PEG-g-poly(GdDTPA-co-L-cystine): effect of PEG chain length on in vivo contrast enhancement in MRI

Biodegradable macromolecular Gd(III) complexes, Gd-DTPA cystine copolymers (GDCP), were grafted with PEG of different sizes to modify the physicochemical properties and in vivo MRI contrast enhancement of the agents and to study the effect of PEG chain length on these properties. Three new PEG-grafted biodegradable macromolecular gadolinium(III) complexes were synthesized and characterized as blood pool MRI contrast agents. One of three different lengths of MPEG-NH(2) (MW = 550, 1000, and 2000) was grafted to the backbone of GDCP to yield PEG(n)()-g-poly(GdDTPA-co-l-cystine), PEG(n)()-GDCP. The PEG chain length did not dramatically alter the T(1) relaxivity, r(1), of the modified agents. The MRI enhancement profile of PEG(n)()-GDCP with different PEG sizes was significantly different in mice with respect to both signal intensity and clearance profiles. PEG(2000)-GDCP showed more prominent enhancement in the blood pool for a longer period of time than either PEG(1000)-GDCP or PEG(550)-GDCP. In the kidney, PEG(2000)-GDCP had less enhancement at 2 min than PEG(1000)-GDCP, but both PEG(550)-GDCP and PEG(1000)-GDCP showed a more pronounced signal decay thereafter. The three agents behaved similarly in the liver, as compared to that in the heart. All three agents showed little enhancement in the muscle. Chemical grafting with PEG of different chain lengths is an effective approach to modify the physiochemistry and in vivo contrast enhancement dynamics of the biodegradable macromolecular contrast agents. The novel agents are promising for further clinical development for cardiovascular and cancer MR imaging.     

Dynamic contrast enhanced MRI of mouse fibrosarcoma using small-molecular and novel macromolecular contrast agents

The aim of the study was a comparison of 2 novel macromolecular contrast agents, Gadomer-17 and Polylysine-Gd-DTPA, with commercially available Gd-DTPA in determining the quality of tumor microvasculature by dynamic contrast enhanced MRI. Three groups of 5 mice with SA-1 tumors were studied. To each group of animals one contrast agent was administered; i.e. the first group got Gd-DTPA, the second group Gadomer-17 and the third group Polylysine-Gd-DTPA. To perform dynamic contrast enhanced MRI a standard keyhole approach was used by which consecutive signal intensity change due to contrast agent accumulation in the tumor was measured. From the obtained data, tissue permeability surface area product PS and fractional blood volume BV were calculated on a pixel-by-pixel basis. PS and BV values were calculated for each contrast agent. Based on the values, contrast agents were classified according to their performance in characterizing tumor microvasculature. Results of our study suggest that Gadomer-17 and Polylysine-Gd-DTPA are significantly superior to Gd-DTPA in characterizing tumor microvasculature.     

Paramagnetic water-soluble metallofullerenes having the highest relaxivity for MRI contrast agents.

Water-soluble gadolinium (Gd) endohedral metallofullerenes have been synthesized as polyhydroxyl forms (Gd@C(82)(OH)(n)(), Gd-fullerenols) and their paramagnetic properties were evaluated by in vivo as well as in vitro for the novel magnetic resonance imaging (MRI) contrast agents for next generation. The in vitro water proton relaxivity, R(1) (the effect on 1/T(1)), of Gd-fullerenols is significantly higher (20-folds) than that of the commercial MRI contrast agent, Magnevist (gadolinium-diethylenetriaminepentaacetic acid, Gd-DTPA) at 1.0 T close to the common field of clinical MRI. This unusually high proton relaxivity of Gd-fullerenols leads to the highest signal enhancement at extremely lower Gd concentration in MRI studies. The strong signal was confirmed in vivo MRI at lung, liver, spleen, and kidney of CDF1 mice after i.v. administration of Gd-fullerenols at a dose of 5 micromol Gd/kg, which was 1/20 of the typical clinical dose (100 micromol Gd/kg) of Gd-DTPA.     

