The Emperor’s New Clothes: HOPE-TOO

April 5, 2005

Reputable American researchers claim that even large amounts of natural Vitamin E do not benefit established atherosclerosis. But their study do not reveal it. The participants got almost no Vitamin E.

Perhaps somebody have heard about the praised American HOPE study from 2000. It was to reveal that natural Vitamin E would not make any difference for people with atherosclerosis. This was a disappointment, and with it the issue could then have been dismissed.

That is not how it went. The HOPE study, which lasted 4,5 years and included 9,000 participants was prolonged with 2,5 years. They wanted to be absolutely sure, they said. In the follow-up study called HOPE-TOO only 4,000 people participated. Some did not want to participate, others had died, and others only wanted to be examined, but did not want any medication.

Half of the participants took 400 units natural Vitamin E daily (alpha-tocopherol), while the rest took placebo. They certainly had serious atherosclerosis: Every other one had had a heart attack, just as many suffered from angina pectoris (atherosclerosis ), and more than every third had diabetes.

The HOPE study showed that Vitamin E did not cause more or less cancer, more or less heart attacks, strokes, deaths or anything else. HOPE-TOO showed the same result, though with a single addition: Those who took Vitamin E slightly more often had heart failure; that is to say a decreased functioning of the heart.

The difference was so small that it could very well have been coincidental, even though it was statistically significant. Nevertheless the authors took the opportunity to strongly warn against dietary supplements. But yet they might as well have taken the opportunity to recommend them. They found that Vitamin E protected against lung cancer!

This finding, which was also statistically significant, was rejected, as an “error.” This conclusion was preceded by a lengthy discussion, in which reference is made to studies with beta-carotene, which as we all know, is something completely different.

No clothes on
But there is a far more serious surprise, which totally overshadows this biased opinion: During the whole study the participants did not have any more Vitamin E in their blood than all other people, who do not take supplements. The average value was 17,6 μmol/l. The normal value is 12 – 42. Despite the Vitamin E they only just managed to get their minimal need covered.

Before the study the participants actually had even lower values, averaging 10 μmol/l. This fits well with the fact that they were seriously ill, overweight heart patients who were kept on a low fat diet. A low fat diet may lead to deficiency of vitamin E.

Here we may also find the explanation of the low blood values. Vitamin E can only be absorbed from the intestine when fat is present. If you eat non-fat foods you might as well not take Vitamin E, even when you take 20 – 40 times the recommended dosage.

One is reminded of the Emperor’s New Clothes. HOPE-TOO has no clothes on. It claims to examine the effects of mega doses of Vitamin E, but the participants are only seemingly getting it. Strangely enough nobody has pointed out this almost ridiculous mistake before. In particular one wonders, why the authors themselves have not seen this mistake. Could it be that they do not know the normal values of Vitamin E in the blood?

This is not completely out of the question although it sounds strange. There are many examples of superficiality in scientific research. You do not have to look any further than the official commentary in the same issue of JAMA, which published the HOPE-TOO study. Here doctor Greg Brown by and large agrees with the conclusion of the study. He was also in charge of a similar study from 2001, which was supposed to show if antioxidants prevent atherosclerosis in the coronary arteries. This study concluded that antioxidants did not prevent atherosclerosis, even though the figures showed in black and white that the antioxidants halved the growth of atherosclerosis in the coronary arteries, compared to placebo.

By: Vitality Council

References:
1. The HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer. JAMA 2005;293:1338-47.
2. B Greg Brown. Is there any hope for vitamin E? JAMA 2005;293:1387-90.
3. Greg Brown et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92.

jama.ama-assn.org
content.nejm.org
www.iom.dk

Listen to this: Vitamins Preserve the Hearing!

February 3, 2005

Studies with guinea pigs and American soldiers show that large doses of the vitamins C and E prevent chronic hearing impairment caused by noise. The conclusion is important, as every tenth grown-up has impaired hearing.

Do you have difficulties hearing? If so, the cause might be a vitamin deficiency. This is the result of a study carried out at the renowned Karolinska University Hospital in Stockholm, Sweden – the hospital is known throughout the world for being the place in which the staff scientists decide who gets the annual Nobel Prize for medicine.

