T1-MPRAGE and T2-FLAIR segmentation of cortical and subcortical brain regions—an MRI evaluation study

Abstract

Purpose

Development of a warp-based automated brain segmentation approach of 3D fluid-attenuated inversion recovery (FLAIR) images and comparison to 3D T1-based segmentation.

Methods

3D FLAIR and 3D T1-weighted sequences of 30 healthy subjects (mean age 29.9 ± 8.3 years, 8 female) were acquired on the same 3T MR scanner. Warp-based segmentation was applied for volumetry of total gray matter (GM), white matter (WM), and 116 atlas regions. Segmentation results of both sequences were compared using Pearson correlation (r).

Results

Correlation of GM segmentation results based on FLAIR and T1 was overall good for cortical structures (mean r across all cortical structures = 0.76). Comparatively weaker results were found in the occipital lobe (r = 0.77), central region (mean r = 0.58), basal ganglia (mean r = 0.59), thalamus (r = 0.30), and cerebellum (r = 0.73). FLAIR segmentation underestimated volume of the central region compared to T1, but showed a better anatomic concordance with the occipital lobe on visual review and subcortical structures, when also compared to manual segmentation. Visual analysis of FLAIR-based WM segmentation revealed frequent misclassification of regions of high signal intensity as GM.

Conclusion

Warp-based FLAIR segmentation yields comparable results to T1 segmentation for most cortical GM structures and may provide anatomically more congruent segmentation of subcortical GM structures. Selected cortical regions, especially the central region and total WM, seem to be underestimated on FLAIR segmentation.

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Experimental peri-implant mucositis around titanium and zirconia implants in comparison to a natural tooth: part 1—host-derived immunological parameters

The purpose of this study was to assess host-derived parameters around dental zirconia and titanium implants and natural teeth during the occurrence of mucositis. After 4 weeks of perfect oral hygiene, 16 clinically profiled patients were asked to refrain from oral hygiene for 2 weeks, resulting in experimental plaque accumulation. This was followed by 4 weeks of perfect oral hygiene to reverse the inflammation. Immunological samples were analyzed for interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α), and interleukin 1β (IL-1β).

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An assessment and comparison of nasolabial aesthetics in bilateral clefts using the anatomical subunit-based scale: a nasoalveolar moulding versus non-nasoalveolar moulding study

Nasoalveolar moulding is a presurgical orthopaedic technique used to improve the outcomes of bilateral clefts. However, the lack of a validated scale tailored to bilateral clefts makes it difficult to quantify the merits of nasoalveolar moulding and compare it to other techniques. In this study, a recently published anatomical subunit scale was used to evaluate and compare the early effects of nasoalveolar moulding. Two groups of similarly treated bilateral cleft patients were included: one in which patients underwent presurgical nasoalveolar moulding and one in which they did not.

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Galectin-1 as an Emerging Mediator of Cardiovascular Inflammation: Mechanisms and Therapeutic Opportunities

Galectin-1 (Gal-1), an evolutionarily conserved β-galactoside-binding lectin, controls immune cell homeostasis and tempers acute and chronic inflammation by blunting proinflammatory cytokine synthesis, engaging T-cell apoptotic programs, promoting expansion of T regulatory (Treg) cells, and deactivating antigen-presenting cells. In addition, this lectin promotes angiogenesis by co-opting the vascular endothelial growth factor receptor (VEGFR) 2 signaling pathway. Since a coordinated network of immunomodulatory and proangiogenic mediators controls cardiac homeostasis, this lectin has been proposed to play a key hierarchical role in cardiac pathophysiology via glycan-dependent regulation of inflammatory responses. Here, we discuss the emerging roles of Gal-1 in cardiovascular diseases including acute myocardial infarction, heart failure, Chagas cardiomyopathy, pulmonary hypertension, and ischemic stroke, highlighting underlying anti-inflammatory mechanisms and therapeutic opportunities. Whereas Gal-1 administration emerges as a potential novel treatment option in acute myocardial infarction and ischemic stroke, Gal-1 blockade may contribute to attenuate pulmonary arterial hypertension.

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Surgical management of recurrent dislocation of the temporomandibular joint: a new treatment protocol

Recurrent dislocation of the temporomandibular joint (TMJ) is rare. It is distinct from acute or chronic dislocation and is associated with considerable morbidity and deterioration in quality of life. To formulate a practical surgical treatment algorithm, we retrospectively reviewed the management and long-term outcomes of 14 patients who presented to a single hospital department over a period of six years (2010–2016), and collected data on demographics, clinical features, operation, and outcome.

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Donor sites for radial forearm flaps: a direct comparison of closure with a local “hatchet” flap and split thickness skin grafts in a single patient

We read the article by Pabst et al1 with interest. Morbidity at the donor site of radial forearm flaps (RFF) has been the subject of much discussion, and we would like to describe a direct comparison of two techniques of closure in a single patient (Taylor et al. Radial forearm flap donor sites − A direct comparison of local hatchet flap closure versus split thickness skin grafting in a single patient. Presented at the British Association of Head and Neck Oncologists Annual Scientific Meeting, London, 2018).

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“Flip-over flap” in two-stage cleft palate repair

This study served to evaluate a two-stage concept in cleft palate repair, including key use of a triangular hinge ("flip-over") flap, in order to prevent palatal fistulae. It uses data from a prospective registry established in 1991.

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Leukocyte CD300a Contributes to the Resolution of Murine Allergic Inflammation [INNATE IMMUNITY AND INFLAMMATION]

CD300a is an inhibitory receptor for mast cells and eosinophils in allergic inflammation (AI); however, the spatiotemporal expression of CD300a and its potential roles in the resolution of AI are still to be determined. In this study, employing a mouse model of allergic peritonitis, we demonstrate that CD300a expression on peritoneal cells is regulated from inflammation to resolution. Allergic peritonitis–induced CD300a^–/– mice had a rapid increase in their inflammatory cell infiltrates and tryptase content in the peritoneal cavity compared with wild type, and their resolution process was significantly delayed. CD300a^–/– mice expressed lower levels of ALX/FPR2 receptor on peritoneal cells and had higher levels of LXA₄ in the peritoneal lavage. CD300a activation on mouse bone marrow–derived mast cells regulated ALX/FPR2 expression levels following IgE-mediated activation. Together, these findings indicate a role for CD300a in AI and its resolution, in part via the specialized proresolving mediator LXA₄ and ALX/FPR2 receptor pathway activation.

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Does T Cell Activation Require a Quorum of Lymphocytes? [BRIEF REVIEWS]

Recent reports suggest a quorum of T cells is required to activate T lymphocytes and that this requirement may help explain why scarce lymphocytes, specific for peripheral self-antigen, are rarely activated by Ag. This proposal runs counter to the commonly held framework that the Ag-dependent, but CD4 T lymphocyte–independent, activation of CD8 T lymphocytes, and the activation of CD4 T lymphocytes themselves, can occur when a single CD8 or CD4 T lymphocyte encounters Ag under appropriately dangerous circumstances. We argue that a review of older literature often ignored, as well as of contemporary studies, supports the quorum concept and is difficult to reconcile with the Danger Model.

