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Societies and institutions in the East and the West have a very long and proud tradition of education in ethics. In recent years, many grand scale embezzlements by top level government officials, infamous scandals in the business world, and other infamous unethical conducts have steered the academics, business leaders, government officials, and other authorities to re-focus their attention and place more efforts and resources on ethics education. This paper will review the relevant Eastern and Western ethics principles, thoughts and maxims. It will also provide enough real-world examples to help the readers learn how to appropriately apply these ethical standards in the conduct of a personal and business environment.

Background It is estimated that 40% to 60% of patients with obsessive-compulsive disorder (OCD) continue to experience symptoms despite adequate medical management. For this population of treatment-refractory patients, promising results have been reported with the use of deep brain stimulation (DBS). Objective To conduct a systematic review of the literature and develop evidence-based guidelines on DBS for OCD. Methods A systematic literature search was undertaken using the PubMed database for articles published between 1966 and October 2012 combining the following words: "deep brain stimulation and obsessive-compulsive disorder" or "electrical stimulation and obsessive-compulsive disorder." Of 353 articles, 7 were retrieved for full-text review and analysis. The quality of the articles was assigned to each study and the strength of recommendation graded according to the guidelines development methodology of the American Association of Neurological Surgeons/Congress of Neurological Surgeons Joint Guidelines Committee. Results Of the 7 studies, 1 class I and 2 class II double-blind, randomized, controlled trials reported that bilateral DBS is more effective in improving OCD symptoms than sham treatment. Conclusion Based on the data published in the literature, the following recommendations can be made: (1) There is Level I evidence, based on a single class I study, for the use of bilateral subthalamic nucleus DBS for the treatment of medically refractory OCD. (2) There is Level II evidence, based on a single class II study, for the use of bilateral nucleus accumbens DBS for the treatment of medically refractory OCD. (3) There is insufficient evidence to make a recommendation for the use of unilateral DBS for the treatment of medically refractory OCD.

Background Inner volume (IV) excitation was explored with respect to scan time reduction of cardiac gated double inversion recovery multi-echo fast spin echo (MEFSE) to measure the transverse relaxation time (T2) in the myocardium. Methods The IV imaging was achieved by applying orthogonal slice selection for the excitation and refocusing pulses. The T2 map accuracy was investigated using different excitation and refocusing pulses. The performance of IV-MEFSE was compared with MEFSE on phantoms and eight healthy volunteers, acquiring eight echo times in a single breath-hold. Results Compared with MEFSE, IV-MEFSE allowed a scan time reduction from 26 s to 16 s, but caused a T2 overestimation of approximately 10% due to stimulated echoes. Conclusion IV successfully reduced the scan time to a single breath-hold feasible for many patients and remarkably facilitated the scan prescription, because there was no image aliasing concern. Care should be taken in using IV for T2 mapping because of T2 relaxation time overestimation. J. Magn. Reson. Imaging 2015;42:175–179. © 2014 Wiley Periodicals, Inc.

Aims In hypertrophic cardiomyopathy (HCM), attempts to associate genotype with phenotype have largely been unsuccessful. More recently, cardiac magnetic resonance (CMR) imaging has enhanced myocardial fibrosis characterization, while next-generation sequencing (NGS) can identify pathogenic HCM mutations. We used CMR and NGS to explore the link between genotype and fibrotic phenotype in HCM. Methods and results One hundred and thirty-nine patients with HCM and 25 healthy controls underwent CMR to quantify regional myocardial fibrosis with late gadolinium enhancement (LGE) and diffuse myocardial fibrosis with post-contrast T1 mapping. Collagen content of myectomy specimens from nine HCM patients was determined. Fifty-six HCM patients underwent NGS for 65 cardiomyopathy genes, including 36 HCM-associated genes. Post-contrast myocardial T1 time correlated histologically with myocardial collagen content ( r = −0.70, P = 0.03). Compared with controls, HCM patients had more LGE (4.6 ± 6.1 vs. 0%, P < 0.001) and lower post-contrast T1 time (483 ± 83 vs. 545 ± 49 ms, P < 0.001). LGE negatively correlated with left-ventricular (LV) ejection fraction and outflow tract obstruction, whereas lower post-contrast T1 time, suggestive of more diffuse myocardial fibrosis, was associated with LV diastolic impairment and dyspnoea. Patients with identifiable HCM mutations had more LGE (7.9 ± 8.6 vs. 3.1 ± 4.3%, P = 0.03), but higher post-contrast T1 time (498 ± 81 vs. 451 ± 70 ms, P = 0.03) than patients without. Conclusion In HCM, contrast-enhanced CMR with T1 mapping can non-invasively evaluate regional and diffuse patterns of myocardial fibrosis. These patterns of fibrosis occur independently of each other and exhibit distinct clinical associations. HCM patients with recognized genetic mutations have significantly more regional, but less diffuse myocardial fibrosis than those without.

International audience; OBJECT:The ability to manipulate image contrast and thus to obtain complementary information is one of the main advantages of MRI. Motion consistency within the whole data set is a key point in the context of multi contrast imaging. In cardiac and abdominal MRI, the acquisition strategy uses multiple breath-holds and often relies on acceleration methods that inherently suffer from a signal to-noise ratio loss. The aim of this work is to propose a free-breathing multi-contrast acquisition and reconstruction workflow to improve image quality and the subsequent data analysis.MATERIALS AND METHODS:We extended a previously proposed motion-compensated image reconstruction method for multi-contrast imaging. Shared information throughout the imaging protocol is now exploited by the image reconstruction in the form of an additional constraint based on image gradient sparsity. This constraint helps to minimize the amount of data needed for efficient non-rigid motion correction. T₁and T₂weighted images were reconstructed from free-breathing acquisitions in 4 healthy volunteers and in a phantom. The impact of multi-contrast motion correction was evaluated in a phantom in terms of precision and accuracy of T₁and T₂quantification.RESULTS:In the phantom, the proposed method achieved an accuracy of 97.5 % on the quantified parameters against 88.0 % before motion correction. In volunteers, motion inconsistency in T₁and T₂quantification were noticeably reduced within 5 min of free-breathing acquisition.CONCLUSION:An efficient, free-breathing, multi-contrast imaging method has been demonstrated that does not require prior assumptions about contrast and that is applicable to a wide range of examinations.

