Magnetic field dependence of proton relaxation rates in tissue with added Mn2+: rabbit liver and kidney

Since contrast in magnetic resonance imaging (MRI) is so sensitive to the magnetic relaxation rates of tissue protons, the use of paramagnetic ions to alter contrast in a tissue-specific fashion is an alluring prospect. The influence of these ions on the proton relaxation rates in homogeneous solutions is known to vary dramatically according to whether the ions are present as hydrated aquoions, in solute chelate, or immobilized in macromolecules. In tissue, there is the additional complication of access of water to the ions. In the present study, Mn2+ ions were introduced into rabbits both orally and intravenously in various chemical complexes. Accumulation of these ions in rabbit liver is demonstrated here, qualitatively, by MRI. The quantitation of the change in relaxation rates is investigated in excised samples of liver and kidney by study of the magnetic field dependence (dispersion) of the relaxation rates of the protons (NMRD profiles) of tissue water. Results are presented for several sets of experiments, including dose-response data for weakly chelated Mn2+ and time-response data for free and complexed Mn2+. The general findings are that, for liver, the response (the increment in the NMRD profile) is relatively rapid (less than 2 m); that it is relatively independent of how, or in what form, the Mn2+ is introduced; that it persists for several hours (at least); and that it saturates with increasing body load of Mn2+. Moreover, from the form of the NMRD profiles of liver, it is clear that the Mn2+ ions are bound irrotationally, perhaps to cell membrane, and, when introduced in chelated form, can become separated even from strongly associated chelate complexes. For kidney, the results are qualitatively similar, though different in detail.     

Magnetic field dependence of solvent proton relaxation induced by Gd3+ and Mn2+ complexes

The effect of solute paramagnetic ions on the longitudinal magnetic relaxation rate 1/T¹ of solvent water protons depends on magnetic field strength and on the chemical environment of the ions. The variation of 1/T¹ with field has been measured for solutions of Gd³⁺ and Mn²⁺ ions in three grossly different environments near physiological pH: the hydrated aquoion; chelated by EDTA (ethylenediaminetetraacetic acid) and DTPA (diethylenetriaminepentaacetic acid); and bound to the protein concanavalin A. It is demonstrated that over the field range at which NMR imaging is currently being done, the chemical environment can alter 1/T¹ of solvent protons by more than an order of magnitude. The relevance of these results to the potential utility of these ions as agents for enhancement of contrast in NMR images is discussed.     

Magnetic field dependence of solvent proton relaxation rates induced by Gd3+ and Mn2+ complexes of various polyaza macrocyclic ligands: implications for NMR imaging

The magnetic field dependence of the solvent water proton longitudinal relaxation rate 1/T1 (the NMRD profile) has been measured for solutions of chelates of Gd3+ and Mn2+ ions with two different polyaza macrocyclic ligands: 1,4,7-triazacyclononane-N,N',N",-triacetic acid (NOTA) and 1,4,7,10-tetraazacyclododecane-N,N',N",N'"-tetraacetic acid (DOTA). Studies were carried out mainly near physiological pH, but the pH dependence was also examined in some cases. The results are compared with published data for complexes of Gd3+ and Mn2+ ions with ethylenediaminetetraacetic acid (EDTA) and diethylenetriaminepentaacetic acid (DTPA). Competition experiments for the NOTA and DOTA chelates with EDTA and DTPA were also performed. It is found that, over the field range in which NMR imaging is currently being done, different symmetries of otherwise similar chemical ligands can alter 1/T1 of solvent protons by factors of up to three. The ligand environment can influence the relaxation times of the electronic spin moments of the ions, as well as their coordination number, thereby changing both the inner and outer sphere contributions to the relaxivities of the complexes. The relevance of these results to questions of efficiency and toxicity of these chelates as agents for enhancement of contrast in NMR images is discussed.     

