|
|
| |
Magnesium
This section was compiled by Frank M. Painter, D.C. Send all comments or additions to:
Frankp@chiro.org
If there are terms in these articles you don't understand, you can get a definition from the Merriam Webster Medical Dictionary. If you want information about a specific disease, you can access the Merck Manual. You can also search Pub Med for more abstracts on this, or any other health topic.
|
|
|
|
|
|
|
| |
Dietary surveys suggest that many Americans do not consume magnesium in the recommended amounts. Treatment with diuretics (water pills), some antibiotics, and some medicines used to treat cancer, such as Cisplatin, can increase the loss of magnesium in urine. Other causes of magnesium loss and deficiency include sweating, poorly controlled diabetes and alcohol use. Signs of magnesium deficiency include confusion, disorientation, loss of appetite, depression, muscle contractions and cramps, tingling, numbness, abnormal heart rhythms, coronary spasm, and seizures.
|
|
|
|
|
|
|
| |
|
Magnesium Status and Stress: The Vicious Circle Concept Revisited
Nutrients 2020 (Nov 28); 12 (12): pii: E3672
To conclude, while there is good evidence from animal and human studies of the bi-directional link between magnesium and stress, further research is needed to better understand the impact of this correlation and the benefit of magnesium supplementation on general health. Additional studies should apply standard methodologies (e.g., magnesium load test) to evaluate the magnesium status in well-characterized stressed population. These studies would help to demonstrate the increased need of magnesium supplementation during stress periods, and further strengthen our initial hypothesis. Further, in line with the GUTS model, repetitive negative thinking could be considered as a cognitive indicator of stress and evaluated in relation to blood magnesium levels in a cohort of subjects exposed to chronic stress. Given the strong association of stress with mental and physical diseases, these studies are fundamental to further support adequate magnesium dietary needs.
|
|
Effect of Oral Magnesium Supplementation On Physical Performance
in Healthy Elderly Women Involved in a Weekly Exercise Program:
A Randomized Controlled Trial
pii: ajcn.080168. [Epub ahead of print]
At baseline, the SPPB scores did not differ between the 2 groups. After 12 wk, the treated group had a significantly better total SPPB score (Δ = 0.41 ± 0.24 points; P = 0.03), chair stand times (Δ = -1.31 ± 0.33 s; P < 0.0001), and 4-m walking speeds (Δ = 0.14 ± 0.03 m/s; P = 0.006) than did the control group.
|
|
Can Magnesium Cure Migraines?
Nutrition Science News (March 2000)
About 18 million women and some 5 million men in the United States suffer from migraine headaches. Only about a third are satisfied with their treatments, which can range from over-the-counter headache remedies to serotonin receptor antagonists, beta-blockers and calcium antagonists. Many of these prescription drugs come with an array of side effects. But what if a mineral could make a difference for migraine sufferers?
|
General Magnesium Information:
|
Consequences of Magnesium Deficiency on the Enhancement of Stress Reactions; Preventive and Therapeutic Implications (A Review)
Magnesium Metabolism in Health and Disease
Vitamin and Mineral Deficiencies Which May Predispose to Glucose Intolerance of Pregnancy
The Pathogenesis of Eclampsia: The 'Magnesium Ischaemia' Hypothesis
Effects of a Combination of Evening Primrose Oil (Gamma linolenic acid) and Fish Oil (Eicosapentaenoic + Docahexaenoic acid) versus Magnesium, and versus Placebo in Preventing Pre-eclampsia
Intakes of Vitamins and Minerals by Pregnant Women with Selected Clinical Symptoms
Magnesium and Premenstrual Syndrome:
|
Clinical and Biochemical Effects of Nutritional Supplementation on the Premenstrual Syndrome
Plasma Copper, Zinc and Magnesium Levels in Patients with Premenstrual Tension Syndrome
Oral Magnesium Successfully Relieves Premenstrual Mood Changes
Magnesium and Heart Disease:
|
Magnesium and Sudden Death
An Expanded Concept of "Insurance": Supplementation--Broad-spectrum
Protection from Cardiovascular Disease
Magnesium in Supraventricular and Ventricular Arrhythmias
Trace Elements in Prognosis of Myocardial Infarction and Sudden Coronary Death
Deficiency of Certain Trace Elements in Children With Hyperactivity
Magnesium and Glucose Regulation:
|
Daily Magnesium Supplements Improve Glucose Handling in Elderly Subjects
Magnesium and Carbohydrate Metabolism
Magnesium Intake and Risk of Type 2 Diabetes in Men and Women
Magnesium and Potassium in Diabetes and Carbohydrate Metabolism. Review of the Present Status and Recent Results
Hypertension, Diabetes Mellitus, and Insulin Resistance: The Role of Intracellular Magnesium
Skeletal Muscle Magnesium and Potassium in Asthmatics Treated with Oral Beta2-agonists
Bronchial Reactivity and Dietary Antioxidants
See also:
Research Perspectives in Asthma: A Rationale for the Therapeutic Application of Magnesium, Pyridoxine, Coleus forskholii and Ginkgo biloba in the Treatment of Adult and Pediatric Asthma
The Internist 1998; 5 (3) Sept: 14–16 ~ FULL TEXT
Magnesium and Chronic Fatigue Syndrome aka Fibromyalgia:
|
Complementary and Alternative Medical Therapies in Fibromyalgia
Magnesium Deficit in a Sample of the Belgian Population Presenting with Chronic Fatigue
Selenium and Magnesium Status in Fibromyalgia
Magnesium and Osteoporosis:
|
Magnesium Deficiency: Possible Role in Osteoporosis Associated with Gluten-sensitive Enteropathy
Magnesium Supplementation and Osteoporosis
Calcium, Phosphorus and Magnesium Intakes Correlate with Bone Mineral Content in Postmenopausal Women
Magnesium and Other Ailments:
|
Magnesium Taurate and Fish Oil for Prevention of Migraine
Prophylaxis of Migraine with Oral Magnesium: Results from a
Prospective, Multi-center, Placebo-controlled and Double-blind Randomized Study
Electromyographical Ischemic Test and Intracellular and Extracellular Magnesium Concentration in Migraine and Tension-type Headache Patients
Experimental and Clinical Studies on Dysregulation of Magnesium
Metabolism and the Aetiopathogenesis of Multiple Sclerosis
Amyotrophic Lateral Sclerosis--Causative Role of Trace Elements
Nutrient Intake of Patients with Rheumatoid Arthritis is Deficient in Pyridoxine, Zinc, Copper, and Magnesium
|
|
|
|
|
|
| |
General Magnesium Information:
|
Consequences of Magnesium Deficiency on the Enhancement of Stress Reactions; Preventive and Therapeutic Implications (A Review)
J Am Coll Nutr 1994 (Oct); 13 (5): 429-446
Stress intensifies release of catecholamines and corticosteroids
that increase survival of normal animals when their lives are
threatened. When magnesium (Mg) deficiency exists, stress
paradoxically increases risk of cardiovascular damage including
hypertension, cerebrovascular and coronary constriction and
occlusion, arrhythmias and sudden cardiac death (SCD). In
affluent societies, severe dietary Mg deficiency is uncommon, but
dietary imbalances such as high intakes of fat and/or calcium
(Ca) can intensify Mg inadequacy, especially under conditions of
stress. Adrenergic stimulation of lipolysis can intensify its
deficiency by complexing Mg with liberated fatty acids (FA), A
low Mg/Ca ratio increases release of catecholamines, which lowers
tissue (i.e. myocardial) Mg levels. It also favors excess release
or formation of factors (derived both from FA metabolism and the
endothelium), that are vasoconstrictive and platelet aggregating;
a high Ca/Mg ratio also directly favors blood coagulation, which
is also favored by excess fat and its mobilization during
adrenergic lipolysis. Auto-oxidation of catecholamines yields
free radicals, which explains the enhancement of the protective
effect of Mg by anti-oxidant nutrients against cardiac damage
caused by beta-catecholamines. Thus, stress, whether physical
(i.e. exertion, heat, cold, trauma--accidental or surgical,
burns), or emotional (i.e. pain, anxiety, excitement or
depression) and dyspnea as in asthma increases need for Mg.