The study showed that if the guinea pigs were given large doses of the vitamins C and -E before and after a violent noise impact, they would avoid the chronic hearing impairment that would otherwise be the result. Studies of American soldiers at target practice have shown similar results.

Impaired hearing is more common than you would probably think. 10% of all adults have so serious hearing difficulties that it affects their everyday communication. The prevalence increases with age, but many people become hearing impaired when they are young if they have a liking for violent music or if they have some sort of genetic predisposition for being sensitive to noise.

Professor Mats Ulfendahl from The Center for Hearing and Communication Research at the Karolinska University Hospital is behind the study. It was based on the knowledge that noise produces free oxygen radicals in the sensory cells of the inner ear and that these radicals are responsible for destroying the sensory cells.

For this reason, it was logical to try to limit the damage by supplying antioxidants to the guinea pigs. Ulfendahl presented the results at a congress about hearing impairment at the Karolinska University Hospital in September 2004.

Mats Ulfendahl is among the world’s leading researchers in hearing impairment and, among other things, he has demonstrated that there are stem cells in the inner ear that can develop into mature auditory- and neve cells. He believes that this discovery can imply that during the next 10 – 20 years, people suffering from aquired deafness can have their hearing restored. If he is right, it is hardly unlikely that his colleagues at the Karolinska University Hospital will nominate him for the Nobel Prize.

At present, there is no method for repairing damaged auditory cells in humans. Birds, however, automatically regenerate their hearing when they become deaf as a result of a noise injury. The thought of restoring hearing, therefore, is not fundamentally impossible. If you are considering some kind of prophylaxis before going to a disco, for example, it would probably be a good idea to consider taking a megadose vitamin supplement.

By: Vitality Council

References:
This time we do not refer to a scientific article, but an online introduction by a Swedish professor and a speech (in Swedish), which you may listen to directly at the web addresses below:
1) Can vitamins really soothe impaired hearing? ( Kan verkligen vitaminer lindra hörselnedsättning? ) http://www.hrf.se/templates/Page2x1____3855.aspx
2) Take a vitamin pill and then listen! ( Ta en vitamin och hör sen! )
http://www.karolinska.se/templates/Page.aspx?id=39736

www.hrf.se/templates/Page2x1____3855.aspx
www.karolinska.se/templates/Page.aspx
www.iom.dk

Vitamin E or false product description

November 12, 2004

Calculations on the basis of old studies leads to claim of increased mortality by antioxidants and vitamin E, but is in reality based on studies with beta-carotene.

Recently, researchers published a study on beta-carotene, but called it antioxidants. Now there is a new study of beta carotene, but this time it is called vitamin E. Both studies are so-called meta-analyzes, ie. calculations of previous research.

The two studies claim to show that respectively antioxidants and vitamin E increase mortality, but they are both based on the results of old beta-carotene tests. Since 1994, it has been known that beta-carotene can cause cancer and increase mortality in at least male smokers.

The latest meta-analysis originates from Johns Hopkins University in the USA. Here, the mortality rate in a total of 19 old treatment trials with vitamin E was investigated. Apparently, doses above 400 units per day slightly increased mortality, although it was decreased in the trial where the dose was the highest (2,000 units/day). There were 11 trials where more than 400 units were used per day. At a lower dose, there was a tendency for decreased mortality.

However, of the 11 trials, the so-called Heart Protection Study (HPS) from the year 2000 is by far the largest. In fact, so large that it completely dominates the calculation. In HPS, almost twice as many died as in all the other 10 trials combined – and more than four times as many as in the other trials with increased mortality. The problem with this is that in HPS, in addition to vitamin E, the treatment consisted of vitamin C and beta-carotene!

Of course, one cannot comment on the risk of vitamin E based on an experiment in which both vitamin E and C and beta-carotene were used. You can only comment on vitamin E and C and beta-carotene!

Also, in the trial in question (HPS), synthetic vitamin E was used. It consists of eight different chemical compounds, only one of which is found in nature. That makes it even more difficult to comment on vitamin E, which most people buy in its natural form.

There are many other objections to the new meta-analysis. If you e.g. arrange the numbers just a little differently, but still fairly, the excess mortality disappears entirely. That happens if you ignore the misleading HPS study and include trials using over 300 units instead of just over 400. That would be entirely plausible.

