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The 2015 Dietary Guidelines Advisory Committee indicated that magnesium was a shortfall nutrient that was underconsumed relative to the Estimated Average Requirement (EAR) for many Americans. Approximately 50% of Americans consume less than the EAR for magnesium, and some age groups consume substantially less. A growing body of literature from animal, epidemiologic, and clinical studies has demonstrated a varied pathologic role for magnesium deficiency that includes electrolyte, neurologic, musculoskeletal, and inflammatory disorders; osteoporosis; hypertension; cardiovascular diseases; metabolic syndrome; and diabetes. Studies have also demonstrated that magnesium deficiency is associated with several chronic diseases and that a reduced risk of these diseases is observed with higher magnesium intake or supplementation. Subclinical magnesium deficiency can exist despite the presentation of a normal status as defined within the current serum magnesium reference interval of 0.75-0.95 mmol/L. This reference interval was derived from data from NHANES I (1974), which was based on the distribution of serum magnesium in a normal population rather than clinical outcomes. What is needed is an evidenced-based serum magnesium reference interval that reflects optimal health and the current food environment and population. We present herein data from an array of scientific studies to support the perspective that subclinical deficiencies in magnesium exist, that they contribute to several chronic diseases, and that adopting a revised serum magnesium reference interval would improve clinical care and public health., Competing Interests: 4 Author disclosures: RB Costello, RJ Elin, A Rosanoff, TC Wallace, F Guerrero-Romero, A Hruby, PL Lutsey, FH Nielsen, M Rodriguez-Moran, Y Song, and LV Van Horn, no conflicts of interest., (© 2016 American Society for Nutrition.)

Background: Treatment of serum with ethanol at 100 ml/l eliminating fibrinogen from electrophoretic pattern produces an additional band at alpha2/beta junction. This study is to determine the source and the nature of this artifact., Methods: The supernatant after ethanol precipitation was used for electrophoresis. Protein concentrations of each fraction in ethanol- and saline-treated samples were compared, and immunofixation electrophoresis (IFE) to identify transferrin, C3, and LDL was performed. C3 IFE was also conducted for fresh sera and sera stored for 2 weeks., Results: The artificial band at alpha2/beta junction was identified in ethanol-treated sera but not in saline-treated sera. Protein concentration in the beta fraction was reduced after ethanol treatment as compared to saline-treated samples (n=10, p<0.01). The spurious band at alpha2/beta junction was recognized in C3 IFE. C3 IFE also showed a band at alpha2/beta junction in samples stored for 2 weeks., Conclusions: Ethanol treatment of serum creates an artificial band with C3 immunoreactivity at alpha2/beta junction. This could be due to the accelerated hydrolysis of C3 by ethanol treatment. Laboratories using ethanol to evaluate a possible fibrinogen band should be aware of this phenomenon, and the serum protein electrophoretic pattern after ethanol treatment should only be used to rule out fibrinogen.

Background: Conflicting data exist regarding the presence of magnesium (Mg) deficiency and the therapeutic efficacy of Mg in premenstrual syndrome or premenstrual dysphoric disorder (PMDD)., Methods: The % Mg retention was determined using 24-hour urinary Mg excretion and the total dose of Mg given intravenously. In women with (n = 17) and without (n = 14) prospectively diagnosed PMDD, several blood measures of Mg and mood were obtained before, immediately after, and the day following an intravenous Mg (.1 mmol/kg) loading dose. A positive mood response was seen under open conditions; as open Mg infusion improved mood, subsequent PMDD patients (n = 10) were randomized in a double-blind, placebo-controlled, crossover fashion., Results: Patients (31.5%) and control subjects (27.5%) retained comparable mean percentages of Mg. Neither group differed in measures of mean Mg before, immediately after, or the day following Mg infusion. Although there was a time effect for all mood measures in the patient group (p < .01 for all), there was neither a treatment nor time-by-treatment effect., Conclusions: Contrary to prior reports, we found no evidence of Mg deficiency in women with PMDD compared with control subjects. Furthermore, Mg was not superior to placebo in the mitigation of mood symptoms in women with PMDD.

