Slide

A Detailed Study of Vitamins & Minerals Written by G.Desmond and

Learning Outcomes Name the key food sources of the given micronutrients
Discuss the absorption and metabolism of dietary and
supplemental sources of these micronutrients
List the major nutrient-nutrient interactions these micronutrients
Describe the metabolic functions and therapeutic uses of these
Outline the signs and symptoms of these micronutrients deficiency,
excess and toxicity
List the major nutrient-drug incompatibilities these micronutrients
Outline the recommended daily allowance and therapeutic doses
for these micronutrients
Discuss the preferred forms for optimal uptake of these
Outline the factors which affect individual requirements for these
micronutrients

Vitamin B9 – Folic Acid Forms: • Folate is a name given to a family of compounds called pteroglutamates • Other names used are: folic acid, folacin
• Its primary active form in the body-THF (tetrahydrofolate) serves as
part of an enzyme complex, active in numerous metabolic reactions • Folic acid is the synthetic form found in supplements and fortified foods. It is not naturally occurring (Bender 2002;Liska et al 2004)

Food Sources of B9 – Folate is especially abundant in foods of plant origin, mainly legumes, vegetables and some fruit – The vitamin name suggests foliage, and indeed, leafy green vegetables are the richest source – Other rich sources: • Legumes • Citrus fruit • Liver (Rolfes et al 2006) Reference Nutrient Intakes • Because bioavailability of folate ranges from 50% upwards in foods and 100% in supplements, taken on an empty stomach, Dietary Folate Equivalents (DFE) have been developed.
– DFE= 1μg food folate + (1.7 x μg synthetic folate)
• Synthetic folate is 1.7 x more available than dietary folate – Thus a person consuming 100 μg from foods and 100 μg from supplements receives 270mcg of DFE – Recommendations for adult people vary from 200 μg (UK)
to 400 μg (US)
(Rolfes et al 2006) Recommended Dietary Allowances Irish Recommendations (1983, revised
(UK) 0.2 – 0.4 Males 11-14 years Recommended Dietary Allowances Irish Recommendations (1983, revised
Reference Nutrient Intakes UK recommendation
US recommendation
Males 11-14 years Males 15-50+ years Females 11-14 years Females 15-50+ years (Geissler and Powers 2005) Food Sources of B9 ( Folic Acid) Food per 100g
Kidney Beans
Soybeans
Beef Liver
Romaine Lettuce
Broccoli
Asparagus
Beef steak
Dosage of B9 (Folic Acid) • RDAs – see table • Supplemental Range: • 400mcg recommended during preconception and first trimester of (Osiecki 2004; FSA 2007; EUFIC 2011) Folic Acid - Absorption and Availability • Heat and oxidation during cooking and storage can
destroy up to 50% of the folate in foods
• Folic acid is quite stable in the presence of light • It is absorbed in the small intestine • The bioavailability of food folate is approximately 80% of that from supplements, higher than previously thought read mor (Mahan and Escott –Stump 2008; Winkels et al 2007) Folic Acid - Metabolism – After asborption a methyl group (–CH3 ) is added to
folate and in this form it is delivered to body cells. – In order for the folate to function in the body the methyl group must be removed by an enzyme that requires vitamin B12. – Without that help folate becomes trapped inside cells in its methyl form (5-methyl THF), unavailable to
perform its functions: DNA synthesis and cell growth –
a metabolic situation called the folate trap.
(Liska et al 2004; Bender 2002) 5-methyl THF;
inactive
THF; active
(Rolfes et al 2006) Folic Acid - Metabolic Functions – Tetrahydrofolate (THF) plays a role in many reactions
metabolising amino acids and nucleotides. • It functions in the synthesis and repair of the DNA
• It is required for the conversion of amino acids
• It provides methyl groups for the synthesis of methionine from
homocysteine (this conversion also needs vit B12)
• Deprivation of vitamin B12 can produce a secondary folate deficiency by interrupting the regeneration of THF from 5-methyl THF (Liska et al 2004; Mahan and Escott-Stump 2008) Metabolic Functions The Role of Folate in the Homocysteine Cycle Metabolic Functions – In their role in the synthesis and repair of DNA, both folate and B12 are crucial in maintaining gene stability

• Lower levels of folate are associated with development of tumours – Folate is essential for the formation of red and white
blood cells in bone marrow and for their maturation
– It is crucial in the formation of haem
(Mahan and Escott-Stump 2008) Folate in Pregnancy • During the 1980s it was discovered that spina bifida and
other neural tube defects were associated with low intakes
of folate and that increased intake in pregnancy may be
associated with reduced risk.
• It is now established that supplements of folic acid taken
periconceptually (before conception) prevent neural tube
defects.
• It is recommended that intakes be increased by 400μg before
conception :
– Closure of the neural tube occurs by day 28 of pregnancy, which is before the woman knows she is pregnant Folate in Pregnancy – A typical Western diet does not supply this amount, that is why supplements are recommended to all women. – However, excellent levels of folate is contained in: • Spinach 1 cup = 260μg • Boiled red kidney beans 1 cup = 230 μg • Boiled lentils 1 cup = 360 μg • Broccoli 1 cup = 95μg • Asparagus 1 cup = 260 μg – If you are not confident the patient is going to change her
diet significantly you should recommend a supplement to
women who may be about to conceive.
Folate - Specific Therapeutics • Homocysteinaemia: taking folic acid orally at 800-1000 μg/day lowers
homocysteine levels by about 20% to 30%. • In people with asymptomatic atherosclerosis, lowering homocysteine
levels with folic acid, reduces the progression of atherosclerosis and improves arterial blood flow. • Consumption of at least 300 mcg per day of dietary folate seems to be
associated with a 20% lower risk of stroke and a 13% lower risk of
cardiovascular disease, when compared with consumption of less than
136 mcg of folate per day.
– Is this effect caused by folate alone, or by the plant foods that contain folate, in which it acts in synergy with other nutrients? ( Liem et al 2003; Usui et al 1999; Vermeulen et al 2000; Bazzano et al 2002) Folate - Specific Therapeutics • Consuming dietary folate seems to decrease the risk of breast cancer,
especially in women who also consume high amounts of vitamin B12, or B6 • Depression: taking folic acid orally (200-500 mcg daily) with conventional
antidepressants might improve treatment response; however, folic acid is not effective as a replacement for conventional antidepressant therapy • Pancreatic Cancer: consuming greater than 280 mcg per day of dietary
folate is associated with a decreased risk of pancreatic cancer
• Vitiligo: taking folic acid orally seems to improve symptoms of vitiligo;
however very high doses (5mg) a day were used, only under medical supervision ( Taylor et al 2003; Passeri et al 1993; Stolzenberg et al 2001; Juhlin et al 1997) Folate Deficiency – Folate deficiency impairs cell division and protein
synthesis - critical metabolic processes in the body
– In folate deficiency, the fast dividing cells of the body are affected first: red blood cells and GI tract cells resulting in: • Anaemia (megaloblastic anaemia)
• Gastrointestinal (GI) tract deterioration
– GI deterioration can be triggered by alcohol abuse, which increases folate loss from the body, leading to further GI tract weakening and folate loss (vicious circle) (Rolfes et al 2006) Folate Deficiency – Homocysteinaemia (increased homocysteine levels in the
• Due to inability of ‘trapped' folate to regenerate methionine from • This increases the risk of cardiovascular disease and is very common among apparently healthy people suggesting that subclinical deficiency might be common – Other symptoms include: • Weakness, depression, dermatologic lesions, poor growth
(Rolfes et al 2006) Factors That Might Affect Individual • Deficiency can develop in infants fed goat's milk, which is very low in folic • Deficiency may also result from: – Impaired absorption (alcoholism)
– Unusually high metabolic need, when cell multiplication speeds up:
• Pregnancy • Cancer • Skin-destroying diseases (chickenpox, measles) • Burns • Blood loss (Rolfes et al 2006) Factors That Might Affect Individual • Of all the vitamins, folate appears to be most vulnerable to interactions with drugs, which can lead to secondary deficiency • Increased risk of deficiency in patients taking: • Anticancer drugs
• Aspirin
• Antacids
• Oral contraceptives
Folic Acid - Toxicity – Naturally occurring folate from foods alone appears to cause no harm
– Folic acid supplements in excess of 350μg/day may impair zinc – Folic acid supplements mask the megaloblastic anaemia of vitamin B12 deficiency and may hasten the development of the irreversible nerve damage – Recent studies suggest that long-term intake in supplemental form
increased the risk of growth of already present colon cancers. Folic
acid supplements may negatively interfere with normal metabolic
processes – you will have more information on genetic variances
responsible for this in your level 2 lectures.
– Tolerable Upper Intake Level for Adults: 1000 μg/day
(Bender 2002; Rolfes et al 2006; AICR 2007) Folic Acid - Drug Interactions • Anticonvulsant drugs - (phenytoin, fosphenytoin,
phenobarbital, primidone): supplemental folic acid can interfere with anticonvulsant drugs and increase seizure frequency • Folic acid can also have a direct convulsant activity ( Lewis et al 1995; Froscher et al 1995) – Vitamin C (ascorbic acid) is a vitamin for only a limited number of species:
humans and other primates, guinea pigs , bats, some birds and most fish – The vitamin C deficiency scurvy has been known for many centuries and was
described by Hippocrates in 1500BC – The Crusaders are said to have lost more men through scurvy than were killed – Recognition that scurvy was due to a dietary deficiency came from James Lind in 1757, who demonstrated that orange and lemon juice is protective – Both ascorbic acid and dehydroascorbic acid have vitamin activity
Food Sources of Vitamin C Vitamin C is abundant in fruits and vegetables such as : • Blackcurrants & redcurrants • Citrus fruits • Guava • Parsley • Pineapple • Rosehips • Strawberries, raspberries, blackberries • Peppers • Kale, rocket watercress, bok choy, spinach Very significant losses occur as vegetables wilt, or when they are cut (as a result of the release of ascorbate oxidase from the plant tissue) (Bender 2002; Osieck 2004) Reference Nutrient Intakes • Vitamin C illustrates well how different criteria of adequacy and different interpretations of experimental evidence can lead to different estimates of requirements and to reference intakes ranging from 30-80mg/day. • The requirement to prevent scurvy - 10mg/day
• The requirement for optimum wound healing - 20mg/day
• Allowing for individual variations in metabolism gives the reference intake for adults of 30mg/day - which was the British recommendation until
1991; then it was changed to 40mg.

