MD Nils Milman
email: nils.milman@webspeed.dk

Anemia -still a major health problem in many parts of the world!

Keywords: anemia, anemia, iron deficiency, developing countries, folic acid deficiency, helminthiasis, malaria, vitamin B 12 deficiency

Anemia is a major global health problem, especially in developing countries. Still this fundamental health issue has not been solved but continues to exist affecting the health, quality of life and working capacity in billions of people all over the world. This paper gives a review on the prevalence and major causes of anemia seen on a global scale. Most cases of anemia are due to iron deficiency, which often work in symphony with folate deficiency and/or vitamin B 12 deficiency as well as with infections. More efforts should be dedicated to tackle this massive problem -we have the tools and we know the ways. Iron fortification of appropriate food items combined with iron supplements in specific population groups has proved to be efficient. Initially, the efforts should be centered on the specific risk groups for iron deficiency anemia, i.e. young children, adolescent females, women of reproductive age as well as pregnant women and postpartum lactating mothers.

Introduction

The presence of anemia is basically defined as a red blood cell count, which is below the accepted lower level of the normal range [1]. However, in the daily clinical routine, anemia is defined by a hemoglobin (Hb) concentration, which is below the recommended lower thresholds established by epidemiological population surveys or by the local laboratory. In order to perform useful comparisons between different countries it is convenient to use the hemoglobin thresholds defined by the World Health Organization (WHO) shown in Table 1 [START_REF]Assessing the iron status of populations[END_REF][START_REF]Worldwide prevalence of anaemia 1993-2005[END_REF]. Table 1. Hemoglobin (Hb) concentration thresholds used to define anemia in subjects living at sea level according to the World Health Organization guidelines [START_REF]Worldwide prevalence of anaemia 1993-2005[END_REF] Age or gender group Hb threshold (g/L) Children [START_REF] Milman | Prepartum anaemia: prevention and treatment[END_REF] These threshold values apparently do not overestimate the prevalence of anemia. In Denmark, epidemiological surveys on presumably healthy subject without iron deficiency have shown that the 5 th percentile for men is 134 g/L, for women of reproductive age 124 g/L [START_REF] Milman | Iron status in Danish men 1984-94: a cohort comparison of changes in iron stores and the prevalence of iron deficiency and iron overload[END_REF][START_REF] Milman | Iron status in Danish women, 1984-1994: a cohort comparison of changes in iron stores and the prevalence of iron deficiency and iron overload[END_REF] and for pregnant women 110 g/L in the 1 st , 105 g/L in the 2 nd and 110 g/L in the 3 rd trimester [START_REF] Milman | Prepartum anaemia: prevention and treatment[END_REF].

The World Health Organization estimates that anemia affects nearly 2 billion people all over the world, what is nearly one third of the rapidly growing world population of approximately 7 billion people [7]. These figures indicate that in many countries, anemia constitutes a serious health problem in the population as shown in Table 2. Table 2. Public health significance of different prevalences of anemia according to the World Health Organization [START_REF]Worldwide prevalence of anaemia 1993-2005[END_REF] Prevalence of anaemia (%)

Public health significance ≤4.9

No public health problem 5.0-19.9

Mild public health problem 20.0-39.9 Moderate public health problem ≥40

Severe public health problem

What are the causes of anemia?

There are many different causes of anemia and they often work in symphony, so in the single individual various nutritional deficiencies, different infections/infestations may all play a role. This may of course have influence on the choice of treatment for the anemia and for the planning of future prophylaxis in the population.

Iron

Iron is an essential mineral for man and an important component of metalloproteins involved in oxygen transport and metabolism. In a well-nourished individual, the body contains approximately 3-4 g of iron. Almost two thirds of the iron is found in hemoglobin, the protein in the red blood cells that carries oxygen to the body's tissues.

The most common nutrition deficiency in both developing as well as in developed countries is iron deficiency [7].

Iron is mandatory for the production of hemoglobin in the red blood cell progenitors (the erythroblasts) and if the iron supply to the bone marrow is inadequate, the hemoglobin production fails and the number of red blood cells in the circulation declines. This subsequently leads to development of iron deficiency anemia (IDA) with a low hemoglobin concentration. A characteristic feature is also that IDA can be corrected or cured by treatment with iron, either by the oral route or by intravenous iron therapy.

In the spectrum of anemia, iron deficiency anemia (IDA) is by far the most important, causing approximately 75-80% of the total burden of anemias [1][START_REF]Assessing the iron status of populations[END_REF][START_REF]Worldwide prevalence of anaemia 1993-2005[END_REF]. Typically, the anemia is microcytic with a low mean red blood cell volume (MCV) and hypochromic with a low hemoglobin content in the red blood cells, i.e. low mean corpuscular hemoglobin (MCH) and low mean corpuscular hemoglobin concentration (MCHC). Basically iron deficiency may arise due to an insufficient dietary iron intake. Dietary surveys have shown that even in developed countries, dietary iron intake is too low in some population groups [START_REF] Pedersen | National Food Agency of Denmark. Danish dietary habits 2003-2008[END_REF]. For example, Danish women of reproductive age women have a mean dietary iron intake of 9 mg/day [START_REF] Pedersen | National Food Agency of Denmark. Danish dietary habits 2003-2008[END_REF], which means that more than 90% of the women have an intake below the recommended daily allowance of ~18 mg/day [START_REF]Nordic nutrition recommendations[END_REF].

Dietary iron consists of heme iron and non-heme iron. Heme iron has a good bioavailability leading to a favorable gastrointestinal iron absorption, whereas non-heme iron has a poor bioavailability indicating a low iron absorption.

Heme iron is present in food products of animal origin (meat, poultry, fish), while nonheme iron predominantly is found in food products of plant origin (vegetables, cereals, grains, legumes). In addition, meat contains the so called "meat factor" which enhances absorption of non-heme iron. Therefore, individuals who regularly consume foods of animal origin, are at a lower risk of iron deficiency than individuals who exclusively consume foods of plant origin.

Ongoing, continuing blood losses predominantly from the gastrointestinal tract due to infections, intestinal parasites and/or inflammatory bowel disease may contribute to IDA in many parts of the world. Furthermore, women with heavy blood losses at their menstrual periods or by recurrent uterine bleeding due to gynecological disease have a highly increased risk of developing IDA.

Vitamin deficiencies

A number of vitamin deficiencies are associated with the development of anemia such as vitamin A deficiency [START_REF] Semba | The anemia of vitamin A deficiency: epidemiology and pathogenesis[END_REF] and vitamin D deficiency [START_REF] Ozsoylu | Vitamin D deficiency and anemia[END_REF]. Vitamin C deficiency may contribute to iron deficiency and IDA due to impaired iron absorption and profuse bleeding from the gastrointestinal tract [START_REF] Alexandrescu | Acute scurvy during treatment with interleukin-2[END_REF].

Folate

The most common vitamin deficiency producing anemia is folate deficiency [START_REF] Benoist | Conclusions of a WHO Technical Consultation on folate and vitamin B 12 deficiencies[END_REF][START_REF] Khatib | Folate deficiency is associated with nutritional anaemia in Lebanese women of childbearing age[END_REF]. So far, folate status in various populations has not been as intensively investigated as iron deficiency and IDA, so further studies are needed before we shall have a more clear picture of the prevalence of folate deficiency in many populations. Folate deficiency causes a specific form of anemia termed megaloblastic anemia with high MCV. It has been estimated that in developing countries, folate deficiency occurs in as many as 25 to 72% of women of reproductive age [START_REF] Benoist | Conclusions of a WHO Technical Consultation on folate and vitamin B 12 deficiencies[END_REF][START_REF] Khatib | Folate deficiency is associated with nutritional anaemia in Lebanese women of childbearing age[END_REF].

In the fetus and newborn baby, folate deficiency is associated with a high risk of neural tube defects as well as other defects [START_REF] Benoist | Conclusions of a WHO Technical Consultation on folate and vitamin B 12 deficiencies[END_REF].

Folate is present in food of plant origin, e.g. green leafy vegetables, grains ect. However, the problem is that food preparation procedures (cooking, frying, milling, baking) actually destroy a high percentage of the folate content in the food.

Vitamin B 12

Vitamin B 12 deficiency is probably the second most common vitamin deficiency causing anemia, which is a megaloblastic anemia with high MCV and typical morphological features such as hyperlobulation of the nuclei of the granulocytes [1]. In developing countries, vitamin B 12 deficiency constitutes a significant problem [START_REF] Benoist | Conclusions of a WHO Technical Consultation on folate and vitamin B 12 deficiencies[END_REF] and studies from Lebanon and Turkey have revealed that ~40% of women of reproductive age have vitamin B 12 deficiency [START_REF] Khatib | Folate deficiency is associated with nutritional anaemia in Lebanese women of childbearing age[END_REF][START_REF] Karaoglu L Pehlivan | The prevalence of nutritional anemia in pregnancy in an east Anatolian province, Turkey[END_REF] which in addition to insufficient dietary vitamin B 12 intake, may be due to the food cobalamin malabsorption syndrome or pernicious anemia [START_REF] Khatib | Folate deficiency is associated with nutritional anaemia in Lebanese women of childbearing age[END_REF].

In addition to anaemia, vitamin B 12 deficiency causes neuropathy with pronounced neurological symptoms. In the fetus and newborn baby, vitamin B 12 deficiency has been associated with an increased risk of neural tube defects [START_REF] Groenen | Marginal maternal vitamin B 12 status increases the risk of offspring with spina bifida[END_REF].

