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PubMed1976

Ionized and total serum calcium and parathyroid hormone in hyperthyroidism.

Total and ionized calcium concentrations as well as parathyroid hormone levels were measured in a group of hyperthyroid persons. Ionized and total calcium levels were elevated in 21 of 45 (47%) and in 12 of 45 (27%) thyrotoxic patients, respectively. Mean ionized and total calcium levels were higher in these 45 patients than in normal persons. Using two different radioimmunoassay systems for a total of 44 determinations, mean parathyroid hormone levels were lower in thyrotoxic patients than in subjects with proved hyperparathyroidism. These data suggest that [1] elevations of both ionized and total calcium concentrations occur frequently in thyrotoxic patients; [2] ionized calcium concentrations may be elevated in a higher percentage of hyperthyroid subjects than are total calcium concentrations; and [3] the hypercalcemia associated with thyrotoxicosis is not associated with elevated parathyroid hormone levels.

Calcium↗
PubMed1977

Furosemide-induced reduction in ionized calcium in hypoparathyroid patients.

Six hypoparathyroid patients were treated with oral furosemide for 4 days. All six had a significant decrease in serum ionized calcium level from the control period (4.05 +/- 0.31 mg/dl) to the furosemide period (3.46 +/- 0.26 mg/dl, P less than 0.005). In five patients, the decrease in serum ionized calcium concentration occurred in association with an increase in urinary calcium excretion. Although serum immunoreactive parathyroid hormone level increased in five patients, it was insufficient to return serum ionized calcium to control levels. Changes in serum phosphorus, magnesium, or pH could not account for the observed decrease in serum ionized calcium concentration. It is necessary to monitor serum ionized calcium level in hypoparathyroid patients during furosemide therapy.

Adult↗
PubMed2000

Acute cord occlusion increases blood ionized magnesium concentration in preterm fetal sheep during maternal magnesium sulfate exposure.

This study tested the hypothesis that a pathophysiologic insult to the fetus that decreases pH (umbilical cord occlusion) produces an increase in physiologically active (i.e., ionized) magnesium concentration. Preterm pregnant sheep (n = 7) were instrumented with maternal and fetal catheters and an inflatable vascular occluder was placed around the umbilical cord. After a 2-day recovery period, each ewe received a 4-g loading dose, followed by continuous intravenous infusion of 1 g magnesium sulfate/h. After 48 h, an episode of acute fetal distress was produced by inflation of the umbilical occluder for 10 min. Maternal and fetal arterial blood samples were collected at regular intervals to quantitate ionized magnesium concentration and monitor physiologic status. Magnesium sulfate infusion increased maternal and fetal blood ionized magnesium concentration. In vitro blood analysis demonstrated that there was a linear inverse correlation (r2 = 0.99) between fetal sheep blood pH and ionized magnesium concentration. In vivo, 10 min of umbilical cord occlusion produced an increase in fetal blood ionized magnesium concentration in all animals (P = 0.02) that was temporally related to the decrease in fetal blood pH. Whether this increase in physiologically active magnesium concentration is beneficial (via neuroprotection) or deleterious (via suppression of stress response) to the distressed fetus remains to be determined.

Animals↗
PubMed2000

Hematopoietic neoplasia in C57BL/6 mice exposed to split-dose ionizing radiation and circularly polarized 60 Hz magnetic fields.

This study assessed the effect of chronic exposure to a 60 Hz circularly polarized magnetic field on the occurrence of ionizing radiation-induced lymphoma and other hematopoietic neoplasia in mice. Female C57BL/6 mice received lifetime exposure to either a magnetic field flux density of 1.42 mT for 18 h/day, or an ambient magnetic field of 0.13 microT. Beginning on the first day of magnetic field exposure, 1710 mice were treated with one of three levels of split-dose Cobalt-60 gamma-radiation (cumulative 3.0, 4.0 or 5.1 Gy). The remaining 570 mice received sham irradiation treatment. Sections from 10 lymphoid tissues were evaluated histopathologically for hematopoietic neoplasia. The primary statistical analysis used the Poly3 method to compare lymphoma incidences in magnetic field (MF)-exposed and control mice. Secondary analyses used the Cox proportional hazards model to analyze incidence rates for mortality and development of specific types of neoplasia. The mortality incidence rate was increased by ionizing radiation treatment, and all neoplasms were observed sooner in irradiated mice. However, the lifetime incidence of hematopoietic neoplasia was similar in all experimental groups, including those that were not exposed to ionizing radiation. Chronic exposure to MFs did not affect the mortality incidence rates and did not change the relative incidences of hematopoietic neoplasia in mice that received the same ionizing radiation treatment, with the exception of a marginally significant reduced relative risk of 0.97 (P = 0.05) for lymphoblastic lymphoma in mice exposed to a magnetic field and treated with 5.1 Gy. Lymphomas and histiocytic sarcomas were first observed approximately 50 days sooner in mice that were exposed to magnetic fields but not ionizing radiation, although this comparison was not statistically significant and the incidence of hematopoietic neoplasia in these mice was not different from that of mice in the 0 T/0 Gy group.

