Magnesium – Looking Through Oxygen’s Prism

Majid Ali, M.D.

Magnesium is an excellent case for looking at nutrition through the prism of oxygen homeostasis. It serves both as the primal liberator of oxygen and one of its chief lieutenants in the initial cellular energetics. Thus, the case study of magnesium offers crucially important insights into the fundamentals of the health/dis-ease/disease continuum, and sheds light on myriad mechanisms by which liberal oral and parenteral supplementation of this mineral sustains and facilitates healing pathways. The first and foremost among them, of course, is the primal role of magnesium in splitting water and liberating oxygen for the ambient air.

Magnesium, The Miracle Mineral

I prescribe magnesium in liberal oral and parenteral doses (1,200 to 2,500 mg daily) for nearly all of my patients.. The rare exceptions to that are individuals with myasthenia gravis and other extremely uncommon instances of inexplicable magnesium intolerance. I prescribe large doses of magnesium primarily because my patients consistently report good short-, intermediate-, and long-term results. Based on personal experience of administering magnesium to nearly 7,000 patients with dysoxygenosis (impaired oxygen homeostasis), I consider magnesium the mineral of choice for supplementation in all acute and chronic disorders. Renal failure with elevated levels of serum magnesium is an exception to that. But magnesium also endlessly fascinates me for its myriad primal roles in cellular energetics and oxygen homeostasis.

Magnesium: The Liberator of Oxygen

Magnesium is the mineral ligand of chlorophyll. For that reason, I place the mineral high on the perch of the most distinguished primal guardian of all life that depends on sunlight.12-15 Oxygen-utilizing life forms, including homo sapiens, evolved as photosynthesis led to accumulation of oxygen in ambient air. When in an excited state, chlorophyll is a powerful reducing agent. The energy of photons of solar light gives the necessary nudge to electrons to fly off and reduce whatever comes in the way, i.e., quinone. The oxidized chlorophyll so generated is a powerful oxidizing agent. It removes hydrogen [H] from water, transferring electrons from water to quinone, and liberating oxygen. Chlorophyll then returns to its original, unexcited state, ready to start the process all over again when it sees the light of sun. Thus, chlorophyll is seen as a sensitizer, allowing water to capture the energy of photons of solar light without itself being used up. The same molecule acts as a powerful reducing agent under one set of conditions and a powerful oxidizing agent under another, much like oxygen, a molecular Dr. Jekyll/Mr. Hyde of primal importance to human biology.

Magnesium: The Facilitator of Oxygen

Magnesium serves diverse and critical roles in enzymatic reactions in both anaerobic and aerobic glycolysis.16,17 The mineral facilitates mitochondrial uptake of phosphate and extrusion of protons.18 Electron transfers in the respiratory chain during ATP production requires thiamine (precursor of nicotinamide adenine dincleotide [NAD]) and riboflavin (precursors of flavin adenine dinucleotide [FAD]).19 Similarly, magnesium is necessary for other types of phosphate transfer reactions. For example, magnesium is the mineral cofactor of malate dehydrogenase in the malate-aspartate shuttle—a reaction that also requires vitamin B6. All three vitamins (thiamine, riboflavin, and B6) require magnesium for activation to their respective bioactive forms following phosphate transfer reactions.

Magnesium: The Driver of Mitochondrial Energetics

Adenosine triphosphate (ATP) is the cellular energy currency. In health, the concentration of ATP in respiring cells is considerably higher than that of its precursors, adenosine biphosphate (ADP) and adenosine monophosphate (AMP). During periods of heightened energy demands, ATP is hydrolyzed to ADP with release of energy to fulfill the increased demands of energy. As a consequence, the cellular ATP/ADP ratio is reduced, the rate of glycolysis is increased, mitochondrial respiration is speeded, and oxidative phosphorylation of ADP to ATP occurs to build back ATP levels. Evidently, that mechanism increases ATP at the expense of reducing ADP which, in turn, serves as the signal for ATP-mediated phosphorylation of AMP to generate ADP. All of those phosphate transfer reactions are mediated by magnesium.20-22

Magnesium: The Sparer of Oxygen

Magnesium exerts an important oxygen-sparing effect that has been carefully delineated in magnesium-deficient competitive swimmers.23 Supplementation with the mineral lowers both blood lactate levels and oxygen consumption under certain condition in spite of concurrent increased glucose utilization. Magnesium deficiency, by slowing down the respiratory electron transfer chain, diminishes the transfer of reducing equivalents from cytosol into the mitochondria.

