamins on cognitive aging: meta-analysis of 11 trials with cognitive data on 22,000 individuals.’ ¹²

Sounds good, so far. In fact, the total number of individuals they looked at was 20,431 – which is a lot nearer to twenty thousand than twenty-two thousand. But, hey ho, what’s sixteen hundred or so people between friends? Having said this deliberate figure inflation is an important indication of researchers trying to ‘big up’ their findings – in my book.

Here’s another thing. A number of the studies had absolutely nothing to do with cognitive function … at all. One of the studies included was HOPE-2. Here is the background to the study.

‘In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke. Folic acid and vitamins B6 and B12 lower homocysteine levels. We assessed whether supplementation reduced the risk of major cardiovascular events in patients with vascular disease.’ ¹³

Yes HOPE-2 was a study on cardiovascular disease. It has absolutely nothing to do with Alzheimer’s, or any other form of dementia. The title of HOPE-2 was ‘Homocysteine Lowering with Folic Acid and B Vitamins in Vascular Disease.’ Cognition, or brain function, was not measured. Yet, it was still included in a meta-analysis of ‘11 trials with cognitive data on 22,000 individuals.’ [20,431 individuals, actually].

Moving on, and this is perhaps more mission critical. In only just over seven thousand of the individuals studied did anyone measure cognitive function at the start of the trial and then again, at the end. Leaving aside such studies as HOPE-2 where it was not measured at all. Which, straight off, means that the vast bulk of this meta-analysis is utterly meaningless.

How can you possibly know what happened to anyone’s cognitive state, if you only measured it once? Did it improve, did it worsen – not the faintest. In two thirds of the individuals included in this meta-analysis we have no idea what happened to cognitive function – at all.

It doesn’t stop here. There were others who felt that this was not meta-analyses finest hour:

‘First and foremost, this meta-analysis excluded trials on mild cognitive impairment (MCI) and Alzheimer’s disease. As a possible consequence, most of the trials included in this meta-analysis either did not see any significant cognitive change (between the start and the end of the trial) in the placebo group or did not look at such change.¹⁴

Yes, they specifically excluded people with existing cognitive impairment, or Alzheimer’s, which would be, by far, most important group to study. As they actually have the condition you are interested in.

Which leads on to the next obvious problem:

… people included in these trials included in the meta-analysis were healthy and did not show any cognitive decline, whether they received B-vitamin treatment or not. So, B-vitamins could hardly prevent or slow down something not happening in the first place.’ ¹⁴

Just to make this point a little clearer, in the minority of studies, where they bothered to measure cognitive function at the start, and also at the end, they found that almost no individuals developed any degree of cognitive impairment – in either group. Not in the treatment group, or the placebo groups. As virtually nothing happened to anyone, nothing could have been proved one way or another.

Attempting to study the progress of dementia, in people who do not have dementia, and who may never get dementia, nor have any signs of cognitive decline … is like doing a blood pressure lowering study on people who do not have a raised blood pressure.

Then, on finding there was no difference in cardiovascular event in either arm of the trial, you proceed to claim that blood pressure lowering does not work. Because there was no difference between those given the drug, and those taking the placebo. Do you think this makes any sense? Answers on a postcard, that should be sent to the Willie Wonka chocolate factory. Care of A.N. Idiot.

Despite begin riddled with fatal flaws, this analysis was greeted as though it was the definitive study. B-vitamins have no effect on cognitive decline, end of. This is what the head of Alzheimer’s Research UK had to say:

‘Although one trial in 2010 showed that for people with high homocysteine, B vitamins had some beneficial effect on the rate of brain shrinkage, this comprehensive review of several trials shows that B vitamins have not been able to slow mental decline as we age, nor are they likely to prevent Alzheimer’s. While the outcome of this new and far-reaching analysis is not what we hoped for, it does underline the need for larger studies to improve certainty around the effects of any treatment.

New and far-reaching analysis. Comprehensive review … ho hum. If I were given the job of marking this meta-analysis, I would hand it back in a rather grumpy fashion. ‘I asked you to look at the benefit of lowering homocysteine, using B-vitamins, in people with cognitive problems, or early-stage Alzheimer’s. Yet, you have not even bothered to look at these groups. In fact, you deliberately excluded them.

In addition, you included trials where the researchers failed to measure mental decline. Added to this, in most of these trials, no-one even had a high homocysteine level to start with, so they cannot – by definition – have had low levels of B-vitamins. So, how could vitamin B supplementation possible have been of any benefit … I am most disappointed. Please try again, and this time READ the brief.’

