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R N Muller

Publications and source records attributed to R N Muller.

At least 37 records · Page 2Linked to original sources
PubMed1999

Multicentre magnetic resonance texture analysis trial using reticulated foam test objects.

Texture analysis in magnetic resonance imaging has the ability to provide useful diagnostic information with respect to the discrimination of disease states of a single tissue or the separation of different tissues. However, for widespread use it is necessary to determine how texture measurements carried out in one center relate to those carried out in another. To this end, a multicentre trial has been performed where reticulated foam test objects have been scanned in six European centers according to a fixed protocol. It has been concluded that texture measurements are not transportable between centers. Principal component models calculated from the texture parameters collected in one center do not fit the data collected in another. Further trials are to investigate whether the reticulated foam test objects may be used to normalize tissue texture data collected in different centers.

Europe↗
PubMed1998

Intravascular and intracellular hepatic relaxivities of superparamagnetic particles: an isolated and perfused organ pharmacokinetics study.

The relative contributions of intravascular and intracellular compartments to the proton transverse relaxation of the isolated and excised rat liver were determined during the phagocytosis of superparamagnetic particles. The evolution of the proton transverse magnetization of the organ perfused with increasing doses of starch-coated magnetic microspheres was followed up using a Carr-Purcell-Meiboom-Gill sequence with various echo times. From the multiexponential fit of the echo train, the amplitudes and the relaxation rates R2 of the liver tissue were obtained. The results clearly indicate that shortly after contrast medium administration, an internalization takes place which can be followed by the rapid and biphasic evolution of the transverse relaxation rate of the water protons. A very fast decaying component looking like an initial loss of the magnetization is observed together with an increase of the relaxation rate of the remaining water tissue. This regime is strongly dependent on both the echo time and the iron concentration, a behavior characteristic of the agglomeration of magnetic particles. The examination of the liver tissues by electron microscopy shows that this clustering arises in cytoplasmic vacuoles.

Animals↗
PubMed1998

Synergistic effects of relaxation and susceptibility in differentiation between compartmentalized and noncompartmentalized tissues.

RATIONALE AND OBJECTIVES: This study illustrates the synergistic effects of relaxation- and susceptibility-based contrast enhancement. Using a combination of gadolinium (Gd) and dysprosium (Dy) complexes and a sequence capable of taking advantage of the particular relaxation behavior of this combination, the difference between compartmentalized and noncompartmentalized regions was significantly enhanced. METHODS: Magnetic resonance imaging of the rat kidney was performed before and immediately after the administration of a combination of Gd and Dy chelates (Gd-DTPA-BMA and Dy-DTPA-BMA). RESULTS: The signal intensity (SI) of the renal parenchyma was reduced by 85%, whereas the collecting tubes had a 100% increase of their SI as demonstrated by a short repetition time (600 msec), long echo time (50 msec), and spin-echo sequence. CONCLUSIONS: The high R2* effect, specific to the compartmentalized tissues, associated with the moderately high R1 and R2 developed in the remaining areas, results in an important improvement in tissue differentiation, which potentially is useful for the evaluation of pathological changes as in tubular necrosis.

Animals↗
PubMed1998

Polylysine-Gd-DTPAn and polylysine-Gd-DOTAn coupled to anti-CEA F(ab')2 fragments as potential immunocontrast agents. Relaxometry, biodistribution, and magnetic resonance imaging in nude mice grafted with human colorectal carcinoma.

