Tag: antioxidants

Much ado about nothing

Claus Hancke

February 12, 2019

One could justifiably use the above-mentioned Shakespeare title about a newly published article (1) that supposedly shows that antioxidant supplements reduce the effectiveness of chemotherapy and radiation therapy in postmenopausal women.

Please note that this assertion is by no means proven; there is much research that points in both directions.

The above-mentioned journal article does not contribute to clarification of the issue, not least because of the weak design of the study.

The data in the study came from interviews of postmenopausal women in two regions in Germany. The researchers used data from the “Mamma Carcinoma Risk Factor Investigation,” a study that was first published more than 10 years ago to report on the risk factors associated with postmenopausal hormone therapy.

Despite the known weaknesses of the interview study, the Danish TV2 reported the results of the study as a great sensation and with a headline that announced:

“New research: Dietary supplements can spread breast cancer.
German researchers have learned that antioxidant supplements can worsen breast cancer in women. The Danish Cancer Society is concerned.
For many years, there have been discussions as to whether antioxidant supplements are good for human health or not. And now a German study makes it clear that they are definitely dangerous for women with breast cancer.”

No, no, and no again.

There is no evidence for the dramatic TV2 news statements.

The German study does not make anything clear.

And the journal article authors’ own conclusion is much more cautious than the TV2 news report.

The journal article authors write:

“Our data do not support an overall association of postdiagnosis supplement use with prognosis in postmenopausal breast cancer survivors. Our results, together with other clinical and experimental evidence, suggest that during breast cancer treatment, antioxidants should potentiall be used with caution.”

In their journal article, the authors do not even advise against the use of antioxidants during chemotherapy and radiation therapy. They just urge caution.

Normally, German research results are shrugged off in Denmark, and interview-format studies get the same treatment. But, this time, the German interview study could be used to advance specific points of view, and so it was.

There are many things in this German study that grab the attention of the alert reader, and a close reading of the study reveals that the authors are biased, not least in their selection of earlier research on the topic.

An interview study, with no blinding of at all, is certainly not the most valid form of research and cannot be compared with prospective randomized controlled trials (RCT’s).

In the German study, the researchers asked some 2000 breast cancer patients whether they took antioxidant supplements before and/or after the time of their diagnosis with breast cancer and/or during their chemotherapy and radiation therapy.

The women in the study were to answer yes if they had just taken one or another supplement three days a week for a year at a given point in time. A “current user” was any woman who used supplement postdiagnosis within the 6 months before the first follow-up interview.

The term “supplement” and the term “antioxidant” are used quite sloppily but with a noticeable consistency. Whenever the researchers discuss the study, the usage, or the statistics, they use the term “supplements.” Whenever they discuss the chemotherapy or the radiation therapy, however, they use the term “antioxidants” without specifying what the term “antioxidants” covers.

In other words, the researchers have had to extend the definition of antioxidants with other supplements in order to achieve sufficient statistical power and thereby just barely sneak over the line into statistical significance.

About this, the authors write in their article:

“The main exposures of interest included postdiagnosis use (no postdiagnosis use, postdiagnosis use, current use) of any type of supplement; specific supplements, such as magnesium and calcium; and supplement group, such as antioxidants, in which there was adequate statistical power to conduct analyses. Only a few women reported postdiagnosis use of multivitamins, vitamins A, C, E, zinc, and selenium, and therefore they were collectively evaluated together as antioxidants in all of our analyses.”

Above and beyond the fact that the researchers have jumbled everything together in a big group that they call “antioxidants,” there is also a total lack of information about daily dosages, single dosages, and preparation types.

This study has a weak design and has unclear results. Therefore, the authors are careful to settle for a cautious conclusion, which speaks for itself.

The misinformation occurs when the Danish media then trumpet the study conclusion as the definitive truth.

Any serious researcher would avoid making such bombastic statements.

Litt:

  1. Jung AY et al. Antioxidant supplementation and breast cancer prognosis in postmenopausal women undergoing chemotherapy and radiation therapy. Am J Clin Nutr 2019;109:69–78.
  2. Flesch-Janys D, Slanger T, Mutschelknauss E, Kropp S, Obi N, Vettorazzi E, Braendle W, Bastert G, Hentschel S, Berger J. Risk of different histological types of postmenopausal breast cancer by type and regimen of menopausal hormone therapy. Int J Cancer 2008;123(4):933–41.