A modified Look–Locker acquisition using saturation recovery (MLLSR) for breath-held myocardial T1 mapping is presented. Despite its reduced dynamic range, saturation recovery enables substantially higher imaging efficiency than conventional inversion recovery T1 mapping because it does not require time for magnetization to relax to equilibrium. Therefore, MLLSR enables segmented readouts, shorter data acquisition windows, and shorter breath holds compared with inversion recovery. T1 measurements in phantoms using MLLSR showed a high correlation with conventional single-point inversion recovery spin echo. In vivo T1 measurements from normal and infarcted myocardium in 41 volunteers and patients were consistent with previously reported values. Twenty subjects were also scanned with MLLSR using an accelerated sampling scheme that required half the scan time (eight vs. 16 heartbeats) but yielded equivalent results. The flexibility afforded by the improved imaging efficiency of MLLSR allows the acquisition to be tailored to particular clinical needs and to individual patient's breath-holding abilities. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.

The author surveys and assesses economic indicators and trends for the period January-May 2010. He concludes that although quantitative growth has resumed there are no signs of a reorientation of the economy toward neoindustrial modernization.

Background— The MRI-compatible electrophysiology system previously used for MR-guided left ventricular electroanatomic mapping was enhanced with improved MR tracking, an MR-compatible radiofrequency ablation system and higher-resolution imaging sequences to enable mapping, ablation, and ablation monitoring in smaller cardiac structures. MR-tracked navigation was performed to the left atrium (LA) and atrioventricular (AV) node, followed by LA electroanatomic mapping and radiofrequency ablation of the pulmonary veins (PVs) and AV node. Methods and Results— One ventricular ablation, 7 PV ablations, 3 LA mappings, and 3 AV node ablations were conducted. Three MRI-compatible devices (ablation/mapping catheter, torqueable sheath, stimulation/pacing catheter) were used, each with 4 to 5 tracking microcoils. Transseptal puncture was performed under x-ray, with all other procedural steps performed in the MRI. Preacquired MRI roadmaps served for real-time catheter navigation. Simultaneous tracking of 3 devices was performed at 13 frames per second. LA mapping and PV radiofrequency ablation were performed using tracked ablation catheters and sheaths. Ablation points were registered and verified after ablation using 3D myocardial delayed enhancement and postmortem gross tissue examination. Complete LA electroanatomic mapping was achieved in 3 of 3 pigs, Right inferior PV circumferential ablation was achieved in 3 of 7 pigs, with incomplete isolation caused by limited catheter deflection. During AV node ablation, ventricular pacing was performed, 3 devices were simultaneously tracked, and intracardiac ECGs were displayed. 3D myocardial delayed enhancement visualized node injury 2 minutes after ablation. AV node block succeeded in 2 of 3 pigs, with 1 temporary block. Conclusions— LA mapping, PV radiofrequency ablation, and AV node ablation were demonstrated under MRI guidance. Intraprocedural 3D myocardial delayed enhancement assessed lesion positional accuracy and dimensions.

The breaking of peripheral T-cell tolerance toward self-antigens expressed by tumor cells and the subsequent establishment of an effective tumor protective immune response remains a major challenge for cancer immunotherapy. We report that both protective and therapeutic anti-tumor immune responses can be achieved in a mouse leukemia/lymphoma tumor model through the strong adjuvant effects provided by allogeneic CD3/CD28 cross-linked Th1 memory cells. The adjuvant effect of these cells is mediated by their ability to produce a variety of 'danger signals' which serve to deviate native non-protective Th2 anti-leukemia immune responses to effective Th1 immune responses.

Fully allogeneic CD3/CD28 cross-linked Th1 cells were found to elicit host-mediated anti-leukemia effects without GVHD toxicity. Mice inoculated with a lethal dose of BCL1 leukemia demonstrated significantly enhanced survival after allogeneic Th1 treatment. Cure rates of 12.5% with a single allogeneic cell infusion and 31.25% with multiple infusions were demonstrated. Cured mice were able to reject rechallenge with a lethal dose of tumor without further treatment. These results suggest that use of intentionally mis-matched, Th1 memory cells infused with cross-linked CD3/CD28 could represent a novel clinical approach to eliciting potent anti-tumor effects in patients without conditioning and without GVHD toxicity.