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MAbTope: A Method for Improved Epitope Mapping [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Abs are very efficient drugs, ~70 of them are already approved for medical use, over 500 are in clinical development, and many more are in preclinical development. One important step in the characterization and protection of a therapeutic Ab is the determination of its cognate epitope. The gold standard is the three-dimensional structure of the Ab/Ag complex by crystallography or nuclear magnetic resonance spectroscopy. However, it remains a tedious task, and its outcome is uncertain. We have developed MAbTope, a docking-based prediction method of the epitope associated with straightforward experimental validation procedures. We show that MAbTope predicts the correct epitope for each of 129 tested examples of Ab/Ag complexes of known structure. We further validated this method through the successful determination, and experimental validation (using human embryonic kidney cells 293), of the epitopes recognized by two therapeutic Abs targeting TNF-α: certolizumab and golimumab.

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The Diverse Family of MR1-Restricted T Cells [BRIEF REVIEWS]

Mucosal-associated invariant T (MAIT) cells are characterized by a semi-invariant TCR that recognizes vitamin B metabolite Ags presented by the MHC-related molecule MR1. Their Ag restriction determines a unique developmental lineage, imbuing a tissue-homing, preprimed phenotype with antimicrobial function. A growing body of literature indicates that MR1-restricted T cells are more diverse than the MAIT term implies. Namely, it is increasingly clear that TCR α- and TCR β-chain diversity within the MR1-restricted repertoire provides a potential mechanism of Ag discrimination, and context-dependent functional variation suggests a role for MR1-restricted T cells in diverse physiological settings. In this paper, we summarize MR1-restricted T cell biology, with an emphasis on TCR diversity, Ag discrimination, and functional heterogeneity.

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Myoferlin-Mediated Lysosomal Exocytosis Regulates Cytotoxicity by Phagocytes [INNATE IMMUNITY AND INFLAMMATION]

During inflammation, phagocytes release digestive enzymes from lysosomes to degrade harmful cells such as pathogens and tumor cells. However, the molecular mechanisms regulating this process are poorly understood. In this study, we identified myoferlin as a critical regulator of lysosomal exocytosis by mouse phagocytes. Myoferlin is a type II transmembrane protein with seven C2 domains in the cytoplasmic region. It localizes to lysosomes and mediates their fusion with the plasma membrane upon calcium stimulation. Myoferlin promotes the release of lysosomal contents, including hydrolytic enzymes, which increase cytotoxicity. These data demonstrate myoferlin's critical role in lysosomal exocytosis by phagocytes, providing novel insights into the mechanisms of inflammation-related cellular injuries.

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Cutting Edge: IL-1{alpha} and Not IL-1{beta} Drives IL-1R1-Dependent Neonatal Murine Sepsis Lethality [CUTTING EDGE]

Sepsis disproportionately affects the very old and the very young. IL-1 signaling is important in innate host defense but may also play a deleterious role in acute inflammatory conditions (including sepsis) by promulgating life-threatening inflammation. IL-1 signaling is mediated by two distinct ligands: IL-1α and IL-1β, both acting on a common receptor (IL-1R1). IL-1R1 targeting has not reduced adult human sepsis mortality despite biologic plausibility. Because the specific role of IL-1α or IL-1β in sepsis survival is unknown in any age group and the role of IL-1 signaling remains unknown in neonates, we studied the role of IL-1 signaling, including the impact of IL-1α and IL-1β, on neonatal murine sepsis survival. IL-1 signaling augments the late plasma inflammatory response to sepsis. IL-1α and not IL-1β is the critical mediator of sepsis mortality, likely because of paracrine actions within the tissue. These data do not support targeting IL-1 signaling in neonates.

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In This Issue [IN THIS ISSUE]

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Cutting Edge: Quantitative Determination of CD40L Threshold for IL-12 and IL-23 Production from Dendritic Cells [CUTTING EDGE]

Early secretion of IL-12 by mouse dendritic cells (DCs) instructs T cells to make IFN-. However, only activated, but not naive T cells are able to license DCs for IL-12 production. We hypothesized that it might be due to different levels of CD40L expression on the surface of these cells, as CD40 signals are required for IL-12 production. Using quantitative cell-free systems incorporating CD40L in lipid bilayers combined with total internal reflection fluorescence microscopy and flow cytometry, we show that as low as ~200 CD40L molecules/μm² in combination with IL-4 is sufficient to induce IL-12 production by DCs. Remarkably, CD40L alone is adequate to induce IL-23 secretion by DCs. Thus, although activated T cells have somewhat higher levels of CD40L, it is the combination of CD40L and the cytokines they secrete that licenses DCs and influences the effector class of the immune response.

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Differential Activation of Hepatic Invariant NKT Cell Subsets Plays a Key Role in Progression of Nonalcoholic Steatohepatitis [INNATE IMMUNITY AND INFLAMMATION]

Innate immune mechanisms play an important role in inflammatory chronic liver diseases. In this study, we investigated the role of type I or invariant NKT (iNKT) cell subsets in the progression of nonalcoholic steatohepatitis (NASH). We used α-galactosylceramide/CD1d tetramers and clonotypic mAb together with intracytoplasmic cytokine staining to analyze iNKT cells in choline-deficient l-amino acid–defined (CDAA)-induced murine NASH model and in human PBMCs, respectively. Cytokine secretion of hepatic iNKT cells in CDAA-fed C57BL/6 mice altered from predominantly IL-17⁺ to IFN-⁺ and IL-4⁺ during NASH progression along with the downmodulation of TCR and NK1.1 expression. Importantly, steatosis, steatohepatitis, and fibrosis were dependent upon the presence of iNKT cells. Hepatic stellate cell activation and infiltration of neutrophils, Kupffer cells, and CD8⁺ T cells as well as expression of key proinflammatory and fibrogenic genes were significantly blunted in Jα18^–/– mice and in C57BL/6 mice treated with an iNKT-inhibitory RAR- agonist. Gut microbial diversity was significantly impacted in Jα18^–/– and in CDAA diet–fed mice. An increased frequency of CXCR3⁺IFN-⁺T-bet⁺ and IL-17A⁺ iNKT cells was found in PBMC from NASH patients in comparison with nonalcoholic fatty liver patients or healthy controls. Consistent with their in vivo activation, iNKT cells from NASH patients remained hyporesponsive to ex-vivo stimulation with α-galactosylceramide. Accumulation of plasmacytoid dendritic cells in both mice and NASH patients suggest their role in activation of iNKT cells. In summary, our findings indicate that the differential activation of iNKT cells play a key role in mediating diet-induced hepatic steatosis and fibrosis in mice and its potential involvement in NASH progression in humans.