RATIONALE AND OBJECTIVES: Immunocontrast agents used for magnetic resonance imaging require antibodies that preserve the immunoreactivity while containing a high number of chelated paramagnetic ions. METHODS: Anti-CEA F(ab')2 fragments were coupled to polylysine-Gd-DOTA and polylysine-Gd-DTPA. A paramagnetic load as high as n = 24 to 28 metal ions per antibody was reached. RESULTS: The immunoreactivity of the gadolinium (Gd)-labeled anti-CEA F(ab')2 immunoconjugates was 80% to 85%. Compared with that of commercial chelates, the relaxivity (R1) increase is as follows: Gd-DTPA < Gd-DOTA < Gd-H2O < PL-Gd-DTPA24-28 < PL-Gd-DTPA24-28 F(ab')2 < PL-Gd-DOTA24-28 < PL-Gd-DOTA24-28 F(ab')2. 1H nuclear magnetic relaxation dispersion data of immunoconjugates showed that the high relaxivity enhancement was the result of a reduction of the molecular tumbling rate. Twenty-four hours after intravenous injection of 50 micrograms (1 mumol Gd/kg) of Gd-labeled immunoconjugates to nude mice grafted with human colorectal carcinoma LS 174T, the tumor uptake was 10% to 15%, resulting in an increase of R1 of up to 15% to 20% versus noninjected mice. No difference was found between PL-Gd-DTPA24-28 F(ab')2 and PL-Gd-DOTA24-28 F(ab')2 immunoconjugates for tumor, liver, and kidney uptake. A high signal intensity of tumor was observed in 50% of the tested mice.

Adenocarcinoma↗
PubMed1998

Paramagnetic liposomes as magnetic resonance imaging contrast agents. Assessment of contrast efficacy in various liver models.

RATIONALE AND OBJECTIVES: Liposomal gadolinium (Gd)-HP-DO3A has been evaluated as a contrast agent for liver magnetic resonance imaging. The influence of various liposomal physicochemical properties on the liver uptake and contrast efficacy was investigated in various ex vivo and in vivo liver models. METHODS: Liposomes of different size and membrane properties were prepared. The liposome size ranged from 74 to 304 nm. Two types of phospholipid compositions were studied; a mixture of hydrogenated phosphatidylcholine (HPC) and hydrogenated phosphatidylserine (HPS) with a phase transition temperature (Tm) of 51 degrees C and, a blend composed of dipalmitoylphosphatidylcholine (DPPC) and dipalmitoylphosphatidylglycerol (DPPG) displaying a Tm of 41 degrees C. Ex vivo tissue relaxometry and in vivo liver imaging were used to study the influence of liposome composition on the liver uptake and contrast efficacy of intravenously injected liposomes. The influence of liposome size and composition on the kinetics of liver uptake and imaging effect was assessed ex vivo in the perfused rat liver. RESULTS: The HPC/HPS preparations showed generally a higher and faster liver uptake than the DPPC/DPPG preparations due to a higher stability in blood/perfusate (high Tm) and to the HPS component. The liposome size modulated the extent and kinetics of liver uptake; the larger the size, the faster and more extensive was the liver uptake. Both types of liposome preparations were shown to be efficient liver susceptibility agents both ex vivo and in vivo due to their uptake by the Kupffer cells of liver. The lack of full correlation between the extent of liver uptake and degree of contrast enhancement might be attributed to different regimes of susceptibility-based relaxation. CONCLUSIONS: The present study has demonstrated the influence of key liposomal physicochemical properties on the liver uptake and contrast efficacy of liposome-encapsulated Gd chelates, exemplified by Gd-HP-DO3A.

Animals↗
PubMed1998

Multinuclear magnetic resonance characterization of paramagnetic contrast agents. The manifold effects of concentration and counterions.

RATIONALE AND OBJECTIVES: Proper fitting of the nuclear magnetic resonance dispersion (NMRD) profiles to the numerous factors governing nuclear relaxation in paramagnetic systems requires knowledge of some parameters usually obtained by other techniques. The rotational correlation time (tau R) for example can be measured by carbon-13, hydrogen-2, or oxygen-17 NMR. Discrepancies between values reported in the literature might be attributed to the different concentration ranges used so far in these modalities. In the present work focussing on commercial nonspecific contrast agents, the influence of the solution composition (type and concentration of the complexes and of the counterions) has been examined with regard to the water proton relaxation enhancement and molecular dynamics. METHODS: The proton relaxation rate enhancement of Magnevist, Dotarem, Omniscan, and ProHance was measured in aqueous solution up to a concentration of 0.5 M. In the same concentration window, the rotational correlation times were obtained from the study of deuterium relaxation rates of the diamagnetic deuterated analogs (lanthanum complexes) of the gadolinium chelates. RESULTS: Above 50 mM, the relaxation rate enhancement versus concentrations strongly deviates from linearity. Magnevist, a clinical formulation containing two meglumine counterions per molecule of paramagnetic complex, exhibits the largest concentration effect. A slowing down of the molecular dynamics accounts for this behavior as confirmed by the analysis of the rotational correlation times obtained by deuterium relaxometry. At low concentrations (< or = 50 mM), tau R values obtained by proton NMRD analysis and by deuterium relaxation are in very good agreement. CONCLUSIONS: This study shows that NMR analyses of small molecular weight complexes should be carried out on solutions containing no more than 50 mM to avoid the biaising effects of concentration. On the other hand, the benefitting relaxivity enhancement induced by highly concentrated solutions has to be taken into account in the context of bolus injection or vesicular entrapment.