Background: We determined the diagnostic value of the trypsin inhibitor, uristatin, that is commonly found in urine and plasma in patients with infections or inflammations of any kind., Methods: We collected urine specimens from patients with infections of the urinary or upper respiratory tract and from healthy controls. We also collected blood from patients with a likely upper respiratory tract infection and healthy controls. A bacterial count of >10(5) organisms/ml in urine was considered to represent infection rather than contamination., Results: The uristatin dipstick test in urine showed acceptable negative predictive values (NPV of up to 93%) for patients without infection or inflammation. Here, the dipsticks could eliminate some urine cultures. For those with infection or inflammation, the positive predictive values (PPV) of the dipsticks were lower (up to 57%). Including the leukocyte esterase and nitrite values increased the PPV of the dipsticks for those with disease., Conclusions: The uristatin strip was more accurate than the leukocyte and nitrite dipsticks for predicting upper respiratory infections (URI) and C-reactive protein for those with infection or inflammation. The uristatin dipstick was able to detect both the bikunin and uristatin inhibitors.

Interleukin 2 (IL-2) can cause partial or complete tumor regression in approximately 20% of patients with renal cell carcinoma. Among the many physiologic effects of IL-2, decreased serum levels of the divalent cations magnesium (Mg) and calcium have been demonstrated, with corresponding decreases in their urinary excretion. We investigated the effect of IL-2 on lymphocyte Mg levels among patients receiving three different dosing regimens. Twenty-eight patients with metastatic renal cell carcinoma were treated with high-dose intravenous, low-dose intravenous, or subcutaneous IL-2 therapy. Serum ionized Mg, urinary Mg, and peripheral blood mononuclear cell Mg levels were measured in samples from patients during treatment and compared with pretreatment levels. Serum Mg and ionized Mg levels decreased for all patients within 12 hours of treatment (P <.005) and remained low for the duration of therapy. Urinary Mg decreased in parallel with serum levels in all patients (P <.005). The peripheral blood mononuclear cell Mg content per cell increased within 24 hours of treatment (P <.005). The magnitude of these changes was similar during the first week of treatment for patients receiving intravenous or subcutaneous administration of IL-2. During IL-2 therapy, lymphocyte Mg increases coincident with serum Mg depletion. Mg availability may have functional implications for lymphocyte proliferation and integrin function.

Hypermagnesemia (6.95 mmol/l) and respiratory arrest occurred to a 20-year-old female (G3P2002) at 26 weeks of gestation during tocolytic treatment with MgSO4.7H2O (density greater than plasmalyte) injected into an i.v. infusion bag containing 1 l of plasmalyte without mixing. The patient was rescued with calcium gluconate and normal pregnancy continued. It is important to adequately mix an i.v. solution after adding a drug particularly when the drug-containing solution has greater density than the parent i.v. solution.

Many activities of magnesium have justified randomized controlled trials of its role in acute myocardial infarction (AMI), which have shown reduction of short term mortality by 25% to over 50%. The Fourth International Study of Infarct Survival (ISIS-4) megastudy failed to confirm these findings, and, based on analysis of pooled findings, it was concluded that magnesium has no place in treatment of AMI. The fixed effects statistical model employed in ISIS-4 for evaluation of pooled data is inappropriate because the studies were not homogeneous. Among the differences between the earlier studies and the megatrial, the most significant was the time at which magnesium infusions were started relative to the time of reperfusion. Animal studies have shown that magnesium is protective only if present before or at the time of reperfusion. Unlike in earlier trials, in which magnesium infusions were started soon after the ischemic event or simultaneously with a lytic agent, in ISIS-4 magnesium treatment was withheld until after iatrogenic or spontaneous reperfusion occurred. This can explain poor therapeutic results in ISIS-4, but not the hypotension and bradycardia encountered in a minority of patients in that study. Dosage difference alone cannot explain this, even though the amounts given in the small studies were 40% to 25% less than that in ISIS-4, because the dose used in the Second Leicester Intravenous Magnesium Intervention Trial (LIMIT-2) was only slightly lower than that used in ISIS-4. Administration of high dose magnesium with an angiotensin-converting enzyme inhibitor (which spares magnesium) or the vasodilating oral nitrate in arms of ISIS-4 may have contributed to adverse effects of hypermagnesemia. Also, the very low mortality rate of controls in ISIS-4 suggests that the patients may have been at relatively low risk, and it is in high risk patients that magnesium has been shown to be most effective. A large scale study of magnesium in such patients is being started.