Genetic differences in Mg utilization may account for differences
in vulnerability to Mg deficiency and differences in body
responses to stress.
Back to the Top
Magnesium Metabolism in Health and Disease
DIS. MON. (USA), 1988, 34/4 (166-218)
Magnesium is an important element for health and disease.
Magnesium, the second most abundant intracellular cation, has
been identified as a cofactor in over 300 enzymatic reactions
involving energy metabolism and protein and nucleic acid
synthesis. Approximately half of the total magnesium in the body
is present in soft tissue, and the other half in bone. Less than
1% of the total body magnesium is present in blood. Nonetheless,
the majority of our experimental information comes from
determination of magnesium in serum and red blood cells. At
present, we have little information about equilibrium among and
state of magnesium within body pools. Magnesium is absorbed
uniformly from the small intestine and the serum concentration
controlled by excretion from the kidney. The clinical laboratory
evaluation of magnesium status is primarily limited to the serum
magnesium concentration, 24-hour urinary excretion, and percent
retention following parenteral magnesium. However, results for
these tests do not necessarily correlate with intracellular
magnesium. Thus, there is no readily available test to determine
intracellular/total body magnesium status. Magnesium deficiency
may cause weakness, tremors, seizures, cardiac arrhythmias,
hypokalemia, and hypocalcemia. The causes of hypomagnesemia are
reduced intake (poor nutrition or IV fluids without magnesium),
reduced absorption (chronic diarrhea, malabsorption, or
bypass/resection of bowel), redistribution (exchange transfusion
or acute pancreatitis), and increased excretion (medication,
alcoholism, diabetes mellitus, renal tubular disorders,
hypercalcemia, hyperthyroidism, aldosteronism, stress, or
excessive lactation). A large segment of the U.S. population may
have an inadequate intake of magnesium and may have a chronic
latent magnesium deficiency that has been linked to
atherosclerosis, myocardial infarction, hypertension, cancer,
kidney stones, premenstrual syndrome, and psychiatric disorders.
Hypermagnesemia is primarily seen in acute and chronic renal
failure, and is treated effectively by dialysis.
Back to the Top
|
|
|
|
|
|
| |
Vitamin and Mineral Deficiencies Which May Predispose to Glucose Intolerance of Pregnancy
Journal of the American College of Nutrition 1996 (Feb); 15(1):14-20
There is an increased requirement for nutrients in normal
pregnancy, not only due to increased demand, but also increased
loss. There is also an increased insulin resistant state during
pregnancy mediated by the placental anti-insulin hormones
estrogen, progesterone, human somatomammotropin; the pituitary
hormone prolactin; and the adrenal hormone, cortisol. If the
maternal pancreas cannot increase production of insulin to
sustain normoglycemia despite these anti-insulin hormones,
gestational diabetes occurs. Gestational diabetes is associated
with excessive nutrient losses due to glycosuria. Specific
nutrient deficiencies of chromium, magnesium, potassium and
pyridoxine may potentiate the tendency towards hyperglycemia in
gestational diabetic women because each of these four
deficiencies causes impairment of pancreatic insulin production.
This review describes the pathophysiology of the hyperglycemia
and the nutrient loss in gestational diabetes and further
postulates the mechanism whereby vitamin/mineral supplementation
may be useful to prevent or ameliorate pregnancy-related glucose
intolerance.
Back to the Top
The Pathogenesis of Eclampsia: The 'Magnesium Ischaemia' Hypothesis
Med Hypotheses 1993 (Apr); 40 (4): 250-256
'Magnesium ischaemia' is a term used to denote the functional
impairment of the ATP-dependent sodium/potassium and calcium
pumps in the cell membranes and within the cell itself. The
production of ATP and the functioning of these pumps is
magnesium-dependent and is critically sensitive to acidosis. Zinc
and iron deficiencies may secondarily impair these pumps and thus
contribute to 'magnesium ischaemia' (as does acidosis). This term
is two-dimensional at its simplest; it refers to a functional
magnesium deficiency, whether actual or induced. It is argued
that chronic acidosis is the most common inducing factor. This
simple hypothesis can begin to unify diverse pathophysiologies:
some spontaneous abortions, aspects of Type II and gestational
diabetes and the curious observation that heroin addicts become
diabetic. It can also unify clinical thinking about
pregnancy-induced hypertension, pre-eclampsia/eclampsia and acute
fatty liver of pregnancy, as well as the coagulopathy of
pregnancy. It makes important predictions about perinatal
morbidity and suggests that early supplementation might prevent
much pregnancy-induced disease.