Vitamin B 12 is present in food of animal origin, which means that subjects consuming a food of predominantly plant origin, e.g. vegetarians are not getting enough vitamin B 12 and therefore are at high risk of deficiency.

Infection/infestations

Both acute and chronic infections/infestations are associated with anemia [1]. Intestinal parasites, including hookworms, which are prevalent in many tropical/subtropical regions play a major cause in the high prevalence of anemia in many countries [START_REF] Smith | Impact of hookworm infection and deworming on anaemia in non-pregnant populations: a systematic review[END_REF]. Anemia caused by intestinal parasites is mainly due to iron deficiency but is often combined with vitamin B 12 deficiency as well as folate deficiency.

In areas where malaria is endemic, anemia is quite common and antimalarial programmes have proven to be effective in reducing the prevalence of anemia [START_REF] Hung | Anemia, malaria and hookworm infections in a Vietnamese ethnic minority[END_REF].

Hemoglobinopathies

In many tropical and subtropical countries, the high prevalence of genetic hemoglobinopathies, e.g. thalassemia, sickle cell disorders, ect. plays a significant role in the prevalence of anemia. Geographically the thalassemia belt includes the Mediterranean passing through West and Central Asian countries like Turkey, Iran, Afghanistan onto Pakistan and India and passes on to the South East Asian countries like Indonesia, Burma and Thailand, Vietnam and Cambodia. This makes it most common in African, Greek, Italian, Middle Eastern and Southern Asian populations. In some of these regions as many as 30% may be carriers of the gene defect [START_REF] Mousa | Diagnosis and management of sickle cell disorders[END_REF][START_REF] Marsella | Better survival and less cardiac morbidity in female patients with thalassemia major: a review of the literature[END_REF]. For example, in Southern Thailand, 27% of women of reproductive age are carriers of the thalassemia trait [START_REF] Sukrat | The prevalence of iron deficiency anemia in pregnant women in Nakhonsawan, Thailand[END_REF].

Anemia caused by thalassemia is a purely genetic disorder/disease, but may of course be associated and thus aggravated by anemia due to nutritional deficiencies and/or infections/infestations (see above).

Who are the major risk groups for anemia?

It appears from many surveys that the major risk groups for IDA are young children and after childhood individuals of female gender, i.e. adolescent females who grow rapidly and in addition have their first menstruations with iron losses, women of reproductive age who lose iron with their menstrual periods, pregnant women with an increased need for iron and lactating women (Table 3, Table 4). 1 Anemia in apparently healthy well-nourished individuals is not very frequent [START_REF] Milman | Iron status in Danish men 1984-94: a cohort comparison of changes in iron stores and the prevalence of iron deficiency and iron overload[END_REF][START_REF] Milman | Iron status in Danish women, 1984-1994: a cohort comparison of changes in iron stores and the prevalence of iron deficiency and iron overload[END_REF]. In Denmark, epidemiological population surveys have shown that the frequency of anemia in men 30 to 60 years of age is ~1% [START_REF] Milman | Iron status in Danish men 1984-94: a cohort comparison of changes in iron stores and the prevalence of iron deficiency and iron overload[END_REF] and in women of reproductive age ~4% [START_REF] Milman | Iron status in Danish women, 1984-1994: a cohort comparison of changes in iron stores and the prevalence of iron deficiency and iron overload[END_REF]. Denmark has a balanced social welfare structure, which gives all residents almost equal access to obtain good nutrition and health services. Consequently, the high prevalence of anemia on a global scale is predominantly due to the extremely high frequency in developing countries as well as in developed countries with large social differences between population groups, for example as in USA [START_REF] Cogswell | Iron supplementation during pregnancy, anemia, and birth weight: a randomized controlled trial[END_REF].

In both developing and developed countries, the prevalence of anemia has a social imbalance. It is more prevalent in the lower social strata, in the lower income groups and in the least educated fraction of a population [7]. This is an important point when it comes to treatment and prophylaxis of anemia.

Newborn infants and young children

It appears from Table 3 that children 0.5-5 years of age on a global scale actually have the highest estimated prevalence of anemia, i.e. 47%. In Europe the prevalence of anemia is estimated to be 17% [START_REF]Worldwide prevalence of anaemia 1993-2005[END_REF] which indicates that the prevalence must be extremely high in other regions, such as Africa, which unfortunately is on the top of the list with a prevalence of anemia of 65% [START_REF]Worldwide prevalence of anaemia 1993-2005[END_REF].

Overall, the fetus' and newborn infant's iron status depend on the iron status of the pregnant woman and therefore, iron deficiency in the mother-to-be means that the growing fetus probably will be iron deficient as well. Iron is an element, which is essential for normal growth and development of most organs in the fetus, especially for the hematopoietic organs and what is very important, also for the normal development of the brain. Studies have shown that infants and children born to iron deficient mothers have a poorer cognitive development of the brain functions and a lower intelligence quotient than infants and children born to iron replete mothers. These findings may have profound implications for the later development and social functions of the growing child. If iron deficiency is very prevalent in the female population, it may therefore affect the health profile as well as the social structure of the society in a negative direction.

It is therefore a serious and frequent problem in childhood anemia that many children are born to mothers who have IDA and therefore already from their birth start out in life with iron deficiency and may be even with IDA. Congenital iron deficiency may later be aggravated by insufficient nutrition both qualitatively and quantitatively.

Adolescent females

The prepubertal growth spurt put great demands on iron nutrition both in males and females. In a Danish epidemiological survey of 16-17-year-old adolescents, 0% of males and 23% of females had small iron stores and 0% of males and 10% of females had iron deficiency [START_REF] Milman | Serum ferritin in children and adolescents. Results from population surveys in 1979 and 1986 comprising 1312 individuals[END_REF]. In Denmark, adolescent males have a higher intake of different kinds of meat than females, who are more reluctant to consume what they often term "dead animals". In addition, adolescent females have their menarche and start to lose iron by their upcoming menstrual periods. The combination of these three factors, growth, iron losses and dietary habits make them more vulnerable to develop iron deficiency and IDA.

Women of reproductive age

In Europe, the prevalence of anemia among women of reproductive age is 15% [START_REF]Worldwide prevalence of anaemia 1993-2005[END_REF]. In Denmark, among apparently healthy women of reproductive age, ~40 % have low iron status (serum ferritin < 30 µg/L); 10% have iron deficiency (serum ferritin <16 µg/L) and ~3% IDA [START_REF] Milman | Iron status in Danish women, 1984-1994: a cohort comparison of changes in iron stores and the prevalence of iron deficiency and iron overload[END_REF].

Due to the regular blood and iron losses at their menstrual periods, women of reproductive age a priori face a difficult situation concerning their iron balance. The amount of iron lost by menstruation varies from woman to woman, but is quite constant in the individual women [START_REF] Milman | Iron status in 268 Danish women aged 18-30 years: influence of menstruation, contraceptive method, and iron supplementation[END_REF]. Natural mechanisms in women have not compensated for these iron losses. In general, both in developed and especially in developing countries, women of reproductive age consume a diet containing an insufficient amount of iron to cover their needs, in part due to the sedentary lifestyle and consequently lower energy intake. Furthermore, the dietary iron they consume is predominantly non-heme iron, which has a very low bioavailability. In other wordstheir consumption of meat, poultry and fish is inadequate. On a world-wide scale, more than 468 millions non-pregnant women suffer from anemia; of these women ~80 millions live in Europe and the Americas and the remaining 388 millions in more or less developed regions of the world (Table 4) [START_REF]Worldwide prevalence of anaemia 1993-2005[END_REF].

Pregnant women

When an iron deficient woman becomes pregnant, her need for iron will increase dramatically. Pregnancy is a setting where the normal physiological demands for iron display an extraordinary increase of such a magnitude, which has not recognized in other physiological situations [START_REF] Milman | Prepartum anaemia: prevention and treatment[END_REF]. When iron deficient women or women with IDA become pregnant, both the prevalence and the severity of IDA may increase markedly during pregnancy unless prophylaxis or treatment is brought into action.

The prevalence of anemia in pregnancy display marked variation from region to region. The lowest prevalence ~25% is found in Europe and the Americas, whereas South-East Asia and Africa present high prevalences of 48% and 57%, respectively [START_REF]Worldwide prevalence of anaemia 1993-2005[END_REF]. In Denmark, pregnant women who do not take iron supplements have a prevalence of anemia of ~25% [START_REF] Milman | Iron status in 268 Danish women aged 18-30 years: influence of menstruation, contraceptive method, and iron supplementation[END_REF]; in contrast, the prevalence of anemia in women taking 40 mg ferrous iron daily is below 5% [START_REF] Milman | Iron supplementation during pregnancy. Effect on iron status markers, serum erythropoietin and human placental lactogen. A placebo controlled study in 207 Danish women[END_REF].

In general, more than 56 millions pregnant women all over the world suffer from anemia; of these women ~7 millions live in Europe and the Americas and the remaining 49 millions in more or less developed countries [START_REF]Worldwide prevalence of anaemia 1993-2005[END_REF].

IDA has severe implications both for the mother-to-be and for the growing fetus and newborn infant. The women may have general symptoms of anemia including fatigue, weakness, dizziness, headache, palpitations, reduced physical working capacity, feeling of poor health and in addition specific symptoms of iron deficiency such as reduced cognitive abilities, emotional instability, depression and restless legs.

