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L J Neuringer

Publications and source records attributed to L J Neuringer.

34 records · Page 2Linked to original sources
PubMed1989

Effects of hydralazine on in vivo tumor energy metabolism, hematopoietic radiation sensitivity, and cardiovascular parameters.

Energy metabolism of murine FSaII foot tumors was studied by in vivo 31P-MRS in C3Hf/Sed mice. Spectroscopy was performed following exposure to escalating doses of hydralazine (HYD) ip. At 0.25 mg/kg, HYD caused a 20% increase in PCr/Pi and had no significant effect on mean arterial blood pressure. HYD doses greater than or equal to 2 mg/kg lead to hypotension which was associated with a decrease in PCr, NTP, pH, and an increase in Pi (p less than 0.01 for control vs 10 mg/kg HYD). When mice were given ip injections of HYD (0.25, 1, 2 and 10 mg/kg) 10 min prior to whole body irradiation, spleen stem cell survival after 6 Gy was increased (2.19 colonies in control animals vs 6.74 colonies per spleen in animals treated with greater than or equal to 2 mg/kg HYD), as was the LD50/30 dose (6.49 Gy [control] vs 9.00 Gy [10 mg/kg HYD]). The data provide evidence that PCr/Pi is a useful indicator of perfusion efficiency (and indirectly of hypoxic cell fraction) in FSaII tumors. These observations suggest that HYD may be a useful adjuvant for hyperthermic treatment of tumors and for potentiation of agents specifically toxic to hypoxic or nutrient-deprived cancer cells. HYD should be used with care in patients receiving radiation treatments or other therapies for which hypoxia can unfavorably affect treatment outcome.

Animals↗
PubMed1989

Evaluation of tumor energy metabolism and microvascular blood flow after glucose or mannitol administration using 31P nuclear magnetic resonance spectroscopy and laser Doppler flowmetry.

The effects of intraperitoneally administered glucose or mannitol (5 mg/g body weight, 25% solutions) on tumor energy metabolism and tumor red blood cell flux were studied using 31P-nuclear magnetic resonance spectroscopy and laser Doppler flowmetry. Isotransplants of a spontaneous murine fibrosarcoma growing in the hind foot dorsum were used. 31P-nuclear magnetic resonance and laser Doppler flowmetry studies in glucose treated animals were performed on small (congruent to 100 mm3) and large (congruent to 300 mm3) tumors. In mannitol treated animals, tumors with an average volume of congruent to 200 mm3 were used. Using this tumor model, intraperitoneally administration of the hypertonic sugar solutions caused similar declines in tumor microcirculation (mannitol, 60 +/- 8% flow reduction; glucose, 72 +/- 4% flow reduction; t = 60 min). These changes were not glucose-specific and can primarily be explained by a water shift into the abdominal cavity and an associated hypovolemic hemoconcentration. A stable (small tumors) or transiently increased (large tumors) tumor energy metabolism which occurred after glucose administration was probably caused by a transiently increased glucose availability. The decline in energy metabolism after mannitol, a non-metabolized sugar alcohol, and the earlier decline in tumor pH seen in the glucose treated animals, supports this conclusion. The differences in the high energy phosphate response to glucose seen in small compared with large tumors, suggests that the baseline metabolic state of larger tumors includes a glucose deficiency in addition to tumor hypoxia.

Animals↗
PubMed1989

Correlations between 31P-NMR spectroscopy and tissue O2 tension measurements in a murine fibrosarcoma.