• The Dutch and US recommendations at 80 and 60mg respectively are
based on different criteria to the British recommendations (they estimate the total body content of vitamin C and then measure the rate at which it is metabolised). Recommended Dietary Allowances Irish Recommendations (1983, revised
Males 11-14 years Recommended Dietary Allowances Irish Recommendations (1983, revised
Reference Nutrient Intakes UK recommendation
US recommendation
Males 11-14 years Males 15-50+ years Females 11-14 years Females 15-50+ years (Geissler and Powers 2005) Vitamin C in Selected Foods Food per 100g
Kale (raw)
Spinach (raw)
Dosage of Vitamin C • RDAs – see table Vitamin C
• Supplemental Range: 250 – • No high doses in third trimester of pregnancy. The baby becomes accustomed to high doses that are unsustainable when it is born. (Osiecki 2004; FSA 2007; EUFIC 2011) Vitamin C-Availability and Absorption • Significant losses occur in cooking : – Through leaching into water – Through atmospheric oxidation which continues when foods are left to stand before serving • Refrigeration and quick freezing can help retain the vitamin : – Most frozen foods are processed so close to the source of supply that their ascorbic acid content is often higher than that of fresh foods that have been shipped and spent a long time in storage. (Mahan and Escott –Stump 2008) Vitamin C - Availability and Absorption • Both ascorbic acid and dehydroascorbic acid are absorbed in the mouth and in the small intestine • Some 80-95% of dietary ascorbate is absorbed at intakes up to • The absorption of larger amounts is lower • Unabsorbed ascorbate from very high doses is a substrate for
intestinal bacterial metabolism causing gastrointestinal
discomfort and diarrhoea