Contradictions about vitamins

Claus Hancke

 April 26, 2012

One may wonder about the Danish newspapers’ poor interest in the latest vitamin report. First of all, the report predicts dead to those who take vitamin pills, secondly, the turn-over for vitamins is one and a half billion kroner a year. The subject must interest many.

Here the report itself will not be discussed. It is already commented. On the other hand, attention must be paid to a very serious issue concerning the marketing of the report: The contradictory statements that a prominent researcher has used the report to make.

The statements are from chief physician Christian Gluud from Rigshospitalet. He has previously said peculiar things. It’s hard to forget how he on television declared antioxidants (like vitamin E and vitamin C) to be carcinogenic, even when they occur in fruit and vegetables. However, in fruit and vegetables there was, he believed, “a lot of other substances that might either correct the potential damage caused by the antioxidants or that could completely neutralize them.”

You might consider this amusing statement the next time you eat broccoli. It is thus an antidote to vitamins, you are eating!

Currently, Gluud said on TV that his latest study, which combined the results of different trials, is based on trials with commonly recommended vitamin doses. And yet, in almost all trials, there were used from five to twenty times the recommended dose or more.

Gluud has further said (the news program Deadline 2.4.2012) that his group has revealed that, for example, the antioxidants Vitamin C and selenium are directly life threatening, as they increase mortality by 4%. And yet, his report frees both of the two antioxidants for this accusation.

In the TV2 news (22.3.2012) Gluud said that “it’s quite common vitamin pills in very common doses that give the increased mortality.” But in an interview with Medwatch.dk he said the opposite: He could not comment on that subject – that multivitamins increase mortality – because no one had studied it!

If you ask chief physician Gluud, you may obviously get the answer that his current state of mind indicates. One moment, common vitamin pills are dangerous poisons, the next, it is not known, and at one time, selenium and vitamin C are poisonous, but at another time and towards another audience – those who read the report – they are harmless.

The contradictions do not prevent Gluud from hoping that the report will have “a practical and industry related consequence,” as he says. What that means is easy to understand. Gluud is/has been chairman of a lobby group that has sought to influence the European Commission to prevent the free sale of vitamins. They must be made into drugs, which in practice will push small vitamin companies out of the lucrative market, which alone in Europe is more than $ 20 billion a year.

When a researcher is politicizing, he invariably throws a dubious light over his research, justly or not. Worse, however, is when the researcher is facing the public, on a topic of great importance, against better knowledge.

In doing so makes him disqualified.

By. Niels Hertz, M.D

Vitamin C inhibits cancer. But How?

Claus Hancke

September 18, 2007

New research sparks new theories about how vitamin C inhibits cancerous growth.

A great deal of research indicates that vitamin C has a considerable inhibitory effect on the growth of cancer cells.

The biochemical effect of high-dose treatment with vitamin C is reasonably understood; vitamin C acts as a pro-oxidant on cancer cells at such doses. This causes increased free radical strain on the cancer cells and thereby acts as a poison to the cancer.

In moderate doses, the kind of doses which we can get through our diets, vitamin C is an antioxidant. But even at these doses, vitamin C has shown an inhibitory effect on the growth of cancer cells.

It was therefore believed that vitamin C blocks the free radicals which cause the cancer forming mutations in the cells, and that the reason for its protective effects is that it protects the cells’ DNA.

This is presumably not the whole truth.

Many years ago a famous professor by the name of Warburg was among the first to maintain that cancer cells grow in oxygen poor tissue. Today this is common knowledge, but there lacks knowledge on how this occurs. Ten years ago Gregg Semenza of John Hopkins University found that cancer cells are dependent on a protein called HIF-1 (hypoxia induced factor), which helps the cells by compensating for lacking oxygen in the surrounding tissue and thus allows cancer cells to convert sugar to energy without oxygen. HIF-1 also catalyses the creation of new blood vessels so that hungry cancer cells can get fresh supplies of nutrients and oxygen. If a cancer grows aggressively, it quickly uses up its oxygen supply and becomes entirely dependent on HIF-1. The HIF-1 protein is dependent on the presence of free radicals, which are also necessary for many other processes in the body. A powerful antioxidant like vitamin C eliminates the surplus of free radicals, which causes HIF-1 to become ineffective and thus inhibits cancer growth.