Size-dependent changes in therapeutically relevant and interrelated metabolic parameters of a murine fibrosarcoma (FSaII) were investigated in vivo using conscious (unanesthetized) animals and tumor sizes less than or equal to 2% of body weight. Tumor pH and bioenergetics were evaluated by 31P nuclear magnetic resonance spectroscopy (31P-MRS), and tumor tissue oxygen tension (pO2) distribution was examined using O2-sensitive needle electrodes. During growth FSaII tumors showed a progressive loss of phosphocreatine (PCr) and nucleoside triphosphate (NTP) with increasing inorganic phosphate (Pi) and phosphomonoester (PME) signals. Ratios for PCr/Pi, PME/Pi, NTP/Pi, and phosphodiester/inorganic phosphate (PDE/Pi) as well as pH determined by 31P-NMR (pHNMR) and the mean tissue pO2 progressively declined as the tumors increased in size. The only relevant ratio increasing with tumor growth was PME/NTP. When the mean tissue pO2 value was plotted against pHNMR, NTP/Pi, PCr/Pi, PME/Pi, and PDE/Pi for tumor groups of similar mean volumes, a highly significant positive correlation was observed. There was a negative correlation between mean tumor tissue pO2 values and PME/NTP. From these results we concluded that 31P-MRS can detect changes in tumor bioenergetics brought about by changes in tumor oxygenation. Furthermore, the close correlation between oxygenation and energy status suggests that the microcirculation in FSaII tumors yields an O2-limited energy metabolism. Finally, a correlation between the proportion of pO2 readings between 0 and 2.5 mmHg and the radiobiologically hypoxic cell fraction in FSaII tumors was observed. The latter finding might be of particular importance for radiation therapy.

Animals↗
PubMed1988

Effects of hydralazine-induced vasodilation on the energy metabolism of murine tumors studied by in vivo 31P-nuclear magnetic resonance spectroscopy.

The effects of hydralazine on tumor energy metabolism and on some cardiovascular parameters were measured. Tumor energy metabolism was studied in C3Hf/Sed mice with isotransplants of a spontaneous murine fibrosarcoma (FSaII, congruent to 100 mm3 in volume) and 31P-NMR. Cardiovascular parameters were measured in anesthetized C3Hf/Sed mice via intracarotid catheter. Hydralazine doses of 0.25 mg/kg given ip caused an increase of the phosphocreatine to inorganic phosphate ratio (PCr: Pi) in 5 of 6 animals. These doses had minimal effects on mean arterial blood pressure, though there may have been an increased cardiac output due to a decreased afterload. Hydralazine doses greater than or equal to 2.0 mg/kg given ip were associated with a decrease in PCr, nucleotide triphosphate, and pH, and an increase in Pi (P less than .01 for control vs. 10 mg hydralazine/kg). This substantial decrease in high-energy phosphates was associated with a pronounced decrement in mean arterial blood pressure. These findings provide a rational basis for the study in experimental systems of hydralazine-induced enhancement of cell killing by hyperthermia and by agents toxic to hypoxic cells. Further, these results can be taken as a sign that hydralazine should be used with care in patients undergoing radiation treatment.

Animals↗
PubMed1988

31P NMR studies of the diabetic lens.

Phosphorus-31 (31P) nuclear magnetic resonance (NMR) spectroscopic analyses of the crystalline lens from the experimental diabetic rat were performed. Qualitative and quantitative alterations in the phosphorus-31 NMR metabolic profile were observed over the course of 3 weeks after the induction of diabetes mellitus. Most striking was the appearance of two new, as yet unidentified, metabolites. These metabolites which resonate at 6.6 and 5.8 ppm were not detected in the normal lens. Compared to the normal lens, glycerol-3-phosphate (G3P) underwent an eightfold increase in concentration and phosphorylcholine decreased to one-third its initial level. The phosphodiesters, glycerophosphorylcholine (GPC) and glycerophosphorylethanolamine (GPE), decreased to barely detectable levels. Oral treatment of the diabetic animal with an aldose reductase inhibitor resulted in the preservation of an essentially normal lens 31P NMR spectrum. Except for the changes observed in glycerol-3-phosphate, these alterations have not been previously reported and raise new questions about the metabolic consequences of diabetes mellitus and the dependence of these alterations on the action of a single enzyme, aldose reductase.

Aldehyde Reductase↗
PubMed1988

Estimation of tumor oxygenation and metabolic rate using 31P MRS: correlation of longitudinal relaxation with tumor growth rate and DNA synthesis.

