bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiolabeled α‐melanocyte‐stimulating hormone analogs for receptor‐mediated targeting of melanoma: from tritium to indium
Authors: Eberle Alex N. , Froidevaux Sylvie
Published: September 2003

Following the first synthesis of tritiated α‐melanocyte‐stimulating hormone (α‐MSH, α‐melanotropin) in 1974 by Medzihradszky et al., several α‐MSH analogs were designed containing between 2 and 12 tritium atoms, the latter of which displayed a specific radioactivity of 12.21 GBq/μmol (330 Ci/mmol). Similarly, radioiodinated α‐MSH analogs of high purity, full biological activity and a specific radioactivity of approximatly 140 GBq/μmol were obtained. Although tritiated and radioiodinated α‐MSH became indispensable tools as tracer molecules for numerous in vitro and in vivo studies, above all for receptor identification and characterization as well as for structure‐activity studies, they did not fulfill the criteria required for therapeutic in vivo targeting of metastatic melanoma. Therefore, we recently developed α‐MSH analogs containing the universal metal chelator 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) in different positions of the molecule. As DOTA can equally well incorporate diagnostic (e.g. 111In, 67,68Ga) and therapeutic (e.g. 90Y, 67Cu) radionuclides, DOTA‐MSH compounds may serve for both melanoma scintigraphy and therapy. The analog DOTA‐[βAla3, Nle4, Asp5, D‐Phe7, Lys10]‐α‐MSH3–10 (DOTA‐MSHOCT), which contains the metal chelator at its N‐terminal end, displayed good in vitro MC1R affinity (IC50 9.21 nm). In vivo, [111In]DOTA‐MSHOCT exhibited a favorable biodistribution profile after injection in B16‐F1 tumor‐bearing mice. The radiopeptide was rapidly cleared from blood through the kidneys and, most importantly, accumulated preferentially in the melanoma lesions. Lung and liver melanoma metastases could be clearly imaged on tissue section autoradiographs 4 h after injection of [111In]DOTA‐MSHOCT. A comparative study of [111In]DOTA‐MSHOCT with [111In]DOTA‐[Nle4, D‐Phe7]‐α‐MSH ([111In]DOTA‐NDP‐MSH) demonstrated the superiority of the DOTA‐MSHOCT peptide, particularly with respect to the amount of radioactivity taken up by non‐malignant organs, including bone, the most radiosensitive tissue. These results demonstrate that [111In]DOTA‐MSHOCT specifically targets melanoma metastases and represents a lead compound for the development of therapeutic DOTA‐MSH analogs. Copyright © 2003 John Wiley & Sons, Ltd.
Molecular tools for targeted imaging and therapy of cancer
Authors: Meares Claude F. , Chmura A. J. , Orton Molly S. , Corneillie Todd M. , Whetstone Paul A
Published: September 2003

Here we review an approach to the design and production of antibody/ligand pairs for use in cell targeting procedures, to achieve functional affinity far greater than avidin/biotin. Using fundamental chemical principles, we have developed antibody/ligand pairs that retain the binding specificity of the antibody, but do not dissociate. By eliminating the dissociation of the ligand from the antibody, we have made the affinity functionally infinite. This methodology is applicable to other biological binding pairs. Copyright © 2003 John Wiley & Sons, Ltd.
Membrane permeability commonly shared among arginine‐rich peptides
Authors: Futaki Shiroh , Goto Susumu , Sugiura Yukio
Published: September 2003

Delivery of proteins and other macromolecules using membrane‐permeable carrier peptides is a recently developed novel technology, which enables us to modulate cellular functions for biological studies with therapeutic potential. One of the most often used carrier peptides is the arginine‐rich basic peptide derived from HIV‐1 Tat protein [HIV‐1 Tat (48–60)]. Using this peptide, efficient intracellular delivery of molecules including proteins, oligonucleic acids and liposomes has been achieved. We have demonstrated that these features were commonly shared among many arginine‐rich peptides such as HIV‐1 Rev (34–50) and octaarginine. Not only the linear peptides but also branched‐chain peptides showed efficient internalization with an optimum number of arginines (approximately eight residues). The structural and mechanistic features of the translocation of these membrane‐permeable arginine‐rich peptides are reviewed. Copyright © 2003 John Wiley & Sons, Ltd.
Cellular utake of the Tat peptide: an endocytosis mechanism following ionic interactions
Authors: Vives Eric
Published: September 2003

The cellular delivery of various biological compounds has recently been improved by conjugating them to short peptides known as protein transduction domains or cell penetrating peptides. These peptides include Tat, Antennapedia and arginine‐rich peptides. The common feature of these peptides is their highly cationic nature. Up to now, the cellular uptake of about 50 different peptides and proteins coupled to Tat or Antennapedia peptides has been reported. The ability to deliver molecules into cells is not limited to peptide moieties, since oligonucleotides, peptide nucleic acids or other low molecular weight entities have been successfully internalized. Moreover, most of these examples have been accompanied by the expected biological response. More surprisingly, the uptake of large structures such as liposomes, phages, nanoparticles or adenoviruses has also been documented. Indeed the mechanism by which these very different entities could enter cells following a putative common pathway appeared more and more intriguing after each new reported example of cellular uptake mediated by these peptides. After a long period of uncertainty regarding the mechanism of entry, data from several groups now argue for an energy‐dependent process of entry. The entry of most of these molecules is likely to be inhibited by low temperature incubation or in the presence of various drugs applied to inhibit the energy‐dependent pathway of cell entry. Moreover, the binding of the highly cationic Tat peptide to various anionic membrane components probably initiates the first step of the cell internalization process. Copyright © 2003 John Wiley & Sons, Ltd.
Membrane translocation of penetratin and its derivatives in different cell lines
Authors: Letoha T. , Gaál S. , Somlai C. , Czajlik A. , Perczel A. , Penke B.
Published: September 2003

