Background/Objectives: Calcium (Ca) and magnesium (Mg) are mutual antagonists that interact in a majority of physiological processes. Thus, maintaining a balance between these two minerals is essential for functional homeostasis. Mg deficiency plays a role in the course and severity of a wide range of chronic health conditions. This knowledge, however, has not translated into active incorporation of serum Mg determination as a reliable diagnostic tool for physiological Mg deficit. Methods: Pioneering work by von Ehrlich and Rosanoff has prompted development of a simple algorithm and scale for using serum Ca and Mg determinations to identify subclinical (i.e., “hidden”) physiological Mg deficiencies. This novel serum Mg/Ca–Ca/Mg scale uses determinations of total serum Ca and Mg and their ratios to alert clinicians to avoidable risks associated with chronic latent Mg deficiency. This review applies this scale to 10 published clinical studies reporting the serum (or plasma) ratio between Mg and Ca. Results: In all 10 studies, application of the serum Mg/Ca–Ca/Mg scale diagnosed deficit Mg status more reliably than serum Mg alone. Conclusions: This review provides both illustrations of the value of the novel scale and support for its consideration in clinical practice and Mg research.

Background/Objectives: Reliable markers of human magnesium (Mg) status are needed. Methods: Current Mg studies report ratios between serum Mg and calcium (Ca) using four interchangeable expressions (i.e., molar or weight calculations of Mg/Ca or Ca/Mg). We propose a scale using ratios of serum Mg and Ca to assess Mg status, unified for all four expressions. We explore its application for case studies and published research. Results:Case Studies (4)-the proposed serum Mg/Ca scale showed better Mg diagnostic value than serum Mg alone. Published Studies-A. The proposed Mg/Ca scale's "depleted Mg" status predicted mortality among hospitalized COVID-19 patients in ROC/AUC analyses. B. The serum Ca/Mg proposed scale, when applied to "healthy" adults with "normal" serum Mg, exposed a "seriously depleted" to "adequate" range of Mg status. C. In a study of periodontal disease, patients designated "adequate" or "mild" Mg depletion by the proposed scale showed greater 5-year improvement than those with scale's "moderate to serious" Mg depletion status. D. Finally, the proposed scale demonstrated appropriate diagnostic value of serum Ca/Mg in acute coronary syndrome patients only when "corrected Ca" was NOT used in ratio calculation. Conclusions: The proposed scale needs both total serum Ca and Mg measures in identical units, i.e., mg/dL or mg% (for weight ratios); mmol/L or mEq/L (for molar ratios). Authors/reviewers/editors need to take care when reporting units/methodology of serum Mg and Ca ratios for clear reporting as to weight or molar ratio and use of total or corrected values. Future trials and statistical testing are needed to determine whether ratios between serum Mg and Ca yield more precise measures of physiological Mg status than serum Mg alone. Our findings indicate the proposed scale is worthy of further study as a marker of Mg deficit.

Total serum magnesium concentration is rarely determined in clinical practice. Moreover, there is currently no standardised and evidence-based reference range for serum magnesium. The aim of this communication is to propose a reference range that is evidence-based and reflects the preventive potential of optimal magnesium levels. A literature search was conducted in the PubMed database using the terms "serum magnesium", "reference interval", "reference range", and "hypomagnesemia". Additionally, citations from relevant studies were consulted. There is considerable variation between laboratories with regards to the lower limit of magnesium in serum. The majority of limits are considerably below the 0.85 mmol/L (2.07 mg/dL) threshold proposed by expert groups. The rationale for this limit is that lower levels are associated with an increased risk of diseases such as type 2 diabetes and cardiovascular diseases. To prevent health risks associated with low magnesium levels, the lower limit of serum magnesium should be raised to 0.85 mmol/L and standardised between laboratories. At least, laboratory reports should note that levels below 0.85 mmol/L are associated with an increased risk of disease. Furthermore, the determination of serum magnesium should be afforded the same importance in routine laboratory diagnostics as the determination of other electrolytes.