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B Cell Development sans B Cell Receptor Responsiveness Due to Unfolded Protein Response-Triggered Mef2c Protein Degradation [IMMUNE REGULATION]

BCR engagement leads to activation and clonal expansion of B cells. The I-A^12% mutant mouse possesses a branch site point mutation in the H2-Aa gene that causes highly reduced I-Aa protein expression. As I-A is a heterodimer made up of I-Aa and I-Ab, reduced I-Aa results not only in reduced surface I-A expression but also in an excess of unpaired I-Ab. B cells that develop in I-A^12% mice proliferated in response to LPS stimulation but failed to do so upon BCR stimulation. Developing I-A^12% B cells were engaged in unfolded protein response due to an excess of unpaired I-Ab. BCR responsiveness was restored by transduced I-Aa expression and by BiP, the unfolded protein response sensor. Reducing the load of unpaired I-Ab also restored BCR responsiveness of I-A^12% B cells. Mef2c protein, a transcription factor required for BCR-stimulated proliferation, was missing in I-A^12% B cells, and that transduced Mef2c expression restored BCR responsiveness. Mef2c protein appeared in I-A^12% B cells after addition of proteasome inhibitors. Mef2c degradation was mediated by Skp2 E3 ligase, and that knockdown of Skp2 mRNA in I-A^12% B cells restored BCR responsiveness. Our results point to a generalized incompatibility between BCR responsiveness and increased Skp2 stability. They also imply the existence of regulatory mechanisms other than Ig gene rearrangement that govern Mef2c turnover in a specific, exquisite, and dynamic fashion.

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RNA Splicing in the Transition from B Cells to Antibody-Secreting Cells: The Influences of ELL2, Small Nuclear RNA, and Endoplasmic Reticulum Stress [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

In the transition from B cells to Ab-secreting cells (ASCs) many genes are induced, such as ELL2, Irf4, Prdm1, Xbp1, whereas other mRNAs do not change in abundance. Nonetheless, using splicing array technology and mouse splenic B cells plus or minus LPS, we found that induced and "uninduced" genes can show large differences in splicing patterns between the cell stages, which could influence ASC development. We found that ~55% of these splicing changes depend on ELL2, a transcription elongation factor that influences expression levels and splicing patterns of ASC signature genes, genes in the cell-cycle and N-glycan biosynthesis and processing pathways, and the secretory versus membrane forms of the IgH mRNA. Some of these changes occur when ELL2 binds directly to the genes encoding those mRNAs, whereas some of the changes are indirect. To attempt to account for the changes that occur in RNA splicing before or without ELL2 induction, we examined the amount of the small nuclear RNA molecules and found that they were significantly decreased within 18 h of LPS stimulation and stayed low until 72 h. Correlating with this, at 18 h after LPS, endoplasmic reticulum stress and Ire1 phosphorylation are induced. Inhibiting the regulated Ire1-dependent mRNA decay with 4u8C correlates with the reduction in small nuclear RNA and changes in the normal splicing patterns at 18 h. Thus, we conclude that the RNA splicing patterns in ASCs are shaped early by endoplasmic reticulum stress and Ire1 phosphorylation and later by ELL2 induction.

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VASP Regulates NK Cell Lytic Granule Convergence [IMMUNE REGULATION]

NK cells eliminate viral-infected and malignant cells through a highly orchestrated series of cytoskeletal rearrangements, resulting in the release of cytolytic granule contents toward the target cell. Central to this process is the convergence of cytolytic granules to a common point, the microtubule-organizing center (MTOC), before delivery to the synapse. In this study, we show that vasodialator-stimulated phosphoprotein (VASP), an actin regulatory protein, localizes to the cytolytic synapse, but surprisingly, shows no impact on conjugate formation or synaptic actin accumulation despite being required for human NK cell–mediated killing. Interestingly, we also find that a pool of VASP copurifies with lytic granules and localizes with lytic granules at the MTOC. Significantly, depletion of VASP decreased lytic granule convergence without impacting MTOC polarization. Using the KHYG-1 cell line in which lytic granules are in a constitutively converged state, we find that either VASP depletion or F-actin destabilization promoted spreading of formerly converged granules. Our results demonstrate a novel requirement for VASP and actin polymerization in maintaining lytic granule convergence during NK cell–mediated killing.

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Potential Use of Genetically Engineered Variable Lymphocyte Receptor B Specific to Avian Influenza Virus H9N2 [NOVEL IMMUNOLOGICAL METHODS]

The variable lymphocyte receptor (VLR) B of jawless vertebrates functions as a secreted Ab of jawed vertebrates and has emerged as an alternative Ab with a single polypeptide chain. After observing an upregulated VLRB response in hagfish immunized with avian influenza virus (AIV) subtype H9N2, we screened AIV H9N2–specific VLRB using a mammalian expression system. To improve the binding avidity of the Ag-specific VLRB to the Ag, we enabled multimerization of the VLRB by conjugating it with C-terminal domain of human C4b-binding protein. To dramatically enhance the expression and secretion of the Ag-specific VLRB, we introduced a glycine–serine linker and the murine Ig leader sequence. The practical use of the Ag-specific VLRB was also demonstrated through various immunoassays, detected by anti-VLRB Ab (11G5). Finally, we found that the Ag-specific VLRB decreased the infectivity of AIV H9N2. Together, our findings suggest that the generated Ag-specific VLRB could be used for various immunoapplications.

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Helminth-Induced Production of TGF-{beta} and Suppression of Graft-versus-Host Disease Is Dependent on IL-4 Production by Host Cells [IMMUNE REGULATION]

Helminths stimulate the secretion of Th2 cytokines, like IL-4, and suppress lethal graft-versus-host disease (GVHD) after bone marrow transplantation. This suppression depends on the production of immune-modulatory TGF-β and is associated with TGF-β–dependent in vivo expansion of Foxp3⁺ regulatory T cells (Treg). In vivo expansion of Tregs is under investigation for its potential as a therapy for GVHD. Nonetheless, the mechanism of induced and TGF-β–dependent in vivo expansion of Tregs, in a Th2 polarized environment after helminth infection, is unknown. In this study, we show that helminth-induced IL-4 production by host cells is critical to the induction and maintenance of TGF-β secretion, TGF-β–dependent expansion of Foxp3⁺ Tregs, and the suppression of GVHD. In mice with GVHD, the expanding donor Tregs express the Th2-driving transcription factor, GATA3, which is required for helminth-induced production of IL-4 and TGF-β. In contrast, TGF-β is not necessary for GATA3 expression by Foxp3⁺ Tregs or by Foxp3^– CD4 T cells. Various cell types of innate or adaptive immune compartments produce high quantities of IL-4 after helminth infection. As a result, IL-4–mediated suppression of GVHD does not require invariant NKT cells of the host, a cell type known to produce IL-4 and suppress GVHD in other models. Thus, TGF-β generation, in a manner dependent on IL-4 secretion by host cells and GATA3 expression, constitutes a critical effector arm of helminthic immune modulation that promotes the in vivo expansion of Tregs and suppresses GVHD.