Experiences from developing countries and the lower social classes in USA have furthermore shown that IDA in pregnant women has a significant negative influence of the outcome of pregnancy. It causes a higher risk of complications at delivery, a higher risk of early and preterm deliveries and a higher risk of delivering premature children and children with a low birth weight for their gestational age [START_REF] Cogswell | Iron supplementation during pregnancy, anemia, and birth weight: a randomized controlled trial[END_REF].

Postpartum lactating women

There is a direct link from IDA in pregnant women to IDA postpartum. If left untreated, anemia in late pregnancy will inevitably continue after delivery into postpartum anemia, which will even be aggravated due to the blood losses at delivery. Therefore preventing postpartum anemia means definitely preventing or treating prepartum anemia.

The lactating mother needs to have good nutrition and an adequate intake of vitamins and minerals in order to be physically fit to take proper care of her newborn baby and in order to produce breastmilk of a good quality. Breastmilk is the main nutritional source for the baby for several months, and the quality and quantity of the breastmilk rely on a proper nutritional status of the mother.

The prevalence of postpartum anemia has not been studied as extensively as prepartum anemia. However, we may extrapolate from the prevalence of anemia in pregnant women (see above) to the prevalence in postpartum women, assuming that the figures may be even higher postpartum due to blood losses at delivery. Therefore, in many regions of the world, postpartum anemia is undoubtedly a very significant, but partly unrecognized problem.

How can we reduce the prevalence of anemia?

Iron deficiency How can we approach the widespread endemic of iron deficiency? There are a number of options, which can be brought into action and it is important to emphasize that these options may vary from region to region and from country to country. Within a specific country, prophylactic options could even vary between different population subgroups.

Prophylactic measures should aim at restoring and maintaining an adequate iron status in the groups at highest risk of iron deficiency, i.e. preschool children, adolescent females, women of reproductive age, pregnant women and postpartum lactating women.

Dietary measures

Ideally, the most natural way of getting enough iron is through a diet with an adequate iron content and a good bioavailability of the iron. However, even in Northern Europe, including Denmark, dietary iron intake in women of reproductive age is too low to maintain a good iron status in ~40% of the women and in ~80% of pregnant women [START_REF] Milman | Prepartum anaemia: prevention and treatment[END_REF]. In contrast, Danish men have an adequate iron and even a high prevalence of slight to moderate iron overload [START_REF] Milman | Iron status in Danish men 1984-94: a cohort comparison of changes in iron stores and the prevalence of iron deficiency and iron overload[END_REF].

In general, women consume less food of animal origin than men [START_REF] Pedersen | National Food Agency of Denmark. Danish dietary habits 2003-2008[END_REF]. Furthermore, due to our sedentary lifestyle in the Western countries, energy intake is relatively low and we know that the total dietary iron intake is dependent on the energy intake [START_REF] Pedersen | National Food Agency of Denmark. Danish dietary habits 2003-2008[END_REF]. The mean dietary iron intake in Danish women of reproductive age is 9 mg/day with a bioavailability of 15-20% [START_REF] Pedersen | National Food Agency of Denmark. Danish dietary habits 2003-2008[END_REF]. This is well below the recommended food iron intake of 18 mg/day [START_REF]Nordic nutrition recommendations[END_REF].

Women do not to a significant extent change their dietary habits once they become pregnant and their needs for food iron increase to ~27 mg/day in order to maintain an adequate iron status [START_REF] Milman | Prepartum anaemia: prevention and treatment[END_REF].

In many developing countries, the diet is composed mainly of foods of plant origin, which per se has a low iron content, consisting of non-heme iron. Furthermore, this nonheme iron has a low bioavailability and diets rich in cereal grains also contain strong inhibitors of iron absorption including phytates. The widespread consumption in some regions of the world of various kinds of teas, which is even taken at meals, will likewise contribute to an impaired iron absorption.

It is therefore apparent that nutritional measures against iron deficiency in the risk groups would imply drastic and unrealistic changes in dietary habits, which most likely cannot be implemented in the populations.

Iron fortification of foods

Many Western countries have previously used iron fortification of bread flour. In Denmark flour was for many years fortified with 30 mg carbonyl iron per kg flour. This fortification was stopped in 1987 according to the regulations of the European Union. A follow-up analysis of iron status in the Danish population was performed 10 years after the abolition of the food iron fortification. The results showed that women of reproductive age had unchanged iron status [START_REF] Milman | Iron status in Danish women, 1984-1994: a cohort comparison of changes in iron stores and the prevalence of iron deficiency and iron overload[END_REF], whereas iron status had increased significantly in men, despite the absence of iron fortification! [START_REF] Milman | Iron status in Danish men 1984-94: a cohort comparison of changes in iron stores and the prevalence of iron deficiency and iron overload[END_REF]. It has been discussed whether iron fortification should be reintroduced, due to the high prevalence of low iron status in women of reproductive age. However, a general food iron fortification would probably increase the prevalence of the already established iron overload in the male population. In addition, it may have deleterious effect on subjects with genetic iron overload, i.e. the hereditary forms of hemochromatosis, especially HFE hemochromatosis, which is quite frequent in populations of Northern European descent [START_REF] Milman N Pedersen | Evidence that the Cys282Tyr mutation of the HFE gene originated from a population in Southern Scandinavia and spread with the Vikings[END_REF][START_REF] Milman | Clinically overt hereditary hemochromatosis in Denmark 1948-1985: epidemiology, factors of significance for long-term survival, and causes of death in 179 patients[END_REF]. Subjects with hereditary hemochromatosis have an abnormally high intestinal iron absorption and certainly do not need extra iron in their diet [START_REF] Milman | Clinically overt hereditary hemochromatosis in Denmark 1948-1985: epidemiology, factors of significance for long-term survival, and causes of death in 179 patients[END_REF].

Therefore, in the Western countries, we should not rely on food iron fortification but on specific iron prophylaxis in the risk groups.

However, the situation is different in other parts of the world. In South-East Asia as many as 46% of women of reproductive age have anemia, mainly IDA, which indicates that probably at least 90% of the this female population are iron deficient. Furthermore, genetic iron overload is infrequent in this region. In such a setting, iron fortification of appropriate food items seems justified.

In South-East Asian countries, regular consumption of NaFeEDTA-fortified fish sauce improves iron status and reduces the prevalence of anemia in anemic women [START_REF] Thuy | Regular consumption of NaFeEDTA-fortified fish sauce improves iron status and reduces the prevalence of anemia in anemic Vietnamese women[END_REF]. Furthermore, several South-East Asian countries are planning to introduce iron fortified flour.

In Africa, where the prevalence of anemia is 48% in women of reproductive age, food iron fortification should be balanced against the prevalence of infections, especially malaria, which possibly may be aggravated by the presence of ample iron [START_REF] Hurrell | Iron fortification: its efficacy and safety in relation to infections[END_REF]. However, prospective controlled human studies on the interaction between iron status and malaria have not yet been performed, but a Cochrane review on oral iron supplementation for anemia in children in malaria-endemic areas did not demonstrate any significant change in the prevalence of malaria in iron supplemented children [START_REF] Ojukwu | Oral iron supplementation for preventing or treating anaemia among children in malaria-endemic areas[END_REF].

Iron supplementation

In the Western countries with easy access to the health care system, it is easy to identify persons with iron deficiency and IDA by analyzing hemoglobin and serum ferritin. According to the outcome, adequate treatment or prophylaxis with oral iron can be instituted.

In developing countries where the health care is less efficient, especially in the rural districts, hemoglobin is often analyzed with a hemoglobinometer, e.g. Hemocue® but there are no facilities for the analysis of ferritin. In regions with a high prevalence of anemia, there is a definite need to establish the ferritin analysis on a broader scale and to use it routinely in association with the analysis of hemoglobin. There is also a need for a simple ferritin analysis, which can be performed under field conditions.

Even if ferritin cannot be analyzed, in regions with a high prevalence of IDA, the finding of anemia should imply generous use of oral iron supplementation in order to benefit the risk groups.

Iron prophylaxis in pregnancy

Due to the drastic increase in the need for iron during pregnancy, the majority of pregnant women have a definite need for iron supplements [START_REF] Milman | Prepartum anaemia: prevention and treatment[END_REF]. This goes both for Western countries and developing countries. Ideally the iron supplement should be tailored to the individual woman according to her iron status, i.e. serum ferritin concentration [START_REF] Milman | Iron prophylaxis in pregnancy -general or individual and in which dose?[END_REF]. But so far, a general iron prophylaxis regime including all pregnant women is used in most countries.

In Denmark and USA, pregnant women are recommended oral iron supplements from their first visit to the antenatal clinic at approximately 10 weeks gestation. The general recommendation in Denmark is 40 mg ferrous iron and in USA 30 mg ferrous iron daily taken between meals.

Some studies suggest that in order to be of optimum benefit for the outcome of pregnancy, iron supplements should be started already when the woman decides to become pregnant in order to establish adequate iron reserves during pregnancy and postpartum. This approach is especially important in regions where iron deficiency and IDA are prevalent among women of reproductive age, such as South-East Asia and Africa. Furthermore, this approach is in accordance with the concept of folic acid supplements, which should be started when conception is planned (see below).

In regions, where iron deficiency and IDA is highly prevalent, the dose of iron should be higher than in the Western countries. An appropriate dose would be 100 mg ferrous iron/day, preferably taken at bedtime or between meals [START_REF] Milman | Iron prophylaxis in pregnancy -general or individual and in which dose?[END_REF].