Macromolecular MRI contrast agents with small dendrimers: pharmacokinetic differences between sizes and cores

Large macromolecular MRI contrast agents with albumin or dendrimer cores are useful for imaging blood vessels. However, their prolonged retention is a major limitation for clinical use. Although smaller dendrimer-based MRI contrast agents are more quickly excreted by the kidneys, they are also able to visualize vascular structures better than Gd-DTPA due to less extravasation. Additionally, unlike Gd-DTPA, they transiently accumulate in renal tubules and thus also can be used to visualize renal structural and functional damage. However, these dendrimer agents are retained in the body for a prolonged time. The purpose of this study was to obtain information from which a macromolecular dendrimer-based MRI contrast agents feasible for use in further clinical studies could be chosen. Six small dendrimer-based MRI contrast agents were synthesized, and their pharmacokinetics, whole-body retention, and dynamic MRI were evaluated in mice to determine an optimal agent in comparison to Gd-[DTPA]-dimeglumine. Diaminobutane (DAB) dendrimer-based agents cleared more rapidly from the body than polyamidoamine (PAMAM) dendrimer-based agents with the same numbers of branches. Smaller dendrimer conjugates were more rapidly excreted from the body than the larger dendrimer conjugates. Since PAMAM-G2, DAB-G3, and DAB-G2 dendrimer-based contrast agents showed relatively rapid excretion, these three conjugates might be acceptable for use in further clinical applications.     

Development of Bifunctional Gadolinium-Labeled Superparamagnetic Nanoparticles (Gd-MnMEIO) for In Vivo MR Imaging of the Liver in an Animal Model

Liver tumors are common and imaging methods, particularly magnetic resonance imaging (MRI), play an important role in their non-invasive diagnosis. Previous studies have shown that detection of liver tumors can be improved by injection of two different MR contrast agents. Here, we developed a new contrast agent, Gd-manganese-doped magnetism-engineered iron oxide (Gd-MnMEIO), with enhancement effects on both T1- and T2-weighted MR images of the liver. A 3.0T clinical MR scanner equipped with transmit/receiver coil for mouse was used to obtain both T1-weighted spoiled gradient-echo and T2-weighted fast spin-echo axial images of the liver before and after intravenous contrast agent injection into Balb/c mice with and without tumors. After pre-contrast scanning, six mice per group were intravenously injected with 0.1 mmol/kg Gd-MnMEIO, or the control agents, i.e., Gd-DTPA or SPIO. The scanning time points for T1-weighted images were 0.5, 5, 10, 15, 20, 25, and 30 min after contrast administration. The post-enhanced T2-weighted images were then acquired immediately after T1-weighted acquisition. We found that T1-weighted images were positively enhanced by both Gd-DTPA and Gd-MnMEIO and negatively enhanced by SPIO. The enhancement by both Gd-DTPA and Gd-MnMEIO peaked at 0.5 min and gradually declined thereafter. Gd-MnMEIO (like Gd-DTPA) enhanced T1-weighted images and (like SPIO) T2-weighted images. Marked vascular enhancement was clearly visible on dynamic T1-weighted images with Gd-MnMEIO. In addition, the T2 signal was significantly decreased at 30 min after administration of Gd-MnMEIO. Whereas the effects of Gd-MnMEIO and SPIO on T2-weighted images were similar (p = 0.5824), those of Gd-MnMEIO and Gd-DTPA differed, with Gd-MnMEIO having a significant T2 contrast effect (p = 0.0086). Our study confirms the feasibility of synthesizing an MR contrast agent with both T1 and T2 shortening effects and using such an agent in vivo. This agent enables tumor detection and characterization in single liver MRI sections.     

Synthesis and characterization of poly(L-glutamic acid) gadolinium chelate: a new biodegradable MRI contrast agent