31P MRS longitudinal relaxation times (T1) were determined for C3H murine fibrosarcomas (FSaII), and mammary carcinomas (MCaIV). Tumors were implanted in the foot dorsum, and were 100-300 mm3 in volume. T1s were repeated after the animal was allowed to breathe 100% oxygen for 30 min and then again 36-48 hr following 30 Gy. The spectrum were obtained using an 8.5 T spectrometer with a 8 cm bore and a 1.4 cm single turn antenna coil. The 31P relaxation times for untreated tumors in air breathing animals were: 3.78 sec for phosphomonoesters, 4.37 sec for inorganic phosphate (Pi), 2.73 sec for phosphocreatine, 1.37 sec for gamma ATP, 1.14 sec for alpha ATP, and 1.18 sec for beta ATP. The Pi T1s were 4.37 and 4.70 sec in control and irradiated tumors in air breathing animals. Respiration of oxygen for 30 min reduced the T1s to 3.02 and 2.62 sec in control and irradiated tumors respectively. The Pi T1 of an anoxic tumor, determined on an in situ tumor 60 min after death was 5.93 sec. The oxygen breathing induced decrease in the T1 of Pi is unlikely to have been caused by the paramagnetic properties of oxygen alone, and suggests a component of increased magnetization transfer secondary to the ATPase reaction. Oxygen breathing following 30 Gy, resulted in a decreased growth time (800 mm3 endpoint) and an increased proportion of cells in S-phase. These results support the hypothesis that the decrease in Pi T1 measured with oxygen breathing is a measure of tumor oxygen tension and metabolic rate, and suggests that T1 measurement may indirectly predict tumor growth rate and DNA synthesis.

Animals↗
PubMed1988

Effects of pentobarbital anesthesia on the energy metabolism of murine tumors studied by in vivo 31P nuclear magnetic resonance spectroscopy.

The effects of pentobarbital anesthesia on the energy metabolism of FSaII and MCaIV foot tumors in mice were studied by 31P MRS. Using an 8.5 T spectrometer, in vivo spectra were obtained in 15 animals before and after pentobarbital anesthesia (0.05 mg/g ip). The average phosphocreatine/inorganic phosphate ratios (PCr/Pi) with and without pentobarbital were similar for both tumor histologies. Effects on individual tumors, however, were greater than 20% in 9/15 animals and greater than 50% in 6/15 animals. Pentobarbital anesthesia increased the variability of tumor intracellular pH, and the phosphomonoester/nucleotide triphosphate (PME/NTP) and nucleotide triphosphate/inorganic phosphate ratios (NTP/Pi). When examining the average in a cohort, pentobarbital anesthesia had no significant effect on the PCr/Pi, PME/NTP, NTP/Pi ratios or the pH. However, approximately equal to 50% of individual tumors do have significant changes in these parameters. The anesthesia-induced variability of tumor energy metabolism may explain the decrease in TCD50 observed in previous studies using multifraction radiation.

Anesthesia↗
PubMed1986

The effects of cerebrosides on model membrane shape.

Model membranes composed of phosphatidylcholine, various cerebrosides, and cholesterol have been studied by electron microscopy, deuterium NMR, and phosphorus-31 NMR. Large variations in phosphatidylcholine membrane morphology are observed when cerebrosides are present in phosphatidylcholine bilayers. Large spherical liposomes, small spherical liposomes, and long tubular liposomes are formed, depending on the relative acyl chain lengths of the phosphatidylcholine and cerebroside. In some cases, cholesterol can reverse the morphological effects of cerebrosides. These results suggest that cerebrosides, which are found in high concentrations in certain highly specialized membranes, can affect membrane shape and may be involved in the mechanism of formation of membranes with unusual morphology, e.g. neural myelin and the brush border membrane of the intestinal epithelium.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1985

Deuterium NMR spectroscopy of biosynthetically deuterated mammalian tissues.