Back to the Top
Effects of a Combination of Evening Primrose Oil (Gamma linolenic acid) and Fish Oil (Eicosapentaenoic + Docahexaenoic acid) versus Magnesium, and versus Placebo in Preventing Pre-eclampsia
Women Health 1992; 19 (2-3): 117-131
In a placebo controlled, partially double-blinded, clinical
trial, a combination of evening primrose oil and fish oil was
compared to Magnesium Oxide, and to a Placebo in preventing
Pre-Eclampsia of Pregnancy. All were given as nutritional
supplements for six months to a group of primiparous and
multiparous pregnant women. Some of these women had personal or
family histories of hypertension (21%). Only those patients who
received prenatal care at the Central Maternity Hospital for
Luanda were included in the study. Compared to the Placebo group
(29%), the group receiving the mixture of evening primrose oil
and fish oil containing Gamma-linolenic acid (GLA),
Eicosapentaenoic acid (EPA), and Docosahexaenoic acid (DHA) had a
significantly lower incidence of edema (13%, p = 0.004). The
group receiving Magnesium Oxide had statistically significant
fewer subjects who developed hypertension of pregnancy. There
were 3 cases of eclampsia, all in the Placebo group.
Back to the Top
Intakes of Vitamins and Minerals by Pregnant Women with Selected Clinical Symptoms
J Am Diet Assoc 1981 (may); 78 (5): 477-482
Toxemia in pregnancy is characterized by a combination of at
least two of the following clinical symptoms: hypertension,
edema, and proteinuria. In this study the dietary intakes of
young pregnant women attending a Maternal and Infant Care Program
at Tuskegee Institute were evaluated for selected vitamins and
minerals. Women with toxemia were identified, and women without
toxemia served as controls. The toxemia group generally consumed
lesser amounts of vitamins and minerals than the controls.
However, both groups were deficient (less than two-thirds RDA) in
calcium, magnesium, vitamin B6, vitamin B12, and thiamin. Milk,
meat, and grains supplied an appreciable proportion of each
vitamin except vitamin A, which was found primarily in the two
vegetable groups. Meat and grains contained the greatest
quantities of minerals, but milk provided a relatively good
proportion of potassium, calcium, magnesium, and phosphorus.
Anemia was not related to the incidence of toxemia. Women
exhibiting anemia consumed smaller amounts of vitamins studied
than did women without anemia.
Back to the Top
|
|
|
|
|
|
| |
Magnesium and Premenstrual Syndrome:
|
Clinical and Biochemical Effects of Nutritional Supplementation on the Premenstrual Syndrome
J Reprod Med1987 (Jun); 32 (6): 435-441
Many different treatments have been suggested for the premenstrual syndrome (PMS), including such nutritional supplements as vitamins, minerals and essential fatty acids. There is little agreement about the causes or treatments of the syndrome. The effect of a nutritional supplement, at high and low dosage, on premenstrual symptoms was assessed in a double-blind, placebo-controlled study. Also, the nutritional state of 11 women with PMS was evaluated. There was laboratory evidence of significant deficiencies in vitamin B6 and magnesium; other deficiencies occurred frequently, also. The multivitamin/multimineral supplement was shown to correct some of these deficiencies and, at the appropriate dosage, to improve the symptoms of premenstrual tension.
Back to the Top
Plasma Copper, Zinc and Magnesium Levels in Patients with Premenstrual Tension Syndrome
Acta Obstet Gynecol Scand 1994 (Jul); 73 (6): 452-5
We measured plasma Cu, Zn and Mg levels in 40 women suffering
from premenstrual tension syndrome (PMTS) and in 20 control
subjects by atomic absorption spectrophotometer. Mean plasma Cu,
Zn and Mg levels, the Zn/Cu ratio were 80.2 plus or minus 6.00
microg/dl, 112.6 plus or minus 8.35 microg/dl, 0.70 plus or minus
0.18 mmol/l, and 1.40 plus or minus 0.10 in the PMTS group; and
77.0 plus or minus 4.50 microg/dl, 117.4 plus or minus 9.50
microg/dl, 0.87 plus or minus 0.10 mmol/l, and 1.51 plus or minus
0.05 in the control group respectively. The mean Mg level and the
Zn/Cu ratio were significantly lower in PMTS patients than in the
control group. Plasma Mg and Zn levels were diminished
significantly during the luteal phase compared to the follicular
phase in PMTS group. Mg deficiency may play a role in the
etiology of PMTS.
Back to the Top
Oral Magnesium Successfully Relieves Premenstrual Mood Changes
Obstet Gynecol 1991 (Aug); 78 (2): 177-81
Reduced magnesium (Mg) levels have been reported in women
affected by premenstrual syndrome (PMS). To evaluate the effects
of an oral Mg preparation on premenstrual symptoms, we studied,
by a double-blind, randomized design, 32 women (24-39 years old)
with PMS confirmed by the Moos Menstrual Distress Questionnaire.
After 2 months of baseline recording, the subjects were randomly
assigned to placebo or Mg for two cycles. In the next two cycles,
both groups received Mg. Magnesium pyrrolidone carboxylic acid
(360 mg Mg) or placebo was administered three times a day, from
the 15th day of the menstrual cycle to the onset of menstrual
flow. Blood samples for Mg measurement were drawn premenstrually,
during the baseline period, andin the second and fourth months of
treatment. The Menstrual Distress Questionnaire score of the
cluster 'pain' was significantly reduced during the second month
in both groups, whereas Mg treatment significantly affected both
the total Menstrual Distress Questionnaire score and the cluster
'negative affect'. In the second month, the women assigned to
treatment showed a significant increase in Mg in lymphocytes and
polymorphonuclear cells, whereas no changes were observed in
plasma and erythrocytes. These data indicate that Mg
supplementation could represent an effective treatment of
premenstrual symptoms related to mood changes.
Back to the Top
|
|
|
|
|
|
| |
Magnesium and Heart Disease:
|
Magnesium and Sudden Death
S Afr Med J 1983 (Nov 12); 64 (21): 820-2
Magnesium deficiency may result from reduced dietary intake of
the ion increased losses in sweat, urine or faeces. Stress
potentiates magnesium deficiency, and an increased incidence of
sudden death associated with ischaemic heart disease is found in
some areas in which soil and drinking water lack magnesium.
Furthermore, it has been demonstrated experimentally that
reduction of the plasma magnesium level is associated with
arterial spasm. Careful studies are required to assess the
clinical importance of magnesium and the benefits of magnesium
supplementation in man.