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mTOR- and SGK-Mediated Connexin 43 Expression Participates in Lipopolysaccharide-Stimulated Macrophage Migration through the iNOS/Src/FAK Axis [INFECTIOUS DISEASE AND HOST RESPONSE]

Connexin 43 (Cx43) deficiency was found to increase mortality in a mouse model of bacterial peritonitis, and Cx43 is upregulated in macrophages by LPS treatment. In this study, we characterized a novel signaling pathway for LPS-induced Cx43 expression in RAW264.7 cells and thioglycolate-elicited peritoneal macrophages (TGEMs). LPS alone or LPS-containing conditioned medium (CM) upregulated Cx43. Overexpression or silencing of Cx43 led to the enhancement or inhibition, respectively, of CM-induced TGEM migration. This response involved the inducible NO synthase (iNOS)/focal adhesion kinase (FAK)/Src pathways. Moreover, CM-induced migration was compromised in TGEMs from Cx43^+/– mice compared with TGEMs from Cx43^+/+ littermates. Cx43 was upregulated by a serum/glucocorticoid-regulated kinase 1 (SGK) activator and downregulated, along with inhibition of CM-induced TGEM migration, by knockdown of the SGK gene or blockade of the SGK pathway. LPS-induced SGK activation was abrogated by Torin2, whereas LPS-induced Cx43 was downregulated by both Torin2 and rapamycin. Analysis of the effects of FK506 and methylprednisolone, common immunosuppressive agents following organ transplantation, suggested a link between these immunosuppressive drugs and impaired macrophage migration via the Cx43/iNOS/Src/FAK pathway. In a model of Escherichia coli infectious peritonitis, GSK650349-, an SGK inhibitor, or Torin2-treated mice showed less accumulation of F4/80⁺CD11b⁺ macrophages in the peritoneal cavity, with a delay in the elimination of bacteria. Furthermore, following pretreatment with Gap19, a selective Cx43 hemichannel blocker, the survival of model mice was significantly reduced. Taken together, our study suggested that Cx43 in macrophages was associated with macrophage migration, an important immune process in host defense to infection.

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Androgen and Androgen Receptor as Enhancers of M2 Macrophage Polarization in Allergic Lung Inflammation [IMMUNE REGULATION]

Allergic asthma is a disease initiated by a breach of the lung mucosal barrier and an inappropriate Th2 inflammatory immune response that results in M2 polarization of alveolar macrophages (AM). The number of M2 macrophages in the airway correlates with asthma severity in humans. Sex differences in asthma suggest that sex hormones modify lung inflammation and macrophage polarization. Asthmatic women have more M2 macrophages than asthmatic men and androgens have been used as an experimental asthma treatment. In this study, we demonstrate that although androgen (dihydrotestosterone) reconstitution of castrated mice reduced lung inflammation in a mouse model of allergic lung inflammation, it enhanced M2 polarization of AM. This indicates a cell-specific role for androgens. Dihydrotestosterone also enhanced IL-4–stimulated M2 macrophage polarization in vitro. Using mice lacking androgen receptor (AR) in monocytes/macrophages (AR^floxLysMCre), we found that male but not female mice exhibited less eosinophil recruitment and lung inflammation due to impaired M2 polarization. There was a reduction in eosinophil-recruiting chemokines and IL-5 in AR-deficient AM. These data reveal an unexpected and novel role for androgen/AR in promoting M2 macrophage polarization. Our findings are also important for understanding pathology in diseases promoted by M2 macrophages and androgens, such as asthma, eosinophilic esophagitis, and prostate cancer, and for designing new approaches to treatment.

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Differentiation of Langerhans Cells from Monocytes and Their Specific Function in Inducing IL-22-Specific Th Cells [INNATE IMMUNITY AND INFLAMMATION]

Human mucosal tissues and skin contain two distinct types of dendritic cell (DC) subsets, epidermal Langerhans cells (LCs) and dermal DCs, which can be distinguished by the expression of C-type lectin receptors, Langerin and DC-SIGN, respectively. Although peripheral blood monocytes differentiate into these distinct subsets, monocyte-derived LCs (moLCs) induced by coculture with GM-CSF, IL-4, and TGF-β1 coexpress both Langerin and DC-SIGN, suggesting that the environmental cues remain unclear. In this study, we show that LC differentiation is TGF-β1 dependent and that cofactors such as IL-4 and TNF-α promote TGF-β1–dependent LC differentiation into Langerin⁺DC-SIGN^– moLCs but continuous exposure to IL-4 blocks differentiation. Steroids such as dexamethasone greatly enhanced TNF-α–induced moLC differentiation and blocked DC-SIGN expression. Consistent with primary LCs, dexamethasone-treated moLCs express CD1a, whereas monocyte-derived DCs (moDCs) express CD1b, CD1c, and CD1d. moDCs but not moLCs produced inflammatory cytokines after stimulation with CD1b and CD1d ligands mycolic acid and α-galactosylceramide, respectively. Strikingly, CD1a triggering with squalene on moLCs but not moDCs induced strong IL-22-producing CD4⁺ helper T cell responses. As IL-22 is an important cytokine in the maintenance of skin homeostasis, these data suggest that CD1a on LCs is involved in maintaining the immune barrier in the skin.

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IL-6 Promotes T Cell Proliferation and Expansion under Inflammatory Conditions in Association with Low-Level ROR{gamma}t Expression [IMMUNE REGULATION]

IL-6 is a critical driver of acute and chronic inflammation and has been reported to act as a T cell survival factor. The influence of IL-6 on T cell homeostasis is not well resolved. We demonstrate that IL-6 signaling drives T cell expansion under inflammatory conditions but not during normal homeostasis. During inflammation, IL-6Rα–deficient T cells are unable to effectively compete with wild type T cells. IL-6 promotes T cell proliferation, and this is associated with low-level expression of the RORt transcription factor. T cells upregulate Rorc mRNA at levels substantially diminished from that seen in Th17 cells. Blockade of RORt through genetic knockout or a small molecule inhibitor leads to T cell expansion defects comparable to those in IL-6Rα–deficient T cells. Our results indicate that IL-6 plays a key role in T cell expansion during inflammation and implicates a role for the transient induction of low-level RORt.

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Differential and Overlapping Immune Programs Regulated by IRF3 and IRF5 in Plasmacytoid Dendritic Cells [INNATE IMMUNITY AND INFLAMMATION]

We examined the signaling pathways and cell type–specific responses of IFN regulatory factor (IRF) 5, an immune-regulatory transcription factor. We show that the protein kinases IKKα, IKKβ, IKK, and TANK-binding kinase 1 each confer IRF5 phosphorylation/dimerization, thus extending the family of IRF5 activator kinases. Among primary human immune cell subsets, we found that IRF5 is most abundant in plasmacytoid dendritic cells (pDCs). Flow cytometric cell imaging revealed that IRF5 is specifically activated by endosomal TLR signaling. Comparative analyses revealed that IRF3 is activated in pDCs uniquely through RIG-I–like receptor (RLR) signaling. Transcriptomic analyses of pDCs show that the partitioning of TLR7/IRF5 and RLR/IRF3 pathways confers differential gene expression and immune cytokine production in pDCs, linking IRF5 with immune regulatory and proinflammatory gene expression. Thus, TLR7/IRF5 and RLR–IRF3 partitioning serves to polarize pDC response outcome. Strategies to differentially engage IRF signaling pathways should be considered in the design of immunotherapeutic approaches to modulate or polarize the immune response for specific outcome.