One of the trials lasted for four months, another for six months. What measurable different in cognitive function can anyone possibly expect to see in those timescales… This was not a flawed meta-analysis. It was simply gibberish.

There was a time when I would have questioned my own sanity in reading a meta-analysis such as this. Surely, I had got it wrong. Researchers would never put together such a steaming pile. If they did, then no-one would publish it. Nowadays I find myself far more in agreement with Drummond Rennie: deputy editor of the Journal of the American Medical Association:

‘There seems to be no study too fragmented, no hypothesis too trivial, no literature citation too biased or too egotistical, no design too warped, no methodology too bungled, no presentation of results too inaccurate, too obscure, and too contradictory, no analysis too self-serving, no argument too circular, no conclusions too trifling or too unjustified, and no grammar and syntax too offensive for a paper to end up in print.’ ¹⁵

A famous quote… in certain circles.

As it turns out, this analysis was done by exactly the same people who rule the research world of cholesterol lowering, known as the Cholesterol Treatment Triallists Collaboration (CTT) in Oxford. This paper came under the banner of the ‘B-vitamin treatment triallists collaboration’. Who knew such a group existed? One wonders exactly why they exist? Does the world really require such an organisation?

They sure as hell slammed the door shut on vitamin B/homocysteine research in cognitive function. Which was, some may say, possibly whey they were set up in the first place.

In my opinion, you can either believe the B-vitamin treatment triallists collaboration from Oxford with their meta-analysis. Which some would call complete and utter rubbish. Not me, of course. Personally, I have never seen a more detailed and error free research paper. I can hardly praise it highly enough.

Or, you can believe the Cambridge researchers, who demonstrated a seven-fold reduction in cerebral atrophy with B-vitamins – in those with raised homocysteine levels. The choice is entirely up to you.

1: https://pubmed.ncbi.nlm.nih.gov/29982150/

2: https://www.jpost.com/business-and-innovation/health-and-science/4000-israelis-die-annually-due-to-lack-of-magnesium-479184

3: https://pubmed.ncbi.nlm.nih.gov/23172839/

4: https://openheart.bmj.com/content/5/1/e000668

5: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359933/#:~:text=Elevated%20homocysteine%20(Hc)%20levels%20have,II%20diabetes%20mellitus%20(T2DM)

6: https://www.webmd.com/alzheimers/news/20030228/elderly-dementia-linked-to-homocysteine#:~:text=A%20new%20study%20suggests%20that,researcher%20with%20University%20Hospital%20S

7: https://www.nytimes.com/1997/08/10/magazine/the-fall-and-rise-of-kilmer-mccully.html

8: https://www.nejm.org/doi/full/10.1056/nejmoa011613

9: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930825/

10: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3677457/

11: https://pubmed.ncbi.nlm.nih.gov/23690582/

12: https://academic.oup.com/ajcn/article/100/2/657/4576556

13: https://www.nejm.org/doi/full/10.1056/nejmoa060900

14: https://www.alzheimersresearchuk.org/blog/b-vitamins-and-alzheimers-disease/

15: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005733/

Let’s talk about C – just you and me

520 Replies

22nd October 2021

Studying cardiovascular disease for over thirty years can take you to some very interesting and seemingly strange places. Places where I never expected to find myself. Connections appear where you least thought they would be, and entirely new worlds of research open up. Very often, into places where mainstream medical thinking simply does not go.

The fascinating thing is how so many things end up looping back round, in ways that you would never have considered. One of those places is within the world of vitamins. Vital…amines, and the connections to cardiovascular disease.

Unfortunately, mainstream medicine has firmly locked vitamins into a tightly constrained box. Yes, it is accepted that vitamins are vital, because you die without them – that is where the ‘vital’, in vitamins, comes from after all.

However, it is universally believed that the exact requirements for all vitamins – known as the recommended daily allowance (RDA) – which were established decades ago. It is also universally believed that everyone gets sufficient vitamin intake from their diet, so there is absolutely no need for supplementation.

But how true are these comfortable assumptions? At one point I looked into Vitamin B12 deficiency. Even mainstream medicine agrees that this can, and does, occur and can lead to very serious medical problems. Irreversible nerve damage and paralysis, for example.

The normal range for Vitamin B12 in the UK varies from 190 to 950 picograms/ml (pg/ml). [A picogram (pg) is one trillionth of a gram]. This at least is the normal range, in some laboratories… in some places the UK. In truth, it is almost impossible to find a consistent figure.

This ‘normal’ range also varies enormously from country to country. In Japan, for example, it is 500 – 1300 pg/ml. Thus, the lower range is nearly three times higher in Japan than the UK¹. If you went to your GP in the UK with a level of four hundred and said you were Vitamin B12 deficient they would point you to the door. In Japan, they would treat you.