Back to the Top
An Expanded Concept of "Insurance": Supplementation-- Broad-spectrum Protection from Cardiovascular Disease
Med Hypotheses 1981 (Oct); 7 (10): 1287-1302
The preventive merits of "nutritional insurance" supplementation
can be considerably broadened if meaningful doses of nutrients
such as mitochondrial "metavitamins" (coenzyme Q, lipoic acid,
carnitine), lipotropes, and key essential fatty acids, are
included in insurance supplements. From the standpoint of
cardiovascular protection, these nutrients, as well as magnesium,
selenium, and GTF-chromium, appear to have particular value.
Sophisticated insurance supplementation would likely have a
favorable impact on many parameters which govern cardiovascular
risk--serum lipid profiles, blood pressure, platelet stability,
glucose tolerance, bioenergetics, action potential
regulation--and as a life-long preventive health strategy might
confer substantial benefit.
Back to the Top
Magnesium in Supraventricular and Ventricular Arrhythmias
Zeitschrift fur Kardiologie 1996; 85 Suppl 6: 135-145
The use of magnesium as an antiarrhythmic agent in ventricular and supraventricular arrhythmias is a matter of an increasing but still controversial discussion during recent years. With regard to the well established importance of magnesium in experimental studies for preserving electrical stability and function of myocardial cells and tissue, the use of magnesium for treating one or the other arrhythmia seems to be a valid concept. In addition, magnesium application represents a physiologic approach, and by this, is simple, cost-effective and safe for the patient. However, when one reviews the available data from controlled studies on the antiarrhythmic effects of magnesium, there are only a few types of cardiac arrhythmias, such as torsade de pointes, digitalis-induced ventricular arrhythmias and ventricular arrhythmias occurring in the presence of heart failure or during the perioperative state, in which the antiarrhythmic benefit of magnesium has been shown and/or established. Particularly in patients with one of these types of cardiac arrhythmias, however, it should be realized that preventing the patient from a magnesium deficit is the first, and the application of magnesium the second best strategy to keep the patient free from cardiac arrhythmias.
Back to the Top
Trace Elements in Prognosis of Myocardial Infarction and Sudden Coronary Death
Journal of Trace Elements in Experimental Medicine (USA), 1996,
9/2 (57-62)
Ca, Cu, Mg, Mn, and Zn concentrates were measured in plasma, RBC,
and hair of 350 men aged 40-59 years with myocardial infarction
(MI) and/or who died from sudden cardiac death (SCD), as compared
with normal controls. Analyses were done by flame atomic
absorption spectrophotometry. Cu in plasma of MI patients was
significantly higher than the controls'. Plasma Mn was
significantly lower in SCD than in MI subjects. No other
consistent and significant changes were observed. Past and
present evidence indicates that high plasma Cu levels may be
associated with heart failure and rhythm disorders. The low
plasma Mn levels may be an indicator of decreased parasympathetic
tonus thus favouring myocardial desynchronization and A-V block.
Cu inhibits phosphodiesterase activity and Mn inhibits andenylate
cyclase activity thus exerting an influence on the contractility
of cardiomyocites and of smooth muscle cells in coronary
arteries. Cu and Mn analyses may thus have a prognostic
significance for MI and SCD.
Back to the Top
|
|
|
|
|
|
| |
Deficiency of Certain Trace Elements in Children with Hyperactivity
Psychiatr Pol (POLAND) May-Jun 1994, 28 (3) p345-53
The magnesium, zinc, copper, iron and calcium level of plasma,
erythrocytes, urine and hair in 50 children aged from 4 to 13
years with hyperactivity, were examined by AAS. The average
concentration of all trace elements was lower compared with the
control group-healthy children from Szczecin. The highest deficit
was noted in hair. Our results show that it is necessary to
supplement trace elements in children with hyperactivity.
Back to the Top
|
|
|
|
|
|
| |
Magnesium and Glucose Regulation:
|
Daily Magnesium Supplements Improve Glucose Handling in Elderly Subjects
Am J Clin Nutr 1992 (Jun); 55 (6): 1161-1167
We demonstrated similar plasma concentrations and urinary losses but lower erythrocyte magnesium concentrations (2.18 +/- 0.04 vs 1.86 +/- 0.03 mmol/L, P less than 0.01) in twelve aged (77.8 +/- 2.1 y) vs 25 young (36.1 +/- 0.4 y), nonobese subjects. Subsequently, aged subjects were enrolled in a double-blind, randomized, crossover study in which placebo (for 4 wk) and chronic magnesium administration (CMA) (4.5 g/d for 4 wk) were provided. At the end of each treatment period an intravenous glucose tolerance test (0.33 g/kg body wt) and a euglycemic glucose clamp with simultaneous [D-3H]glucose infusion and indirect calorimetry were performed. CMA vs placebo significantly increased erythrocyte magnesium concentration and improved insulin response and action. Net increase in erythrocyte magnesium significantly and positively correlated with the decrease in erythrocyte membrane microviscosity and with the net increase in both insulin secretion and action. In aged patients, correction of a low erythrocyte magnesium concentration may allow an improvement of glucose handling.
Back to the Top
Magnesium and Carbohydrate Metabolism
THERAPIE (France), 1994, 49/1 (1-7)
The interrelationships between magnesium and carbohydrate
metabolism have regained considerable interest over the last few
years. Insulin secretion requires magnesium: magnesium deficiency
results in impaired insulin secretion while magnesium replacement
restores insulin secretion. Furthermore, experimental magnesium
deficiency reduces the tissues sensitivity to insulin.
Subclinical magnesium deficiency is common in diabetes. It
results from both insuficient magnesium intakes and increase
magnesium losses, particularly in the urine. In type 2, or
non-insulin-dependent, diabetes mellitus, magnesium deficiency
seems to be associated with insulin resistance. Furthermore, it
may participate in the pathogenesis of diabetes complications and
may contribute to the increased risk of sudden death associated
with diabetes. Some studies suggest that magnesium deficiency may
play a role in spontaneous abortion of diabetic women, in fetal
malformations and in the pathogenesis of neonatal hypocalcemia of
the infants of diabetic mothers. Administration of magnesium
salts to patients with type 2 diabetes tend to reduce insulin
resistance. Long-term studies are needed before recommending
systematic magnesium supplementation to type 2 diabetic patients
with subclinical magnesium deficiency.