Background— X-ray fluoroscopy constitutes the fundamental imaging modality for catheter visualization during interventional electrophysiology procedures. The minimal tissue discriminative capability of fluoroscopy is mitigated in part by the use of electroanatomic mapping systems and enhanced by the integration of preacquired 3-dimensional imaging of the heart with computed tomographic or magnetic resonance (MR) imaging. A more ideal paradigm might be to use intraprocedural MR imaging to directly image and guide catheter mapping procedures. Methods and Results— An MR imaging–based electroanatomic mapping system was designed to assess the feasibility of navigating catheters to the left ventricle in vivo using MR tracking of microcoils incorporated into the catheters, measuring intracardiac ventricular electrograms, and integrating this information with 3-dimensional MR angiography and myocardial delayed enhancement images to allow ventricular substrate mapping. In all animals (4 normal, and 10 chronically infarcted swine), after transseptal puncture under fluoroscopic guidance, catheters were successfully navigated to the left ventricle with MR tracking (13 to 15 frames per second) by both transseptal and retrograde aortic approaches. Electrogram artifacts related to the MR imaging gradient pulses were successfully removed with analog and digital signal processing. In all animals, it was possible to map the entire left ventricle and to project electrogram voltage amplitude maps to identify the scarred myocardium. Conclusions— It is possible to use MR tracking to navigate catheters to the left ventricle, to measure electrogram activity, and to render accurate 3-dimensional voltage maps in a porcine model of chronic myocardial infarction, completely in the MR imaging environment. Myocardial delayed enhancement guidance provided dense sampling of the proximity of the infarct and accurate localization of complex infarcts.

In Accounting, it is a well-known problem that many students often have difficulty in deciding whether to debit or credit an account to increase its balance. After practicing and teaching Accounting for more than forty years, the authors have developed a simple, practical and fault-proof method of handling debits and credits -- the Cash is King Method. In this workshop manual, ten instructional examples are provided to demonstrate how to use the Cash is King Method to assist the students in navigating debits and credits and guiding them in recording all accounting transactions correctly.

Patients with myelodysplastic syndrome (MDS) commonly present with pancytopenia, suggesting that the marrow stroma fails to support the growth of both malignant and normal stem cells. We therefore retrospectively analyzed the duration to engraftment of neutrophils (or =0.5 x 10(9)/l andor =1.0 x 10(9)/l) and platelets (or =20 andor =50 x 10(9)/l) in 37 MDS patients and 42 patients suffering from primary AML, following allogeneic SCT. A significantly shorter time to engraftment was documented in AML as compared to MDS patients in all four parameters. These results held true even when we subgrouped the patients according to gender, age (50 years being the cutoff age between young and elderly patients), patient-donor relationship, donor match and intensity of conditioning. To the best of our knowledge, this is the first time that such a comparison has been made. We suggest that the longer duration of post transplant pancytopenia that is frequently observed in MDS patients may also influence post transplant outcome.

The only radical cure for thalassemia major patients today is the replacement of the defective hematopoietic system by allogeneic stem cell transplantation (allo-SCT). The major obstacles for the application of allo-SCT even from matched family members have been the transplant-related morbidity and mortality and graft failure that is usually associated with the recurrence of the thalassemia hematopoiesis. The outcome of allo-SCT from HLA-identical family donors is largely dependent on the age of the recipient as well as on pretransplant parameters reflecting the degree of organ damage from iron overload. In this study we report our experience of allo-SCT from matched related and unrelated donors, using a reduced toxicity conditioning consisting of fludarabine, busulfan or more recently busulfex and antithymocyte globulin, in a cohort of 20 patients with thalassemia major. The regimen-related toxicity was minimal, while the incidence of acute grade II-IV and chronic GVHD was 25 and 25%, respectively. With a median follow-up period of 39 months (range: 5-112 months) the overall survival was 100%, while thalassemia-free survival was 80%. Although the results of our study look promising, larger cohorts of patients and prospective clinical trials are required to confirm the benefits of our approach as a possible better alternative to the existing protocols.

Progress in the development of less toxic conditioning for bone marrow transplantation (BMT) came with the understanding that acceptance of mismatched BM does not require myeloablation of recipients. Lymphocyte deletion by a cocktail of immunosuppressive drugs is generally sufficient to ensure engraftment of compatible BM cells. However, reduced intensity conditioning (RIC) protocols available today do not provide robust tolerance to mismatched allogeneic BM. Herein we discuss 2 new experimental approaches to RIC protocols with the aim of facilitating allogeneic BM engraftment. Both conditioning regimens are based on selective deletion/inactivation of donor-reactive cells before BMT. Our data show that the first conditioning protocol, comprising priming of recipients by a donor-specific lymphocyte transfusion (DST) on day −2 and a single injection of cyclophosphamide, a drug that is predominantly toxic for proliferating cells, on day −1, consistently improves engraftment of allogeneic BM (day 0) in all experimental models tested. The second engraftment enhancing approach is based on the blockade by antagonistic reagents of the signaling pathways that govern the antigen-induced immune response. Combining the signaling blockade with the deletion of activated donor-reactive cells by cytoreductive agents provides additional benefits for transplantation across major histocompatibility barriers.

Purpose To develop a method for fat suppression in myocardial delayed enhancement (MDE) studies that achieves effective signal intensity reduction in fat but does not perturb myocardial signal suppression. Materials and Methods A new approach to fat suppression that uses a spectrally-selective inversion-recovery (SPEC-IR) tip-up radio frequency (RF) pulse following the conventional nonselective IR RF pulse together with a second SPEC-IR RF pulse is proposed. The tip-up pulse restores the fat longitudinal magnetization after the nonselective IR pulse and allows the fat magnetization to recover more fully toward its equilibrium value, providing for better fat suppression by the second SPEC-IR RF pulse. This new approach was validated in phantom studies and in five patients. Results Effective fat suppression was achieved using the proposed technique with minimal impact on normal myocardial signal suppression. Mean fat suppression achieved using this approach was 67% ± 8%, as measured in the chest wall immediately opposite the heart. Conclusion The results indicate this modular-type approach optimizes fat suppression in myocardial delayed enhancement studies but does not perturb the basic IR pulse sequence or change basic acquisition parameters. J. Magn. Reson. Imaging 2007;26:927–933. © 2007 Wiley-Liss, Inc.