The third helix of the homeodomain of the Antennapedia homeoprotein can translocate through the cell membrane into the nucleus and can be used as an intracellular vehicle for the delivery of oligopeptides and oligonucleotides. A 16‐amino acid‐long peptide fragment, called penetratin, is internalized by the cells in a specific, non‐receptor‐mediated manner. For a better understanding of the mechanism of the transfer, penetratin and two analogs were synthesized:

(1) penetratin

RQIKIWFQNRRMKWKK  (peptide 1);

(2) (6,14‐Phe)‐penetratin,

RQIKIFFQNRRMKFKK  (peptide 2);

(3) dodecapeptide,

RQIKIWF‐R‐KWKK  (peptide 3);

The conformation of penetratin peptides 1–3 was examined in both extracellular matrix‐mimetic and membrane‐mimetic environments. 1H‐NMR and CD spectroscopic measurements were performed in mixtures of TFE/water with different ratios. Peptides 1–3 were labeled by reacting their N‐terminal free amino group with fluorescein isothiocyanate (FITC). Membrane translocation of the labelled peptides was studied with cell cultures [WEHI 164 murine fibrosarcoma cells (WC/1); chicken fibroblast cells (CEC‐32); chicken monocytic cells (HD‐11); human fibroblast (SV 80) and human monocytic cells (MonoMac‐6)]. Confocal laser scanning microscopy and flow cytometry assay were used to study membrane translocation. Amphiphilicity was calculated for each peptide. In our experiments all the penetratin peptides penetrated into the cells. Helical conformation and membrane translocation ability showed little correlation: substitution of the two Trp with Phe increased the stability of helical conformation but decreased membrane translocation activity. The results of fluorescence microscopy and flow cytometry show that penetratin can be translocated into the cells by two mechanisms: endocytosis and direct transport through the cell membrane. Copyright © 2003 John Wiley & Sons, Ltd.
Novel daunorubicin‐carrier peptide conjugates derived from human calcitonin segments
Authors: Krauss Ulrike , Kratz Felix , Beck‐Sickinger Annette G.
Published: September 2003

Severe and often therapy‐limiting side effects are a major obstacle in cancer chemotherapy. New delivery concepts reducing systemic side effects are needed in order to optimize anticancer therapies. Several approaches have been followed, most of them concentrating on macromolecular carriers like liposomes, monoclonal antibodies, serum proteins or polyethylene glycol. We present here a novel type of anthracycline conjugate, using a small carrier peptide derived from the peptide hormone human calcitonin (hCT). The carrier peptide hCT(9–32) has so far been shown to be capable of transporting fluorophores or proteins across cellular membranes. Two different carrier peptide–daunorubicin conjugates were prepared, one with an acid‐stable amide bond, the second with an acid‐labile hydrazone bond. In vitro studies with daunorubicin linked to the carrier peptide via an acid‐labile hydrazone bond demonstrated comparable cytotoxicity to daunorubicin in various daunorubicin sensitive cell lines (neuroblastoma cell lines SK‐N‐MC and SMS‐KAN; HEK 293 T cells). In addition, fluorescence microscopy provided further insight into the mechanism of uptake of the carrier peptide hCT(9–32), indicating that endosomal compartments with reduced pH are involved in the intracellular release of daunorubicin. Copyright © 2003 John Wiley & Sons, Ltd.
Drug targeting by macromolecules without recognition unit?
Authors: Hudecz Ferenc , Reményi Judit , Szabó Rita , Kóczán György , Mező Gábor , Kovács Péter , Gaál Dezső
Published: September 2003

his review will summarize available information on the ability of macromolecular conjugates containing no specific recognition motifs to deliver anthracyclines (daunomycin, adriamycin) or methotrexate to target cells such as tumour cells or macrophages. Conjugates with natural (proteins, DNA, carbohydrates) and synthetic macromolecules (linear and branched chain poly‐α‐amino acids, non‐biodegradable DIVEMA, HPMA etc.) will be reviewed. Experimental data from several laboratories indicate that these conjugates are taken up by cells mainly by fluid‐phase or adsorptive endocytosis. It is believed that these processes do not involve ‘specific receptors’. Two examples of methotrexate and daunomycin conjugates will be discussed to show the effect of the chemical structure of branched chain polypeptides on the uptake and antitumour or antiparasitic (Leishmania donovani infection) efficacy of conjugates. Copyright © 2003 John Wiley & Sons, Ltd.
Recombinant antibodies with MHC‐restricted, peptide‐specific, T‐cell receptor‐like specificity: new tools to study antigen presentation and TCR–peptide–MHC interactions
Authors: Cohen Cyril J. , Denkberg Galit , Lev Avital , Epel Malka , Reiter Yoram
Published: September 2003

