Parallel magnetic resonance imaging (pMRI) using multichannel receiver coils has emerged as an effective tool to reduce imaging time in various applications. However, the issue of accurate estimation of coil sensitivities has not been fully addressed, which limits the level of speed enhancement achievable with the technology. The self-calibrating (SC) technique for sensitivity extraction has been well accepted, especially for dynamic imaging, and complements the common calibration technique that uses a separate scan. However, the existing method to extract the sensitivity information from the SC data is not accurate enough when the number of data is small, and thus erroneous sensitivities affect the reconstruction quality when they are directly applied to the reconstruction equation. This paper considers this problem of error propagation in the sequential procedure of sensitivity estimation followed by image reconstruction in existing methods, such as sensitivity encoding (SENSE) and simultaneous acquisition of spatial harmonics (SMASH), and reformulates the image reconstruction problem as a joint estimation of the coil sensitivities and the desired image, which is solved by an iterative optimization algorithm. The proposed method was tested on various data sets. The results from a set of in vivo data are shown to demonstrate the effectiveness of the proposed method, especially when a rather large net acceleration factor is used. Magn Reson Med 57: 1196 -1202, 2007.

Structural brain networks were constructed based on diffusion tensor imaging (DTI) data of 59 young healthy male adults. The networks had 68 nodes, derived from FreeSurfer parcellation of the cortical surface. By means of streamline tractography, the edge weight was defined as the number of streamlines between two nodes normalized by their mean volume. Specifically, two weighting schemes were adopted by considering various biases from fiber tracking. The weighting schemes were tested for possible bias toward the physical size of the nodes. A novel thresholding method was proposed using the variance of number of streamlines in fiber tracking. The backbone networks were extracted and various network analyses were applied to investigate the features of the binary and weighted backbone networks. For weighted networks, a high correlation was observed between nodal strength and betweenness centrality. Despite similar small-worldness features, binary networks and weighted networks are distinctive in many aspects, such as modularity and nodal betweenness centrality. Inter-subject variability was examined for the weighted networks, along with the test–retest reliability from two repeated scans on 44 of the 59 subjects. The inter-/intra-subject variability of weighted networks was discussed in three levels — edge weights, local metrics, and global metrics. The variance of edge weights can be very large. Although local metrics show less variability than the edge weights, they still have considerable amounts of variability. Weighting scheme one, which scales the number of streamlines by their lengths, demonstrates stable intra-class correlation coefficients against thresholding for global efficiency, clustering coefficient and diversity. The intra-class correlation analysis suggests the current approach of constructing weighted network has a reasonably high reproducibility for most global metrics.

In our earlier work, we had shown that GM-CSF treatment of CBA/J mice can suppress ongoing thyroiditis by inducing tolerogenic CD8α(-) DCs, which helped expand and/or induce CD4(+)Foxp3(+) Tregs. To identify the primary cell type that was affected by the GM-CSF treatment and understand the mechanism by which Tregs were induced, we compared the effect of GM-CSF on matured spDCs and BMDC precursors in vitro. Matured spDCs exposed to GM-CSF ex vivo induced only a modest increase in the percentage of Foxp3-expressing T cells in cocultures. In contrast, BM cells, when cultured in the presence of GM-CSF, gave rise to a population of CD11c(+)CD11b(Hi)CD8α(-) DCs (BMDCs), which were able to expand Foxp3(+) Tregs upon coculture with CD4(+) T cells. This contact-dependent expansion occurred in the absence of TCR stimulation and was abrogated by OX40L blockage. Additionally, the BMDCs secreted high levels of TGF-β, which was required and sufficient for adaptive differentiation of T cells to Foxp3(+) Tregs, only upon TCR stimulation. These results strongly suggest that the BMDCs differentiated by GM-CSF can expand nTregs and induce adaptive Tregs through different mechanisms.

Previous studies have reported alterations in numbers or function of regulatory T cells (Tregs) in myasthenia gravis (MG) patients, but published results have been inconsistent, likely due to the isolation of heterogenous “Treg” populations. In this study, we used surface CD4, CD25high, and CD127low/− expression to isolate a relatively pure population of Tregs, and established that there was no alteration in the relative numbers of Tregs within the peripheral T cell pool in MG patients. In vitro proliferation assays, however, demonstrated that Treg-mediated suppression of responder T cells (Tresp) was impaired in MG patients and was associated with a reduced expression of FOXP3 in isolated Tregs. Suppression of both polyclonal and AChR-activated Tresp cells from MG patients could be restored using Tregs isolated from healthy controls, indicating that the defect in immune regulation in MG is primarily localized to isolated Treg cells, and revealing a potential novel therapeutic target.