Another thing to note here is that the range is almost always ridiculously wide. It can vary by a factor of five! This alone suggests that people are pretty much guessing at what “is” normal. Despite this, most doctors remain perfectly content that a normal/healthy level has been well established and is based on robust science. There is no need to look again.

This is not the case, not even remotely. Here, for example, are the first three key recommendations on determining what constitutes Vitamin B12 ‘deficiency’ from the British Society for Haematology – with some of the highly technical text removed. They use the term cobalamin here, not Vitamin B12, although it is (basically) the same thing [Cobalamin (Vitamin B12) comes in several different formulations e.g., hydroxycobalamin, methylcobalamin, cyanocobalamin]

The clinical picture is the most important factor in assessing the significance of test results assessing cobalamin status because there is no ‘gold standard’ test to define deficiency

Serum cobalamin currently remains the first‐line test… Serum holotranscobalamin has the potential as a first‐line test, but an indeterminate ‘grey area’ may still exist.

Definitive cut‐off points to define clinical and subclinical deficiency states are not possible, given the variety of methodologies used and technical issues, and local reference ranges should be established²

There you are, clear…. as mud. What the British Haematology Society informs us is that: there is no gold standard test for vitamin B12 deficiency, there are also ‘grey’ areas, and ‘definitive cut-off points to define deficiency states are not possible.’

As with almost all areas of medical research, the more you dig down, the more uncertain things become. The authors of the report are not even sure if you should be measuring cobalamin, or holotranscobalamin – whatever that may be. It sounds like something from Star Trek.

When it comes to vitamin D there is a similar lack of clarity. In the UK, recent guidelines on vitamin D suggested more people should take supplements… finally. However, the NHS advice on vitamin D then goes on to make this statement:

‘…although roughly one in five people has low vitamin D levels, this is not the same as a vitamin D deficiency. It is not accurate to say that millions of people are at risk of deficiency.’³

So, according to the NHS, a low level is not a deficiency. However, a low level cannot, by definition, be normal. For, if it were normal, you could not call it “low”! So, what is it? Here is where words really start tripping over each other. Low, deficient, normal…optimal, inadequate, sub-optimal? Trying to pin any clear definition down is, I can assure you, like trying to pick up mercury using your fingertips.

In the same article it is stated that a blood level of 20nmol/l is ‘sufficient’. Again, what does sufficient mean? Is it the same thing as normal, or is it optimal? Is this really the level we should be aiming for? The National Institutes of Health in the US provides completely different figures for vitamin D deficiency. Or, as they choose to call it – ‘inadequacy.’

‘Some people are potentially at risk of inadequacy at 30 to 50 nmol/L (12–20 ng/mL). Levels of 50 nmol/L (20 ng/mL) or more are sufficient for most people. In contrast, the Endocrine Society stated that, for clinical practice, a serum 25(OH)D concentration of more than 75 nmol/L (30 ng/mL) is necessary to maximize the effect of vitamin D on calcium, bone, and muscle metabolism.’

The truth is that, wherever you look the figures are all over the place. Made more complicated by the fact that the US uses different units of measurement to everyone in the civilised world, by which I mean Europe… of course. When they say seventy-five, they really mean thirty. ‘You say nanograms per millimole, I say nanomoles per litre – let’s call the whole thing off.’

So, should you be aiming for 20nmol/l? Or is it thirty or forty, or fifty? If in doubt aiming higher would be my advice, better safe than sorry. After all, it has been found that the majority of people with cancer have ‘low’, if not ‘deficient’ levels of Vitamin D.

‘More than three-fourths of people with a variety of cancers have low levels of vitamin D, and the lowest levels are associated with more advanced cancers, a new study suggests.’⁴

If having a low level of Vitamin D means you are more likely to get cancer, then I would certainly define this as deficient, not low, and I would certainly want to do something about it.

And it is not just cancer. There are studies linking low vitamin D to many other diseases, such as kidney disease and, more importantly for the sake of this article, diabetes, and cardiovascular disease. As highlighted in this paper: ‘Vitamin D deficiency increases risk of nephropathy and cardiovascular diseases in Type 2 diabetes mellitus patients.’

‘Vitamin D (VD) deficiency is associated with insulin function and secretion. It is linked with diabetes mellitus (DM) progression, and complications were also recorded…The evidence from this study suggest that patients with Type 2 diabetes with vitamin D deficiency are at higher risk for developing CVD and nephropathy [kidney damage].’ ⁵

Additionally, a low Vitamin D level can be a factor that drives obesity and diabetes in the first place. Here, from the study: ‘Vitamin D deficiency is a risk factor for obesity and diabetes type 2 in women at late reproductive age.’