The magnetic field dependence of proton spin relaxation in tissues

The magnetic field dependence of water-proton relaxation is reported for a simple protein solution, a cross-linked protein solution, and a series of rat tissues, fresh, dried and rehydrated. The shape of the magnetic field dependence associated with water proton relaxation in tissues is accounted for by magnetic dipole-dipole interactions between the mobile water spins and the immobile spin populations of the nonrotating components of the tissue coupling the behavior of the immobilized spin system to that of the mobile water spin system. The effect of this coupling is to impart the field dependence of the relaxation associated with the immobilized spin population to that of the mobile water spins that are observed in most relaxation and imaging experiments.     

Renal effects of iopentol and iohexol after intravenous injection

Renal effects of the 2 non-ionic contrast media iopentol and iohexol were investigated and compared in a double-blind, randomized parallel study where 30 patients received iopentol, and 31 patients iohexol intravenously for abdominal CT. The dosage of contrast medium (350 mg I/ml) was 700 mg I/kg body weight. Only one patient (in the iohexol group) had an increase in serum creatinine of more than 50%. Iopentol and iohexol had no effects on the mean serum values of creatinine, urea, and beta 2-microglobulin (beta 2-MG) nor on creatinine clearance. The urinary excretion of albumin and beta 2-MG was also unchanged. The excretion of the proximal tubular enzymes alkaline phosphatase and N-acetyl-beta-glucosaminidase was increased. No significant difference between iopentol and iohexol was found.     

Correlation of proton transverse relaxation rates (R2) with iron concentrations in postmortem brain tissue from alzheimer's disease patients

Iron accumulates in the Alzheimer's disease (AD) brain and is directly associated with β‐amyloid pathology. The proton transverse relaxation rate (R₂) has a strong linear relationship with iron concentrations in healthy brain tissue; however, an independent test of this relationship has not been extended to AD brain tissue. In this study in vitro single spin‐echo (SE) measurements were made on tissue samples from four human AD brains using a 4.7T MRI research scanner. R₂ values were calculated for 14 cortical and subcortical gray matter (GM) and white matter (WM) regions. Atomic absorption spectroscopy was used to measure iron concentrations in the corresponding excised brain regions. Significant positive linear correlations were observed between R₂ values and iron concentrations in GM regions assessed across individual tissue samples and data averaged by brain region. With the use of a predictive model for R₂, a threshold iron concentration of 55 μg Fe/g wet tissue was determined above which R₂ appears to be dominated by the affects of iron in AD brain tissue. High‐field MRI may therefore be a useful research tool for assessing brain iron changes associated with AD. Magn Reson Med 57:172–180, 2007. © 2006 Wiley‐Liss, Inc.     

细胞因子诱导杀伤细胞在动物体内的分布

目的 观察细胞因子诱导杀伤(CIK)细胞在动物体内分布的特点.方法 99Tcm标记CIK细胞采用亚锡还原法.昆明种小白鼠40只,按随机数字表法分为8组,每组5只,进行小鼠体内分布实验,计算每克组织百分注射剂量率(%ID/g).新西兰家兔3只行动态显像,连续观察99Tcm-CIK细胞体内分布图像特点.结果 分离纯化后99Tcm-CIK细胞的放化纯＞95%,室温下6 h内保持稳定.小白鼠体内99Tcm-CIK细胞血液清除较快,观察到血液中1和24 h的再分布现象.99Tcm-CIK细胞主要分布于肺、肝、脾和肾,心脏、脑、骨骼和肌肉等其他脏器组织均分布较少.家兔动态显像示99Tcm-CIK细胞早期分布以肺为主,随时间延长肺内放射性逐渐减少,肝放射性逐渐增多,并超过肺部放射性,2 d后仍可见肝放射性浓聚.心脏、脑、骨骼和肌肉等其他脏器组织均未见明显放射性分布.结论 99Tcm-CIK细胞在血循环中滞留时间较短,注射后1 h内主要聚集于肺,随后肺的摄取逐渐减少,其主要浓聚于肝和脾,尤以肝为甚.     