Contrast Media↗
PubMed1997

A multinuclear MR study of Gd-EOB-DTPA: comprehensive preclinical characterization of an organ specific MRI contrast agent.

The characterization of the hepatobiliary contrast agent Gd-EOB-DTPA (gadolinium 3, 6, 9-triaza-3, 6, 9-tris(carboxymethyl)-4-(4-ethoxybenzyl)-undecandicarboxylic acid) in various media (water solution, protein containing solution, phosphorylated metabolites solution, and excised and perfused liver) was performed using different NMR approaches: water 1H nuclear magnetic relaxation dispersion profiles, 2H NMR longitudinal and transverse relaxation rates of labeled complex, water 17O transverse relaxation rates and chemical shifts, 31P relaxation rates and peak area of phosphorylated metabolites. The higher proton relaxivity of Gd-EOB-DTPA in water compared with Gd-DTPA is related to a shorter distance (r) between the water proton and the gadolinium ion and to a longer rotational correlation time (tauR) of the hydrated complex. Although the thermodynamic stability of Gd-EOB-DTPA is identical to the one of Gd-DTPA, its kinetic stability in solutions containing phosphorylated metabolites (ATP, phosphocreatine, and inorganic phosphate) as measured by 31P relaxation rates analysis is higher than for the parent compound. Gd-EOB-DTPA binds noncovalently to serum proteins. Its interaction with human serum albumin is characterized by a dissociation constant of 1-4.1 mM as calculated from proton and deuterium relaxation rates and equilibrium dialysis. This noncovalent interaction involves the subdomain IIA of human serum albumin. 31P spectroscopy of the excised and perfused rat livers was used to monitor the uptake of Gd-EOB-DTPA by the hepatocytes where it enhances the nuclear relaxation of the intracellular metabolites without impairing the adenosine triphosphate metabolism of the cells.

Adenosine Triphosphate↗
PubMed1997

Spectroscopic and metabolic effects of MnCl2 and MnDPDP on the isolated and perfused rat heart.

RATIONALE AND OBJECTIVES: Several works have shown that the hepatobiliary magnetic resonance imaging contrast agent manganese dipyridoxyl diphosphate (MnDPDP) partly releases its metallic ion and exhibits cardiovascular effects that are supposed to arise from the free manganese ions (Mn++). In the current study, the cellular internalization of Mn by the isolated rat heart is monitored through the mechanical function of the organ and the relative broadening of the P-31 nuclear magnetic resonances. METHODS: Rat hearts were perfused with manganese chloride (MnCl2; 15 and 25 microM) or MnDPDP (25 microM). Variations of the linewidths, heights, and surfaces of phosphocreatine and adenosine triphosphate peaks were monitored. Cardiac function was monitored simultaneously through heart rate, left ventricular pressure, and coronary flow. RESULTS: Influx of Mn++ induces a significant broadening of the P-31 resonances of adenosine triphosphate and phosphocreatine because of a strong scalar paramagnetic interaction between the nuclei and the ion. Compared with MnDPDP administered at the same concentration, MnCl2 induced a more pronounced and dose-dependent line broadening as well as a coronary vasodilation. Calcium channel blockers (nifedipine and verapamil) and EDTA inhibit MnCl2 influx. Similarly, verapamil, EDTA, and DPDP reduce the alterations provoked by MnDPDP. CONCLUSIONS: The effects of MnDPDP are smaller but of the same type than those induced by MnCl2. Their inhibition by calcium channel blockers (verapamil and nifedipine) and by an excess of strong chelators such as DPDP or EDTA confirms that they originate from a partial release of Mn++ by the contrast agent.

