Induction of annexin-1 at transcriptional and posttranscriptional level in rat brain by methylprednisolone and the 21-aminosteroid U74389F

Jan Kornelis de Cock-Foundation

Clonal expansion of CD4+CD8+ T cells in an adult patient with Mycoplasma pneumoniae-associated Erythema multiforme majus

Background: Erythema multiforme (EM) is an acute, immune-mediated mucocutaneous disease, most often preceded by herpes simplex virus (HSV) infection or reactivation. Mycoplasma pneumoniae (Mp) is considered the second major trigger of EM and is often associated with an atypical and more severe presentation of disease, characterized by prominent mucosal involvement. However, contrary to HSV-associated Erythema multiforme (HAEM), immunological mechanisms of Mp-associated EM remain unclear. Case presentation: We present the case of a 50-year-old male patient presenting with community-acquired pneumonia (CAP) and erythema multiforme majus (EMM). Acute Mp infection was diagnosed by seroconversion, with no evidence of HSV infection as a cause of EMM. We performed immune phenotyping of blister fluid (BF) and peripheral blood (PB) T cells and detected a clonally expanded TCRV beta 2(+) T cell population that was double positive for CD4 and CD8, and expressed the cytotoxic markers granulysin and perforin. This CD4(+)CD8(+) population comprised up to 50.7% of BF T cells and 24.9% of PB T cells. Two years prior to the onset of disease, the frequency of PB CD4(+)CD8(+)T cells had been within normal range and it gradually returned to baseline levels with the resolution of symptoms, suggesting an involvement of this population in EMM disease pathophysiology. Conclusions: This report is the first to provide a phenotypic description of lesional T cells in Mp-associated EMM. Characterizing the local immune response might help to address pathophysiological questions and warrants further systematic research

Re-municipalization of public services: trend or hype?

Re-municipalization is part of a broader set of reverse privatization reforms. We argue the term re-municipalization lacks conceptual clarity and often confuses municipal level reversals from national ones, new service delivery from reversals, and mixed market positions (such as corporatization) from full public control. This conceptual confusion makes measurement of re-municipalization difficult. While more case studies are being discovered, studies based on quantitative time series do not show re-municipalization as an increasing trend. Much case study based research argues re-municipalization is politically transformative, but quantitative research generally finds re-municipalization to be part of a pragmatic market management process, a position confirmed by the papers in this special issue

The Checkpoint Regulator SLAMF3 Preferentially Prevents Expansion of Auto-Reactive B Cells Generated by Graft-vs.-Host Disease

Absence of the mouse cell surface receptor SLAMF3 in SLAMF3-/- mice suggested that this receptor negatively regulates B cell homeostasis by modulating activation thresholds of B cell subsets. Here, we examine whether anti-SLAMF3 affects both B and T cell subsets during immune responses to haptenated ovalbumin [NP-OVA] and in the setting of chronic graft vs. host disease (cGVHD) induced by transferring B6.C-H2 bm12/KhEg (bm12) CD4+ T cells into B6 WT mice. We find that administering αSLAMF3 to NP-OVA immunized B6 mice primarily impairs antibody responses and Germinal center B cell [GC B] numbers, whilst CXCR5+, PD-1+, and ICOS+ T follicular helper (TFH) cells are not significantly affected. By contrast, administering αSLAMF3 markedly enhanced autoantibody production upon induction of cGVHD by the transfer of bm12 CD4+ T cells into B6 recipients. Surprisingly, αSLAMF3 accelerated both the differentiation of GC B and donor-derived TFH cells initiated by cGVHD. The latter appeared to be induced by decreased numbers of donor-derived Treg and T follicular regulatory (TFR) cells. Collectively, these data show that control of anti-SLAMF3-induced signaling is requisite to prevent autoantibody responses during cGVHD, but reduces responses to foreign antigens

Tolerance Induction to Cytoplasmic β\beta-Galactosidase by Hepatic AAV Gene Transfer — Implications for Antigen Presentation and Immunotoxicity

