MR identification of white matter abnormalities in multiple sclerosis: a comparison between 1.5 T and 4 T

BACKGROUND AND PURPOSE: Although MR spectroscopy and functional MR imaging of the brain have been successful at 4 T, conventional fast spin-echo imaging of the brain at 4 T has not been adequately evaluated. The purpose of this study was to compare the detection of white matter abnormalities in multiple sclerosis (MS) at 1.5 T and 4 T. METHODS: Fifteen patients with clinically definite MS were imaged at both 1.5 T and 4 T within a 1-week period. Comparison was made between fast spin-echo long-TR images at both field strengths. Pulse sequences were tailored to maximize resolution and signal-to-noise ratio in clinically relevant imaging times (< 7 min). Four interpreters independently reviewed the images obtained at both field strengths in separate sessions and evaluated them for lesion identification, size, characterization, and subjective resolution. Differences in interpretations at 1.5 T and 4 T were subsequently recorded. RESULTS: Images obtained at 4 T showed a mean of 88 more lesions as compared with images obtained at 1.5 T. All the lesions measured less than 5 mm and were typically aligned along perivascular spaces. Twenty-five consensually identified lesions on 4-T images were not seen at all on 1.5-T images. Moreover, 4-T images showed 56 additional consensually identified lesions, which were indistinct and seen only in retrospect on 1.5-T images. These lesions were frequently (n = 48) identified in large confluent areas of white matter signal intensity abnormality at 1.5 T. All observers also agreed that 4-T images subjectively enhanced the perception of normal perivascular spaces and small perivascular lesions. CONCLUSION: MR imaging at 4 T can depict white matter abnormalities in MS patients not detectable at 1.5 T through higher resolution with comparable signal-to-noise ratio and imaging times.     

Downregulation of T cell receptor expression by CD8(+) lymphocytes in kidney allografts

Allospecific CD8(+) T lymphocytes are an important component of the cellular response in allograft rejection. These cells recognize and engage MHC class I antigens, leading to allospecific cytolytic responses and graft rejection. In mouse kidney allografts that survive to 3 wk after transplantation, we noted that the majority of CD8(+) cells do not express surface alpha/beta T cell receptor alpha/beta(TCR), gamma/deltaTCR, or CD3. However, these CD8(+)TCR- cells did express surface markers characteristic of T cells, including Thy1.2, CD2, and CD5. In addition, the CD8(+)TCR- cells expressed mRNA for TCR Vbeta gene families, and nearly half stained positive for cytoplasmic Vbeta8 protein, suggesting that they are T cells that have downregulated alpha/betaTCR protein expression from their cell surfaces. When these surface TCR- cells were isolated from kidney allografts by flow cytometry and cultured in the presence of either allogeneic or syngeneic stimulators, nearly 100% of cells reacquired normal levels of alpha/betaTCR expression with disproportionate usage of Vbeta8 chains. After recovery of their surface TCR expression, the CD8(+)TCR- population demonstrated strong alloreactivity in culture. These results suggest that the substantial number of CD8(+)TCR- cells found in long-term surviving mouse kidney allografts are alpha/beta-T cells that have downregulated their cell surface expression of TCR. While in other systems this phenotype may identify cells that have engaged antigen, our results indicate that loss of TCR expression by CD8(+) kidney graft-infiltrating cells may not depend on antigen engagement and that elements in the microenvironment of the kidney graft play a key role in this process. Factors that modulate expression of TCR by graft-infiltrating lymphocytes may have an important role in regulating rejection responses.     