We previously found an inverse correlation between platelet ionized magnesium concentration ((Mg2+)i) and serum total cholesterol concentration in normal male but not female subjects. In the present study, we determined the platelet (Mg2+)i by using a fluorescent ionized magnesium (Mg2+) indicator, FURAPTRA, and measured the serum concentrations of the following: total cholesterol; very-low-density lipoprotein cholesterol (VLDL-C); low-density lipoprotein cholesterol (LDL-C); high-density lipoprotein cholesterol (HDL-C); antioxidized low-density lipoprotein (LDL) autoantibodies; lipoprotein(a); apolipoproteins A-I (apo A-I) and B (apo B); triglycerides; estradiol-17 (E2); ceruloplasmin (Cp); and selected electrolytes, including total and ionized magnesium and calcium and total protein and albumin. In men, but not in women, platelet (Mg2+)i significantly inversely correlated with serum total cholesterol (r = -0.52, p < 0.02), LDL-C (r = -0.54, p < 0.009 by a "direct" method; r = -0.40, p < 0.05 by an electrophoretic method), and apo B (r = -0.42, p < 0.04). We found no significant correlations between platelet (Mg2+)i and any other variables, including serum total and ionized magnesium, antioxidized LDL autoantibodies, Cp, and E2. We speculate that decreased platelet (Mg2+)i is a possible marker for platelet membrane alterations that may affect platelet involvement in thrombosis and atherogenesis.

The current laboratory approach to assessing magnesium status is based on determining the concentration of total Mg ((Mg)) in serum or plasma. This strategy is problematic in that the amount of Mg in blood is less than 1% of total body Mg and does not accurately reflect (Mg) in other tissues. Furthermore, the (Mg) of blood does not distinguish biologically active, ionized Mg from the bound fraction. The goal of this study was to determine intracellular ionized Mg ((Mg++)i) of skeletal muscle in vivo and to compare results with the (Mg) of blood constituents. (Mg++)i was determined in resting skeletal muscle by using phosphorus 31 magnetic resonance (31P-MR) spectroscopy. (Mg) was measured in serum (S(Mg)), serum ultrafiltrate (UF(Mg)), mononuclear blood cells (MBC(Mg)), and red blood cells (RBC(Mg)) by using atomic absorption spectroscopy or a colorimetric assay. In a sample of 60 healthy adult subjects, skeletal muscle (Mg++)i = 557 +/- 97 mumol/L (mean +/- SD); S(Mg) = 0.78 +/- 0.09 mmol/L; UF(Mg) = 0.60 +/- 0.12 mmol/L; MBC(Mg) = 13.8 +/- 2.3 mmol/L; and, RBC(Mg) = 1.92 +/- 0.33 mmol/L. A significant negative correlation was found between (Mg++)i and S(Mg) (r = -0.43, p < 0.05). S(Mg) was significantly lower (p < 0.05) and (Mg++)i significantly higher (p < 0.05) in women than in men, but neither was related to age. These findings provide new insight into the relationship between blood Mg measures and (Mg++)i of the largest soft tissue mass of the human body.

The purpose of this study was to evaluate blood magnesium (Mg) measures across the menstrual cycle in women with premenstrual syndrome (PMS) and control women. Longitudinal determinations of plasma, red blood cell (RBC) and mononuclear blood cell (MBC) Mg were made in 26 women with prospectively confirmed PMS and in a control group of 19 women. Data were analyzed using analysis of variance with repeated measures and Spearman rank correlations. Significant diagnostic group effects were observed for RBC and MBC Mg concentrations (p < 0.05). These effects reflected lower Mg concentrations in PMS patients at each sampling time. No significant effects were observed for either plasma Mg or MBC Mg content, nor were there significant time by diagnosis effects for any of the measures. Consistent with earlier studies, we found decreased RBC Mg concentrations and additionally observed decreased MBC Mg concentrations in women with PMS. However, neither of these relative deficits were confined to the luteal phase.