The choline-containing phospholipids of mammalian membranes have been biosynthetically deuterated by raising rats on a diet supplemented with [HOCH2CH2N(CD3)3]+Cl- or [HOCD2CH2N(CH3)3]+Cl-. Deuterium NMR spectra have been obtained from excised deuterated brain, sciatic nerve, heart, and lung, from isolated brain myelin and brain microsomes, and from aqueous dispersions of lipid extracts. Measurements of residual quadrupole splittings for excised deuterated neural tissues demonstrate that the orientational order of the choline head group is similar to that observed in model membranes. The spin-lattice relaxation time of the choline head group in deuterated neural tissue is indistinguishable from that observed in model membranes. These results support the proposal that the conformation and motional dynamics of the choline head groups of the bulk choline-containing lipids of neural tissue are similar to those in model membranes. Spectra of biosynthetically deuterated brain myelin and brain microsomes exhibit similar quadrupole splittings. Since these membranes have significantly different protein contents, these results indicate that no strong polar interactions exist between membrane proteins and the choline head groups of choline-containing membrane lipids. Spectra of intact deuterated heart and lung exhibit broad lines and a range of quadrupole splittings. Due to the heterogeneous nature of these tissues, interpretation is difficult. However, no strong ordering of the lipid head group by protein is indicated.

Animals↗
PubMed1985

A calorimetry and deuterium NMR study of mixed model membranes of 1-palmitoyl-2-oleylphosphatidylcholine and saturated phosphatidylcholines.

Binary phase diagrams have been constructed from differential scanning calorimetry (DSC) data for the systems 1-palmitoyl-2-oleylphosphatidylcholine (POPC)/dimyristoylphosphatidylcholine (DMPC), POPC/dipalmitoylphosphatidylcholine (DPPC) and POPC/distearoylphosphatidylcholine (DSPC). Mixtures of POPC with DMPC exhibit complete miscibility in the gel and liquid crystalline states. Mixtures of POPC with DPPC or with DSPC exhibit gel phase immiscibility over the composition range 0-75% DPPC (or DSPC). These results, when taken together with previous studies of mixtures of phosphatidylcholines, are consistent with the hypothesis that PCs whose order-disorder transition temperatures (Tm values) differ by less than 33 deg. C exhibit gel state miscibility. Those whose Tm values differ by more than 33 deg. C exhibit gel state immiscibility. 2H-NMR spectroscopy has been used to further study mixed model membranes composed of POPC and DPPC, in which either lipid has been labeled with deuterium in the 2-, 10- or 16-position of the palmitoyl chain(s) or in the N-methyls of the choline head group. POPC/DPPC mixtures in the liquid crystalline state are intermediate in order between pure POPC and DPPC at the same temperature. The POPC palmitoyl chain is always more disordered than the palmitoyl chains of DPPC in liquid crystalline POPC/DPPC mixtures. This is attributed to the fact that a POPC palmitoyl chain is constrained by direct bonding to have at least one oleyl chain among its nearest neighbors, while a DPPC palmitoyl chain must have at least one neighboring palmitoyl chain. When liquid crystalline POPC, DPPC and POPC/DPPC mixtures are compared at a reduced temperature (relative to the acyl chain order-disorder transition), POPC/DPPC mixtures are more disordered than predicted from the behavior of the pure components, in agreement with enthalpy data derived from DSC studies. Within the temperature range of the broad phase transition of 1:1 POPC/DPPC, a superposition of gel and liquid crystalline spectra is observed for 1:1 POPC/[2H]DPPC, while 1:1[2H]POPC/DPPC exhibits only a liquid crystalline spectrum. Thus, at temperatures within the phase transition region, the liquid crystalline phase is POPC-rich and the gel phase is DPPC-rich. Comparison of the liquid crystalline quadrupole splittings within the thermal phase transition range suggests that mixing of the residual liquid crystalline POPC and DPPC is highly non-ideal.

Calorimetry, Differential Scanning↗
PubMed1979

Deuterium NMR studies of cerebroside-phospholipid bilayers.

2H-NMR was used to probe the interaction of non-hydroxy fatty acid cerebroside and 2-hydroxy fatty acid cerebroside with the polar head group and with the acyl chains of dipalmitoylphosphatidylcholine in unsonicated bilayers. It is shown that the interior of the bilayer exhibits uniformly increasing orientational order as the concentration of both types of cerebroside increases, whereas the surface of the bilayer, as reflected by the head group motion, becomes disordered. The extent of the disorder at the surface is dependent upon the type and concentration of the cerebroside. These results are discussed in terms of hydrogen-bonding interactions.