Tablets, which combine iron, folic acid, vitamin B 12 and vitamin C will be much easier for the women to administrate instead of taking the single components in separate tablets.

Iron treatment of iron deficiency anemia

IDA should initially be treated with oral ferrous iron in doses of 100-200 mg/day. It is essential to check the hemoglobin concentration after 2-4 weeks to see if the treatment works and induces an increase in hemoglobin. Iron should be continued for at least 6 months after hemoglobin concentrations have reached normal levels in order to rebuild a minimum of body iron reserves. In profound IDA with hemoglobin <90 g/L intravenous iron should be considered.

Treatment of iron deficiency anemia in pregnancy

Prophylaxis is better than cure! However, some women have so severe IDA at their first visit to the antenatal clinic that oral ferrous iron in prophylactic doses of 40-50 mg may be inadequate in order to correct the anemia prior to delivery. The Guidelines by the Swiss Society for Gynecology and Obstetrics recommend that if the woman's hemoglobin is <105 g/L, first-line treatment is to increase the dose of oral iron to 200 mg/day. Hemoglobin should be checked after 2 weeks and if there is an increase of 10 g/L or more, oral iron should be continued throughout pregnancy. In women who after 2 weeks do not respond to oral iron by an increase in hemoglobin of 10 g/L or more, intravenous iron treatment should be considered [START_REF] Breymann | Diagnostik und Therapie der Anämie in der Schwangerschaft und postpartal[END_REF].

For treatment of IDA in pregnancy, The Network for Advancements of Transfusion Alternatives (NATA) recommends oral ferrous iron 100-200 mg/day in the 1 st and 2 nd trimester. If there is no increase in hemoglobin after 2 weeks, intravenous iron therapy should be considered. In the 3 rd trimester intravenous iron is advocated as first-line treatment, because oral iron, even in high doses, has too short time to work in order to correct the anemia before delivery [START_REF] Boris | on behalf of the NATA working group on intravenous iron therapy. Guidelines on intravenous iron supplementation in surgery and obstetrics/gynecology[END_REF].

Studies from the Indian subcontinent have demonstrated that intravenous iron therapy can be very efficient in the correction of IDA in late pregnancy. Intravenous iron can be administered as a single dose infusion, which is convenient for the patient and reduces the costs of the health care system.

Treatment of postpartum iron deficiency anemia

Postpartum anemia is a poorly recognized problem. In many developed countries, including Denmark, the mothers are discharged from the public birth clinics within hours after delivery. So far it has not been possible to measure hemoglobin at 48 hours after delivery in order to estimate the prevalence of postpartum anemia. The prevalence of major maternal bleeding >500 ml in association with delivery is in the range of 5-7%. The Guidelines by the Swiss Society for Gynecology and Obstetrics recommend that if the woman's hemoglobin is 95-120 g/L, first-line treatment is to increase the oral iron to 80-200 mg/day. If hemoglobin has dropped to <95 g/L intravenous iron 500-1000 mg is recommended and at hemoglobin levels <80 g/L it should be considered giving recombinant human erythropoietin in addition to intravenous iron [START_REF] Breymann | Diagnostik und Therapie der Anämie in der Schwangerschaft und postpartal[END_REF].

The Network for Advancements of Transfusion Alternatives recommends intravenous iron at hemoglobin levels 60-95 g/L and blood transfusion at hemoglobin levels <60 g/L [START_REF] Boris | on behalf of the NATA working group on intravenous iron therapy. Guidelines on intravenous iron supplementation in surgery and obstetrics/gynecology[END_REF].

Folate deficiency

In order to prevent neural tube defects in the fetus it is important to maintain a good folate status in women of reproductive age who may become pregnant as well as in pregnant women. The neural tube is formed within approximately 30 days after conception, so it is essential that the woman's folate status is good already prior to conception. This can be obtained by a general folic acid fortification of appropriate food items, usually flour [START_REF] Benoist | Conclusions of a WHO Technical Consultation on folate and vitamin B 12 deficiencies[END_REF] as well as by individual folic acid supplementation. The general recommendation for supplemental folic acid is 400 µg/day [START_REF] Benoist | Conclusions of a WHO Technical Consultation on folate and vitamin B 12 deficiencies[END_REF]. The nutrition authorities in USA have implemented folic acid fortification of flour, but nevertheless still recommend that women of reproductive age should take additional folic acid supplements of 400 µg/day [START_REF]Healthy Eating During Pregnancy Aug[END_REF].

Vitamin B 12 deficiency

Although the recommended daily intake of vitamin B 12 is ~2.4 µg/day, many elderly persons appear to require much higher supplement doses to achieve optimum vitamin B 12 status, probably due to a limited gastrointestinal absorption. In order to increase the dietary intake of vitamin B 12 , the diet should be rich in foods of animal origin. This would, however, be almost impossible for the majority of people in many developing countries due to the high costs of meat and poultry. If the deficiency is caused by malabsorption of vitamin B 12 , dietary measures would be insufficient and prophylaxis/treatment should rely on oral supplementation of synthetic vitamin B 12 in adequate doses. The synthetic form of vitamin B 12 is absorbed much better than the food forms, and may in high doses bypass the "natural" absorption mechanism [START_REF] Benoist | Conclusions of a WHO Technical Consultation on folate and vitamin B 12 deficiencies[END_REF].

Infections/infestations

In communities where infections/infestations are frequent and contribute significantly to a high prevalence of anemia, treatment and prophylactic eradication of infections are important in order to improve the situation [START_REF] Barrett-Connor | Anemia and infection[END_REF].

In areas with high frequencies of parasitic diseases such as malaria and intestinal helminth infestations, antimalarial programmes as well as deworming programmes should be effectuated [START_REF] Hung | Anemia, malaria and hookworm infections in a Vietnamese ethnic minority[END_REF].

In Africa, ~30 million women living in malaria-endemic areas become pregnant each year. For these women, malaria is a threat both to themselves and to their babies, with up to 200 000 newborn deaths each year as a result of malaria in pregnancy. Pregnant women are particularly vulnerable to malaria as pregnancy reduces a woman's immunity to malaria, the parasites being resident in the placenta, making her more susceptible to malaria infection and increasing the risk of illness, severe anemia and death. For the unborn child, maternal malaria increases the risk of spontaneous abortion, stillbirth, premature delivery and low birth weightand is therefore a leading cause of child mortality [37].

Hemoglobinopathies

The management of the hemoglobinopathy issue relies primarily on genetic counseling in order to limit or avoid the occurrence of severe disease, which demands expensive treatment and is associated with a poor quality of life and a poor survival rate. Systematic follow-up and case management of abnormal newborn screen for hemoglobinopathy can improve the acceptance of genetic counselling [START_REF] Kladny | Systematic follow-up and case management of the abnormal newborn screen can improve acceptance of genetic counseling for sickle cell or other hemoglobinopathy trait[END_REF].

Conclusion

Anemia has been recognized as a major health problem in developing countries for many years: Still this basic problem has not been solved but continues to exist affecting the health, quality of life and working capacity in billions of people around the world. Most cases of anemia are due to iron deficiency, which often work in symphony with folate and/or vitamin B 12 deficiency as well as infections/infestations.

The World Health Organization has initiated successful campaigns against a number of infectious diseases -but the battle against anemia is far from being won and more efforts should be concentrated on tackling this massive problem -we have the tools and we know the ways. Initially, the efforts should be centered on the risk groups for iron deficiency anemia, i.e. young children, adolescent females, women of reproductive age as well as pregnant women and postpartum lactating mothers.

  months to under 5 years) 110 Children (5 years to under 12 years) 115 Children (12 years to under 15 years) 120 Non-pregnant women (15 years and over) 120 Pregnant women 110 Men (15 years and over ) 130

Table 3 .

 3 Global prevalence of anemia and estimated number of individuals affected[START_REF]Worldwide prevalence of anaemia 1993-2005[END_REF]

	Gender or age group	Anemia*	Population affected
		(%)	(millions)
	Children, preschool-age	47	293
	Children, school-age	25	305
	Men	13	260
	Non-pregnant women	30	468
	Pregnant women	42	56
	Elderly men and women	24	164

*) According to hemoglobin thresholds in Table

Table 4 .

 4 Global prevalence of anemia in non-pregnant women and pregnant women by World Health Organization (WHO) region (data collected 1993-2005)[START_REF]Worldwide prevalence of anaemia 1993-2005[END_REF]

	WHO region	Non-pregnant women	Pregnant women
		(%)	(%)
	Africa	47.5	57.1
		(43.4-51.6) †	(52.8-61.3)
	Americas	17.8	24.1
		(12.9-22.7)	(17.3-30.8)
	South-East Asia	45.7	48.2
		(41.9-49.4)	(43.9-52.5)
	Europe	19.0	25.1
		(14.7-23.3)	(18.6-31.6)
	Eastern Mediterranean	32.4	44.2
		(29.2-35.6)	(38.2-50.3)
	Western Pacific	21.5	30.7
		(20.8-22.2)	(28.8-32.7)
	Global	30.2	41.8
		(28.7-31.6)	(39.9-43.8)
	Non-pregnant women: 15 to <50 years of age. Pregnant women no age range indicated
	†95% confidence interval

Acknowlegdement

This study was supported by a grant from Abbott International Pharmaceuticals, Dublin, Ireland.