Back to the Top
Magnesium Intake and Risk of Type 2 Diabetes in Men and Women
Diabetes Care 2004 (Jan); 27 (1): 134-140
OBJECTIVE: To examine the association between magnesium intake and risk of type 2 diabetes.
RESEARCH DESIGN AND METHODS: We followed 85,060 women and 42,872 men who had no history of diabetes, cardiovascular disease, or cancer at baseline. Magnesium intake was evaluated using a validated food frequency questionnaire every 2-4 years. After 18 years of follow-up in women and 12 years in men, we documented 4,085 and 1,333 incident cases of type 2 diabetes, respectively.
RESULTS: After adjusting for age, BMI, physical activity, family history of diabetes, smoking, alcohol consumption, and history of hypertension and hypercholesterolemia at baseline, the relative risk (RR) of type 2 diabetes was 0.66 (95% CI 0.60-0.73; P for trend <0.001) in women and 0.67 (0.56-0.80; P for trend <0.001) in men, comparing the highest with the lowest quintile of total magnesium intake. The RRs remained significant after additional adjustment for dietary variables, including glycemic load, polyunsaturated fat, trans fat, cereal fiber, and processed meat in the multivariate models. The inverse association persisted in subgroup analyses according to BMI, physical activity, and family history of diabetes.
CONCLUSIONS: Our findings suggest a significant inverse association between magnesium intake and diabetes risk. This study supports the dietary recommendation to increase consumption of major food sources of magnesium, such as whole grains, nuts, and green leafy vegetables.
Back to the Top
Magnesium and Potassium in Diabetes and Carbohydrate Metabolism. Review of the Present Status and Recent Results
Magnesium. 1984. 3(4-6). P 315-23
Diabetes mellitus is the most common pathological state in which
secondary magnesium deficiency occurs. Magnesium metabolism
abnormalities vary according to the multiple clinical forms of
diabetes: plasma magnesium is more often decreased than red blood
cell magnesium. Plasma Mg levels are correlated mainly with the
severity of the diabetic state, glucose disposal and endogenous
insulin secretion. Various mechanisms are involved in the
induction of Mg depletion in diabetes mellitus, i.e. insulin and
epinephrine secretion, modifications of the vitamin D metabolism,
decrease of blood P, vitamin B6 and taurine levels, increase of
vitamin B5, C and glutathione turnover, treatment with high
levels of insulin and biguanides. K depletion in diabetes
mellitus is well known. Some of its mechanisms are concomitant to
those of Mg depletion. But their hierarchic importance is not the
same: i.e., insulin hyposecretion is more important versus K+
than versus Mg2+. Insulin increases the cellular inflow of K+
more than that of Mg2+ because there is more free K+ (87%) than
Mg2+ (30%) in the cell. The consequences of the double Mg-K
depletion are either antagonistic: i.e. versus insulin secretion
(increased by K+, decreased by Mg2+) or agonistic i.e. on the
membrane: (i.e. Na+K+ATPase), tolerance of glucose oral load,
renal disturbances. The real importance of these disorders in the
diabetic condition is still poorly understood. Retinopathy and
microangiopathy are correlated with the drop of plasma and red
blood cell Mg. K deficiency increases the noxious cardiorenal
effects of Mg deficiency. The treatment should primarily insure
diabetic control.
Back to the Top
Hypertension, Diabetes mellitus, and Insulin Resistance: The Role of Intracellular Magnesium
Am J Hypertens (UNITED STATES) Mar 1997, 10 (3) p346-55
Magnesium is one of the most abundant ions present in living
cells and its plasma concentration is remarkably constant in
healthy subjects. Plasma and intracellular magnesium
concentrations are tightly regulated by several factors. Among
them, insulin seems to be one of the most important. In fact, in
vitro and in vivo studies have demonstrated that insulin may
modulate the shift of magnesium from extracellular to
intracellular space. Intracellular magnesium concentration has
also been shown to be effective on modulating insulin action
(mainly oxidative glucose metabolism), offset calcium-related
excitation-contraction coupling, and decrease smooth cell
responsiveness to depolarizing stimuli, by stimulating
Ca2+-dependent K+ channels. A poor intracellular magnesium
concentration, as found in non-insulin-dependent diabetes
mellitus (NIDDM) and in hypertensive (HP) patients, may result in
a defective tyrosine-kinase activity at the insulin receptor
level and exaggerated intracellular calcium concentration. Both
events are responsible for the impairment in insulin action and a
worsening of insulin resistance in non-insulin-dependent diabetic
and hypertensive patients. By contrast, in NIDDM patients daily
magnesium administration, restoring a more appropriate
intracellular magnesium concentration, contributes to improve
insulin-mediated glucose uptake. Similarly, in HP patients
magnesium administration may be useful in decreasing arterial
blood pressure and improving insulin-mediated glucose uptake. The
benefits deriving from daily magnesium supplementation in NIDDM
and HP patients are further supported by epidemiological studies
showing that high daily magnesium intake to be predictive of a
lower incidence of NIDDM and HP. In conclusion, a growing body of
studies suggest that intracellular magnesium may play a key role
on modulating insulin-mediated glucose uptake and vascular tone.
We further suggest that a reduced intracellular magnesium
concentration might be the missing link helping to explain the
epidemiological association between NIDDM and hypertension.
Back to the Top
|
|
|
|
|
|
| |
Skeletal Muscle Magnesium and Potassium in Asthmatics Treated with Oral Beta2-agonists
European Respiratory Journal (Denmark), 1996, 9/2 (237-240)
Dietary magnesium has been shown to be important for lung
function and bronchial reactivity. Interest in electrolytes in
asthma has so far mainly been focused upon serum potassium,
especially linked to beta2-agonist treatment. It is known that
serum levels of magnesium and potassium may not correctly reflect
the intracellular status. We therefore investigated whether
asthmatics treated with oral beta2-agonists had low magnesium or
potassium in skeletal muscle and serum, and whether withdrawal of
the oral beta2-agonists would improve the electrolyte levels.