Animals↗
PubMed2002

Tissue-specific deletion and discontinuous loss of heterozygosity are signatures for the mutagenic effects of ionizing radiation in solid tissues.

The mouse Aprt locus on chromosome 8 was used as the selectable target for the study of spontaneous and ionizing radiation-induced mutations in kidney epithelia and ear fibroblasts. Fifty-two Aprt heterozygous mice were exposed to 7.5 Gy of (137)Cs-gamma radiation on their right sides, and Aprt-deficient clones were isolated from enzymatically digested tissues at times ranging from 1 day to 14 months after irradiation. A statistically significant increase in the mutant frequencies for the irradiated tissues was observed when compared with the spontaneous mutant frequencies for the nonirradiated tissues. A molecular analysis of spontaneous mutations observed for the nonirradiated tissues revealed tissue-specific differences; apparent chromosome loss was common in kidney mutants but infrequent in the ear mutants, whereas apparent deletions were common in the ear mutants but not detected in the kidney mutants. For the irradiated kidneys, apparent deletions were observed commonly demonstrating that these events are markers for ionizing radiation mutagenesis in this tissue. All of the loss of heterozygosity (LOH) tracts observed in the spontaneous mutants were continuous, but discontinuous LOH patterns were observed in 6--8% of ionizing radiation-induced ear and kidney cell mutants. Work with kidney-derived cell lines showed that discontinuous LOH is a novel signature for delayed ionizing radiation mutagenesis. Considered together, these results suggest that ionizing radiation-induced mutations in vivo can result from both direct and delayed mutagenic effects.

Animals↗
PubMed1975

[Acid-base properties and the thermodynamics of amphotericin B ionization in aqeous solutions].

Acid-base properties of amphotericin B, polyenic antibiotic in aqueous solutions was studied. A special procedure provided the use of potentiometric titration for investigation of ionization of the groups of the water-insoluble substance. The ionization constants of the carboxylic and amine groups of the antibiotic were determined at several temperatures. It was found that ionization of the acid group did not depend on the temperature. At the same time the heat effect of the amine group ionization was significant and amounted to about 10 kcal/mole. Thermodynamic analysis of the ionization process of amphotericin B in aqueous solutions was performed. Integral components defining the process energetics were calculated.

Acid-Base Equilibrium↗
PubMed2003

Tumor response to ionizing radiation combined with antiangiogenesis or vascular targeting agents: exploring mechanisms of interaction.

Recent preclinical studies have suggested that radiotherapy in combination with antiangiogenic/vasculature targeting agents enhances the therapeutic ratio of ionizing radiation alone. Because radiotherapy is one of the most widely used treatments for cancer, it is important to understand how best to use these two modalities to aid in the design of rational patient protocols. The mechanisms of interaction between antiangiogenic/vasculature targeting agents and ionizing radiation are complex and involve interactions between the tumor stroma and vasculature and the tumor cells themselves. Vascular targeting agents are aimed specifically at the existing tumor vasculature. Antiangiogenic agents target angiogenesis or the new growth of tumor vessels. These agents can decrease overall tumor resistance to radiation by affecting both tumor cells and tumor vasculature, thereby breaking the codependent cycle of tumor growth and angiogenesis. The hypoxic microenvironment of the tumor also contributes to the mechanisms of interactions between antiangiogenic/vasculature targeting agents and ionizing radiation. Hypoxia stimulates up-regulation of angiogenic and tumor cell survival factors, giving rise to tumor proliferation, radioresistance, and angiogenesis. Preclinical evidence suggests that antiangiogenic agents reduce tumor hypoxia and provides a rationale for combining these agents with ionizing radiation. Optimal scheduling of combined treatment with these agents and ionizing radiation will ultimately depend on understanding how tumor oxygenation changes as tumors regress and regrow during exposure to these agents. This review article explores the complex interactions between antiangiogenic/vasculature targeting agents and radiation and offers insight into the mechanisms of interaction that may be responsible for improved tumor response to radiation.

Angiogenesis Inhibitors↗
PubMed1992

Ionized calcium in patients with chronic renal failure.