E Athanassoula

F.-S Ling

E Nezri

R Teyssier

Gamma ray and Neutrinos fluxes from a cosmological dark matter simulation

In this paper, we estimate the gamma-ray and neutrino fluxes coming from dark matter annihilation in a Milky Way framework provided by a recent N-BODY HORIZON simulation. We first study the characteristics of the simulation and highlight the mass distribution within the galactic halo. The general dark matter density has a typical r -3 power law for large radii, but the inner behaviour is poorly constrained below the resolution of the simulation (∼ 200 pc). We identify clumps and subclumps and analyze their distribution, as well as their internal structure. Inside the clumps, the power law is rather universal, r -2.5 in the outer part with again strong uncertainties for smaller radii, especially for light clumps. We show a full-sky map of the astrophysical contribution to the gamma-ray or neutrino fluxes in this N-body framework. Using quite model independent and general assumptions for the high energy physics part, we evaluate the possible absolute fluxes and show some benchmark regions for the experiments GLAST, EGRET, and a km3 size extension of ANTARES like the KM3NeT project. While individual clumps seem to be beyond detection reach, the galactic center region is promising and GLAST could be sensitive to the geometry and the structure of its dark matter distribution. The detection by a km3 version of ANTARES is, however, more challenging due to a higher energy threshold. We also point out that the lack of resolution leaves the inner structure of subhalos poorly constrained. Using the same clump spectrum and mass fraction, a clump luminosity boost of order ten can be achieved with a steeper profile in the inner part of the sub-halos.

Introduction

An ever increasing number of observational and theoretical results strongly suggest, or even require the existence of dark matter, whose enigma becomes thus crucial for the understanding of our universe. Let us mention amongst others the WMAP results on CMB [START_REF] Spergel | Wilkinson microwave anisotropy probe (wmap) three year results: Implications for cosmology[END_REF], the rotation curves of disk galaxies [START_REF] Bosma | Dark matter in galaxies: Observational overview[END_REF], the formation of large scale structures [START_REF] Simon | Clusters, filaments, and voids in a universe dominated by cold dark matter[END_REF], the bullet cluster observation [START_REF] Clowe | Weak lensing mass reconstruction of the interacting cluster 1e0657-558: Direct evidence for the existence of dark matter[END_REF], merger modeling and lensing results e.g. [START_REF] Ferreras | Unveiling dark halos in lensing galaxies[END_REF]. Finally, the possibility of numerous extensions of high energy physics beyond the standard model (BSM) to provide new weakly interacting massive particle (WIMP) candidates for dark matter makes the hypothesis very appealing.

Nevertheless, the nature, the identification and the distribution of the dark matter are still open questions, intimately linked with the proof of its existence. Present and near future instrumental projects could bring welcome input to these questions. Namely, both astroparticle physics and collider searches will reach higher sensitivities with experiments like LHC (accelerator); EDELWEISS II, superCDMS and ZEPLIN (direct detection); ANTARES and ICECUBE (neutrino telescopes); GLAST (gamma space telescope) and PAMELA (charged particle search satellite). Amongst the different possibilities, indirect detection is particularly promising. Indeed, relic dark matter particles can accumulate in cosmic storage rings and annihilate. The decay of their annihilation products will give rise to secondary particle fluxes (γ, ν, e + , p), which could be detected by dedicated experiments indirectly indicating the presence of dark matter.

In this paper, we will focus on indirect detection of dark matter through gamma rays and neutrinos. Galaxies are thought to be interesting sources for this kind of detection, seen the amount of dark matter they are believed to harbour. As we will discuss later, the detectability of such gamma rays or neutrinos depends strongly on both the astrophysical assumptions on the dark matter distribution in the halo and on the assumed high energy physics BSM scenario. Some studies concerning different particle physics models can be found in the literature (see [START_REF] Jungman | Supersymmetric dark matter[END_REF][START_REF] Bertone | Particle dark matter: Evidence, candidates and constraints[END_REF] for reviews). The popular BSM dark matter scenarios are typically supersymmetric models, models with extra dimensions, light dark matter, little Higgs model, inert doublet model ... or any extensions providing WIMP. The Milky Way astrophysical framework is commonly simplified with assumptions of spherical symmetry, now known to be incorrect [START_REF] Athanassoula | Bars and the connection between dark and visible matter[END_REF][START_REF] Allgood | The shape of dark matter haloes: dependence on mass, redshift, radius and formation[END_REF][START_REF] Athanassoula | A bar in the inner halo of barred galaxies i. structure and kinematics of a representative model[END_REF][START_REF] Heller | Structure formation inside triaxial dark matter halos: Galactic disks, bulges and bars[END_REF], and typical smooth dark matter density functions extracted from N-body simulations [START_REF] Navarro | A universal density profile from hierarchical clustering[END_REF][START_REF] Kravtsov | The cores of dark matter dominated galaxies: theory vs. observations[END_REF][START_REF] Moore | Cold collapse and the core catastrophe[END_REF]. Few recent works [START_REF] Stoehr | Dark matter annihilation in the milky way's halo[END_REF][START_REF] Diemand | Dark matter substructure and gamma-ray annihilation in the milky way halo[END_REF][START_REF] Michael Kuhlen | Glast and dark matter substructure in the milky way[END_REF] and especially [START_REF] Michael Kuhlen | The Dark Matter Annihilation Signal from Galactic Substructure: Predictions for GLAST[END_REF] with an impressive resolution treat in detail the astrophysical aspects of the gamma ray fluxes coming from dark matter annihilation in realistic simulation frameworks. Other works e.g [START_REF] Tasitsiomi | The detectability of neutralino clumps via atmospheric cherenkov telescopes[END_REF][START_REF] Pieri | On dark matter annihilation in the local group[END_REF][START_REF] Savvas | The observability of gamma-rays from neutralino annihilations in milky way substructure[END_REF][START_REF] Bi | Gamma rays from the neutralino dark matter annihilations in the milky way substructures[END_REF][START_REF] Pieri | Dark matter annihilation in substructures revised[END_REF] consider also more sophisticated parametrization inspired by extrapolations of simulation results.

Typical simulation canvas consist of 1-100 millions of particles with mass around 10 5 -10 6 solar masses. The results reproduce well the large-scale structure formation and have now shown that virialized systems are still left with surviving subhalos, also called clumps . The results are more and more promising with computing upgrades and resolution improvements. Nevertheless, some questions are still open with regard to observations. For instance, the radial density profiles predicted for the innermost region of galactic halos are quite cuspy, whereas observations suggest flat cores (see [START_REF] Bosma | Dark matter in galaxies: Observational overview[END_REF] for a review). Furthermore, simulations predict more numerous galactic satellites than observed for the Milky Way. Even if N-body calculations may generate too concentrated objects, the simulated haloes are the only realistic or advanced dark matter distribution framework. Specifically, the estimation of dark matter detectability in our neighborhood depends on both the dark matter distribution in the Milky Way -especially in the innermost region -and on the number, the size and the concentration of the clumps. Depending on the assumptions or results on these key points, different results have been proposed in previous works [START_REF] Savvas | The observability of gamma-rays from neutralino annihilations in milky way substructure[END_REF][START_REF] Evans | A 'Baedecker' for the dark matter annihilation signal[END_REF][START_REF] Pieri | Difficulty of detecting minihalos via gamm rays from dark matter annihilation[END_REF][START_REF] Oda | Gamma-ray background from neutralino annihilation in the first cosmological objects[END_REF][START_REF] Savvas | Proper motion of gamma-rays from microhalo sources[END_REF][START_REF] Bi | Gamma rays from the neutralino dark matter annihilations in the milky way substructures[END_REF][START_REF] Baltz | Can astrophysical gamma ray sources mimic dark matter annihilation in galactic satellites[END_REF][START_REF] Strigari | Precise constraints on the dark matter content of Milky Way dwarf galaxies for gamma-ray experiments[END_REF][START_REF] Pieri | Dark matter annihilation in substructures revised[END_REF][START_REF] Strigari | The Most Dark Matter Dominated Galaxies: Predicted Gamma-ray Signals from the Faintest Milky Way Dwarfs[END_REF].

The present article is devoted mainly to the astrophysical contribution concerning dark matter gamma and neutrino indirect detection. We calculated the possible gamma and neutrino fluxes sky map in a N-body simulation framework provided by a HORIZON project simulation [START_REF]The horizon project[END_REF]. The paper is organized as follows: section 2 gives the analysis of the numerical simulation and highlights the resulting dark matter distribution. In section 3, the gamma ray and neutrino flux calculation is shortly reviewed and a comparison of our estimates with regard to GLAST and ANTARES reach is presented. Conclusion and perspectives are given in section 4.

Simulation characteristics

General features

The data used for this paper were provided by the Horizon collaboration. The simulation was performed using the Adaptive Mesh Refinement code RAMSES [START_REF] Teyssier | Cosmological hydrodynamics with adaptive mesh refinement. a new high resolution code called ramses[END_REF]. The initial conditions are set by the WMAP3 results (Ω m = 0.24, Ω Λ = 0.76, Ω b = 0.042, n = 0.958, H 0 = 73, σ 8 = 0.77) and the effective number of particles is N p = 1024 3 in a box of size L = 20h -1 Mpc. At z = 0 we selected a Milky-Way sized halo. Using the so-called "zoom" technique, we re-defined the grid outside a sphere of diameter 5h -1 , using high-mass particles to sample the large scale tidal field and smaller ones for the selected halo region. In the high-resolution region, we increase the resolution of the grid on a cell-by-cell basis, with a maximum of 7 additional levels of refinement, corresponding to a maximum linear resolution of about 200 pc. Cells are refined if the local number of dark matter particles exceeds 10. Our smallest particle mass is M p = 7.46 10 5 in solar mass (M sun ) units. Our The size of a galactic halo is characterized by its virial radius, r vir , often defined as the size of the sphere centered on the galaxy center with an average density equal to 200 times the cosmological matter density. In our simulation, the virial radius is equal to 253 kpc, corresponding to an enclosed mass of 6.05 × 10 11 M or 8.1 × 10 5 particles.

