B-lymphopoiesis gains sensitivity to subsequent inhibition by estrogens during final phase of fetal development

Adult B-lymphopoiesis is suppressed by the inhibitory effects of elevated estrogens during pregnancy. At the same time, hematopoietic cells in the fetal liver are resistant to this suppression by estrogens and ensure active production of B-cells. We investigated whether this unresponsiveness to estrogens of fetal cells also applies to cells obtained from a newborn liver and projects into the adult hematopoiesis when fetal liver cells are transplanted to adult mice. Mixtures of fetal liver (E14.5), neonatal liver (P0.5) and adult bone marrow (BM) cells were co-transplanted into adult primary and secondary recipients treated with high doses of estrogen in the Ly5.1/Ly5.2 congenic mouse model. Total chimerism as a proportion of all nucleated blood cells, chimerism as a proportion of B220+ B-cells, and of other blood cell lineages as well, were determined by flow cytometry. B-lymphopoiesis derived from fetal liver (E14.5) stem cells remained resistant to estrogen after transplantation into both primary and secondary adult recipients, for up to 280 days. In contrast, B-lymphopoiesis derived from neonatal liver (P0.5) stem cells was resistant to estrogen only for approximately 50 days after the primary transplantation to the adult BM microenvironment. These results provide further evidence for a critical developmental period of B-lymphopoiesis during its fetal liver stage. In the mouse, critical developmental events that allow for the subsequent expressed sensitivity of B-lymphopoiesis for suppression by estrogens after sexual maturation appear to occur during the period of late-stage fetal liver hematopoiesis before its migration to the bone marrow.     

Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients

The anti-α4 monoclonal antibody natalizumab inhibits lymphocyte extravasation into the central nervous system and increases peripheral T and B lymphocytes in multiple sclerosis patients. To investigate whether the lymphocyte accumulation was due to a higher lymphocyte production, an altered homeostasis, or a differential transmigration of lymphocyte subsets through endothelia, T-cell receptor excision circles and kappa-deleting recombination excision circles were quantified before and after treatment, T-cell receptor repertoire was analyzed by spectratyping, and T- and B-lymphocyte subset migration was studied using transwell coated with vascular and lymphatic endothelial cells. We found that the number of newly produced T and B lymphocytes is increased because of a high release and of a low propensity of naïve subsets to migrate across endothelial cells. In some patients this resulted in an enlargement of T-cell heterogeneity. Because new lymphocyte production ensures the integrity of immune surveillance, its quantification could be used to monitor natalizumab therapy safety.     

B-1 cells in the bone marrow are a significant source of natural IgM

Natural IgM antibodies secreted in the absence of antigenic challenge are important contributors to antimicrobial immunity and tissue homeostasis. Early studies identified BM and, to a lesser extent the spleen, as main tissue sources of this spontaneously secreted IgM. However, the responsible B-cell subset has never been identified. Using multicolor flow cytometry, cell sorting and chimeric mice in which B-1 and B-2 cells and their secreted antibodies are distinguished by their Ig-allotype, we unequivocally identify the natural IgM-secreting cells in spleen and, for the first time, in the BM as IgM(+) IgD(lo/-) CD19(hi) CD43(+) CD5(+/-) B-1 cells. The newly identified population of BM B-1 cells shows many of the phenotypic characteristics of splenic B-1 cells but is distinct from B-1 cells in the peritoneal cavity, which generate at best very small amounts of IgM. Antibody-secreting spleen and BM B-1 cells are distinct also from terminally differentiated plasma cells generated from antigen-induced conventional B cells, as they express high levels of surface IgM and CD19 and lack expression of CD138. Overall, these data identify populations of non-terminally differentiated B-1 cells in spleen and BM as the most significant producers of natural IgM.     

The adaptor Lnk (SH2B3): an emerging regulator in vascular cells and a link between immune and inflammatory signaling

A better knowledge of the process by which inflammatory extracellular signals are relayed from the plasma membrane to specific intracellular sites is a key step to understand how inflammation develops and how it is regulated. This review focuses on Lnk (SH2B3) a member, with SH2B1 and SH2B2, of the SH2B family of adaptor proteins that influences a variety of signaling pathways mediated by Janus kinase and receptor tyrosine kinases. SH2B adaptor proteins contain conserved dimerization, pleckstrin homology, and SH2 domains. Initially described as a regulator of hematopoiesis and lymphocyte differentiation, Lnk now emerges as a key regulator in hematopoeitic and non hematopoeitic cells such as endothelial cells (EC) moderating growth factor and cytokine receptor-mediated signaling. In EC, Lnk is a negative regulator of TNF signaling that reduce proinflammatory phenotype and prevent EC from apoptosis. Lnk is a modulator in integrin signaling and actin cytoskeleton organization in both platelets and EC with an impact on cell adhesion, migration and thrombosis. In this review, we discuss some recent insights proposing Lnk as a key regulator of bone marrow-endothelial progenitor cell kinetics, including the ability to cell growth, endothelial commitment, mobilization, and recruitment for vascular regeneration. Finally, novel findings also provided evidences that mutations in Lnk gene are strongly linked to myeloproliferative disorders but also autoimmune and inflammatory syndromes where both immune and vascular cells display a role. Overall, these studies emphasize the importance of the Lnk adaptor molecule not only as prognostic marker but also as potential therapeutic target.     

The Outcome of Revision Surgery for Failed Metal-on-Metal Total Hip Arthroplasty

BackgroundMetal-on-metal total hip arthroplasties (MoM THAs) are frequently revised, though there is a paucity of functional outcome data. We report on outcomes and prognostic factors predictive of outcome from the largest series of MoM THA revisions to date.MethodsA single-center consecutive series of revisions from MoM THAs was identified. The cohort was divided by the presence or absence of symptoms prior to revision. The primary outcome was functional outcome (Oxford Hip Score [OHS]). Secondary outcomes were complication data, pre-revision and post-revision blood metal ions, and modified Oxford classification of pre-revision magnetic resonance imaging.ResultsOne hundred eighty revisions at median follow-up of 5.48 years were identified. Median OHS improved from 29 to 37 with revision (P < .001). Symptomatic patients experienced the greatest functional benefit (ΔOHS 6.5 vs 1.4, P = .012), while the function of asymptomatic patients was unaffected by revision (P = .4). Use of a cobalt-chromium-containing bearing surface at revision and increased body mass index were predictive of poor functional outcome.ConclusionSymptomatic patients experience greater functional benefit from revision surgery but do not regain the same level of function as patients who were asymptomatic prior to revision. Body mass index and use of cobalt-chromium-containing bearing surfaces are prognostic for poor functional outcome.     

Myoclonus subtypes in tertiary referral center. Cortical myoclonus and functional jerks are common

Objective

To evaluate the accuracy of clinical phenotyping of myoclonus patients and to determine differentiating clinical characteristics between cortical (CM), subcortical (SCM), spinal (SM), peripheral (PM) myoclonus, and functional jerks (FJ).

工作倦怠的测量与诊断

目的阐述工作倦怠的测量工具和诊断标准。方法对工作倦怠的三种测量工具和三种诊断标准进行介绍。结果工作倦怠是指在以人为主要服务对象的职业领域中,从业人员所体验到的一种情感耗竭、人格解体和个人成就感降低的症状,工作倦怠的测量有MBI、MBI-GS和BM。工作倦怠的诊断存在三种不同的标准。结论工作倦怠的测量和诊断问题的研究近年来进展很快,工作倦怠对心身健康有着重要影响。