Parameters of various renal disorders were studied in 31 patients (17 men and 14 women) who all were in the stage of chronic renal failure (CRF). These parameters included total serum creatinine, ionized calcium, serum creatinine, creatinine clearance and acid-base balance. The results were compared with a control group of 30 healthy subjects. In the patients with first stage CRF, the total serum calcium did not significantly decrease (mean = 2.19 +/- 0.12 mmol/l) and ionized calcium was within reference value limits (mean = 1.28 +/- 0.02 mmol/l). The percentage of ionized calcium in total serum calcium was higher for these patients (mean = 58.43%) than for the control group (mean = 52.25%). For patients with first and second stage CRF, the total serum was significantly lower (mean = 1.92 +/- 0.03 mmol/l) than for the healthy controls (p < 0.001) as well as for patients with first stage CRF (p < 0.05). The ionized calcium in these patients was not significantly lower (mean = 1.14 +/- 0.01 mmol/l); however, its percentage was higher than that of serum calcium (mean = 59.38%). There was a slight negative correlation between the levels of ionized calcium and serum creatinine in patients with first stage CRF (r = -0.30) and a significant correlation in patients with second and third stage CRF.

Adult↗
PubMed1992

Down-regulation of cell cycle control genes by ionizing radiation.

The cellular responses to ionizing radiation include growth arrest, DNA repair, and lethality. However, little is known about the signaling events responsible for these responses. The present studies have examined the effects of ionizing radiation on the expression of genes involved in cell cycle control. The results demonstrate that the treatment of asynchronous cells with 20 Gy ionizing radiation is associated with transient down-regulation of the cdc2, cyclin A, cyclin B, and cdc25 genes. This effect was associated with transient induction of the c-jun gene. RNA stability studies demonstrate that the down-regulation of gene expression following ionizing radiation exposure is at least in part due to a decrease in transcript half-life. Other studies were performed with elutriated cells enriched for populations in G1 and S phases. Treatment of G1 enriched cell populations with 10 Gy resulted in a selective decrease in cyclin B mRNA levels, whereas this effect on cyclin B expression was less pronounced at 5 Gy and undetectable at 1 Gy. Similar results were obtained with S phase enriched cells. Taken together with clonogenic survival studies, these findings indicate that down-regulation of cell cycle control gene expression is associated with lethality, whereas lower doses of ionizing radiation have little, if any, effect on the expression of these genes. The findings also suggest that DNA damage may activate signaling events which regulate expression of cell cycle control genes.

CDC2 Protein Kinase↗
PubMed1992

Effects of ionizing radiation and beta-adrenergic stimulation on the expression of early response genes in rat parotid glands.

There is little known about the regulation of gene expression in rat parotid glands after exposure to ionizing radiation. The present studies investigate the effects of in vivo ionizing radiation, with subsequent stimulation of beta-adrenergic receptors by isoproterenol, on parotid gland function and on the expression of the early response genes, c-fos, c-jun, and jun B. Ionizing radiation diminished parotid gland weight and saliva output. Treatment of irradiated rats with isoproterenol increased the gland weight to levels similar to those in nonirradiated rats. However, such treatment had no effect on saliva output as indicated by measurements of parotid salivary flow rate. Irradiation alone increased the expression of c-fos, c-jun, and jun B. The combination of irradiation and isoproterenol had an additional effect on the levels of c-fos and jun B mRNAs and proteins particularly at earlier experimental times (1 to 8 h). Isoproterenol alone induced high levels of c-fos and jun B mRNA but not of c-jun mRNA. However, c-jun mRNA was induced markedly by radiation and 8 h of isoproterenol treatment, indicating a combined effect on c-jun gene expression. These observations suggest that the expression of the proto-oncogenes c-fos, c-jun, and jun B is probably regulated through differential signal transduction pathways which may be activated by these external stimuli and may be associated with functional changes induced in the rat parotid gland by ionizing radiation and by ionizing radiation and isoproterenol.

Animals↗
PubMed2006

Evaluation of ionized and total serum magnesium concentrations in hyperthyroid cats.

Hyperthyroidism can increase the renal excretion of magnesium and thus cause hypomagnesemia in various species. Anaerobically collected blood samples from 15 hyperthyroid and 40 normal, healthy cats were analyzed with an ion-selective electrode analyzer and a serum biochemical analyzer. There was no significant difference in ionized or total serum magnesium concentration between the 2 groups, but there was a significant difference (P = 0.004) in the ratio of ionized to total serum magnesium concentrations between the healthy cats and the hyperthyroid cats with thyroxine (T4) concentrations at or above the median. There was a significant correlation (r = 0.894, P = 0.000) between the ionized and total magnesium concentrations in the hyperthyroid cats. The hyperthyroid cats had a significantly lower (P = 0.003) total serum protein concentration than the healthy cats. A significant negative correlation (r = -0.670, P = 0.006) was detected between the ionized magnesium and logarithmically transformed total T4 concentrations in the hyperthyroid cats, which suggests that the severity of hyperthyroidism may contribute to a decrease in the ionized magnesium concentration.

