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R J Elin

Publications and source records attributed to R J Elin.

At least 37 records · Page 2Linked to original sources
PubMed1996

The differentiating agent phenylacetate increases prostate-specific antigen production by prostate cancer cells.

The prostatic-specific antigen (PSA) is the tumor marker most widely relied upon for the monitoring of patients with prostate cancer. Recently, declines in the serum concentrations of PSA have been advocated as a surrogate marker of tumor response in clinical trials of investigational antitumor agents. We examined the hypothesis that this postulate may not apply to the evaluation of drugs such as phenylacetate, a differentiating agent endowed with mechanisms of action different from those of classic cytotoxic chemotherapy. Using human prostatic carcinoma LNCaP cells as a model, we show that phenylacetate induces PSA production despite inhibition of tumor cell proliferation. Incubation of LNCaP cultures with cytostatic doses of phenylacetate (3-10 mM) resulted in a three- to fourfold increase in PSA secretion per cell. This appears to result from upregulation of PSA gene expression, as indicated by elevated PSA mRNA steady-state levels in treated cells. The increase in PSA production per cell was confirmed in rats bearing subcutaneous LNCaP tumor implants that were treated systemically with phenylacetate. Further comparative studies indicate that upregulation of PSA is common to various differentiation inducers, including all-trans-retinoic acid, 1,25-dihydroxyvitamin D3, and butyrate but is not induced by other antitumor agents of clinical interest such as suramin. We conclude that declines in PSA may be treatment specific and that the exclusive use of this criterion as a marker of disease response may mislead the proper evaluation of differentiating agents in prostate cancer patients.

Animals↗
PubMed1996

Is there a place for magnesium in the treatment of acute myocardial infarction?

Infusions of solutions of magnesium sulfate for patients with acute myocardial infarction were shown by a meta-analysis of seven small studies and a larger study of 2316 patients (LIMIT-2) to have clinical efficacy. However, the ISIS-4 study of 58,050 patients found no improvement in short-term mortality rates with magnesium therapy in patients with acute myocardial infarction. In this article we explore the following four differences between the ISIS-4 study and the earlier studies: (1) Time of initiation of magnesium treatment after acute myocardial infarction and thrombolytic therapy; (2) dosage of magnesium in the first 24 hours after acute myocardial infarction; (3) duration of magnesium infusion after acute myocardial infarction; and (4) differences in patient risks in control and treatment groups. These four differences may explain the different outcomes among these studies and indicate the type of additional studies that are needed to define the clinical utility of magnesium infusion in the treatment of patients with acute myocardial infarction.

Calcium Channel Blockers↗
PubMed1996

Relationship between skeletal muscle intracellular ionized magnesium and measurements of blood magnesium.

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.

Adult↗
PubMed1996

Role of endotoxemia in cardiovascular dysfunction and lethality: virulent and nonvirulent Escherichia coli challenges in a canine model of septic shock.

We investigated whether the severity of septic shock is determined by virulence factors associated with or the levels of endotoxemia produced by two Escherichia coli strains. Canines were challenged intraperitoneally with an E. coli strain (O6:H1:K2) that has virulence factors associated with human disease or with an equal dose of a nonvirulent strain (O86:H8) that lacks these factors. Both strains were administered in viable, heat-killed, and purified endotoxin forms. Median survival times with the virulent strain compared with the nonvirulent strain were shorter with viable bacteria (5 x 10(10) CFU/kg) (144 h versus > 672 h; Wilcoxon, P = 0.03), longer with heat-killed bacteria (5 x 10(9) CFU/kg) ( > 676 h versus 26 h; P = 0.03), and similar with purified endotoxin (15 mg/kg) (28 h versus 48 h; P = 0.71). However, whether the challenge contained viable bacteria, heat-killed bacteria, or purified endotoxin, the virulent strain produced less endotoxemia (P = 0.001). Hence, the changing outcomes with differing forms of the two strains cannot be attributed solely to endotoxin levels. The viable virulent strain caused less endotoxemia but more harm, and this does not appear to be explained by a more potent endotoxin or other heat-stable component. This study suggests that circulating endotoxin levels per se are less important in the outcome of septic shock than virulence factors associated with E. coli strains. Furthermore, the data call into question the significance of the endotoxin concentration in the blood in predicting the severity of shock and the lethality of gram-negative infections.