Since the report of an emergence of severe respiratory viral infections of unknown etiology in China in December 2019, termed COVID-19-associated acute respiratory distress syndrome (ARDS), a large number of cases and deaths have been documented worldwide, with the pandemic still spreading around the world. In most critical cases, the acute symptoms may be accompanied by uncontrolled inflammatory cytokine responses and by multiorgan failure. The clinical observation that in severely ill patients, COVID-19 was characterized by cytokine storm and endothelial dysfunction, leading to fast and fatal progression of the disease, has prompted many investigators to consider COVID-19 as a systemic disease that primarily injures the vascular endothelium. Aim of this brief review is not to refute or even question a quite possible role of the vascular endothelial dysfunction as a potential trigger for ARDS, but rather to highlight a more probable role for the main function of the smooth muscle cells in the microcirculation, called "vasomotion", which helps physiologically to ensure an optimized energy supply to the tissues. Alterations in the rhythms of this microcirculatory vaso motion might thus play a similar role as a trigger of the ARDS diagnosed in COVID-19 patients. Furthermore, since obesity, type 2 diabetes, arterial hypertension, decrease in immune response, cytokine storm, endothelial dysfunction, and arrhythmias, which are frequent in COVID-19 patients, have been reported to be associated with hypomagnesemia, an adequate treatment with magnesium supplementation could be beneficial for COVID-19 patients in some specific cases and should also be taken into consideration.

Purpose Serum magnesium is the most frequently used laboratory test for evaluating clinical magnesium status. Hypomagnesemia (low magnesium status), which is associated with many chronic diseases, is diagnosed using the serum magnesium reference range. Currently, no international consensus for a magnesemia normal range exists. Two independent groups designated 0.85 mmol/L (2.07 mg/dL; 1.7 mEq/L) as the low cut-off point defining hypomagnesemia. MaGNet discussions revealed differences in serum magnesium reference ranges used by members' hospitals and laboratories, presenting an urgent need for standardization. Methods We gathered and compared serum magnesium reference range values from our institutions, hospitals, and colleagues worldwide. Results Serum magnesium levels designating "hypomagnesemia" differ widely. Of 43 collected values, only 2 met 0.85 mmol/L as the low cut-off point to define hypomagnesemia. The remainder had lower cut-off values, which may underestimate hypomagnesemia diagnosis in hospital, clinical, and research assessments. Current serum magnesium reference ranges stem from "normal" populations, which unknowingly include persons with chronic latent magnesium deficit (CLMD). Serum magnesium levels of patients with CLMD fall within widely used "normal" ranges, but their magnesium status is too low for long-term health. The lower serum magnesium reference (0.85 mmol/L) proposed specifically prevents the inclusion of patients with CLMD. Conclusions Widely varying serum magnesium reference ranges render our use of this important medical tool imprecise, minimizing impacts of low magnesium status or hypomagnesemia as a marker of disease risk. To appropriately diagnose, increase awareness of, and manage magnesium status, it is critical to standardize lower reference values for serum magnesium at 0.85 mmol/L (2.07 mg/dL; 1.7 mEq/L).

Convincing data from in-vivo and in-vitro experiments, from epidemiologic and dietary studies, and from numerous clinical trials justify the notion that magnesium - in addition to its role as "physiologic calcium blocker" (Iseri and French [112]) - can be classified as potent "physiologic mood stabilizer". The important clinical role of Mg as a mood stabilizer has to be seen in the context of the high prevalence of hidden Mg deficiency in Western populations and the increasing prevalence of mood disorders. Mg therapy is safe, and hence the acceptance among concerned patients is very good.