Because of the nature of digital imaging, the number of pixels in a reconstructed image is often unrelated to the actual spatial resolution of the image. Similarly, the number of reconstructed frames of a dynamic or cine examination can be unrelated to the acquired temporal resolution. These discrepancies can result in misinterpretations and inaccuracies when image resolution is reported in the literature. The goal of this report is to clarify the differences between acquired and displayed resolution, both spatial and temporal, in magnetic resonance imaging. The effects of imaging parameters on acquired resolution are discussed, as are the mathematic effects of the reconstruction process on the displayed resolution of the resulting image. Finally, recommendations to authors are offered to promote accurate and unambiguous reporting of spatiotemporal resolution in the literature.

Linomide (quinoline-3-carboxamide) is an immunomodulator with anti-inflammatory effects in rodents with autoimmune diseases. Its mode of action still remains to be elucidated. We hypothesized that an investigation of T cell interactions with the extracellular matrix (ECM), composed of glycoproteins such as fibronectin (FN) and laminin (LN), might provide better understanding of their in vivo mode of action in extravascular inflammatory sites. We examined the effect of Linomide on T cell adhesion to intact ECM, and separately to LN, and FN, and on the release and production of tumor necrosis factor (TNFalpha) and nitrogen oxide (NO) in relation to adhesive molecules in non-obese diabetic (NOD) female spleen cells, focusing on intracellular adhesion molecule-1 (ICAM-1) and CD44. NOD female mice that developed spontaneous autoimmune insulitis, which destroys pancreatic islets and subsequently leads to insulin-deficient diabetes mellitus, were studied. Linomide, given in the drinking water or added to tissue cultures in vitro, inhibited the beta1 integrin-mediated adhesion of T cells to ECM, FN and LN, as well as the production and release of TNFalpha and NO, which play a major role in the induction and propagation of T cell-mediated insulitis. In addition, exposure of T cells to Linomide resulted in increased expression of CD44 and ICAM-1 molecules on spleen cells of Linomide-treated mice; such an increase in adhesion molecule expression may lead to more effective arrest of T cell migration in vivo. The regulation of T-cell adhesion, adhesion receptor expression, and inhibition of TNFalpha and NO secretion by Linomide may explain its beneficial role and provide a new tool for suppressing self-reactive T cell-dependent autoimmune diseases.

Unintentional acute exposure to whole body radiation has become a serious threat in recent years. Whole body irradiation leads to the acute radiation syndrome, with manifestations depending on the dose to which the patient was exposed. At high doses of radiation, a large number of cells die as a result of impairment of DNA replication owing to irreversible double-strand DNA damage. A whole body absorbed dose greater than 4–6 Gy causes severe gastrointestinal and bone marrow damage, and ultimately leads to death in most cases. Patients exposed to a total dose of ionising irradiation up to 12–14 Gy may be rescued with autologous or allogeneic stem cells, however the role of stem cell transplantation for patients exposed to higher doses of radiation is questionable and depends on the degree of damage to non-haematopoietic tissues. Here we report on a patient following an accidental exposure to whole body irradiation (estimated dose 10–20 Gy) from a γ-source in a commercial atomic reactor. The patient was tre...

Natural killer (NK) cells are important for their ability to recognize and lyse tumor cells and virus infected cells. NK cells express triggering receptors that are specific for non-MHC ligands. This article describes the 35S release cytotoxic assay, which measures the ability of NK cells derived from spleen cells taken from polyIC-treated mice to lyse B-cell leukemia (BCL1) cells. BCL1 cells express ligands for NKp46 on the cell surface membrane and they are sensitive to allogeneic but not syngeneic IL-2 activated natural killer cells.

This work describes a technique that combines multishot echo-planar imaging (EPI) with steady-state free precession (SSFP, also known as TrueFISP, FIESTA, and balanced FFE) for multislice, cine MR imaging of the heart. Unlike recently reported methods, the technique presented here (FIESTA-ET) is high-resolution and does not require offline reconstruction or postprocessing. It is therefore suitable for use on standard clinical scanners. FIESTA-ET was compared with conventional FIESTA imaging in 10 volunteers and quantitative analyses of myocardial signal-to-noise ratios (SNR) and ventricular volumes were performed. While providing comparable image quality, FIESTA-ET required half the acquisition time per slice of conventional FIESTA. Because multiple slices could be imaged in a single breathhold, the entire heart could be scanned in less than 2 min. Although the FIESTA-ET images exhibited an unexpected increase (P < 0.0005) in myocardial SNR of 16% over FIESTA, the volumetric measurements showed excellent correlation.

The pathophysiology of heart failure is characterized by abnormalities not only of the cardiomyocytes, but also by expansion of the extracellular space. Evolving recognition of these changes, and their important functional consequences, has prompted a search for accurate characterization of the myocardial interstitium. Previously, this has only been possible using histologic analysis; however, T1 mapping with cardiac magnetic resonance imaging has recently provided a noninvasive method to measure expansion of the myocardial interstitium. Literature over the past 6 years suggests T1 mapping could potentially provide crucial information for diagnosis, prognostication and for optimizing therapeutic targeting. However, the ideal methodology for both image acquisition and analysis remains an unresolved issue. Consequently, variations in methodology have complicated interpretation of the data, and limit comparisons between studies. This review provides a summary of important initial validation papers, and subsequent diagnostic, mechanistic and longitudinal studies of T1 mapping in heart failure. In addition, variations in methodology are discussed; highlighting current challenges facing scientists and clinicians interested in this evolving field.