Animals↗
PubMed1996

Comparison of precision and effect of pH and calcium on the AVL and NOVA magnesium ion-selective electrodes.

We compared the precision of the AVL 988-4 and NOVA CRT instruments for determining ionized magnesium (iMg) and assessed the effect of pH and ionized calcium (iCa) concentration on the results Within-run and day-to-day precision for the iMg electrodes were determined using three levels of control material supplied by each manufacturer. The effect of pH on iMg results was assessed by analyzing anaerobic serum samples from patients, reanalyzing those same samples after pH was increased by in vitro loss of CO2 and comparing the results. To assess the effect of iCa concentration on the iMg results, we added CaCl2 to aqueous standards from both manufacturers and to a normal serum pool. The results show comparable coefficients of variation for the two iMg electrodes both within-run (0.68-2.05 for NOVA; 0.77-2.60 for AVL) and day-to-day (2.90-6.48 for NOVA; 1.71-4.93 for AVL). The AVL results were not affected by the increase in serum pH and agreed with the NOVA results that were adjusted to a pH of 7.4 (paired t-test; p > 0.2). There was a significant direct relationship between the iCa and iMg results for both analyzers, but the AVL slopes were smaller (0.026, 0.083) than the NOVA slopes (0.129, 0.165). Thus, these two iMg electrodes have comparable precision but differ in response to an increase in pH and iCa.

Calcium↗
PubMed1996

Determination of ionized magnesium in platelets and correlation with selected variables.

We describe a method for determining the intracellular ionized magnesium concentration ([Mg2+]i) in platelets by using the fluorescent probe FURAPTRA. We determined the dissociation constant (KD) of FURAPTRA for Mg2+ (2.26 +/- 0.29 mmol/L), within-day assay variability (CV = 6.8%), among-day intraindividual variability (CV = 11.0%), variability after a 4-h delay in processing the blood specimen (t = 1.2, P >0.2; F = 6.2, P <0.02), and the reference interval (0.23-0.59 mmol/L) for this assay. We also evaluated the correlation between platelet [Mg2+]i and concentrations of selected serum electrolytes, proteins, and total cholesterol; age; body mass index; and gender. Only the inverse correlation between platelet [Mg2+]i and serum total cholesterol concentration in men was significant (r=-0.66, P <0.005).

Adult↗
PubMed1996

Linearity and stability of the AVL and Nova magnesium and calcium ion-selective electrodes.

We studied the stability and linearity of the AVL and Nova Mg and Ca ion-selective electrodes and the relation between the ionized Ca and ionized Mg results reported by each analyzer. The response of the electrodes to different concentrations of Mg and Ca was determined for saline solutions, aqueous solutions, and serum samples. The electrodes from both manufacturers demonstrated acceptable stability for the time of the study. The response of the electrodes was linear within the range specified by each manufacturer, but relative nonlinearity and the values for the linear limits differed between the AVL and Nova analyzers. The ionized Mg results varied with the concentration of Ca. The relation between ionized Ca and ionized Mg results was nonlinear and differed between the AVL and Nova electrodes. Intermethod comparison between the electrodes showed poor agreement for ionized Mg results, especially at low and high concentrations of total Ca and total Mg.

Calcium↗
PubMed1995

Skeletal muscle intracellular ionized magnesium measured by 31P-NMR spectroscopy across the menstrual cycle.

OBJECTIVE: The hormonal regulation of magnesium (Mg) metabolism is poorly understood. Preliminary evidence suggests that reproductive hormones may influence Mg concentrations in various tissues. The purpose of this study was to determine if Mg concentrations in blood and muscle are affected by the phase of the menstrual cycle. METHODS: Magnesium measures were obtained from 16 women over the course of one complete menstrual cycle. The principal outcome measure was intracellular ionized Mg ([Mg++]i) in skeletal muscle as measured by 31P nuclear magnetic resonance spectroscopy. Three blood measures (serum, red blood cell, and mononuclear blood cell) of total Mg ([Mg]) were also obtained. RESULTS: Mean Mg concentrations were stable across the menstrual cycle with no evidence of a menstrual cycle phase effect for any of the measures. Furthermore, skeletal muscle [Mg++]i was not correlated with any blood measure of [Mg]. CONCLUSION: These results suggest that physiologic fluctuations in reproductive hormones do not influence either blood [Mg] or skeletal muscle [Mg++]i in healthy, regularly cycling women.