Animals↗
PubMed1991

Dry electrolyte-balanced heparinized syringes evaluated for determining ionized calcium and other electrolytes in whole blood.

By analyzing whole blood containing no anticoagulants (uncoagulated whole blood) immediately after collection, we evaluated the relative changes in the concentrations of ionized calcium and other electrolytes in whole blood collected in dry heparinized syringes and in serum prepared from blood collected in evacuated blood-collection tubes. Using these dry heparinized syringes, we collected and analyzed whole blood that contained either 33 or 13 int. units of lithium heparin or 40 int. units of electrolyte-balanced heparin per milliliter of blood. We evaluated the effects both of these heparins at different concentrations of ionized calcium and of the incomplete filling of the syringes. We conclude that: (a) when analyzed within 2-3 min after collection, uncoagulated whole blood provides ionized calcium results unaffected by anticoagulants or cellular metabolism; (b) the preparation of serum unpredictably changes ionized calcium; (c) the use of dry electrolyte-balanced heparin virtually eliminates the interference in ionized calcium concentrations between 0.9 and 1.6 mmol/L; and (d) incomplete filling of electrolyte-balanced heparinized syringes produces no effect in syringes two-thirds full (60 int. units/mL heparin concentration) and a small effect in syringes one-third full (120 int. units/mL heparin).

Adult↗
PubMed1991

The pH variation of steady-state kinetic parameters of site-specific Co(2+)-reconstituted liver alcohol dehydrogenase. A mechanistic probe for the assignment of metal-linked ionizations.

To identify ionizations of the active site metal-bound water in horse liver alcohol dehydrogenase (alcohol:NAD+ oxidoreductase; EC 1.1.1.1), the pH, solvent isotope, temperature, and anion dependences of the steady-state kinetic parameters kcat and kcat/KM have been evaluated under initial velocity conditions for the native and the active site-specific Co(2+)-reconstituted enzyme. In the oxidation of benzyl alcohol, a bell-shaped pattern of four prototropic equilibria was observed under conditions of saturating concentrations of NAD+. It is shown that the ionizations governing kcat (pK1 congruent to 6.7, pK2 congruent to 10.6) belong to the ternary enzyme-NAD(+)-alcohol complex, whereas the ionizations governing kcat/KM (pK1' congruent to 7.5, pK2' congruent to 8.9) belong to the binary enzyme-NAD+ complex. The ionizations pK1 and pK1' are not influenced by metal substitution and are ascribed to His-51 on the basis of experimental estimates of their associated enthalpies of ionization. On the other hand, pK2 and pK2' are significantly decreased (delta pKa congruent to 1.0) in the Co(2+)-enzyme and are attributed to the active site metal-bound water molecule. The shape of the pH profiles requires that the metal ion coordinates a neutral water molecule in the ternary enzyme-NAD(+)-alcohol complex under physiological conditions. The possible catalytic role of the water molecule within a pentacoordinate metal ion complex in the active site is discussed.

1-Propanol↗
PubMed1990

Determination of phenolic ionization constants of anthracyclines with modified substitution pattern of anthraquinone chromophore.

The phenolic ionization constants in aqueous solution of doxorubicin, daunorubicin and nine daunorubicin analogues with different substitution patterns at the anthraquinone moiety have been determined spectrophotometrically upon taking into account aggregation effects with extrapolation to infinite dilution. In contrast with an early literature report [Sturgeon, R.J. & Schulman, S.G. J. Pharm. Sci. 66, 958-961; 1977] the perturbation from amino group ionization on daunosamine sugar was found to be negligible in our spectrophotometric titrations. Accordingly, only phenol hydroxyl ionization constants could be determined in these experiments, but a crude estimate of daunosamine pKa was obtained in a fluorometric titration. From a comparison of suitable analogues it is concluded that the phenolic function at C11 in doxorubicin and daunorubicin is the most acidic one. The higher pKa of the C6-OH group is ascribed in part to electronic effects leading to higher strength of the corresponding hydrogen bond with quinone oxygen, and in part to a steric effect from the bulky sugar group at C7. Ionization constants of nitro or amino substituted derivatives follow the expected trend. In the cases of carminomycin and 6-deoxycarminomycin, which both have another phenolic group at C4, two phenolic ionization processes can be detected in the experimentally accessible pH range (5-12): these are ascribed to C4-OH and C11-OH. An application of the compiled parameters to studies of chemical reactivity and biological activity of anthracyclines is foreseen.