‘Our results showed that vitamin D insufficiency is highly prevalent in the population of healthy women. Low 25(OH)D [a form of vitamin D] levels correlated with high body fat, glucose levels and decreased insulin sensitivity. We conclude that vitamin D deficiency is a potential risk factor for obesity and development of insulin resistance leading to diabetes type 2. ⁶

If you choose to look, the evidence for the potential harms of low… deficient… inadequate…insufficient… suboptimal Vitamin D stretch on, and on, and on. Cancer, diabetes, obesity, kidney failure, cardiovascular disease. In the era of COVID19, there are also significant benefits from vitamin D in boosting of the immune system and reducing the risk of infection.⁷

Cutting to the chase, most doctors are eager to dismiss the benefits of Vitamin D on, pretty much, anything. However, I think the evidence for benefits on overall, and cardiovascular health are overwhelming.

Of equal importance is the fact that vitamin D is incredibly safe to take. It is true that toxicity has been seen in a few people, very few. However, it took sixty thousand units a day for several months to reach this point.

‘Taking 60,000 international units (IU) a day of vitamin D for several months has been shown to cause toxicity.⁸^‘

Frankly, taking that dose would be nuts, and would not be required by anyone, ever. Personally, I take nine thousand units a day from October to March. I am l looking to get my levels above 50nmol/l, and keeping them there, if possible.

And why on earth would you not? Vitamin D is remarkably safe, and cheap. In the summer you don’t need to take any at all. You can get all you need by going out in the sun when it shines and, shock, horror, exposing your skin for an hour or so. Even more if you like.

Why do doctors dislike vitamins so much? It is complicated, but primarily driven by the pharmaceutical industry, who absolutely hate the idea of people buying ‘health’ products that they cannot make any money from. So, they make wild claims about vitamins damaging health, and suchlike. They are simply trying to take out the opposition, usual tactics. For example:

‘….a USA TODAY investigation finds that a wide array of dietary supplement companies caught with drug-spiked products are run by people with criminal backgrounds and regulatory run-ins. Consumers buying products from these firms are in some cases entrusting their health and safety to people with rap sheets for crimes involving barbiturates, crack cocaine, Ecstasy and other narcotics, as well as arrests for selling or possessing steroids and human growth hormone. Other supplement company executives have records of fraud, theft, assault, weapons offenses, money laundering or other offenses, the investigation shows.⁹’

Blah de blah. I amuse myself by reading the title of the book by Peter Gøtzsche: ‘Deadly Medicines and Organised Crime. How big pharma has corrupted healthcare.’ As he says. ‘If you don’t think the system is out of control, please email me and explain why drugs are the third leading cause of death… If such a hugely lethal epidemic had been caused by a new bacterium or a virus, or even one-hundredth of it, we would have done everything we could to get it under control…’

Something reinforced by Richard Smith (previous long-time editor of the British Medical Journal) in the foreword to Gøtzsche’s book:

‘It is scary how many similarities there are between this industry (the pharmaceutical industry) and the mob. The mob makes obscene amounts of money, as does this industry. The side effects of organised crime are killings and death, and the side effects are the same in this industry. The mob bribes politicians and others, and so does the drug industry.’

Just in case you think Gøtzsche and Smith are over-reacting, here is what Harvard University states:

‘Few know that systematic reviews of hospital charts found that even properly prescribed drugs (aside from misprescribing, overdosing, or self-prescribing) cause about 1.9 million hospitalizations a year. Another 840,000 hospitalized patients are given drugs that cause serious adverse reactions for a total of 2.74 million serious adverse drug reactions. About 128,000 people die from drugs prescribed to them. This makes prescription drugs a major health risk, ranking 4th with stroke as a leading cause of death. The European Commission estimates that adverse reactions from prescription drugs cause 200,000 deaths; so together, about 328,000 patients in the U.S. and Europe die from prescription drugs each year. The FDA does not acknowledge these facts and instead gathers a small fraction of the cases.¹⁰’

Ouch. And there are those who think I am highly critical of the pharmaceutical industry. I’m a pussy cat in comparison. How many deaths have there been from vitamins? Last time I looked; it was one, over a ten-year period. I think a large crate of vitamin D fell off a lorry and squashed someone… (joke).

Anyway, yes, as you may have noticed, I have not yet talked about C… Vitamin C. I have just been setting the scene. Rearranging the mental furniture. So, now to vitamin C. How much do you need? What good does it do?