Most currently evaluated macromolecular contrast agents for magnetic resonance imaging (MRI) are not biodegradable. The goal of this study is to synthesize and characterize poly(l-glutamic acid) (PG) gadolinium chelates as biodegradable blood-pool MRI contrast agents. Two PG chelates of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) were synthesized through the use of difunctional and monofunctional DTPA precursors. The conjugates were characterized with regard to molecular weight and molecular weight distribution, gadolinium content, relaxivity, and degradability. Distributions of the polymeric MRI contrast agents in various organs were determined by intravenous injection of (111)In-labeled polymers into mice bearing murine breast tumors. MRI scans were performed at 1.5 T in mice after bolus injection of the polymeric chelates. PG-Hex-DTPA-Gd, obtained from aminohexyl-substituted PG and DTPA-dianhydride, was partially cross-linked and was undegradable in the presence of cathepsin B. On the other hand, PG-Bz-DTPA-Gd synthesized directly from PG and monofunctional p-aminobenzyl-DTPA(acetic acid-tert-butyl ester) was a linear polymer and was degradable. The relaxivities of the polymers at 1.5 T were 3-8 times as great as that of Gd-DTPA. Both polymers had high blood concentrations and were primarily accumulated in the kidney. However, PG-Bz-DTPA-Gd was gradually cleared from the body and had significantly less retention in the blood, the spleen, and the kidney. MRI with PG-Bz-DTPA-Gd in mice showed enhanced vascular contrast at up to 2 h after the contrast agent injection. The ability of PG-Bz-DTPA-Gd to be degraded and cleared from the body makes it a favorable macromolecular MRI contrast agent.     

TOF-SIMS analysis of lipid accumulation in the skeletal muscle of ob/ob mice

Skeletal muscle lipid accumulation is associated with several chronic metabolic disorders, including obesity, insulin resistance (IR) and type 2 diabetes. The aim of this study is to evaluate whether static imaging time-of-flight-secondary-ion mass spectrometry (TOF-SIMS) equipped with a Bismuth-cluster ion source can be used for studying skeletal muscle lipid accumulation associated with obesity. Mouse gastrocnemius muscle tissues in 10-week-old obese ob/ob (n = 8) and lean wild-type C57/BL6 (n = 6) mice were analyzed by TOF-SIMS. Our results showed that signal intensities of fatty acids (FAs) and diacylglycerols (DAGs) were significantly increased in skeletal muscle of the obese ob/ob mice as compared to the lean wild-type mice. These differences were revealed through a global analytical approach, principal component analysis (PCA) of TOF-SIMS spectra, and ion-specific TOF-SIMS images. Region-of-interest (ROI) analysis showed that FA signal intensities within the muscle cell were significantly increased in ob/ob mice. Moreover, analysis of the ratio between different FA peaks revealed changes in monounsaturated FAs (MUFAs) and polyunsaturated FAs (PUFAs), which is in agreement with previous reports on obesity. These changes in FA composition were also reflected in the ratio of different DAGs or phosphatidylcholines (PCs) that contain different FA residues. Imaging TOF-SIMS together with PCA of TOF-SIMS spectra is a promising tool for studying skeletal muscle lipid accumulation associated with obesity.     

Synergistic enhancement of iron oxide nanoparticle and gadolinium for dual-contrast MRI

PurposeThe use of MR contrast agents allows accurate diagnosis by exerting an influence on the longitudinal (T₁) or transverse (T₂) relaxation time of the surrounding tissue. In this study, we combined the use of iron oxide (IO) particles and nonspecific extracellular gadolinium chelate (Gd) in order to further improve the sensitivity and specificity of lesion detection.ProceduresWith a 7-Tesla scanner, pre-contrasted, IO-enhanced and dual contrast agent enhanced MRIs were performed in phantom, normal animals, and animal models of lymph node tumor metastases and orthotopic brain tumor. For the dual-contrast (DC) MRI, we focused on the evaluation of T₂ weighted DC MRI with IO administered first, then followed by the injection of a bolus of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA).ResultsBased on the C/N ratios and MRI relaxometry, the synergistic effect of coordinated administration of Gd-DTPA and IO was observed and confirmed in phantom, normal liver and tumor models. At 30 min after administration of Feridex, Gd-DTPA further decreased T₂ relaxation in liver immediately after the injection. Additional administration of Gd-DTPA also immediately increased the signal contrast between tumor and brain parenchyma and maximized the C/N ratio to ?4.12 ± 0.71. Dual contrast MRI also enhanced the delineation of tumor borders and small lesions.ConclusionsDC-MRI will be helpful to improve diagnostic accuracy and decrease the threshold size for lesion detection.     