The intragraft CD8+ T cell response in renal allograft rejection in the mouse

To identify the role of donor class I alloantigens in regulating the CD8+ T cell response to a kidney allograft, we analyzed and compared the CD8+ infiltrate in kidney transplants from MHC class I-deficient (class I-) mouse donors and class I+ controls. One week after transplantation, there was a prominent CD8+ infiltrate in control allografts, whereas CD8+ T cells were virtually absent in grafts from class I- donors. In class I+ allografts, infiltrating CD8+ cells utilized a wide range of T cell receptor (TCR) Vbeta families and their Vbeta usage was similar to that of the systemic CD8+ population. However, there was a modest but significant overrepresentation of cells bearing Vbeta8 in the graft compared with the spleen due to an expansion of CD8+ Vbeta8.3+ cells. This could be detected as early as 1 week and became more pronounced by 3 weeks after transplantation. In 3-week allografts, only 52% of CD8+ cells expressed alphabetaTCR. Among T cells isolated from class I+ grafts, the CD8+ Vbeta8+ cells demonstrated allospecific responses that were numerically larger than responses of the CD8+ Vbeta8- population. In contrast to the early (1 week) time point, significant numbers of CD8+ cells could be isolated from class I- grafts by 3 weeks after transplantation and their Vbeta repertoire resembled that seen in controls. While increasing numbers of CD8+ Vbeta8+ were present in the class I- grafts at 3 weeks, this increase was not statistically significant. Thus, expression of class I alloantigens on a kidney graft plays an important role in regulating the rate of accumulation of CD8+ T cells in rejecting kidney grafts. However, the TCR Vbeta repertoire of the CD8+ T cell infiltrate is largely determined by factors that are independent of normal class I expression on the graft.     

Vascular Endothelial Growth Factor,a Key Modulator of the Anti-Tumor Immune Response

During tumor growth, angiogenesis is required to ensure oxygen and nutrient transport to the tumor. Vascular endothelial growth factor (VEGF) is the major inducer of angiogenesis and appears to be a key modulator of the anti-tumor immune response. Indeed, VEGF modulates innate and adaptive immune responses through direct interactions and indirectly by modulating protein expressions on endothelial cells or vascular permeability. The inhibition of the VEGF signaling pathway is clinically approved for the treatment of several cancers. Therapies targeting VEGF can modulate the tumor vasculature and the immune response. In this review, we discuss the roles of VEGF in the anti-tumor immune response. In addition, we summarize therapeutic strategies based on its inhibition, and their clinical approval.     

Isolated U-fiber involvement in MS: preliminary observations

Mantle cell lymphoma is a distinct clinicopathological entity associated with t(11;14) and cyclin D1 overexpression. The majority of cases show uniform morphological and phenotypic features characterized by a monotonous proliferation of small-to-medium-sized irregular B cells that express CD5 and bright surface immunoglobulin IgM and IgD. By sequence analysis of the rearranged immunoglobulin heavy chain variable genes (VH), it has been shown that these lymphoma cells carry little if no somatic mutations, as described for the fetal CD5+ cells or B1 cells. Besides mantle cell lymphoma with classic histological features, a morphological variant of mantle cell lymphoma with blastic features and a more aggressive clinical course has been described. To investigate whether this variant is closely related, by the cell of origin, to typical cases, we analysed the presence and the pattern of somatic mutations of the VH genes in a series of nine cases diagnosed as such. Our cases of blastic mantle cell lymphomas rearrange most frequently VH4 and VH3 family genes. In three cases there was a complete homology to published germline genes, and a near complete homology was documented in another three. In contrast, the remaining three cases showed somatic mutations in their rearranged VH genes. Mutation analysis revealed evidence for antigen selection in one of these three cases. Taken together, these data are similar to those of normal adult-type B1 cells and those described for chronic lymphocytic leukaemia (CLL) but slightly different to those reported for classic mantle cell lymphoma. It is likely that blastic mantle cell lymphoma as well as CLL originates from adult-type B1 cells. More cases will need to be studied to determine whether classic mantle cell lymphoma is different from the blastic subtype and if it arises from fetal-type B1 cells.     

Elevated expression levels of ANXA11, integrins β3 and α3, and TNF-α contribute to a candidate proteomic signature in urine for kidney allograft rejection

Purpose: Kidney transplantation is the treatment of choice for end stage renal disease, with long-term allograft loss being the major obstacle, and for which potential treatments are based on a histological diagnosis. The problem is that markers for predicting graft rejection are limited in number, are invasive, and are quite non-specific. We have hypothesized that protein biomarkers might be discovered in the urine of patients when acute or chronic rejection might be occurring. Experimental design: We have established a workflow in which initial screening for candidate biomarkers is first performed using urine samples on large-scale antibody microarrays. This approach generated several dozen candidates. The next step is to qualify some of the strongest signals using the high-throughput Reverse Capture Protein Microarray platform. Results: Four top candidates including ANXA11, Integrin α3, Integrin β3 and TNF-α, initially identified by the antibody microarray platform, were all qualified using Reverse Capture Protein Microarrays. We also used receiver operating condition (ROC) curves to independently quantify the specificity and sensitivity of these four analytes. Conclusions and clinical relevance: The present data suggest that these novel four analytes in the urine, together or independently, may contribute to a robust and quantitative urine proteomic signature for diagnosing acute or chronic rejection of renal allografts.     