This new theory is based on a study done by a research group at the centre of oncology at John Hopkins University in conjunction with Dean Felsher of Stanford.

They set out to study antioxidants’ roles in cancer growth and found, to their great surprise, that antioxidants destabilise the protein on which cancer cells are dependent. As professor Chi Dang from John Hopkins University wisely stated, “By uncovering the mechanism behind anti-oxidants, we are now better suited to maximize their therapeutic use.”

By: Claus Hancke, MD

Reference

HIF-Dependent Antitumorigenic Effect of Antioxidants In Vivo. Cancer Cell, Volume 12, Issue 3, 11 September 2007, Pages 230-238Ping Gao, Huafeng Zhang, Ramani Dinavahi, Feng Li, Yan Xiang, Venu Raman, Zaver M. Bhujwalla, Dean W. Felsher, Linzhao Cheng, Jonathan Pevsner et al.

www.cancercell.org

New slander against antioxidants

Niels Hertz

March 13, 2007

A new article maintains that antioxidants cause death, but the article is based on a comparison of results from incomparable studies.

Once again a scientific article has created a commotion regarding antioxidants. It claims that they cause death. This has been heard, and disproved, before. Because of the common uncertainty regarding this subject, we are nonetheless forced to take a stand regarding this claim.

The man behind this claim is a Serbian professor from a university located in the town of Nis. One of the co-authors is a Danish physician who has, among other things, declared antioxidants to be poisonous and cancer causing on Danish TV. He even suggested that they are poisonous in the amounts found in vegetables.

The study is a so called Meta analysis. It combines as many old studies on antioxidants as possible and extracts a kind of average from their results. Small four week studies are blended up with larger studies which have gone on for up to 12 years. Studies where very small doses were used are blended up with studies on mega doses, studies using one antioxidant are blended up with studies on combinations of antioxidants (e.g. vitamin E, vitamin C, and selenium), and so on. Among the studies used, there are at least eight different combination treatments using vitamin E. This enormous mess alone causes the study to be somewhat questionable. One cannot calculate an average between apples and oranges.

This is not even the worst part. In an attempt to prove that vitamin E increases risk of death (the articles primary claim), the ignored studies where selenium was used together with vitamin E. The selenium studies often showed reduced mortality and lowered cancer risk. This was not good for the Meta analysis authors, it disturbed their theory. They eliminated 11 essential studies on vitamin E and selenium from the analysis.

Selenium was ignored, but that wasn’t enough. The still couldn’t prove that vitamin E is harmful. The numbers wouldn’t work. To solve this, the article uses the fact that the antioxidant beta-carotene, the yellow colouring in carrots, increases death rates in smokers. This is commonly accepted (although not completely certain). In two of the largest studies conducted on antioxidants, a very slightly increased death rate was found due to a combination of beta-carotene and vitamin E.

More peculiarities
Common sense lends to the conclusion that beta-carotene is the villain in these studies. This was known in advance. Combinations of vitamin E with e.g. vitamin C and/or selenium do not increase mortality. More likely the opposite is true. In the large and very thorough French SU.VI.MAX study, death rates in men fell by over a third when they received vitamin E and vitamin C as well as selenium (besides zinc and beta-carotene!). This introduced a new era because this was the first time in our part of the world that a large array of antioxidants was used in study; which is what most people recommend. The antioxidants in our food are an orchestra, not solo instruments. They must play together to work. In a Chinese study from Linxian the same thing was found: lower mortality after supplements of vitamins E and C, selenium, beta-carotene, and vitamin A.

But the article in question maintains that vitamin E causes death. The claim is built, along with the discussed “manoeuvres,” on the two aforementioned studies, because the other vitamin E studies are insignificantly small in comparison. In these studies vitamin E was used with beta-carotene, and vitamin E was blamed in the Meta analysis for the poor results.

This is like claiming that mineral water is deadly if someone dies after drinking water mixed with arsenic. This conclusion is insane. The arsenic is deadly, not the water. Even though A+B is dangerous, it can naturally not be claimed that both A and B are dangerous alone.

There are other peculiarities in the article. Among other things, in at least two of the studies used, mortality was calculated many years after the end of the study. This is comparable to blaming a traffic accident for back pain when the pain became apparent eight years after the traffic accident. This type of measure was apparently necessary to get the desired results.