Noninvasive monitoring of therapy-induced microvascular changes in a pancreatic cancer model using dynamic contrast-enhanced magnetic resonance imaging with P846, a new low-diffusible gadolinium-based contrast agent

A predictive technique in the management of patients with cancer could improve the therapeutic index by allowing better individualization of treatment. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive technique that can provide anatomical and physiological information on the tumor and its microenvironment. We studied the effect of chemotherapy (gemcitabine), anti-angiogenesis therapy (sunitinib) and radiotherapy on the kinetics of DCE-MRI parameters in a preclinical model of pancreatic cancer using P846, a new low-diffusible contrast agent. Mice underwent DCE-MRI before treatment (MRI1), after 1 week of treatment (MRI2), and after 1 additional week (MRI3). Combined treatment with radiotherapy and sunitinib had a synergistic effect on tumor growth. In radiotherapy/sunitinib-treated mice, a decrease in K(trans) at MRI2 predicted its superior antivascular and antitumor effect at an early time. An increased K(trans) at MRI2, as seen in gemcitabine- and gemcitabine/sunitinib-treated mice, reflects increased permeability for P846 and might predict a smaller therapeutic effect at this early time. This study shows that the kinetics of DCE-MRI parameters depends on the contrast agent used. P846 appears to be a promising low-diffusible agent to monitor therapeutic effects in this preclinical cancer model, but further studies are needed to compare its behavior with Gd-DTPA and macromolecular-weight contrast agents. Sunitinib as a radiosensitizer is promising for future clinical trials in human pancreatic cancer.     

Contrast Enhanced MRI Assessment of Tumor Blood Volume After Application of Electric Pulses

The effect of application of short, intense electric pulses on tumor blood volume was investigated using albumin-(Gd-DTPA)₃₀ contrast-enhanced magnetic resonance imaging (MRI). One of paired SA-1 fibrosarcoma tumors implanted in each flank of A/J mice was treated with electric pulses. MRI was performed dynamically before and after intravenous administration of albumin-(Gd-DTPA)₃₀ (0.02 mmol Gd/kg), and fractional tumor blood volume was estimated. MRI images of tumors exposed to electric pulses showed no enhancement at 30 min after injection of albu-min-(Gd-DTPA)₃₀. However, marked enhancement was observed in paired tumors of the same mice that were not exposed to electric pulses. A significant difference in blood volume was observed between nontreated tumors and tumors treated with electric pulses. Application of electric pulses to the tumors significantly reduced blood volume in the tumors. Therefore, through a reduction in tumor blood volume, electric pulses may, besides producing electroporation of cells, exert antitumor effectiveness by entrapping drugs within the tumors.     

Significance of magnetic resonance image and blood manganese measurement for the assessment of brain manganese during total parenteral nutrition in rats

In this study, we report on the influence of trace elements (TE) on signal intensities of nuclear magnetic resonance images (MRI), both in vivo and in vitro. Optimal parameters for the assessment of Mn concentration in the brain of rats on total parenteral nutrition were established. For the in vitro study, Mn and trace element solutions, one containing Zn, Cu, Fe, and I (TE-4) and another containing the above elements plus Mn (TE-5), were diluted with physiological saline or with rat brain homogenate and used to measure signal intensities in MRI. Concentration-dependent signal hyperintensity was observed in both cases in the Mn and the TE-5 solutions, but no effect was observed with the TE-4 solution. The signal increase was greater for brain tissue homogenates. In the in vivo study, the experimental animals were maintained under total parenteral nutrition (TPN) with a standard clinical dose of TE-5 and/or with 10-fold the clinical dose of TE-4 and TE-5 for 1 wk. Only rats that were receiving the increased TE-5 dose showed signal hyperintensity on MRI. Positive correlations were observed among the signal hyperintensity, the blood Mn concentrations, and that of the rat brain. Our results suggest that Mn in TE preparations may be the cause of signal hyperintensity on MRI in a concentration-dependent fashion, and that MRI and measurement of blood Mn may be used to estimate Mn accumulation in brain tissue.     

Identification of cholesteryl esters in human carotid atherosclerosis by ex vivo image-guided proton MRS