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IL-4 and IL-13 Guide Early Thymic Progenitors To Mature toward Dendritic Cells [IMMUNE SYSTEM DEVELOPMENT]

Recently we reported that IL-4 and IL-13 signaling in murine early thymic progenitors (ETPs) expressing the heteroreceptor (HR) comprising IL-4 receptor α (IL-4Rα) and IL-13 receptor α 1 (IL-13Rα1) activate STAT6 and inhibit ETP maturation potential toward T cells. In this study, we asked whether IL-4 and IL-13 signaling through the HR mobilizes other STAT molecules to shape ETP fate decision. The findings indicate that HR⁺ ETPs undergoing cytokine signaling display increased STAT1, but not STAT3, phosphorylation in addition to STAT6 activation. In parallel, the ETPs had a STAT1-dependent heightened expression of IRF-8, a transcription factor essential for development of CD8α⁺ dendritic cells (DCs). Interestingly, STAT1 phosphorylation and IRF-8 upregulation, which are independent of STAT6 activation, guided ETP maturation toward myeloid cells with a CD8α⁺ DC phenotype. Furthermore, these CD8α⁺ DCs display a thymic resident phenotype, as they did not express SIRPα, a molecule presumed to be involved in cell migration. These findings suggest that IL-4 and IL-13 cytokine-induced HR signaling provides a double-edged sword that simultaneously blocks T cell lineage potential but advances myeloid maturation that could impact T cell selection and central tolerance.

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Acoustic Comparison of Lower and Higher Belt Ranges in Professional Broadway Actresses

Current research on the female belt voice has generally been limited to the range of C5, which is not representative of the current requirements on Broadway. Additionally, much belt research uses voice teachers or college students. The goal of this study was to acoustically examine both higher and lower belt ranges in 10 women who have performed belt roles on Broadway during the last decade.

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Post-obturation pain following the use of carrier-based system with AH Plus or iRoot SP sealers: a randomized controlled clinical trial

Abstract

Objectives

The aim of this study was to compare the postoperative pain after root canal treatment using a carrier-based obturation system and two different sealers.

Materials and methods

In this prospective randomized clinical trial, 160 patients were selected. Patients with vital and devital teeth were randomized into four groups using a randomized block design with block sizes of 10 patients each. The groups were devital/vital teeth treated with iRoot SP sealer and devital/vital teeth treated with AH Plus sealer. Patients were prescribed ibuprofen, a 200-mg analgesic, if needed, and postoperative pain was recorded by visual analogue scale at 6, 12, 24, and 72 h after obturation. Pain score and frequency of tablet intake were recorded and statistically analyzed.

Results

Results showed that there was no significant difference between groups in the incidence of postoperative pain; however, iRoot SP sealer was associated with less analgesic intake compared to AH Plus sealer.

Conclusion

The use of different sealers did not significantly affect pain levels.

Clinical relevance

iRoot SP sealer was associated with less analgesic intake compared to AH Plus sealer.

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Pharmacologic inhibition of hypoxia inducible factor (HIF)‐hydroxylases ameliorates allergic contact dermatitis

Allergy, Volume 0, Issue ja, -Not available-.


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Preventive sublingual immunotherapy with House Dust Mite extract modulates epitope diversity in pre‐school children

Allergy, Volume 0, Issue ja, -Not available-.


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Corrigendum to “Redox Signaling in Diabetic Nephropathy: Hypertrophy versus Death Choices in Mesangial Cells and Podocytes”

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Diagnostic performance of temporal artery ultrasound for the diagnosis of giant cell arteritis: a systematic review and meta-analysis of the literature

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Marina Rinagel, Emmanuel Chatelus, Sandrine Jousse-Joulin, Jean Sibilia, Jacques-Eric Gottenberg, François Chasset, Laurent Arnaud

Abstract

Despite major recent advances in the therapeutic management of Giant cell arteritis (GCA), the diagnosis accuracy of temporal artery ultrasound remains controversial in this disease. We performed a systematic review to determine the sensitivity, specificity, and summary positive (LR+) and negative (LR-) likelihood ratios of temporal artery ultrasound for the diagnosis of GCA. For this, we searched EMBASE, MEDLINE and the Cochrane Database of Systematic Reviews without language restriction. Original articles reporting on diagnostic accuracy of temporal artery ultrasound compared to temporal artery biopsy, for the diagnosis of GCA, were selected. Sensitivity and specificity from each study were used to fit a bivariate diagnosis accuracy model. Of 1280 articles identified, 48 underwent full-text review, and 25 were included. Based on a total of 20 studies, the sensitivity and specificity of hypoechoic halo compared to positive temporal artery biopsy were respectively of 68% (95% CI: 57–78) and 81% (95%CI: 75–86). The summary mean positive and negative likelihood ratios were respectively of 3.64 (95%CI: 2.76–4.73) and 0.40 (0.28–0.52). Taking into account 11 studies reporting on the presence of any abnormal sign on temporal artery ultrasound yielded similar results with largely overlapping 95% confidence interval regions. This study provides the summary estimates of the diagnostic properties of temporal artery ultrasound compared to temporal artery biopsy, for the diagnosis of GCA. Those parameters allow the calculation of the post-test probability of GCA in a given patient, based on the results of temporal artery ultrasound and will help improving the diagnosis strategy for this common disease.

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Autoimmune diseases in myelodysplastic syndrome favors patients survival: A case control study and literature review

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Julie Seguier, Véronique Gelsi-Boyer, Mikael Ebbo, Zeinab Hamidou, Aude Charbonnier, Emmanuelle Bernit, Jean-Marc Durand, Jean-Robert Harlé, Norbert Vey, Nicolas Schleinitz

Abstract

Background

We conducted a monocentric retrospective study of patients with myelodysplastic syndromes (MDS) and autoimmune or inflammatory disorders (AIMs) and a literature review. We analyzed the association with subgroups of the WHO 2016 MDS classification and patient's survival in a case control study. Risk factors associated with survival were analyzed by uni- and multivariate analysis.

Results

From all MDS patients 11% presented with AIMs. These were heterogeneous and the most frequent where polyarthritis (25%) and autoimmune cytopenias (17%). No difference for frequency and type of AIMs was observed for the WHO 2016 MDS subgroups (p = .3). In the case control study WHO classification, karyotype abnormalities, IPSS-R and IPSS were similar in both groups. The overall survival from MDS diagnosis was better in the group with AIMs [10.3 ± 0.6 (IC95% 6.2–12.9) versus 4.8 ± 1.1 years (IC95% 4.2–8.7), p = .04]. The better survival was restricted to MDS with low or intermediate-1 IPSS [11.1 ± 1.5 (IC95% 9.9-NR) versus 8.7 ± 1.3 years (IC95% 4.8–10.3), p = .006]. The better survival was only observed when AIMs diagnosis was timely associated or appeared after MDS diagnosis (p = .04). Factors associated with a better overall survival and survival without AML were steroid dependence [respectively HR = 0.042, p = .003, (IC95% 0.005–0.33) and HR = 0.07, p = .002, (IC95% 0.013–0.39)], a diagnosis of AIMs and MDS timely associated [respectively HR = 0.05, p = .009, (IC95% 0.006–0.478) and HR = 0.1, p = .008, (IC95% 0.018–0.54)] or a diagnosis of AIMs after MDS [respectively HR = 0.024, p = .009, (IC95% 0.001–0.39) and HR = 0.04, p = .008, (IC95% 0.003–0.43)].