Magnesium: The Redox Regulator

Magnesium is a redox regulator par excellence. Next to oxygen, the cysteine-glutathione sulfhydryl and methionine-homocysteine-cysteine-taurine antioxidant systems form the core of human redox defenses. Both pathways are magnesium dependent.24,25

Magnesium: Oxygen’s Right Arm in Mitochondria

The aspects of cellular genetics presented above — in my view — establish magnesium as the right arm of oxygen in mitochondrial dynamics. This, indeed, is the central issue in both the pathogenesis of dysoxygenosis and the liberal oral and parenteral supplementation of magnesium (1,500 to 2,500 mg) in chronic energy deficit states. Such magnesium therapy has been completely safe in our practice when administrered slowly and monitored closely. I summarize the aspects of oxygen-magnesium dynamics in the Table.

Magnesium: The Controller of Cellular Transistors

In transistors, the electron flow through a semiconductor is governed by the voltage applied to one of the electrodes. The semiconductor essentially serves as a channel for the transfer of electrons, while the electrode at the site of the change in voltage serves as the ‘gate’ of that channel. Biomembranes of microbes and humans house proteins that essentially function as field-effect transistors, and are designated as voltage-gated ion channels. Application of appropriate voltage imposed across biomembranes cause those channels to open and allow a current of ions—energetically, a wave of energy —to cross through the membrane. During the early 1950s, Hodgkin and Huxley described the conceptual functional model of such channel proteins.26 Recently, the structure and function of voltage-gated ion channels has drawn intense scrutiny.27-30 Indeed, It was only in 2003 that the x-ray structure of a potassium ion channel was made visible and tests of a hypothesis for voltage-sensor motion were described by the Nobelist Roderick MacKinnon and colleagues.31

Magnesium influences the traffic of ions into and out of cells in many ways. It serves as a cofactor in many biochemical reactions that are involved in the maintenance of intracellular concentration of other cations such as potassium, sodium and calcium. Magnesium is also a cofactor for a large number of enzymes such as kinases. The Na+-K+ membrane pump is magnesium dependent. The integrity of this pump, of course, is of fundamental importance to maintenance of fluid and electrolyte homeostasis. Magnesium deficiency has been linked to many types of biomembrane dysfunction.32-35 Specifically, magnesium has been designated as nature’s calcium channel blocker.36

Table. Magnesium in Mitochondrial Dynamics and Dysoxygenosis
Element Mitochondrial Function and Dysfunction
Oxygen Function preserved during oxygen homeostasis. Dysfunction caused by cardiac, pulmonary, and hematologic disorders as well as poisons, like arsenic
Magnesium Function preserved with ample intake. Dysfunction caused by diminished intake (malnutrition and malabsorption) and excess of calcium
High-Phosphate Bonds Function preserved with ample phosphorus intake. Dysfunction caused by diminished intake of phosphorus, excess of calcium, and deficiency of malate
Facilitators Vitamins of central importance in electron transport system (thiamine, riboflavin, and pyridoxin)
Disruptors Extraneous, such as aluminum and pesticides. Endogenous, such as excess metabolites of Krebs cycle, glycolysis, and others that lead to dysoxygenosis

Magnesium: The Mineral for Metabolism

Magnesium is a mineral for metabolism par excellence. The first step in glucose metabolism is conversion of glucose to glucose-6-phosphate. This reaction requires hexokinase, which is a magnesium-dependent enzyme. Magnesium is the mineral cofactor involved in the regulation of most steps of glycolytic pathways.16 Delta-6-desaturase is a critical enzyme in the conversion of fatty acids of plant and animal origin into longer chains and unsaturated fatty acids essential for human metabolism. Delta-6-desaturase is a magnesium dependent enzyme. As in the case of glycolysis, magnesium also exerts regulatory influences in most steps of lipolytic pathways.17 Magnesium is essential for many enzymatic reactions involved in protein synthesis as well as in protein degradation.37 Biosynthesis of essential neurotransmitters — serotonin, GABA (gamma-amino-butyric acid), acetylcholine, melatonin, and others — requires vitamin cofactors (thiamine, pyridoxin, and others) that require activation by magnesium. Magnesium plays myriad roles as a cofactor in enzyme pathways involving absorptive-digestive and hepatic detoxification, Kreb’s cycle and related energy functions, and neurotransmitter pathways.