Erosion of the dental hard tissues and enlarged parotid and submandibular saliva glands are commonly associated with bulimia nervosa. In 15 patients and controls, no significant difference was detected in the concentrations of potassium, chloride, calcium, urea nitrogen or albumin. There was also no evidence of olfactory dysfunction.

To evaluate the incidence, pattern and clinical importance of endotoxemia in septic shock, frequent, serial endotoxin determinations were made prospectively in patients with shock. Detectable endotoxin occurred in 43 of 100 patients with septic shock, but in only one of ten patients with shock due to nonseptic causes. During septic shock, endotoxemia frequently occurred in the absence of Gram-negative bacteremia. Using a logistic regression model, multiple organ failure occurred 10.3 times more frequently and depression of left ventricular ejection fraction (less than or equal to 45 percent) 4.8 times more frequently in endotoxemic patients. In patients with positive blood cultures, endotoxemia was associated with a high mortality. We conclude that endotoxemia occurs frequently in septic shock and is associated with severe manifestations of this syndrome, including cardiac depression and multiple organ failure. This study suggests that endotoxin is an important mediator of septic shock and supports efforts to develop anti-endotoxin therapies for treating patients with this disease.

We investigated the effects of two different Gram-negative bacteria and radiation-induced leukopenia on endotoxemia, cardiovascular abnormalities, and mortality in a canine model of septic shock. Serial hemodynamics were measured in conscious dogs using radionuclide heart scans and thermodilution cardiac output catheters. Plasma endotoxin concentrations were determined with a chromogenic Limulus amebocyte lysate assay. Viable Pseudomonas aeruginosa or Escherichia coli implanted intraperitoneally produced concordant hemodynamic patterns of septic shock (p less than 0.01). Endotoxin concentrations were more than tenfold lower in dogs infected with P aeruginosa compared with E coli (p less than 0.0001). Despite lower endotoxin levels, P aeruginosa-infected dogs had a higher mortality (p less than 0.01), more severe hypotension (p less than 0.05), and greater depression of the left ventricular ejection fraction (p less than 0.05) than dogs with E coli sepsis. A nonlethal E coli challenge combined with leukopenia (induced by a nonlethal dose of radiation) resulted in a mortality of 60 percent (p less than 0.01) without greater cardiovascular dysfunction or higher endotoxin concentrations. These findings suggest that bacterial products other than endotoxin and host-related factors may be important contributors to the toxicity, cardiovascular instability, and mortality of Gram-negative septic shock. Quantitative determinations of plasma endotoxin are unlikely to correlate with the clinical severity of septicemia in heterogeneous patient populations infected with different Gram-negative organisms.

In vitro von Willebrand factor is released from endothelial cells by a variety of stimuli. These studies have provided information on the synthesis, multimeric organization, sites of storage, and release of von Willebrand factor. We have administered endotoxin (Escherichia coli, 4 ng/kg) intravenously to 11 normal volunteers and have followed changes in levels of factor VIII, von Willebrand factor antigen, von Willebrand factor activity (ristocetin cofactor assay), and the multimeric organization of von Willebrand factor. Within 2 hours after injection, the levels of factor VIII, von Willebrand factor antigen, and von Willebrand factor activity rose significantly compared with the preinjection values (p less than 0.001, p less than 0.005, and p less than 0.001, respectively). The levels peaked 4 to 6 hours after the endotoxin injection. The mean peak values of von Willebrand factor antigen and activity were 4.67 microns/ml and 4.62 microns/ml, respectively. The factor VIII level rose to a mean of 2.87 microns/ml. Forty-eight hours after the administration of endotoxin, the von Willebrand factor antigen and activity levels remained significantly elevated (2.62 micrograms/ml and 2.20 microns/ml, respectively), but by 24 hours, the factor VIII level was not significantly elevated (1.47 microns/ml). After endotoxin administration, the agarose gel electrophoresis of von Willebrand factor demonstrated an increase in the largest von Willebrand factor multimers normally present and the appearance of von Willebrand factor multimers larger than those normally present in plasma. The largest von Willebrand factor multimers were present for 2 to 4 hours after the administration of endotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)