Background: Hepatic gene transfer, in particular using adeno-associated viral (AAV) vectors, has been shown to induce immune tolerance to several protein antigens. This approach has been exploited in animal models of inherited protein deficiency for systemic delivery of therapeutic proteins. Adequate levels of transgene expression in hepatocytes induce a suppressive T cell response, thereby promoting immune tolerance. This study addresses the question of whether AAV gene transfer can induce tolerance to a cytoplasmic protein. Major Findings: AAV-2 vector-mediated hepatic gene transfer for expression of cytoplasmic $\beta$-galactosidase ($\beta$-gal) was performed in immune competent mice, followed by a secondary $\beta$-gal gene transfer with E1/E3-deleted adenoviral Ad-LacZ vector to provoke a severe immunotoxic response. Transgene expression from the AAV-2 vector in $\sim$2% of hepatocytes almost completely protected from inflammatory T cell responses against $\beta$-gal, eliminated antibody formation, and significantly reduced adenovirus-induced hepatotoxicity. Consequently, $\sim$10% of hepatocytes continued to express $\beta$-gal 45 days after secondary Ad-LacZ gene transfer, a time point when control mice had lost all Ad-LacZ derived expression. Suppression of inflammatory T cell infiltration in the liver and liver damage was linked to specific transgene expression and was not seen for secondary gene transfer with Ad-GFP. A combination of adoptive transfer studies and flow cytometric analyses demonstrated induction of Treg that actively suppressed CD8$^+$ T cell responses to $\beta$-gal and that was amplified in liver and spleen upon secondary Ad-LacZ gene transfer. Conclusions: These data demonstrate that tolerance induction by hepatic AAV gene transfer does not require systemic delivery of the transgene product and that expression of a cytoplasmic neo-antigen in few hepatocytes can induce Treg and provide long-term suppression of inflammatory responses and immunotoxicity

Self-reported attitudes, skills and use of evidence-based practice among Canadian doctors of chiropractic: a national survey

Objectives: To identify Canadian chiropractors' attitudes, skills and use of evidence based practice (EBP), as well as their level of awareness of previously published chiropractic clinical practice guidelines (CPGs). Methods: 7,200 members of the Canadian Chiropractic Association were invited by e-mail to complete an online version of the Evidence Based practice Attitude & utilisation SurvEy (EBASE) a valid and reliable measure of participant attitudes, skills and use of EBP. Results: Questionnaires were completed by 554 respondents. Most respondents (>75%) held positive attitudes toward EBP. Over half indicated a high level of self-reported skills in EBP, and over 90% expressed an interest in improving these skills. A majority of respondents (65%) reported over half of their practice was based on evidence from clinical research, and only half (52%) agreed that chiropractic CPGs significantly impacted on their practice. Conclusions: While most Canadian chiropractors held positive attitudes towards EBP, believed EBP was useful, and were interested in improving their skills in EBP, many did not use research evidence or CPGs to guide clinical decision making. Our findings should be interpreted cautiously due to the low response rate. (JCCA. 2015 59(4): 332-348) KEY WORDS: chiropractic complementary and alternative medicine evidence-based practice survey Objectifs: Cerner les comportements, les competences et la mise en oeuvre de la pratique factuelle (pratique fondee sur des donnees probantes) des chiropraticiens canadiens, ainsi que leur niveau de connaissance des guides de pratique clinique chiropratiques precedemment publies. Methodes: 7 200 membres de l'Association chiropratique canadienne ont ete invites par courriel pour remplir une version en ligne du sondage sur l'utilisation et le comportement associes a la pratique factuelle une evaluation valable et fiable des comportements, des competences et de la mise en oeuvre de la pratique factuelle par les participants. Resultats: Les questionnaires ont ete remplis par 554 repondants. La plupart des repondants (> 75 %) ont revele des comportements positifs vis-a-vis de la pratique factuelle. Plus de la moitie d'entre eux ont rapporte un niveau eleve d'aptitudes autodeclarees en matiere de pratique factuelle, et plus de 90 % d'entre eux ont fait part de leur interet a ameliorer ces competences. La majorite des repondants (65 %) a indique que plus de la moitie de leur pratique etait fondee sur des donnees probantes issues de la recherche clinique, et seulement la moitie de ces derniers (52 %) a reconnu que les guides de pratique clinique chiropratiques avaient des repercussions importantes sur leur pratique. Conclusions: Si la plupart des chiropraticiens canadiens ont revele des comportements positifs vis-a-vis de la pratique factuelle, pensaient que celle-ci etait utile et etaient interesses a l'idee d'ameliorer leurs competences en la matiere, un grand nombre d'entre eux n'utilisaient pas les donnees probantes issues de la recherche ou les guides de pratique clinique pour orienter leurs prises de decisions cliniques. Nos conclusions doivent etre interpretees avec precaution en raison du faible taux de reponse. (JCCA. 2015 59(4): 332-348) MOTS-CLES: chiropratique, medecine parallele et medecine douce, pratique factuelle, sondag