Adenosine Triphosphate↗
PubMed1997

Multinuclear MR characterization of a new hepatobiliary contrast agent. Preliminary results.

PURPOSE: The aim of this work was to characterize the hepatobiliary contrast agent Gd-EOB-DTPA in various media: water solution, protein solution, phosphorylated metabolite solution, and excised and perfused liver tissue. MATERIAL AND METHODS: Different NMR techniques were used: analyses of H-1 NMRD profiles, H-2 NMR relaxation rates, O-17 relaxation rates and chemical shifts, and P-31 relaxation rates and peak area. RESULTS: The higher proton relaxivity of Gd-EOB-DTPA in water as compared to that of Gd-DTPA is due to a smaller distance r and to a longer tau R. The kinetic stability of the former compound in ATP solution is higher and it forms noncovalent bonds with human serum albumin. Internalization of the contrast agent by the hepatocytes does not impair the ATP metabolism of the cells but induces relaxation effects on the intracellular metabolites of the liver. CONCLUSION: Multinuclear MR studies allow the extensive characterization of MR contrast agents in in-vitro and ex-vivo model systems.

Animals↗
PubMed1996

Assessment of microvascular integrity in the isolated perfused rat liver by contrast-enhanced MRI. Attenuation of reperfusion injury by conjugated deferoxamine.

Reperfusion of an ischemic organ can lead to microcirculatory impairment caused, in part, by the generation of reactive free radicals. The iron-catalyzed formation of these deleterious substances can be counteracted by strong metal chelators like deferoxamine. In this study, the protective effect of deferoxamine conjugate was evaluated by assessment of the hepatic microcirculation in the post-ischemic phase. Assessment of the microvasculature was performed by MRI on the isolated perfused rat liver. The restriction of sinusoids subsequent to reperfusion injury was demonstrated by the use of a particulate superparamagnetic contrast agent trapped in the microvasculature. The protective effect of conjugated deferoxamine was evaluated by both MRI and release of alanine aminotransferase. Contrast-enhanced MRI demonstrated a marked impairment of the microcirculation subsequent to the unprotected reperfusion of the ischemic tissue. This injury was attenuated by deferoxamine conjugated to hydroxyethyl-starch (HES-DFO).

Alanine Transaminase↗
PubMed1995

31P NMR kinetics study of cardiac metabolism under mild hypoxia.

The effects of mild hypoxia on the metabolic and mechanical functions of isovolumic perfused rat hearts have been studied. 31P NMR has been used to follow the metabolite concentrations as well as the intracellular pH. Additionally, the energy transfer through the creatine kinase reaction was estimated by the magnetization-transfer technique. The needs of myofibrillar energy and of mitochondrial ATP production have been assessed through mechanical activity and oxygen-consumption rate. It has been observed that mild hypoxia simultaneously impairs contractile and metabolic functions. The aerobic ATP production is maintained under these conditions while anaerobic energy metabolism seems accelerated. The accumulation of some metabolites (ADP and P(i)) and the decrease of creatine kinase forward flux (Vfor) tend, however, to prove that ATP availability for myofibrils is lowered. The large aerobic energy production observed must therefore be explained by an energy wastage in the mitochondria. In spite of normal ATP concentration, a contractile dysfunction is observed and can be explained by the P(i) accumulation, which is known to impair the use of the myofibrillar ATP. Another hypothesis supported by the magnetization-transfer experiments is the poor ATP availability resulting from the ATP wastage in the mitochondria and from the inefficient energy transport by the PCr-Cr shuttle.

Adenosine Triphosphate↗
PubMed1995

Preparation, physico-chemical characterization, and relaxometry studies of various gadolinium(III)-DTPA-bis(amide) derivatives as potential magnetic resonance contrast agents.