(Mahan and Escott –Stump 2008) Vitamin C - Availability and Absorption • Both vitamers are transported into cells by glucose transport and high blood glucose levels (e.g. in diabetics) can inhibit
vitamin C uptake significantly.
• It has been suggested that hyperglycaemia (high blood sugar) induces cellular vitamin C deficiency which may lead to oxidative stress in cells and contribute to an increased risk of atherosclerosis. • There is no specific storage organ for vit C; leukocytes, adrenals, and pituitary gland show the highest concentrations. (Mahan and Escott –Stump 2008) Vitamin C - Metabolic Functions • As an antioxidant: vitamin C loses electrons easily, which
allows it to perform as an antioxidant, defending against free radicals and thus against tissue damage • In the intestines, vitamin C enhances iron absorption by
protecting iron from oxidation (it keeps it in Fe2+ form, not allowing it to become Fe3+ , which is not bioavailable)
• A dose of 25mg of vitamin C taken together with a meal increases
iron absorption by 65% • Optimum iron absorption may require more than 100mg/day (Rolfes et al 2006; Bender 2002) Vitamin C - Metabolic Functions – As a prooxidant: high levels of supplementation with vitamin C
can create a pro-oxidant stress in the body – Vitamin C has antioxidant activity when it reduces oxidizing substances such as hydrogen peroxide, however, it can also reduce metal ions which leads to the generation of free radicals through the fenton reaction: – 2 Fe3+ + Ascorbate → 2 Fe2+ + Dehydroascorbate free radicals
– The metal ion in this reaction can be reduced, oxidized, and then re-reduced, in a process that can generate reactive oxygen species (free radicals) (Rolfes et al 2006; Bender 2002) Vitamin C - Metabolic Functions • As a cofactor in collagen formation: vitamin C helps
to form the fibrous structural protein of connective tissues known as collagen: – Collagen serves a matrix on which bones and teeth are formed – When a person is wounded, collagen glues the separated tissues together – Collagen helps the arteries expand and contract (Rolfes et al 2006; Bender 2002) Vitamin C - Metabolic Functions • As a cofactor for other reactions:
– Hydroxylation of carnitine (a compound that transports
long-chain fatty acids into the mitochondria for energy production) – Conversion of tryptophan and tyrosine to the
neurotransmitters serotonin and norepinephrine
– Synthesis of thyroxin (thyroid hormone)
– Synthesis of adrenal steroid hormones
(Rolfes et al 2006) Vitamin C - Metabolic Functions As a cofactor for other reactions:
• Inhibition of nitrosamine formation
– The additives nitrates and nitrites in cured meats are suspected to be responsible for increased colon cancer risk resulting from eating cured meats – Nitrates and nitrites can be converted into carcinogens – Vitamin C can prevent formation of nitrosamines from nitrates and nitrites Vitamin C - Metabolic Functions • In stress: the adrenal gland contains more vitamin C than any
– During stress the adrenals release vitamin C with other hormones into the blood – The exact role of vitamin C in stress is unknown, but it is known that stress raises vitamin C needs – Burns, infections, toxic metal intakes, chronic use of medications and cigarette smoking are among the stresses that increase vitamin C need (Rolfes et al 2006) Vitamin C -Metabolic Functions • As a cure for the common cold: newspaper headlines touting vitamin C as
a cure for colds have appeared frequently over the years, but research supporting such claims has been conflicting and controversial. • A review of all the research in this area reveals a modest benefit: – A difference in duration of less than 1 day per cold in favour of those taking daily dose of at least 1g/day – Interestingly, those who received the placebo, but thought they were receiving vitamin C had fewer colds than the group who received vitamin C but thought they were receiving placebo –the healing
power of faith?
(Douglas et al 2007) Vitamin C - Specific Therapeutics • Age-related macular degeneration (AMD): taking vitamin C
500 mg orally, in combination with elemental zinc 80 mg, vitamin E 400 IU, and beta-carotene 15 mg/day - seems to provide a reduction in visual loss and some reduction of progression of AMD in patients with advanced AMD.
• Albuminuria (protein in urine): taking vitamin C (1250mg)
plus vitamin E (680IU) can reduce the excretion of protein by about 19%, when given for 4 weeks, in patients with type 2 diabetes. This might also reduce the risk of end-stage renal disease in patients with type 2 diabetes. – Excretion of protein in diabetes type 2 is a sign of vascular kidney damage triggered off by diabetes. ( AREDSRG 2001; Gaede et al 2001) Vitamin C - Specific Therapeutics • Atherosclerosis and peripheral arterial disease: taking vitamin C (250mg)
orally seems to decrease the risk of atherosclerosis; patients with atherosclerosis appear to have lower levels of vitamin C and higher levels of C-reactive protein, a marker of inflammation. • Cancer: dietary vitamin C might decrease the risk of developing mouth
cancer and other cancers; some evidence suggests that a diet low in vitamin C might increase the risk of mortality due to all cancers. • Gallbladder disease: there is some evidence that vitamin C
supplementation and increased vitamin C serum levels decreases the risk of developing gallbladder disease in women; however, it doesn't seem to have this effect in men. ( Langlois et al 2001; Khaw et al 2001; Simon et al 2000) Vitamin C - Specific Therapeutics • Helicobacter pylori (H pylori): taking vitamin C orally (1g)
seems to decrease gastritis associated with antacid therapy in patients with H. pylori infection; after H. pylori is eradicated, vitamin C appears to decrease the incidence of precancerous changes in stomach tissue. • Osteoarthritis: consuming vitamin C from dietary sources
seems to reduce the risk of cartilage loss and disease progression in people with osteoarthritis. • Sunburn: taking vitamin C orally (2g) in combination with
vitamin E (1000IU) seems to reduce redness of ultraviolet (UV) radiation-induced sunburn; guard against toxicity at these ( Zullo et al 2000; Yoshinaga et al 2001; McAlindon et al 2001; Pannelli et al 1989) 47CNM 2014 Vitamin C - Deficiency • The two most notable signs of vitamin C deficiency reflect its role maintaining the integrity of blood vessels: – The gums bleed easily around the teeth
– Capillaries under the skin break spontaneously producing pinpoint
• When the intake falls to about 1/5 of its optimal store size (ca. 1 month on a vitamin C depleted diet), scurvy symptoms begin to appear :
– Further haemorrhaging from inadequate collagen synthesis – Muscle degeneration – Rough, brown scaly skin; wounds do not heal resolved in 5 days
of vitamin C
– Bone rebuilding falters-fractures develop – Teeth become loose (Rolfes et al 2006) Factors That Might Affect Individual • Insufficiency can occur in people with low fruit and vegetable intake on the following medications: • Aspirin • Barbiturates • Oral contraceptives • Smokers have lower levels of serum vitamin C, and the reference nutrient intake for this group is 80mg/day, however many practitioners recommend upwards of 1000mg/day in divided doses. • 25mg of vitamin C is lost with every cigarette smoked. (Rolfes et al 2006) Factors That Might Affect Individual Suspect insufficiency, when patients present with: – Fatigue accompanied with petechiae (smaller bleeding lesions under the skin) – Gingivitis – Poor wound healing – History of recurrent infections and colds – Thickening of the skin on the buttocks and lower (Liska et al 2004) Vitamin C - Toxicity – At high levels 3000mg day, toxic effects are reported : • Nausea • Abdominal cramps • Diarrhoea – People with kidney disease and those with tendency toward gout are prone to forming kidney stones if they take large doses of vitamin C long-term – Long-term high-dose vitamin C supplements can adversely affect people with iron overload (exacerbating cellular damage through iron-
induced free radicals)-in this case vitamin C will act as a prooxidant
– Tolerable Upper Intake Level for Adults: 2000 mg/day
Vitamin C - Drug Interactions • Cancer Drugs: the use of high-dose vitamin C as an adjunctive therapy, in
combination with other antioxidants to treat cancer, is controversial. • Some experts think these supplements might increase the sensitivity of tumour cells to radiation and reduce toxicity in normal cells. • Other experts worry that antioxidants might protect cancer cells from the effects of radiation. • Preliminary evidence suggests that vitamin C might reduce the effectiveness of some chemotherapy drugs, including doxorubicin, cisplatin, vincristine, methotrexate, and imatinib. ( Prasad et al 2002; Heaney et al 2008) Vitamin C -Drug Interactions • Oestrogens: increases in plasma oestrogen levels of up to 55% occur
under some circumstances when vitamin C is taken with oral contraceptives or hormone replacement therapy, including topical • Niacin/Statins: a combination of niacin and simvastatin (Zocor) effectively
raises HDL cholesterol ("good cholesterol") levels in people with coronary disease and low HDL levels; a combination of antioxidants (vitamin C, vitamin E, beta-carotene, and selenium) seems to blunt this rise in HDL. • Warfarin: massive doses of vitamin C can counteract the effect of anti-
clotting medications. • Diabetes tests: large amounts of vitamin C obscure the results of tests
used to detect diabetes giving false positive or false negative results.
( Vihtamaki et al 2002; Brown et al 2001; Rolfest et al 2006) Forms and Sources: Biotin was originally discovered as: – Part of the complex called bios which promoted the growth of yeast,
and separately as vitamin H, the curative factor in ‘egg white injury' –the
disease caused by consuming high amounts of uncooked egg whites • Biotin is widely distributed in many foods like liver, soybean, egg yolk, peanuts, walnuts, bean sprouts, kidneys, milk. • It is also synthesized by intestinal flora (however it is not know to what extent it is available to the host) (Osiecki 2004; Bender 2002) • The Food Safety Authority of Ireland's Working Group also has not established a RDA for biotin. (FSAI 1999) Reference Nutrient Intakes The Food Standards Authority in the UK stated: • Biotin is widely distributed in natural foodstuffs but at very low levels compared to other water-soluble vitamins. Liver contains approximately 1 mg/kg biotin Fruits and most other meats contain approximately 0.01 mg/kg biotin. Biotin, usually either in the form of crystalline D-biotin or brewer's yeast, is included in many dietary supplements, infant milk formulas and baby foods. The maximum dose in supplements sold in the UK is 2 mg. Several medicines containing biotin, which are available only from pharmacies, are licensed for the prevention and treatment of nutrient deficiency, supplementation of special diets and malabsorption. The maximum daily dose of biotin in licensed medicines is 0.50 mg. Due to insufficient data, COMA was unable to set Dietary Reference Values for biotin, but considered that intakes between 0.010 and 0.20 mg/day are both safe and adequate (COMA, 1991). Dosage of Biotin • RDAs – see table • Supplemental Range: • Synergistic nutrients B2, B3, B5, B6, B9, B12, Mg, Mn, Cr (Osiecki 2004; FSA 2007; EUFIC 2011) Biotin - Availability and Absorption – Most biotin in foods is protein bound, which is then metabolised in the intestines to yield free biotin – Free biotin is absorbed in the small intestine – It is not known to what extent biotin bound in foods is biologically available to humans – Absorption is impaired by chronic alcohol intake
and raw egg whites containing avidin (a
glycoprotein that may irreversibly bind biotin)
• Avidin is denatured by cooking (Bender 2002; Mahan and Escott –Stump 2008) Biotin- Availability and Absorption – Smaller amounts of biotin can also be absorbed from the colon, which facilitates the use of biotin produced by colon microflora – Colon absorption may be enhanced by the effects of a vegetarian diet on gut flora (Liska et al 2004) Biotin - Metabolic Functions • Biotin is involved in reactions crucial for energy
metabolism and fatty acid synthesis
– Biotin deficiency has been observed to lead to accumulation of odd-numbered fatty acids • Biotin is also involved in the promotion of healthy hair
and nails, a benefit that may come from its ability to
positively affect the metabolism of oils in the
integumentary system
• It is also involved in creating the active form of folate
(Liska et al 2004) Biotin - Specific Therapeutics • Cradle cap: in infants, cradle cap appears to be a
common manifestation of biotin insufficiency – This may be due to biotin influence on fatty acid – However supplementation does not seem to improve • Seborrhoeic dermatitis (adult version of cradle cap) is
characterised by biotin deficiency, however there are no studies on the efficacy of supplementation in this condition ( Brenner et al 1988; Keipert et al 1976; Inaloz et al 2002) Biotin - Specific Therapeutics • Brittle nails: preliminary evidence shows that biotin might increase
the thickness of fingernails and toenails in people with brittle nails • Diabetes: preliminary evidence shows that a combination of biotin
(2mg) and chromium (600mcg) might lower blood glucose and
haemoglobin A1c levels in type 2 diabetes patients for whom oral
diabetic drugs are not effective; however, biotin alone doesn't seem
to have any effects
– Haemoglobin A1c is a marker of long-term blood sugar levels
– Average supplemental range of biotin is from 300-600μg/d
– No toxicity has been reported in patients taking up to 10mg/day
( Hochman et al 1993; Geohas et a 2004; Baez-Saldana et al 2004; Liska et al 2004) Biotin - Deficiency • Biotin is widely distributed in foods and deficiency is unknown, except among people who are: – Maintained on total parenteral nutrition – Consuming very large amounts of uncooked egg whites (ca. 10 a day) • Deficiency symptoms: – Scaly and seborrhoeic dermatitis – Dry scaly rash around openings of eyes, mouth, nose, anus – Hair loss – Nausea cured with supplements of
– Anorexia – Burning /tingling sensations – Dry greyish skin – Extreme fatigue – Glossitis or smooth pale tongue (Bender 2002; Osiecki 2004) Minerals represent about 4-5% of body weight (2.8-3.5kg in adult men and women respectively) and out of this: 50% - calcium (Ca)
99% of Ca and 70% of phosphate
25% - phosphorus (P)
are found in bones
25% -other macrominerals and microminerals
Mg (magnesium), Na (sodium), Fe (iron), Zn(zinc), I (iodine), Se (selenium),
K(potassium), Cl (chlorine),
Mn (manganese), F (fluoride), Mo (molybdenum),
S (sulphur)
Cu (copper),Cr (chromium), Co (cobalt), B (boron)
Ultratrace elements -negligible amount of weight
(As) arsen, (Al) aluminium, (Sn) tin, (Ni) nickel, (V) vanadium, (Si) silicon
( Mahan and Escott-Stump 2008) • Macrominerals exist in the body and food mainly in the ionic state