The advent in recent years of the application of tetrameric arrays of class I peptide–MHC complexes now enables us to detect and study rare populations of antigen‐specific CD8+ T cells. However, available methods cannot visualize or determine the number and distribution of these TCR ligands on individual cells or detect antigen‐presenting cells (APCs) in tissues. Here we describe a new approach that enables study of human class I peptide–MHC ligand‐presentation as well as TCR–peptide–MHC interactions. Such studies are facilitated by applying novel tools in the form of peptide‐specific, HLA‐A2‐restricted human recombinant antibodies directed toward a large variety of tumor‐associated as well as viral T‐cell epitope peptides. Using a large human antibody phage display library, a large panel of recombinant antibodies that are specific for a particular peptide–MHC class I complex in a peptide‐dependent, MHC‐restricted manner was isolated. These antibodies were used to directly visualize the specific MHC–peptide complex on tumor cells, antigen‐presenting cells or virus‐infected cells by flow cytometry. They enabled direct quantitation of the number of MHC–peptide complexes as well as in situ detection of the complex on the surface of APCs after naturally occurring active intracellular processing of the cognate antigen. These studies will enable also the development of a new class of targeting molecules to deliver drugs or toxins to tumor or virus‐infected cells. Thus, we demonstrate our ability to transform the unique fine specificity but low intrinsic affinity of TCRs into high‐affinity soluble antibody molecules endowed with a TCR‐like specificity toward human tumor or viral epitopes. These molecules may prove to be crucial useful tools for studying MHC class I antigen presentation in health and disease as well as for therapeutic purposes in cancer, infectious diseases and autoimmune disorders. Copyright © 2003 John Wiley & Sons, Ltd.
The molecular basis of celiac disease
Authors: Koning Frits
Published: September 2003

Celiac disease is caused by inflammatory, gluten specific T cell responses in the small intestine. Invariably such responses are HLA‐DQ2 or HLA‐DQ8 restricted, providing an explanation for the strong association between celiac disease and these HLA‐class II alleles. It is now clear that some native gluten sequences can bind to HLA‐DQ2/8 and induce T cell responses. In addition, modification of gluten peptides by the enzyme tissue transglutaminase results in high affinity HLA‐DQ2/8 binding peptides that can induce T cell responses. Thus, gluten molecules contain a large number of immunogenic peptides and this is likely to play an important role in the breaking of oral tolerance to gluten. Copyright © 2003 John Wiley & Sons, Ltd.
Targeting with scFv: immune modulation by complement receptor specific constructs
Authors: Molnár Eszter , Prechl József , Isaák Andrea , Erdei Anna
Published: September 2003

The fate of a microbe in the host is determined by various molecules of the innate immune system, which recognize the microbe and enhance its interaction with antigen presenting cells. This ‘natural targeting’ phenomenon, however, does not function when antigens with limited immunogenicity enter the host. Peptide vaccines, for instance, require adjuvants to induce immune responses. As a surrogate for the natural targeting mechanisms, antibodies against selected receptors of antigen presenting cells, conjugated with the peptides, could be used as targeting devices. Here we review various antibody‐mediated antigen‐targeting strategies, paying special attention to complement receptor‐mediated targeting. We also describe and summarize our method of single‐chain antibody‐mediated targeting of viral epitopes to complement receptor type two and discuss the perspectives of single‐chain antibody‐mediated antigen targeting. Copyright © 2003 John Wiley & Sons, Ltd.
Destination ‘Lysosome’: a target organelle for tumour cell killing?
Authors: Castino Roberta , Démoz Marina , Isidoro Ciro
Published: September 2003

Lysosomes and lysosome‐related organelles constitute a system of acid compartments that interconnect the inside of the cell with the extracellular environment via endocytosis, phagocytosis and exocytosis. In recent decades it has been recognized that lysosomes are not just wastebaskets for disposal of unused cellular constituents, but that they are involved in several cellular processes such as post‐translational maturation of proteins, degradation of receptors and extracellular release of active enzymes. By complementing the autophagic process, lysosomes actively contribute to the maintenance of cellular homeostasis. Proteolysis by lysosomal cathepsins has been shown to mediate the death signal of cytotoxic drugs and cytokines, as well as the activation of pro‐survival factors. Secreted lysosomal cathepsins have been shown to degrade protein components of the extracellular matrix, thus contributing actively to its re‐modelling in physiological and pathological processes. The malfunction of lysosomes can, therefore, impact on cell behaviour and fate. Here we review the role of lysosomal hydrolases in several aspects of the malignant phenotype including loss of cell growth control, altered regulation of cell death, acquisition of chemoresistance and of metastatic potential. Based on these observations, the lysosome is proposed as a potential target organelle for the chemotherapy of tumours. We will also present some recent data concerning the technologies for delivering chemotherapeutic drugs to the endosomal–lysosomal compartment and the strategies to improve their efficacy. Copyright © 2003 John Wiley & Sons, Ltd.
Targeting dendritic cells for priming cellular immune responses
Authors: Gogolák Péter , Réthi Bence , Hajas György , Rajnavölgyi Éva
Published: September 2003

The cardinal role of dendritic cells (DC) in priming adaptive immunity and in orchestrating immune responses against all classes of pathogens and also against tumors is well established. Their unique potential both to maintain self‐tolerance and to initiate protective immune responses against foreign and/or dangerous structures is based on the functional diversity and flexibility of these cells. Tissue DC lining antigenic portals such as mucosal surfaces and the skin are specialized to take up a wide array of compounds including proteins, lipids, carbohydrates, glycoproteins, glycolipids and oligonucleotides, particles carrying such structures and apoptotic or necrotic cells. This process is facilitated by specialized receptors with high endocytic capacity, which provides potential targets for delivering designed molecules. The best route for targeting B‐ and/or T cell epitopes, however, is still the subject of intense investigation. Immature DC, which reside in various tissues, can be activated by pathogens, stress and inflammation or modified metabolic products, which induce mobilization of cells to draining lymph nodes where they act as highly potent professional antigen presenting cells. This is brought about by the ability to present their accumulated intracellular content for both CD4+ helper (Th) and CD8+ cytotoxic/cytolytic T lymphocytes (Tc/CTL). Engulfed proteins are processed intracellularly and their peptide fragments are transported to the cell surface in the context of major histocompatibility complex encoded class I and II molecules for presentation to Th cells and CTLs, respectively. The T cell priming capacity of DC, however, depends not only on antigen presentation but also on other features of DC.