Macroscopic protonation constants were measured for a series of DTPA mono- and bis-amide ligands using potentiometric titrations. Proton NMR pH titrations yielded protonation populations of the various nitrogen and oxygen basic sites of the ligands for the different protonation stages. Amide formation decreased the basicity of the backbone nitrogens of the ligands and the thermodynamic stability of the corresponding Gd3+ chelates. Nuclear magnetic relaxation dispersion (NMRD) profiles and ESR linewidths were measured for the Gd3+ chelates. Some of these exhibited an elevated high field relaxivity relative to Gd(DTPA)2-, in response to their high molecular weight. As opposed to Gd(DTPA)2-, at 5 degrees C the chemical exchange process of the single inner-sphere water molecule of the bis-amide complexes becomes so slow that it governs the paramagnetic relaxation process, causing the observed NMRD profiles to be close to those expected for the outer-sphere contribution. The chelates containing long alkyl side chains, such as Gd(DTPA-HPA2), showed increased relaxivity values in the presence of human serum albumin (HSA), indicative of noncovalent interaction with the protein. These chelates could be useful as nonionic hepatobiliary contrast agents.

Contrast Media↗
PubMed1995

Mechanical and biochemical cardiac disturbances induced by bolus administration of iodinated contrast media and noniodinated solutions.

RATIONALE AND OBJECTIVES: Bolus injection of iodinated contrast media has been observed to alter myocardial mechanical function, but the consequences on cellular metabolism are poorly documented. Modifications of metabolic parameters (intracellular pH as well as adenosine triphosphate [ATP], phosphocreatine, and inorganic phosphate contents) and of mechanical function (coronary flow, heart rate, and left ventricular developed pressure) were simultaneously recorded on isolated rat hearts perfused over 2 minutes with a high osmolality contrast medium (HOCM) and two low osmolality contrast media (LOCM). In addition, the effects of test solutions mimicking the ionicity and the osmolality of LOCM were evaluated. METHODS: Isovolumic rat hearts were submitted to a 2-minute perfusion with oxygenated Radioselectan, Hexabrix, and Omnipaque (320 mgI/mL) at 37 degrees C. Metabolic parameters were obtained by P-31 nuclear magnetic resonance spectroscopy at 4.7 Tesla. Noniodinated ionic and nonionic solutions also were tested for comparison. RESULTS: HOCM irreversibly impairs the metabolic and mechanical functions, whereas ionic and nonionic LOCM and test solutions induce transient cardiac failure but no permanent alteration of the metabolic or mechanical parameters. CONCLUSION: In this protocol, HOCM causes irreversible degradation of the biochemical status and definitive heart failure, whereas ionic and nonionic LOCM only induce transient changes of myocardial function. Treatments with the LOCM do not induce any modification of the ATP and PCr content, and, at the end of the reperfusion period, the mechanical function is equivalent to that of control hearts. Depending on the ionic content of the solutions (iodinated or not), the evolution of the ventricular developed pressure after injection differs from one group of hearts to another. From these experiments, it is concluded that ionic imbalance and viscosity of the solutions, rather than iodine content or hyperosmolality, should be considered the causes of heart failure.

Animals↗
PubMed1994

31P nuclear magnetic resonance study of the effects of the calcium ion channel antagonist fantofarone on the rat heart.

The biochemical and mechanical effects of a new calcium ion channel antagonist, fantofarone ((2-isopropyl-1-((4-(3-(N-methyl-N-(3,4-dimethoxy-beta-phenethyl)-amino) propyloxy)benzenesulfonyl))-indolizine), on isovolumic perfused rat heart have been assessed by using 31P nuclear magnetic resonance (NMR) spectroscopy together with simultaneous monitoring of myocardial mechanical function. Cytosolic pH and phosphocreatine, adenosine triphosphate and inorganic phosphate contents were monitored by using 31P NMR. Heart rate, coronary flow and left ventricular developed pressure were measured routinely to assess mechanical function. Perfusion with 10 nM, 100 nM or 1 microM fantofarone for a period of 48 min did not cause any measurable metabolic changes. However, coronary vasodilatation and a partial positive inotropic effect were noted. A 15-min pretreatment with 100 nM did not protect against the deleterious effects of an 18-min period of normothermic, zero-flow ischemia. In contrast, a 20-min pretreatment period with 1 microM fantofarone significantly improved the recovery of mechanical performance, metabolic activity and pH after the same 18 min of ischemia. While only a slight protection of the ATP pool was noted during the ischemic period, major beneficial effects were observed during the reperfusion period, such that reflow was characterized by high recoveries of left ventricular pressure and rate pressure product (70-80%), low end diastolic pressure (< 10 mm Hg), significant recovery of ATP content (to 55%), a complete repletion of the phosphocreatine pool and a fast return of cytosolic pH to normal value.