Dark matter halos are often parameterized by spherically symmetric profiles of the form

ρ(r) = ρ 0 r r 0 -γ 1 + (r 0 /a) α 1 + (r/a) α β-γ α , ( 1
)
where ρ 0 is the local density in the solar neighborhood, r 0 = 8 kpc is the distance from the sun to the galactic centre, γ is the inner slope, β is the outer slope. α describes the transition behavior around r = a. The popular NFW profile [START_REF] Navarro | A universal density profile from hierarchical clustering[END_REF] has α = 1, β = 3 and γ = 1 and, adapted to the Milky Way, corresponds to , a = 20 kpc and r 0 = 8 kpc. Fig. 2 depicts the radial distribution of the density for all particles in our simulation, calculated by the method of Casertano and Hut [START_REF] Casertano | Core radius and density measurements in N-body experiments Connections with theoretical and observational definitions[END_REF], as will be discussed below. The center is taken as the densest point of the galactic halo. Due to resolution limits, this distribution is globally consistent both with a NFW-like profile (α = 1, β = 3 and γ = 1, a = 10 kpc) and a cored profile (α = 0.5, β = 3.3, γ = 0, a = 4.5 kpc), with r 0 = R sun = 8 kpc in both cases. At any given radius, the densities exhibit a large spread due to non sphericities, local fluctuations and also statistical biases. Moreover, numerous density peaks from substructures are also apparent. Notice that the best fit profile is given by the set of parameters (α = 0.39, β = 3.72, γ = 0.254, and a = 13.16 kpc), but its physical significance is arguable, given the large density fluctuations aforementioned.

As there is no baryonic component in this simulation, the sun location can be chosen in any direction. For the full skymap pictures in the next section, two positions were chosen, one along the positive z axis (which is also the projection axis in Figs. 1 and3) and one along the positive x axis. The corresponding dark matter densities coincide to within 10% and are ρ 0 = 0.0046 M pc -3 = 0.17 GeVcm -3 and ρ 0 = 0.0043 M pc -3 = 0.165 GeVcm -3 respectively. Throughout the rest of the paper, we will use the former for normalization purposes.

The density around a simulation point i was calculated with the algorithm of Casertano and Hut [START_REF] Casertano | Core radius and density measurements in N-body experiments Connections with theoretical and observational definitions[END_REF], namely

ρ i j = j -1 V (r j ) M p (2)
where V (r j ) = 4π/3r 3 j is the volume of the smallest sphere around the particle i that includes j neighbors. Excluding the particle i itself as well as the jth neighbor in the mass count gives an unbiased estimator of the density, with a variance σ 2 j = ρ 2 /(j -2). The choice of the number of neighbors used to calculate the density is a trade-off between reducing fluctuations and preserving the locality of the value computed by this method. A value j 10 seems to give a satisfactory compromise, as we could check on some Plummer test models. Higher values of j wash out substructures and inhomogeneities present in the data, while smaller values of j imply large statistical uncertainties that mask these inhomogeneities with Poissonian noise. As can be seen in Fig. 2, the density inside clumps can be several orders of magnitude higher than the density of the smooth component at that location.

Clumps

To identify clumps and subclumps in our simulation, we used the code ADAPTAHOP [START_REF] Aubert | The origin and implications of dark matter anisotropic cosmic infall on l* haloes[END_REF], which is an improved algorithm based on HOP that enables to build a tree of structures and substruc- tures. Basically, the algorithm divides the simulation points into disconnected groups, or leaves, corresponding to local density maxima. To decrease statistical noise, smoothing techniques are applied to calculate the density. The connections between leaves are created by performing a search of saddle points between groups. The density of a saddle point is then compared with the local maxima on each side, as well as a threshold parameter, to decide whether the structures are connected or not. By progressively raising this threshold from a minimum value corresponding to a galactic halo overdensity, and performing recursively the last check, the algorithm constructs a tree of (sub)structures. We note that the peak patches output by ADAPTAHOP are disconnected in space, as they are limited by the closest saddle points. As a consequence, clump masses given by this algorithm are often underestimated if other structures are present in their neighborhood. We found 108 (sub)clumps attached to the galaxy. Their spatial distribution is illustrated in Fig. 3, where each clump is represented by a circle whose radius scales as the 1/3 power of its mass, M 1/3 . A comparison with Fig. 1 shows that the two pictures are consistent. All the clumps within the virial radius are successfully identified by the algorithm. Outside this radius, some clumps are found as disconnected from the main galaxy, and therefore not visible on Fig. 3.

Rvir

From this, we derived a cumulative subhalo mass function shown on Fig. 4a. The clumps mass fraction inside the virial radius is equal to 3.6% of the total mass within that radius when taking the mass values output by ADAPTAHOP. We have corrected these masses by fitting a density profile on each clump, and then extrapolating it to the clump virial radius. The adjusted clumps mass fraction inside the virial radius is then equal to 5.4%. The mass adjustment has an impact on the mass function, as can be seen on Fig. 4a. The result is compatible with a power-law with index -1 above a mass threshold of 5 ×10 8 M . For smaller masses, a flattening of the curve is apparent, due to the resolution limit of the simulation, which does not allow the survival of clumps with mass below a given threshold. This is around 200 particles, in agreement with [START_REF] Diemand | Dark matter substructure and gamma-ray annihilation in the milky way halo[END_REF]. The effect of the mass adjustment further enhances this flattening at low masses. Even after this correction, the final mass function that we get is still lower than that found by other authors [START_REF] Stoehr | Dark matter annihilation in the milky way's halo[END_REF][START_REF] Diemand | Dark matter substructure and gamma-ray annihilation in the milky way halo[END_REF], but this deviation is not statistically significant. For example, we found 3 [START_REF] Bertone | Particle dark matter: Evidence, candidates and constraints[END_REF] clumps with mass before (after) adjustment higher than 10 9 M , compared to 13 in [START_REF] Diemand | Dark matter substructure and gamma-ray annihilation in the milky way halo[END_REF].

For the clump radial number density distribution, the statistics is too low to obtain reliable information about the behavior near the galactic center (GC). Instead, it is preferable to look at the cumulative mass profile as a function of the radius (distance from the GC), shown on Fig. 4b andc. When the clumps with a mass > 10 9 M are removed, the cumulative mass profile is well fit by a power-law with index n 1.75 up to the virial radius. The corresponding clump mass density profile with index n -3 -1.25 is thus flatter than the smooth component. The mass fraction in the form of clumps is therefore increasing with radius. This can be intuitively understood, since clump merging should be easier in the central parts. However, the clump density in this simulation is too low to dominate the mass fraction at any radius up to the virial radius.

Examples of density profiles within two clumps are given in Fig. 5. Except for the inner parts, they are compatible with a power law with slope -2.5 (Fig. 5). It is clear that further in there is a sharp transition, but we do not have sufficient points to constrain the inner slopes. In Fig. 5 we have, as an illustration, plotted two power laws with slopes 0 and 1, respectively. The transition between the outer slope and the inner slope is described by a concentration parameter c vir = r cl vir /r -2 , where r -2 is the radius at which d/dr r 2 ρ(r) = 0 and r cl vir is the virial radius of the clump. Several models predict that the concentration parameter strongly correlates with the virial mass (figure 2 of [START_REF] Pieri | Dark matter annihilation in substructures revised[END_REF]).

Gamma and neutrino fluxes from dark matter annihilation

In this work, we consider that the dark matter particle candidate is a typical WIMP provided by some new physics beyond the standard model. The gamma ray or neutrino flux per solid angle unit from the annihilation of dark matter particles (with mass m DM , density ρ DM , cross-section σv , and branching ratios BR i into final state i) can be written as

dΦ γ,ν dΩ = 1 4π 1 δ σv m 2 DM E γ,ν max E γ,ν min i dN i γ,ν dE γ,ν BR i . =HEPγ,ν l( Ω) ρ 2 DM dl , . =AST RO ( 3
)
where dN i γ,ν /dE γ,ν is the differential gamma/neutrino spectrum per annihilation coming from the decay of annihilation products of final state i, the integral is taken along the line of sight with direction Ω, and δ = 2 for a self conjugate dark matter particle and 4 otherwise. We have separated into two brackets factors that arise from particle physics and from astrophysics.

The annihilation signal is proportional to the density squared, and can therefore benefit from a strong enhancement if the dark matter distribution is highly clumpy. This enhancement is known as the boost factor.

Astrophysics factor

To further discuss the enhancement due to the distribution, it is useful to define the dimensionless quantity

J(∆Ω) = 1 ∆Ω 1 ρ 2 0 r 0 ρ 2 dl dΩ, (4)
where the solid angle ∆Ω can be taken as the experimental solid angle resolution of a given experiment such as GLAST.