Human monocyte‐derived DC provide an excellent tool to study the internalizing, antigen‐presenting and T cell‐activating functions of DC at their immature and activated differentiation states. These biological activities of DC, however, are highly dependent on their migratory potential from the peripheral non‐lymphoid tissues to the lymph nodes, on the expression of adhesion molecules, which support the interaction of DC with T lymphocytes, and the cytokines secreted by DC, which polarize immune responses to Th1‐mediated cellular or Th2‐mediated antibody responses. These results altogether demonstrate that monocyte‐derived DC are useful candidates for in vitro or in vivo targeting of antigens to induce efficient adaptive immune responses against pathogens and also against tumors. Copyright © 2003 John Wiley & Sons, Ltd.
Passive tracking exploiting local signal conservation: The white marker phenomenon
Authors: Seppenwoolde Jan‐Henry , Viergever Max A. , Bakker Chris J.G.
Published: September 2003

This article presents a novel approach to passive tracking of paramagnetic markers during endovascular interventions, exploiting positive contrast of the markers to their background, so‐called “white marker tracking.” The positive contrast results from dephasing of the background signal with a slice gradient, while near the marker the signal is conserved because a dipole field induced by the marker compensates the dephasing gradient. Theoretical investigation shows that a local gradient induced by the local dipole field will nearly always cancel the dephasing gradient somewhere, regardless of marker composition, gradient strength, orientation, and acquisition parameters. The actual appearance of the white marker is determined by the marker strength, echo‐time, slice thickness, and gradient strength, as shown both theoretically and experimentally. The novel concept is demonstrated by tracking experiments in a flow phantom and in pig models and is shown to allow reliable and robust depiction of paramagnetic markers with positive contrast and significant suppression of the background signal. Magn Reson Med 50:784–790, 2003. © 2003 Wiley‐Liss, Inc.
Impact of intravascular signal on quantitative measures of cerebral oxygen extraction and blood volume under normo‐ and hypercapnic conditions using an asymmetric spin echo approach
Authors: An Hongyu , Lin Weili
Published: September 2003

An asymmetric spin echo (ASE) single shot echo planar imaging (EPI) sequence is proposed for obtaining quantitative estimates of R2′, cerebral venous blood volume fraction (vCBV), and oxygen extraction fraction (OEF) noninvasively in normal volunteers. The impact of the presence of intravascular signal on the estimates of vCBV and OEF were examined in five subjects with different levels of flow attenuation. A significant reduction in the estimates of vCBV and a small increase in the measurements of OEF were observed in the presence of flow suppression gradients. In addition, mild hypercapnia was induced in normal subjects (n = 4). R2′, vCBV, and OEF were measured under both normocapnia and experimentally induced hypercapnia. In agreement with the well‐documented cerebral vascular responses to hypercapnia, estimates of R2′ and OEF decrease, while measures of vCBV increase during hypercapnia. Magn Reson Med 50:708–716, 2003. © 2003 Wiley‐Liss, Inc.
Sources of plasma glucose by automated bayesian analysis of 2H NMR spectra
Authors: Merritt Matthew , Bretthorst G. Larry , Burgess Shawn C. , Sherry A. Dean , Malloy Craig R.
Published: September 2003

Sources of blood glucose can be determined after oral ingestion of 2H2O followed by isolation of plasma glucose and measurement of the relative 2H enrichments in select positions within the glucose molecule. Typically, 2H enrichments are obtained by mass spectrometry but 2H NMR offers an alternative. Here it is demonstrated that the entire analysis may be automated by Bayesian analysis of a 2H free induction decay signal of monoacetone glucose to obtain a direct readout of the relative contributions of glycogenolysis, glycerol, and phosphoenol pyruvate to plasma glucose production. Furthermore, Markov Chain Monte Carlo (MCMC) simulations of the posterior probability density provide uncertainties in all metabolic parameters from a single patient, thereby allowing comparisons in glucose metabolism from one individual to another. The combined MCMC Bayesian methodology is operationally simple and requires little intervention from the operator. Magn Reson Med 50:659–663, 2003. © 2003 Wiley‐Liss, Inc.
Statistical model for diffusion attenuated MR signal
Authors: Yablonskiy Dmitriy A. , Bretthorst G. Larry , Ackerman Joseph J.H.
Published: September 2003

A general statistical model that can describe a rather large number of experimental results related to the structure of the diffusion‐attenuated MR signal in biological systems is introduced. The theoretical framework relies on a phenomenological model that introduces a distribution function for tissue apparent diffusion coefficients (ADC). It is shown that at least two parameters—the position of distribution maxima (ADC) and the distribution width (σ)—are needed to describe the MR signal in most regions of a human brain. A substantial distribution width, on the order of 36% of the ADC, was found for practically all brain regions examined. This method of modeling the MR diffusion measurement allows determination of an intrinsic tissue‐specific ADC for a given diffusion time independent of the strength of diffusion sensitizing gradients. The model accounts for the previously found biexponential behavior of the diffusion‐attenuated MR signal in CNS. Magn Reson Med 50:664–669, 2003. © 2003 Wiley‐Liss, Inc.
Magnetic resonance measurement of tetramethylammonium diffusion in rat brain: Comparison of magnetic resonance and ionophoresis in vivo diffusion measurements
Authors: Kroenke Christopher D. , Ackerman Joseph J.H. , Neil Jeffrey J.
Published: September 2003