Cerebrosides↗
PubMedDate not supplied

Chemical exchange magnetic resonance imaging (CHEMI).

Systems investigated with NMR spectroscopy are sometimes heterogeneous with respect to chemical composition, rates of chemical exchange, and other properties influencing magnetic resonance parameters. A method was developed to spatially encode reaction kinetic information and produce NMR images sensitive to chemical exchange. A modified spin-echo pulse sequence was used to allow chemical shift-selective imaging and chemical exchange encoding. 1H and 31P images with microscopic resolution were obtained which yielded chemical exchange as a function of position. Chemical exchange images of the base-catalyzed proton exchange of acetylacetone and of the enzyme-catalyzed 31P transfer between PCr and ATP were obtained at 8.4 T in phantoms at 360 and 146 MHz, respectively. These images demonstrate a means of investigating kinetic heterogeneity and compartmentalization of reactions that are important in the study of both living and non-living systems.

Adenosine Triphosphate↗
PubMedDate not supplied

Gradient moment nulling for steady-state free precession MR imaging of cerebrospinal fluid.

Steady-state free precession (SSFP) pulse sequences can produce magnetic resonance (MR) images rapidly, in which cerebrospinal fluid (CSF) is several times more intense than the other tissues. However, motion in the presence of magnetic field gradients reduces the intensity of CSF drastically, unless the time integral of the gradient waveform between each radio-frequency (rf) pulse vanishes. The consequences of motion on SSFP are explored here in detail theoretically and experimentally. The principle of gradient moment nulling is applied with the objective of giving CSF in SSFP images uniformly high intensity everywhere, in spite of motion. Theoretical analysis of the phase of the transverse magnetization from a group of isochromats, with a trajectory described by a Taylor series, reveals how motion along each direction disrupts SSFP and also causes ghost artifacts. Images of CSF in the cervical spine are found to have less extensive flow voids and weaker ghosts from pulsation if the first moment calculated from the rf pulse to the center of the gradient echo vanishes for both the frequency encoding and slice selection gradient waveforms. However, first-order moment nulling of the phase encoding gradient waveform is unnecessary for SSFP imaging of CSF.

Cerebrospinal Fluid↗
PubMedDate not supplied

In vivo 31P-NMR spectroscopy of murine tumours before and after localized hyperthermia.

In vivo 31P-NMR spectroscopy was used to monitor the energy metabolism, apparent intracellular pH (pHNMR), and phospholipid turnover in subcutaneous fibrosarcomas (FSall) and mammary carcinomas (MCaIV) treated with hyperthermia (HT). Treatment consisted of elevation of tumour temperature to 43.5 degrees C for 15, 30 or 60 min (FSall) and 30 min (MCaIV). Experiments were performed on conscious mice with biologically relevant tumour sizes. Using water bath immersion, this study focused on acute heat-induced metabolic changes (up to 7 h post-HT). 31P-NMR spectra of both murine tumours were characterized by relatively high pretreatment levels of PME, Pi and NTP, and lower levels of PDE, PCr and DPDE. Following hyperthermia, NTP and PCr levels, as well as pHNMR, decreased in both tumour lines. This drop was accompanied by a prompt and dramatic increase in Pi. After heating for 15 min, the limited spectral changes observed for the high-energy phosphates and the marginal decline in pHNMR were nullified within 7 h, whereas Pi remained significantly elevated. With the exception of PME/NTP and PME/PDE, all relevant metabolic ratios (PCr/Pi, NTP/Pi, PME/Pi) decreased after heating and did not resolve thereafter. Upon longer heat exposure times the high-energy phosphates, pHNMR, NTP/Pi, PCr/Pi, and PME/Pi all decreased in a dose-dependent manner and remained at the respective lower levels. The PME/PDE ratio was increased after 43.5 degrees C/15 min whereas at longer heating times this ratio did not change. At comparable heat doses MCaIV tumours seem to exhibit changes similar to FSall tumours.

Adenocarcinoma↗