I find it somewhat strange that almost all animals can synthesize their own Vitamin C, but we cannot. Along with a few great apes, a couple of fruit bats and guinea pigs. Animals synthesize it from glucose, in four steps.

Humans have retained the first three steps but lack the fourth. We lost this fourth step about forty million years ago. Perhaps because we learned to re-cycle vitamin C within our red blood cells, so we need far less of it. The ‘electron transfer hypothesis.’ If making Vitamin C uses up resources that we need for other things… why bother. Just eat it, there is plenty about¹¹.

Anyway, for whatever the exact reason, we lost the ability to make vitamin C. So, we now have to eat it. Mostly from fruit and plants. Tricky if you are Inuit. However, animal meat does contain enough vitamin C to keep the Inuit going.

There is a hypothesis that the Inuit ensure that they eat the adrenal glands of various animals they kill, because this is where there is the highest concentration of vitamin C lies. I don’t think I have seen this proven. Anyway, how could the Inuit possibly have known where vitamin C was concentrated? A clever trick indeed. Do they have secret biochemical labs hidden within glaciers?

Moving on. What happens if you do not eat enough vitamin C? Well, a whole lot of different things. But the most serious problem is that vitamin C is required to create collagen. Think of collagen as being like the steel bars in concrete, providing support and strength for tissues around the body. Without collagen, things can start to break apart quite dramatically.

Blood vessels, for example, need a lot of collagen, as they have to withstand a lot of pressure, and squeezing and bending and suchlike. So, one of the first clinical signs of scurvy (Vitamin C deficiency) is often bleeding gums. Followed by bleeding everything else. Followed by bleeding to death. Not recommended.

What is both pertinent, and fascinating at this point in the vitamin C story, is that evolution came up with a plug to reduce the risk of bleeding to death in vitamin C deficiency. Until enough vitamin C could be found and consumed again, and collagen synthesis got back to normal.

This plug is called Lipoprotein(a). Or Lp(a).

If blood vessels start to crack, this action attracts a Lp(a) to the scene. It then flings itself at the cracks, to form a plug that is highly resistant to being broken apart. More so, than any other part of a blood clot. It achieves this resistance by using a very clever trick, which is that it blocks the activation of the enzyme specifically designed to break down blood clots.

At this point I need to explain a bit more about blood clots… So, off we go once more, on a detour.

The enzyme designed to break clots apart is plasmin, which does the job of slicing apart strands of fibrin. Fibrin is the very tough strand of protein that wraps around all blood clots, then binds them together, then tightens up the entire clot up and makes it very tough and difficult to ‘lyse’ i.e. slice apart.

Fibrin is constructed when smaller pieces of protein, called fibrinogen are linked up, end to end, to form the much longer fibrin strand. This is the final step of the monstrously complex ‘clotting cascade’. [You could not allow long strands of fibrin to float about freely in the blood. They would just end getting tangled around everything else and getting stuck in various vital places.]

So, whilst fibrin has a critical function in blood clot formation, if you cannot break it down – once the bleeding has stopped, and repair has started – then you cannot break apart the blood clot either – at least not easily. And if you cannot break apart blood clots, then they are going to hang around – almost forever. Which is not a good thing, as you can probably imagine.

Which is where the enzyme known as plasmin comes in. Once bleeding has stopped, plasmin is ‘activated’ to slice – or lyse – the clot apart, and then it is gone.

How do you activate plasmin? Well, this process starts with another protein called plasminogen – which is incorporated into all blood clots as they form. Plasminogen then sits there doing nothing much. However, you can convert plasminogen into plasmin using another enzyme called tissue plasminogen activator (TPa).

TPa + plasminogen → plasmin → fibrin sliced apart ‘lysed’

Yes, step after step… after step. Tissue plasminogen activator is now made commercially and is colloquially known as a ‘clotbuster’. It is often given to people having a stroke to ‘bust’ the clot apart. [Unless you are having a stroke due to a bleed, not a clot, at which point given TPa would not be a great idea].

So, and keep holding on here, because I am going to get back to Vitamin C in a bit… so, what if you could not break up clots? At least, not so easily. Well, whilst this is a good thing if your blood vessels are cracking due to a lack of collagen, as the blood clot ‘plugs’ will need to last for a long time. At least until Vitamin C intake goes up, and collagen can be made.

However, if you do not have scurvy, having blood clots that resist lysis is a bad thing, because these clots are more likely going to hang around for ages. They will be stuck to blood vessel walls for quite a long time. Which means that they can become the focus for atherosclerotic plaques. [At least this is what happen if you believe in the thrombogenic hypothesis – which I do].