Vulnerable atherosclerotic plaques may be identified by their large lipid component, particularly liquid cholesteryl ester (CE), covered by a fibrous cap. We hypothesized that image-guided 1H proton magnetic resonance spectroscopy (MRS) would identify mobile CE in discrete, preselected regions of atherosclerotic plaque. Human carotid endarterectomy specimens (n = 10) were imaged ex vivo by magnetic resonance imaging (MRI) at high field (11.7 T) utilizing standard T1- and T2-weighted spin echo protocols. MRS spectra were acquired from 1 mm3 voxels, localized to plaque regions that we judged by MRI to be lipid rich or lipid poor. The spectra revealed methyl and methylene resonances of fatty acyl chains with relative intensities and linewidths characteristic of pure CE, by comparison with lipid standards. Regions judged to be lipid rich by MRI showed much more intense CE resonances than did lipid-poor regions. The integrated intensities of lipid peaks were 5.5 +/- 2.0% (lipid-rich regions) versus 0.9 +/- 0.6% (lipid-poor regions) of the unsuppressed water peak (P < 0.0001). Lipid distribution by histology, MRS, and MRI showed strong correlation. Image-guided proton MRS accurately identified CE in selected regions of atherosclerotic plaque as small as 1 mm3 in an ex vivo setting. This procedure may permit the noninvasive detection and quantification of CE in atherosclerotic plaque in vivo.     

Polyaspartamide gadolinium complexes containing sulfadiazine groups as potential macromolecular MRI contrast agents

Both diethylenetriaminepentaacetic acid (DTPA) and sulfadiazine (SD) were incorporated into polyaspartamides with different side chains, including poly-alpha,beta-[N-(2-hydroxyethyl)-L-aspartamide] (PHEA), poly-alpha,beta-[N- (3-hydroxypropyl)-L-aspartamide] (PHPA), poly-alpha,beta-[N-(2-aminoethy1)-L-aspartamide] (PAEA), poly-alpha,beta-[N-(4-aminobuty1)-L-aspartamide] (PABA), and poly-alpha,beta-[N-(6-aminohexyl)-L-aspartamide] (PAHA). The polyaspartamide ligands containing DTPA and SD groups were further reacted with gadolinium chloride to give the corresponding macromolecular gadolinium complexes. Experimental data of 1H NMR, IR, UV, and elemental analysis exhibited the formation of the polyaspartamide ligands and gadolinium complexes. Relaxivity studies indicated that the macromolecular chelates possess higher relaxivities than that of the clinically used Gd-DTPA. MR imaging showed that the macromolecular chelate PAEA-Gd-DTPA-SD greatly enhanced the contrast of MR images of hepatoma in the lower limb of mice and provided prolonged intravascular duration. Thus the polyaspartamide gadolinium complex containing SD groups is expected to be used as the potential macromolecular MRI contrast agents for hepatoma in mice.     

PEG-g-poly(GdDTPA-co-L-cystine): a biodegradable macromolecular blood pool contrast agent for MR imaging

Biodegradable PEGylated Gd-DTPA l-cystine copolymers, PEG-g-poly(GdDTPA-co-l-cystine), were prepared and tested as a blood pool contrast agent in mice. The biodegradable macromolecular agent was designed to be broken down into smaller Gd complexes by endogenous thiols via the disulfide-thiol exchange reaction to facilitate the clearance of Gd complexes after the contrast-enhanced MRI examination. Gd-DTPA l-cystine copolymers were synthesized by condensation polymerization of l-cystine and DTPA-dianhydride in water followed by chelating with Gd(OAc)(3). MPEG-NH(2) (MW = 2000) was then conjugated to the polymeric backbone in different ratios. The macromolecular contrast agent was readily degraded with the incubation of l-cysteine. It also demonstrated superior contrast enhancement in the heart and blood vessels as compared to a low molecular weight control agent, Gd-(DTPA-BMA). At 1 h postcontrast, the PEGylated macromolecular agent still showed prominent enhancement, while little contrast enhancement was detectable in the blood pool by the control agent. PEG-g-poly(GdDTPA-co-l-cystine) shows promise as an MR blood pool imaging agent.     

The effect of dietary folic acid deficiency on the cytotoxic and mutagenic responses to methyl methanesulfonate in wild-type and in 3-methyladenine DNA glycosylase-deficient Aag null mice