Conclusion

Autoimmune and inflammatory diseases associated to MDS are heterogeneous. AIMs diagnosed after or concomitantly to MDS seems associated with a better survival. Prospective studies are necessary to demonstrate that autoimmunity is associated to a better control of the MDS clone.

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Guidelines for biomarkers in autoimmune rheumatic diseases - evidence based analysis

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Roberto Giacomelli, Antonella Afeltra, Alessia Alunno, Elena Bartoloni-Bocci, Onorina Berardicurti, Michele Bombardieri, Alessandra Bortoluzzi, Roberto Caporali, Francesco Caso, Ricard Cervera, Maria Sole Chimenti, Paola Cipriani, Emmanuel Coloma, Fabrizio Conti, Salvatore D'Angelo, Salvatore De Vita, Salvatore Di Bartolomeo, Oliver Distler, Andrea Doria, Eugen Feist

Abstract

Autoimmune rheumatic diseases are characterised by an abnormal immune system response, complement activation, cytokines dysregulation and inflammation. In last years, despite many progresses in managing these patients, it has been shown that clinical remission is reached in less than 50% of patients and a personalised and tailored therapeutic approach is still lacking resulting in a significant gap between guidelines and real-world practice. In this context, the need for biomarkers facilitating early diagnosis and profiling those individuals at the highest risk for a poor outcome has become of crucial interest. A biomarker generally refers to a measured characteristic which may be used as an indicator of some biological state or condition. Three different types of medical biomarkers has been suggested: i. mechanistic markers; ii. clinical disease markers; iii. therapeutic markers. A combination of biomarkers from these different groups could be used for an ideal more accurate diagnosis and treatment. However, although a growing body of evidence is focused on improving biomarkers, a significant amount of this information is not integrated on standard clinical care.

The overarching aim of this work was to clarify the meaning of specific biomarkers during autoimmune diseases; their possible role in confirming diagnosis, predicting outcome and suggesting specific treatments.

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Immunogenicity, safety and tolerability of anti-pneumococcal vaccination in systemic lupus erythematosus patients: An evidence-informed and PRISMA compliant systematic review and meta-analysis

Publication date: Available online 5 November 2018

Source: Autoimmunity Reviews

Author(s): Nicola Luigi Bragazzi, Dennis McGonagle, Samaa Watad, Mohammad Adawi, Naim Mahroum, Giovanni Damiani, Rosalynn Conic, Charlie Bridgewood, Hussein Mahagna, Luca Giacomelli, Roberto Eggenhöffner, Mahmud Mahamid, Paolo Daniele Maria Pigatto, Howard Amital, Abdulla Watad

Abstract

The immunological perturbations associated with systemic lupus erythematosus (SLE) puts many patients at higher risk of infections including pneumococcal pneumonia. However, the uptake and utility of anti-pneumococcal vaccines in SLE patient is both controversial and not completely agreed on. Indeed, several epidemiological studies of anti-pneumococcal vaccine safety and efficacy in SLE have reported short term immunogenicity with elevated anti-pneumococcal antibody titres but inconsistent long term findings with some studies finding poor responses, mainly for long-term immune protection. Moreover, the safety and efficacy of the pneumococcal vaccine in SLE patients remains controversial due to the different types of anti-pneumococcal vaccines, and the heterogeneity of SLE patients. Several reviews addressing anti-pneumococcal vaccination in SLE patients exist, however, to the best of our knowledge, the present is the first systematic review and meta-analysis. To better understand the efficacy and safety of pneumococcal vaccination in SLE, a comprehensive literature search was performed identifying 18 studies in the present systematic reviews and meta-analysis. All studies were designed as longitudinal investigations, two, in particular, were of high quality, being randomized, double-blind trials (RCTs). Four studies had control groups. Sample size ranged from 12 to 204 participants. Vaccine immunogenicity in terms of subjects with protective antibody titers ranged from 36.0% to 97.6%. According to our metanalysis high erythrocyte sedimentation rate (ESR), older earlier SLE, high disease activity, and immunosuppressive therapy were predictors of poor immunogenicity, although belimumab was found to have no significant impact. With regard to safety, no serious adverse events were found, with up to third of cases reporting mild/low-grade and complaints.

In conclusion, due to the high risk of pneumococcal infection in SLE patients and given the safety and, at least partial, effectiveness according our study in such patients, preventive strategies mainly by immunization are required in all age groups and in those needing immunosuppressive therapy, immunization should be given prior the initiation of the treatment.

PROSPERO registration code 103605.

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Systemic sclerosis and exposure to heavy metals

Publication date: Available online 4 November 2018

Source: Autoimmunity Reviews

Author(s): Isabelle Marie

Abstract

As a mirror image of the Roman god Janus Bifrons, the environment has a hidden face. To highlight this hidden face of the environment in the field of systemic sclerosis (SSc) will allow to identify responsible agents emerging in the future. To date, there is, in fact, a growing scientific evidence that environmental factors have a crucial impact on both alterations and modulation of epigenetic determinants, resulting in SSc onset and progression. It has been well established that there is a marked correlation between SSc onset and occupational exposure to crystalline silica and organic solvents. More recently, an association between SSc and exposure to heavy metals has further been found, including: antimony, cadmium, lead, mercury. These latter findings interestingly underscore that occupational exposure to heavy metals should be systematically checked in all SSc patients at diagnosis, as the identification of the occupational toxic agent will allow its interruption, which may result in potential improvement of SSc outcome.

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Magnetic resonance imaging of sacroiliitis in children: reply to Jalalvandi and Naderi

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Modular architecture of metabolic brain network and its effects on the spread of perturbation impact

Publication date: Available online 5 November 2018

Source: NeuroImage

Author(s): Tianhao Zhang, Qi Huang, Chunxiang Jiao, Hua Liu, Binbin Nie, Shengxiang Liang, Panlong Li, Xi Sun, Ting Feng, Lin Xu, Baoci Shan

Abstract

Metabolic brain network, which is based on functional correlation patterns of ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET) images, has been widely applied in both basic and clinical neuroscience. Exploring the properties of the metabolic brain network can provide valuable insight to the physiologic and pathologic processes of the brain. Based on the network theory, modular architecture has the ability to limit the spread of local perturbation impact and therefore modular networks are more robust against external damage. However, whether the metabolic brain network has modular architecture remains unknown.