– Na ( sodium), K ( Potassium), Ca ( Calcium) - as positive ions
(cations)- e.g. Na+, K+, Ca 2+ – Cl, S, P- as negative ions (anions) –e.g. chlorine as chloride;
sulphur and sulphate, phosphorus as phosphates • Minerals also exist as components of organic
compounds :
– Phosphoproteins, phospholipids, metalloenzymes, metalloproteins (e.g. haemoglobin) ( Mahan and Escott-Stump 2008) • Minerals are absorbed in their ionic state (exception-haem iron)
– Therefore minerals that are : are not bioavailable;
• Bound to organic molecules (chelated)
minerals that are better • Bound to inorganic complexes absorbed bound to amino acids (e.g. selenomethionine) • Unabsorbed minerals are excreted in the faeces • Absorbed minerals are: – Transported into the blood
– Or kept in the intestinal cells bound to protein, and when the cell dies,
they are sloughed off into the intestinal lumen for excretion (probably a mechanism for protecting from toxicity) ( Mahan and Escott-Stump 2008) • Bioavailability: absorption of a mineral after its digestion from food
and before its use in tissues and cells • Several factors can affect bioavailability: – Body mineral statuts (e.g. in Fe deficiency, Fe absorption increases
– Substances present in food like phytates, vitamin C, etc
– Other minerals present in food ( e.g. Zn absorption is reduced by iron
– Disease states: e.g. fat malabsorption can cause formation of soaps
from Mg and Ca with fatty acids and render those minerals unabsorbable – High concentration of one mineral in the intesines (e.g. excess Ca
binds to phosphates and precipitates) ( Mahan and Escott-Stump 2008) Bioavailability:
Examples of Mineral-Mineral Interactions
– In general in mineral deficiency states, more mineral transport proteins appear in the intestinal tract - which may allow for greater absorption of toxic elements • Essential mineral deficiency can thus increase a person's vulnerability to toxic element exposure – Excess intake of Zn antagonizes intestinal Cu absorption to the point that copper deficiency may result despite adequate copper intake! – Cu deficiency exacerbates iron deficiency anaemia ( Lord and Bralley 2008) • Minerals with high bioavailability from foods:
Sodium( Na), potassium (K), chloride (Cl), iodide (I) fluoride (F) • Minerals with medium bioavailability from foods:
Calcium (Ca), magnesium (Mg) • Minerals with low bioavailability from foods: Iron (Fe), chromium (Cr), manganese (Mn)
( Mahan and Escott-Stump 2008) Mineral deficiencies or excesses are involved in the pathogenesis of many health conditions e.g. heart disease, hypertension, cancer • Certain groups demonstrate relatively high incidence of elemental Children and adolescents Those with certain diseases (e.g. those who are immuno compromised) • Causes of deficiency: factors that decrease supply and increase demand
( Lord and Bralley 2008) Causes of Iron-Deficiency ( Lord and Bralley 2008) • Government objective: to derive safe and effective levels of
intake to prevent frank deficiency and possible toxicity
• Practitioner objective: to assess the patient, taking into
account all the individual factors that might cause deficiency/excess. To provide optimum mineral supply through manipulating diet and if that is not sufficient-introducing supplementation ( Lord and Bralley 2008) objective is to
estimate the
ideal level of
patient's
nutrient intake
Mineral Concentration
lower level of intake (mainly
higher level of intake (mainly
through faulty diet; increased
through supplementation)
needs) increases the risk of
increases the risk of negative
negative effects
( Lord and Bralley 2008) Calcium (Ca) is the most abundant mineral in the body Ca was among the first substances known to be essential in the diet It makes up about 1.5%-2% of the body weight; 39% of body minerals The majority of it is contained in the skeleton (as hydroxyapatite-complex of calcium and phosphate) (Strain and Cashman 2002; Sharp 2005) Food Sources of Calcium Milk and dairy products are the most concentrated food sources of calcium All foods of vegetable origin contain Ca, though not as concentrated, but often more bioavailable: Dark green leafy and cruciferouces vegetables Kale, collards, broccoli, chinese cabbage, Brussel sprouts Almonds, sesame seeds Soybeans; calcium set tofu Calcium fortifeid orange juice Small bones of sardines and salmon-another animal source Reference Nutrient Intakes • The maintenance of bone calcium reserves is the major determinant of calcium needs • Therefore the needs vary throughout life considerably, with greater needs during growth, pregnancy and lactation • There is considerable disagreement over human calcium requirements, which is reflected in the wide variation in estimates of daily requirements – UK recommendation for adults above 24years -700mg/day – US recommendation for adults above 24years -1000-1200mg/day • Different recommendations stem from applying different
methods to establish Ca needs

(Strain and Cashman 2002) Recommended Dietary Allowances Irish Recommendations (1983, revised
Males 11-14 years Recommended Dietary Allowances Irish Recommendations (1983, revised
Reference Nutrient Intakes UK recommendation
US recommendation
Males 11-18years Males 19- 50+ years 1000 (1200 after 50) Females 11-18 years Females 19-50+ years 1000 (1200 after 50) (Geissler and Powers 2005; FSA 2007) Dosage of Calcium RDAs – see table Supplemental Range: (Osiecki 8th Ed; FSA 2007; EUFIC 2011) Daily Reference Intakes • It is difficult to establish optimum dietary intakes as calcium
balance depends on numerous lifestyle factors:

• High protein, salt, caffeine intake
• Low sun exposure or vitamin D intake
calcium wasting factors
• Low physical activity
(see slides further on)
• There is a wide variation of calcium intakes around the world • Higher intakes, when accompanied by calcium-wasting lifestyle factors are not necessarily linked to lower rates of calcium deficiency diseases (e.g. of bone fractures) • In Western societies, where Ca wasting factors are very common, higher recommendations are justified!
(Strain and Cashman 2002) % Calcium Absorption cruciferous
vegetables
is absorbed
efficiently as
(USDA 2009; % absorption estimated based on published absorption fractions) Calcium - Availability and Absorption • Ca is absorbed by all parts of the small intestine, but the most rapid absorption after a meal occurs in the more aicidic duodenum • Only about 30% of ingested Ca is absorbed, very few individuals may absorb only 10% and some (rarely) as much as 60% • Ca is absorbed by an acitve and passive mechanism
• The active absorption of Ca is controlled by 1.25-
dihydroxyvitamin D
– Vitamin D stimulates the production of calcium-binding proteins – It is important when Ca intakes are below recommended levels • The passive absorption occurs without the help of vit D
– When a lot of Ca at once is consumed, e.g. from dairy foods (Mahan and Escott –Stump 2008) Calcium- Availability and Absorption • Numerous factors affect Ca bioavailability: – The greater the need and/or the smaller the
dietary supply-the more efficient the absorption
• e.g. pregnancy, lactation, during resistance exercise (resistance exercise leads to higher bone density) – Low vitamin D intake or/and inadequate sunlight
exposure reduces Ca absorption, esp. among the
elderly
• The efficiency of vitamin D production in older adults is lower (Mahan and Escott –Stump 2008) Calcium - Availability and Absorption – Ca is absorbed only in an ionic form, an acidic
medium increases its absorption
• HCl secreted by the stomach lowers the pH of the duodenum, increasing the absorption • Thus taking Ca supplements with meals increases its • Ageing is associated by achlorhydria (lack of gastric acid secretion) which results in less gastric acidity and reduced Ca absorption (Mahan and Escott –Stump 2008) Calcium - Availability and Absorption • Lactose (sugar in milk) increases Ca absorption,
however it is only significant in infants • Oxalic acid in rhubarb, spinach, chard, beet greens
forms insoluble calcium oxalate in the digestive tract-decreasing Ca absorption – Spinach is a rich source of Ca, however the bioavailability of spinach Ca is low (Mahan and Escott –Stump 2008) Calcium- Availability and Absorption – Phytic acid (phytate) , a phosphorous compound found in
outer husks of grains combines with Ca forming calcium phytate, which cannot be absorbed – Dietary fibre may decrease absorption but only in higher
– Some medications may decrease absorption or increase Ca
excretion leading to bone loss – In individuals with fat malabsorption-Ca forms fatty acids-Ca
soaps, which decreases absorption – Unless the intake of dietary phosphate (P) is very high, Ca
absorption does not seem to be impaired by dietary P (Mahan and Escott –Stump 2008) Calcium Metabolism – 99% of body Ca is found in mineralised tissues (bones and teeth)-as calcium phosphate and calcium carbonate – The rest-1% is found in extra cellular fluid, muscle and other – Ca levels in blood are tightly regulated by: • Hormones such as parathyroid hormone (PTH),
• Vitamin D 1.25-dihydroxycholecalciferol
• Calcitonin
– These serve to decrease or increase the entry of Ca into the (Mahan and Escott –Stump 2008; Strain and Cashman 2002) Calcium Metabolism Only in extreme situations (e.g. severe malnutrition or hyperparathyroidism) is the serum Ca concentration below or above normal range; normally Ca balance is tightly regulated by hormones (Rolfes et 2006; ) Calcium Excretion • Urinary Ca excretion varies throughout life cycle:
• It is usually lowest during rapid skeletal growth (adolescents) • In menopause-Ca excretion increases • Dietary factors increasing urinary calcium excretion:
• Diet high in animal protein (meat, poultry, fish, cheese) due to the
generation of acids (sulphuric acid) from sulphur-containing amino acids abundant in animal products • High caffeine intake (several cups of coffee a day)
• A high-salt diet ( more evidence still needed)
(Mahan and Escott –Stump 2008; ) Calcium Wasting Factors Higher Ca intakes
are NOT the causes
of the higher
fracture rates, rather
accompanied by
higher protein, salt
consumption, lower
physical activity and
sun exposure
(Frassetto 2000; Abelow 1992) Calcium Wasting Factors Focus: High Protein Diets and Calcium Excretion
• High protein intake increases urinary Ca excretion = protein-
induced hypercalciuria; 3 mechanisms:
• Excess amino acids → urea, a powerful diuretic- → increase in glomerular filtration rate → increase in Ca excretion • Excess amino acids → decrease in kidney reabsorption of calcium • Liver metabolizes the S-containing amino acids methionine and cysteine (abundant in animal proteins and isolated soy protein) to acid H2SO4 → reduction in blood pH → increased bone resorption → increased urinary Ca losses (Bushinsky 2001; Remer and Manz 1995; Remer 2000) Calcium Wasting Factors • Every 10g dietary protein in excess of our needs increases daily urinary calcium loss by 16mg • Doubling protein intake increases calcium loss by 50% • Amount of calcium lost in the urine of a woman after eating a hamburger: 28 milligrams Calcium Wasting Factors The relationship between urinary calcium excretion and protein intake is generally well accepted, however confirmation of the source of this excreted calcium is not. The below meta-analysis and systematic review found little evidence to support a negative relationship between protein intake and bone. In fact there was a slight positive association for protein intake and bone density. Calcium Wasting Factors Among the elderly women of Bantu osteoporosis does not exist!
– when the researchers were studying this population (in the 1970s) it was considered a scientific phenomenon They had a huge calcium drain, having an average of 10 children and nursing each child for 14 months. Their diet included 440 mg of calcium per day, 30%-50% of the Western recommendation; huge amount of physical activity, adequate sun exposure Their protein consumption was 50 g/d protein (their diet was mostly plant-based) When they move to Western civilization and their dietary and lifestyle pattern changes and they develop osteoporosis (Walker 1965; Walker et al 1972 ) Calcium - Metabolic Functions • Building Bone Mass: adequate Ca, especially in the
prepubertal and adolescent years - is critical to permit optimal gains in bone mass – The critical period to acquire adequate bone mass and density is during teenage years, and in this period Ca intakes should be optimised • Preserving Bone Mass: sufficient Ca intakes are
critical in postmenopausal women to maintain bone health – Oestrogen promotes bone formation and lowering levels can precipitate osteoporosis (Mahan and Escott-Stump 2008) Calcium - Metabolic Functions Focus: Childhood Calcium Intake and Adult Bone Density
Although adequate Ca intake during adolescence is one of the conditions
for healthy bones in adulthood; high calcium intakes per se do not
protect from future fractures
Metaanalysis, Journal of the American Academy of Paediatrics:
– 37 good quality studies on Ca and dairy product intakes during childhood and future bone health – 10 showed: Ca supplements and dairy increase bone mineral density in children; however the effect is very small
– 27 showed: no effect
– Conclusion: ‘Neither consumption of dairy products, nor total dietary Ca
has shown even a modestly consistent benefit for child or young adult
bone health'
What has shown the benefit:
Highest physical activity in childhood!
(Lanou et al 2005) Calcium - Metabolic Functions • Blood Clot Formation:
– Ca is required as a cofactor for numerous enzymatic reactions in the process of blood clot formation • Weight Control
– High dietary calcium is associated with decreased prevalence of being overweight or obese – Mechanism:
• Depression of PTH and 1.25 hydroxyvitamin D, which leads to inhibition of lipogenesis (fat formation) and increased lipolysis (fat burning) • Increased excretion of faecal fat due to soap formation (Mahan and Escott-Stump 2008) Calcium - Metabolic Functions Other Functions at Cellular Level:
– Ca affects cell membrane stability – It influences the transport of ions across membranes of cell – It helps the release of neurotransmitters – It affects the activation of intracellular enzymes – It is required for nerve transmission – Adequate Ca intake might help lower blood pressure
(Mahan and Escott-Stump 2008; Rolfes et al 2006) Metabolic Functions Other Functions at Cellular Level:
• It regulates heart muscle function and smooth muscle contractibility: – The proper balance of Ca, Na, K and Mg maintains muscle tone
and controls nerve irritability