Magnesium in the Immune Response

The immune response — in my view — is but one facet of oxygen. In that context, I consider magnesium as one of the most important components of the immune response. The immune response, at another level, is a facet of cellular energetics. Again, in that context, magnesium distinguishes itself, as shown above. In classical immunology, the immune response is confined to molecular-cellular events initiated by the union of an antigen and its corresponding antibody. In that context, the example of the C3 convertases — the family of enzymes involved in the triggering of both classical and alternate complement pathways — may be cited. Those enzymes are activated by magnesium.32,28 The complement activation, of course, is central to innumerable host defense responses.

Magnesium in Acute Illness

Acutely ill hospitalized patients almost always become magnesium-poor within a few days.38-41 Such deficiency almost always goes unrecognized because we continue to insist that a deficiency state must be documented with blood tests before embarking upon magnesium replacement therapy. The fact that only less than 1% of total body magnesium exists in the blood does not seem important to us (skeletal and intracellular compartments contain approximately 53% and 46% of magnesium respectively). We fail to see the obvious: Increased oxidant stress on cell membranes associated with illness and resulting in hospitalization leads to leakage of magnesium out of the cell and into the extracellular space. In addition, it masks the intracellular magnesium deficiency. When looked for carefully, hypomagnesemia in hospitalized patients is not uncommon.42,43 Indeed, magnesium administration has been found to be clinically beneficial in nearly all studies in which its use has been investigated.44,45

Magnesium and Nervous System

Magnesium has well-established depressant effects on the central nervous system40,41,46-50 and neuromuscular transmission.44-47 Severe magnesium deficiency leads to neurasthenia, irritability, muscle weakness and cramps, disorders of the mood, memory and mentation, tremors and convulsions.51-53 Hypomagnesemic tetany results from increased neuromuscular excitability. The author has observed the unexplained sadness which accompanies disabling chronic disorders such as fibromylagia, chronic fatigue syndrome, and chemical sensitivity respond especially well to liberal magnesium supplementation (2,000 to 3,000 mg daily). Magnesium is intricately involved with calcium homeostasis at the neuromuscular receptor-ligand interplays, central nervous system, and myriad intracellular energy , metabolic and detoxication reactions. Among its roles in calcium homeostasis are inhibition of binding of calcium to calmodulin and regulatory influence over the functionality of calcium channel. What are the long-term consequences of calcium channel blockade on magnesium (and calcium) homeostasis?

Magnesium depresses CNS and neuromuscular transmission.54,55 Magnesium influences the action of excitatory neurotransmitter N-methyl-D-aspartate ((NMDA).56,57 Magnesium influences voltage-gated K channels.58,59 Magnesium enhances the sensitivity of cerebral arteries to the regulatory influences of pH and CO2. Thus, magnesium deficiency may unmask certain cerebral vasospastic disorders, including TIA and migraine attacks.60,61

Magnesium deficiency has been suspected t play a role in the pathogenesis of hyperventilation syndrome.62 The lack of magnesium impairs oxidative mitochondrial functions. The resultant anaerobic glycolysis produces local lactic acidosis, which provokes hyperventilation. Acidosis, unless corrected expediently, also sets the stage for intracellular acidosis and dysoxygenosis, both of which seem to create a sense of air hunger and feed into the pathophysiology of hypervention (personal observations).