To evaluate this quantity for our simulation, two different methods can be used. In the first method, ρ 2 can be calculated at any coordinate of the simulation box space with the Casertano-Hut algorithm. Note that the estimator of ρ 2 is smaller than the square of the estimator for ρ by a factor (j -2)/(j -1). The integral along a given line of sight is then calculated with the method of rectangles, with a variable step equal to half of the distance to the j = 10th closest neighbor. This ensures that the integral will not be overestimated when local density peaks are encountered along the line of sight. Finally, the value of J in a cone is the average of the values for different lines of sight within that cone. Fig. 6 presents an all-sky view of the astrophysical factor J in a Hammer projection for a value ∆Ω = 10 -5 relevant for GLAST. Since the simulation does not include a baryonic component, the position of the observed is only constraied by its distance from the center, i.e. can be anywhere on a sphere of radius 8 kpc. We calculated the J all sky map for two different viewing positions to allow comparisons. The shape of the iso-J contours differs significantly between the two cases and is not circular-like. Indeed cosmological simulations show that dark matter halos are not spherical, but have the shape of triaxial ellipsoids (e.g. [START_REF] Bailin | Internal and External Alignment of the Shapes and Angular Momenta of LCDM Halos[END_REF][START_REF]The shape of dark matter haloes: dependence on mass, redshift, radius and formation[END_REF]) and this is true also for the simulation we analyze here. Thus, the observed signal will depend on the viewing angle, since the integral in Eq. ( 4) will have different values if the integration is e.g. along a major or a minor axis of the ellipsoidal shape. This is also noted in the zoom of the central region, shown in Fig. 7. In this figure we also see that the relevant size of the central region is of the order of a kpc, which has been found by galactic dynamic simulations to have a rich structure in the baryonic component, including inner bars, inner discs, rings and/or spirals. Whether these influence in any way the dark matter in that region still remains to be studied.

We also evaluated the astrophysical factor with a second method, in which the integral in Eq. ( 4) is replaced by a finite sum over simulation points.

Ĵ(∆Ω) = 1 ∆Ω 1 ρ 2 0 r 0 i∈∆Ω ρ i M p l 2 i ( 5
)
The presence of a pole in l -2 is potentially dangerous in this method, and can lead to an overestimation of the fluxes in case a simulation point is very close to the observer's location. Nevertheless for this simulation and for the chosen sun locations, we get comparable results for the two methods, although fluxes from low density regions suffer more from statistical noise. To compare the two numerical methods more globally, we calculated J and Ĵ for the whole sky, ∆Ω = 4π. We found a good agreement (∼ 2%) between the two methods.

Particle Physics factor

The evaluation of the particle physics contribution (HEP γ,ν ) in Eq. ( 3) is highly dependent on the physics beyond the standard model that one assumes. Let us rewrite the HEP term as

HEP γ,ν = 1 δ σv m 2 DM N γ,ν , (6)
where N γ,ν is the number of photons/neutrinos per annihilation

N γ,ν = E γ,ν max E γ,ν min i dN i γ,ν dE γ,ν BR i . ( 7
)
The spectra coming from dark matter particles annihilation spread up to m DM . The number of photons/neutrinos depends on the decay chain of the dark matter annihilation products and these annihilations are determined by the particular particle physics model considered. We can estimate this number by using an effective and quite model independent approach. Namely, we will assume, as in typical BSM model, that dark matter particles (like those coming from SUSY, extra-dimendions ...) annihilate into SM (Standard Model) particles (W + W -, τ + τ -, b b, t t...) whose decays will , in turn, produce the gamma/neutrino continuum. The spectrum can then be evaluated from Pythia [START_REF] Sjostrand | PYTHIA 6.4 physics and manual[END_REF] simulations. For gamma rays, the actual number of photons in a given experiment depends on its energy range. For GLAST, the energy range will be ≈ 1 -300 GeV. These threshold values fix the actual limits for E γ min and E γ max . In the 1-300 GeV GLAST energy range, the number of photons estimated from Pythia simulations [START_REF] Mambrini | Adiabatic compression and indirect detection of supersymmetric dark matter[END_REF] typically yields N γ ∼ 1, 10, 50 and 200 for m DM ∼ 10, 100, 1000 GeV and 10 TeV respectively.

For neutrinos, we will consider the ANTARES sensitivity and a possible improvement for a km3 size telescope located in the mediterranean sea. The typical energy threshold for such a neutrino telescope is ∼ 100 GeV leading to 1 N ν 10 for 100 GeV m DM 10 4 GeV (derived from Pythia neutrino spectrum [START_REF] Labonne | The suppression of neutralino annihilation into Z h[END_REF]).

The other important quantity in Eq. ( 6) is the annihilation rate σv . From the cosmological point of view, σv can be related to the relic abundance of dark matter, roughly Ω DM ∼ 1/ σv , even if strictly speaking the temperature is higher in the primordial plasma at the freeze-out than in the surrounding sky at the present epoch and σv T0 = σv f reeze-out . For a standard annihilation scenario with thermal freeze-out, a value of Ω DM like what was found by WMAP implies σv ∼ 10 -26 cm 3 s -1 . Of course, different hypotheses can lead to variations in this value. For instance, one can consider some models where coannihilations drive the number of relic particles. Moreover, cosmological scenarios with low reheating temperature could allow to decrease the annihilation cross section and still satisfy the WMAP constraint. Conversely, scenarios with dark matter particle production through late decays (out of equilibrium) of heavier particles could lead to a higher annihilation cross section to respect the WMAP relic density. Considering those sources of variability, almost independently of any specific particle physics framework, we will assume the reasonable range 10 -27 σv [cm 3 .s -1 ] 10 -24 . Consequently, taking into account the production of photons and neutrinos and the annihilation rate uncertainties, a typical range for the HEP contribution to the gamma and neutrinos fluxes are given by

10 -33 HEP γ [photons cm 3 .s -1 .GeV -2 ] 10 -26 , ( 8
)
10 -34 HEP ν [neutrinos cm 3 .s -1 .GeV -2 ] 10 -28 , ( 9
)
where the difference between gamma and neutrino is due to the higher energy threshold in neutrino experiments, which reduces N ν and leads to consider higher values of the dark matter mass 1 .

Figure 6: J all sky map in a Hammer projection. The observer positions are (0, 0, R sun ) (top figure) and

(R sun , 0, 0) (bottom figure). The values range from less than 1 in the anticenter to more than 10 3 in the direction of the center.

Comparison with experiments

With typical values for the local dark matter density ρ 0 0.3 GeVcm -3 [START_REF] Kamionkowski | Galactic substructure and direct detection of dark matter[END_REF] and for the Sun to Galactic Center distance r 0 8 kpc, one has Φ γ,ν [photons/neutrinos cm -2 .s -1 ] ∼ 10 20 HEP γ,ν J ∆Ω.

(10)

GLAST

GLAST [START_REF] Gehrels | Glast: The next-generation high energy gamma-ray astronomy mission[END_REF] is a satellite which should be launched this year. Its angular resolution should be ∆Ω ∼ 10 -5 srad (i.e. an opening angle of 0.1 degrees ). Considering the sky sensitivity of GLAST given by [START_REF] Bertone | Glast sensitivity to point sources of dark matter annihilation[END_REF], we take 10 -10 photons cm -2 s -1 as a reasonable value to determine the interesting benchmark region in excess of which we could expect a signal to be detected by GLAST. In Fig. 7, we show a zoom of the central region of Fig. 6 for the two viewing angles analyzed. The image size is 60 deg × 60 deg. To smooth the artificial substructures that are due to noise in the simulation, we averaged the fluxes in a 5x5=25 pixels square that corresponds to a linear resolution of 200 pc. Taking into account the HEP γ contribution, we indicate the J values of 10 3 and 10 2 as quite optimistic GLAST benchmarks. The two figures show J values normalized with the same local density. One has to keep in mind that the local density can well vary by an order of magnitude depending on the Sun location (see Fig. 2) and that this will influence accordingly the calculated flux value.

ANTARES and a km3 size neutrino telescope

AMANDA and ICECUBE are located at the south pole, so that the galactic center region, which is the most promising one, is very challenging for those experiments. Thus, we consider in this section the ANTARES experiment, whose deployment completion is imminent, and extrapolate the sensitivity for a possible km3 size neutrino telescope in the mediterranean sea like the KM3NeT project [START_REF] Carr | Sensitivity studies for the cubic-kilometre deep-sea neutrino telescope KM3NeT[END_REF] associating ANTARES, NEMO and NESTOR collaborations. The resolution of Antares depends on the neutrino-muon angle, but is typically ∆Ω ∼ 10 -3 srad. We consider the galactic center sensitivity of ANTARES for dark matter derived in [START_REF] Bailey | Monte Carlo tools and analysis methods for understanding the ANTARES experiment and predicting its sensitivity to Dark Matter[END_REF], the recent improvement of effective area due to trigger update [START_REF] Lim | Indirect search for Dark Matter with the ANTARES neutrino telescope[END_REF] and the expected performance for a km3 size telecope [START_REF] Carr | Sensitivity studies for the cubic-kilometre deep-sea neutrino telescope KM3NeT[END_REF]. Taking those references into account, we believe that the sensitivity above 100 GeV of a future km3 size neutrino telescope located in the mediterranean sea should be around 10 -9 neutrinos cm -2 s -1 for point sources in the sky. In Fig. 8 we show the central region J skymap but calculated with a ∆Ω = 10 -3 resolution corresponding to the proposed km3 neutrino telescope resolution. The contour shows an optmistic benchmark region corresponding to J = 100 in the zoom for GLAST (no region is available for J = 10 3 ).