The environmental stress response regulates ribosome content in cell cycle-arrested S. cerevisiae

Prolonged cell cycle arrests occur naturally in differentiated cells and in response to various stresses such as nutrient deprivation or treatment with chemotherapeutic agents. Whether and how cells survive prolonged cell cycle arrests is not clear. Here, we used S. cerevisiae to compare physiological cell cycle arrests and genetically induced arrests in G1-, meta- and anaphase. Prolonged cell cycle arrest led to growth attenuation in all studied conditions, coincided with activation of the Environmental Stress Response (ESR) and with a reduced ribosome content as determined by whole ribosome purification and TMT mass spectrometry. Suppression of the ESR through hyperactivation of the Ras/PKA pathway reduced cell viability during prolonged arrests, demonstrating a cytoprotective role of the ESR. Attenuation of cell growth and activation of stress induced signaling pathways also occur in arrested human cell lines, raising the possibility that the response to prolonged cell cycle arrest is conserved

Terminal Pleistocene Alaskan genome reveals first founding population of Native Americans

Despite broad agreement that the Americas were initially populated via Beringia, the land bridge that connected far northeast Asia with northwestern North America during the Pleistocene epoch, when and how the peopling of the Americas occurred remains unresolved. Analyses of human remains from Late Pleistocene Alaska are important to resolving the timing and dispersal of these populations. The remains of two infants were recovered at Upward Sun River (USR), and have been dated to around 11.5 thousand years ago (ka). Here, by sequencing the USR1 genome to an average coverage of approximately 17 times, we show that USR1 is most closely related to Native Americans, but falls basal to all previously sequenced contemporary and ancient Native Americans. As such, USR1 represents a distinct Ancient Beringian population. Using demographic modelling, we infer that the Ancient Beringian population and ancestors of other Native Americans descended from a single founding population that initially split from East Asians around 36 ± 1.5 ka, with gene flow persisting until around 25 ± 1.1 ka. Gene flow from ancient north Eurasians into all Native Americans took place 25–20 ka, with Ancient Beringians branching off around 22–18.1 ka. Our findings support a long-term genetic structure in ancestral Native Americans, consistent with the Beringian ‘standstill model’. We show that the basal northern and southern Native American branches, to which all other Native Americans belong, diverged around 17.5–14.6 ka, and that this probably occurred south of the North American ice sheets. We also show that after 11.5 ka, some of the northern Native American populations received gene flow from a Siberian population most closely related to Koryaks, but not Palaeo-Eskimos, Inuits or Kets, and that Native American gene flow into Inuits was through northern and not southern Native American groups. Our findings further suggest that the far-northern North American presence of northern Native Americans is from a back migration that replaced or absorbed the initial founding population of Ancient Beringians

The Checkpoint Regulator SLAMF3 Preferentially Prevents Expansion of Auto-Reactive B Cells Generated by Graft-vs.-Host Disease

Absence of the mouse cell surface receptor SLAMF3 in SLAMF3-/- mice suggested that this receptor negatively regulates B cell homeostasis by modulating activation thresholds of B cell subsets. Here, we examine whether anti-SLAMF3 affects both B and T cell subsets during immune responses to haptenated ovalbumin [NP-OVA] and in the setting of chronic graft vs. host disease (cGVHD) induced by transferring B6.C-H2bm12/KhEg (bm12) CD4+ T cells into B6 WT mice. We find that administering αSLAMF3 to NP-OVA immunized B6 mice primarily impairs antibody responses and Germinal center B cell [GC B] numbers, whilst CXCR5+, PD-1+, and ICOS+ T follicular helper (TFH) cells are not significantly affected. By contrast, administering αSLAMF3 markedly enhanced autoantibody production upon induction of cGVHD by the transfer of bm12 CD4+ T cells into B6 recipients. Surprisingly, αSLAMF3 accelerated both the differentiation of GC B and donor-derived TFH cells initiated by cGVHD. The latter appeared to be induced by decreased numbers of donor-derived Treg and T follicular regulatory (TFR) cells. Collectively, these data show that control of anti-SLAMF3-induced signaling is requisite to prevent autoantibody responses during cGVHD, but reduces responses to foreign antigens