Magnetic resonance (MR) and ionophoresis are two experimental methods that provide measurements of molecular diffusion in living tissue. Typical experimental settings yield MR studies that are sensitive to mean molecular displacements of ∼5 μm, and ionophoresis experiments to displacements of ≥100 μm. An assessment of the correspondence between the methods is hampered by the fact that no common probe molecule has been used. One of the most frequently utilized probe molecules in ionophoresis measurements is the tetramethylammonium (TMA) ion. In the current work the diffusion properties of TMA were studied in rat brain in vivo with localized1H MR spectroscopy (MRS). Standard treatment of the MR data yielded a 3.6‐fold lower apparent diffusion coefficient (ADC) compared to ionophoresis. To explore the source of this discrepancy, a separate data processing scheme was applied to the MR data to monitor individual elapsed displacement‐distance subpopulations of TMA molecules. This analysis revealed a dependence of the ADC estimation on a given subpopulation's elapsed displacement distance. The MR‐derived ADC approached the ionophoresis‐derived value as the elapsed displacement distance increased to 15 μm. These observations demonstrate that MR and ionophoresis studies provide complementary information, and that ADC estimates obtained from the two techniques are sensitive to different biophysical determinants. Magn Reson Med 50:717–726, 2003. © 2003 Wiley‐Liss, Inc.
Scalar couplings as pH probes in compartmentalized biological systems: 31P NMR of phosphite
Authors: Eykyn Thomas R. , Kuchel Philip W.
Published: September 2003

The use of scalar couplings in nuclear magnetic resonance (NMR) spectra was investigated as a possible tool for the measurement of pH in different compartments of biological systems. The proposed method is attractive because no internal reference is required, unlike more widely used chemical shift titrations. The phosphite anion is shown to be ideal for the measurement of pH in the physiological range. In isotonic solution, the divalent anion PHO has a one‐bond 1JPH of 568.1 Hz, increasing to 620.7 Hz for the monovalent anion PH(OH)O, with a measured pKa of 6.19. The technique was applied to the measurement of pH in a suspension of human erythrocytes. The 31P spectra of these species give well‐resolved doublets for the intra‐ and extracellular spaces, and can be used to measure the pH difference across the cell membrane with errors on the order of about 0.01 pH units in the range of pH 5–7. Variations in erythrocyte pH due to metabolic changes are clearly observed. Magn Reson Med 50:693–696, 2003. © 2003 Wiley‐Liss, Inc.
Characterization of continuously distributed cortical water diffusion rates with a stretched‐exponential model
Authors: Bennett Kevin M. , Schmainda Kathleen M. , Bennett (Tong) Raoqiong , Rowe Daniel B. , Lu Hanbing , Hyde James S.
Published: September 2003

Experience with diffusion‐weighted imaging (DWI) shows that signal attenuation is consistent with a multicompartmental theory of water diffusion in the brain. The source of this so‐called nonexponential behavior is a topic of debate, because the cerebral cortex contains considerable microscopic heterogeneity and is therefore difficult to model. To account for this heterogeneity and understand its implications for current models of diffusion, a stretched‐exponential function was developed to describe diffusion‐related signal decay as a continuous distribution of sources decaying at different rates, with no assumptions made about the number of participating sources. DWI experiments were performed using a spin‐echo diffusion‐weighted pulse sequence with b‐values of 500–6500 s/mm2 in six rats. Signal attenuation curves were fit to a stretched‐exponential function, and 20% of the voxels were better fit to the stretched‐exponential model than to a biexponential model, even though the latter model had one more adjustable parameter. Based on the calculated intravoxel heterogeneity measure, the cerebral cortex contains considerable heterogeneity in diffusion. The use of a distributed diffusion coefficient (DDC) is suggested to measure mean intravoxel diffusion rates in the presence of such heterogeneity. Magn Reson Med 50:727–734, 2003. © 2003 Wiley‐Liss, Inc.
Generalized reconstruction of phase contrast MRI: Analysis and correction of the effect of gradient field distortions
Authors: Markl M. , Bammer R. , Alley M.T. , Elkins C.J. , Draney M.T. , Barnett A. , Moseley M.E. , Glover G.H. , Pelc N.J.
Published: September 2003

To characterize gradient field nonuniformity and its effect on velocity encoding in phase contrast (PC) MRI, a generalized model that describes this phenomenon and enables the accurate reconstruction of velocities is presented. In addition to considerable geometric distortions, inhomogeneous gradient fields can introduce deviations from the nominal gradient strength and orientation, and therefore spatially‐dependent first gradient moments. Resulting errors in the measured phase shifts used for velocity encoding can therefore cause significant deviations in velocity quantification. The true magnitude and direction of the underlying velocities can be recovered from the phase difference images by a generalized PC velocity reconstruction, which requires the acquisition of full three‐directional velocity information. The generalized reconstruction of velocities is applied using a matrix formalism that includes relative gradient field deviations derived from a theoretical model of local gradient field nonuniformity. In addition, an approximate solution for the correction of one‐directional velocity encoding is given. Depending on the spatial location of the velocity measurements, errors in velocity magnitude can be as high as 60%, while errors in the velocity encoding direction can be up to 45°. Results of phantom measurements demonstrate that effects of gradient field nonuniformity on PC‐MRI can be corrected with the proposed method. Magn Reson Med 50:791–801, 2003. Published 2003 Wiley‐Liss, Inc.
Comparison of dendrimer‐based macromolecular contrast agents for dynamic micro‐magnetic resonance lymphangiography
Authors: Kobayashi Hisataka , Kawamoto Satomi , Choyke Peter L. , Sato Noriko , Knopp Michael V. , Star Robert A. , Waldmann Thomas A. , Tagaya Yutaka , Brechbiel Martin W.
Published: September 2003