Adult↗
PubMed1995

Differential hemodynamic effects of L-NMMA in endotoxemic and normal dogs.

We studied the differential hemodynamic effects of N omega-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthesis, in normal and endotoxemic dogs and examined its activity across the venous, pulmonary, and systemic circulations. Survival was used to determine therapeutic efficacy. In both normal and endotoxemic animals, L-NMMA similarly increased systemic (P = 0.01) and pulmonary (P = 0.047) vascular resistance, marginally increased mean arterial pressure (P = 0.07), and decreased oxygen delivery (P = 0.01) compared with normal saline. In contrast, the effect of L-NMMA on mean pulmonary arterial pressure, central venous pressure, and pulmonary capillary wedge pressure was different in endotoxemic than in normal animals (P < 0.05), but this differential effect occurred > 6 h after endotoxin challenge. L-NMMA (1-10 mg.kg-1.h-1) did not significantly increase survival rates or times in endotoxemic animals, but the highest dose decreased survival times (P < 0.05). Thus the effect of L-NMMA was similar on the systemic arterial circulation in endotoxemic dogs compared with normal dogs but was increased in the venous and pulmonary vascular beds after endotoxin, suggesting that the induction of NO production was greater in low-resistance vessels. We were unable to show that nonselective inhibition of NO production was beneficial in endotoxemic dogs.

Animals↗
PubMed1995

Analyzer-dependent differences in results for ionized calcium, ionized magnesium, sodium, and pH.

We compared two ion-selective analyzers (AVL 988-4 and NOVA CRT) for determining ionized calcium (iCa2+), ionized magnesium (iMg2+), sodium (Na+), and pH in serum specimens from healthy and diseased individuals. For assays of three levels of protein-based control materials, total imprecision (CV) was < 3% for all analytes except iMg2+ (< or = 6.5% on NOVA, and < or = 4.9% on AVL). We found a significant difference between the analyzers (P < 0.001) for the mean iMg2+ concentration in patients but no significant correlation (r = 0.253) between the analyzers for iMg2+ in specimens from healthy volunteers, even though the mean iMg2+ concentration did not differ significantly between these groups. The reference interval (central 95 percentiles) for iMg2+ with AVL (0.44-0.60 mmol/L) was contained within that of NOVA (0.39-0.64 mmol/L). The AVL gave higher values for iCa2+ (P < 0.001) and lower values for pH (P < 0.001) in specimens from normal volunteers and patients. The mean value for Na+ in patients' samples was significantly higher by the NOVA (P < 0.01) than by the AVL analyzer. Thus, we found significant differences between these two analyzers for all four analytes.

Calcium↗
PubMed1995

Therapeutic trial of reconstituted human high-density lipoprotein in a canine model of gram-negative septic shock.

In a controlled, randomized trial, the authors investigated the effects of reconstituted human high-density lipoprotein (R-HDL) on survival, endotoxemia, cytokine production and pathophysiologic and metabolic events in an animal model of gram-negative septic shock. At 0.5, 8 and 16 hr after implantation of a clot infected with Escherichia coli, canines received intravenous R-HDL (n = 13), control lipid (n = 7) or human serum albumin (HSA, n = 7) divided into three doses (0.3, 0.1 and 0.1 g/kg, respectively) at an hourly rate of 0.1 g/kg. All animals were treated with antibiotics and fluids. Animals treated with R-HDL had lower levels of circulating endotoxin and tumor necrosis factor and a smaller decrease in white blood cell counts than did animals treated with lipids and HSA (all P < .05). The survival times of lipid- and HSA-treated animals were similar (P = .3) and were significantly greater than those of R-HDL-treated animals (P = .02). During the first 6 hr after clot implantation, R-HDL-treated animals had significantly greater abnormalities in liver function test findings compared with lipid- and HSA-treated animals (all P < .05). For the first 24 hr, R-HDL-treated animals had significant increases in HDL levels; however, there were no significant relationships between these levels and the constituents of HDL (apolipoprotein AI and phosphatidylcholine) or liver function abnormalities and survival times (all r < .2, P > .3). In normal animals, administration of R-HDL (in similar doses) caused transient elevation of liver enzymes; in animals given sterile clot i.p., R-HDL caused seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Magnesium measures across the menstrual cycle in premenstrual syndrome.

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.