Now, getting back to Lp(a). How does it stop clots being broken down? Well, the(a) in Lp(a) stands for apolipoprotein(a). This protein is almost identical to plasminogen – the protein that is incorporated into all blood clots as they form. However, apolipoprotein(a) cannot be converted to plasmin by tissue plasminogen activator. Instead, it acts as a tissue plasminogen activator inhibitor. It jams up the active site of TPa.

So, deep breath. If you have a lot of Lp(a) around, you are in danger of creating difficult to shift blood clots. As outlined in the paper ‘Lipoprotein(a) as a modifier of fibrin clot permeability and susceptibility to lysis.’

‘We here provide the first evidence that elevated plasma Lp(a) levels correlate with decreased fibrin clot permeation and impaired susceptibility to fibrinolysis both in apparently healthy subjects and patients with advanced coronary artery disease. The relationship between Lp(a) and clots …are associated with extremely unfavourable clot properties¹².’

Therefore, if you have a lot of Lp(a) in you blood, you will have blood clots with ‘extremely unfavourable clot properties.’ And so, you may end up dying of cardiovascular disease. Here is an article from the New York Times:

‘To millions of Americans, Bob Harper was the picture of health, a celebrity fitness trainer who whipped people into shape each week on the hit TV show “The Biggest Loser.”

But last February, Mr. Harper, 52, suffered a massive heart attack at a New York City gym and went into cardiac arrest. He was saved by a bystander who administered CPR and a team of paramedics who rushed him to a hospital, where he spent two days in a coma.

When he awoke, Mr. Harper was baffled, as were his doctors. His annual medical checkups had indicated he was in excellent health. How could this have happened to someone seemingly so healthy?

The culprit, it turned out, was a fatty particle in the blood called lipoprotein(a). While doctors routinely test for other lipoproteins like HDL and LDL cholesterol, few test for lipoprotein(a), also known as lp(a), high levels of which triple the risk of having a heart attack or stroke at an early age.’

You may think, why have I never heard of Lp(a). Fear not, you are not alone, as most doctors have never heard of it either. The surprising fact is that, although you may think you have never heard of Lp(a) you have. Because it is actually….

Drum roll, great suspense…

It is…. Low Density Lipoprotein (LDL). Yes, it is ‘bad cholesterol’ itself. The evil substance of doom itself. What a remarkable coincidence…

You think I am pulling your leg. I am, but only slightly. In fact, to be fully accurate, Lp(a) is actually low-density lipoprotein (LDL), with an extra strand of protein attached to it. And that protein is apolipoprotein(a).

Yes, apolipoprotein(a), the very protein that pretends to be plasminogen. The protein that inhibits blood clots from being broken apart. This is all a bit like a Sherlock Holmes story. Ladies and Gentlemen, I give you…

‘The tragic case of mistaken identity.’

‘I put it to you sir, that when you looked at atherosclerotic plaques and saw LDL within them, you were actually looking at Lp(a) molecules, but you did not recognise them. Because you miserably failed to look for the apolipoprotein(a).’

Or, to switch metaphors in a heavy-handed manner to Cluedo.

‘It was Lp(a) wot done it, in the left anterior descending artery, with an apolipoprotein(a) molecule.’

Or, to put it more technical speak, from the paper ‘Quantification of apo[a] and apoB in human atherosclerotic lesions.’:

‘These results suggest that Lp[a] accumulates preferentially to LDL in plaques, and that plaque apo[a] is directly associated with plasma apo[a] levels and is in a form that is less easily removable than most of the apo B. This preferential accumulation of apo[a] as a tightly bound fraction in lesions, could be responsible for the independent association of Lp[a] with cardiovascular disease in humans¹³.’

Oh, my goodness, it is all so very complicated, is it not? Well, it is both complicated, and fascinating. You start looking at Vitamin C, and you end up comparing the molecular structure of plasminogen and apolipoprotein(a). Then you find that Lp(a) is, to all intents and purposes, LDL.

Now, let me see. Where does vitamin C properly fit into this tale?

Well, if you don’t have enough vitamin C, then you are more likely to end up with cracks in your blood vessels. These cracks will then be plugged by small blood clots, containing a lot of Lp(a). If you have a high Lp(a) level, then these small blood clots will be even bigger, and even more difficult to remove.

Which means that if you have a high Lp(a) level, it would be a splendid idea to ensure that you never become vitamin C deficient. Indeed, even if you do not have a high Lp(a) level it would be a splendid idea to ensure that you do not become vitamin C deficient. Because cracks in blood vessel walls are never a good thing. Ending up, potentially, as the focus for atherosclerotic plaques.