Few methods are currently available to visualize the entire lymphatic system. A method known as micro‐magnetic resonance lymphangiography (MRL), which employs a dendrimer‐based MRI contrast agent (PAMAM‐G8) and a clinical‐grade 1.5T MRI instrument, was recently developed for use in mice. In the present study, three dendrimer‐based MRI contrast agents (PAMAM‐G8, DAB‐G5, and PAMAM‐G4) with different pharmacokinetic characteristics were compared to determine the best reagent to visualize the lymphatic system under physiological or pathological conditions. In addition, two established MRI contrast agents (Gadomer‐17 and Gd‐[DTPA]‐dimeglumine (Magnevist)) were used as control agents. In experiments with mice, most of the deep lymphatic system was visualized by micro‐MRL with all agents except Gd‐[DTPA]‐dimeglumine. PAMAM‐G8 was best for visualizing lymphatic vessels, whereas DAB‐G5 was better for visualizing lymph nodes. PAMAM‐G4 was intermediate in character between PAMAM‐G8 and DAB‐G5, except in exhibiting a low background signal (especially in the liver). The lymphatic system was not clearly visualized with Gd‐[DTPA]‐dimeglumine; however, the lymph nodes were visualized with Gadomer‐17, although not as well as with dendrimer‐based agents. In conclusion, DAB‐G5 and PAMAM‐G4 can be used to identify lymph nodes and lymphatic vessels, respectively. Their rapid excretion makes these compounds potentially attractive for human use. Magn Reson Med 50:758–766, 2003. Published 2003 Wiley‐Liss, Inc.
RINGLET motion correction for 3D MRI acquired with the elliptical centric view order
Authors: Bernstein Matt A. , Shu Yunhong , Elliott Andrew M.
Published: September 2003

A new rigid‐body motion correction algorithm is described that is compatible with 3D image sets acquired with the elliptical centric (EC) view order. With this view order, an annular ring of k‐space data is acquired in the ky‐kz plane during any short time interval. Images for tracking motion can be reconstructed in the yz‐plane from any ring of the acquisition data. In these tracking images, a point source (such as an external marker) shows a characteristic bull's‐eye pattern that permits motion monitoring and correction. The true position of the point object is located at the center of the bull's‐eye pattern. Cross correlation can be performed to automatically track the positions of markers reconstructed from adjacent rings of k‐space. To increase the marker signal, the markers are encased in inductively coupled RF coils. Rigid‐body motion in the yz‐plane is calculated directly with the Euclidean group for rotation and translation, and corrected by rotating and applying phase shifts to any corrupted rings of data. In the current work we present a theoretical analysis of this method, as well as results of volunteer and controlled phantom experiments that demonstrate its initial feasibility. Although the EC view order has mainly been used for MR angiography (MRA), it can also be used for most 3D acquisitions. Magn Reson Med 50:802–812, 2003. © 2003 Wiley‐Liss, Inc.
Imaging the fate of implanted bone marrow stromal cells labeled with superparamagnetic nanoparticles
Authors: Jendelová Pavla , Herynek Vít , DeCroos Jane , Glogarová Kateřina , Andersson Benita , Hájek Milan , Syková Eva
Published: September 2003

Bone marrow stromal cells (MSCs) are pluripotent progenitor cells that have the capacity to migrate toward lesions and induce or facilitate site‐dependent differentiation in response to environmental signals. In animals with a cortical photochemical lesion, the fate of rat MSCs colabeled with magnetic iron‐oxide nanoparticles (Endorem®) and bromodeoxyuridine (BrdU) was studied. MSCs were either grafted intracerebrally into the contralateral hemisphere of adult rat brain or injected intravenously. In vivo MRI was used to track their fate; Prussian blue staining and transmission electron microscopy (TEM) confirmed the presence of iron‐oxide nanoparticles inside the cells. During the first week posttransplantation, the transplanted cells migrated to the lesion site and populated the border zone of the damaged cortical tissue. The implanted cells were visible on MR images as a hypointense area at the injection site and in the lesion. The hypointense signal persisted for more than 50 days. The presence of BrdU‐positive and iron‐containing cells was confirmed by subsequent histological staining. Three to 4 weeks after injection, <3% of MSCs around the lesion expressed the neuronal marker NeuN. Our study demonstrates that a commercially available contrast agent can be used as a marker for the long‐term noninvasive MR tracking of implanted cells. Magn Reson Med 50:767–776, 2003. © 2003 Wiley‐Liss, Inc.
Effects of barrier‐induced nuclear spin magnetization inhomogeneities on diffusion‐attenuated MR signal
Authors: Sukstanskii A.L. , Ackerman J.J.H. , Yablonskiy D.A.
Published: September 2003

The spatial distribution of the transverse nuclear spin magnetization, appearing in a single compartment with impermeable boundaries in a Stejskal‐Tanner gradient pulse MR experiment, is analyzed in detail. At short diffusion times the presence of diffusion‐restrictive barriers (membranes) reduces effective diffusivity near the membranes and leads to an inhomogeneous spin magnetization distribution (the edge‐enhancement effect). In this case, the signal reveals a quasi‐two‐compartment behavior and can be empirically modeled remarkably well by a biexponential function. The current results provide a framework for interpreting experimental MR data on various phenoma, including water diffusion in giant axons, metabolite diffusion in the brain, and hyperpolarized gas diffusion in lung airways. Magn Reson Med 50:735–742, 2003. © 2003 Wiley‐Liss, Inc.
Single‐shot magnetic field mapping embedded in echo‐planar time‐course imaging
Authors: Roopchansingh Vinai , Cox Robert W. , Jesmanowicz Andrzej , Ward B. Douglas , Hyde James S.
Published: September 2003