Investigations of the mechanism(s) of subclinical tetany and positive Chvostek’s sign and Trousseau’s sign led to the proposal that neuromuscular transmission in such cases “adapts” to gradual decline in transmembrane electrical potential by adjusting the voltage requirement for generating action potential.63-65 In one study of 5,645 cases of tetany syndrome with dominant symptoms of insomnia; headache; numbness, tingling, and burning; dizziness, muscle weakness, cramps, and twitching episodic chest pain, and dyspepsia. Electromyographic (EMG) abnormalities were present in 89% of the cases, but the plasma magnesium levels showed no significant differences between patients and control subjects. Significantly, however, erythrocytic magnesium was 10% lower in the tetany group.66

Magnesium and Cell Death

From a teleologic perspective alone, the central importance of magnesium in preserving the integrity of the immune system should be abundantly clear from the preceding discussion of the myriad roles of magnesium in redox homeostasis, energetic and detoxification enzyme pathways, and dynamics of oxidative cell membrane injury. The case for magnesium is equally strong from an empirical perspective. The author has managed about six thousand patients with chronic immune dysfunctions, such as fibromyalgia, chronic fatigue syndrome, inflammatory bowel disease, and others. As stated earlier, clinical experience with liberal magnesium supplementation in such disorders bears incontrovertible evidence of the efficacy of this mineral in restoring the immune integrity. Yet, a review of magnesium literature reveals papers in which magnesium is deliberately belittled as regards its contribution to the immune system.67,68

An incomplete listing of deficits reported in magnesium deficiency states includes the following: (1) thymic atrophy and decreased thymosin production 69; (2) impaired cell-mediated immunity 70,71; (3) diminished production of antigen-specific antibody following sensitization72; (4) reduced number of colonies of antibody-forming cells in the spleen 73; (5) decreased production of 7-gamma globulin74; (6) lower levels of C3 in acutely ill hospitalized children with hypomagnesemia75; (7) decreased production of cytotoxic strains of T-cells in magnesium-deficient media76; (8) enhanced activity of histadine decarboxylase activity and raised levels of histamine and eosinophilia in Mg-deficient rodents77,78; (9) increased synthesis of prostanoids in magnesium deficiency-associated latent tetany syndromes such as dysmenorrhea, migraine, and irritable bowel syndrome79-81; (10) lymphocytosis and increased lymphocyte phospholipase A2 activity in Mg-deficient rats82; (11) increased sensitivity of Na-K ion channels to voltage changes in Mg-deficient animals83; and (12) enhanced release of histamine from Mg-deficient leukocytes.84 The author and others have observed relief of bronchospasm in asthma attacks following intravenous administration of magnesium. Asthma, of course, is an immune-inflammatory disorder.

Magnesium and Stress

The literature concerning the roles of magnesium in the states of acute and chronic stress is voluminous.40,41 Stress shifts intracellular magnesium to plasma.85 Remarkably, two hours of noise stress in guinea pigs reduces mean erythrocytic magnesium by 2mmol/g dry weight. Chronic noise stress produces similar results in rats, with serum magnesium levels rising and myocardial levels falling.86,87 Such abnormalities are only partly reversed when the animals are allowed to rest in silence for 24 hours, indicating a net loss of magnesium caused by noise stress. The ill-effects of Mg deficiency and noise stress were found to be synergistic in a study of collagen content (indicative of physiologic aging) in the rat myocardium.88 It is well known that rats injected with sympathomimetic amines show an increase in intracellular calcium (indicating activation of the second messenger system). Less well recognized is the phenomenon of intracellular magnesium depletion.89 Not unexpectedly, dietary Mg deficiency accentuates such responses.

Type A behavior (characterized by impatience, overzealous competitiveness, and easily provoked hostility) is associated with a hyperadrenergic state. When exposed to mental stress, Type A individuals show increased serum and decreased erythrocytic levels of magnesium compared with Type B persons.90-92

Magnesium therapies increase serum potassium levels but are not known to influence erythrocyte Ca or Na levels.93 It is not clear from the literature review whether such therapy downregulates catecholamine metabolism. Thus, the use of beta blockers is often recommended along with magnesium. However, the author’s clinical experience suggests otherwise. At the Institute, beta blockers are rarely used to complement magnesium therapies. It should be pointed out, however, that a heavy emphasis is placed on the use of effective self-regulatory methods for abrogating hyperadrenergic responses for our patients.