Rats placed on a magnesium-deficient diet show decreased erythrocyte magnesium concentration, shortened erythrocyte survival, and erythrocyte membrane ultrastructure defects and become progressively anemic. Whether these pathologic processes are due to abnormal erythropoiesis or occur in the peripheral circulation is unknown. In the present study, magnesium and hemoglobin concentrations, reticulocyte count, erythrocyte pyrophosphatase, and pyruvate kinase activities were determined at weekly intervals for 6 weeks in whole blood and age-dependent erythrocyte fractions isolated from inbred Fisher rats fed a diet deficient in magnesium or the same diet with added magnesium. Freeze-fracture electron microscopic examinations were performed on age-dependent erythrocyte fractions to evaluate the membrane defect. The youngest red cells from magnesium-deficient rats were similar to those of control animals with respect to erythrocyte magnesium concentrations, pyrophosphatase activities, and membrane morphology. The older erythrocyte fractions from magnesium-deficient rats showed significant decreases in magnesium concentrations, pyrophosphatase activity, and the presence of membrane abnormalities. Thus, new erythrocytes produced in magnesium-deficient rats appear to be normal but rapidly develop biochemical and morphologic abnormalities with aging in a magnesium-deficient plasma environment.

Transplantation of normal bone marrow to mice with the Chediak-Higashi syndrome (CHS) resulted in normal granulopoiesis and a reversal of their increased susceptibility to challenge with intravenous Candida albicans. These findings suggest that (1) the leukocyte defect in CHS can be reversed by marrow transplantation and (2) the mechanism for increased susceptibility to infection in these animals is due to a bone-marrow-derived cellular defect. Because of similarities between murine and human CHS, bone marrow transplantation might be considered as a mode of therapy in selected cases of the human disease.

Previous reports have shown that endotoxin decreases serum iron in experimental animals. In this study fever was produced in nine female and nine male normal subjects in order to define the temporal and quantitative changes in serum iron and ferritin concentrations. Six volunteers were randomly given bacterial endotoxin (5 ng/kg) or saline intravenously and received the alternative compound a week later. Serial blood samples were drawn at 4-hr intervals for a 24-hr period, beginning when the compound was administered, for the determination of serum iron and ferritin concentrations. The same study was performed with intramuscular etiocholanolone (0.3 mg/kg) or the vehicle, propylene glycol, as a control, but the first blood sample was obtained 9 hr after the compound was given. In addition, blood samples were obtained at 12-hr intervals in six volunteers for 11 days after an intramuscular injection of etiocholanolone. The results showed a significant increase (p less than 0.005 for etiocholanolone, P less than 0.01 for endotoxin) in serum ferritin and a significant decrease (p less than 0.005 for etiocholanolone, p less than 0.001 for endotoxin) in serum iron for both pyrogenic compounds compared with the control compounds. However, the amount of fever and the changes in the iron parameters were greater with etiocholanolone. One episode of induced fever with etiocholanolone effected changes in serum ferritin and iron concentrations that lasted 10 days. Thus this study demonstrated that a single episode of fever in man produced rapid and prolonged changes in serum iron and ferritin concentrations.

Pseudomonas aeruginosa pneumonia was produced in dogs with radiation-induced leukopenia to study the comparative efficacy of several different therapies. In a randomized control trial, five treatment regimens were compared: no antibiotics or granulocytes (controls), gentamicin (5 mg/kg/day), carbenicillin (500 mg/kg/day), gentamicin and carbenicillin (same dosages), and daily granulocyte transfusion (minimum 5 x 10(9) cells/day) plus gentamicin (5 mg/kg/day). The most effective therapy was gentamicin plus granulocyte transfusions. Gentamicin alone was not significantly better than no specific therapy. Carbenicillin with or without gentamicin gave intermediate results. This study further supports the utility of granulocyte replacement therapy of infections in severely granulocytopenic subjects. The results also indicate that the relative value of granulocyte transfusions depends upon the specific antibiotic regimen with which these transfusions are compared.