Although the relevance of magnesium in obstetrics has been known for a long time and its effect in many diseases is well documented, oral magnesium supplementation during pregnancy is a subject of discussion. The evaluation of the variety of studies regarding magnesium supplementation in pregnancy clearly shows positive effects of oral substitution, in contrast to the Cochrane analysis. In addition to the needs of the growth of the fetus and the maternal tissue, elevated renal magnesium excretion is a reason for an increased magnesium requirement during pregnancy. This enhanced renal loss leads to a decreased serum magnesium concentration, which can also be recognized in the myometrium.

The erroneous and widely held assumption that subjective tinnitus is generated in the inner ear, was for a long time an obstacle to an adequate and effective treatment of this symptom. Its continued persistence after section of the auditory nerve, and the observation that in many patients tinnitus is still perceived, even after restoration of their hearing, support the view that the associated "phantom-like" perceptions must originate in the brain; as we know today, these perceptions have their origin in neuroplastic reorganization processes occurring in the auditory cortex. Such processes might be triggered by damages to the synapses between the inner hair cells (IHC) and the terminals of the peripheral branches of the spiral ganglion neurons, leading to frequency-specific deafferentiations in the auditory pathway. The highly specialized sensory cell synapses of the auditory pathway are extremely vulnerable to ionic disturbances occurring in the synaptic cleft, particularly to fluctuations of the Mg concentrations. Physiologically, the high discharge rate related to their sensory function is modulated in the afferent neurons through Mg-blockade of the N-methyl-D-aspartate (NMDA) receptors channels. The removal of the Mg-blockade brought about by a reduction of Mg ion concentrations in the synaptic cleft, results in an increased Ca-conductance through NMDA receptor channels, leading to permanent depolarization of the postsynaptic membrane and consequently to deafferentation of auditory pathways, a dysfunction possibly aggravated by the neurotoxic effects of external glutamate. If care is taken that Mg ions concentrations is restored to physiologic levels in the vicinity of the postsynaptic side of IHC, or that the deafferentiated acoustic fibers are blocked in the initial stage by local anesthesia, the tinnitus would not arise. These new findings have led to the development of several promising methods (such as the repetitive transcranial magnetic stimulation and the combination of vagus nerve stimulation with selected, multiple sound frequencies), that are based on a modulation of cortical neuroplasticity aiming at best to a "suppression" of the acoustic "phantom perception" at the cortical level.

About 100 mu L of capillary blood of 22 officer trainees of the Theresan Military Academy in Wiener Neustadt, Austria, have been analyzed before and after a 2,400 m run for ionized magnesium, pH, pCO(2), pO(2), and lactate. The investigated group was divided into two subgroups. One of them comprised 10 persons with ionized Mg values of 0.5 mM and below. The other with higher Mg levels. Although the mean values of pH, pCO(2), pO(2), and lactate of the two subgroups were not significantly different, correlative analyses between the parameters before and after the run showed significantly less CO2 loss, less alkaline blood, and therefore less O-2 binding and lower lactate levels before the run. After the run ionized Mg values of the groups are no more different, however, correlative pCO(2) loss with changing pH stabilizes pH in the high Mg group significantly. We concluded that low Mg before the run is due to fatigue in the past, but that even acute Mg supplementation may be effective. An inability of Mg increase during mental anticipation reactions seems to strongly indicate Mg deficiency with significant metabolic shortcomings.

About 100 mu L of capillary blood of 15 female and male farmers from Upper Styria (Austria), have been analyzed for ionized magnesium, pH, pCO(2), pO(2), and base excess after mental provocation, superimposed upon self-inflicted multiple chronic workload. After 1 year of intensive advice and multiple therapies including organizational amelioration, the same proceedings have been performed. The outcome was a significant improvement of metabolic stress markers, a much more accurate individual positioning by linear and non-linear regressions revealing the altered relationship of those stress markers to each other, dependent upon a more fatigued or recovered organism. The prominent inclusion of ionized Mg values into the stress markers provides not only a sensitive diagnostic tool, but also an apt possibility to compare magnesium- and not magnesium induced improvement of a metabolism after heavy demands.