In humans, working with traffic noise for a period of seven hours increased serum Mg levels by an average of 2.4%, urinary Mg excretion increased by 15%, and erythrocytic Mg decreased by 1.5%.94 In another study, brewery workers in a noisy hall lost 5% of their erythrocyte Mg content when compared to a control group who wore ear protectors.95 Such changes correlated well with increased catecholamine metabolism.96-98

Magnesium and Chronic Energy Deficit States

I consider fibromyalgia, chronic fatigue syndrome, chemical sensitivity syndrome, persistent fatigue following chemotherapy for malignant disorders, and other forms of disabling fatigue as chronic energy deficit states. This designation draws a sharp focus on global cellular energetics, rather than preoccupation with any single pathogenic microbe or the putative deficiency of any single nutrient as the cause of the syndrome. Beyond that, it provides a rational, logical, and scientific basis for designing effective therapeutic regimens for satisfactory long-term clinical outcome. For my patients, next to oxygen, magnesium is the single most important nutrient for inclusion in the integrative plan. Below, I include some information to provide my rationale for that.

Blood flow in the muscles of patients with fibromyalgia during aerobic exercise is diminished.99 Not unexpectedly, oxygen pressure in muscle tissue of such patients is also reduced.100 Biopsy tissues taken from trigger points exhibit myocytolysis, swollen mitochondria with distortion of cristae, dilatation of sarcoplasmic reticulum, and glycogen deposition.101 One would expect that the amounts of high-energy phosphate bonds — ATP, ADP, and phosphocreatinine — would be diminished in tissues showing those morphologic abnormalities. That, indeed, occurs.102 It might also be noted in this context that serum levels of several amino acids are reduced in fibromyalgia.103 Hypoxic muscle contains an excess of cytosolic reducing equivalents which inhibit glycolysis, stimulate gluconeogenesis, and lead to degradation of muscle proteins and amino acid substrates for ATP synthesis.104,105

Most important from the standpoint of understanding the energetic basis of the total clinical spectrum of fibromyalgia — dysautonomic symptoms involving the cardiovascular and gastrointestinal systems, disorders of the mood, memory, and mentation, and other symptom-complexes — is the crucial biochemical finding of increased urinary excretion of metabolites of the Krebs cycle, glycolysis, and other pathways of cellular oxygen utilization.1-5 Data concerning increased urinary excretion of organic acids in dysoxygenosis have been presented in Table 1 and 2 in this chapter.

Magnesium and the Heart

A large body of data showing a relationship between low dietary intake of magnesium and the incidence of cardiac arrhythmias, sudden death, atherogenesis, ischemic coronary artery disease, hypertension, and stroke has been reviewed.106-108 Furthermore, low serum magnesium levels have been associated with coronary vasospasm, hypertension, and sudden death. In experimental studies, magnesium plays several regulatory roles in lipid metabolism, lipid uptake by macrophages, and intimal and smooth muscle responses to oxidative stress (oxidative coagulopathy) on blood elements.

There is an inverse relationship between serum and free erythrocyte magnesium and blood pressure. A similar relationship was observed in some, but not all, studies.107 Increased urinary catecholamines are often associated with increased urinary magnesium clearance, providing yet additional insight into the cardioprotective roles of magnesium.

Low magnesium content of drinking water has been epidemiologically recognized as a cardiovascular risk factor.108 On the other hand, magnesium supplementation was associated with lower incidence of hypomagnesemia, hypokalemia, and cardiovascular risk factors.109 Magnesium supplementation has also been thought to be associated with reduced myocardial oxygen demand. In other studies, the regulatory role of magnesium on myocardial membrane potential and the duration of such potential has been proposed.109

In Sweden, water hardness — reflecting content of magnesium, calcium and other minerals — was inversely related to ischemic coronary artery disease and stroke in seven mid-region counties where a large regional east-west gradient in cardiovascular mortality was observed during the years 1969-1983.110 I may point out here that serum and lymphocyte magnesium levels do not show any correlation with myocardial or skeletal muscle magnesium levels as determined with biopsy during cardiac surgery.111

I include below some text from Integrative Cardiology, the fourth volume of this series, to provide a framework of reference for understanding the clinical observations concerning the use of magnesium in cardiac disorders.

Three types of cell membrane channels play critical roles in nodal excitation and conducting phenomena: (1) fast sodium channels; (2) slow calcium-sodium channels; and (3) potassium channels.