It is very easy to make these arguments in a scientific journal. If not for the press, it would be ignored. The article is based on a comparison of a number of incomparable articles, and this makes it hardly worth the effort it takes to make it better. It has also been exposed to sharp criticism. It has been clearly dismissed by two unrelated statisticians and by a professor of nutrition at Harvard University, Meir Stampfer. Stampfer is world renown and among the leading figures in nutrition studies encompassing over 300,000 people. He says that he will continue taking his vitamin supplements, unfazed by the article. But he adds that the article can lead to misinterpretation of the information that we have.

This is unfortunately an all too real possibility. Not in the least because the analysis’s authors insistently do the same.

By: Niels Hertz MD

 

References
1. Bjelakovic G, Nikolova D, Gluud LL et al. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention trials. JAMA 2007;297:842-857.
2. Virtamo J et al. ATBC Study Group. Incidence of cancer and mortality following alpha-tocoferol and beta carotene supplementation: A postintervention follow up. JAMA 2003;290:476-485.
3. Lee IM et al. Vitamin E in the primary prevention of cardiovascular disease and cancer. The Women’s Health Study. A randomized, controlled trial. JAMA 2005;294:56-65.

jama.ama-assn.org

Green Diet And Antioxidants Act Against Prostate Cancer

Claus Hancke

August 16, 2005

A radically changed lifestyle together with antioxidant supplementation seems to stop the growth of early prostate cancer, while the blood becomes eight times more capable of fighting cancer cells.

Some studies with humans and numerous animal trials and population surveys have indicated that antioxidants counteract cancer. Nevertheless, only a few researchers have examined whether they help against cancer in humans when the disease is a reality. An American trial now shows that this may be the case, at least by cancer in the prostate.

The trial, which has just been published, included 93 men with early-stage prostate cancer. They were selected because they had refused to accept usual cancer treatment.

44 of them were instructed to follow a fairly strict diet where only 10% of calories were allowed to come from fat. They had to have a pure plant diet and avoid dairy products, but in return received a protein supplement in the form of a soy drink. In addition, they had to exercise equivalent to half an hour of brisk walking a day and had to perform various yoga exercises and meditate for another hour. Of course they weren’t allowed to smoke!

You’d think most people would quickly give up such a strict lifestyle. But the vast majority persist, perhaps because they are doing well. The leader of the trial, Dean Ornish, has described that when he let a group of men with bad hearts follow this recipe, their atherosclerosis in the coronary arteries of the heart decreased – mind you, not just in the first year, but quietly in a continuing process that all in all lasted at least five years.

In the current trial, however, Ornish supplemented with nutritional supplements:

  • Vitamin E 400 units/day.
  • Vitamin C: 2 grams/day.
  • Selenium: 200 micrograms/day.
  • Fish oil: 3 grams/day.

Better after a year
All had the so-called PSA value measured, first at the start of the experiment, and again after one year. PSA (Prostate-Specific Antigen) is an approximate expression of the spread of the cancer. That was the main purpose of the trial to measure what happened to PSA.

What happened was that when a year had passed, the PSA value had fallen by an average of 4% in the 44 in active treatment, while that in the control group – which was closely followed by their own doctor – had increased by 6%.

That in itself was an exciting result. But in addition, six men from the placebo group became so ill that they had to withdraw from the trial and undergo traditional treatment. If the six men from the control group had not dropped out – because they became very ill – the difference would have been even greater.

No actively treated patients left the trial
As a supplement to the PSA measurements, one more experiment was performed. They took serum from all participants and examined how it affected the growth of prostate cancer cells in laboratory experiments. After a year, a huge difference had emerged: the treated men’s serum inhibited the growth of cancer cells eight times as much as the control group’s!

These results are statistically very confident. One must therefore expect that there is an effect, but what causes it? Was it the predominantly green diet, soy, exercise – or perhaps yoga and meditation? Or was it the antioxidants?

One can only guess. Dean Ornish believes that overall lifestyle changes made the difference. But the assumption that antioxidants help against cancer is of course supported. In any case, the experiment is highly thought-provoking.