Quantitative studies of hydrodynamic effects and cross-relaxation in protein solutions and tissues with proton and deuteron longitudinal relaxation times

Longitudinal relaxation times T1 of water protons were measured in 5% protein solutions at different static magnetic fields (0.47, 2, and 7 T), for proteins with molecular weight ranging between 1.4 and 480 kDa and in solvents of varying degrees of deuteration. T1 values were also obtained for rat liver soaked with Krebs-Ringer solutions of varying degrees of deuteration at the above fields. For the samples containing D2O, T1 for deuterium was also measured at fields 2 and 7 T. The deuterium measurements were used to estimate water rotational correlation times which were in turn used to estimate the contribution of so-called "hydrodynamic effects" of macromolecules to proton relaxation. The proton relaxation rates at full deuteration were compared with those in protonated solvent (water) to obtain a second, direct measurement of this effect. Both measurements provide quantitation of the hydrodynamic effects, free from the contributions of other effects that are transparent to deuteration, and results from both measurements agree with each other reasonably well. The cross-relaxation rate between solute and solvent protons, and the contribution of paramagnetic impurities in the samples were also obtained from the proton T1 studies. The experimental results show that the hydrodynamic effects (intramolecular and intermolecular water-water interactions) are about the same magnitude in all the proteins studied as well as in rat liver. However, the cross-relaxation rate generally increases with increasing protein molecular weight. Measurements in soaked rat liver indicate that the cross-relaxation rate per unit mass of solute is much higher in tissues than in simple solutions of proteins of similar mean molecular weight. The results challenge the prevailing concept that the relaxation properties of biological tissues may be treated as a simple superposition of the properties of their constituents.     

Magnetic field dependence of solvent proton relaxation in aqueous solutions of Fe3+ complexes

It might appear that the Fe3+ ion would be particularly useful as an agent for enhancing contrast in NMR images since it has a relatively large magnetic moment and occurs in vivo in a variety of forms. Moreover, the concentration of Fe3+ changes locally in certain disease states (e.g., beta-thalassemia) and in trauma (formation of methemoglobin), and can be altered in the gastrointestinal tract by the ingestion of readily available dietary supplements. However, the Fe3+ ion is insoluble above pH approximately 4, and soluble chelate and protein complexes of Fe3+ tend to sequester the ions from solvent; hence, the efficacy of Fe3+ ions for relaxing water protons ought to be low under typical physiological conditions. We report the magnetic field dependence of the relaxation rate of solvent protons (NMRD profiles) for solutions of a variety of Fe3+ complexes to demonstrate the phenomenology relevant to NMR imaging. From these data we make some estimates to show that, despite the low relaxation rates of solvent protons in solutions of Fe3+ complexes, certain observed changes in image contrast are consistent, quantitatively, with inferences that can be drawn from solution data.     

The usefulness of 18F-FDG PET images obtained 2 hours after intravenous injection in liver tumor

Liver tumors, especially hepatocellular carcinomas (HCCs), often exhibit no contrast with surrounding non-tumorous liver tissue in F-18-fluoro-2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET) images obtained at the usual interval of one hour after intravenous FDG injection. We evaluated the usefulness of FDG PET studies of liver tumors performed 2 hours after intravenous injection. METHODS AND MATERIALS: Fifteen pretherapeutic patients with 33 liver tumors were studied, including 11 patients with 18 HCCs, and 4 patients with 15 metastatic liver tumors (METAs) from 3 colorectal carcinomas and 1 esophageal carcinoma. After transmission scans, emission scans were obtained 45-55 minutes and 115-125 minutes after intravenous injection of 185-370 MBq FDG as early images and delayed FDG PET images, respectively. Visual analysis of early and delayed images was performed, and the FDG uptake in the tumor to that in nontumorous liver ratio (T/N ratio), the FDG uptake in tumor to that in soft-tissue ratio (T/S ratio) and the FDG uptake in non-tumorous liver to that in soft-tissue ratio (N/S ratio) were calculated for each image. RESULTS: In visual analysis, visual improvement seen in images was observed in 6 of 18 HCC lesions and all 15 META lesions. In quantitative analysis, the mean T/S ratio and T/N ratio of HCCs in early images were 4.97 and 1.90, respectively, and those in delayed images were 6.24 and 2.20, respectively. The mean T/S ratio and T/N ratio of METAs in early images were 5.97 and 2.21, respectively, and those in delayed images were 6.99 and 3.80, respectively. The T/S ratio of HCCs and T/S ratio and T/N ratio of METAs were significantly higher in delayed images than in early images. The mean N/S ratios of HCC cases were 2.58 in the early images and 2.57 in the delayed images, but the ratio showed no constant tendency in the images. All N/S ratios of META cases were decreased in delayed images, although the significance of the difference between early and delayed images in N/S ratios was not analyzed because of the small number of cases. CONCLUSION: FDG PET studies performed 2 hours after intravenous injection were useful for clear visualization of liver tumors, especially metastatic liver tumors.     