Allogeneic cell-mediated immunotherapy with donor lymphocyte infusion (DLI) can successfully reverse chemoradiotherapy-resistant relapse in patients with chronic myeloid leukemia treated by allogeneic bone marrow transplantation (BMT). We describe the first successful attempt in 1992 to treat DLI-resistant relapse in a patient with CML in full hematologic relapse, using immunized donor lymphocytes. Donor lymphocytes were pulsed in vitro with a mixture of irradiated peripheral blood lymphocytes (PBL) obtained from both parents, in order to trigger alloactivation of donor lymphocytes against host alloantigens presented by parental cells, using as stimulating cells maternal PBL expressing the shared maternal haplotype and paternal PBL expressing the shared paternal haplotype of the patient. Full hematologic, cytogenetic and molecular remission was induced for the first time, independently of GVH, and has persisted for more than 9 years. To the best of our knowledge, this report represents the first successful immunotherapy with donor lymphocytes activated against host-type antigens. We suggest that immune donor PBL may be superior to DLI, possibly effective even when all other modalities fail, perhaps even independently of GVHD.

The authors evaluated a magnetization preparation scheme with a "notched" section profile for T1-weighted first-pass myocardial perfusion magnetic resonance (MR) imaging at 1.5 T. The pulse sequence consisted of a preparation sequence followed by an interleaved gradient-echo echo-planar sequence. Image contrast was evaluated in a feasibility study in 12 adult patients. The notched saturation pulse allowed long magnetization recovery times without sacrificing section coverage. Image contrast between normal and ischemic myocardium was excellent.

The application of a magnetohydrodynamic (MHD) generator as a power source on a hypersonic airplane is analyzed. A new type of an MHD generator is considered, using nonuniform gas ‐plasma e ows, where production ofplasma pistons (T-layers)isrealizedby special provokingofan overheating instability.Thisprocessisinitiated in cold air, transforming the kinetic energy of the incoming aire ow directly into electric energy without further heat addition or seed injection. Calculations show that, in e ight at M o 7 and at an altitude of 30 km, the rate of power transformation will be approximately 30%, the optimal value of magnetic e eld being Boo 0:3 T. An experiment to investigate the stability of a plasma piston interacting with the air stream and magnetic e eld has been carried out. A shock tube facility was used to create conditions corresponding to those of an MHD generator on a hypersonic airplane. A plasma layer was established within the MHD channel (» 1.5 m length), and its parameters agreed with calculations based on a piston model. A nonstationary quasi-one-dimensional computing program was used to simulate the experimental conditions. Because of energy expenses on gasdynamic dilatation and ionization of air and radiation, heat input into a discharge is nearly twice as large as the internal energy of the working medium.

Following engraftment of donor hematopoietic cells and induction of host-versus-graft tolerance, immunocompetent lymphocytes of donor origin can induce graft-versus-leukemia (GVL) and graft-versus-tumor (GVT) effects. Engraftment of allogeneic bone marrow cells can be accomplished following non-myeloablative conditioning while possibly controlling graft-versus-host disease (GVHD). GVL and GVT effects may thus be successfully accomplished following non-myeloablative stem cell transplantation (NST) as shown by data derived from experimental animals and man. Bone Marrow Transplantation (2000) 25, Suppl. 25, S54–S57.

Soybean agglutin (SBA) is a plant lectin that has been used to fractionate bone marrow cells. It binds bone marrow mononuclear cells, including mature myeloid, erythroid, and lymphoid cells, but has very low binding affinity and no toxic effect to the human hematopoietic cells. In this article we describe the possibilities of enriching bone-marrow-derived CD34+ hematopoietic progenitor cells using SBA. As the method is simple and elegant. SBA is of vast importance to the field of clinical bone marrow transplantation.

This work presents a two-dimensional (2D) multishot echo-planar imaging (EPI) technique for magnetic resonance angiography (MRA) of individual coronary arteries in a 17-heartbeat breath-hold. Conventional 2D and 3D segmented gradient-echo (GRE) coronary MRA requires repetitive excitation of the same slice or slab within each cardiac cycle, which can result in reduced blood signal and in motion artifacts. Two-dimensional multishot EPI can address these limitations by eliminating multiple excitations per cardiac cycle, using large flip-angle excitations, markedly reducing the data acquisition window, and performing oblique multislice 2D imaging. The goal of this study was to assess the feasibility of breath-hold 2D multishot EPI for multislice coronary MRA and to demonstrate its reliability by consistently acquiring high-quality images of the coronary arteries in a series of 16 volunteers.

Indomethacin, an inhibitor of cyclo-oxygenase given orally, reduced the tumorigenicity of cancer cells in a non-immunogenic murine model of mammary adenocarcinoma (4T1). In the presence of indomethacin, a dose-dependent immune protection could be induced most effectively by immunizing mice with 1 to 3 doses of irradiated tumor cells inoculated at intervals of 7 days prior to challenge with a tumorigenic cell dose. Three immunizations given without indomethacin resulted in tumor growth in 88% of the recipients, and indomethacin treatment started 28 days prior to the challenge dose and given without immunizations led to tumor onset in 83% of mice. In contrast, tumor was documented only in 12% of mice vaccinated with 3 immunization doses and given concomitantly indomethacin. Moreover, 53% of disease-free survivors resisted a second challenge with a high tumorigenic dose. Induction of an anti-tumor immunity in indomethacin-treated mice was further studied as a therapy for tumor-bearing mice. Complete cure was induced in 50% of mice, and a significant reduction in tumor size as well as prolonged survival time were observed in the remaining animals. Immunostimulation by tumor cell vaccination given in the presence of a tolerable dose of indomethacin, therefore, may be incorporated into immunotherapy protocols to activate an anti-tumor response against residual tumor cells that escaped surgery and/or high-dose chemo/radiotherapy.