Magnesium and potassium levels in skeletal muscle biopsies, serum
and urine were analysed in 20 asthmatics before and 2 months
after withdrawal of long-term oral beta2-agonists, and for
comparison in 10 healthy subjects. Skeletal muscle magnesium in
the asthmatics was lower both before (3.62plus or minus0.69
mmol-100 g-1 (meanplus or minusSD)) and after (3.43plus or
minus0.60 mmol.100 g-1) withdrawal of oral beta2-agonists
compared with the controls (4.43plus or minus0.74 mmol-100 g-1)
Skeletal muscle potassium and serum magnesium did not differ
between the groups. Serum potassium was significantly lower both
before (4.0plus or minus0.2 mmol.L-1) and after (3.9plus or
minus0.2 mmol.L-1) the withdrawal of oral beta2-agonists compared
with the control group (42plus or minus0.2 mmol.L-1). The
asthmatics had lower skeletal muscle magnesium and lower serum
potassium than the healthy controls, both with and without oral
beta2-agonists. Whether the findings are related to asthma
pathophysiology or treatment is currently being investigated.
Back to the Top
Bronchial Reactivity and Dietary Antioxidants
Thorax (United Kingdom), 1997, 52/2 (166-170)
BACKGROUND - It has been postulated that dietary antioxidants may
influence the expression of allergic diseases and asthma. To test
this hypothesis a case-control study was performed, nested in a
cross sectional study of a random sample of adults, to
investigate the relationship between allergic disease and dietary
antioxidants.
METHODS - The study was performed in rural general practices in
Grampian, Scotland. A validated dietary questionnaire was used to
measure food intake of cases, defined, firstly, as people with
seasonal allergic-type symptoms and, secondly, those with
bronchial hyperreactivity confirmed by methacholine challenge,
and of controls without allergic symptoms or bronchial
reactivity.
RESULTS - Cases with seasonal symptoms did not differ from
controls except with respect to the presence of atopy and an
increased risk of symptoms associated with the lowest intake of
zinc. The lowest intakes of vitamin C and manganese were
associated with more than five-fold increased risks of bronchial
reactivity. Decreasing intakes of magnesium were also
significantly associated with an increased risk of
hyperreactivity.
CONCLUSIONS - This study provides evidence that diet may have a
modulatory effect on bronchial reactivity, and is consistent with
the hypothesis that the observed reduction in antioxidant intake
in the British diet over the last 25 years has been a factor in
the increase in the prevalence of asthma over this period.
Back to the Top
|
|
|
|
|
|
| |
Magnesium and Chronic Fatigue Syndrome aka Fibromyalgia:
|
Complementary and Alternative Medical Therapies in Fibromyalgia
Curr Pharm Des 2006; 12 (1): 47-57
This article describes the studies that have been performed evaluating complementary or alternative medical (CAM) therapies for efficacy and some adverse events fibromyalgia (FM). There is no permanent cure for FM; therefore, adequate symptom control should be goal of treatment. Clinicians can choose from a variety of pharmacologic and nonpharmacologic modalities. Unfortunately, controlled studies of most current treatments have failed to demonstrate sustained, clinically significant responses. CAM has gained increasing popularity, particularly among individuals with FM for which traditional medicine has generally been ineffective. Some herbal and nutritional supplements (magnesium, S- adenosylmethionine) and massage therapy have the best evidence for effectiveness with FM. Other CAM therapies such as chlorella, biofeedback, relaxation have either been evaluated in only one randomised controlled trials (RCT) with positive results, in multiple RCTs with mixed results (magnet therapies) or have positive results from studies with methodological flaws (homeopathy, botanical oils, balneotherapy, anthocyanidins and dietary modifications). Another CAM therapy such as chiropractic care has neither well-designed studies nor positive results and is not currently recommended for FM treatment. Once CAM therapies have been better evaluated for safety and long-term efficacy in randomised, placebo-controlled trials, they may prove to be beneficial in treatments for FM. It would then be important to assess studies assessing cost-benefit analyses comparing conventional therapies and CAM.
Back to the Top
Magnesium Deficit in a Sample of the Belgian Population Presenting with Chronic Fatigue
Magnes Res 1997 (Dec); 10 (4): 329-337
97 patients (25 per cent males, ages ranging from 14 to 73 years, median 38 years) with complaints of chronic fatigue (chronic fatigue syndrome, fibromyalgia or/and spasmophilia) have been enrolled in a prospective study to evaluate the Mg status and the dietary intake of Mg. An IV loading test (performed following the Ryzen protocol) showed a Mg deficit in 44 patients. After Mg supplementation in 24 patients, the loading test showed a significant decrease (p = 0.0018) in Mg retention. Mean values of serum Mg, red blood cell Mg and magnesuria showed no significant difference between patients with or without Mg deficiency. No association was found between Mg deficiency, CFS or FM. However serum Mg level was significantly lower in the patients with spasmophilia than in the other patients.
Back to the Top
Selenium and Magnesium Status in Fibromyalgia
Magnes Res 1994 (Dec); 7 (3-4): 285-288
Muscle pain has been associated with magnesium (Mg) and selenium (Se) deficiency: magnesium and selenium status were investigated in fibromyalgia (FM). Erythrocyte (E), leucocyte (L) and serum (S) magnesium, serum selenium and zinc, and vitamin B1, B2, A or E status were assessed in 22 patients with fibromyalgia and in 23 age-matched healthy controls. LMg is significantly increased (P < 0.05) and EMg slightly decreased in fibromyalgia. These magnesium abnormalities are associated with previously-reported impairment of thiamin metabolism. Antioxidant status (as well as plasma malondialdehyde) is unchanged in fibromyalgia and serum selenium levels, slightly but not significantly correlated with serum magnesium, is normal.