Evidence for a contribution of paramagnetic ions to water proton spin-lattice relaxation in normal and malignant mouse tissues.

Paramagnetic ions complexed to proteins may lose, retain, or enhance solvent paramagnetic relaxation (SPR) relative to free solution. We measured T1 and T2 of three mouse cancers, their normal counterparts, and six additional tissues. Long T1 of cancers was not caused by necrosis or by different contents of water, fat, or blood. Dissociable (TCA-extractable) and nondissociable (ashed) Mn, Cu, and Fe were measured by AA. Cancers had less Mn, Cu, and Fe than did normal counterparts. All 12 tissues had inverse correlations between T1 and dissociable Mn and Cu. For Mn alone to account for reduced T1, the extent to which SPR of the Mn-protein complexes would be enhanced is by factors of 0.6 to 13, below the maximum observed in Mn-enzymes. Different amounts of paramagnetic ion-protein complexes may account for part of the differences in T1 of water protons in different tissues, and the longer T1 of cancer cell water may be caused in part by reduced amounts of such complexes.     

The distribution of laudanosine in tissues after death from atracurium injection

A case is presented involving an acute fatality resulting from self-administration of atracurium, a muscle relaxant by a 45-year-old nurse. In the body, atracurium undergoes a spontaneous non-enzymatic degradation to laudanosine and an acrylate moiety. Laudanosine was quantified using gas chromatography coupled to mass spectrometry after extraction with chloroform-isopropanol-n-heptane (50 : 17 : 33 v/v) at pH 9.5 and separation on a HP5-MS capillary column. Laudanosine was subject to postmortem redistribution due to release from drug-rich tissues such as the lung and heart. The heart blood (917 ng/ml) to peripheral blood (390 ng/ml) ratio was 2.4. No other drugs, including ethanol were detected. Received: 8 July 1999 / Accepted: 17 December 1999     

Pattern of radioactivity in the CSF after intravenous injection of 99mTc

Summary It has been shown that intravenously injected pertechnetate enters the CSF space and also that a transport of pertechnetate ions to the blood occurs when injected into the ventricles. Activity curves obtained by repeated samplings of CSF after intravenous injection of pertechnetate appears to differ at different levels of the intraventricular pressure but also in patients with different types of intracranial pathology, i. e. in patients with ventricular dilatation due to hydrocephalus and due to cerebral atrophy.     

Granulocyte adherence after intravenous and intraarterial injection of ioxaglate or iohexol.

The effect of iohexol and ioxaglate on granulocyte adherence to nylon fibers was investigated with blood from 15 patients undergoing angiography, and from 24 patients undergoing excretory urography. Decreased adherence and increased numbers of granulocytes in the circulation were observed soon after injection of iohexol or ioxaglate in the aorta, or injection of ioxaglate i.v. Increased adherence and decreased numbers of granulocytes in the circulation were observed soon after injection of iohexol i.v. The differences were small soon after the injection of contrast media (CM). More pronounced decreased adherence and increased numbers of granulocytes were detected 2 and 5 hours after injection in the aorta for both CM.     