A technique for acquiring magnetic field maps simultaneously with gradient‐recalled echo‐planar time‐course data is described. This technique uses a trajectory in which the central part of k‐space is collected twice. For a 64 × 64 image acquired with a 125‐kHz bandwidth, a field map suitable for geometric correction can be collected simultaneously with the echo‐planar time‐course data in <70 ms. The field maps generated by this technique are registered with the magnitude images because they are calculated using the same data. They do not suffer from errors due to subject motion, or from different geometric distortions that can result from using different pulse sequences. In addition to correcting geometric distortions that resulted from dynamic magnetic field perturbations, this method was used to measure field shifts arising from respiration and jaw motion across five subjects. Values ranged from 0.035 to 0.165 parts per million (ppm). Magn Reson Med 50:839–843, 2003. © 2003 Wiley‐Liss, Inc.
Electrical conductivity imaging by magnetic resonance electrical impedance tomography (MREIT)
Authors: Oh Suk H. , Han Jae Y. , Lee Soo Y. , Cho Min H. , Lee Byung I. , Woo Eung J.
Published: September 2003

Magnetic resonance electrical impedance tomography (MREIT) is a recently developed imaging technique that combines MRI and electrical impedance tomography (EIT). In MREIT, cross‐sectional electrical conductivity images are reconstructed from the internal magnetic field density data produced inside an electrically conducting subject when an electrical current is injected into the subject. In this work the results of an electrical conductivity imaging experiment are presented, along with some practical considerations regarding MREIT. The MREIT experiment was performed with a 0.3 Tesla MRI system on a phantom made of two compartments with different electrical conductivities. The current density inside the phantom was measured by the MR current density imaging (MRCDI) technique. The measured current density was then used for conductivity image reconstruction by the J‐substitution algorithm. The conductivity phantom images obtained with an injection current of 28mA showed conductivity errors of about 25.5%. Magn Reson Med 50:875–878, 2003. © 2003 Wiley‐Liss, Inc.
Importance of k‐space trajectory in echo‐planar myocardial tagging at rest and during dobutamine stress
Authors: Kim Daniel , Bove Christina M. , Kramer Christopher M. , Epstein Frederick H.
Published: September 2003

Hybrid fast gradient echo/echo‐planar imaging (FGRE‐EPI) can be used to increase temporal resolution, enhance tag contrast, and/or decrease scan time for breathhold myocardial tagging. However, off‐resonance effects and motion can lead to local phase discontinuities in FGRE‐EPI raw data when a conventional interleaved bottom‐up k‐space trajectory is used. These discontinuities can be particularly problematic for myocardial tagging, where the image energy is not only concentrated near the k‐space origin, but is also concentrated in multiple spectral peaks centered throughout k‐space. In this study, tag distortion artifacts in FGRE‐EPI tagging due to off‐resonance and velocity‐induced phase discontinuities were characterized at rest and dobutamine stress, and the flyback and gradient moment smoothing (GMS) methods were shown to reduce these artifacts. For the specific parameters used in this study, flyback and GMS resulted in improved image quality at rest and stress, increased myocardium‐tag contrast‐to‐noise ratio (11.4 ± 2.1 vs. 10.0 ± 2.9, P < 0.01 at rest; 11.1 ± 1.8 vs. 8.1 ± 2.4, P < 0.01 at stress), and reduced full width at half maximum of the tag profile (3.6 vs. 3.8 pixels at rest; 4.0 vs. 5.1 pixels at stress) compared to the conventional trajectory. A limitation of the improved trajectory is a parameter‐dependent decrease in data acquisition efficiency. For the specific imaging protocol used, the repetition time of the improved trajectory increased by 36% compared to the conventional trajectory. Magn Reson Med 50:813–820, 2003. © 2003 Wiley‐Liss, Inc.
Dynamic 3He imaging for quantification of regional lung ventilation parameters
Authors: Dupuich David , Berthezène Yves , Clouet Pierre‐Louis , Stupar Vasile , Canet Emmanuelle , Crémillieux Yannick
Published: September 2003

Dynamic ventilation imaging using laser‐polarized 3He has a promising potential for elucidating the physiology and physiopathology of the lungs. In this study, a methodological approach is proposed for the assessment and quantification of local ventilation parameters. High‐temporal‐resolution coronal ventilation image series were obtained with a projection‐reconstruction (PR) sequence combined with the sliding‐window technique. After image series were processed, parametric pixel‐by‐pixel maps of the gas arrival time, filling time constant, inflation rate, and gas volume were generated. The acquisition technique and the signal processing procedure, which are referred to collectively as sliding pulmonary imaging for respiratory overview (SPIRO), were tested in vivo in healthy rat lungs using a contrast media injector for controlled 3He flow and volume injection in the animal lungs. The same protocol was applied to broncho‐constriction animal models using intravenous injection of methacholine solution. Inflation rate values measured in the lungs were found to decrease with increasing doses of injected methacholine solution. This study demonstrates that it is possible to obtain quantitative regional gas dynamic information using the SPIRO technique in a single polarized gas inspiration. Magn Reson Med 50:777–783, 2003. © 2003 Wiley‐Liss, Inc.
Cerebral blood volume measurements by T‐weighted MRI and contrast infusion
Authors: Newman G.C. , Delucia‐Deranja E. , Tudorica A. , Hospod F.E. , Patlak C.S.
Published: September 2003