Adult↗
PubMed1994

The third component of complement protects against Escherichia coli endotoxin-induced shock and multiple organ failure.

We investigated whether the third component of complement (C3) is involved in the pathophysiology of endotoxic shock, and if it is involved, whether it plays a protective role or whether it mediates shock and multiple organ failure. In a prospective, controlled investigation, six Brittany spaniels that were homozygous for a genetically determined deficiency of C3 (C3 deficient, < 0.003% of normal serum C3 levels) and six heterozygous littermates (controls, approximately 50% of mean normal serum C3 level) were given 2 mg/kg of reconstituted Escherichia coli 026:B6 acetone powder as a source of endotoxin, intravenously. All animals were given similar fluid and prophylactic antibiotic therapy, and had serial hemodynamic variables obtained. After E. coli endotoxin infusion, C3-deficient animals had higher peak levels of endotoxin and less of a rise in temperature than controls (P < 0.05). During the first 4 h after E. coli endotoxin infusion, C3-deficient animals had significantly greater decreases in mean central venous pressure and mean pulmonary artery pressure than controls (P < 0.02). During the first 48 h after E. coli endotoxin infusion, C3-deficient animals had significantly greater decreases in mean arterial pH, left ventricular ejection fraction, and mean pulmonary capillary wedge pressure, and greater increases in mean arterial lactate, arterial-alveolar O2 gradient, and transaminases (aspartate aminotransferase and alanine aminotransferase) than controls, (all P < 0.05). After E. coli endotoxin infusion, C3-deficient animals compared to controls had significantly less of a decrease in mean C5 levels (P < 0.01), but similar (P = NS) increases in circulating tumor necrosis factor levels, bronchoalveolar lavage neutrophils, and protein, and similar (P = NS) decreases in blood leukocytes and platelets. Two of six C3-deficient animals and two of six controls died. In summary, after intravenous infusion of E. coli endotoxin, canines with C3 deficiency have decreased endotoxin clearance and worse E. coli endotoxin-induced shock and organ damage. Thus, the third component of the complement system plays a beneficial role in the host defense against E. coli endotoxic shock.

Analysis of Variance↗
PubMed1994

Effect of dextroamphetamine and methylphenidate on calcium and magnesium concentration in hyperactive boys.

Levels of calcium in plasma, red blood cells, and mononuclear blood cells, levels of calcium in plasma, and the plasma calcium-to-magnesium ratio were measured at baseline and after 3 weeks of each drug phase of a double-blind, placebo-controlled study of methylphenidate and dextroamphetamine in hyperactive boys. Levels of magnesium in plasma were significantly higher after 3 weeks of dextroamphetamine treatment, and the calcium-to-magnesium ratio was significantly lower after 3 weeks of either drug compared with the baseline or placebo condition. There was no change in magnesium levels in red blood cells or mononuclear blood cells. These measures were obtained 30 minutes before the morning dose and at 9 a.m., 9:30 a.m., 10:30 a.m., 11:00 a.m., and noon on the last day of each 3-week phase. Analysis of variance revealed a drug effect on plasma magnesium and on the calcium-to-magnesium ratio but no drug x time interaction. Although these changes were not correlated with the time course of acute symptomatic response to stimulant therapy, the decrease in the ratio may be relevant to side effects and treatment resistance associated with stimulant use.

Attention Deficit Disorder with Hyperactivity↗
PubMed1994

Erythrocyte and mononuclear blood cell magnesium concentrations are normal in hypomagnesemic patients with chronic renal magnesium wasting.

OBJECTIVE: The purpose of this study was to determine the plasma, erythrocyte, and mononuclear blood cell (MBC) magnesium concentrations in patients with chronic, severe hypomagnesemia due to a chronic magnesium-wasting tubulopathy. METHODOLOGY: Six patients with Bartter's syndrome and five patients with magnesium-wasting tubulopathy were compared with normal subjects. We determined magnesium in plasma, erythrocytes, and MBCs. RESULTS: Patients with chronic magnesium-wasting tubulopathy had a significantly lower plasma magnesium concentration than controls, but erythrocyte magnesium concentration and MBC magnesium concentration and content did not differ significantly between patients and controls. CONCLUSION: Two disorders with chronic magnesium-wasting tubulopathies are associated with a low plasma magnesium concentration but normal erythrocyte and MBC magnesium.

Bartter Syndrome↗