– A significant increase in the serum calcium level can stop the heart and cause respiratory failure – A significant decrease-tetany (contraction) of skeletal muscles
(Mahan and Escott-Stump 2008) Calcium - Specific Therapeutics • Bone loss: in premenopausal women over age 40,
following Western diet bone loss can be reduced significantly by supplementing with 1000 mg calcium/day • But in the 5 years immediately after menopause, calcium supplementation has very little effect on bone loss – Right after the onset of menopause, the rapid loss of oestrogen causes a high bone resorption rate, which increases serum calcium levels and therefore decreases intestinal absorption of calcium at that time (Bryant et al 1999; Heaney 2000; Chiu et al 1999 ) Calcium - Specific Therapeutics Bone loss:
• After this period, calcium supplementation has a significant benefit on bone loss among Western women with numerous Ca –wasting lifestyle factors • The typical rate of bone loss in postmenopausal women who are not taking calcium supplements is 2% per year • Calcium 1000-1600 mg/day (as carbonate, citrate, lactate gluconate, or citrate malate) decreases this rate by 0.25% to 1% annually • For optimum results, optimal vitamin D status through sun
exposure or supplementation (400IU/d) and avoidance of Ca –
wasting lifestyle factors should be recommended
( Maton et al 1999; Koo et al 1999; Nieves 1998; Castelo-Branco 1999; Jackson et al 2006) Calcium - Specific Therapeutics • Foetal bone mineralization: calcium supplementation in pregnant
women who have low dietary Ca intake (less than 560 mg per day),
increases foetal bone mineralization and density; however, in
women with adequate dietary intake, calcium supplementation does
not offer any additional benefit; 300-1300 mg/day beginning at week
20-22 –always consult patient's doctor first!

• Premenstrual syndrome (PMS): there seems to be a link between
low dietary calcium intake and symptoms of PMS; taking calcium 1-1.2 grams daily seems to significantly reduce depressed mood, water retention, and pain associated with PMS • Dyspepsia: taking calcium carbonate 0.5-1.5g orally as an antacid
is effective for treating dyspepsia ( Maton et al 1999; Koo et al 1999; Thys-Jacobs 1998) Calcium - Specific Therapeutics • Hypertension: dietary Ca may protect against
hypertension; restricting Na without increasing Ca (along with K, and Mg) is not enough to optimally reduce high blood pressure – The DASH diet, very successful in lowering blood pressure, was not particularly low in sodium but high in Ca, K and Mg – The Dietary Approaches to Stop Hypertension (DASH) study- emphasized high fruit, vegetable, whole grain, and beans along with low meat intake with adequate Ca through plant foods and low fat dairy ( Rolfes et al 2006) Calcium - Deficiency • A low Ca intake during the growing years limits the bones' ability to reach their optimal mass and density – Most people achieve their peak bone mass by their late 20s – Dense bones best protect against age-related bone loss – Adults lose bone beginning in the early 30s – Unlike other diseases-bone loss is asymptomatic, and even blood calcium levels offer no clues as Ca levels remain constant in the serum despite suboptimal intakes Remember: adequate Ca intake is not a guarantee for healthy
bones; equally as important is avoidance of Ca-wasting
lifestyle factors!
(Rolfes et al 2006) Factors That Might Affect Individual • Insufficiency can easily develop among: • Pregnant and lactating women • Adolescents who eat a junk-food diet • The elderly • Vegans eating vegan junk-foods with low whole food intake • Insufficiency may also result from: • High caffeine and alcohol consumption • People on high animal protein diets (e.g. Atkins, Zone, etc.) • Gastrointestinal dysfunction (Liska et al 2004) Factors That Might Affect Individual • Symptoms suggesting inadequate calcium status: – Frequent fractures – Blood clotting problems – Chronically low blood Ca levels (although it might indicate other abnormality, e.g. Vit. D deficiency) – Muscle cramps, twitches and symptoms of (Liska et al 2004) Meeting Your Ca Needs It is possible to achieve 1000mg from both dairy or plant foods. You
need to eat more plant foods, but they come in a healthier package:
• broad beans-100g
milk 1%-2 cups
• broccoli-1 cup
• 5 dried figs
cheese- 2 slices
• 2 cups of lettuc
• tofu (80g)
• chickpeas -1 cup
• soy milk (1 cup)
saturated fat : 12.5g
saturated fat: 1g
cholesterol: 64g
• cholesterol: 0g
sodium: 546 mg
• sodium: 219mg
phytochemicals, fibre-none!
• fibre, phytonutrients- plenty!
Calcium - Toxicity • Excessive calcium intake from supplements in the long-term has been shown to increase risk of : – Kidney stone formation – Hypercalcaemia (high blood Ca levels) and renal insufficiency – Impaired absorption of Fe, Zn, Mg, P • Excessive Ca intakes from diet (mainly dairy products-very concentrated sources of Ca) and supplements have been show to increase the risk of: – Prostate cancer
• The mechanism: excessive Ca suppresses the synthesis of 1.25 hydroxyvitamin D; vit D suppresses prostate cancer cell proliferation
Tolerable Upper Intake Level for Adults: 2500mg/day
(Strain and Cashman 2002; WCRF 2007) Calcium - Drug Interactions • Biphosphonates (a class of drugs that prevents bone loss ): Ca
supplementation decreases the absorption of those drugs – Biphosphonates include: (Fosamax), etidronate (Didronel),
ibandronate (Boniva), risedronate (Actonel), and tiludronate (Skelid) • Calcipotriene is a vitamin D analogue used topically for psoriasis. It
can be absorbed in sufficient amounts to cause hypercalcaemia; theoretically, combining calcipotriene with calcium supplements might increase the risk of hypercalcaemia (high blood calcium) • Digoxin (drug used for heart conditions): hypercalcaemia increases
the risk of fatal cardiac arrhythmias with digoxin; Ca supplements should be consulted with GP ( Peters et al 2001; Bourke et al 1997; Vella et al 1999 ) Calcium - Drug Interactions • Hypothyroid medications (levothyroxine): calcium
reduces levothyroxine absorption • Quinolone and Tetracycline Antibiotics: taking
calcium at the same time as quinolones/tetracyclins reduces their absorption – Quinolones: include ciprofloxacin (Cipro), levofloxacin
(Levaquin), ofloxacin (Floxin), moxifloxacin (Avelox), gatifloxacin (Tequin), gemifloxacin (Factive), and others – Tetracyclines: include demeclocycline (Declomycin),
doxycycline (Vibramycin), and minocycline (Minocin). ( Peters et al 2001; Bourke et al 1997; Vella et al 1999; Schneyer 1998; Murry et al 1991; Maton et 1 Drug Interactions • Thiazide Diuretics: reduce calcium excretion
• Using thiazides along with moderately large amounts of calcium increases the risk of milk-
alkali syndrome (hypercalcaemia, renal failure)
• Advise patients to consult their physician about appropriate calcium doses ( Friedman et al 1999) – Magnesium (Mg) is the second most common cation found in the body – It is evently distributed between skeleton (50-60%) and soft tissues (40-50%) – Bone magnesium pool is exchangeable and may serve to maintain serum or soft-tissue magnesium concentrations in times of need – 99% of body magnesium is inside cells
Food Sources of Magnesium Magnesium is mostly concentrated in plant foods, the richest sources involve: – Dark leafy green vegetables (& all green vegetables) – Nuts and seeds – Whole grains – Soybeans & tofu (Strain and Cashman 2002; Osiecki 2004) Reference Nutrient Intakes • The RDA for Mg has been revised upwards for most groups and is currently EU RDA 375mg • According to these guidelines most Europeans (and Americans alike) are not meeting their magnesium recommendations • However, the significance of this is still being debated, as there is not a universally accepted reliable magnesium status assessment tool, which makes it difficult to determine the actual consequence of this apparent low intake (Strain and Cashman 2002) • The Food Safety Authority of Ireland Working Group has not set a RDA for magnesium, except for infants 0-12 months, where the RDA is 55-80 mg/d (UK). Reference Nutrient Intakes (mg/day) (Geissler and Powers 2005; FSA 2007; USAD 2009) UK recommendation
US recommendation
Males 11-14 years Males 15-18 years Males 19-50+ years Females 11-14 years Females 15-18 years Females 19-50 years Females 50+ years Mg in Selected Foods Food per 100g
Pumpkin Seeds
Flaxseeds
Brazil nuts
Soybeans
Mung Beans
Buckwheat
Sundried Tomatoes
Dried Corn
Beef steak
( USDA 2009; FSA 2007) • Supplemental Range: 300 - 1000mg in divided doses • High doses of Mg can cause diarrhoea, abdominal discomfort and cramping. • RDAs – see table (Osiecki 2004; FSA 2007; EUFIC 2011) Magnesium - Availability and Absorption • Mg is absorbed in the small intestine • In normal healthy humans Mg absorption ranges from 20-70% from a meal • Due to chemical similarity between Mg and Ca, large
changes in vitamin D status affect Mg status as well • Phosphate (especially from high-phytate containing foods) and Ca may be an inhibitor of Mg absorption • Protein and fructose may enhance Mg absorption (Strain and Cashman 2002) Magnesium - Metabolic Functions • Magnesium participates in hundreds of enzyme systems where it acts as a catalyst:
– Its major role is in the reaction that adds the last phosphate to the high-energy compound ATP;
making it essential in energy production
– As a component of ATP metabolism, Mg is essential • The use of glucose
• Synthesis of fat, protein and nucleic acids
• The cell's membrane transport systems
(Rolfes et al 2006) Metabolic Functions • Together with Ca, it is involved in:
• Blood clotting:
– Ca promotes blood clotting, Mg inhibits it • Muscle contraction
• Regulating blood pressure
• Lung function
• Mg also prevents dental caries by holding Ca in tooth
• It is essential in the functioning of the immune system
(Rolfes et al 2006) Magnesium - Metabolic Functions Ion transport across cell membranes • Magnesium is required for the active transport of K and Ca ions across cell membranes. As a result of Mg's role in ion transport systems, magnesium affects the conduction of nerve impulses, muscle contraction, and normal heart rhythm • Cell signalling requires MgATP for the phosphorylation of proteins and the formation of the cell-signalling molecule cAMP. cAMP is involved in many processes i.e. secretion of parathyroid hormone (Linus Pauling Institute 2007) Magnesium - Specific Therapeutics • Constipation: taking magnesium orally is helpful as a
laxative for constipation; magnesium citrate, sulphate,
and hydroxide salts are typically used for this indication;