Linus Pauling, a famous double Nobel Prize winner, believed that ‘sub-clinical’ Vitamin C deficiency was ‘the’ cause of cardiovascular disease. He also believed that if everyone took enough vitamin C, cardiovascular disease would disappear.

Personally, I do not think it is ‘the’ cause of cardiovascular disease, but I do think that it is ‘a’ cause. That is, whether or not you have a high Lp(a) level. Of course, a high Lp(a) level is likely to make things far worse, were you to end up vitamin C deficient.

However, the vitamin C, cardiovascular disease story does not end here. Because vitamin C has many other critical functions that link back to cardiovascular disease in one way, or another. For example, it has a more general function in protecting endothelial cells from harm, and supports the integrity of the vascular system. Here, from the paper ‘Role of Vitamin C in the function of the vascular endothelium’:

‘Vitamin C, or ascorbic acid, has long been known to participate in several important functions in the vascular bed in support of endothelial cells. These functions include increasing the synthesis and deposition of type IV collagen in the basement membrane, stimulating endothelial proliferation, inhibiting apoptosis (endothelial cell death), scavenging radical species, and sparing endothelial cell-derived nitric oxide to help modulate blood flow. Although ascorbate may not be able to reverse inflammatory vascular diseases such as atherosclerosis, it may well play a role in preventing the endothelial dysfunction that is the earliest sign of many such diseases.’

Supplementation to upper normal plasma ascorbate levels is clearly indicated in most diseases and conditions in which ascorbate is depleted. However, it is seldom a priority, because patients, physicians, and health authorities are unaware of the increasing evidence for multiple potentially important functions of ascorbate. With regard to the endothelium, it is worth emphasizing observations made more than 50 years ago that early scurvy generates endothelial disruption in guinea pigs, which resembles atherosclerosis and is fully and rapidly reversible with ascorbate repletion.¹⁴’

Yes, with regard to the last part about guinea pigs. Many years ago, a researcher deliberately made guinea pigs ‘scorbutic’ – the medical term for the state of vitamin C deficiency, a.k.a. scurvy. At which point they developed atherosclerotic plaques.

When the vitamin C was added back into their diet, the atherosclerotic plaque disappeared. [Unless you left it too long, in which case, the plaques remained]. Best animal experiment on atherosclerosis ever done – never repeated.

Having just said all of this. I do not believe that most of us, most of the time, are lacking vitamin C – to any degree. At least I do not think so. However, if we become infected – with almost anything – the requirement for vitamin C shoots up. Because Vitamin C gets burned up protecting the endothelium, and it also supports the immune system

‘The role of vitamin C in lymphocytes is less clear, but it has been shown to enhance differentiation and proliferation of B- and T-cells, likely due to its gene regulating effects. Vitamin C deficiency results in impaired immunity and higher susceptibility to infections. In turn, infections significantly impact on vitamin C levels due to enhanced inflammation and metabolic requirements.¹⁵’

Another key thing to know about vitamin C, again closely related, is that people with type II diabetes, and people who smoke, have reduced circulating levels of Vitamin C.

‘Although T2DM [type II diabetes mellitus] is not traditionally considered a risk factor for vitamin C deficiency, our research indicates that those with prediabetes or T2DM are more likely to have inadequate or deficient plasma vitamin C concentrations. This did not appear to be due to a lower dietary vitamin C intake, so dietary advice needs to emphasise the importance of consuming high vitamin C foods.¹⁶’

What links smoking, type II diabetes, and vitamin C? Here I am hypothesizing a little. What links them is that with smoking, and type II diabetes, the endothelium is under ‘attack’. High blood sugar levels damage the glycocalyx (the protective lining of endothelium), and so do the nanoparticles that enter the bloodstream if you smoke.

Here is a quote from the paper: ‘Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo.’ (In vivo means in a real live person, not just in vitro – in a test tube). Jargon alert:

‘Hyperglycemia is associated with increased susceptibility to atherothrombotic stimuli. The glycocalyx, a layer of proteoglycans covering the endothelium, is involved in the protective capacity of the vessel wall. We therefore evaluated whether hyperglycemia affects the glycocalyx, thereby increasing vascular vulnerability…

In the present study, we showed that the glycocalyx constitutes a large intravascular compartment in healthy volunteers that can be estimated in a reproducible fashion in vivo. More importantly, we showed that hyperglycemic clamping elicits a profound reduction in glycocalyx volume that coincides with increased circulating plasma levels of glycocalyx constituents like hyaluronan, an observation that is consistent with the release of glycocalyx constituents into the circulation¹⁷.’