A reliable, accurate, and accessible method for measuring cerebral blood volume (CBV) has been developed based on T‐weighted MRI and a 1‐min infusion of gadolinium instead of a bolus. Computer simulations predict that this infusion CBV method will have a signal‐to‐noise ratio (SNR) 3–5 times greater than that obtained by area‐under‐the‐curve (AUC) methods, with high accuracy over a wide range of arterial, tissue, and MRI conditions. In six healthy controls, the CBV was 1.87 ± 0.44 in white matter (WM), 3.40 ± 0.44 in deep gray matter (DGM), and 3.84 ± 1.87 ml blood/100 g tissue in cortical GM (CGM). The mean GM/WM ratio was 1.94. In five patients with bilateral carotid disease, the corresponding values were 2.63 ± 0.33, 4.72 ± 0.33, and 5.27 ± 2.40 ml blood/100 g tissue, all of which were significantly different from controls. AUC values were generally higher and failed to demonstrate differences between controls and patients. The infusion method shows great potential for providing reliable, accurate, and accessible CBV values with the ability to discriminate physiologic or pathological volume changes under a wide range of conditions. Magn Reson Med 50:844–855, 2003. © 2003 Wiley‐Liss, Inc.
High‐resolution diffusion‐weighted 3D MRI, using diffusion‐weighted driven‐equilibrium (DW‐DE) and multishot segmented 3D‐SSFP without navigator echoes
Authors: Jeong Eun‐Kee , Kim Seong‐Eun , Parker Dennis L.
Published: September 2003

In this work we report on the development of a novel technique for high‐resolution diffusion‐weighted (DW) MRI based upon 3D steady‐state free precession (3D‐SSFP). First the 3D‐SSFP acquisition was segmented (each segment consisting of a series of RF pulses and gradient‐recalled echoes), and then DW‐driven equilibrium (DE) was inserted between each segment. The in‐plane imaging matrix was typically 256 × 192 or 256 × 160, which resulted in high‐resolution DW images. The DW‐DE segmented SSFP signal was contaminated by the non‐DW magnetization, which recovered and contributed signal during the readout train (T1 contamination). Center‐out slice encoding was used to place the greatest diffusion weighting at the center of k‐space. A numerical simulation and supporting experiments were performed to evaluate the relationship of the transverse magnetization to imaging parameters, such as the b‐value, echo‐train length (ETL), echo‐train (group) repetition time (TRg), and RF excitation TR (Δt). Both the numerical simulation and the experiments suggested that the effect of T1 contamination would be reduced with a longer TRg, smaller b‐value, shorter ETL, and center‐out slice phase encoding. Phase errors caused by microscopic motions during the diffusion gradients were converted into amplitude errors by the tip‐up pulse at the end of the diffusion‐weighting segment. As a result, small bulk motions, such as CSF pulsation, did not cause motion‐related ghosting artifacts, which would be typical in images from other multishot DWI techniques. This technique can be used for high‐resolution DWI of nonbrain anatomies. Magn Reson Med 50: 821–829, 2003. © 2003 Wiley‐Liss, Inc.
Application of continuous‐wave EPR spectral‐spatial image reconstruction techniques for in vivo oxymetry: Comparison of projection reconstruction and constant‐time modalities
Authors: Matsumoto Ken‐ichiro , Chandrika Baby , Lohman Joost A.B. , Mitchell James B. , Krishna Murali C. , Subramanian Sankaran
Published: September 2003

In this study we report the application of continuous‐wave (CW) electron paramagnetic resonance (EPR) constant‐time spectral spatial imaging (CTSSI) for in vivo oxymetry. 2D and 3D SSI studies of a phantom and live mice were carried out using projection reconstruction (PR) and constant‐time (CT) modalities using a CW‐EPR spectrometer/imager operating at 300 MHz frequency. Distortion of line shape, which is inherent in the PR method, was minimized by the CTSSI modality. It was also found that CTSSI offers improved noise reduction, restores a smoother line shape, and gives high convergence of estimated values. Spatial resolution was also improved by CTSSI, although fundamental spectral line‐width broadening was observed. Although additional corrections are required for accurate estimations of spectral line width, CTSSI was able to demonstrate distinct differences in oxygen tension between a tumor and the normal legs of a C3H mouse. The PR method, on the other hand, was unable to make such a distinction unequivocally with the triarylmethyl spin probes. CTSSI promises to be a more suitable method for quantitative in vivo oxymetric studies using radiofrequency EPR imaging (EPRI). Magn Reson Med 50:865–874, 2003. Published 2003 Wiley‐Liss, Inc.
Independent component analysis for automated decomposition of in vivo magnetic resonance spectra
Authors: Ladroue Christophe , Howe Franklyn A. , Griffiths John R. , Tate A. Rosemary
Published: September 2003

Fully automated methods for analyzing MR spectra would be of great benefit for clinical diagnosis, in particular for the extraction of relevant information from large databases for subsequent pattern recognition analysis. Independent component analysis (ICA) provides a means of decomposing signals into their constituent components. This work investigates the use of ICA for automatically extracting features from in vivo MR spectra. After its limits are assessed on artificial data, the method is applied to a set of brain tumor spectra. ICA automatically, and in an unsupervised fashion, decomposes the signals into interpretable components. Moreover, the spectral decomposition achieved by the ICA leads to the separation of some tissue types, which confirms the biochemical relevance of the components. Magn Reson Med 50:697–703, 2003. © 2003 Wiley‐Liss, Inc.