Improved healing of transected rabbit Achilles tendon after a single injection of cartilage-derived morphogenetic protein-2

BACKGROUND: Achilles tendon ruptures in humans might be treated more efficiently with the help of a growth factor. Cartilage-derived morphogenetic protein-2 has been shown to induce formation of tendon-like tissue. HYPOTHESIS: Cartilage-derived morphogenetic protein-2 has a positive effect on mechanical parameters for tendon healing in a rabbit model with Achilles tendon transection. STUDY DESIGN: Controlled laboratory study. METHODS: The right Achilles tendon of 40 rabbits was transected without tendon suture. Cartilage-derived morphogenetic protein-2 (10 micro g) or vehicle control (acetate buffer) was injected locally 2 hours postoperatively. All tendons were tested biomechanically at 8 and 14 days, and treated tendons were histologically and radiographically evaluated at 56 days. RESULTS: At 14 days, both failure load and stiffness of treated tendons were increased by 35%. The treated tendons had significantly larger callus size at 8 and 14 days. Histologic and radiographic examination showed no signs of ossification in the treated tendons after 56 days. CONCLUSIONS: A single injection of cartilage-derived morphogenetic protein-2 led to a stronger and stiffer tendon callus than that in the controls without inducing bone formation. Clinical Relevance: Similar results from a larger animal model would suggest a possible future use of cartilage-derived morphogenetic protein-2 in the treatment of human Achilles tendon ruptures.     

Identification and characterization of tissues by T2-selective whole-body proton NMR imaging

T₂-selective proton imaging at 10 MHz is based on a Carr-Purcell-Meiboom-Gill pulse sequence with at least 36 echoes and 2τ ? 6 ms employing the projection reconstruction technique. The transverse magnetization decay of the volume elements is multiexponential composed of up to three monoexponential T₂ components. The T₂ values are arranged in T₂ histograms which are slice specific. T₂ windows are defined in the T₂ histogram and used for imaging and for selecting T₂ values which are assigned to proton classes and tissues. Tissue characterization is based on the visualization of differences in T₂ behavior. The T₂ values are transformed into 256 gray levels or, by use of a red-green-blue lookup table, into a rainbow code. Two display techniques have been developed and implemented in the RWTH Aachen Magnetic Resonance Software System (RAMSES): (i) for nonselective T₂ imaging with secondary T₂ selection and encoding of molecular classes on the basis of T₂ values; (ii) for T₂-selective imaging by employing combined primary and secondary T₂ selection and encoding particular tissues and variations therein. The tissues can be identified by selecting different classes of molecules, like water, lipids, and proteins, when shifting the primary T₂ window on the T₂ axis of the T₂ histogram.     

Hepatic intra-arterial injection of 3-bromopyruvate in rabbit VX2 tumor

PURPOSE: To evaluate the antitumoral effects of an intra-arterial injection of 3-bromopyruvate (3-BrPA) on liver VX2 tumor in rabbits. MATERIAL AND METHODS: Twenty rabbits with surgically implanted liver VX2 tumors were used. The rabbits were divided into three groups: a control, a saline, and a 3-BrPA group. Four rabbits were not treated at all, and they served as the control group. The saline group (n = 6) received only intra-arterial saline injection. The 3-BrPA group (n = 10) received an intra-arterial injection of 3-bromopyruvate through the hepatic artery. The delivered amounts of 3-bromopyruvate were as follows: 25 ml of 0.5 mM in six rabbits, 25 ml of 1.0 mM in two rabbits, and 25 ml of 2.0 mM in two rabbits. Four days after intra-arterial injection, the rabbits were sacrificed and histopathologic analysis of the explanted livers was performed with comparison of the tumor necrosis ratio (a percentage of the necrotic area versus the entire tumorous area) in each group. RESULTS: The mean tumor necrosis ratio was 12.5+/-4.2%, 44.8+/-24.7%, and 49.4+/-14.3% in the control, saline, and 3-BrPA groups, respectively. Between the control and the saline group, and between the control and the 3-BrPA group the mean tumor necrosis ratio appeared to be significantly different (P<0.05). However, there was no statistical difference in the mean tumor necrosis ratio between the saline and the 3-BrPA group (P = 0.416). CONCLUSION: A single session of intra-arterial injection of 3-BrPA showed no better results in terms of tumor necrosis than that of saline injection in a rabbit VX2 tumor model.