– Remember: changing a patient's diet is the most effective way to help constipation and should always be the first step • Dyspepsia: taking magnesium orally as an antacid
reduces symptoms of gastric hyperacidity; magnesium carbonate, hydroxide, oxide are used • Coronary artery disease: taking magnesium orally may
reduce angina attacks in people with coronary artery
disease; always consult the GP
(Anderson et al 1997; Swain et al 1999; Lasserre et al 1994) Magnesium - Specific Therapeutics • Diabetes: higher dietary magnesium intake is
associated with a reduced risk of developing type 2 diabetes • A100 mg/day increase in dietary magnesium intake might be associated with a 15% risk reduction for developing type 2 diabetes; 100mg of Mg is contained in: – 4 slices of whole grain bread – 1 cup of beans – 1/4 cup of nuts – 1/2 cup of cooked spinach – 3 bananas (Song et al 2004; Meyer et al 2000; Lopez-Ridaura et al 2004) Magnesium - Specific Therapeutics • Diabetes: results of clinical studies using magnesium
supplements in patients with type 2 diabetes or insulin resistance have been mixed – Some research suggests magnesium supplements can decrease fasting blood glucose and improve insulin sensitivity – However, other research suggests no effect of magnesium on insulin or glucose levels • Kidney stones: taking magnesium orally (as
magnesium hydroxide) may prevent the recurrence of kidney stones odriguez-Moran et al 2003; Yokota et al 2004; de Valk et al 1998; Eibl et al 1995; Johansson et al 1980) Magnesium - Specific Therapeutics • Metabolic Syndrome: higher magnesium intake from
diet is associated with a 27% lower risk of developing
metabolic syndrome in healthy women and a 31% lower
risk in healthy young adults
• Migraine headaches: taking high-dose magnesium
citrate orally (600mg/day) seems to reduce the frequency and severity of migraine headaches; however, other research suggests that magnesium doesn't have any effect • Osteoporosis: epidemiological research suggests that
high dietary magnesium intake is related to greater
bone mineral density
(King et al 2005; He et al 2006; Pfaffenrath et al 1996; Tranquilli et al 1994 ) Magnesium - Specific Therapeutics • Premenstrual syndrome (PMS): taking magnesium orally (200-360
mg/d) seems to relieve symptoms of PMS; magnesium supplementation can improve symptoms including mood changes and fluid retention in some patients with PMS • Stroke: there is some evidence that increasing dietary magnesium
intake might decrease the risk of stroke in men; however, there is no proof that taking magnesium supplements has this same effect • Hypertension: Mg is critical to heart function and high dietary Mg
seems to protect against hypertension and heart disease; in Mg deficiency the walls of the arteries and capillaries tend to constrict (Bendich et al 2000; Ascherio et al 1998; Rolfes et al 2006 ) Magnesium - Deficiency Mg deficiency is uncommon, however lowered Mg
status is very common!
Some symptoms include:
• Muscle cramps, twitches, weakness
• Anxiety, nervous tension, tension headaches, depression, irritability,
insomnia, behavioural disturbances, seizures • Fatigue, chronic fatigue syndrome • Heart arrthymias, hypertension, MIs, palpitations, cold hands and feet, atherosclerosis • Poor immunity, free radical damage, decreased membrane integrity • Asthma • PMS • Osteoporosis • Reduced pain threshold Factors That Might Affect Individual • Deficiency of Mg in humans is rare, mostly it is associated with the presence of other illnesses • Poor magnesium status has been found in patients with: • Cardiovascular disease
• Renal disease
• Diabetes mellitus
• Hypertension
• Athletes
• Reasons to suspect magnesium insufficiency • Alcoholism • The elderly with eating difficulties • Pregnant women with poor dietary habits • Anyone with poor dietary habits! (Gropper et al 2005; Liska et al 2004) Magnesium -Toxicity • Magnesium ingested from foods has not been shown to exert any adverse effects • Excessive intakes from supplements in the long- term have been shown to cause: • Diarrhoea • Nausea • Abdominal cramping Tolerable Upper Intake Level for Adults: 400mg/day of
non-food magnesium
(Strain & Cashman 2002; Brewer 2002) Magnesium - Drug Interactions • Biphosphonates (drugs that prevent loss of bone mass) :
magnesium can decrease bisphosphonate absorption; advise patients to separate doses of magnesium and these drugs by at least 2 hours • Calcium Channel Blockers (anti-hypertension drugs): magnesium
inhibits calcium entry into smooth muscle cells and may therefore have additive effects with calcium channel blockers; severe hypotension can occur when high doses of Mg are given with these drugs • Potassium-sparing diuretics: also have magnesium-sparing
properties, which can counteract the magnesium losses and lead to excessive magnesium levels when taken with Mg supplements – they include (miloride (Midamor), triamterene (Dyrenium), and spironolactone (Aldactone) ( Dunn et al 2001; Hansten et al 1997; Ryan et al 1987) Magnesium - Drug Interactions • Quinolone Antibiotics: magnesium can form insoluble
complexes with quinolones and decrease their absorption • Tetracyclin antibiotics: magnesium can form insoluble
complexes with tetracyclines and decrease their absorption and antibacterial activity • Advise patients to take these drugs at least 2 hours before, or 4 to 6 hours after, magnesium supplements ( Dunn et al 2001; Hansten et al 1997; Ryan et al 1987) – Zinc (Zn) is the most abundant intracellular trace element – Human body contains 2g of Zn of which about 60% is in skeletal muscles and 30% in bones, 4-6% in skin – Zn in those tissues is not accessible at times of deprivation – Body has no specific zinc reserve and is dependent on a regular dietary supply of the element (Strain and Cashman 2002) Food Sources of Zinc • Zinc is highest in protein-rich foods like oysters, meats, poultry • Legumes and whole grains are also good Zn sources when eaten in considerable quantity – in a typical Western diet, phytate content is not high enough to impair Zn absorption • Vegetables vary in Zn content depending on the soil in which • Oysters, seafood • Pumpkin seeds, sunflower seeds, cashews • Fresh root Ginger • Whole grains • Beef, lamb, liver Strain and Cashman 2002; Osiecki 2004) Recommended Dietary Allowances Irish Recommendations (1983, revised
Males 11-14 years Recommended Dietary Allowances Irish Recommendations (1983, revised
Reference Nutrient Intakes UK recommendation
US recommendation
7 months-3 years Males 11-14 years Males 15-18 years Males 19-50+ years Females 11-14 years Females 15-18 years (Geissler and Powers 2005; FSA 2007; USDA 2009) Zinc Sources in Selected Foods Food per 100g
Oysters Raw
Beef Liver
Pulses raw
Whole Wheat Flour
Brown Rice
Wheat Flour
Green Leafy Vegetables
Cod, plaice, whiting
Potatoes
(FSA 2007; USDA 2009) • RDAs – see table • Supplemental Range: 10-100mg (divided doses will avoid any • Watch out for copper deficiencies as Zn supplementation interferes with Cu absorption and metabolism Child (under 10 yrs) (Osiecki 2004; FSA 2007; EUFIC 2011) Zinc – Availability and Absorption • The bioavailability of Zn depends on dietary enhancers and • Enhancers:
– low Zinc status-the more is needed, the more is absorbed • Inhibitors:
– Phytates, oxalates and polyphenols bind Zn and make it less – Excess iron, copper and calcium may inhibit Zn absorption • Absorption from a mixed animal and plant based diet-20-30% • Absorption from a plant-based diet (high in phytates)-15% (Strain and Cashman 2002) Metabolism of Zinc • Upon absorption Zn is retained by a storage protein- • Metallothionein regulates zinc absorption by holding it in
reserve until the body needs zinc-then metallothionein releases it into the blood where it can be transported around • Some Zn reaches the pancreas where it is incorporated into digestive enzymes, released during meals – This Zn is recycled back to the pancreas through enterohepatic Zn circulation
(Rolfest et al 2006) Enterohepatic Zn Circulation (Rolfest et al 2006) Zinc - Metabolic Functions Zn is a component of numerous metalloenzymes (at least 70). E.g:
• Superoxide Dismutase (SOD) –which serves in cell antioxidant
• Alcohol Dehydrogenase – important in the conversion of alcohols
to aldehydes (e.g. breakdown of consumed alcohol) • Carboxypeptidase-secreted by the pancreas needed for the
digestion of protein
• Other enzymes involved in:
– Haem synthesis – Digestion of folate (poor Zn status can diminish folate – Nucleic acid synthesis (DNA, RNA) (Gopper et al 2005) Zinc -Metabolic Functions Zn is also involved in: • Cell growth and cell replication
• Sperm formation
• Bone formation
• Skin integrity
• Cell-mediated immunity
• Carbohydrate metabolism i.e Zn deficiency decreases insulin
response, resulting in impaired glucose tolerance • Basal Metabolic Rate (BMR) i.e. a decrease in thyroid hormones
and BMR has been observed in subjects receiving a zinc-restricted diet (Gopper et al 2005) Zinc - Specific Therapeutics • Zinc deficiency: taking zinc orally prevents and treats zinc
deficiency; however, routine zinc supplementation is not recommended due to mineral-mineral interactions • Acne: taking zinc orally (30mg) might help treat acne;
research suggests that people with acne might have lower serum and skin zinc levels; clinical trials have been small, but most suggest that zinc can improve acne • Age Related Macular Degeneration (AMD): large scale
population studies suggest that increasing dietary intake of
zinc might reduce the risk of developing AMD
(Whitney et al 1998; Goransson et al 1978; Orris et al 1978; Birmingham et al 1994; van Leeuwen et al 2005 ) Zinc - Specific Therapeutics • Attention deficit - hyperactivity disorder (ADHD): taking zinc orally in
combination with conventional treatment might modestly improve
symptoms of hyperactivity, impulsivity, and impaired socialization, but not
attention deficit in some children with ADHD; zinc sulphate 55 mg was
used in those studies (always consult the GP)