Folic acid deficiency (FA-) augments DNA damage caused by alkylating agents. The role of DNA repair in modulating this damage was investigated in mice. Weanling wild-type or 3-methyladenine glycosylase (Aag) null mice were maintained on a FA- diet or the same diet supplemented with folic acid (FA+) for 4 weeks. They were then treated with methyl methanesulfonate (MMS), 100mg/kg i.p. Six weeks later, spleen cells were collected for assays of non-selected and 6-thioguanine (TG) selected cloning efficiency to measure the mutant frequency at the Hprt locus. In wild-type mice, there was no significant effect of either MMS treatment or folate dietary content on splenocyte non-selected cloning efficiency. In contrast, non-selected cloning efficiency was significantly higher in MMS-treated Aag null mice than in saline treated controls (diet-gene interaction variable, p=0.04). The non-selected cloning efficiency was significantly higher in the FA+ diet than in the FA- diet group after MMS treatment of Aag null mice. Mutant frequency after MMS treatment was significantly higher in FA- wild-type and Aag null mice and in FA+ Aag null mice, but not in FA+ wild-type mice. For the Aag null mice, mutant frequency was higher in the FA+ mice than in the FA- mice after either saline or MMS treatment. These studies indicate that in wild-type mice treated with MMS, dietary folate content (FA+ or FA-) had no effect on cytotoxicity, but FA- diet increased DNA mutation frequency compared to FA+ diet. In Aag null mice, FA- diet increased the cytotoxic effects of alkylating agents but decreased the risk of DNA mutation.     

Kinetics of MRI Contrast Agents with a Size Ranging Between Gd-DTPA and Albumin-Gd-Dtpa Use of CASCADE-Gd-DTPA-24 Polymer

A unified kinetic theory describing the dynamic properties of magnetic resonance imaging (MRI) contrast agents with a size ranging between that of Gd-DTPA and albumin-(Gd-DTPA)₃₀ was developed and tested in disease models of cancer and myocardial reperfusion injury. Specifically, a two-compartment kinetic model was solved analytically, and a range of special cases of the model was studied. MRI was performed with strongly T₁-weighted sequences before and dynamically after administration of albumin-(Gd-DTPA)₃₀, a prototype macromolecular contrast medium (MMCM) designed for blood-pool enhancement; a new MMCM: Gd-DTPA-cascade polymer (Schering AG, Berlin, Germany, MW < 30 kDa); or Gd-DTPA, representing small paramagnetic extracellular agents. The greatest dynamic range of contrast-agent sensitivity to disease was found for albumin-(Gd-DTPA)₃₀.     

Magnetic resonance and confocal imaging of solute penetration into the lens reveals a zone of restricted extracellular space diffusion

It has been proposed that in the absence of blood supply, the ocular lens operates an internal microcirculation system that delivers nutrients to internalized fiber cells faster and more efficiently than would occur by passive diffusion alone. To visualize the extracellular space solute fluxes potentially generated by this system, bovine lenses were organ cultured in artificial aqueous humor (AAH) for 4 h in the presence or absence of two gadolinium-based contrast agents, ionic Gd(3+), or a chelated form of Gd(3+), Gd-diethylenetriamine penta-acetic acid (Gd-DTPA; mol mass = 590 Da). Contrast reagent penetration into the lens core was monitored in real time using inversion recovery-spin echo (IR-SE) magnetic resonance imaging (MRI), while steady-state accumulation of [Gd-DTPA](-2) was also determined by calculating T1 values. After incubation, lenses were fixed and cryosectioned, and sections were labeled with the membrane marker wheat germ agglutinin (WGA). Sections were imaged by confocal microscopy using standard and reflectance imaging modalities to visualize the fluorescent WGA label and gadolinium reagents, respectively. Real-time IR-SE MRI showed rapid penetration of Gd(3+) into the outer cortex of the lens and a subsequent bloom of signal in the core. These two areas of signal were separated by an area in the inner cortex that limited entry of Gd(3+). Similar results were obtained for Gd-DTPA, but the penetration of the larger negatively charged molecule into the core could only be detected by calculating T1 values. The presence of Gd-DTPA in the extracellular space of the outer cortex and core, but its apparent absence from the inner cortex was confirmed using reflectance imaging of equatorial sections. In axial sections, Gd-DTPA was associated with the sutures, suggesting these structures provide a pathway from the surface, across the inner cortex barrier to the lens core. Our studies have revealed inner and outer boundaries of a zone within which a narrowing of the extracellular space restricts solute diffusion and acts to direct fluxes into the lens core via the sutures.     