Back to the Top
|
|
|
|
|
|
| |
Magnesium and Osteoporosis:
|
Magnesium Deficiency: Possible Role in Osteoporosis Associated with Gluten-sensitive Enteropathy
Osteoporosis International (United Kingdom), 1996, 6/6 (453-461)
Osteoporosis and magnesium (Mg) deficiency often occur in
malabsorption syndromes such as gluten-sensitive enteropathy
(GSE). Mg deficiency is known to impair parathyroid hormone (PTH)
secretion and action in humans and will result in osteopenia and
increased skeletal fragility in animal models. We hypothesize
that Mg depletion may contribute to the osteoporosis associated
with malabsorption. It was our objective to determine Mg status
and bone mass in GSE patients who were clinically asymptomatic
and on a stable gluten-free diet, as well as their response to Mg
therapy. Twenty-three patients with biopsy-proven GSE on a
gluten-free diet were assessed for Mg deficiency by determination
of the serum Mg, red blood cell (RBC) and lymphocyte free Mg2+,
and total lymphocyte Mg. Fourteen subjects completed a 3-month
treatment period in which they were given 504-576 mg MgCl2 or Mg
lactate daily. Serum PTH, 25-hydroxyvitamin D,
1,25-dihydroxyvitamin D and osteocalcin were measured at baseline
and monthly thereafter. Eight patients who had documented Mg
depletion (RBC Mg2+ < 150 microM) underwent bone density
measurements of the lumbar spine and proximal femur, and 5 of
these patients were followed for 2 years on Mg therapy. The mean
serum Mg, calcium, phosphorus and alkaline phosphatase
concentrations were in the normal range. Most serum calcium
values fell below mean normal and the baseline serum PTH was high
normal or slightly elevated in 7 of the 14 subjects who completed
the 3-month treatment period. No correlation with the serum
calcium was noted, however. Mean serum 25-hydroxyvitamin D,
1,25-dihydroxy vitamin D and osteocalcin concentrations were also
normal. Despite only 1 patient having hypomagnesemia, the RBC
Mg2+ (153 + or - 6.2 microM; mean plus or minus SEM) and
lymphocyte Mg2+ (182 plus or minus 5.5 microM) were significantly
lower than normal (202 + or - 6.0 microM, P < 0.001, and 198 + or
- 6.8 microM, p < 0.05, respectively). Bone densitometry revealed
that 4 of 8 patients had osteoporosis of the lumbar spine and 5
of 8 had osteoporosis of the proximal femur (T-scores less than
or equal to -2.5). Mg therapy resulted in a significant rise in
the mean serum PTH concentration from 44.6 + or - 3.6 pg/ml to
55.9 plus or minus 5.6 pg/ml (p < 0.05). In the 5 patients given
Mg supplements for 2 years, a significant increased in bone
mineral density was observed in the femoral neck and total
proximal femur. This increase in bone mineral density correlated
positively with a rise in RBC Mg2+. This study demonstrates that
GSE patients have reduction in intracellular free Mg2+, despite
being clinically asymptomatic on a gluten-free diet. Bone mass
also appears to be reduced. Mg therapy resulted in a rise in PTH,
suggesting that the intracellular Mg deficit was impairing PTH
secretion in these patients. The increase in bone density in
response to Mg therapy suggests that Mg depletion may be one
factor contributing to osteoporosis in GSE.
Back to the Top
Magnesium Supplementation and Osteoporosis
Nutrition Reviews 1995; 53 (3): 71-74
Among other things, magnesium regulates active calcium transport.
As a result, there has been a growing interest in the role of
magnesium (Mg) in bone metabolism. A group of menopausal women
were given magnesium hydroxide to assess the effects of magnesium
on bone density. At the end of the 2-year study, magnesium
therapy appears to have prevented fractures and resulted in a
significant increase in bone density.
Back to the Top
Calcium, phosphorus and magnesium intakes correlate with bone
mineral content in postmenopausal women
GYNECOL. ENDOCRINOL. (United Kingdom), 1994, 8/1 (55-58)
Qualitative and quantitative differences in the dietary habits of
postmenopausal women were studied to assess their influence on
bone health and osteoporosis. A total of 194 postmenopausal women
were studied with forearm DEXA densitometry. 70 were osteoporotic
and 124 served as controls. Women had been menopausal for 5-7
years and had never been treated with hormone replacement or drug
therapy. A 3-day dietary recall was completed on Sunday, Monday
and Tuesday after the examination: the results were processed by
computer and daily calcium, phosphorus and magnesium intakes were
related to bone mineral content (BMC). Data were compared with
Student's t-test and significance was assessed at p < 0.05.
Regression analysis was performed to correlate BMC and intake
levels. The dietary intake of calcium phosphorus and magnesium
was significantly reduced in osteoporotic women and correlated
with BMC. Calcium and magnesium intakes were lower than the
recommended daily allowance even in normal women. The results
suggest that nutritional factors are relevant to bone health in
postmenopausal women, and dietary supplementation may be
indicated for the prophylaxis of osteoporosis. Adequate
nutritional recommendations and supplements should be given
before the menopause, and dietary evaluation should be mandatory
in treating postmenopausal osteoporosis.
Back to the Top
|
|
|
|
|
|
| |
Magnesium and Other Ailments:
|
Magnesium taurate and fish oil for prevention of migraine
Med Hypotheses (ENGLAND) Dec 1996, 47 (6) p461-6
Although the pathogenesis of migraine is still poorly understood,
various clinical investigations, as well as consideration of the
characteristic activities of the wide range of drugs known to
reduce migraine incidence, suggest that such phenomena as
neuronal hyperexcitation, cortical spreading depression,
vasospasm, platelet activation and sympathetic hyperactivity
often play a part in this syndrome. Increased tissue levels of
taurine, as well as increased extracellular magnesium, could be
expected to dampen neuronal hyperexcitation, counteract
vasospasm, increase tolerance to focal hypoxia and stabilize
platelets; taurine may also lessen sympathetic outflow. Thus it
is reasonable to speculate that supplemental magnesium taurate
will have preventive value in the treatment of migraine. Fish
oil, owing to its platelet-stabilizing and antivasospastic
actions, may also be useful in this regard, as suggested by a few
clinical reports. Although many drugs have value for migraine
prophylaxis, the two nutritional measures suggested here may have
particular merit owing to the versatility of their actions, their
safety and lack of side-effects and their long-term favorable
impact on vascular health
Back to the Top
Prophylaxis of migraine with oral magnesium: results from a
prospective, multi-center, placebo-controlled and double-blind randomized
study
Cephalalgia (NORWAY) Jun 1996, 16 (4) p257-63
In order to evaluate the prophylactic effect of oral magnesium,
81 patients aged 18-65 years with migraine according to the
International Headache Society (IHS) criteria (mean attack
frequency 3.6 per month) were examined. After a prospective
baseline period of 4 weeks they received oral 600 mg (24 mmol)
magnesium (trimagnesium dicitrate) daily for 12 weeks or placebo.
In weeks 9-12 the attack frequency was reduced by 41.6% in the
magnesium group and by 15.8% in the placebo group compared to the
baseline (p < 0.05). The number of days with migraine and the
drug consumption for symptomatic treatment per patient also
decreased significantly in the magnesium group. Duration and
intensity of the attacks and the drug consumption per attack also
tended to decrease compared to placebo but failed to be
significant. Adverse events were diarrhea (18.6%) and gastric
irritation (4.7%). High-dose oral magnesium appears to be
effective in migraine prophylaxis.