EGRET

A few years ago, the EGRET collaboration reported an excess in gamma ray fluxes above 1 GeV [START_REF]Egret observations of the diffuse gamma ray emission from the galactic plane[END_REF]. After subtracting the cosmic ray background, a residual flux of around 5 × 10 -8 photons cm -2 s -1 remains. The excess is hard to accommodate with natural cosmic ray propagation models, as it requires a harder electron injection spectrum or average spectrum in the galaxy different from the local ones [START_REF] Strong | Diffuse Galactic continuum gamma rays. A model compatible with EGRET data and cosmic-ray measurements[END_REF]. As an alternative, the annihilation of dark matter has been suggested. To fit the energy spectrum, the dark matter candidate should have a mass around 50 GeV. With an angular resolution ∆Ω = 10 -3 srad (i.e. an opening angle of 0.1 degrees), the value of the residual flux would show as the contour on Fig. 8, when taking an optimistic HEP γ that would correspond to J = 10 2 for GLAST. The central region would indeed be observable by Egret, while the regions at higher longitudes or latitudes remain in the background. However, this is not what was observed by Egret, as the excess is found to be rather constant with latitude or longitude, except close to the galactic center region where it is mildly higher. When fitted to the data, the hypothesis of dark matter yields a structure which is incompatible with the NFW profile. Instead, an prolate isothermal halo supplemented by two rings gives good results [START_REF] Wim De Boer | EGRET excess of diffuse galactic gamma rays interpreted as a signal of dark matter annihilation[END_REF]. As a consequence, a constant boost factor of order 40 is needed in this WIMP candidate scenario, and this implies excessive secondary antiprotons fluxes, in clear contradiction with observations [START_REF] Bergstrom | Is the dark matter interpretation of the EGRET gamma excess compatible with antiproton measurements?[END_REF]. Moreover, it has been recently argued that the EGRET excess might be due to a calibration problem rather than any unknown astrophysical or exotic contribution [START_REF] Stecker | The Likely Cause of the EGRET GeV Anomaly and its Implications[END_REF].

Sensitivity to clumps and resolution

Taken at face value, our results seem to argue that no clump in the simulation seems to be within the reach of GLAST. The intrinsic luminosity of an individual clump is determined by its mass and its concentration, but the corresponding flux is damped by the distance square factor. Inside the virial radius, the clumps contribute for 8.2% of the total luminosity for a mass fraction of 5.4%, but only for 0.2% of the total flux. This, however, depends strongly on the distance from the nearest clump. A further point to take into account is the resolution limit of the simulation. Due to that, the innermost behavior of the clumps profile in poorly determined, as already mentioned. The intrinsic luminosity of a clump can be boosted by increasing the inner slope γ. In Fig. 5c, we show the clump luminosity boost factor as a function of γ, at constant mass and concentration. For γ values less than 1.3 or 1.4 the boost factor is moderate. In particular, the boost for γ = 1 (NFW profile) compared to γ = 0 (core) is only around a factor of 2. However, for values of γ above 1.3 the boost factor increases very spectacularly, to reach a a factor of 10 around γ = 1.4.

To have a much stronger effect, the concentration parameter should be increased. If we take a NFW profile for the clump, it is easy to check that the concentration parameter is directly expressed in terms of the scale radius a and the virial radius of the clump r cl as c vir = r cl /a. Then the total annihilation J resulting from a clump of virial mass M cl vir sitting at a distance l r cl will be given by

J cl 4π 3 r 2 cl l 2 r cl r 0 ρ 2 vir ρ 2 0 f cl (c vir ), (11)
where ρ vir is the virial density (200 times the cosmological matter density), and

f (x) = (1 + x 2 ) 2 x 1 - 1 (1 + x) 3 x 3 (12)
for x 1. The clump mass and clump size are related by the following relation

M cl = 4πρ vir r 3 cl ln(1 + c vir ) - c vir (1 + c vir ) (13)
From this -as ρ vir /ρ 0 10 -3 and since the probability of having a clump in our immediate neighborhood is low -we see that small (in angular size) clumps will be visible by GLAST only if they are highly concentrated, c vir ∼ 10 2 -10 3 .

Conclusion & Perspectives

We evaluated the gamma and neutrino fluxes from dark matter annihilation in a galactic halo framework extracted from a cosmological N-body simulation of the HORIZON project. Although such simulations are the most elaborate and realistic framework for this kind of studies, there are very few works concerning dark matter detection in N-body frameworks. With reasonable assumptions on the new physics beyond the standard model and on the cosmological scenario for dark matter particles, we proposed an absolute evaluation of gamma and neutrino fluxes. This allowed to test the galactic simulation framework with regard to dark matter indirect detection in future experiments like GLAST and the proposed km3 size neutrino telescope in the mediterranean sea extrapolated from ANTARES sensitivity and preliminary KM3NeT studies.

Our framework and even other cosmological simulations have a resolution limit which is lower than what would be desirable for this type of studies. Nevertheless, it was possible to reach a number of interesting results in our framework. In particular, we showed that the galactic center region is a good benchmark part of the sky with regard to the GLAST sensitivity. Even if it is more challenging, this region should also be studied by future neutrino telescopes, especially a km3 size telescope. Individual clumps stand out clearer in the direction of the galactic anticenter. The concentration parameters of the clumps are then the crucial information that will determine the flux. Unfortunately, our simulation does not provide enough information on scales below 100 pc to clearly conclude about the detectability of individual subhalos. Furthermore, it should be stressed that our results for the central region of the Galaxy and for the clumps should be considered as a lower bound. A resolution improvement will increase the values of the central density and decrease the size of the central region within which we have little or no information. This will increase the signal in the direction of the Galactic center, as well as in the directions of the clumps. We can Galactic center. The horizontal bar gives the distance of 1 kpc, which is roughly the region which will be an interesting target for GLAST. The contours correspond to J = 10 3 (solid) and J = 10 2 (dotted). b) Same as a) but with observer position at (R sun , 0, 0) instead of (0, 0, R sun ) in a). The two plots are normalized with the same local density value.

1 kpc 1 kpc a) b)

Figure 8: a) Same as figure 7 with ∆Ω = 10 -3 for a km3 neutrino telescope and EGRET, i.e. the 60 • ×60 • region around the Galactic center of the J(∆Ω = 10 -3 ) skymap. The light contour corresponds to an hypothetical km3 size neutrino telescope, the dark one corresponds to the level of the controversial EGRET excess. b) Same as a) but with observer position at (R sun , 0, 0) instead of (0, 0, R sun ) in a). The two plots are normalized with the same local density value.

hope that specific geometry, non sphericity and structures especially in the central region will be highlighted by future gamma and neutrino observations. Cosmological simulations made very important progress in the last few years, and a study of gamma-ray induced by dark matter annihilation in the most precise N-BODY framework can be found in [START_REF] Michael Kuhlen | Glast and dark matter substructure in the milky way[END_REF] with a resolution allowing the identification of 10 6 M sun clumps. Though the quality of this work is impressive, this minimal scale is still more than 10 orders of magnitude above the typical WIMP free-streaming scale (∼ 10 -12-4 M sun [START_REF] Profumo | What Mass Are the Smallest Protohalos?[END_REF]) and also considerably bigger than the minimal surviving clump mass, which anyway is still under debate.

Figure 1 :

 1 Figure 1: View of the galactic dark matter halo in the HORIZON simulation (projected along the z axis). The box size corresponds to 750 kpc.

Figure 2 :

 2 Figure 2: Density at all the positions of the particles in the simulation as a function of their distance to the center. This is compared to NFW (α = 1, β = 3 and γ = 1, a = 10 kpc, solid line) and core (α = 0.5, β = 3.3, γ = 0, a = 4.5 kpc, dashed line) profiles.

Figure 3 :

 3 Figure 3: Clump distribution in the galaxy, projected along the z axis. The location of each clump is identified by a circle, whose size scales as M 1/3 . The red (largest) circle shows the virial radius (as defined in the text) of the galaxy (253 kpc).

Figure 4 :

 4 Figure 4: a) Cumulative subhalo mass function of the clumps in the galaxy obtained with ADAPTAHOP masses (red -dark grey) and after the virial mass adjustment procedure (green -lighter grey). b) Cumulative mass for the simulation (tot), the smooth component and the clumps. c) A closer look at the cumulative mass profile for the clumps (all clumps in red, and only clumps lighter than 10 9 M in pink).

Figure 5 :

 5 Figure 5: a) and b) Density profile inside two clumps. The outer slope of the profile corresponds to β = 2.5. c) Clump luminosity boost factor as a function of the exponent of the clump inner density profile (γ).

Figure 7 :

 7 Figure 7: a) Zoom in the 60 • × 60 • central region of Fig. 6, i.e. a region centered around the direction of the

This gives typically

2-3 orders of magnitude between EGRET and ANTARES performances despite their similar sensitivities (∼ 10 -8-7 γ(ν) cm -2 s -1 ). The same is true for explicit SUSY models[START_REF] Bertone | Neutrinos from dark matter annihilations at the galactic centre[END_REF].

Acknowledgments

We would like to thank V. Bertin, A. Bosma and J. Lavalle for helpful discussions. FSL work is supported by a FNRS belgium grant and the IAP. EN work was also partially supported by a FNRS grant. We also acknowledge the french Astroparticle Program and the grant ANR-06-BLAN-0172 for financial support.