Accumulating clinical and experimental evidence suggests an involvement of the prevalent excitatory neurotransmitter glutamate in the CNS in the pathogenesis of tinnitus. A more important trigger however than damages to the outer hair cells attributable to a loss of control of an active, amplifier function primarily due to the presence of prestin on their basolateral membrane, seems to result from disturbances of synaptic transmission between the inner hair cells (IHC) and the peripheral axons of spiralganglion neuron, which unlike the plain synapses between neurons, indicates extensive functional complexity in the human cochlea, designed for the evolutionary perception of wider frequency ranges and minimum time differences, the perception of sound being realized at a much fastest transfer rates of the signals. The premise for this extreme specialization is the equipment of IHC with numerous so-called "synaptic ribbons", which massively enhances the otoferlin-dependent exocytosis at the "active zone", each IHC being thereby able to trigger postsynaptically hundreds of action potentials per second. The protection against overstimulation provided to postsynaptic afferents by the reversible Mg blockade of NMDA receptors might however be pathologically compromised by a nutritional vitamine B-6 (pyridoxine) deficiency, since the accompanying inhibition of cytosolic kynurinase would metabolize the essential amino acid tryptophan through an accessory metabolic pathway, leading to the production of two quinoline derivatives (xanthurenic acid and kynurenic acid), which act as strong chelators of membranous Mg ions. The resulting release of the Mg-block may cause on one hand a postsynaptic overexcitation, leading to a sustained depolarization of afferent neurons, and on the other hand to neurodegeneration caused by the excitotoxic effects of glutamate. In the initial phase of the development of tinnitus it is conceivable that the restoration of adequate physiologic Mg ion concentrations in the synaptic cleft would prevent the triggering of tinnitus. This could possibly also be reached by supplementary moderate doses of specific glutamate receptors antagonists. However, other more complex methods of treatment will be necessary in order to get a more successful management of chronic tinnitus, such as e.g., the technique clinically used nowadays via transcranial magnetic stimulation.

Out of 100 mu l of capillary blood of 15 ensigns from the Theresian Military Academy, ionized magnesium was determined with a CCX device (NOVA Biomedical) and CSA Software (PLK, Judendorf-Strassengel, Austria), before and after a 2,400 m run, both before and after an 8 week-long supplementation of 300 mg magnesium per day. It turned out that Mg changes in blood mainly follow two inter-linked phenomena: 1. Mg substitution leads to more controlled Mg input into the blood after the same sporting challenge, and 2. Mg clearance is strictly proportional to Mg concentration in blood. Varying permutations of those two points explain the entire performance of Mg dynamics in blood, including the hitherto unexplained paradox decrease of blood Mg during substitution [1, 2].

Out of 100111 of capillary blood of 15 ensigns of the Theresianische Militarakademie, ionized magnesium, ionized potassium, ionized calcium pH, basexcess, pCO2 and HCO3 were determined with a CCX device (NOVA Biomedical, Vienna, Austria) and CSA Software (PLK, Judendorf-Strassengel, Austria), before and after a 2,400-m run, and before and after an 8-week supplementation of 300 mg Magnesium per day. It turned out that neither averages of the ionized Mg levels in blood [5] nor those of the concomitantly determined metabolic parameters changed progressively with the duration of supplementation. However, correlative analyses did show that a progressive amelioration of the efficacy of metabolic reactions went along with advancing substitution time. Born out of significantly increasing metabolic efficacy, roughly three groups of Mg replenishment could be ascertained: Small Mg response along with low metabolic efficiency characterized an un-substituted low Mg state, ample Mg response along with fairly efficient metabolism characterized tolerable Mg replenishment, small Mg response along with highly efficient metabolism stood for an optimal Mg state. The gradual proceeding through those conditions takes both time and continuous replenishment.