Differential uptake of MRI contrast agents indicates charge-selective blood-brain interface in the crayfish

This study provides a new perspective on the long-standing problem of the nature of the decapod crustacean blood-brain interface. Previous studies of crustacean blood-brain interface permeability have relied on invasive histological, immunohistochemical and electrophysiological techniques, indicating a leaky non-selective blood-brain barrier. The present investigation involves the use of magnetic resonance imaging (MRI), a method for non-invasive longitudinal tracking of tracers in real-time. Differential uptake rates of two molecularly distinct MRI contrast agents, namely manganese (Mn(II)) and Magnevist? (Gd-DTPA), were observed and quantified in the crayfish, Cherax destructor. Contrast agents were injected into the pericardium and uptake was observed with longitudinal MRI for approximately 14.5?h. Mn(II) was taken up quickly into neural tissue (within 6.5?min), whereas Gd-DTPA was not taken up into neural tissue and was instead restricted to the intracerebral vasculature or excreted into nearby sinuses. Our results provide evidence for a charge-selective intracerebral blood-brain interface in the crustacean nervous system, a structural characteristic once considered too complex for a lower-order arthropod.     

Reversibility of the changes induced by n-3 fatty acids in mouse plasma, liver and blood cell lipids

The changes induced by dietary n-3 fatty acids (FA) in the lipids and FA of plasma, liver and blood cells, and their reversibility, was studied in mice given a diet containing 9% fish oil (FO) for 2 weeks and then returned to, and kept for another 2 weeks on, the usual standard lab chow diet. In plasma, the concentrations of phospholipids (PL), mostly phosphatidylcholine (PC), triacylglycerols (TG), cholesterol and cholesterol esters (CE) decreased rapidly after starting the FO diet, and remained low from day 3 onwards. This decrease was concomitant with a remarkable reduction in the n-6 FA, especially 18:2n-6, not compensated for by the relative enrichment in n-3 FA induced by FO. In liver, TG and CE decreased and PL slightly increased, all of them showing reduced n-6/n-3 ratios. Sphingomyelin, which lacks polyunsaturated FA other than small amounts of 18:2 and 24:2n-6, showed altered ratios between its very long chain monoenes and saturates. In the washout phase, the most rapid event was an immediate increase in 18:2n-6 and after a few days in 20:4n-6 in plasma and liver, where most of the lipid and FA changes were reversed completely in about 10 days. In the case of blood cells even 2 weeks were insufficient for a reversal to the initial n-6/n-3 ratios. The lipid class responsible for this lack of reversibility was phosphatidylethanolamine, PC having returned to the initial fatty acid composition during the stated period.     

New concepts in characterization of ischemically injured myocardium by MRI

New concepts regarding the assessment of ischemic myocardial injuries have been addressed in this Minireview using magnetic resonance imaging (MRI). MRI, with its different techniques, brings not only anatomic, but also physiologic, information on ischemic heart disease. It has the ability to measure identical parameters in preclinical and clinical studies. MRI techniques provide the ideal package for repeated and noninvasive assessment of myocardial anatomy, viability, perfusion, and function. MR contrast agents can be applied in a variety of ways to improve MRI sensitivity for detecting and assessing ischemically injured myocardium. With MR contrast agents protocol, it becomes possible to identify ischemic, acutely infarcted, and peri-infarcted myocardium in occlusive and reperfused infarctions. Necrosis specific and nonspecific extracellular contrast-enhanced MRI has been used to assess myocardial viability. Contrast-enhanced perfusion MRI can explore the disturbances in large (angiography) and small coronary arteries (myocardial perfusion) as the underlying cause of myocardial dysfunction. Perfusion MRI has been used to measure myocardial perfusion (ml/min/g) and to demonstrate the difference in transmural myocardial blood flow. Information on no-reflow phenomenon is derived from dynamic changes in regional signal intensity after bolus injection of MR contrast agents. Another development is the near future availability of blood pool MR contrast agents. These agents are able to assess microvascular permeability and integrity and are advantageous in MR angiography (MRA) due to their persistence in the blood. Noncontrast-enhanced MRI such as cine MRI at rest/stress, sodium MRI, and MR spectroscopy also have the potential to noninvasively assess myocardial viability in patients. Futuristic applications for MRI in the heart will focus on identifying coronary artery disease at an early stage and the beneficial effects of new therapeutic agents such as intra-arterial gene therapy. MR techniques will have great future in the drug discovery process and in testing the effects of drugs on myocardial biochemistry, physiology, and morphology. Molecular imaging is going to bloom in this decade.