Ghosting in MRI due to modulation of k-space data can be caused by motion of the subject or characteristics of the sequence. A general solution for 2DFT MRI that reduces ghosting without causal modeling is presented. Separate image data sets are acquired in which the phase and frequency directions are swapped. In these two data sets, the image signal is correlated, whereas the ghost signals are not. By taking a correlation of these two data sets, an image with greatly reduced ghosting is obtained. The reduction is shown to depend both on the correct signal intensity of the image, as well as the ghost intensity in the ghosted region. The reduction approaches 100% in regions of low image signal, and is more moderate in regions of higher image signal. The process was applied to conventional spin-echo, fast-spin-echo, and gradient echo imaging of volunteers and a phantom. Results of a reader study of the volunteer images reflected a significant overall reduction of ghosting artifacts in all volunteer experiments.

This work identifies an additional source of phase error across ky in multi-shot echo-planar imaging resulting from flow or motion along the phase-encoding direction. A velocity-independent flow compensation technique, gradient moment smoothing, is presented that corrects this error by forcing the phase to have smooth quadratic behavior. The correction is implemented, without compromising scan time, by changing the first moment of a bipolar prephaser pulse on a shot-by-shot basis. In phantom and in vivo experiments, gradient moment smoothing effectively eliminates ghosting and signal loss due to phase-encoding flow. When used in conjunction with a "flyback" echo-planar readout, which compensates for flow in the frequency-encoding direction, gradient moment smoothing renders multi-shot echo-planar imaging relatively insensitive to in-plane flow. This can make multi-shot echo-planar imaging a viable technique for accurately imaging in-plane flow and may desensitize it to the otherwise serious problem of in-plane motion.

Immune-mediated effects appear to play a major role in controlling minimal residual disease (MRD). We, therefore, investigated the role of recombinant human interleukin-2 (rIL-2) given concomitantly with interferon-α (IFN-α) in malignant lymphoma (ML) patients with responding disease following autologous bone marrow or blood stem cell transplantation (ABSCT). Fifty-six patients were included in this investigation. Thirty-two patients had non-Hodgkin's lymphoma (NHL) and 24 patients had Hodgkin's disease (HD). Sixty-one patients (NHL 36, HD 25) served as historical controls. Patients from both groups had similar demographic characteristics, the same stage of disease at presentation, status of disease at transplantation, conditioning regimens, and type of transplant. rIL-2 and IFN-α were selfadministered in two cycles beginning 2.5 to 10.5 months (median, 4 months) posttransplant and separated by a 4-week interval. Each cycle consisted of IFN-α subcutaneously (SC) 3 × 106 U/d × 5 d/wk combined with rIL-2 SC 3 to 6 IU/m2/d × 5 d/wk for 4 weeks. The incidence of survival and disease-free survival (DFS) was significantly higher in the group under investigation than in the historical controls (P < .01). Of 56 patients with ML treated with IFN-α + rIL-2, 45 patients are DFS (80.4%) after a follow-up of 7 to 78 months (median, 34 months), whereas in the historical controls, 32 of 61 (52.5%) patients are disease free, in a follow-up of 4 to 84 months (median, 23 months) posttransplant (P < .01). Our preliminary results are encouraging and suggest that home administered immunotherapy with IFN-α and rIL-2 is relatively well tolerated and may intensify remission in ML patients with MRD following ABSCT.

Lethally irradiated BALB/c mice were reconstituted by syngeneic bone marrow transplantation (BMT), and injected with recombinant interleukin 7 (rIL-7), recombinant interleukin 2 (rIL-2), or saline 10 days post-transplantation. Intranasal infection with A/PR8/34 influenza virus 2 weeks after BMT was associated with the highest survival rate in the rIL-7 treated group. The protective mechanism elicited by rIL-7, as manifested by very low virus titers in the lung, involves T and B cell functions. High hemagglutinin inhibition antibody levels were observed on days 7 and 12 post-challenge in the rIL-7 mice. Moreover, the anti-influenza cytotoxic T lymphocyte activity was induced primarily by rIL-7, leaving the effect of rIL-2 on the same level as that of the control. Thus, rIL-7 promotes both T cell-mediated function and B cell production during the immunodeficient state after BMT. This cytokine may prove a potential immunotherapeutic modality in BMT recipients.

Objectives The purpose of this study was to use cardiac magnetic resonance (CMR) imaging and invasive left ventricular (LV) pressure-volume (PV) measurements to explore the relationship between diffuse myocardial fibrosis and indexes of diastolic performance in a cohort of cardiac transplant recipients. Background The precise mechanism of LV diastolic dysfunction in the presence of myocardial fibrosis has not previously been established. Methods We performed CMR with T1 mapping and obtained invasive LV PV measurements via a conductance catheter in 20 cardiac transplant recipients at the time of clinically-indicated coronary angiography. Results Both post-contrast myocardial T1 time and extracellular volume fraction correlated with β, the load-independent passive LV stiffness constant (r = −0.71, p = 0.001, and r = 0.58, p = 0.04, respectively). After multivariate analysis, post-contrast myocardial T1 time remained the only independent predictor of β. No significant associations were observed between myocardial T1 time and τ, the active LV relaxation constant, or other load-dependent parameters of diastolic function. Conclusions Diffuse myocardial fibrosis, assessed by post-contrast myocardial T1 time, correlates with invasively-demonstrated LV stiffness in cardiac transplant recipients. In patients with increased diffuse myocardial fibrosis, abnormal passive ventricular stiffness is therefore likely to be a major contributor to diastolic dysfunction.