• Common cold: using zinc oral lozenges seems to help decrease the
duration of the common cold in adults; the majority of studies show a significant decrease in the duration of symptoms when adults take zinc gluconate or acetate lozenges providing 9-24 mg elemental zinc per dose; lozenges should be taken every 2 hours while awake, starting within 48 hours of symptom onset – However, not all studies have been positive (Akhondzadeh et al 2004; Bilici et al 2004; Godfrey et al 1992; Petrus et al 1998; Douglas et al 1997 ) Zinc - Specific Therapeutics • Hypogeusia (lack of taste): taking zinc orally (25mg)
might be effective for taste dysfunction in some patients with zinc depletion • Osteoporosis: lower dietary zinc intake and zinc
serum levels seem to be associated with lower bone mineral density (BMD) in men and women (Henkinet al 1976; Atik 1983) Zinc - Deficiency Zn deficiency can be caused by: • A diet very high in unrefined grains and unleavened breads due to their high phytate content with little Zn-rich food sources like meats or pulses • Bread fermentation increases Zn absorption • Malabsorption • Increased losses via urinary, pancreatic or secretions (Mahan and Escott-Stump 2008) Zinc- Deficiency Symptoms include: • Short stature
• Decreased taste acuity – loss of taste or smell
• Delayed wound healing, skin lesions, itchy skin
• Alopecia (hair loss)
• Alcohol intolerance
• Immune system impairment (even mild Zn deficiency)
– decreased immune cell activity, atrophy of the thymus • Anorexia nervosa, depression, over the top stress response, learning disorders, poor memeory • Reproductive disorders, infertility, stretch marks
• Hypogonadism
• Mild anaemia (which may reflect coexisitng Fe deficiency from the
(Mahan and Escott-Stump 2008; Osiecki 2004) Factors That Might Affect Individual • Groups at increased risk of insufficiency: • Patients with alcoholism • Pregnant women • Older adults • Athletes • Insufficiency symptoms may include: • Sleep disturbances, slow wound healing, dandruff, reduced appetite, skin disorders (Mahan and Escott-Stump 2008) • High doses (40-45-mg) of Zn may cause: • Vomiting • Diarrhoea • Headaches • Exhaustion
Tolerable Upper Intake Level for Adults: 40mg/day –
based on the interference with copper metabolism-
an effect that in animals leads to degeneration of
the heart muscle!
(Rolfes et al 2006) Zinc - Drug Interactions • Penicillamine (used as a form of immunosuppression to
treat rheumatoid arthritis) : Zinc forms an insoluble
complex with penicillamine, interfering with penicillamine
absorption and activity
• Quinolone Antibiotics and Tetracyclin Antibiotics:
quinolones and tetracyclins form complexes with zinc in the gastrointestinal tract, reducing absorption their absorption and that of and zinc if taken at the same time ( Brewer et al 1993; Lomaestro et al 1995; Neuvonen et al 1976) • Phosphorus (P) is the second most abundant mineral in the body • About 85% of it is found combined with Ca in the hydroxyapatite crystals of bones and teeth • Phosphorus is never found free in nature • It is mostly found bound to oxygen as phosphate (Strain and Cashman 2002; Rolfes et al 2006) Food Sources of Phosphorus • Phosphate is an essential constituent of all known plant and animal tissues and thus widely distributed in all foods • Diets that provide enough energy and protein also supply adequate phosphorus-dietary deficiencies of
phosphorus are unknown

• Foods especially rich in phosphorus include: – Beans and legumes – Dairy – Meats – Processed foods (especially soft-drinks) (Strain and Cashman 2002; Rolfes et al 2006) Recommended Dietary Allowances Irish Recommendations (1983, revised
Males 11-14 years Recommended Dietary Allowances Irish Recommendations (1983, revised
Reference Nutrient Intakes • The RDA for phosphorus for adults =700mg/day • No adverse effects of high dietary phosphorus intakes have been reported – In the past a high intake of dietary phosphorus (mostly from soft drinks) was blamed for bone loss; today we know that it is the displacement of calcium-rich foods by soft drinks and not their phosphorus content that is responsible for bone loss – Tolerable Upper Intake Level for Adults: 4000mg/day

Phosphorus Sources in Selected Foods (Linus Pauling Institute 2011) Phosphorus (mg)
Yogurt, plain nonfat Cheese, mozzarella; part skim Bread, whole wheat Bread, enriched white Carbonated cola drink
Dosage of Phosphorus • RDAs – see table • Supplemental Range: (Osiecki 2004; FSA 2007; EUFIC 2011) Phosphorus - Availability and Absorption • P absorption ranges from 50-70% • There appears to be no adaptive mechanism to improve P absorption at low intakes (unlike Ca) • P absorption is reduced by aluminium-containing antacids and excessive calcium carbonate supplementation (Strain and Cashman 2002) Phosphorus- Metabolic Functions Anything requiring Phosphate: • Bone growth • Intracellular fluids • Calcium homeostasis, maintains blood pH • Component of DNA & RNA, Phosphoproteins/lipids (cell membranes), nucleic acids • Energy metabolism, ATP (adenosine tri-phosphate) • Muscle contraction, creatine phosphate • Phosphorylation reactions (Linus Pauling Institute 2011; Osiecki 2004) Phosphorus- Toxicity • Phosphorus intakes from natural foods will not lead to • However, phosphorus from regular consumption of processed foods (as additives, mainly soft drinks) could possible lead to hyperphosphataemia (high P in the blood) • This could result in decreased Ca absorption as P can complex Ca in the chyme • Polyphosphates from food additives can interfere with Zn, Cu and Fe absorption (Rolfes et al 2006; Strain and Cashman 2002) Introduction/Absorption