Dendritic cells (DCs) have the potential to activate or tolerize T cells in an Ag-specific manner. Although the precise mechanism that determines whether DCs exhibit tolerogenic or immunogenic functions has not been precisely elucidated, growing evidence suggests that DC function is largely dependent on differentiation status, which can be manipulated using various growth factors. In this study, we investigated the effects of mobilization of specific DC subsets—using GM-CSF and fms-like tyrosine kinase receptor 3-ligand (Flt3-L)—on the susceptibility to induction of experimental autoimmune myasthenia gravis (EAMG). We administered GM-CSF or Flt3-L to C57BL/6 mice before immunization with acetylcholine receptor (AChR) and observed the effect on the frequency and severity of EAMG development. Compared with AChR-immunized controls, mice treated with Flt3-L before immunization developed EAMG at an accelerated pace initially, but disease frequency and severity was comparable at the end of the observation period. In contrast, GM-CSF administered before immunization exerted a sustained suppressive effect against the induction of EAMG. This suppression was associated with lowered serum autoantibody levels, reduced T cell proliferative responses to AChR, and an expansion in the population of FoxP3+ regulatory T cells. These results highlight the potential of manipulating DCs to expand regulatory T cells for the control of autoimmune diseases such as MG.

GM-CSF plays an essential role in the differentiation of dendritic cells (DCs). Our studies have shown that GM-CSF treatment can induce semi-mature DCs and CD4+CD25+ regulatory T cells (Tregs) and suppress ongoing autoimmunity in mouse models. In this study, we examined the differences in the potential of GM-CSF to exert tolerogenic function on CD8a+ and CD8a- sub-populations of DCs in vivo. We show that GM-CSF modulates CD8a-, but not CD8a+ DCs in vivo, by inhibiting the surface expression of activation markers MHC II and CD80 and production of inflammatory cytokines such as IL-12 and IL-1beta. Self-antigen [mouse thyroglobulin (mTg)] presentation by GM-CSF-exposed CD8a- DCs to T cells from mTg-primed mice induced a profound increase in the frequency of forkhead box P3 (FoxP3)-expressing T cells compared with antigen presentation by GM-CSF-exposed CD8a+ DCs and control CD8a+ and CD8a- DCs. This tolerogenic property of GM-CD8a- DCs was abrogated when IL-12 was added. GM-CSF-exposed CD8a- DCs could also induce secretion of significantly higher amounts of IL-10 by T cells from mTg-primed mice. Importantly, adoptive transfer of CD8a- DCs from GM-CSF-treated SCID mice, but not untreated mice, into wild-type CBA/J mice prevented the development of experimental autoimmune thyroiditis (EAT) in the recipient animals upon immunization with mTg. Collectively, our results show that GM-CSF renders CD8a- DCs tolerogenic, and these DCs induce Foxp3+ and IL-10+ Tregs.

We had previously observed that treatment utilizing granulocyte-macrophage colony-stimulating factor (GM-CSF) had profound effects on the induction of experimental autoimmune myasthenia gravis (EAMG), a well-characterized antibody-mediated autoimmune disease. In this study, we show that EAMG induced by repeated immunizations with acetylcholine receptor (AChR) protein in C57BL6 mice is effectively suppressed by GM-CSF treatment administered at a stage of chronic, well-established disease. In addition, this amelioration of clinical disease is accompanied by down-modulation of both autoreactive T cell, and pathogenic autoantibody responses, a mobilization of DCs with a tolerogenic phenotype, and an expansion of regulatory T cells (Tregs) that potently suppress AChR-stimulated T cell proliferation in vitro. These observations suggest that the mobilization of antigen-specific Tregs in vivo using pharmacologic agents, like GM-CSF, can modulate ongoing anti-AChR immune responses capable of suppressing antibody-mediated autoimmunity.

In parallel imaging, the signal-to-noise ratio (SNR) of sensitivity encoding (SENSE) reconstruction is usually degraded by the ill-conditioning problem, which becomes especially serious at large acceleration factors. Existing regularization methods have been shown to alleviate the problem. However, they usually suffer from image artifacts at high acceleration factors due to the large data inconsistency resulting from heavy regularization. In this paper, we propose Bregman iteration for SENSE regularization. Unlike the existing regularization methods where the regularization function is fixed, the method adaptively updates the regularization function using the Bregman distance at different iterations, such that the iteration gradually removes the aliasing artifacts and recovers fine structures before the noise finally comes back. With a discrepancy principle as the stopping criterion, our results demonstrate that the reconstructed image using Bregman iteration preserves both sharp edges lost in Tikhonov regularization and fines structures missed in total variation (TV) regularization, while reducing more noise and aliasing artifacts. Magn Reson Med 61: 145-152, 2009.