By: Vitality Council

References:
Ornish D et al. Intensive lifestyle changes may affect the progression of prostate cancer. The Journal of Urology 2005;174:1065-70.
Ornish D et al. Intensive lifestyle changes for reversal of coronary heart disease. JAMA 1998;280:2001-7.

The Role of Antioxidants May Have To Be Reassessed

Claus Hancke

February 27, 2004

British scientists have discovered that it is enzymes and not antioxidants that are the active factor, when white blood cells attack bacteria.

Free radicals are aggressive molecules that are capable of destroying the structure of other molecules. For example, the body uses free radicals to cut large molecules into pieces and build complex protein structures. So far so good.

But an abundance of free radicals has been shown to be able to damage the body due to the deterioration (oxidation) of certain molecules, such as LDL cholesterol, which then becomes dangerous because it causes arteriosclerosis in its rancid (oxidized) form.

In order to slow down this harmful oxidation, we form the so-called antioxidants. These are also found in our diet and in several dietary supplements. For example, vitamins C and E are such antioxidants.

However, a British research team has investigated the reactions that occur in the white blood cells when these attack bacteria. And they found that free radicals did not play a role, but rather that it was enzymes that the white blood cells use to attack and destroy bacteria.

Until now, it has been believed that the white blood cells used free radicals, and therefore people have been reluctant to use excessive doses of antioxidants, because it was believed that this would neutralize the white blood cells’ free radicals, so that they could not fight bacteria.

The new theory may explain why even large doses of antioxidants have not shown an inhibitory effect on the antibacterial effect of the white blood cells.

A large number of questions now remain, including the scientifically documented inhibitory effect on the occurrence of cancer and cardiovascular diseases.

There is no doubt that there will be renewed debate about this every time we see new research in this very exciting area. – Also because opinions are divided. But one thing is theory, another is practice.

We must remember that the knowledge of medical science today is wrong. All the history of science has taught us that. In 100 years, our current theories will be replaced by new ones, and people will smile at the official knowledge of today.

We must therefore be careful, and above all let ourselves be guided by the large clinical studies. The theories must then try to explain these results.

By: Vitality Council

Reference:
Nature, vol 427;6977:853.

www.nature.com/index.html
www.iom.dk

Fruit and vegetable antioxidants could significantly reduce cancer risk

Admin

June 25,  2003

Eating sufficient fruit and vegetables to maintain antioxidant vitamin and mineral levels could reduce the risk of cancer and mortality in men, report researchers from the French health and medical institute Inserm.

An eight-year study found a 30 per cent reduction in cancers and 37 per cent reduction in mortality among men who received a daily antioxidant supplement compared to placebo. The researchers claim that the study, called SU.VI.MAX, is the first randomised trial to show that an adequate intake of vitamins and minerals from fruit and vegetables can reduce the risk of cancer.

The double-blind, placebo-controlled study tested the impact of a daily dose of antioxidants on 13000 healthy subjects. The dose included 6mg of beta-carotene, 120mg of vitamin C, 30mg of vitamin E, 100ug of selenium and 20mg of zinc. The 7886 women, aged 35 to 60 years old, and 5141 men, from 45 to 60 years old, were divided into two groups and followed up over an average of 7.5 years.

There was no difference between the two groups concerning heart disease, supporting other studies testing the effects of antioxidants on cardiovascular health, but cancer risk was reduced by 31 per cent among men. This included most cancers, especially digestive, respiratory and skin cancers.

The absence of such effects in women was not due to the different cancers they developed but rather their better state of health at baseline, explained the Inserm researchers.

Again, while risk of death was 37 per cent lower among men receiving the supplements, the same effect was not seen in women. The researchers also found a higher risk of cancer and heart disease among men with the lowest levels of beta-carotene. The lower the level of the nutrient, the higher the risk of disease. The team stressed however that the findings should support a nutritious diet with regular consumption of fruit and vegetables rather than supplements.

Use of antioxidant supplements was necessary to be able to compare to placebo, but they claim that this effect applies equally to nutrients found readily in plant foods. The results back nutrition advice to consume at least five portions of fruit and vegetables daily rather than relying on supplements, claim the researchers.

They add that the observed effect is likely weaker than would be seen from fruit and vegetables, which have additional nutrients not included in the supplement used in the study. Further, they pointed to fears that people taking supplements may eat less fruit and vegetables, calorie sources which often lead to reduction in consumption of fatty and sugary products.