This and much else may be why several independent statisticians told the New York Times that they did not believe the conclusion.

One can debate whether there is a real need for these sometimes arbitrary concoctions of old experiments, which easily lead to misinterpretations. Far greater is the need for large-scale investigations into whether, for example, a combination of natural vitamin E and C prevents atherosclerosis in people who are not overwhelmingly atherosclerosis already. This is where one can expect an effect, but these experiments have not been carried out.

Sales of vitamin E are increasing in the United States, where many doctors in particular take it. The combination of vitamin E and C can be seen i.a. as a competitor to the tremendous expensive, but almost ineffective, prescription drugs for Alzheimer’s. According to a report earlier this year – also from Johns Hopkins – users of both of these vitamins have approx. 80% reduced risk of getting Alzheimer’s – compared to those who get only one of them or none at all.

Most recently, the Nobel laureate Louis Ignarro, based on his own experiments, strongly recommended the same combination as prevention against atherosclerosis.

By: Vitality Council

 

References:
1) Metaanalysis: High-dosage vitamin E supplementation may increase all-cause mortality. Ann Int Med 2004;142.
2) Bjelakowic G, Nikolova D, Simonetti R G, Gluud C. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. The Lancet 2004;364:1219-28.
3) Ignarro L J et al. “Long Term Beneficial Effects of Physical Training and Metabolic Treatment on Atherosclerosis in Hypercholesterolemic Mice. PNAS 2004 (May 24).
4) Zandi PP et al. Reduced risk of Alzheimer disaease in users of antioxidant vitamin supplements. Arch Neurol 2004;61:82-88.
5) Gina Kolata: Large Doses of Vitamin E May Be Harmful. New York Times 11.11.04.

Vitamin E Competes with Viagra

October 26, 2004

Diabetic mice who are not able to obtain erection are helped nearly as well by taking vitamin E as with taking Viagra. A combination is even better, and the treatment is recommended for diabetic men with the same problem.

Based on animal studies, Canadian researchers believe that male diabetics suffering from erectile dysfunction can be helped with vitamin E.

Diabetic men must, due to a weak erection, often resort to Viagra. However, despite the widespread use of this preparation, its effect is not rarely inadequate.

A supplement with a high dose of vitamin E might help, according to researchers at the Urology Department at St. Joseph Health Care, University of Western Ontario (Canada).

By: Vitality Council

Reference:
De Young L, Yu D, Bateman RM, Brock GB. Oxidative stress and antioxidant therapy: their impact in diabetes-associated erectile dysfunction. J Androl. 2004 Sep-Oct;25(5):830-6.

www.andrologyjournal.org
www.iom.dk

Vitamin E Against Alzheimer’s Disease and Colds

October 11, 2004

The World’s leading experts in vitamin E participated in a congress in New York in the spring which was sponsored by the New York Academy of Sciences. The last time such a congress was held was in 1989 and some of the news have now been described in the October issue of the Academy’s scientific magazine.

It is astounding that we are still discussing nature’s purpose of Vitamin E. It can actually be difficult to find obvious deficiency symptoms in humans. However, it is certain that the vitamin is highly important. All higher animals – including fish – produce the protein TTT with the single task of transporting vitamin E in the blood. Natures probably would not have gone to such trouble of making a transport protein for a substance that the body could easily do without.

“When nature has chosen exactly alpha-tocopherol from the thousands of antioxidants in our surroundings, there must be a reason”, declared Angelo Azzi of the University of Bern. Vitamin E slows down the blood platelets when they are about to clog and form blood clots.

This is significant to the tendency of other cells to stick to each other, divide, and to send signals to each other. Furthermore, it increases the production of nitric oxide (NO) which is an important signalling molecule that relaxes the blood vessels and thereby lowers the blood pressure. How can we translate these fundamental abilities into something we can see and feel, though?

The participants at the congress presented results showing that Vitamin E delays Alzheimer’s disease. According to a French study, the combination of vitamin C and vitamin E can prevent the disease from occuring in the first place. The same combination of vitamins also prevents pre-eclampsia. Finally, a randomized trial has shown that vitamin E reduces the frequency of colds in elderly people by 25%.