The ability to manipulate image contrast and thus to obtain complementary information is one of the main advantages of MRI. Motion consistency within the whole data set is a key point in the context of multi contrast imaging. In cardiac and abdominal MRI, the acquisition strategy uses multiple breath-holds and often relies on acceleration methods that inherently suffer from a signal to-noise ratio loss. The aim of this work is to propose a free-breathing multi-contrast acquisition and reconstruction workflow to improve image quality and the subsequent data analysis.We extended a previously proposed motion-compensated image reconstruction method for multi-contrast imaging. Shared information throughout the imaging protocol is now exploited by the image reconstruction in the form of an additional constraint based on image gradient sparsity. This constraint helps to minimize the amount of data needed for efficient non-rigid motion correction. T₁and T₂weighted images were reconstructed from free-breathing acquisitions in 4 healthy volunteers and in a phantom. The impact of multi-contrast motion correction was evaluated in a phantom in terms of precision and accuracy of T₁and T₂quantification.In the phantom, the proposed method achieved an accuracy of 97.5 % on the quantified parameters against 88.0 % before motion correction. In volunteers, motion inconsistency in T₁and T₂quantification were noticeably reduced within 5 min of free-breathing acquisition.An efficient, free-breathing, multi-contrast imaging method has been demonstrated that does not require prior assumptions about contrast and that is applicable to a wide range of examinations.

Oral therapy with linomide protects prediabetic nonobese diabetic (NOD) mice from insulin-dependent diabetes mellitus. The mechanisms by which linomide exerts its protective effect are not fully understood. A decreased TCR-mediated activity of the GTP-GDP binding p21(ras) proto-oncogene is associated with prediabetes in NOD mice. However, the role of this signal transduction defect in the pathogenesis of autoimmune diabetes is not known. The TCR-mediated and protein kinase C-induced activations of p21(ras) were determined in mononuclear cells from lymph nodes of linomide-treated and untreated prediabetic NOD mice. TCR cross-linking by Con A induced an increase of 13 +/- 6.8% and a decrease of 0.8 +/- 1.8% in p21(ras) activity in the linomide-treated group and the untreated controls, respectively. Cell stimulation with PMA resulted in a 15 +/- 2% increase in p21(ras) activity in the linomide-treated mice and a 10 +/- 11.4% decrease in the untreated mice. Protein levels of p21(ras) and its regulatory elements, the GTPase-activating protein and the guanine nucleotide-releasing factor, mSOS, were comparable in both groups. We, therefore, conclude that prevention of autoimmune diabetes by linomide is associated with up-regulation of the p21(ras) T cell signal transduction defect in NOD mice.

Soluble interleukin-6 receptor (sIL-6R) has previously been shown to potentiate the activity of interleukin (IL)-6, which may display antitumor activity. We evaluated sIL-6R and IL-6 levels in the sera of 24 patients following transplantation (allogeneic, n=17; autologous, n=7). Five patients developed acute graft-versus-host disease (AGVHD), three had early graft rejection, and three had an early relapse following bone marrow transplantation (BMT). Soluble IL-6R levels were evaluated at day - 10, day 0, day of engraftment, and during BMT-related complications, using IL-6R-specific monoclonal antibodies (mAb) and double-sandwich ELISA. In normal controls, sIL-6R and IL-6 levels were 20+/-3 ng/ml and 0.01+/-0.005 ng/ml, respectively. Soluble IL-6R levels increased in direct correlation with engraftment in the uneventful allogeneic transplants (17.7+/-2.1 ng/ml at day 0 to 49.7+/-2.6 ng/ml at day of engraftment, n=6, P

Graft rejection and graft failure represent major obstacles in allogeneic bone marrow transplantation (BMT). Cytokines possibly play a central role in the inflammatory and allospecific components of allograft rejection. Therefore, we evaluated inflammatory cytokine levels following BMT in 12 consecutive patients with graft rejection (GR). Seven of the patients underwent BMT from siblings (6 matched and 1 mismatched), 4 patients received bone marrow from other family members (3 mismatched and 1 matched), and 1 patient underwent HLA-matched unrelated BMT. Nine of 12 had a sex-mismatched BMT and 5/12 had an ABO-mismatched BMT. Nine of 12 underwent T cell-depleted (Campath anti-CDw52 moAb) BMT. Rejection was defined as marrow hypoplasia with a peripheral white blood cell count0.5 x 10(9)/L 21 days after BMT, in conjunction with the absence of donor cells by polymerase chain reaction analysis using a sex-mismatched probe and/or a tumor-specific probe (BCR/ABL). Twenty-five patients who underwent uneventful BMT with no GR served as controls. The levels of tumor necrosis factor (TNF), interleukin-6 (IL-6), and interleukin-1 (IL-1) were evaluated by a high sensitive RIA or an enzyme immunoassay. The levels of TNF and IL-6 were found to be higher in 10/12 and 7/7 evaluated GR patients, respectively, as compared with controls (P0.05). The level of IL-1 was high only in 2/12 patients. TNF elevation occurred in all patients immediately after GR. TNF and IL-6 levels were significantly higher for patients with early rejection (35 days after BMT) as compared with patients with late rejection (35 days after BMT) (P0.049 and P0.006, respectively). Eight patients engrafted after the second transplant (2 only transient). All 6 patients with stable engraftment are alive (4 with basic disease), while the 4 patients who did not engraft and the 2 patients with only transient engraftment died. In the 6 patients with no engraftment or only transient engraftment, the elevated TNF levels remained high; in the 6 patients who had stable engraftment after retransplant, TNF levels, but not IL-6 levels, decreased. In conclusion, a majority of the patients with GR displayed high levels of inflammatory cytokines (TNF and IL-6). Dysregulation of inflammatory cytokines may be involved in the pathogenesis of GR.