• Potassium (K) is the principal cation inside the body
• Potassium, sodium and chloride comprise the
principal electrolytes within the body
• More than 90% of potassium is absorbed from the diet – Olive oil can increase the absorption – Fibre can slightly decrease the absorption (Strain and Cashman 2002; Rolfes et al 2006) Food Sources of Potassium Potassium is widely distributed in natural, unprocessed foods, the richest sources are fruits and vegetables: Dates and raisins Almonds and sunflower seeds Herring and sardines Food processing (leaching) and the addition of salt decreases K content (Strain and Cashman 2002; Osiecki 2004) Reference Nutrient Intakes • Adult requirements are estimated to be 2g/day • However, due to the high salt content of the Western diet, 3.5g-4.7/day is thought to be more adequate • In order to meet this requirement, more fruits and vegetables need to be added to a typical Western diet • Intakes of more than 6g may be dangerous for people with impaired renal function

(Strain and Cashman 2002; Rolfes et al 2006) Recommended Dietary Allowances Irish Recommendations (1983, revised
Males 11-14 years Recommended Dietary Allowances Irish Recommendations (1983, revised
Potassium in Foods and Dosages • EU RDA for an adult Potassium Content in 100mg
is 2000mg per day Pinto Beans
• Supplemental Range: Banana
Winter Squash
Cheddar Cheese
Corn Flakes
(Geissler and Powers 2005; FSA 2007; USDA 2009) Potassium Metabolism • An average 70kg male contains ca. 120g of • Various hormonal factors regulate potassium – In hyperkalaemia: insulin, aldosterone and
adrenaline promote uptake of K by body cells; aldosterone promotes K kidney excretion – In hypokalaemia: potassium is released from the
(Strain and Cashman 2002) Potassium - Metabolic Functions • Potassium, together with sodium and chloride, is the major determinant of osmotic pressure and electrolyte balance

• The concentration difference of potassium and sodium across cell membranes is – Nerve transmission
– Muscle function
• Potassium is a cofactor for enzymes involved in energy
metabolism, glycogenesis, cellular growth and division
(Rolfes et al 2006) Potassium Deficiency Potassium deficiency symptoms: • Muscle cramps • Muscle fatigue and weakness • Irregular heartbeat • Fatigue mental • Mental confusion • Irritability • Abnormally dry skin • Insatiable thirst • Insomnia • Diarrhoea • Low blood pressure Strain and Cashman 2002) Potassium - Specific Therapeutics – Low potassium intakes contribute to the development of high blood pressure – High food potassium intakes (fruits, vegetables, beans) both prevent and correct hypertension – Potassium rich fruits and vegetables also appear to reduce the risk of stroke-more so than can be explained by the reduction in blood pressure alone – Decreasing salt intake combined with increasing K intake is more effective in correcting hypertension than decreasing salt intake alone (Rolfes et al 2006; Strain and Cashman 2002) Potassium - Deficiency • Potassium levels are very tightly regulated by homeostatic mechanisms • Deficiency results from excessive losses rather than deficient intakes: • Hypokalaemia (low K levels in plasma) can result from:
• Cushing's disease (excess steroids) • Diuretics that enhance potassium loss • Chronic renal disease • Diarrhoea • Vomiting • Laxative abuse (Strain and Cashman 2002) Potassium - Toxicity • Potassium toxicity does not result from overeating foods high in potassium; therefore Upper Level was not set: • It can result from: overconsumption of potassium salts or supplements (including some ‘energy fitness shakes') or certain diseases and treatments • Excess potassium from supplements can stop the heart; try increase potassium levels with foods!
• Acute: cardiac arrhythmias, CNS paralysis, diarrhoea, fever,
polydipsia, renal necrosis, convulsions
• Chronic: cardiac and CNS depression, paralytic extremities, mental
confusion, tingling, weakness, cardiac arrest, kidney failure, dehydration, adrenal insufficiency. (Rolfes et al 2006; Osiecki 2004) Sodium and Chloride • One of the sodium salts-sodium chloride (table salt) is the major source of sodium in foods • Sodium and chloride intakes in humans are closely matched • Salt was of major importance in early civilisations and in prehistory • Humans have special taste and salt appetite systems – This led to special culinary uses for salt • Nowadays salt is used to modify flavour, alter the texture and control microbial growth in foods (Strain and Cashman 2002) Sodium & Chloride • Sodium and chloride are present in most natural foods • However the richest sources of both sodium and chloride are processed foods, where NaCl has been added (Strain and Cashman 2002) Reference Nutrient Intakes Diets consisting of natural foods (with no salt added
at all) will provide adequate amounts of both sodium
and chloride!

• Average minimum requirements for sodium-500mg/day • Average minimum requirements for chloride-750mg/day • Average Western sodium intake – 2000-14000 mg/day (with chloride following sodium intake slightly in excess) • Recommended maximum sodium intake: 2300mg/day (Strain and Cashman 2002; Rolfes et al 2006) Sodium Intake in Various Populations there is almost
hypertension
among those
communities
Japan in the
highest rates
and therefore
strokes in the
(Strain and Cashman 2002) Sodium Content of Food & RDAs EU has no established RDA for sodium Sodium Content in 100gm
Crisp bread (Wheat) 264mg Adults < 18yrs (Geissler and Powers 2005; Osiecki 2004; FSA 2007; USDA 2009) Sodium and Chloride : Absorption and • Sodium (Na) is the major extracellular electrolyte and exists as a water-soluble cation: Na+ • Chloride (Cl) is also mainly found in extracellular fluid as the chloride anion Cl- • Both are easily absorbed from the digestive tract (95-
100% absorption rate) • Average 70kg male has about 90g sodium with up to 75% contained in the mineral apatite of bone

(Strain and Cashman 2002) Sodium and Chloride : Metabolism • Plasma sodium is tightly regulated through a hormone system,
which also regulates water balance, pH and osmotic pressure • Angiotensin and aldosterone: conserve sodium by increasing
sodium reabsorption by the kidney • When Na levels go down, renin is secreted that generates active
angiotensin in the circulation, which:
– Stimulates vasoconstriction – Increases blood pressure – Decreases water loss – Stimulates aldosterone release (Strain and Cashman 2002) Sodium and Chloride : Metabolism • Atrial natriuretic hormone counteracts sodium retention
mechanisms by suppressing renin, aldosterone and angiotensin release • A raised plasma sodium stimulates the release of antidiuretic hormone that stimulates renal
reabsorption of water
• Chloride is passively distributed throughout the body and moves to replace anions lost from cells via other processes (Strain and Cashman 2002) Sodium and Chloride : Metabolic Functions • Sodium is a principal cation of the extracellular fluid and the primary active regulator of its volume; chloride is a
passive regulator of the volume

• Na and Cl help maintain acid-base balance
• Na is essential in nerve impulse transmission
• Na helps in muscle contraction
• Chloride is a constituent of a hydrochloric stomach
(Rolfes et al 2006) Specific Therapeutics Sodium & Blood Volume (Rolfes et al 2006) Specific Therapeutics Sodium & Blood Volume Sodium is considered the primary factor responsible for high blood pressure Salt (NaCl) has a greater effect on blood pressure than either sodium or chloride alone Certain individuals appear to be particularly sensitive to high salt intakes: – Those with family history of hypertension
– Those with chronic kidney disease
– Those with diabetes
– People of African origin
– People over 50
– Overweight people
– Additionally, low Ca, K, and Mg intakes encourage the
Na-induced hypertension (Strain and Cashman 2002) NaCl & Evolution – During the long period of human evolution no salt was added to
foods and therefore the body has evolved a very efficient
mechanism conserving sodium
– At the same time, potassium intake was high and humans
have developed efficient mechanisms to excrete excess K – K: Na ratio in the original human diet: 10:1
– K: Na ratio in the Western diet: 1:3 (!)
(Frasetto et al 2001) NaCl & Evolution processed
is, the less
more Na it
contains
(Strain and Cashman 2002) NaCl and Evolution – Humans are better adapted physiologically to the diet our ancestors were exposed to during millions of years of hominid evolution – Mismatch between our genetically determined nutritional requirements and our current diet: • The deficiency of potassium alkali salts (K-base) (present in
plant foods that our ancestors ate in abundance) • The exchange of those salts for sodium chloride (NaCl)
– This results in an increase of the net systemic acid load- chronic
metabolic acidosis imposed by the Western diet
(Frasetto et al 2001) NaCl and Evolution • It is thought that a lifetime of eating diets that deliver evolutionarily superphysiologic loads of acid to the body contribute to chronic metabolic acidosis that leads to:
• Decrease in bone mass
– metabolic acidosis increases urinary Ca excretion • Increase the risk of kidney stones
– excess urinary Ca can promote stone formation • Decrease in muscle mass
– metabolic acidosis increases muscle protein degradation • Decrease of growth hormone secretion
(Frasetto et al 2001) The Effects of Processing on Na/K Content (Rolfes et al 2006) Sodium and Chloride : Deficiency Deficiency of sodium and chloride is very difficult to induce as the human body is very efficient at conserving sodium Low plasma sodium can be caused by a variety of clinical conditions: • Major trauma • Cachexia (wasting condition seen in advanced cancer patients) • Overuse of diuretics • Anorexia nervosa • Excessive water intake • Liver disease • Ulcerative colitis • Persistent diarrhoea Low plasma chloride can be caused by : • Vomiting • Chronic renal disease • Renal failure (Strain and Cashman 2002) Sodium and Chloride: Toxicity • Ingestion of 1 ounce (28gm) of table salt (NaCl) was a traditional way to commit suicide in China • Excessive salt intakes can contribute to: • Hypertension • Coronary artery disease • Stroke • Stomach cancer • Osteoporosis • Asthma (Rolfes et al 2006 )

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