Back to the Top
Electromyographical ischemic test and intracellular and
extracellular magnesium concentration in migraine and
tension-type headache patients
Headache (UNITED STATES) Jun 1996, 36 (6) p357-61
Headache has often been described in the hyperexcitability
syndrome which recognizes an alteration of calcium and magnesium
status in its etiopathogenesis. Moreover, in migraine patients
magnesium has been shown to play an important role as a regulator
of neuronal excitability and, therefore hypothetically, of
headache. The present research involves a neurophysiological
evaluation and magnesium status assessment of a group of headache
patients. Nineteen patients (15 women and 4 men) with episodic
tension-type headache and 30 patients (27 women and 3 men) with
migraine without aura were examined. An ischemic test was carried
out on the right arm with electromyographic (EMG) recording of
motor unit potential activity during the interictal period. The
determination of extracellular (serum and saliva) and
intracellular (red and mononuclear blood cells) magnesium was
also performed. The EMG test was positive in 25 of 30 migraine
patients and in 2 of 19 tension-type headache patients. Between
the two patient groups, there were no significant variations in
the concentration of extracellular and white blood cell
magnesium, while the red blood cell concentration of this mineral
in the group of migraineurs was significantly reduced with
respect to that in the group of tension-type headache patients (P
< 0.05). The positive EMG test was significantly associated with
a low concentration of red blood cell magnesium (P < 0.0001).
These results confirm previous findings by demonstrating
different etiopathogenic mechanisms as the basis of migraine and
tension-type headache. Migraine seems to be related to an altered
magnesium status, which manifests itself by a neuromuscular
hyperexcitability and a reduced concentration in red blood cells.
Back to the Top
Experimental and clinical studies on dysregulation of magnesium
metabolism and the aetiopathogenesis of multiple sclerosis.
Magnes Res (ENGLAND) Dec 1992, 5 (4) p295-302
The proposed aetiologies of multiple sclerosis (MS) have included
immunological mechanisms, genetic factors, virus infection and
direct or indirect action of minerals and/or metals. The
processes of these aetiologies have implicated magnesium.
Magnesium and zinc have been shown to be decreased in central
nervous system (CNS) tissues of MS patients, especially tissues
such as white matter where pathological changes have been
observed. The calcium content of white matter has also been found
to be decreased in MS patients. The interactions of minerals
and/or metals such as calcium, magnesium, aluminium and zinc have
also been evaluated in CNS tissues of experimental animal models.
These data suggest that these elements are regulated by pooling
of minerals and/or metals in bones. Biological actions of
magnesium may affect the maintenance and function of nerve cells
as well as the proliferation and synthesis of lymphocytes. A
magnesium deficit may induce dysfunction of nerve cells or
lymphocytes directly and/or indirectly, and thus magnesium
depletion may be implicated in the aetiology of MS. The action of
zinc helps to prevent virus infection, and zinc deficiency in CNS
tissues of MS patients may also be relevant to its aetiology.
Magnesium interacts with other minerals and/or metals such as
calcium, zinc and aluminium in biological systems, affecting the
immune system and influencing the content of these elements in
CNS tissues. Because of these interactions, a magnesium deficit
could also be a risk factor in the aetiology of MS.
Back to the Top
Amyotrophic lateral sclerosis--causative role of trace elements
Nippon Rinsho (JAPAN) Jan 1996, 54 (1) p123-8
Although numerous hypotheses have been proposed for the cause of
amyotrophic lateral sclerosis (ALS), conclusive decision still
remains vague. Recent epidemiological investigation disclosed an
aggregation of ALS cases in the Western Pacific, including the
Kii Peninsula of Japan, the island of Guam in Marianas and West
New Guinea. Extensive environmental studies in these foci
indicated an important role of trace elements in ALS etiology. It
is postulated that chronic environment deficiencies of calcium
and magnesium may provoke secondary hyperparathyroidism,
resulting in increased intestinal absorption of toxic metals
under the presence of excess levels of divalent or trivalent
cations and lead to the mobilization of calcium and metals from
the bone and deposition of these elements in nervous tissue. This
hypothesis, called metal-induced calcifying degeneration of CNS,
has been supported by experimental studies using several animal
species.
Back to the Top
Nutrient intake of patients with rheumatoid arthritis is
deficient in pyridoxine, zinc, copper, and magnesium
Journal of Rheumatology (Canada), 1996, 23/6 (990-994)
OBJECTIVE: To determine nutrient intake of patients with active
rheumatoid arthritis and compare it with the typical American
diet (TAD) and the recommended dietary allowance (RDA). Methods.
41 patients with active RA recorded a detailed dietary history.
Information collected was analyzed for nutrient intake of energy,
fats, protein, carbohydrate, vitamins and minerals, which were
then statistically compared with the TAD and the RDA.
RESULTS:
Both men and women ingested significantly less energy from
carbohydrates (women 47.4% (6.4) vs 55% RDA, p = 0.0001; men =
48.9% (7.4), p = 0.025) and more energy from fat (women = 36.8%
(4.5) vs 30% RDA. p = 0.001 and men = 35.2% (5.9) p = 0.02).
Women ingested significantly more saturated and mono-unsaturated
fat than the RDA (p = 0.02 and p = 0.04 respectively) while men
ingested significantly less polyunsaturated fat (PUFA)(p =
0.0001). Both groups took in less fiber (p = 0.0001). Deficient
dietary intake of pyridoxine was observed vs the RDA for both
sexes (men and women p = 0.0001). Deficient folate intake was
seen vs the TAD for men (p = 0.02) with a deficient trend in
women (p = 0.06). Zinc and magnesium intake was deficient vs the
RDA in both sexes (p values less than or equal to 0.001) and
copper was deficient vs the TAD in both sexes (p = 0.004 women
and p = 0.02 men). Conclusion. Patients with RA ingest too much
total fat and too little PUFA and fiber. Their diets are
deficient in pyridoxine, zinc and magnesium vs the RDA and copper
and folate vs the TAD. These observations, also documented in
previous studies, suggest that routine dietary supplementation
with multivitamins and trace elements is appropriate in this
population.
Back to the Top
Thanks to
Pub Med for their
excellent MEDLINE search tool!
Return to NUTRITION
Since 10-01-1999
Updated 5-22-2022
|
|
|
|