Methods

77 rats performed ¹⁸F-FDG PET brain imaging. The metabolic brain network was then constructed by measuring interregional metabolic correlation in inter-subject manner. Afterwards, modular architecture of the network was detected by a greedy algorithm. Further, we perturbed the metabolic brain network by inducing focal photothrombotic ischemia in the bilateral motor cortex and then measured the glucose metabolic change of each brain region using FDG-PET.

Results

A significant modular architecture was found in the metabolic brain network. The network could be divided into four modules which corresponding approximately to executive, learning/memory, visual/auditory and sensorimotor processing functional domains. After inducing the focal ischemia on the bilateral motor cortex, most of the significantly changed brain regions (13 of 17) belong to the sensorimotor module.

Conclusion

Our results revealed an inherent modular architecture in the metabolic brain network and gave an experimental evidence that the modularity of the metabolism brain network could limit the spread of local perturbation impact.

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Coarse-to-fine information integration in human vision

Publication date: Available online 4 November 2018

Source: NeuroImage

Author(s): Kirsten Petras, Sanne ten Oever, Christianne Jacobs, Valerie Goffaux

Abstract

Coarse-to-fine theories of vision propose that the coarse information carried by the low spatial frequencies (LSF) of visual input guides the integration of finer, high spatial frequency (HSF) detail. Whether and how LSF modulates HSF processing in naturalistic broad-band stimuli is still unclear. Here we used multivariate decoding of EEG signals to separate the respective contribution of LSF and HSF to the neural response evoked by broad-band images. Participants viewed images of human faces, monkey faces and phase-scrambled versions that were either broad-band or filtered to contain LSF or HSF. We trained classifiers on EEG scalp-patterns evoked by filtered scrambled stimuli and evaluated the derived models on broad-band scrambled and intact trials. We found reduced HSF contribution when LSF was informative towards image content, indicating that coarse information does guide the processing of fine detail, in line with coarse-to-fine theories. We discuss the potential cortical mechanisms underlying such coarse-to-fine feedback.

Graphical abstract

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Effect of temperature on the cyclic fatigue resistance of thermally treated reciprocating instruments

Abstract

Objectives

The aim of this study was to evaluate the impact of body temperature on the cyclic fatigue resistance of different NiTi alloys used for the manufacturing of Reciproc Blue R25 (RB 25.08; VDW, Munich, Germany), X1 Blue File 25 (X1 25.06; MK Life Medical and Dental Products, Porto Alegre, Brazil) and WaveOne Gold Primary (WOG 25.07; Dentsply Maillefer, Ballaigues, Switzerland).

Materials and methods

Sixty instruments of the RB 25.08, X1 25.06 and WOG 25.07 systems were used (n = 20). Cyclic fatigue tests were performed at room temperature (20° ± 1 °C) and at body temperature (37° ± 1 °C). The instruments were reciprocated until fracture occurred in an artificial stainless steel canal with a 60° angle and a 5-mm radius of curvature. The time to fracture (TTF) was recorded. Also, the number of cycles to fracture (NCF) was calculated. Data were analysed using one-way ANOVA and Tukey's tests for inter-group comparison at both temperatures and for the reduction of cyclic fatigue at body temperature. For intra-group comparison at the different temperatures, the unpaired t test was used.

Results

The cyclic fatigue test at 20 °C showed that RB 25.08 and X1 25.06 presented significantly higher TTF and NCF than WOG 25.07 (P < 0.05). At 37 °C, all groups presented significant reduction of TTF and NCF (P < 0.05). RB 25.08 presented significant higher TTF than WOG 25.07 (P < 0.05). Regarding the NCF, there was no significant difference among the groups (P > 0.05). The WOG 25.07 presented the lowest percentage reduction of cyclic fatigue (P < 0.05).

Conclusion

The body temperature treatment caused a marked reduction of the cyclic fatigue resistance for all reciprocating instruments tested. The RB 25.08 and X1 25.06 systems presented similar results at both temperatures tested. However, WOG 25.07 presented the lowest percentage reduction in fatigue resistance at body temperature.

Clinical relevance

The cyclic fatigue resistance of NiTi reciprocating instruments has been evaluated at room temperature. However, the fatigue resistance significantly decreases upon exposure to body temperature, which could affect the mechanical behaviour of the NiTi instruments during root canal preparation.

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Impact of a modified motion on the fatigue life of NiTi reciprocating instruments: a Weibull analysis

Abstract

Objectives

To evaluate the impact of a modified motion on the fatigue life of four brands of nickel–titanium (NiTi) reciprocating instruments.

Materials and methods

Cyclic fatigue (CF) resistance of 160 instruments was evaluated in an artificial stainless-steel canal (90° angle, 5-mm radius of curvature). WaveOne and WaveOne Gold (Denstply Maillefer, Baillagues, Switzerland) and Reciproc and Reciproc Blue (VDW, Munich, Germany) were tested with two different motions: (1) X-Smart Plus (Denstply Maillefer) endodontic motor and (2) a 4:1 contra-angle with an experimental motion (EVO) with different rotation angles and based on a sinusoidal acceleration. Motions with X-Smart Plus and EVO were recorded and analyzed at a reduced speed with VLC Media Player software for a more accurate analysis. Mean half-life, beta, and eta Weibull parameters were determined and compared.

Results

Reciproc Blue resulted the most resistant instruments either with EVO or X-Smart. WaveOne Gold lasted significantly longer than WaveOne with EVO (probability of 91%) while no significant differences were found with X-Smart. Considering NCF, Reciproc, WaveOne Gold, and Reciproc Blue lasted significantly longer with EVO (probabilities of 66%, 80%, and 89% respectively). WaveOne Gold showed the highest beta parameter.

Conclusions

The experimental motion was found to have a positive impact on fatigue lifetime of reciprocating instruments.

Clinical relevance

Current findings provide insight for future improvements in the clinical use of reciprocating files. Experimental motions may be considered when searching for additional strategies in order to increase the safer use of NiTi files during endodontic procedures.

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The Impact of Different Magnetic Resonance Imaging Equipment and Scanning Parameters on Signal Intensity Ratio Measurements in Phantoms and Healthy Volunteers: Implications for Interpreting Gadolinium Signal Changes Within the Brain