Blood concentrations of six acute phase reactants (ESR, neutrophil count, fibrinogen, haptoglobin, alpha 1-antitrypsin, and ferritin), parameters of muscle necrosis (myoglobin, CK, ALT, and AST) as well as hemopexin, iron, and TIBC were determined before and for 7 consecutive days after muscle biopsy in patients and in a control group. A muscle biopsy was chosen as a standardized surgical procedure that induces a mild transient inflammatory response. After muscle biopsy, a significant increase occurred in five (ESR, neutrophil count, fibrinogen, haptoglobin, and alpha 1-antitrypsin) of the six acute phase reactants. The concentration of serum ferritin did not show a significant change. A significant decrease was noted in the serum iron concentration and a significant increase occurred with CK and myoglobin secondary to the muscle biopsy. Thus the inflammation of a muscle biopsy produces a significant acute phase reaction.

This study investigated the anemia of dietary magnesium deficiency in inbred Fisher white rats using freeze-fracture electron microscopy. The plasma membranes of erythrocytes from animals receiving two different magnesium-deficient and control diets were observed at weekly or biweekly intervals for 6 wk. The earliest changes were small plaques on the external surface (ES) and fracture face (PF) of erythrocyte plasma membranes, which occurred after 2 wk of either magnesium-deficient diet. These plaques persisted and increased in size with progressive magnesium deficiency. When fully developed, the plaques consisted of round or oval elevations approximately 30-50 nm in diameter outlined by a narrow raised border. The surface of the plaques was smooth and devoid of intramembranous particles. Incubation of erythrocytes from magnesium-deficient rats in a physiologic solution containing 2 meq/liter magnesium for 1 hr at 37degrees C did not alter the appearance of the plaques. Erythrocytes from control rats, obtained during the same time periods, showed no plaques. Thus, a deficiency of magnesium in rats altered erythrocyte membrane structure.

Bacteremia that occurs after dental extraction is common. This study assessed the effect of topical antisepsis on the incidence and magnitude of post-extraction bacteremia. On hundred patients scheduled for elective tooth extraction were randomized among four groups: contr-l, mouthrinsing with sodium-p-toluene sulfonchloramide (chloramine-T), toothbrushing with chloramine-T, and irrigation with Lugol's solution. The results showed that 84% of the control group and 59% of the treatment groups had positive blood cultures (290 organisms isolated) after dental extraction. The duration and magnitude of these bacteremias were diminutive as documented by the six serial blood cultures taken for each patient, colony counts per milliliter of blood, and nitroblue tetrazolium and Limulus assays. Brushing the teeth or rinsing the mouth with chloramine-T before dental extraction significantly reduced the incidence of bacteremia (P less than .025) and the number of different organisms recovered from each patient (P less than .05). Thus, topical treatment with chloramine-T is a simple and effective means of reducing the incidence of postextraction bacteremia.

Magnesium deficiency in rats causes anemia, the mechanism of which is unknown. The effect of dietary magnesium, splenectomy, and magnesium content of erythrocytes on erythrocyte survival was studied in Fisher rats. Half of the animals were splenectomized, the remainder sham-splenectomized; each group was subdivided, and some were placed on a magnesium-deficient diet, the rest on a control diet. After 6 weeks, each of the four subgroups was divided, half were given 51Cr-labeled red cells from magnesium-deficient rats, the remainder, labeled normal red cells. The survival functions of the labeled erythrocytes were fitted to a mathematical model composed of both first-order and accelerating components. The results show that the most important factor influencing erythrocyte survival was dietary magnesium intake. The magnesium content of the transfused red cells affected erythrocyte survival only in the rats fed the control diet, whereas splenectomy affected erythrocyte survival only in rats receiving the magnesium-deficient diet. The accelerating component of the survival function was increased eightfold in the animals fed the magnesium-deficient diet, whereas much smaller changes occurred in the first-order components.