Adenosine Triphosphate↗
PubMed1994

Stability assessment of gadolinium complexes by P-31 and H-1 relaxometry.

Longitudinal P-31 relaxation rate enhancements of phosphate groups have been measured at pH 7-7.2 and 310 degrees K on aqueous solutions containing adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi) and some lanthanide complexes (Gd-DOTA, Gd-HPDO3A, Gd-DO3A, Gd-DTPA, Gd-DTPA-BMA). The macrocyclic complexes induce linear enhancements of the relaxation rates of all phosphorus nuclei. For Gd-DOTA and Gd-HPDO3A, the mechanism of the interaction with the P-31 nuclei seems to be of the outer sphere type and a better efficiency is noted for the "neutral" Gd-HPDO3A. A short-lived ternary complex between Gd-DO3A and the phosphorylated metabolites appears to be formed enabling an inner sphere interaction. In solutions containing the open chain complexes, Gd-DTPA and Gd-DTPA-BMA, P-31 relaxation rates of ATP exhibit significant and nonlinear enhancements that are much larger than those observed for PCr and Pi. A ternary complex involving the lanthanide ion, its original chelator, and the ATP molecule is precluded by various experiments which confirm that the lanthanide ion shifts from the original complexes to the ATP phosphate groups.

Contrast Media↗
PubMed1994

Relaxivity enhancement of low molecular weight nitroxide stable free radicals: importance of structure and medium.

The longitudinal relaxivities of seven water-soluble nitroxide derivatives of low-molecular weight have been measured at 5 degrees C and 37 degrees C in water and in serum between 0.01 and 200 MHz. The nuclear magnetic relaxation dispersion (NMRD) profiles show a clear relationship between the relaxivity observed in serum and the relative balance of the hydrophobic/hydrophilic character of the paramagnetic molecules. From the data analysis, contributions arising from a population of nitroxides characterized by reduced mobility can be extracted. The values of the correlation times are consistent with a system involving nitroxides adsorbed at the surface of albumin and magnetically interacting with the protons of hydrogen bonded water molecules.

Cyclic N-Oxides↗
PubMed1994

pH and temperature effects on kinetics of creatine kinase in aqueous solution and in isovolumic perfused heart. A 31P nuclear magnetization transfer study.

Phosphorylated metabolites concentrations and creatine kinase kinetics are measured by 31P NMR in solution and in isovolumic perfused rat hearts submitted to hypo- and hyperthermia as well as to acidosis (37 degrees C). In the organ, temperature variation from 40 to 25 degrees C induces an increase of phosphocreatine (PCr) stores, a decrease of Pi and ADP concentrations, but does not affect the ATP pool. Creatine kinase forward flux (Vfor) is gradually reduced when the temperature is lowered both in vitro and in perfused heart. In normothermic and hypothermic conditions, a relationship is found between cardiac performance (rate pressure product, RPP), Vfor and ATP synthesis estimated through the myocardial oxygen consumption rate (MVO2). At 40 degrees C however, the RPP is reduced although both Vfor and MVO2 increase. In vitro experiments show an optimum pH of 7.7 for the forward creatine kinase reaction. In perfused heart submitted to acidosis, a decrease of PCr concentration is observed, whereas ATP and ADP contents remain unchanged. Heart creatine kinase flux increased as in hyperthermia. These high fluxes are attributed to the coupling of the creatine kinase reaction with energy consuming or producing reactions: the increase of energy demand related to non-contractile processes could explain the high MVO2 and Vfor observed in those conditions.

Adenosine Triphosphate↗