A constant controversial question is why only a single randomized trial have been able to show that vitamin E prevents coronary thrombosis when there are so many other indications of this effect. The explanation could be that synthetic Vitamin E has often been used instead of natural vitamin E. Synthetic Vitamin E consists of eight different substances of which only a single one is present in nature.

Another reason might be that the Vitamin E has not been supplemented with vitamin C; automatic supplementation with Vitamin C happens in animals because of their ability to produce Vitamin C themselves.

However, the reason might also be that the participants of almost all the studies had been severely atherosclerotic from the start. “Once calcification has damaged an artery, the damage will heal very poorly”, professor Meydani of Tufts University, USA. Vitamin E is probably better at preventing than curing diseases!

Professor Maret Traber from Oregon estimates that 70 – 80% of all adults get less than the recommended 30 mg. of Vitamin E weekly. Her advice is to live healthily and that there is no harm in taking an extra Vitamin E supplement.
The exact reason for its beneficial effect will perhaps not be elucidated for another 15 years.

By: Vitality Council

Reference:
Hopkin K. New York Academy of Sciences Magazine 2004; October: 4-6.

www.nyas.org/publications
www.iom.dk

Vitamin E Prevents Colds

September 13, 2004

By taking a modest vitamin E supplement, the elderly can be spared every fifth cold they would normally get. This is the result of the best randomized trial in this field so far. It was recently published in the Journal of the American Medical Association, JAMA.

The study was carried out by a university-based team of researchers in Boston belonging under the American Ministry of Agriculture. In charge of this group was Simin Meydani, a professor and specialist in nutrition and ageing. She has previously established that it is not belief but reality that Vitamin E stimulates the T cells of the immune system.

The study included 617 people in 33 nursing homes and they were all above 65 years old. Half of them were given a supplement of 200 I.U. of Vitamin E every day for a year. The other half were given placebo and during the study, it was calculated which group suffered the fewest respiratory infections.

It turned out that the ones who were given vitamin E had fewer infections than the others and particularly the number of colds were reduced by a statistical significance of 20%. There was no effect, however, on the frequency of pneumonia.

Meydani emphasized that even though only every fifth cold was prevented, the result is still important. Vitamin E is completely harmless and colds are the cause of 30% of all absence due to illness in the US.

Another perspective is the possibility that Vitamin E perhaps has a particular effect on viral infections like colds but not on diseases like pneumonia which are mostly caused by bacteria. Based on this, other researchers wanted to know if vitamin E can have an importance in the fight against AIDS, where it is exactly the T cells that are being targeted, but Meydani herself did not want to speak on this subject.

The results were originally displayed in May of this year at a closed scientific symposium on vitamin E arranged by the New York Academy of Science. Almost all of the world’s élite in vitamin E research participated.

Among other things, also the highly sensational findings were displayed that a combination of Vitamin C and Vitamin E supplements reduces the aggravation of Alzheimer’s disease by 50% and that the same combination prevents eclampsia in every other pregnant woman who are at risk of developing this serious disease.

By: Vitality Council

Reference:
Vitamin E and Respiratory Tract Infections in Elderly Nursing Home Residents A Randomized Controlled Trial Simin Nikbin Meydani, DVM, PhD; Lynette S. Leka, BS; Basil C. Fine, MD; Gerard E. Dallal, PhD; Gerald T. Keusch, MD; Maria Fiatarone Singh, MD; Davidson H. Hamer, MD JAMA. 2004;292:828-836.

jama.ama-assn.org
www.iom.dk

Vitamins Prevent Sport-related Attrition

August 23, 2004

Strenuous and exhausting physical exercise is not beneficial to your health, as it may result in damage to both the DNA (hereditary material) and the cell walls through the process of oxidation.

Vigorous and exhausting physical exercise is not beneficial to your health. The oxidation that takes place during this kind of exercise both damages the DNA (our hereditary material) and destroys the cells walls.

Actually, a general attrition takes place similar to the one our body is exposed to during an operation, a heart attack, or another kind of violent strain. The proofs of the damages can be found in blood samples and urine tests.

However, a new study has shown that a lot of the damages can be prevented in athletes if they take a supplement of the vitamins E and -C before demanding performances. Both of the vitamins are antioxidants, i.e. they prevent the unintentional oxidation of the cell walls and thereby the destruction of the cellular functions.