Objectives The aim of this study was to examine the variation in signal intensity ratio (SIR) values in Eurospin gel phantoms and healthy volunteer (HV) brain images in response to different magnetic resonance imaging hardware and software settings. Materials and Methods Gel phantoms with T1 relaxation times similar to the dentate nucleus (DN), pons (P), globus palladus (GP), and thalamus (Th) were scanned using a T1-weighted 2-dimensional spin-echo sequence on 2 magnetic resonance imaging scanners (3 T and 1.5 T). Imaging was performed by sequentially altering selected magnetic resonance (MR) parameters relative to a default pulse sequence, and the protocol was implemented repeatedly over 3 months. The experiment was also repeated on a cohort of 15 young HVs. Calculations of DN/P and GP/Th SIR values were derived for the images of the gels (GelDN/P and GelGP/Th) and the HVs (HVDN/P and HVGP/Th). Results For the default sequence, the mean SIR values of GelDN/P and GelGP/Th varied by ±2.20% and ±0.75%, respectively, when measured over multiple imaging sessions (3 T). Within a single imaging session, these variations were smaller (±0.17% for GelDN/P and ±0.15% for GelGP/Th). At 1.5 T, the equivalent SIR variations for GelDN/P were ± 1.41% (multiple sessions) and ±0.41% (single session), and that for GelGP/Th were ±0.47% (multiple sessions) and ±0.33% (single session). Sequential changes to the MR sequence parameters resulted in gel SIR variations as follows: 14.07% ± 2.43% (with/without normalization filters), −7.80% ± 0.28% (different echo times, TE), and −5.06% ± 0.59% (selective activation of RF coil elements). The largest variations were noted when the gels were positioned below the scanner isocenter, where SIR measurements were different by 22%. For the HVs, the SIR values were found to be consistently within 0.64% (single session) for the default sequence. Sequential changes to the MR sequence parameters resulted in SIR variations of −24.47% ± 2.47% (with/without normalization filters), −15.32% ± 7.71% (different echo times, TE), and −2.90% ± 0.78% (selective activation of RF coil elements). Conclusions This study has demonstrated that SIR percentage changes from baseline of a similar magnitude to brain gadolinium contrast agent signal hyperintensities can be replicated in phantom models and HVs by altering common MR acquisition parameters and hardware. Received for publication August 8, 2018; and accepted for publication, after revision, September 12, 2018. Conflicts of interest and sources of funding: Financial support for the study was provided via the Renal Dialysis for Venous Access (ReDVA) project (a European Union's Seventh Framework Program grant agreement no. 324487). The authors would like to state that we have received funding from Guerbet. L.Y. is currently receiving PhD sponsorship, while S.M. and G.H. have previously received research and educational support grants. Guerbet, however, were not involved in the study or publication processes. Correspondence to: J. Graeme Houston, MD, FRCR, Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, James Arrnott Drive Dundee DD1 9SY, United Kingdom. E-mail: j.g.houston@dundee.ac.uk. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Does Age Interfere With Gadolinium Toxicity and Presence in Brain and Bone Tissues?: A Comparative Gadoterate Versus Gadodiamide Study in Juvenile and Adult Rats

Objectives The main objective of the study was to assess the effect of age on target tissue total gadolinium (Gd) retention after repeated administration of gadodiamide (linear) or gadoterate (macrocyclic) Gd-based contrast agent (GBCA) in rats. The secondary objective was to assess the potential developmental and long-term consequences of GBCA administration during neonatal and juvenile periods. Materials and Methods A total of 20 equivalent human clinical doses (cumulated dose, 12 mmol Gd/kg) of either gadoterate or gadodiamide were administered concurrently by the intravenous route to healthy adult and juvenile rats. Saline was administered to juvenile rats forming the control group. In juvenile rats, the doses were administered from postnatal day 12, that is, once the blood-brain barrier is functional as in humans after birth. The tests were conducted on 5 juvenile rats per sex and per group and on 3 adult animals per sex and per group. T1-weighted magnetic resonance imaging of the cerebellum was performed at 4.7 T during both the treatment and treatment-free periods. Behavioral tests were performed in juvenile rats. Rats were euthanatized at 11 to 12 weeks (ie, approximately 3 months) after the last administration. Total Gd concentrations were measured in plasma, skin, bone, and brain by inductively coupled plasma mass spectrometry. Cerebellum samples from the juvenile rats were characterized by histopathological examination (including immunohistochemistry for glial fibrillary acidic protein or GFAP, and CD68). Lipofuscin pigments were also studied by fluorescence microscopy. All tests were performed blindly on randomized animals. Results Transient skin lesions were observed in juvenile rats (5/5 females and 2/4 males) and not in adult rats having received gadodiamide. Persisting (up to completion of the study) T1 hyperintensity in the deep cerebellar nuclei (DCNs) was observed only in gadodiamide-treated rats. Quantitatively, a slightly higher progressive increase in the DCN/brain stem ratio was observed in adult rats compared with juvenile rats, whereas no difference was noted visually. In all tissues, total Gd concentrations were higher (10- to 30-fold higher) in the gadodiamide-treated groups than in the gadoterate groups. No age-related differences were observed except in bone marrow where total Gd concentrations in gadodiamide-treated juvenile rats were higher than those measured in adults and similar to those measured in cortical bone tissue. No significant treatment-related effects were observed in histopathological findings or in development, behavior, and biochemistry parameters. However, in the elevated plus maze test, a trend toward an anxiogenic effect was observed in the gadodiamide group compared with other groups (nonsignificant). Moreover, in the balance beam test, a high number of trials were excluded in the gadodiamide group because rats (mainly males) did not completely cross the beam, which may also reflect an anxiogenic effect. Conclusions No T1 hyperintensity was observed in the DCN after administration of the macrocyclic GBCA gadoterate regardless of age as opposed to administration of the linear GBCA gadodiamide. Repeated administration of gadodiamide in neonatal and juvenile rats resulted in similar total Gd retention in the skin, brain, and bone to that in adult rats with sex having no effect, whereas Gd distribution in bone marrow was influenced by age. Further studies are required to assess the form of the retained Gd and to investigate the potential risks associated with Gd retention in bone marrow in juvenile animals treated with gadodiamide. Regardless of age, total Gd concentration in the brain and bone was 10- to 30-fold higher after administration of gadodiamide compared with gadoterate. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Received for publication July 13, 2018; and accepted for publication, August 10, 2018, after revision, August 10, 2018. Conflicts of interest and sources of funding: All authors (except F.B.) were Guebert employees at the time of the study. This study was funded by Guebert through the Atlantic Bone Screen funding within the common research project. Supplemental digital contents are available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (https://ift.tt/2kq7jVD). Correspondence to: Nathalie Fretellier, PhD, Research and Innovation Department, Guerbet Group, BP57400, 95943 Roissy CDG Cedex, France. E-mail: nathalie.fretellier@guerbet.com. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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T2 Mapping in Prostate Cancer

Objectives The aim of the study was to determine the quantitative T2 values in prostate tissue and evaluate them for detection and grading of prostate cancer. Materials and Methods After approval from the local ethics committee, morphological T2-weighted (T2w) images, apparent diffusion coefficient (ADC) maps from diffusion-weighted images, quantitative T2 maps, and calculated T2w images from 75 men (median age, 66.3 years; median PSA, 8.2 ng/mL) were acquired at 3 T magnetic resonance imaging (MRI). Data were retrospectively evaluated for their distinction between prostate pathologies.  Eight hundred fifty-seven areas of normal gland (n = 378), prostate cancer (54x Gleason score 6, 98x Gleason score 7, 25x Gleason score 8), benign prostatic hyperplasia (BPH) nodes (n = 150), prostatitis (n = 119), and precancerous lesions (n = 33) were determined on calculated and morphological T2w images. Histological criterion standards were whole gland sections (16 patients), MRI-guided in-bore biopsies (32 patients), MRI/transrectal ultrasound-fusion biopsies (15 patients), and systematic 12-core transrectal ultrasound-guided biopsies (12 patients). Significance was assumed to be P

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