Investigation of hydrodynamic/biomass growth coupling in a pilot scale granular bioreactor at low pore Reynolds number

Through a coupled experimental/modelling approach, this study investigates the functioning of a fixed bed bioreactor of Biolite beads, inoculated with Pseudomonas putida, in order to biotreat phenol contaminated waters at low Reynolds number. In particular the coupling between water flow and biomass growth is studied through the evaluation of the relationship between bed permeability reduction and biomass content as well as hydrodynamic effects on biological kinetics. In term of bioclogging, our results showed a very sharp decrease of the relative bed permeability well correlated with measured biofilm growth (for relative permeability greater than 0.8) as well as a saturation of the bed permeability at low relative porosity. However, most of the models available in the literature failed to describe our observed results. Our work permitted to show a strongly heterogeneous longitudinal biofilm development along the bed and thus a strongly heterogeneous longitudinal occupation of the porosity that decreased rapidly at the bed entry. Furthermore, the observed measured porosity saturation was shown to correspond to a biomass distribution involving the existence of channelling, through a growth/detachment equilibrium, rather than a complete clogging of the bed reactor. Biofilm microstructure built at the pore scale by bacteria (e.g. via the modulation of EPS production) probably explains the observed permeability/porosity results in the early stage of bed bioclogging. However, the present experiments do not allow measuring such a microstructuration effect. Through the analysis of a simple 1D model written at the mesoscale, we showed that the closure laws accounting for the different biological kinetics (growth, detachment, etc.) are flow dependent, as they represent effective properties and complex biological processes averaged at the mesoscale. Given the low Reynolds number investigated in the present paper, this dependency appears not only controlled by mass transfer evolution but may also involve more complex biological regulation (biological response to physical chemical stresses). As a consequence, formulations that are strictly valid at the cell scale (e.g. Monod formulation) should be used with care if no averaging or upscaling methods are used. The main conclusion of the present work is that the knowledge of macroscopic laws, such as the permeability–porosity relationship is not sufficient to account for the coupling between hydrodynamics and biomass growth in porous media. As bacterial biofilms are formed of populations able to adapt their metabolism to their evolving microenvironment, and in particular to hydrodynamic conditions, it appears that the predictive character of such models could be largely improved if these closure laws were not postulated a priori but deduced either from upscaling techniques, or, as in this paper, from ad hoc experiments performed at the global scale.     

Coagulation defects and altered hemodynamic responses in mice lacking receptors for thromboxane A2

Thromboxane A2 (TXA2) is a labile metabolite of arachidonic acid that has potent biological effects. Its actions are mediated by G protein-coupled thromboxane-prostanoid (TP) receptors. TP receptors have been implicated in the pathogenesis of cardiovascular diseases. To investigate the physiological functions of TP receptors, we generated TP receptor-deficient mice by gene targeting. Tp-/- animals reproduce and survive in expected numbers, and their major organ systems are normal. Thromboxane agonist binding cannot be detected in tissues from Tp-/- mice. Bleeding times are prolonged in Tp-/- mice and their platelets do not aggregate after exposure to TXA2 agonists. Aggregation responses after collagen stimulation are also delayed, although ADP-stimulated aggregation is normal. Infusion of the TP receptor agonist U-46619 causes transient increases in blood pressure followed by cardiovascular collapse in wild-type mice, but U-46619 caused no hemodynamic effect in Tp-/- mice. Tp-/- mice are also resistant to arachidonic acid-induced shock, although arachidonic acid signifi-cantly reduced blood pressure in Tp-/- mice. In summary, Tp-/- mice have a mild bleeding disorder and altered vascular responses to TXA2 and arachidonic acid. Our studies suggest that most of the recognized functions of TXA2 are mediated by the single known Tp gene locus.