Many athletes take supplements but proof of the supplements actually working have now been established in a thorough study of American ultramarathon runners.

The study was carried out in a scientific sports institute under Oregon State University. Starting six weeks prior to the long 50 km. (31 miles) race, 11 out of the 22 participants each took 1 g. of vitamin C and 400 I.U. of vitamin E every day while the other 11 participants were given placebo. Both before and after the race a number of tests were performed on both groups.

It turned out that the vitamins completely prevented the fats in the cell walls from going rancid (oxidation) both during and after the race. In the men who had not taken vitamins, the consequences of the exertions were measurable for at least six days while they were non-existent in the ones who had been given vitamins. Interestingly, the women got off lighter in that their tests were only elevated for a couple of hours after the race even though they had not taken any supplements.

The spokesperson for the researchers is professor Maret Traber. With a background including several honorary tasks and more than 160 scientific articles, she is considered one of the world’s leading experts on the subject of Vitamin E.

Based on the study, she declared that if you suffer from chronic health problems, you may very well benefit from larger doses of the two vitamins than what is normally recommended. In this context, she mentions diabetes, Alzheimer’s disease, and cardiac diseases, but also overweight and smoking. They are all conditions involving increased rancidity of the fats in the cell walls.

By: Vitality Council

Reference:
Mastaloudis A., Morrow JA, Hopkins DW, Devaraj S, Traber M. Antioxidant supplementation prevents exercise-induced lipid peroxidation, but not inflammation, in ultramarathon runners. Free Radical Biology & Medicine 2004;36(10):1329-1341.

www.sciencedirect.com/science
www.iom.dk

Antioxidants Prevent Lung Cancer After All

August 4, 2004

Smokers taking a wide range of antioxidants through their diet, reduce their risk of getting lung cancer. This is demonstrated by a follow up study from a world famous research study (ATBC). The ATBC study has been the source of the opposite interpretation for ten years.

The startling result is sourced from the so called ATBC-study, a Finnish study from 1994, which demonstrated that the risk for male smokers getting lung cancer did not decrease, but increased, when they were given large dosages of betacarotene – the yellow colouring substance in carrots.

The ATBC study was a shock for researchers all over the world, who on the basis of numerous animal studies were convinced that antioxidants prevent cancer. Since then the ATBC study has been the standing argument for recurrent warnings against antioxidants on TV etc.

In the new study, staticians from the prestigious American Yale University together with Finnish colleages looked through 1,787 cases of lung cancer, approximately the amount of the 27,000 male heavy smokers in the ATBC group, who got lung cancer during the 14 years.

In the new study, measurements were taken not just for one single antioxidant, but for the total intake of the antioxidants selenium, Vitamin E, Vitamin C as well as coloured parts in plants, the so called carotenoids and flavonoids. The most updated inclusive index was calculated in advance stating the total antioxidant intake with just one figure.

It turned out that the fifth of the smokers, who had the highest index statisticly seen through their diet, had a 16% less risk of lung cancer! Smokers who ate large amounts of meat had a 25% decrease, despite of red meat having a high oxidative effect! This supports the fact that it was the antioxidative effect that made the difference.

It is not the first time such results are seen, but they are of great importance, because they are sourced from the same ATBC study, which has been one of the most outspoken arguments to warn against antioxidants. Two other larger studies has found the risk of lung cancer decreased up to as much as 32% and 68%.

The researchers emphasize in a commentary, that when the original study was a disappointment, the explanation may lie in the fact that smokers did not get a combination of vitamins etc., but were given betacarotene alone. They recommend smokers to always take a wide selection of antioxidants as a protection against cancer.

By: Vitality Council

References:
1. Wright ME et al. Development of a comprehensive dietary antioxidant index and application to lung cancer risk in a corhort of male smokers. Am J Epidemiol 2004;160:68-76.
2. Yong LC et al.Intake og vitamins E, C and A and risk of lung cancer: The NHANES I epidemiologic follow-up study. Am J Epidemiol 1997;146:231-43.
3. Michaud DS et al. Intake of specific carotenoids and risk of lung cancer in 2 prospective US cohorts. Am J Clin Nutr 2000;72:990-7.

jama.ama-assn.org/cgi/content/abstract/290/4/476
www.aje.oupjournals.org
www.ajcn.org
www.iom.dk

Nobel Prize Award Winner: Vitamin E and C Prevent Hardening of the Arteries!