Looking specifically at smoking:

‘Vascular dysfunction induced by smoking is initiated by reduced nitric oxide (NO) bioavailability and further by the increased expression of adhesion molecules and subsequent endothelial dysfunction. Smoking-induced increased adherence of platelets and macrophages provokes the development of a procoagulant and inflammatory environment.¹⁸’

Essentially, smoking and high blood glucose both damage the endothelium, which results in low vitamin C levels, as the endothelial cells burn through Vitamin C to maintain themselves. Ergo, fi you have type II diabetes, or smoke, you need more Vitamin C to maintain healthy levels….

Now, before I introduce you to far too many new and difference concepts – I did mention everything starts linking back together in completely unexpected ways – it is time to draw our little tale of Vitamin C together.

The first thing to say about vitamin C is that it is vital. I have only covered a few of the essential functions that it has in the human body. Those most closely related to cardiovascular disease. Importantly, it is almost impossible to cause harm by overconsumption. It is just about as safe to take, as anything can possibly be.

The next thing to say is that most of us, most of the time, probably have sufficient vitamin C intake, and require no supplements.

However, if you have a high Lp(a) level, then any damage caused by a lack of vitamin C will be amplified, dure the fact that Lp(a) sticks very tightly to areas of endothelial damage, making the resultant blood clot very difficult to remove. So, for those with high Lp(a) levels, I would recommend one gram of vitamin C a day – forever.

If you smoke, or have diabetes, the lining of your artery walls (glycocalyx and endothelium) are under constant attack from nasty substances – smoke nanoparticles and high blood glucose. This, too, will create ‘cracks’ in blood vessels.

In both situations Vitamin C is also used up more rapidly, trying to protect against this damage. So your vitamin C level is likely to be low. Which means that you too, should take one gram of vitamin C a day – forever. [Or you could try stopping smoking]

In addition, in many infections, the endothelium is under severe attack. Either directly from the microorganisms entering and killing endothelial cells (see under COVID19), or from the exotoxins (toxic waste products) released by any bacteria in the bloodstream.

The most severe endothelial attack occurs in sepsis (infection of the blood), where the exotoxins strip away the endothelium, resulting in widespread blood clotting (disseminated intravascular coagulation DIC). Which is the thing that, primarily, kills you with sepsis.

Whilst sepsis represents an extreme situation, it is still the case that if you are suffering from an infection, of any sort (gingivitis or periodontal disease) your requirement for vitamin C will shoot up. Which means that you should take as much Vitamin C as you can tolerate. Up to ten grams a day. I cannot take this amount due to the impact it has on my gastrointestinal tract. Loose, is the word. Very loose. Looser than loose.

But if you can tolerate it, Vitamin C will help to protect your endothelium. It will also boost the functioning of your immune system.

So, there we are then, vitamin C. My second favourite vitamin, after vitamin D. In the winter I take a gram a day. Along with my nine thousand units of vitamin D. Almost all medics will instantly dismiss this as ‘woo woo’ nonsense. I would tend to argue that this is because they know absolutely nothing about vitamins, or their critical roles in human physiology, and have never bothered to find out.

Pop quiz for your doctor, next time you see them. Ask them how a lack of vitamin C causes scurvy. What is the primary disease process? Watch them scrabble to bring up a Google search. Then ask them about Lp(a). What it is, what it does… I guarantee that silence will be the stern reply.

1: https://advances.augusta.edu/1014#:~:text=Interestingly%2C%20in%20Japan%20the%20reference,methylmalonate%20levels%20are%20not%20checked.

2: https://onlinelibrary.wiley.com/doi/full/10.1111/bjh.12959

3: https://www.nhs.uk/news/food-and-diet/the-new-guidelines-on-vitamin-d-what-you-need-to-know/

4: https://www.webmd.com/cancer/news/20111004/low-vitamin-d-levels-linked-to-advanced-cancers#1

5: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6540771/

6: https://pubmed.ncbi.nlm.nih.gov/23924693/

7: https://vitamindforall.org/letter.html

8: https://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/expert-answers/vitamin-d-toxicity/faq-20058108#:~:text=Advertisement&text=The%20main%20consequence%20of%20vitamin,the%20formation%20of%20calcium%20stones.

9: https://eu.usatoday.com/story/news/nation/2013/12/19/dietary-supplements-executives-criminal-records-spiked/4114451/

10: https://ethics.harvard.edu/blog/new-prescription-drugs-major-health-risk-few-offsetting-advantages

11: https://academic.oup.com/emph/article/2019/1/221/5556105

12: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1538-7836.2006.01903.x