Source: NutraIngredients.com

Press Release from the Danish Society for Orthomolecular Medicine (DSOM)

Per Larsen

November 12, 2002

The Danish Society for Orthomolecular Medicine (DSOM):
Rumours that antioxidants should have no general effect on secondary prevention of heart disease originates from The Heart Protection Study published in July 2002 in the magazine The Lancet. The study was financed by e.g. the pharmaceutical companies Merck & Co. and Roche Vitamins.

The purpose of the study was, among others, to investigate Merck’s cholesterol lowering drug Zocor’s effect on various parameters such as blood clots in the heart and heart disease, etc. The study included 20,536 high-risk patients – ie. patients with known cardiovascular disease or dispositions for this – eg. diabetes.

The patients were randomized to 4 groups, of which 5000 patients received 600 mg vitamin E, 250 mg Vitamin C and 20 mg betacarotene. 5000 patients received both Zocor and vitamins. 5000 patients received Zocor only and 5,000 patients served as a joint control group. This means that the part of the study containing the vitamin group plus a joint control group comprised 10,000 people and not 20,536 persons as stated elsewhere.

Not surprisingly, the main result of the study showed that Zocor had a positive effect even at very low cholesterol values, which undoubtedly significantly increases the indication range for Zocor.

However, there are several criticisms, apart from the fact that the number of trial participants is exaggerated:

  • Dosage of vitamin E and vitamin C are not proportional to each other. The two vitamins are closely linked in the antioxidant protection of the cell. If there is an excess of one vitamin, it can have a pro-oxidant effect.
  • One will usually not give more than 100 – 200 mg of Vitamin E. Vitamin C should be given several times a day or as a prolonged-release preparation.
  • Vitamin C, as a single dose in a dose of 250 mg will only have an effect for a few hours. The half-life of vitamin C is approx. 4 hours, i.e. that from a daily dose alone you can not expect an effect at all – rather the opposite.
  • Beta-carotene has previously been tried alone in a major trial for lung cancer and smokers. Here, it appeared that this vitamin had a prooxidant effect with a prevalence of lung cancer in smokers as a result. The Heart Protection Study has not been able to confirm such an effect of an incorrectly unbalanced dosage.

The results of the study also coincide with the results found in the HOPE study, namely that there was no secondary preventive effect when consuming individual vitamins.

  • You can not study the effect of individual vitamins on diseases that have taken decades to develop. Vitamins act as co-factors and as antioxidants, they are involved in a complicated interaction with the body’s own enzymatic antioxidants in a way that we do not yet fully understand.
  • Individual vitamins or random combinations of two or three individual vitamins should not be perceived as a medicine that cures a disorder in the traditional sense, but as a method that can strengthen the body’s own antioxidant defenses.
  • You cannot simplify and define 3 different vitamins in an illogical mutual dosage for antioxidants generally. The antioxidant system reduces oxidized molecules. This is done according to the thermodynamic laws. The individual steps in this process, of which there are many, depend on the redox potential of the individual molecule. For example, urate is part of this chain. Urate is not an antioxidant in the traditional sense in everyday speech but possesses antioxidant properties just like albumin. A generalization is therefore completely incorrect.
  • The individual may have several or individual nutrient deficiencies. It is therefore not correct to study the effect of individual vitamins on chronic diseases.

Only in the last year has it become common knowledge that a substance such as Homocysteine (indicator of low B vitamins) has the greatest significance for risk and heart disease.

The content of the B vitamins: B12, B6, and folic acid in our food has decreased significantly since the Danish Ministry of Food began systematic studies of these in 1993. Thus 24% to 50% of the male population is at risk of deficiency diseases. Despite the private Nutrition Council’s stubborn adherence to the opposite, the Ministry of Food, Agriculture and Fisheries in Denmark is aware of this, but states that they are simply keeping an eye on developments.

The iron content of e.g. oatmeal has been reduced by 10% within just the last 5 years. The website of the British Ministry of Agriculture reports a 50% drop in selenium intake compared to 1983 and today.

………………………

By: Per Tork Larsen, M.D., DSOM

(No references)

rum.ctsu.ox.ac.uk/~hps
www.heartprotectionstudy.com/heartprotection/heartprotection/index.jsp
www.akudoc.dk
www.iom.dk