July 13, 2004

The theory that antioxidants protects against arteriosclerosis and thereby cardiac thrombosis, brain haemorrhage, and more, is now supported by one of the World’s leading experts in the field.

The American Nobel laureate Louis J Ignarro from UCLA University in California recommends in clear terms that you take supplements of the antioxidants vitamin E and C.

– It works on mice, he says. It will work on humans too!

Ignarro is a chemist and pharmacologist by training, but he is first and foremost a world-renowned expert when it comes to blood vessels. In 1998, aged only 57, he received the Nobel Prize in Medicine for his discoveries of NO’s (nitrogen oxide) effect on the blood vessels.

It was a groundbreaking discovery. Previously, it was believed that this simple molecule was just a nuisance part of the air pollution over big cities.

Ignarro demonstrated that NO is a biologically active molecule that forms in the blood vessels and ensures that they stay open. He also showed that NO dramatically prevents platelets from clumping together and forming blood clots.

In the years around 1980, he discovered that the well-known heart medicine nitroglycerin – whose mode of action until then was a mystery – dilates the heart’s coronary arteries precisely by being converted to NO.

Ignarro’s research has been overwhelmingly inspiring for other researchers. Without his efforts, e.g. Viagra, which increases the NO content in the penis’ blood vessels, has been unthinkable.

In the new and very meticulous experiments, mice were used which, due to high cholesterol, were strongly predisposed to atherosclerosis. When the mice were allowed to complete a swimming program, the content of NO in the blood vessels increased and the extent of atherosclerosis was 35% less than in inactive mice.

When the mice were supplemented with both vitamin E and C instead of exercise, the protection was slightly greater than with exercise! But when they both swam and got vitamins, the effect was significantly enhanced.

The enhanced protection is explained by Ignarro with the fact that vitamins E and C are antioxidants that protect NO from being destroyed by oxygen. Thus, the two vitamins ensure, when taken together, a higher NO concentration in the blood vessels. Ignarro declares that what is good for mice – in this regard – is also good for humans!

He recommends exercising moderately and taking dietary supplements if you want to avoid atherosclerosis. Consequences of atherosclerosis is the most common cause of death in the Western world!

By: Vitality Council

 

Reference:
Ignarro L J et al. Long Term Beneficial Effects of Physical Training and Metabolic Treatment on Atherosclerosis in Hypercholesterolemic Mice. PNAS 2004.

www.pnas.org
www.iom.dk

Vitamin C and E Protects Children Against Arteriosclerosis

September 1, 2003

Children and young people with increased cholesterol levels may reduce the risk of developing arteriosclerosis if they take a daily supplement of Vitamin C and E. This is the conclusion of a study published in Circulation, published by the American Heart Association.

15 children and young people of the age of 9 to 20 years were part of this study. Half of the children took a daily 500mg Vitamin C and 400i.e. (international units) Vitamin E supplement. The rest of the children took placebo. After 6 weeks the groups were switched.

After 6 weeks of active treatment the results showed a significant betterment of the inner wall of the artery. Vitamins alone do not reduce increased cholesterol, but the vitamins seem to be able to protect the blood vessels against sclerosis and thereby secure that the arteries remain their elasticity.

“This is the first time anyone has studied how antioxidants like Vitamin C and E can better circulatory function,” says the chairman of the Vitality Council, specialist doctor in general medicine, Claus Hancke.

“Even if it is a small study, the results are important for children with increased cholesterol. If they alternatively must have cholesterol lowering medicine for several years, the risk of serious side effects will be pretty high. It is therefore wise to give priority to diet changes and extra Vitamin C and E supplements as a first choice in therapy,” Claus Hancke says.

The American study also involved diet recommendations, but they did not follow those recommendations. Among other things the children got too much animal fat and too little fruit and vegetables. Therefore the doctors chose to combine the diet changes with Vitamin C and E supplementation.

The study is carried out at the University of California, under the supervision of Marguerite Engler, M.D.

By: Per Tork Larsen, DSOM

Reference:
Circulation 2003;108:802

www.circulationaha.org
www.amhrt.org/presenter.jhtml