Anthraquinones↗
PubMed1989

Comparison of serum total calcium, albumin-corrected total calcium, and ionized calcium in 1213 patients with suspected calcium disorders.

The correlations between serum ionized calcium, serum total calcium, total calcium corrected for albumin and calculated ionized calcium were investigated in a prospective multicentre investigation of 1213 patients suspected of having calcium metabolic disease. Diagnostic discordance between serum total calcium and measured ionized calcium was found in 31% of the patients. With the calculation of albumin-corrected total calcium or calculated ionized calcium the discordance decreased to 17.9%. The diagnostic discordance which could be ascribed to the analytical imprecision (CV = 1.5%) amounted to only 6.7%. Although we found highly significant correlations between the parameters, a considerable scatter around the regression line made prediction of ionized calcium from albumin-corrected total calcium unreliable in many patients.

Algorithms↗
PubMed1989

Effects of in vivo and in vitro production of lactic acid on ionized, protein-bound, and complex-bound calcium in blood.

We have studied, both in vitro and in vivo, the quantitative effects of lactic acid production on concentrations of ionized calcium, bound calcium, pH, bicarbonate, and albumin. To do so, we examined the effects of addition of aqueous solutions of either hydrochloric acid, lactic acid, or lithium lactate to blood; we studied in vitro accumulation by storing blood sealed in tubes at room temperature for 5 h, then exposing the blood to air; and we induced in vivo production of lactic acid in healthy individuals who climbed stairs for 10 min. Lactic acid evidently affects the ionized, protein-bound, and complex-bound calcium concentrations in the following ways: (a) hydrogen ions from lactic acid bind to protein, which decreases protein-bound calcium; (b) lactate chelates calcium ions from free ionized calcium and protein-bound calcium about equally; and (c) the loss of a millimole of bicarbonate, either by exposure of blood to air or by respiratory alkalosis, results in the release of about 7 mumol of calcium ions, which re-equilibrate with both the protein-bound and ionized calcium. Because lactate apparently removes calcium ions directly from albumin, our study indicates that protein-bound calcium readily provides calcium ions that buffer changes in the concentration of ionized calcium.

Acidosis, Lactic↗
PubMed1978

Dependence of the catalytic activity of papain on the ionization of two acidic groups.

The pH dependence of kcat/Km for the papain-catalyzed hydrolysis of ethyl hippurate, N-alpha-benzoyl-L-citrulline methyl ester, and the p-nitroanilide, amide, and ethyl ester derivatives of N-alpha-benzoyl-L-arginine was determined below pH 6.4. The value of kcat/Km was observed to be modulated by two acid ionizations rather than a single ionization as previously believed. For the five substrates studied, the average pK values for the two ionizations are 3.78 +/- 0.2 and 3.95 +/- 0.1 at T/2 0.3, 25 degrees C. The observation that similar pK values were obtained with different substrates was taken as evidence that the kinetically determined pK values are close in value to true macroscopic ionization constants for ionization of groups on the free enzyme.

Hydrogen-Ion Concentration↗
PubMed1972

Effect of ionization and cation selectivity on the expansion of stearic acid monolayers.

Force-area isotherms of stearic acid and stearic acid-stearyl alcohol mixtures were investigated on alkaline subphases that contained Tris, Na(+), or K(+) cations and that varied in pH and ionic strength. The monolayer behaved as though ionization was effectively complete in the expanded region of the force-area isotherm. Surface pressure in this region was independent of pH and varied inversely with ionic strength as predicted by the Davies equation. The monolayer behaved as a partially ionized film in the plateau region of the force-area isotherm. Surface pressure in this region varied directly with pH and ionic strength as predicted by a modified Davies equation for partially ionized monolayers. The neutral molecule, stearyl alcohol, exerted a large condensing effect on the ionized film at pH 12.8, and this condensing effect also supported the concept that a partially ionized stearic acid film existed in the plateau region of the force-area isotherm. A greater binding affinity for Na(+) than for K(+) showed that the stearate anion surface behaved as a strong field at pH 10 and above, and a greater binding affinity for K(+) than for Na(+) showed that the stearate anion surface behaved as a weak field at pH 9. The weak field explained in part the anomalous binding affinity of the large Tris cation for the stearate monolayer at pH 9.

Buffers↗