Beta-thalassemia major (TM) is caused by any of approximately 150 mutations within the beta-globin gene. To establish the degree of chimerism after bone marrow transplantation (BMT), we have performed molecular analysis of beta-globin mutations in 14 patients with TM over a period of 10 years. All patients underwent T cell-depleted allogeneic BMT from HLA-identical related donors, using either in vitro T-cell depletion with CAMPATH 1M and complement or in vivo depletion using CAMPATH 1G in the bone marrow collection bag. To date, at different time periods after BMT, seven patients have some degree of chimerism; six of these patients, all blood transfusion-independent, have donor cells in the range of 70% to 95%, with stable mixed chimerism (MC). The seventh patient has less than 10% donor cells with, surprisingly, only minimal transfusion requirements. The detection of beta-globin gene point mutation, as used here, is a highly specific and sensitive marker for engraftment and MC in patients with thalassemia. In light of its specificity, the method is applicable in all cases of TM, as it is independent of sex and other non-globin-related DNA markers. The high incidence of MC found in our patients may be a consequence of the pre-BMT T-cell depletion. Because MC was associated with transfusion independence, complete eradication of residual host cells for effective treatment of TM and possibly other genetic diseases may prove not to be essential.

Previously, we have shown the ability to induce experimental autoimmune conditions (e.g. SLE, APLS, Wegener's granulomatosis) following active immunization with the pathogenic autoantibody emulsified in adjuvant. The mice first develop anti-autoantibodies (Ab2: anti-id) and eventually generate anti-anti-autoantibodies (Ab3: anti-anti-id) which carry the same antigen binding characteristic as the autoantibody (Ab1). The appearance of the specific autoantibodies in mice sera was associated with the emergence of the compatible laboratory and with the clinical findings characteristic to the respective autoimmune disease. The effects of syngeneic bone marrow transplantation (BMT) on experimental anti-phospholipid syndrome (APS) were investigated. BALB/c mice were immunized with anti-cardiolipin monoclonal antibody (MoAb) named CAM and developed elevated serum titres of anti-phospholipid Abs accompanied by prolonged activated partial thromboplastin time, thrombocytopenia and a high percentage of fetal resorptions. These mice were then lethally irradiated and transfused with bone marrow (BM) cells (T cell depleted) from syngeneic naive mice. The titres of antiphospholipid antibodies were reduced in the recipients. The decrease in titre of autoantibodies was found to be related to depletion of antibody forming cells in vivo, associated with reduced proliferative response of lymph node cells to anti-cardiolipin MoAbs. The recipients showed improvement in clinical parameters following syngeneic BMT. The same recipients developed specific unresponsiveness to a second challenge with the anticardiolipin MoAb (CAM), but developed experimental systemic lupus erythematosus upon immunization with a monoclonal anti-DNA antibody. We conclude that acute myeloablative immunosuppression combined with syngeneic bone marrow transplantation may induce a state of tolerance to the pathogenic autoantibodies in mice with experimental APLS. Our results suggest that a similar approach may be useful in treating life-threatening autoimmune syndromes (e.g. catastrophic APLS) in clinical practice.

SUMMARYCurrent treatment options for cGVHD are limited. Mast cells (MC) and fibroblasts have been shown to play a role in the murine model of cGVHD. Ketotifen is an anti-H-1 antihistamine with MC-stabilizing properties. We therefore treated eight patients with cGVHD with ketotifen (6μg/ day for 3 months). Three additional age- and sex-matched cGVHD patients served as controls. MC count and activation state in cGVHD skin biopsies and the in vitro effect of peripheral blood mononuclear cell (PBMC) supernatants on (i) histamine release by MC; (ii) 3T3-fibroblast proliferation; and (iii) prostaglandin E2 (PGE2) production, were evaluated. Ketotifen therapy resulted in clinical improvement in 4/8 patients, stabilization of the disease in 2/8, while in 2/8 patients the cGVHD progressed and they died of bacterial sepsis. Side effects were minimal. In the skin biopsies the number of MC was found to be 0.58±0.17 (n= 8) (field ± 400) and the MC looked degranulated (toluidine blue staining). Following ketotifen therapy MC number was increased to 1.2±0.28 (n= 8) (P < 0.05). PBMC supernatants of cGVHD patients stimulated histamine release from cultured rat MC(n= 8)(2.7±0.5 μg/ml; normal values are 2±1.0±4 μg/ml, n = 5). Ketotifen therapy reduced the histamine release level to the normal range (2.0±0.5 μg/ml, P < 0.05) (n= 8). Ketotifen therapy had no significant effect on; (i) 3T3 fibroblast proliferation which was suppressed by cGVHD PBMC supernatants; (ii) the elevated PGE2 production which we observed when fibroblasts were incubated with the PBMC supernatants. These results indicate that ketotifen may play a therapeutic role in cGVHD.

Within the last several years a number of technical developments have been made in magnetic resonance imaging (MRI) that can potentially impact clinical and research MR imaging applications in epilepsy. These include developments in instrumentation and in pulse sequences. Advances in instrumentation include higher capacity gradient systems and multiple receiver coils as directed to brain imaging. Advances in pulse sequence include use of fast or turbo-spin-echo techniques, variants of echo-planar imaging, and sequences such as fluid-attenuation inversion recovery (FLAIR) targeted to specific applications of brain imaging. The purpose of this paper is to review several of these developments.