The speed of electron and ion transfer during the creation and conductance of action potentials (propagating energy waves) is astounding. Opening of the fast sodium channels for a few 10,000ths of a second results in massive influx of positively charged sodium ions with a quick spike-like onset of action potential (up to +20 mV), which creates an observable contraction of the ventricular myocyte. This is followed by a plateau-like action potential (from +20 to about -10 mV) at the cell membrane produced by much slower opening of the slow calcium-sodium channels. The plateau-like action potential lasts for a few tenths of a second. The cycle is completed when potassium channels open at the end of that period, permitting a rapid movement of positively charged potassium ions out of the cell, thus restoring the original ‘resting’ level of the electrical state.

The A-V node links the atrial myocytes to the ventricular musculature through right and left bundles of Purkinje cell. The action potentials of the ventricular cells are faster both in development and dissipation than those of the sinus node. This is due to the lower negativity (-55 to -60 mV) of the sinus node than of the ventricular fibers (due to the natural membrane leakiness of some of the nodal cells as described above). On the inside aspect of the cell membrane, the ‘gates’ of the fast sodium channel remain closed when the value is -60 mV or greater.

As indicated earlier, magnesium not only is involved in the synthesis of ion channel proteins (as components of the overall protein synthetic pathways), it also specifically influences the function of calcium channels and, through them, of sodium, potassium, and other channels.

When Is Magnesium Superior to Calcium Channel Blockers?

One of my clearest memories from medical school is of giving intravenous magnesium sulfate to women critically ill with eclampsia in 1961. In 2003, the New England Journal of Medicine112 published an article conclusively demonstrating the superiority of magnesium sulfate over the calcium channel blocker nimopidine. It is gratifying to note that 42 years later, magnesium still remains the most effective therapy for this devastating disorder.

About four percent of pregnancies are complicated by preeclampsia charcaterized by rapid onset hypertension, proteinuria, water retention, weight gain, and edema. In one-fourth of those cases, preeclapsia proceeds to life-threatening full blown eclampsia charcaterized by diffuse vascular spasticity, malignant hypertension, hepatic failure, generalized toxicity, and clonic convulsions followed by coma. Delivery of the baby or and termination of pregnancy leads to rapid resultion of eclampsia.113-120

Two etiologic mechanisms have been proposed for eclampsia: an elusive toxin of pregnancy and a hypersensitivity response elicited by fetal tissues. I believe that all of the features of eclamsia are mediated through fulminant oxidative coagulopathy121 (see Integrative Cardiology, the fourth volume for a detailed description of morphologic features of oxidopathy), though direct evidence of that is not yet forthcoming. Notwithstanding, the clinical efficacy of magnesium sulfate in eclapsia provides a strong, albeit indirect, evidence for my view that intravenously administered magnesium controls the destructive effects of oxidative coagulopathy.

The ideal test for functional magnesium deficiency, in my judgment, is an intravenous therapeutic trial.

It is the author’s clinical observation that oral magnesium supplements frequently fail to replenish magnesium stores within the cells. In patients with chronic fatigue, myalgia, fibromyositis, and persistent muscle spasms and pain, oral magnesium supplements often give poor results, while intravenous magnesium therapy almost always gives rapid and satisfactory clinical benefits. The same holds for patients with asthma, irregular heart rhythm, and severe backache. The author once used intravenous magnesium along with other micronutrients for one of my patients with severe depression in a desperate — and fortunately successful — attempt to avoid hospitalization (this patient had very traumatic memory of previous hospital admission for depression). Indeed, there is extensive evidence that disorders of mood, memory and mentation, and psychiatric symptoms such as confusion, disorientation, agitation and depression are common in magnesium-deficient patient.122

Magnesium is often poorly absorbed; clinical studies indicate absorption rate ranging from 50% to 70% in healthy subjects on normal diet.123 The intestinal absorption of magnesium is further decreased in magnesium-deficient states.124 Indeed, correction of magnesium deficiency in many patients is so problematic that a genetic basis for reduced magnesium absorption has been considered.124

My recommendation to use intravenous magnesium drip as a test for functional magnesium deficiency in states of accelerated oxidative stress may rankle some. However, it is based on a personal experience with nearly seven thousand patients treated at the Institute for a host of nutritional, autoimmune, ecologic, and degenerative disorders. It has been reassuring to me to learn that most of my colleagues in the American Academy of Environmental Medicine and the American College for Advancement in Medicine—the associations of medicine really committed to advancing the field of clinical nutrition — agree with my recommendation.

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